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Blood Disorders: Common Anemias
Date Prepared: April 2007
S. Rutledge Harding, MD, FRCPC
Anemia is typically defined as a hemoglobin (Hgb) value that is two standard deviations below the mean, according
to sex, age and, sometimes, race. This defines the lower limit of the normal range provided by most clinical
laboratories with their patient reports. Recently, arguments have been advanced to establish optimal rather than
1
statistical lower limits of Hgb, especially in older adults, based on morbidity and mortality data. Optimal Hgb
concentrations were found to be 130 g/L in elderly women and 140 g/L in elderly men.
Goals of Therapy
Alleviate the signs and symptoms of anemia

Determine and address the underlying cause(s) of the anemia
Restore normal or adequate Hgb level
improve quality of life2
3
possibly prolong survival
Avoid allogeneic red cell transfusion
Investigations
Signs and symptoms of anemia occur when the oxygen-carrying capacity of the blood is unable to meet the
1
oxygen requirements of body tissues (Figure 1 - Evaluation of Anemia).
Identify the underlying cause of anemia. Underlying cause(s) may include medications (cytotoxic agents,
antiretrovirals, ribavirin, folate antagonists, etc.), alcohol use, diet (vegans are at particular risk for vitamin B12
deficiency), gastrointestinal complaints (blood loss, malabsorption, gastric or terminal ileal surgery),
menorrhagia history, cancer, impaired kidney/liver/thyroid function and chronic inflammation. Seek signs and
symptoms that point to the etiology of the anemia (e.g., glossitis and koilonychia in iron deficiency, paresthesia
in B12 deficiency).
Diagnostic algorithms are given as guidelines in Figure 2 - Diagnostic Algorithm for Microcytic Anemia, Figure 3
- Diagnostic Algorithm for Normocytic Anemia and Figure 4 - Diagnostic Algorithm for Macrocytic Anemia,
based on the traditional classification of anemia according to red cell size, as reflected in the mean cell volume
(MCV).4
The serum folate level is prone to short-term fluctuations and may be misleading. The red blood cell (RBC)
folate level reflects time-averaged folate availability and is a more reliable indicator of tissue folate adequacy.5
There is significant intra- and inter-individual variation in serum cobalamin levels, so patients with macrocytosis
6
and borderline (as defined by the local laboratory) cobalamin levels need further assessment. Cobalamin levels
drop during pregnancy without other evidence of deficiency.7
Iron-deficiency Anemia
Nonpharmacologic Choices
Pharmacologic Choices
Therapeutic Tips
Dietary iron, especially from foods rich in heme iron (i.e., liver; lean red meats; seafood such as oyster, clams,
tuna, salmon, sardines and shrimp), can contribute to the treatment of iron deficiency anemia, but works more
slowly than pharmacologic replacement therapy,8 and may not be sufficient in the face of more severe or persistent
causes of iron deficiency.
Vitamin C enhances the absorption of iron but the effect is small. Consumption of foods that are good sources of
vitamin C has a minimal impact on the therapy of iron deficiency anemia.
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https://www.e-therapeutics.ca/tc.showPrintableChapter.action?chapterId=c0082 3/1/2011
Therapeutic Choice
Pharmacologic Choices (Table 1)
Simple oral iron salts are the mainstay of iron supplementation therapy in most circumstances of iron
deficiency anemia.
a variety of salts are available, with differing amounts of elemental iron per tablet; however, the gut is
limited in its ability to absorb iron and such differences have little effect on the outcome of replacement
therapy
the usual target dose is 105-200 mg/day of elemental iron, in divided doses
Parenteral iron is reserved for patients with malabsorption or true intolerance to oral iron therapy, or where
ongoing losses exceed the capacity of the gut to absorb oral iron. Although newer formulations are somewhat
9
safer and better tolerated than older preparations, anaphylaxis remains a risk.
in those who can tolerate and absorb oral iron salts, the use of parenteral iron does not lead to a more
rapid resolution of anemia
Therapeutic Tips
Search for the cause of iron deficiency, including very careful consideration of occult gastrointestinal bleeding
(see Suggested Readings). Menorrhagia must be convincing before it is accepted as the sole cause of iron
10
deficiency. This may be an opportunity for early recognition of a gastrointestinal malignancy—don’t miss it!
A reticulocyte response should be evident within one week of beginning iron therapy, with subsequent
improvement in the Hgb of about 10 g/L every 7–10 days.
If the Hgb fails to respond as anticipated, consider that there may be:
ongoing blood loss
use of other medications that impair iron absorption (Table 1)
a different or concurrent cause of anemia and/or an impaired erythropoietic response
compliance issues
Gastrointestinal side effects are the most common reasons for non-compliance:
use a graduated approach to dosing. Begin with a single tablet taken after a meal. On a weekly basis, as
tolerance permits, add another tablet until the patient is taking one dose with each meal. Thereafter,
gradually shift the timing of the doses to the beginning of meals
small oral doses may be adequate in patients that are susceptible to gastrointestinal upset.
In the elderly, daily doses of elemental iron as low as 15 to 50 mg are effective in the treatment of iron
deficiency anemia9
In pregnant women, 20 mg/day of elemental iron, started at 20 weeks' gestation, is sufficient to prevent
11
iron deficiency
iron contained in enteric-coated tablets is poorly absorbed. These products should be avoided
Some physicians replenish iron stores while others prefer to stop therapy when the Hgb normalizes, so that
further blood loss will not be masked by robust iron stores. As a compromise:
completely replenish iron stores when the cause of iron deficiency has been identified and corrected
do not replenish iron stores when investigation has failed to identify the cause of the iron deficiency.
Recurrence of anemia flags the need and provides the opportunity for further investigation.
Megaloblastic Anemia
Therapeutic Tips
Megaloblastic anemias arise because of impaired DNA synthesis from deficiencies of cobalamin (vitamin B12) or folic
acid (folate). Other causes of impaired DNA and RNA metabolism (i.e., drugs, myelodysplasia) produce similar
hematologic findings.
Cobalamin deficiency may also lead to subacute combined degeneration of the spinal cord. Folate may partially
alleviate and mask the hematologic effects of cobalamin deficiency, but does nothing to slow the progression of the
neurologic lesion.
Systemic symptoms of megaloblastosis may be subtle in older adults and may precede the development of anemia.
12
A high index of suspicion is warranted.
Cobalamin (Vitamin B12) Deficiency

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Therapeutic Choice
Meat and dairy products are the only dietary sources of cobalamin. The typical Canadian diet exceeds the daily
requirement, provided that absorption is normal.
Cobalamin stores are usually sufficient to last several years.
Strict vegans are at risk of deficiency unless they take cobalamin supplements. Vegetarians may be at risk of
deficiency during times of high demand, such as pregnancy.
The most common cause of cobalamin deficiency is malabsorption due to pernicious anemia, gastrectomy,
gastritis, ileal resection, Crohn’s disease, blind loops, pancreatic insufficiency and certain drugs (i.e., neomycin,
metformin, proton pump inhibitors). Some patients have trouble absorbing cobalamin from food but are able to
absorb pharmaceutical cobalamin.
Folic Acid Deficiency
Dietary deficiency and alcoholism are the most common causes of folate deficiency.
Although folate is plentiful in a variety of foods (i.e., leafy green vegetables, liver, legumes) it is labile and
easily destroyed by exposure to light and during cooking.
Alcohol inhibits folate absorption and interferes with its enterohepatic cycle.
Folate deficiency can develop within a few months of adopting a folate-deficient diet and even more quickly in
the setting of increased alcohol intake.
Increased folate requirements are seen in pregnancy, hemolytic anemia and therapy with certain drugs (i.e.,
methotrexate, phenytoin, trimethoprim).
Restoring normal dietary intake of cobalamin and folate may be sufficient to completely reverse megaloblastosis.
However, patients with neurologic deficits due to cobalamin deficiency should be treated pharmacologically to
maximize the likelihood of full neurologic recovery.
Abstinence from alcohol may be necessary.
Cobalamin (Vitamin B12)
Cobalamin deficiency is treated with either cyanocobalamin or hydroxocobalamin (hydroxycobalamin).

The daily requirement is 6–9 µg. Doses greater than 100 µg/day exceed the physiologic binding capacity, but
the excess is not toxic and is readily excreted by the kidneys. For this reason there is a tendency to give more
rather than less cobalamin, especially in patients with neurologic deficits.
Cobalamin has traditionally been given parenterally because deficiency is most often due to malabsorption, and
most cases of malabsorption are attributable to pernicious anemia with its lack of intrinsic factor.
13 14 , 15 16
High-dose oral cobalamin therapy is effective, feasible and cost-effective, but concerns about patient
17
compliance and the need for more attentive monitoring limit adoption of this approach in North America.
As a compromise:
administer parenteral cobalamin until all neurologic and hematologic findings resolve
provide maintenance therapy by the route that best fits the patient’s circumstances.
Where dietary deficiency is clearly the cause of the cobalamin deficiency and the patient has no neurologic
deficits, oral supplementation is adequate.
Folic Acid
Prophylaxis with folate before and during pregnancy is strongly recommended for the prevention of neural tube
defects. (See Endocrine and Metabolic Disorders: Nutritional Supplements for Adults for specific dosing
recommendations.)
Otherwise, folate should be given only for confirmed folate deficiency or in situations of increased demand,
such as hemolysis.
The oral route is sufficient to correct folate deficiency, even in patients with malabsorption syndromes.
Therapeutic Tips
A reticulocyte response should be evident within three to four days of beginning therapy, with improvement in
the Hgb level by about day ten. Full resolution of the anemia should occur within about two months.
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Therapeutic Choice
The rapid production of new hematopoietic cells leads to a potentially dramatic shift of potassium from
extracellular to intracellular compartments, which may cause profound hypokalemia.
monitor potassium carefully in the first few days of therapy; consider early and generous potassium
supplementation
older patients on diuretic therapy for heart failure are at particular risk
If the Hgb fails to respond as anticipated, consider that there may be:
a different or concurrent cause of anemia and/or an impaired erythropoietic response
concomitant iron deficiency may show itself with an MCV that shifts from the macrocytic to the
microcytic range
compliance issues, particularly in patients using oral supplements
Neurologic deficits may take six months or more to resolve; if severe, some deficits may persist.
Anemias Responsive to Pharmacologic Stimulation of Erythropoiesis
Investigations
Therapeutic Tips
Most patients with nutritional anemias, hemolysis or bleeding have elevated levels of endogenous erythropoietin.
There are, however, a number of situations in which pharmacologic stimulation of red cell production is beneficial
including:
Chronic renal failure

18
HIV-infected patients receiving antiretroviral therapy
19
Chronic hepatitis C patients receiving ribavirin
Patients receiving chemotherapy for non-hematologic cancers20 , 21
20
Surgery patients
22
Low-risk myelodysplasia
23 , 24
Other clinical applications are beyond the scope of this discussion.
Investigations
Selection of patients is determined in part by baseline endogenous erythropoietin levels (approximately 3–30 IU/L in
healthy individuals).
For example:
A zidovudine-treated HIV patient is unlikely to respond if the baseline erythropoietin level is > 500 IU/L
A chemotherapy-treated cancer patient is unlikely to respond if the baseline erythropoietin level is > 200 IU/L
It is important to ensure an adequate iron supply in conjunction with erythropoietic stimulation.
The choice of agent and dosage regimen varies according to the clinical situation. Both available agents may be
given by intravenous or subcutaneous injection. Epoetin alfa is a recombinant human erythropoietin with a
relatively short half-life that is typically given at least three times per week; daily in some circumstances.
Darbepoetin alfa is a synthetic erythropoietin analogue with a longer half-life that is typically given weekly or
biweekly, and monthly in some patients.
Therapeutic Tips
Erythropoietins have significant potential for toxicity and adverse consequences so they should be used
judiciously in patients who would otherwise require transfusion support.
Doses are titrated to achieve a gradual improvement in anemia, without overshooting the target Hgb.
25 , 26 , 27
in patients with renal failure, higher Hgb targets are not associated with better outcomes
survival was worse in patients treated to higher Hgb targets ( > 120 g/L) with erythropoietin as compared
with placebo in patients with head and neck cancer28 and those with breast cancer29
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Rapid and/or excessive correction of anemia may provoke hypertension and seizures in susceptible individuals;
erythrocytosis may predispose patients to thrombotic complications. Monitor blood pressure three times per
week initially, and after each dose thereafter.
Erythropoietins have been associated with the development of pure red cell aplasia (PRCA), a
potentially devastating complication in which neutralizing antibodies to the exogenous protein
cross-react with endogenous erythropoietin, resulting in profound anemia. Changes in the
formulation and handling of these proteins have greatly reduced the risk of PRCA.3 Nevertheless,
PRCA should be considered if a patient becomes refractory to therapy. Useful Info?
Figure 1-Evaluation of Anemia
Signs and symptoms of anemia occur when the oxygen-carrying capacity of the blood is unable to meet the oxygen
requirements of body tissues. Modified from Semin Oncol, Volume 25 (Suppl 7), Ludwig H, Fritz, E. Anemia in cancer patients,
pages 2–6, Copyright 1998, with permission from Elsevier Inc.
Figure 2-Diagnostic Algorithm for Microcytic Anemia
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Therapeutic Choice
Adapted with permission from: Tefferi A, Hanson DA, Inwards DJ. How to interpret and pursue an abnormal complete blood cell
count in adults. Mayo Clin Proc. 2005;80:923-936
Figure 3-Diagnostic Algorithm for Normocytic Anemia
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Therapeutic Choice
Abbreviations: AIHA = autoimmune hemolytic anemia; DIC = disseminated intravascular coagulation; SH = hereditary
spherocytosis; PBS = peripheral blood smear;
TTP/HUS = thrombotic thrombocytopenic purpura/hemolytic uremic syndrome
Adapted with permission from: Tefferi A, Hanson DA, Inwards DJ. How to interpret and pursue an abnormal complete blood cell
count in adults. Mayo Clin Proc. 2005;80:923-936
Figure 4-Diagnostic Algorithm for Macrocytic Anemia
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Abbreviations: MCV = mean cell volume; MDS = myelodysplastic syndrome
Adapted with permission from: Tefferi A, Hanson DA, Inwards DJ. How to interpret and pursue an abnormal
complete blood cell count in adults. Mayo Clin Proc. 2005;80:923-936
Table 1: Drugs for the Treatment of Iron-deficiency and Megaloblastic Anemias
Costa
Class Drug Dose Adverse Effects Comments
Iron ferrous fumarate 105–200 mg Gastrointestinal: There is no evidence that $

Supplements, Palafer, generics elemental iron nausea, dyspepsia, one preparation is more
oral (Fe) daily in three constipation and/or effective than another.
divided doses diarrhea. Avoid enteric-coated
preparations.
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Therapeutic Choice
a
Cost
(100 mg Ameliorated by step-
elemental Fe/300 wise initiation of Vitamin C enhances
mg ferrous therapy (see text). absorption, but the effect is
fumarate) minimal and may aggravate
GI upset (not routinely
recommended).
Absorption is ↓ by food and

certain drugs: antacids,
calcium carbonate,
cholestyramine, levodopa,
methyldopa, penicillamine,
quinolones, sodium
bicarbonate, tetracyclines.
Separate administration by ~
2 hours.
Efficacy is delayed by
concomitant use of vitamin
E.
Iron ferrous gluconate 105–200 mg Gastrointestinal: There is no evidence that $

Supplements, generics elemental iron nausea, dyspepsia, one preparation is more
oral daily in three constipation and/or effective than another.
(35 mg elemental Ameliorated by step- preparations.
Fe/300 mg wise initiation of
ferrous therapy (see text). Vitamin C enhances
gluconate) absorption, but the effect is
minimal and may aggravate
recommended).

calcium carbonate,
quinolones, sodium
2 hours.
E.
Iron ferrous sulfate 105–200 mg Gastrointestinal: There is no evidence that $

Supplements, Fer-In-Sol, elemental iron nausea, dyspepsia, one preparation is more
oral generics daily in three constipation and/or effective than another.
(60 mg elemental Ameliorated by step- preparations.
Fe/300 mg wise initiation of
ferrous sulfate) therapy (see text). Vitamin C enhances
absorption, but the effect is
minimal and may aggravate
recommended).

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Therapeutic Choice
a
Cost
calcium carbonate,
quinolones, sodium
2 hours.
E.
Iron polysaccharide- 105–200 mg Gastrointestinal: There is no evidence that $$

Supplements, iron complex elemental iron nausea, dyspepsia, one preparation is more
oral Triferexx daily in three constipation and/or effective than another.
(150 mg Ameliorated by step- preparations.
elemental Fe/150 wise initiation of
mg therapy (see text). Vitamin C enhances
polysaccharide absorption, but the effect is
iron complex) minimal and may aggravate
recommended).

calcium carbonate,
quinolones, sodium
2 hours.
E.
Iron iron dextran Total dose Anaphylaxis (rare). Consult prescribing $$$$
Supplements, DexIron, Infufer infusion: Anaphylactoid information for dose
parenteral iv dose calculated reactions, calculation, dilution and
to restore iron hypotension (avoid administration details.
deficit in red cell rapid iv infusion). 0.9% NaCl is the preferred
mass and iron vehicle. D5W causes more
stores. Fever, chills, local irritation and phlebitis.
headache, myalgia,
In chronic dialysis arthralgia, urticaria, Give a 25 mg test dose one
patients: dizziness. May have h before the initial dose,
delayed onset, 24– with epinephrine available.
100 mg iv 1–3 48 hours after iv
×/wk for 10 infusion and 3–4 Side effects are more
doses or until days after im common with larger doses
replete; adjust as administration. and in underweight patients.
able to maintain
adequate iron
availability
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Therapeutic Choice
Costa
Iron sodium ferric Chronic dialysis Anaphylaxis (rare). Test doses are no longer $$$$
Supplements, gluconate patients: Anaphylactoid recommended by the
parenteral Ferrlecit 125 mg iv 1–3 reactions, manufacturer.
×/wk × 8 doses; hypotension (avoid Incidence of life-threatening
adjust as able to rapid iv infusion). adverse effects is lower than
maintain with iron dextran.
adequate iron Fever, chills,
availability headache, myalgia,
arthralgia, urticaria,
dizziness. May have
delayed onset, 24–
48 hours after iv
infusion and 3–4
days after im
administration.
Iron iron sucrose Chronic dialysis Anaphylaxis (rare). Test doses are not $$$$
Supplements, Venofer patients: Anaphylactoid recommended by the
parenteral 100 mg iv 1–3 reactions, manufacturer.
×/wk until hypotension (avoid Lowest incidence of life-
replete; adjust as rapid iv infusion). threatening adverse effects
able to maintain among iv iron preparations.
adequate iron Fever, chills,
availability headache, myalgia,
arthralgia, urticaria,
dizziness. May have
delayed onset, 24–
48 hours after iv
infusion and 3–4
days after im
administration.
Vitamins cobalamin Pernicious Occasional Oral absorption is ↓ by $

(vitamin B12) anemia/other peripheral vascular anticonvulsants, colchicine,
chronic thrombosis, rash, metformin, neomycin and
malabsorption pruritus, headache, omeprazole.
disorders: 100 µg nausea and Consider generous
sc/im daily × 1 vomiting, diarrhea. potassium supplementation
wk; 200 µg Occasional heart with initiation of therapy.
sc/im/wk until failure.
Hgb normalizes Folate supplementation may
Life-long Possibility of mask hematologic findings
maintenance: profound of B12 deficiency, without
200 µg sc/im hypokalemia due to halting progression of the
monthly or 1000– intracellular neurologic deficits.
2000 µg po daily potassium shift.
Vitamins cyanocobalamin Pernicious Occasional Oral absorption is ↓ by $

generics anemia/other peripheral vascular anticonvulsants, colchicine,
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Therapeutic Choice
a
Cost
Cobalamin has traditionally
been given parenterally
because deficiency is most
often due to malabsorption,
and most cases of
malabsorption are
attributable to pernicious
anemia with its lack of
intrinsic factor. High-dose
oral cobalamin therapy is
effective, feasible and cost-
effective, but concerns about
patient compliance and the
need for more attentive
monitoring limit adoption of
this approach in North
America.
Vitamins hydroxocobalamin Pernicious Occasional Oral absorption is ↓ by $

generics anemia/other peripheral vascular anticonvulsants, colchicine,
Vitamins folic acid (folate) 1 mg po daily Occasional allergic Available for iv use in $
generics reactions—rash, patients who are fasting.
pruritus, flushing,
bronchospasm.
a.
Cost of 30-day supply; includes drug cost only.
Legend: $ < $10 $$ $10–20 $$$ $20–250 $$$$ > $250
Table 2: Erythropoiesis-Stimulating Drugs
Class Drug Dose Adverse Effects Comments Cost
Erythropoietics epoetin alfa Chronic renal Hypertension, Usually given by sc $150/10 000 IU
a failure headache, seizures, injection. May be given
Eprex Initial: 50–100 thrombosis, iv if access already
IU/kg sc/iv 3×/wk, nausea, vomiting, established.
then: ↑ 25% Q4–8 diarrhea, Do not exceed target
wk to max 300 arthralgia, chest Hgb.
IU/kg/dose to pain, edema,
achieve Hgb of 120 cough. If no response to the
g/L Increases risk of maximum dose after 8
deep venous wk, discontinue.
thrombosis and
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Therapeutic Choice

As Hgb approaches other thrombotic If Hgb ↑ by more than
120 g/L, ↓ dose by complications in 10 g/L/2 wk, ↓ dose by
25% spine surgery 25%. Target Hgb ≤ 120 g/L.
patients. If no response to the
maximum dose after 8
HIV, on Pure red cell wk, discontinue.
antiretrovirals aplasia (rare)
(endogenous In patients with renal
erythropoietin failure, achievement of
level ≤ 500 higher Hgb targets is not
IU/L) associated with better
Initial: 100 IU/kg outcomes. Survival was
sc/iv 3×/wk, then: worse in patients treated
↑ by 50 IU/kg/dose Q4 to higher Hgb targets
–8wk to max 300 ( > 120 g/L) with
IU/kg/dose. erythropoietin as
compared with placebo
in patients with head
Cancer and neck cancer and in
chemotherapy those with breast
(endogenous cancer.
erythropoietin
level ≤ 200
IU/L)
Initial: 50 IU/kg
sc/iv 3×/wk, or
40 000 IU sc/iv
Qwk, then: ↑ by 50
IU/kg/dose Q8wk to
max 300
IU/kg/dose.
Chronic hepatitis
C, on ribavirin
40 000 IU sc/iv
weekly
Surgery
600 IU/kg sc/iv 21,
14 and 7 days
before surgery and
then on the day of
surgery
Erythropoietics darbepoetin Chronic renal Hypertension, May be able to shift to $283/ 100 µg
a failure hypotension, biweekly or monthly
alfa
Aranesp 0.45 µg/kg sc/iv headache, dosing in some patients.
Qwk, then: ↑ by thrombosis, Target Hgb ≤ 120 g/L
25% monthly if no nausea, vomiting, with ↑ limited to 10 g/L per
response. ↓ by 25% diarrhea, 2 wk.
as Hgb approaches constipation,
120 g/L arthralgia, myalgia, If excessive response, ↓
chest pain, dose by 40%. If still
arrhythmia, edema, excessive, hold dose until
Cancer dyspnea, cough. Hgb falls.
chemotherapy
(endogenous
erythropoietin
level ≤ 200
IU/L)
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Therapeutic Choice

2.25 µg/kg sc/iv
Qwk
If inadequate
response after 6
wk, ↑ to 4.5 µg/kg
sc/iv Qwk.
a.
Use the lowest dose that will gradually increase the Hgb concentration to the lowest level sufficient to avoid blood transfusions
(FDA update, Mar 9, 2007). Dosing recommendations are to be reassessed by the FDA Oncologic Drugs Advisory committee.
Suggested Readings
Kwong JC, Carr D, Dhalla IA et al. Oral vitamin B12 therapy in the primary care setting: a qualitative and
quantitative study of patient perspectives. BMC Fam Pract 2005;6(1):8.
Macdougall IC, Eckardt KU. Novel strategies for stimulating erythropoiesis and potential new treatments for
anaemia. Lancet 2006;368(9539):947-53.
Manning-Dimmitt LL, Dimmitt SG, Wilson GR. Diagnosis of gastrointestinal bleeding in adults. Am Fam Physician
2005;71(7):1339-46.
Nilsson M, Norberg B, Hultdin J et al. Medical intelligence in Sweden. Vitamin B12: oral compared with parenteral?
Postgrad Med J 2005;81(953):191-3.
Tefferi A, Hanson CA, Inwards DJ. How to interpret and pursue an abnormal complete blood cell count in adults.
Mayo Clin Proc 2005;80(7):923-36.
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3. Macdougall IC, Eckardt KU. Novel strategies for stimulating erythropoiesis and potential new treatments for
anaemia. Lancet 2006;368(9539):947-53.
4. Tefferi A, Hanson CA, Inwards DJ. How to interpret and pursue an abnormal complete blood cell count in
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Am J Clin Nutr 2001;74(5):650-6.
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26. Phrommintikul A, Haas SJ, Elsik M et al. Mortality and target haemoglobin concentrations in anaemic patients
with chronic kidney disease treated with erythropoietin: a meta-analysis. Lancet 2007;369(9559):381-8.
27. Singh AK, Szczech L, Tang KL et al. Correction of anemia with epoetin alfa in chronic kidney disease. N Engl J
Med 2006;355(20):2085-98.
28. Henke M, Laszig R, Rube C et al. Erythropoietin to treat head and neck cancer patients with anaemia
undergoing radiotherapy: randomised, double-blind, placebo-controlled trial. Lancet 2003;362(9392):1255-
60.
29. Leyland-Jones B, Semiglazov V, Pawlicki M et al. Maintaining normal hemoglobin levels with epoetin alfa in
mainly nonanemic patients with metastatic breast cancer receiving first-line chemotherapy: a survival study. J
Clin Oncol 2005;23(25):5960-72.
30. Ludwig H, Fritz E. Anemia in cancer patients. Semin Oncol 1998;25(3 Suppl 7):2-6.
Therapeutic Choices. © Canadian Pharmacists Association, 2011. All rights reserved.
Page 15
e-Therapeutics+ : Therapeutics : Cancer Chemotherapy Toxicity: Chemotherapy-induced ... Page 1 of 12
Therapeutic Choice
Print Close
Cancer Chemotherapy Toxicity: Chemotherapy-induced Nausea and Vomiting
Date Prepared: March 2007

Date Revised: September 2009
Lynne Nakashima, PharmD
Goals of Therapy
Prevent or minimize acute (starting within 24 hours of chemotherapy), delayed (starting > 24 hours after
chemotherapy) and anticipatory (starting before chemotherapy as a conditioned response) nausea and vomiting
to help patient adherence with active treatment and to maintain quality of life
Decrease incidence of nausea and vomiting (once it has occurred) and maintain patient comfort1
Prevent complications such as esophageal tears, dehydration, anorexia, malnutrition, weight loss, pathological
bone fractures, metabolic alkalosis, chloride and potassium depletion1
Investigations
A thorough history including:

onset and duration of symptoms
timing of nausea and/or retching and/or vomiting
impact on the patient, e.g., weight loss, asthenia
description of the vomiting episodes
medications the patient is taking
Physical examination with particular attention to:
orthostatic hypotension
abdominal pain, distention, constipation, hemorrhage
neurologic assessment including cranial nerves, vestibular and pupillary function, extrapyramidal signs
Laboratory tests:
electrolytes: BUN, creatinine, sodium, potassium, chloride (to assess hydration status); calcium, albumin
(to assess for hypercalcemia)
drug screening, such as for digoxin if suspected as a cause of nausea and vomiting
Although medication is the most likely cause of nausea and vomiting in a patient receiving chemotherapy, other
potential causes (e.g., fluid/electrolyte abnormalities, bowel obstruction, CNS or hepatic metastases, infections and
radiation therapy) should be ruled out. Other drugs (e.g., opioids, digoxin, antibiotics) may cause or exacerbate
nausea and vomiting so a thorough medication history is essential. Some chemotherapeutic agents are more likely
to cause nausea and vomiting than others (Table 1). Therefore it is important to consider both the emetogenic
potential and the expected pattern of emesis of the chemotherapy regimen when choosing antiemetics.3 , 4 , 5 , 6 , 7
Table 1: Emetogenic Potential of Chemotherapy Agentsa
High (> 60%)
carmustine cytarabine (> 500 mg/m2) lomustine

cisplatin (> 50 mg/m2) dacarbazine mechlorethamine
cyclophosphamide (> 550 mg/m2) dactinomycin (> 1.5 g/m2) streptozocin
Moderate (30–60%)
capecitabine epirubicin methotrexate (dose-dependent)

carboplatin ifosfamide oxaliplatin
daunorubicin irinotecan procarbazine
doxorubicin vinblastine
Low (< 30%)
altretamine (hexamethylmelamine) fludarabine rituximab

amsacrine gemcitabine 6-thioguanine
androgens hydroxyurea tamoxifen
aromatase inhibitors L-asparaginase teniposide
Page 16
Therapeutic Choice
bevacizumab melphalan thiotepa

bleomycin mercaptopurine topotecan
bortezomib mitomycin trastuzumab
busulfan mitoxantrone vincristine
cetuximab paclitaxel vindesine
chlorambucil pemetrexed vinorelbine
docetaxel progestins
estramustine ralitrexed
estrogens
etoposide
5-fluorouracil
a. Slowing infusion rate of certain chemotherapeutic agents (e.g., cisplatin) may decrease emesis.2
Patient-specific factors such as age less than 50 years, female gender, previous motion sickness or pregnancy-
related nausea and vomiting, limited alcohol use and nausea and vomiting with previous chemotherapy regimens
may predispose the patient to nausea and vomiting; therefore, antiemetic regimens must also be tailored to the
individual patient.
Therapeutic Choices (Figure 1 - Management of Chemotherapy-induced Nausea and

Vomiting (low emetogenic potential))
Nonpharmacologic Choices1 , 8 , 9 , 10
Dietary adjustments
try small, light meals several times daily.
avoid foods high in fat or those with a heavy aroma.
try dry, starchy foods such as crackers.
if unable to tolerate solid foods, try ice chips and small sips of clear liquids.
avoid food preparation because the smell of food cooking often worsens nausea.
Behavioural methods
relaxation techniques may help decrease physiologic arousal and anxiety.
individualized exercise programs may help decrease anxiety and depression.
systemic desensitization may be helpful for anticipatory nausea and vomiting.
Other
keep movement to a minimum; rest in bed or a chair to avoid vestibular stimulation.
acupuncture and acupressure have been shown to have some effect on chemotherapy-induced emesis.11
sleep has been shown to protect against chemotherapy-induced nausea and vomiting.12
Pharmacologic Choices (Figure 1 - Management of Chemotherapy-induced Nausea and

Vomiting (low emetogenic potential), Table 2)
Phenothiazines
The most commonly used is prochlorperazine. Considered moderately effective, it is usually used in low
emetogenic regimens or as rescue medication.3 , 13 The availability of a wide variety of dosage forms (tablet,
suppository, injectable) facilitates prochlorperazine use, especially for outpatients.
Metoclopramide
Metoclopramide blocks the dopaminergic receptors in the chemoreceptor trigger zone and has serotonin antagonistic
activity at higher doses. Low doses (10– 20 mg) are generally as effective as prochlorperazine; however, in high
doses (1– 3 mg/kg), metoclopramide provides significantly higher antiemetic activity.3 , 14 When metoclopramide is
compared to serotonin antagonists for acute antiemetic efficacy against highly emetogenic chemotherapy, serotonin
antagonists are superior and have fewer side effects.15 , 16 , 17 , 18 For delayed nausea and vomiting,
metoclopramide plus a corticosteroid are as effective as a serotonin antagonist plus a corticosteroid
and are more cost effective.15,19 A limitation to metoclopramide use is the development of
extrapyramidal side effects. Useful Info?
Page 17
Therapeutic Choice
Corticosteroids
Dexamethasone is the most commonly used corticosteroid, although several others including
methylprednisolone have been studied.20 The actual mechanism of action is unknown, but the efficacy of
corticosteroids is documented. They appear to be effective as single agents, in combination with other antiemetics
and for delayed nausea and vomiting.20 , 21 Dexamethasone in combination with a serotonin antagonist is the
most effective antiemetic regimen for acute nausea and vomiting.19 , 22 , 23 Dexamethasone alone or in combination
with metoclopramide appears to be the most effective regimen for delayed nausea and vomiting.21 , 24 , 25 , 26
The optimal dose has not been identified; the usual range is from 6 to 60 mg daily.20
Serotonin Antagonists
The serotonin antagonists dolasetron, granisetron and ondansetron are equivalent in efficacy and toxicity.27 , 28
Two newer serotonin antagonists are now available in the US: palonosetron and tropisetron.29 , 30 Single agent
efficacy is reported, but when used in combination with corticosteroids, efficacy is improved. The combination is
recommended for the prevention of acute nausea and vomiting unless the patient has a contraindication to
corticosteroids.22 , 23 Serotonin antagonists plus corticosteroids are no more effective for delayed nausea and
vomiting than metoclopramide plus corticosteroids or corticosteroids alone.24 , 25 These drugs are well tolerated. At
equivalent doses, oral formulations are equally effective and as safe as intravenous.31 The major drawback to their
use is cost. However, because of their superior efficacy, serotonin antagonists should be used for the prophylaxis of
acute nausea and vomiting for moderately and highly emetogenic regimens. Choose serotonin antagonist based on
cost.
Benzodiazepines
Benzodiazepines provide useful antianxiety, amnesic and sedating effects. Lorazepam and alprazolam are the
most commonly used, and have been studied in cases of anticipatory nausea.32 , 33 They are usually used in
combination with other antiemetics.
Butyrophenones
Haloperidol has reported efficacy and is generally used as an alternative to high-dose metoclopramide or
ondansetron in refractory nausea and vomiting.34 , 35
Cannabinoids
Nabilone and dronabinol are of limited use because they are available only as oral formulations and are
associated with several side effects including mood alterations, hallucinations, delusions and increases in heart rate
and blood pressure.3 , 36 , 37 , 38 They are generally used in refractory nausea and vomiting or in combination with
other antiemetics.3 , 36
Dimenhydrinate
An antihistamine useful for treating vomiting due to motion sickness, dimenhydrinate is considered no more
effective than placebo against chemotherapy-induced nausea and vomiting.39
Scopolamine
Available as a transdermal system placed behind the ear, scopolamine can prevent vomiting related to motion
sickness but is generally ineffective in managing nausea and vomiting associated with chemotherapy.39 , 40
Propofol
Propofol is an anesthetic agent with antiemetic properties.5 Several studies suggest that a continuous infusion at
low doses ( 1 mg/kg/hour) is effective in patients with cisplatin-induced nausea and vomiting that is refractory to
Page 18
Therapeutic Choice
serotonin antagonists combined with corticosteroids.41 , 42 , 43 Its use is still considered investigational; however,
propofol use may be considered in severe, refractory vomiting. Expertise in administration is required.
Neurokinin-1 Receptor Antagonists
Neurokinin-1 (NK1) receptor antagonists bind to substance P, found in the brainstem and GI tract. Aprepitant is an
oral NK1 receptor antagonist while its pro-drug, fosaprepitant, is used intravenously. When added to a serotonin
antagonist plus dexamethasone regimen for highly emetogenic chemotherapy, it improves prevention of acute and
delayed emesis.44 , 45 Aprepitant is a moderate inhibitor of CYP3A4, and interacts with corticosteroids. Therefore the
dose of dexamethasone as an antiemetic should be decreased. Aprepitant appears to be well tolerated, with
asthenia/fatigue and hiccoughs being the most commonly reported side effects.46
Therapeutic Tips
Prevention of acute nausea and vomiting is the best way to prevent delayed nausea and vomiting.
Use antiemetic therapy to prevent anticipatory nausea and vomiting, which usually worsens with each cycle; up
to 30% of patients refuse further chemotherapy because of intolerable nausea and vomiting.3 , 4
Regularly scheduled and administered antiemetics (i.e., not PRN) are more effective at preventing nausea and
vomiting.
If the patient can tolerate oral antiemetics, this is the recommended route of administration. However, rectally
administered antiemetics such as prochlorperazine are especially useful in patients who are vomiting or unable
to take oral medications and who are at home. For hospitalized patients, the iv route of administration is
recommended in patients who are vomiting.
Figure 1- Management of Chemotherapy-induced Nausea and Vomiting (low emetogenic potential)
Page 19
Therapeutic Choice
Figure 2- Management of Chemotherapy-induced Nausea and Vomiting (moderate/high emetogenic

potential)
Page 20
Therapeutic Choice
Table 2: Drugs Used for Chemotherapy-induced Nausea and Vomiting
Costa
Class Drug Dose Adverse Effects Drug Interactions
Benzamides metoclopramide Low: 10–20 mg Sedation (up to 80%), Sedating po:$

generics po Q6H dose-related diarrhea medications. Additive iv:
High: 1–3 mg/kg (up to 45%), sedation occurs with,
po/iv Q3H extrapyramidal effects for example, opioid $$$$$
(3%). analgesics,
hypnotics, alcohol;
avoid or minimize
use if possible.
Anticholinergic
agents antagonize
effects of
metoclopramide on
GI motility.
Benzodiazepines lorazepam Sedation (up to 80%). Sedating $

Ativan, generics 1 mg po/sl pre- medications. Additive
chemo, then 1– sedation occurs with,
4 mg Q4H PRN for example, opioid
analgesics,
hypnotics, alcohol;
avoid or minimize
use if possible.
Butyrophenones haloperidol 1–2 mg po/im Sedation, Sedating $

generics pre-chemo and extrapyramidal effects. medications. Additive
Q8H sedation occurs with,
for example, opioid
analgesics,
hypnotics, alcohol;
avoid or minimize
use if possible.
Cannabinoids nabilone Sedation (4–89%), Sedating $

Cesamet 1 mg po BID dizziness, ataxia (12– medications. Additive
65%), psychotropic sedation occurs with,
Page 21
Therapeutic Choice
Costa
effects (“high”) (27%), for example, opioid

tachycardia (7%), analgesics,
orthostatic hypotension hypnotics, alcohol;
(10%), dry mouth (6– avoid or minimize
62%). use if possible.
Cannabinoids dronabinol Sedation (4–89%), Sedating $b

Marinol 5 mg/m 2 po Q2– dizziness, ataxia (12– medications. Additive
4H 65%), psychotropic sedation occurs with,
Max 6 doses/day. effects (“high”) (27%), for example, opioid
May ↑ by tachycardia (7%), analgesics,
2.5 mg/m2 to orthostatic hypotension hypnotics, alcohol;
max (10%), dry mouth (6– avoid or minimize
62%). use if possible.
10 mg/m2 per
dose
Corticosteroids dexamethasone 4–10 mg po pre- Mood changes, $

Dexasone, generics chemo and Q6– increased appetite, GI
12H irritation, ulceration,
8–20 mg iv pre- fluid retention, weight
chemo and Q6– gain, may mask signs
12H of infection.
In combination
with aprepitant:
Highly
emetogenic
chemotherapy:
12 mg po day 1
then 8 mg po
days 2–4
Moderately
emetogenic
chemotherapy:
12 mg po on first
day only
Corticosteroids methylprednisolone 0.5–1 mg/kg po Mood changes, po:$

Medrol, Solu- or iv pre-chemo increased appetite, GI iv:$$
and Q4 and 8H irritation, ulceration,
Medrol, generics
post-chemo fluid retention, weight
(max 4 mg/kg gain, may mask signs
total dose) of infection.
May also give as

single
4 mg/kg dose 30
min pre-chemo
Neurokinin-1 aprepitant Day 1: 125 mg Asthenia/fatigue, Contraindicated with $$$$$

Receptor Emend po 1 h before diarrhea, dizziness, cisapride, pimozide.
Antagonists chemotherapy dyspepsia, hiccoughs. ↑ levels of drugs
Day 2 & 3: 80 metabolized by
mg po in the CYP3A4 (e.g.,
morning dexamethasone,
midazolam).
Administered in ↓ levels of drugs
combination with metabolized by
Page 22
Therapeutic Choice
Costa
dexamethasone CYP2C9 (e.g.,

and a serotonin phenytoin,
antagonist tolbutamide,
warfarin).
↑ levels of aprepitant
with CYP3A4
inhibitors (e.g.,
clarithromycin,
ketoconazole).
↓ levels of aprepitant
with CYP3A4
inducers
(carbamazepine,
phenytoin, rifampin).
Possible ↓
effectiveness of oral
contraceptives.
Neurokinin-1 fosaprepitant Day 1: 115 mg iv Asthenia/fatigue, Contraindicated with $$$

Receptor Emend IV 30 min before diarrhea, dizziness, cisapride, pimozide.
Antagonists chemotherapy dyspepsia, hiccoughs. ↑ levels of drugs
Administered in metabolized by
combination with CYP3A4 (e.g.,
dexamethasone dexamethasone,
and a serotonin midazolam).
antagonist ↓ levels of drugs
metabolized by
CYP2C9 (e.g.,
phenytoin,
tolbutamide,
warfarin).
↑ levels of aprepitant
with CYP3A4
inhibitors (e.g.,
clarithromycin,
ketoconazole).
↓ levels of aprepitant
with CYP3A4
inducers
(carbamazepine,
Possible ↓
effectiveness of oral
contraceptives.
Phenothiazines prochlorperazine PO: Sedation, Sedating $

Apo-Prochlorazine, 10 mg Q6–8H anticholinergic effects medications. Additive
other generics PR: 10 mg Q6– (dry mouth, blurred sedation occurs with,
8H vision, constipation, for example, opioid
nasal congestion, analgesics,
IM: 10 mg Q8– urinary retention), hypnotics, alcohol;
12H extrapyramidal effects, avoid or minimize
hypotension, use if possible.
hypersensitivity
(1.4%), rare
Page 23
Therapeutic Choice
Costa
pancytopenia.
Serotonin dolasetron Headache (6–43%), Potential interaction po:$$

Antagonists Anzemet 1.8 mg/kg iv pre- constipation (4–19%), with other drugs that iv:$
chemo or 100 mg diarrhea (1–16%), prolong QTc
po pre-chemo sedation (4–10%), intervals.
transient ↑ in LFTs (< Blood levels ↑ when
1–19%), bradycardia coadministered with
(4%), dizziness (3%). cimetidine and ↓
ECG interval changes when coadministered
have been reported. with rifampin.
Serotonin granisetron Headache (6–43%), $$

Antagonists Kytril, Apo- 10 µg/kg iv or constipation (4–19%),
Granisetron, other 2 mg po pre- diarrhea (1–16%),
generics chemo or sedation (4–10%),
1 mg pre-chemo transient ↑ in LFTs (<
and 12 h post 1–19%), bradycardia
(4%), dizziness (3%).
Serotonin ondansetron Headache (6–43%), po:$

Antagonists Zofran, generics 8 mg po/iv pre- constipation (4–19%), iv:
chemo diarrhea (1–16%),
In combination sedation (4–10%), $$$$
with aprepitant: transient ↑ in LFTs (<
Highly 1–19%), bradycardia
emetogenic (4%), dizziness (3%).
chemotherapy: Transient ECG changes
32 mg iv pre- have been reported.
chemo
Moderately
emetogenic
chemotherapy:
8 mg po pre-
chemo and 8 h
post
a. Cost of 1-day supply (except 3 days for aprepitant) based on 50 kg body weight; includes drug cost only.
b. Cost for dronabinol based on 5 mg TID.
Dosage adjustment may be required in renal impairment; see Appendices: Dosage Adjustment in Renal Impairment.
Abbreviations: LFTs=liver function tests
Legend: $ < $15 $$ $15–30 $$$ $30–45 $$$$ $45–60 $$$$$ > $60
Suggested Readings
American Society of Clinical Oncology; Kris MG, Hesketh PJ et al. American Society of Clinical Oncology guideline
for antiemetics in oncology: update 2006. J Clin Oncol 2006;24(18):2932-47.
ESMO recommendations for prophylaxis of chemotherapy-induced nausea and vomiting (NV). Ann Oncol 2001;12
(8):1059-60.
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Therapeutic Choice
Ioannidis JP, Hesketh PJ, Lau J. Contribution of dexamethasone to control of chemotherapy-induced nausea and
vomiting: a meta-analysis of randomized evidence. J Clin Oncol 2000;18(19):3409-22.
Jordan K, Kasper C, Schmoll HJ. Chemotherapy-induced nausea and vomiting: current and new standards in the
antiemetic prophylaxis and treatment. Eur J Cancer 2005;41(2):199-205.
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Page 26
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e-Therapeutics+ : Therapeutics : Cancer Chemotherapy Toxicity: Management of Side Effe... Page 1 of 6
Therapeutic Choice
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Cancer Chemotherapy Toxicity: Management of Side Effects of Chemotherapy and

Radiation Therapy

Date Revised: February 2009
Pierre Fortin, MD, FACP, FRCPC
Cancer therapy encompasses three modalities of treatment: surgery, systemic therapies (chemotherapy, targeted
agents, hormones) and radiation therapy. An initial decision regarding the goal of therapy has to be made: curative
or palliative. Usually a combination of modalities is used in the treatment plan. Surgery remains the mainstay of
curative treatments, with chemo- and/or radiotherapy reserved for neoadjuvant therapies to downstage the tumor
before the surgery, or for adjuvant therapies in order to sterilize the surgical bed from suspected residual
microscopic disease. If surgery is not feasible as in the case of hematologic malignancies, then chemotherapy with
or without radiation is employed with curative or palliative intent.
If a decision is made to palliate the patient’s symptoms, radiation is usually used to control the disease locally,
while chemotherapy or other systemic agents are used to decrease the tumor burden throughout the whole body.
Surgery can also be used with palliative intent. These therapies are less intense and the goal is an acceptable quality
of life for the patient.
The following discussion will focus on managing the adverse effects of chemotherapy (Table 1 and Table 2) and
radiation therapy (Table 3).1 These tables outline treatments that are generally initiated by the oncology treatment
team but include issues that may be encountered by generalists when following cancer patients.
Side Effects of Chemotherapy
Cancer cells grow and divide faster than normal cells. This difference is exploited when using chemotherapy. The
drugs usually affect fast-growing cells during replication, killing more cancer cells than normal cells.
This characteristic also explains many of the side effects of chemotherapy. Fast-growing cells like the hematopoietic
cells, the skin and its appendages and the epithelium of the intestine often suffer adverse effects of chemotherapy.
Table 1: Acute Side Effects of Antineoplastic Drugs
Acute Side Effect Management Prevention
Extravasation Optimal management is unknown. Stop the Take all possible precautions to ensure
Vesicant drugs: infusion and aspirate any residual drug good blood return from and fluid flow
amsacrine remaining in tissues. Local measures such as into the iv line before injection.
bleomycin topical dimethylsulfoxide (DMSO),2 , 3 Be aware of potential damage to
carmustine subcutaneous injections of saline, steroids, tendons. Avoid dorsum of the hand or
cisplatin hyaluronidase or bicarbonate may be cubital fossa.
dactinomycin helpful. There is weak evidence that ice
daunorubicin packs may worsen the skin toxicity with
doxorubicin vinca alkaloids.
epirubicin Severe cases may require plastic surgery
etoposide intervention.
idarubicin
mechlorethamine
melphalan
mitomycin
mitoxantrone
plicamycin
streptozocin
vinblastine
vincristine
vindesine
vinorelbine
Hypersensitivity Stop chemotherapy infusion. Administer Premedicate with antihistamines (H1-
Page 28
Therapeutic Choice
Acute Side Effect Management Prevention
Reactions antihistamines, steroids, and H2-blockers) and corticosteroids.

Seen especially with vasoconstrictors. Use slower infusion rates.
etoposide and taxanes. Supportive care.
Also seen with
rituximab, trastuzumab
and other biologics.
Tumor Lysis Syndrome Rapid release of intracellular contents into IV hydration, allopurinol
the blood stream, resulting in hyperuricemia, 300–600 mg/day until normal uric acid
hyperkalemia, hyperphosphatemia and levels. Close monitoring of serum
hypocalcemia. Seen in diseases with large electrolytes with accordant adjustments
tumor burden and exquisitely sensitive to of contents of iv fluids.
chemotherapy, e.g., leukemia, lymphomas. Rasburicase is a uricolytic that may
be used at a dose of
0.20 mg/kg/day for up to seven days in
the treatment and prophylaxis of
hyperuricemia. Since it is a protein it
may induce allergic responses. When
administered to patients with G-6-PD
deficiency it can cause severe
hemolysis.
Table 2: Specific Side Effects of Antineoplastic Drugs
Side Effect Management Prevention
Alopecia Cosmetic intervention using wigs, hats or Cryotherapy caps or scalp

scarves. tourniquets are not effective and may
Hair usually begins regrowth 1–2 months be unsafe.
after completion of chemotherapy.
Anemia Packed red blood cells given to patients Decrease doses of chemotherapy for
with hemoglobin < 80 g/L, chest pain or subsequent cycles.
shortness of breath with little exertion.
Although these agents have significant
potential for toxicity, in select patients
erythropoetin as epoetin alfa or
darbepoetin may reduce the need for
transfusions.
Hemoglobin targets of > 120 g/L were
associated with increased risk of death and
serious adverse events.4
Cardiotoxicity Treat symptomatically with nitrates. Avoid administration in patients with

5-FU, capecitabine cause Discontinue therapy if necessary. known coronary artery disease.
coronary vasospasms,
mimicking a myocardial
infarct.
Trastuzumab can cause Left ventricular function should be

cardiac dysfunction including evaluated at baseline and during therapy.
severe heart failure. Manage clinically significant cardiac
dysfunction symptomatically.
Discontinuation of trastuzumab usually
recommended.
Anthracyclines can cause Perform ECG and serial ejection fractions. Limit cumulative doses of
acute inflammation Treat symptomatically. Discontinue therapy anthracyclines. Consider
(myocarditis/pericarditis if necessary. discontinuing anthracyclines if serial
Page 29
Therapeutic Choice
syndrome). Chronically, a ejection fraction is ↓ 25% from

dose-dependent congestive baseline. Dexrazoxane is a
myopathy may develop. cardioprotective agent used at a dose
of 500 mg/m2 to reduce the
incidence and severity of
cardiotoxicity associated with
doxorubicin. Dexrazoxane may add
to the myelosuppressive effects
caused by chemotherapeutic agents.
As a result, blood counts and hepatic
function tests should be performed
regularly. Cardiac function should
also be monitored.
Taxanes may cause Observe patient.

bradycardia. Treat symptomatically.
Carcinogenesis Case specific. Use the least amount of

chemotherapy possible to control the
disease.
Diarrhea IV hydration and supportive care if Decrease the dose of chemotherapy

Seen with irinotecan, 5-FU, dehydration secondary to diarrhea. in subsequent cycles or change the
antimetabolites. Loperamide and/or diphenoxylate PRN chemotherapy regimen.
or octreotide.5
Gonadal Toxicity Discuss assisted reproduction techniques Sperm banking. Use chemotherapy
with patients. with the least effect on
spermatogenesis or ovarian
function.
Hepatotoxicity Perform LFTs and bilirubin measurement. Avoid offending agent or decrease
Seen with methotrexate, Discontinue chemotherapy depending on doses.
azathioprine, cytarabine, extent of damage.
nitrosoureas, etoposide.
Mucositis Rule out infectious causes. Educate patients on basic oral

Avoid “magic mouthwash” with topical hygiene. Treat pre-existing oral
steroids and antihistamines that can problems before starting
increase chances of fungal infection or chemotherapy. Avoid alcohol and
sensitization. Combinations of spicy foods, which are irritating to
xylocaine viscous, sucralfate, nystatin, the mucosa. Ice chips reduce the
fluconazole, antacids and sodium incidence and severity of 5-FU-
bicarbonate are used in local induced mucositis.7
institutions. For severe mucositis in Withhold offending agent until
patients with hematologic episode resolves.
malignancies receiving myelotoxic
therapy and requiring stem cell
support, the growth factor palifermin
can be used at a dose of 60 µg/kg/day
for 3 days before and 3 days after
chemotherapy.6 Adverse effects
include mild to moderate taste
alteration, mouth and tongue
disorders, rash and edema.
Useful Info?
Myelosuppression/ Febrile Start oral antibiotics in those at low risk of Growth factors such as filgrastim or
Neutropenia complications. Ciprofloxacin or pegfilgrastim used to increase the
amoxicillin-clavulanate are commonly rate of neutrophil count recovery can
Page 30
Therapeutic Choice
used. be administered to allow

Those at higher risk of complications chemotherapy to be given without
include those with septic shock or signs of delays or decreasing doses. It can
organ failure, neutropenia for > 6 days, improve quality of life and decrease
signs of infections in lines, temperature ≥ hospitalization. CBC must be
39°C and receiving bacterial/fungal performed regularly during G-CSF
prophylaxis.8 These high-risk patients (filgrastim) therapy. Bone pain
should receive broad gram-negative and related to these agents can generally
antipseudomonal coverage with two agents. be controlled with nonopioid
Add vancomycin if gram-positive infection analgesics. Serious allergic or
suspected (see Infectious Diseases: anaphylactic reactions have occurred
and require discontinuation of G-
Infections in the Cancer Patient). Perform
CSF.
cultures and adjust antibiotics according to
results.8
Nausea/Vomiting See Cancer Chemotherapy Toxicity:

Chemotherapy-induced Nausea and
Vomiting
Nephrotoxicity IV hydration to achieve urine output of > 3 Mesna is a uroprotectant used to

L/24 h while administering chemotherapy. prevent hemorrhagic cystitis
Monitor creatinine, BUN and serum uric secondary to cyclophosphamide or
acid. ifosfamide. Most adverse effects of
mesna are immediate and include
nausea and vomiting, headache and
urticaria.
Allopurinol 300–600 mg/day po
starting 24–48 h before
chemotherapy for uric acid
nephropathy.
Neurotoxicity Dose reduction may be necessary with For vinca alkaloid constipation, use
Peripheral nerve damage is severe toxicity, or the drugs may have to stool softeners or stimulant
common with the vinca be avoided altogether. laxatives if necessary. Suggest
alkaloids, platinum-based Rule out other causes such as CNS increased physical activity and
chemotherapy and metastases or leptomeningeal disease. hydration if possible. Anticholinergic
taxanes. It can be drugs may help.
irreversible.
Neurotoxicity can present as
peripheral or central
neuropathy, impotence,
urinary retention. It can lead
to muscle atrophy, motor
weakness or loss of deep
tendon reflexes.
Autonomic neuropathy from
vinca alkaloids presents with
constipation and abdominal
pain.
High-dose methotrexate
may cause transient cerebral
dysfunction.
Ocular Discontinuation of the offending agent may For conjunctivitis, corticosteroid

Blepharitis, epiphora, tear be necessary. eye drops or artificial tears may
duct stenosis; conjunctivitis be preventative.
with 5-FU and taxanes.
Ototoxicity Can be irreversible. Reduce doses or avoid Audiograms every 3–4 cycles.
Seen with platinum completely if possible.
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Therapeutic Choice
compounds.
Pulmonary Rule out infectious causes. Withhold Avoid offending agent.

Interstitial pneumonitis and offending agent; supportive care, steroids
fibrosis with methotrexate, (prednisone 50 mg/day with tapering
bleomycin, anthracyclines, doses). Ventilatory support may be
vinca alkaloids, alkylating necessary.
agents. Acute respiratory
distress syndrome with
gemcitabine.
Teratogenicity Contraception necessary while patient Avoid pregnancy while on

receiving chemotherapy. chemotherapy.
Side Effects of Radiation Therapy
Radiation treatment is used to control the disease locally, not unlike surgery. A target, whether the tumor itself or
the surgical bed, is acquired with the help of a CT scan, and treatment fields are designed to encompass it. When
the x-rays are delivered, they travel through the tissues from an entry point to an exit point. The enormous quantity
of energy carried by the x-rays damage chromosomes either directly or indirectly by the production of free radicals
in the neighbourhood of the chromosomes. As with chemotherapy, the cell cannot divide and dies. A normal
inflammatory reaction ensues, producing the common side effects of radiation.
Contrary to chemotherapy, where the side effects are generally seen in a matter of minutes to days, the side effects
of radiation are seen many days to weeks and even years after the treatment. Acute side effects in this context
means within 30 days of the end of the treatments, subacute within 6 months and late side effects over 6 months
after the completion of the therapy.
Side effects could be decreased by lowering the total radiation dose or its fractionation or keeping the field size as
small as possible. However, the whole tumor has to be treated in order to control the disease appropriately.
Table 3: Organ-specific Side Effects of Radiation Therapy9
Organ/System Side Effect Management
CNS/Spinal Cord Edema Steroids, typically dexamethasone 4 mg po QID.
ENT/Esophagus Mucositis/ esophagitis Mouthwashes containing nystatin, fluconazole, sucralfate,

xylocaine viscous may help symptoms. Amifostine is a
cytoprotectant that may be used to reduce xerostomia. It may
cause hypotension that can lead to dizziness or fainting. Monitor
blood pressure and consider holding antihypertensives for 24 h
prior to amifostine administration. Prophylactic serotonin
antagonists may be used to reduce nausea and vomiting caused by
amifostine.
Systemic analgesics can be used for pain.
Heart Pericarditis NSAIDs.
Lungs Pneumonitis Prednisone (starting dose 1 mg/kg/day, to taper over weeks).
Skin Desquamation/itchiness If dry desquamation, use glaxal base or other moisturizers (e.g.,
Lubriderm, plain Keri Lotion) or vitamin E cream. If itchiness, use
hydrocortisone 0.5% cream. If moist desquamation, use silver
sulfadiazine cream.
Small Intestine/ Enteritis/proctitis Medical support: fluid replacement by po or iv route, loperamide,

Colon/Rectum diphenoxylate. Topical steroids by enema or suppository.
Antispasmodics such as hyoscine butylbromide (Buscopan) or
pinaverium may provide symptomatic relief.
Page 32
Therapeutic Choice
Organ/System Side Effect Management
Stomach Nausea Antiemetics, e.g., ondansetron, granisetron, dolasetron,

dimenhydrinate, prochlorperazine, metoclopramide.10
Suggested Readings
Schuchter LM, Hensley ML, Meropol NJ et al. 2002 update of recommendations for the use of chemotherapy and
radiotherapy protectants: clinical practice guidelines of the American Society of Clinical Oncology. J Clin Oncol
2002;20(12):2895-903.
Smith TJ, Khatcheressian J, Lyman GH et al. 2006 update of recommendations for the use of white blood cell growth
factors: an evidence-based clinical practice guideline. J Clin Oncol 2006;24(19):3187-205.
References
1. DeVita VT, Hellman S, Rosenberg SA, editors. Cancer: principles and practice of oncology. 7th ed. Philadelphia
(PA): Lippincott, Williams & Wilkins; 2005.
2. Olver IN, Aisner J, Hament A et al. A prospective study of topical dimethylsulfoxide for treating anthracycline
extravasation. J Clin Oncol 1988;6(11):1732-5.
3. Bertelli G, Gozza A, Forno GB et al. Topical dimethylsulfoxide for the prevention of soft tissue injury after
extravasation of vesicant cytotoxic drugs: a prospective clinical study. J Clin Oncol 1995;13(11):2851-5.
4. Health Canada endorsed important safety information on Erythropoiesis-Stimulating Agents (ESAs): Aranesp
(darbepoetin alfa) and Eprex (epoetin alfa). Ottawa (ON): Health Canada; 2007. Available from:
http://www.hc-sc.gc.ca/dhp-mps/medeff/advisories-avis/public/_2007/aranesp_eprex_pc-cp-eng.php.
Accessed February 24, 2009.
5. Harris AG, O'Dorisio TM, Woltering EA et al. Consensus statement: octreotide dose titration in secretory
diarrhea. Diarrhea Management Consensus Development Panel. Dig Dis Sci 1995;40:1464-73.
6. Keefe DM, Schubert MM, Elting LS et al. Updated clinical practice guidelines for the prevention and treatment
of mucositis. Cancer 2007;109(5):820-31.
7. Worthington HV, Clarkson JE, Eden OB. Interventions for preventing oral mucositis for patients with cancer
receiving treatment. Cochrane Database Syst Rev 2006;(2):CD000978.
8. Hughes WT, Armstrong D, Bodey GP et al. 2002 guidelines for the use of antimicrobial agents in neutropenic
patients with cancer. Clin Infect Dis 2002;34(6):730-51.
9. Perez CA, Brady LW, editors. Principles and practice of radiation oncology. 3rd ed. Philadelphia (PA):
Lippincott-Raven; 1998.
10. Kris MG, Hesketh PJ, Somerfield MR et al. American Society of Clinical Oncology guideline for antiemetics in
oncology: update 2006. J Clin Oncol 2006;24(18):2932-47.
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e-Therapeutics+ : Therapeutics : Cardiovascular Disorders: Acute Coronary Syndromes Page 1 of 21
Therapeutic Choice
Print Close
Cardiovascular Disorders: Acute Coronary Syndromes
Date Prepared: January 2011
Michelle Graham, MD, FRCPC
The term “acute coronary syndrome” (ACS) refers to any clinical symptoms compatible with acute myocardial
ischemia, from ST segment elevation myocardial infarction (STEMI) to non-ST segment elevation myocardial
infarction and unstable angina. Centres should have a standardized approach to ACS patients to ensure the most rapid
assessment and initiation of treatment possible.
The following discussion relates to ACS that are associated with primary coronary events caused by plaque erosion
and/or rupture, fissuring or dissection.
Unstable Angina and Non-ST Segment Elevation Myocardial Infarction (NSTEMI)
Goals of Therapy
Investigations
Therapeutic Choices
Therapeutic Tips
Goals of Therapy
Decrease mortality and complications

Reduce the severity or eliminate episodes of ischemia
Prevent further myocardial injury
Investigations
Careful history with special attention to pain (quality, severity, location, radiation, precipitating and relieving
factors), duration of symptoms, previous cardiac history, cardiac risk factors (smoking status, diabetes mellitus,
hyperlipidemia, hypertension, family history of first-degree relative with myocardial infarction before age 55 if
male or 65 if female) and effect of nitroglycerin
Physical examination, with attention to the presence of hypertension, heart failure or valvular heart disease
Laboratory tests:
ECG, CBC, electrolytes, glucose, creatinine and lipid profile (within 24 hours of presentation)
troponin, creatine kinase (if troponin is unavailable). Troponin is a highly accurate, sensitive and specific
indicator of myocardial injury.1 Its measurement allows reliable stratification of risk and prediction of
outcomes in individual patients.2 , 3 Elevation of cardiac troponin levels may result from pulmonary embolus
or non-ischemic mechanisms of myocardial injury, such as increased wall stress (e.g., myocarditis, severe
heart failure, left ventricular hypertrophy), or cardiac trauma. Additionally, troponins are elevated in 30–50%
of patients with pericarditis as a result of epicardial inflammation, and have also been reported in critical
illness, sepsis, neurological events, hypothyroidism, chemotherapy-induced myocardial toxicity and renal
insufficiency.
A careful search for secondary causes of ischemia, e.g., anemia, fever, infection, arrhythmia, thyroid disease
Echocardiography can be used early when clinical history and ECG are nondiagnostic—the presence of regional
wall motion abnormalities with chest pain is suggestive of underlying ischemia
The TIMI (Thrombolysis in Myocardial Infarction) Risk Score is a risk stratification tool for patients with NSTEMI or
unstable angina, using clinical features present at the time of initial assessment in the emergency department (Table
1). It predicts the risk of both death and early recurrent ischemic events and is used to target different evidence-
based therapies to appropriate patients. As the risk score increases, so too do adverse outcomes; for example, there
is a 5% risk of major adverse cardiac events in patients with a risk score of 0 or 1, and a 41% risk in those with a risk
score of 6 or 7.4
Table 1: Clinical Features Used to Calculate TIMI Risk Score4
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Therapeutic Choice
One point is assigned for each of the following clinical features:

• age >65 y
• ≥3 cardiac risk factors (hypercholesterolemia, hypertension, diabetes mellitus, current smoker, family history of
coronary artery disease)
• ≥50% coronary artery stenosis
• any ASA use within 7 d
• ≥2 episodes of angina within the last 24 h
• elevation in cardiac markers (troponin or creatine kinase-myocardial band)
• ST segment deviation ≥0.5 mm on ECG
The Global Registry of Acute Coronary Events (GRACE) score is a more comprehensive risk stratification tool
(www.outcomes-umassmed.org/grace/acs_risk/acs_risk_content.html ). While more complicated, it is a web-based
tool that can be easily used to improve risk calculation. When compared to the TIMI Risk Score, GRACE has been
found to better discriminate risk for 1-month and 1-year mortality in ACS patients.5
Therapeutic Choices (Figure 1 - Early Management of UA/NSTEMI)
The management of patients with NSTEMI or unstable angina has evolved significantly. Evidence from randomized
clinical trials now strongly supports the use of the “invasive strategy”—early, urgent coronary angiography followed if
possible by revascularization with percutaneous coronary intervention (PCI) or bypass surgery in all high-risk
patients. Patients are at high risk if they have one or more of the following features: positive cardiac enzymes, ST
segment changes, TIMI Risk Score ≥3, recurrent ischemic symptoms, heart failure, hemodynamic instability,
sustained ventricular tachycardia or a prior revascularization procedure—coronary artery bypass graft (CABG) or PCI.6
All patients admitted with NSTEMI or unstable angina should be placed on bedrest while ischemia is ongoing, then
gradually mobilized when symptoms have stabilized. Use supplemental oxygen in patients with inadequate arterial
oxygen saturation to keep the SaO2 above 90%. Continuous ECG monitoring for potentially lethal arrhythmias and ST
segment shifts (if available) is indicated in all high-risk patients.
Nitrates
Initial attempts at symptom relief should involve the use of nitroglycerin, first with sublingual tablets or spray.
Intravenous nitroglycerin is indicated in patients whose symptoms are not relieved promptly (within 15–20 minutes).
Longer acting oral or topical nitrates can be used when patients are symptom free to prevent recurrent episodes of
ischemia. The use of sildenafil, tadalafil or vardenafil in the previous 24 hours or the presence of significant
hypotension is a contraindication to the use of nitrates.
Beta-blockers and Calcium Channel Blockers
Start beta-blockers as soon as possible in all patients without contraindications: reactive airways disease;
bradycardia, i.e., heart rate (HR) ≤50 beats per minute (BPM); second- or third-degree heart block without a
functioning pacemaker; hypotension (SBP <100 mm Hg). The dose should be titrated to a resting HR of 50–60 BPM. I
anginal pain is ongoing at presentation, beta-blockers are initially administered intravenously followed by oral dosing
Calcium channel blockers can be used to control ongoing symptoms of ischemia in patients who are receiving
maximum tolerated doses of beta-blockers and adequate doses of nitrates. In addition, these agents are used in
patients who cannot tolerate beta-blockers, and in those with variant angina (coronary spasm). Avoid immediate-
release nifedipine because controlled trials suggest increased adverse outcomes such as stroke.
Angiotensin Converting Enzyme (ACE) Inhibitors
ACE inhibitors reduce mortality in patients with recent myocardial infarction, left ventricular systolic dysfunction or
clinical heart failure, diabetes and a broad spectrum of patients with high-risk chronic coronary artery disease.7 , 8
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Therapeutic Choice
Therefore, use these agents in all of these patient groups and in patients with hypertension not controlled with beta-
blockers and nitrates.
Antiplatelet and Anticoagulation Therapy
ASA
ASA provides a striking benefit in patients with acute coronary syndromes. If patients with suspected UA/NSTEMI
are not already receiving ASA, it should be initiated promptly and continued long term.
Thienopyridines
In the CURE (Clopidogrel in Unstable angina to prevent Recurrent ischemic Events) trial, clopidogrel (plus ASA)
significantly reduced the incidence of major adverse cardiac events in ACS patients compared with ASA alone, and
reduced the incidence of recurrent ischemia, an effect which was evident within a few hours.9 The benefit of
clopidogrel was consistent among patients regardless of TIMI Risk Score.10 The major benefits were noted at 30
days, with small additional benefits observed over the subsequent treatment period (average 8 months). There was
an excess of both major and minor bleeding in the clopidogrel group during the trial, with an insignificant trend
towards an increase in life-threatening bleeding. Bleeding risks increase with increasing ASA dose.11 Because of this
risk, many hospitals with cardiac catheterization facilities do not initiate clopidogrel until it is clear that bypass
surgery is not needed for appropriate revascularization. Clopidogrel should be held for a minimum of 5 days in
patients scheduled for bypass surgery.9 , 10 Clopidogrel is the preferred agent in this class due to its more rapid
onset of action and better safety profile compared with ticlopidine.
The FDA issued a black-box warning on clopidogrel due to the diminished effectiveness of this drug in patients who
are unable to convert it to active form.12 Patients with diminished CYP 2C19 function due to genetic
polymorphisms metabolize clopidogrel poorly and have higher cardiovascular event rates, both
following an ACS and after percutaneous coronary intervention. Tests are available to identify these
individuals and modified dosing strategies or an alternative agent can be considered. However, routine
genetic testing is not recommended at this time.13 Useful Info?
Prasugrel is a more potent platelet inhibitor than clopidogrel, and in a large clinical trial was associated with lower
ischemic event rates including stent thrombosis. However, there was a significant increase in bleeding events,
particularly in those older than age 75, those having body weight <60 kg and in patients with a history of stroke or
transient ischemic attack.14 The use of prasugrel should be considered in those patients with ACS undergoing stent
implantation who are at higher risk for stent thrombosis (previous stent thrombosis, STEMI, history of diabetes
mellitus).
Unfractionated Heparin (UFH) or Low Molecular Weight Heparins (LMWH)
Heparin is a key component in the successful management of patients with ACS. Studies of ASA with either UFH or
LMWH have shown a 3–3.5% absolute reduction (50–60% relative reduction) in the rate of death or MI in the first
week.15 , 16 UFH has important limitations due to significant variability in anticoagulant response. LMWH have the
advantage of ease of administration, predictable anticoagulant response and lack of need for monitoring. Clinical
trials have demonstrated the superiority of enoxaparin over UFH, but have shown neutral or unfavourable trends
with other LMWH (dalteparin and nadroparin).17 , 18 , 19 , 20 A direct comparison favoured enoxaparin over
tinzaparin.21 Enoxaparin is therefore the preferred agent in patients with UA/NSTEMI who do not have significant
renal dysfunction (estimated creatinine clearance >30 mL/min). In those with an estimated creatinine clearance ≤30
mL/min, UFH is appropriate.
Fondaparinux, a direct inhibitor of factor Xa, is as effective as enoxaparin in patients with non-ST segment
elevation ACS and is associated with a lower incidence of major bleeding according to the results of a large
randomized trial.22
Glycoprotein IIb/IIIa Inhibitors
Numerous trials have demonstrated the efficacy of these agents in the treatment of high-risk patients with
UA/NSTEMI undergoing coronary angiography and subsequent PCI. Clinical trials support the use of eptifibatide
and tirofiban at the time of admission or immediately before PCI.23 , 24 , 25 , 26 , 27 Abciximab is also effective,
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Therapeutic Choice
but its expense limits its use to the cardiac catheterization laboratory. The benefit of these agents is less clear for
patients for whom an initial conservative management approach is planned. Patients receiving any of these agents
must be carefully monitored for bleeding. However, the combined use of glycoprotein IIb/IIIa inhibitors and heparin
does appear to be safe.28 Thrombocytopenia is an unusual complication of treatment with these agents.
Direct Thrombin Inhibitors
Bivalirudin, a reversible direct thrombin inhibitor with a quick onset of action and short half-life, has a predictable
antithrombotic response. Clinical studies demonstrate positive outcomes in ACS patients. Bivalirudin use is considered
a reasonable strategy in patients with ACS undergoing PCI with concomitant thienopyridine and/or glycoprotein
IIb/IIIa inhibitor use.
Therapeutic Tips
The standard dose of ASA is 325 mg daily. This dose can be decreased to 81 mg enteric-coated tablet in those
patients receiving long-term clopidogrel.
Discontinue clopidogrel 5 days prior to bypass surgery to decrease the risk of bleeding.
ST Segment Elevation Myocardial Infarction (STEMI)
Goals of Therapy
Investigations
Therapeutic Choices
Patients with STEMI represent the extreme of the acute coronary syndrome spectrum, are considered to be a medical
emergency and, therefore, require urgent assessment and treatment.
Goals of Therapy
Decrease mortality and complications

Reduce or contain infarct size
Salvage functioning myocardium and prevent remodelling
Re-establish patency of the infarct-related artery
Investigations
Rapid, targeted history and physical examination, with particular attention to onset of symptoms,
contraindications to use of thrombolytic agents (see Table 2) and evidence of high-risk features (tachycardia,
hypotension, heart failure)
ECG STAT, then every 8 hours for the first 24 hours, then daily for 3 days. In addition, repeat the ECG with each
recurrence of chest pain
Baseline troponin STAT, (creatine kinase if troponin is unavailable) and then every 8 hours until enzymatic
confirmation of the diagnosis (see Investigations; Unstable Angina and Non-ST Segment Elevation Myocardial
Infarction (NSTEMI) for more discussion of troponin)
CBC to rule out the presence of anemia, baseline electrolytes, creatinine, fasting lipid profile (within 24 hours of
presentation) and liver function tests
Portable chest x-ray (CXR) STAT
Echocardiography to assess LV function after stabilization and treatment. Echocardiography is also used
emergently when there is suspicion of acute mechanical complications post-MI
Therapeutic Choices (Figure 2 - Early Management of STEMI)
Place all patients on bedrest with supplemental oxygen and continuous ECG monitoring. Begin gradual mobilization
after stabilization provided there is no evidence of complications.
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Therapeutic Choice
Primary Percutaneous Coronary Intervention (PCI)
Urgent coronary angiography with PCI is an excellent alternative to thrombolytics if appropriate high-volume cardiac
catheterization facilities are available. Primary PCI is indicated in patients with contraindications to thrombolytic
therapy and in those with cardiogenic shock, and is preferred in patients over the age of 75 because of a higher risk
of intracranial hemorrhage and higher overall early mortality seen with thrombolytic agents in this age group.29 ,
30 , 31
Thrombolytic Therapy
Thrombolytic therapy administered early in the course of STEMI substantially reduces morbidity and mortality,
particularly if the patient presents within 6 hours of symptom onset. The benefit is reduced for patients who present
6–12 hours after the onset of symptoms, and evidence of benefit is much less clear for those who present more than
12 hours after the onset of symptoms. The greatest absolute benefit is seen where the risk of mortality is highest
(anterior MI, previous MI).
Heparins
Give intravenous unfractionated heparin to all STEMI patients receiving alteplase, tenecteplase or reteplase.
Enoxaparin is an alternative, and has been shown to be superior to heparin in patients treated with tenecteplase,
but must be used with caution in patients older than 75 (dosage adjustment required) or those with renal
insufficiency (estimated ClCr <30 mL/min) because of an increased risk of bleeding.32 Heparin should be continued
for a minimum of 48 hours and use can be extended in patients with high-risk features. The indications for heparin
after streptokinase are unclear, but its use can be considered in patients with an anterior MI, atrial fibrillation, heart
failure or a history of embolism.
ASA
ASA provides a significant benefit in patients with STEMI. If patients are not already receiving ASA, it should be
initiated promptly and continued long term.33
Beta-blockers
These agents are recommended in all STEMI patients without contraindications, and are particularly useful when
sinus tachycardia and hypertension are present. They should be initiated once hemodynamic stability is achieved.
Titrate doses to a resting heart rate of 50–60 BPM.
Calcium Channel Blockers
Calcium channel blockers increase morbidity and mortality in patients with STEMI and are not recommended.34 They
may be used cautiously to relieve ischemia or to achieve rate control in patients with atrial fibrillation if beta-
blockers are contraindicated. Consider a low dose of diltiazem with heart rate monitored closely.
Nitroglycerin
Unlike NSTEMI or unstable angina, IV, oral or topical nitrates should be used in patients with STEMI only if ischemia
is persistent or recurrent, or if the patient has a large anterior MI, hypertension or heart failure.35
ACE Inhibitors and Angiotensin Receptor Blockers
ACE inhibitors are routinely recommended, unless contraindicated, in all patients post-STEMI and should ideally be
started within 24 hours of the event unless the patient is hypotensive (SBP <100 mm Hg). Doses should be
increased every 24 hours as tolerated for inpatients and at 1- to 2-week intervals for outpatients. Based on the
results of the HOPE trial, it is reasonable to continue an ACE inhibitor indefinitely even in patients with preserved LV
Page 38
Therapeutic Choice
function.8 An angiotensin receptor blocker should be used in STEMI patients who cannot tolerate an ACE inhibitor
and have either clinical or radiological signs of heart failure or documented LV dysfunction.
Aldosterone Antagonists
Long-term use of an aldosterone antagonist such as spironolactone or eplerenone reduces morbidity and
mortality in STEMI patients with clinical evidence of heart failure, LV ejection fraction <40% or both, based on the
results of 2 randomized trials.36 , 37 Caution must be used in patients with renal insufficiency or pre-existing
hyperkalemia, and in those receiving ACE inhibitors concomitantly.36 , 37
Clopidogrel
In patients with STEMI treated with fibrinolysis, clopidogrel increases patency of the infarct-related artery and
decreases ischemic complications according to the results of 2 randomized trials;38 , 39 therefore routine use should
be considered in these patients.
Complications of STEMI
Recurrent or Ongoing Ischemia
Optimize anti-anginal therapy, and consider urgent coronary angiography and possible revascularization for all
patients with recurrent or ongoing ischemia.
Heart Failure
Treat heart failure aggressively (see Cardiovascular Disorders: Heart Failure). In addition, consider angiography and
possible revascularization in patients with LV ejection fraction <40% after MI.
Arrhythmias
Asymptomatic premature ventricular contractions (PVCs) do not require therapy. Symptomatic ectopy may require
therapy, usually with a beta-blocker. Class IC agents are contraindicated. Patients with sustained ventricular
arrhythmias require investigation to rule out recurrent ischemia and may require subsequent electrophysiologic
assessment.40 Consider urgent electrical or pharmacologic cardioversion in patients with atrial fibrillation causing
ischemia or heart failure. Treat all patients with atrial fibrillation to control ventricular rate (usually with a beta-
blocker or digoxin if there is concomitant heart failure) and consider oral anticoagulant therapy.
Patients with an ejection fraction <30% 1 month post-MI or 3 months post-revascularization should be referred for
automatic implantable cardioverter-defibrillator therapy (AICD).41
Pericarditis
Pericarditis, although uncommon, usually presents within 72 hours post-MI, and symptoms usually resolve within 3–
4 days. Symptomatic pericarditis can be treated by increasing the dose of ASA to 650 mg QID for 1–2 weeks. If
ASA is ineffective, a nonsteroidal anti-inflammatory drug (NSAID) or corticosteroid can be added. Discontinuation
of anticoagulants is unnecessary if pericarditis occurs early post-infarction, but caution is required if a patient
presents with pericarditis weeks or months after MI (Dressler’s syndrome) because of the risk of pericardial bleeding
and tamponade.42
Mechanical Complications
Ruptured papillary muscle (and severe mitral regurgitation), ventricular septal defects or ventricular free wall
rupture are infrequent but devastating problems that can present with acute cardiac arrest or cardiogenic shock.
Patients should be considered for emergency angiography and surgical intervention, but even with urgent treatment
the mortality rate associated with these conditions is very high.
Page 39
Therapeutic Choice
Clopidogrel Use in Percutaneous Coronary Intervention
Pretreatment with clopidogrel prior to PCI reduced the risk of death, MI and repeat revascularization in the PCI-CURE
substudy.43 Therapy must be continued for at least 1 month post-procedure, particularly if a coronary stent is used.
However, if drug-eluting stents are used, the duration of thienopyridine therapy must be extended due to delayed
endothelialization and an increased risk of late stent thrombosis. It is recommended that clopidogrel be continued
for 1 year. Under urgent circumstances that prevent the use of clopidogrel for a full year, the drug should be
continued for a minimum of 3 months in patients with a sirolimus-eluting stent and for 6 months in those with a
paclitaxel-eluting stent.44 Elective surgery should be postponed until after the course of clopidogrel has been
completed in patients with stents. If surgery cannot be postponed, continue clopidogrel throughout the perioperative
period if possible. Early discontinuation of clopidogrel results in a high risk of acute stent thrombosis with high
morbidity and mortality.
Therapeutic Tips
The goal for thrombolytic treatment is a door-to-needle time of 30 minutes or less.

The goal for primary PCI is a door-to-dilatation time of 90 minutes or less.
Careful attention to maximum pain relief is important.
In patients with right ventricular infarcts:
avoid nitrates and diuretics
use fluids and inotropes to treat hypotension
Administer beta-blockers early to all patients without contraindications. Increase the dose every 12 hours (every
24 hours for once-daily beta-blockers), if tolerated (monitor blood pressure and heart rate), until the patient
has reached adequate beta-blockade (HR ≤55–65 BPM).
Start ACE inhibitors early. The choice of agent can depend on practitioner preference, hospital formulary or
financial constraints for the individual patient.
In smokers, reinforce early (within 24 hours) and frequently the need to quit smoking.
Stool softeners are often used in the immediate post-MI period to prevent straining with bowel movements.
Anxiolytics are often used on an as-needed basis in the immediate post-MI period.
Figure 1- Early Management of UA/NSTEMI
Page 40
Therapeutic Choice
Figure 2-Early Management of STEMI
Page 41
Therapeutic Choice
Table 2: Drugs Used in Acute Coronary Syndromes
Drug
Class Drug Dose Adverse Effects Interactions Costa
Beta1- acebutolol Initial: Bronchospasm, HF, Enhanced $

adrenergic Rhotral, Sectral, 100–200 mg BID po hypotension, sleep cardiodepressant
Antagonists, Apo-Acebutolol, Usual: disturbances, effect with
selective with other generics 400 mg BID po dizziness, fatigue, calcium channel
ISA anorexia, nausea, AV blockers,
block, bradycardia, antiarrhythmics,
claudication, anesthetics.
Raynaud's, lethargy, Increased
drowsiness. bradycardia with
digoxin.
Hypertension with
alpha-agonists.
Beta1- atenolol Initial: Bronchospasm, HF, Enhanced $

adrenergic Tenormin, 50 mg/day po hypotension, sleep cardiodepressant
Antagonists, generics Usual: disturbances, effect with
selective 100 mg/day po dizziness, fatigue, calcium channel
Page 42
Therapeutic Choice
Drug
without ISA anorexia, nausea, AV blockers,

digoxin.
Hypertension with
alpha-agonists.
Beta1- metoprolol iv: Bronchospasm, HF, Enhanced $

adrenergic Betaloc, Lopresor, 5 mg over 1–2 min hypotension, sleep cardiodepressant
Antagonists, generics repeat Q5 min disturbances, effect with
selective (maximum 15 mg) dizziness, fatigue, calcium channel
without ISA Initial: anorexia, nausea, AV blockers,
25–50 mg QID po block, bradycardia, antiarrhythmics,
Usual: claudication, anesthetics.
100 mg BID po Raynaud's, lethargy, Increased
po can be started drowsiness. bradycardia with
15 min after iv digoxin.
Hypertension with
alpha-agonists.
Beta1- nadolol Initial: Bronchospasm, HF, Enhanced $

adrenergic generics 40–80 mg/day po hypotension, sleep cardiodepressant
Antagonists, Usual: disturbances, effect with
nonselective 160 mg/day po dizziness, fatigue, calcium channel
digoxin.
Hypertension with
alpha-agonists.
Beta1- propranolol Initial: Bronchospasm, HF, Enhanced $

adrenergic generics 40 mg BID/TID po hypotension, sleep cardiodepressant
Antagonists, Usual: disturbances, effect with
nonselective 60 mg QID po dizziness, fatigue, calcium channel
digoxin.
Hypertension with
alpha-agonists.
Beta1- timolol Initial: Bronchospasm, HF, Enhanced $

adrenergic Apo-Timol, other 5–10 mg BID po hypotension, sleep cardiodepressant
Antagonists, generics Usual: disturbances, effect with
nonselective 10 mg BID po dizziness, fatigue, calcium channel
digoxin.
Hypertension with
alpha-agonists.
Calcium amlodipine Hypotension, flushing, $$

Channel Norvasc, GD- 5–10 mg/day po marked peripheral
Blockers edema.
Page 43
Therapeutic Choice
Drug
amlodipine,
other generics
Calcium diltiazem Bradycardia, heart Additive effect $-$$$

Channel Cardizem CD, 120–360 mg/day po block, edema, with β-blockers,
Blockers Give IR formulations hypotension. digoxin,
Tiazac, Tiazac XC,
TID or QID; CD and XC amiodarone.
generics
once daily Monitor for
excessive
bradycardia.
Calcium verapamil Bradycardia, heart Additive effect $-$$$

Channel Isoptin SR, 180–480 mg/day po block, hypotension, with β-blockers,
Blockers generics Give IR formulations constipation, flushing, digoxin,
TID; SR BID edema. amiodarone.
Monitor for
excessive
bradycardia.
Nitrates isosorbide Initial: 30–90 mg/day Headache (up to 50%; Potential $

dinitrate, IR po tolerance may hypotensive effect
generics IR: give TID (allow a develop), tachycardia, with vasodilators.
12 h nitrate-free palpitation, Contraindicated
period) hypotension, syncope with recent
(rare), dizziness, (<24 h) use of
nausea, flushing, sildenafil,
weakness. tadalafil or
vardenafil; use
with caution when
hypotension
present.
Nitrates isosorbide-5- Headache (up to 50%; Potential $

mononitrate 30–60 mg daily po tolerance may hypotensive effect
develop), tachycardia, with vasodilators.
Imdur, generics
palpitation, Contraindicated
hypotension, syncope with recent
(rare), dizziness, (<24 h) use of
vardenafil; use
with caution when
hypotension
present.
Nitrates nitroglycerin Initial: Frequent BP Potential $b

intravenous 10–150 µg/min iv monitoring is required hypotensive effect
generics (titrate to symptoms for iv nitroglycerin. with vasodilators.
and blood pressure) Headache (up to 50%; Contraindicated
tolerance may with recent
develop), tachycardia, (<24 h) use of
palpitation, sildenafil,
hypotension, syncope tadalafil or
(rare), dizziness, vardenafil; use
nausea, flushing, with caution when
weakness. hypotension
present.
Page 44
Therapeutic Choice
Drug
Nitrates nitroglycerin Headache (up to 50%; Potential $-$$

transdermal 0.2–0.8 mg/h patch tolerance may hypotensive effect
applied daily for 10–12 develop), tachycardia, with vasodilators.
Minitran, Nitro-
h palpitation, Contraindicated
Dur, Transderm- hypotension, syncope with recent
Nitro, Trinipatch (rare), dizziness, (<24 h) use of
Contact dermatitis. vardenafil; use
with caution when
hypotension
present.
ACE Inhibitors captopril Initial: Proteinuria (1%), ↑ risk of $$

Capoten, generics 6.25 mg Q8H po neutropenia (rare), neutropenia with
Target: rash, angioedema, antiarrhythmics,
50 mg Q8H po hypotension, allopurinol,
alterations in taste, corticosteroids.
nausea, anorexia, Hyperkalemia
dizziness, with
hyperkalemia, dry spironolactone,
cough (common). triamterene,
Caution in patients amiloride.
with renovascular Hypotension with
hypertension, renal diuretics.
insufficiency, bilateral
renal artery stenosis Avoid concurrent
or single kidney with therapy with
renal artery stenosis. lithium.
ACE Inhibitors cilazapril Initial: Proteinuria (1%), ↑ risk of $

Inhibace, 0.5 mg daily po neutropenia (rare), neutropenia with
generics Target: rash, angioedema, antiarrhythmics,
2.5 mg daily po hypotension, allopurinol,
dizziness, with
ACE Inhibitors enalapril Initial: Proteinuria (1%), ↑ risk of $$

Vasotec, generics 2.5 mg BID po neutropenia (rare), neutropenia with
10 mg BID po hypotension, allopurinol,
dizziness, with
Page 45
Therapeutic Choice
Drug

ACE Inhibitors fosinopril Initial: 5 mg daily po Proteinuria (1%), ↑ risk of $

Monopril, Target: neutropenia (rare), neutropenia with
generics 20 mg daily po rash, angioedema, antiarrhythmics,
hypotension, allopurinol,
dizziness, with
ACE Inhibitors lisinopril Initial: 2.5 mg daily po Proteinuria (1%), ↑ risk of $

Zestril, Prinivil, Target: neutropenia (rare), neutropenia with
generics 20 mg daily po rash, angioedema, antiarrhythmics,
dizziness, with
ACE Inhibitors quinapril Initial: 5 mg daily po Proteinuria (1%), ↑ risk of $

Accupril Target: neutropenia (rare), neutropenia with
20 mg daily po rash, angioedema, antiarrhythmics,
dizziness, with
Page 46
Therapeutic Choice
Drug
ACE Inhibitors ramipril Initial: 1.25–2.5 mg Proteinuria (1%), ↑ risk of $

Altace, generics BID po neutropenia (rare), neutropenia with
5 mg BID or hypotension, allopurinol,
10 mg daily po alterations in taste, corticosteroids.
dizziness, with
Aldosterone spironolactone Initial: 12.5 mg daily Rash, urticaria, Hyperkalemia $

Antagonists Aldactone, po gynecomastia, nausea, with ACE
generics Target 25–50 mg daily vomiting, diarrhea, inhibitors,
po confusion, digoxin, NSAIDs.
hyperkalemia,
agranulocytosis, SLE.
Antiplatelet ASA Gastritis, Heparin, warfarin $

Agents Aspirin, Coated 80–325 mg/day po gastric/duodenal (bleeding risk
ulceration (rarely with heparin is
Aspirin,
bronchospasm). low); other
Asaphen/Asaphen
Nausea, vomiting, GI NSAIDs.
EC, Entrophen,
hemorrhage, tinnitus,
generics
vertigo,
hypersensitivity.
Antiplatelet clopidogrel Loading dose pre-PCI Bleeding, rash, Caution with $$$$
Agents Plavix or STEMI: 300–600 mg, purpura. Similar NSAIDs. PPI use
then 75 mg daily po tolerability to ASA. may reduce
clopidogrel
efficacy.45
Antiplatelet prasugrel Loading dose: 60 mg, Increased risk of Caution with $$$$
Agents Effient then 10 mg daily po bleeding. Caution in NSAIDs.
patients >75 y, body
weight <60 kg.
Contraindicated if
history of ischemic
stroke.
Antiplatelet ticlopidine Diarrhea, rash, Caution with $$

Agents generics 250 mg BID po neutropenia, purpura. NSAIDs. May ↑
Measure neutrophils theophylline
Q2 wk × 3 mo levels.
initially.
Heparin, heparin sodium Bleeding, ASA, warfarin $b

Unfractionated Hepalean, 60–70 U/kg iv bolus thrombocytopenia. (bleeding risk
Maximum: 5000 U then with ASA is low);
Heparin LEO,
aPTT response
generics
Page 47
Therapeutic Choice
Drug
12–15 U/kg/h. may be blunted

Adjust to maintain aPTT with concurrent iv
at 1.5–2 × control. nitroglycerin
First aPTT 4 h after (controversial).
bolus
Post-thrombolytic:
bolus
60 U/kg iv
Maximum: 4000 U then
12 U/kg/h.
Adjust to maintain aPTT

at 1.5–2 × control.
First aPTT 6 h after
bolus
Heparins, Low dalteparin Hematoma at injection ASA, warfarin $b

Molecular Fragmin 120 IU/kg BID sc site, bleeding, (bleeding risk
Weight Maximum: thrombocytopenia; with ASA is low).
10 000 IU/dose caution if ClCr <30
mL/min.
Heparins, Low enoxaparin 1 mg/kg BID sc Hematoma at injection ASA, warfarin $b

Molecular Lovenox Maximum: site, bleeding, (bleeding risk
Weight 100 mg/dose thrombocytopenia; with ASA is low).
caution if ClCr <30
Post-thrombolytic: 30 mL/min.
mg iv bolus in addition Caution in elderly
to first sc dose patients and those
with renal
When ≥75 y, omit insufficiency.
bolus and reduce dose
to 0.75 mg/kg BID (75 Preferred LMWH in
mg maximum for first 2 ACS.
doses)
Specific Factor fondaparinux 2.5 mg daily sc Bleeding, allergic Use caution with $b
Xa Inhibitors Arixtra First dose iv if STEMI reactions (rare). other drugs that
Not recommended as affect hemostasis.
sole agent in patients
undergoing PCI due to
risk of catheter
thrombosis.
Direct bivalirudin Bolus: 0.75 mg/kg iv, Bleeding, allergic Use caution with $447
Thrombin Angiomax then 1.75 mg/kg/h reactions (rare). other drugs that (250 mg
Inhibitors affect hemostasis. vial)b
Thrombolytics alteplase Bolus: 15 mg iv, then Bleeding (can be $2746

Activase rt-PA 0.75 mg/kg × 30 min fatal). (100 mg
(maximum 50 mg), Absolute vial)b
then 0.5 mg/kg × 60 contraindications:
min (maximum 35 mg) previous intracranial
Maximum dose 100 mg hemorrhage; known
malignant intracranial
Page 48
Therapeutic Choice
Drug
Start heparin with neoplasm, known

infusion cerebral vascular
lesion, ischemic stroke
within 3 mo EXCEPT
acute stroke within 3
h; suspected aortic
dissection; active
bleeding or bleeding
diathesis (excluding
menses); significant
closed head or facial
trauma within 3 mo.
Relative
contraindications:
history of chronic
severe, poorly
controlled HTN, severe
uncontrolled HTN (BP
>180/110 mm Hg)c;
prior CVA greater than
3 mo or known
intracerebral
pathology not covered
above; traumatic or
prolonged (>10 min)
CPR or major surgery
(<3 wk);
noncompressible
venous punctures;
recent (2–4 wk)
internal bleeding;
pregnancy; active
peptic ulcer; current
use of anticoagulants.
Thrombolytics streptokinase 1.5 million units iv over Bleeding (can be $730

Streptase 1h fatal). (1.5 MU
Absolute vial)b
contraindications:
previous intracranial
hemorrhage; known
malignant intracranial
neoplasm, known
cerebral vascular
lesion, ischemic stroke
within 3 mo EXCEPT
acute stroke within 3
h; suspected aortic
dissection; active
trauma within 3 mo.
Relative
contraindications:
history of chronic
severe, poorly
Page 49
Therapeutic Choice
Drug

>180/110 mm Hg)c;
3 mo or known
intracerebral
above; traumatic or
prolonged (>10 min)
(<3 wk);
noncompressible
venous punctures;
recent (2–4 wk)
internal bleeding;
pregnancy; active
Thrombolytics tenecteplase <60 kg: Bleeding (can be $2746

TNKase 30 mg iv × 1 fatal). (50 mg
60–69 kg: Absolute vial)b
35 mg iv × 1 contraindications:
70–79 kg: previous intracranial
40 mg iv × 1 hemorrhage; known
80–89 kg: malignant intracranial
45 mg iv × 1 neoplasm, known
≥90 kg: cerebral vascular
50 mg iv × 1 lesion, ischemic stroke
Given as iv bolus over within 3 mo EXCEPT
5s acute stroke within 3
h; suspected aortic
dissection; active
trauma within 3 mo.
Relative
contraindications:
history of chronic
severe, poorly
>180/110 mm Hg)c;
3 mo or known
intracerebral
above; traumatic or
prolonged (>10 min)
(<3 wk);
noncompressible
venous punctures;
recent (2–4 wk)
internal bleeding;
pregnancy; active
Page 50
Therapeutic Choice
Drug
Glycoprotein eptifibatide Bolus: 180 µg/kg iv Bleeding (risk of Use caution with $$$$ b
IIb/IIIa Integrilin over 1–2 min, then serious bleeding other drugs that
Inhibitors 2 µg/kg/min appears to be low), affect hemostasis.
Maximum: primarily at puncture
15 mg/h sites.
ClCr <50 mL/min: Thrombocytopenia.
infuse at 1 µg/kg/min
Allergic reactions.
Glycoprotein tirofiban Bleeding (risk of Use caution with $$$$ b

IIb/IIIa Aggrastat 0.4 µg/kg/min iv × 30 serious bleeding other drugs that
Inhibitors min then appears to be low), affect hemostasis.
0.1 µg/kg/min × primarily at puncture
48–72 h sites.
ClCr Thrombocytopenia.
<30 mL/min:
0.2 µg/kg/min iv × 30 Allergic reactions.
min then
0.05 µg/kg/min × 72 h
a. Cost of 30-day supply, includes drug cost only except where noted.
b. Cost of average 1-day supply.
c. Could be an absolute contraindication in low-risk patients with STEMI.
Abbreviations: aPTT=activated partial thromboplastin time; HF=heart failure; CVA=cerebrovascular accident; DBP=diastolic
blood pressure; GI=gastrointestinal; GU=genitourinary; HTN=hypertension; IR=immediate-release; ISA=intrinsic
sympathomimetic activity; NSAIDs=nonsteroidal anti-inflammatory drugs; NTG=nitroglycerin; PCI=percutaneous coronary
intervention; PPI=proton pump inhibitor; SBP=systolic blood pressure; SCr=serum creatinine; SR=slow-
release; TTP=thrombotic thrombocytopenic purpura; U=units
Legend: $ < $25 $-$$ < $25–50 $$ $25–50 $-$$$ < $25–75 $$$ $50–75 $$$$ $75–100
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College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on the Management
of Patients With Unstable Angina). Circulation 2002;106(14):1893-900.
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Unstable Signs and Symptoms (PRISM-PLUS) Study Investigators. N Engl J Med 1998;338(21):1488-97.
25. Labinaz M, Kilaru R, Pieper K et al. Outcomes of patients with acute coronary syndromes and prior coronary
artery bypass grafting: results from the platelet glycoprotein IIb/IIIa in unstable angina: receptor suppression
using integrilin therapy (PURSUIT) trial. Circulation 2002;105(3):322-7.
26. Moliterno DJ, Yakubov SJ, DiBattiste PM et al. Outcomes at 6 months for the direct comparison of tirofiban
and abciximab during percutaneous coronary revascularisation with stent placement: the TARGET follow-up
study. Lancet 2002;360(9330):355-60.
27. O'Shea JC, Hafley GE, Greenberg S et al. Platelet glycoprotein IIb/IIIa integrin blockade with eptifibatide in
coronary stent intervention: the ESPRIT trial: a randomized controlled trial. JAMA 2001;285(19):2468-73.
28. Braunwald E, Antman EM, Beasley JW et al. ACC/AHA guidelines for the management of patients with unstable
angina and non-ST-segment elevation myocardial infarction. A report of the American College of
Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on the Management of
Patients With Unstable Angina). J Am Coll Cardiol 2000;36(3):970-1062.
29. Grines CL, Browne KF, Marco J et al. A comparison of immediate angioplasty with thrombolytic therapy for
acute myocardial infarction. The Primary Angioplasty in Myocardial Infarction Study Group. N Engl J Med
1993;328(10):673-9.
30. Hochman JS, Sleeper LA, White HD et al. One-year survival following early revascularization for cardiogenic
shock. JAMA 2001;285(2):190-2.
31. Thiemann DR, Coresh J, Schulman SP et al. Lack of benefit for intravenous thrombolysis in patients with
myocardial infarction who are older than 75 years. Circulation 2000;101(19):2239-46.
32. Antman EM, Morrow DA, McCabe CH et al. Enoxaparin versus unfractionated heparin with fibrinolysis for ST-
elevation myocardial infarction. N Engl J Med 2006;354(14):1477-88.
33. Antman EM, Anbe DT, Armstrong PW et al. ACC/AHA guidelines for the management of patients with ST-
elevation myocardial infarction--executive summary: a report of the American College of Cardiology/American
Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 1999 Guidelines for the
Management of Patients With Acute Myocardial Infarction). Circulation 2004;110(5):588-636.
34. Yusuf S, Held P, Furberg C. Update of effects of calcium antagonists in myocardial infarction or angina in light
of the second Danish Verapamil Infarction Trial (DAVIT-II) and other recent studies. Am J Cardiol 1991;67
(15):1295-7.
35. Yusuf S, Collins R, MacMahon S et al. Effect of intravenous nitrates on mortality in acute myocardial
infarction: an overview of the randomised trials. Lancet 1988;1(8594):1088-92.
36. Pitt B, Zannad F, Remme WJ et al. The effect of spironolactone on morbidity and mortality in patients with
severe heart failure. Randomized Aldactone Evaluation Study Investigators. N Engl J Med 1999;341(10):709-
17.
37. Pitt B, Remme W, Zannad F et al. Eplerenone, a selective aldosterone blocker, in patients with left ventricular
dysfunction after myocardial infarction. N Engl J Med 2003;348(14):1309-21.
38. Chen ZM, Jiang LX, Chen YP et al. Addition of clopidogrel to aspirin in 45,852 patients with acute myocardial
infarction: randomised placebo-controlled trial. Lancet 2005;366(9497):1607-21.
39. Sabatine MS, Cannon CP, Gibson CM et al. Addition of clopidogrel to aspirin and fibrinolytic therapy for
myocardial infarction with ST-segment elevation. N Engl J Med 2005;352(12):1179-89.
40. Moss AJ, Zareba W, Hall WJ et al. Prophylactic implantation of a defibrillator in patients with myocardial
infarction and reduced ejection fraction. N Engl J Med 2002;346(12):877-83.
41. Gregoratos G, Abrams J, Epstein AE et al. ACC/AHA/NASPE 2002 guideline update for implantation of cardiac
pacemakers and antiarrhythmia devices: summary article: a report of the American College of
Cardiology/American Heart Association Task Force on Practice Guidelines (ACC/AHA/NASPE Committee to
Update the 1998 Pacemaker Guidelines). Circulation 2002;106(16):2145-61.
42. Berman J, Haffajee CI, Alpert JS. Therapy of symptomatic pericarditis after myocardial infarction:
retrospective and prospective studies of aspirin, indomethacin, prednisone, and spontaneous resolution. Am
Heart J 1981;101(6):750-3.
43. Mehta SR, Yusuf S, Peters RJ et al. Effects of pretreatment with clopidogrel and aspirin followed by long-term
therapy in patients undergoing percutaneous coronary intervention: the PCI-CURE study. Lancet 2001;358
(9281):527-33.
44. Popma JJ, Berger P, Ohman EM et al. Antithrombotic therapy during percutaneous coronary intervention: the
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Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004;126( 3 Suppl):576S-
599S.
45. Lau WC, Gurbel PA. The drug-drug interaction between proton pump inhibitors and clopidogrel. CMAJ
2009;180(7):699-700.
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e-Therapeutics+ : Therapeutics : Cardiovascular Disorders: Acute Stroke Page 1 of 11
Therapeutic Choice
Print Close
Cardiovascular Disorders: Acute Stroke
Date Prepared: May 2009
Stephen J. Phillips, BSc, MBBS, FRCPC
Gord Gubitz, BSc, MD, FRCPC (Edin)
Stroke, recognized clinically as the sudden onset of a focal disturbance of central nervous system function, may be
caused by cerebral infarction (ischemic stroke, responsible for about 85% of all strokes) or intracerebral
hemorrhage.1 Warning signs promoted by the Heart and Stroke Foundation that suggest the presence of stroke are
shown in Table 1. The third main stroke subtype, subarachnoid hemorrhage, more often causes sudden onset severe
headache with or without impaired consciousness.
There is no acute-phase intervention of proven value for intracerebral hemorrhage. Post-acute treatment of primary
intracerebral hemorrhage is similar to that of ischemic stroke except that antithrombotic drugs are avoided.
Treatment of subarachnoid hemorrhage is primarily nonpharmacologic (i.e., ablation of the bleeding source). Refer
patients with suspected subarachnoid hemorrhage to a neurosurgical centre.
Table 1: Warning Signs of Stroke
Weakness − sudden loss of strength or numbness in the face, arm or leg
Difficulty with speech − sudden confusion or trouble speaking
Vision problems − sudden trouble with vision
Headache − sudden severe and unusual headache
Dizziness − loss of balance, especially with any of the above signs
Goals of Therapy 2 , 3 , 4
Minimize brain damage

Prevent complications
Reduce risk of recurrence
Restore function of the individual
Investigations
The evaluation of patients with suspected stroke is highly time dependent. Specific stroke treatments (alteplase) can
only be provided within the first 4.5 hours of symptom onset in patients with ischemic stroke (see Figure 1 -
Emergency Department Management of Patients with Suspected Stroke).
Use the clinical history, physical examination, imaging studies and other ancillary investigations to confirm the
diagnosis and exclude stroke mimics such as subdural hematoma, Todd's paresis (post seizure), brain abscess,
herpes simplex encephalitis, hypoglycemia, brain tumour (primary or secondary), multiple sclerosis, migraine and
conversion disorder.
History
time of onset, symptoms at onset, course of symptoms since onset
antecedent trauma or illness, previous neurovascular events
vascular comorbidity (angina, MI, heart failure, atrial fibrillation, peripheral and renal vascular disease)
vascular disease risk factors (hypertension, smoking, diabetes mellitus, dyslipidemia, excessive alcohol
intake, body mass index, exercise, family history of vascular disease or hemostatic disorders)
other health problems (particularly peptic ulcer disease or other disorders that predispose to bleeding)
pre-stroke cognitive and functional status
family history of premature vascular disease
place of residence and social supports
medications (particularly warfarin, ASA and other antiplatelet drugs)
Physical examination
to localize the lesion by brain region and vascular territory
to determine stroke syndrome, severity and cause
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Therapeutic Choice
to assess comorbid conditions
Laboratory and radiological tests
CBC, INR, PTT, glucose (to rule out hypoglycemia as a stroke mimic), electrolytes, urea, creatinine, liver
function tests, albumin
fasting glucose, hemoglobin A1c, cholesterol panel (for risk factor modification)
ECG (to look for atrial fibrillation, MI and left ventricular hypertrophy)
chest x-ray (to look for heart disease, lung cancer)
CT (or MR) brain scan is required immediately2 for all patients to rule out intracerebral hemorrhage and
stroke mimics. For patients who are found to have intracranial hemorrhage, the location of the hemorrhage
determines subsequent treatment (see Figure 2 - Approach to a Finding of Intracranial Hemorrhage on CT
Scan)
lumbar puncture if subarachnoid hemorrhage suspected and CT scan negative for blood
urgent (same or next day) vascular imaging (duplex carotid ultrasonography, CT angiography or MR
angiography) to determine the degree of carotid stenosis in patients with nondisabling carotid territory
strokes who are fit for carotid endarterectomy2
echocardiography (transthoracic +/− transesophageal) to search for a cardiac source of emboli in patients
with a recent history of MI or cardiac surgery, and any patient with a large-vessel territory (nonlacunar)
stroke and neurovascular imaging studies showing no large-vessel disease, provided anticoagulation is not
contraindicated
other investigations if indicated:
blood cultures to rule out endocarditis
inflammatory markers (ESR, CRP, ANA) as a screen for vasculitis
syphilis serology
antiphospholipid antibodies, protein C, protein S, antithrombin, factor V Leiden and prothrombin gene
mutation if hypercoagulable state suspected
malignancy work-up (CT chest, abdomen, pelvis)
Therapeutic Choices
I. Minimize Brain Damage
Ischemic Stroke
Alteplase should be administered (iv) as soon as possible following stroke onset for patients who meet
strict eligibility criteria2,5 (Figure 1 - Emergency Department Management of Patients with Suspected
Stroke, Table 2, Table 3, Table 4). A meta-analysis concluded that thrombolysis within 3 hours
provided a significant reduction (odds ratio 0.71, 95% confidence interval 0.52–0.96) in the chance of
death and dependency 3–6 months after ischemic stroke.6 Health Canada currently approves
administration within 3 hours of stroke onset, though evidence from randomized trials demonstrates
benefit up to 4.5 hours.2 Useful Info?
Intra-arterial administration of thrombolytic agents is presently of limited clinical application, except in highly
specialized centres, where randomized trials are ongoing.
Nonpharmacologic methods of achieving recanalization are under investigation. Mechanical clot-retrieving devices
have been approved for removing thrombus (but not for treating stroke) in the United States, but not in Canada.
Subarachnoid Hemorrhage
Nimodipine 60 mg po/ng Q4H for 3 weeks reduces the risk of secondary vasospasm and cerebral infarction.7 Use
30 mg po/ng Q2H in patients who are very sensitive to the blood pressure lowering effects (Table 5).
Neurosurgical Intervention
Ischemic stroke
Decompressive craniectomy may be performed on patients with massive hemispheric infarcts whose level of
consciousness is declining. Evidence from a pooled analysis of 3 smaller randomized trials found an increase in
survival for these patients when treated with craniectomy. However, survivors did incur significant amounts of
disability.8 Consensus opinion is that patients with large cerebellar infarcts may benefit from surgical
decompression.
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Therapeutic Choice
Table 2: Alteplase in Acute Ischemic Stroke: Treatment Criteria
Treatment criteria
Ischemic stroke in a patient ≥ 18 years
Stroke onset > 1 h and ≤ 4.5 h before alteplase administration
Stroke deficit that is disabling or measurable on the NIH Stroke Scale
No intracranial hemorrhage on CT or MRI scan
Exclusion criteria
Time of stroke onset unknown or > 4.5 h
Any hemorrhage on brain CT or MRI scan
Symptoms suggestive of subarachnoid hemorrhage
CT or MRI signs of acute hemispheric infarction involving more than 1/3 of the middle cerebral artery territory
(Alberta Stroke Program Early CT Score < 5)
History of intracranial hemorrhage
Stroke or serious head or spinal trauma within the preceding 3 mo
Seizure at stroke onset
Systolic blood pressure ≥ 185 mm Hg or diastolic blood pressure ≥ 110 mm Hg or aggressive treatment
(intravenous medication) necessary to reduce blood pressure to these limits
Recent major surgery
Arterial puncture at a noncompressible site within the previous 7 days
Elevated activated partial thromboplastin time
International normalized ratio > 1.7
Platelet count < 100 × 109/L
Blood glucose concentration < 2.7 or > 22 mmol/L
Any other condition that could increase the risk of hemorrhage after alteplase administration
Adapted with permission from “Canadian best practice recommendations for stroke care (updated 2008)”, CMAJ December
2008;179(12 Suppl), pages E1-93. [Online English Version] © 2008 Canadian Medical Association.
Abbreviations: CT=computed tomography; NIH=National Institutes of Health; MRI=magnetic resonance imaging
Intracerebral hemorrhage (see Figure 2 - Approach to a Finding of Intracranial Hemorrhage on CT Scan)

Patients with cerebellar hemorrhage should have an urgent neurosurgical consultation for consideration of
craniotomy and evacuation of the hemorrhage.2 There is no specific acute-phase neurosurgical intervention of
proven value for supratentorial intracerebral hemorrhage.9 Patients with supratentorial intracerebral hemorrhage
should be cared for on a stroke unit.2 The medical treatment of patients with intracerebral hemorrhage is similar
to that of ischemic stroke, except that antithrombotic drugs and statins are avoided.10
Subarachnoid hemorrhage (see Figure 2 - Approach to a Finding of Intracranial Hemorrhage on CT Scan)

Refer patients with suspected subarachnoid hemorrhage immediately to a neurosurgical centre.2
Table 3: Alteplase in Acute Ischemic Stroke: Monitoring5
Blood Pressure and Neurological Signs

• Baseline, then Q15min × 2 h after starting alteplase
• Then Q30min × 6 h
• Then Q1H until 24 h after starting alteplase
• Call MD if the systolic BP is > 180 mm Hg or if the diastolic BP is > 110 mm Hg on 2 or more occasions taken
5–10 min apart
• Stop the infusion, obtain emergency CT scan and notify MD if there is neurologic deterioration, severe headache,
or new onset of nausea or vomiting
Blood Glucose
• Call MD if glucose > 12 mmol/L
Lines and Tubes

• Delay placement of nasogastric tubes, indwelling catheters or intra-arterial pressure catheters
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Therapeutic Choice
Medications
• No ASA, ticlopidine, clopidogrel, heparin or warfarin for 24 h
• Acetaminophen 650 mg po or pr Q4H if body temperature is ≥ 38°C or for analgesia
• O2 via nasal prongs or face mask to keep O2 saturation > 90%
• After the alteplase infusion is completed, continue iv normal saline (with or without KCl)
Investigations
• CT brain scan after 24 h
II. Prevent Complications
General Supportive Care
Expert nursing care and early mobilization are the mainstays of treatment.
Use oxygen if pulse oximetry shows desaturation (SaO2 < 90%).5
Elevated body temperature is associated with poor outcome after stroke.11 , 12 , 13 Symptomatic treatment of
pyrexia (and investigation of its cause) is recommended.2
Hyperglycemia is associated with poor outcome after stroke and should be treated,2 but there is no definitive
clinical trial data to support the use of intravenous insulin.14
Aspiration Pneumonia and Malnutrition2
Review the nutritional status (pre-albumin, weight) on admission to identify patients who were malnourished
before their stroke.
Give nothing by mouth if any of the following are present: reduced level of consciousness, severe dysarthria,
wet voice, weak cough, impaired palatal sensation, inability to sit, suspected aspiration.
Monitor recovery of dysphagia using serial bedside swallowing assessments, best performed by an experienced
dysphagia team.
A videofluoroscopic examination (modified barium swallow) may be required to exclude significant aspiration
when the results of the bedside examination are ambiguous.
Tube feeding may be required if significant aspiration is demonstrated or suspected. Initially, this is usually
done via a nasogastric tube. If swallowing does not recover, tube feeding via percutaneous endoscopic
gastrostomy (PEG) may be necessary. The results of the FOOD trial did not support a policy of early initiation of
PEG feeding in dysphagic stroke patients.15
Parenteral nutrition is required only in exceptional circumstances.
Give a texture-modified diet for dysphagic patients at lower risk of aspiration. Additional iv fluids are often
necessary for these patients.
Venous Thromboembolism2
Early mobilization (even if only up in a chair) is recommended (i.e., within the first day of admission to
hospital).
Maintain adequate hydration.
ASA (80–325 mg daily) reduces the risk of thromboembolism.16
In the absence of contraindications, the following interventions may also be used for patients with acute
ischemic stroke at high risk of venous thromboembolism (patients with inability to move one or both lower
limbs and those patients unable to mobilize independently):
graduated compression stockings.
low molecular weight heparin or unfractionated heparin in prophylactic doses (see Cardiovascular
Disorders: Venous Thromboembolism).
For patients with hemorrhagic stroke use graduated compression stockings and avoid antithrombotic drugs.
III. Reduce the Risk of Stroke Recurrence
Aneurysmal subarachnoid hemorrhage
Ablation of the aneurysm reduces the risk of rebleeding. Endovascular coiling is superior to neurosurgical clipping
Page 58
Therapeutic Choice
for ruptured intracranial aneurysm anatomically suitable for either procedure.17
Carotid endarterectomy (CEA)2
Patients with carotid territory transient ischemic attack or nondisabling stroke and ipsilateral 70–95% internal
carotid artery stenosis (measured on a catheter angiogram or by 2 concordant non-invasive imaging modalities)
should be offered carotid endarterectomy within 2 weeks of the incident transient ischemic attack or stroke unless
contraindicated. CEA is also appropriate for selected patients with moderate (50–69%) symptomatic stenosis. These
patients should be evaluated by a physician with expertise in stroke management. Carotid stenting may be
considered for patients who are not CEA candidates for technical, anatomical or medical reasons.
Antithrombotic Drug Treatment
Avoid in patients with hemorrhagic stroke.
Antiplatelet therapy2
If intracranial hemorrhage is excluded by CT scan, but alteplase is not indicated, give ASA 160 mg immediately.
This is followed by ASA 80–325 mg daily.
When alteplase is used, wait until intracranial hemorrhage is excluded by CT scan 24 hours later and give ASA
160 mg once. This is followed by ASA 80–325 mg daily.
Administer ASA as a suppository or via nasogastric tube to dysphagic patients. Use enteric-coated formulation
for patients who can swallow. No evidence supports the use of ASA doses greater than 325 mg/day for
secondary stroke prevention. The GI side effects of ASA are dose related.
For patients who were taking ASA prior to their stroke, consider other antiplatelet agents, such as clopidogrel
75 mg daily or a combination of ASA and sustained-release dipyridamole 25/200 mg twice daily,
although these regimens have not been tested in acute stroke.
The combination of ASA and clopidogrel is not recommended for long-term secondary stroke prevention.
Anticoagulant therapy2
Immediate systemic anticoagulation with unfractionated heparin, low molecular weight heparin, heparinoids or
specific thrombin inhibitors is not recommended in the setting of acute ischemic stroke, not even for patients in
atrial fibrillation (AF), because there is no evidence of short- or long-term benefit. Specifically, reduction in
early recurrent ischemic stroke is completely offset by an increase in major intracranial and extracranial
bleeding.18
ASA is as effective as warfarin for secondary stroke prevention in patients in normal sinus rhythm, and does not
require laboratory monitoring.
For patients in AF, use warfarin at a dose to maintain the INR in the range 2.0 to 3.0, provided there are no
contraindications to anticoagulation. For patients who cannot take warfarin, use enteric-coated ASA 80–325 mg
daily.
The best time to initiate anticoagulant therapy is unclear. For patients with minor strokes, start warfarin as soon
as intracranial hemorrhage has been excluded by CT scan. For patients with major strokes, delay warfarin until
a CT scan done about a week or two after the stroke has excluded hemorrhagic transformation of the infarct.
For post-acute antithrombotic treatment, carotid endarterectomy and risk-factor modification, see Cardiovascular
Disorders: Prevention of Ischemic Stroke.
Blood pressure lowering treatment2
Randomized controlled trials have not defined the optimal time to initiate blood pressure lowering therapy after
stroke.19 Oral blood pressure lowering treatment should be initiated (or modified) prior to discharge from hospital
in patients whose blood pressure is ≥ 140/90.
IV. Restore Function of the Individual2
Outcomes are optimized by care on a stroke unit provided by a coordinated interdisciplinary team (see Figure 3
- General Management of the Stroke Patient).
Start rehabilitation as soon as the patient is medically stable.
Family and community supports are important for social reintegration.
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Therapeutic Choice
Therapeutic Tips
The effectiveness of thrombolytic therapy with alteplase is exquisitely time dependent; delays of any sort should
not be tolerated. A minority of patients present to hospital within the first 90 minutes of stroke onset, leaving
limited time to act. Immediate contact with the patient, rapid triage, and (most importantly) staying with the
patient continuously during the clinical assessment, CT scan, blood tests and consent procedures are vital in
ensuring that the appropriate steps are being taken as rapidly as possible prior to alteplase administration. For
example, it is not necessary to wait for hospital porters to take the patient to the CT scanner.
Determining the time of stroke onset is critical in deciding to use alteplase, but checking the clock is not a
natural reaction in the setting of an acute stroke. Encourage patients and families to think of “time
anchors” (e.g., what was on the radio or TV at the time, or at what point in the patient's daily routine did the
symptoms first occur).
Patients with acute stroke are often unable to communicate. When possible, the next-of-kin should travel with
the patient to hospital (or between hospitals if the patient is transferred) to provide collateral history and
consent for treatment before the time window for intervention closes.
If the patient is referred to a tertiary care hospital, have the stat blood work (CBC, INR) drawn at the community
hospital and the results faxed to the referral centre as soon as possible.
Point-of-care INR testing , if available, can provide results quickly.
Signs of infarction on a CT scan done within 4.5 hours of stroke onset are usually subtle. If the CT scan of a
patient being considered for treatment with alteplase shows a very definite infarct in a location that explains the
presenting clinical symptoms and signs, recheck the time of onset.
Figure 1- Emergency Department Management of Patients with Suspected Stroke
a. Notify neurosurgeon if cerebellar infarct with mass effect on 4th ventricle (see text).
Abbreviations: CBC = complete blood count; CT = computed tomography; CXR = chest x-ray;
ECG = electrocardiogram; INR = International Normalized Ratio; PTT = partial thromboplastin time
Adapted with permission from Nova Scotia Guidelines for Stroke Care. Halifax (NS): Cardiovascular Health Nova Scotia; 2008.
Figure 2- Approach to a Finding of Intracranial Hemorrhage on CT Scan
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Therapeutic Choice
Abbreviations: CT = computed tomography
Adapted with permission from Nova Scotia Guidelines for Stroke Care. Halifax (NS): Cardiovascular Health Nova Scotia;
2008.
Figure 3- General Management of the Stroke Patient
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Therapeutic Choice
a. Hematoma volume (cm3) = A+B+C/2 where A = largest diameter (cm) on CT scan, B = diameter (cm) perpendicular to A, C =
number of scan slices (cm) showing hematoma.20 , 21

b. Hemiparesis and hemianopia with either aphasia or visuospatial deficit.22
Table 4: Drugs Used for Acute Ischemic Stroke
Class Drug Dose Adverse Effects Comments Costa
Antiplatelet ASA Initial: 160 mg Nausea, vomiting, If alteplase is to be < $1

Agents Aspirin, Maintenance: 80– hemorrhage, administered, wait 24 h
Bufferin, 325 mg daily hypersensitivity reactions before initiating ASA. If
(rarely bronchospasm). alteplase is not used, start
Coated
ASA as soon as
Aspirin, intracranial hemorrhage is
generics excluded by CT scan.
Use enteric-coated
formulations for patients
who can swallow.
Give via a nasogastric

tube or as a suppository
to dysphagic patients.
Fibrinolytic alteplase 0.9 mg/kg (max 90 Superficial bleeding, Review inclusion and $2746/100
Agents Activase mg) iv over 60 internal bleeding (i.e., exclusion criteria before mg vial
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Therapeutic Choice
rt-PA min. Give 10% of gastrointestinal, administering (Table 2).

the total dose as an genitourinary, respiratory No ASA, clopidogrel,
initial bolus over 1 tract, retroperitoneal), ticlopidine, heparin or
min. intracranial hemorrhage. warfarin for 24 h after
Cerebral edema, cerebral administration.
herniation, seizures and
new onset ischemic
stroke may occur and be
life threatening.
a. Cost of a 1-day supply; includes drug cost only.
Table 5: Drugs Used for Subarachnoid Hemorrhage
Costa
Calcium nimodipine 60 mg Hypotension (5%), Crushing tablets for nasogastric $2600

Channel Q4H for nausea, bradycardia administration is not recommended since
Blockers Nimotop 21 days and rash. bioavailability reduces with time. If
necessary, crush and administer immediately.
a. Cost of 21-day supply; includes drug cost only.
Suggested Readings
Donnan GA, Fisher M, Macleod M et al. Stroke. Lancet 2008;371(9624):1612-23.
Internet Stroke Center at Washington University School of Medicine. Stroke trials registry. Available from:
www.strokecenter.org/trials/. Accessed July 22, 2010.
Lindsay P, Bayley M, Hellings C et al. Canadian best practice recommendations for stroke care (updated 2008). CMAJ
2008;179(12 Suppl):E1-93. Available from: www.cmaj.ca/cgi/data/179/12/S1/DC1/1. Accessed July 22, 2010.
Stroke Unit Trialists' Collaboration. Organised inpatient (stroke unit) care for stroke. Cochrane Database Syst Rev
2007;(4):CD000197.
Wardlaw JM, Murray V, Berge E et al. Thrombolysis for acute ischaemic stroke. Cochrane Database Syst Rev 2009;
(4):CD000213.
References
1. Warlow C, Sudlow S, Dennis M et al. Stroke. Lancet 2003;362(9391):1211-24.

2. Lindsay P, Bayley M, Hellings C et al. Canadian best practice recommendations for stroke care (updated 2008).
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22, 2010.
3. Lindsay P, Bayley M, McDonald A et al. Toward a more effective approach to stroke: Canadian best practice
recommendations for stroke care. CMAJ 2008;178(11):1418-25.
4. Bayley M, Lindsay P, Hellings C et al. Balancing evidence and opinion in stroke care: the 2008 best practice
recommendations. CMAJ 2008;179(12):1247-9.
5. Adams HP, del Zoppo G, Alberts MJ et al. Guidelines for the early management of adults with ischemic stroke:
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17. Molyneux A, Kerr R, Stratton I et al. International Subarachnoid Aneurysm Trial (ISAT) of neurosurgical
clipping versus endovascular coiling in 2143 patients with ruptured intracranial aneurysms: a randomised
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18. Sandercock PA, Counsell C, Kamal AK. Anticoagulants for acute ischemic stroke. Cochrane Database Syst Rev
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19. Sare GM, Geeganage C, Bath PM. High blood pressure in acute stroke: to treat or not to treat? Int J Stroke
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predictor of 30-day mortality. Stroke 1993;24(7):987-93.
21. Broderick JP, Brott TG, Grotta JC. Intracerebral hemorrhage volume measurement. Stroke 1994;25(5):1081.
22. Bamford J, Sandercock P, Dennis M et al. Classification and natural history of clinically identifiable subtypes of
cerebral infarction. Lancet 1991;337(8756):1521-6.
Pharmacoeconomic Considerations: Acute Ischemic Stroke

Date of preparation: 2007-06-30
Nicole Mittmann, MSc, PhD
Epidemiology
Country (Year) Incidence and Prevalence (%)
Canada (2002)1 40 000–50 000 strokes per year

300 000 individuals live with the effects of stroke
Cost of Illness Data
Country and Year of Estimate Direct Costsa Indirect Costsb
Canada $529 million $328 million

(Ontario 1994-95)2
Canada $27 500 for acute stroke admission Not reported

(Ontario 1991-92)3
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Canada $9763 for acute stroke admission Not reported

(Ontario 1996)4
Commentary
Ischemic stroke is a significant disease in the aging population. From an economic perspective, the impact of
stroke on society will increase significantly as the population ages. Of every 100 people hospitalized for stroke,
50 will be discharged home, 20 will die before leaving the hospital, 15 will require long-term care and 10 will
enter an inpatient rehabilitation program. Stroke incidence is related to increased age and has an economic
impact on the patient, health care system and society.
Direct medical and nonmedical costs associated with stroke are significant. In acute stroke, hospitalization, length
of stay and rehabilitation are the cost drivers.5 Direct nonmedical costs including informal care, out-of-pocket
expenses and caregiver time are not well documented but have been estimated to be significant for informal
care.5 Indirect costs have not been well documented. Depending on the severity of the stroke, work productivity
and regular daily activities may be severely restricted. Long-term costs are significant.
Quality of life is significantly impaired by stroke.6 Predictors of poor quality of life included physical impairment,
disability and anxiety/depression.
Alteplase, which is used in patients with acute stroke, is expensive and must be administered expeditiously.
Researchers in Australia assessed the relative benefits of various interventions for acute stroke from a community
perspective.7 For every 1000 patients with stroke, death or dependency could be prevented in 46 individuals by
management in a stroke unit, in 6 individuals through use of ASA and in 11 individuals through use of alteplase
within 3 hours. The authors concluded that the greatest benefit to the community could be provided through the
establishment of dedicated stroke units.
a. Direct costs include those associated with physician services, nursing care, diagnostic procedures, drugs and hospitalization.
b. Indirect costs include those associated with lost productivity and days off work due to morbidity or premature mortality.
1. Heart and Stroke Foundation. Stroke statistics. Available from:

www.heartandstroke.com/site/c.ikIQLcMWJtE/b.3483991/k.34A8/Statistics.htm. Accessed July 22, 2010.
2. Chan B, Hayes B. Cost of stroke in Ontario, 1994/95. CMAJ 1998;159(6 Suppl):S2-S8. Available from:
www.cmaj.ca/cgi/data/159/6/DC1/2. Accessed July 22, 2010.
3. Smurawska LT, Alexandrov AV, Bladin CF et al. Cost of acute stroke care in Toronto, Canada. Stroke 1994;25
(8):1628-31.
4. Tran C, Nadareishvili Z, Smurawska L et al. Decreasing costs of stroke hospitalization in Toronto. Stroke
1999;30(1):185-6.
5. Dewey HM, Thrift AG, Mihalopoulos C et al. Informal care for stoke survivors: results from the north east
Melbourne stroke incidence study (NEMESIS). Stroke 2002;33(4):1028-33.
6. Sturm JW, Donnan GA, Dewey HM et al. Quality of life after stroke: the North East Melbourne Stroke
Incidence Study (NEMESIS). Stroke 2004;35(10):2340-5.
7. Gilligan AK, Thrift AG, Sturm JW et al. Stroke units, tissue plasminogen activator, aspirin and
neuroprotection: which stroke intervention could provide the greatest community benefit? Cerebrovasc Dis
2005;20(4):239-44.
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e-Therapeutics+ : Therapeutics : Cardiovascular Disorders: Dyslipidemias Page 1 of 15
Therapeutic Choice
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Cardiovascular Disorders: Dyslipidemias
Date Prepared: December 2010
Ghislaine O. Roederer, MD, PhD
The majority of dyslipidemias result from interaction between environmental and genetic factors. Understanding the contribution of
each factor in the dyslipidemic patient is beyond the scope of this chapter. Nevertheless, it is essential to rule out secondary causes of
dyslipidemia that, when identified and potentially eliminated, can prevent unnecessary treatment. In addition, the use of lipid-lowering
agents in the management of cardiovascular disease is increasingly emphasized.
Screening of the lipid-profile is recommended in children with a family history of hypercholesterolemia or chylomicronemia, men 40
years old and over, women older than 50 years or postmenopausal and all patients with the following conditions independent of age:
diabetes
hypertension
current cigarette smoking
obesity
family history of premature CAD (<60 years in first-degree relatives)
inflammatory diseases (SLE, RA, psoriasis)
chronic renal disease (eGFR <60 mL/min/1.73 m2)
evidence of atherosclerosis
HIV infection treated with HAART
clinical manifestations of hyperlipidemias (xanthomes, xanthelasmas, premature arcus cornealis)
erectile dysfunction
Goals of Therapy
Reduce risk of cardiovascular disease (CVD)

Prevent pancreatitis from severe hypertriglyceridemia
Investigations
Clinical evaluation should focus on:
Medical history
CVD (past or present): MI, angina, TIA, CVA, claudication, erectile dysfunction
possible causes of secondary dyslipidemia (Table 1)
major cardiovascular risk factors (Figure 1 - Management of Dyslipidemia1 , Figure 2 - Estimating the 10-year Risk of Total
Cardiovascular Disease (Framingham Heart Study)23 )
Family history:
premature CVD (before age 60) in first-degree relatives
dyslipidemia
Physical examination:
waist circumference
bilateral brachial blood pressure
funduscopy (lipemia retinalis, retinopathies)
cardiovascular evaluation (bruits, heart sounds, peripheral pulses)
hepatosplenomegaly
lipid deposits (premature arcus corneae, xanthomas, xanthelasmas)
Laboratory tests:
lipid and lipoprotein levels1
Note that the Friedewald equation, LDL-C=Total-C - (HDL-C+TG/2.2) cannot be used if triglyceride levels are >4.52 mmol/L, if
type III dysbetalipoproteinemia or if chylomicrons are present.
use the same laboratory for repeated measurements
a 12-hour fast is required for triglyceride levels
obtain 2 or 3 measurements at 4- to 6-week intervals to establish a baseline before initial diagnosis of a dyslipidemic
phenotype. At least one measurement should include a lipoprotein profile, i.e., high-density lipoprotein cholesterol (HDL-C)
and low-density lipoprotein cholesterol (LDL-C)
other lab investigations to rule out frequent causes of secondary dyslipidemias (Table 1) and establish baseline levels for CK
and liver transaminases
high-sensitivity C-reactive protein (hsCRP), a marker of inflammation: recommended in men older than 50 and
women older than 60, at moderate risk according to the Framingham Risk Score and who do not qualify for lipid-
lowering therapy (LDL <3.5 mmol/L). Two measurements at least 2 weeks apart are
recommended1 Useful Info?
Table 1: Common Causes of Secondary Hyperlipidemia
Conditions Medicationsa
Alcohol excess Beta-blockers without intrinsic sympathomimetic or alpha-blocking activity
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Conditions Medicationsa
Chronic renal failure Corticosteroids

Diabetes/Metabolic syndrome Highly active antiretroviral therapy (HAART)
Excess weight Hormone replacement therapy (HRT)
Hypothyroidism Oral contraceptives
Nephrotic syndrome Thiazide diuretics
Obstructive liver disease
Pregnancy
a. Medication-induced dyslipidemia should not preclude the use of these medications if clinically indicated.
Criteria for Intervention
Global cardiovascular risk assessment described in the 2009 recommendations from the Canadian Cardiovascular Society1 stratifies
patients into 1 of 3 categories of cardiovascular risk, using the Framingham Risk Score or the Reynolds Risk Score (RRS)
(www.reynoldsriskscore.org). While both scores include the same major CV risk factors, the RRS includes the family history and hsCRP
levels. This provides an optional tool to better stratify intermediate risk patients in whom hsCRP measurements are indicated. Based on
the risk score, the target lipid levels are shown in Figure 1 - Management of Dyslipidemia1 .
Optional targets, after reaching LDL-C goals may be:

TC/HDL-C ratio <4
Non-HDL-C <3.5 mmol/L
Triglycerides <1.7 mmol/L
Apolipoprotein B / apolipoprotein A ratio <0.8
hsCRP <2 mg/L
Table 2: International Diabetes Federation Classification of the Metabolic Syndrome2
Risk Factor Defining Level
Central obesitya Waist circumference:
Europids
Men ≥94 cm; Women ≥80 cm
South Asians
Chinese
Japanese
Ethnic South and Central Americans, First Nations Use South Asian recommendations until more specific data
are available
Eastern Mediterranean and Middle East (Arabic) populations, Sub- Use European data until more specific data are available
Saharan Africans
Triglyceride level ≥1.7 mmol/L
HDL-C level
Men <1.0 mmol/L

Women <1.3 mmol/L
Blood pressure ≥130/85 mm Hg
Fasting glucose level 5.7–7.0 mmol/L
a. Criteria: central obesity required, plus 2 or more other risk factors.
Abbreviations: HDL-C=high density lipoprotein cholesterol
Adapted with permission from the International Diabetes Federation.
Metabolic syndrome is an association of metabolic abnormalities. The classification used by the International Diabetes Federation is
suggested to reflect the ethnic make-up of Canada (Table 2). Management includes weight reduction, increased physical activity and
treatment of lipid and nonlipid risk factors.
Diabetics, end-stage renal disease and renal transplant patients are considered very high risk. High triglyceride levels (2.3–11.3
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mmol/L) are an additional CV risk factor when associated with atherogenic dyslipidemias, e.g., familial combined hyperlipidemia,
insulin resistance, diabetes, renal failure. Very high triglyceride levels (>10 mmol/L) are a risk factor for pancreatitis.
Therapeutic Choices
Diet, aimed at reducing blood lipid levels and weight (if needed), should always be part of the treatment. For secondary prevention
and very high risk individuals, medication is introduced simultaneously. For primary prevention, a 6-month dietary trial (Table 3) is
recommended before considering medication; during this time, take 2 (ideally 3) lipid and lipoprotein measurements.
Encourage other lifestyle changes to further modify lipoprotein profile and reduce the risk of CVD, e.g., weight loss, physical
activity and smoking cessation. Smoking cessation can help raise HDL-C.
Table 3: Dietary Interventions
Step I Step II
Primary Prevention Secondary Preventiona
(patients with no previous CVD) (patients with prior CVD/atherosclerotic disease and/or at very high risk)
↓ dietary cholesterol intake to <300 mg/day Same as Step I, but further

Restrict fat intake to 30% of calories ↓ dietary cholesterol intake to <200 mg/day
Increase proportion of mono- and Restrict fat intake to 20% of calories and less than 7% of daily calories as saturated
polyunsaturated fats in diet fat and trans-fatty acids
Restrict saturated and trans-fatty acids in diet
Favour fruit and vegetable intake
Increase omega-3 fatty acids from fish and plant
sources
Favour high-fibre intake
Limit simple sugars to 8% of total calories
Limit alcohol consumption to 5% of total
calories
a. A dietitian's help is usually required to reach and maintain these goals.
Table 4 summarizes the effects of lipid-lowering drugs on lipoproteins.
Table 4: Lipid-lowering Agents—Effect on Lipoproteins
LDL HDL TG
Resins ↓↓ ↑ ↑
HMG CoA reductase inhibitors ↓↓↓ ↑ ↓↔a
Niacin ↓↓ ↑↑ ↓↓↓
Fibrates ↓↔ ↑↑ ↓↓↓
Ezetimibe ↓↓ ↑↔ ↓↔
a. Atorvastatin and rosuvastatin have the greatest TG-lowering effect.
Resins
The bile acid-sequestering resins cholestyramine and colestipol reduce plasma LDL and can slightly increase HDL levels. They have
a strong safety record. Resins are appropriate lipid-lowering agents in children and in pregnant or breastfeeding women.
HMG CoA Reductase Inhibitors (Statins)
HMG CoA reductase inhibitors, the most potent LDL-lowering agents, interfere with the atherosclerotic disease process. Significant
reductions in CVD morbidity, CVD mortality and total deaths in both primary and secondary prevention have been associated with their
use.3 , 4 Initiating a statin for primary prevention depends on the individual’s global cardiovascular risk (Figure 2 - Estimating the 10-
year Risk of Total Cardiovascular Disease (Framingham Heart Study)23 ). For patients at high risk of coronary artery disease, statins
should be initiated at the recommended starting doses and titrated to reach targets (Figure 1 - Management of Dyslipidemia1 ).
However, different statins have different degrees of lipid-lowering potential 5 , 6 (Table 4). Some statins are indicated for use in children
>10 years old with heterozygous and homozygous familial hypercholesterolemia.7 , 8 Refer these patients for care by a specialist.
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Therapeutic Choice
Effect on HDL is modest. Statins differ in their structure, pharmacokinetics, in vitro properties and potency. Increasing the dose may
result in further decrease in LDL and global cardiovascular risk.9 Statin- and patient-related factors influencing potential myotoxic
effects must be considered to avoid this complication10 (Table 5). There are no consensual recommendations regarding the
management of myotoxic effects. An algorithm has been proposed by Sithasivam and Lecky10 that could prove very useful (Figure 3 -
Diagnosis and Management of Statin-induced Myopathy10 ).
Table 5: Patient- and Statin-related Factors That May Influence Myotoxic Effects
Patient Characteristics Concomitant Medications Statin Properties
Advanced age (>80 y) Amiodarone High bioavailability

Alcohol abuse Azole antifungals (itraconazole, Limited protein binding
Chronic renal insufficiency ketoconazole) Lipophilicity
Excessive grapefruit or Calcium channel blockers Membrane transporter affinity
cranberry juice intake (nondihydropyridine type) Potential for drug–drug interactions metabolized by cytochrome
Frailty, small body frame Cyclosporine P450 pathways, especially 3A4 and 2C9 (Table 6)
Hepatic dysfunction Fibrates (particularly gemfibrozil)
Hypothyroidism (untreated) HIV protease inhibitors
Inherited myopathies Macrolide antibiotics (erythromycin,
Intercurrent infections clarithromycin)
Perioperative periods Nicotinic acid (rarely)
Polypharmacy
Vigorous exercise
Women are more affected than
men
Nicotinic Acid (Niacin)
Niacin is a B vitamin that, at high doses, lowers triglycerides and LDL and raises HDL more than any other lipid-lowering agent. It
lowers lipoprotein(a), although the clinical significance of this effect is not yet known. The unpleasant side effects of niacin make
patient compliance difficult, limiting its usefulness. Slow-release formulations appear to be more hepatotoxic than standard-release
products.11 A “no-flush” formulation combining inositol and niacin purports to reduce this adverse effect. A “once a day at night”
extended-release formulation of niacin combined with a selective prostaglandin D(2) receptor-1 antagonist appears promising in terms
of rapid titration and tolerability.12 Further, it seems to have a lower rate of hepatotoxicity than other formulations. More clinical
experience with these formulations are nevertheless required. Glucose intolerance is not an absolute contraindication to the use of
niacin. Antihyperglycemic agents can be pre-emptively adjusted to maintain glycemic control.
Fibrates
Bezafibrate, fenofibrate and gemfibrozil lower triglyceride levels and raise HDL and may benefit patients with diabetic
dyslipidemias. The effect of fibrates on LDL is variable; bezafibrate and fenofibrate lower LDL more consistently. Except for gemfibrozil,
combining a fibrate with a statin can be safe. Fenofibrate was shown to significantly reduce total CVD events, particularly due to
reductions in nonfatal MI and coronary revascularization, without reducing fatal events in patients with type 2 diabetes.13 The
combination of a fibrate and a statin in this population is not routinely recommended, although it could be beneficial for patients with a
high baseline triglyceride level and low HDL.14
Cholesterol Absorption Inhibitors
Ezetimibe, which inhibits intestinal cholesterol absorption, is useful as monotherapy or in combination with statins. It is better
tolerated than resins, has low potential for drug interactions with cytochrome P450 substrates and does not affect the absorption of fat-
soluble vitamins.15 Hard end-point data using ezetimibe in combination with a statin should soon be available.
Combination Therapy
Agents from different classes can be combined to reach maximal efficacy with an acceptable level of safety, especially if a single drug
fails to achieve targets. However, since some combination therapies (such as fibrates and statins) carry an increased risk of drug
toxicity, consider referral for such patients.16
Nonprescription Agents
The only nonprescription agents that can be recommended are psyllium and omega-3 fatty acids. The American Heart Association
recommends patients with documented coronary heart disease consume about 1 gram of omega-3 fatty acids daily.17 Patients taking
more than 3 grams of omega-3 fatty acids from supplements should do so only under a physician’s care. High intakes could cause
excessive bleeding in some people.
Choices During Pregnancy and Breastfeeding
Due to hormonal changes, plasma lipids increase throughout the duration of pregnancy. Total cholesterol concentrations increase 25–
50% and total triglycerides by 2- to 4-fold. By mid-gestation, there is a 50% increase in LDL-C and a 30% rise in HDL-C, followed at
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term by a slight decrease in HDL-C.18
Risk factors for hyperlipidemia are also true for pregnancy and include obesity, weight gain, hypothyroidism, gestational and non-
gestational diabetes, alcohol consumption, prescription medications and genetic predisposition.19 Very severe forms of
hypertriglyceridemia may hence increase the risk of pancreatitis.20
Pre-pregnancy Considerations
Risk factor control is recommended throughout the pregnancy. The teratogenicity of lipid-lowering drugs in humans is not well
established but appears to be small, if present at all, with statins and termination of pregnancy is not warranted. However, in order to
reduce the risks as much as possible, it is advisable to discontinue all lipid-lowering drugs, with the exception of resins.21
Management During Pregnancy
Patients must be reassured that interrupting the treatment for the duration of the child-bearing period has little impact on the overall
cardiovascular risk. Although resins may be continued, their gastrointestinal effects may limit their use. If tolerated, lipid-soluble
vitamin supplementation should be implemented. In the very severe cases of pregnancy-induced hyperlipoproteinemia, other
nonpharmacologic extreme measures can be used.22
Management During Postpartum/Breastfeeding
Treatment may be resumed unless breastfeeding is considered. Lipid-lowering drugs are currently not recommended during
breastfeeding.
A discussion of general principles on the use of medications in these special populations can be found in Appendix: Drug Use During
Pregnancy and Appendix: Drug Use During Breastfeeding. Other specialized reference sources are also provided in these appendices.
Therapeutic Tips
Global cardiovascular management initially involves modification of health behaviours (smoking cessation, diet, weight reduction
and maintenance, exercise, stress management) in addition to lipid lowering medication.
Lipid-lowering drugs must always be an adjunct to, not a substitution for, diet therapy.
Treat to reach the target levels.
Try different agents within the same class in cases of intolerance or insufficient efficacy.
Long-term clinical and laboratory follow-up is essential to monitor lipid-lowering efficacy and safety of therapy. From the authors
experience, follow-up is suggested every 4 months for the first year, every 6 months for the second year and yearly thereafter,
unless some other condition requires closer monitoring.
Allow 3 months for a stabilized and representative plasma lipid profile after a major medical event. Acute coronary syndromes
require immediate statin therapy regardless of the lipid profile.
Doubling the dose of a statin will further reduce the LDL-C level by only 6% (Figure 1 - Management of Dyslipidemia1 , Figure 2 -
Estimating the 10-year Risk of Total Cardiovascular Disease (Framingham Heart Study)23 ).
It appears safe to lower target LDL-C levels to 1.8 mmol/L (<70 mg/dL) in individuals with overt coronary heart disease and
multiple risk factors.
Figure 1- Management of Dyslipidemia1
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Figure 2- Estimating the 10-year Risk of Total Cardiovascular Disease (Framingham Heart Study)23
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Therapeutic Choice
Adapted with permission from D'Agostino RB, Vasan RS, Pencina MJ et al. General cardiovascular risk profile for use in primary care: the Framingham
Heart Study. Circulation 2008;117(6):743-53.
Figure 3- Diagnosis and Management of Statin-induced Myopathy10
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Reproduced from Sathasivam S, Lecky B. Statin induced myopathy. BMJ 2008;337:a2286, with permission from BMJ Publishing Group Ltd.
Table 6: Drugs Used in the Management of Dyslipidemias
Class Drug Dose Adverse Effects Drug Interactions Comments Costa
Resins cholestyramine Adult: 4 g Common: Administer 1 h before Start with daily dosing $$$$$
generics BID–TID AC Constipation or 4–6 h after to improve tolerability.
po. Maximum (>10%), bloating, concurrent Recommend high-fibre
24 g divided abdominal fullness, medications due to diet and high water
in 3 flatulence, ↑ possible adsorption of intake to minimize
doses/day triglycerides, ↑ other drugs in the GI constipation. Monitor
Children: 240 transaminases tract. serum electrolytes
mg/kg/day (reversible). periodically. Long-term
divided in Rare: and high-dose use can
3 doses po hyperchloremic prevent the absorption
acidosis, of fat-soluble vitamins
cholecystitis, and folic acid. May be
cholelithiasis, mixed with juice, soups
pancreatitis, and applesauce. Can be
malabsorption used to lower
syndrome, GI cholesterol and LDL in
bleeding, peptic pregnancy and in
ulceration. children. Add granules
to at least 90 mL of
fluid.
Contraindications:
biliary obstruction,
dysbetalipoproteinemia,
TG >4.6 mmol/L;
phenylketonurics.
Resins colestipol Granules: 5 g Common: Administer 1 h before Start with daily dosing Granules:$$$$
Colestid BID–TID AC Constipation or 4–6 h after to improve tolerability. Tablets:$$
po. Maximum (>10%), bloating, concurrent Recommend high-fibre
30 g/day abdominal fullness, medications due to diet and high water
Tablets: 2 g flatulence, ↑ possible adsorption of intake to minimize
once daily– triglycerides, ↑ other drugs in the GI constipation. Monitor
BID po. transaminases tract. serum electrolytes
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Maximum 16 (reversible). periodically. Long-term

g/day. Rare: and high-dose use can
hyperchloremic prevent the absorption
acidosis, of fat-soluble vitamins
cholecystitis, and folic acid. May be
cholelithiasis, mixed with juice, soups
pancreatitis, and applesauce. Can be
malabsorption used to lower
syndrome, GI cholesterol and LDL in
bleeding, peptic pregnancy and in
ulceration. children. Add granules
to at least 90 mL of
fluid.
Contraindications:
biliary obstruction,
dysbetalipoproteinemia,
TG >4.6 mmol/L;
phenylketonurics.
Cholesterol ezetimibe 10 mg once Well tolerated. Low potential for drug Monitor liver function $$$
Absorption Ezetrol daily po at Common: back pain, interactions. and CK.
Inhibitor any time arthralgia, diarrhea, Potential In general, can use in
abdominal pain, pharmacokinetic children ≥12 y. Not
fatigue, dizziness, interaction with recommended in
headache. cyclosporine. Exercise moderate to severe
caution when hepatic impairment.
Rare: myopathy, initiating ezetimibe in
rhabdomyolysis, patients receiving
hepatitis, acute cyclosporine,
pancreatitis, especially if severe
thrombocytopenia. renal insufficiency.
HMG CoA atorvastatin Adult: 10–80 Common: ↑ CK, ↑ Avoid with CYP3A4 Start with low doses $$
Reductase Lipitor, mg daily po transaminases inhibitors: macrolide and titrate up to reach
Inhibitors generics Children:b (reversible), mild antibiotics, targets while monitoring
10–20 mg upper GI gemfibrozil, grapefruit biochemical markers.
daily po disturbances, juice, azoles, protease Monitor liver function
myalgias (with and inhibitors, and CK at 3, 6 and 12
without CK amiodarone, mo, then yearly. If LFTs
elevation), sleep cyclosporine, (AST, ALT) >3 ×
disturbances, nondihydropyridine normal, discontinue
headache, rash. calcium channel statin. LFT elevations
Rare: myopathy, blockers, e.g., are dose dependent.
rhabdomyolysis, verapamil. Excellent safety profile.
peripheral
neuropathy, lupus- Use caution in patients
like symptoms, with moderate to severe
impotence. renal impairment
(<60 mL/min).
Contraindications:
active liver disease,
high alcohol
consumption,
pregnancy.
HMG CoA fluvastatin 20–80 mg po Common: ↑ CK, ↑ Avoid with CYP P450 Start with low doses $$
Reductase Lescol, Lescol with evening transaminases 2C9 inhibitors: and titrate up to reach
Inhibitors meal (reversible), mild amiodarone, targets while monitoring
XL
Give XL upper GI fluconazole, biochemical markers.
formulation disturbances, fluoxetine, Monitor liver function
once daily myalgias (with and fluvoxamine. and CK at 3, 6 and 12
anytime without CK mo, then yearly. If LFTs
elevation), sleep (AST, ALT) >3 ×
disturbances, normal, discontinue
headache, rash. statin. LFT elevations
Rare: myopathy, are dose dependent.
rhabdomyolysis, Excellent safety profile.
peripheral
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(<60 mL/min).
Contraindications:
high alcohol
consumption,
pregnancy.
HMG CoA lovastatin 20–80 mg po Common: ↑ CK, ↑ Avoid with CYP3A4 Start with low doses $$–$$$$$
Reductase Mevacor, with evening transaminases inhibitors: macrolide and titrate up to reach
Inhibitors generics meal. (reversible), mild antibiotics, targets while monitoring
Maximum 40 upper GI gemfibrozil, grapefruit biochemical markers.
mg BID disturbances, juice, azoles, protease Monitor liver function
myalgias (with and inhibitors, and CK at 3, 6 and 12
peripheral
(<60 mL/min).
Contraindications:
high alcohol
consumption,
pregnancy.
HMG CoA pravastatin 10–40 mg Common: ↑ CK, ↑ Not metabolized Start with low doses $$
Reductase Pravachol, QHS po transaminases through CYP P450 and titrate up to reach
Inhibitors generics (reversible), mild pathway, thus low targets while monitoring
upper GI potential for drug biochemical markers.
disturbances, interactions. Monitor liver function
myalgias (with and and CK at 3, 6 and 12
without CK mo, then yearly. If LFTs
elevation), sleep (AST, ALT) >3 ×
disturbances, normal, discontinue
headache, rash. statin. LFT elevations
Rare: myopathy, are dose dependent.
peripheral
(<60 mL/min).
Contraindications:
high alcohol
consumption,
pregnancy.
HMG CoA rosuvastatin Adult: 10–40 Common: ↑ CK, ↑ Avoid with CYP P450 Start with low doses $$$
Reductase Crestor mg daily po transaminases 2C9 inhibitors: and titrate up to reach
Inhibitors Initial dose 10 (reversible), mild amiodarone, targets while monitoring
mg/day po upper GI fluconazole, biochemical markers.
except in disturbances, fluoxetine, Monitor liver function
Asian patients myalgias (with and fluvoxamine. and CK at 3, 6 and 12
and those without CK ↓ levels with mo, then yearly. If LFTs
receiving elevation), sleep concomitant use of (AST, ALT) >3 ×
cyclosporine. disturbances, magnesium/aluminum normal, discontinue
(Initial dose 5 headache, rash. hydroxide-containing statin. LFT elevations
mg/day po) Rare: myopathy, antacids. are dose dependent.
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Children:b 5– peripheral
10 mg daily neuropathy, lupus- Use caution in patients
po like symptoms, with moderate to severe
(<60 mL/min).
Contraindications:
high alcohol
consumption,
pregnancy.
Administer antacids 2 h
after rosuvastatin.
HMG CoA simvastatin Adult: 10–80 Common: ↑ CK, ↑ Avoid with CYP3A4 Start with low doses $$
Reductase Zocor, mg po with transaminases inhibitors: macrolide and titrate up to reach
Inhibitors generics evening meal (reversible), mild antibiotics, targets while monitoring
Children:b10– upper GI gemfibrozil, grapefruit biochemical markers.
40 mg po with disturbances, juice, azoles, protease Monitor liver function
evening meal myalgias (with and inhibitors, and CK at 3, 6 and 12
peripheral
(<60 mL/min).
Contraindications:
high alcohol
consumption,
pregnancy.
Niacin niacin, Start with 50 Common: hot Use caution if using Greatest HDL-raising $-$$
(Nicotinic immediate mg TID po; flushes and pruritus, with statins because effect.
Acid) double dose dry skin, acanthosis of potential Monitor blood glucose,
release
Derivatives Q5 days to nigricans hepatotoxicity and uric acid, transaminases
Niacin,
1.5–2 g/day. (reversible), myopathy. at 3, 6 and 12 months,
generics
If tolerated, reactivation of peptic then yearly.
maximum is 4 ulcer, GI
g/day after disturbances, ↑ Contraindications:
meals blood glucose, severe peptic ulcer
Usual dose: glucose intolerance, disease, uncontrolled
1.5–4 g/day uric acid and hyperglycemia, severe
divided TID transaminases. gout, hepatic disease.
po, PC Rare: torsades de
pointes, severe Flushing abates with
Reassure and hepatotoxicity (more time. Avoid hot drinks,
instruct the frequent with slow- hot showers, spicy
patient (see release formulation), food, alcohol for 1–2 h
comments) ↑ blood glucose, uric after a dose; uncoated
acid, transaminases. ASA 325 mg daily in the
first few weeks of
treatment or when
increasing the dose may
be helpful.
Tolerance develops
within several weeks.
Avoid missing a dose.
Niacin niacin, slow 0.5–2 g/day Same as niacin Use caution if using Similar to niacin $-$$
(Nicotinic release (SR) divided BID immediate release, with statins because immediate release,
Acid) po after meals although less of potential although fewer
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Derivatives generics flushing. hepatotoxicity and measures required.

myopathy.
Common: hot Greatest HDL-raising
flushes and pruritus, effect.
dry skin, acanthosis Monitor blood glucose,
nigricans uric acid, transaminases
(reversible), at 3, 6 and 12 months,
reactivation of peptic then yearly.
ulcer, GI
disturbances, ↑ Contraindications:
blood glucose, severe peptic ulcer
glucose intolerance, disease, uncontrolled
uric acid and hyperglycemia, severe
transaminases. gout, hepatic disease.
Rare: torsades de
pointes, severe Flushing abates with
hepatotoxicity (more time. Avoid hot drinks,
frequent with slow- hot showers, spicy
release formulation), food, alcohol for 1–2 h
↑ blood glucose, uric after a dose; uncoated
acid, transaminases. ASA 325 mg daily in the
first few weeks of
Severe treatment or when
hepatotoxicity more increasing the dose may
frequent with slow- be helpful.
release formulation,
thus not Tolerance develops
recommended. within several weeks.
Avoid missing a dose.
Niacin niacin, Titrate the Similar adverse Use caution if using Less flushing because $$$–$$$$
(Nicotinic extended dose: 0.5 g effects to niacin with statins because taken at bedtime. Less
Acid) HS po after a immediate release, of potential hepatotoxic effects
release (ER)
Derivatives low-fat snack although less hepatotoxicity and relative to SR
Niaspan, × 1 month severe. myopathy. formulations.
Niaspan-FCT then 1 g HS x Common: hot
1 mo, then flushes and pruritus,
1.5 g HS. May dry skin, acanthosis
↑ to 2 g HS if nigricans
required (reversible),
reactivation of peptic
ulcer, GI
disturbances, ↑
blood glucose,
glucose intolerance,
uric acid and
transaminases.
Rare: torsades de
pointes, severe
hepatotoxicity (more
frequent with slow-
release formulation),
↑ blood glucose, uric
acid, transaminases.
Fibrates bezafibrate SR: 400 Upper GI Caution when Monitor CK, liver and $$$
Bezalip mg/day po disturbances combining with renal function at 3, 6
with evening (nausea, abdominal statins. and 12 mo, then yearly.
meal pain, flatulence), Monitor INR with Useful in diabetic
myalgias concomitant warfarin dyslipidemias.
↑ bile lithogenicity, ↑ use. Contraindications:
CK, ↑ creatinine (not hepatic impairment,
representative of ↑ ezetimibe levels. renal dysfunction, pre-
renal function Monitor for signs of existing gallbladder
deterioration). cholelithiasis. disease.
Fibrates fenofibrate 100 mg BID– Upper GI Caution when Monitor CK, liver and $$$–$$$$
Apo- QID po with disturbances combining with renal function at 3, 6
meals (nausea, abdominal statins. and 12 mo, then yearly.
Page 77
Therapeutic Choice
Fenofibrate, pain, flatulence), Monitor INR with Useful in diabetic

other myalgias concomitant warfarin dyslipidemias.
generics ↑ bile lithogenicity, ↑ use. Contraindications:
Monitor renal function

with concomitant
cyclosporine use.
Fibrates fenofibrate 160 mg/day, Upper GI Caution when Monitor CK, liver and $$
microcoated once daily po disturbances combining with renal function at 3, 6
Lipidil Supra, with largest (nausea, abdominal statins. and 12 mo, then yearly.
generics meal pain, flatulence), Monitor INR with Useful in diabetic

with concomitant
cyclosporine use.
micronized once daily po disturbances combining with renal function at 3, 6
Lipidil Micro, with largest (nausea, abdominal statins. and 12 mo, then yearly.
Apo-Feno- meal pain, flatulence), Monitor INR with Useful in diabetic
Micro, other
generics hepatic impairment,
CK, ↑ creatinine (not

with concomitant
cyclosporine use.
nanocrystals once daily po disturbances combining with renal function at 3, 6
with or (nausea, abdominal statins. and 12 mo, then yearly.
Lipidil EZ, without food pain, flatulence), Monitor INR with Useful in diabetic
generics Recommended myalgias concomitant warfarin dyslipidemias.
starting dose ↑ bile lithogenicity, ↑ use. Contraindications:
for patients CK, ↑ creatinine (not hepatic impairment,
with renal representative of ↑ ezetimibe levels. renal dysfunction, pre-
impairment renal function Monitor for signs of existing gallbladder
and in the deterioration). cholelithiasis. disease.
elderly is 48
mg daily Monitor renal function
with concomitant
cyclosporine use.
Fibrates gemfibrozil 300–1200 Upper GI Not to be used in Monitor CK, liver and $–$$
Lopid, mg/day po disturbances combination with renal function at 3, 6
generics divided BID (nausea, abdominal statins. and 12 mo, then yearly.
30 min prior pain, flatulence), May increase Useful in diabetic
to meals myalgias repaglinide and dyslipidemias.
↑ bile lithogenicity, ↑ rosiglitazone levels; Contraindications:
CK, ↑ creatinine (not metabolized by hepatic impairment,
representative of CYP2C8. renal dysfunction, pre-
renal function existing gallbladder
deterioration). Monitor INR with disease.
concomitant warfarin
Page 78
Therapeutic Choice
use.
Combination niacin, Dose is Niacin: Niacin:Use caution if Not recommended as $$$

products extended individualized. Similar adverse using with statins initial therapy. May
release / 500 mg/20 effects to niacin because of potential switch to combination
lovastatin mg or 1000 immediate release, hepatotoxicity and therapy when on stable
Advicor mg/20 mg po: although less myopathy. doses of lovastatin and
1 tab HS with severe. Lovastatin:Avoid with niacin, extended
low-fat snack CYP3A4 inhibitors: release.
Common: hot macrolide antibiotics, Less flushing because
flushes and pruritus, gemfibrozil, grapefruit taken at bedtime. Less
dry skin, acanthosis juice, azoles, protease hepatotoxic effects
nigricans inhibitors, relative to SR
(reversible), amiodarone, formulations.
reactivation of peptic cyclosporine,
ulcer, GI nondihydropyridine Start with low doses
disturbances, ↑ calcium channel and titrate up to reach
blood glucose, blockers, e.g., targets while monitoring
glucose intolerance, verapamil. biochemical markers.
uric acid and Monitor liver function
transaminases. and CK at 3, 6 and 12
Rare: torsades de mo, then yearly. If LFTs
pointes, severe (AST, ALT) >3 ×
hepatotoxicity (more normal, discontinue
frequent with slow- statin. LFT elevations
release formulation), are dose dependent.
↑ blood glucose, uric Excellent safety profile.
acid, transaminases.
Use caution in patients
Lovastatin:Common: with moderate to severe
↑ CK, ↑ renal impairment
transaminases (<60 mL/min).
(reversible), mild
upper GI Contraindications:
disturbances, active liver disease,
myalgias (with and high alcohol
without CK consumption,
elevation), sleep pregnancy.
disturbances,
headache, rash.
Rare: myopathy,
rhabdomyolysis,
peripheral
neuropathy, lupus-
like symptoms,
impotence.

b. Children aged 10 to 17 years (boys and post-menarchal girls).
ALT=alanine transaminase; AST=aspartate transaminase; CK=creatine kinase; LFT=liver function test
Legend: $ <$20 $-$$ <$20–40 $$ $20–40 $$$ $40–60 $$$-$$$$ $40–80 $$$$ $60–80 $$-$$$$$ $20– >80 $$$$$
>$80
Suggested Readings
Genest J, McPherson R, Frohlich J et al. 2009 Canadian Cardiovascular Society/Canadian guidelines for the diagnosis and treatment of
dyslipidemia and prevention of cardiovascular disease in the adult–2009 recommendations. Can J Cardiol 2009;25(10):567-79.
Grundy SM, Cleeman JI, Merz CN et al. Implications of recent clinical trials for the National Cholesterol Education Program Adult
Treatment Panel III guidelines. Circulation 2004;110(2):227-39.
Jialal I. A practical approach to the laboratory diagnosis of dyslipidemia. Am J Clin Pathol 1996;106(1):128-38.
Page 79
Therapeutic Choice
Kuoppala J, Lamminpaa A, Pukkala E. Statins and cancer: a systematic review and meta-analysis. Eur J Cancer 2008;44(15):2122-32.
Mattar M, Obeid O. Fish oil and the management of hypertriglyceridemia. Nutr Health 2009;20(1):41-9.
NACB LMPG Committee Members, Myers GL, Christenson RH et al. NACB LMPG Committee Members, National Academy of Clinical
Biochemistry Laboratory Medicine Practice guidelines: emerging biomarkers for primary prevention of cardiovascular disease. Clin Chem
2009;55(2):378-84.
Sathasivam S, Lecky B. Statin induced myopathy. BMJ 2008;337:a2286.
Seth Loomba R, Arora R. Fibrates: where are we now? Ther Adv Cardiovasc Dis 2009;3(1):91-6.
References
1. Genest J, McPherson R, Frohlich J et al. 2009 Canadian Cardiovascular Society/Canadian guidelines for the diagnosis and
treatment of dyslipidemia and prevention of cardiovascular disease in the adult–2009 recommendations. Can J Cardiol 2009;25
(10):567-79.
2. International Diabetes Federation. The IDF consensus worldwide definition of the metabolic syndrome. Brussels (BE); [2006].
Available from: www.idf.org/webdata/docs/MetSyndrome_FINAL.pdf. Accessed March 9, 2010.
3. Vrecer M, Turk S, Drinovec J et al. Use of statins in primary and secondary prevention of coronary heart disease and ischemic
stroke. Meta-analysis of randomized trials. Int J Clin Pharmacol Ther 2003;41(12):567-77.
4. Yusuf S, Lonn E, Bosch J. Lipid lowering for primary prevention. Lancet 2009;373(9670):1152-5.
5. Brugts JJ, Yetgin T, Hoeks SE et al. The benefits of statins in people without established cardiovascular disease but with
cardiovascular risk factors: meta-analysis of randomised controlled trials. BMJ 2009;338:b2376.
6. Beth Smith ME, Lee NJ, Haney E et al. Drug class review: HMG-CoA reductase inhibitors (statins) and fixed-dose combination
products containing a statin. Final Report Update 5. Portland (OR): Oregon Health & Science University; November 2009.
Available from: derp.ohsu.edu/final/Statins_final%20evidence%20tables_update%205_unshaded_NOV_09.pdf. Accessed March
4, 2010.
7. Kavey RE, Allada V, Daniels SR et al. Cardiovascular risk reduction in high-risk pediatric patients: a scientific statement from the
American Heart Association Expert Panel on Population and Prevention Science et al. Circulation 2006;114(24):2710-38.
8. Daniels SR, Greer FR; Committee on Nutrition. Lipid screening and cardiovascular health in childhood. Pediatrics 2008;122
(1):198-208.
9. LaRosa JC, Grundy SM, Waters DD et al. Intensive lipid lowering with atorvastatin in patients with stable coronary disease. N
Engl J Med 2005;352(14):1425-35.
10. Sathasivam S, Lecky B. Statin induced myopathy. BMJ 2008;337:a2286.
11. Guyton JR, Bays HE. Safety considerations with niacin therapy. Am J Cardiol 2007;99(6A):22C-31C.
12. Maccubbin D, Koren MJ, Davidson M et al. Flushing profile of extended-release niacin/laropiprant versus gradually titrated niacin
extended-release in patients with dyslipidemia with and without ischemic cardiovascular disease. Am J Cardiol 2009;104(1):74-
81.
13. Keech A, Simes RJ, Barter P et al. Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2
diabetes mellitus (the FIELD study): randomised controlled trial. Lancet 2005;366(9500):1849-61.
14. ACCORD Study Group, Ginsberg HN, Elam MB et al. Effects of combination lipid therapy in type 2 diabetes mellitus. N Engl J Med
2010;362(17):1563-74.
15. Cannon CP, Giugliano RP, Blazing MA et al. Rationale and design of IMPROVE-IT (IMProved Reduction of Outcomes: Vytorin
Efficacy International Trial): comparison of ezetimibe/simvastatin versus simvastatin monotherapy on cardiovascular outcomes in
patients with acute coronary syndromes. Am Heart J 2008;156(5):826-32.
16. Tenenbaum A, Fisman EZ, Motro M et al. Optimal management of combined dyslipidemia: what have we behind statins
monotherapy? Adv Cardiol 2008;45:127-53.
17. Kris-Etherton PM, Harris WS, Appel LJ. Fish consumption, fish oil, omega-3 fatty acids, and cardiovascular disease. Circulation
2002;106(21):2747-57.
18. Lain KY, Catalano PM. Metabolic changes in pregnancy. Clin Obstet Gynecol 2007;50(4):938-48.
19. Basaran A. Pregnancy-induced hyperlipoproteinemia: review of the literature. Reprod Sci 2009;16(5):431-7.
20. Glueck CJ, Christopher C, Mishkel MA et al. Pancreatitis, familial hypertriglyceridemia, and pregnancy. Am J Obstet Gynecol
1980;136(6):755-61.
21. Kazmin A, Garcia-Bournissen F, Koren G. Risks of statin use during pregnancy: a systematic review. J Obstet Gynaecol Can
2007;29(11):906-8.
22. Klingel R, Gohlen B, Schwarting A et al. Differential indication of lipoprotein apheresis during pregnancy. Ther Apher Dial 2003;7
(3):359-64.
23. D’Agostino RB, Vasan RS, Pencina MJ et al. General cardiovascular risk profile for use in primary care: the Framingham Heart
Study. Circulation 2008;117(6):743-53.
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e-Therapeutics+ : Therapeutics : Cardiovascular Disorders: Heart Failure Page 1 of 19
Therapeutic Choice
Print Close
Cardiovascular Disorders: Heart Failure
Simon de Denus, B. Pharm, MSc
Michel White, MD, FRCPC, FACC, FESC
Heart failure (HF) is associated with a 5-year mortality rate of 5–50% depending on the severity of symptoms.1 HF may
require frequent hospitalizations and significantly reduces quality of life and exercise tolerance.1 Typical symptoms of HF
include dyspnea, fatigue and fluid retention.1
HF is characterized by impaired left ventricular (LV) function and reduced LV reserve. HF is generally categorized as systolic
HF or HF with preserved systolic function (PSF).2 Less common types of HF will not be discussed. Systolic HF is characterized
by decreased pump function, dilatation of the left ventricle and decreased LV ejection fraction (LVEF ≤ 40%). Most clinical
trials have been conducted in patients with systolic HF. There is no strong consensus on the definition of HF with PSF or its
treatment.1 , 2 , 3 , 4 , 5 It is variably defined as the presence of signs and symptoms of HF with LVEF > 40 or 50%. HF with
PSF can be associated with many conditions (hypertension, arterial stiffness, diabetes mellitus), although abnormal
myocardial relaxation, hypertrophy and/or fibrosis are generally present.1 , 2 , 3 , 4 , 5
Goals of Therapy1 , 2 , 3 , 4 , 5
Treat risk factors

Prevent disease progression
Improve symptoms, exercise tolerance and quality of life
Reduce morbidity and mortality
Table 1: Laboratory Investigations for Evaluation of Patients with Heart Failure
All patients
Complete blood count

Serum creatinine, electrolytes, blood urea nitrogen and transaminase levels
Fasting plasma glucose and serum lipids
Thyroid function tests
Urinalysis
Select patients
Brain natriuretic peptide (BNP) or N-terminal proBNP (NT-proBNP)a

Iron studies, ferritin and transferrin
HIV test
a. BNP or NT-proBNP is potentially useful in the emergency care setting. Value in primary care is not definitive.
Investigations1 (Figure 1 - Evaluation of Patients with Heart Failure)
A history, physical examination and select laboratory tests should be performed to establish the diagnosis (Table 1)
Identify and correct modifiable risk factors and exacerbating factors (Table 2)
Determine ventricular size and function with transthoracic echocardiography or isotopic ventriculography in all patients
with suspected HF. Echocardiography allows for identification of valvular abnormalities and other myocardial problems
Additional tests should be performed in select individuals to identify the etiology of HF and to guide specific treatment
when appropriate
The New York Heart Association functional classification is commonly used to describe patients with HF (Table 3)
Table 2: Factors That Can Exacerbate Heart Failure
Patient-specific factors
Noncompliance with drug therapy or dietary restrictions

Anemia
Arrhythmias
Infections
Myocardial ischemia
Pulmonary embolism
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Therapeutic Choice
Renal dysfunction
Thyroid dysfunction
Uncontrolled hypertension
Valvular heart disease
Drugs
Drugs that cause sodium and fluid retention:

NSAIDs including selective COX-2 inhibitors and high-dose salicylates
Corticosteroids
Minoxidil
Androgens
Thiazolidinediones (pioglitazone, rosiglitazone)
Drugs with high sodium content
Licorice-containing products
Negative inotropes:
Antiarrhythmic agents except amiodarone and dofetilide
Beta-blockers at maintenance doses
Calcium channel blockers: diltiazem, nifedipine, verapamil, but not amlodipine or felodipine
Itraconazole
Cardiotoxic drugs
Alcohol
Anthracyclines (doxorubicin)
Cocaine
Cyclophosphamide
Imatinib
Trastuzumab
Table 3: New York Heart Association (NYHA) Functional Classification
Class Characteristics
I No symptoms
II Symptoms occur with ordinary activity
III Symptoms occur with less than ordinary activity
IV Symptoms occur at rest or with minimal activity
Therapeutic Choices
Nonpharmacologic Choices1 , 3 , 4 , 5
Control HF risk factors (hypertension, obesity, diabetes mellitus, supraventricular arrhythmia, dyslipidemia, coronary
artery disease and other vascular diseases).
Recommend moderate regular physical activity in stable patients.
Recommend no more than moderate alcohol consumption in all patients.
avoid completely in alcoholic cardiomyopathy
Restrict sodium intake in all patients (< 2–3 g/day; 1–2 g/day in those with severe HF).
Restrict fluid intake (< 1.5–2 L/day) in patients with fluid retention that is not easily controlled with diuretics, or in
patients with hyponatremia.
Annual influenza vaccination in all patients.
Pneumococcal vaccination in all patients.
Daily weight.
patients who gain 0.5 kg/day on several consecutive days or 2 kg in 3 days should alert their team or physician
Device Therapy
Given their high cost, the following devices should generally be reserved for patients who do not have significant
comorbidities that are expected to significantly limit survival.
Implantable cardioverter defibrillators (ICD) are recommended for stable patients with a history of sudden cardiac arrest,
ventricular fibrillation (VF) or hemodynamically unstable sustained ventricular tachycardia (VT) in the absence of
reversible factors; or coronary artery disease with or without mild to moderate symptoms and an LVEF ≤ 30%.1 An ICD
may also be considered for stable patients with nonischemic NYHA class II–III HF and an LVEF ≤ 30%; or ischemic HF
and a history of myocardial infarction, NYHA class II–III HF and an LVEF of 31–35% and inducible VT/VF during an
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Therapeutic Choice
electrophysiology study.
Cardiac resynchronization therapy (CRT) should be considered in patients with NYHA class III–IV HF despite optimal
medical therapy who are in sinus rhythm and have an LVEF ≤ 35% and a QRS interval ≥ 120 msec.1
Left ventricular assist devices (LVAD) should be used as a bridge to transplantation. Use of LVADs as a bridge to
recovery is controversial.6
Continuous positive airway pressure (CPAP) should be considered in patients with obstructive sleep apnea.4
Reperfusion and Surgery
Revascularization, either by percutaneous coronary intervention or coronary artery bypass surgery, should be performed
in select patients with symptomatic ischemia.1
Cardiac transplantation should be considered in patients with severe refractory HF, despite optimal therapy, who would
otherwise have a good life expectancy.1
Systolic Heart Failure
In the absence of contraindications, the cornerstone of therapy for systolic HF in all patients with an LVEF ≤ 40% (NYHA
class I–IV) is long-term treatment with the combination of an angiotensin converting enzyme (ACE) inhibitor and a beta-
blocker (Figure 2 - Management of Systolic Heart Failure). Diuretics are used to control signs and symptoms of
hypervolemia. Digoxin, angiotensin II receptor blockers (ARBs), aldosterone antagonists or the combination of isosorbide
dinitrate/hydralazine are used in select individuals.5
Consideration should be given to the use of agents for which mortality and morbidity benefits have been established in large
randomized clinical trials (Table 4). Drugs used in the treatment of HF are presented in Table 5. Target doses are those used
in such trials.
Consider a patient’s comorbid conditions when contemplating the use of a particular class of medication, a specific agent and
the target dosage.
ACE Inhibitors
ACE inhibitors are recommended in all patients because they improve symptoms and reduce the risk of hospitalization,
myocardial infarction and death in patients with systolic HF.7 , 8 , 9 Start with a low dose and titrate the dose at 7- to 14-day
intervals to the target dose, or maximum tolerated dose if the target dose cannot be reached. Treatment with target doses is
more effective than low doses.10 Measure serum creatinine, potassium and blood pressure before initiating an ACE inhibitor
or increasing the dose and 7–14 days after any increase in dosage.5 An increase in serum creatinine of up to 30% is expected
and acceptable after initiation of an ACE inhibitor.1 Patients at greatest risk of hyperkalemia are those with moderate to
severe renal dysfunction, high baseline potassium, diabetes mellitus and those receiving potassium-sparing diuretics.11
Beta-blockers
Beta-blockers improve symptoms and reduce the risk of hospitalization and death in patients with systolic HF.12 , 13 , 14 , 15
They are recommended in all patients with an LVEF ≤ 40%.5 Only beta-blockers that have been shown to reduce mortality
should be used: carvedilol, bisoprolol and metoprolol succinate (not available in Canada).5 Metoprolol tartrate is
available in Canada, but has not been shown to reduce mortality in patients with HF. Titrate the dose at 2- to 4-week
intervals.5 Monitor blood pressure and heart rate before initiating a beta-blocker and before any increase in dose. Watch for
the signs and symptoms of HF decompensation when initiating or increasing the dose of a beta-blocker. Pay particular
attention to the daily morning weight.5 Beta-blockers should not be stopped abruptly.1 Refer patients with severe HF (NYHA
class III–IV) to an HF specialist for initiation of a beta-blocker.1
Diuretics
Diuretics are recommended to control signs and symptoms of congestion. Thiazide diuretics can be used in patients with
minimal fluid retention, but loop diuretics, usually furosemide, are required in most patients.1 , 3 , 4 , 5 Use of
ethacrynic acid is limited to patients with an allergy to furosemide. Thiazides have poor efficacy as monotherapy in patients
with creatinine clearance < 50 mL/min.16 Higher doses of furosemide are required in patients with renal dysfunction.16 The
lowest effective dose should be used.5 Serum creatinine and electrolytes should be measured before and 3–7 days after
initiation of a diuretic and then as indicated (until serum potassium and renal function are stable) after increasing the dose.
Thiazide and loop diuretics deplete potassium and magnesium. Serum potassium should be maintained at ≥ 4 mmol/L
because hypokalemia increases the risk of fatal ventricular arrhythmias and digoxin toxicity.1 In patients with refractory
volume overload, consider the addition of a low-dose thiazide intermittently (e.g., a few times/week) to a loop diuretic.1 , 3 ,
Page 83
Therapeutic Choice
4 , 5 This strategy should be used only by experienced clinicians with close monitoring of weight, renal function and serum
potassium because of the risk of severe and potentially fatal dehydration and electrolyte imbalances.1 , 3 , 4 , 5 When
prescribed once a day, diuretics should generally be taken in the morning. When prescribed twice daily or more, the last dose
should be taken before 4:00 p.m. to avoid diuresis during the night.
With the exception of spironolactone (see Aldosterone Antagonists below), the role of potassium-sparing diuretics is
limited to prevention of hypokalemia and hypomagnesemia in patients treated with thiazides or loop diuretics.3
Angiotensin II Receptor Blockers
Angiotensin II receptor blockers (ARBs) are an alternative to ACE inhibitors in patients with ACE inhibitor–induced cough or
angioedema. Patient education and follow-up are essential because ARB-induced angioedema has been reported.4 , 17 Similar
to ACE inhibitors, ARBs are associated with renal dysfunction and hyperkalemia; thus, ARBs should not be substituted for
ACE inhibitors specifically for these adverse events.18 Considerations for initiation, dosage titration and monitoring for ARBs
are the same as for ACE inhibitors.
Addition of an ARB may be considered in patients with persistent symptoms despite optimal therapy with an ACE inhibitor
and a beta-blocker.1 , 19 In this setting, candesartan reduced cardiovascular mortality and hospitalizations for HF.19
Reductions in morbidity but not mortality were obtained with valsartan in another trial.20 Limited data suggest that an ARB
may be a valuable addition to an ACE inhibitor in patients not receiving a beta-blocker.1 Close monitoring of vital signs,
serum creatinine and potassium is essential when combining an ACE inhibitor and an ARB. The combination of an ACE
inhibitor, an ARB and an aldosterone antagonist is not recommended because of the uncertainty regarding the benefit and
safety of this combination.1
Aldosterone Antagonists
Aldosterone antagonists reduce the risk of mortality and morbidity in patients with chronic severe HF (NYHA class III–IV and
LVEF < 35%) and in post-MI patients with an LVEF ≤ 40% and either clinical HF or diabetes mellitus.4 , 21 , 22 The benefit of
these agents in patients with stable mild to moderate symptoms is unknown.4 Aldosterone antagonists should not be used in
patients with a baseline potassium > 5 mmol/L, a serum creatinine > 221 µmol/L or a creatinine clearance < 30 mL/min.4
Start spironolactone at a dose of 12.5 mg daily or every other day. Alternatively use eplerenone at a dose of 25 mg daily
or every other day. Monitor vital signs, serum creatinine and potassium 3 days and 1 week after initiating or titrating the
dose of aldosterone antagonists and repeat as necessary until the potassium level and renal function are stable.5 Monitoring
should then be performed monthly for 3 months and then every 3 months.5
Eplerenone is a new selective aldosterone antagonist that does not produce gynecomastia.5 Currently available data with
this agent are limited to post-MI patients. In chronic heart failure its use should be restricted to patients who cannot tolerate
spironolactone because of gynecomastia. Eplerenone appears to have a similar risk of hyperkalemia and renal dysfunction as
spironolactone, so should not be used as a substitute in these situations.
Digoxin
Digoxin improves symptoms and reduces the risk of hospitalization for HF, but does not reduce mortality in patients with
moderate to severe persistent symptoms (NYHA class II–IV) despite optimal medical therapy.4 , 23 It may also be considered
for control of the ventricular rate in patients with atrial fibrillation that cannot be controlled by beta-blockers, or in patients
who cannot tolerate beta-blockers.5 The dosage is individualized based on the patient’s age, weight, renal function and
concomitant drugs, but usually ranges from 0.0625 to 0.25 mg daily. Lower doses may be appropriate in select patients.
Given the narrow therapeutic index of digoxin, particular attention should be devoted to identifying and preventing potential
drug interactions. Digoxin serum concentrations should be monitored when renal function changes significantly, an
interacting drug is added or discontinued, or when digoxin toxicity is suspected. Serum concentrations may also be
monitored once steady state is achieved after initiating digoxin, particularly in elderly patients and those with renal
dysfunction.4 , 24 Measure trough serum concentrations at least 8 hours after administration and adjust the dose to maintain
the serum concentration between 0.6 and 1 nmol/L, which is associated with greater reductions in hospitalization and,
possibly, a reduction in all cause and HF mortality.25 , 26
Nitrates/hydralazine
The combination of isosorbide dinitrate plus hydralazine reduces mortality and morbidity in black patients with NYHA class
III–IV HF and is recommended in addition to standard therapy in this setting.27 Use of this combination may also be
considered in black patients with NYHA class II HF1 , 4 , 27 and in other HF patients who do not tolerate ACE inhibitors and
ARBs.1
Nitrate monotherapy is valuable to treat symptoms of exercise-induced dyspnea or angina, paroxysmal nocturnal dyspnea
and orthopnea. Nitrates have not been shown to reduce mortality in the absence of hydralazine.1
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Therapeutic Choice
Omega-3 Polyunsaturated Fatty Acid Supplementation
Based on a recent trial that suggested a modest reduction of cardiovascular events with low-dose omega-3
polyunsaturated fatty acid (n-3 PUFA),28 the 2009 update of the Canadian Cardiovascular Society Guidelines
suggest that low-dose n-3 PUFA (1 g/day) may be considered in patients with mild to moderate
HF.29 Useful Info? The more recent joint American Heart Association and American College of Cardiology guideline has
not included a recommendation for or against the use of n-3 PUFA.5 Whether higher doses of n-3 PUFA are more effective is
unknown, but doses of more than 3 g/day have been associated with excessive bleeding.29 Monitoring the INR is suggested
in patients receiving warfarin following n-3 PUFA initiation.29 Finally, because n-3 PUFA are food supplements, patients
should consult their pharmacist to help in the selection of a reliable n-3 PUFA brand that most closely matches the
formulation studied in HF (850–882 mg eicosapentaenoic acid and docosahexaenoic acid as ethyl esters in an average ratio
of 1:1.2).
Felodipine and amlodipine are safe, but do not reduce mortality or morbidity in patients with systolic HF.30 , 31 They may
be useful in select patients with persistent angina despite the use of beta-blockers (and nitrates) or in patients with
uncontrolled hypertension despite the use of an ACEI, ARB, beta-blocker and a diuretic.3
Avoid use of diltiazem and verapamil in patients with systolic HF because of their negative inotropic effects.1 , 3 , 4 , 5 Avoid
nifedipine because of the lack of data and availability of safe alternatives.
Antiarrhythmics4
Consider amiodarone to maintain sinus rhythm in select patients with atrial fibrillation. Amiodarone also reduces the
frequency of repetitive ICD discharges. Avoid other antiarrhythmic drugs. Antiarrhythmics are not recommended to prevent
sudden cardiac death because they do not reduce mortality. It should be emphasized that a strategy of maintaining sinus
rhythm in patients with HF is not superior to ventricular rate control in patients with a history of atrial fibrillation.32
Although the benefit of statins in the primary and secondary prevention of coronary artery disease is well established, 2
recent trials have suggested that the benefits of statins in patients with HF may be more limited, even if they have coronary
artery disease.33 , 34 Nevertheless, patients included in these trials were relatively old (mean age at baseline of 69 and 73
years) and presented with a baseline LDL cholesterol of only 3.2 mmol/L and 3.5 mmol/L, respectively. Consequently, it
appears reasonable to continue treating younger patients and/or patients who are at high risk of cardiovascular events
(recent myocardial infarction, diabetes and known vascular disease). Moreover, because these trials did not study the impact
of statin discontinuation, it also appears reasonable to continue the use of these agents in patients who are receiving them.
Heart Failure with Preserved Systolic Function
Treatment of HF with PSF has been studied to a limited extent. Control risk factors (hypertension, diabetes mellitus,
ventricular rate in patients with supraventricular arrhythmias) and volume status and decrease heart rate to optimize filling
time.1 , 4 Recent trials have suggested that the chronic use of renin-angiotensin system modulators does not significantly
reduce the risk of mortality in patients with HF with PSF.35 , 36 , 37 Nevertheless, these agents should be used to treat
hypertension, particularly in patients with diabetes, left ventricular hypertrophy, nephropathy or coronary artery disease
because of their established efficacy and end-organ protection in these patient populations. Beta-blockers are
recommended in most patients,1 particularly those with CAD, prior MI, hypertension or atrial fibrillation (Figure 3 -
Management of Heart Failure with Preserved Systolic Function).4 Diuretics should be used to optimize volume status.1 Use
of verapamil or diltiazem may be considered to control the ventricular rate in patients with supraventricular arrhythmias1 ,
4 or angina, in those who cannot tolerate a beta-blocker,4 and may be particularly useful in patients with hypertrophic
cardiomyopathy. Calcium channel blockers may also be considered in patients with hypertension.4
Decompensated Heart Failure
Few large, randomized trials have been performed in patients with decompensated or acute HF. Intravenous loop diuretics
are recommended in patients with signs and symptoms of fluid retention (e.g., furosemide 40–200 mg 2 or 3 times daily
based on renal function or the patient’s usual dose of furosemide).1 , 4 , 16
Combinations of diuretics, or the addition of a vasodilator such as nitroglycerin, nesiritide or nitroprusside should be
given to hospitalized patients who do not respond to intravenous furosemide.1 , 4 Intravenous vasodilators with a loop
Page 85
Therapeutic Choice
diuretic can be used initially in patients with moderate to severe symptoms of pulmonary congestion or those with severe
hypertension.1 , 4 Sublingual nitroglycerin can be given before intravenous nitroglycerin. Invasive monitoring is
recommended when administering nitroprusside.4 Great care should be taken to prevent cyanide and thiocyanide toxicity with
nitroprusside; avoid in patients with hepatic or renal failure.3
In patients with low cardiac output, milrinone or dobutamine should be given if the systolic blood pressure is > 90 mm
Hg,1 and dobutamine if the systolic blood pressure is < 90 mm Hg.1 The use of vasopressors (dopamine or
norepinephrine) should be limited to patients with significant hypotension.1 Dosages of these agents are based on vital
signs, clinical status, comorbidities and the treatment regimen of the patient. In select patients, invasive monitoring of
hemodynamic parameters may be used to adjust the dose.
Therapeutic Tips
The choice of whether to start an ACE inhibitor or a beta-blocker first in a given patient is based on the vital signs, blood
pressure and comorbidities. Most clinicians will start both agents simultaneously at low doses.
If introduced sequentially, it is not necessary to reach the target doses of one agent before starting the other.
The doses of ACE inhibitors and beta-blockers should generally not be increased simultaneously.
Hypotension or worsening renal function when initiating or increasing the dose of an ACE inhibitor usually indicates the
need to reduce the dose of a diuretic.
The formulation of metoprolol available in Canada (metoprolol tartrate) has not been shown to reduce mortality in a
randomized trial of patients with HF, is not available in a commercial dosage form that is suitable for initial treatment of
HF and is not included in Canadian guidelines. Mortality and hospital admissions were significantly more frequent in
patients treated with metoprolol tartrate (target dose 50 mg BID) than with carvedilol (25 mg BID) in a large randomized
trial.38 The target dose of metoprolol tartrate used in this trial was lower than the target dose of controlled-release
metoprolol succinate that has been shown to significantly decrease mortality in a large placebo-controlled trial.12
In patients with hypotension, consider administering the blood pressure-lowering drugs at different times during the
day.
Cough is a symptom of HF decompensation. Careful evaluation is necessary when evaluating a cough in a patient
receiving an ACE inhibitor.
Electrolyte abnormalities are common in patients with HF. Patients need to be closely monitored, especially when taking
combinations that have additive effects, for example, increased serum potassium due to the combination of an ACE
inhibitor or ARB plus spironolactone.
Figure 1- Evaluation of Patients with Heart Failure
Page 86
Therapeutic Choice
a. Echocardiography (two dimensional or transthoracic) is used to determine LVEF, chamber size, wall thickness, valve function and
presence of pericardial disease. Consider other diagnostic investigations if inconclusive (e.g., magnetic resonance imaging or cardiac
catheterization).
Abbreviations: HF = heart failure; LV = left ventricular; LVEF = LV ejection fraction
Figure 2- Management of Systolic Heart Failure
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Therapeutic Choice
a. Identify and manage risk factors, educate all patients about their disease and implement nonpharmacologic treatment. Consider ICD and
resynchronization therapy in select patients.
b. Use an ARB in patients with ACEI-induced cough that is intolerable or angioedema (although there is a low risk of angioedema with
ARBs). Alternatively, substitute hydralazine/isosorbide dinitrate combination therapy for ACEI and/or ARB-induced hyperkalemia, renal
dysfunction or angioedema.
c. Consider using ACEI/ARB combination therapy to prevent disease progression in patients with minimal to moderate symptoms (i.e.,
NYHA II) who cannot tolerate a beta-blocker.
d. Use diuretics to minimize fluid retention. Consider combination diuretic therapy in patients with severe symptoms.
e. Avoid the combination of an ACEI plus an ARB and spironolactone because of the risk of hyperkalemia.
Abbreviations: ACEI = angiotensin converting enzyme inhibitor; ARB = angiotensin II receptor blocker; LVEF = left
ventricular ejection fraction; NYHA = New York Heart Association
Figure 3- Management of Heart Failure with Preserved Systolic Function
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Therapeutic Choice
a. There is no strong consensus on the definition of HF with PSF or its treatment.

b. Diuretics should be used with care because excessive diuresis may decrease cardiac output and compromise renal function in HF with
PSF.
c. CCBs may improve symptoms by decreasing heart rate and increasing diastolic filling time.
Abbreviations: ACEI = angiotensin converting enzyme inhibitor; ARB = angiotensin II receptor antagonist;
CCB = calcium channel blocker; HF with PSF = heart failure with preserved systolic function
Table 4: Outcomes Associated with Drugs Used for Systolic Heart Failure
Number needed to
Relative risk Absolute risk treat to prevent one
Outcome Intervention Comparator reduction (%) reduction (%) outcome
Death prevented ACE inhibitor8 Placebo 16 4.5 23
Beta-blocker13 Placebo 32 5.5 29
Aldosterone antagonist22 Placebo 30 11 10
Hydralazine/isosorbide Placebo 39 4 25
dinitrate27
Hospitalizations ACE inhibitor8 Placebo 30 10.8 9

avoided
Beta-blocker13 Placebo 33 6 17
Digoxin23 Placebo 28 7.9 13
Table 5: Drugs Used for Heart Failure
Drug Costa
Class Drug Dose Adverse Effects Interactions Comments
ACE captopril Initial: Hypotension, Diuretics: Monitor $$$

Inhibitorsb Capoten, generics TID hyperkalemia, dry hypotension serum
Target: 50 mg TID cough, renal (monitor BP). creatinine
insufficiency, Potassium-sparing and
angioedema (rare), diuretics, potassium
skin rashes, taste potassium after
disturbance, supplements, initiation of
proteinuria, ARBs: therapy.
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Therapeutic Choice
Drug Costa
neutropenia (rare), hyperkalemia Some

headache, dizziness. (monitor K+). experienced
clinicians
NSAIDs: ↓ use doses
hypotensive effect higher than
(monitor BP), fluid usual target
retention, renal doses.
failure.
Lithium: lithium
toxicity (monitor
lithium levels).
ACE enalapril Initial: Hypotension, Diuretics: Monitor $$$

Inhibitorsb Vasotec, generics 1.25–2.5 mg BID hyperkalemia, dry hypotension serum
Target: 10 mg BID cough, renal (monitor BP). creatinine
clinicians
failure.
Lithium: lithium
toxicity (monitor
lithium levels).
ACE lisinopril Initial: Hypotension, Diuretics: Monitor $$

Inhibitorsb Prinivil, Zestril, 2.5–5 mg once daily hyperkalemia, dry hypotension serum
generics Target: 20–35 mg cough, renal (monitor BP). creatinine
once daily insufficiency, Potassium-sparing and
clinicians
failure.
Lithium: lithium
toxicity (monitor
lithium levels).
ACE ramipril Initial: Hypotension, Diuretics: Monitor $$

Inhibitorsb Altace, generics 1.25–2.5 mg BID hyperkalemia, dry hypotension serum
Target: 5 mg BID cough, renal (monitor BP). creatinine
Page 90
Therapeutic Choice
Drug Costa

clinicians
failure.
Lithium: lithium
toxicity (monitor
lithium levels).
ACE trandolapril Initial: Hypotension, Diuretics: Monitor $$

Inhibitorsb Mavik 1 mg once daily hyperkalemia, dry hypotension serum
Target: 4 mg once cough, renal (monitor BP). creatinine
daily insufficiency, Potassium-sparing and
clinicians
failure.
Lithium: lithium
toxicity (monitor
lithium levels).
Angiotensin candesartan Initial: 4 mg once Hypotension, Diuretics: $$

Receptor Atacand daily hyperkalemia, renal hypotension
Blockers Target: 32 mg once insufficiency, (monitor BP).
daily angioedema (rare, Potassium-sparing
less frequent than diuretics and ACE
with ACE inhibitors), inhibitors:
headache, dizziness. hyperkalemia
(monitor K+).
Potassium:
hyperkalemia
(monitor K+).
NSAIDs: ↓
hypotensive effect
(monitor BP), fluid
retention, renal
failure.
Lithium: lithium
toxicity (monitor
lithium levels).
Angiotensin valsartan Initial: 40 mg BID Hypotension, Diuretics: $$$

Receptor Diovan Target: 160 mg BID hyperkalemia, renal hypotension
Blockers insufficiency, (monitor BP).
angioedema (rare, Potassium-sparing
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Therapeutic Choice
Drug Costa
less frequent than diuretics and ACE

with ACE inhibitors), inhibitors:
headache, dizziness. hyperkalemia
(monitor K+).
Potassium:
hyperkalemia
(monitor K+).
NSAIDs: ↓
hypotensive effect
(monitor BP), fluid
retention, renal
failure.
Lithium: lithium
toxicity (monitor
lithium levels).
Thiazides chlorthalidone Dehydration, Lithium: lithium Use in $

and Related generics 50–100 mg once hypokalemia, toxicity (monitor patients
Diuretics daily nausea, lithium levels). with mild
Max: 200 mg/day hypotension, Digoxin: digoxin HF or with a
(use lower doses azotemia, toxicity if K+ loop
when used in hypomagnesemia, depleted (monitor diuretic.
combination with a hypercalcemia, K+).
loop diuretic) hyponatremia,
hyperglycemia Corticosteroids:
(more with hypokalemia
thiazides),
(monitor K+).
hyperuricemia, rash,
↑ total cholesterol.
NSAIDs: ↓ diuretic
effect; increased
renal toxicity
(monitor).
Loop diuretics:
hypokalemia,
hypomagnesemia,
dehydration, renal
dysfunction
(monitor).
Thiazides hydrochlorothiazide 25–100 mg/day Dehydration, Lithium: lithium Use in $

and Related given in 1 or 2 hypokalemia, toxicity (monitor patients
Diuretics Apo-Hydro, other divided doses nausea, lithium levels). with mild
generics Max: 200 mg/day hypotension, Digoxin: digoxin HF or with a
(use lower doses in azotemia, toxicity if K+ loop
combination with a hypomagnesemia, depleted (monitor diuretic.
loop diuretic) hypercalcemia, K+).
hyponatremia,
hyperglycemia Corticosteroids:
thiazides),
(monitor K+).
effect; increased
renal toxicity
(monitor).
Loop diuretics:
hypokalemia,
hypomagnesemia,
dehydration, renal
dysfunction
Page 92
Therapeutic Choice
Drug Costa
(monitor).
Thiazides metolazone Dehydration, Lithium: lithium Use in $

and Related Zaroxolyn 2.5–10 mg once daily hypokalemia, toxicity (monitor patients
Diuretics (use lower doses in nausea, lithium levels). with mild
combination with a hypotension, Digoxin: digoxin HF or with a
loop diuretic) azotemia, toxicity if K+ loop diuretic
hypomagnesemia, depleted (monitor in those
hypercalcemia, K+). with
hyponatremia, refractory
hyperglycemia Corticosteroids: HF.
thiazides),
(monitor K+).
effect; increased
renal toxicity
(monitor).
Loop diuretics:
hypokalemia,
hypomagnesemia,
dehydration, renal
dysfunction
(monitor).
Loop bumetanide Dehydration, Lithium: lithium 1 mg = 40 $$$

Diuretics Burinex 1–4 mg/day hypokalemia, toxicity (monitor mg
hypocalcemia, lithium levels). furosemide.
nausea, Digoxin: digoxin
hypotension, toxicity if K+
azotemia, depleted (monitor
hypomagnesemia, K+).
anorexia,
hyperglycemia (less Corticosteroids:
than with thiazides), hypokalemia
hyperuricemia,
(monitor K+).
weakness, fatigue,
rash, ↑ total
cholesterol,
effect; ↑ renal
ototoxicity with high
toxicity (monitor).
doses.
Thiazide diuretics:
hypokalemia,
hypomagnesemia,
dehydration, renal
dysfunction
(monitor).
Loop furosemide Dehydration, Lithium: lithium $

Diuretics Lasix, generics 20–500 mg/day hypokalemia, toxicity (monitor
given daily to BID hypocalcemia, lithium levels).
For decompensated nausea, Digoxin: digoxin
HF: may be given hypotension, toxicity if K+
BID or TID azotemia, depleted (monitor
hypomagnesemia, K+).
anorexia,
hyperglycemia (less Corticosteroids:
than with thiazides), hypokalemia
hyperuricemia,
(monitor K+).
weakness, fatigue,
rash, ↑ total
cholesterol,
effect; ↑ renal
Page 93
Therapeutic Choice
Drug Costa
doses. toxicity (monitor).

Thiazide diuretics:
hypokalemia,
hypomagnesemia,
dehydration, renal
dysfunction
(monitor).
Loop ethacrynic acid 50–200 mg daily or Dehydration, Lithium: lithium An $$$$$

Diuretics Edecrin divided BID hypokalemia, toxicity (monitor alternative
hypocalcemia, lithium levels). diuretic in
nausea, Digoxin: digoxin patients
hypotension, toxicity if K+ with
azotemia, depleted (monitor allergies to
hypomagnesemia, K+). loop
anorexia, diuretics.
hyperglycemia (less Corticosteroids: Higher risk
than with thiazides), hypokalemia of
hyperuricemia, ototoxicity
(monitor K+).
weakness, fatigue, than
rash, ↑ total furosemide.
cholesterol,
effect; ↑ renal
toxicity (monitor).
doses.
Thiazide diuretics:
hypokalemia,
hypomagnesemia,
dehydration, renal
dysfunction
(monitor).
Aldosterone eplerenone Initial: 25 mg daily Hyperkalemia, ACE inhibitors, Monitor $$$$

Antagonists Inspra or every 2 days dehydration, ARBs, potassium serum
Target: 50 mg daily dizziness, diarrhea, supplements: creatinine
nausea. hyperkalemia. and
NSAIDs: ↓ diuretic potassium 3
effect, worsening days and 1
renal function, week after
hyperkalemia. initiating or
titrating the
Strong dose.
inhibitors/inducers Repeat
of CYP 3A4. every 1–3
mo once
stable.
Aldosterone spironolactone Initial: 12.5 mg daily Hyperkalemia, ACE inhibitors, Monitor $

Antagonists Aldactone, generics or every 2 days dehydration, nausea, ARBs, potassium serum
Target (for mortality gynecomastia supplements: creatinine
benefit): 25–50 (usually reversible hyperkalemia. and
mg/day upon NSAIDs: ↓ diuretic potassium 3
discontinuation). effect, worsening days and 1
Higher doses can be renal function, week after
used for stronger hyperkalemia. initiating or
diuretic effects, but titrating the
rarely dose.
used/appropriate, Repeat
unless patient has every 1–3
severe right HF mo once
stable.
eplerenone.
Beta1- bisoprolol Initial: 1.25 mg po Orthostatic Digoxin, Selective $

adrenergic generics daily hypotension, fluid amiodarone, beta-
Target: 10 mg daily retention, diltiazem, blocker.
Page 94
Therapeutic Choice
Drug Costa
Antagonists bronchospasm (less verapamil: ↑

with beta1- bradycardia.
selective), dyspnea, Nondihydropyridine
bradycardia, calcium channel
malaise, fatigue, blockers: additive
asthenia, erectile cardiodepressant
dysfunction, may effect.
mask hypoglycemia.
Beta1- carvedilol Initial: 3.125 mg po Orthostatic Digoxin, Nonselective $$

adrenergic Apo-Carvedilol, BID hypotension, fluid amiodarone, beta-blocker
Antagonists other generics Target: 25 mg BID retention, diltiazem, with alpha-
bronchospasm (less verapamil: ↑ blocking
with beta1- bradycardia. activity. Has
selective), dyspnea, Nondihydropyridine some
bradycardia, calcium channel vasodilating
malaise, fatigue, blockers: additive effects.
asthenia, erectile cardiodepressant
dysfunction, may effect.
mask hypoglycemia.
More likely to cause CYP 2D6 inhibitors.
orthostatic
hypotension than
bisoprolol.
Vasodilators hydralazine Initial: 10–25 mg po Hypotension, Used in $$

Apo-Hydralazine, TID gastrointestinal combination
other generics complaints, lupus- with
Target: 75 mg TID like syndrome. isosorbide
dinitrate in
black
patients.
Vasodilators isosorbide dinitrate Initial: 10–20 mg po Headache, Sildenafil, Use in $

generics TID hypotension. vardenafil and combination
Target: 40 mg TID tadalafil: severe with
hypotension. hydralazine
in black
patients.
Vasodilators nesiritide 2 μg/kg iv bolus Hypotension, ↑ ↑ hypotensive For hospital $$$$$

Natrecor followed by 0.01 serum creatinine effects with ACE use only.
μg/kg/min infusion. inhibitors; possible There is
May ↑ dose at ≥ 3- additive limited
hour intervals by hypotension with experience
giving a 1 μg/kg other vasodilators with doses
bolus over 1 min > 0.01
then ↑ infusion rate µg/kg/min
by 0.005 μg/kg/min
Max: 0.03 μg/kg/min
Vasodilators nitroglycerin 5–200 µg/min iv Hypotension, Sildenafil, $$$$$

generics headache, vardenafil and
tachycardia, tadalafil: severe
bradycardia. hypotension.
Vasodilators nitroprusside 0.1–5 µg/kg/min iv Hypotension, $$$$$

generics cyanide toxicity,
thiocyanate toxicity,
methemoglobinemia,
coronary artery
steal, tachycardia, ↑
intracranial
Page 95
Therapeutic Choice
Drug Costa
pressure.
Calcium amlodipine 2.5–10 mg daily Hypotension, $$-

Channel Norvasc, generics constipation, $$$
Blockers peripheral edema,
gingival hyperplasia,
headache, dizziness.
Calcium felodipine 2.5–10 mg daily Hypotension, $

Channel Plendil, Renedil, constipation,
Blockers generics peripheral edema,
gingival hyperplasia,
headache, dizziness.
Inotropic digoxin 0.0625–0.25 mg Anorexia, nausea, Amiodarone, Adjust dose $

Agents Lanoxin, Toloxin daily (lower doses vomiting, visual clarithromycin, based on
may be appropriate disturbances, cyclosporine, patient’s
in select patients) fatigue, dizziness, erythromycin, age, weight,
confusion, delirium. itraconazole, renal
Cardiac arrhythmia. propafenone, function and
Noncardiovascular quinidine, concomitant
adverse effects do ritonavir, drugs.
not always precede tetracycline and
potentially fatal verapamil ↑ digoxin
arrhythmias. serum levels.
Antacids,
cholestyramine,
colestipol,
neomycin,
rifampin, St. John’s
wort and
sulfasalazine ↓
digoxin serum
levels.
Amiodarone, beta-
blockers, diltiazem
and verapamil ↑
risk of bradycardia.
Inotropic milrinone 0.1–0.75 µg/kg/min Tachyarrhythmias, $$$$$

Agents Apo-Milrinone, other hypotension,
generics myocardial
ischemia,
thrombocytopenia.
Inotropic dobutamine 2–20 µg/kg/min Tachyarrhythmias, Beta-blockers $$$$$

Agents generics hypokalemia, reduce positive
myocardial inotropic effects of
ischemia. dobutamine.
a. Cost of 30-day supply for target doses; includes drug cost only. For ACE inhibitors, cost was calculated for the targeted dose.
b. Only captopril, enalapril, ramipril and trandolapril have been shown to reduce morbidity and prolong survival in heart failure or in
patients with LV dysfunction post-MI.
Dosage adjustment may be required in renal impairment; see Appendices: Dosage Adjustment in Renal Impairment
Legend: $ < $25 $$ $25–50 $$–$$$ $25–75 $$$ $50–75 $$$$ $75–100 $$$$$ > $100
Suggested Readings
Arnold JM, Liu P, Demers C et al. Canadian Cardiovascular Society consensus conference recommendations on heart failure
Page 96
Therapeutic Choice
2006: diagnosis and management. Can J Cardiol 2006;22(1):23-45.
Dickstein K, Cohen-Solal A, Filippatos G et al. ESC Guidelines for the diagnosis and treatment of acute and chronic heart
failure 2008: the Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2008 of the European
Society of Cardiology. Developed in collaboration with the Heart Failure Association of the ESC (HFA) and endorsed by the
European Society of Intensive Care Medicine (ESICM). Eur Heart J 2008;29(19):2388-442.
Heart Failure Society Of America. HFSA 2006 comprehensive heart failure practice guideline. J Card Fail 2006;12(1):e1-122.
Howlett JG, McKelvie RS, Arnold JM et al. Canadian Cardiovascular Society Consensus Conference guidelines on heart failure,
update 2009: diagnosis and management of right-sided heart failure, myocarditis, device therapy and recent important
clinical trials. Can J Cardiol 2009;25(2):85-105.
Hunt SA. ACC/AHA 2005 guideline update for the diagnosis and management of chronic heart failure in the adult: a report of
the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to
Update the 2001 Guidelines for the Evaluation and Management of Heart Failure). J Am Coll Cardiol 2005;46(6):e1-82.
Jessup M, Brozena S. Heart failure. N Engl J Med 2003;348(20):2007-18.
References
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28. Tavazzi L, Maggioni AP, Marchioli R et al. Effect of n-3 polyunsaturated fatty acids in patients with chronic heart failure
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31. Packer M, O'Connor CM, Ghali JK et al. Effect of amlodipine on morbidity and mortality in severe chronic heart failure.
Prospective Randomized Amlodipine Survival Evaluation Study Group. N Engl J Med 1996;335(15):1107-14.
32. Roy D, Talajic M, Nattel S et al. Rhythm control versus rate control for atrial fibrillation and heart failure. N Engl J Med
2008;358(25):2667-77.
33. Gissi-HF Investigators, Tavazzi L, Maggioni AP et al. Effect of rosuvastatin in patients with chronic heart failure (the
GISSI-HF trial): a randomised, double-blind, placebo-controlled trial. Lancet 2008;372(9645):1231-9.
34. Kjekshus J, Apatrei E, Barrios V et al. Rosuvastatin in older patients with systolic heart failure. N Engl J Med 2007;357
(22):2248-61.
35. Yusuf S, Pfeffer MA, Swedberg K et al. Effects of candesartan in patients with chronic heart failure and preserved left-
ventricular ejection fraction: the CHARM-Preserved Trial. Lancet 2003;362(9386):777-81.
36. Massie BM, Carson PE, McMurray JJ et al. Irbesartan in patients with heart failure and preserved ejection fraction. N
Engl J Med 2008;359(23):2456-67.
37. Cleland JG, Tendera M, Adamus J et al. The perindopril in elderly people with chronic heart failure (PEP-CHF) study.
Eur Heart J 2006;27(19):2338-45.
38. Poole-Wilson PA, Swedberg K, Cleland JG et al. Comparison of carvedilol and metoprolol on clinical outcomes in
patients with chronic heart failure in the Carvedilol Or Metoprolol European Trial (COMET): randomised controlled trial.
Lancet 2003;362(9377):7-13.
Pharmacoeconomic Considerations: Heart Failure

Date of preparation: 2007-06-30
Blair Jarvis, MSc, BSP
Epidemiology
Country (Year) Prevalence
Canada (2000-2001)1 85 679 people spent a total of 1.4 million days in hospital for heart failure
Median length of stay: 7 days
Country and Year of Estimate Direct Costsa
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Therapeutic Choice
United States (2000)2 Direct costs over a 5-year period for:

• patients with left ventricular ejection fraction < 50%: US $33 023
• patients with preserved left ventricular ejection fraction: US $32 580
Commentary
Heart failure is the most common cause of hospitalization in the elderly, and 80% of hospitalizations for heart failure and
90% of deaths due to heart failure occur in those older than 65 years.3 In Canada, the mean age of a person hospitalized
for heart failure in 2000-2001 was 76 years and the in-hospital mortality rate was 15.5%.1 There were more than 100 000
hospital discharges for heart failure in that year, approximately one-third of which were after re-admissions. The burden of
heart failure in Canada is projected to increase as the population ages.4 Measures that stabilize the disease and reduce the
rate of hospitalization are likely to be highly cost-effective.
Drug therapy for heart failure reduces symptoms, improves health-related quality of life, retards disease progression,
prevents hospitalizations and prolongs life. The most extensive evidence of benefit pertains to the use of ACE inhibitors
and beta blockers.
There is evidence of substantial care gaps where the benefits of heart failure therapies are not being realized in routine
clinical practice.5 The difference in impact of interventions in clinical trials and clinical practice has been likened to a
“diffusion gradient.” Removing this diffusion gradient and increasing adherence with treatment guidelines is likely to be
cost-effective. For example, increasing use of ACE inhibitors, beta-blockers, digoxin and spironolactone by 10% would be
expected to reduce the rate of hospitalization for heart failure and save as much as $6.6 million in one year based on
Alberta data.6 This would result in a net savings of $2.3 million.6 Canadian treatment guidelines provide target doses for
each medication, so clinicians should be sure not only to prescribe appropriate drugs, but to titrate the dose to a level
shown to produce benefits in clinical trials. Programs of follow-up by nurses or pharmacists with patients released from
hospital have been shown to reduce re-admissions and hospital costs within six months.7
Most pharmacoeconomic studies are conducted from the societal rather than an individual perspective. The relative cost of
individual medications for heart failure is inexpensive because of the availability of generic products; however, because
patients must take a number of drugs to achieve optimal outcomes, the total cost for an individual may be substantial.
Patients who perceive the medical costs of heart failure to be a burden have worse health status than those without a
perceived economic burden.8 Thus, inquiring about financial constraints and involving other members of the health care
team (e.g., nurses, social workers, pharmacists) may be helpful in addressing the needs of patients with diminished health
status.
1. Tsuyuki RT, Shibata MC, Nilsson C et al. Contemporary burden of illness of congestive heart failure in Canada. Can J
Cardiol 2003;19(4):436-8.
2. Liao L, Jollis JG, Anstrom KJ et al. Costs for heart failure with normal vs reduced ejection fraction. Arch Intern Med
2006;166(1):112-8.
3. Haldeman GA, Croft JB, Giles WH et al. Hospitalization of patients with heart failure: National Hospital Discharge
Survey, 1985 to 1995. Am Heart J 1999;137(2):352-60.
4. Johansen H, Strauss B, Arnold JM et al. On the rise: the current and projected future burden of congestive heart
failure hospitalization in Canada. Can J Cardiol 2003;19(4):430-5.
5. Kosiborod M, Lichtman JH, Heidenreich PA et al. National trends in outcomes among elderly patients with heart failure.
Am J Med 2006;119(7):616.e1-7.
6. Shibata MC, Nilsson C, Hervas-Malo M et al. Economic implications of treatment guidelines for congestive heart
failure. Can J Cardiol 2005;21(14):1301-6.
7. Tsuyuki RT, Fradette M, Johnson JA et al. A multicentre disease management program for hospitalized patients with
heart failure. J Card Fail 2004;10(6):473-80.
8. Conard MW, Heidenreich P, Rumsfeld JS et al. Patient-reported economic burden and the health status of heart failure
patients. J Card Fail 2006;12(5):369-74.
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e-Therapeutics+ : Therapeutics : Cardiovascular Disorders: Hypertension Page 1 of 42
Therapeutic Choice
Print Close
Cardiovascular Disorders: Hypertension
Date Prepared: November 2010
Norm R.C. Campbell, MD, FRCPC
Paul Gibson, MD, FRCPC
Ross T. Tsuyuki, PharmD, MSc, FCSHP, FACC
Goals of Therapy
Reduce the risk of premature cardiac, cerebrovascular and renal morbidity and mortality
Achieve blood pressure targets in treated patients. The targets presented in Table 1 are maximums; thus, the desired systolic
blood pressure (SBP) and diastolic blood pressure (DBP) values are below these thresholds.
Table 1: Blood Pressure Targets in Treated Patients1
Setting Target SBP/DBP (mm Hg)
Homea <135/85
Office
General patient population <140/90
Isolated systolic hypertension SBP <140
Diabetes mellitus <130/80
Chronic kidney disease <130/80
a. Measured by a validated home blood pressure monitor.
Adapted with permission from Canadian Hypertension Education Program.
Abbreviations: DBP=diastolic blood pressure; SBP=systolic blood pressure
Investigations
History:
duration of hypertension, usual level of blood pressure and any sudden change in severity of hypertension
history of antihypertensive drug use, reason for changing therapy, effectiveness, side effects and intolerance
drugs that may cause hypertension (Table 2)
drugs that may interact with antihypertensive drugs (those that induce or inhibit metabolism)
adherence with lifestyle recommendations and drug therapy
family history of hypertension, cardiovascular risk factors and premature cardiovascular disease
personal history of cigarette and alcohol use, usual physical activity, usual diet and sodium intake, current weight and
recent weight change, waist circumference, diabetes and dyslipidemia
cerebrovascular, cardiac and peripheral vascular symptoms to assess for target organ damage
symptoms of secondary hypertension, which include, for example, pheochromocytoma (hyperadrenergic symptoms), hyper-
and hypothyroidism, Cushing’s syndrome, renal/urinary symptoms or a past history of renal disease
Table 2: Drugs and Other Exogenous Factors That Can Induce or Aggravate Hypertension
Drugs/Substances Alcohol (excessive use)
Calcineurin inhibitors, e.g., cyclosporine, tacrolimus
Corticosteroids and anabolic steroids
Erythropoietin and analogues
Licorice root
Midodrine
Monoamine oxidase inhibitors
NSAIDs including “coxibs” (celecoxib)
Oral contraceptive and sex hormones
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Therapeutic Choice
Stimulants, including cocaine
Vasoconstricting, sympathomimetic decongestants
Venlafaxine (dose ≥300 mg/day)
Other Factors High salt (sodium) intake
Sleep apnea
Adapted with permission from Canadian Hypertension Education Program. 2010 Hypertension
Recommendations for the Management of Hypertension.
Diagnosis:1
the diagnosis of hypertension is immediate in the case of hypertensive emergencies and urgencies. This includes patients
with hypertension that is compromising vital organ function (encephalopathy, cardiac, or rapidly decreasing renal function),
hypertension and a major artery dissection, or those with DBP ≥130 mm Hg
hypertension may be diagnosed in 2 office visits if the blood pressure averages ≥180/110, or ≥140/90 mm Hg in the
presence of diabetes, renal disease, atherosclerotic cardiovascular disease or cerebrovascular disease
the diagnosis may be arrived at after 2 visits if home pressure measurement or ambulatory blood pressure measurement is
used
the diagnosis may require 3 visits if the blood pressure averages ≥160/100 mm Hg. However, 5 or more visits may be
required to establish the diagnosis if the initial blood pressure average is <160/100 mm Hg and there is no target organ
dysfunction. Attention to the details of measuring blood pressure is essential to making a correct diagnosis.1 Automated
blood pressure measurements (using an approved monitor) in the office is recommended.
home measurement of blood pressure can aid in the diagnosis of hypertension, identify white coat and masked
hypertension, improve blood pressure control and improve medication adherence in poorly adherent patients
Table 3: Hypertensive Patients Requiring Additional Laboratory Testing1
If these characteristics are present: Check for:
• High serum creatinine (high normal in the elderly) Renal disease
• Urinary albumin Diabetes, renal

disease
Two or more of: Renovascular disease

• Sudden onset or worsening of hypertension in patients aged >55 or <30 y
• Abdominal bruit
• Uncontrolled hypertension despite use of ≥3 drugs
• Decreased renal function associated with use of an ACE inhibitor or ARB
• Overt atherosclerotic vascular disease
• Recurrent episodes of hypertension and flash pulmonary edema
• Paroxysmal and/or severe sustained hypertension refractory to usual antihypertensive therapy Pheochromocytoma
• Hypertension and symptoms suggestive of catecholamine excess (2 or more of headaches,
palpitations, sweating, etc.)
• Hypertension triggered by beta-blockers, monoamine oxidase inhibitors, micturition or changes in
abdominal pressure
• Incidentally discovered adrenal adenoma
• MEN 2A or 2B; von Recklinghausen’s neurofibromatosis or von Hippel-Lindau disease
• Spontaneous hypokalemia Hyperaldosteronism

• Profound diuretic-induced hypokalemia (K+ <3 mmol/L)
• Hypertension refractory to treatment with ≥3 drugs
• Incidental adrenal adenoma
Abbreviations: ARB=angiotensin receptor blocker; MEN=multiple endocrine neoplasia
Physical exam:
fundi for hypertensive retinopathy
bruits and peripheral pulses for vascular disease and renovascular hypertension
edema and lung fields for signs of heart failure
heart sounds (4th heart sound), sustained and displaced apex for left ventricular hypertrophy
abdominal mass for polycystic kidneys and aortic aneurysm
neurologic exam for cerebrovascular disease
Initial laboratory testing:
serum potassium, sodium and creatinine
urinalysis
fasting glucose, total cholesterol, HDL-C, LDL-C, triglycerides
standard 12-lead ECG
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Therapeutic Choice
select patients should have additional testing (Table 3)
Therapeutic Choices
All individuals should be advised about a healthy lifestyle to prevent or control hypertension and cardiovascular disease (Table 4).
Table 4: Effect of Lifestyle Changes on Blood Pressure in Adults with Hypertension
Intervention Change in Blood Pressure (systolic/diastolic) mm Hg
Reduction in sodium intake ↓ by 1800 mg (78 mmol) per day −5.8/−2.5
Weight loss 4.5 kg −7.2/−5.9
Reduction in alcohol intake ↓ by 2.7 drinks/day −4.6/−2.3
Exercise 3 times/week −10.3/−7.5
Dietary recommendations DASH dieta −11.4/−5.5
a. Available from: www.nhlbi.nih.gov/health/public/heart/hbp/dash/new_dash.pdf .
Adapted with permission from Campbell N. Canadian Hypertension Education

Program. Brief overview of 2004 recommendations. Can Fam Physician 2004;50:1411-5.
Weight loss of 4 kg or more if overweight (target body mass index: 18.5 to 24.9 kg/m2; waist circumference <102 cm in men
and <88 cm in women).
Healthy diet—high in fresh fruits, vegetables, soluble fibre and low-fat dairy products, low in saturated fats and sodium, e.g.,
DASH diet available at www.nhlbi.nih.gov/health/public/heart/hbp/dash/new_dash.pdf.
Sodium intake of 1500 mg (65 mmol) per day for those aged 19–50 years, 1300 mg (56 mmol) per day for those aged 51–70
years and 1200 mg (52 mmol) per day in those 71 years and older.
Regular, moderate intensity cardiorespiratory physical activity for 30–60 minutes on most days.
Low risk alcohol consumption (0 to 2 drinks/day, < 9 drinks/week for women and < 14 drinks/week for men).
Smoke-free environment.
Pharmacologic Choices1 (Table 6)
If the average SBP/DBP is 140–159/90–99 mm Hg, treatment is recommended in the presence of either:
hypertensive target organ damage or
other independent risk factors for cardiovascular disease, e.g., cigarette smoking, dyslipidemia, strong family history of
premature cardiovascular disease, truncal obesity, sedentary lifestyle, males older than 55 years, females older than 60 years.
More than 90% of patients with hypertension have other cardiovascular risks or overt cardiovascular disease so pharmacologic
therapy is almost always recommended.2
If the average SBP/DBP is 140–159/90– 99 mm Hg and the individual does not have additional risk factors, the short-term benefits
of pharmacotherapy are small; discuss the risks and benefits of therapy with the patient. Monitor blood pressure and other risk
factors regardless of whether such a patient chooses to begin drug therapy as generally the risks accumulate and blood pressure
increases over time.
Consider low-dose ASA in patients over age 50 once blood pressure is controlled. Consider therapy for dyslipidemia if the patient
meets the current Canadian criteria (see Cardiovascular Disorders: Dyslipidemias).
In general, the reduction in cardiovascular risk depends more on the extent of the reduction in blood pressure than on the specific
blood pressure medication. Pharmacologic therapy should usually be started with a low dose of the initial drug. Consider concurrent
risk factors and disease states when selecting initial therapy (Table 5). Dose titration to achieve goal blood pressure should be done
every 4–8 weeks for all but those with severe hypertension or target organ damage or high cardiovascular risk, for whom closer
follow-up and more frequent dosage titration is required. Lack of control over blood pressure is in most cases due to a failure to up-
titrate therapy (adding drugs and/or increasing doses) in response to high office readings. Greater confidence in office readings can
result from supplementing with home blood pressure measurements or ambulatory 24-hour monitors. Generally, high office readings
should trigger a dosage increase, addition of another medication, investigations to identify the cause of the high readings or a
follow-up appointment within 2–8 weeks to reassess blood pressure.
Diuretics
Diuretics are first-line therapy for uncomplicated hypertension. They are inexpensive and well tolerated, and extensive evidence
supports their efficacy. Therefore, low-dose thiazide or related diuretics (e.g., indapamide) should generally be selected first, unless
there are specific indications for other drugs (see Table 5). Diuretics have proven antihypertensive effectiveness in patients with
isolated systolic hypertension, the elderly and black patients.
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Therapeutic Choice
Diuretics can cause hypokalemia that may be associated with adverse cardiovascular outcomes. Consider alternative first-line agents
in those with or strongly predisposed to a serious arrhythmia, for example, prolonged QT syndrome. Consider using a combination
product to minimize the risk of hypokalemia (hydrochlorothiazide plus a potassium-sparing diuretic—spironolactone, amiloride or
triamterene). Reserve the use of high doses (e.g., >25 mg/day of hydrochlorothiazide) for patients with resistant hypertension
unresponsive to treatment with multiple drugs or secondary to renal impairment. Consider using a loop diuretic in patients with
renal impairment. Diuretics may worsen dysglycemia, although cardiovascular outcomes in patients with diabetes who are treated
with diuretics are similar to those treated with ACE inhibitors.3
Beta-blockers
Beta-blockers are first-line therapy in patients who are younger than 60 years, or who have stable angina, heart failure or a history
of myocardial infarction. Beta-blockers are also useful in patients who have migraine headaches, tachycardia or essential tremor.
However, beta-blockers are not as effective as angiotensin II receptor blockers (ARBs), calcium channel blockers (CCBs) or diuretics
as initial therapy for primary prevention of cardiovascular events in patients over the age of 60 years. In addition, they may be
ineffective in preventing cardiovascular events in people who smoke.4
Drugs that Act via the Renin Angiotensin Aldosterone System (RAAS)
The renin angiotensin aldosterone system (RAAS) plays a crucial role in modulating blood pressure, kidney function, electrolyte
balance and vascular and cardiac structure. Drugs that act directly on this system include angiotensin converting enzyme (ACE)
inhibitors, angiotensin receptor antagonists, direct renin inhibitors and spironolactone. Antihypertensive drugs that stimulate the
RAAS axis (e.g., diuretics) are as effective as those that block this system in preventing cardiovascular events in patients with
hypertension. However, some inhibitors of the RAAS do provide additional benefits in certain patients, including those with heart
failure, diabetes and/or chronic kidney disease. ACE inhibitors, ARBs and direct renin inhibitors are contraindicated in pregnant
women.5 , 6 , 7 Thus drugs from these classes should not be prescribed in women of child-bearing potential unless the risks are
carefully weighed and adequate measures are taken to prevent pregnancy (see Choices during Pregnancy and Breastfeeding).
Angiotensin Converting Enzyme Inhibitors
Angiotensin converting enzyme (ACE) inhibitors are first-line agents for non-black patients with uncomplicated hypertension and for
patients with diabetes, ischemic heart disease, recent myocardial infarction, heart failure or chronic kidney disease.
Angiotensin II Receptor Blockers
ARBs are first-line agents for patients with uncomplicated hypertension, for patients with diabetes or ischemic heart disease. They
are good alternatives to ACE inhibitors when the latter are specifically indicated but not tolerated.
Direct Renin Inhibitors
Aliskiren, the first direct renin inhibitor, prevents renin from converting angiotensinogen to angiotensin I. The drug has a long
duration of action and lowers blood pressure to the same extent as drugs from other antihypertensive classes. Until data become
available on the effect of aliskiren on cardiovascular events the drug should be used only when first-line therapies cannot be used.
Long-acting Calcium Channel Blockers
Long-acting dihydropyridine CCBs can be used as first-line agents but in practice they are generally used in combination therapy.
Short-acting formulations of these agents have caused an increase in cardiovascular events in randomized controlled trials and should
not be used. Elderly patients with isolated systolic hypertension and black patients are particularly responsive to CCBs.
Other Antihypertensive Drugs
In general, other classes of antihypertensive drugs should not be prescribed unless there are specific indications (Table 5),
contraindications or intolerance to first-line therapy, or a requirement for additional blood pressure lowering in combination with
first-line antihypertensive drugs.
Combination Therapy
About 50% of patients will require more than one antihypertensive agent to achieve blood pressure targets. If the goal blood
pressure is not achieved with moderate doses of a suitable first-line drug, add, rather than substitute, a second drug. Combining
drugs has a 5-fold better blood pressure lowering efficacy than a dose increase.8 In high-risk patients (hypertension with diabetes
or known cardiovascular disease) an ACE inhibitor (benazapril) with amlodipine was superior to an ACE inhibitor with a diuretic at
preventing cardiovascular events. The Canadian Hypertension Education Program (CHEP) recommends consideration of the ACE
inhibitor with amlodipine in high-risk patients whose blood pressure requires 2 or more medications for control.9 CHEP recommends
initiating therapy with a combination of 2 first-line agents if a patient's SBP is ≥20 or DBP is ≥10 mm Hg above the recommended
target.10 Use of a diuretic is desirable in combination with all other drug classes. In contrast, any combination of a beta-blocker,
ACE inhibitor and/or an ARB has less than additive antihypertensive effects when combined in a 2-drug regimen. These
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Therapeutic Choice
combinations should be avoided unless there is a specific indication, for example, use of an ACE inhibitor and a beta-blocker in
post-myocardial infarction patients or in those with heart failure (Table 5). All possible combinations of first-line agents are
rational choices to lower blood pressure when 3 or 4 drugs are required, with the exception of the simultaneous
prescription of ACE inhibitors and ARBs. A combination of ACE inhibitor plus ARB may further lower blood pressure
but is associated with more adverse effects (e.g., hyperkalemia, renal impairment) and no clear benefit in terms of
cardiovascular events.11 This combination is generally not recommended for the treatment of hypertension, though it
may be appropriate in some medical circumstances such as refractory heart failure. Useful Info?
Adherence
Medication adherence should be assessed at each visit. Poor adherence to therapy is a major cause of poor blood pressure control
and is indicated by:
Admitting poor adherence when questioned in a nonthreatening manner

Failure to keep scheduled appointments
Poor blood pressure control
Lack of secondary physiologic effects, e.g., decreased heart rate on beta-blocker
Failure to renew prescriptions on time
Lack of awareness of usual pill-taking routine and prescriptions
Poor adherence can be prevented. Routine care should include the following:
Ensure patients are well informed about hypertension and its treatment, preferably verbally and with patient information
pamphlets (available at www.hypertension.ca in the General Public section)
Include family or social support in lifestyle modification
Use a simplified regimen of long-acting, once-daily drugs, and use tablets that contain 2 drugs in combination when appropriate
Ensure the patient can afford the prescribed drugs
Advise the patient to establish a daily routine for pill-taking, e.g., putting their pills by their toothbrush and taking them every
morning prior to brushing
Treat poor adherence:
Determine the reason for poor adherence and tailor advice or interventions to the cause
Increase the frequency of office visits
Advise use of adherence-enhancing medication dispensers, e.g., Dosette
Advise self-measurement of blood pressure
Consider assessing adherence with an electronic pill dispenser
Advise home-monitoring of adherence with pill counts and marking on a calendar when the prescription needs renewing
Consider regular telephone contact with the patient if feasible
Resistant Hypertension
Many patients with hypertension require multiple drugs for blood pressure control. In those with resistant hypertension, investigate
for a white coat effect, secondary hypertension, renal dysfunction, poor adherence, and in those with a poor response to an
adequate combination of medications, consider the possibility of an “interfering lifestyle.” Refer (to a hypertension specialist,
nephrologist or internist) those who do not achieve blood pressure targets with medication regimens you feel comfortable
prescribing.
Hypertensive Emergencies
It is uncommon for elevated blood pressure alone, without new or progressive target organ damage, to require emergency therapy.
Refer true hypertensive emergencies to experienced centres with facilities to continuously monitor blood pressure. In stabilizing
patients for transfer, the use of intermediate-acting drugs (e.g., felodipine) with close blood pressure monitoring is generally safer
than using short-acting drugs that can rapidly produce hypotension with complications.
Choices during Pregnancy and Breastfeeding
Inform women with pre-existing hypertension who are of child-bearing potential, particularly those who are considering pregnancy,
that they are at an increased risk for adverse pregnancy outcomes including: intrauterine growth restriction; placental abruption;
preterm delivery and the attendant neonatal risks of prematurity; and particularly a heightened risk of preeclampsia, with a crude
risk of about 10% (varying with the severity and duration of the pre-existing hypertension). Enhanced surveillance is required
during pregnancy to monitor for these complications. Prior to conception, or immediately upon recognition of an unplanned
pregnancy, review the choice of antihypertensive medication for these women.
While there remains a dearth of high quality data on the effects of many common antihypertensive medications on the developing
fetus, international guidelines 12 , 13 , 14 have reached some consensus regarding a list of “preferred” medications for use in
pregnancy, as well as a few “avoid” and “must avoid” drugs. Medications widely considered “first-line” for the management of
hypertension in pregnancy include: methyldopa (250 mg BID to 1000 mg TID), labetalol (100 mg BID to 800 mg TID) and
nifedipine XL (30 mg OD to 60 mg BID). These medications are preferred as they have evidence and/or a strong clinical record of
safe and effective use in pregnancy,15 , 16 as well as an absence of demonstrated adverse effects on subsequent neonatal and
childhood development. Other antihypertensive medications considered appropriate for use in pregnancy include clonidine,
hydralazine and other beta-blockers (oxprenolol, pindolol, propranolol, metoprolol). The data regarding the use of
nondihydropyridine calcium channel blockers 17 , 18 and alpha-blockers in pregnancy is very limited, so these agents are
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Therapeutic Choice
typically deferred or exchanged for other preferred agents.
Avoid atenolol, as its use for the treatment of hypertension in pregnancy has been associated with fetal intrauterine growth
restriction (IUGR).19 The other beta-blockers, in contrast, are only weakly associated with IUGR and have been used widely in
pregnancy for various indications. Thiazides and loop diuretics are other classes of medications which most experts caution to
avoid during pregnancy. These medications may prevent the physiologic volume expansion seen in normal pregnancy, and thereby
impair uteroplacental perfusion and fetal growth.18 Available data do not support an adverse effect on perinatal outcome,13
however, and these medications may therefore be considered or continued in women felt to have volume-dependent hypertension
(renal impairment). They should be avoided in settings in which uteroplacental perfusion is already reduced (preeclampsia or IUGR).
Spironolactone should not be used at all in pregnancy, due to its anti-androgenic effects.20
ACE inhibitors have been clearly shown to be fetotoxic when taken during the second and third trimesters,21 leading to
oligohydramnios, IUGR, fetal/neonatal renal failure and other growth effects. First trimester exposure has also been shown to lead
to teratogenic effects, mainly to the fetal cardiovascular and central nervous system.22 Discontinue these drugs prior to conception,
or immediately upon discovery of an unplanned pregnancy. The data regarding the risk of fetal harm from ARBs 23 and direct
renin inhibitors 24 are less robust (mainly animal data), but they appear to have similar harmful effects and should be avoided just
as strictly as ACE inhibitors during pregnancy.
Following the completion of a pregnancy, many women require ongoing antihypertensive therapy. The choice of antihypertensive
agent may be influenced by whether or not the woman is breastfeeding her newborn child, as all oral medications appear in breast
milk to some degree.25 Breastfeeding women may safely continue treatment with any “pregnancy-preferred” drug. Most other
antihypertensive medications may also be safely utilized, but a few choices to avoid in these women include diuretics (which may
suppress lactation), atenolol and other beta-blockers with low serum protein-binding (which concentrate in breast milk), as well as
long-acting ACE inhibitors and those for which there is little or no lactation data (ramipril, lisinopril, cilazapril and perindopril).
Most women with pre-existing hypertension, particularly those with longstanding, difficult-to-control hypertension or end-organ
damage, should be followed throughout pregnancy by a specialist in obstetrics and gynecology. These clinicians are skilled at
ongoing maternal management as well as appropriate monitoring of fetal growth and well being. Women with difficult-to-control
hypertension or other medical issues benefit from assessment and follow-up with a hypertension specialist or obstetric medicine
physician during their pregnancy.
A discussion of general principles on the use of medications in these special populations can be found in Appendix: Drug Use During
Pregnancy and Appendix: Drug Use During Breastfeeding. Other specialized reference sources are also provided in these appendices.
Therapeutic Tips
Prescribe a lower starting dose of antihypertensive drugs in elderly patients.

Recent onset of hypertension or change in blood pressure control suggests an identifiable or secondary cause, such as drugs
known to exacerbate hypertension or new onset of significant renal artery stenosis.
Many drugs ineffective as monotherapy for hypertension are effective components in a rational combination regimen.
Consider concurrent cardiovascular risk factors and disease states when prescribing therapy (Table 5)
Cardiovascular risk can vary 10-fold in persons with the same blood pressure. Assess global cardiovascular risk in all
hypertensive patients using a risk form, chart or computer program (see Cardiovascular Disorders: Dyslipidemias, Figure 2 as
an example).
Blood pressure measurements taken at home correlate better with cardiovascular outcomes than office-based measurements.26 ,
27 Recommend monitors approved by the Canadian Hypertension Society and train patients to use the proper technique. To allay
anxiety, caution patients that some variation throughout the day is normal. Patient instructions for selecting and using home
blood pressure monitors can be found in the General Public section of www.hypertension.ca.
Pharmacists and nurses can play an important role in hypertension screening, medication selection, patient education, follow-up
and adherence monitoring. Dietitians can assist patients in managing their sodium and caloric intake.
A team approach to hypertension management is more effective than usual care. In patients with hypertension and diabetes,
joint care by a family physician, community pharmacist and nurse resulted in an approximate 6 mm Hg greater reduction in SBP
over 6 months, compared with usual physician-based care.28
Table 5: Individualization of Antihypertensive Therapy1
Risk Factor/
Disease Initial Therapy Second-line Therapy Notes/Cautions
Hypertension Without Other Compelling Indications (Target SBP/DBP <140/90 mm Hg)
Diastolic +/- Thiazide diuretic, beta-blocker, Combinations of first-line drugs Beta-blockers are not
systolic ACE inhibitor, ARB or long- recommended as initial therapy in
hypertension acting CCB. patients over 60 years of age.
Consider ASA and statins in Avoid hypokalemia in those who
select patients. are prescribed diuretics as
Consider initiating therapy with monotherapy by using K+-sparing
a combination of first-line agents.
drugs if SBP is ≥20 mm Hg or ACE inhibitors are not
DBP is ≥10 mm Hg above recommended as initial therapy in
target black patients.
ACE inhibitors, ARBs and direct
renin inhibitors are teratogenic.
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Therapeutic Choice
Risk Factor/
Marked caution is required if

prescribing to women of child-
bearing potential.
Combination of an ACE inhibitor
with an ARB is not recommended.
Isolated systolic Thiazide diuretic, ARB or long- Combinations of first-line drugs See diastolic +/- systolic
hypertension acting dihydropyridine CCB. hypertension above.
without other
compelling
indications
Diabetes Mellitus (Target SBP/DBP <130/80 mm Hg)
Diabetes mellitus ACE inhibitor or ARB Add a thiazide diuretic, cardioselective If the SCr is >150 µmol/L, use a
with albuminuria beta-blocker, long-acting CCB loop diuretic rather than a low-
dose thiazide if volume control is
required.
Diabetes mellitus ACE inhibitor, ARB, long-acting Combine first-line drugs Albuminuria is defined as an
without albuminuria dihydropyridine CCB or If first-line agents are not tolerated albumin to creatinine ratio (ACR)
thiazide diuretic add a cardioselective beta-blocker >2 mg/mmol in men and >2.8
and/or a long-acting mg/mmol in women.
nondihydropyridine CCB
Cardiovascular and Cerebrovascular Disease (Target SBP/DBP <140/90 mm Hg)
Coronary Artery ACE inhibitor or ARB (except in Long-acting CCB. When combination Avoid short-acting nifedipine.
Disease low-risk patients); beta- therapy is being used for high-risk Combination of an ACE inhibitor
blocker for patients with stable patients, an ACE with an ARB is specifically not
angina inhibitor/dihydropyridine CCB is recommended.
preferred
Prior myocardial Beta-blocker and ACE inhibitor Long-acting CCB Combination of an ACE inhibitor
infarction (ARB if ACE inhibitor not with an ARB is specifically not
tolerated) recommended.
Heart failure ACE inhibitor (ARB if ACE ARB added to ACE inhibitor or Avoid nondihydropyridine CCB
inhibitor not tolerated) and hydralazine/isosorbide dinitrate (diltiazem, verapamil).
beta-blocker Thiazide or loop diuretic as additive Titrate doses of ACE inhibitors and
Spironolactone in patients with therapy ARBs to those used in clinical
NYHA class III or IV symptoms trials. Monitor serum K+ and SCr
with the combination of ACE
inhibitor and ARB.
Left ventricular Does not affect initial Combination of additional agents Hydralazine and minoxidil can
hypertrophy treatment recommendations increase left ventricular
hypertrophy.
Past stroke or TIA ACE inhibitor/diuretic Combination of additional agents Does not apply to patients with
combination acute stroke.
Blood pressure reduction reduces
recurrent cerebrovascular events in
patients with stable past
cerebrovascular disease.
with an ARB is specifically not
recommended.
Nondiabetic Chronic Kidney Disease (Target SBP/DBP <130/80 mm Hg)
Nondiabetic chronic ACE inhibitor (ARB if ACE Combinations of additional agents Avoid ACE inhibitors or ARBs in
kidney disease with inhibitor not tolerated) patients with bilateral renal artery
proteinuria diuretics as additive therapy stenosis or unilateral disease with
a solitary kidney.
Carefully monitor serum K+ and
SCr in patients on an ACE inhibitor
or an ARB.
with an ARB is specifically not
recommended in patients with
chronic kidney disease without
Page 106
Therapeutic Choice
Risk Factor/
proteinuria.
Renovascular Does not affect initial Combinations of additional agents Avoid ACE inhibitors or ARBs in
disease treatment recommendations patients with bilateral renal artery
stenosis or unilateral disease with
a solitary kidney.
Other Conditions (Target SBP/DBP <140/90 mm Hg)
Peripheral arterial Does not affect initial Combinations of additional agents Avoid beta-blockers in patients
disease treatment recommendations with severe disease.
Dyslipidemia Does not affect initial Combinations of additional agents

treatment recommendations
Overall vascular Statin therapy for patients with

protection hypertension and 3 or more
cardiovascular risk factors or
with atherosclerotic disease
Low-dose ASA in patients over Exercise caution if blood pressure

50 y with controlled blood is not controlled.
pressure
Adapted with permission from Canadian Hypertension Education Program.
Abbreviations: ACE=angiotensin converting enzyme; ARB=angiotensin II receptor blocker; CCB=calcium channel blocker; NYHA =New York
Heart Association; SCr=serum creatinine; TIA=transient ischemic attack
Table 6: Drugs for Hypertension
Adverse Costa
Class Drug Dose Effects Drug Interactions Comments
Diuretics hydrochlorothiazide Initial: Hypotension, ↓ Li + excretion Particularly $

12.5 mg/day weakness, (monitor Li + levels, effective in ISH,
Apo-Hydro, other Usual: muscle cramps, adjust dose). the elderly and
generics 25 mg/day impotence. NSAIDs ↓ black patients.
Once daily po Hypokalemia, hypotensive efficacy. Monitor SCr and
hyponatremia, K+.
hyperuricemia, Diuretic-induced
hyperglycemia, hypokalemia ↑ the Consider
hyperlipidemia. alternatives in
risk of digoxin
Rare: azotemia, patients with or
toxicity.
blood predisposed to
dyscrasias, arrhythmias.
↓ efficacy of
allergic
antihyperglycemic
reactions Can exacerbate
agents.
(potential cross gout and diabetes
sensitivity with (biochemical
other abnormalities are
sulfonamide less frequent at
derivatives), 12.5–25 mg/day).
photosensitivity,
fatigue. Ineffective in
patients with ClCr
<30 to 40 mL/min.
Diuretics chlorthalidone Initial: 12.5 Hypotension, ↓ Li + excretion Lowest available $

generics mg/day weakness, (monitor Li + levels, tablet strength is
Usual: 12.5–25 muscle cramps, adjust dose). 50 mg. Tablet (or
mg/day impotence. NSAIDs ↓ “pill”) splitters,
Hypokalemia, hypotensive efficacy. widely available in
Once daily po hyponatremia, pharmacies, can be
hyperuricemia, Diuretic-induced used to derive a
hyperglycemia, hypokalemia ↑ the dose of 12.5 mg
hyperlipidemia. (¼ tablet) with
risk of digoxin
Rare: azotemia, reasonable
toxicity.
blood accuracy.
Page 107
Therapeutic Choice
Adverse Costa
dyscrasias, Particularly
allergic ↓ efficacy of effective in ISH,
reactions antihyperglycemic the elderly and
(potential cross agents. black patients.
sensitivity with Monitor SCr and
other K+.
sulfonamide
derivatives), Consider
photosensitivity, alternatives in
fatigue. patients with or
predisposed to
arrhythmias.
Can exacerbate
gout and diabetes
(biochemical
abnormalities are
less frequent at
12.5–25 mg/day).
Ineffective in
patients with ClCr
<30 to 40 mL/min.
Diuretics indapamide Initial: Hypotension, ↓ Li + excretion Particularly $

Lozide, generics 1.25 mg/day weakness, (monitor Li + levels, effective in ISH,
Usual: muscle cramps, adjust dose). the elderly and
2.5 mg/day impotence. NSAIDs ↓ black patients.
Once daily po Hypokalemia, hypotensive efficacy. Monitor SCr and
hyponatremia, K+.
risk of digoxin
toxicity.
↓ efficacy of
allergic
antihyperglycemic
agents.
photosensitivity,
patients with ClCr
<30 to 40 mL/min.
Diuretics metolazone Initial: Hypotension, ↓ Li + excretion Particularly $

Zaroxolyn 2.5 mg/day weakness, (monitor Li + levels, effective in ISH,
Usual: muscle cramps, adjust dose). the elderly and
5 mg/day impotence. NSAIDs ↓ black patients.
Maximum: Hypokalemia, hypotensive efficacy. Monitor SCr and
10 mg/day hyponatremia, K+.
Once daily po hyperuricemia, Diuretic-induced
risk of digoxin
toxicity.
↓ efficacy of
allergic
antihyperglycemic
agents.
Page 108
Therapeutic Choice
Adverse Costa
photosensitivity,
patients with ClCr
<30 to 40 mL/min.
Metolazone is
effective in patients
with moderate to
severe renal
dysfunction.
Diuretic hydrochlorothiazide/ ½ tab/day Hypotension, ↓ Li + excretion Particularly $

Combinations amiloride (50/5) Once daily po weakness, (monitor Li + levels, effective in ISH,
generics muscle cramps, adjust dose). the elderly and
impotence. NSAIDs ↓ black patients.
Hypokalemia, hypotensive efficacy. Monitor SCr and
hyponatremia, K+.
risk of digoxin
toxicity.
↓ efficacy of
allergic
antihyperglycemic
agents.
May exacerbate ACE
inhibitor-induced
hyperkalemia.
photosensitivity,
patients with ClCr
<30 to 40 mL/min.
Lower incidence of
hypokalemia than
with
hydrochlorothiazide
alone.
Diuretic hydrochlorothiazide/ Initial: Hypotension, ↓ Li + excretion Particularly $

Combinations triamterene ½ tab/day weakness, (monitor Li + levels, effective in ISH,
(25/50) Usual: 1 tab/day muscle cramps, adjust dose). the elderly and
generics Once daily po impotence. NSAIDs ↓ black patients.
Hypokalemia, hypotensive efficacy. Monitor SCr and
hyponatremia, K+.
risk of digoxin
toxicity.
↓ efficacy of
allergic
antihyperglycemic
agents.
May exacerbate ACE
inhibitor-induced
hyperkalemia.
photosensitivity,
patients with ClCr
<30 to 40 mL/min.
Lower incidence of
hypokalemia than
with
Page 109
Therapeutic Choice
Adverse Costa
hydrochlorothiazide
alone.
Diuretic hydrochlorothiazide/ Initial: ½ Hypotension, ↓ Li + excretion Particularly $

Combinations spironolactone tab/day weakness, (monitor Li + levels, effective in ISH,
(25/25) Usual: 1 tab/day muscle cramps, adjust dose). the elderly and
Aldactazide, Once daily po impotence. NSAIDs ↓ black patients.
generics Hypokalemia, hypotensive efficacy. Monitor SCr and
hyponatremia, K+.
risk of digoxin
toxicity.
↓ efficacy of
allergic
antihyperglycemic
agents.
May exacerbate ACE
inhibitor-induced
hyperkalemia.
photosensitivity,
patients with ClCr
Gynecomastia in <30 to 40 mL/min.
men and breast
tenderness in Lower incidence of
women. hypokalemia than
with
hydrochlorothiazide
alone.
Beta1-adrenergic nadolol Initial: Fatigue, Bradycardia with Beta-blockers $

Antagonists, generics 20 mg/day bradycardia, digoxin or should not be used
nonselective Usual: decreased nondihydropyridine as initial therapy in
160 mg/day exercise CCBs. patients aged >60
Maximum: capacity, Cardiodepressant y unless
320 mg/day headache, effects with specifically
Once daily po impotence, vivid nondihydropyridine indicated.
dreams. CCBs and Avoid in patients
Less common: amiodarone. with asthma.29
hyperglycemia,
depression, Avoid abrupt
heart failure, withdrawal (may
heart block. precipitate
ischemia). Taper
the dose before
discontinuation.
Avoid in patients
with severe PAD.
Contraindicated in
patients with 2nd or
3rd degree heart
block in the
absence of a
pacemaker.
Beta1-adrenergic propranolol, Initial: Fatigue, Bradycardia with Beta-blockers $$$$

Antagonists, controlled release 80 mg/day bradycardia, digoxin or should not be used
nonselective Usual: decreased nondihydropyridine as initial therapy in
Inderal-LA
Page 110
Therapeutic Choice
Adverse Costa
SR (once daily impotence, vivid nondihydropyridine indicated.

po) formulation dreams. CCBs and Avoid in patients
recommended Less common: amiodarone. with asthma.29
hyperglycemia,
depression, CYP2D6 inhibitors ↑ Avoid abrupt
heart failure, levels of propranolol withdrawal (may
heart block. and metoprolol. precipitate
ischemia). Taper
Propranolol ↑ serum the dose before
levels of rizatriptan. discontinuation.
Avoid in patients
with severe PAD.
Contraindicated in
3rd degree heart
block in the
absence of a
pacemaker.
Propranolol is more
likely to cause CNS
side effects
(insomnia,
depression, vivid
dreams) than other
agents because of
greater lipid
solubility.
Beta1-adrenergic timolol Initial: Fatigue, Bradycardia with Beta-blockers $$

Antagonists, Apo-Timol, other 5 mg BID bradycardia, digoxin or should not be used
nonselective generics Usual: decreased nondihydropyridine as initial therapy in
20 mg BID exercise CCBs. patients aged >60
30 mg BID po headache, effects with specifically
impotence, vivid nondihydropyridine indicated.
hyperglycemia,
ischemia). Taper
the dose before
discontinuation.
Avoid in patients
with severe PAD.
Contraindicated in
3rd degree heart
block in the
absence of a
pacemaker.
Beta1-adrenergic atenolol Initial: Fatigue, Bradycardia with Beta-blockers $

Antagonists, β1- Tenormin, generics 25 mg/day bradycardia, digoxin or should not be used
Usual: decreased nondihydropyridine as initial therapy in
selective
Once daily or dreams. CCBs and Avoid in patients
BID po Less common: amiodarone. with asthma.29
hyperglycemia,
Page 111
Therapeutic Choice
Adverse Costa

ischemia). Taper
Fewer non- the dose before
cardiac effects discontinuation.
due to
cardioselectivity. Avoid in patients
with severe PAD.
Contraindicated in
3rd degree heart
block in the
absence of a
pacemaker.
Beta1-adrenergic bisoprolol Initial: Fatigue, Bradycardia with Beta-blockers $

Antagonists, β1- generics 5 mg/day bradycardia, digoxin or should not be used
Usual: decreased nondihydropyridine as initial therapy in
selective
Once daily po impotence, vivid nondihydropyridine indicated.
hyperglycemia,
ischemia). Taper
due to
with severe PAD.
Contraindicated in
3rd degree heart
block in the
absence of a
pacemaker.
Beta1-adrenergic metoprolol Initial: Fatigue, Bradycardia with Beta-blockers $

Antagonists, β1- Betaloc, Lopresor, 50 mg/day bradycardia, digoxin or should not be used
generics Usual: decreased nondihydropyridine as initial therapy in
selective
100–200 mg/day exercise CCBs. patients aged >60
capacity, Cardiodepressant y unless
Maximum: headache, effects with specifically
400 mg/day impotence, vivid nondihydropyridine indicated.
Give regular dreams. CCBs and Avoid in patients
formulations BID Less common: amiodarone. with asthma.29
po; SR hyperglycemia,
formulations depression, CYP2D6 inhibitors ↑ Avoid abrupt
once daily po heart failure, levels of propranolol withdrawal (may
heart block. and metoprolol. precipitate
ischemia). Taper
due to
with severe PAD.
Contraindicated in
3rd degree heart
Page 112
Therapeutic Choice
Adverse Costa
block in the
absence of a
pacemaker.
Beta1-adrenergic pindolol Initial: Fatigue, Bradycardia with Beta-blockers $$

Antagonists, Visken, generics 5 mg BID po bradycardia, digoxin or should not be used
nonselective with Usual: decreased nondihydropyridine as initial therapy in
intrinsic 15 mg BID po exercise CCBs. patients aged >60
sympathomimetic Maximum: capacity, Cardiodepressant y unless
activity (ISA) 60 mg/day headache, effects with specifically
hyperglycemia,
ischemia). Taper
the dose before
discontinuation.
Avoid in patients
with severe PAD.
Contraindicated in
3rd degree heart
block in the
absence of a
pacemaker.
Agents with ISA

have less effect on
resting heart rate
than those without
ISA.
Beta1-adrenergic acebutolol Initial: Fatigue, Bradycardia with Beta-blockers $

Antagonists, β1- Apo-Acebutolol, 100 mg/day bradycardia, digoxin or should not be used
Rhotral, Sectral, Usual: decreased nondihydropyridine as initial therapy in
selective with ISA
other generics 400 mg/day exercise CCBs. patients aged >60
Once daily or impotence, vivid nondihydropyridine indicated.
BID po dreams. CCBs and Avoid in patients
hyperglycemia,
ischemia). Taper
due to
with severe PAD.
Contraindicated in
3rd degree heart
block in the
absence of a
pacemaker.
Agents with ISA

have less effect on
resting heart rate
than those without
ISA.
Page 113
Therapeutic Choice
Adverse Costa
Beta1-adrenergic labetalol Initial: Fatigue, Bradycardia with Beta-blockers $$

Antagonists with Trandate, generics 50 mg BID po bradycardia, digoxin or should not be used
alpha1-blocking Usual: decreased nondihydropyridine as initial therapy in
200 mg BID po exercise CCBs. patients aged >60
activity
hyperglycemia,
ischemia). Taper
Edema, the dose before
dizziness and discontinuation.
nasal congestion
and postural Avoid in patients
hypotension due with severe PAD.
to alpha1
antagonism. Contraindicated in
3rd degree heart
block in the
absence of a
pacemaker.
ACE Inhibitors benazepril Initial: Dry cough, Marked ↑ in serum Contraindicated $$

Lotensin, generics 10 mg/day hyperkalemia. K+ in patients in pregnancy—
Usual: Unusual: receiving K+ caution when
20 mg/day angioedema. supplements and/or prescribing to
Maximum: Can precipitate women of child-
K+-sparing diuretics.
40 mg/day renal failure in bearing
↓ hypotensive effect
Once daily or renovascular
with NSAIDs and ↑ potential. 5 , 6
BID po disease, volume Use lower (50%)
risk of renal
depletion or initial doses if on
those receiving dysfunction.
diuretics (↑ risk of
NSAIDs. hypotension with
Elevated Li + levels
hypovolemia).
(potential toxicity).
Hyperkalemia
usually occurs only
in those on K+
supplements or
drugs that cause
K+ retention, those
with renal
impairment or
diabetics with high
serum K+ levels.
Assess SCr and K+
after a few days,
then regularly.
ACE Inhibitors captopril Initial: Dry cough, Marked ↑ in serum Contraindicated $$

Capoten, generics 25 mg/day hyperkalemia. K+ in patients in pregnancy—
Divide BID or renovascular
TID po disease, volume Use lower (50%)
depletion or risk of renal
initial doses if on
dysfunction.
those receiving diuretics (↑ risk of
hypovolemia).
Hyperkalemia
Page 114
Therapeutic Choice
Adverse Costa
usually occurs only

in those on K+
supplements or
drugs that cause
K+ retention, those
with renal
impairment or
diabetics with high
serum K+ levels.
Assess SCr and K+
after a few days,
then regularly.
ACE Inhibitors cilazapril Initial: Dry cough, Marked ↑ in serum Contraindicated $$

Inhibace, generics 2.5 mg/day hyperkalemia. K+ in patients in pregnancy—
2.5–5 mg/day angioedema. supplements and/or prescribing to
risk of renal
hypovolemia).
Hyperkalemia
usually occurs only
in those on K+
supplements or
drugs that cause
K+ retention, those
with renal
impairment or
diabetics with high
serum K+ levels.
Assess SCr and K+
after a few days,
then regularly.
ACE Inhibitors enalapril Initial: Dry cough, Marked ↑ in serum Contraindicated $$-
Vasotec, generics 5 mg/day hyperkalemia. K+ in patients in pregnancy— $$$
10–40 mg/day angioedema. supplements and/or prescribing to
initial doses if on
dysfunction.
hypovolemia).
Hyperkalemia
usually occurs only
in those on K+
supplements or
drugs that cause
K+ retention, those
with renal
impairment or
diabetics with high
serum K+ levels.
Assess SCr and K+
after a few days,
then regularly.
Page 115
Therapeutic Choice
Adverse Costa
ACE Inhibitors fosinopril Initial: Dry cough, Marked ↑ in serum Contraindicated $

Monopril, generics 10 mg/day hyperkalemia. K+ in patients in pregnancy—
40 mg/day Once renal failure in bearing
daily or BID po renovascular
disease, volume Use lower (50%)
initial doses if on
hypovolemia).
Hyperkalemia
usually occurs only
in those on K+
supplements or
drugs that cause
K+ retention, those
with renal
impairment or
diabetics with high
serum K+ levels.
Assess SCr and K+
after a few days,
then regularly.
ACE Inhibitors lisinopril Initial: Dry cough, Marked ↑ in serum Contraindicated $

Prinivil, Zestril, 10 mg/day hyperkalemia. K+ in patients in pregnancy—
generics Usual: Unusual: receiving K+ caution when
Once daily po renovascular
initial doses if on
hypovolemia).
Hyperkalemia
usually occurs only
in those on K+
supplements or
drugs that cause
K+ retention, those
with renal
impairment or
diabetics with high
serum K+ levels.
Assess SCr and K+
after a few days,
then regularly.
ACE Inhibitors perindopril Initial: Dry cough, Marked ↑ in serum Contraindicated $$-
Coversyl, generics 4 mg/day hyperkalemia. K+ in patients in pregnancy— $$$
Maximum: Unusual: receiving K+ caution when
Once daily or Can precipitate women of child-
BID po renal failure in bearing
renovascular
initial doses if on
dysfunction.
hypovolemia).
Hyperkalemia
usually occurs only
in those on K+
Page 116
Therapeutic Choice
Adverse Costa
supplements or
drugs that cause
K+ retention, those
with renal
impairment or
diabetics with high
serum K+ levels.
Assess SCr and K+
after a few days,
then regularly.
ACE Inhibitors quinapril Initial: Dry cough, Marked ↑ in serum Contraindicated $$

Accupril 10 mg/day hyperkalemia. K+ in patients in pregnancy—
BID po renal failure in bearing
renovascular
risk of renal
hypovolemia).
Hyperkalemia
usually occurs only
in those on K+
supplements or
drugs that cause
K+ retention, those
with renal
impairment or
diabetics with high
serum K+ levels.
Assess SCr and K+
after a few days,
then regularly.
ACE Inhibitors ramipril Initial: Dry cough, Marked ↑ in serum Contraindicated $

Altace, generics 2.5 mg/day hyperkalemia. K+ in patients in pregnancy—
initial doses if on
dysfunction.
hypovolemia).
Hyperkalemia
usually occurs only
in those on K+
supplements or
drugs that cause
K+ retention, those
with renal
impairment or
diabetics with high
serum K+ levels.
Assess SCr and K+
after a few days,
then regularly.
ACE Inhibitors trandolapril Initial: Dry cough, Marked ↑ in serum Contraindicated $$

Mavik 1 mg/day hyperkalemia. K+ in patients in pregnancy—
Page 117
Therapeutic Choice
Adverse Costa

Once daily po Can precipitate K+-sparing diuretics. women of child-
renal failure in ↓ hypotensive effect bearing
renovascular with NSAIDs and ↑ potential. 5 , 6
disease, volume risk of renal Use lower (50%)
depletion or dysfunction. initial doses if on
(potential toxicity). hypovolemia).
Hyperkalemia
usually occurs only
in those on K+
supplements or
drugs that cause
K+ retention, those
with renal
impairment or
diabetics with high
serum K+ levels.
Assess SCr and K+
after a few days,
then regularly.
Angiotensin candesartan Initial: Hyperkalemia. Marked ↑ in serum Contraindicated $$

Receptor Blockers Atacand 8 mg/day Can precipitate K+ in patients in pregnancy—
(ARB) Usual: renal failure in receiving K+ caution when
8–16 mg/day susceptible supplements and/or prescribing to
Once daily po patients women of child-
(bilateral bearing
May elevate Li +
renovascular potential. 7
disease, those levels (monitor Li + Use lower initial
with volume levels, adjust dose). doses in patients
depletion or who are volume
with concurrent depleted or on
NSAID use). diuretics (↑ risk of
hypotension in
Angioedema has hypovolemia).
been reported,
but a causal Hyperkalemia
association has usually occurs only
not been in those on K+
established. supplements or
drugs that cause
K+ retention, those
with renal
impairment or
diabetics with high
serum K+ levels.
Assess SCr and K+
after a few days,
then regularly.
Angiotensin eprosartan Initial: Hyperkalemia. Marked ↑ in serum Contraindicated $$

Receptor Blockers Teveten 600 mg/day Can precipitate K+ in patients in pregnancy—
(ARB) Maximum: renal failure in receiving K+ caution when
800 mg/day susceptible supplements and/or prescribing to
Once daily or patients women of child-
BID po (bilateral bearing
May elevate Li +
hypotension in
Page 118
Therapeutic Choice
Adverse Costa
been reported,
drugs that cause
K+ retention, those
with renal
impairment or
diabetics with high
serum K+ levels.
Assess SCr and K+
after a few days,
then regularly.
Angiotensin irbesartan Initial: Hyperkalemia. Marked ↑ in serum Contraindicated $$

Receptor Blockers Avapro 150 mg/day Can precipitate K+ in patients in pregnancy—
(bilateral bearing
May elevate Li +
hypotension in
been reported,
drugs that cause
K+ retention, those
with renal
impairment or
diabetics with high
serum K+ levels.
Assess SCr and K+
after a few days,
then regularly.
Angiotensin losartan Initial: Hyperkalemia. Marked ↑ in serum Contraindicated $$

Receptor Blockers Cozaar 50 mg/day Can precipitate K+ in patients in pregnancy—
Maximum: patients women of child-
100 mg/day (bilateral bearing
May elevate Li +
Once daily or renovascular potential. 7
BID po disease, those levels (monitor Li + Use lower initial
hypotension in
been reported,
drugs that cause
K+ retention, those
with renal
impairment or
Page 119
Therapeutic Choice
Adverse Costa
diabetics with high

serum K+ levels.
Assess SCr and K+
after a few days,
then regularly.
Angiotensin olmesartan Initial: Hyperkalemia. Marked ↑ in serum Contraindicated $$

Receptor Blockers Olmetec 20 mg/day Can precipitate K+ in patients in pregnancy—
(ARB) Maximum: renal failure in receiving K+ caution when
(bilateral bearing
May elevate Li +
hypotension in
been reported,
drugs that cause
K+ retention, those
with renal
impairment or
diabetics with high
serum K+ levels.
Assess SCr and K+
after a few days,
then regularly.
Angiotensin telmisartan Initial: Hyperkalemia. Marked ↑ in serum Contraindicated $$

Receptor Blockers Micardis 80 mg/day Can precipitate K+ in patients in pregnancy—
(bilateral bearing
May elevate Li +
hypotension in
been reported,
drugs that cause
K+ retention, those
with renal
impairment or
diabetics with high
serum K+ levels.
Assess SCr and K+
after a few days,
then regularly.
Angiotensin valsartan Initial: Hyperkalemia. Marked ↑ in serum Contraindicated $$
Page 120
Therapeutic Choice
Adverse Costa
Receptor Blockers Diovan 80 mg/day Can precipitate K+ in patients in pregnancy—

(bilateral bearing
May elevate Li +
hypotension in
been reported,
drugs that cause
K+ retention, those
with renal
impairment or
diabetics with high
serum K+ levels.
Assess SCr and K+
after a few days,
then regularly.
Direct Renin aliskiren Initial: Diarrhea. The Low potential for May take 4 wk to $$
Inhibitors Rasilez 150 mg/day incidence of dry drug interactions. realize maximum
Maximum: cough and antihypertensive
300 mg/day hyperkalemia is effect.
Once daily po low compared Effect on
with ACE cardiovascular
inhibitors. outcomes not yet
established.
Limited data in
patients with
greater than
moderate renal
dysfunction.
Avoid use in
pregnancy.
Calcium Channel amlodipine Initial: Ankle edema, CYP3A4 substrate $$

Blockers, Norvasc, generics 2.5 mg/day flushing, (many potential
dihydropyridine Maximum: headache and interactions).
10 mg/day palpitations. Strong inhibitors
Once daily po include azole
antifungals, protease
inhibitors,
macrolides and
quinidine.
Grapefruit juice may

↑ serum
concentrations.
Calcium Channel felodipine Initial: Ankle edema, CYP3A4 substrate Grapefruit juice $$
Blockers, Plendil, Renedil, 2.5 mg/day flushing, (many potential causes marked
dihydropyridine generics Usual: headache and interactions). elevations in
10 mg/day palpitations. Strong inhibitors felodipine serum
Maximum: include azole levels and adverse
20 mg/day antifungals, protease events.
Page 121
Therapeutic Choice
Adverse Costa
Once daily po inhibitors,

macrolides and
quinidine.

↑ serum
concentrations.
Calcium Channel nifedipine XL Initial: Ankle edema, CYP3A4 substrate Do not use short- $$
Blockers, Adalat XL, generics 30 mg/day flushing, (many potential acting nifedipine
dihydropyridine Usual: headache and interactions). formulations for
60 mg/day palpitations. Strong inhibitors treatment of
Maximum: include azole essential
120 mg/day antifungals, protease hypertension.
Once daily po inhibitors,
macrolides and
quinidine.

↑ serum
concentrations.
Calcium Channel diltiazem Initial: Headache, CYP3A4 substrate Caution in patients $$

Blockers, Cardizem CD, Tiazac, 120 mg/day dizziness, (many potential with heart failure,
nondihydropyridine
Tiazac XC, generics
Usual: bradycardia, interactions). or 2nd or 3rd
240–360 mg/day heart block, new Strong inhibitors degree heart block
onset or include azole without a
Maximum: worsening of antifungals, protease functioning
360 mg/day heart failure. inhibitors, pacemaker.
Give CD or XC macrolides and
formulation once quinidine.
daily po, SR
formulation BID Grapefruit juice may
po ↑ serum
concentrations.
Nondihydropyridines
inhibit the
metabolism of
carbamazepine,
cyclosporine,
lovastatin,
simvastatin.
Rifampin induces
metabolism of
nondihydropyridines.
Additive negative
inotropic effects with
amiodarone, beta-
blockers and
digoxin.
Calcium Channel verapamil Initial: Headache, CYP3A4 substrate Caution in patients $$-
Blockers, Isoptin SR, generics 80 mg TID po dizziness, (many potential with heart failure, $$$
nondihydropyridine Maximum: bradycardia, interactions). or 2nd or 3rd
160 mg TID po heart block, new Strong inhibitors degree heart block
onset or include azole without a
worsening of antifungals, protease functioning
SR (once daily heart failure. inhibitors, pacemaker.
or BID po): Constipation. macrolides and
Initial: 180 quinidine.
mg/day; Usual:
180–480 Grapefruit juice may
mg/day; ↑ serum
Maximum: 480 concentrations.
mg/day
Page 122
Therapeutic Choice
Adverse Costa
Nondihydropyridines
inhibit the
metabolism of
carbamazepine,
cyclosporine,
lovastatin,
simvastatin.
Rifampin induces
metabolism of
Additive negative
amiodarone, beta-
blockers and
digoxin.
Verapamil ↑ digoxin
levels by 50–75%
within 1 wk (monitor
levels).
Centrally Acting methyldopa Initial: Drowsiness, dry Iron salts ↓ Positive Coombs’ $$
Antihypertensive generics 500 mg/day mouth, nasal absorption (separate test is common,
Agents Usual: congestion, administration). but usually
2000 mg/day depression, Additive hypotension unimportant;
Maximum: orthostatic with levodopa. hemolytic anemia
3000 mg/day hypotension, is rare.
Divide BID or palpitations, May exacerbate Li + Drug fever with or
TID po sexual adverse events without an
dysfunction, without increasing influenza-like
sodium and Li + levels. illness; hepatic
water retention. disorders have
occurred.
Alpha1-adrenergic doxazosin Initial: Orthostatic Caution when adding Not for initial $
Antagonists Cardura, generics 1 mg/day hypotension, other hypotensive therapy.
Usual: headache, drugs, may cause
1–8 mg/day drowsiness, syncope.
Maximum: palpitations,
16 mg/day nasal
Once daily po congestion.
Syncope usually
occurs at the
start of therapy,
with rapid dose
titration or on
addition of other
agents. Titrate
slowly. If
interrupted for
several days
restart at initial
dose.
Alpha1-adrenergic prazosin Initial: Orthostatic Caution when adding Not for initial $-$$
Antagonists Apo-Prazo, other 0.5 mg with hypotension, other hypotensive therapy.
generics p.m. meal headache, drugs, may cause
(day 1), then drowsiness, syncope.
0.5 mg BID-TID palpitations,
po × 3 days nasal
Maximum: congestion.
20 mg/day Syncope usually
occurs at the
start of therapy,
with rapid dose
titration or on
addition of other
agents. Titrate
Page 123
Therapeutic Choice
Adverse Costa
slowly. If
interrupted for
several days
restart at initial
dose.
Alpha1-adrenergic terazosin Initial: Orthostatic Caution when adding Not for initial $
Antagonists Hytrin, generics 1 mg QHS po hypotension, other hypotensive therapy.
Usual: headache, drugs, may cause
1–5 mg/day drowsiness, syncope.
Maximum: palpitations, Verapamil ↑ serum
20 mg/day nasal concentrations of
Once daily or congestion. terazosin.
BID po Syncope usually
occurs at the
start of therapy,
with rapid dose
titration or on
addition of other
agents. Titrate
slowly. If
interrupted for
several days
restart at initial
dose.
Beta1-adrenergic atenolol/ 50/25 mg, or Fatigue, Bradycardia with Beta-blockers $

Antagonist/ chlorthalidone 100/25 mg once bradycardia, digoxin or should not be used
Diuretic Tenoretic, generics daily pob decreased nondihydropyridine as initial therapy in
Combinations exercise CCBs. patients aged >60
headache, effects with specifically
hyperglycemia,
depression, ↓ Li + excretion Avoid abrupt
heart failure, (monitor Li + levels, withdrawal (may
heart block. adjust dose). precipitate
NSAIDs ↓ ischemia). Taper
Hypotension, hypotensive efficacy. the dose before
weakness, discontinuation.
muscle cramps, Diuretic-induced
impotence. hypokalemia ↑ the Avoid in patients
Hypokalemia, risk of digoxin with severe PAD.
hyponatremia, toxicity.
hyperuricemia, Contraindicated in
hyperglycemia, ↓ efficacy of patients with 2nd or
hyperlipidemia.
antihyperglycemic 3rd degree heart
Rare: azotemia,
agents. block in the
blood
absence of a
dyscrasias,
pacemaker.
allergic
reactions
Particularly
(potential cross
effective in ISH,
sensitivity with
the elderly and
other
black patients.
sulfonamide
Monitor SCr and
derivatives),
photosensitivity, K+.
fatigue.
Consider
alternatives in
patients with or
predisposed to
arrhythmias.
Can exacerbate
gout and diabetes
Page 124
Therapeutic Choice
Adverse Costa
(biochemical
abnormalities are
less frequent at
12.5–25 mg/day).
Ineffective in
patients with ClCr
<30 to 40 mL/min.
The Canadian
Hypertension
Education Program
recommends
initiating therapy
with a combination
of two first-line
agents if a patient's
SBP is ≥20 or DBP
is ≥10 mm Hg
above the
recommended
target.
Beta1-adrenergic pindolol/ 10/25 mg or Fatigue, Bradycardia with Beta-blockers $$

Antagonist/ hydrochlorothiazide 10/50 mg once bradycardia, digoxin or should not be used
Diuretic daily pob decreased nondihydropyridine as initial therapy in
Combinations Viskazide exercise CCBs. patients aged >60
headache, effects with specifically
hyperglycemia,
depression, ↓ Li + excretion Avoid abrupt
heart failure, (monitor Li + levels, withdrawal (may
heart block. adjust dose). precipitate
NSAIDs ↓ ischemia). Taper
Hypotension, hypotensive efficacy. the dose before
weakness, discontinuation.
muscle cramps, Diuretic-induced
impotence. hypokalemia ↑ the Avoid in patients
Hypokalemia, risk of digoxin with severe PAD.
hyponatremia, toxicity.
hyperuricemia, Contraindicated in
hyperglycemia, ↓ efficacy of patients with 2nd or
hyperlipidemia.
antihyperglycemic 3rd degree heart
Rare: azotemia,
agents. block in the
blood
absence of a
dyscrasias,
pacemaker.
allergic
reactions
Particularly
(potential cross
effective in ISH,
sensitivity with
the elderly and
other
black patients.
sulfonamide
Monitor SCr and
derivatives),
photosensitivity, K+.
fatigue.
Consider
alternatives in
patients with or
predisposed to
arrhythmias.
Can exacerbate
gout and diabetes
(biochemical
abnormalities are
less frequent at
12.5–25 mg/day).
Ineffective in
Page 125
Therapeutic Choice
Adverse Costa
patients with ClCr

<30 to 40 mL/min.
The Canadian
Hypertension
Education Program
recommends
initiating therapy
with a combination
of two first-line
SBP is ≥20 or DBP
is ≥10 mm Hg
above the
recommended
target.
ACE Inhibitor/ trandolapril/ Trandolapril 1–4 Dry cough, Marked ↑ in serum Contraindicated $$$
Calcium Channel verapamil mg/day plus hyperkalemia. K+ in patients in pregnancy—
Blocker Tarka verapamil 180– Unusual: receiving K+ caution when
Combinations 480 mg/day. angioedema. supplements and/or prescribing to
BID po b renal failure in
bearing
renovascular
risk of renal
hypovolemia).
Headache, (potential toxicity).
Hyperkalemia
dizziness, usually occurs only
bradycardia, CYP3A4 substrate
(many potential in those on K+
heart block, new supplements or
onset or interactions).
Strong inhibitors drugs that cause
worsening of
include azole K+ retention, those
heart failure.
antifungals, protease with renal
inhibitors, impairment or
Constipation.
macrolides and diabetics with high
quinidine. serum K+ levels.
Assess SCr and K+
Grapefruit juice may after a few days,
↑ serum then regularly.
concentrations.
Caution in patients
with heart failure,
Inhibits metabolism or 2nd or 3rd
of carbamazepine, degree heart block
cyclosporine, without a
lovastatin, functioning
simvastatin. pacemaker.
Rifampin ↑ The Canadian

metabolism of Hypertension
verapamil. Education Program
recommends
Additive inotropic initiating therapy
effects with with a combination
amiodarone, beta- of two first-line
blockers, digoxin. agents if a patient's
SBP is ≥20 or DBP
Verapamil ↑ digoxin is ≥10 mm Hg
levels by 50–75% above the
within 1 wk (monitor recommended
levels). target.
ACE Inhibitor/ cilazapril/ 5/12.5 mg once Dry cough, Marked ↑ in serum Contraindicated $$
Diuretic hydrochlorothiazide daily pob hyperkalemia. K+ in patients in pregnancy—
Page 126
Therapeutic Choice
Adverse Costa
Combinations Unusual: receiving K+ caution when

Inhibace Plus, angioedema. supplements and/or prescribing to
generics Can precipitate K+-sparing diuretics. women of child-
renal failure in ↓ hypotensive effect bearing
NSAIDs. + hypotension with
Elevated Li levels
Hypotension, Hyperkalemia
weakness, + usually occurs only
muscle cramps, ↓ Li excretion
+ in those on K+
impotence. (monitor Li levels,
supplements or
Hypokalemia, adjust dose).
drugs that cause
hyponatremia, NSAIDs ↓ +
hyperuricemia, hypotensive efficacy. K retention, those
with renal
hyperglycemia,
Diuretic-induced impairment or
hyperlipidemia.
hypokalemia ↑ the diabetics with high
Rare: azotemia,
blood risk of digoxin serum K+ levels.
dyscrasias, toxicity. Assess SCr and K+
allergic after a few days,
reactions ↓ efficacy of then regularly.
(potential cross antihyperglycemic
sensitivity with agents. Particularly
other effective in ISH,
sulfonamide the elderly and
derivatives), black patients.
photosensitivity, Monitor SCr and
fatigue. K+.
Consider
alternatives in
patients with or
predisposed to
arrhythmias.
Can exacerbate
gout and diabetes
(biochemical
abnormalities are
less frequent at
12.5–25 mg/day).
Ineffective in
patients with ClCr
<30 to 40 mL/min.
The Canadian
Hypertension
Education Program
recommends
initiating therapy
with a combination
of two first-line
SBP is ≥20 or DBP
is ≥10 mm Hg
above the
recommended
target.
ACE Inhibitor/ enalapril/ 5/12.5 mg or Dry cough, Marked ↑ in serum Contraindicated $$

Diuretic hydrochlorothiazide 10/25 mg once hyperkalemia. K+ in patients in pregnancy—
Combinations daily pob Unusual: receiving K+ caution when
Vaseretic angioedema. supplements and/or prescribing to
Can precipitate women of child-
renal failure in bearing
Page 127
Therapeutic Choice
Adverse Costa

NSAIDs. Elevated Li + levels hypotension with
weakness, ↓ Li + excretion usually occurs only
muscle cramps, in those on K+
(monitor Li + levels,
impotence. supplements or
adjust dose).
Hypokalemia, drugs that cause
NSAIDs ↓
hyponatremia,
hypotensive efficacy. K+ retention, those
hyperuricemia,
with renal
hyperglycemia,
Diuretic-induced impairment or
hyperlipidemia.
hypokalemia ↑ the diabetics with high
Rare: azotemia,
fatigue. K+.
Consider
alternatives in
patients with or
predisposed to
arrhythmias.
Can exacerbate
gout and diabetes
(biochemical
abnormalities are
less frequent at
12.5–25 mg/day).
Ineffective in
patients with ClCr
<30 to 40 mL/min.
The Canadian
Hypertension
Education Program
recommends
initiating therapy
with a combination
of two first-line
SBP is ≥20 or DBP
is ≥10 mm Hg
above the
recommended
target.
ACE Inhibitor/ lisinopril/ 10/12.5 mg, Dry cough, Marked ↑ in serum Contraindicated $-$$
Diuretic hydrochlorothiazide 20/12.5 mg or hyperkalemia. K+ in patients in pregnancy—
Combinations 20/25 once daily Unusual: receiving K+ caution when
Prinzide, Zestoretic, po b angioedema. supplements and/or prescribing to
generics K+-sparing diuretics.
renovascular
initial doses if on
dysfunction.
Page 128
Therapeutic Choice
Adverse Costa
NSAIDs. Elevated Li + levels hypotension with

weakness, ↓ Li + excretion usually occurs only
muscle cramps,
(monitor Li + levels, in those on K+
impotence. supplements or
adjust dose).
Hypokalemia, drugs that cause
NSAIDs ↓
hyponatremia, +
hypotensive efficacy. K retention, those
hyperuricemia, with renal
hyperglycemia, impairment or
Diuretic-induced
hyperlipidemia. diabetics with high
hypokalemia ↑ the
Rare: azotemia,
risk of digoxin serum K+ levels.
blood
dyscrasias,
toxicity. Assess SCr and K+
↓ efficacy of then regularly.
reactions
fatigue. K+.
Consider
alternatives in
patients with or
predisposed to
arrhythmias.
Can exacerbate
gout and diabetes
(biochemical
abnormalities are
less frequent at
12.5–25 mg/day).
Ineffective in
patients with ClCr
<30 to 40 mL/min.
The Canadian
Hypertension
Education Program
recommends
initiating therapy
with a combination
of two first-line
SBP is ≥20 or DBP
is ≥10 mm Hg
above the
recommended
target.
ACE Inhibitor/ perindopril/ 4/1.25 mg once Dry cough, Marked ↑ in serum Contraindicated $$
Diuretic indapamide daily pob hyperkalemia. K+ in patients in pregnancy—
Combinations Coversyl Plus, Unusual: receiving K+ caution when
Coversyl Plus LD angioedema. supplements and/or prescribing to
renovascular
initial doses if on
dysfunction.
hypovolemia).
Hypotension, (potential toxicity).
Hyperkalemia
weakness, usually occurs only
muscle cramps, ↓ Li + excretion
Page 129
Therapeutic Choice
Adverse Costa
impotence. (monitor Li + levels, in those on K+

Hypokalemia, adjust dose). supplements or
hyponatremia, NSAIDs ↓ drugs that cause
hyperuricemia, hypotensive efficacy. K+ retention, those
hyperglycemia, with renal
hyperlipidemia. Diuretic-induced impairment or
Rare: azotemia, hypokalemia ↑ the diabetics with high
dyscrasias, toxicity.
allergic Assess SCr and K+
reactions after a few days,
↓ efficacy of then regularly.
sensitivity with agents.
other Particularly
sulfonamide effective in ISH,
derivatives), the elderly and
photosensitivity, black patients.
fatigue. Monitor SCr and
K+.
Consider
alternatives in
patients with or
predisposed to
arrhythmias.
Can exacerbate
gout and diabetes
(biochemical
abnormalities are
less frequent at
12.5–25 mg/day).
Ineffective in
patients with ClCr
<30 to 40 mL/min.
The Canadian
Hypertension
Education Program
recommends
initiating therapy
with a combination
of two first-line
SBP is ≥20 or DBP
is ≥10 mm Hg
above the
recommended
target.
ACE Inhibitor/ quinapril/ 10/12.5 mg, Dry cough, Marked ↑ in serum Contraindicated $$
Diuretic hydrochlorothiazide 20/12.5 mg or hyperkalemia. K+ in patients in pregnancy—
Combinations 20/25 mg once Unusual: receiving K+ caution when
Accuretic daily pob angioedema. supplements and/or prescribing to
renovascular
initial doses if on
dysfunction.
hypovolemia).
Hyperkalemia
muscle cramps, ↓ Li + excretion
in those on K+
impotence. (monitor Li + levels, supplements or
Hypokalemia, adjust dose). drugs that cause
hyponatremia, NSAIDs ↓
K+ retention, those
hyperuricemia, hypotensive efficacy.
Page 130
Therapeutic Choice
Adverse Costa
hyperglycemia, with renal

hyperlipidemia. Diuretic-induced impairment or
Rare: azotemia, hypokalemia ↑ the diabetics with high
fatigue.
K+.
Consider
alternatives in
patients with or
predisposed to
arrhythmias.
Can exacerbate
gout and diabetes
(biochemical
abnormalities are
less frequent at
12.5–25 mg/day).
Ineffective in
patients with ClCr
<30 to 40 mL/min.
The Canadian
Hypertension
Education Program
recommends
initiating therapy
with a combination
of two first-line
SBP is ≥20 or DBP
is ≥10 mm Hg
above the
recommended
target.
ACE Inhibitor/ ramipril/ 2.5/12.5 mg, Dry cough, Marked ↑ in serum Contraindicated $
Diuretic hydrochlorothiazide 5/12.5 mg, hyperkalemia. K+ in patients in pregnancy—
Combinations 10/12.5 mg, Unusual: receiving K+ caution when
Altace HCT, generics 5/25, mg or angioedema. supplements and/or prescribing to
10/25 mg once Can precipitate women of child-
daily pob renal failure in
bearing
renovascular
initial doses if on
dysfunction.
+
Elevated Li levels
hypovolemia).
Hyperkalemia
+
↓ Li excretion
muscle cramps, in those on K+
impotence. (monitor Li + levels, supplements or
Hypokalemia, adjust dose). drugs that cause
hyponatremia, NSAIDs ↓
K+ retention, those
hyperuricemia, hypotensive efficacy.
with renal
hyperglycemia,
impairment or
hyperlipidemia. Diuretic-induced
diabetics with high
Rare: azotemia, hypokalemia ↑ the
blood serum K+ levels.
risk of digoxin
Page 131
Therapeutic Choice
Adverse Costa

fatigue. K+.
Consider
alternatives in
patients with or
predisposed to
arrhythmias.
Can exacerbate
gout and diabetes
(biochemical
abnormalities are
less frequent at
12.5–25 mg/day).
Ineffective in
patients with ClCr
<30 to 40 mL/min.
The Canadian
Hypertension
Education Program
recommends
initiating therapy
with a combination
of two first-line
SBP is ≥20 or DBP
is ≥10 mm Hg
above the
recommended
target.
ARB/ candesartan/ 16/12.5 mg Hyperkalemia. Marked ↑ in serum Contraindicated $$

Diuretic hydrochlorothiazide once daily pob Can precipitate K+ in patients in pregnancy—
Combinations renal failure in receiving K+ caution when
Atacand Plus susceptible supplements and/or prescribing to
patients women of child-
(bilateral bearing
May elevate Li +
with concurrent ↓ Li + excretion depleted or on
NSAID use). (monitor Li + levels, diuretics (↑ risk of
adjust dose). hypotension in
Angioedema has NSAIDs ↓ hypovolemia).
been reported, hypotensive efficacy.
association has Diuretic-induced usually occurs only
not been hypokalemia ↑ the in those on K+
established. risk of digoxin supplements or
toxicity. drugs that cause
Hypotension,
K+ retention, those
weakness, ↓ efficacy of with renal
muscle cramps, antihyperglycemic impairment or
impotence. agents. diabetics with high
Hypokalemia,
hyponatremia, serum K+ levels.
hyperuricemia, Assess SCr and K+
Page 132
Therapeutic Choice
Adverse Costa
hyperglycemia, after a few days,

hyperlipidemia. then regularly.
Rare: azotemia,
blood Particularly
dyscrasias, effective in ISH,
allergic the elderly and
reactions black patients.
(potential cross Monitor SCr and
sensitivity with K+.
other
sulfonamide Consider
derivatives), alternatives in
photosensitivity, patients with or
fatigue. predisposed to
arrhythmias.
Can exacerbate
gout and diabetes
(biochemical
abnormalities are
less frequent at
12.5–25 mg/day).
Ineffective in
patients with ClCr
<30 to 40 mL/min.
The Canadian
Hypertension
Education Program
recommends
initiating therapy
with a combination
of two first-line
SBP is ≥20 or DBP
is ≥10 mm Hg
above the
recommended
target.
ARB/ eprosartan/ 600/12.5 mg Hyperkalemia. Marked ↑ in serum Contraindicated $$

Teveten Plus susceptible supplements and/or prescribing to
(bilateral bearing
May elevate Li +
Hypotension,
K+ retention, those
Hypokalemia,
Page 133
Therapeutic Choice
Adverse Costa

Rare: azotemia,
blood Particularly
other
arrhythmias.
Can exacerbate
gout and diabetes
(biochemical
abnormalities are
less frequent at
12.5–25 mg/day).
Ineffective in
patients with ClCr
<30 to 40 mL/min.
The Canadian
Hypertension
Education Program
recommends
initiating therapy
with a combination
of two first-line
SBP is ≥20 or DBP
is ≥10 mm Hg
above the
recommended
target.
ARB/ irbesartan/ 150/12.5, Hyperkalemia. Marked ↑ in serum Contraindicated $$

Diuretic hydrochlorothiazide 300/12.5 or Can precipitate K+ in patients in pregnancy—
Combinations 300/25 mg once renal failure in receiving K+ caution when
Avalide daily pob susceptible supplements and/or prescribing to
(bilateral bearing
May elevate Li +
Hypotension,
K+ retention, those
Hypokalemia,
Page 134
Therapeutic Choice
Adverse Costa
Rare: azotemia,
blood Particularly
other
arrhythmias.
Can exacerbate
gout and diabetes
(biochemical
abnormalities are
less frequent at
12.5–25 mg/day).
Ineffective in
patients with ClCr
<30 to 40 mL/min.
The Canadian
Hypertension
Education Program
recommends
initiating therapy
with a combination
of two first-line
SBP is ≥20 or DBP
is ≥10 mm Hg
above the
recommended
target.
ARB/ losartan/ 50/12.5 mg or Hyperkalemia. Marked ↑ in serum Contraindicated $$

Diuretic hydrochlorothiazide 100/25 mg once Can precipitate K+ in patients in pregnancy—
Combinations daily pob renal failure in receiving K+ caution when
Hyzaar, Hyzaar DS susceptible supplements and/or prescribing to
(bilateral bearing
May elevate Li +
Hypotension,
K+ retention, those
Hypokalemia,
Rare: azotemia,
Page 135
Therapeutic Choice
Adverse Costa
blood Particularly
other
arrhythmias.
Can exacerbate
gout and diabetes
(biochemical
abnormalities are
less frequent at
12.5–25 mg/day).
Ineffective in
patients with ClCr
<30 to 40 mL/min.
The Canadian
Hypertension
Education Program
recommends
initiating therapy
with a combination
of two first-line
SBP is ≥20 or DBP
is ≥10 mm Hg
above the
recommended
target.
ARB/ olmesartan/ 20/12.5 mg, Hyperkalemia. Marked ↑ in serum Contraindicated $$

Diuretic hydrochlorothiazide 40/12.5 mg or Can precipitate K+ in patients in pregnancy—
Olmetec Plus daily pob susceptible supplements and/or prescribing to
(bilateral bearing
May elevate Li +
Hypotension,
K+ retention, those
Hypokalemia,
Rare: azotemia,
blood Particularly
Page 136
Therapeutic Choice
Adverse Costa

other
arrhythmias.
Can exacerbate
gout and diabetes
(biochemical
abnormalities are
less frequent at
12.5–25 mg/day).
Ineffective in
patients with ClCr
<30 to 40 mL/min.
The Canadian
Hypertension
Education Program
recommends
initiating therapy
with a combination
of two first-line
SBP is ≥20 or DBP
is ≥10 mm Hg
above the
recommended
target.
ARB/ telmisartan/ 80/12.5 mg Hyperkalemia. Marked ↑ in serum Contraindicated $$

Micardis Plus susceptible supplements and/or prescribing to
(bilateral bearing
May elevate Li +
Hypotension,
K+ retention, those
Hypokalemia,
Rare: azotemia,
blood Particularly
Page 137
Therapeutic Choice
Adverse Costa

other
arrhythmias.
Can exacerbate
gout and diabetes
(biochemical
abnormalities are
less frequent at
12.5–25 mg/day).
Ineffective in
patients with ClCr
<30 to 40 mL/min.
The Canadian
Hypertension
Education Program
recommends
initiating therapy
with a combination
of two first-line
SBP is ≥20 or DBP
is ≥10 mm Hg
above the
recommended
target.
ARB/ valsartan/ 80/12.5 mg, Hyperkalemia. Marked ↑ in serum Contraindicated $$

Diuretic hydrochlorothiazide 160/12.5 mg or Can precipitate K+ in patients in pregnancy—
Diovan-HCT daily pob susceptible supplements and/or prescribing to
(bilateral bearing
May elevate Li +
Hypotension,
K+ retention, those
Hypokalemia,
Rare: azotemia,
blood Particularly
Page 138
Therapeutic Choice
Adverse Costa

other
arrhythmias.
Can exacerbate
gout and diabetes
(biochemical
abnormalities are
less frequent at
12.5–25 mg/day).
Ineffective in
patients with ClCr
<30 to 40 mL/min.
The Canadian
Hypertension
Education Program
recommends
initiating therapy
with a combination
of two first-line
SBP is ≥20 or DBP
is ≥10 mm Hg
above the
recommended
target.
Calcium Channel amlodipine/ Amlodipine 5 or Ankle edema, CYP3A4 substrate For patients with $$$$
Blocker/ atorvastatin 10 mg plus flushing, (many potential hypertension and
HMG CoA Caduet atorvastatin 10, headache and interactions). an indication for an
Reductase Inhibitor 20, 40 or 80 mg palpitations. Strong inhibitors HMG-CoA inhibitor.
Combinations once daily pob Adverse effects include azole
of atorvastatin antifungals, protease
include inhibitors,
constipation, macrolides and
flatulence, quinidine.
dyspepsia,
abdominal pain Grapefruit juice may
and myalgia. ↑ serum
concentrations.
Amlodipine and
atorvastatin are both
substrates of
CYP3A4.
Direct Renin aliskiren/ 150/12.5 mg, Diarrhea. The Low potential for May take 4 wk to $$
Inhibitor/ hydrochlorothiazide 150/25 mg, incidence of dry drug interactions. realize maximum
Diuretic cough and ↓ Li + excretion antihypertensive
Combinations Rasilez HCT 300/12.5 mg hyperkalemia is (monitor Li + levels, effect.
or 300/25 mg low compared adjust dose). Effect on
with ACE NSAIDs ↓ cardiovascular
once daily pob inhibitors. hypotensive efficacy. outcomes not yet
Hypotension, established.
weakness, Diuretic-induced
muscle cramps, hypokalemia ↑ the Limited data in
impotence. risk of digoxin patients with
Hypokalemia, toxicity. greater than
hyponatremia, moderate renal
Page 139
Therapeutic Choice
Adverse Costa
hyperuricemia, ↓ efficacy of dysfunction.

hyperglycemia, antihyperglycemic
hyperlipidemia. agents. Avoid use in
Rare: azotemia, pregnancy.
blood
dyscrasias, Particularly
allergic effective in ISH,
reactions the elderly and
(potential cross black patients.
sensitivity with Monitor SCr and
other K+.
sulfonamide
derivatives), Consider
photosensitivity, alternatives in
fatigue. patients with or
predisposed to
arrhythmias.
Can exacerbate
gout and diabetes
(biochemical
abnormalities are
less frequent at
12.5–25 mg/day).
Ineffective in
patients with ClCr
<30 to 40 mL/min.
a. Cost of 30-day supply of usual dose of drug; includes drug cost only.
b. It is generally recommended that the dose of the each component is titrated before starting a combination product.
Abbreviations: CV=cardiovascular; IR=immediate-release; ISA=intrinsic sympathomimetic activity; ISH=isolated systolic

hypertension; PAD=peripheral arterial disease; SR=slow-release; TCA=tricyclic antidepressant
Legend: $ <$20 $-$$ <$20–40 $$ $20–40 $$-$$$ $20–60 $$$ $40–60 $$$$ >$60
Suggested Readings
Adrogue HJ, Madias NE. Sodium and potassium in the pathogenesis of hypertension. N Engl J Med 2007;356(19):1966-78.
Canadian recommendations on the management of hypertension are updated annually. A summary of the important and new
recommendations can be found at www.hypertension.ca/ in the For General Public section and is also broadly published in
multidisciplinary journals annually.
Hackam DG, Khan NA, Hemmelgarn BR et al. The 2010 Canadian Hypertension Education Program recommendations for the
management of hypertension: part 2–therapy. Can J Cardiol 2010;26(5):249-58.
Quinn RR, Hemmelgarn BR, Padwal RS et al. The 2010 Canadian Hypertension Education Program recommendations for the
management of hypertension: part 1–blood pressure measurement, diagnosis and assessment of risk. Can J Cardiol 2010;26
(5):241-8.
References
1. Campbell NR, Kaczorowski J, Lewanczuk RZ et al. 2010 Canadian Hypertension Education Program (CHEP) recommendations:
the scientific summary—an update of the 2010 theme and the science behind new CHEP recommendations. Can J Cardiol
2010;26(5):236-40.
2. Khan N, Chockalingam A, Campbell NR. Lack of control of high blood pressure and treatment recommendations in Canada. Can
J Cardiol 2002;18(6):657-61.
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Therapeutic Choice
3. ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. The Antihypertensive and Lipid-Lowering
Treatment to Prevent Heart Attack Trial. Major outcomes in high-risk hypertensive patients randomized to angiotensin-
converting enzyme inhibitor or calcium channel blocker vs diuretic: the Antihypertensive and Lipid-Lowering Treatment to
Prevent Heart Attack Trial (ALLHAT). JAMA 2002;288(23):2981-97.
4. MRC trial of treatment of mild hypertension: principal results. Medical Research Council Working Party. Br Med J (Clin Res Ed)
1985;291(6488):97-104.
5. Cooper WO, Hernandez-Diaz S, Arbogast PG et al. Major congenital malformations after first-trimester exposure to ACE
inhibitors. N Engl J Med 2006;354(23):2443-51.
6. Friedman JM. ACE inhibitors and congenital anomalies. N Engl J Med 2006;354(23):2498-500.
7. Alwan S, Polifka JE, Friedman JM. Angiotensin II receptor antagonist treatment during pregnancy. Birth Defects Res A Clin Mol
Teratol 2005;73(2):123-30.
8. Wald DS, Law M, Morris JK et al. Combination therapy versus monotherapy in reducing blood pressure: meta-analysis on
11,000 participants from 42 trials. Am J Med 2009;122(3):290-300.
9. Weber MA, Bakris GL, Dahlof B et al. Baseline characteristics in the Avoiding Cardiovascular events through Combination
therapy in Patients Living with Systolic Hypertension (ACCOMPLISH) trial: a hypertensive population at high cardiovascular
risk. Blood Press 2007;16(1):13-9.
10. Hackam DG, Khan NA, Hemmelgarn BR et al. The 2010 Canadian Hypertension Education Program recommendations for the
management of hypertension: part 2–therapy. Can J Cardiol 2010;26(5):249-58.
11. Mann JF, Schmieder RE, McQueen M et al. Renal outcomes with telmisartan, ramipril, or both, in people at high vascular risk
(the ONTARGET study): a multicentre, randomised, double-blind, controlled trial. Lancet 2008;372(9638):547-53.
12. Magee LA, Helewa M, Moutquin JM et al. Diagnosis, evaluation, and management of hypertensive disorders of pregnancy. J
Obstet Gynaecol Can 2008;30(3):S1-S48.
13. Report of the National High Blood Pressure Education Program Working Group on High Blood Pressure in Pregnancy. Am J
Obstet Gynecol 2000;183(1):S1-22.
14. Lowe SA, Brown MA, Dekker GA et al. Guidelines for the management of hypertensive disorders of pregnancy 2008. Aust N Z J
Obstet Gynaecol 2009;49(3):242-6.
15. Podymow T, August P. Update on the use of antihypertensive drugs in pregnancy. Hypertension 2008;51(4):960-9.
16. Magee LA. Drugs in pregnancy. Antihypertensives. Best Pract Res Clin Obstet Gynaecol 2001;15(6):827-45.
17. Magee LA, Schick B, Donnenfeld AE et al. The safety of calcium channel blockers in human pregnancy: a prospective,
multicentre cohort study. Am J Obstet Gynecol 1996;174(3):823-8.
18. Papatsonis DN, Lok CA, Bos JM et al. Calcium channel blockers in the management of preterm labor and hypertension in
pregnancy.Eur J Obstet Gynecol Reprod Biol 2001;97(2):122-40.
19. Butters L, Kennedy S, Rubin PC. Atenolol in essential hypertension during pregnancy. BMJ 1990;301(6752):587-9.
20. Groves TD, Corenblum B. Spironolactone therapy during human pregnancy. Am J Obstet Gynecol 1995;172(5):1655-6.
21. Shotan A, Widerhorn J, Hurst A et al. Risks of angiotensin-converting enzyme inhibition during pregnancy: experimental and
clinical evidence, potential mechanisms, and recommendations for use. Am J Med 1994;96(5):451-6.
22. Cooper WO, Hernandez-Diaz S, Arbogast PG et al. Major congenital malformations after first trimester exposure to ACE
inhibitors. N Engl J Med 2006;354(23):2443-51.
23. Lambot MA, Vermeylen D, Noel JC. Angiotensin-II-receptor inhibitors in pregnancy. Lancet 2001;357(9268):1619-20.
24. Cheng JW. Aliskiren: renin inhibitor for hypertension management. Clin Ther 2008;30(1):31-47.
25. Beardmore KS, Morris JM, Gallery ED. Excretion of antihypertensive medication into human breast milk: a systematic review.
Hypertens Pregnancy 2002;21(1):85-95.
26. Ohkubo T, Imai Y, Tsuji I et al. Home blood pressure measurement has a stronger predictive power for mortality than does
screening blood pressure measurement: a population-based observation in Ohasama, Japan. J Hypertens 1998;16(7):971-5.
27. Ohkubo T, Asayam K, Kikuya M et al. How many times should blood pressure be measured at home for better prediction of
stroke risk? Ten-year follow-up results from the Ohasama study. J Hypertens 2004;22(6):1099-104.
28. McLean DL, McAlister FA, Johnson JA et al. A randomized trial of the effect of community pharmacist and nurse care on
improving blood pressure management in patients with diabetes mellitus: Study of Cardiovascular Risk Intervention by
Pharmacists-Hypertension (SCRIP-HTN). Arch Intern Med 2008;168(21):2355-61.
29. Salpeter S, Ormiston T, Salpeter E. Cardioselective beta-blockers for chronic obstructive pulmonary disease. Cochrane
Database Syst Rev 2005;(4):CD003566.
Page 141
e-Therapeutics+ : Therapeutics : Cardiovascular Disorders: Intermittent Claudication Page 1 of 5
Therapeutic Choice
Print Close
Cardiovascular Disorders: Intermittent Claudication
Date Prepared: October 2010
Richard I. Ogilvie, MD, FRCPC, FACP
Goals of Therapy
Improve mobility and quality of life

Increase walking distance and time to claudication
Increase capacity for regular dynamic leg exercise
Prevent associated cardiovascular events
Investigations
History with special attention to cardiovascular disease risk factors and associated conditions:
hypertension
diabetes mellitus
smoking
dyslipidemia
angina pectoris/MI
TIA/stroke
Define walking time to claudication (severe <1/2 city block; moderate 1/2 to 1 block; mild >1 block)
Define duration of symptoms (6–12 months are required to develop collateral circulation)
signs of hypertension, dyslipidemia, diabetes mellitus, atherosclerosis (aortic aneurysm, bruits), heart
failure
signs of peripheral artery obstruction as indicated by diminished pulses in the femoral, popliteal, posterior
tibial and/or dorsalis pedis arteries. Alternatively, the absence of a bruit or decreased pulse reduces the
likelihood of obstruction
evidence of acute peripheral artery occlusion (acute onset of continuous pain, pale and cool limb or mottled
discolouration, thickened, swollen, stiff muscles plus pain over the muscle)
resting pain, dependent rubor, cyanosis, muscle atrophy and/or trophic ulcers suggest severe obstruction
Laboratory tests:
fasting blood glucose, serum creatinine and lipid profile
hemoglobin (anemia may exacerbate symptoms), hematocrit, platelet count
increased levels of D-dimer and inflammatory markers (C-reactive protein, amyloid A) are associated with
higher short-term (within 1–2 years) risk of cardiovascular and all-cause mortality1
resting Doppler-derived or sphygmomanometric ankle/arm systolic pressure index (ankle-brachial index)
(Figure 1 - Treatment of Intermittent Claudication)2
consider invasive angiography for patients with signs of severe limb ischemia (resting pain, muscle
atrophy, cyanosis, nonhealing ischemic ulcers or gangrene) in preparation for possible angioplastic or
surgical revascularization
Therapeutic Choices (Figure 1 - Treatment of Intermittent Claudication)
Discontinuation of smoking (active and passive) (see Psychiatric Disorders: Smoking Cessation).
Time (collateral flow develops over 6–12 months).
Nondrug treatment of obesity (see Endocrine and Metabolic Disorders: Obesity), lipid disorders (see
Cardiovascular Disorders: Dyslipidemias), hypertension (see Cardiovascular Disorders: Hypertension) and
associated conditions.
Regular dynamic leg exercise (5 times per week for 8 weeks initially).3 , 4 , 5 Dynamic leg exercise for 6–12
months after the onset of claudication allows collateral circulation to develop; continued exercise 3 or more
times a week over 24–36 months slows functional decline.3
For patients with chronic intermittent claudication, and without signs of severe arterial obstruction, the role of
angioplasty remains to be defined.
For patients with severe ischemia, bypass surgery or angioplasty have similar effects on amputation-free
survival and all-cause mortality over a 6-month period, although morbidity and costs are higher for patients
receiving surgery first rather than angioplasty.6 , 7 Amputation-free survival is higher and all-cause mortality is
Page 142
Therapeutic Choice
lower 2 and 3 years after surgery compared with angioplasty according to a post-hoc analysis of a large
randomized trial.6
Paresthesia and paralysis require immediate surgical revascularization (fibrinolysis may be considered where
symptoms present for <14 days).
Pharmacologic options for improving mobility, walking distance and time to claudication are limited. Drug therapy is
most effective in reducing the risk of cardiovascular events.
Cardiovascular Risk Reduction
Intermittent claudication occurs as a symptom of atherosclerotic occlusion in peripheral arterial disease (PAD). In
this condition it is essential to optimize treatment of hypertension (see Cardiovascular Disorders: Hypertension),
dyslipidemia (see Cardiovascular Disorders: Dyslipidemias) and diabetes mellitus (see Endocrine and Metabolic
Disorders: Diabetes Mellitus).8
Antiplatelet agents reduce the relative risk of vascular death in high-risk patients by about 25% and are equally
effective in those with coronary artery disease (CAD) and PAD.9 Clopidogrel may be more effective than ASA in
patients with PAD10 but is usually reserved for those who cannot tolerate ASA or continue to have events while on
ASA. Clopidogrel plus ASA is not significantly better than ASA alone in patients with atherothrombosis, but
combination therapy increases the risk of bleeding,11 and is therefore not recommended.
The ACE inhibitor ramipril reduces the risk of ischemic events beyond that expected from lowering
blood pressure in patients with PAD.12 Ramipril demonstrated similar effects in patients with or
without PAD in the HOPE study. Ramipril also increases walking time and distance over a 6-month
period in patients with PAD, according to the results of a small randomized study.13 Useful Info?
Beta-blockers reduce the risk of MI and death in patients with atherosclerosis, but use of these agents in patients
with peripheral vascular disease, including PAD, was previously discouraged because they were thought to worsen
symptoms. Beta-blockers do not affect walking capacity in patients with PAD14; thus, it is reasonable to use them to
treat hypertension in this population,15 although they should be used cautiously in those with severe PAD.15 Beta-
blockers are not recommended for the treatment of hypertension in patients over 60 years of age unless there are
other compelling indications such as angina, recent MI or a supraventricular arrhythmia.
Lipid-lowering drugs reduce the risk of cardiovascular events in patients with atherosclerosis and may improve
symptoms and increase walking distance in patients with intermittent claudication.16 , 17
Specific Therapy for Intermittent Claudication
Pentoxifylline, a methylxanthine derivative, alters erythrocyte deformability and reduces blood viscosity, platelet
reactivity and plasma hypercoagulability.18 Pentoxifylline produces marginal but statistically significant improvement
in pain-free and maximal walking distance and thus is not indicated for mild claudication. Smoking cessation and
regular dynamic leg exercise are probably more beneficial than pentoxifylline for moderate claudication. If
pentoxifylline is used, a total of 24 weeks of therapy followed by an 8-week drug-free period (as exercise tolerance
increases) can decrease or eliminate the need for pentoxifylline.
Pentoxifylline may be beneficial adjunctive therapy for trophic ulcers in diabetic and nondiabetic patients.19 Assess
therapy at 4-week intervals. Cost of therapy is unlikely to be justified beyond 24 weeks of treatment.
Cilostazol inhibits platelet aggregation by selectively inhibiting phosphodiesterase III and is a vasodilator that
improves maximal treadmill walking distance.20 , 21 , 22 It is not available in Canada.
Other Therapies
The role of vasoactive agents, buflomedil,23 prostaglandin analogues,24 L-carnitine or arterial gene therapy25 has
not been defined by adequate clinical trials. Low molecular weight heparin, oral anticoagulants, vitamin E and
chelation therapy are not effective for PAD.
Figure 1-Treatment of Intermittent Claudication
Page 143
Therapeutic Choice
Table 1: Drug Treatment for Intermittent Claudication
Adverse Costa
Class Drug Dose Effects Comments Drug Interactions
Antiplatelet acetylsalicylic 80– GI ↑ bleeding risk with $

Agents acid (ASA) 325 intolerance, anticoagulants and
mg GI bleeding, clopidogrel.
Aspirin, Coated
daily nausea,
Aspirin, po heartburn.
generics
Antiplatelet clopidogrel 75 mg Skin rash, ↑ bleeding risk with $$$$

Agents Plavix daily diarrhea, ASA. PPI use may
po bleeding. reduce clopidogrel
efficacy.26
Rheologic pentoxifylline 400 Nausea, Clinical effectiveness is ↓ effect of adenosine; ↑ $$

Modifiers Trental, mg SR vomiting, marginal. Not effect of theophylline,
generics TID po dizziness, recommended in patients warfarin,
Page 144
Therapeutic Choice
Adverse Costa
Class Drug Dose Effects Comments Drug Interactions
headache, with marked hepatic or sympathomimetics,

flushing. renal dysfunction. antihypertensives,
Contraindications: acute hypoglycemics.
MI, hemorrhage, peptic
ulcer disease, xanthine
intolerance.
a.Cost of 30-day supply; includes drug cost only.
Abbreviations: SR=sustained release
Legend: $ <$20 $$ $20-40 $$$$ $60-80
Suggested Readings
Ankle Brachial Index Collaboration, Fowkes FG, Murray GD et al. Ankle brachial index combined with Framingham
Risk Score to predict cardiovascular events and mortality: a meta-analysis. JAMA 2008;300(2):197-208.
Gardner AW, Montgomery PS, Afaq A. Exercise performance in patients with peripheral arterial disease who have
different types of exertional leg pain. J Vasc Surg 2007;46(1):79-86.
Rowlands TE, Donnelly R. Medical therapy for intermittent claudication. Eur J Vasc Endovasc Surg 2007;34(3):314-
21.
Sutton-Tyrrell K, Venkitachalam L, Kanaya AM et al. Relationship of ankle blood pressures to cardiovascular events
in older adults. Stroke 2008;39(3):863-9.
White C. Clinical practice. Intermittent claudication. N Engl J Med 2007;356(12):1241-50.
References
1. Vidula H, Tian L, Liu K et al. Biomarkers of inflammation and thrombosis as predictors of near-term mortality
in patients with peripheral arterial disease: a cohort study. Ann Intern Med 2008;148(2):85-93.
2. Feringa HH, Bax JJ, Hoeks S et al. A prognostic risk index for long-term mortality in patients with peripheral
arterial disease. Arch Intern Med 2007;167(22):2482-9.
3. McDermott MM, Liu K, Ferrucci L et al. Physical performance in peripheral arterial disease: a slower rate of
decline in patients who walk more. Ann Intern Med 2006;144(1):10-20.
4. Kim DH. Exercise and peripheral arterial disease. Ann Intern Med 2006;144(9):699-700.
5. Wind J, Koelemay MJ. Exercise therapy and the additional effect of supervision on exercise therapy in patients
with intermittent claudication. Systematic review of randomised controlled trials. Eur J Vasc Endovasc Surg
2007;34(1):1-9.
6. Adam DJ, Beard JD, Cleveland T et al. Bypass versus angioplasty in severe ischaemia of the leg (BASIL):
multicentre, randomised controlled trial. Lancet 2005;366(9501):1925-34.
7. Goy JJ, Urban P. Life and limb: bypass versus angioplasty in the ischaemic limb. Lancet 2005;366
(9501):1905-6.
8. Hirsch AT, Haskal ZJ, Hertzer NR et al. ACC/AHA 2005 practice guidelines for the management of patients with
peripheral arterial disease (lower extremity, renal, mesenteric, and abdominal aortic). Circulation 2006;113
(11):e463-654.
9. Collaborative overview of randomised trials of antiplatelet therapy--I: Prevention of death, myocardial
infarction, and stroke by prolonged antiplatelet therapy in various categories of patients. Antiplatelet Trialists'
Collaboration. BMJ 1994;308(6921):81-106.
Page 145
Therapeutic Choice
10. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE).
CAPRIE Steering Committee. Lancet 1996;348(9038):1329-39.
11. Bhatt DL, Fox KA, Hacke W et al. Clopidogrel and aspirin versus aspirin alone for the prevention of
atherothrombotic events. N Engl J Med 2006;354(16):1706-17.
Engl J Med 2000;342(3):145-53.
13. Ahimastos AA, Lawler A, Reid CM et al. Brief communication: ramipril markedly improves walking ability in
patients with peripheral arterial disease: a randomized trial. Ann Intern Med 2006;144(9):660-4.
14. Radack K, Deck C. Beta-adrenergic blocker therapy does not worsen intermittent claudication in subjects with
peripheral arterial disease. A meta-analysis of randomized controlled trials. Arch Intern Med 1991;151
(9):1769-76.
15. Heintzen MP, Strauer BE. Peripheral vascular effects of beta-blockers. Eur Heart J 1994;15 (Suppl C):2-7.
16. Mohler ER, Hiatt WR, Creager MA. Cholesterol reduction with atorvastatin improves walking distance in
patients with peripheral arterial disease. Circulation 2003;108(12):1481-6.
17. Mondillo S, Ballo P, Barbati R et al. Effects of simvastatin on walking performance and symptoms of
intermittent claudication in hypercholesterolemic patients with peripheral vascular disease. Am J Med
2003;114(5):359-64.
18. Hood SC, Moher D, Barber GG. Management of intermittent claudication with pentoxifylline: meta-analysis of
randomized controlled trials. CMAJ 1996;155(8):1053-9.
19. Jull A, Waters J, Arroll B. Pentoxifylline for treatment of venous leg ulcers: a systematic review. Lancet
2002;359(9317):1550-4.
20. Dawson DL, Cutler BS, Hiatt WR et al. A comparison of cilostazol and pentoxifylline for treating intermittent
claudication. Am J Med 2000;109(7):523-30.
21. Money SR, Herd JA, Isaacsohn JL et al. Effect of cilostazol on walking distances in patients with intermittent
claudication caused by peripheral vascular disease. J Vasc Surg 1998;27(2):267-74.
22. Rowlands TE, Donnelly R. Medical therapy for intermittent claudication. Eur J Vasc Endovasc Surg 2007;34
(3):314-21.
23. de Backer TL, Bogaert M, Vander Stichele R. Buflomedil for intermittent claudication. Cochrane Database Syst
Rev 2008;(1):CD000988.
24. Milio G, Mina C, Cospite V et al. Efficacy of the treatment with prostaglandin E-1 in venous ulcers of the lower
limbs. J Vasc Surg 2005;42(2):304-8.
25. Lederman RJ, Mendelsohn FO, Anderson RD et al. Therapeutic angiogenesis with recombinant fibroblast
growth factor-2 for intermittent claudication (the TRAFFIC study): a randomised trial. Lancet 2002;359
(9323):2053-8.
2009;180(7):699-700.
Page 146
e-Therapeutics+ : Therapeutics : Cardiovascular Disorders: Post-myocardial Infarction Page 1 of 17
Therapeutic Choice
Print Close
Cardiovascular Disorders: Post-myocardial Infarction

Date Revised: January 2009
William L. Williams, MDCM, FRCPC
About 70% of patients presenting with myocardial infarction (MI) qualify for acute reperfusion by thrombolysis or
primary coronary angioplasty.1 The reperfused patient with an aborted MI presents a particular challenge with
respect to recurrent ischemic complications. Reperfusion therapy has reduced 30-day mortality from 10% to
between 3 and 4% and improved overall prognosis.2 The prognosis of the post-MI patient depends on the
interaction between residual left ventricular dysfunction, the potential for recurrent ischemia and the risk of
arrhythmia (Table 1).3 Older patients with comorbid conditions such as diabetes mellitus or renal failure have worse
outcomes. Patients who receive timely reperfusion therapy with thrombolysis or primary angioplasty enjoy a much
better prognosis than those treated conservatively.1
Table 1: Investigation and Therapy of the Post-Infarction Patient to Improve Prognosis
Factor
Affecting
Prognosis Investigation Therapy
Left Ventricular Ejection fraction: echocardiogram, gated nuclear or contrast Beta-blockers, ACE
Dysfunction ventriculogram inhibitors, ARBs, warfarin
for LV thrombus or atrial
fibrillation
Ischemia Low-risk outpatients post-thrombolysis: physiologic stress test Beta-blockers, statins, ACE
using exercise, dipyridamole or dobutamine with ECG; nuclear inhibitors, ARBs,
scintigraphy or echocardiographic wall motion assessment. Perform antiplatelet agents
coronary angiography if the result is abnormal
High-risk patients: coronary angiography
Arrhythmia Holter monitor, event recorder, implantable arrhythmia detector Beta-blockers, possibly
amiodarone or ICD
Abbreviations: ACE inhibitor = angiotensin converting enzyme inhibitor; ARB = angiotensin receptor blocker;
ICD = implantable cardioverter/defibrillator; LV = left ventricle.
Cardiovascular disease in women remains the leading cause of death and accounts for more than half of all deaths
among women over the age of 50 years. Sex differences are apparent with respect to prevalence, presentation,
treatment and outcome. Some risk factors, for example diabetes mellitus, appear to be more malignant in women
than in men. Mortality rates in men have been declining, while those in women have remained stable.4
Historically, women have been under-represented in clinical trials, perhaps due to exclusion with advanced age and
comorbidities. This has led to a knowledge gap whereby little is known about why cardiovascular disease affects
women differently from men.
Investigation and treatment of patients after myocardial infarction should be gender neutral as the vast majority of
post-MI interventions benefit patients of both sexes.4
Goals of Therapy
Establish a risk profile

Prevent death and prevent or delay recurrent events (MI, heart failure and angina)
Retard progression of coronary disease
Return patient to a meaningful quality of life
Target modifiable risk factors that are responsible for 90% of risk
Investigations
Page 147
Therapeutic Choice
A simple algorithm for evaluating post-infarction patients who have been treated with or without fibrinolysis is
presented in Figure 1 - Stratifying Post-MI Patients to Conservative or Invasive Therapy. The higher the risk, the
more likely the patient will benefit from an invasive strategy.5 Identifying patients at high risk begins with an
assessment of readily accessible clinical predictors.
Predictors of early recurrent events (i.e, one to six months post-MI) include:6
recurrent ischemia or angina with an ST-segment shift
bigger infarction as evidenced by: pulmonary congestion, hypotension, tachycardia, higher Killip class
(Table 2), azotemia
Table 2: The Killip Classification
Killip Class Patient Characteristics
I No clinical signs of heart failure
II Mild heart failure, rales, elevated jugular venous pulse (SBP ≥ 90 mm Hg)
III Frank pulmonary edema (SBP ≥ 90 mm Hg)
IV Cardiogenic shock (SBP < 90 mm Hg)
Predictors of late recurrent events (i.e., one to two years post-MI):6

residual left ventricular ejection fraction < 30%
older age and comorbidity (diabetes, renal failure, other vascular disease)
ventricular irritability, as evidenced by resuscitated VF or sustained or nonsustained VT, especially in
patients with low ejection fraction
An important determinant of prognosis after MI is left ventricular dysfunction, which is reflected by the left
ventricular ejection fraction (LVEF). LVEF can be measured by echocardiography or inferred from clinical signs
present at the time of infarction such as pulmonary congestion, resting tachycardia, hypotension, new bundle branch
block or recurrent arrhythmia. The extent of the current of injury pattern on ECG and the degree of enzyme release
also reflect infarct size. If a low LVEF is suspected (< 40%), refer the patient to a tertiary care centre for further
investigation. Otherwise, smaller centres without access to echocardiography can perform a modified treadmill test
prior to discharge.
Indications for post-infarction coronary arteriography sanctioned by current guidelines are listed in Table 3.
However, in many centres most patients treated with thrombolytics also visit the angiography suite before hospital
discharge,7 as the prognosis is improved among those with demonstrable ischemia.8
A decision algorithm for the unique situation presented by post-MI patients following primary angioplasty is
illustrated in Figure 2 - Management of MI Patients After Primary PCI.
Table 3: Evidence-based Indications for Post-infarction Coronary Angiography4
Spontaneous or provocable ischemia, especially when present after fibrinolysis
LV dysfunction/LVEF ≤ 40%
Hemodynamic instability
Prior repair of a mechanical complication
Malignant ventricular arrhythmia
Patients with non-ST-segment elevation MI
Abbreviations: LV = left ventricle; LVEF = LV ejection fraction.
Select patients may be investigated for arrhythmia (Holter monitor, event recorder, implantable arrhythmia
detector); however, this is not routinely recommended.4
Therapeutic Choices
Vascular inflammation contributes to the pathogenesis of plaque rupture. Thus agents with anti-inflammatory and
antithrombotic properties now have a well-established role in the management of the post-MI patient.
Page 148
Therapeutic Choice
Comprehensive management of the post-MI patient should include treatment of hypertension, dyslipidemia and
diabetes mellitus. Smoking cessation decreases the relative risk of death and re-infarction by 50% in patients with
MI.9 The rate of re-infarction and death decreased from 16 to 6% during two years of observation among men who
succeeded in stopping smoking.10 Weight loss and physical activity are also important components of secondary
prevention of MI.
Essential elements of cardiac rehabilitation are provided in Figure 3 - Elements of Cardiac Rehabilitation.
Weight loss is indicated if the patient’s BMI is > 25 or the waist circumference is > 100 cm in men or > 90 cm
in women. The goal is a sustained 5 to 10% decrease in body weight.9 Nutritional counselling is beneficial for
patients attempting to lose weight.9
Regular exercise with an individual prescription that accounts for age, obesity, level of fitness and
biomechanical capability. Generally, the goal of burning off 1000 kcal/week can be attained by engaging in 30-
45 minutes of moderate aerobic activity three or four times per week.9
Revascularization is indicated in select patients (Figure 1 - Stratifying Post-MI Patients to Conservative or
Invasive Therapy and Figure 2 - Management of MI Patients After Primary PCI).
An implantable cardioverter/defibrillator may be indicated in select patients.
Among high-risk patients, antiplatelet agents, beta-blockers, ACE inhibitors and lipid-lowering therapies
independently reduce the incidence of vascular events by approximately 25% (Table 4).11 An overview of individual
agents is provided in Table 6.
Table 4: Potential Cumulative Impact of Four Treatments for Secondary Prevention of Cardiovascular Events
2-year Event Rate

(death, MI or stroke)
Relative Risk Reduction
None — 8%
ASA 25% 6%
Beta-blocker 25% 4.5%
Lipid lowering (↓ LDL-C by 1.5 mmol/L) 30% 3%
ACE inhibitor 25% 2.3%
Cumulative relative risk reduction if all four drugs are used is about 75%
To calculate the cumulative risk reduction a multiplicative scale was used. For example, two interventions each
reducing the risk of an event by 30% would be expected to have about a 50% relative risk reduction (1–[0.7 ×
0.7]). No interactions in treatment effects are observed in trials, suggesting that the proportionate risk reduction
of a specific drug in the presence or absence of other effective interventions would be expected to be similar.
Smoking cessation lowers the risk of recurrent MI by about half after two years. In a smoker with vascular
disease, quitting smoking and the use of the four preventive strategies could theoretically have a large potential
benefit (approximately 80% relative risk reduction)
Reprinted from The Lancet. Volume 360(9326). Yusuf S. Two decades of progress in preventing vascular disease. Lancet pages
2-3. Copyright 2002. With permission from Elsevier.
Antiplatelet Agents12 , 13 , 14 , 15
Antiplatelet agents are effective in preventing vascular events, including nonfatal MI and death, in post-MI
patients.5 , 16 ASA is the antiplatelet agent of choice due to its effectiveness and low cost, and is recommended as
chronic therapy in all CAD patients without contraindications, including those who are post-MI. Low doses (80 to
325 mg daily) are usually well tolerated.
Clopidogrel is recommended in patients who have contraindications to or cannot tolerate ASA. Acute and long-term
Page 149
Therapeutic Choice
outcomes in patients treated conservatively or with thrombolysis are improved by clopidogrel.17 Clopidogrel is
essential therapy for those undergoing stent deployment. When used with ASA, clopidogrel has been effective in
improving coronary patency and reducing the risk of infarction or death among those with unstable angina, ST-
segment elevation MI treated with thrombolytics18 and after stent deployment. When drug-eluting stents are
used according to the approved indications, it is recommended that clopidogrel be continued for at
least one year after deployment; when these devices are used in more complex, off-label settings, it is
recommended that clopidogrel be continued indefinitely.19 Useful Info?
Beta-Blockers20 , 21 , 22
Beta-blockers reduce cardiovascular mortality and re-infarction rates, and increase the probability of long-term
survival by up to 40%.5 In the absence of contraindications, these drugs are recommended in all patients post-MI
including those with non-ST-segment elevation MI (NSTEMI) and those receiving thrombolytic therapy or primary
angioplasty (Figure 2 - Management of MI Patients After Primary PCI). They should be started within a few days of
MI, if not earlier, and therapy should be continued indefinitely.5 Beta-blockers should be avoided among patients
with hypotension, bradycardia and active heart failure.
Higher-risk patients with reduced LV function, especially when associated with heart failure, receive the greatest
benefit from beta-blockers provided they can be closely monitored. As a class, all beta-blockers that lower resting
heart rate improve outcome. Moreover, this benefit extends to those already on ACE inhibitors.
Beta-blockers are underused in the post-MI population,5 with less than half of patients receiving long-term therapy.
However, the benefit of therapy with these drugs outweighs the risk in patients with type 1 diabetes mellitus,
chronic obstructive pulmonary disease (COPD), severe peripheral vascular disease, a PR interval > 0.24 sec and
moderate or severe heart failure (Figure 2 - Management of MI Patients After Primary PCI).5 Low-dose beta-blockers
may be safely administered in some patients with a history of asthma. The appropriate use of beta-blockers after MI
is illustrated in Figure 4 - Beta-Blockers in the Chronic Post-MI Period.
ACE Inhibitors23 , 24 , 25
ACE inhibitors improve heart failure, reduce mortality and may reduce the likelihood of a recurrent MI.5 These
agents have greater relative and absolute benefits among high-risk patients with LV dysfunction or pulmonary
congestion. Start ACE inhibitors early in all patients without contraindications post-STEMI. Long term treatment with
ACE inhibitors is recommended for patients with STEMI, with the greatest benefit conferred among the higher-risk
subgroup with previous myocardial infarction, heart failure, depressed LVEF and tachycardia.5 Among patients with
evidence of atherosclerosis or multiple risk factors, chronic use of an ACE inhibitor reduces the risk of MI.25
Angiotensin Receptor Blockers
Angiotensin receptor blockers (ARBs) have similar benefits to ACE inhibitors. A large randomized trial demonstrated
equivalence between the ACE inhibitor captopril and the ARB valsartan in MI patients with heart failure and LV
dysfunction.26 There was no advantage of combined therapy with captopril and valsartan. ARBs may be used instead
of ACE inhibitors in patients who do not tolerate the latter due to cough or angioedema. Data are accumulating to
suggest that ARBs may be used in lieu of ACE inhibitors as primary therapy, especially among patients with heart
failure or an LVEF < 40%.5
There is a linear relationship between LDL-C levels and cardiovascular risk. Lipid-lowering therapy to achieve a 1
mmol/L decrease in LDL-C reduces the absolute risk by 1% and relative risk by 20% over five years.27 The
pleiotropic benefits of statin therapy may extend beyond mere lipid lowering.28 Aggressive lipid lowering not only
decreases the atherosclerotic burden, but may reduce coronary events by stabilizing fragile coronary plaques.29 , 30
Recommended targets for LDL-C have become progressively lower as the safety and efficacy of cholesterol-lowering
treatment have become established. Among high-risk patients, attainment of an LDL-C < 2 mmol/L provides optimal
benefits.31 Lipid-lowering therapy should be considered for most individuals with an LDL-C of 5 mmol/L or a total
cholesterol to high-density lipoprotein cholesterol ratio (TC:HDL-C) of 6.0.31 Attainment of more aggressive targets
may require more intensive treatment with, for example, atorvastatin 80 mg/day32 or rosuvastatin 40 mg/day.
Page 150
Therapeutic Choice
Only 1% of patients discontinue therapy due to muscle discomfort, and there is no increase in myopathy with more
aggressive therapy.31
A small minority of patients may require additional therapy with an agent that inhibits cholesterol absorption (i.e.,
ezetimibe or a bile acid sequestrant such as cholestyramine).
Recommendations from the Canadian Cardiovascular Society Guidelines are categorized by cardiovascular risk
(Table 5).31 Starting a statin prior to discharge after an acute MI improves both early and late outcomes. The benefit
is independent of the lipid level at the start of treatment.29 , 33
Table 5: Canadian Cardiovascular Society 2006 Guidelines for Lipid-lowering Treatment
Risk Level 10-year CAD Risk Recommendations
Primary treatment target:

LDL-C < 2.0 mmol/L
High ≥ 20% Secondary treatment target:
TC:HDL-C < 4.0
Initiate treatment when:

LDL-C ≥ 3.5 mmol/L
Moderate 10–19%
TC:HDL-C ≥ 5.0
Initiate treatment when:

LDL-C ≥ 5.0 mmol/L
Low < 10%
TC:HDL-C ≥ 6.0
Adapted from McPherson R et al. Can J Cardiol 2006;22(11):913-27.31
Abbreviations: HDL-C=high-density lipoprotein cholesterol; LDL-C =low-density lipoprotein cholesterol; TC=total cholesterol
Oral Anticoagulants
Oral anticoagulants are recommended for post-MI patients with persistent or paroxysmal atrial fibrillation,
demonstrable LV thrombus, or large infarcts with extensive dyskinetic segments or aneurysm.34 , 35
All post-MI patients seem to benefit modestly from warfarin therapy with a 20% risk reduction relative to ASA in the
combined end-point of death, re-infarction or embolic stroke (ARR 3%). Moderate to high intensity anticoagulation
with warfarin, administered alone or in combination with ASA, is superior to ASA alone in reducing composite
events but is associated with a higher risk of bleeding.36 The increased risk of bleeding and the demands of
adjusting the dose to maintain the INR prevent routine use of warfarin for the secondary prevention of
cardiovascular events post-MI. Consequently, warfarin tends to be reserved for select patients at identifiable risk for
a thrombotic accident.
Therapeutic Tips
It is anticipated that a larger proportion of patients receiving timely reperfusion therapy will qualify as low-risk
survivors of MI.
Patients receiving therapy that closely adheres to published guidelines do significantly better than those whose
therapy does not.
Refer motivated patients to cardiac rehabilitation programs, where available, especially those who are older,
deconditioned, overweight or have modifiable risk factors.
Depression is associated with increased mortality post-MI. Maintain a high level of awareness and treat the
condition appropriately. Avoid the use of tricyclic antidepressants.
The return to usual activity can be guided by a baseline exercise stress test undertaken in the fully ambulated
patient using a modified rehabilitation protocol. Poor exercise endurance, provocation of angina or ischemic
ECG abnormalities may prompt further evaluation and more caution on the path to increased activity. Patients
deemed to be at low risk with good exercise characteristics can often progress to full activity and return to work
in two or three weeks.
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Therapeutic Choice
Give all patients sl nitroglycerin with instructions on how to respond to recurrent chest pain.
Provide an unequivocal recommendation to quit smoking. Encourage the use of nicotine replacement or
bupropion as aids to smoking cessation.
Hormone therapy is not indicated for primary or secondary prevention of cardiovascular events in
postmenopausal women.
Routine use of antioxidant vitamins (vitamin E, vitamin C, beta carotene) for prevention of cardiovascular
events is not recommended
Selective Cox-2 inhibitors and some nonselective NSAIDs such as ibuprofen may reduce the protective effects
of ASA, resulting in atherothrombotic complications.37
Figure 1-Stratifying Post-MI Patients to Conservative or Invasive Therapy
Abbreviations: EF = ejection fraction; HR = heart rate; METS = metabolic equivalents; CABG = coronary
artery bypass graft surgery; PCI = percutaneous coronary intervention
Figure 2-Management of MI Patients After Primary PCI
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Therapeutic Choice
Figure 3-Elements of Cardiac Rehabilitation
Reproduced from Ades PA. Cardiac rehabilitation and secondary prevention of coronary heart disease. N Engl J Med 2001;345
(12):892-902. With permission. Copyright© 2001 Massachusetts Medical Society.
Figure 4-Beta-Blockers in the Chronic Post-MI Period
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Therapeutic Choice
Abbreviations: AV = atrioventricular; BP = blood pressure; DM = diabetes mellitus; HR = heart rate; LV = left ventricular
Adapted with permission from Fig. 2. Gheorghiade M, Goldstein S. Beta blockers in the post-myocardial infarction patient.
Circulation 2002;106:394-8.
Table 6: Drugs Used in the Post-MI Patient
Adverse Costa
Drug Class Drug Dose Effects Drug Interactions Comments
Antiplatelet ASA Nausea, Increased risk of $

Agents Aspirin, 80–325 mg/day vomiting, GI bleeding when
Bufferin, hemorrhage, antiplatelets are
tinnitus, vertigo, given with
Coated
hypersensitivity. anticoagulants (e.g.,
Aspirin, warfarin). Caution
generics with NSAIDs.
Antiplatelet clopidogrel Rash, purpura, Caution with NSAIDs. $$$$

Agents Plavix 75 mg/day diarrhea, PPI use may reduce
bleeding. clopidogrel
efficacy.38
Antiplatelet ticlopidine Diarrhea, rash, Caution with NSAIDs. Rarely used. $$

Agents generics 250 mg BID bleeding, Must monitor
neutropenia neutrophil
(usually counts Q 2 wk
Page 154
Therapeutic Choice
Adverse Costa
reversible), for the first 3

purpura. mo.
Beta1- nadolol Initial: 40–80 Fatigue, Bradycardia with See Figure 4 - $

adrenergic generics mg/day bradycardia, digoxin or Beta-Blockers in
Antagonists, Usual: 120 decreased nondihydropyridine the Chronic
nonselective mg/day exercise capacity, CCBs. Post-MI Period.
headache, Cardiodepressant
impotence, vivid effects with
dreams. nondihydropyridine
Less common: CCBs
hyperglycemia, antiarrhythmics,
depression, heart anesthetics.
failure, heart
block.
Beta1- propranolol Initial: 40 mg Fatigue, Bradycardia with See Figure 4 - $

adrenergic generics BID-TID bradycardia, digoxin or Beta-Blockers in
Antagonists, Usual: 40 mg decreased nondihydropyridine the Chronic
nonselective QID exercise capacity, CCBs. Post-MI Period.
headache, Cardiodepressant Propranolol is
impotence, vivid effects with more likely to
dreams. nondihydropyridine cause CNS side
Less common: CCBs effects
hyperglycemia, antiarrhythmics, (insomnia,
depression, heart anesthetics. depression,
failure, heart vivid dreams)
block. CYP2D6 inhibitors ↑ because of
levels of propranolol greater lipid
and metoprolol. solubility.
Beta1- timolol Initial: 5–10 Fatigue, Bradycardia with See Figure 4 - $

adrenergic Apo-Timol, mg BID bradycardia, digoxin or Beta-Blockers in
Antagonists, other generics Usual: 10 mg decreased nondihydropyridine the Chronic
nonselective BID exercise capacity, CCBs. Post-MI Period.
Less common: CCBs
failure, heart
block.
Beta1- atenolol Initial: 50 Fatigue, Bradycardia with See Figure 4 - $

adrenergic Tenormin, mg/day bradycardia, digoxin or Beta-Blockers in
Antagonists, generics Usual: 100 decreased nondihydropyridine the Chronic
selective mg/day exercise capacity, CCBs. Post-MI Period.
Less common: CCBs
failure, heart
block.
Page 155
Therapeutic Choice
Adverse Costa
Beta1- bisoprolol Initial: 2.5 Fatigue, Bradycardia with See Figure 4 - $

adrenergic generics mg/day bradycardia, digoxin or Beta-Blockers in
Antagonists, Usual: 10 decreased nondihydropyridine the Chronic
selective mg/day exercise capacity, CCBs. Post-MI Period.
Less common: CCBs
failure, heart
block.
Beta1- metoprolol Initial: 100 Fatigue, Bradycardia with See Figure 4 - $

adrenergic Betaloc, mg/day bradycardia, digoxin or Beta-Blockers in
Antagonists, Lopresor, Usual: 200 decreased nondihydropyridine the Chronic
selective generics mg/day exercise capacity, CCBs. Post-MI Period.
IR: give in 2 impotence, vivid effects with
divided doses dreams. nondihydropyridine
Less common: CCBs
SR: give once hyperglycemia, antiarrhythmics,
daily depression, heart anesthetics.
failure, heart
block. CYP2D6 inhibitors ↑
levels of propranolol
and metoprolol.
Beta1- acebutolol Initial: 100– Fatigue, Bradycardia with See Figure 4 - $$

adrenergic Rhotral, 200 mg BID bradycardia, digoxin or Beta-Blockers in
Antagonists, Sectral, Apo- Usual: 400 mg decreased nondihydropyridine the Chronic
selective BID exercise capacity, CCBs. Post-MI Period.
Acebutolol,
with ISA headache, Cardiodepressant Agents with ISA
other impotence, vivid effects with
generics have less effect
dreams. nondihydropyridine on resting heart
Less common: CCBs rate than those
hyperglycemia, antiarrhythmics, without ISA.
failure, heart
block.
Beta1- carvedilol Initial: 3.125 Fatigue, Bradycardia with See Figure 4 - $$

adrenergic Apo- mg BID bradycardia, digoxin or Beta-Blockers in
Antagonists Usual: 25 mg decreased nondihydropyridine the Chronic
Carvedilol,
with alpha1- BID exercise capacity, CCBs. Post-MI Period.
other
blocking generics
activity
Less common: CCBs
failure, heart
block.
Edema, dizziness,
nasal congestion
and postural
hypotension due
Page 156
Therapeutic Choice
Adverse Costa
to alpha1
antagonism.
ACE captopril Initial: 6.25 mg Dry cough, Marked ↑ in serum Use lower (i.e., $$
Inhibitors Capoten, TID hyperkalemia, K+ in patients 50%) initial
generics Target dose angioedema receiving K+ doses in
post-MI: 50 mg (unusual). supplements and/or patients on
TID Can precipitate diuretics (↑ risk
renal failure in of hypotension
patients with with
with NSAIDs ↑ risk of
renovascular hypovolemia).
renal dysfunction.
disease, volume Hyperkalemia
depletion or in usually occurs
those receiving Elevated Li + levels only in those on
NSAIDs. K+ supplements
or drugs that
cause K+
retention, those
with renal
impairment or
diabetics with
high serum K+
levels. Assess
SCr and K+ after
a few days, then
regularly.
ACE enalapril Initial: 2.5 mg Dry cough, Marked ↑ in serum Use lower (i.e., $$$
Inhibitors Vasotec, BID hyperkalemia, K+ in patients 50%) initial
generics Target dose in angioedema receiving K+ doses in
HF: 10 mg BID (unusual). supplements and/or patients on
Can precipitate diuretics (↑ risk
patients with with
renal dysfunction.
or drugs that
cause K+
retention, those
with renal
impairment or
diabetics with
high serum K+
levels. Assess
SCr and K+ after
a few days, then
regularly.
ACE lisinopril Initial: 2.5 Dry cough, Marked ↑ in serum Use lower (i.e., $-$$
Inhibitors Zestril, mg/day hyperkalemia, K+ in patients 50%) initial
Target dose: angioedema receiving K+ doses in
Prinivil,
20–35 mg once (unusual). supplements and/or patients on
generics daily Can precipitate diuretics (↑ risk
Page 157
Therapeutic Choice
Adverse Costa
renal failure in ↓ hypotensive effect of hypotension

patients with with NSAIDs ↑ risk of with
renovascular renal dysfunction. hypovolemia).
depletion or in Elevated Li + levels usually occurs
those receiving (potential toxicity). only in those on
or drugs that
cause K+
retention, those
with renal
impairment or
diabetics with
high serum K+
levels. Assess
SCr and K+ after
a few days, then
regularly.
ACE perindopril Initial: 2 Dry cough, Marked ↑ in serum Use lower (i.e., $$
Inhibitors Coversyl mg/day hyperkalemia, K+ in patients 50%) initial
Target dose for angioedema receiving K+ doses in
CAD: 8 mg/day (unusual). supplements and/or patients on
Can precipitate diuretics (↑ risk
patients with with
disease, volume renal dysfunction.
Hyperkalemia
NSAIDs. (potential toxicity).
K+ supplements
or drugs that
cause K+
retention, those
with renal
impairment or
diabetics with
high serum K+
levels. Assess
SCr and K+ after
a few days, then
regularly.
ACE ramipril Initial: 2.5 Dry cough, Marked ↑ in serum Use lower (i.e., $$
Inhibitors Altace, mg/day hyperkalemia, K+ in patients 50%) initial
generics Target dose angioedema receiving K+ doses in
BID or 10 mg Can precipitate diuretics (↑ risk
daily renal failure in of hypotension
patients with with
renal dysfunction.
or drugs that
cause K+
retention, those
Page 158
Therapeutic Choice
Adverse Costa
with renal
impairment or
diabetics with
high serum K+
levels. Assess
SCr and K+ after
a few days, then
regularly.
ACE trandolapril Initial: 1 Dry cough, Marked ↑ in serum Use lower (i.e., $$
Inhibitors Mavik mg/day hyperkalemia, K+ in patients 50%) initial
Target dose angioedema receiving K+ doses in
daily Can precipitate diuretics (↑ risk
patients with with
disease, volume renal dysfunction.
Hyperkalemia
or drugs that
cause K+
retention, those
with renal
impairment or
diabetics with
high serum K+
levels. Assess
SCr and K+ after
a few days, then
regularly.
Angiotensin candesartan Initial: 4 or 8 Hyperkalemia. Marked ↑ in serum Use lower (i.e., $$$
Receptor mg/day Can precipitate K+ in patients 50%) initial
Blockers Atacand Target dose in renal failure in receiving K+ doses in
HF: 32 mg/day susceptible supplements and/or patients on
once daily patients (bilateral diuretics (↑ risk
renovascular of hypotension
disease, those May elevate Li + with
with volume levels (potential hypovolemia).
depletion or with toxicity). Hyperkalemia
concurrent NSAID usually occurs
use). only in those on
K+ supplements
Angioedema has or drugs that
been reported, cause K+
but a causal retention, those
association has with renal
not been impairment or
established. diabetics with
high serum K+
levels. Assess
SCr and K+ after
a few days, then
regularly.
Page 159
Therapeutic Choice
Adverse Costa
Angiotensin valsartan Initial dose Hyperkalemia. Marked ↑ in serum Use lower (i.e., $$$$$
Receptor Diovan post-MI: 20 mg Can precipitate K+ in patients 50%) initial
Blockers BID renal failure in receiving K+ doses in
Target dose susceptible supplements and/or patients on
post-MI:21 160 patients (bilateral
diuretics (↑ risk
mg BID renovascular of hypotension
disease, those May elevate Li + with
with volume levels (potential hypovolemia).
depletion or with toxicity). Hyperkalemia
concurrent NSAID usually occurs
use). only in those on
K+ supplements
Angioedema has or drugs that
been reported, cause K+
but a causal retention, those
association has with renal
not been impairment or
established. diabetics with
high serum K+
levels. Assess
SCr and K+ after
a few days, then
regularly.
HMG CoA atorvastatin Initial: 10 or 20 GI disturbances, CYP3A4 inhibitors Start with 40 $$$
Reductase Lipitor, mg/day sleep (e.g., amiodarone, mg/day if the
Inhibitors generics Maximum: 80 disturbances, cyclosporine, desired ↓ in
mg/day headache, rash, macrolides, protease LDL-C is >
myalgia (with inhibitors, 45%. Maximum
Once daily with and without ↑ gemfibrozil, response is
or without CPK levels), ↑ grapefruit juice, usually evident
meals CPK and azole antifungals, within 4 wk.
transaminase verapamil) increase
levels serum levels of
(reversible). atorvastatin,
Rare: myopathy, lovastatin and
rhabdomyolysis. simvastatin.
HMG CoA fluvastatin Initial: 20 or 40 GI disturbances, Fluconazole inhibits Start with 40 $$$$$
Reductase Lescol mg/day sleep the metabolism and mg/day if the
Inhibitors Maximum: 80 disturbances, increases serum desired ↓ in
mg/day headache, rash, levels of fluvastatin. LDL-C is >
myalgia (with 25%.
Once daily with and without ↑
or without CPK levels), ↑
meals CPK and
transaminase
levels
(reversible).
Rare: myopathy,
rhabdomyolysis.
HMG CoA lovastatin Initial: 20 GI disturbances, CYP3A4 inhibitors $$$$$

Reductase Mevacor, mg/day sleep (e.g., amiodarone,
Inhibitors generics Maximum: 80 disturbances, cyclosporine,
mg/day headache, rash, macrolides, protease
myalgia (with inhibitors,
Page 160
Therapeutic Choice
Adverse Costa
Take with the and without ↑ gemfibrozil,

evening meal CPK levels), ↑ grapefruit juice,
CPK and azole antifungals,
HMG CoA pravastatin Initial: 20 GI disturbances, Low potential for $$

Reductase Pravachol, mg/day sleep drug interactions
Inhibitors generics Maximum: 80 disturbances, (not metabolized by
mg/day headache, rash, CYP450 isozymes).
myalgia (with
Take at bedtime and without ↑
CPK levels), ↑
CPK and
transaminase
levels
(reversible).
Rare: myopathy,
rhabdomyolysis.
HMG CoA rosuvastatin 10–40 mg/day GI disturbances, May increase the INR $$$
Reductase Crestor sleep in patients taking
Inhibitors disturbances, warfarin.
headache, rash,
myalgia (with
and without ↑
CPK levels), ↑
CPK and
transaminase
levels
(reversible).
Rare: myopathy,
rhabdomyolysis.
HMG CoA simvastatin 10–80 mg/day GI disturbances, CYP3A4 inhibitors $$

Reductase Zocor, with the sleep (e.g., amiodarone,
Inhibitors generics evening meal disturbances, cyclosporine,
headache, rash, macrolides, protease
myalgia (with inhibitors,
and without ↑ gemfibrozil,
CPK levels), ↑ grapefruit juice,
CPK and azole antifungals,
a. Cost of 30-day supply of usual or target doses; includes drug cost only.
Page 161
Therapeutic Choice
Abbreviations: IR=immediate release; SR=sustained release; HF=heart failure; PPI=proton pump inhibitor
Legend: $ < $25 $-$$ < $25–50 $$ $25–50 $$$ $50–75 $$$$ $75–100 $$$$$ > $100
Suggested Readings
Antman EM, Anbe DT, Armstrong PW et al. ACC/AHA guidelines for the management of patients with ST-elevation
myocardial infarction. Circulation 2004;110(9):e82-292.
Braunwald,E, Antman EM, Beasley JW et al. ACC/AHA guideline update for the management of patients with unstable
angina and non-ST-segment elevation myocardial infarction--2002. Circulation 2002;106(14):1893-900.
Califf RM, Pieper KS, Lee KL et al. Prediction of 1-year survival after thrombolysis for acute myocardial infarction in
the global utilization of streptokinase and TPA for occluded coronary arteries trial. Circulation 2000;101(19):2231-8.
Libby P. Current concepts of the pathogenesis of the acute coronary syndromes. Circulation 2001;104(3):365-72.
Libby P, Ridker PM. Inflammation and atherothrombosis from population biology and bench research to clinical
practice. J Am Coll Cardiol 2006;48(9 Suppl):A33-46.
Singh M, Reeder GS, Jacobsen SJ et al. Scores for post-myocardial infarction risk stratification in the community.
Circulation 2002;106(18):2309-14.
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for the diagnosis and treatment of dyslipidemia and prevention of cardiovascular disease. Can J Cardiol
2006;22(11):913-27.
32. LaRosa JC, Grundy SM, Waters DD et al. Intensive lipid lowering with atorvastatin in patients with stable
coronary disease. N Engl J Med 2005;352(14):1425-35.
33. Schwartz GG, Olsson AG, Ezekowitz MD et al. Effects of atorvastatin on early recurrent ischemic events in
acute coronary syndromes: the MIRACL study: a randomized controlled trial. JAMA 2001;285(13):1711-8.
34. van Es RF, Jonker JJ, Verheugt FW et al. Aspirin and coumadin after acute coronary syndromes (the ASPECT-2
study): a randomised controlled trial. Lancet 2002;360(9327):109-13.
35. Hurlen M, Abdelnoor M, Smith P et al. Warfarin, aspirin, or both after myocardial infarction. N Engl J Med
2002;347(13):969-74.
36. Hirsh J, Fuster V, Ansell J et al. American Heart Association/American College of Cardiology Foundation guide
to warfarin therapy. Circulation 2003;107(12):1692-711.
37. Antman EM, Bennett JS, Daugherty A et al. Use of nonsteroidal antiinflammatory drugs: an update for
clinicians: a scientific statement from the American Heart Association. Circulation 2007;115(12):1634-42.
2009;180(7):699-700.
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e-Therapeutics+ : Therapeutics : Cardiovascular Disorders: Prevention of Ischemic Stroke Page 1 of 7
Therapeutic Choice
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Cardiovascular Disorders: Prevention of Ischemic Stroke
Robert Côté, MD, FRCPC
Identification of high-risk individuals based on their vascular risk profile is the most efficient strategy for preventing
stroke. Risk factors for a first stroke are classified either as nonmodifiable (e.g., age, sex, family history) or
modifiable (hypertension, dyslipidemia, smoking, diabetes mellitus, carotid disease, atrial fibrillation). Primary
prevention of stroke is covered in detail elsewhere (see Cardiovascular Disorders: Primary Prevention of Vascular
Disease). Secondary prevention of ischemic stroke is the main subject of this chapter.
The occurrence of a first transient ischemic attack (TIA) or ischemic stroke increases the risk of experiencing a
second ischemic event. The short-term prognosis after a first TIA may be worse for patients with certain
characteristics and a particular constellation of symptoms; 8% of these individuals will present with a stroke within
2 days.1 Adverse prognostic indicators include age >60 years, blood pressure ≥140/90 mm Hg, diabetes mellitus,
speech and/or motor symptoms and duration of the symptoms for >10 minutes. Accordingly, these higher risk
patients should be promptly investigated and treated, optimally within 2 weeks of the initial ischemic event.
Goals of Therapy
Prevent disabling neurologic deficits (stroke) and recurrent TIA

Prevent cerebrovascular- and cardiovascular-related mortality
Investigations
Complete history with attention to:

nature, frequency, duration and distribution of symptoms (cerebral localization)
identification of vascular risk factors
complete neurologic assessment
visual assessment including eye movements, visual fields, acuity and funduscopy
complete vascular examination including auscultation (cranium, neck, cardiac), palpation (temporal artery,
peripheral pulses) and blood pressure in both arms
Laboratory tests—indicated in most patients with TIAs or mild strokes (without disabling deficits):
CT brain scan (to exclude a hemorrhagic process and/or TIA mimics), neck and transcranial
ultrasonography
CBC, coagulation parameters, blood glucose, renal, lipid and hepatic enzyme profile
in select patients (young patients or older patients with possible arteritis), more specialized blood tests
(e.g., ESR, immunologic work-up, testing for hypercoagulable states, antiphospholipid antibodies,
homocysteine) should be performed
baseline ECG (exclude atrial fibrillation)
other cardiac tests (e.g., transthoracic or transesophageal echocardiography, Holter monitoring) may be
indicated (usually have a higher yield in patients with established cardiac disease or in young stroke
patients)
MRI, MR angiography (MRA) or CT angiography may be required to confirm the degree of arterial occlusion
and/or exclude other neurologic conditions mimicking cerebral ischemia. Cerebral angiography may be
required in select patients to confirm occlusive vascular disease and appropriateness of endarterectomy.
Therapeutic Choices (Figure 1 - Secondary Prevention of Cerebral Ischemia)
Stop smoking (see Psychiatric Disorders: Smoking Cessation).

Control vascular risk factors through weight reduction, diet modification (reducing alcohol, fat and salt
consumption) and diabetes management if required (see Endocrine and Metabolic Disorders: Obesity, Endocrine
and Metabolic Disorders: Diabetes Mellitus).
Start rehabilitative therapy (physiotherapy, occupational and speech therapy) if indicated.
Carotid Endarterectomy
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Therapeutic Choice
The prevalence of asymptomatic carotid disease in patients aged >65 years can be as high as 10% for the
presence of a stenosis (≥50%). The risk of ischemic stroke increases with the degree of stenosis, progression
of the stenosis and with the presence of coronary disease, hypertension and/or peripheral vascular disease.2
The annual rate of unheralded stroke ipsilateral to a substantial (≥50%) stenosis is about 1.5%. In addition, the
presence of carotid disease is a marker of concomitant coronary disease which accounts for about half of all
ischemic events in these individuals. Presently, no evidence supports the use of ASA for ischemic stroke
prevention in this clinical context although it may be required for its cardioprotective effects in patients with
evidence of coronary disease. The role of prophylactic carotid endarterectomy for asymptomatic carotid disease
may be considered in select individuals with a high degree (≥60%) of stenosis and when performed by
surgeons with low complication rates (≤3%).3 In many cases, however, close follow-up with patient education
about potential neurologic symptoms and elimination or control of vascular risk factors is also acceptable.
Consider carotid endarterectomy in addition to long-term antithrombotic therapy for patients with carotid
symptoms, ipsilateral to a significant (≥70%) carotid stenosis documented by angiography, cervical duplex,
MRA or CT angiography.
Antiplatelet agents are the drugs of choice for long-term prevention of atherothrombotic events (intra-arterial
disease with secondary embolic phenomena).4 , 5
Oral anticoagulants are used to prevent cerebral ischemic events from emboli presumed to be of cardiac origin (see
Cardiovascular Disorders: Supraventricular Tachycardia); however, ASA or other antiplatelet medications are
preferred for the prevention of noncardioembolic ischemic strokes.5
Antihypertensive and lipid-lowering treatments have been shown to be effective for patients who have previously
experienced a TIA or a stroke, especially those who are hypertensive (BP >140/90) or have elevated cholesterol
(LDL-C >2.6 mmol/L).6 , 7 Discussion of appropriate treatment options and targets can be found in the
Cardiovascular Disorders: Hypertension and Cardiovascular Disorders: Dyslipidemias chapters.
Antiplatelet Agents
Acetylsalicylic Acid (ASA)
Often given as initial therapy for stroke prevention, use of ASA in high-risk individuals results in about a 25%
relative risk reduction of vascular events (cardiac and cerebral). Its protective effect is more modest in patients with
TIA or ischemic stroke with a relative risk reduction of approximately 15% for the prevention of major vascular
events.4 It is well tolerated with few (dose-dependent) side effects. Patient acceptability and low cost are
advantages. The recommended dosage for stroke prevention is 50–325 mg/day, depending on the patient's
tolerance and the clinical situation. For example, in patients with concomitant coronary disease the recommended
minimum dosage is 75 mg/day.
When combined with an oral anticoagulant, ASA 100 mg/day provides better protection against cardioembolic
events than an anticoagulant alone in patients with prosthetic heart valves.8 , 9 This combination, however, does
increase the risk of systemic minor bleeding and should be used with caution.
Thienopyridines
Clopidogrel 75 mg daily is somewhat more effective than ASA for the prevention of ischemic events, including
stroke, in patients at high risk of ischemic events.10 The absolute difference in annual rate of ischemic stroke, MI or
vascular death between clopidogrel and ASA is 0.5%, corresponding to an 8.7% relative risk reduction in favour of
clopidogrel. Thus clopidogrel is an alternative antiplatelet agent, albeit an expensive one, in patients who are
allergic to or cannot tolerate ASA.10 It can be prescribed in patients who have new cerebral ischemic events while
on ASA, although there are no clinical trials to support this.
The combination of low-dose ASA and clopidogrel did not significantly reduce the rate of ischemic
events, including stroke, in patients with recent stroke or TIA when compared with clopidogrel
alone,11 or in patients with multiple risk factors, when compared with low-dose ASA alone.12 However,
combination therapy significantly increased the risk of bleeding in clinical trials,11,12 and the risk of
intracranial hemorrhage in the study that enrolled patients with a history of stroke or TIA.11 Thus,
although ASA plus clopidogrel is more effective than ASA alone in patients with acute coronary
syndromes,13 the combination should not be used for long-term secondary prevention of ischemic
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Therapeutic Choice
events in patients with a history of stroke or TIA. Useful Info?
Ticlopidine 250 mg twice daily is comparable to ASA for prevention of all vascular events in patients at risk and
may be slightly superior for stroke prevention.14 Diarrhea and skin rash are common adverse events of ticlopidine.
Neutropenia occurs infrequently but is potentially serious and requires frequent monitoring (every 2 weeks for the
first 3 months). For these reasons, ticlopidine is not recommended for routine use in stroke prevention. Clopidogrel
is as effective as ticlopidine and is better tolerated.
Dipyridamole/ASA
The combination of dipyridamole SR plus low-dose ASA (200/25 mg) given twice daily reduces the relative risk
of stroke by 23% (mostly for ischemic strokes) when compared with ASA in patients with cerebral ischemic
symptoms.15 This finding was confirmed in a randomized controlled trial in which the incidence of death, stroke, MI
or major bleeding complications occurred significantly less often in patients with cerebral ischemia treated with
dipyridamole/ASA than ASA alone (13% vs. 16% over a mean of 3.5 years).16 No increased risk of cardiac events
was reported in the dipyridamole/ASA groups in either study; however, a higher daily dose of ASA may be desirable
in patients with concomitant coronary artery disease. The addition of ASA 81 mg to the dipyridamole/ASA
combination appears reasonable in these patients, though the efficacy and safety of this measure is unknown.
Anticoagulants
Vitamin K antagonists
Oral anticoagulants prevent cerebral and systemic emboli in patients with acute MI, valvular and nonvalvular atrial
fibrillation and prosthetic cardiac valves. The risk of bleeding is influenced by many factors (e.g., the intensity of
anticoagulation, concomitant use of high doses of ASA or other drugs with antiplatelet effects, and the presence of
cerebral white matter changes in the elderly).17 Vitamin K antagonist (nicoumalone, warfarin) therapy is superior
to clopidogrel plus ASA for prevention of vascular events in patients with atrial fibrillation at high risk for stroke.18
Patients with nonvalvular atrial fibrillation and prior TIA/stroke may require a higher target International Normalized
Ratio (INR) of 3 instead of 2.5.19
Others agents
Health Canada has approved dabigatran, a direct thrombin inhibitor, for the prevention of systemic embolism in
patients with atrial fibrillation based on the results of the RE-LY study.20 Other agents, such as oral factor Xa
inhibitors, are also under investigation for this indication.
Therapeutic Tips
In most cases antithrombotic treatment should be continued long term, especially in older individuals with
atherosclerosis and vascular risk factors.
The combination of low-dose ASA and slow-release dipyridamole appears to be more protective than ASA alone
in patients with a recent cerebral ischemic event. For the prevention of recurrent stroke, low dose ASA/slow
release dipyridamole and clopidogrel appear to provide comparable protection.21
It is common practice to switch treatment to dipyridamole/ASA or clopidogrel in patients who experience
recurrent attacks of cerebral ischemia while on low-dose ASA (325 mg/day or less), although this has not been
validated in clinical trials.
It is common practice to prescribe the combination of low-dose ASA (81 mg/day) plus an oral anticoagulant in
patients who have new events on an anticoagulant alone and who are at risk for a cardioembolic stroke,
although this has not been validated in clinical trials. Such patients should be followed very closely, as the risk
for hemorrhagic complications is increased.
Combination therapy (oral anticoagulant plus low-dose ASA) is superior to anticoagulant alone in patients with
prosthetic heart valves but carries an increased risk of minor bleeding episodes. For patients intolerant of ASA,
dipyridamole (400 mg/day) plus an oral anticoagulant may be used. This approach has not been validated in
clinical trials.
In healthy postmenopausal women, the risks associated with combination estrogen/progestin therapy
(increased risk of coronary heart disease, breast cancer and a 40% increase in stroke risk) exceed the beneficial
effects on colorectal cancer and hip fracture.22
In postmenopausal women who have suffered a recent stroke or TIA, hormonal therapy with estrogen does not
Page 166
Therapeutic Choice
have a protective effect.23

The risk of ischemic stroke is increased in users of low-dose oral contraceptives compared with non-users.
This translates into a relatively small increase in the absolute risk of stroke,24 except possibly in the presence of
other risk factors such as hypertension, smoking and prior thromboembolic events. In these settings, oral
contraceptives should probably be avoided.
Figure 1- Secondary Prevention of Cerebral Ischemia
a. Mild or minor stroke = No substantial impact on activities of daily living.

b. If symptomatic carotid stenosis, consider surgery.
Table 1: Drugs Used in Secondary Prevention of Stroke
Drug Costa
Class Drug Dose Adverse Effects Interactions
Anticoagulants warfarin Oral: Dose to maintain Bleeding. Many potential $

Coumadin, INR between 2 and 3 for Skin necrosis. interactions.
generics most cerebrovascular Substrate for CYP
indications; for stroke Coumarin 2C9 and other
prevention in patients anticoagulants are isoenzymes.b
with mechanical heart contraindicated in
valves, maintain INR pregnancy.
between 2.5 and 3.5
Anticoagulants nicoumalone Oral: Dose to maintain Bleeding. Many potential $$$-

Sintrom INR between 2 and 3 for Skin necrosis. interactions. $$$$
most cerebrovascular Substrate for CYP
indications; for stroke Coumarin 2C9 and other
prevention in patients anticoagulants are isoenzymes.b
with mechanical heart contraindicated in
valves, maintain INR pregnancy.
between 2.5 and 3.5
Page 167
Therapeutic Choice
Drug Costa
Anticoagulants dabigatran Usual: 150 mg BID po Bleeding, gastric Combination with $$$$$
Pradax Patients with ↑ bleeding intolerance. strong inhibitors of
risk or >80 years of age: P-gp (e.g.,
110 mg BID po ketoconazole)
contraindicated.
Caution with other
drugs acting on P-
gp.
Antiplatelet ASA Bleeding, usually Hemorrhagic risk ↑ $

Agents Aspirin, Bufferin, 50–325 mg/day po minor (epistaxis, with concomitant
etc.). Gastric use of
Coated Aspirin,
intolerance, GI anticoagulants.
generics
bleeding (gastric
ulcers, erosions),
nausea, heartburn,
constipation, tinnitus
usually dose-related.
Antiplatelet clopidogrel Bleeding, usually Hemorrhagic risk ↑ $$$$

Agents Plavix 75 mg daily po minor. Skin rash with concomitant
(4%); diarrhea use of
(5%). anticoagulants.
PPI use may reduce
clopidogrel
efficacy.25
Antiplatelet ticlopidine Bleeding, usually Hemorrhagic risk ↑ $$$

Agents generics 250 mg BID po minor. Diarrhea (up with concomitant
to 20%), skin rash, use of
neutropenia; anticoagulants.
contraindicated in ↓ digoxin levels.
severe hepatic
impairment. Absorption ↓ by
antacids.
Antiplatelet dipyridamole/ASA Bleeding, usually Hemorrhagic risk ↑ $$$

Agents 200/25 mg 1 capsule BID po minor. Headache, with concomitant
Aggrenox diarrhea. use of
anticoagulants.

b. Clinically significant warfarin interactions listed in Cardiovascular Disorders: Venous Thromboembolism, Table 3.
Dose adjustment may be required in renal impairment; seeAppendices: Dosage Adjustment in Renal Impairment.
CYP=cytochrome P450; GI=gastrointestinal; P-gp=P-glycoprotein
Legend: $ <$20 $$ $20–40 $$$ $40–60 $$$-$$$$ $40–$80 $$$$ $60–80 $$$$$ $80–100
Suggested Readings
Albers GW, Amarenco P, Easton JD et al. Antithrombotic and thrombolytic therapy for ischemic stroke: American
College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th edition). Chest 2008;133(6
Page 168
Therapeutic Choice
Suppl):630S-69S.
Antithrombotic Trialists' Collaboration. Collaborative meta-analysis of randomised trials of antiplatelet therapy for
prevention of death, myocardial infarction, and stroke in high risk patients. BMJ 2002;324(7329):71-86.
Goldstein LB, Adams R, Alberts MJ et al. Primary prevention of ischemic stroke.Circulation 2006;113(24):e873-923.
Hart RG, Pearce LA, Aguilar MI. Meta-analysis: antithrombotic therapy to prevent stroke in patients who have
nonvalvular atrial fibrillation. Ann Intern Med 2007;146(12):857-67.
Sacco RL, Adams R, Albers G et al. Guidelines for prevention of stroke in patients with ischemic stroke or transient
ischemic attack. Stroke 2006;37(2):577-617.
References
1. Johnston SC, Rothwell PM, Nguyen-Huynh MN et al. Validation and refinement of scores to predict very early
stroke risk after transient ischaemic attack. Lancet 2007;369(9558):283-92.
2. Mackey AE, Abrahamowicz M, Langlois Y et al. Outcome of asymptomatic patients with carotid disease.
Asymptomatic Cervical Bruit Study Group. Neurology 1997;48(4):896-903.
3. Goldstein LB, Adams R, Alberts MJ et al. Primary prevention of ischemic stroke: a guideline from the American
Heart Association/American Stroke Association Stroke Council: cosponsored by the Atherosclerotic Peripheral
Vascular Disease Interdisciplinary Working Group; Cardiovascular Nursing Council; Clinical Cardiology
Council; Nutrition, Physical Activity, and Metabolism Council; and the Quality of Care and Outcomes Research
Interdisciplinary Working Group. Circulation 2006;113(24):e873-923.
5. Albers GW, Amarenco P, Easton JD et al. Antithrombotic and thrombolytic therapy for ischemic stroke:
American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th edition). Chest
2008;133(6 Suppl):630S-69S.
6. Amarenco P, Bogousslavsky J, Callahan A et al. High-dose atorvastatin after stroke or transient ischemic
attack. N Engl J Med 2006;355(6):549-59.
7. Chapman N, Huxley R, Anderson C et al. Effects of a perindopril-based blood pressure-lowering regimen on
the risk of recurrent stroke according to stroke subtype and medical history: the PROGRESS Trial. Stroke
2004;35(1):116-21.
8. Dentali F, Douketis JD, Lim W et al. Combined aspirin-oral anticoagulant therapy compared with oral
anticoagulant therapy alone among patients at risk for cardiovascular disease: a meta-analysis of randomized
trials. Arch Intern Med 2007;167(2):117-24.
9. Salem DN, O'Gara PT, Madias C et al. Valvular and structural heart disease: American College of Chest
Physicians Evidence-Based Clinical Practice Guidelines (8th edition). Chest 2008;133 (6 Suppl):593S-629S.
10. CAPRIE Steering Committee. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of
ischaemic events (CAPRIE). Lancet 1996;348(9038):1329-39.
11. Diener HC, Bogousslavsky J, Brass LM et al. Aspirin and clopidogrel compared with clopidogrel alone after
recent ischaemic stroke or transient ischaemic attack in high-risk patients (MATCH): randomised, double-
blind, placebo-controlled trial. Lancet 2004;364(9431):331-7.
12. Bhatt DL, Fox KA, Hacke W et al. Clopidogrel and aspirin versus aspirin alone for the prevention of
atherothrombotic events. N Engl J Med 2006;354(16):1706-17.
14. Hass WK, Easton JD, Adams HP et al. A randomized trial comparing ticlopidine hydrochloride with aspirin for
the prevention of stroke in high-risk patients. Ticlopidine Aspirin Stroke Study Group. N Engl J Med 1989;321
(8):501-7.
15. Diener HC, Cunha L, Forbes C et al. European Stroke Prevention Study. 2. Dipyridamole and acetylsalicylic
acid in the secondary prevention of stroke. J Neurol Sci 1996;143(1-2):1-13.
16. SPRIT Study Group; Halkes PH, van Gijn J et al. Aspirin plus dipyridamole versus aspirin alone after cerebral
ischaemia of arterial origin (ESPRIT): randomised controlled trial. Lancet 2006;367(9523):1665-73.
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Therapeutic Choice
17. Singer DE, Albers GW, Dalen JE et al. Antithrombotic therapy in atrial fibrillation: American College of Chest
Physicians Evidence-Based Clinical Practice Guidelines (8th edition). Chest 2008;133 (6 Suppl):546S-92S.
18. ACTIVE Writing Group of the ACTIVE Investigators, Connolly S, Pogue J et al. Clopidogrel plus aspirin versus
oral anticoagulation for atrial fibrillation in the Atrial fibrillation Clopidogrel Trial with Irbesartan for
prevention of Vascular Events (ACTIVE W): a randomised controlled trial. Lancet 2006;367(9526):1903-12.
19. The European Atrial Fibrillation Trial Study Group. Optimal oral anticoagulant therapy in patients with
nonrheumatic atrial fibrillation and recent cerebral ischemia. N Engl J Med 1995;333(1):5-10.
20. Connolly SJ, Ezekowitz MD, Yusuf S et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl
J Med 2009;361(12):1139-51.
21. Sacco RL, Diener HC, Yusuf S et al. Aspirin and extended-release dipyridamole versus clopidogrel for
recurrent stroke. N Engl J Med 2008;359(12):1238-51.
22. Rossouw JE, Anderson GL, Prentice RL et al. Risks and benefits of estrogen plus progestin in healthy
postmenopausal women: principal results From the Women's Health Initiative randomized controlled trial.
JAMA 2002;288(3):321-33.
23. Viscoli CM, Brass LM, Kernan WN et al. A clinical trial of estrogen-replacement therapy after ischemic stroke.
N Engl J Med 2001;345(17):1243-9.
24. Gillum LA, Mamidipudi SK, Johnston SC. Ischemic stroke risk with oral contraceptives: a meta-analysis. JAMA
2000;284(1):72-8.
2009;180(7):699-700.
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e-Therapeutics+ : Therapeutics : Cardiovascular Disorders: Primary Prevention of Vascular... Page 1 of 8
Therapeutic Choice
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Cardiovascular Disorders: Primary Prevention of Vascular Disease

Date Revised: November 2008
Tania Mysak, BSP, PharmD
Vascular disease remains a top contributor to morbidity and mortality in Canada. It is well recognized that many
modifiable risk factors are undertreated, leaving a care gap with costly consequences for our health care system.1 , 2
Prevention of morbidity and mortality from vascular disease requires early recognition and management of
modifiable risk factors such as poor diet, sedentary lifestyle, obesity, elevated blood pressure, elevated cholesterol,
diabetes mellitus and smoking.
Primary prevention of vascular disease involves management of risk factors before the patient suffers a vascular
event such as myocardial infarction or stroke.3 While the data supporting pharmacologic therapies in secondary
prevention of vascular disease (i.e., management of risk factors after the patient has suffered a vascular event) are
fairly robust, evidence supporting primary prevention strategies is relatively sparse in comparison.
Goals of Therapy
Prevent vascular events, including myocardial infarction, stroke or amputation

Prevent vascular mortality
Minimize adverse effects from drug therapy
Preserve quality of life
Investigations
At all appropriate visits determine:

blood pressure using standardized techniques4
smoking status3
patient weight. Calculate hip-to-waist ratio and body mass index (BMI)3
All men ≥ 40 years, all women who are postmenopausal or ≥ 50 years, and any adult with vascular risk factors
including diabetes mellitus, cigarette smoking, hypertension, obesity and/or a family history of premature
coronary artery disease should:
have a lipid profile done every one to three years. The more frequent screening is for patients with
abnormal values or those requiring treatment5
be screened for peripheral arterial disease (PAD) on the basis of symptoms and measurement of the ankle-
brachial index (ABI).5 , 6 , 7 This recommendation is controversial. The ABI is the ratio of systolic blood
pressure in the dorsalis pedis or posterior tibial artery to the systolic blood pressure in the brachial artery
and is performed using a blood pressure cuff assisted by an ultrasound Doppler device instead of a
stethoscope. An ABI < 0.9 is indicative of PAD
All individuals ≥ 40 years of age should be screened for diabetes by measuring fasting plasma glucose every
three years. More frequent and/or earlier testing should be considered in people with first-degree relatives with
diabetes, members of high-risk populations (e.g., Aboriginal, Hispanic, Asian, South Asian or African) and those
with hypertension, dyslipidemia, obesity or schizophrenia8
Calculate the patient's cardiovascular risk (see Figure 1 - Global Cardiovascular Risk Assessment). Management
of the patient depends on their risk score. Most patients with type 1 or 2 diabetes mellitus are considered “high
risk”5
Rule out secondary causes of hypertension, dyslipidemia and elevated blood glucose
Figure 1-Global Cardiovascular Risk Assessment
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Therapeutic Choice
Therapeutic Choices
Lifestyle modification including weight loss, increased physical activity, reduced sodium intake and adherence
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Therapeutic Choice
to the DASH (Dietary Approaches to Stop Hypertension) diet can improve control of risk factors and, potentially,
reduce vascular risk.9 , 10
Based primarily on observational studies, current guidelines recommend a diet that emphasizes fruits,
vegetables, fish and low-fat dairy products, and limits intake of saturated and trans fatty acids, simple sugars
and refined carbohydrates.4 , 5 , 6 , 10 , 11
Encourage regular physical activity to maintain physical fitness, vascular health, optimal body weight and
sustain weight loss. Most guidelines suggest 30-60 minutes of moderate intensity exercise (walking, jogging,
cycling or swimming) four to seven days of the week.12
Encourage patients to achieve and maintain a healthy body weight (BMI of 18.5-24.9 kg/m2).3 , 4 , 5 Bariatric
surgery may be required for the morbidly obese.13
Counsel patients to stop using tobacco and minimize exposure to second-hand smoke.14 Nonpharmacologic
therapies may include psychological counselling.
Patients should limit alcohol intake to a maximum of two standard drinks per day for men and one standard
drink per day for women.3
Absolute risk reductions (ARR) for primary preventive strategies are small compared with secondary preventive
strategies. Refer to Table 1 for the ARR and number needed to treat (NNT) to prevent vascular events with the
pharmacologic therapies discussed below.
Hypertension
Lowering blood pressure (BP) with antihypertensive therapy reduces the relative risk of a first major vascular event
by ~20-40% when compared with placebo.15 , 16 Larger reductions in BP produce larger reductions in risk.15 ARR
are small (Table 1); however, the higher the BP, the greater the potential benefits.17 In the absence of other
vascular risk factors (e.g., age > 55, male gender, positive family history, abdominal obesity) or macrovascular
target organ damage, antihypertensive treatment should be initiated if the average BP is ≥ 160/100 mm Hg. In the
presence of target organ damage or other vascular risk factors, treatment should be initiated if the average BP is ≥
140/90 mm Hg. The target BP is <140/90 mm Hg for most patients. In patients with diabetes mellitus or chronic
kidney disease, the target BP is < 130/80 mm Hg.4 The choice of antihypertensive agent is less important than
achieving target BP. See Cardiovascular Disorders: Hypertension for current recommendations on the choice of
antihypertensive agents.
Dyslipidemia
Cholesterol-lowering therapy with HMG Co-A reductase inhibitors (statins) reduces the relative risk of a first
major vascular event by ~15-30% (Table 1) when compared with placebo.18 The primary target of therapy is LDL-C
with the specific target number based on individual patient risk (as per Framingham Risk Score; see Figure 2,
Cardiovascular Disorders: Dyslipidemias). While controversial, current guidelines recommend patients at low risk
should target LDL-C < 5.0 mmol/L; those at medium risk, < 3.5 mmol/L; and those at high risk, < 2.0 mmol/L.5
The lower LDL target for high-risk individuals is based on secondary prevention trials, and the routine use of statins
in medium-risk individuals is controversial.5 , 18 Data for aggressive LDL reduction in primary prevention are
limited. The majority of primary prevention trials involving statins included primarily younger (< 65 years) men,
therefore robust evidence for primary prevention in women and older adults is lacking.19 , 20
Most patients are able to achieve target levels of LDL-C on statin monotherapy, however some patients may require
combination therapy to achieve targets. Evidence is lacking for the use of agents aside from statins in primary
prevention. See Cardiovascular Disorders: Dyslipidemias for current recommendations on the choice of
antihyperlipidemic agents.
Diabetes Mellitus
The target hemoglobin A1c for most patients with type 1 or type 2 diabetes is ≤ 7% and ≤ 6% for those in whom it
can be safely achieved.8 Such tight control of blood glucose reduces the risk of microvascular complications (e.g.,
retinopathy), but evidence linking tight glycemic control to prevention of macrovascular complications is less
robust.21 , 22 The Canadian Diabetes Association Guidelines provide an algorithm to assist in evidence-based
choices for drug therapy.8 See Endocrine and Metabolic Disorders: Diabetes Mellitus for current recommendations
on the choice of antihyperglycemic agents.
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Therapeutic Choice
Antithrombotics
The role of antiplatelet therapy in primary prevention of vascular disease is controversial. A meta-analysis of data
from five major primary prevention trials suggests that treating 143 patients for five years with ASA prevents one
nonfatal MI (30% RRR) and treating 270 patients for five years prevents one “important vascular event” (15% RRR).
This benefit is offset by a 1% increase in the annual risk of a GI bleed. The risk of stroke was not significantly
reduced by ASA.23 , 24 Guidelines recommend ASA 75-162 mg/day for patients at “moderate risk” (defined as 10-
year CV risk > 10% according to FRS).3
The data on which this recommendation is based were obtained from studies that enrolled predominantly men. The
Women’s Health Study (WHS) found that ASA 100 mg every other day reduces the relative risk of stroke in women
aged 45 years or older by 17% (ARR 0.3%, NNT 333), but not the risk of MI or vascular death.25 A subsequent
meta-analysis of this and other studies of ASA concluded that there are differences between men and women.26
However, older women in the WHS (those aged 65 years and older) experienced a vascular benefit from ASA in the
form of a 26% relative reduction in the risk of major vascular events (ARR 2.2%, NNT 46), a 34% relative reduction
in the risk of MI (ARR 1%, NNT 100), but no reduction in the risk of stroke.25 Epidemiologic data from the Nurses'
Health Study also suggest a possible age-related vascular benefit from ASA.27 At this time a standard
recommendation for use of ASA that applies to all persons cannot be made.
Patients with atrial fibrillation are at high risk for cardioembolic stroke and may be candidates for warfarin therapy
to prevent a first stroke or transient ischemic attack (TIA). CHADS2 is a risk assessment tool that can be used to
stratify patients by their risk of stroke on the basis of risk factors including congestive heart failure (“C”),
hypertension (“H”), age > 75 years (“A”), diabetes mellitus (“D”) and history of stroke or TIA (“S”).23 ASA 325 mg
daily is an alternative to warfarin for low-risk patients.28 , 29 A complete description of CHADS2 is provided in
Cardiovascular Disorders: Supraventricular Tachycardia.
Smoking Cessation
Observational studies suggest that the elevated vascular risk induced by cigarette smoking can be decreased by
quitting and reversed after five years of abstinence.30 Successful smoking cessation can be enhanced by nicotine
replacement therapy (NRT) (gum, patch, inhalers), bupropion and varenicline. Bupropion and NRT are roughly
equivalent in terms of efficacy, and either varenicline or the combination of bupropion and NRT may provide higher
success rates.31 , 32 , 33
Nonpharmacologic interventions, in combination with pharmacologic therapies, are effective in optimizing success
rates, and may be superior to pharmacologic therapies alone.32 See Psychiatric Disorders: Smoking Cessation for
current recommendations on the choice of nonpharmacologic and pharmacologic therapies.
Obesity
Orlistat is approved for obesity management. It produces a 5–10% weight loss that is maintained over 2 years in
~60% of patients; however, the impact of drug-induced weight loss of this magnitude on vascular morbidity and
mortality is unknown.34 Discontinuation of orlistat generally leads to weight regain, therefore, effective management
must focus on lifestyle changes. Drug therapy should be regarded as a therapeutic trial and stopped if significant
weight loss is not achieved after several months.35 See Endocrine and Metabolic Disorders: Obesity for current
recommendations on the choice of nonpharmacologic and pharmacologic therapies.
Nutritional Supplements
There is no conclusive evidence that omega-3 supplementation reduces vascular risk, although dietary
recommendations suggest including these foods in a balanced diet.36 Interpretation of data regarding
omega-3 fatty acids (found in oily fish and plants) is hindered by poor study design. Reduction of risk
by vitamin therapy (e.g., folic acid, vitamin E) in patients with established vascular disease has largely
been shown to be ineffective, and current data do not support supplementation in primary
prevention.37,38,39,40 Useful Info?
Hormone Therapy (HT)
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Therapeutic Choice
Women should not be encouraged to continue HT if the sole reason is vascular protection. While observational data
suggested a vascular risk reduction benefit of hormone therapy in postmenopausal women, experimental data have
refuted that claim.41
Therapeutic Tips
View every patient encounter as an opportunity to identify risk factors, discuss risk factor modification and
encourage patient progress.
Consider nonpharmacologic management to be an essential component of risk reduction strategies. Drugs can
have adverse effects. Patients suitable for primary prevention have not yet experienced symptoms of disease
and may not wish to be “medicalized.”
Individualize patient goals based on the risk of having an event. The comparatively small absolute benefits of
many drug therapies for primary prevention warrant discussion with patients regarding their personal health
goals and willingness to undertake drug therapy.
Patients must make the link between risk factors and potential consequences (i.e., major vascular events).
Stress the importance of risk factor reduction in these terms, not simply to reduce surrogate markers (e.g.,
cholesterol, blood pressure).
Pharmacologic choices should include consideration of significant cost differences between therapies that are
equally effective.
Table 1: Primary Prevention of Coronary Events and Stroke
ARR
Outcome (%)
Prevented Intervention Comparator NNT Potential Risks
Coronary event42 Antihypertensive Placebo 0.7a 143 over 4–5 Symptoms of hypotension
therapy years Side effects of drug
therapy
Coronary event18 Statin Placebo 1.4 73 over 4–5 Rhabdomyolysis 0.2% per
years year43
Coronary event26
• Men ASA Placebo 0.85 118 over 5 GI bleed 1% per year24

years
• Women ASA Placebo NS NS GI bleed 1% per year24
Stroke42 Antihypertensive Placebo 1.3 77 over 4–5 Symptoms of hypotension

therapy years Side effects of drug
therapy
Stroke18 Statin Placebo 0.4 280 over 5 Rhabdomyolysis 0.2% per

years year43
Stroke26
• Men ASA Placebo NS NS GI bleed 1% per year24
• Women ASA Placebo 0.24 417 over 10 GI bleed 1% per year24

years
a. Absolute benefits are correlated with baseline risk.17
Abbreviations: ARR =absolute risk reduction; NNT =number needed to treat to prevent one outcome; NS=not significant
Suggested Readings
Abramson BL, Huckell V, Anand S et al. Canadian Cardiovascular Society Consensus Conference: peripheral arterial
disease—executive summary. Can J Cardiol 2005;21(12):997-1006.
Page 175
Therapeutic Choice
Canadian Diabetes Association Clinical Practice Guidelines Expert Committee. Canadian Diabetes Association 2003
clinical practice guidelines for the prevention and management of diabetes in Canada. Can J Diabetes 2003:27(Suppl
2):S1-152.
Canadian Hypertension Education Program. CHEP 2007 recommendations.
Lau DC, Douketis JD, Morrison KM et al. 2006 Canadian clinical practice guidelines on the management and
prevention of obesity in adults and children [summary]. CMAJ 2007;176(8):S1-13.
McPherson R, Frohlich, J, Fodor G et al. Canadian Cardiovascular Society position statement—recommendations for
the diagnosis and treatment of dyslipidemia and prevention of cardiovascular disease. Can J Cardiol 2006;22
(11):913-27.
References
1. Joffres MR, Ghadirian P, Fodor JG et al. Awareness, treatment, and control of hypertension in Canada. Am J
Hypertens 1997;10(10 Pt 1):1097-102.
2. McLean DL, Simpson SH, McAlister FA et al. Treatment and blood pressure control in 47,964 people with
diabetes and hypertension: a systematic review of observational studies. Can J Cardiol 2006;22(10):855-60.
3. Pearson TA, Blair SN, Daniels SR et al. AHA Guidelines for Primary Prevention of Cardiovascular Disease and
Stroke: 2002 Update: Consensus Panel Guide to Comprehensive Risk Reduction for Adult Patients Without
Coronary or Other Atherosclerotic Vascular Diseases. American Heart Association Science Advisory and
Coordinating Committee. Circulation 2002;106(3):388-91.
4. Canadian Hypertension Education Program. CHEP 2007 recommendations.
5. McPherson R, Frohlich, J, Fodor G et al. Canadian Cardiovascular Society position statement—
recommendations for the diagnosis and treatment of dyslipidemia and prevention of cardiovascular disease.
Can J Cardiol 2006;22(11):913-27.
6. Abramson BL, Huckell V, Anand S et al. Canadian Cardiovascular Society Consensus Conference: peripheral
arterial disease-executive summary. Can J Cardiol 2005;21(12):997-1006.
7. Beckman JA, Jaff MR, Creager MA. The United States preventive services task force recommendation statement
on screening for peripheral arterial disease: more harm than benefit? Circulation 2006;114(8):861-6.
8. Canadian Diabetes Association Clinical Practice Guidelines Expert Committee. Canadian Diabetes Association
2003 clinical practice guidelines for the prevention and management of diabetes in Canada. Can J Diabetes
2003:27(Suppl 2):S1-152.
9. Elmer PJ, Obarzanek E, Vollmer WM et al. Effects of comprehensive lifestyle modification on diet, weight,
physical fitness and blood pressure control: 18-month results of a randomized trial. Ann Intern Med 2006;144
(7):485-95.
10. Appel LJ, Moore TJ, Obarzanek E et al. A clinical trial of the effects of dietary patterns on blood pressure.
DASH Collaborative Research Group. N Engl J Med 1997;336(16):1117-24.
11. Health Canada. Eating well with Canada’s food guide. Ottawa (ON): Health Canada; 2007. Available from:
http://www.hc-sc.gc.ca/fn-an/food-guide-aliment/index-eng.php. Accessed December 9, 2008.
12. American Heart Association Nutrition Committee; Lichtenstein AH, Appel LJ, Brands M et al. Diet and lifestyle
recommendations revision 2006: a scientific statement from the American Heart Association Nutrition
Committee. Circulation 2006;114(1):82-96.
13. Kral JG. ABC of obesity. Management part III–surgery. BMJ 2006;333(7574):900-3.
14. [No authors listed]. A clinical practice guideline for treating tobacco use and dependence: A US Public Health
Service report. The Tobacco Use and Dependence Clinical Practice Guideline Panel, Staff, and Consortium
Representatives. JAMA 2000;283(24):3244-54.
15. Neal B, MacMahon S, Chapman N et al. Effects of ACE inhibitors, calcium antagonists, and other blood-
pressure-lowering drugs: results of prospectively designed overviews of randomised trials. Blood Pressure
Lowering Treatment Trialists' Collaboration. Lancet 2000;355(9246):1955-64.
16. Turnbull F; Blood Pressure Lowering Treatment Trialists' Collaboration. Effects of different blood-pressure-
lowering regimens on major cardiovascular events: results of prospectively designed overviews of randomized
trials. Lancet 2003;632(9395):1527-35.
17. Ogden L, He J, Lydick E et al. Long-term absolute benefit of lowering blood pressure in hypertensive patients
Page 176
Therapeutic Choice
according to JNC VI risk stratification. Hypertension 2000;35(2):539-43.
18. Thavendiranathan P, Bagai A, Brookhart MA et al. Primary prevention of cardiovascular diseases with statin
therapy: a meta-analysis of randomized controlled trials. Arch Intern Med 2006;166(21):2307-13.
19. Walsh JM, Pignone M. Drug treatment of hyperlipidemia in women. JAMA 2004;291(18):2243-52.
20. Shepherd J, Blauw GJ, Murphy MB et al. Pravastatin in elderly individuals at risk of vascular disease
(PROSPER): a randomized controlled trial. Lancet 2002;360(9346):1623-30.
21. [No authors listed]. Intensive blood-glucose control with sulphonylureas or insulin compared with
conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective
Diabetes Study (UKPDS) Group. Lancet 1998;352(9131):837-53.
22. Nathan DM, Cleary PA, Blacklund JY et al. Intensive diabetes treatment and cardiovascular disease in patients
with type 1 diabetes. N Eng J Med 2005;353(25):2643-53.
23. Eidelman RS, Hebert PR, Weisman SM et al. An update on aspirin in the primary prevention of cardiovascular
disease. Arch Intern Med 2003;163(17):2006-10.
24. Derry S, Loke YK. Risk of gastrointestinal hemorrhage with long term use of aspirin: meta-analysis. BMJ
2000;321(7270):1183-7.
25. Ridker PM, Cook NR, Lee IM et al. A randomized trial of low-dose aspirin in the primary prevention of
cardiovascular disease in women. N Engl J Med 2005;352(13):1293-304.
26. Berger JS, Roncaglioni MC, Avanzini F et al. Aspirin for the primary prevention of cardiovascular events in
women and men; a sex specific meta-analysis of randomized controlled trials. JAMA 2006;295(3):306-13.
27. Chan AT, Manson JE, Feskanich D et al. Long-term aspirin use and mortality in women. Arch Intern Med
2007;167(6):562-72.
28. Goldstein LB, Adams R, Alberts MJ et al. Primary prevention of ischemic stroke: a guideline from the American
Heart Association/American Stroke Association Stroke Council: cosponsored by the Atherosclerotic Peripheral
Vascular Disease Interdisciplinary Working Group; Cardiovascular Nursing Council; Clinical Cardiology
Council; Nutrition, Physical Activity, and Metabolism Council; and the Quality of Care and Outcomes Research
Interdisciplinary Working Group: the American Academy of Neurology affirms the value of this guideline.
Stroke 2006;37(6):1583-633.
29. Singer DE, Albers GW, Dalen JE et al. Antithrombotic therapy in atrial fibrillation: the Seventh ACCP
Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004;126(3 Suppl ):429S-56S.
30. Wolf PA, D’Agostino RB, Kannel WB et al. Cigarette smoking as a risk factor for stroke. The Framingham
Study. JAMA 1988;259(7):1025-9.
31. Okuyemi KS, Nollen NL, Ahluwalia JS. Interventions to facilitate smoking cessation. Am Fam Physician
2006;74(2):262-71.
32. Ranney L, Melvin C, Lux L et al. Systematic review: smoking cessation intervention strategies for adults and
adults in special populations. Ann Intern Med 2006;145(11):845-56.
33. Wu P, Wilson K, Dimoulas P et al. Effectiveness of smoking cessation therapies: a systematic review and
meta-analysis. BMC Public Health 2006;6:300.
34. Padwal RS, Majumdar SR. Drug treatments for obesity: orlistat, sibutramine, and rimonabant. Lancet
2007;369(9555):71-7.
35. Lean M, Finer N. ABC of obesity. Management: part II—drugs. BMJ 2006;333(7572):794-7.
36. Hooper L, Thompson RL, Harrison RA et al. Omega 3 fatty acids for prevention and treatment of cardiovascular
disease. Cochrane Database Syst Rev 2004;(4):CD003177.
37. Toole JF, Malinow MR, Chambless LE et al. Lowering homocysteine in patients with ischemic stroke to prevent
recurrent stroke, myocardial infarction, and death: the Vitamin Intervention for Stroke Prevention (VISP)
randomized controlled trial. JAMA 2004;291(5):565-75.
38. Bonaa KH, Njolstad I, Ueland PM et al. Homocysteine lowering and cardiovascular events after acute
myocardial infarction. N Engl J Med 2006;354(15):1578-88.
39. Lonn E, Yusuf S, Arnold MJ et al. Homocysteine lowering with folic acid and B vitamins in vascular disease. N
Engl J Med 2006;354(15):1567-77.
40. Lonn E, Bosch J, Yusuf S et al. Effects of long-term vitamin E supplementation on cardiovascular events and
cancer: a randomized controlled trial. JAMA 2005;293(11):1338-47.
41. Gabriel SR, Carmona L, Roque M et al. Hormone replacement therapy for preventing cardiovascular disease in
post-menopausal women. Cochrane Database Syst Rev 2005;(2):CD002229.
42. Herbert PR, Moser M, Mayer J et al. Recent evidence on drug therapy of mild to moderate hypertension and
decreased risk of coronary heart disease. Arch Intern Med 1993;153(5):578-81.
43. Kashani A, Phillips CO, Foody JM et al. Risks associated with statin therapy: a systematic overview of
randomized clinical trials. Circulation 2006;114(25):2788-97.
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Page 178
e-Therapeutics+ : Therapeutics : Cardiovascular Disorders: Raynaud’s Phenomenon Page 1 of 5
Therapeutic Choice
Print Close
Cardiovascular Disorders: Raynaud’s Phenomenon
André Roussin, MD, FRCPC
Goals of Therapy
Reduce the frequency and severity of attacks

Decrease symptoms (cold-induced blanching of the fingers) in patients with primary or secondary Raynaud’s
phenomenon
Prevent local and systemic deterioration in secondary Raynaud’s phenomenon
Heal lesions in patients with secondary Raynaud’s phenomenon
Investigations (Figure 1 - Investigation and Management of Raynaud’s Phenomenon)
Thorough history to differentiate between:

primary Raynaud’s phenomenon (no associated illness or trauma)
secondary Raynaud’s phenomenon (secondary to occupational hazards, vascular diseases, connective tissue
diseases [CTD], carpal tunnel syndrome, hypothyroidism or other disorders)
possible drug-induced Raynaud’s phenomenon (see Table 1)
Physical examination for:
altered pulsations between attacks
abnormal Allen's test, which is done by compressing both the radial and ulnar arteries while clenching the
hand, then releasing compression alternately to demonstrate the patency of the arteries
local signs of CTD (e.g., sclerodactyly) and carpal tunnel syndrome
systemic signs of CTD (e.g., telangiectasis, pulmonary fibrosis), vascular diseases and hypothyroidism
evidence of digital ischemic lesions
Laboratory tests:
nailfold capillary microscopy where available to detect megacapillaries and other abnormalities suggestive
of scleroderma and other CTD. Where available, capillaroscopy will help to diagnose early scleroderma in
patients with recent onset of Raynaud’s phenomenon, especially when the presentation is atypical or if
symptoms suggestive of collagen vascular disease are suspected
ANA (antinuclear antibodies), ENA (extractable nuclear antibodies), ACA (anticentromere antibodies) and
rheumatoid factor to detect CTD
other tests (ESR, serum electrophoresis, cryoglobulins and all other immunologic tests) are less useful as
early markers of secondary Raynaud’s phenomenon
normal test results suggest primary Raynaud’s phenomenon
Table 1: Drugs Implicated in Secondary Raynaud’s Phenomenon
Drug Comment
Antineoplastic Bleomycin-, vinblastine- and cisplatin-containing regimens have been associated with
agents Raynaud’s phenomenon
Beta-blockers Unlikely but controversial. Evidence implicating beta-blockers in Raynaud’s phenomenon is

equivocal 1
Cyclosporine Not dose related
Ergot derivatives Bromocriptine, ergonovine maleate, methysergide
Interferon alfa, beta When used for treatment of cancer, viral hepatitis and multiple sclerosis. May persist for
several months after withdrawal
Therapeutic Choices (Figure 1 - Investigation and Management of Raynaud’s

Phenomenon)
Minimize cold exposure.
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Therapeutic Choice
Avoid prescribing medications with vasoconstrictive potential (e.g., ergot derivatives, beta-blockers) unless
there is a compelling reason, such as use of a beta-blocker in a patient with coronary artery disease.
Reassure patients that no complications arise from primary Raynaud’s phenomenon.
Teach warming exercises such as swinging the arms vigorously (windmill effect).
Instruct patients to dress warmly (including the head and neck) to avoid a sympathetically mediated
vasoconstrictive reflex and use warming devices in mittens or boots if appropriate and affordable.
Encourage patients to stop smoking and to avoid using vibrating tools (grinders, pneumatic hammers, drills,
chain saws).
Acupuncture was ineffective in patients with secondary Raynaud’s phenomenon enrolled in a randomized,
double-blind, placebo-controlled trial.2
Many negative studies of pharmacologic therapy for Raynaud’s phenomenon have never been published. This
complicates the interpretation of the numerous small studies and case reports that report positive outcomes for a
variety of drugs.
There are no evidence-based or consensus-based guidelines for the pharmacologic treatment of Raynaud’s
phenomenon. Figure 1 - Investigation and Management of Raynaud’s Phenomenon is based on the clinical
experience of the author.
Dihydropyridine calcium channel blockers (CCB) reduce the frequency and severity of attacks and are first-line
agents in patients with primary and secondary Raynaud’s phenomenon.3 Nifedipine is the best studied among this
class.4
Patients with primary or secondary Raynaud’s phenomenon may be advised to use a CCB of the dihydropyridine
class (e.g., nifedipine XL 30 mg or felodipine 5–10 mg) 30−60 minutes before cold exposure, or regularly during
the winter months. If a dihydropyridine drug (including amlodipine) is not well tolerated, nondihydropyridine CCBs
may be considered, although they are less effective for Raynaud’s phenomenon.3 , 4 Higher doses may be used in
patients with severe primary or secondary Raynaud’s phenomenon, or if ulcers are present, e.g., scleroderma.
Peripheral alpha-blockers (e.g., prazosin) are less effective than calcium channel blockers, although there are no
head-to-head data to substantiate this opinion. Prazosin was more effective than placebo in patients with
scleroderma secondary to Raynaud’s phenomenon in 2 randomized trials.5 However, the dosage is limited by side
effects in nonhypertensive patients.5
Angiotensin converting enzyme inhibitors, angiotensin II receptor blockers, topical nitrates and pentoxifylline are
generally not effective for Raynaud’s phenomenon.
Intravenous iloprost, a PGI2 analogue, may be useful for short-term treatment of severe secondary Raynaud’s
phenomenon to reduce the frequency and severity of attacks and, in some cases, increase the rate of digital ulcer
healing; oral iloprost is less effective.6 , 7 Oral ketanserin (a serotonin receptor antagonist) reduces the duration
of symptoms somewhat.8 Neither drug is commercially available in Canada.
Newer, unproven and off-label therapies, such as bosentan and phosphodiesterase type 5 inhibitors,
should be considered only for patients with severe secondary Raynaud’s phenomenon. Useful Info?
These drugs are not currently approved for this indication, are costly and have a number of contraindications and
significant side effects. Specialist consultation is recommended before prescribing such therapies.
Bosentan, an endothelin-1 inhibitor approved for pulmonary hypertension, heals digital ulcers and reduces the
Raynaud’s phenomenon in select patients with scleroderma.9
Phosphodiesterase type 5 inhibitors reduce the severity of Raynaud’s phenomenon according to the results of several
small studies.10 Sildenafil 50 mg twice daily reduced the frequency and duration of Raynaud attacks and had
acceptable tolerability in patients with severe secondary Raynaud’s phenomenon resistant to vasodilator therapy in a
randomized, double-blind, placebo-controlled crossover study.11 Vardenafil has also been shown to be effective at
a dose of 10 mg twice daily.12 Several case reports suggest phosphodiesterase inhibitors may be effective in healing
digital ulcers.10
Surgical Choices
Extremity sympathectomy, particularly by thoracoscopy, in patients with difficult secondary Raynaud’s

phenomenon with digital ulcers is not effective in the long term.
Page 180
Therapeutic Choice
Digital sympathectomy may be more effective, although the evidence is very limited.
Choices During Pregnancy and Breastfeeding
Both primary and secondary Raynaud’s phenomenon usually decrease substantially in frequency and intensity during
pregnancy and for at least a few months after delivery. Most patients return to their usual situation afterwards.
Management During Pregnancy and Postpartum Period
For the majority of women whose Raynaud’s phenomenon improves during pregnancy, nonpharmacologic measures
suffice (see Nonpharmacologic Choices). For women with persistent severe Raynaud’s, usually related to
scleroderma, nifedipine can be considered if previous clear benefit has already been experienced with a low dose
of 20 or 30 mg of the long-acting formulation. Nifedipine, although causing fetus malformations in rodents at high
dosage, has not resulted in such problems in humans. Nevertheless, the fact that nifedipine only reduces symptoms
and does not reduce complications such as digital ulcers should be kept in mind and explained to the pregnant
patient, especially since nifedipine is not approved in Canada for use during pregnancy.
Raynaud's and Breastfeeding
Similar considerations regarding pregnancy hold for breastfeeding. Calcium channel blockers are passed on to the
newborn via breastmilk so their use during this period should be avoided. Other classes of drugs have no proven
benefit.
A discussion of general principles on the use of medications in these special populations can be found in Appendix:
Drug Use During Pregnancy and Appendix: Drug Use During Breastfeeding. Other specialized reference sources are
also provided in these appendices.
Therapeutic Tips
Since pharmacologic prophylaxis of Raynaud’s phenomenon is effective in only 60% of patients at most (usually
40%), it is important to stress nonpharmacologic approaches and reassure patients. Only about 5% of patients
with primary Raynaud’s phenomenon will go on to develop secondary Raynaud’s phenomenon. It is the
underlying disease itself rather than the phenomenon that causes complications.
Taking medication daily rather than as needed during the winter will increase tolerance to side effects, e.g.,
headaches.
If dihydropyridines are ineffective, other vasodilators are not likely to be effective.
Laboratory cold-induced tests, such as hand immersion with Doppler measurement of the drop in digital blood
pressure or blood flow, do not reliably predict a patient's response to any given drug, despite the accentuated
response in patients with Raynaud’s phenomenon.
Patients with primary and secondary Raynaud’s phenomenon generally respond equally well to medications; it is
the frequency of attacks, rather than intensity and duration, that is most likely to be reduced with effective drug
therapy.
Figure 1- Investigation and Management of Raynaud’s Phenomenon
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Therapeutic Choice
Table 2: Drugs Used for the Treatment of Raynaud’s Phenomenon
Costa
Class Drug Dose Adverse Effects
Calcium Channel nifedipine PA 20 mg or XL 30 Tachycardia, flushing, headache, $$

Blockers, Adalat XL, mg po 30–60 min dizziness, orthostatic hypotension and
dihydropyridines generics before cold exposure edema.
Calcium Channel felodipine 5–10 mg po 60 min Tachycardia, flushing, headache, $$

Blockers, Renedil, before cold exposure dizziness, orthostatic hypotension and
dihydropyridines Plendil, edema.
generics
Calcium Channel amlodipine 5 mg po 60 min Tachycardia, flushing, headache, $$

Blockers, Norvasc, before cold exposure dizziness, orthostatic hypotension and
dihydropyridines generics edema.
Calcium Channel diltiazem Extended release Usually well tolerated. Occasional $$$
Blockers, Cardizem CD, 180–240 mg po 60– hypotension or orthostatic hypotension,
nondihydropyridines 90 min before cold flushing, arrhythmia and bradycardia.
Tiazac, Tiazac
exposure Use with caution in patients with heart
XC, generics disease.
Alpha1-Adrenergic prazosin 1–2 mg BID po Most common: dizziness, drowsiness, $

Antagonists Minipress, Apo- (regular dosage, to lightheadedness, lack of energy,
Page 182
Therapeutic Choice
Costa
Prazo, other avoid risk of syncope weakness, palpitations, nausea.

generics with irregular use) Less frequent adverse effects include
syncope, edema and angina.
a. Cost per dose; includes drug cost only.
Legend: $ <$0.50 $$ $0.50–1.00 $$$ $1.00–1.50
Suggested Readings
Block JA, Sequeira W. Raynaud’s phenomenon. Lancet 2001;357(9273):2042-8.
Coffman JD. Vasospastic diseases. In: Young JR, editor. Peripheral vascular diseases. St. Louis (MO): Mosby; 1996.
p. 823-9.
Fries R, Shariat K, von-Wilmowsky H et al. Sildenafil in the treatment of Raynaud’s phenomenon resistant to
vasodilatory therapy. Circulation 2005;112(19):2980-5.
Wigley FM. Clinical practice. Raynaud’s phenomenon. N Engl J Med 2002;347(13):1001-8.
References
1. Franssen C, Wollersheim H, de Haan A et al. The influence of different beta-blocking drugs on the peripheral
circulation in Raynaud’s phenomenon and in hypertension. J Clin Pharmacol 1992;32(7):652-9.
2. Hahn M, Steins A, Mohrle M et al. Is there a vasospasmolytic effect of acupuncture in patients with secondary
Raynaud phenomenon? J Dtsch Dermatol Ges 2004;2(9):758-62.
3. Thompson AE, Pope JE. Calcium channel blockers for primary Raynaud’s phenomenon: a meta-analysis.
Rheumatology (Oxford) 2005;44(2):145-50.
4. Thompson AE, Shea B, Welch V et al. Calcium-channel blockers for Raynaud’s phenomenon in systemic
sclerosis. Arthritis Rheum 2001;44(8):1841-7.
5. Pope J, Fenlon D, Thompson A et al. Prazosin for Raynaud’s phenomenon in progressive systemic sclerosis.
Cochrane Database Syst Rev 2000;(2):CD000956.
6. Pope J, Fenlon D, Thompson A et al. Iloprost and cisaprost for Raynaud’s phenomenon in progressive
systemic sclerosis. Cochrane Database Syst Rev 2000;(2):CD000953.
7. Wigley FM, Wise RA, Seibold JR et al. Intravenous iloprost infusion in patients with Raynaud phenomenon
secondary to systemic sclerosis. A multicenter, placebo-controlled, double-blind study. Ann Intern Med
1994;120(3):199-206.
8. Pope J, Fenlon D, Thompson A et al. Ketanserin for Raynaud’s phenomenon in progressive systemic sclerosis.
9. Launay D, Diot E, Pasquier E et al. [Bosentan for treatment of active digital ulcers in patients with systemic
sclerosis]. Presse Med 2006;35(4 Pt 1):587-92. French.
10. Levien TL. Phosphodiesterase inhibitors in Raynaud’s phenomenon. Ann Pharmacother 2006;40(7-8):1388-93.
11. Fries R, Shariat K, von Wilmowsky H et al. Sildenafil in the treatment of Raynaud’s phenomenon resistant to
vasodilatory therapy. Circulation 2005;112(19):2980-5.
12. Caglayan E, Huntgeburth M, Karasch T et al. Phosphodiesterase type 5 inhibition is a novel therapeutic option
in Raynaud disease. Arch Intern Med 2006;166(2):231-3.
Page 183
e-Therapeutics+ : Therapeutics : Cardiovascular Disorders: Stable Angina Page 1 of 10
Therapeutic Choice
Print Close
Cardiovascular Disorders: Stable Angina
Date Prepared: June 2007

P.J. Devereaux, MD
Angina pectoris is a discomfort in the chest and/or an adjacent area resulting from myocardial ischemia (i.e., inadequate blood
supply to the myocardium). Coronary artery disease (CAD) is the most common cause of myocardial ischemia; the therapeutic
discussions in this chapter assume CAD is the underlying etiology, unless indicated otherwise. Other conditions that can cause
myocardial ischemia should be considered when evaluating a patient with angina pectoris (e.g., critical aortic stenosis,
hypertrophic cardiomyopathy, arrhythmia, coronary arterial spasm, anemia). Identifying these less common causes of angina
pectoris is important not only to ensure that appropriate treatments are given, but also to ensure that inappropriate treatments
are not (e.g., to ensure a patient with angina due to hypertrophic cardiomyopathy is not treated with long-acting nitrate therapy).
Goals of Therapy
Minimize the risk of cardiovascular death and nonfatal myocardial infarction

Improve quality of life by decreasing or preventing angina and improving exercise tolerance
Minimize modifiable risk factors
Investigations
History
a thorough history focusing on the patient’s age, sex and discomfort characteristics (i.e., location, precipitating factors
and alleviating factors) is the most important tool for estimating the likelihood that significant CAD is the cause of a
patient’s discomfort (Table 1)
modifiable risk factors for CAD (i.e., diabetes mellitus, smoking, hyperlipidemia and hypertension)
Physical examination to assess for:
hypertension
evidence of atherosclerotic disease, e.g., arterial bruits
evidence of critical aortic stenosis, hypertrophic cardiomyopathy or arrhythmia
Noninvasive cardiovascular testing:
resting ECG
exercise stress test, radionuclide myocardial perfusion imaging or stress echocardiography is helpful in revising the
probability of CAD in patients who have a > 10% or < 90% probability of coronary artery disease based on Table 1 1
echocardiography if critical aortic stenosis or hypertrophic cardiomyopathy is suspected
Laboratory tests:
nonfasting total cholesterol and fasting cholesterol panel
fasting blood glucose
serum creatinine and electrolytes
hemoglobin if anemia is suspected
Table 1: Likelihood of Significant Coronary Artery Disease According to Age, Sex and Character of Symptoms
a a a
Age (y) Nonanginal (%) Atypical Angina (%) Typical Angina (%)
Men Women Men Women Men Women
30–39 5 1 22 4 70 26
40–49 14 3 46 13 87 55
50–59 22 8 59 32 92 79
60–69 28 19 67 54 94 91
a.
The following three questions establish if the discomfort is considered nonanginal chest pain, atypical angina or typical angina.
1. Is the discomfort substernal?
2. Are the symptoms precipitated by exertion?
3. Are the symptoms relieved within ten minutes of rest?
If the patient responds “yes” to all three questions, they have typical angina. If the patient responds “yes” to two of the above, they have
atypical angina. If the patient responds “yes” to one or none of these questions, they have nonanginal chest pain.
Adapted with permission from Diamond GA, Forrester JS. Analysis of probability as an aid in the clinical diagnosis of coronary-artery disease. N
Engl J Med 1979;300(24):1350-8. Copyright © 1979 Massachusetts Medical Society. All rights reserved.
Therapeutic Choices
Page 184
Therapeutic Choice
Educate patients about their disease state and treatment options.

Encourage patients to exercise regularly. Ideally, patients should attend a rehabilitation exercise program with trained
personnel. If not available, instruct patients to undertake dynamic exercise (e.g., walking, jogging, cycling, swimming) and
not isometric exercise (e.g., weight lifting). The frequency and intensity of exercise should increase gradually over a six- to
eight-week period, ultimately targeting 20 to 45 minutes of exercise three to six times a week.
Encourage patients who are overweight to lose weight and see a dietitian.
Pharmacologic Choices (Figure 1 - Medical Management of Stable Angina Pectoris)
Drugs that Decrease the Risk of Cardiovascular Death, Nonfatal Myocardial Infarction or Stroke
There is clear evidence from large randomized controlled trials that patients with angina pectoris benefit from an angiotensin-
converting enzyme (ACE) inhibitor, an antiplatelet agent, and an HMG CoA reductase inhibitor (statin therapy).2 , 3 , 4 Therefore,
unless there is a significant risk or financial restriction, all patients with angina pectoris due to CAD should be treated with an
ACE inhibitor and an antiplatelet agent, and all patients with a nonfasting total cholesterol level ≥ 3.5 mmol/L should receive
statin therapy. Current recommendations are to treat all high-risk patients to a target low-density lipoprotein cholesterol (LDL-C)
5
level < 2 mmol/L.
Antiplatelet Agents (Figure 1)
A systematic review of randomized controlled trials demonstrated that antiplatelet agents decrease the relative risk of
cardiovascular death, nonfatal myocardial infarction (MI) or nonfatal stroke by 30% compared with placebo. It also showed that
ASA 80 to 160 mg daily is as effective as higher doses.2 Randomized controlled trials comparing ASA with clopidogrel or
ticlopidine have not been conducted exclusively in patients with stable angina. Clopidogrel is at least as effective
2
as ASA in patients with a history of MI. The combination of ASA plus clopidogrel offers no advantage over ASA
6
alone in reducing cardiovascular event rates in patients with atherosclerosis. In patients with vascular disease
(i.e., patients with a prior stroke/transient ischemic attack, post-angioplasty or with peripheral vascular disease),
ticlopidine is at least as effective as ASA therapy.7 Clopidogrel is appropriate for those who cannot take ASA.
Ticlopidine is associated with neutropenia, thrombocytopenia and thrombotic thrombocytic purpura, which is rare
but potentially fatal. Thus, the use of ticlopidine should be considered only when a patient cannot take ASA and
cannot afford clopidogrel. Useful Info?
ACE Inhibitors
ACE inhibitors have a number of potential anti-ischemic mechanisms including decreasing sympathetic adrenergic transmission,
reducing afterload and blood pressure and improving coronary flow reserve. ACE inhibitors prevent major cardiovascular events
8
in patients with stable angina who do not have heart failure or left ventricular systolic dysfunction.
In the HOPE trial, which enrolled patients at high risk of cardiovascular events, ramipril 10 mg/day decreased the relative risk of
4
cardiovascular death, nonfatal MI or nonfatal stroke by 20% as compared with placebo in the subgroup of patients with angina.
The mechanism of action of statins is not limited to reducing cholesterol levels but includes improving endothelial function.
The Heart Protection Study (HPS) trial randomized patients with a nonfasting total cholesterol ≥ 3.5 mmol/L and demonstrated
that simvastatin 40 mg daily decreased the relative risk of death by 13%, nonfatal MI by 37% and nonfatal stroke by 26%
compared with placebo.3 For more information on statins, see Cardiovascular Disorders: Dyslipidemias.
Drugs that Decrease or Prevent Angina
There is a paucity of randomized controlled trials comparing anti-ischemic drugs (nitrates, beta-blockers and calcium channel
blockers) in patients with angina.9 , 10 As such, it is reasonable to use any of these drugs, and the choice of which drug to start
with should include consideration of patient-specific factors. For example, a patient with a history of MI should be treated with a
beta-blocker as a first choice.
Nitrates (Table 2)
Nitrates are effective for acute and chronic angina. Sublingual nitroglycerin tablets or spray alleviate anginal pain and, if taken in
advance, can prevent symptoms that occur with activity. Advise patients to sit when taking sublingual nitrates to reduce the risk
Page 185
Therapeutic Choice
of syncope. Long-acting nitrate preparations prevent angina but frequently cause headaches. Tolerance to the anti-anginal effects
of nitrates develops unless a nitrate-free period of 10 to 12 hours is prescribed each day.
Beta-blockers (Table 2)
Beta-blockers lower heart rate, blood pressure and free fatty acid levels, and prevent angina by decreasing myocardial oxygen
demand. Both selective and nonselective beta-blockers are effective. Beta-blockers reduce the risk of MI and mortality in patients
with a prior MI. Avoid beta-blocker therapy in patients with coronary arterial spasm (Prinzmetal's angina).
Calcium Channel Blockers (Table 2)
Verapamil and diltiazem lower heart rate and reduce blood pressure, whereas the dihydropyridines (nifedipine, felodipine,
amlodipine) exert their effects primarily by arteriolar dilatation. Calcium channel blockers are the treatment of choice in patients
with coronary arterial spasm.
Short-acting nifedipine has been associated with higher mortality rates when used in the treatment of acute ischemic syndromes
11 , 12
and hypertension and should be avoided.
Minimize Modifiable Risk Factors
Observational studies demonstrate smoking cessation decreases mortality and morbid cardiac events. Patients who smoke must
be made aware of the risk and encouraged to stop smoking (see Psychiatric Disorders: Smoking Cessation).
Based on the results of the Heart and Estrogen/progestin Replacement Study (HERS trial) and the Women’s Health Initiative trial,
13 , 14
avoid hormone therapy (HT) in postmenopausal women when possible. If HT is required to prevent symptoms, keep the
duration of therapy to a minimum and consider alternative interventions (see Sexual Health: Menopause).
Although observational studies have suggested lower homocysteine levels and vitamin E therapy are beneficial for patients with
angina, large randomized controlled trials have not shown any benefit to folic acid, B vitamins and vitamin E in patients with
angina.
Treat hypertension and diabetes according to the current Canadian guidelines (see Cardiovascular Disorders: Hypertension and
Endocrine and Metabolic Disorders: Diabetes Mellitus).
Coronary Artery Revascularization
Coronary artery revascularization is indicated for medically refractory angina pectoris to improve patients' quality of life by
decreasing frequency of angina. It is also indicated to prolong life in any patient with > 50% stenosis of the left main descending
artery, > 70% stenosis of the proximal left anterior descending coronary artery or > 70% stenosis in three coronary arteries.
Therapeutic Tips
When an ACE inhibitor is prescribed to a patient with renal dysfunction, monitor the serum potassium and creatinine. If a
patient with renal dysfunction can tolerate an ACE inhibitor, the drug will preserve renal function.
Start nitrate therapy at low doses and titrate according to symptoms, ensuring a 10- to 12-hour nitrate-free period each day
to avoid tolerance. Schedule the nitrate-free period for a time when minimal symptoms are expected, usually at night.
If the use of a beta-blocker is desired in a patient with resting bradycardia, try one with intrinsic sympathomimetic activity
(e.g., acebutolol).
Titrate the dose of beta-blockers, diltiazem and verapamil to achieve a resting heart rate between 50 and 60 beats per minute
(BPM) and an exercise heart rate that does not exceed 100 to 110 BPM. The dose of dihydropyridines (e.g. amlodipine,
nifedipine) should be titrated to achieve maximum symptom relief with minimal adverse effects.
In patients with left ventricular systolic dysfunction (ejection fraction < 40%), start beta-blocker therapy at very low doses
and titrate slowly (e.g., no more frequently than every two weeks).
Do not withdraw beta-blocker therapy abruptly in patients who have been on chronic high dose beta-blocker therapy, as this
may precipitate an acute coronary syndrome. Taper the dose over a 10- to 14-day period.
Avoid verapamil and diltiazem in patients with left ventricular systolic dysfunction and use with caution in patients with AV
nodal disease.
As a general rule, when adding a calcium channel blocker to the regimen of a patient with persistent angina who is already
on a beta-blocker, use a long-acting dihydropyridine.
Close monitoring of heart rate and AV nodal function is required if verapamil or diltiazem is combined with beta-blocker
therapy.
Cyclooxygenase-2 (COX-2) inhibitors and all traditional nonsteroidal anti-inflammatory drugs (NSAIDs) increase the risk of
vascular events and thus physicians should minimize their use in patients with angina.15
Figure 1-Medical Management of Stable Angina Pectoris
Page 186
Therapeutic Choice
a.
Agents are not listed in order of preference.
Abbreviations: ACE = angiotensin-converting enzyme; CCB = calcium channel blocker; NTG = nitroglycerin
Table 2: Drugs for Stable Angina
a
Adverse Cost
Nitrates nitroglycerin, SL tab: Headache Potentiates the If discomfort $

sublingual 0.3–0.6 mg (usually hypotensive effects persists after 5
SL PRN Q5min resolves if the of vasodilators. min after 1 dose,
Nitrolingual
Spray: patient persists Potentially fatal patient should
Pumpspray, 0.4 mg PRN Q5min with therapy), hypotension with seek medical
Nitrostat, tachycardia, sildenafil, tadalafil attention
Rho-Nitro hypotension, and vardenafil. immediately.
Pumpspray, syncope (rare), Continue to total
generics dizziness, of 3 doses until
flushing ambulance
edema. arrives.
Nitrates nitroglycerin, Ointment: 1.25–5 cm Headache Potentiates the Ensure a 10–12 h $

topical applied BID-TID (usually hypotensive effects nitrate-free period
Nitrol Remove at end of the resolves if the of vasodilators. daily to prevent
dosing interval patient persists Potentially fatal tolerance.
with therapy), hypotension with
tachycardia, sildenafil, tadalafil
hypotension, and vardenafil.
syncope (rare),
dizziness,
flushing
edema.
Nitrates nitroglycerin, Initial: Headache Potentiates the Ensure a 10–12 h $$

transdermal 0.2 mg/h patch applied (usually hypotensive effects nitrate-free period
& removed daily resolves if the of vasodilators. daily to prevent
Minitran,
patient persists Potentially fatal tolerance.
Nitro-Dur, Max: 0.8 mg/h patch with therapy), hypotension with
Transderm- tachycardia, sildenafil, tadalafil
Nitro, hypotension, and vardenafil.
Trinipatch syncope (rare),
dizziness,
flushing
edema.
Contact
dermatitis.
Page 187
Therapeutic Choice
Adverse Costa
Nitrates isosorbide SL: 5 mg PRN Q5min Headache Potentiates the Ensure a 10–12 h SL: $
dinitrate IR: (usually hypotensive effects nitrate-free period IR: $
generics 10–30 mg TID (allow resolves if the of vasodilators. daily to prevent
for a 10–12 h nitrate- patient persists Potentially fatal tolerance. CR:
free period) with therapy), hypotension with $$-
CR: tachycardia, sildenafil, tadalafil $$$
20–40 mg BID (7 h hypotension, and vardenafil.
apart) syncope (rare),
dizziness,
flushing
edema.
Nitrates isosorbide-5 Initial: Headache Potentiates the To minimize $$

-mononitrate 30 or 60 mg/day (usually hypotensive effects headache, start
resolves if the of vasodilators. with 30 mg once
Imdur,
Max: 240 mg/day patient persists Potentially fatal daily.
generics
with therapy), hypotension with
Once daily tachycardia, sildenafil, tadalafil
hypotension, and vardenafil.
syncope (rare),
dizziness,
flushing
edema.
Antiplatelet Agents ASA 80–325 mg once daily Nausea, Increased risk of Serious GI $
Aspirin, vomiting, bleeding when bleeding is less
Bufferin, gastritis, combined with other common with
bleeding antiplatelets or lower doses
Coated
(epistaxis to anticoagulants. (80–160 mg/day).
Aspirin, major GI
generics bleeds), rash.
Antiplatelet Agents clopidogrel Bleeding, Increased risk of $$$$

Plavix 75 mg once daily diarrhea, rash. bleeding when
combined with other
antiplatelets or
anticoagulants.
PPI use may reduce
clopidogrel
16
efficacy
Antiplatelet Agents ticlopidine Bleeding, Increased risk of Monitor $$

generics 250 mg BID diarrhea, rash, bleeding when neutrophils every
purpura, combined with other 2 wk for the first
neutropenia. antiplatelets or 3 mo of therapy.
anticoagulants.
Beta1-adrenergic nadolol Initial: Fatigue, Bradycardia with Avoid abrupt $

Antagonists, generics 20 mg/day hypotension, digoxin or withdrawal (may
nonselective Max: bradycardia, nondihydropyridine precipitate
320 mg/day impotence, CCBs. ischemia). Taper
Once daily sleep Cardiodepressant the dose before
disorders. effects with discontinuation.
Less common: nondihydropyridine Avoid in severe
hyperglycemia, CCBs and peripheral arterial
depression, amiodarone. disease.
heart failure,
heart block. Contraindicated in
nd
asthma and in 2
or 3rd degree
heart block in the
absence of a
pacemaker.
Page 188
Therapeutic Choice
Adverse Costa
Beta1-adrenergic propranolol, Initial: Fatigue, Bradycardia with Avoid abrupt $

Antagonists, immediate 40–60 mg QID hypotension, digoxin or withdrawal (may
nonselective Usual: bradycardia, nondihydropyridine precipitate
release
80–320 mg/day (divided impotence, CCBs. ischemia). Taper
generics
BID-QID) sleep Cardiodepressant the dose before
heart failure,
heart block. CYP2D6 inhibitors ↑ Contraindicated in
levels of propranolol nd
asthma and in 2
and metoprolol. rd
or 3 degree
heart block in the
Propranolol ↑ serum
absence of a
levels of rizatriptan.
pacemaker.
More likely to
cause CNS side
effects (insomnia,
depression, vivid
dreams) than
other agents
because of greater
lipid solubility.
Beta1-adrenergic propranolol, Fatigue, Bradycardia with Initiate therapy $$$

Antagonists, controlled 60–320 mg/day hypotension, digoxin or with immediate
nonselective bradycardia, nondihydropyridine release
release
impotence, CCBs. preparation.
Inderal-LA sleep Cardiodepressant
disorders. effects with
Less common: nondihydropyridine
hyperglycemia, CCBs and
depression, amiodarone.
heart failure,
heart block. CYP2D6 inhibitors ↑
levels of propranolol
and metoprolol.
Propranolol ↑ serum
levels of rizatriptan.
Beta1-adrenergic timolol Initial: Fatigue, Bradycardia with Avoid abrupt $$

Antagonists, Apo-Timol, 10 mg BID hypotension, digoxin or withdrawal (may
nonselective other Max: bradycardia, nondihydropyridine precipitate
generics 30 mg BID impotence, CCBs. ischemia). Taper
sleep Cardiodepressant the dose before
heart failure,
nd
asthma and in 2
rd
or 3 degree
heart block in the
absence of a
pacemaker.
Beta1-adrenergic atenolol Initial: Fatigue, Bradycardia with Avoid abrupt $

Antagonists, Tenormin, 25 mg/day hypotension, digoxin or withdrawal (may
selective generics Max: 200 mg/day bradycardia, nondihydropyridine precipitate
impotence, CCBs. ischemia). Taper
Once daily or BID sleep Cardiodepressant the dose before
Page 189
Therapeutic Choice
Adverse Costa
heart failure,
asthma and in 2nd
rd
or 3 degree
heart block in the
absence of a
pacemaker.
Beta1-adrenergic bisoprolol Initial: Fatigue, Bradycardia with Avoid abrupt $

Antagonists, generics 2.5 mg/day hypotension, digoxin or withdrawal (may
selective Max: bradycardia, nondihydropyridine precipitate
20 mg/day impotence, CCBs. ischemia). Taper
Once daily sleep Cardiodepressant the dose before
heart failure,
nd
asthma and in 2
rd
or 3 degree
heart block in the
absence of a
pacemaker.
Beta1-adrenergic metoprolol Initial: Fatigue, Bradycardia with Avoid abrupt $

Antagonists, Betaloc, 50 mg/day hypotension, digoxin or withdrawal (may
selective Lopresor, Max: bradycardia, nondihydropyridine precipitate
generics 400 mg/day impotence, CCBs. ischemia). Taper
Give regular sleep Cardiodepressant the dose before
formulations BID; SR disorders. effects with discontinuation.
once daily Less common: nondihydropyridine Avoid in severe
heart failure,
heart block. CYP2D6 inhibitors Contraindicated in
increase levels of asthma and in 2nd
propranolol and
or 3rd degree
metoprolol.
heart block in the
absence of a
pacemaker.
Beta1-adrenergic pindolol Initial: Fatigue, Bradycardia with Avoid abrupt $$

Antagonists, Visken, 5 mg TID hypotension, digoxin or withdrawal (may
nonselective with generics Max: bradycardia, nondihydropyridine precipitate
ISA 15 mg TID or QID impotence, CCBs. ischemia). Taper
heart failure,
nd
asthma and in 2
rd
or 3 degree
heart block in the
absence of a
pacemaker.
Agents with ISA

have less effect on
resting heart rate
Page 190
Therapeutic Choice
Adverse Costa
than those without
ISA.
Beta1-adrenergic acebutolol Initial: Fatigue, Bradycardia with Avoid abrupt $

Antagonists, Rhotral, 200 mg BID hypotension, digoxin or withdrawal (may
selective with ISA Sectral, Apo- Max: bradycardia, nondihydropyridine precipitate
400 mg BID impotence, CCBs. ischemia). Taper
Acebutolol,
other disorders. effects with discontinuation.
generics
heart failure,
asthma and in 2nd
or 3rd degree
heart block in the
absence of a
pacemaker.
Agents with ISA

have less effect on
resting heart rate
than those without
ISA.
Beta1-adrenergic labetalol Initial: Fatigue, Bradycardia with Avoid abrupt $

Antagonists with Trandate, 100 mg BID hypotension, digoxin or withdrawal (may
alpha1-blocking generics Max: bradycardia, nondihydropyridine precipitate
activity 1200 mg BID impotence, CCBs. ischemia). Taper
heart failure,
nd
asthma and in 2
Edema, rd
or 3 degree
dizziness,
heart block in the
nasal
absence of a
congestion and
pacemaker.
postural
hypotension
due to alpha1
antagonism.
Calcium Channel amlodipine Initial: Ankle edema, CYP3A4 substrate $$

Blockers, Norvasc, 2.5 mg/day flushing, (many potential
dihydropyridine generics Max: headache, interactions).
10 mg/day hypotension Strong inhibitors
Once daily and include azole
tachycardia. antifungals, protease
inhibitors,
macrolides and
quinidine. Grapefruit
juice may ↑ serum
concentrations.
Calcium Channel nifedipine XL Initial: Ankle edema, CYP3A4 substrate $$$

Blockers, Adalat XL, 30 mg/day flushing, (many potential
dihydropyridine generics Max: headache, interactions).
120 mg/day hypotension Strong inhibitors
Once daily include azole
antifungals, protease
Page 191
Therapeutic Choice
Adverse Costa
and inhibitors,
tachycardia. macrolides and
juice may ↑ serum
concentrations.
Calcium Channel diltiazem Initial: Headache, CYP3A4 substrate Caution in $$$

Blockers, Cardizem, 120 mg/day dizziness, (many potential patients with heart
nondihydropyridine Max: bradycardia, interactions). nd
Cardizem failure or 2 or
360 mg/day heart block, Strong inhibitors rd
CD, Tiazac, 3 degree heart
Give CD and XC new onset or include azole
Tiazac XC, block without a
formulations once daily worsening of antifungals, protease
functioning
generics heart failure. inhibitors,
pacemaker.
macrolides and
juice may ↑ serum
concentrations.
Nondihydropyridines
inhibit the
metabolism of
carbamazepine,
cyclosporine,
lovastatin,
simvastatin.
Rifampin induces
metabolism of
Additive negative
amiodarone, beta-
blockers and
digoxin.
Calcium Channel verapamil Initial: Headache, CYP3A4 substrate Caution in $$–

Blockers, Covera HS, 80 mg; dizziness, (many potential patients with heart $$$
nondihydropyridine Isoptin SR, Max: 160 mg TID bradycardia, interactions). failure or 2nd or
generics Covera HS (QHS): heart block, Strong inhibitors rd
3 degree heart
Initial: 180 mg/day; new onset or include azole
block without a
Max: 480 mg/day worsening of antifungals, protease
functioning
SR (once daily or BID): heart failure. inhibitors,
pacemaker.
Initial: 180 mg/day; Constipation. macrolides and
Max: 480 mg/day quinidine. Grapefruit
juice may ↑ serum
concentrations.
Nondihydropyridines
inhibit the
metabolism of
carbamazepine,
cyclosporine,
lovastatin,
simvastatin.
Rifampin induces
metabolism of
Additive negative
amiodarone, beta-
blockers and
digoxin.
Verapamil ↑ digoxin
levels by 50–75%
within 1 wk (monitor
levels).
Page 192
Therapeutic Choice
a.
Cost of a 30-day supply of usual dose of drug; includes drug cost only.
Abbreviations: CCBs=calcium channel blockers; IR=immediate release; ISA=intrinsic sympathomimetic activity; PPI=proton pump
inhibitor
Legend: $ < $20 $$ $20–40 $$-$$$ $20–60 $$$ $40–60 $$$$ $ > 60
Suggested Readings
Bennett NM, Paris MC. Coronary artery disease. In: Black ER, Bordley DR, Tape TG et al, editors. Diagnostic strategies for
common medical problems. 2nd ed. Philadelphia (PA): American College of Physicians; 1999. p.47-60.
Sudlow C, Lonn E, Pignone M, Ness A, Rihal C. Secondary prevention of ischaemic cardiac events. Clin Evid 2002;(7):124-60.
References
1. Bennett NM, Paris MC. Coronary artery disease. In: Black ER, Bordley DR, Tape TG et al, editors. Diagnostic strategies for
common medical problems. 2nd ed. Philadelphia (PA): American College of Physicians; 1999. p.47-60.
2. Antithrombotic Trialists' Collaboration. Collaborative meta-analysis of randomised trials of antiplatelet therapy for
prevention of death, myocardial infarction, and stroke in high risk patients. BMJ 2002;324(7329):71-86.
3. Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in
20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet 2002;360(9326):7-22.
4. Yusuf S, Sleight P, Pogue J et al. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events
in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med 2000;342(3):145-53.
5. McPherson R, Frohlich J, Fodor G et al. Canadian Cardiovascular Society position statement--recommendations for the
diagnosis and treatment of dyslipidemia and prevention of cardiovascular disease. Can J Cardiol 2006;22(11):913-27.
6. Bhatt DL, Fox KA, Hacke W et al. Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic
events. N Engl J Med 2006;354(16):1706-17.
7. Cairns JA, Theroux P, Lewis HD et al. Antithrombotic agents in coronary artery disease. Chest 2001;119(1 Suppl):228S-
252S.
8. Danchin N, Cucherat M, Thuillez C et al. Angiotensin-converting enzyme inhibitors in patients with coronary artery disease
and absence of heart failure or left ventricular systolic dysfunction: an overview of long-term randomized controlled trials.
Arch Intern Med 2006;166(7):787-96.
9. Dargie HJ, Ford I, Fox KM. Total Ischaemic Burden European Trial (TIBET). Effects of ischaemia and treatment with
atenolol, nifedipine SR and their combination on outcome in patients with chronic stable angina. The TIBET Study Group.
Eur Heart J 1996;17(1):104-12.
10. Rehnqvist N, Hjemdahl P, Billing E et al. Effects of metoprolol vs verapamil in patients with stable angina pectoris. The
Angina Prognosis Study in Stockholm (APSIS). Eur Heart J 1996;17(1):76-81.
11. Alderman MH, Cohen H, Roque R et al. Effect of long-acting and short-acting calcium antagonists on cardiovascular
outcomes in hypertensive patients. Lancet 1997;349(9052):594-8.
12. Opie LH, Yusuf S, Kubler W. Current status of safety and efficacy of calcium channel blockers in cardiovascular diseases: a
critical analysis based on 100 studies. Prog Cardiovasc Dis 2000;43(2):171-96.
13. Hulley S, Grady D, Bush T et al. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart
disease in postmenopausal women. Heart and Estrogen/progestin Replacement Study (HERS) Research Group. JAMA
1998;280(7):605-13.
14. Rossouw JE, Anderson GL, Prentice RL et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal
women: principal results from the Women's Health Initiative randomized controlled trial. JAMA 2002;288(3):321-33.
15. Kearney PM, Baigent C, Godwin J et al. Do selective cyclo-oxygenase-2 inhibitors and traditional non-steroidal anti-
inflammatory drugs increase the risk of atherothrombosis? Meta-analysis of randomised trials. BMJ 2006;332(7553):1302-
8.
16. Lau WC, Gurbel PA. The drug-drug interaction between proton pump inhibitors and clopidogrel. CMAJ 2009;180(7):699-
700.
Page 193
e-Therapeutics+ : Therapeutics : Cardiovascular Disorders: Supraventricular Tachycardia Page 1 of 13
Therapeutic Choice
Print Close
Cardiovascular Disorders: Supraventricular Tachycardia
Date Prepared: August 2010

David Birnie, MD
Pablo Nery, MD
Supraventricular tachycardia (SVT) includes all tachyarrhythmias arising from above the ventricles. SVT usually has
a narrow QRS width (≤120 ms). Occasionally the QRS complex during tachycardia is broad because there is co-
existent bundle branch block. In this situation the initial step in the differential diagnosis is to exclude ventricular
tachycardia (see Figure 1 - Differential Diagnosis of Supraventricular Tachycardia ).
The classification of common forms of SVT is shown in Table 1.
Table 1: Classification of Supraventricular Tachycardia
Arrhythmia Clinical Significance of Arrhythmia
Atrial Fibrillation Significant because of thromboembolic risk
Atrial Flutter Probably similar thromboembolic risk to atrial fibrillation
Atrioventricular Nodal Re-entry Usually benign

Tachycardia (AVNRT)
Atrioventricular Re-entry Tachycardia Usually benign. There is a risk of sudden death if AVRT degenerates
(AVRT) into pre-excited SVT (rare)
Atrial Tachycardia Usually benign unless it persists for prolonged period (rare)
The terms “permanent,” “persistent” and “paroxysmal” are now used to classify atrial fibrillation and flutter; the
older term “chronic atrial fibrillation” is obsolete (Table 2).
Management of atrial fibrillation and atrial flutter is similar. The risk of thromboembolic complications should be
assessed in both situations. Many patients will have a combination of both arrhythmias. However, there are some
important differences in the management of the two arrhythmias. Firstly, it is often more difficult to achieve heart
rate control in patients with atrial flutter than atrial fibrillation. Secondly, the threshold for catheter ablation for
atrial flutter is lower than the threshold for considering ablation for atrial fibrillation.
An algorithm for the management of newly discovered atrial fibrillation is provided in Figure 2 - Therapy of Newly
Discovered Atrial Fibrillation or Flutter (AF).
1
Table 2: Classification of Atrial Fibrillation or Flutter
Paroxysmal Recurrent self-limiting episodes (lasting less than 7 days)
Persistent Episodes lasting more than 7 days and sinus rhythm achievable (spontaneously or by cardioversion)
Permanent Cardioversion failed or not attempted/planned
The heart is usually structurally normal in patients with atrioventricular re-entry tachycardia (AVRT), atrioventricular
nodal re-entry tachycardia (AVNRT) and focal atrial tachycardia (AT). AVRT is due to a congenital accessory bypass
track between the atria and ventricles. The circuit usually follows an antegrade limb through the AV node and a
retrograde limb through the accessory pathway, although the opposite occasionally occurs. If the accessory pathway
is capable of antegrade conduction during sinus rhythm it usually manifests on the resting ECG as a delta wave and
is known as Wolff-Parkinson-White (WPW) syndrome. AVNRT involves a localized short circuit within the AV node.
Focal AT arises from a localized area of atrial myocardium that is capable of accelerated automatic firing.
Goals of Therapy
Page 194
Therapeutic Choice
In the acute stage the goal is to restore sinus rhythm. Rhythm control should always be possible in re-entrant
arrhythmias (AVRT or AVNRT)
Rhythm control may not be possible or desirable in some patients with atrial fibrillation or atrial flutter or atrial
tachycardia. In these situations the goal is to control the rate of the SVT
In the longer term the goal is to prevent arrhythmia recurrence, or substantially reduce the overall arrhythmia
burden
Reduce the risk of thromboembolic events (stroke) in patients with atrial fibrillation/atrial flutter
Investigations
Detailed history including a description of the onset, frequency and duration of episodes and identification of
possible triggers, e.g., alcohol, caffeine, exercise, hyperthyroidism. In most patients there are no consistant
triggers.
Document the arrhythmia, ideally on 12-lead ECG, but a Holter or loop monitor is also acceptable
Echocardiography to assess left ventricular function, left atrial size and valvular status
Therapeutic Choices
Cardioversion
In general, any tachycardia that produces hemodynamic compromise, heart failure or angina, and is resistant to
prompt medical management should be terminated electrically. Most supraventricular arrhythmias, with the
exception of atrial flutter and fibrillation, are usually responsive to medical therapy and hence cardioversion is
seldom necessary. Furthermore, cardioversion can be a useful adjunctive therapy in patients with persistent atrial
fibrillation or flutter. A synchronized shock on the R wave is used and there is no evidence that any paddle position
is more effective than another. It is normal to start with the anterior-apex position, and if this is unsuccessful, then
another position, usually antero-posterior, is tried. The initial success rate of cardioversion for atrial fibrillation is 70
–90% but only about 20% of patients will remain in sinus rhythm at 12-months' follow-up. Using additional
antiarrhythmic therapy can improve maintenance of sinus rhythm. For example, 50–70% of patients treated with
amiodarone are still in sinus rhythm at 12 months. Direct current cardioversion has a low incidence of side effects.
Arrhythmias induced by the cardioversion generally are caused by inadequate synchronization.
Catheter Ablation
The success rate for ablation of typical atrial flutter is usually about 95% with a low rate of complications; hence,
catheter ablation should be considered as first-line treatment for most patients with typical atrial flutter. Suitable
patients can usually be rate controlled while awaiting elective ablation. If patients cannot be rate controlled,
expedited ablation or electrical cardioversion are reasonable options.
Catheter ablation for atrial fibrillation is an option for patients who have failed at least one antiarrhythmic drug.
Ablation is often not a complete cure for atrial fibrillation but can significantly reduce the arrhythmia burden.
Success rates vary from 30% to 90% depending on technique, atrial fibrillation subtype and the extent of structural
heart disease. Patients with paroxysmal atrial fibrillation have the highest success rates; by contrast patients with
long-lasting (>3–5 years), persistent atrial fibrillation have much lower success rates. The technique involves
extensive ablation of the left atrium, primarily focusing on the areas around the pulmonary veins. The success of
ablation seems to relate to disconnection of atrial fibrillation triggers arising from the pulmonary veins and/or
modification of the arrhythmogenic left atrial substrate. Procedural complications specifically related to atrial
fibrillation ablation include a 2% risk of vascular access complications, 1–2% risk of tamponade, 0.25% risk of
stroke and a 0.15% risk of death, usually due to atrial esophageal fistula.
In patients with re-entrant tachycardias or focal atrial tachycardia, the reported cure rates after catheter ablation
range from 90% to 98%. The associated risk is much less than the risk with catheter ablation for atrial fibrillation.
Hence the threshold for nonpharmacologic management of these arrhythmias is low. Catheter ablation is strongly
recommended for patients with WPW and rapidly conducted pre-excited SVT. Catheter ablation should be considered
as a first-line treatment option in patients with recurrent symptomatic AVRT, AVNRT or focal atrial tachycardia.
Catheter ablation is also an option for patients with occasional episodes of AVNRT who desire complete rhythm
control and for patients with asymptomatic pre-excitation.
Page 195
Therapeutic Choice
Long-term Management of Atrial Fibrillation or Flutter
This first decision is whether to choose rate control (leaving atrial arrhythmia as the permanent rhythm) or to
actively pursue sinus rhythm (rhythm control). The AFFIRM Study compared these 2 treatment strategies in 4060
patients and found no difference in stroke or death rates between the 2 groups.2 However, patients in the AFFIRM
study were relatively old (mean age 69.7) and were either asymptomatic or had minimal symptoms. Therefore,
rhythm control should be actively pursued in patients with more than minimal symptoms, in asymptomatic young
patients and in patients with possible tachycardia-related cardiomyopathy. Data suggest that this latter diagnosis is
a more frequent problem than previously thought.3
An overview of the rhythm control management of patients with atrial fibrillation is provided in Figure 3 - Methods
to Maintain Sinus Rhythm in Patients with Atrial Fibrillationa . Selection of antiarrhythmic drug (AAD) therapy is
determined by coexisting structural heart disease. Amiodarone is more effective than sotalol or propafenone for
4
the prevention of recurrences of atrial fibrillation as shown by the Canadian Trial of Atrial Fibrillation (CTAF).
However, amiodarone may require discontinuation due to side effects in up to 18% of patients. Breakthrough
episodes can be terminated by either electrical or chemical cardioversion. Options for chemical cardioversion include
oral flecainide or propafenone, intravenous amiodarone, ibutilide or procainamide(Table 5).
In 2009 dronedarone became available for the treatment of atrial fibrillation. This new class III AAD is a
benzofuran derivative structurally related to amiodarone but without the iodine component so it does not possess
amiodarone’s iodine-related organ toxicity. The ATHENA trial evaluated the effect of dronedarone in 4628 patients
5
with AF and additional risk factors for death. Dronedarone was associated with a 24% relative risk reduction in the
combined endpoint of cardiovascular (CV) hospitalization or death. This was mainly driven by reduced
hospitalization for AF and reduced arrhythmic death. Of note, dronedarone may not be as efficacious as amiodarone
in preventing AF recurrences. The DYONISOS trial 6 compared amiodarone 200 mg daily (after appropriate loading
dose) with dronedarone 400 mg twice daily in maintaining sinus rhythm in 504 patients with AF. More patients
given dronedarone had recurrence of atrial fibrillation or discontinued the drug at 12 months (75.1% vs 58.8%).
Heart Rate Control in Patients with Persistent or Permanent Atrial Fibrillation or Flutter
Most patients will need drugs to achieve rate control. Some patients with intrinsic AV nodal disease (usually elderly
individuals) will not need drugs for rate control. Pharmacologic control of heart rate should initially be attempted
with a beta-blocker or a calcium channel blocker (diltiazem or verapamil). Digoxin is usually inadequate
alone for rate control. Because of its potential toxicity, amiodarone should only be used as a last resort (Table 6).
The medication dose should be titrated to achieve a resting heart rate of <80 bpm and a mean heart rate of <100
bpm on 24-hour Holter monitoring. A recent randomized study suggests that these criteria may be too strict.7
However, these findings need to be confirmed by further research. Finally, if rate control cannot be achieved with
medication then AV nodal ablation and permanent pacemaker implantation should be considered.
Anticoagulation for Paroxysmal and Persistent and Permanent Atrial Fibrillation or Flutter
Antithrombotic agents are indicated for the prevention of thromboembolic stroke in patients with atrial flutter or
fibrillation (Table 7). The choice of agent is based on the presence of risk factors (Table 3). The estimated annual
8
risk of stroke in a patient with a CHADS2 score of 0 not receiving warfarin is 1.9%. In the absence of
antithrombotic therapy, the risk of stroke increases by a factor of about 1.5 for each 1 unit increase in CHADS2
score in patients with atrial fibrillation. Most experts recommend warfarin (aiming for an INR range of 2–3) for
patients with a CHADS2 score of >1 (Table 3). ASA 81–325 mg daily is recommended for patients with atrial
fibrillation/flutter and a CHADS2 score of 0. Management of patients with a score of 1 is controversial. Guidelines
9
suggest that either ASA in the above dosage or warfarin are reasonable choices.
10
The RE-LY study randomized patients to warfarin or dabigatran, a direct thrombin inhibitor. One
group received dabigatran 110 mg twice a day and another group received dabigatran 150 mg twice a
day. The higher dose of dabigatran, 150 mg BID, provided a 34% relative reduction in stroke and
thromboembolic events compared to warfarin. The lower dose of dabigatran was noninferior to
warfarin. Importantly, this new agent was safer than warfarin, with reductions in all types of bleeding
including intracranial hemorrhage. Health Canada has approved dabigatran for prevention of systemic
embolism in patients with AF. Useful Info?
Page 196
Therapeutic Choice
Table 3: Stroke Risk in Patients with Nonvalvular Atrial Fibrillation or Flutter8
CHADS 2 Risk Criteria Assigned Score
C Congestive heart failure 1
H Hypertension 1
A Age >75 years 1
D Diabetes mellitus 1
S Prior stroke or transient ischemic attack 2
Management of Re-entrant Tachycardias and Focal Atrial Tachycardia
There have been no large randomized controlled trials in patients with re-entry tachycardias or focal atrial
tachycardia. An overview of the acute management of a patient with AVRT, AVNRT and AT is illustrated in Figure 4 -
Acute Management of Atrioventricular Re-entry Tachycardia, Atrioventricular Nodal Re-entry Tachycardia and Atrial
Tachycardia. Indications for chronic pharmacologic therapy are presented in Table 4.
1
Table 4: Medical Therapy of Re-entrant Tachycardias and Focal Atrial Tachycardia
Arrhythmia Details Recommendation
Atrioventricular Re-entry Asymptomatic WPW No therapy

Tachycardia (AVRT)
Single or infrequent episode(s) No therapy
Vagal manoeuvres
Pill-in-the-pocketa verapamil,
diltiazem or beta-blocker
Frequent symptomatic Any of the following:

Flecainide, propafenone
Sotalol, beta-blocker
Verapamil, diltiazem
Atrioventricular Nodal Re- Single or infrequent episode(s) No therapy

entry Tachycardia (AVNRT) Vagal manoeuvres
a
Pill-in-the-pocket verapamil,
Frequent symptomatic Verapamil, diltiazem, beta-

blockers
Recurrent AVNRT unresponsive to a beta blocker or Flecainide, propafenone or

calcium channel blocker in a patient not desiring sotalol
radiofrequency ablation
Focal Atrial Tachycardia Single or infrequent episode(s) No therapy

(AT) Pill-in-the-pocketa verapamil,
Recurrent symptomatic Any of the following:

Beta-blocker, verapamil,
diltiazem
b
Flecainide, propafenone
Sotalol, amiodaronec
Page 197
Therapeutic Choice
a.
Single dose oral pill-in-the-pocket approach is an option in carefully selected patients. Suitable candidates should not have
significant LV dysfunction or sinus bradycardia. Intermittent single-dose therapy minimizes exposure to unnecessary therapy
between events.
b.
Flecainide and propafenone should not be used in patients with coronary artery disease or structural heart disease.
c.
Ablation should be considered before amiodarone.
Abbreviations: WPW=Wolff-Parkinson-White
Therapeutic Tips
Either rate or rhythm control is reasonable for elderly asymptomatic or mildly symptomatic patients with atrial
fibrillation or atrial flutter.
Rhythm control should be pursued in younger patients or symptomatic older patients with atrial fibrillation or
atrial flutter.
Rhythm control for atrial fibrillation should initially be with antiarrhythmic drugs.
Rhythm control with catheter ablation should be considered second- or third-line in atrial fibrillation and first-
line in atrial flutter.
Rhythm control with catheter ablation for paroxysmal atrial fibrillation has a high success rate; results in
patients with persistent or permanent atrial fibrillation are more modest.
Rhythm control should always be the objective in patients with re-entry tachycardia (AVRT or AVNRT). Rhythm
control should be attempted with either antiarrhythmic drugs or catheter ablation.
Rhythm control should usually be the objective in patients with AT. Rate control is acceptable if rhythm control
cannot be achieved.
Avoid use of flecainide and propafenone in patients with structural heart disease.
Use only immediate-release dosage forms when prescribing single-dose “pill-in-the-pocket” oral therapy.
All patients with a possible indication for ablation should be referred to an electrophysiologist.
All patients with possible tachycardia-mediated cardiomyopathy should be referred to an electrophysiologist.
Patients in whom it is difficult to achieve rate or rhythm control should be referred to a cardiologist.
Figure 1-Differential Diagnosis of Supraventricular Tachycardia
Page 198
Therapeutic Choice
Abbreviations: AV = atrioventricular; AVNRT = atrioventricular nodal re-entry tachycardia; AVRT = atrioventricular re-entry
tachycardia
Modified from Circulation 2003;108(15):1871-909 with permission of the American Heart Association.
Figure 2-Therapy of Newly Discovered Atrial Fibrillation or Flutter (AF)
Page 199
Therapeutic Choice
Abbreviations: AF = atrial fibrillation or flutter; HF = heart failure
Modified from Circulation 2006;114(7):e257-354 with permission of the American Heart Association.
a
Figure 3-Methods to Maintain Sinus Rhythm in Patients with Atrial Fibrillation
a.
A similar algorithm can be followed for atrial flutter. However, catheter ablation for atrial flutter should be considered first-line.
b.
An AV nodal blocking agent should always be co-prescribed with propafenone or flecainide.
Abbreviations: LVH = left ventricular hypertrophy; NYHA = New York Heart Association
Modified from Circulation 2006;114(7):e257-354 with permission of the American Heart Association.
Page 200
Therapeutic Choice
Figure 4-Acute Management of Atrioventricular Re-entry Tachycardia, Atrioventricular Nodal Re-entry

Tachycardia and Atrial Tachycardia
a.
Pre-excited SVT is an extremely rare and occasionally lethal arrhythmia due to rapid conduction down an accessory pathway.
b.
IV sotalol is not available in Canada.
Abbreviations: AV = atrioventricular; DC = direct current; LV = left ventricular; SVT = supraventricular tachycardia; VT =

ventricular tachycardia
Modified from Circulation 2003;108(15):1871-909 with permission of the American Heart Association.
Table 5: Drug Therapy for Control of Heart Rhythm in Patients with Supraventricular Tachycardia
a
Adverse Drug Cost
Class Drug Dose Effects Interactions Comments
Antiarrhythmics, flecainide 50 mg Q12H VT Metabolized by In patients with $$

Class IC Tambocor, po proarrhythmia, CYP2D6 (many atrial fibrillation
generics Titration: ↑ by tremor, blurred potential and/or atrial flutter,
50 mg vision, HF. interactions e.g., a beta-blocker or
increments celecoxib, nondihydropyridine
based on QRS desipramine, calcium channel
intervals. ↓ risperidone.) blocker should
dose if QRS always be co-
increases prescribed with a
>20% from Class IC agent.
baseline
Page 201
Therapeutic Choice
a
Adverse Drug Cost
Maximum Not to be used in
200 mg Q12H patients with
po coronary artery
disease or
structural heart
Renal disease.
dysfunction:
↓ initial dose
50%
Antiarrhythmics, propafenone 150 mg Q8H Constipation, ↓ digoxin dose by 25 Active metabolites $$

Class IC po headache, –50%. accumulate in rapid
Rythmol, ↓ dose if QRS metallic taste, Metabolized by metabolizers.
prolonged VT CYP2D6 (many Monitor QRS
generics
>20% from proarrhythmia. potential duration carefully.
baseline interactions e.g., In patients with
celecoxib, atrial fibrillation
Maximum desipramine, and/or atrial flutter,
300 mg Q8H risperidone.) a beta-blocker or
po nondihydropyridine
calcium channel
blocker should
Renal/hepatic always be co-
dysfunction: prescribed with a
↓ initial dose Class IC agent.
50% and ↑ Not to be used in
dosing interval patients with
to Q12H coronary artery
disease or
structural heart
disease.
Antiarrhythmics, sotalol 80 mg Q12H Hypotension, Digoxin, diltiazem, Since sotalol is a $

Class III Apo-Sotalol, po bradycardia, verapamil, other beta-blocker, use
other Titration: ↑ by wheezing, VT beta-blockers: may with great caution
generics 80 mg proarrhythmia. cause AV block, in view of the risk
increments if Torsades de bradycardia. of QT prolongation
QTc pointes, and torsades de
<460 msec. ↓ especially at pointes.
dose if QTc higher doses or
≥500 msec with renal
Maximum dysfunction.
240 mg Q12H
po
Elderly: ↓
initial dose to
40 mg Q12H
po
Renal
dysfunction:
↓ initial dose in
renal failure
Antiarrhythmics, amiodarone Usually 200 Various ↓ doses of beta- Monitor $

Class III Cordarone, mg TID po × gastrointestinal, blockers, digoxin, transaminases and
generics 2 wk then dermatologic, procainamide, thyroid function Q6
200 mg daily neurologic, quinidine and months, CXR
po when ophthalmologic warfarin by 50%. annually.
Page 202
Therapeutic Choice
a
Adverse Drug Cost
treating atrial and thyroid
arrhythmias. abnormalities.
Loading Pulmonary
doses may fibrosis, hepatic
vary dysfunction and
aggravation of
arrhythmias are
rare but
potentially life-
threatening.
Antiarrhythmics, dronedarone 400 mg BID Diarrhea, Drugs metabolized Contraindicated $$$$

Class III Multaq po dyspepsia, by CYP 3A4 (e.g., with:
nausea. diltiazem, –severe heart
Slight increase simvastatin). failure (NYHA class
in plasma IV)
creatinine
related to – strong CYP 3A4
inhibition of inhibitors, e.g.,
secretion, no azole antifungals,
change in GFR. macrolide
antibiotics.
Antiarrhythmics, dofetilide 125–500 µg Headache, ↑ levels with Requires b

Class III Tikosyn BID po nausea, torsades cimetidine, prescription by an
↓ dose if QT de pointes. ketaconazole, electrophysiologist:
interval trimethoprim (alone must be initiated in
prolonged by or combined with hospital.
15% after sulfamethoxazole),
first dose verapamil.
a.
b.
Available through Special Access Programme, Health Canada.
Dosage modification may be required in renal dysfunction; see Appendices: Dosage Adjustment in Renal Impairment.
Abbreviations: BPM=beats per minute; CXR=chest x-ray; GFR=glomerular filtration rate; HF=heart failure; HR=heart
rate; IR=immediate release; NYHA=New York Heart Association; SLE=systemic lupus erythematosus
Legend: $ < $30 $$ $30–60 $$$ $60–90 $$$$ >$90
Table 6: Drug Therapy for Control of Heart Rate in Patients with Supraventricular Tachycardia
a
Adverse Drug Cost
Cardiac Glycosides digoxin Loading: 1–1.5 mg in Bradycardia, With beta- Rarely $

Lanoxin, divided doses po/iv nausea, blockers, indicated.
Maintenance: vomiting, calcium Check serum
Toloxin
0.125–0.375 mg/day visual channel potassium,
po/iv disturbances, blockers, correct
proarrhythmia. amiodarone, hypokalemia if
propafenone, present.
quinidine: ↓
digoxin dose by
25–50%.
Page 203
Therapeutic Choice
Adverse Drug Costa

Beta1-adrenergic propranolol 1–3 mg Q2min x 2 Bradycardia, With digoxin, Monitor iv:$$

c
Antagonists Inderal-LA, iv. May repeat in 4h hypotension, calcium carefully in -$$$
generics 80–240 mg/day po dyspnea, channel diabetic po:$
fatigue, blockers, patients;
depression. amiodarone: ↓ caution in
dose 25–50%. patients with
Hypoglycemic HF or
agents. bronchospastic
lung disease.
Beta1-adrenergic atenolol 50–150 mg/day po Bradycardia, With digoxin, Monitor $

c hypotension, calcium carefully in
Antagonists Tenormin,
generics dyspnea, channel diabetic
Less likely to dose 25–50%. patients with
cause CNS Hypoglycemic HF or
effects, e.g., agents. bronchospastic
depression. lung disease.
Beta1 selective.
Beta1-adrenergic metoprolol 5–10 mg Q5min x3 iv Bradycardia, With digoxin, Monitor $

c Betaloc, 100–400 mg/day po hypotension, calcium carefully in
Antagonists
Lopresor, dyspnea, channel diabetic
generics fatigue, blockers, patients;
dose 25–50%. patients with
Hypoglycemic HF or
agents. bronchospastic
lung disease.
Beta1 selective.
Beta1-adrenergic nadolol 20–160 mg/day po Bradycardia, With digoxin, Monitor $

c hypotension, calcium carefully in
Antagonists generics
dyspnea, channel diabetic
Less likely to dose 25–50%. patients with
cause CNS Hypoglycemic HF or
effects, e.g., agents. bronchospastic
depression. lung disease.
Calcium Channel verapamil 5–10 mg iv. May give Bradycardia, Beta-blockers, Caution in iv:$$
Blockers, Isoptin SR, extra 10 mg iv in 30 hypotension, digoxin, patients with -$$$
Nondihydropyridine generics minutes constipation, amiodarone. HF. po:$
Usual starting dose flushing.
120 mg/day po;
maximum
480 mg/day po. IR
given TID-QID; SR
given daily or BID
Calcium Channel diltiazem 0.25 mg/kg iv. May Bradycardia, Beta-blockers, Caution in ivb:$
Blockers, Cardizem give another hypotension. digoxin, patients with po:$-
Nondihydropyridine 0.35 mg/kg iv after amiodarone. HF. $$
CD, Tiazac,
15 min if necessary
180–540 mg/day po.
IR given TID-QID;
Page 204
Therapeutic Choice
Adverse Drug Costa

Tiazac XC, SR given BID; CD
generics and Tiazac given
daily
a.
Cost of 30-day supply of oral doses and 1-day supply for IV doses; includes drug cost only.
b.
Cost based on 70 kg body weight.
c.
The beta-blockers suggested are examples only. Acebutolol, labetalol and timolol would also be effective. Some agents are
available as sustained-release preparations.
Abbreviations: CD=controlled delivery; HF=heart failure; IR=immediate release; SR=sustained release
Legend: $ < $30 $–$$ < $30–60 $$ $30–60 $$–$$$ $30–90 $$$ $60–90
Table 7: Drug Therapy for Prevention of Systemic Embolism in Patients with Supraventricular Tachycardia
Costa
Vitamin K warfarin Dose to Bleeding, skin necrosis. Many potential interactions. $

Antagonists Coumadin, maintain INR Contraindicated in Substrate for CYP 2C9 and
generics between 2 and pregnancy. other isoenzymes.
3
Thrombin dabigatran Usual: 150 mg Bleeding, gastric intolerance. Combination with strong ~$100
Inhibitors Pradax BID po inhibitors of P-gp (e.g.,
Patients with ↑ ketoconazole)
bleeding or contraindicated. Caution
>80 years of with other drugs acting on P
age: 110 mg -gp.
BID po
Antiplatelet ASA 81–325 Bleeding, usually minor Hemorrhagic risk ↑ with $

Agents Aspirin, mg/day po (epistaxis, etc.), gastric concomitant use of
Bufferin, intolerance, GI bleeding anticoagulants.
Coated (gastric ulcers, erosions),
tinnitus usually dose related.
Aspirin,
generics
a.
Abbreviations: CYP =cytochrome P450; P-gp =P-glycoprotein
Legend: $ <$5
Suggested Readings
Delacretaz E. Clinical practice. Supraventricular tachycardia. N Engl J Med 2006;354(10):1039-51.
Page 205
Therapeutic Choice
Dewire J, Calkins H. State-of-the-art and emerging technologies for atrial fibrillation ablation. Nat Rev Cardiol
2010;7(3):129-38.
Fox DJ, Tischenko A, Krahn AD et al. Supraventricular tachycardia: diagnosis and management. Mayo Clin Proc
2008;83(12):1400-11.
Fuster V, Ryden LE, Cannom DS et al. ACC/AHA/ESC 2006 Guidelines for the Management of Patients with Atrial
Fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice
Guidelines and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Revise
the 2001 Guidelines for the Management of Patients With Atrial Fibrillation). Circulation 2006;114(7):e257-354.
Prystowsky EN, Camm J, Lip GY et al. The impact of new and emerging clinical data on treatment strategies for atrial
fibrillation. J Cardiovasc Electrophysiol 2010;21(8):946-58.
Wellens HJ. Contemporary management of atrial flutter. Circulation 2002;106(6):649-52.
References
1. Blomstrom-Lundqvist C, Scheinman MM, Aliot EM et al. ACC/AHA/ESC guidelines for the management of
patients with supraventricular arrhythmias—executive summary. Circulation 2003;108(15):1871-909.
2. Wyse DG, Waldo AL, DiMarco JP et al. A comparison of rate control and rhythm control in patients with atrial
fibrillation. N Engl J Med 2002;347(23):1825-33.
3. Umana E, Solares CA, Alpert MA. Tachycardia-induced cardiomyopathy. Am J Med 2003;114(1):51-5.
4. Roy D, Talajic M, Dorian P et al. Amiodarone to prevent recurrence of atrial fibrillation. Canadian Trial of Atrial
Fibrillation Investigators. N Engl J Med 2000;342(13):913-20.
5. Hohnloser SH, Crijns HJ, van Eickels M et al. Effect of dronedarone on cardiovascular events in atrial
6. Le Heuzey JY, De Ferrari GM, Radzik D et al. A short-term, randomized, double-blind, parallel-group study to
evaluate the efficacy and safety of dronedarone versus amiodarone in patients with persistent atrial
fibrillation: the DIONYSOS Study. J Cardiovasc Electrophysiol 2010;21(6):597-605.
7. Van Gelder IC, Groenveld HF, Crijns HJ et al. Lenient versus strict rate control in patients with atrial
fibrillation. N Engl J Med 2010;362:1363-73.
8. Gage BF, Waterman AD, Shannon W et al. Validation of clinical classification schemes for predicting stroke:
results from the National Registry of Atrial Fibrillation. JAMA 2001;285(22):2864-70.
9. Fuster V, Ryden LE, Cannom DS et al. ACC/AHA/ESC 2006 guidelines for the management of patients with
atrial fibrillation: full text. Europace 2006;8(9):651-745.
10. Connolly SJ, Ezekowitz MD, Yusuf S et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl
J Med 2009;361(12):1139-51.
Page 206
e-Therapeutics+ : Therapeutics : Cardiovascular Disorders: Syncope Page 1 of 6
Therapeutic Choice
Print Close
Cardiovascular Disorders: Syncope
Robert Sheldon, MD, PhD
Syncope is defined as a reversible loss of consciousness not requiring specific resuscitative measures, and not
associated with generalized seizures. Probably 40% of people faint at least once in their life, and many faint
recurrently.1 , 2 Most people who faint have a benign cause but a few are at risk of death. Common causes of
syncope are listed in Table 1.
Table 1: Common Causes of Syncope
Volume depletion and drugs

Volume depletion
Diarrhea
Diminished oral intake
Polyuria
Drugs
ACE inhibitors
Alcohol
Alpha- and beta-adrenergic blockers
Antiparkinsonian drugs
Diuretics
Nitrates
Phosphodiesterase type 5 inhibitors (sildenafil, tadalafil, vardenafil)
Vasodilators
Orthostatic intolerance disorders

Reflex syncope syndromes
Carotid sinus hypersensitivity
Vasovagal syncope syndromes
Autonomic neuropathies
Pure autonomic failure syndromes
Multiple system atrophy syndromes
Arrhythmias
Bradycardias
Complete (third degree) and bifasicular heart block
Sinus node disease
Tachycardias
Supraventricular arrhythmias (uncommon)
Torsades de pointes polymorphic ventricular tachycardia
Ventricular tachycardia
Obstruction
Aortic stenosis
Pulmonary emboli
Many other rare causes
Goals of Therapy
Identify potentially fatal causes of syncope

Aggressively investigate and treat high-risk patients
Remove reversible causes of syncope
Treat patients with therapies appropriate to the degree of their symptoms
Investigations
Page 207
Therapeutic Choice
In patients with transient loss of consciousness perform a complete cardiovascular and neurologic history and
physical examination.3 , 4 , 5 Rule out seizures, then screen for life-threatening causes such as obstruction,
ventricular tachycardia and asystole or heart block (Figure 1 - Diagnostic Approach to the Patient with Syncope)
Tailor laboratory investigations to the individual patient:
ECG (most patients)
older patients ( >55 years) should have ambulatory ECG monitoring unless the history is strongly
persuasive for vasovagal syncope. Implanted patient-activated loop recorders may be useful in patients
6
with infrequent syncope that eludes conventional attempts at diagnosis
ambulatory ECGs and stress tests are of limited use in younger patients
echocardiogram or other noninvasive measure of left ventricular function if structural heart disease is
suspected
coronary angiography as indicated
refer patients with structural heart disease for electrophysiologic assessment
unless contraindicated, carotid sinus massage should be performed in patients >50 years old to screen for
carotid sinus hypersensitivity (do not perform in patients with carotid bruits)
7 , 8
tilt table testing might be useful in diagnosing vasovagal syncope in patients with atypical symptoms
After potentially fatal causes are eliminated and reversible causes are removed, most patients will have one of
3
several syndromes of orthostatic intolerance:
reflex syncope syndromes
vasovagal syncope
carotid sinus hypersensitivity in the elderly
pure autonomic failure syndromes
multiple system atrophy syndromes
The orthostatic intolerance syndromes can be distinguished based on history and a simple stand test in the
office. To perform the stand test, first measure blood pressure and heart rate after the patient has been supine
for 5 minutes, then after 2 and 4 minutes of standing. These responses are seen:
Normal and vasovagal syncope: modest rises in heart rate (about 10 BPM) and blood pressure (about
10 mm Hg).
Autonomic failure: progressive fall in blood pressure of ≥20 mm Hg systolic or ≥10 mm Hg diastolic with
development of presyncope; often no increase in heart rate.
Therapeutic Choices
Treatment is directed at the cause of syncope. Treat any reversible causes. Refer patients with syncope secondary to
bradycardia (asystole or complete heart block) for a permanent pacemaker. Refer patients with suspected or
diagnosed ventricular tachycardia, and all patients with structural heart disease to a cardiologist, preferably an
electrophysiologist. The following addresses treatment of syndromes of orthostatic intolerance.
Vasovagal Syncope
Reassure the patient that this syndrome is not life threatening and that it is a physical problem, not a
psychiatric disorder. Encourage increased dietary salt intake of about 3–5 g daily, in the absence of
5 , 8
contraindications such as hypertension or heart failure.
Teach the patient to use physical counterpressure manoeuvres at the onset of presyncope.9 , 10 These include
squatting, crossing the legs with isometric contraction if standing, and vigorous hand clenching with upper
10
girdle isometric contraction. All should be tried. The evidence is based on a good physiologic study and an
open label randomized clinical trial.9
Pacemaker therapy is no longer indicated, based on the results of an adequately powered randomized placebo-
11
controlled trial. The occasional patient with asystole documented during vasovagal syncope might benefit, and
these uncommon patients should be assessed at a tertiary referral clinic.
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Therapeutic Choice
Drug therapy may be effective in some, although the evidence is mixed. Few drugs have been evaluated in large
randomized trials. Therapy may be unnecessary in patients with infrequent vasovagal syncope who have
recognizable premonitory symptoms.
Fludrocortisone can be tried if simple salt supplements are ineffective. The goal is fluid retention, which may
12
precipitate heart failure. A single randomized trial in children was negative. Fludrocortisone has not been
evaluated in adults in randomized trials.
Alpha-agonists increase venous return, thereby preventing the onset of vasovagal syncope. Midodrine improved
13 , 14
symptoms in patients enrolled in small randomized trials, including one that showed midodrine to be more
13
effective after 6 months than salt and fluid supplementation. Supine hypertension may complicate treatment.
Beta-blockers are no longer indicated as first line treatment for vasovagal syncope. This is based on
one adequately powered, randomized placebo-controlled trial 15 and 4 smaller studies.5 Useful Info?
Serotonin reuptake inhibitors are of uncertain benefit in preventing vasovagal syncope. Paroxetine significantly
reduced the frequency of spontaneous syncope over 2 years compared with placebo in one randomized trial,16
although it was not helpful in a second trial. 17
Orthostatic Hypotension
Therapeutic Tips
The goal of therapy is to relieve symptoms of cerebral hypoperfusion while avoiding treatment side effects.
Orthostatic hypotension is often associated with supine hypertension, which complicates its therapy.
Remove as many hypotensive and volume-depleting drugs as possible. Increase dietary salt intake if not
contraindicated. Elevate the head of the bed on blocks or bricks by 15– 30 cm (this is often not well tolerated).
Instruct patients to avoid hemodynamic stress such as getting up quickly, eating large meals, warm environments or
hot baths and heavy exertion.
Sodium and water retention may be beneficial in patients with orthostatic hypotension. Fludrocortisone increases
blood volume and sensitizes peripheral alpha receptors. NSAIDs promote fluid retention and also indirectly cause
vasoconstriction. Try indomethacin 25–50 mg three times daily or equivalent doses of related drugs.
Midodrine is a pressor amine that causes both venoconstriction (thereby increasing venous return) and arteriolar
constriction (which directly increases blood pressure). Midodrine significantly increased standing blood pressure and
decreased the severity of symptoms in placebo-controlled trials.18 , 19 As noted above, supine hypertension may
complicate treatment.
The acetylcholinesterase inhibitor pyridostigmine, given alone or in combination with midodrine, significantly
improved standing blood pressure without increasing supine blood pressure in a short-term randomized placebo-
20
controlled trial. Further study is needed before this agent can be recommended.
Octreotide, a somatostatin analogue that blocks production of gut vasodilator hormones and reduces splanchnic
21
blood flow, may be useful in postprandial hypotension. The combination of octreotide plus midodrine significantly
increased postprandial blood pressure and standing time before onset of symptoms, to a greater extent than either
22
drug alone, in a small randomized crossover study. Octreotide is given by SC injection.
Nonselective beta-blockers (e.g., propranolol, timolol, nadolol) block vasodilatory beta2-receptors and reduce
23
or abolish the fall in blood pressure upon standing in patients with orthostatic hypotension.
Page 209
Therapeutic Choice
Therapeutic Tips
All physicians treating syncope patients should be familiar with provincial regulations for the ability of syncope
patients to drive. The regulations vary with the cause of syncope and with the therapy. The Canadian
Cardiovascular Society has guidelines on the fitness of syncope patients to drive.24
Figure 1- Diagnostic Approach to the Patient with Syncope
Abbreviations: ER=emergency room; PE=pulmonary emboli
Table 2: Drugs for Treatment of Syndromes of Orthostatic Intolerance
Adverse Costa
Electrolytes sodium Gastric upset, Diuretics interfere Fluid retention $

chloride 3–5 g Na+ fluid retention. with effect. may precipitate
daily HF in
susceptible
patients.
Mineralocorticoids fludrocortisone Initial: Mild edema, Diuretics interfere Check serum $$

0.1 mg daily supine with effect. +
Florinef K and supine
po hypertension, BP 1 wk after
↑ by 0.1 mg hypokalemia,
each dose ↑; K+
Q1–2 wk to eczema, thin
supplements
0.4 mg skin.
are often
necessary.
Fluid retention
may precipitate
HF in
susceptible
patients.
Page 210
Therapeutic Choice
Adverse Costa
Alpha1-adrenergic midodrine Initial: 2.5– Supine Digoxin Check supine $$$

Agonists generics 5 mg TID po hypertension, (bradycardia, BP 2 h after
ac; none shivering, arrhythmia); each dose ↑.
after 5 pm paresthesias, sympathomimetics Dose intervals
↑ by 2.5 mg piloerection, (↑ pressor effect); and ↑ require
TID Q1–2 wk pruritus, sympatholytics careful
(Maximum: dysuria. (↓ effect). adjustment.
15 mg TID) ↑ dose until
effective or
limited by
tolerance.
a.
Abbreviations: HF=heart failure
Legend: $ < $10 $$ $10–25 $$$ $25–100
Suggested Readings
European Heart Rhythm Association (EHRA); Heart Failure Association (HFA); Heart Rhythm Society (HRS) et al.
Guidelines for the diagnosis and management of syncope (version 2009): the Task Force for the Diagnosis and
Management of Syncope of the European Society of Cardiology (ESC). Eur Heart J 2009;30(21):2631-71.
Grubb BP, Karas B. Clinical disorders of the autonomic nervous system associated with orthostatic intolerance: an
overview of classification, clinical evaluation, and management. Pacing Clin Electrophysiol 1999;22(5):798-810.
Kuriachan V, Sheldon RS, Platonov M. Evidence-based treatment for vasovagal syncope. Heart Rhythm 2008;5
(11):1609-14.
Sheldon R, Morillo CA, Krahn A. Management of vasovagal syncope: 2004. Expert Rev Cardiovasc Ther 2004;2
(6):915-23.
References
1. Serletis A, Rose S, Sheldon AG et al. Vasovagal syncope in medical students and their first-degree relatives.
Eur Heart J 2006;27(16):1965-70.
2. Colman N, Nahm K, Ganzeboom KS et al. Epidemiology of reflex syncope. Clin Auton Res 2004;14(Suppl 1):9-
17.
3. Brignole M, Alboni P, Benditt DG et al. Guidelines on management (diagnosis and treatment) of syncope--
update 2004. Europace 2004;6(6):467-537.
4. Sheldon R, Rose S, Connolly S et al. Diagnostic criteria for vasovagal syncope based on a quantitative history.
Eur Heart J 2006;27(3):344-50.
5. Sheldon R, Morillo CA, Krahn A. Management of vasovagal syncope: 2004. Expert Rev Cardiovascular Ther
2004;2(6):915-23.
6. Moya A, Brignole M, Menozzi C et al. Mechanism of syncope in patients with isolated syncope and in patients
with tilt-positive syncope. Circulation 2001;104(11):1261-7.
7. Sheldon R. Tilt testing for syncope: a reappraisal. Curr Opin Cardiol 2005;20(1):38-41.
8. Kuriachan V, Sheldon RS, Platonov M. Evidence-based treatment for vasovagal syncope. Heart Rhythm 2008;5
(11):1609-14.
Page 211
Therapeutic Choice
9. van Dijk N, Quartieri F, Blanc JJ et al. Effectiveness of physical counterpressure maneuvers in preventing
vasovagal syncope: the Physical Counterpressure Maneuvers Trial (PC-Trial). J Am Coll Cardiol 2006;48
(8):1652-7.
10. Krediet CT, van Dijk N, Linzer M et al. Management of vasovagal syncope: controlling or aborting faints by leg
crossing and muscle tensing. Circulation 2002;106(13):1684-9.
11. Connolly SJ, Sheldon R, Thorpe KE et al. Pacemaker therapy for prevention of syncope in patients with
recurrent severe vasovagal syncope: Second Vasovagal Pacemaker Study (VPS II): a randomized trial. JAMA
2003;289(17):2224-9.
12. Salim MA, Di Sessa TG. Effectiveness of fludrocortisone and salt in preventing syncope recurrence in children:
a double-blind, placebo-controlled, randomized trial. J Am Coll Cardiol 2005;45(4):484-8.
13. Perez-Lugones A, Schweikert R, Pavia S et al. Usefulness of midodrine in patients with severely symptomatic
neurocardiogenic syncope: a randomized control study. J Cardiovasc Electrophysiol 2001;12(8):935-8.
14. Ward CR, Gray JC, Gilroy JJ et al. Midodrine: a role in the management of neurocardiogenic syncope. Heart
1998;79(1):45-9.
15. Sheldon R, Connolly S, Rose S et al. Prevention of Syncope Trial (POST): a randomized, placebo-controlled
study of metoprolol in the prevention of vasovagal syncope. Circulation 2006;113(9):1164-70.
16. Di Girolamo E, Di Iorio C, Sabatini P et al. Effects of paroxetine hydrochloride, a selective serotonin reuptake
inhibitor, on refractory vasovagal syncope: a randomized, double-blind, placebo-controlled study. J Am Coll
Cardiol 1999;33(5):1227-30.
17. Theodorakis GN, Leftheriotis D, Livanis EG et al. Fluoxetine vs. propranolol in the treatment of vasovagal
syncope: a prospective, randomized, placebo-controlled study. Europace 2006;8(3):193-8.
18. Low PA, Gilden JL, Freeman R et al. Efficacy of midodrine vs placebo in neurogenic orthostatic hypotension. A
randomized, double-blind multicenter study. Midodrine Study Group. JAMA 1997;277(13):1046-51.
19. Wright RA, Kaufmann HC, Perera R et al. A double-blind, dose-response study of midodrine in neurogenic
orthostatic hypotension. Neurology 1998;51(1):120-4.
20. Singer W, Sandroni P, Opfer-Gehrking TL et al. Pyridostigmine treatment trial in neurogenic orthostatic
hypotension. Arch Neurol 2006;63(4):513-8.
21. Hoeldtke RD, Davis KM, Joseph J et al. Hemodynamic effects of octreotide in patients with autonomic
neuropathy. Circulation 1991;84(1):168-76.
22. Hoeldtke RD, Horvath GG, Bryner KD et al. Treatment of orthostatic hypotension with midodrine and
octreotide. J Clin Endocrinol Metab 1998;83(2):339-43.
23. Cleophas TJ, Kauw FH, Bijl C et al. Effects of beta adrenergic receptor agonists and antagonists in diabetics
with symptoms of postural hypotension: a double-blind, placebo-controlled study. Angiology 1986;37
(11):855-62.
24. Simpson C, Dorian P, Gupta A et al. Assessment of the cardiac patient for fitness to drive: drive subgroup
executive summary. Can J Cardiol 2004;20(13):1314-20.
Page 212
e-Therapeutics+ : Therapeutics : Cardiovascular Disorders: Venous Thromboembolism Page 1 of 10
Therapeutic Choice
Print Close
Cardiovascular Disorders: Venous Thromboembolism

Alexander G.G. Turpie, MD, FRCP(Lond), FRCP(Glas), FACP, FACC, FRCPC
This chapter addresses both the treatment and prophylaxis of venous thromboembolism.
Treatment of Venous Thromboembolism
Goals of Therapy
Investigations
Therapeutic Choices
General Measures
Goals of Therapy
Deep Vein Thrombosis (DVT)
Prevent major pulmonary embolism

Prevent thrombus extension
Prevent postphlebitic syndrome
Reduce morbidity of the acute event
Pulmonary Embolism (PE)
Prevent death
Prevent recurrent thromboembolism
Prevent chronic thromboembolic pulmonary hypertension
Investigations
Because the clinical diagnosis of DVT and PE is insensitive and nonspecific, objective diagnosis using specific
procedures is important for optimal management.
DVT: B-mode compression ultrasound (most practical and useful clinically), ascending venography, impedance
plethysmography
PE: Pulmonary angiography, perfusion lung scan, ventilation lung scan, spiral CT, MRI, tests for DVT as
described immediately above
Patients under the age of 40 with recurrent venous thromboembolism (VTE) or a family history should be
screened for thrombophilia (see Clinical Risk Categories, Table 4)
D-dimer
Therapeutic Choices
General Measures
The majority of patients with DVT can be treated as outpatients. Likewise, many patients with PE who do not have
compromised cardiopulmonary function may be treated as outpatients.
Deep Vein Thrombosis
Rest if symptoms warrant (reduces pain and swelling).
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Therapeutic Choice
Elevate limb (reduces edema and pain).
Avoid pressure on the swollen leg.
Analgesics for pain (NSAIDs are effective but may increase the risk of bleeding, especially when used with
anticoagulants). Acetaminophen is commonly used. Narcotics are not usually required for analgesia.
Pulmonary Embolism
Oxygen.
Intravenous fluids.
Vasopressor agents.
Other resuscitory measures (depending on the patient's clinical status).
Subcutaneous low molecular weight heparin (LMWH) or fondaparinux, or unfractionated heparin (UFH) is
recommended for the initial treatment of established DVT and/or PE. UFH can be administered iv or in a monitored
or fixed-dose sc regimen. Oral vitamin K antagonists such as warfarin can be started at the same time and
administered concurrently for several days. LMWH, fondaparinux or UFH is continued for a minimum of 5 days or
until the International Normalized Ratio (INR, an indicator of the intensity of anticoagulation induced by warfarin) is
≥ 2 for at least 24 hours. The duration of oral anticoagulation is dependent on the risk of recurrence of VTE (Table
1). Treatment of a first episode in a patient with a transient risk factor should continue for 3 months. In those with
unprovoked VTE or irreversible risk factors, treatment should continue for a longer period. In these patients,
treatment with oral anticoagulants for an indefinite period may be considered because it further reduces the risk of
1 2 , 3
recurrence. LMWH may be used as an alternative to warfarin in some circumstances and is particularly useful in
cancer-associated thrombosis.
1
Table 1: Duration of Secondary Prophylaxis for Symptomatic Venous Thromboembolism
3 months
First event with reversible or time-limited risk factor such as surgery
First episode of unprovoked distal DVT
Minimum of 3 months (consider indefinite treatment)

First unprovoked event
3–6 months (consider indefinite treatment)

Cancer until resolved. LMWH for first 3–6 months
Long-term treatment
Second episode of unprovoked VTE
Low Molecular Weight Heparins
The kinetics of LMWHs are more predictable than those of UFH, and their elimination half-life is longer. These
properties make weight-adjusted fixed-dose sc dosing of LMWHs an excellent alternative to adjusted-dose iv UFH in
the initial treatment of VTE. LMWHs have become the management of choice for initial treatment of DVT for many
outpatients. They are also effective in the treatment of PE.
Unfractionated Heparin
For treatment of VTE, UFH is most commonly given by iv infusion in a dose adjusted to prolong the activated partial
thromboplastin time (aPTT) to 1.5–2.5 times control (the target therapeutic range should be determined by an
institution’s coagulation laboratory). It is also effective by sc injection if sufficiently high doses are given (generally
15 000– 25 000 units Q12H) or if it is monitored. An iv bolus (5000– 10 000 units) should be given with the sc
injection in the initial treatment. Monitoring 4–6 hours after the sc dose should aim for an aPTT of 2–2.5 times
control. A practical weight-based nomogram has been developed for adjusting iv heparin (Table 2).4
a
Table 2: Body Weight-based Dosing of Intravenous Heparin in Adults
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Therapeutic Choice
aPTT (seconds) Dose Change (units/kg/h) Additional Action Next aPTT (h)
< 35 (< 1.2 × mean normal) +4 Rebolus with 80 units/kg 6
35–45 (1.2–1.5 × mean normal) +2 Rebolus with 40 units/kg 6
46–70b (1.5–2.3 × mean normal) 0 0 6c
71–90 (2.3–3 × mean normal) -2 0 6
> 90 (> 3 × mean normal) -3 Stop infusion for 1 h 6
a.
Initial dosing: 80 units/kg iv bolus; maintenance infusion of heparin, at a rate dictated by body weight through an infusion
apparatus calibrated for low flow rates: 18 units/kg/h (aPTT in 6 hours).
b.
The therapeutic range in seconds should correspond to a plasma heparin level of 0.2–0.4 units/mL by protamine sulfate
titration. When aPTT is checked at 6 hours or longer, steady-state kinetics can be assumed.
c.
During the first 24 hours, repeat aPTT every 6 hours. Thereafter, monitor aPTT once every morning unless it is outside the
therapeutic range.
Adapted with permission from Hyers TM et al. Antithrombotic therapy for venous thromboembolic disease.
Chest 1998;114(5 Suppl):561S-578S.
Vitamin K Antagonists
Warfarin is the more widely used vitamin K antagonist (VKA). Warfarin therapy is monitored using the INR. It is
5
given in a dose to maintain the INR at 2–3. When therapy is initiated the INR is measured frequently, then less
often as it stabilizes. It is generally measured daily or every other day for the first 3–4 days, then every 3 days for a
week, then 1 or 2 times weekly, then every 2–4 weeks when stable. While a less intense level of anticoagulation
(INR 1.5–2) has been shown to be effective, it is less so than the standard treatment (INR 2–3).
A common cause of poor anticoagulant control is drug interactions (Table 3). ASA and NSAIDs contribute to
bleeding by inhibiting platelet function. Several herbal or alternative products interact with warfarin, for example
gingko, ginseng and St. John’s wort. Patients should be discouraged from using such products. The Thrombosis
Interest Group of Canada provides information that can be used for patient education at
www.tigc.org/eguidelines/PatientsTakingOralAnticoagulants.htm
If an alternate VKA is required, nicoumalone (acenocoumarol) is available. It is used in a similar way to

warfarin, with a similar drug interaction profile.
Parenteral warfarin is now available for iv use. It is used to replace oral warfarin in patients who temporarily cannot
take medications by mouth.
Table 3: Clinically Significant Warfarin Drug Interactionsa
Class Drug
Drugs that increase INR and potentiate the effects of warfarin
Anti-inflammatory analgesics and b

Acetaminophen, ASA, celecoxib, dextropropoxyphene, interferon,
immunologics phenylbutazone, piroxicam, sulfinpyrazone, tramadol
Antimicrobials
Azole antifungals Fluconazole, itraconazole, miconazole (including vaginal preparations),

voriconazole
Fluoroquinolones Ciprofloxacin, levofloxacin
Macrolides Azithromycin, clarithromycin, erythromycin
Other Amoxicillin/clavulanate, sulfamethoxazole/trimethoprim, isoniazid,

metronidazole, ritonavir, tetracycline
Cardiovascular Drugs
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Therapeutic Choice
Class Drug
Fibrates Fenofibrate
Statins Fluvastatin, simvastatin
Other Amiodarone, diltiazem, propafenone, propranolol, quinidine
CNS Drugs
Antiparkinsonian drugs Entacapone, ropinirole
SSRIs Citalopram, fluvoxamine, sertraline
Other Alcohol (large amounts; patients with liver disease), chloral hydrate,
disulfiram, phenytoin
Gastrointestinal Drugs Cimetidine, omeprazole
Foods, Chinese medicines, herbs Boldo-fenugreek,c Danshen,d Dong quai,e fish oil, grapefruit juice,
f
Lycium barbarum, mango fruit, PC-SPES, Quilinggao
Other Anabolic steroids, fluorouracil, gemcitabine, levamisole/fluorouracil,

paclitaxel, tamoxifen, tolterodine, zileuton
Drugs that decrease INR and diminish the effects of warfarin
Antimicrobials Griseofulvin, ribavirin, rifampin, ritonavir
Cardiovascular Drugs Bosentan, cholestyramine
CNS Drugs Barbiturates, carbamazepine, chlordiazepoxide
Gastrointestinal Drugs Azathioprine, mesalamine, sucralfate
Foods and Herbs Avocado (large amounts); ginseng; foods, enteral feeds or
multivitamins that contain large amounts of vitamin K
Other Chelation therapy, influenza vaccine, mercaptopurine, raloxifene
a. 6
Rated as “highly-probably” or “probably” clinically significant according to a systematic review.
b. 7
Doses > 2 g/day.
c.
A herbal combination of boldo (Peumus boldus) and fenugreek (Trigonella foenum-graecum).
d.
A Chinese medicine derived from Salvia miltiorrhiza.
e.
A Chinese medicine derived from Chinese Angelica (Angelica sinensis).
f.
A Chinese medicine that contains several herbs. The composition varies between manufacturers.
Thrombolytic Agents8
The use of thrombolytic therapy for the treatment of acute DVT or PE is uncommon as clinical trials have not
demonstrated reductions in acute morbidity or improved long-term outcomes. There is also a significant risk of
intracranial hemorrhage.
Less than 20% of VTE patients are eligible for thrombolytic therapy (i.e., young patients with massive ileofemoral
vein thrombosis or patients with hemodynamically unstable PE). Streptokinase (SK) and alteplase are approved
for treatment of VTE. The best results are obtained with recent thrombi, but substantial lysis may be obtained in
patients with symptoms of up to 14 days' duration. Consider use on a case-by-case basis for patients with life- or
limb-threatening VTE and no bleeding contraindications.
SK is the least expensive, but requires prolonged infusions in VTE. Alteplase, with its short infusion, may be more
cost effective.
Prophylaxis of Venous Thromboembolism
Goals of Therapy
Therapeutic Choices
Page 216
Therapeutic Choice
Therapeutic Tips
Clinical Risk Categories
Venous thromboembolism (VTE) is a common cause of morbidity and mortality in hospitalized patients; the
frequency varies according to patients' risk. The risk of VTE is increased in the presence of factors related to venous
stasis and coagulopathy (Table 4). Consensus conferences have defined risk categories based on clinical criteria and
made specific recommendations for thrombosis prophylaxis according to risk group (Table 5).9 , 10 Prophylaxis
against clot formation should be continued while the patient is at risk, likely until discharge from
hospital. In certain high-risk patients, prophylaxis following discharge may be considered. For example,
following hip replacement surgery, patients may benefit from a total of 35 days' pharmacologic
10
treatment post-operatively. Useful Info?
Table 4: Risk Factors for Venous Thromboembolism
Surgery Acute medical illness

Trauma (major or lower extremity) Inflammatory bowel disease
Immobility, paresis Nephrotic syndrome
Cancer (active or occult) Myeloproliferative disorders
Cancer therapy (hormonal, chemotherapy or radiotherapy) Paroxysmal nocturnal hemoglobinuria
Venous compression (tumor, hematoma, arterial abnormality) Obesity
Previous VTE Central venous catheterization
Increasing age Inherited or acquired thrombophilia:
Pregnancy and the postpartum period protein C, S or antithrombin deficiency
Drugs: prothrombin 20210 gene mutation
estrogen-containing contraceptives factor V Leiden
or hormone therapy antiphospholipid antibody
selective estrogen receptor modulators lupus anticoagulant
(raloxifene) hyperhomocysteinemia
erythropoiesis-stimulating agents elevated factor VIII
Adapted with permission from Geerts WH et al. Prevention of venous thromboembolism: American College of Chest Physicians
Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 2008:133:381S-453S.
Goals of Therapy
Prevent deep vein thrombosis (DVT) and pulmonary embolism (PE)

Reduce mortality
Prevent the postphlebitic syndrome
Prevent chronic thromboembolic pulmonary hypertension
Therapeutic Choices
Graduated compression stockings and intermittent pneumatic compression devices reduce the risk of VTE and are
particularly useful in clinical settings where the risk of bleeding is high (e.g., after neurosurgery).
Caval interruption by filter is rarely indicated for primary prophylaxis but should be considered in patients in whom
10
anticoagulants have failed or are absolutely contraindicated. A variety of removable filters are now available and
are preferred over the permanent ones.
Table 5: Risk Categories and Thrombosis Prophylaxis
Page 217
Therapeutic Choice
Approximate
Levels of Risk DVT Risk Suggested Thromboprophylaxis Options
Low risk < 10% No specific thromboprophylaxis

Minor surgery in mobile patients Early and aggressive ambulation
Medical patients who are fully mobile
Moderate risk 10–40% Low molecular weight heparin, low-dose

Most general, open gynecologic or unfractionated heparin, (Table 7)
urologic surgery patients
Medical patients, bed rest or sick
Moderate VTE risk plus high a

Mechanical thromboprophylaxis
bleeding risk
High risk 40–80% Low molecular weight heparin, fondaparinux (Table

Hip or knee arthroplasty, hip-fracture 7), oral vitamin K antagonist (INR 2–3) (Table 6)
surgery, major trauma, spinal cord
injury
High VTE risk plus high bleeding Mechanical thromboprophylaxisa

risk
a.
Includes graduated compression stockings and intermittent pneumatic compression. Consider switch to pharmacologic agent
when high bleeding risk decreases.
Abbreviations: DVT = deep vein thrombosis; VTE = venous thromboembolism
Adapted with permission from Geerts WH et al. Prevention of venous thromboembolism: American College of Chest Physicians
Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 2008;133:381S-453S.
, 10 , 11
Dalteparin, enoxaparin, nadroparin and tinzaparin are approved for both the treatment of VTE and prophylaxis
12
in conjunction with surgery. Unfractionated heparin is only effective for procedures with moderate risk.
Fondaparinux is a specific factor Xa inhibitor. It is approved for the prophylaxis of VTE in high-risk orthopedic
11
patients and for the treatment of DVT and PE. Fondaparinux also prevents VTE with minimal risk of bleeding in
13
older acute medical patients, although this is not an approved indication in Canada. Vitamin K antagonists can
be used with the dose adjusted to target an INR of 2–3. Dabigatran and rivaroxaban are new oral anticoagulants
indicated for VTE prophylaxis following elective total hip or total knee replacement surgery. Their role in therapy is
not yet established.
Choices During Pregnancy and Lactation14
VTE during pregnancy and the postpartum period is an important cause of maternal morbidity and mortality.
Anticoagulants may be required for the treatment of new episodes of VTE, or for prophylaxis in mothers with a
history of prior VTE.
UFH or LMWH is the anticoagulant of choice during pregnancy. UFH and LMWHs do not cross the placental
barrier.
Subcutaneous injections of UFH twice daily can be monitored and adjusted to achieve therapeutic levels.
UFH or LMWH should be stopped at the first sign of labour.
Warfarin, sc UFH or LMWH may be used for about 6 weeks after delivery for secondary prevention.
Women can breastfeed while being treated with warfarin, UFH or LMWH.
The management of pregnant women with a previous DVT or PE is controversial; UFH 5000 units sc Q12H or
LMWH throughout pregnancy is recommended in some women.
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Therapeutic Choice
Therapeutic Tips
Danaparoid, lepirudin and argatroban are approved for treatment of heparin-induced thrombocytopenia
15
(HIT) in Canada. Limited data indicate that bivalirudin may also be effective.
Table 6: Drugs for Treatment of Venous Thromboembolism
a
Cost
Drug Class Drug Dose Adverse Effects Comments
Indirect Factor fondaparinux < 50 kg: 5 mg sc daily Bleeding; Use caution in $$$
Xa Inhibitor Arixtra 50–100 kg: 7.5 mg sc daily thrombocytopenia; patients with renal
allergic reactions dysfunction. Use
> 100 kg: 10 mg sc daily (rare). with caution in
patients with a
history of HIT.
Low Molecular dalteparin 200 IU/kg sc Q24H Bleeding; HIT and Contraindicated in $$
Weight Fragmin Max: 18 000 IU/day osteoporosis are both those with a history
Heparins less common than of HIT; caution in
with UFH. those with renal
dysfunction.
Low Molecular enoxaparin 100 IU/kg sc BID or 150 Bleeding; HIT and Contraindicated in $$
Weight Lovenox IU/kg sc Q24H osteoporosis are both those with a history
Heparins Max: 18 000 IU/day less common than of HIT; caution in
dysfunction.
100 IU = 1 mg.
Low Molecular nadroparin 171 IU/kg sc Q24H or Bleeding; HIT and Contraindicated in $$
Weight Fraxiparine, 86 IU/kg sc BID osteoporosis are both those with a history
Heparins Max: 17 100 IU/day less common than of HIT; caution in
Fraxiparine
Forte dysfunction.
Low Molecular tinzaparin 175 IU/kg sc Q24H Bleeding; HIT and Contraindicated in $$
Weight Innohep Max: 18 000 IU/day osteoporosis are both those with a history
Heparins less common than of HIT; caution in
dysfunction.
Unfractionated heparin, Treatment: iv infusion most Bleeding, HIT, Monitor platelets $

Heparin (UFH) unfractionated common (see Table 2 for osteoporosis. closely during first
Hepalean, dosing nomogram). Also week.
Heparin Leo can use sc Contraindicated in
5000–10 000 units iv pts with a history of
followed by HIT.
15 000–20 000 sc Q12H
adjusted to maintain
therapeutic aPTT
Vitamin K warfarin Usual dose: Bleeding; hair loss, See Table 3 for $
Antagonists Coumadin, 0.5–6 mg po daily. blue fingers and toes drug interactions.
generics (uncommon); skin The iv formulation
Adjust dose to maintain INR necrosis (rare). is suitable for
2–3; higher doses may be patients who cannot
necessary in some patients take oral drugs.
IV dose: same as po
administered as a slow
bolus over 1–2 min. Do not
give im
Page 219
Therapeutic Choice
Costa
Vitamin K nicoumalone Usual dose: Bleeding; hair loss, See Table 3 for $
Antagonists Sintrom 0.5–4 mg po daily blue fingers and toes drug interactions.
(uncommon); skin
Adjust dose to maintain INR necrosis (rare).
2–3; higher doses may be
necessary in some patients
a.
Costs provided are for the first week of therapy, based on 50 kg; includes drug cost only.
Abbreviations: HIT=heparin-induced thrombocytopenia
Legend: $ < $50 $$ $50-150 $$$ $150-250
Table 7: Drugs for Prophylaxis of Venous Thromboembolisma
Costb
Direct Factor Xa rivaroxaban 10 mg daily starting 6– Bleeding. Combination with strong $

Inhibitor Xarelto 10 hr after surgery inhibitors of both CYP3A4
THR surgery: 35 day & P-gp, e.g.,
treatment itraconazole, ritonavir,
contraindicated.
TKR surgery: 14 day Not recommended in
treatment severe renal impairment.
Direct Thrombin dabigatran 110 mg 1–4 hr after Bleeding. Combination with strong $
Inhibitor Pradax surgery, then 220 mg inhibitors of P-gp
daily (quinidine)
THR surgery: 28 to 35 contraindicated. Caution
day treatment with other drugs acting
on P-gp.
TKR surgery: 10 day Reduce dose in > 75
treatment years of age and
moderate renal
impairment.
Indirect Factor fondaparinux Patients ≥ 50 kg: 2.5 Bleeding, allergic Not recommended in $$
Xa Inhibitor Arixtra mg sc daily after high- reactions (rare). patients with renal
risk orthopedic surgery dysfunction.
Patients < 50 kg: not
recommended
Low Molecular dalteparin General surgery: Bleeding, HIT and Contraindicated in those $
Weight Heparins Fragmin 2500 IU sc daily osteoporosis (less with a history of HIT.
Orthopedics: 5000 IU sc common than
daily UFH).
Page 220
Therapeutic Choice
Costb
Low Molecular enoxaparin General surgery: Bleeding, HIT and Contraindicated in those $
Weight Heparins Lovenox 4000 IU sc Q24H osteoporosis (less with a history of HIT.
Orthopedics: 3000 IU sc common than 100 IU = 1 mg.
Q12H UFH).
Low Molecular nadroparin General surgery: Bleeding, HIT and Contraindicated in those $
Weight Heparins Fraxiparine, 2850 IU sc daily osteoporosis (less with a history of HIT.
Orthopedics: 38 IU/kg common than
Fraxiparine
sc Q12H × 2; then UFH).
Forte 38 IU/kg sc Q24H
through postoperative
day 3, then 57 IU/kg sc
Q24H
Low Molecular tinzaparin General surgery: Bleeding, HIT and Contraindicated in those $
Weight Heparins Innohep 3500 IU sc Q24H osteoporosis (less with a history of HIT.
Orthopedics: 50– common than
75 IU/kg sc Q24H UFH).
Unfractionated heparin, General surgery: 5000 Bleeding, HIT, Monitor platelets closely $
Heparin (UFH) unfractionated units sc Q12H or Q8H osteoporosis. during first week of
Hepalean, therapy. Contraindicated
Heparin Leo in those with a history of
HIT.
a.
For vitamin K antagonist information see Table 6.
b.
Costs provided are for 1 day of therapy, based on 50 kg; includes drug cost only.
Abbreviations: HIT=heparin-induced thrombocytopenia; THR=total hip replacement; TKR=total knee replacement
Legend: $ < $10 $$ $10–20
Suggested Readings
Goldhaber SZ, Turpie AG. Prevention of venous thromboembolism among hospitalized medical patients. Circulation
2005;111(1):e1-3.
Kyrle PA, Eichinger S. Deep vein thrombosis. Lancet 2005;365(9465):1163-74.
Qaseem A, Snow V, Barry P et al. Current diagnosis of venous thromboembolism in primary care: a clinical practice
guideline from the American Academy of Family Physicians and the American College of Physicians. Ann Fam Med
2007;5(1):57-62.
Scarvelis D, Wells PS. Diagnosis and treatment of deep-vein thrombosis. CMAJ 2006;175(9):1087-92.
Snow V, Qaseem A, Barry P et al. Management of venous thromboembolism: a clinical practice guideline from the
American College of Physicians and the American Academy of Family Physicians. Ann Intern Med 2007;146(3):204-
10.
Wells PS, Owen C, Doucette S et al. Does this patient have deep vein thrombosis? JAMA 2006;295(2):199-207.
References
Page 221
Therapeutic Choice
1. Kearon C, Kahn SR, Agnelli G et al. Antithrombotic therapy for venous thromboembolic disease: American
College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th edition). Chest 2008;133(6
Suppl):454S-545S.
2. Hyers TM, Agnelli G, Hull RD et al. Antithrombotic therapy for venous thromboembolic disease. Chest
2001;119(1 Suppl):176S-93S.
3. Turpie AG. Looking forward in the treatment of deep-vein thrombosis. Semin Hematol 2001;38(2 Suppl 5):49-
57.
4. Hirsh J, Fuster V. Guide to anticoagulant therapy. Part 1: Heparin. American Heart Association. Circulation
1994;89(3):1449-68.
5. Hirsh J, Fuster V. Guide to anticoagulant therapy. Part 2: Oral anticoagulants. American Heart Association.
Circulation 1994;89(3):1469-80.
6. Holbrook AM, Pereira JA, Labiris R et al. Systematic overview of warfarin and its drug and food interactions.
Arch Intern Med 2005;165(10):1095-106.
7. Gebauer MG, Nyfort-Hansen K, Henschke PJ et al. Warfarin and acetaminophen interaction. Pharmacother
2003;23(1):109-12.
8. Dalen JE, Alpert JS, Hirsh J. Thrombolytic therapy for pulmonary embolism: is it effective? Is it safe? When is
it indicated? Arch Intern Med 1997;157(22):2550-6.
9. [No authors listed]. Risk of and prophylaxis for venous thromboembolism in hospital patients.
Thromboembolic Risk Factors (THRIFT) Consensus Group. BMJ 1992;305(6853):567-74.
10. Geerts WH, Bergqvist D, Pineo GF et al. Prevention of venous thromboembolism: American College of Chest
Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 2008;133(6 Suppl):381S-453S.
11. Turpie AG, Bauer KA, Eriksson BI et al. Fondaparinux vs enoxaparin for the prevention of venous
thromboembolism in major orthopedic surgery: a meta-analysis of 4 randomized double-blind studies. Arch
Intern Med 2002;162(16):1833-40.
12. Weitz JI. Low-molecular-weight heparins. N Engl J Med 1997;337(10):688-98.
13. Cohen AT, Davidson BL, Gallus AS et al. Efficacy and safety of fondaparinux for the prevention of venous
thromboembolism in older acute medical patients: randomised placebo controlled trial. BMJ 2006;332
(7537):325-9.
14. Bates SM, Greer IA, Hirsh J et al. Use of antithrombotic agents during pregnancy: the Seventh ACCP
Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004;126(3 Suppl):627S-44S.
15. Campbell KR, Mahaffey KW, Lewis BE et al. Bivalirudin in patients with heparin-induced thrombocytopenia
undergoing percutaneous coronary intervention. J Invasive Cardiol 2000;12(Suppl F):14F-9.
Page 222
e-Therapeutics+ : Therapeutics : Cardiovascular Disorders: Ventricular Tachyarrhythmias Page 1 of 9
Therapeutic Choice
Print Close
Cardiovascular Disorders: Ventricular Tachyarrhythmias

Paul Dorian, MD, MSc, FRCPC
Ventricular tachycardia (VT) is defined as ≥3 consecutive ventricular complexes at a rate >100 BPM on an ECG
recording.
Ventricular fibrillation (VF) is defined as a rapid, disorganized rhythm without recognizable QRS complexes on the
ECG. It is invariably associated with cardiovascular collapse and is almost invariably fatal unless the patient is
electrically defibrillated.
, 2
Goals of Therapy1
Relieve symptoms, including restoring a perfusing rhythm as quickly as possible in sustained VT, VF or cardiac
arrest
Prevent the potentially fatal occurrence or recurrence of sustained VT or VF
, 4
Investigations3
Careful history with special reference to:

syncope or severe presyncope
angina, heart failure symptoms
history suggesting structural heart disease, especially prior MI, or heart failure
symptom correlation with exercise or stress
recent ingestion of medications that might cause or contribute to arrhythmias, e.g. antiarrhythmics, drugs
that prolong the QT interval (see Suggested Readings)
the presence of an implanted defibrillator
Physical examination for signs of structural heart disease
12-lead ECG:
signs of prior MI
repolarization abnormalities (prolonged QT interval)
Note: A 12-lead ECG documenting ventricular tachycardia is very helpful. If available, an ECG at
tachycardia onset (or offset) is also very useful
Echocardiogram with special reference to:
left ventricular size and function
right ventricular size
Consider Holter or loop event recorder monitoring with special reference to:
presence and morphology of ventricular ectopy and symptom-rhythm correlation
Consider treadmill exercise test with special reference to:
exercise-induced VT
ECG signs and symptoms of myocardial ischemia (or scintigraphic evidence of ischemia if necessary)
All wide-complex tachycardias (QRS duration ≥0.12 seconds) in patients over the age of 50 years should be
considered to be VT until proven otherwise. Wide-complex tachycardia in an older patient with a history of heart
disease is almost always VT, regardless of the morphology of ECG complexes. Most wide-complex tachycardias in
any patient of any age group are due to VT.
Significance of VT/VF
The clinical and prognostic importance and management of VT depends on whether it is sustained or nonsustained
and whether there is associated structural heart disease, particularly left ventricular systolic dysfunction.
Asymptomatic: Asymptomatic VT is usually discovered during routine screening ECG or other electrocardiographic
monitoring. In the presence of structural heart disease, especially left ventricular dysfunction, asymptomatic VT
3
(usually nonsustained) may indicate a risk of future serious, symptomatic, sustained VT or VF.
Symptomatic: Symptoms may include palpitations, dyspnea, chest discomfort, presyncope, loss of consciousness or
cardiac arrest. The severity of symptoms does not determine the prognostic importance of VT and its management
Page 223
Therapeutic Choice
(e.g., even severe symptoms in a patient with nonsustained VT and no structural heart disease are prognostically
5
benign; such patients require reassurance, but not necessarily specific antiarrhythmic therapy).
Cardiac arrest: Most episodes of out-of-hospital cardiac arrest are likely the result of VF, although the initial cardiac
rhythm documented by first responders is often asystole. VF almost always leads to cardiac arrest, whereas
sustained VT may lead to cardiac arrest after a variable duration, usually one to several minutes.
Sustained VT: Lasts ≥30 seconds or requires immediate medical intervention. For management decisions, >15 beats
is a reasonable working definition. It is most often associated with structural heart disease, typically coronary
disease with previous MI. Sustained VT requires investigation and therapy with antiarrhythmic drugs, an implanted
cardioverter defibrillator or antitachycardia surgery.
Nonsustained VT: Lasts <30 seconds but usually only a few seconds. Most commonly there are <10 consecutive
ventricular complexes. Unless symptomatic, it requires treatment only if the likelihood of subsequent sustained VT
or cardiac arrest is high (ejection fraction <35%, or associated with marked QT prolongation).
VT associated with structural heart disease (e.g., coronary, valvular or hypertensive heart disease): Is usually
symptomatic and associated with a high risk of sudden death or recurrence (if sustained), or is asymptomatic and
associated with at least a moderate risk of sudden death (if nonsustained). The magnitude of left ventricular
dysfunction is the most important prognostic factor.
VT associated with a structurally normal heart: May be symptomatic but rarely is life-threatening even if sustained; it
5
requires no therapy if asymptomatic and nonsustained.
Monomorphic VT: Usually implies an abnormal automatic focus in the ventricle or a fixed re-entrant pathway
associated with a scar. It does not by itself suggest prognosis or therapy.
Polymorphic VT: Usually presents as long runs of nonsustained VT. Consider myocardial ischemia and abnormalities
of repolarization (torsades de pointes VT associated with QT prolongation and a characteristic long-short initiating
sequence).4
VF may complicate acute MI. However, the prognosis for resuscitated patients with VF occurring during the first 48
hours post-MI is similar to that in patients with an infarction of equivalent severity uncomplicated by VF. The most
common underlying cause is coronary artery disease (CAD), often with prior MI, with or without acute ischemia or
infarction.
Most patients with VF are at high risk of recurrence. These individuals should be investigated in a similar fashion to
patients with sustained VT and should be treated to prevent recurrences.1 , 2 , 3
Therapeutic Choices
Immediate Therapy for Sustained VT or VF
For sustained monomorphic VT, if the patient is unstable (e.g., has hypotension, angina, heart failure or marked
1 , 6
symptoms), cardioversion is effective and safe. A synchronized biphasic shock of 120 J or more is usually
effective for VT. If immediate conversion to sinus rhythm is not considered necessary, antiarrhythmic drug therapy
6
can be given.
For polymorphic VT or VF, an immediate nonsynchronized shock of 120–200 J (biphasic) is required, repeated as
necessary (with minimum interruptions in CPR) until defibrillation is achieved.
Amiodarone: iv amiodarone is effective in terminating VT and is especially effective in preventing early recurrence.
It is likely the most effective therapy for electrical storm (characterized by frequent recurrences of VT/VF) and is
probably useful in shock-resistant VF.6 , 7 , 8 , 9 The usual dose is 3–5 mg/kg iv over 5–10 minutes followed by a
0.5–1 mg/min infusion. There are few randomized studies to guide dosing, but the product monograph recommends
150 mg iv over 10 minutes followed by 1 mg/min for 6 hours then 0.5 mg/min for 18 hours.10 If necessary, an
ongoing infusion of 0.5–1 mg/min can be continued for 24–48 hours. Hypotension may occur, especially if the drug
is administered very rapidly.
Procainamide: 10–15 mg/kg iv over 30–45 minutes will often slow VT and terminate tachycardia. Hypotension
6 , 9
may occur, especially at more rapid infusion rates, and blood pressure should be carefully monitored.
Page 224
Therapeutic Choice
Magnesium: 2–5 g iv over 3–5 minutes is the treatment of choice for torsades de pointes VT, and may be useful in
4 , 11
the presence of myocardial ischemia . It is probably of no benefit in monomorphic VT. Magnesium is generally
safe, but may rarely cause hypotension.
Beta-blockers (e.g., metoprolol, propranolol, esmolol): iv beta-blockers can prevent VT or VF in the setting of
1 , 4 , 9
acute myocardial ischemia, recent MI or electrical storm. Bradycardia or hypotension may occur.
Lidocaine: 1–1.5 mg/kg iv followed by a 1–3 mg/minute infusion is occasionally effective (in <20% of cases of
2
sustained monomorphic VT). If conversion does not occur within 10–15 minutes, lidocaine will probably not be
effective. There is no good evidence that lidocaine is useful in shock-resistant VF.2 , 6 , 9 Lidocaine rarely causes
hypotension and at high doses can cause CNS adverse events.
Chronic Therapy—Prevention of VT/VF Recurrence (Figure 1 - Management of

Nonsustained Ventricular Tachycardia (< 15 beats), Figure 2 - Long-term Management of
Sustained Ventricular Tachycardia (> 15 beats), Ventricular Fibrillation, or Resuscitated
Cardiac Arresta )
Therapeutic choices for long-term management of sustained VT/VF include both drug therapy (Table 1)1 , 2 , 4 , 9
and nondrug therapy (implanted cardioverter defibrillator, ICD, map-guided endocardial resection, catheter
5 , 12 , 13 , 14 , 15 , 16
ablation).
Sustained monomorphic VT/VF is likely to recur in the absence of treatment. Objective documentation of efficacy
(e.g., electrophysiologic testing or reduction of VT episodes on Holter monitoring) can be considered. In patients
with LV dysfunction, drug therapy should rarely be used as the only therapy for the prevention of recurrent
sustained VT or prevention of first occurrence of VT in at-risk patients (primary prophylaxis).
Indicators of efficacy of drugs in individual patients include: the ability of a drug to prevent induction of VT during
an electrophysiologic study or with exercise; and the marked reduction of the frequency or elimination of
nonsustained VT episodes or premature ventricular contractions (PVCs). The latter indicator is unproven and not
recommended.
Patients with a history of VF or cardiac arrest are at risk of recurrence of VF or VT, since their original arrhythmia
may have been VT degenerating to VF. Their treatment is similar to that of patients with sustained VT, although
markers to judge drug efficacy (inducible VT or VF; PVCs or nonsustained VT on Holter monitoring) are present less
18
often.
Beta-blockers, if tolerated, should be administered to all patients in whom drug therapy is used (and will be
indicated in any event in almost all patients with CAD or severe LV dysfunction). They are particularly useful in
patients with exercise-, stress- or ischemia-induced VT.
Amiodarone and sotalol are effective in preventing VT or VF but almost all studies show they are less effective
than implanted defibrillators in preventing sudden death and decreasing all-cause mortality in patients at high risk
2 , 5 , 12 , 13 , 14 , 15 , 16 , 17 , 18
for sustained VT or VF. No randomized study has shown that antiarrhythmic drugs
reduce mortality. However, amiodarone or sotalol can be used as an adjunct to ICD implantation to prevent ICD
19
shocks, which are painful.
In patients with multiple, frequent recurrences of VT or VF (electrical storm) resistant to the combination of a beta-
blocker and amiodarone, or if amiodarone is ineffective or not tolerated, Class I agents such as mexiletine,
quinidine or procainamide can be cautiously added. Such combinations are entirely empiric and should be used
4 20
only as a last resort. In highly selected cases, empiric combinations of sotalol and quinidine or procainamide, or
quinidine and mexiletine,21 or other combinations of drugs with class Ia, Ib, and III activity can be considered.
Quinidine is available only through the Health Canada, Special Access Programme and is rarely used.
Nonpharmacologic Choices for VT
An implanted cardioverter defibrillator (ICD) is very effective in treating VT or VF but requires

12,13,14,15,16,17
complex evaluation and follow-up. The AVID trial reported a 39% reduction in total
mortality after one year in ICD-treated patients relative to antiarrhythmic therapy (primarily
15
amiodarone). Current guidelines recommend an ICD as preferred treatment in patients with a
22,23
history of cardiac arrest, VF or sustained VT with no reversible cause. Useful Info?
Page 225
Therapeutic Choice
Map-guided endocardial ablation (catheter ablation) or surgical ablation requires careful patient selection,
specialized facilities and complex mapping equipment. It may be very effective in certain patient subsets.
Catheter ablation using radiofrequency energy may be especially effective for VT arising from the right or left
ventricles in patients with apparently normal hearts. In patients with LV dysfunction, it is usually reserved for
patients with an ICD who have frequent VT recurrences despite antiarrhythmic drug therapy.
Figure 1- Management of Nonsustained Ventricular Tachycardia (< 15 beats)
Abbreviations: CAD = coronary artery disease; ICD = implanted cardioverter defibrillator; LV = left ventricular
Figure 2- Long-term Management of Sustained Ventricular Tachycardia (> 15 beats), Ventricular

Fibrillation, or Resuscitated Cardiac Arrest a
Page 226
Therapeutic Choice
a. 24
Current guidelines indicate that in most cases an ICD is the preferred therapy for any patient with sustained VT and
symptoms in the presence of structural heart disease (with no reversible cause). Electrophysiologic studies are not necessarily
indicated in such patients. Cardiac catheterization may be reasonable but is also not necessarily indicated in such patients.
b.
Patients with monomorphic VT.
c.
An ICD may be considered for any patient with sustained VT, and most patients with VF or cardiac arrest. In addition to the
therapies listed, all patients should receive beta-blockers unless contraindicated.
Abbreviations: CAD = coronary artery disease; ICD = implanted cardioverter defibrillator; LV = left ventricular; LVEF = LV
ejection fraction; VT = ventricular tachycardia
Page 227
Therapeutic Choice
Table 1: Drug Therapy for Ventricular Tachycardia and Ventricular Fibrillation
Drug Costa
Class Drug Dose Interactions Adverse Effects Comments
Class IA Usual: 800– ↓ digoxin dose Frequent GI Active metabolites c

quinidine
Antiarrhythmics generics 1600 by 50%. intolerance. accumulate in
b mg/day Inhibits Rare fever, renal failure, but
(sulfate CYP2D6 (many thrombocytopenia. therapeutic blood
equivalent) potential monitoring is not
po interactions). Torsades de pointes; readily available.
(proarrhythmic) VT. Monitor ECG
intervals to guide
dosing decisions.
Class IA procainamide Usual: 2–4 Amiodarone Frequent arthralgias Metabolism $$$$–

b g/day po. may ↑ after long-term use. depends on rate of $$$$$
Antiarrhythmics
Procan SR Administer procainamide May cause SLE acetylation. The
Q6H if using plasma level. syndrome. active metabolite
an SR NAPA accumulates
preparation Rare in fast acetylators
granulocytopenia. and in renal
failure. Monitor
Occasional torsades procainamide and
de pointes. NAPA levels;
monitor ECG
intervals.
Class IB mexiletine Usual: 600– Phenytoin and Frequent CNS side Rarely used as $$$$$
Antiarrhythmics generics 900 mg/day rifampin may ↓ effects. monotherapy.
b po effect (may need
to ↑ mexiletine
dose).
Class 1C flecainide Usual: Metabolized by Dizziness and visual Titrate dose based $$–
Antiarrhythmics Tambocor, 100–200 CYP2D6 (many disturbances on QRS intervals. $$$
b mg/day po potential common. Do not use in
generics
interactions). patients with LV
dysfunction,
especially prior MI
(increases
mortality in
patients who have
frequent PVCs after
MI).
Class 1C propafenone Usual: ↓ digoxin dose Depresses LV Weak beta- $$$

b 600–900 by 25–50%. function. blocking effect.
Antiarrhythmics
Rythmol, mg/day po Metabolized by Use with care, if at
generics CYP2D6 all, in patients with
Hepatic LV dysfunction,
failure: ↓ especially prior MI.
initial dose by Active metabolites
50% and ↑ accumulate in
dosing rapid metabolizers.
interval to Monitor QRS
Q12H duration.
Class III sotalol Usual: Digoxin, Torsades de pointes, Sotalol is a beta $$–
Antiarrhythmics Apo-Sotalol, 160–480 verapamil, especially at higher blocker. $$$
mg/day po other beta- doses or with renal May be especially
blockers may dysfunction. effective in
Page 228
Therapeutic Choice
a
Drug Cost
Class Drug Dose Interactions Adverse Effects Comments
other Elderly: ↓ cause AV exercise-related
generics initial dose to block, Fatigue, bradycardia, arrhythmias. Likely
40 mg po bradycardia. AV block, decreased more effective than
Q12H With digoxin, exercise capacity, other drugs in
++ headache, suppressing
Ca channel
blockers, impotence, vivid inducibility of VT.
amiodarone, ↓ dreams. Contraindicated in
dose 25–50%. Less common: asthma.
hyperglycemia,
depression, heart
failure.
Class III amiodarone Loading ↓ digoxin dose Various Slows conduction, $$$-
Antiarrhythmics Cordarone, dose: 800– by 50%. gastrointestinal, blocks adrenergic $$$$
generics 1600 ↓ beta-blocker dermatologic, activity, blocks
mg/day po dose by 50%. neurologic, ++
Ca channels.
for 7–10 ophthalmologic and Very long half-life.
days ↓ quinidine or thyroid Likely the most
Maintenance procainamide abnormalities. effective
dose: 200– dose by 50%. Pulmonary fibrosis, antiarrhythmic
400 mg/day hepatic dysfunction drug. Usually used
po ↓ warfarin dose and aggravation of empirically.
by 50%. arrhythmias are rare
Avoid high but potentially life-
loading dose threatening.
in setting of
sinus
bradycardia
(HR <50
BPM).
Beta1-adrenergic metoprolol 100–400 With digoxin, Fatigue, bradycardia, Monitor carefully in $–$$
Antagonists d Betaloc, mg/day po Ca++ channel AV block, decreased diabetic patients.
Lopresor, blockers, exercise capacity, Caution in patients
generics amiodarone, ↓ headache, with HF.
dose 25–50%. impotence, vivid
dreams. Especially useful in
Less common: exercise-induced
hyperglycemia, VT, with ischemia,
depression, heart or VT in the
failure. absence of
structural heart
disease. Of
probable but
unclear benefit in
patients with
sustained VT and
prior MI. May
enhance efficacy of
other
antiarrhythmic
drugs in this
setting. Very low
proarrhythmic risk.
Contraindicated in
asthma.
Page 229
Therapeutic Choice
a.
b.
There is no evidence that any drug with primarily class I activity is of long-term benefit in reducing mortality from VT or VF; in
particular, Class I drugs are not recommended in patients with VT or VF and structural heart disease (in the absence of an ICD).
c.
Available through the Special Access Programme, Therapeutic Products Directorate, Health Canada.
d.
The beta1-adrenergic antagonist suggested is an example only. Other beta1-adrenergic antagonists may be used.
Abbreviations: HF=heart failure; LV=left ventricular; NAPA=n-acetylprocainamide; PVC=premature ventricular

contraction; SLE=systemic lupus erythematosus; VF=ventricular fibrillation; VT=ventricular tachycardia
Legend: $ < $15 $-$$ < $15–30 $$ $15–30 $$–$$$ $15–60 $$$ $30–60 $$$–$$$$ $30–90 $$$$ $60
–90 $$$$-$$$$$ $60– >90 $$$$$ > $90
Suggested Readings
American Heart Association. 2005 American Heart Association guidelines for cardiopulmonary resuscitation and
emergency cardiovascular care. Part 5: Electrical therapies: automated external defibrillators, defibrillation,
cardioversion, and pacing. Circulation 2005;112(24 Suppl):IV35-46. Available from:
circ.ahajournals.org/cgi/content/full/112/24_suppl/IV-35. Accessed March 10, 2010.
Arizona Center for Education and Research on Therapeutics. QT drug lists by risk groups. Available from:
www.azcert.org/medical-pros/drug-lists/drug-lists.cfm. Accessed March 10, 2010.
Atkins DL, Dorian P, Gonzalez ER et al. Treatment of tachyarrhythmias. Ann Emerg Med 2001;37(4 Suppl):S91-109.
Connolly SJ, Hallstrom AP, Cappato R et al. Meta-analysis of the implantable cardioverter defibrillator secondary
prevention trials. AVID, CASH and CIDS studies. Eur Heart J 2000;21(24):2071-8.
European Heart Rhythm Association; Heart Rhythm Society; Zipes DP et al. ACC/AHA/ESC 2006 guidelines for
management of patients with ventricular arrhythmias and the prevention of sudden cardiac death. J Am Coll Cardiol
2006;48(5):e247-346.
Kudenchuk PJ. Advanced cardiac life support antiarrhythmic drugs. Cardiol Clin 2002;20(1):79-87.
References
1. Atkins DL, Dorian P, Gonzalez ER et al. Treatment of tachyarrhythmias. Ann Emerg Med 2001;37(4 Suppl):S91
-109.
2. Dorian P, Philippon F. The management of acute ventricular tachycardia or fibrillation. Can J Cardiol 2000;16
(Suppl C):16C-9C.
3. Green MS, Ricci J, Wolfe K. The appropriate evaluation of the patient at risk for sudden death from ventricular
arrhythmias. Can J Cardiol 2000;16(Suppl C):13C-5C.
4. Gillis AM. Intractable ventricular tachyarrhythmias: immediate evaluation and management, role of
pharmacological therapy. Card Electrophysiol Rev 2001;5:354-8.
5. Gillis AM, Hamilton RM, LeFeuvre CA. Unusual causes of sudden cardiac death due to ventricular
tachyarrhythmias. Can J Cardiol 2000;16(Suppl C):34C-40C.
6. [No authors listed]. Guidelines 2000 for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care.
Part 6: advanced cardiovascular life support: section 1: Introduction to ACLS 2000: overview of recommended
changes in ACLS from the guidelines 2000 conference. The American Heart Association in collaboration with
the International Liaison Committee on Resuscitation. Circulation 2000;102(8 Suppl):I86-9.
7. Dorian P, Cass D, Schwartz B et al. Amiodarone as compared with lidocaine for shock-resistant ventricular
8. Kowey PR, Levine JH, Herre JM et al. Randomized, double-blind comparison of intravenous amiodarone and
bretylium in the treatment of patients with recurrent, hemodynamically destabilizing ventricular tachycardia or
fibrillation. The Intravenous Amiodarone Multicenter Investigators Group. Circulation 1995;92(11):3255-63.
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Therapeutic Choice
9. Kudenchuk PJ. Advanced cardiac life support antiarrhythmic drugs. Cardiol Clin 2002;20(1):79-87.
10. Amiodarone Hydrochloride for Injection Sandoz Standard [product monograph]. In: Repchinsky C, editor.
Compendium of pharmaceuticals and specialties: the Canadian drug reference for health professionals. Ottawa
(ON): CPhA; 2010. p. 157-60.
11. Tzivoni D, Banai S, Schuger C et al. Treatment of torsade de pointes with magnesium sulfate. Circulation
1988;77(2):392-7.
12. Buxton AE, Lee KL, Fisher JD et al. A randomized study of the prevention of sudden death in patients with
coronary artery disease. Multicenter Unsustained Tachycardia Trial Investigators. N Engl J Med 1999;341
(25):1882-90.
13. Moss AJ, Zareba W, Hall WJ et al. Prophylactic implantation of a defibrillator in patients with myocardial
infarction and reduced ejection fraction. N Engl J Med 2002;346(12):877-83.
14. Connolly SJ, Gent M, Roberts RS et al. Canadian implantable defibrillator study (CIDS): a randomized trial of
the implantable cardioverter defibrillator against amiodarone. Circulation 2000;101(11):1297-302.
15. [No authors listed]. A comparison of antiarrhythmic-drug therapy with implantable defibrillators in patients
resuscitated from near-fatal ventricular arrhythmias. The Antiarrhythmics versus Implantable Defibrillators
(AVID) Investigators. N Engl J Med 1997;337(22):1576-83.
16. Moss AJ, Hall WJ, Cannom DS et al. Improved survival with an implanted defibrillator in patients with
coronary disease at high risk for ventricular arrhythmia. Multicenter Automatic Defibrillator Implantation Trial
Investigators. N Engl J Med 1996;335(26):1933-40.
17. Connolly SJ, Krahn A, Klein G. Long term management of the survivor of ventricular fibrillation or sustained
ventricular tachycardia. Can J Cardiol 2000;16(Suppl C):20C-2C.
18. Connolly SJ, Hallstrom AP, Cappato R et al. Meta-analysis of the implantable cardioverter defibrillator
secondary prevention trials. AVID, CASH and CIDS studies. Antiarrhythmics vs Implantable Defibrillator study.
Cardiac Arrest Study Hamburg. Canadian Implantable Defibrillator Study. Eur Heart J 2000;21(24):2071-8.
19. Connolly SJ, Dorian P, Roberts RS et al. Comparison of beta-blockers, amiodarone plus beta-blockers, or
sotalol for prevention of shocks from implantable cardioverter defibrillators: the OPTIC Study: a randomized
trial. JAMA 2006;295(2):165-71.
20. Lee SD, Newman D, Ham M et al. Electrophysiologic mechanisms of antiarrhythmic efficacy of a sotalol and
class Ia drug combination: elimination of reverse use dependence. J Am Coll Cardiol 1997;29(1):100-5.
21. Duff HJ, Mitchell LB, Wyse DG et al. Mexiletine/quinidine combination therapy: electrophysiologic correlates
of anti-arrhythmic efficacy. Clin Invest Med 1991;14(5):476-83.
22. Kusumoto F. A comprehensive approach to management of ventricular arrhythmias.Cardiol Clin 2008;26
(3):481-96.
23. Goldberger JJ, Cain ME, Hohnloser SH et al. American Heart Association/American College of Cardiology
Foundation/Heart Rhythm Society scientific statement on noninvasive risk stratification techniques for
identifying patients at risk for sudden cardiac death: a scientific statement from the American Heart
Association Council on Clinical Cardiology Committee on Electrocardiography and Arrhythmias and Council on
Epidemiology and Prevention. J Am Coll Cardiol 2008;52(14):1179-99.
24. European Heart Rhythm Association; Heart Rhythm Society; Zipes DP et al. ACC/AHA/ESC 2006 guidelines for
management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: a report of
the American College of Cardiology/American Heart Association Task Force and the European Society of
Cardiology Committee for Practice Guidelines (Writing Committee to Develop Guidelines for Management of
Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death). J Am Coll Cardiol 2006;48
(5):e247-346.
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e-Therapeutics+ : Therapeutics : Endocrine and Metabolic Disorders: Diabetes Mellitus Page 1 of 16
Therapeutic Choice
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Endocrine and Metabolic Disorders: Diabetes Mellitus

Date Revised: June 2009
M.A. Boctor, MD, DMSc, FRCPC
Diabetes mellitus is a chronic metabolic disturbance characterized by fasting or postprandial hyperglycemia. Rather than a single disease entity,
diabetes mellitus is a heterogeneous syndrome that is caused by an absolute or relative lack of insulin, resistance to the action of insulin, or both.
When severe, it affects carbohydrate, lipid and protein metabolism.
Severe long-term diabetes mellitus may lead to complications involving small blood vessels (microangiopathy), large blood vessels
(macroangiopathy) and nerve damage (neuropathy), affecting multiple organs and systems.
Dysglycemia describes abnormal blood glucose levels without a definite threshold. The term reflects current evidence that even minor degrees of
blood glucose abnormalities increase cardiovascular risk, but that optimal blood glucose levels have not yet been identified.
Classification
Type 1 diabetes mellitus is due to beta cell destruction, usually leading to absolute insulin deficiency. It is most often immune mediated, but
occasionally is idiopathic. Type 1 diabetes usually presents as acute metabolic symptoms of relatively short duration in a child, adolescent or
young adult. If untreated, ketoacidosis may supervene. Onset is unusual after 30 years of age; the presentation may be more gradual in older
individuals. In North America, type 1 accounts for 5–10% of all patients with diabetes.
Type 2 diabetes mellitus ranges from predominant insulin resistance with relative insulin deficiency, to a predominant insulin secretory defect
with insulin resistance. This entity is commonly discovered incidentally, or is diagnosed in an adult who is often obese and has nonspecific
symptoms. Presentation with chronic complications is becoming increasingly frequent. The incidence and prevalence of type 2 diabetes is rising
rapidly in certain ethnic groups, notably aboriginal populations around the world. It is also being diagnosed more frequently in obese children
and adolescents.
Gestational diabetes is defined as onset or recognition of glucose intolerance in pregnancy.
Other specific causes of diabetes mellitus include genetic syndromes such as maturity-onset diabetes of the young, pancreatic diseases, infectious
agents, other diseases leading to carbohydrate intolerance or drug-induced carbohydrate intolerance. Drugs that can perturb blood glucose levels
and interfere with glycemic control in patients with diabetes are presented in Table 1.
Table 1: Drugs That Can Cause Dysglycemia
Atypical antipsychotic agents, e.g., clozapine, olanzapine, quetiapine, risperidone, ziprasidone

Beta-adrenergic antagonists, e.g. atenolol, metoprolol, propranolol
Diazoxide
Glucocorticoids, e.g., prednisone
Interferon alfa
Nicotinic acid
Pentamidine
Phenytoin
Protease inhibitors (amprenavir, atazanavir, darunavir, fosamprenavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, tipranavir)
Thiazide diuretics, e.g., hydrochlorothiazide
Goals of Therapy
Control symptoms
Establish and maintain optimum metabolic control, while avoiding hypoglycemia
Prevent or minimize the risk of complications
Achieve optimal control of comorbidities such as hypertension and dyslipidemia
Investigations (Figure 1 - Diagnosis of Diabetes Mellitus)
Diabetes mellitus may present in a variety of settings:

asymptomatic; incidental discovery through screening
nonspecific signs and symptoms such as fatigue, lassitude, weight changes
presence of diabetic complications such as macrovascular or microvascular changes, neuropathy, kidney disease, erectile dysfunction
acute metabolic symptoms such as polyuria, polydipsia, weight loss
diabetic ketoacidosis
1
The diagnosis of diabetes is established by:
a casual (random) plasma glucose ≥ 11.1 mmol/L in the presence of classic symptoms of diabetes (polyuria, polydipsia and unexplained
weight loss)
or
a fasting plasma glucose (FBG) ≥ 7 mmol/L confirmed by a second test done on a subsequent day (fasting is defined as no caloric intake
for ≥ 8 hours)
or
a plasma glucose level ≥ 11.1 mmol/L 2 hours after a 75 g oral glucose load
Screening
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Therapeutic Choice
All individuals should be evaluated annually for diabetes risk. A fasting plasma glucose level should be measured every 3 years in individuals over
2
40 years of age. Consider earlier and more frequent testing in individuals at a higher risk (Table 2).
Fasting plasma glucose (FPG) levels are less sensitive screening tests than postprandial glucose levels or those measured by oral glucose
3 4
tolerance testing. They also are not as good at predicting cardiovascular risk in patients with diabetes or states of carbohydrate intolerance.
However, measurement of FPG is the recommended screening test because it is less expensive, more reproducible and easier to standardize than
other alternatives.
2
Table 2: Risk Factors for Diabetes Mellitus
st
1 degree relative with diabetes mellitus
History of impaired glucose tolerance or impaired fasting glucose
Vascular disease
Hypertension
Overweight
Polycystic ovary syndrome
Schizophrenia
Type 1 and Type 2 Diabetes Mellitus
Therapeutic Choices
Therapeutic Tips
Therapeutic Choices
Therapy for type 2 diabetes should be aimed at achieving glycemic targets as close to normal as possible as early as possible. Aim to achieve
5
target glycosylated hemoglobin (HbA1c) within 6–12 months. If nonpharmacologic therapy fails to establish euglycemia, institute drug therapy
promptly. In patients with marked hyperglycemia (HbA1c ≥ 9%) at the time of diagnosis, institute drug therapy in conjunction with
nonpharmacologic therapy.
Nonpharmacologic therapy plays a pivotal role in the treatment of both type 1 and type 2 diabetes. Those with type 1 diabetes must be initiated
on insulin therapy at the time of diagnosis, along with nonpharmacologic therapy.
Education is vital in making the patient a full participant in the diabetes health care delivery team and ensuring that they can effectively and
safely manage the disease. A well-structured educational program teaches the patient:
a basic understanding of diabetes
the role of diet, exercise and medications
how and when to self-monitor blood glucose and why it is necessary
management of sick days
recognition and treatment of hypoglycemia
knowledge of the major side effects of medications and how to adjust drugs in response to changes in diet and activity
care of the feet
Nutritional management should be individualized. Provide counselling by a registered dietitian and include instruction on nutrients from all
the basic food groups. Total caloric consumption in patients with type 2 diabetes should be reduced to decrease weight and improve
metabolic control. For patients on insulin, tailor the distribution of food intake into meals and snacks according to the individual's preference,
lifestyle and medications. In patients with type 1 diabetes, the amount and type of carbohydrate have the most immediate impact on blood
glucose levels. Advise patients to fix carbohydrate consumption or count the amount of carbohydrate ingested and adjust the insulin dose
accordingly.
Self-monitoring of blood glucose levels usually results in improved control of blood glucose, allows appropriate recognition of low blood
glucose levels and provides immediate feedback about the effects of therapy. Monitoring blood sugar levels before each meal and before
bedtime is an absolute minimum in individuals on intensive therapy, and postprandial testing (2 hours after meals) is recommended. Self-
monitoring is an integral component of therapeutic plans for patients treated with insulin and oral antihyperglycemic agents. It is also useful
in those treated with diet alone.4
Physical activity and exercise improve cardiovascular function, enhance insulin sensitivity, lower blood pressure and lipid levels and improve
glycemic control in type 2 diabetes. Educate patients treated with insulin about the effect of exercise on blood glucose and how to adjust the
insulin dosage. Teach patients how to time their meals and/or regulate food consumption to ensure the safety of the prescribed exercise
regimen.
Periodic reassessments including directed histories and physical examinations are intended to detect comorbidities and complications;
assessments should include:
blood pressure measurements
foot examinations
tests of long-term control (HbA1c). Individualize the frequency of testing—every 3–4 months for patients on insulin; at least every 6
months for those on nutritional therapy or oral antihyperglycemic agents
assuring the accuracy of blood glucose measurements made by the patient
reinforcing skills learned in education and dietary counselling
urinary albumin excretion rate, using the albumin-creatinine ratio, at least annually
fasting lipid profile, at the time of diagnosis and every 1–3 years if initially normal
eye examination using dilated funduscopy or wide-angle stereoscopic retinal photography at the time of diagnosis in patients with type 2
diabetes, and 5 years after diagnosis or at puberty in patients with type 1 diabetes; repeat at least every 2 years if initially normal
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Therapeutic Choice
annual influenza immunization and one-time pneumococcal immunization
Type 1 Diabetes
Insulin may be administered by syringe, pen or continuous subcutaneous insulin infusion (CSII). Inhaled insulin, which has a rapid onset and a
short duration of action, was not widely used and has been withdrawn from the world market. Either human insulin preparations or insulin
analogues may be used (Table 6). Pure pork insulin preparations are still available, but beef/pork preparations are no longer produced in North
America. The long-acting insulin analogues (insulin glargine and insulin detemir) produce more predictable effects than other intermediate- or
6 , 7 , 8
long-acting insulin preparations, allowing for better control of FPG levels with fewer hypoglycemic episodes, especially over night.
Insulin Regimens (Table 3)
The Diabetes Control and Complications Trial (DCCT) showed that intensive treatment regimens control blood glucose more effectively than
9
conventional regimens and reduce the risk of long-term diabetic microangiographic complications (retinopathy, nephropathy, neuropathy).
10
Follow-up data from the trial demonstrate a long-term benefit of intensive therapy on the risk of cardiovascular events. Newly diagnosed
patients and those with poor glycemic control on conventional regimens should be offered the option of an intensive diabetes management
regimen.
Most patients require approximately 0.5 U of insulin per kilogram of lean body mass. To avoid hypoglycemia, initiate therapy with a lower dose
and adjust the dose according to blood glucose response. Regular home monitoring allows patients to adjust the dose of insulin to correct
abnormal blood glucose levels, to adjust the dose more accurately for diet and exercise and to readjust the insulin dose based on blood glucose
patterns. For optimal control, regular insulin should be administered 20–30 minutes before meals. Alternatively, a very rapid acting insulin
analogue may be more conveniently administered shortly before eating.
The use of CSII or regimens involving multiple doses of rapid-acting insulin improves the stability of postprandial glucose levels and may also
diminish the frequency and severity of hypoglycemia, especially early nocturnal hypoglycemia. CSII using insulin pumps can achieve a tighter and
more reproducible degree of glycemic control, but at a significantly increased cost to the patient.
Table 3: Insulin Regimens in Type 1 Diabetes Mellitus
Rapid- or Short-acting Intermediate- or Long-acting Comments
Intensive: Multiple Dose Insulin R, insulin aspart, glulisine or lispro N, insulin glargine, insulin Flexible
Regimens before each meal detemir at supper or bedtime Usually good BG control
R, insulin aspart, glulisine or lispro N, twice daily at breakfast and Better for people with varying
before each meal supper or bedtime schedules
Intensive: Continuous R, insulin aspart, glulisine or lispro None Most flexible and expensive
Subcutaneous Insulin Infusion basal and boluses as per program May have advantages over
multiple dose regimens
DKA may occur quickly after
discontinuation
Conventional None N or long-acting analogue once Unlikely to control BG

daily before breakfast
None N at breakfast and supper Improved a.m. BG levels
R, insulin aspart, glulisine or lispro N at breakfast and supper Most widely used regimen;
at breakfast and supper better meal control
R, insulin aspart, glulisine or lispro N at breakfast and bedtime More likely to be effective until
at breakfast and supper morning
Abbreviations: BG =blood glucose; DKA=diabetic ketoacidosis; N=NPH insulin; R=Regular insulin
Adverse Effects of Insulin Therapy
Hypoglycemia is the most common side effect of insulin therapy and occurs more frequently in patients on tight diabetic control.
the only way to completely avoid hypoglycemia is through unacceptably loose glycemic control. Hypoglycemia is most commonly the
result of either a missed meal or an unusual amount of exercise. Frequent hypoglycemic events may lead to hypoglycemia unawareness.
Teach patients to account for diet and physical activity when planning insulin treatment regimens.
mild hypoglycemia is manifested by adrenergic symptoms: sweating, tremors, tachycardia, hunger and a general sensation of weakness.
It can easily be treated by the patient with an oral source of sugar. A small glass of unsweetened juice will usually raise the blood
glucose approximately 2 mmol/L.
severe hypoglycemia requires assistance in its recognition and/or treatment. Neuroglycopenic symptoms, confusion, altered behaviour
and disorientation can progress to seizures and coma and prevent the patient from appropriately treating the hypoglycemic episode. If
the patient is conscious, an oral glucose preparation should be used. Unsweetened juice, Lifesavers or sugar cubes may be useful. Oral
glucose and dextrose do not require digestion before absorption.
in unconscious patients, 1 mg of glucagon im or sc temporarily increases blood glucose, allowing for the intake of oral carbohydrate.
Glucagon is not effective in malnourished patients or in alcohol-induced hypoglycemia. Intravenous administration of 50 mL of 50%
dextrose in water is the treatment of choice under these circumstances.
Localized fat hypertrophy is most often the result of frequent use of the same injection site.
Allergic reactions, such as urticaria, angioedema, rashes and local erythema, are rare with human insulin.
Immune-mediated insulin resistance, due to the production of anti-insulin antibodies, is rare with human insulin. Patients who have
developed immune-mediated resistance to animal insulins should be switched to human insulin. Reduce the dose substantially at the
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Therapeutic Choice
initiation of the switch. Concentrated regular insulin, 500 U/mL, may be useful in the treatment of patients requiring very large doses of
insulin.
Type 2 Diabetes Mellitus (Figure 2 - Stepwise Approach to Type 2 Diabetes)
Pharmacologic therapy for type 2 diabetes is indicated if blood glucose control is not achieved within 2–3 months after initiating
nonpharmacologic therapy. Drug treatment is warranted initially (without delay) in the presence of severe hyperglycemia (HbA1c ≥ 9%) or
5
diabetic symptoms.
The choice of therapeutic agent should be tailored to the patient's needs, the desired therapeutic effect and the presence of contraindications.
Patients are usually started on 1 oral drug; however, if the clinical condition warrants it, or if it is unreasonable to expect excellent control with
oral monotherapy, treatment may be initiated with a combination of oral agents and/or insulin. In patients with HbA1c ≥ 9% at presentation,
5 , 11
combination therapy with 2 antihyperglycemic agents from different classes or insulin is recommended. If adequate control is not achieved
with monotherapy within 2–3 months, the addition of a second oral agent from a different therapeutic class should not be delayed. If blood
glucose is not controlled by a combination of oral agents, insulin therapy may be instituted.
Oral agents (Table 7) can be divided into several broad categories: insulin secretagogues (sulfonylureas and meglitinides); drugs that
decrease hepatic glucose production (the biguanide metformin); drugs that increase tissue sensitivity to insulin (thiazolidinediones and
metformin); drugs that enhance insulin secretion (dipeptidyl peptidase-4 inhibitors); and drugs that delay or prevent the digestion of
complex carbohydrates (the alpha-glucosidase inhibitor acarbose) or lipids (the intestinal lipase inhibitor orlistat). The mean decrease in HbA1c
achieved with metformin, sulfonylureas, repaglinide and the thiazolidinediones has generally ranged from 1–1.5% in clinical trials. In contrast,
11
the mean decrease in HbA1c achieved with acarbose, nateglinide and orlistat has been lower (≤ 1%).
When used as initial monotherapy, rosiglitazone, metformin and glyburide were associated with therapeutic failure rates, defined as a confirmed
FPG > 10 mmol/L, of 15%, 21% and 34% after 5 years of follow-up in the ADOPT trial (p < 0.001 for rosiglitazone vs. either comparator).12
Consistent with the primary outcome, 40%, 36% and 26% of patients treated with rosiglitazone, metformin and glyburide, respectively, had
HbA1c levels < 7% after 4 years of treatment. Patients eligible for the randomized double-blind trial had been diagnosed with diabetes mellitus
within the previous 3 years, had previously been treated with diet and exercise alone, and had a baseline FPG between 7 and 10 mmol/L.
The adverse event profile of the 3 therapies differed markedly in ADOPT. Rosiglitazone was associated with the highest rates of weight gain
(6.9% of patients) and edema (14.1%); metformin was associated with the highest overall rate of gastrointestinal events (38.3%), the most
13
common of which was diarrhea (23.7%); and glyburide was associated with the highest rate of hypoglycemia (38.7%). Among the 3
therapies, glyburide was associated with the lowest risk of cardiovascular events. The risk of heart failure was similar in patients treated with
rosiglitazone (1.5%) and metformin (1.3%), but was lowest in those treated with glyburide (0.6%).13
The ADOPT trial did not address the merits of early use of combination therapy. The results of smaller trials with shorter durations of follow-up
suggest that the combination of a thiazolidinedione and metformin is associated with overall lower glucose and HbA1c levels and a higher
14 , 15
probability of reaching control targets as compared with monotherapy with either agent alone.
The results of the UK Prospective Diabetes Study suggest that obese patients with good blood sugar control on metformin therapy have better
16
outcomes than those treated with insulin or sulfonylureas. In general, consider metformin the initial drug of choice for obese patients unless
contraindicated.
The addition of metformin or a thiazolidinedione to the regimen of patients not well controlled on insulin may improve control in some patients
and lower insulin requirements. The combination of a thiazolidinedione plus insulin has not been approved by Health Canada.
Liraglutide, a recently introduced injectable glucagon-like peptide-1 analogue, was not available to be included in the current Canadian
treatment guidelines. Its place in therapy is therefore not defined, though it is indicated when response to metformin or metformin plus a
sulfonylurea is inadequate.
Insulin Secretagogues, Sulfonylureas
Sulfonylureas (gliclazide, glimepiride, glyburide, chlorpropamide and tolbutamide) stimulate basal insulin secretion and increase meal-
stimulated insulin release. They do not correct the impaired early-phase insulin response. Sulfonylureas can cause hypoglycemia and weight gain
to varying degrees.16 , 17 , 18 , 19 They differ from each other in the dose, rate of absorption, duration of action, route of elimination and site of
attachment to the receptor on pancreatic beta cells. Some agents, notably gliclazide, produce an earlier insulin release than others.
Insulin Secretagogues, Meglitinides
Repaglinide and nateglinide induce an early insulin response to meals, thereby lowering postprandial glucose levels. Both are short acting, and
11
should be taken only with meals. Repaglinide produces a dose-related increase in insulin release. FPG usually drops after about 1 month of
20 21
regular use. Nateglinide results in a metabolically sensitive insulin response that is modulated by blood glucose level.
Biguanides
Metformin decreases hepatic glucose production and may lower glucose absorption and enhance insulin-mediated glucose uptake. Metformin is
the only oral antihyperglycemic agent not associated with weight gain. When used alone, metformin does not cause hypoglycemia, but it can
potentiate the hypoglycemic effects of insulin and sulfonylureas. Metformin should not be used in patients at high risk of lactic acidosis, such as
those with renal disease, hepatic disease or hypoxemic states.
Thiazolidinediones (TZDs)
Rosiglitazone and pioglitazone are agonists at nuclear PPARγ receptors that enhance insulin sensitivity and lower both blood glucose and
22
circulating insulin levels. These drugs increase peripheral glucose uptake, enhance fat cell sensitivity to insulin and lower hepatic glucose
output. They do not produce hypoglycemia, although they may enhance the hypoglycemic effects of insulin and sulfonylureas. Individual TZDs
may differ in their effects on serum lipids. TZDs are associated with weight gain due to increased subcutaneous fat deposition, fluid retention and
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Therapeutic Choice
22 , 23 24
edema, and also with an increased incidence of heart failure. They have also been associated with worsening macular edema and an
25
increased risk of fractures, particularly of the hip and wrist.
The cardiovascular safety of thiazolidinediones is under scrutiny.26 , 27 , 28 Meta-analysis of data from 42 clinical trials concluded that patients
treated with rosiglitazone have a small but significant increase in the incidence of myocardial infarction (MI) as compared with placebo or other
26
antihyperglycemic agents. These findings are yet to be confirmed. In contrast, interim analysis of a randomized trial designed to examine the
cardiovascular safety of rosiglitazone suggested that there is no evidence of an increased incidence of death from cardiovascular or other causes
29
as compared with metformin plus sulfonylurea, but confirmed the increased risk of heart failure.
Alpha-glucosidase Inhibitors
Acarbose and miglitol (not available in Canada) inhibit intestinal alpha-glucosidases, which delay the digestion of starches and disaccharides,
thereby reducing postprandial glucose levels. They do not significantly inhibit intestinal lactase. Acarbose does not cause hypoglycemia but can
increase the risk of hypoglycemia when combined with insulin or insulin secretagogues. Because the digestion of sucrose is impaired by acarbose,
hypoglycemia in patients taking acarbose should be treated with glucose rather than sucrose.
Dipeptidyl Peptidase-4 Inhibitors
Dipeptidyl peptidase-4 (DPP-4) inhibitors slow the breakdown of glucagon-like peptide 1 and thereby enhance insulin secretion and suppress
30
glucagon secretion. Saxagliptin and sitagliptin (but not vildagliptin) are approved for use in Canada. They have been shown to reduce
31 , 32
HbA1c by approximately 0.7% after 12–52 weeks of treatment and are not associated with weight gain. To date there are no data available
on the effects of these agents on mortality, diabetic complications or health-related quality of life; thus, their place in therapy is unclear.
Intestinal Lipase Inhibitors
Orlistat is an intestinal lipase inhibitor used initially as an anti-obesity agent, which can produce modest improvements in glycemic control in
33
patients with type 2 diabetes. The hypoglycemic effect is small and in proportion to the degree of weight loss. Orlistat should not be used as
monotherapy for glycemic control.
Insulin Regimens for Type 2 Diabetes Mellitus
In patients with type 2 diabetes, insulin may be used singly or in combination with oral agents in a nighttime insulin/daytime pill regimen.34
Because of their underlying resistance to insulin, many patients require high doses of insulin. There are several commonly used insulin regimens:
Single bedtime injection of insulin added to an ongoing oral antihyperglycemic regimen. Start with a dose of 0.1–0.2 units/kg of insulin NPH
or long-acting analogue and adjust the dose to achieve morning euglycemia. The dose of oral agents may need to be reduced once control is
achieved. Reduce the dose of sulfonylurea if necessary.
Twice-daily injections of a premixed insulin with two-thirds of the daily dose (0.5 units/kg) administered in the morning before breakfast and
the remaining one-third of the daily dose administered before the evening meal (usually 30/70 in the a.m. and 50/50 or 30/70 in the p.m.).
These regimens provide convenience at the expense of flexibility and the ability to correct for abnormal results. The dose and type of mixture
may have to be adjusted to achieve glycemic targets.
Intensive insulin therapy may be started with 40% of the total daily dose (0.5 units/kg) administered as a basal insulin (NPH or long-acting
analogue) and 20% of the daily dose administered before meals 3 times daily (regular or very rapid acting analogues). The dose is then
adjusted to achieve glycemic targets.
Targets for Control
Control of blood glucose (Table 4) reduces the risk of long-term complications in type 1 and type 2 diabetes. Euglycemia is difficult to attain and
9
maintain. Tight control of blood glucose levels increases the risk of hypoglycemic episodes. Frequent hypoglycemia may lead to hypoglycemia
35
unawareness.
38
Table 4: Recommended Targets for Blood Glucose Control
HbA1c FPG/ preprandial glucose 2-hour PPG

(%) (mmol/L) (mmol/L)
Target for most patients ≤7 4–7 5–10
Abbreviations: HbA1C =glycosylated hemoglobin; FPG=fasting plasma glucose; PPG=postprandial plasma glucose
Vascular protection encompassing a comprehensive reduction of cardiovascular risk is a priority in patients with diabetes. In addition to glycemic
control, achieve blood pressure (see Cardiovascular Disorders: Hypertension) and serum lipid targets (see Cardiovascular Disorders:
36
Dyslipidemias), encourage smoking cessation (see Psychiatric Disorders: Smoking Cessation) and prescribe antiplatelet therapy as indicated.
The 2008 Canadian Diabetes Association Guidelines recommend that low-dose ASA (80–325 mg/day) be considered in patients with diabetes
36
and evidence of cardiovascular disease. Clopidogrel (75 mg) may be considered in people unable to tolerate ASA.
Control of serum lipids reduces the risk of cardiovascular events, which are the main cause of morbidity and mortality in diabetes. Patients
aged > 30 years are at very high risk for coronary artery disease. Therapy includes statins for elevated LDL-C and fibrates for elevated
triglycerides and/or low HDL-C. Niacin can increase blood glucose levels; thus antihyperglycemic therapy will require adjustment if this
agent is used to manage dyslipidemia.
Control of blood pressure (< 130/80 mm Hg) is an additional goal of therapy. Diabetes, particularly type 2, is frequently associated with
hypertension. Monitor blood pressure regularly and control hypertension if it occurs, especially in the elderly.
An intensive, multifactorial intervention involving behaviour modification and pharmacologic therapy targeting hyperglycemia, hypertension,
dyslipidemia and microalbuminuria, and secondary prevention of cardiovascular disease with low-dose ASA and ACE-inhibitor therapy,
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Therapeutic Choice
improves HbA1c levels, blood pressure and serum lipid control, and reduces albumin excretion and the incidence of cardiovascular endpoints,
nephropathy, retinopathy and autonomic neuropathy.37
Therapeutic Tips
Assess all patients every 3–6 months. Study their home monitoring records and note the occurrence and frequency of hypoglycemia. Monitor
blood sugar and blood pressure, body weight and the presence of complications. Foot examination is an integral part of such monitoring.
Inadequate control is frequently related to inadequate dietary compliance or poor adherence to medications.
The use of snacks is important in patients on conventional insulin therapy and may be important in those treated with a sulfonylurea. Those
treated with acarbose, metformin, thiazolidinedione, meglitinide or a multidose rapid-acting insulin regimen may not require snacks.
Encourage all patients to wear a Medic Alert bracelet or the equivalent.
Diabetes Mellitus in Pregnancy
Therapeutic Choices
Carbohydrate intolerance during pregnancy can occur in patients with diabetes prior to pregnancy and in those who become diabetic during
pregnancy.
Pre-existing Diabetes
Poor diabetic control at the time of conception increases the risk of spontaneous abortion, prenatal mortality and morbidity and congenital
malformations. Both retinal and renal disease may worsen significantly during pregnancy. Pregnancy should therefore be planned carefully.
Patients should be followed by specialized diabetes health care teams with experience in the management of diabetic pregnancy.
Optimize diabetic control prior to pregnancy and screen for microvascular complications. Women with pre-existing diabetes are at risk of
progressive retinopathy if glycemic control is suboptimal during pregnancy. Microalbuminuria is associated with increased risk of maternal and
fetal complications.
39
Discontinue oral antihyperglycemic agents, and certain teratogenic antihypertensive agents (ACE inhibitors and angiotensin II receptor
antagonists) prior to conception. Optimize glycemic control with diet or, if necessary, diet and insulin. Prescribe folic acid at a dose of 1–4
mg/day before conception until 13 weeks of gestation. If conception occurs in a patient treated with oral antihyperglycemics, stop these drugs as
soon as pregnancy is diagnosed and switch the patient to insulin.
Gestational Diabetes (Figure 3 - Diagnosis of Gestational Diabetes)
Gestational diabetes mellitus is carbohydrate intolerance of varying severity that is detected, or first recognized, during pregnancy. It is
associated with increased risk of macrosomia (high birth weight), neonatal hypoglycemia, hyperbilirubinemia, hypocalcemia and polycythemia. It
may be associated with an increased risk of childhood obesity and diabetes in the offspring and an increased risk for future diabetes in the
mother. Gestational diabetes is usually detected towards the end of the second trimester based on an abnormal response to a 75 g oral glucose
tolerance test.
Women who have had gestational diabetes should have a 2-hour oral glucose tolerance test 6 weeks to 6 months postpartum, to rule out the
presence of ongoing glucose intolerance.
Therapeutic Choices
Dietary counselling by a registered dietitian is essential. The diet is divided into meals and snacks, and should provide for the nutritional
needs of the pregnant woman and the fetus while avoiding starvation and ketosis.
Self-monitoring of pre- and postprandial blood glucose levels is important. Targets for control are an FPG < 5.3 mmol/L, and 1- and 2-hour
PPG < 7.8 mmol/L and < 6.7 mmol/L, respectively. Elevated PPG is more predictive of macrosomia than is FPG.
Aerobic exercise, particularly use of the upper body, should be encouraged.
Insulin is the only approved pharmacologic therapy for hyperglycemia in pregnant women. Tailor its use to achieve the targets outlined above.
Tight control frequently necessitates multidose insulin regimens. Rapid-acting insulin analogues, although not specifically approved for this
purpose, are now widely used to better control postprandial glucose levels. Limited data are available regarding the use of insulin glargine during
40 , 41 , 42 , 43
pregnancy.
Oral agents have been evaluated as alternatives to insulin for the treatment of gestational diabetes. Metformin and glyburide
have been shown to be effective in this setting.44,45 The 2008 Canadian Diabetes Association Clinical Practice Guidelines
recommend insulin as the treatment of choice, but oral agents can be considered in patients who are nonadherent to or refuse
insulin.46 Useful Info?
Preventing Type II Diabetes Mellitus
Page 237
Therapeutic Choice
Individuals with blood glucose elevations below the diabetic thresholds may be described as having prediabetes or dysglycemia. The term
includes both impaired fasting glucose (FPG 6.1–7 mmol/L) and impaired glucose tolerance (plasma glucose of 7.8–11 mmol/L 2 hours after a 75
g oral glucose load).
Metabolic syndrome is a common, multifeatured constellation of central obesity, hypertension, dyslipidemia, insulin resistance and glucose
47 , 48
abnormalities. It carries a significant risk of diabetes and cardiovascular disease.
Several large studies have examined nonpharmacologic and pharmacologic strategies aimed at preventing the onset of type 2 diabetes mellitus in
high-risk individuals.
The Finnish Diabetes Prevention Study (DPS)49 and the Diabetes Prevention Program (DPP)50 showed that calorie restriction and reduced fat
intake combined with supervised, moderately intense physical activity of about 150 minutes/week significantly reduced the relative risk of
progression from prediabetes to diabetes by 58% at 4 years. In the DPS the incidence of diabetes was 11% in those randomized to the lifestyle
intervention versus 23% in the control group; in the DPP the incidence of diabetes was 4.8%, 7.8% and 11% in those randomized to the lifestyle
intervention, metformin and placebo, respectively. The weight loss associated with lifestyle interventions was about 5–6% of initial body weight
in these studies.
The benefits of the lifestyle changes were maintained after the discontinuation of the active intervention in the DPS. The relative risk of diabetes
remained 36% lower in those originally randomized to the lifestyle intervention compared with the control group after a further 3 years of follow-
up (4.3% vs 7.4%).51
Metformin 850 mg twice daily reduced the relative risk of progression from prediabetes to diabetes by 31% versus placebo in the DPP. After a 1-
52
to 2-week washout period, the risk of progression to diabetes remained 25% lower in those treated with metformin than placebo.
53
Acarbose has also been evaluated in prevention trials. In STOP-NIDDM, acarbose 100 mg TID resulted in a 30% reduction of progression to
54
diabetes at 14 months (32% vs 42% with placebo).
TZDs also reduce the risk of progression from prediabetes to diabetes.56 , 58 , 59
55 , 56 , 57
The DREAM study evaluated the effects of rosiglitazone and ramipril on progression from prediabetes to type 2 diabetes.
Rosiglitazone significantly reduced the risk of progression to diabetes or death by 60% over 3 years compared with placebo (11.6% vs 26%) in
patients with prediabetes and no other cardiovascular risk factors. The benefit of rosiglitazone in preventing progression to diabetes was offset to
56
some extent by a significantly higher incidence of heart failure relative to placebo (0.5% vs 0.1%). In contrast to the demonstrated benefit of
57
rosiglitazone, ramipril did not prevent the progression from prediabetes to diabetes in the DREAM trial. The use of ramipril was, however,
associated with higher rates of normalization of glucose tolerance and lower overall blood glucose levels.
58 59
The results of DREAM are consistent with 2 large prospective studies (TRIPOD and the DPP ) demonstrating that troglitazone, a TZD that is no
longer available, delayed progression from prediabetes to diabetes.
There are no known safe and effective measures to prevent type 1 diabetes.
Diabetic Ketoacidosis
Diabetic ketoacidosis is a potentially fatal complication that results from severe insulin deficiency and is characterized by severe hyperglycemia,
60
volume depletion, acidosis, depressed levels of consciousness and marked ketonemia. Patients are depleted in sodium, potassium, chloride and
water. Despite potassium depletion, serum potassium is frequently elevated at the time of presentation. Prerenal azotemia may be present.
Hyperglycemia, as well as high triglycerides and free fatty acids, may result in pseudohyponatremia. Diabetic ketoacidosis may be seen at first
presentation in patients with type 1 diabetes and may also occur when insulin is discontinued. It often occurs in patients with established diabetes
who have a severe stressful illness (e.g., severe infection), surgery, trauma or MI. Patients with diabetic ketoacidosis should be hospitalized
(Table 5).
Table 5: Management of Diabetic Ketoacidosis
Fluids: Patients are always volume depleted (average 7 L). Give iv NS (0.9% NaCl) 2 L in the first 2 h, then individualize. Good urinary output
is reassuring. May use 0.45% NaCl (½ NS) initially if the blood glucose is > 50 mmol/L. Change to 5% D5W when blood glucose drops to ≤ 14
mmol/L.
Insulin: Give 10 units of insulin R iv bolus, then infuse at 0.1 U/kg/hr (5–10 U/h). Mix 50 U in 500 mL NS and piggyback into a main iv.
Continue iv insulin until the anion gap resolves.
+
Potassium: Potassium chloride is the preparation of choice. If serum K is < 3.5 mmol/L, add 40 mmol/L of fluid; if 3.5–5.5 mmol/L, add 20
+
mmol/L; if > 5.5 mmol/L, do not add K , especially if anuric.
Bicarbonate: Give sodium bicarbonate if acidosis is severe (e.g., pH < 7) but only for partial correction (e.g., 10 mL 8.4% NaHCO3), then
reassess.
Laboratory tests: Initial CBC, glucose, electrolytes, urea, creatinine and ABG. Cultures as indicated. Radiology as indicated. Repeat electrolyte
and glucose hourly, ABG only if severe acidosis persists.
Supportive care: Keep the patient warm and rested. Insert an NG tube if vomiting, and a urinary catheter if anuric (urinary retention may be
significant).
Pitfalls:
• Acetone smell may be absent, undetected or unrecognized by some.
• Temperature may be low initially—absence of fever does not rule out infection.
• Leukocytosis is usually present and does not necessarily mean infection.
• Low serum sodium may be due to pseudohyponatremia.
Page 238
Therapeutic Choice
• High serum potassium is caused by acidosis and may be seen in spite of severe total body potassium depletion.
• Ketostix detects aceto-acetate but not hydroxybutyrate.
• Dehydration may mask a respiratory infection; reassess after rehydration and stabilization.
• Severe abdominal pain or signs of an acute abdomen need to be reassessed after stabilization—they often disappear.
• A premature switch to sc insulin and/or discharge results in high recurrence and readmission rates.
Abbreviations: R=regular; NS=normal saline
Figure 1- Diagnosis of Diabetes Mellitus
Figure 2- Stepwise Approach to Type 2 Diabetes
Page 239
Therapeutic Choice
a.
Reinforce the need to continue lifestyle interventions at every opportunity.
b.
Combined use of thiazolidinediones plus insulin has not been approved by Health Canada. When used in combination with insulin, thiazolidinediones may
increase the risk of edema and heart failure.
c.
Drug regimens should be adjusted in a timely fashion so as to achieve the target HbA1c level within 6–12 months.
d.
If using preprandial insulin, do not use an insulin secretagogue.
Abbreviation: HbA1c = glycosylated hemoglobin
Figure 3- Diagnosis of Gestational Diabetes
a.
Screening may be done earlier if very high risk or previous gestational diabetes mellitus.
b.
Abnormal values: fasting blood glucose ≥ 5.3 mmol/L; blood glucose ≥ 10.6 mmol/L 1 h post glucose load; blood glucose ≥ 8.9 mmol/L 2 h post glucose load.
Table 6: Human Insulin and Analogues
a
Cost
Class Drug Onset Peak Duration Comments
Very Rapid-acting insulin aspart 10–15 60–90 min 4–5 h Appearance: clear. $$$
Insulin Analogues NovoRapid min
Very Rapid-acting insulin glulisine 10–15 60–90 min 4–5 h Appearance: clear. $$$
Insulin Analogues Apidra min
Very Rapid-acting insulin lispro 10–15 60–90 min 4–5 h Appearance: clear. $$$
Insulin Analogues Humalog min
Rapid-acting Human insulin regular 30–60 2–4 h 5–8 h Appearance: clear. $$

Insulin Humulin R, Novolin min
ge Toronto
Intermediate-acting insulin NPH 1–2 h 5–8 h 14–18 h Appearance: cloudy. $$

Human Insulin Humulin N, Novolin
ge NPH
Long-acting Insulin insulin detemir 1.5 h Flat, no 24 h Appearance: clear. $$$$$

Analogues Levemir discernible Do not mix with other insulins.
peak. Contains a C14 fatty acid chain and is highly bound
(98%) to serum albumin.
Page 240
Therapeutic Choice
a
Cost
Class Drug Onset Peak Duration Comments
Long-acting Insulin insulin glargine 1.5 h Flat, no 24 h Appearance: clear. $$$$$

Analogues Lantus discernible Do not mix with other insulins.
peak. An acidic solution (pH 4). After injection the
solution is neutralized, and microprecipitates form,
from which the drug is slowly released.
Do not inject im or iv.
Mixed (regular/NPH) insulin Combination of individual Appearance: cloudy. $$

Human Insulin regular/insulin NPH components
Humulin 30/70,
Novolin ge 30/70,
40/60, 50/50
Mixed Insulin insulin lispro/lispro 10–15 not available not Appearance: cloudy. $$$
Analogues protamine min available
Humalog Mix25,
Humalog Mix50
Mixed Insulin insulin 10–15 60–90 min 15–18 h Appearance: cloudy. $$$
Analogues aspart/aspart min
protamine
NovoMix 30
a.
Cost of 5 × 3 mL cartridges unless otherwise specified; drug cost only.
Legend: $ < $40 $$ $40–50 $$$ $50–60 $$$$ $60–90 $$$$$ > $90
Table 7: Antihyperglycemic Agents
b
Cost
a
Class Drug Dose Adverse Effects Drug Interactions Comments
Insulin chlorpropamide 100–500 mg daily in 1 Sulfonylureas: Hypoglycemic effect Contraindicated in $

Secretagogues, generics dose prolonged potentiated by type 1 diabetes,
Sulfonylureas hypoglycemia; salicylates, pregnancy.
weight gain. sulfonamides and
Chlorpropamide: monoamine oxidase
alcohol-associated inhibitors; beta-
flushing; blockers may mask
hyponatremia. hypoglycemic
symptoms.
Insulin gliclazide 40–320 mg/day; give Prolonged Hypoglycemic effect Contraindicated in $

Secretagogues, Diamicron, generics in 2 divided doses if hypoglycemia; potentiated by type 1 diabetes,
Sulfonylureas daily dose ≥ 160 mg weight gain. salicylates, pregnancy.
Antiplatelet effect. sulfonamides and
monoamine oxidase
inhibitors; beta-
blockers may mask
hypoglycemic
symptoms.
Insulin gliclazide, long-acting 30–120 mg once daily Prolonged Hypoglycemic effect Contraindicated in $-$$
Secretagogues, Diamicron MR, hypoglycemia; potentiated by type 1 diabetes,
Sulfonylureas generics weight gain. salicylates, pregnancy.
Antiplatelet effect. sulfonamides and
monoamine oxidase
inhibitors; beta-
blockers may mask
hypoglycemic
symptoms.
Insulin glimepiride 1–4 mg once daily Prolonged Hypoglycemic effect Contraindicated in $$

Secretagogues, Amaryl, generics hypoglycemia; potentiated by type 1 diabetes,
Sulfonylureas weight gain. salicylates, pregnancy.
sulfonamides and
monoamine oxidase
inhibitors; beta-
blockers may mask
hypoglycemic
symptoms.
Insulin glyburide 2.5–20 mg/day; give in Prolonged Hypoglycemic effect Contraindicated in $

Secretagogues, Diabeta, generics 2 divided doses if daily hypoglycemia; potentiated by type 1 diabetes
Sulfonylureas dose > 10 mg weight gain. salicylates,
sulfonamides and
monoamine oxidase
Page 241
Therapeutic Choice
b
Cost
Class Druga Dose Adverse Effects Drug Interactions Comments
inhibitors; beta-
blockers may mask
hypoglycemic
symptoms.
Insulin tolbutamide 500 mg BID–TID Prolonged Hypoglycemic effect Contraindicated in $

Secretagogues, generics Maximum 3 g/day hypoglycemia; potentiated by type 1 diabetes,
Sulfonylureas weight gain. salicylates, pregnancy.
GI upset, skin sulfonamides and
rash, hemolytic monoamine oxidase
anemia, jaundice. inhibitors; beta-
blockers may mask
hypoglycemic
symptoms.
Alcohol and rifampin
may accelerate
clearance.
Insulin nateglinide 60–180 mg Hypoglycemia, Clearance of Contraindicated in $$$

Secretagogues, Starlix 0–30 min before meals especially if meal meglitinides is reduced type 1 diabetes,
Meglitinides not taken. by strong CYP3A4 pregnancy.
inhibitors, e.g.,
imidazole antifungals,
macrolides, protease
inhibitors.
Clearance of
meglitinides is
enhanced by strong
CYP3A4 inducers, e.g.,
rifampin,
carbamazepine.
Insulin repaglinide 0.5–4 mg Hypoglycemia, Clearance of Contraindicated in $$

Secretagogues, GlucoNorm, generics 0–30 min before meals especially if meal meglitinides is reduced type 1 diabetes,
Meglitinides not taken; weight by strong CYP3A4 pregnancy.
gain. inhibitors, e.g.,
macrolides, protease
inhibitors.
Clearance of
meglitinides is
enhanced by strong
CYP3A4 inducers, e.g.,
rifampin,
carbamazepine.
Strong inhibitors of
CYP2C8 have the
potential to ↓
metabolism of repaglinide,
e.g., atazanavir, ritonavir,
gemfibrozil. Enhanced
and prolonged
hypoglycemia occurs
when taken with
gemfibrozil (avoid
combined use).
Cyclosporine ↑ plasma
concentrations of
repaglinide.
Biguanides metformin 500–2500 mg/day Nausea, diarrhea, Potentiates other oral No weight gain. $
Glucophage, divided BID or TID; abdominal antihyperglycemic Contraindicated in
start low and go slow discomfort, agents; alcohol hepatic
Glumetza,
to minimize GI side anorexia, metallic potentiates impairment, renal
generics
effects; little additional taste, lactic hypoglycemic effect. impairment,
benefit above 1500 acidosis if hepatic previous lactic
mg/day or renal disease. acidosis.
Alpha-glucosidase acarbose 50–100 mg TID with Flatulence, Potentiates other No weight gain; $-$$$
Inhibitors Glucobay each meal; start low diarrhea, antihyperglycemic not absorbed;
and go slow abdominal pain, agents; may ↓ contraindicated in
cramps, nausea. metformin irritable bowel
bioavailability. syndrome or
Page 242
Therapeutic Choice
b
Cost
inflammatory
bowel disease.
Thiazolidinediones pioglitazone 15–45 mg once daily Weight gain, fluid Potentiates the effect Avoid in patients $$$
(TZDs) Actos, generics retention and of other with heart failure.
hemodilution; antihyperglycemic TZDs have
worsening heart agents. variable effects on
failure; macular Gemfibrozil inhibits lipids
degeneration; metabolism and ↑ (pioglitazone
increased risk of plasma levels. ↑ HDL, ↓ TG;
fractures rosiglitazone
↑ HDL, ↑ LDL).
Ovulation resumes
in previously
anovulatory
women, e.g.,
polycystic ovarian
syndrome; ↑ risk of
pregnancy if
adequate
contraception not
used.
Thiazolidinediones rosiglitazone 4–8 mg daily in 1–2 Weight gain, fluid Potentiates the effect Avoid in patients $$$$
(TZDs) Avandia doses retention and of other with heart failure.
hemodilution; antihyperglycemic TZDs have
worsening heart agents. variable effects on
↑ HDL, ↑ LDL).
Ovulation resumes
in previously
anovulatory
women, e.g.,
polycystic ovarian
pregnancy if
adequate
contraception not
used.
Dipeptidyl saxagliptin 5 mg once daily Nasopharyngitis, Clearance of May be taken with $$$$
peptidase-4 Onglyza hypersensitivity saxagliptin is reduced or without food.
Inhibitors (DPP- reactions. by strong CYP3A4/5
4s) inhibitors, e.g.,
macrolides.
Clearance of
saxagliptin is enhanced
by strong CYP3A4/5
inducers, e.g.,
rifampin.
Dipeptidyl sitagliptin 100 mg once daily Nasopharyngitis, Does not inhibit May be taken with $$$$
peptidase-4 Januvia hypersensitivity cytochrome P450 or without food.
Inhibitors (DPP- reactions. isozymes. Low
4s) potential for drug
interactions.
Glucagon-Like- liraglutide Initial: 0.6 mg daily sc Nausea, vomiting, No significant Causes weight $$$$$
Peptide 1 (GLP-1) Victoza Increase to 1.2–1.8 mg diarrhea, interactions. loss.
Agonists daily sc nasopharyngitis. Caution in
patients with heart
rhythm
disturbances.
Contraindicated in
pregnancy and
those with
personal or family
history of
medullary thyroid
carcinoma or
Page 243
Therapeutic Choice
b
Cost
multiple endocrine
neoplasia
syndrome type 2
Intestinal Lipase orlistat 120 mg TID with meals Diarrhea, May impair absorption $$$$$
Inhibitors Xenical steatorrhea, of fat-soluble vitamins
abdominal (A, D, E, K).
discomfort, oily
leakage.
Combination rosiglitazone/glimepiride Initial: 4 mg/1 mg or Weight gain, fluid Potentiates the effect Avoid in patients $$$$
Products Avandaryl 4 mg/2 mg once daily retention and of other with heart failure.
Maximum: 4 mg/4 mg hemodilution; antihyperglycemic TZDs have
once daily worsening heart agents. variable effects on
Sulfonylureas: Hypoglycemic effect ↑ HDL, ↑ LDL).
prolonged potentiated by
hypoglycemia; salicylates, Ovulation resumes
weight gain. sulfonamides and in previously
monoamine oxidase anovulatory
inhibitors; beta- women, e.g.,
blockers may mask polycystic ovarian
hypoglycemic syndrome; ↑ risk of
symptoms. pregnancy if
adequate
contraception not
used.
Contraindicated in
type 1 diabetes,
pregnancy.
Combination rosiglitazone/metformin If on metformin Weight gain, fluid Potentiates the effect Avoid in patients $$$$–
Products Avandamet monotherapy: start retention and of other with heart failure. $$$$$
with rosiglitazone 2 mg hemodilution; antihyperglycemic TZDs have
BID. If on rosiglitazone worsening heart agents. variable effects on
monotherapy start with failure; macular Gemfibrozil inhibits lipids
metformin 500 mg BID degeneration; metabolism and ↑ (pioglitazone
Maximum: 8 mg/ 1000 increased risk of plasma levels. ↑ HDL, ↓ TG;
mg BID fractures rosiglitazone
Nausea, diarrhea, Potentiates other oral ↑ HDL, ↑ LDL).
abdominal antihyperglycemic
discomfort, agents; alcohol Ovulation resumes
anorexia, metallic potentiates in previously
taste, lactic hypoglycemic effect. anovulatory
acidosis if hepatic women, e.g.,
or renal disease. polycystic ovarian
pregnancy if
adequate
contraception not
used.
Contraindicated in
hepatic
impairment, renal
impairment,
previous lactic
acidosis.
Combination sitagliptin/metformin If on metformin Nasopharyngitis, Does not inhibit Contraindicated in $$$$

Products Janumet monotherapy: continue hypersensitivity cytochrome P450 hepatic
metformin dose, add reactions. isozymes. Low impairment, renal
sitagliptin 50 mg BID. Nausea, diarrhea, potential for drug impairment,
If on both agents abdominal interactions. previous lactic
already: continue discomfort, Potentiates other oral acidosis.
current doses anorexia, metallic antihyperglycemic
Maximum: 50 mg/1000 taste, lactic agents; alcohol
mg BID acidosis if hepatic potentiates
or renal disease. hypoglycemic effect.
a.
Combination therapy: always use agents from different classes; combinations can be used as initial therapy if hyperglycemia is not expected to be controlled by
a single agent.
Page 244
Therapeutic Choice
b.
Legend: $ < $10 $–$$ < $10–25 $$ $10–25 $–$$$ <$10– 50 $$$ $25–50 $$$–$$$$ $25–100 $$$$ $50–100 $$$$–$$$$$ $50–
>100 $$$$$ > $100
Suggested Readings
Canadian Diabetes Association. 2008 Clinical practice guidelines for the prevention and management of diabetes in Canada. Canadian Journal of
Diabetes 2008;32(Suppl 1):S1-201. Available from: www.diabetes.ca/files/cpg2008/cpg-2008.pdf. Accessed December 15, 2009.
Cheng AY, Fantus IG. Oral antihyperglycemic therapy for type 2 diabetes mellitus. CMAJ 2005;172(2):213-26.
Daneman D. Type 1 diabetes. Lancet 2006;367(9513):847-58.
Drucker DJ, Nauck MA. The incretin system: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes.
Lancet 2006;368(9548):1696-705.
Heine RJ, Diamant M, Mbanya JC et al. Management of hyperglycaemia in type 2 diabetes: the end of recurrent failure? BMJ 2006;333(7580):1200
-4.
[No authors listed]. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-
dependent diabetes mellitus. The Diabetes Control and Complications Trial Research Group. N Engl J Med 1993;329(14):977-86.
Stumvoll M, Goldstein BJ, van Haeften TW. Type 2 diabetes: principles of pathogenesis and therapy. Lancet 2005;365(9467):1333-46.
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diabetes mellitus. Diabetes 1998;47(9):1472-9.
36. Canadian Diabetes Association Clinical Practice Guidelines Expert Committee. Vascular protection in people with diabetes. Canadian Journal
of Diabetes 2008;32(Suppl 1):S102-6. Available from: www.diabetes.ca/files/cpg2008/cpg-2008.pdf. Accessed December 15, 2009.
37. Gaede P, Vedel P, Larsen N et al. Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes. N Engl J Med
2003;348(5):383-93.
38. Canadian Diabetes Association Clinical Practice Guidelines Expert Committee. Targets for glycemic control. Canadian Journal of Diabetes
2008;32(Suppl 1):S29-31. Available from: www.diabetes.ca/files/cpg2008/cpg-2008.pdf. Accessed December 15, 2009.
39. Cooper WO, Hernandez-Diaz S, Arbogast PG et al. Major congenital malformations after first-trimester exposure to ACE inhibitors. N Engl J
Med 2006;354(23):2443-51.
40. Di Cianni G, Volpe L, Lencioni C et al. Use of insulin glargine during the first weeks of pregnancy in five type 1 diabetic women. Diabetes
Care 2005;28(4):982-3.
41. Graves DE, White JC, Kirk JK. The use of insulin glargine with gestational diabetes mellitus. Diabetes Care 2006;29(2):471-2.
42. Holstein A, Plaschke A, Egberts EH. Use of insulin glargine during embryogenesis in a pregnant woman with Type 1 diabetes. Diabet Med
2003;20(9):779-80.
43. Woolderink JM, van Loon AJ, Storms F et al. Use of insulin glargine during pregnancy in seven type 1 diabetic women. Diabetes Care
2005;28(10):2594-5.
44. Rowan JA, Hague WM, Gao W et al. Metformin versus insulin for the treatment of gestational diabetes. N Engl J Med 2008;358(19):2003-
15.
45. Langer O, Conway DL, Berkus MD et al. A comparison of glyburide and insulin in women with gestational diabetes mellitus. N Engl J Med
2000;343(16):1134-8.
46. Canadian Diabetes Association Clinical Practice Guidelines Expert Committee. Diabetes and pregnancy. Canadian Journal of Diabetes
2008;32(Suppl 1):S168-80. Available from: www.diabetes.ca/files/cpg2008/cpg-2008.pdf. Accessed December 15, 2009.
47. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive Summary of The Third Report of The
National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, And Treatment of High Blood Cholesterol In Adults
(Adult Treatment Panel III). JAMA 2001;285(19):2486-97.
48. Alberti KG, Zimmet PZ. Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: diagnosis and
classification of diabetes mellitus provisional report of a WHO consultation. Diabet Med 1998;15(7):539-53.
49. Tuomilehto J, Lindstrom J, Eriksson JG et al. Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired
glucose tolerance. N Engl J Med 2001;344(18):1343-50.
50. Knowler WC, Barrett-Connor E, Fowler SE et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N
Engl J Med 2002;346(6):393-403.
51. Lindstrom J, Ilanne-Parikka P, Peltonen M et al. Sustained reduction in the incidence of type 2 diabetes by lifestyle intervention: follow-up
of the Finnish Diabetes Prevention Study. Lancet 2006;368(9548):1673-9.
52. Diabetes Prevention Program Research Group. Effects of withdrawal from metformin on the development of diabetes in the diabetes
prevention program. Diabetes Care 2003;26(4):977-80.
53. Van de Laar FA, Lucassen PL, Akkermans RP et al. Alpha-glucosidase inhibitors for people with impaired glucose tolerance or impaired
fasting blood glucose. Cochrane Database Syst Rev 2006;(4):CD005061.
54. Chiasson JL, Josse RG, Gomis R et al. Acarbose for prevention of type 2 diabetes mellitus: the STOP-NIDDM randomised trial. Lancet
2002;359(9323):2072-7.
55. Gerstein HC, Yusuf S, Holman R et al. Rationale, design and recruitment characteristics of a large, simple international trial of diabetes
prevention: the DREAM trial. Diabetologia 2004;47(9):1519-27.
56. Gerstein HC, Yusuf S, Bosch J et al. Effect of rosiglitazone on the frequency of diabetes in patients with impaired glucose tolerance or
impaired fasting glucose: a randomised controlled trial. Lancet 2006;368(9541):1096-105.
57. Bosch J, Yusuf S, Gerstein HC et al. Effect of ramipril on the incidence of diabetes. N Engl J Med 2006;355(15):1551-62.
58. Buchanan TA, Xiang AH, Peters RK et al. Preservation of pancreatic beta-cell function and prevention of type 2 diabetes by pharmacological
treatment of insulin resistance in high-risk Hispanic women. Diabetes 2002;51(9):2796-803.
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59. Knowler WC, Hamman RF, Edelstein SL et al. Prevention of type 2 diabetes with troglitazone in the Diabetes Prevention Program. Diabetes
2005;54(4):1150-6.
60. Kitabchi AE, Umpierrez GE, Murphy MB et al. Hyperglycemic crises in adult patients with diabetes: a consensus statement from the
American Diabetes Association. Diabetes Care 2006;29(12):2739-48.
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e-Therapeutics+ : Therapeutics : Endocrine and Metabolic Disorders: Nutritional Supplem... Page 1 of 7
Therapeutic Choice
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Endocrine and Metabolic Disorders: Nutritional Supplements for Adults
L. John Hoffer, MD, CM, PhD, FRCPC
Goals of Therapy
Prevent or treat nutritional deficiency disease

Prevent or treat nondeficiency diseases whose progression may be mitigated by increased intake of certain
nutrients
Therapeutic Choices
Preventive Supplements
Table 1: Indications For Preventive Supplementsa
Clinical evidence of deficient intake:b

Voluntary or involuntary weight loss (< 1500 kcal/d)
History of inadequate intake of certain nutrient groups:
dairy products and fluid milk (calcium, vitamin D)
deeply coloured vegetables and fruits (folic acid, carotenoids, vitamin C)
whole grains (folic acid, vitamin B6, vitamin E)
Patient populations at risk of deficient intake or malabsorption:

Prolonged hospital admission
Institutionalization
Poverty, social isolation
GI tract symptoms (nausea, pain, diarrhea, anorexia)
GI disease known to cause malabsorption or maldigestion
Reduced functional and activity status
Multiple comorbidities, especially organ failure
Swallowing, chewing or dental problems
Psychiatric or neurologic disease
Chronic substance abuse, especially alcoholism
Increased vitamin/mineral needs

Hemo- or peritoneal dialysis
Pregnancy
Drug-nutrient interactions
a. This table identifies situations in which the risk of overt deficiency is sufficiently great that preventive therapy is indicated.
Large segments of the normal population consume inadequate amounts of calcium, zinc, certain B vitamins and vitamin D, and
for this reason some authorities now advise all adults to use a daily preventive supplement.1 , 2 , 3 , 4
b. Formal dietetic assessment advised
Preventive supplements are vitamin or vitamin/mineral supplements formulated to compensate for inadequacies in
the diet of normal persons. They are also useful for patients with excellent diets but increased requirements, mild
malabsorption or increased nutrient losses (Table 1).
Traditionally, preventive supplements contained 50 to 150% of the recommended dietary allowance (RDA) for some
or many vitamins, but products currently on the market vary considerably, especially with regard to folic acid,
vitamin B12, vitamin C, vitamin A, iron and zinc. Some common vitamin/mineral deficiencies and recommendations
are listed in Table 2. See Table 3 for preventive supplementation in special populations.
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Prevention of Deficiencies (Table 2, Table 3)
Table 2: Common Vitamin/Mineral Deficiencies
Preventive
Supplement Recommendations
Calcium Children age 9 to 18 require 1300 mg/day, adults age 19 to 50 require 1000 mg/day and
persons over 50 require 1200 mg/day. Most people need supplements to accomplish this.
In order to maximize absorption, calcium carbonate (1200 mg provides 500 mg elemental
calcium) should generally be taken with food in individual divided doses not exceeding 500 mg
of calcium.
In addition to preventing osteoporosis-associated bone fractures, calcium and vitamin D
supplements may delay tooth loss in the elderly.5
Folic acid All women of child-bearing potential should consume a supplement providing 0.4 mg/day of folic
acid prior to conception to reduce the risk of congenital birth defects. Women with a history of
neural tube defect pregnancy require 5 mg/day.
Better folic acid status is associated with lower plasma homocysteine levels, which in turn are
predictive, in epidemiologic studies, of a reduced risk of vascular disease,6 , 7 stroke,
Alzheimer’s disease,7 , 8 osteoporosis9 and colon cancer.10 Prospective clinical trials using very
high-dose folic acid and pyridoxine to reduce plasma homocysteine levels in non-folate deficient
patients with cardiovascular disease have, so far, been disappointing.11 The Canadian and
American food supply has been fortified with synthetic folic acid since 1999 to prevent
congenital birth defects.
Iron Because it is potentially toxic, iron supplementation at or above the recommended intake should
be used only on a case-by-case basis for at-risk persons (e.g., adolescents and women with
heavy menstrual losses) or people clearly not meeting the recommended intake, until the dietary
inadequacy is corrected.
Dietary iron deficiency occurs in the elderly but there is a comparable risk of iron storage
disease from excessive intake.
Multivitamin Select a preventive multiple vitamin/mineral containing the daily iron recommendation for
persons who require supplementation or whose diet lacks iron, and a product specific to patients
over age 50 containing less iron (~4 mg) for more general use.
A multivitamin should be taken with food containing some fat. It should provide approximately
800 retinol activity equivalents (RAE) equivalent to ~2500 IU retinol, but preferably partly as
beta-carotene; 0.4 to 1 mg folic acid; at least 2 μg vitamin B12; other B vitamins; 400 IUvitamin
D3; and 10 to 15 mg zinc.
Vitamin A and The recommended daily vitamin A intake of ~800 RAE can be achieved by 2500 IU of retinol or
beta-carotene 10 mg (equivalent to 1600 IU) of its plant-derived precursor, beta-carotene. Multivitamins
typically contain a mixture of the two forms.
Vitamin B12 All persons over age 50 are advised to consume approximately 2 μg of synthetic vitamin B12
daily in enriched foods (e.g., some cold breakfast cereals) or as a supplement since achlorhydria
is common and impairs the absorption of food-bound vitamin B12.12
Doses range from 50 μg/day orally for mild deficiency to 1 to 2 mg orally daily or 1 mg monthly
im or sc in pernicious anemia.13 Patients lacking their stomach or terminal ileum require
parenteral vitamin B12.
Vitamin D Canadians consuming less than 1 litre of fluid milk/day (which provides 400 IU vitamin D3) are
dependent on endogenous skin photosynthesis for this vitamin, but this is lessened in fall and
winter, prevented by sun block and decreases with age. Biochemical vitamin D deficiency is
highly prevalent in Canada, and the amount of dietary vitamin D and sunlight exposure required
for optimum vitamin D nutrition is controversial.2 , 14 , 15
Institutionalized persons and those who shield themselves from sunlight are
extremely likely to be vitamin D deficient if not provided with
supplements.16 Useful Info?
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Preventive
Persons with or at high risk of osteoporosis, including those being treated with bisphosphonates,
should consume 800 to 1200 IU vitamin D3/day (as well as calcium).
Vitamin D2 (ergocalciferol) is less active than vitamin D3. Some patients with fat malabsorption
will benefit from the better water solubility of calcitriol (1,25-dihydroxycholecalciferol), but must
be monitored for toxicity (hypercalciuria, hypercalcemia).
Table 3: Preventive Supplementation in Special Populations
Special
Population Recommendations
Pregnancy All pregnant women should have taken folic acid prior to conception, and continue it during
pregnancy with a standard supplement containing folic acid and a moderate increase in iron
during the second and third trimesters. Adequate vitamin A nutrition is very important, but do
not exceed ~3300 IU of supplemental vitamin A in the form of retinol.
Vegetarian Vegans require a vitamin D3 supplement unless direct skin sunlight exposure is guaranteed and,
diet unless a dietetic evaluation demonstrates otherwise, also require calcium supplements.
Both vegans and lacto-ovo-vegetarians should use a vitamin B12 supplement providing 2
μg/day.
Vegetarians are not especially iron deficient and do not routinely require iron supplements.
Therapeutic Supplementation
Therapeutic supplements contain 5 to 50-times more than the RDA of specific vitamins for therapeutic or
pharmacologic purposes. Some indications for the use of therapeutic supplements are listed in Table 4. Examples of
common therapeutic supplements and recommendations are listed in Table 5.
Table 4: Indications for Therapeutic Supplements
Overt deficiency diseasea
Compensation for maldigestion or malabsorption:a

extensive gastric resection (calcium, folic acid, vitamin B12 and iron)
absent or diseased terminal ileum (vitamin B12)
decreased absorptive surface area (most micronutrients)
fat maldigestion (vitamins A, D, E, calcium, magnesium and essential fatty acids)
Certain inborn errors of metabolism
Nutrient-responsive nondeficiency diseases
a. Formal dietetic assessment advised
Table 5: Therapeutic Supplements
Therapeutic
Antioxidant vitamin Despite epidemiologic, biologic and metabolic clinical data indicating that combination
therapy antioxidant vitamin therapy could prevent atherosclerotic events, several hard endpoint
clinical trials have failed to confirm this.
Clinical trials have employed greatly varying doses of vitamin E, ignored its very poor
bioavailability when not consumed with fat, and/or included high-dose beta-carotene,
which may specifically increase cardiovascular and cancer risk.17 Nevertheless, current
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Therapeutic
evidence does not justify the use of vitamin E or other antioxidant vitamins to prevent
cardiovascular disease, with the possible exception of hemodialysis patients.18
In sufficiently high doses (1200 mg/day of the natural form), vitamin E may arrest
neuroleptic-induced tardive dyskinesias.19
Combination A nutritional supplement providing vitamin C 500 mg, synthetic vitamin E 400 IU,
supplementation for beta-carotene 15 mg, zinc 80 mg (as zinc oxide) and copper 2 mg reduced the risk of
age-related macular progression to advanced disease by ~25% from baseline in patients with intermediate
degeneration macular degeneration, from a baseline risk of roughly 20 to 30%. However, the trial
was not sufficiently powered to detect a treatment effect on the low rate of progression
in persons with only mild disease.20 , 21
Omega-3 fatty acids Consumption of the marine oil–derived polyunsaturated omega-3 fatty acids,
docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) substantially reduces the
risk of cardiac arrhythmias and cardiac death.22 , 23
Persons with cardiovascular disease and especially those at risk of arrhythmias should
eat certain fatty fish (e.g., salmon) two to three times/week to achieve an average
daily intake of ~1 g DHA plus EPA/day, or use supplements.24 The quality of fish oil
capsules on the market is not standardized. Flaxseed oil contains the 18-carbon
omega-3 fatty acid, alpha-linolenic acid, which, although not significantly converted to
EPA and DHA by humans, could theoretically benefit by reducing formation of the
potential antagonist omega-6 fatty acid, arachidonic acid.22
Thiamine Wernicke's encephalopathy is under-diagnosed in malnourished persons because it

frequently presents nonspecifically as confusion or decreased consciousness. All
patients at risk (chronic alcoholism, hyperemesis gravidarum and AIDS) should receive
oral thiamine, and those with altered mental status should be treated presumptively
with 50 to 100 mg parenterally for three days.
Zinc Zinc intake is marginal in adults consuming diets low in meat, fish or fowl. Zinc
deficiency impairs immunity and wound healing, and may impair taste sensation; skin
rash and diarrhea occur in severe cases. Deficiency should be suspected and treated in
patients with poor diet, malabsorption, inflammatory diarrhea or severe sickle cell
disease.25
Zinc lozenges or nasal gels may shorten the duration of the common cold through a
direct antiviral action, but the product must actually release zinc; effective products
may be identified by an astringent feeling in the mouth.26
Micronutrient Toxicity
Although often considered innocuous, micronutrients can cause toxicities and be involved in drug–nutrient
interactions. Table 6 lists some vitamin/mineral toxicities and Table 7 provides examples of some drug–nutrient
interactions.
Table 6: Vitamin/Mineral Toxicities
Supplement Toxicity
Folic Acid In doses greater than 1 mg/day, folic acid may mask the hematologic picture of concurrent
vitamin B12 deficiency, delaying the diagnosis and allowing the neurologic lesion to progress.
Iron Therapy with iron should be monitored (e.g., to normalize serum ferritin) and/or time limited to
avoid iron storage disease. There is also theoretical concern that increased tissue iron may
catalyze free radical production even in persons without classical iron storage disease. In the
absence of an obvious explanation, the diagnosis of iron deficiency should prompt investigation
(e.g., GI blood loss, occult celiac disease).
Vitamin A and Except in malabsorption/maldigestion and the treatment of retinitis pigmentosa, there is no
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Supplement Toxicity
beta-carotene indication for intakes of vitamin A (as retinol) in excess of the recommended intake of 2500 IU.
Patients with renal failure accumulate retinol and hence are not normally prescribed
supplements containing it.
Heavy cigarette smokers who used a specially formulated 30 mg beta-carotene product had an
increased death rate from lung cancer and cardiac causes. It is possible that high dose beta-
carotene could mitigate the beneficial effects of other antioxidants.27 No increased risk (or
benefit) was seen in smokers or nonsmokers in a large clinical trial that combined vitamins E
and C and high-dose beta-carotene.28
Despite having depleted liver retinol, patients with chronic liver disease and alcohol abusers are
prone to hepatotoxicity from retinol and high-dose beta-carotene.29
Retinol consumption of 10 000 IU or more from fish has been associated with lower bone
density and a higher hip fracture rate.10 , 30
Pregnant women require adequate vitamin A, but should not exceed a daily supplement of 3300
IU.
Vitamin C There is no good evidence of toxicity especially below ~2 g/day.31

High-dose vitamin C is an osmotic laxative with predictable effects.
Although it is metabolized to oxalate, the risk of urolithiasis is not increased by high-dose
vitamin C consumption, at least in persons lacking a prior history of oxalate stone formation.
Vitamin C can theoretically increase iron absorption and interact with iron to promote oxidative
damage, so large doses should be avoided in persons with iron storage disease.
It should also be avoided by persons with advanced renal disease, whose renal oxalate
clearance is reduced. “Chewable” vitamin C is somewhat acidic and if used as a lozenge could
promote tooth enamel loss.
Vitamin D The upper safe daily intake of 2000 IU/day16 is a conservative estimate, and toxicity due to
vitamin D has not been well described except as a result of errors by food producers.14
At potential risk, either from vitamin D ingestion or sunlight exposure, are some patients with
granulomatous diseases (lymphoma, sarcoidosis, tuberculosis), in which cholecalciferol may be
converted in an uncontrolled fashion to the active vitamin, 1,25-dihydroxycholecalciferol. Early
toxicity manifests as hypercalciuria, progressing to hypercalcemia.
Vitamin E Daily intake of 1600 mg of natural vitamin E appears to be safe.31 A meta-analysis suggested
that long-term intake of 400 mg/day or the equivalent dose of the synthetic form marginally
increased all-cause mortality,32 but may have been biased by including studies in which high-
dose beta-carotene was co-administered.33
High-dose vitamin E has a mild antiplatelet effect, potentially increasing the risk of hemorrhage;
it should, like aspirin, be avoided in persons with a bleeding diathesis or uncontrolled
hypertension. There is a theoretical risk that high-dose vitamin E can increase prothrombin time
although a systematic study failed to show this.34
Zinc The RDA for zinc is approximately 15 mg/day. Long-term high-dose zinc intake (e.g., 50
mg/day) may block iron and copper absorption.
Table 7: Drug–Nutrient Interactions
Drug Interaction
Anticonvulsants Anticonvulsant drugs induce folic acid and vitamin D deficiency. Preventive folic acid and
vitamin D supplements are indicated.
Antidepressants Depression may not respond optimally to antidepressant therapy when folic acid status is
marginal or deficient.35 , 36 Assess nutritional status of depressed patients and prescribe a
multiple vitamin providing the RDA for thiamine, folic acid and synthetic vitamin B12 .
Glucocorticoids The adverse bone effects of systemic glucocorticoids are magnified when calcium or vitamin
D intake are inadequate. Routine supplementation with calcium and vitamin D is
recommended.
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Therapeutic Choice
Drug Interaction
Isoniazid Isoniazid increases pyridoxine (vitamin B6) needs and can induce peripheral neuropathy.
Patients who require this drug should be prescribed a preventive supplement. Clinically
malnourished patients should receive 10 to 50 mg pyridoxine every day.
Loop diuretics Especially when used in high doses or in combination with other diuretics, loop diuretics
increase urinary loss of calcium, magnesium, potassium, thiamine and zinc. Supplementation
may be indicated.
Metformin Metformin use may cause malabsorption of dietary vitamin B12. Hematologic testing for
vitamin B12 levels should be considered.
Methotrexate Patients receiving low-dose methotrexate therapy (as used to treat rheumatoid arthritis)
should receive folic acid (1 to 5 mg/day) to reduce the risk of GI and liver toxicity.
Orlistat Orlistat induces fat malabsorption; suggest a preventive multivitamin containing the fat-
soluble vitamins and beta-carotene.
Suggested Readings
Institute of Medicine (US). Panel on Dietary Antioxidants and Related Compounds. Dietary reference intakes for
vitamin C, vitamin E, selenium and carotenoids. Washington (DC): National Academy Press; 2000.
calcium, phosphorus, magnesium, vitamin D and fluoride. Washington (DC): National Academy Press; 1997.
thiamin, riboflavin, niacin, vitamin B6, folate, vitamin B12, pantothenic acid, biotin and choline. Washington (DC):
National Academy Press; 1998.
Fletcher RH, Fairfield KM. Vitamins for chronic disease prevention in adults: clinical applications. JAMA 2002; 287
(23):3127-9.
References
1. Dollahite J, Franklin D, McNew R. Problems encountered in meeting the Recommended Dietary Allowances for
menus designed according to the Dietary Guidelines for Americans. J Am Diet Assoc 1995; 95(3):341-4.
2. Willett WC, Stampfer MJ. Clinical practice. What vitamins should I be taking, doctor? N Engl J Med 2001;345
(25):1819-24.
3. Fletcher RH, Fairfield KM. Vitamins for chronic disease prevention in adults: clinical applications. JAMA
2002;287(23):3127-9.
4. Centers for Disease Control and Prevention (CDC). Use of vitamins containing folic acid among women of
childbearing age--United States, 2004. MMWR Morb Mortal Wkly Rep 2004;53(36):847-50.
5. Krall EA, Wehler C, Garcia RI et al. Calcium and vitamin D supplements reduce tooth loss in the elderly. Am J
Med 2001;111(6):452-6.
6. Malinow MR, Bostom AG, Krauss RM. Homocyst(e)ine, diet, and cardiovascular diseases: a statement for
healthcare professionals from the Nutrition Committee, American Heart Association. Circulation 1999;99
(1):178-82.
7. Goldstein LB, Adams R, Becker K et al. Primary prevention of ischemic stroke: a statement for healthcare
professionals from the Stroke Council of the American Heart Association. Circulation 2001;103(1):163-82.
8. Seshadri S, Beiser A, Selhub J et al. Plasma homocysteine as a risk factor for dementia and Alzheimer's
disease. N Engl J Med 2002;346(7):476-83.
9. Raisz LG. Homocysteine and osteoporotic fractures--culprit or bystander? N Engl J Med 2004;350(20):2089-
90.
10. Fairfield KM, Fletcher RH. Vitamins for chronic disease prevention in adults: scientific review. JAMA 2002;287
Page 253
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(23):3116-26.
11. Loscalzo J. Homocysteine trials--clear outcomes for complex reasons. N Engl J Med 2006;354(15):1629-32.
12. Baik HW, Russell RM. Vitamin B12 deficiency in the elderly. Annu Rev Nutr 1999;19:357-77.
13. Seal EC, Metz J, Flicker L, Melny J. A randomized, double-blind, placebo-controlled study of oral vitamin B12
supplementation in older patients with subnormal or borderline serum vitamin B12 concentrations. J Am
Geriatr Soc 2002;50(1):146-51.
14. Vieth R. Vitamin D supplementation, 25-hydroxyvitamin D concentrations, and safety. Am J Clin Nutr 1999;69
(5):842-56.
15. Vieth R, Fraser D. Vitamin D insufficiency: no recommended dietary allowance exists for this nutrient. CMAJ
2002;166(12):1541-2.
16. Institute of Medicine (US). Panel on Dietary Antioxidants and Related Compounds. Dietary reference intakes
for calcium, phosphorus, magnesium, vitamin D and fluoride. Washington (DC): National Academy Press;
1997.
17. Omenn GS, Goodman GE, Thornquist MD et al. Effects of a combination of beta carotene and vitamin A on
lung cancer and cardiovascular disease. N Engl J Med 1996;334(18):1150-5.
18. Boaz M, Smetana S, Weinstein T et al. Secondary prevention with antioxidants of cardiovascular disease in
endstage renal disease (SPACE): randomised placebo-controlled trial. Lancet 2000;356(9237):1213-8.
19. Soares KV, McGrath JJ. Vitamin E for neuroleptic-induced tardive dyskinesia. Cochrane Database Syst Rev
2001;(4):CD000209.
20. Age-related Eye Disease Study Group. A randomized, placebo-controlled, clinical trial of high-dose
supplementation with vitamins C and E, beta carotene, and zinc for age-related macular degeneration and
vision loss: AREDS report no. 8. Arch Ophthalmol 2001;119(10):1417-36.
21. Jampol LM. Antioxidants and zinc to prevent progression of age-related macular degeneration. JAMA 2001;286
(19):2466-8.
22. De Lorgeril M, Salen P. Fish and N-3 fatty acids for the prevention and treatment of coronary heart disease:
nutrition is not pharmacology. Am J Med 2002;112(4):316-9.
23. Kris-Etherton PM, Harris WS, Appel LJ et al. Fish consumption, fish oil, omega-3 fatty acids, and
cardiovascular disease. Circulation 2002;106(21):2747-57.
24. Holub BJ. Clinical nutrition: 4. Omega-3 fatty acids in cardiovascular care. CMAJ 2002;166(5):608-15.
25. Prasad AS, Beck FW, Kaplan J et al. Effect of zinc supplementation on incidence of infections and hospital
admissions in sickle cell disease (SCD). Am J Hematol 1999;61(3):194-202.
26. Eby GA. Elimination of efficacy by additives in zinc acetate lozenges for common colds. Clin Infect Dis
2000;32(10):1520.
27. Baron JA, Cole BF, Mott L et al. Neoplastic and antineoplastic effects of beta-carotene on colorectal adenoma
recurrence: results of a randomized trial. J Natl Cancer Inst 2003;95(10):717-22.
28. Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of antioxidant vitamin
supplementation in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet 2002;360
(9326):23-33.
29. Leo MA, Lieber CS. Alcohol, vitamin A, and beta-carotene: adverse interactions, including hepatotoxicity and
carcinogenicity. Am J Clin Nutr 1999;69(6):1071-85.
30. Feskanich D, Singh V, Willett WC, Colditz GA. Vitamin A intake and hip fractures among postmenopausal
women. JAMA 2002;287(1):47-54.
31. Hathcock JN, Azzi A, Blumberg J et al. Vitamins E and C are safe across a broad range of intakes. Am J Clin
Nutr 2005;81(4):736-45.
32. Miller ER, Pastor-Barriuso R, Dalal D et al. Meta-analysis: high-dosage vitamin E supplementation may
increase all-cause mortality. Ann Intern Med 2005;142(1):37-46.
33. Greenberg ER. Vitamin E supplements: good in theory, but is the theory good? Ann Intern Med 2005;142
(1):75-6.
34. Kim JM, White RH. Effect of vitamin E on the anticoagulant response to warfarin. Am J Cardiol 1996;77
(1):545-6.
35. Alpert JE, Fava M. Nutrition and depression: the role of folate. Nutr Rev 1997;55(5):145-9.
36. Coppen A, Bailey J. Enhancement of the antidepressant action of fluoxetine by folic acid: a randomised,
placebo controlled trial. J Affect Disord 2000;60(2):121-30.
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e-Therapeutics+ : Therapeutics : Endocrine and Metabolic Disorders: Obesity Page 1 of 9
Therapeutic Choice
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Endocrine and Metabolic Disorders: Obesity
Arya M. Sharma, MD
Obesity is a complex heterogeneous disorder that places individuals at increased risk for adverse mental and/or
physical health consequences from excess body fat. The current definition of obesity is based on body mass index
(BMI = weight/height2 [kg/m2]; Table 1). In 2004, 23.1% of Canadians aged 18 or older—an estimated 5.5 million
adults—had a body mass index (BMI) of 30 kg/m2 or more; the prevalence of class II and III obesity was 5.1% and
2.7%, respectively.1 Childhood obesity is likewise on the rise, currently affecting more than 500 000 children in
Canada.1
These figures likely underestimate the impact of excess body weight on health, as weight distribution (central versus
peripheral) and ectopic adiposity (hepatic steatosis, increased intramyocellular fat) may increase health risks, even
at BMI levels well below the conventional BMI cut-offs.2 Thus, measures of abdominal obesity, such as waist
circumference values exceeding 102 cm (40 inches) in men and 88 cm (35 inches) in women, have been suggested
as markers of increased cardiometabolic risk. Limitations to the BMI and waist circumference classification system
exist with respect to young adults who have not yet reached full growth, lean or muscular adults, adults over age
65, and some racial and ethnic groups such as Asian, Black and Canadian First Nations, including Inuit.
Table 1: WHO Classification of Overweight and Obesity in Adults According to Body Mass Index
Classification BMIa Risk of Comorbiditiesb
Underweight <18.5 Mildly increased
Normal 18.5–24.9 Average
Overweight 25–29.9 Mildly increased
Obese ≥30
Class I 30–34.9 Moderate
Class II 35–39.9 Severe
Class III ≥40 Very severe
a. Values are age and gender independent.

b. Both BMI and a measure of fat distribution (e.g., waist circumference) are important in estimating the risk of comorbidities
(type 2 diabetes, hypertension, dyslipidemia).
Adapted with permission from the National Heart, Lung and Blood Institute. Preventing and Managing the Global Epidemic of
Obesity. Report of the World Health Organization Consultation of Obesity. Geneva (SZ): WHO; June 1997.
Goals of Therapy
The overall aim is to reduce excess body fat for health and not for cosmetic reasons; reducing weight by 5–10%
can result in important health benefits
Minimum goal: stabilize and prevent further weight gain
Prevent weight regain
Prevent and treat obesity-related comorbidities and complications
Strategies for Obesity Treatment
As obesity is a heterogeneous condition, no single management strategy works for every patient. Psychosocial,
emotional or physical barriers may make it difficult for patients to adhere to management strategies. There is
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Therapeutic Choice
currently no “cure” for obesity, implying that any strategy has to be a long-term “coping” strategy that allows the
patient to reduce their body weight and prevent weight regain. Typically, treatment is characterized by intermittent
periods of “remission” and “relapse,” commonly referred to as “weight cycling.” The health risks of weight cycling
versus maintaining a long-term stable weight remain controversial.
Treatment strategies should acknowledge 2 distinct phases in obesity management:3
Phase 1: Induction of weight loss
Weight loss requires caloric restriction. A negative energy balance of about 500 kcal/day results in weight loss of
about 1–2 kg (2–4 lb) per month. A kilogram of fat is equivalent to 7780 kcal (3500 kcal/lb). A challenge in this
phase is to prevent the concomitant loss of lean body mass, which can be minimized by ensuring the intake of high-
quality protein and participation in resistance training. This phase lasts until the patient achieves the weight-loss
plateau (usually 3–6 months into the weight-loss phase), at which time the focus of treatment changes to phase 2.
Phase 2: Prevention of weight regain
The induction of weight loss results in complex hormonal and neurobehavioural changes that seek to restore body
weight to its original level. There is no evidence that these responses diminish over time. The patient will thus have
to continue restricting energy intake indefinitely to the same level as was consumed at the time of the weight-loss
plateau. Any increase in energy intake will result in weight regain. Deep-rooted lifestyle changes, intense physical
activity, medication and surgery can significantly reduce the likelihood of weight regain.
Setting Treatment Goals
Treatment goals should focus on improving health status and/or quality of life rather than on just reducing
numbers on the scale.
Significant health benefits can be achieved with a 5–10% weight loss; further weight loss in class I and II
obesity may be difficult to achieve and maintain.
In phase 2 of treatment, the principal goal is to prevent weight regain.
Increased physical activity in phase 2 can help maintain weight loss and result in further improvements in
health and quality of life.
Investigations
Thorough history including:

weight history, including previous attempts at weight loss, precipitating events (e.g., pregnancy, injury)
and contributing factors (e.g., steroids, antihyperglycemic, anticonvulsant or antipsychotic medications)
lifestyle (diet and activity), readiness for change, psychosocial, emotional and physical barriers to lifestyle
change, smoking, alcohol, substance abuse
reasons for willingness to change and possible health and quality-of-life goals
family history of obesity and comorbidities
support system and insurance coverage for obesity treatment
assess as indicated for depression (see Psychiatric Disorders: Depression), anxiety (see Psychiatric
Disorders: Anxiety Disorders), attention deficit (see Psychiatric Disorders: Attention-Deficit Hyperactivity
Disorder), insomnia (see Psychiatric Disorders: Insomnia) and eating disorders (see Psychiatric Disorders:
Eating Disorders)
weight, height, waist circumference, visual impression of weight distribution; calculate BMI
vital signs
target organ damage, including hepatomegaly, abdominal wall hernias, acanthosis nigricans, intertrigo
identify genetic and associated conditions
assess for osteoarthritis (see Musculoskeletal Disorders: Osteoarthritis) and low back pain (see
Musculoskeletal Disorders: Low Back Pain) as indicated
assess for fibromyalgia (see Musculoskeletal Disorders: Fibromyalgia) and chronic fatigue syndrome (see
Musculoskeletal Disorders: Chronic Fatigue Syndrome) as indicated
Laboratory and diagnostic procedures:
screen for hypertension (see Cardiovascular Disorders: Hypertension), diabetes mellitus (see Endocrine and
Metabolic Disorders: Diabetes Mellitus), dyslipidemia (see Cardiovascular Disorders: Dyslipidemias) and
gout (see Musculoskeletal Disorders: Gout and Hyperuricemia)
liver function tests—liver ultrasound where indicated
discourage routine TSH testing
pulmonary functions and sleep studies where indicated
ECG, exercise test and echocardiography where indicated
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Therapeutic Choice
assess for gastroesophageal reflux and gallbladder disease where indicated
Therapeutic Choices (Figure 1 - Management of Obesity)
Nutrition Planning and Diet Composition
Regular eating (3 meals, 3 snacks) is an important measure for weight control. Discourage prolonged fasting
and skipping of meals — people who eat breakfast are less likely to be obese than people who do not.
Weight-management strategies include grocery shopping after meals, using smaller dishes and glasses and
avoiding energy-dense foods, empty calories in soda pop and snacking in front of the TV.
All weight-loss diets must be nutritionally adequate to ensure optimal health and well balanced with respect to
macronutrient composition. Discourage extreme diets.
Ensure an adequate carbohydrate intake of ≥100 g/day (400 kcal/day) to avoid protein breakdown and muscle
wasting, and to avoid large shifts in fluid balance. Complex carbohydrates that are high in fibre (e.g., kidney
beans) and have a low glycemic index require more time to eat and digest and are associated with greater
satiety.
Ensure a protein intake of ≥1 g/kg/day of high quality mixed proteins to maintain lean body mass and other
essential body functions. When energy intake falls below that needed to maintain energy balance, protein
requirements increase by 1.75 g for every 100 kcal deficit.
Fat intake should not exceed 30–35% of total calories consumed, with ≤10% from trans and saturated fat. Low-
fat diets are not more effective in weight loss than other hypocaloric diets, but they do reduce cardiovascular
risk.
Use of commercial meal replacements can provide a simple and sustainable adjunct to weight management. A
comparison of adult nutrition products, including meal replacement products, is available in the current edition
of Compendium of Self-Care Products published by the Canadian Pharmacists Association.
All popular diets result in weight loss, but weight maintenance is generally disappointing. The long-term
efficacy and safety of various diets have not been established in randomized controlled trials.
Physical Activity
Increased physical activity and fitness are clearly associated with a reduction in cardiometabolic risk.4 Regular
physical activity also enhances the patient's sense of well-being, promotes weight maintenance, improves insulin
resistance and reduces the loss of bone mineral density that is associated with weight loss.5 However, exercise
alone is not an effective strategy for weight loss.
Individual patients should be assessed to determine the level of fitness before starting an exercise program. A
treadmill stress test should be considered for individuals with elevated cardiovascular risk.
Exercise coupled with a judicious caloric-deficit meal plan accelerates fat loss while maintaining lean body
mass, and helps sustain weight loss over the long term.
Encourage all patients to spend ≥30 minutes doing continuous or intermittent (minimum of 10-minute bouts
accumulated throughout the day) physical activity at least 5 days each week. Initially, physical activity could
begin with 5–10 minute bouts, with increasing frequency, duration and intensity over time.
The initial goal is to increase energy expenditure by 700–1000 kcal/week or about 100–130 kcal daily (Table 2).
Walking 10 000 steps a day (measured by a pedometer) is associated with increased weight maintenance.
Promote a daily energy expenditure of about 300 kcal. Recommend a variety of activities that are enjoyable and
can be continued for life.
Resistance training to build lean body mass sustains weight loss in the long term.
Table 2: Average Energy Consumption Per Hour of Low-intensity Forms of Physical Activity
Average Energy Costa
Activity Kilocalories Kilojoules
Shopping 150 630
Light housework (cleaning, vacuuming) 220 920
Dancing 250 1050
Walking
4 km/h or 2.5 mph
200 840
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Average Energy Costa
Activity Kilocalories Kilojoules
6 km/h or 4 mph 300 1260
a. 1 kilocalorie is approximately 4.2 kilojoules. The calories consumed per hour depend on the intensity of the activity and can
range from 150 calories for shopping to just over 300 calories for brisk walking at 6 km/h. An example of low-intensity
endurance exercise activity is walking at a brisk pace ( 6 km/h) for 60 minutes daily (about 50% of maximal oxygen
consumption, VO2max).
The combination of lifestyle modification and anti-obesity drug therapy is superior to lifestyle modification
alone in achieving a target weight loss of 5–10% over the long term, and may improve health status.
Discontinuation of anti-obesity medication generally results in weight regain and should therefore be continued
as long as there is benefit.
No anti-obesity drugs have yet shown an effect on mortality.
Sibutramine, a serotonin and norepinephrine reuptake inhibitor (SNRI), was voluntarily withdrawn from the
Canadian market in 2010 due to concerns about heart-related adverse events.
There is no indication that currently available anti-obesity medications are associated with pulmonary
hypertension, valvular dysfunction or other cardiovascular abnormalities associated with earlier anti-obesity
medications.
Appetite Suppressants
Bupropion is a sympathomimetic drug that has a mild appetite-suppressant effect and can be used for short-term
induction of weight loss.
Lipase Inhibitors
Orlistat is a pancreatic and gastric lipase inhibitor that reduces dietary fat absorption by 30%, resulting in an
effective reduction in caloric intake of around 180 kcal/day on a diet containing 60 g of fat.6 A high fat intake is
poorly tolerated during orlistat therapy because of an increased incidence of gastrointestinal adverse effects,
including bloating, steatorrhea and oily discharge. Orlistat is less effective in patients on low-fat diets and is difficult
to take for individuals with irregular eating patterns. In randomized, double-blind long-term trials, patients lost on
average 2.9% more weight over 1 year than those on placebo.7 Orlistat is approved for use in obese patients with
type 2 diabetes mellitus, in whom it improves glycemic and metabolic control.
Bariatric Surgery
There is good evidence that bariatric surgery provides significant psychosocial and health benefits in
patients with morbid obesity.8 The best outcomes are achieved by interdisciplinary teams working in
high-volume centres and are largely dependent on appropriate patient selection and follow-up.
Patients must be counseled on the need for lifelong nutritional changes to avoid nutritional
complications. Patients with underlying psychiatric or emotional issues should be carefully
evaluated. Useful Info?
Obesity and Pregnancy
Obesity during pregnancy has been associated with gestational diabetes, gestational hypertension, pre-eclampsia,
birth defects, Cesarean delivery, fetal macrosomia, perinatal deaths, postpartum anemia and childhood obesity.9
Recent guidelines recommend that preconceptional and interconceptional counselling about possible complications
associated with obesity and how to prevent those problems be available to all women of reproductive age.10
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Adipose tissue is critical in controlling the regulation of estrogen production and the concentration of sex hormone-
binding globulin in the blood. Body weight and composition play an important role in pubertal maturation, whereby
excessive weight gain at younger ages is associated with earlier menarche and menstrual problems including
amenorrhea, oligomenorrhea and long menstrual cycles.11 Obesity is a strong risk factor for polycystic ovarian
syndrome, which results in menstrual irregularities and chronic anovulation. In the United States, 25% of ovulatory
infertility may be attributable to overweight and obesity.12
Menstrual functioning, ovulation and infertility improve with weight loss. In women with polycystic ovarian
syndrome, as little as a 5% reduction in weight has been associated with improved fertility.13 Maintaining this
weight loss may prove challenging for women of childbearing age. Restrained eating, dieting or weight cycling prior
to pregnancy have been associated with gaining more weight during pregnancy.
Bariatric surgery for morbidly obese women has been associated with better outcomes in mother and child.
However, due to the possibility of nutritional deficiencies, women becoming pregnant after bariatric surgery are
advised to seek care from an obstetrician specializing in high-risk pregnancies.
Management During Pregnancy and Postpartum Period
Maternal Complications during Pregnancy
During pregnancy, obese women are at increased risk for gestational diabetes mellitus (GDM) and preeclampsia.
Obese women should be screened for glucose intolerance early in prenatal care. Tight glucose control in women
with GDM seems to reduce the risk for preeclampsia.
Maternal Complications in the Peripartum Period
Cesarean deliveries and associated morbidities are more common among obese women. Overweight or obese
women have more postoperative complications following cesarean delivery. These include: wound
infection/breakdown, excessive blood loss, deep venous thrombophlebitis and postpartum endometritis. Labour is
also longer in overweight and obese women.
Birth Outcomes
Congenital anomalies are more common in infants born to obese mothers. Neural tube defects (NTDs) are
approximately twice as high, with spina bifida being more common than anencephaly. Other birth defects that can
occur more frequently include: oral clefts, heart anomalies, hydrocephaly and abdominal wall abnormalities.
Maternal obesity has been found to be a risk factor for intrauterine fetal death and stillbirth.14
Management
During pregnancy all overweight and obese women should be informed about current gestational weight gain target
goals, but also advised to not lose weight during pregnancy. They should be counselled about eating healthy diets
and be encouraged to be physically active. Because of the potential effect on vitamin absorption, orlistat is not
recommended during pregnancy. It is not known whether bupropion use is safe during pregnancy.
Obesity and Breastfeeding
Maternal overweight or obesity may be associated with decreased rates of breastfeeding.10 This is concerning, as
breastfeeding has been associated with reduced development of obesity later in life. A high BMI before conception
has been shown to be inversely related to the successful initiation of breastfeeding, the duration of lactation and the
amount of milk produced. Overweight and obesity adversely affect lactation performance in a variety of ways.10
There are mechanical difficulties associated with latching on and proper positioning of the infant. The high cesarean
section rates among this subpopulation delays the onset of first suckling. The lower prolactin response to suckling
at 48 hours and more after delivery may compromise milk production and over time lead to early cessation of
lactation.
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Overweight and obese mothers should be encouraged to breastfeed as well as eat a healthy diet and engage in
regular exercise. It is not known if orlistat passes through breast milk. Although only traces of orlistat are
absorbed, the drug can cause vitamin deficiencies, which may be undesirable in breastfeeding women. Its use is
therefore not recommended. Buproprion is excreted in breast milk and its effects on the infant are unknown.
Therapeutic Tips
Obesity is a chronic disease—focus on long-term strategies rather than short-term interventions.

Identify psychosocial, emotional and physical barriers—addressing these may be required before obesity
treatment is initiated.
Focus on improvements in health and quality of life, not on changes in body weight.
Correct disordered eating; encourage 3 meals and 3 snacks. Avoid hunger, which leads to bingeing.
Meal replacements are an easy, efficient and inexpensive way to facilitate portion control. Recommend meal
replacements that do not contain trans fats, have a low glycemic load and are high in fibre.
Exercise is not the best way to lose weight, but can reduce visceral fat, increase cardiovascular fitness and help
with weight maintenance.
Prepare the patient for the weight-loss plateau; managing expectations is an important part of obesity
management.
Figure 1- Management of Obesity
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Table 3: Drugs Used for the Management of Obesity
Drug Costa
Noradrenergic bupropion Initial: 150 Dry mouth, Avoid concurrent Not approved for $
Appetite Wellbutrin mg daily po constipation, use of drugs that obesity. To minimize
Suppressants SR, Maximum: agitation, lower the seizure seizure risk, single
generics 150 mg BID insomnia and threshold. doses should not exceed
anxiety. Seizures 150 mg and the total
occur rarely (risk daily dose should not
increases with exceed 300 mg. Caution
dose). in patients with hepatic
impairment.
Lipase orlistat 120 mg Oily spotting, Decreased Contraindicated in $$$

Inhibitors Xenical daily to TID flatus with absorption of patients with chronic
po with each discharge, fecal soluble vitamins. malabsorption syndrome
meal urgency. Administer or cholestasis.
containing cyclosporine at Minimal systemic
fat least 2 h apart absorption.
from orlistat.
Advise patients to take a
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Therapeutic Choice
Drug Costa
multivitamin daily ≥2 h
before or after orlistat or
at bedtime.
Legend: $ <$20 $$ $75–100 $$$ $125–150
Suggested Readings
Dietz WH, Robinson TN. Clinical practice. Overweight children and adolescents. N Engl J Med 2005;352(20):2100-9.
Freedhoff Y, Sharma AM. Best weight: a practical guide to office-based obesity management. Edmonton (AB):
Canadian Obesity Network; 2010.
Haslam DW, James WP. Obesity. Lancet 2005;366(9492):1197-209.
Lau DC, Douketis JD, Morrison KM et al. 2006 Canadian clinical practice guidelines on the management and
prevention of obesity in adults and children [summary]. CMAJ 2007;176(8):S1-13.
Padwal RS, Majumdar SR. Drug treatments for obesity: orlistat, sibutramine, and rimonabant. Lancet 2007;369
(9555):71-7.
Strychar I. Diet in the management of weight loss. CMAJ 2006;174(1):56-63.
References
1. Tjepkema M. Measured obesity. Adult obesity in Canada: measured height and weight. In: Nutrition: findings
from the Canadian Community Health Survey 2004;(1). Available from: www.statcan.gc.ca/pub/82-620-
m/2005001/pdf/4224906-eng.pdf. Accessed December 17, 2010.
2. Franzosi MG. Should we continue to use BMI as a cardiovascular risk factor? Lancet 2006;368(9536):624-5.
3. Merchant A, Yusuf S, Sharma AM. A cardiologist's guide to waist management. Heart 2006;92(7):865-6.
4. Shaw K, Gennat H, O'Rourke P et al. Exercise for overweight or obesity. Cochrane Database Syst Rev 2006;
(4):CD003817.
5. Villareal DT, Fontana L, Weiss EP et al. Bone mineral density response to caloric restriction-induced weight
loss or exercise-induced weight loss: a randomized controlled trial. Arch Intern Med 2006;166(22):2502-10.
6. Hutton B, Fergusson D. Changes in body weight and serum lipid profile in obese patients treated with orlistat
in addition to a hypocaloric diet: a systematic review of randomized clinical trials. Am J Clin Nutr 2004;80
(6):1461-8.
7. Rucker D, Padwal R, Li SK et al. Long term pharmacotherapy for obesity and overweight: updated meta-
analysis. BMJ 2007;335(7631):1194-9.
8. Buchwald H, Avidor Y, Braunwald E et al. Bariatric surgery: a systematic review and meta-analysis. JAMA
2004;292(14):1724-37.
9. Waller DK, Shaw GM, Rasmussen SA et al. Prepregnancy obesity as a risk factor for structural birth defects.
Arch Pediatr Adolesc Med 2007;161(8):745-50.
10. Siega-Riz AM, King JC. Position of the American Dietetic Association and American Society for Nutrition:
obesity, reproduction, and pregnancy outcomes. J Am Diet Assoc 2009;109(5):918-27.
11. Pasquali R, Pelusi C, Genghini S et al. Obesity and reproductive disorders in women. Hum Reprod Update
2003;9(4):359-72.
12. Rich-Edwards JW, Goldman MB, Willett WC et al. Adolescent body mass index and infertility caused by
ovulatory disorder. Am J Obstet Gynecol 1994;171(1):171-7.
13. Sarwer DB, Allison KC, Gibbons LM et al. Pregnancy and obesity: a review and agenda for future research. J
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Womens Health (Larchmt) 2006;15(6):720-33.
14. King JC. Maternal obesity, metabolism, and pregnancy outcomes. Annu Rev Nutr 2006;26:271-91.
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e-Therapeutics+ : Therapeutics : Endocrine and Metabolic Disorders: Thyroid Disorders Page 1 of 10
Therapeutic Choice
Print Close
Endocrine and Metabolic Disorders: Thyroid Disorders

Date Revised: December 2009
Heather Lochnan, MD, FRCPC
Thyroid disease is extremely common, with women more frequently affected than men. The symptoms associated with
thyroid disease are often nonspecific. A high index of suspicion coupled with a low threshold for screening for thyroid
disease will capture most affected patients.
Goals of Therapy
Achieve a euthyroid state in patients with hyperthyroidism or hypothyroidism

Recognize which patients with goitre or thyroid nodules require treatment
Manage patients with thyroid disease during all stages of life, including pregnancy
Hypothyroidism
Investigations
Therapeutic Choices
Therapeutic Tips
Hypothyroidism is a clinical syndrome that usually results from a deficiency of thyroid hormone (Table 1). Rarely, it can
be due to resistance to thyroid hormone. A thyroid-stimulating hormone (TSH) measurement is a very sensitive
indicator of hypothyroidism but may be low or normal in pituitary or hypothalamic disease. Subclinical hypothyroidism
is defined by an elevated TSH with normal thyroid hormone levels.1 If subclinical hypothyroidism is confirmed, consider
treatment, especially in patients with TSH > 10 mU/L (normally 0.3 to 6.0 mU/L, depending on the laboratory), an
abnormal lipid profile, symptoms of hypothyroidism and in patients who are antithyroid peroxidase (anti-TPO) positive
or who are planning a pregnancy.2
Investigations
Thorough history with attention to:

symptoms such as fatigue, weight gain, impaired memory, constipation and cold intolerance
Physical examination with attention to:
appearance, e.g., coarse features, dry skin and hair
hypertension, bradycardia
delayed relaxation phase of reflexes
extreme cases may present with myxedema coma (hypotension, coma, hypothermia)
Laboratory investigations:
TSH
free triiodothyronine (fT3)
free thyroxine (fT4)
antithyroid peroxidase (anti-TPO or antimicrosomal antibodies)
Table 1: Causes of Hypothyroidism
Cause Comments
Hashimoto's thyroiditis Most common cause; anti-TPO levels very high
Iatrogenic Surgical removal of thyroid; 131I therapy; drugs such as lithium, amiodarone,
sulfonylureas, iodinated contrast agents
Hypothyroid phase of subacute Usually transient

thyroiditis
Congenital Aplasia of thyroid; dyshormonogenesis
Iodine deficiency Rare in North America
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Therapeutic Choice
Cause Comments
Recovering phase of Transiently elevated TSH

nonthyroidal illness
Pituitary disorder Secondary hypothyroidism; TSH low or normal; fT4 usually low
Hypothalamic disorder Tertiary hypothyroidism; TSH low or normal; fT4 usually low
Resistance to thyroid hormone High TSH, fT3 and fT4
Abbreviations: fT3 = free triiodothyronine; fT4 = free thyroxine
Therapeutic Choices
Levothyroxine (L-T4)
The goal of L-T4 replacement therapy is to normalize the TSH level. Replacement dosages average 1.6 µg/kg/day in
adults and 10 to 16 µg/kg/day in newborns. Dosage adjustment is made every four to six weeks as needed. Generally, it
takes six weeks to attain a new steady state after dosage adjustments. In the elderly, or in patients with coronary artery
disease, start with a dose as low as 12.5 µg/day as tolerated, and titrate every four weeks.
Liothyronine (Triiodothyronine, T3)
T3 is used for short-term management of patients with thyroid cancer undergoing withdrawal of L-T4. The combination of
L-T4 and T3 is occasionally used for replacement therapy, though recent studies have shown little or no benefit of
combination therapy and there is concern of causing adverse effects with T3.3
Therapeutic Tips
Because thyroid binding globulins increase during pregnancy, requirements for L-T4 replacement may increase by up
to 50% during pregnancy to maintain TSH at around 1 to 3 mU/mL.5
Numerous drugs can interfere with the absorption and metabolism of L-T4 (Table 4). Iron supplementation frequently
decreases L-T4 absorption.
Myxedema coma is treated with L-T4 300 to 500 µg iv initially, followed by 100 µg iv daily. These patients are
concomitantly treated with corticosteroids, such as hydrocortisone 100 mg iv Q8H. Supportive therapy and passive
rewarming are indicated as required.
Hyperthyroidism
Investigations
Therapeutic Choices
Therapeutic Tips
Hyperthyroidism (thyrotoxicosis) is defined as the syndrome of excessive thyroid hormone production and its effects
(Table 2). Subclinical hyperthyroidism is common and can be a risk factor for atrial fibrillation.6 , 7 In subclinical
hyperthyroidism, TSH is suppressed while thyroid hormone levels are normal. Treatment is indicated if the patient is frail
and/or elderly, has other risk factors for atrial fibrillation or has symptoms of hyperthyroidism.
Thyroid storm is a life-threatening medical emergency characterized by severe thyrotoxicosis as well as other signs and
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symptoms. It can be precipitated by many causes including radioactive iodine, infection, trauma, surgery or withdrawal
from antithyroid drugs.
Investigations
A thorough history with attention to:

symptoms such as weight loss, palpitations, diarrhea, heat intolerance and anxiety
signs such as eyelid lag, stare and the ophthalmopathy associated with Graves’ disease; tachycardia;
hyperreflexia; warm, moist skin; goitre or nodules
Laboratory tests, nuclear medicine and imaging:
TSH, fT3, fT4
thyroid scan
radioactive iodine uptake (RAIU)
Note: Suppression of TSH can be seen in nonthyroidal illness, depression or treatment with corticosteroids and some
centrally acting medications (e.g., domperidone, metoclopramide, dopamine).
Table 2: Causes of Hyperthyroidism
Cause Comments
Graves' disease Due to thyroid-stimulating immunoglobulins activating the TSH receptor; most
common cause of hyperthyroidism; patients frequently have eye disease and possibly
pretibial myxedema;8 RAIU is elevated and thyroid scan with pertechnetate or 123I
shows a diffuse pattern
Subacute thyroiditis Scan poorly defines the gland; RAIU is very low
Postpartum thyroiditis Scan poorly defines the gland; RAIU is very low (not usually done if patient is
lactating)
Toxic nodule Thyroid scan shows hot area
Toxic multinodular goitre Scan shows multiple hot areas; RAIU is slightly elevated
Iodine excess Usually in setting of multinodular goitre; RAIU is low
Iatrogenic Due to overtreatment with thyroid hormones; scan shows no thyroid; 0% RAIU
Struma ovarii Very rare; thyroid hormone production in ectopic sites; RAIU is 0%; body scan will
show thyroid tissue in ovary
Metastatic thyroid cancer With large tumor burden
TSH–producing pituitary TSH elevated

adenoma
Stimulation of TSH receptor Examples are hydatidiform mole, hyperemesis gravidarum, other tumors
by excessive human chorionic
gonadotropin
Abbreviations: RAIU = radioactive iodine uptake; TSH = thyroid-stimulating hormone
Therapeutic Choices
Consider thyroid surgery in patients with thyroid nodules, large goitre, and occasionally in patients with Graves’
disease. Surgery is part of the management of thyroid cancer and ectopic production of thyroid hormone. Medical
therapy is frequently initiated prior to surgery to make the patient euthyroid if possible.
Use radioactive iodine (131I) to ablate thyroid tissue in patients with Graves’ disease, toxic autonomous nodules and
toxic multinodular goitres. Inducing hypothyroidism is the main risk associated with its use. It is contraindicated in
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pregnancy. Use with caution, or concomitantly with corticosteroids, in patients with significant ophthalmopathy.9
Methimazole (MMI) and propylthiouracil (PTU) decrease the production of thyroid hormones; PTU can also block
the conversion of T4 to T3. PTU is the drug of choice for the treatment of hyperthyroidism in pregnant women. Both
drugs must be stopped about five days prior to a thyroid scan, RAIU or treatment with 131I. PTU may make the thyroid
more resistant to 131I.10 Side effects of these agents include allergy, rash, agranulocytosis and, rarely, hepatotoxicity
and nephrotoxicity.
Beta-adrenergic blockers ameliorate the symptoms of adrenergic excess and are usually used adjunctively in the
management of Graves’ disease or toxic nodules. Nonselective agents such as propranolol can decrease the conversion
of T4 to T3. Avoid beta-blockers in patients with asthma.
Iodine, in the form of oral Lugol’s solution (6.3 mg iodide per drop) or iv sodium iodide, blocks thyroid hormone
production. Iodine can be used in the acute management of severe hyperthyroidism.
Consider corticosteroids as adjuvant therapy in treatment-resistant cases.
The management of thyroid storm involves supportive therapy in conjunction with aggressive treatment with antithyroid
medications, beta-blockers and corticosteroids. Use acetaminophen for hyperthermia, and avoid ASA and other
NSAIDs.11 Plasmapheresis can be considered in unresponsive cases.
Therapeutic Tips
Patients with Graves' disease may have prolonged suppression of TSH, despite normalization or decreased levels of
thyroid hormones. Follow TSH, fT4 and fT3 levels.
Patients on propylthiouracil or methimazole can develop a gradual neutropenia which may be detected by regular
measurement of white blood cell counts with a differential. In many cases it occurs suddenly, and patients should
be advised to contact their physician immediately if symptoms of infection occur.
Warn patients who decline treatment of the risks of untreated hyperthyroidism, which include myopathy, cardiac
arrhythmias, cardiomyopathy and osteoporosis.
Thyroid Nodules and Goitre
Therapeutic Choices
Therapeutic Tips
Individuals with goitre may be at higher risk for disorders of thyroid function and should be screened with a TSH level.
Goitres in euthyroid patients can be problematic if growing or causing compressive symptoms. The usual treatment is
surgery. Thyroid suppression with L-T4 may help prevent further growth and occasionally shrink the gland.
Thyroid nodules are very common. They may be identified incidentally by ultrasound, CT or MRI of the neck.12 Solitary
nodules are concerning, but large or growing nodules within a multinodular goitre should be investigated similarly to a
solitary nodule. Thyroid suppression therapy is no longer routinely used for nodules.13 Useful Info? Table
3 lists risk factors for thyroid cancer.
Table 3: Risk Factors for Thyroid Cancer14
< 20 or > 60 years of age
Prior radiation exposure
Male gender
Family history of thyroid cancer
Previous malignancy
Nodule > 4 cm in size or rapidly growing
Nodule fixed to soft tissue
Vocal cord paralysis
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Therapeutic Choice
Lymphadenopathy
Therapeutic Choices (Figure 1 - Management of Thyroid Nodules)
Surgery is the definitive therapy. Surgical pathology will confirm or exclude malignancy and reduce compressive
symptoms. The risks associated with surgery include hypothyroidism, hypoparathyroidism and vocal cord paralysis.
Consider surgery if two or more risk factors for malignancy are present.
Radioactive iodine therapy can be used to treat a multinodular goitre or a hot nodule, with an associated risk of
hypothyroidism.
Levothyroxine can be considered to prevent further growth of a benign nodule.15 The goal is to keep TSH below 1.0
mU/L, and above the lower limit of the normal range. In this setting, the risk of inducing hyperthyroidism is minimal.
Therapeutic Tips
Ultrasound can be helpful to document the size of a goitre or nodule and whether it is changing in size. Some
features on ultrasound may raise suspicion of malignancy.
A thyroid scan is rarely needed if the TSH is normal.
Repeat fine needle aspiration biopsy (FNAB) if a nodule is growing.
Figure 1-Management of Thyroid Nodules
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Therapeutic Choice
Abbreviations: TSH = thyroid-stimulating hormone; FNAB = fine needle aspiration biopsy.
Table 4: Drugs Used in the Management of Hypothyroidism
Adverse Costa
Thyroid levothyroxine Average adult Symptoms of Absorption may be ↓ Monitor TSH $

Hormones Eltroxin, replacement: hyperthyroidism by iron salts, calcium levels to adjust
Synthroid 1.6 µg/kg/day; if over-treated; salts, cholestyramine initial dosage
elderly patients possible (separate after 6–8 wk,
Page 269
Therapeutic Choice
Adverse Costa
may need less exacerbation of administration by 6 then as required

Start with angina. hours), colestipol and or annually;
12.5–25 µg/day sucralfate. Response adrenal
in those at risk to warfarin may vary. insufficiency may
of angina Glycemic control may be uncovered;
decline with initiation dosage may have
of levothyroxine, to be increased
potentially during pregnancy
necessitating dosage to maintain TSH
adjustment of in desired range;
antihyperglycemic check TSH each
agents. trimester and 4–
6 wk after any
dosage
adjustment.
Thyroid liothyronine Up to 25 µg BID Symptoms of $$$

Hormones (triiodothyronine) for short-term hyperthyroidism
management of if over-treated;
Cytomel thyroid cancer possible
patients off L-T4 exacerbation of
angina.
Legend: $ < $5 $$ $5–30 $$$ $30–35
Table 5: Drugs Used in the Management of Hyperthyroidism
Adverse Drug
Class Drug Dose Effects Interactions Comments Costa
Antithyroid methimazole 10–30 mg daily in Risk of skin Thyroid status Warn patient to $$–$$$
Agents (MMI) 2–3 divided doses; rash, allergic influences stop medication
Tapazole higher doses are reaction, response to if rash, fever,
sometimes necessary agranulocytosis, warfarin. sore throat, or
Thyroid storm: up to rarely Monitor INR jaundice
40 mg BID may be hepatotoxicity, when develop.
required nephrotoxicity. antithyroid
medication
dose altered.
Antithyroid propylthiouracil Initially Risk of skin Thyroid status Warn patient to $$

Agents (PTU) 50–100 mg TID in rash; allergic influences stop medication
Propyl-Thyracil most cases; reduce reaction; response to if rash, fever,
dose in renal failure agranulocytosis; warfarin. sore throat, or
Thyroid storm: up to rarely, Monitor INR jaundice
1200 mg daily in hepatotoxicity. when develop.
divided doses antithyroid Preferred drug
medication during
dose altered. pregnancy and
lactation; in
pregnancy, use
the lowest dose
necessary to
maintain
thyroid
hormone in the
upper normal
range.
Iodine iodine Thyroid storm: Allergy, Administer 1 h $

sodium iodide hypersensitivity. after PTU or
Page 270
Therapeutic Choice
Adverse Drug
0.5–1 g iv Q12H for MMI; blocks

several days, or radioactive
Lugol's solution, iodine uptake.
3–5 drops Q6H po, 1
h after antithyroid
drug
Prior to
thyroidectomy: if
hyperthyroidism
reasonably
controlled, use
Lugol's solution 2–6
drops TID po × 7 d
preceding operation
Beta1- propranolol Hyperthyroidism: Fatigue, Avoid in $–$$

adrenergic generics 10–40 mg QID bradycardia. patients with
Antagonists, Thyroid storm: asthma or
nonselective 40–120 mg Q6H po conditions
or 0.5–2 mg iv associated with
slowly Q4–6H, if no bradycardia;
evidence of cardiac taper once
decompensation thyrotoxicosis
improved.
Controls
tachycardia.
Beta1- atenolol Initial dose: 25–50 Fatigue, Avoid in $$

adrenergic Tenormin, mg daily, may ↑ to bradycardia. patients with
Antagonists, generics 200 mg daily asthma or
selective conditions
associated with
bradycardia;
taper once
thyrotoxicosis
improved.
Controls
tachycardia.
May have faster

onset of action
compared to
propranolol.
Controls
tachycardia.
Beta1- metoprolol 50 mg QID, may ↑ to Fatigue, Avoid in $$–$$$

adrenergic Betaloc, 100 mg QID bradycardia. patients with
Antagonists, Lopresor, asthma or
selective generics conditions
associated with
bradycardia;
taper once
thyrotoxicosis
improved.
Controls
tachycardia.
May have faster

onset of action
compared to
Page 271
Therapeutic Choice
Adverse Drug
propranolol.
Controls
tachycardia.
Corticosteroids, dexamethasone Thyroid storm: Numerous Effects can be Reserved for $ (3

systemic generics 2 mg Q6H po or iv; effects especially diminished emergency days'
continue until free T3 if prolonged with adjunctive oral
level controlled use; acutely: concomitant management of therapy)
elevated blood medications hyperthyroidism
glucose, risk of such as or myxedema
avascular phenytoin. coma, in
necrosis, altered conjunction
mood. with specific
management of
thyroid
disorder.
Corticosteroids, hydrocortisone Myxedema coma: Numerous Effects can be Reserved for $$$$ (3
systemic sodium 100 mg iv Q8H; taper effects especially diminished emergency days' iv
when stable if prolonged with adjunctive therapy)
succinate
use; acutely: concomitant management of
Solu-Cortef, elevated blood medications hyperthyroidism
generics glucose, risk of such as or myxedema
avascular phenytoin. coma, in
necrosis, altered conjunction
mood. with specific
management of
thyroid
disorder.
Iodine, sodium iodide Graves' disease: High risk of Given as single $$$$
radioactive 131I ~ 370 MBq (10 mCi); hypothyroidism; oral dose; (per
Iodotope more might be used possible usually only dose)
for a toxic nodule or worsening of one dose
nodular goitre, or Graves' required.
less if uptake is very ophthalmopathy;
high risk of radiation
thyroiditis.
a. Cost of 30-day supply unless otherwise specified; includes drug cost only.
Abbreviations: TSH=thyroid-stimulating hormone; T3

=triiodothyronine; MBq=megabecquerels; mCi=megacurie; MMI=methimazole; PTU=propylthiouracil
Legend: $ < $10 $–$$ < $10–20 $$ $10–20 $$–$$$ $10–30 $$$ $20–30 $$$$ > $30
Suggested Readings
AACE/AME Task Force on Thyroid Nodules. American Association of Clinical Endocrinologists and Associazione Medici
Endocrinologi medical guidelines for clinical practice for the diagnosis and management of thyroid nodules. Endocr
Pract 2006;12(1):63-102. Available from: http://www.aace.com/pub/pdf/guidelines/thyroid_nodules.pdf Accessed May
29, 2007.
American Association of Clinical Endocrinologists. American Association of Clinical Endocrinologists medical guidelines
for clinical practice for the evaluation and treatment of hypothyroidism and hyperthyroidism. Endocr Pract 2002;8
(6):457-69. Available from: http://www.aace.com/pub/pdf/guidelines/hypo_hyper.pdf Accessed May 29, 2007.
Cooper DS. Antithyroid Drugs. N Engl J Med 2005;352(9):905-917.
Page 272
Therapeutic Choice
Klein I, Ojamaa K. Thyroid hormone and the cardiovascular system. N Engl J Med 2001;344(7):501-9.
Thyroid disease manager. South Dartmouth (MA): Endocrine Education. Available from:
http://www.thyroidmanager.org/ Accessed May 29, 2007.
References
1. Cooper DS. Clinical practice. Subclinical hypothyroidism. N Engl J Med 2001;345(4):260-5.

2. Surks MI, Ortiz E, Daniels GH et al. Subclinical thyroid disease: scientific review and guidelines for diagnosis and
management. JAMA 2004;291(2):228-38.
3. Escobar-Morreale HF, Botella-Carretero JI, Escobar del Rey F et al. Review: Treatment of hypothyroidism with
combinations of levothyroxine plus liothyronine. J Clin Endocrinol Metab 2005;90(8):4946-54.
4. Bunevicius R, Kazanavicius G, Zalinkevicius R et al. Effects of thyroxine as compared with thyroxine plus
triiodothyronine in patients with hypothyroidism. N Engl J Med 1999;340(6):424-9.
5. Alexander EK, Marqusee E, Lawrence J et al. Timing and magnitude of increases in levothyroxine requirements
during pregnancy in women with hypothyroidism. N Engl J Med 2004;351(3):241-9.
6. Weetman AP. Graves' disease. N Engl J Med 2000;343(17):1236-48.
7. Toft AD. Clinical practice. Subclinical hyperthyroidism. N Engl J Med 2001;345(7):512-6.
8. Sawin CT, Geller A, Wolf PA et al. Low serum thyrotropin concentrations as a risk factor for atrial fibrillation in
older persons. N Engl J Med 1994;331(19):1249-52.
9. Bartalena L, Marcocci C, Bogazzi F et al. Relation between therapy for hyperthyroidism and the course of Graves'
ophthalmopathy. N Engl J Med 1998;338(2):73-8.
10. Imseis RE, Vanmiddlesworth L, Massie JD et al. Pretreatment with propylthiouracil but not methimazole reduces
the therapeutic efficacy of iodine-131 in hyperthyroidism. J Clin Endocrinol Metab 1998;83(2):685-7.
11. Larsen PR. Salicylate-induced increases in free triiodothyronine in human serum: Evidence of inhibition of
triiodothyronine binding to thyroxine-binding globulin and thyroxine-binding prealbumin. J Clin Invest
1972;51:1125-1134.
12. Tan GH, Gharib H. Thyroid incidentalomas: management approaches to nonpalpable nodules discovered
incidentally on thyroid imaging. Ann Intern Med 1997;126(3):226-31.
13. Gharib H, Mazzaferri EL. Thyroxine suppressive therapy in patients with nodular thyroid disease. Ann Intern Med
1998;128(5):386-94.
14. Mazzaferri EL, Kloos RT. Clinical review 128: current approaches to primary therapy for papillary and follicular
thyroid cancer. J Clin Endocrinol Metab 2001;86(4):1447-63.
15. Ridgway EC. Medical treatment of benign thyroid nodules: have we defined a benefit? Ann Intern Med 1998;128
(5):403-5.
Page 273
e-Therapeutics+ : Therapeutics : End-of-Life Care: Palliative Care Page 1 of 8
Therapeutic Choice
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End-of-Life Care: Palliative Care
David Duperé, MD, FRCP(C)
Symptoms confronted at the end of life (Table 1) require a team approach. This chapter focuses on management of
common end-of-life symptoms with medications selected by experienced palliative care teams for use in the home
setting (Table 4).
1 , a
Table 1: Symptoms at the End of Life
Symptom Incidence (%)
Noisy and moist breathing 56

Urinary dysfunction 53
Pain 51
Restlessness and agitation 42
Dyspnea 22
Nausea and vomiting 14
Sweating 14
Jerking, twitching 12
a.
End of life refers to the final 48 hours of life.
Goals of Therapy
Limit physical and emotional suffering by adequately managing pain and other symptoms
Support the ability to enjoy remaining life while avoiding inappropriate prolongation of death
Investigations
History and physical exam to determine the nature and severity of symptoms
Detailed medication history including nonprescription medications, herbals, vitamins and other natural
therapies. Knowledge of prior experience of treatment benefit or intolerance saves time
Minimal diagnostic testing will help preserve quality of life. Avoid invasive investigations whenever possible
Therapeutic Choices
Four rules are essential for optimal symptom management in the palliative setting:
Any symptom is as distressing as a patient claims it to be.

Treatment risks, benefits and alternatives need to be discussed in the context of the dying patient’s values,
culture, goals and fears.
Individualize choice and dose of medication—preset recipes are not adequate.
Cause of symptoms is irrelevant and investigation pointless when disease is advanced and death very near,
unless detection would direct a useful change in symptomatic treatment.
Dyspnea
The uncomfortable awareness of one’s own breathing is completely subjective and easily misinterpreted;
therefore, observer opinion or objective measurements are irrelevant.
Management based on the symptom’s impact on activities of daily living makes for more effective therapeutic
choices. Treat reversible causes or components when appropriate. Associated anxiety requires special
management.
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Therapeutic Choice
2
Oxygen is a potent symbol of medical care that clearly has a role in the hypoxic patient. Carefully consider
oxygen use in the hypoxic patient who senses no benefit or the nonhypoxic patient who does sense benefit,
e.g., try it on a continuous or as-needed basis and ask the patient if it helps. Similarly, let the patient choose
the flow rate. Sometimes a mask with compressed air flow provides a sense of security.
Relaxation therapies.
Physical therapies, e.g., exercise program to avoid deconditioning.
Electric fan for cool air flow to face.
Open window; allow clear line of sight to the outside if bedbound.
Respiratory Sedatives
Opioids
3 , 4
Morphine and hydromorphone can be highly effective in relieving dyspnea. The acute situation may require
frequent parenteral dosing (e.g., morphine 5–10 mg sc or iv Q30 minutes until settled). Otherwise Q4H dosing with
appropriate Q1H breakthrough doses is usually indicated. Intermittent dyspnea can be treated with intermittent
opioids. Tolerance to the respiratory depressant effects of opioids develops quickly. If titrated to control dyspnea,
opioids will not hasten death. Increases in carbon dioxide partial pressure (pCO2) and significant hypoventilation
are dependent on previous exposure to opioids, the rate of increase of opioid dose and perhaps the route of
administration. At present there is no clear evidence for the role of nebulized opioids.5
Fentanyl parenteral solution administered sublingually can also be beneficial for dyspnea in the home
setting when parenteral access may be limited. Starting doses of 25–50 µg sublingually are well
tolerated. Onset is quick but duration of effect is only about 40–60 minutes.6 Useful Info?
Nonopioids
Benzodiazepines such as clonazepam, diazepam, lorazepam and midazolam have been widely used to manage
dyspnea in the palliative care setting, despite a lack of strong evidence of efficacy.7 , 8 Though their use is not
validated, benzodiazepines may provide improved control of dyspnea compared to opioids in terms of duration of
action, potency and reduced adverse effects, especially in the absence of pain or when there is a clear component of
anxiety.
Phenothiazines (e.g., promethazine, chlorpromazine) can effectively relieve refractory cases of dyspnea without
causing respiratory depression.9
Corticosteroids have a specific role in the management of dyspnea resulting from obstructive lesions, lymphangitic
carcinomatosis or COPD. CNS adverse effects may limit their utility.
Pain
Determine the cause. Differentiate nociceptive (somatic, visceral) pain from neuropathic (dysesthetic, neuralgic)
pain to facilitate the choice of treatment options (see Neurologic Disorders: Neuropathic Pain).
Measure the intensity. A report of quantity of pain on a 0 to 10 scale (0 being no pain) is easy to use and
reproducible.
Review multidimensional aspects of pain. Address response and adverse effects to previously used analgesics,
coping skills, past drug/alcohol abuse and concerns about addiction, metabolic abnormalities, cognitive
impairment and finances.
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Therapeutic Choice
A step-wise approach to pain management is mandated in all cases (see Neurologic Disorders: Acute Pain and
Neurologic Disorders: Neuropathic Pain for discussions of acute pain and neuropathic pain). For mild pain,
nonopioid analgesics can be tried (e.g., acetaminophen, NSAIDs or ASA) with or without codeine. In the acute
palliative care setting the mainstays of therapy are usually the opioids (e.g., morphine and hydromorphone).
The goal is opioid titration to achieve adequate pain control without opioid toxicity.
Q4H dosing (po/sc/iv/pr) is best for dose titration. The acute situation may require more frequent parenteral
dosing (e.g., morphine 5–10 mg sc or iv Q30 min until settled).
There are no maximum doses as responses to opioids vary greatly and can reach hundreds of milligrams Q4H.
Providing a breakthrough dose (estimated as 10% of the total 24-hour dose) ordered as Q1H PRN allows for
control of interdose pain and provides the essential dosing information required for opioid titration. Therefore,
the new Q4H dose = (all Q4H + all PRN doses in previous 24 hours)/6.
Adjuvant drugs may be useful in particular pain syndromes (e.g., corticosteroids in bone pain or hepatic
capsular pain) (Table 2).
Anticipate and educate patient and caregivers about side effects of opioid use (Table 3).
Opioid toxicity resulting from altered opioid metabolism (e.g., dehydration, renal failure) may respond to dose
reduction and correction of the altered metabolism when possible. The presence of significant toxicity requires a
switch to another opioid at 50–75% of the equianalgesic dose. Avoid meperidine as its neurotoxic metabolite
can accumulate in patients with reduced renal function, possibly causing seizures.
Table 2: Adjuvant Analgesics
Type/Description of
Pain Suggested Drug Treatment
Bone pain NSAID with cytoprotection (e.g., naproxen a 500 mg po/pr BID with misoprostol
10
200 µg po BID or omeprazole 20 mg po daily )
Severe cases: dexamethasone 4 mg po/sc/iv TID-QID; high doses sometimes
required (e.g., 24–32 mg/day)
Closed space pain Dexamethasone as for bone pain
Pleuritic pain NSAID as for bone pain
Neuropathic pain See Neurologic Disorders: Neuropathic Pain
Burning/dysesthetic Add tricyclic antidepressant (TCA),b e.g., amitriptyline or imipramine, 25 mg po BID

-TID; increase gradually up to 150 mg/day if necessary
Shock-like/lancinating a
Add gabapentin 300 mg po QHS; increase gradually up to 1200 mg TID if necessary
Severe cases: dexamethasone as above for severe bone pain
a.
b.
Decrease doses of TCAs by 50% in the presence of hepatic or renal impairment or in the frail elderly.
Table 3: Management of Adverse Effects of Opioids
General Comments Management
Nausea Very common, tolerance develops in 2– Dimenhydrinate/metoclopramide PRN

3 days
Constipation Ongoing treatment is mandatory Daily laxatives (softener & stimulant)
Somnolence Very common, tolerance develops in 2– Reassure patient

3 days
Pruritus Less common May require change of opioid,

antihistamines
Dry mouth Less common Chew gum; suck on hard candy
Neurotoxic
Myoclonus Uncommon in early titrated opioid use May require change of opioid
Page 276
Therapeutic Choice
General Comments Management
Delirium See myoclonus May require change of opioid
Visual See myoclonus May require change of opioid

hallucinations
Terminal Delirium and Agitation
With progressive multi-organ failure, patients often develop increasing confusion, drowsiness and/or
restlessness and moaning.
Search for reversible causes (e.g., dehydration, visual or hearing impairment)11 although this is rarely
successful.
Never give opioids as sedatives.
Palliative sedation: in the event of a severe symptom (e.g., pain, dyspnea, restlessness, hemorrhage) where
adequate interventions have not resulted in an acceptable level of comfort, heavy sedation may be considered to
render the patient unaware of the symptom. Commonly used agents are midazolam and methotrimeprazine.
Review the option with the patient and/or caregivers and provide an understanding that this usually involves
cessation of nutrition and hydration.
Reassure and educate the caregivers about the possibility of delirium and agitation.
Review present medications for adjustment of dosages or discontinuation (e.g., sedatives).

Haloperidol is the mainstay of treatment. If ineffective at doses of greater than 20 mg/day, consider more
sedating agents such as methotrimeprazine or midazolam in regular doses or as a continuous infusion if
necessary.
Respiratory Secretions
Therapeutic Tips
Pooling of secretions is common with decreased levels of consciousness.

This symptom (unfortunately named “death rattle”) is usually of no consequence to the patient but can be quite
distressing to the caregivers.
Educate the caregivers that the patient is unaware of the distressful breathing sounds and that it is not a source
of suffering.
Position patient semi-prone if possible.
If possible and not too distressing for the patient, remove secretions directly using mouth swabs.
Anticholinergics will not dry out built-up secretions, so use medications regularly at the very onset of excessive
secretions.
12
Scopolamine is the usual choice but is sedating. To avoid sedation, glycopyrrolate may be given.
Therapeutic Tips
Page 277
Therapeutic Choice
With the approach of end of life, focus the goals of care on achieving patient comfort. Discontinue interventions
not playing a role in supporting comfort (e.g., blood work, vital signs, blood glucose monitoring). The routine
medical approach (e.g., iv fluid rehydration) often is best replaced by what the patient truly needs to be kept
comfortable (e.g., good mouth care to control thirst).
Choose medications with the goal of providing comfort. Most medications used for the treatment of chronic
diseases (e.g., anti-anginal agents) rarely have a role at end of life and should be discontinued. Opioids and
medications with sedating properties are frequently required and their use should be guided solely by any
ongoing need to control symptoms.
Successful end-of-life care in the home requires 24-hour access to a supportive multidisciplinary team ready to
deal rapidly with issues as they arise.
Table 4: Drugs for End-of-Life Symptoms
Starting
a
Class Drug Indication Doses Adverse Effects Comments Cost
Analgesics morphine Pain, PO, Nausea, vomiting, Highly PO:$

M.O.S., MS-IR, dyspnea immediate- constipation, individual IV/SC:$$
release: 5– sedation, dosing
Statex, generics
10 mg Q4– drowsiness, requirements.
6H po + confusion, Dose
appropriate respiratory escalation
PRN depression, urinary based on pain
IV/SC: 2.5– retention, dry mouth, relief and
5 mg Q4– myoclonus. adverse
6H + effects.
appropriate
PRN
Analgesics hydromorphone Pain, PO, Nausea, vomiting, Highly PO:$

Dilaudid, dyspnea immediate- constipation, individual IV/SC:
generics release: 2– sedation, dosing $$
4 mg Q4– drowsiness, requirements.
6H + confusion, Dose
appropriate respiratory escalation
PRN depression, urinary based on pain
IV/SC: 1– retention, dry mouth, relief and
2 mg Q4– myoclonus. adverse
6H + effects.
appropriate
PRN
Analgesics fentanyl Dyspnea SL: 25–50 Nausea, vomiting, Highly $$$$

generics µg constipation, individual
(0.5–1 mL sedation, dosing
parenteral drowsiness, requirements.
solution 50 confusion, Dose
µg/mL) respiratory escalation
Q1H PRN depression, urinary based on pain
Ask patient retention, dry mouth, relief and
to hold myoclonus. adverse
liquid under effects.
tongue for
about 10
min without
swallowing
if possible
Antiemetics b Nausea, PO/IM/PR: Sedation, Additive PO:$

dimenhydrinate
Gravol vomiting 25–50 mg anticholinergic sedation with IM/PR:$$
Q4–6H PRN effects, confusion. other sedating
The elderly may be medications.
Page 278
Therapeutic Choice
Starting
a
Preparations, particularly
generics susceptible.
Antiemetics metoclopramide Nausea, PO/SC: 5– Diarrhea, abdominal Additive PO:$

generics vomiting 10 mg Q4– cramps and sedation with SC: $$$
6H PRN distention, headache, other sedating
hyperprolactinemia, medications.
drowsiness, fatigue,
extrapyramidal
effects.
Antiemetics prochlorperazine Nausea, PO/IM/PR: Sedation, Additive PO:$

Apo- vomiting 5–10 mg anticholinergic sedation with IM: $$$
Q4–6H PRN effects (dry mouth, other sedating
Prochlorazine,
blurred vision, medications. PR:$$
other generics
constipation, nasal
congestion, urinary
retention),
extrapyramidal
effects, hypotension,
hypersensitivity;
pancytopenia (rare).
Antipsychotics haloperidol Agitation, PO/SC: 0.5 Sedation, Usual drug of PO:$

generics nausea –2 mg Q4– extrapyramidal choice. SC:$$
8H PRN effects.
Antipsychotics methotrimeprazine Agitation, PO/SC: 5– Sedation, PO:$

Nozinan, generics nausea, 10 mg Q4– extrapyramidal SC:$$
adjuvant 6H PRN effects.
analgesia
Antipsychotics chlorpromazine Dyspnea, PO/SC: Sedation, PO/SC:$

generics nausea 10 mg Q6H extrapyramidal
effects.
Hypotension with
im/iv administration.
Benzodiazepines midazolam Agitation, SC: 1–2 mg Sedation, $$$$

generics dyspnea Q30min to hypotension,
Q1H PRN transient apnea.
Benzodiazepines lorazepam Agitation, PO/SL: 1– Sedation (up to $

Ativan, generics dyspnea 2 mg Q6– 80%), dizziness.
8H PRN
Benzodiazepines clonazepam Agitation, PO: 0.25– Sedation, dizziness. $

Rivotril, generics dyspnea 0.5 mg Q8–
12H PRN
Corticosteroids dexamethasone Nausea, PO/SC: Mood changes, PO/SC:$$

Dexasone, dyspnea, 4 mg Q6– increased appetite,
generics adjuvant 8H GI irritation,
analgesia ulceration, fluid
retention, weight
gain, may mask
signs of infection.
Page 279
Therapeutic Choice
Starting
a
Antimuscarinics glycopyrrolate Respiratory SC: 0.2–0.6 Dizziness, blurred Rarely causes $$$$
generics secretions mg Q2–4H vision, dry mouth, sedation or
PRN (or Q4 urinary retention. delirium.
–8H PRN)
Antimuscarinics scopolamine Respiratory SC: 0.3– Sedation, dizziness, $$$$

(hyoscine secretions 0.8 mg Q2– blurred vision, dry
4H PRN (or mouth, urinary
hydrobromide) b Q4–8H retention.
generics PRN)
a.
b.
Available without a prescription.
Legend: $ <$2 $$ $2–10 $$$ $10–20 $$$$ >$20
Suggested Readings
Lo B, Rubenfeld G. Palliative sedation in dying patients: “we turn to it when everything else hasn't worked”. JAMA
2005;294(14):1810-6.
Morrison RS, Meier DE. Clinical practice. Palliative care. N Engl J Med 2004;350(25):2582-90.
Quigley C. The role of opioids in cancer pain. BMJ 2005;331(7520):825-9.
Stevenson J, Abernethy AP, Miller C et al. Managing comorbidities in patients at the end of life. BMJ 2004;329
(7471):909-12.
University of Toronto, Faculty of Medicine, Continuing Education. Ian Anderson continuing education program in end
-of-life care. Toronto (ON): University of Toronto. Available from: www.cme.utoronto.ca/endoflife/. Accessed
October 14, 2010.
References
1. Lichter I, Hunt E. The last 48 hours of life. J Palliat Care 1990;6(4):7-15.

2. Bruera E, de Stoutz N, Velasco-Leiva A et al. Effects of oxygen on dyspnoea in hypoxaemic terminal-cancer
patients. Lancet 1993;342(8862):13-4.
3. Bruera E, Macmillan K, Pither J et al. Effects of morphine on the dyspnea of terminal cancer patients. J Pain
Symptom Manage 1990;5(6):341-4.
4. Robin ED, Burke CM. Single-patient randomized clinical trial. Opiates for intractable dyspnea. Chest 1986;90
(6):888-92.
5. Jennings AL, Davies AN, Higgins JP et al. A systematic review of the use of opioids in the management of
dyspnoea. Thorax 2002;57(11):939-44.
6. Zhang H, Zhang J, Streisand JB. Oral mucosal delivery: clinical pharmacokinetics and therapeutic applications.
Clin Pharmacokinet 2002;41(9):661-80.
7. Simon ST, Higginson IJ, Booth S et al. Benzodiazepines for the relief of breathlessness in advanced malignant
and non-malignant diseases in adults. Cochrane Database Syst Rev 2010;20(1):CD007354.
8. Wedzicha JA, Wallis PJ, Ingram DA et al. Effect of diazepam on sleep in patients with chronic airflow
obstruction. Thorax 1988;43(9):729-30.
9. O'Neill PA, Morton PB, Stark RD. Chlorpromazine--a specific effect on breathlessness? Br J Clin Pharmacol
1985;19(6):793-7.
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Therapeutic Choice
10. Singh G, Triadafilopoulos G. Appropriate choice of proton pump inhibitor therapy in the prevention and
management of NSAID-related gastrointestinal damage. Int J Clin Pract 2005;59(10):1210-7.
11. Casarett DJ, Inouye SK et al. Diagnosis and management of delirium near the end of life. Ann Intern Med
2001;135(1):32-40.
12. Wildiers H, Menten J. Death rattle: prevalence, prevention and treatment. J Pain Symptom Manage 2002;23
(4):310-7.
Page 281
e-Therapeutics+ : Therapeutics : Eye Disorders: Age-related Macular Degeneration Page 1 of 7
Therapeutic Choice
Print Close
Eye Disorders: Age-related Macular Degeneration

Date Revised: March 2008
Michael J. Potter, MD, FRCSC
Age-related macular degeneration (AMD) is classified as dry or wet (exudative) AMD. The dry form is characterized
by drusen (white to yellow spots in the central retina) and may or may not be associated with gradual deterioration
in central vision. Wet AMD is responsible for the vast majority of severe vision loss, and always occurs in the setting
of pre-existing dry AMD. The wet form is caused by the presence of a choroidal neovascular membrane (CNV). There
are a number of similar conditions causing central visual loss, the most common of which is pathologic myopia.
1
In the Western world, almost a third of people over the age of 75 develop the dry form of AMD. About 90% of
severe vision loss, however, is seen in the 5% of these individuals who go on to develop the wet form of the
disease.
2 2 , 3 , 4 2
Up to 30% of the risk of vision loss in AMD is attributable to smoking. Hypertension and family history of
5 , 6 , 7
AMD are also risk factors. Vision loss from wet AMD in one eye is associated with a 50% risk of vision loss in
the unaffected eye over five years. Whether nutrition (aside from eating a balanced diet) or wearing sunglasses
makes a significant impact is currently unclear.
Goals of Therapy
Minimize loss of vision

Improve vision if possible
Minimize enlargement of central scotomas
Optimize function and quality of life
Investigations

vision loss
recent changes
central visual changes such as a central scotoma (blank spot in centre of visual field)
metamorphopsia (distortion such that straight lines appear curved or crooked)
AMD in patient or first-degree relatives
visual acuity
Amsler grid (available at www.stlukeseye.com/eyeq/AmslerPrint.htm)
funduscopy (dilated fundus exam with slit-lamp biomicroscopy; performed by ophthalmologist)
Note: The retinal exam alone may be inadequate to exclude the presence of a treatable lesion in wet AMD.
Fluorescein angiography
available only at large centres and interpreted by retinal specialists
involves intravenous injection of fluorescein sodium, followed by photography of the ocular fundus
considered the gold standard for investigating AMD
Note: Some patients have allergic reactions to fluorescein sodium, which is chemically unrelated to x-ray
contrast and contains no iodine. Severe reactions are quite rare.
Optical coherence tomography
widely available
uses infrared light to generate a cross-sectional view of the macula in false colours
considered the gold standard for treatment decisions using vascular endothelial growth factor inhibitors
Therapeutic Choices (Figure 1 - Management of Age-related Macular Degeneration)
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Therapeutic Choice
The Amsler grid is useful for self-monitoring by patients. A central blur or distortion in either eye can indicate the
onset of the wet form of AMD. The test must be performed with one eye closed, then repeated with the other eye.
Reading glasses must be used for the test, if the patient customarily requires them.
Aids such as magnifiers, high-power glasses and reading machines can enable many visually handicapped persons
to read enough to perform common household tasks. Low vision clinics sponsored by the Canadian National
Institute for the Blind (CNIB) are widely available in Canada.
Photodynamic Therapy (PDT)

8 , 9 , 10 , 11
In patients with a suitable CNV lesion from wet AMD or related conditions, photodynamic therapy with
verteporfin may be indicated. Verteporfin is a porphyrin derivative that, when activated by light in the presence of
oxygen, generates free radicals that damage the neovascular endothelium and occlude the vessels. Verteporfin is
contraindicated in patients with porphyria; severe liver disease is a relative contraindication.
PDT has been shown to significantly reduce vision loss compared to placebo.9 , 10 , 11 Patients usually do not
recover lost vision, and indeed often lose further vision after the initiation of therapy before plateauing at levels
higher than untreated patients. Individual patient response may vary from the averages in the large studies.
Treatment decisions require the interpretation of fluorescein angiograms together with clinical evaluation by a
retinal specialist. PDT involves administration of intravenous verteporfin followed by a low-level (nonthermal) laser
light that is aimed at the CNV lesion through a magnifying contact lens using a slit-lamp. The 10-minute infusion is
followed by a 5-minute waiting period. The laser light is then applied for 83 seconds.
Patients must be in semi-darkness for the treatment, and remain so for 48 hours afterward. Skin is photosensitive
during this time, and a severe burn may result if sunlight or bright lights strike the patient anywhere on the body.
This warning includes tanning salons, halogen examination lights used in emergency wards, surgical lights and
lighting used for dental procedures. Ultraviolet sunscreens provide no protection from this photosensitivity reaction.
Inadvertent subcutaneous extravasation of verteporfin can cause pain and prolonged photosensitivity of the
overlying skin until the drug has been metabolized.
Severe back pain during verteporfin infusion, occurring in 2.2% of patients, is an idiosyncratic reaction that
improves immediately upon discontinuing the infusion. Uncommonly (less than 5%), patients may experience a
severe decrease in vision following therapy, and some may recover this loss with time. It is important to note that
the likelihood of severe decrease in vision associated with verteporfin therapy is lower than in untreated patients.
Patients are monitored every three months for choroidal neovascular leakage; treatment may need to be repeated at
these intervals.
Vascular Endothelial Growth Factor (VEGF) Inhibitors (Table 2)
Recent studies have proven the efficacy of inhibitors of vascular endothelial growth factor in decreasing vision loss
in wet AMD.12 , 13 , 14 , 15 These drugs decrease VEGF levels in the extracellular space, which inhibits growth and
causes regression of new blood vessels in CNV membranes. They also stabilize the blood-retinal barrier and thereby
reduce macular edema, restoring normal anatomy.
Three VEGF inhibitors, pegaptanib, ranibizumab and bevacizumab, are available in Canada. Large multicentre
randomized controlled clinical trials have been performed with pegaptanib; it was shown to reduce vision loss at a
rate similar to that of PDT.12 , 13 Bevacizumab is in widespread use worldwide since it was approved in 2005 for the
treatment of colon cancer. It is frequently used off-label for several retinal diseases, including wet AMD. Large-scale
studies currently underway are evaluating the efficacy of bevacizumab in AMD, but preclinical and small-scale
16 , 17 , 18 , 19
clinical reports support its safety and clinical effectiveness.
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Therapeutic Choice
Ranibizumab is derived from a fragment of bevacizumab but has a higher binding affinity for VEGF. Ninety percent
of patients receiving ranibizumab lost less than three lines on a specialized vision chart and 40% showed
improvement at two years.14 There is excellent evidence supporting the use of ranibizumab, which became available
in Canada in 2007.14 , 15
VEGF inhibitors are injected into the vitreous cavity of the eye (intravitreal injection) every one to two months. The
endpoints of treatment have yet to be established, but six injections or more are often required. Optical coherence
tomography studies are performed at each visit to determine whether further treatment is needed.
Combination therapy including PDT and VEGF inhibitors is sometimes used.20 Studies are currently underway to
determine optimal treatment guidelines.
Side effects of these drugs are uncommon; the most worrisome is bacterial endophthalmitis from the injection
procedure, which occurs at a frequency of 2 in 1000 procedures or less.21 Severe loss of vision is the hallmark of
endophthalmitis. Pain and redness of the eye may also be present. Because irreversible blindness may occur,
endophthalmitis is considered a medical emergency that requires immediate treatment by an ophthalmologist;
management includes biopsy for bacterial culture followed by intravitreal injection of antibiotics. Often surgery is
necessary, and outcomes vary widely depending on the duration and etiology of the infection. Patients receiving
intravitreal VEGF inhibitors are warned to come to medical attention immediately if they develop symptoms of
endophthalmitis. Many patients will have mild pain from the drug injection procedure, which does not necessarily
indicate a problem. Subconjunctival hemorrhage is also common and generally resolves within two weeks.
Prevention
A combination of beta-carotene 25 000 IU, vitamin C 500 mg, vitamin E 400 IU, zinc 80 mg and copper 2 mg
per day reduced AMD-associated vision loss in suitable patients by 25% over seven years in the Age-Related Eye
22
Disease Study (AREDS), a large multicentre trial. Copper was included to reduce the likelihood of anemia in
patients taking large amounts of zinc. A commercial preparation of the above vitamins and supplements is available
(see Table 1). The ingredients and strengths of such products should be carefully checked to ensure they reflect the
evidenced-based combination.
Smokers who take supplemental beta-carotene have an increased risk of lung cancer, and should not
23,24
take such preparations. Patients who have smoked within the last five to ten years may also be
advised not to take supplemental beta-carotene; this duration has not been firmly established.
Useful Info? Contraindications to beta-carotene also include severe liver disease, renal insufficiency, renal dialysis
and pregnancy. While beta-carotene appears to be less teratogenic than vitamin A, no definitive data on risk are
available. Women of child-bearing potential are below the age for which vitamins have been proven effective. High-
dose vitamin C and E supplementation is contraindicated in renal disease, and vitamin C has been noted to cause
oxalosis in such patients. High-dose zinc may cause gastric disturbances as well as severe anemia. Fish liver oils
may contain high doses of vitamins A and E, and toxicity could result from taking multiple supplements with
overlapping constituents.
Lutein and zeaxanthin are carotenoids similar in structure and function to beta-carotene. They occur naturally in
foods and are concentrated in the macula. There is some evidence that they may play a role in normal macular
function, and that supplementation may be helpful. Studies are currently underway to determine the efficacy of
these compounds, and the same cautions apply as to beta-carotene. Effective and safe doses of lutein and
zeaxanthin have not been established.
Omega-3 and -6 fatty acids may also play a role in macular function. Their role in prevention of vision loss is the
subject of current investigations.
Figure 1-Management of Age-related Macular Degeneration
Page 284
Therapeutic Choice
a.
If smoker, vitamin-mineral therapy without beta-carotene and counsel to quit smoking
Abbreviations: AMD = age-related macular degeneration; CNV = choroidal neovascular membrane; CNIB = Canadian National
Institute for the Blind; PDT = photodynamic therapy; VEGF = vascular endothelial growth factor
Table 1: Vitamin-mineral Supplements for Wet AMD
a
Cost
Class Drug Dose Comments
Combination beta-carotene 12 500 IU + 1 tablet Formulated to match the doses in $$

Vitamin/Mineral vitamin C 250 mg + vitamin E twice 22
the AREDS trial.
Supplements, for 200 IU + copper 1 mg + zinc daily Do not use this formula containing
nonsmokers 40 mg beta-carotene in smokers, due to
Vitalux increased risk of lung cancer.
Page 285
Therapeutic Choice
Costa
Contraindicated in renal failure,

pregnancy.
Caution with other vitamin-mineral

supplements containing overlapping
ingredients.
Combination vitamin C 250 mg + vitamin E 1 tablet Alternative formulation for smokers $$

Vitamin/Mineral 200 IU + copper 1 mg + twice and those who have smoked within
Supplements, for zinc 40 mg daily the last 5–10 y (duration uncertain)
smokers Vitalux-S – no beta-carotene.
Caution with other vitamin-mineral
supplements containing overlapping
ingredients.
a.
Legend: $ < $10 $$ $10–15
Table 2: VEGF Inhibitors and Photodynamic Therapy for Wet AMD
a
Cost
Vascular pegaptanib 0.3 mg intravitreal Mild eye pain common; does not necessarily $$-
Endothelial Macugen injection every 6 weeks indicate a problem. Subconjunctival $$$
Growth Factor hemorrhage also common and resolves
(VEGF) Inhibitors spontaneously. Endophthalmitis occurs rarely
but is a medical emergency requiring
immediate treatment by an ophthalmologist.
Vascular ranibizumab 0.5 mg intravitreal Mild eye pain common; does not necessarily $$$
Endothelial Lucentis injection every 1–2 indicate a problem. Subconjunctival
Growth Factor months hemorrhage also common and resolves
Vascular bevacizumab 1.25 mg intravitreal Mild eye pain common; does not necessarily $$
Endothelial Avastin injection every 1–2 indicate a problem. Subconjunctival
Growth Factor months hemorrhage also common and resolves
Widely used off-label and economical.
Photodynamic verteporfin 6 mg/m2 diluted to a IV infusion is followed by laser light delivery, $$$
Therapy Visudyne 2 2
total volume of 30 mL i.e., 50 J/cm at a fluence of 600 mW/cm
and given iv over 10 (standard fluence); 25 J/cm2 at a fluence of
minutes; may need to
300 mW/cm2 (low fluence) is also in use.
be repeated at 3-month
Patients must avoid exposure of skin or eyes
intervals
to sunlight or bright indoor light for 2 days.
Severe back pain, which occurs rarely during
verteporfin infusions, remits when the infusion
is stopped. Severe and potentially irreversible
vision loss occurs rarely following therapy.
Page 286
Therapeutic Choice
Costa
a.
Cost per vial; includes drug cost only.
Legend: $ < $100 $-$$ < $100–1000 $$ $100–1000 $$-$$$ $1000–2000 $$$ > $1000–2000
Suggested Readings
Age-Related Eye Disease Study Research Group. A randomized, placebo-controlled, clinical trial of high-dose
supplementation with vitamins C and E, beta carotene, and zinc for age-related macular degeneration and vision
loss: AREDS report no. 8. Arch Ophthalmol 2001;119(10):1417-36.
Bressler NM; Treatment of Age-Related Macular Degeneration with Photodynamic Therapy (TAP) Study Group.
Photodynamic therapy of subfoveal choroidal neovascularization in age-related macular degeneration with
verteporfin: two-year results of 2 randomized clinical trials-TAP Report 2. Arch Ophthalmol 2001;119(2):198-207.
de Jong PT. Age-related macular degeneration. N Engl J Med 2006;355(14):1474-85.
Klein R, Klein BE, Tomany SC et al. Ten-year incidence and progression of age-related maculopathy: the Beaver
Dam eye study. Ophthalmology 2002;109(10):1767-79.
Verteporfin In Photodynamic Therapy Study Group. Verteporfin therapy of subfoveal choroidal neovascularization in
age-related macular degeneration: two-year results of a randomized clinical trial including lesions with occult with
no classic choroidal neovascularization—Verteporfin in Photodynamic Therapy Report 2. Am J Ophthalmol 2001;131
(5):541-60.
Verteporfin Roundtable 2000 and 2001 Participants; Treatment of age-related macular degeneration with
photodynamic therapy (TAP) study group principal investigators; Verteporfin in photodynamic therapy (VIP) study
group principal investigators. Guidelines for using verteporfin (Visudyne) in photodynamic therapy to treat choroidal
neovascularization due to age-related macular degeneration and other causes. Retina 2002;22(1):6-18.
References
1. Leibowitz HM, Krueger DE, Maunder LR et al. The Framingham Eye Study monograph: an ophthalmological
and epidemiological study of cataract, glaucoma, diabetic retinopathy, macular degeneration, and visual acuity
in a general population of 2631 adults, 1973-1975. Surv Ophthalmol 1980;24(Suppl):335-610.
2. Hyman LG, Lilienfeld AM, Ferris FL et al. Senile macular degeneration: a case-control study. Am J Epidemiol
1983;118(2):213-27.
3. Kahn HA, Leibowitz HM, Ganley JP et al. The Framingham Eye Study. II. Association of ophthalmic pathology
with single variables previously measured in the Framingham Heart Study. Am J Epidemiol 1977;106(1):33-
41.
4. Klein BE, Klein R. Cataracts and macular degeneration in older Americans. Arch Ophthalmol 1982;100(4):571-
3.
5. Bressler SB, Bressler NM, Fine SL et al. Natural course of choroidal neovascular membranes within the foveal
avascular zone in senile macular degeneration. Am J Ophthalmol 1982;93(2):157-63.
6. Chandra SR, Gragoudas ES, Friedman E et al. Natural history of disciform degeneration of the macula. Am J
Ophthalmol 1974;78(4):579-82.
7. Gass JD. Drusen and disciform macular detachment and degeneration. Arch Ophthalmol 1973;90(3):206-17.
8. Verteporfin Roundtable Participants. Guidelines for using verteporfin (Visudyne) in photodynamic therapy for
choroidal neovascularization due to age-related macular degeneration and other causes: update. Retina
2005;25(2)119-34.
9. Verteporfin Roundtable 2000 and 2001 Participants; Treatment of age-related macular degeneration with
photodynamic therapy (TAP) study group principal investigators; Verteporfin in photodynamic therapy (VIP)
study group principal investigators. Guidelines for using verteporfin (Visudyne) in photodynamic therapy to
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Therapeutic Choice
treat choroidal neovascularization due to age-related macular degeneration and other causes. Retina 2002
(1);6-18.
10. Verteporfin In Photodynamic Therapy Study Group. Verteporfin therapy of subfoveal choroidal
neovascularization in age-related macular degeneration: two-year results of a randomized clinical trial
including lesions with occult with no classic choroidal neovascularization—Verteporfin in Photodynamic
Therapy Report 2. Am J Ophthalmol 2001;131(5)541-60.
11. Bressler NM; Treatment of Age-Related Macular Degeneration with Photodynamic Therapy (TAP) Study Group.
Photodynamic therapy of subfoveal choroidal neovascularization in age-related macular degeneration with
verteporfin: two-year results of 2 randomized clinical trials-TAP Report 2. Arch Ophthalmol 2001;119(2):198-
207.
12. Gragoudas ES, Adamis AP, Cunningham ET et al. Pegaptanib for neovascular age-related macular
degeneration. N Engl J Med 2004;351(27):2805-16.
13. VEGF Inhibition Study in Ocular Neovascularization (V.I.S.I.O.N.) Clinical Trial Group; Chakravarthy U,
Adamis AP et al. Year 2 efficacy results of 2 randomized controlled clinical trials of pegaptanib for neovascular
age-related macular degeneration. Ophthalmology 2006;113(9):1508.e1-25.
14. Rosenfeld PJ, Brown DM, Heier JS et al. Ranibizumab for neovascular age-related macular degeneration. N
Engl J Med 2006;355(14):1419-31.
15. Brown DM, Kaiser PK, Michels M et al. Ranibizumab versus verteporfin for neovascular age-related macular
degeneration. N Engl J Med 2006;355(14):1432-44.
16. Avery RL, Pieramici DJ, Rabena MD et al. Intravitreal bevacizumab (Avastin) for neovascular age-related
macular degeneration. Ophthalmology 2006;113(3):363-372.e5.
17. Lazic R, Gabric N. Intravitreally administered bevacizumab (Avastin) in minimally classic and occult choroidal
neovascularization secondary to age-related macular degeneration. Graefes Arch Clin Exp Ophthalmol
2007;245(1):68-73.
18. Rich RM, Rosenfeld PJ, Puliafito CA, et al. Short-term safety and efficacy of intravitreal bevacizumab (Avastin)
for neovascular age-related macular degeneration. Retina 2006;26(5):495-511.
19. Yoganathan P, Deramo VA, Lai JC et al. Visual improvement following intravitreal bevacizumab (Avastin) in
exudative age-related macular degeneration. Retina 2006;26(9):994-8.
20. Heier JS, Boyer DS, Ciulla TA et al. Ranibizumab combined with verteporfin photodynamic therapy in
neovascular age-related macular degeneration: year 1 results of the FOCUS Study. Arch Ophthalmol 2006;124
(11):1532-42.
21. Chakravarthy U, Soubrane G, Bandello F et al. Evolving European guidance on the medical management of
neovascular age related macular degeneration. Br J Ophthalmol 2006;90(9):1188-96.
22. Age-Related Eye Disease Study Research Group. A randomized, placebo-controlled, clinical trial of high-dose
supplementation with vitamins C and E, beta carotene, and zinc for age-related macular degeneration and
vision loss: AREDS report no. 8. Arch Ophthalmol 2001;119(10):1417-36.
23. Albanes D, Heinonen OP, Huttunen JK et al. Effects of alpha-tocopherol and beta-carotene supplements on
cancer incidence in the Alpha-Tocopherol Beta-Carotene Cancer Prevention Study. Am J Clin Nutr 1995;62(6
Suppl):1427S-1430S.
24. Omenn GS, Goodman GE, Thornquist MD et al. Risk factors for lung cancer and for intervention effects in
CARET, the Beta-Carotene and Retinol Efficacy Trial. J Natl Cancer Inst 1996;88(21):1550-9
Page 288
e-Therapeutics+ : Therapeutics : Eye Disorders: Cataract Surgery Postoperative Care Page 1 of 9
Therapeutic Choice
Print Close
Eye Disorders: Cataract Surgery Postoperative Care

Stan P. George, MD, FRCSC
It is understandably difficult for a primary care practitioner to manage and diagnose the complications of a
postoperative cataract patient without the benefit of a slit lamp, indirect ophthalmoscope, and frequently without
even a Snellen acuity chart. The goal of this chapter is to review symptoms and signs that would allow a primary
care practitioner to identify cases that should be urgently referred to the ophthalmologist.
Goals of Therapy
Control inflammation
Prevent infection
Maintain eye comfort
Promote early visual rehabilitation
The goals of the postoperative assessment are to:
Detect intraocular infection in its early stages
Detect postoperative uveitis or intraocular pressure (IOP) elevation
Detect other abnormalities in the postoperative course such as a retinal detachment, iris prolapse, wound leak,
flat anterior chamber or intraocular hemorrhage
Investigations
Pain:
the postoperative eye should be comfortable; at worst, patient may have a mild foreign-body sensation
more intense pain suggests increased IOP, increased inflammation and/or infection
History of recent trauma:
any trauma to the eye in the early postoperative phase requires thorough reassessment with a slit lamp
Change in vision (worsening, darkening, loss of detail or peripheral visual loss):
any significant change could indicate infection, hemorrhage, retinal detachment or other acute intraocular
pathology requiring immediate attention
Visual phenomena (flashing lights, dark shadows or floaters):
requires thorough reassessment to rule out infection, retinal tear or detachment or uveitis
using a pinhole to test visual acuity will eliminate the effect of refractive error if the patient has apparent
reduced acuity
Itching of the eye (as predominant symptom):
suggests allergy to medications
Examination of eye:
swelling of lids and/or conjunctiva suggests drug allergy or infection
pupil(s) should react normally to light unless a mydriatic agent has been used. Photophobia (glare
sensitivity and pain from light exposure) can indicate anterior uveitis or corneal haze (from infection,
inflammation or increased IOP)
the cornea should be clear of any clouding or infiltrates (to rule out corneal or anterior segment infection,
inflammation or intraocular pressure elevation); the cornea should reflect a clear, well-demarcated image
when the direct ophthalmoscope or pupil light is shined on it
use the ophthalmoscope to see if the disc is clearly viewed and a red reflex is present (to rule out vitreous
clouding, inflammation or infection)
Review of ocular medications:
reinforce proper use
clarify any confusion
discuss with family member
Verify follow-up visits with surgeon
Therapeutic Choices (Figure 1 - Evaluation of the Postoperative Cataract Patient by the

Primary Care Practitioner)
Postoperative ophthalmic medications may include:
Page 289
Therapeutic Choice
Antibacterials (Table 1)
a broad-spectrum antibacterial is used perioperatively to reduce the risk of endophthalmitis. Although there
1 2
is some evidence that prophylactic antibacterials are beneficial, the evidence is weak. Nonetheless, not
using perioperative topical antibacterials could be problematic from a medical-legal point of view.
one study demonstrated the efficacy of preoperative topical povidone iodine in reducing the rate of
endophthalmitis.3 The use of perioperative fourth-generation topical fluoroquinolones (besifloxacin,
gatifloxacin, moxifloxacin)4 , 5 is gaining widespread acceptance; however, many surgeons still prefer
an agent that combines the antibacterial with a corticosteroid in the same bottle, e.g.,
tobramycin/dexamethasone (Tobradex).
Dilators and cycloplegics (Table 2)
used to keep iris away from implant during early healing period and to improve comfort by decreasing
ciliary muscle spasm.
Anti-inflammatory agents (Table 3)
used during the first few weeks to reduce postoperative inflammation.
Glaucoma medications (Table 4)
used to lower the intraocular pressure after eye surgery; in patients with pre-existing glaucoma, medication
regimen may be modified in postoperative period to protect against early postoperative intraocular pressure
rise.
A mild analgesic may be required (e.g., acetaminophen 500 mg every four to six hours).
Sedation is rarely needed.
Other systemic medications should be continued.
Therapeutic Tips
No changes to postoperative ophthalmic medications should be made without discussion with the treating
ophthalmologist.
Advise patients not to administer different eye drops at the same time, and to separate their administration by a
period of 15 minutes.
Worsening vision, floaters and increasing eye redness, especially in the first postoperative week,
should be considered an endophthalmitis until proven otherwise, and necessitates an urgent
assessment by an ophthalmologist. Useful Info?
Because treatment with many medications in this setting is for a limited course, any remaining ophthalmic
medication should be disposed of properly.
Figure 1-Evaluation of the Postoperative Cataract Patient by the Primary Care Practitioner
Table 1: Antibacterials for Cataract Surgery Postoperative Care
Page 290
Therapeutic Choice
a
Duration of Cost
Class Drug Use Adverse Effects Comments
Miscellaneous bacitracin ± 7–10 days Allergic/hypersensitivity Good broad-spectrum $

Antibacterials polymyxin B ± reactions. coverage but
gramicidin, hypersensitivity
ophthalmic reactions in some
Polysporin, patients, especially
generics with longer use.
Miscellaneous chloramphenicol, 7–10 days Very small risk of Bacteriostatic; well $

Antibacterials ophthalmic idiosyncratic aplastic tolerated.
Pentamycetin, anemia.
generics
Aminoglycosides gentamicin, 7–10 days Extended use may cause High concentrations on $
ophthalmic conjunctivitis or and in the eye lead to
epitheliopathy reactions to broader bacterial
Garamycin
the eye. coverage than
Ophthalmic, traditional in vitro
generics testing suggests.
Aminoglycosides neomycin 7–10 days Extended use may cause High concentrations on $
combinations, conjunctivitis or and in the eye lead to
ophthalmic epitheliopathy reactions to broader bacterial
Neosporin, the eye. coverage than
generics traditional in vitro
testing suggests.
Aminoglycosides tobramycin, 7–10 days Extended use may cause High concentrations on $
ophthalmic conjunctivitis or and in the eye lead to
Tobrex, generics epitheliopathy reactions to broader bacterial
the eye. coverage than
traditional in vitro
testing suggests.
Fluoroquinolones besifloxacin 7–10 days Blurred vision, local 4th generation $$

Besivance irritation or discomfort. fluoroquinolone;
improved broad-
spectrum activity,
especially against
gram-positive
organisms.
Fluoroquinolones ciprofloxacin, 7–10 days Formation of white Excellent broad- $

ophthalmic crystalline precipitate after spectrum profile and
Ciloxan, generics administration. minimal ocular surface
toxicity; very
commonly used; may
be used orally if lens
capsule ruptured
during cataract
surgery.
Fluoroquinolones ciprofloxacin, oral 500 mg po Abdominal pain, headache, Used orally if lens $$$
Q12H dizziness, photosensitivity, capsule ruptured
Cipro, generics × 7–10 days hepatitis, during cataract
pseudomembranous colitis, surgery.
cartilage toxicity.
Fluoroquinolones gatifloxacin, 7–10 days Formation of white 4th generation $$

ophthalmic crystalline precipitate after fluoroquinolone;
administration. improved broad-
Zymar
spectrum activity,
especially against
gram-positive
organisms.
Page 291
Therapeutic Choice
Duration of Costa
Fluoroquinolones moxifloxacin, 7–10 days Formation of white th $$

4 generation
ophthalmic crystalline precipitate after fluoroquinolone;
administration. improved broad-
Vigamox
spectrum activity,
especially against
gram-positive
organisms.
Fluoroquinolones ofloxacin, 7–10 days Formation of white Excellent broad- $

ophthalmic crystalline precipitate after spectrum profile and
administration. minimal ocular surface
Ocuflox, generics
toxicity; very
commonly used; may
be used orally if lens
capsule ruptured
during cataract
surgery.
Fluoroquinolones ofloxacin, oral 400 mg po Abdominal pain, headache, Used orally if lens $$$
generics Q12H dizziness, photosensitivity, capsule ruptured
× 7–10 days hepatitis, during cataract
pseudomembranous colitis, surgery.
cartilage toxicity.
a.
Cost of smallest available pack size or 10-day supply for oral treatment; includes drug cost only.
Legend: $ < $10 $$ $10–20 $$$ $20–30
Table 2: Ophthalmic Dilators and Cycloplegics for Cataract Surgery Postoperative Care
a
Duration of Cost
Dilators and cyclopentolate First few Uncommonly, systemic Less commonly used with $$
Cycloplegics Cyclogyl, weeks after anticholinergic side effects modern cataract surgery in
generics surgery. (e.g., flushing, tachycardia, light of smaller incisions and
urinary retention). less postoperative
inflammation.
Dilators and phenylephrine First few Rarely, tachycardia and Less commonly used with $
Cycloplegics Mydfrin, weeks after hypertension. modern cataract surgery in
generics surgery. light of smaller incisions and
less postoperative
inflammation.
Dilators and tropicamide First few Less commonly used with $$

Cycloplegics Mydriacil, weeks after modern cataract surgery in
generics surgery. light of smaller incisions and
less postoperative
inflammation.
a.
Cost of smallest available pack size; includes drug cost only.
Legend: $ < $10 $$ $10–20
Table 3: Ophthalmic Anti-inflammatories for Cataract Surgery Postoperative Care
Page 292
Therapeutic Choice
a
Duration of Cost
Corticosteroids dexamethasone 3–4 wk; Elevated intraocular Commonly used after all types $
Maxidex, longer if pressure; anti- of eye surgery.
generics evidence of inflammatory effects
cystoid can mask signs of
macular infection.
edema.
Corticosteroids fluorometholone 3–4 wk; Elevated intraocular Commonly used after all types $$
Flarex, FML, longer if pressure; anti- of eye surgery.
generics evidence of inflammatory effects
macular infection.
edema.
Corticosteroids loteprednol 0.5% 3–4 wk; Elevated intraocular Commonly used after all types $$$
Lotemax longer if pressure; anti- of eye surgery. May cause less
evidence of inflammatory effects elevation of intraocular
cystoid can mask signs of pressure compared to other
macular infection. corticosteroids.
edema.
Corticosteroids prednisolone 3–4 wk; Elevated intraocular Commonly used after all types $$
Pred Mild, Pred longer if pressure; anti- of eye surgery.
Forte, generics evidence of inflammatory effects
macular infection.
edema.
Corticosteroids rimexolone 3–4 wk; Elevated intraocular Commonly used after all types $$
Vexol longer if pressure; anti- of eye surgery.
evidence of inflammatory effects
macular infection.
edema.
NSAIDs diclofenac 3–4 wk; Mild to moderate Used as a substitute for $

Voltaren Ophtha longer if burning on steroids to ↓ inflammation without
evidence of instillation; the risk of elevating intraocular
cystoid epitheliopathy with pressure; should not be used in
macular prolonged and asthmatics or patients with
edema. frequent use. allergies to ASA or NSAIDs.
NSAIDs ketorolac 3–4 wk; Mild to moderate Used as a substitute for $$

Acular, generics longer if burning on steroids to ↓ inflammation without
evidence of instillation; the risk of elevating intraocular
cystoid epitheliopathy with pressure; should not be used in
macular prolonged and asthmatics or patients with
edema. frequent use. allergies to ASA or NSAIDs.
a.
Cost of smallest available pack size; includes drug cost only.
Legend: $ < $10 $$ $10–20 $$$ $20–30
Table 4: Glaucoma Medications for Cataract Surgery Postoperative Care
Page 293
Therapeutic Choice
a
Duration of Cost
Beta1- timolol Used as long as Symptoms of systemic beta Efficacious and cost $
adrenergic Timoptic, intraocular blockade can be precipitated effective with minimal
Antagonists generics pressure is or aggravated with beta- ocular toxicity; avoid in
elevated, or blocking eye drops (e.g., asthmatics or patients
permanently in bradycardia, arrhythmia, with obstructive lung
patients with hypotension, disease or borderline
pre-existing bronchospasm); potentially cardiac function.
glaucoma. serious systemic effects in
asthmatics or patients with
obstructive lung disease or
borderline cardiac function.
Beta1- timolol gel- Used as long as Symptoms of systemic beta Efficacious and cost $
adrenergic forming intraocular blockade can be precipitated effective with minimal
Antagonists solution pressure is or aggravated with beta- ocular toxicity; avoid in
Timoptic XE, elevated, or blocking eye drops (e.g., asthmatics or patients
generics permanently in bradycardia, arrhythmia, with obstructive lung
Beta1- betaxolol Used as long as Symptoms of systemic beta Efficacious and cost $
adrenergic Betoptic S, intraocular blockade can be precipitated effective with minimal
Beta1- levobunolol Used as long as Symptoms of systemic beta Efficacious and cost $
adrenergic Betagan, intraocular blockade can be precipitated effective with minimal
Alpha2- apraclonidine Used as long as Common ocular reactions Potent in controlling $$$
adrenergic Iopidine intraocular include hyperemia and a postoperative pressure
Agonists pressure is burning sensation. spikes; avoid in patients
elevated, or with severe
permanently in cardiovascular disease
patients with in light of alpha-
pre-existing adrenergic effects; use
glaucoma. with caution in patients
taking tricyclic
antidepressants.
Page 294
Therapeutic Choice
a
Duration of Cost
Alpha2- brimonidine Used as long as Common ocular reactions Potent in controlling $$

adrenergic 0.2% intraocular include hyperemia and a postoperative pressure
Agonists Alphagan, pressure is burning sensation. spikes; avoid in patients
generics elevated, or with severe
taking tricyclic
antidepressants.
Alpha2- brimonidine Used as long as Common ocular reactions Potent in controlling $$

adrenergic 0.15% intraocular include hyperemia and a postoperative pressure
Agonists Alphagan P, pressure is burning sensation. spikes; avoid in patients
generics elevated, or with severe
taking tricyclic
antidepressants.
Contains purite as
preservative rather than
benzalkonium chloride;
may have slightly lower
incidence of ocular
allergy than brimonidine
0.2%.
Prostaglandins bimatoprost Used as long as Brown pigmentation of the Very potent pressure- $$$
Lumigan, intraocular iris or darkening or lowering agents with
Lumigan RC pressure is thickening of eye lashes once-daily application.
elevated, or may develop.
permanently in
patients with
pre-existing
glaucoma.
Prostaglandins latanoprost Used as long as Brown pigmentation of the Very potent pressure- $$$
Xalatan intraocular iris or darkening or lowering agents with
pressure is thickening of eye lashes once-daily application.
permanently in
patients with
pre-existing
glaucoma.
Prostaglandins travoprost Used as long as Brown pigmentation of the Very potent pressure- $$$
Travatan intraocular iris or darkening or lowering agents with
pressure is thickening of eye lashes once-daily application.
permanently in
patients with
pre-existing
glaucoma.
Carbonic acetazolamide 250 mg up to Should not be used in Carbonic anhydrase $

Anhydrase , oral QID; used for patients with sulfonamide inhibitors more
Inhibitors generics very high allergy; conjunctivitis and commonly used topically
intraocular blepharitis are not as adjunctive agents to
pressure on a uncommon side effects; reduce intraocular
short-term systemic hypersensitivity pressure.
basis. reactions may develop.
Page 295
Therapeutic Choice
Duration of Costa
Carbonic methazolamide, 50–100 mg BID Should not be used in Carbonic anhydrase $$$$
Anhydrase oral -TID; used for patients with sulfonamide inhibitors more
Inhibitors Apo- very high allergy; conjunctivitis and commonly used topically
intraocular blepharitis are not as adjunctive agents to
Methazolamide,
pressure on a uncommon side effects; reduce intraocular
other generics
short-term systemic hypersensitivity pressure.
basis. reactions may develop.
Carbonic brinzolamide Topical use may Should not be used in Carbonic anhydrase $$
Anhydrase Azopt be long term. patients with sulfonamide inhibitors more
Inhibitors allergy; conjunctivitis and commonly used topically
blepharitis are not as adjunctive agents to
uncommon side effects; reduce intraocular
systemic hypersensitivity pressure.
reactions may develop.
Carbonic dorzolamide Topical use may Should not be used in Carbonic anhydrase $$
Anhydrase Trusopt be long term. patients with sulfonamide inhibitors more
Inhibitors allergy; conjunctivitis and commonly used topically
blepharitis are not as adjunctive agents to
uncommon side effects; reduce intraocular
systemic hypersensitivity pressure.
reactions may develop.
a.
Cost of smallest available pack size or 30-day supply of oral therapy; includes drug cost only.
Legend: $ < $10 $$ $10–20 $$$ $20–30 $$$$ > $30
Suggested Readings
American Academy of Ophthalmology. Cataract and Anterior Segment Panel. Preferred practice pattern: cataract in
the adult eye. San Francisco (CA): The Academy; 2006. Available from:
http://one.aao.org/CE/PracticeGuidelines/PPP_Content.aspx?cid=a80a87ce-9042-4677-85d7-4b876deed276.
Accessed December 8, 2008.
Bradford CA, editor. Basic ophthalmology for medical students and primary care residents. 7th ed. San Francisco
(CA): American Academy of Ophthalmology; 2004.
Kunimoto DY, Kanitkar KD, Makar MS, editors. The Wills eye manual: office and emergency room diagnosis and
treatment of eye disease. 4th ed. Philadelphia (PA): Lippincott Williams & Wilkins; 2004.
Tasman W, Jaeger EA, editors. Duane’s ophthalmology. Philadelphia (PA): Lippincott Williams & Wilkins; 2006.
References
1. Allen HF, Mangiaracine AB. Bacterial endophthalmitis after cataract extraction. II. Incidence in 36,000
consecutive operations with special reference to preoperative topical antibiotics. Arch Ophthalmol 1974;91
(1):3-7.
2. Ciulla TA, Starr MB, Masket S. Bacterial endophthalmitis prophylaxis for cataract surgery: an evidence-based
update. Ophthalmology 2002;109(1):13-24.
3. Speaker MG, Menikoff JA. Prophylaxis of endophthalmitis with topical povidone-iodine. Ophthalmology
1991;98(12):1769-75.
4. Callegan MC, Ramirez R, Kane ST et al. Antibacterial activity of the fourth generation flouroquinolones
gatifloxacin and moxifloxacin against ocular pathogens. Adv Ther 2003;20(5): 246-52.
Page 296
Therapeutic Choice
5. Deramo VA, Lai JC, Fastenberg DM et al. Acute endophthalmitis in eyes treated prophylactically with
gatifloxacin and moxifloxacin. Am J Ophthmol 2006;142(5):721-5.
Page 297
e-Therapeutics+ : Therapeutics : Eye Disorders: Glaucoma Page 1 of 13
Therapeutic Choice
Print Close
Eye Disorders: Glaucoma

Date Revised: July 2010
Mark R. Lesk, MSc, MD, FRCSC
Paul Rafuse, MD, PhD, FRCSC
Glaucoma is a group of ocular diseases that have in common an optic neuropathy that causes visual loss.
Characteristically, the optic disc is cupped, and peripheral field loss precedes deterioration of visual acuity. Elevated
1
intraocular pressure (IOP) is the most important, and only modifiable, risk factor for glaucoma. Other risk factors
2
(Table 1) are likely important in the pathogenesis of this neurodegenerative condition.
Goals of Therapy
Prevent, halt or slow progressive visual loss

Preserve the structure and function of the optic nerve
Eliminate pain and improve vision in acute forms
Investigations
Thorough history with special attention to:

nature of any ocular disturbances, e.g., loss of peripheral vision, halos around lights, decreased visual
acuity
quality of any pain, e.g., deep orbital, brow or headache
associated systemic symptoms, e.g., abdominal pain, nausea and vomiting
Note: The most common varieties of glaucoma are chronic. Generally, symptoms are associated only with acute
types of glaucoma, which warrant urgent referral to an ophthalmologist or emergency room. Most patients with
chronic glaucoma are asymptomatic until they reach the advanced stages of the disease.
Careful assessment of risk factors (Table 1)
History of drug use that can cause or worsen glaucoma
corticosteroids (common)
drugs with antimuscarinic activity (rare), e.g., antihistamines, decongestants, antidepressants,
antispasmodics
the anticonvulsant topiramate has been associated with acute angle-closure glaucoma3
positive findings include constricted visual field, optic disc cupping and elevated IOP
Note: Screening for elevated IOP alone lacks adequate sensitivity and specificity for the detection of glaucoma,
4
as up to 50% of people with glaucoma have IOP in the normal range (< 21 mm Hg). Further, about 90% of
people with elevated IOP do not have glaucoma, although they are at increased risk of developing it.5
Comprehensive eye examination by an ophthalmologist or optometrist
Laboratory tests:
automated perimetry
optic disc photography
Table 1: Risk Factors for the Development of Glaucoma
Angle-closure Glaucoma
Type of
Glaucoma Open-angle Glaucoma Acute Chronic
Acquired, Elevated IOP Female gender Advanced

Primary Advanced age6 Advanced age6 age6
7 Positive family history Black
Black ethnicity
Positive family history Hyperopia ethnicity7
White ethnicity
Page 298
Therapeutic Choice
Angle-closure Glaucoma
Type of
Glaucoma Open-angle Glaucoma Acute Chronic
8 Positive
Myopia
Vascular diseases such as family history
Hyperopia
migraine,9 hypertension10 or
11
nocturnal hypotension
Acquired, Blunt or penetrating trauma Proliferative diabetic retinopathy and central

Secondary Previous intraocular surgery retinal vein occlusion (neovascular angle-
Previous intraocular inflammation closure glaucoma)
Corticosteroid use (ophthalmic,
systemic, nasal or inhaled)
Congenital Positive family history
Therapeutic Choices (Figure 1 - Management of Open-angle Glaucoma)
The therapeutic goals (see Goals of Therapy) are achieved by lowering the IOP, even in patients with glaucoma
whose pressures are in the normal range, through the use of medications, laser and/or surgery.
There are no lifestyle modifications proven to alter the outcome of the disease. Aerobic exercise can lower IOP
modestly in some patients with glaucoma.12
Laser or surgical procedures are options if drug therapy is unsuccessful (Figure 1 - Management of Open-angle
Glaucoma, Table 2).
Table 2: Laser and Surgical Treatment of Glaucoma
Procedure Indication Description
Laser Treatment
Laser trabeculoplasty (argon or Open-angle glaucoma Laser applications to trabecular meshwork

selective laser) (drainage system).
Effect is short term, e.g., 2 y; most suitable for
elderly patients.
Laser iridotomy Angle-closure glaucoma A neodymium: yttrium-aluminum-garnet (Nd:YAG)

laser cuts holes in iris to permit flow of aqueous
humor directly from posterior to anterior chamber;
can be done without incising eyeball.
Simple office procedure.
Laser ciliary body ablation Advanced refractory Used where other options are limited.
glaucomas
Surgical Treatment
Filtration procedures (e.g., Open-angle glaucoma, in A channel is created, allowing aqueous flow from
trabeculectomy, nonpenetrating cases refractory to anterior chamber to a subconjunctival space.
deep sclerotomy, medical or laser Healing and surgical success improved with topical
viscocanalostomy) treatment use of antiproliferative agents, such as mitomycin
C or 5-fluorouracil, during or following procedure.
Iridectomy Angle-closure glaucoma Used in affected eye and prophylactically in other

eye.
Reserved for rare cases refractory to Nd:YAG laser
iridotomy.
Page 299
Therapeutic Choice
Procedure Indication Description
Drainage tube insertion Any form of glaucoma, Small tube, inserted into anterior chamber, drains
where other surgical aqueous to a plate that is implanted on the sclera,
procedures have not beneath the conjunctiva.
succeeded
Treat reversible causes of secondary and angle-closure glaucoma.
Note: The definitive treatment for acute angle-closure glaucoma is a surgical or laser iridectomy. Aggressive
medical treatment is required to ameliorate the damaging effects of extreme IOP elevation until the iridectomy
is performed.
Treat excessive IOP, the only modifiable risk factor in chronic primary open-angle glaucoma (the most prevalent
form); all treatment measures in Figure 1 - Management of Open-angle Glaucoma are believed to exert their
therapeutic effect by lowering IOP.
Selected patients with risk factors in addition to elevated IOP may require treatment even in the absence of
glaucomatous optic disc and visual field damage.5
13
Patients with open-angle glaucoma at normal pressures will benefit from further lowering of their IOP.
Target IOPs for a specific patient are set on the basis of:
the extent of glaucomatous damage
the IOP range believed to have been associated with that damage
the burden of therapy to achieve the desired IOP.
Target pressure is adjusted downward if progressive damage to the optic disc or visual field occurs at the target
14
IOP.
In some cases, clinicians may want to consider the potential neuroprotective effects or improvement in ocular
blood flow afforded by some of the existing ocular hypotensive agents.15
Open-angle Glaucoma
Beta-blockers
Topical timolol, levobunolol and betaxolol are effective ocular hypotensive agents that lack significant ocular
side effects.16 They decrease IOP by inhibiting the formation of aqueous humor. Beta-blockers are contraindicated
when certain pulmonary and cardiac diseases are present (Table 3). Betaxolol hydrochloride is relatively specific for
beta1-receptor blockade and may be used with caution in selected patients with mild obstructive pulmonary
17
disease.
Topical Carbonic Anhydrase Inhibitors
Dorzolamide and brinzolamide are the two available agents in this class. Like oral carbonic anhydrase inhibitors,
they decrease IOP by inhibiting an enzyme involved in the formation of aqueous humor. Both have limited systemic
effects when compared to oral formulations, but they do not lower IOP to the same extent.18 Brinzolamide appears
to be as efficacious as dorzolamide and may be more comfortable on instillation.19 These drugs can be considered
for adjunctive therapy, or for primary treatment in patients with cardiopulmonary contraindications to beta-blockers.
Prostaglandin Analogues
Latanoprost and travoprost are prostaglandin F2α analogues that lower IOP by increasing outflow through the
20
uveoscleral pathway. Bimatoprost, a prostamide analogue, may act by increasing both uveoscleral and trabecular
21
outflow. These agents are slightly more efficacious than nonselective beta-blockers. Clinical experience with this
class has not revealed any significant systemic adverse effects, but a few ocular effects have been noted, including
22
darkening of some brown-coloured irides, lengthening of the eyelashes and mild conjunctival hyperemia. Any of
these agents may be considered first-line therapy because of their potencies and excellent safety profiles.
Page 300
Therapeutic Choice
Alpha2-Adrenergic Agonists
Topical epinephrine, the prototype in this class, has not been available in Canada for some time, because of
unacceptable adverse ocular effects. The epinephrine prodrug dipivefrin has also been discontinued. Apraclonidine
was the first alpha2-specific agonist introduced, but local allergic reactions have limited its use to the management
of acute IOP spikes.23 Also with a significant incidence of allergy, brimonidine has a higher specificity for the
24
alpha2-receptor and is associated with a less severe conjunctival hyperemia. A new formulation of brimonidine
(0.15%, preserved with purite rather than benzalkonium chloride) may have a slightly lower rate of ocular allergy
than brimonidine 0.2%. Like apraclonidine, brimonidine suppresses the formation of aqueous humor and can be
25
used for a variety of open-angle and angle-closure glaucomas. Brimonidine may also increase uveoscleral outflow.
Cholinergic Agonists
The topical cholinergic agonists pilocarpine and carbachol directly stimulate muscarinic receptors to contract the
26
ciliary muscle and increase trabecular outflow. These drugs are characterized by ocular side effects, including
miosis (with reduced night vision), accommodative spasm (including myopia) and brow ache, and rarely, in
predisposed patients, retinal detachment. Rarely is sufficient drug absorbed systemically to cause abdominal
cramping or diarrhea. These drugs are poorly tolerated in children and young adults.
Fixed-combination Preparations
There are currently four fixed-combination topical glaucoma therapies, each containing timolol, available in Canada.
Dorzolamide/timolol,27brimonidine/timolol,28latanoprost/timolol29 and travoprost/timolol30 are all
more effective than the individual agents, and they have similar ocular hypotensive effects. Useful Info?
Dorzolamide/timolol has by far the longest track record. The combined agents are thought to have advantages with
respect to adherence to therapy.
Oral Carbonic Anhydrase Inhibitors
Acetazolamide and methazolamide lower IOP by decreasing the production of aqueous humor. Their use is
normally reserved for emergencies because of significant side effects. Approximately 50% of patients are unable to
use these agents long term because of GI or CNS difficulties, paresthesias or renal lithiasis.31 Oral and topical
carbonic anhydrase inhibitors can show cross-reactivity in patients allergic to sulfonamides.
Therapeutic Tips
Topical glaucoma medications are highly concentrated to allow adequate intraocular penetration. Systemic
absorption occurs through the nasal mucosa. This can be reduced through digital occlusion of the nasolacrimal
drainage system for several minutes following instillation of the drops,32 or through eyelid closure for three to
five minutes.
Nonprescription antihistamine products (which carry a caution against use in glaucoma patients due to
anticholinergic side effects) and anticholinergic drugs will rarely cause a problem in open-angle glaucoma with
intermittent use. The caution is included primarily to warn that, rarely, drugs with anticholinergic activity can
33
precipitate angle-closure glaucoma in predisposed individuals (e.g., elderly white or Asian females who are
significantly hyperopic, have a positive family history and have not yet had a therapeutic or prophylactic
iridectomy — see Table 1).
Figure 1-Management of Open-angle Glaucoma
Treatment is stepped up if optic disc cupping progresses, the visual field deteriorates or intraocular pressure control
is inadequate.
Page 301
Therapeutic Choice
Page 302
Therapeutic Choice
Page 303
Therapeutic Choice
Table 3: Drugs Used in Glaucoma
Costa
Beta1-adrenergic timolol 0.25%, Q12H Local adverse effects Avoid in patients with $
Antagonists, 0.5% usually minimal — bronchial asthma; caution
ophthalmic Timoptic, stinging, dry eyes, in patients with a history
generics rarely conjunctivitis; of syncope or bradycardia.
systemic effects can
include bronchospasm,
exacerbation of CHF,
bradycardia, syncope,
depression, impotence,
altered response to
hypoglycemia,
reduction of high-
density lipoproteins.
Beta1-adrenergic timolol gel- Once daily Local adverse effects Avoid in patients with $
Antagonists, forming usually minimal — bronchial asthma; caution
ophthalmic solution 0.25%, stinging, dry eyes, in patients with a history
0.5% rarely conjunctivitis; of syncope or bradycardia.
Timoptic-XE, systemic effects can
generics include bronchospasm,
altered response to
hypoglycemia,
reduction of high-
Beta1-adrenergic betaxolol Q12H Local adverse effects Avoid in patients with $$

Antagonists, 0.25% usually minimal — bronchial asthma; caution
ophthalmic Betoptic S stinging, dry eyes, in patients with a history
rarely conjunctivitis; of syncope or bradycardia.
altered response to
hypoglycemia,
reduction of high-
Beta1-adrenergic levobunolol Q12H Local adverse effects Avoid in patients with $

Antagonists, 0.25%, 0.5% usually minimal — bronchial asthma; caution
ophthalmic Betagan, stinging, dry eyes, in patients with a history
generics rarely conjunctivitis; of syncope or bradycardia.
altered response to
hypoglycemia,
reduction of high-
Carbonic Anhydrase dorzolamide Q8–12H Bitter, sour or unusual Cross-reactivity in patients $$

Inhibitors, 2% taste, stinging, local allergic to sulfonamides.
ophthalmic Trusopt allergic reaction.
Page 304
Therapeutic Choice
a
Cost
Carbonic Anhydrase dorzolamide Q8–12H Bitter, sour or unusual Advantageous for patients $$
Inhibitors, 2% taste, stinging, local with allergies to
ophthalmic preservative- allergic reaction. benzalkonium chloride.
free Cross-reactivity in patients
Trusopt allergic to sulfonamides.
Carbonic Anhydrase brinzolamide Q12H Bitter, sour or unusual Cross-reactivity in patients $$

Inhibitors, 1% taste, stinging, local allergic to sulfonamides;
ophthalmic Azopt allergic reaction. dose can be increased to
Q8H after 4 wk if
inadequate response.
Prostaglandin latanoprost Once daily Foreign body Once-daily dosing should $$$
Analogues, 0.005% sensation, burning, not be exceeded; more
ophthalmic Xalatan stinging, itching, frequent administration
increased iris may reduce effectiveness.
pigmentation,
increased eyelash
length.
Prostaglandin travoprost Once daily Conjunctival Once-daily dosing should $$$

Analogues, 0.004% hyperemia, foreign not be exceeded; more
ophthalmic Travatan body sensation, frequent administration
burning, stinging, may reduce effectiveness.
itching, increased iris
pigmentation,
increased eyelash
length.
Prostaglandin bimatoprost Once daily Conjunctival Once-daily dosing should $$$$

Analogues, 0.01%, 0.03% hyperemia, foreign not be exceeded; more
ophthalmic Lumigan RC body sensation, frequent administration
(0.01%), burning, stinging, may reduce effectiveness.
Lumigan itching, increased iris
(0.03%) pigmentation,
increased eyelash
length.
Alpha2-Adrenergic apraclonidine Q8H Local allergic reaction, Contraindicated with MAO $$$
Agonists, ophthalmic 0.5%, 1% tachycardia, inhibitors. Can rarely be
Iopidine hypotension, headache, used chronically due to
tremor. more than 40% incidence
of marked
blepharoconjunctivitis.
Alpha2-Adrenergic brimonidine Q12H Local allergic reaction, Contraindicated with MAO $

Agonists, ophthalmic 0.2% tachycardia, inhibitors; not
Alphagan, hypotension, headache, recommended in pediatric
generics tremor. patients.
Lower incidence of allergy
than apraclonidine when
used chronically.
Alpha2-Adrenergic brimonidine Q12H Local allergic reaction, Contraindicated with MAO $$

Agonists, ophthalmic 0.15% tachycardia, inhibitors; not
Alphagan P hypotension, headache, recommended in pediatric
tremor. patients.
Lower incidence of allergy
than apraclonidine when
used chronically.
Contains purite as
preservative rather than
benzalkonium chloride;
Page 305
Therapeutic Choice
a
Cost
may have slightly lower
incidence of ocular allergy
than brimonidine 0.2%.
Cholinergic Agonists, pilocarpine 1%, Drops: QID Reduced vision in Poorly tolerated in Drops:
ophthalmic 2%, 4%, 6% Gel: QHS patients with cataracts, children and younger $
Isopto Carpine blurred vision due to adults. Gel:
drops, others; refractive shift, brow $$
Pilopine HS gel ache, GI upset (rare).
Cholinergic Agonists, carbachol Q8H Reduced vision in Poorly tolerated in $

ophthalmic Isopto patients with cataracts, children and younger
Carbachol blurred vision due to adults.
refractive shift, brow
ache, GI upset (rare).
Carbonic Anhydrase dorzolamide Q12H Bitter, sour or unusual Cross-reactivity in patients $$$
Inhibitor/Beta- 2%/timolol taste, stinging, local allergic to sulfonamides.
blocker 0.5% allergic reaction.
Combinations, Cosopt Local adverse effects
ophthalmic Carbonic usually minimal —
Anhydrase Inhibitors, stinging, dry eyes,
ophthalmic rarely conjunctivitis;
altered response to
hypoglycemia,
reduction of high-
Carbonic Anhydrase dorzolamide Q12H Bitter, sour or unusual Advantageous for patients $$$
Inhibitor/Beta- 2%/ timolol taste, stinging, local with allergies to
blocker 0.5%, allergic reaction. benzalkonium chloride.
Combinations, preservative- Local adverse effects Cross-reactivity in patients
ophthalmic free usually minimal — allergic to sulfonamides.
Preservative- stinging, dry eyes,
free Cosopt rarely conjunctivitis;
altered response to
hypoglycemia,
reduction of high-
Prostaglandin/Beta- latanoprost Once daily Foreign body Once-daily dosing should $$$$
blocker 0.005%/ sensation, burning, not be exceeded; more
Combinations, timolol 0.5% stinging, itching, frequent administration
ophthalmic Xalacom increased iris may reduce effectiveness.
pigmentation, Avoid in patients with
increased eyelash bronchial asthma; caution
length. in patients with a history
Local adverse effects of syncope or bradycardia.
usually minimal —
Page 306
Therapeutic Choice
Costa
stinging, dry eyes,
rarely conjunctivitis;
altered response to
hypoglycemia,
reduction of high-
Prostaglandin/Beta- travoprost Once daily Conjunctival Once-daily dosing should $$$$

blocker 0.004%/ hyperemia, foreign not be exceeded; more
Combinations, timolol 0.5% body sensation, frequent administration
ophthalmic DuoTrav burning, stinging, may reduce effectiveness.
itching, increased iris Avoid in patients with
pigmentation, bronchial asthma; caution
increased eyelash in patients with a history
length. of syncope or bradycardia.
Local adverse effects
usually minimal —
stinging, dry eyes,
altered response to
hypoglycemia,
reduction of high-
Alpha2-adrenergic brimonidine Q12H Local allergic reaction, Contraindicated with MAO $$

Agonist/Beta-blocker 0.2%/ tachycardia, inhibitors; not
Combinations, timolol 0.5% hypotension, headache, recommended in pediatric
ophthalmic Combigan tremor. patients.
Local adverse effects Lower incidence of allergy
usually minimal — than apraclonidine when
stinging, dry eyes, used chronically.
systemic effects can Avoid in patients with
include bronchospasm, bronchial asthma; caution
exacerbation of CHF, in patients with a history
bradycardia, syncope, of syncope or bradycardia.
altered response to
hypoglycemia,
reduction of high-
Carbonic Anhydrase acetazolamide 250 mg up Paresthesias of the Cross-reactivity in patients $$

Inhibitors, oral generics to QID extremities, metabolic allergic to sulfonamides.
acidosis, hypokalemia,
GI upset, urolithiasis,
lethargy and
depression, aplastic
anemia (rare), Stevens-
Page 307
Therapeutic Choice
Costa
Johnson syndrome
(rare).
Carbonic Anhydrase methazolamide Paresthesias of the Cross-reactivity in patients $$$$

Inhibitors, oral Apo- 50–100 mg extremities, metabolic allergic to sulfonamides.
BID-TID acidosis, hypokalemia,
Methazolamide
GI upset, urolithiasis,
lethargy and
depression, aplastic
anemia (rare), Stevens-
Johnson syndrome
(rare).
Side effects are less
severe than with
acetazolamide.
a.
Cost of smallest available pack size or 30-day supply for oral medications; includes drug cost only.
Legend: $ < $10 $$ $10–20 $$-$$$ $10–30 $$$ $20–30 $$-$$$$ $10– >30 $$$$ > $30
Suggested Readings
American Academy of Ophthalmology. Glaucoma Panel. Preferred practice pattern: primary angle closure. San
Francisco (CA): AAO; 2005.
American Academy of Ophthalmology. Glaucoma Panel. Preferred practice pattern: primary open-angle glaucoma.
San Francisco (CA): AAO; 2005.
American Academy of Ophthalmology. Glaucoma Panel. Preferred practice pattern: primary open-angle glaucoma
suspect. San Francisco (CA): AAO; 2005.
Morrison JC, Pollack IP, editors. Glaucoma: science and practice. New York (NY): Thieme; 2003.
Rafuse PE. Screening those at risk for glaucoma. Can J Diagn 1999;16:105-12.
References
1. Sommer A, Tielsch JM, Katz J et al. Relationship between intraocular pressure and primary open angle
glaucoma among white and black Americans. The Baltimore Eye Survey. Arch Ophthalmol 1991;109(8):1090-
5.
2. Drance SM. Bowman Lecture. Glaucoma--changing concepts. Eye 1992;6(Pt 4):337-45.
3. Fraunfelder FW, Fraunfelder FT, Keates EU. Topiramate-associated acute, bilateral, secondary angle-closure
glaucoma. Ophthalmology 2004;111(1):109-11.
4. Grodum K, Heijl A, Bengtsson B. A comparison of glaucoma patients identified through mass screening and in
routine clinical practice. Acta Ophthalmol Scand 2002;80(6):627-31.
5. Kass MA, Heuer DK, Higginbotham EJ et al. The Ocular Hypertension Treatment Study: a randomized trial
determines that topical ocular hypotensive medication delays or prevents the onset of primary open-angle
glaucoma. Arch Ophthalmol 2002;120(6):701-13.
6. Quigley HA, Vitale S. Models of open-angle glaucoma prevalence and incidence in the United States. Invest
Ophthalmol Vis Sci 1997;38(1):83-91.
Page 308
Therapeutic Choice
7. Tielsch JM, Sommer A, Katz J et al. Racial variations in the prevalence of primary open angle glaucoma. The
Baltimore Eye Survey. JAMA 1991;266(3):369-74.
8. Hitchings R. Normal-tension glaucoma. In: Yanoff M, Duker JS, editors. Ophthalmology. London (UK): Mosby;
1999. p.1-4.
9. Phelps CD, Corbett JJ. Migraine and low-tension glaucoma. A case-control study. Invest Ophthalmol Vis Sci
1985;26(8):1105-8.
10. Tielsch JM, Katz J, Sommer A et al. Hypertension, perfusion pressure, and primary open-angle glaucoma. A
population-based assessment. Arch Ophthalmol 1995;113(2):216-21.
11. Graham SL, Drance SM, Wijsman K et al. Ambulatory blood pressure monitoring in glaucoma. The nocturnal
dip. Ophthalmology 1995;102(1):61-9.
12. Passo MS, Goldberg L, Elliot DL et al. Exercise training reduces intraocular pressure among subjects suspected
of having glaucoma. Arch Ophthalmol 1991;109(8):1096-8.
13. [No authors listed]. Comparison of glaucomatous progression between untreated patients with normal-tension
glaucoma and patients with therapeutically reduced intraocular pressures. Collaborative Normal-Tension
Glaucoma Study Group. Am J Ophthalmol 1998;126(4):487-97.
14. Damji KF, Behki R, Wang L et al. Canadian perspectives in glaucoma management: setting target intraocular
pressure range. Can J Ophthalmol 2003;38(3):189-97.
15. Lesk MR, Lachaine J. Medical therapy of glaucoma: focus on newer agents. Ophthalmic Practice 2003;21(2):46
-52.
16. Rafuse PE. Adrenergic antagonists. In: Morrison JC, Pollack IP, editors. Glaucoma: science and practice. New
York (NY): Thieme; 2003.
17. Berry DP, Van Buskirk EM, Shields MB. Betaxolol and timolol. A comparison of efficacy and side effects. Arch
Ophthalmol 1984;102(1):42-5.
18. Goldberg I. Carbonic anhydrase inhibitors. In: Morrison JC, Pollack IP, editors. Glaucoma: science and
practice. New York (NY): Thieme; 2003.
19. Stewart R. Invest Ophthalmol Vis Sci 1997;38(Suppl):559.
20. Lawlor D et al. Prostaglandin analogs. In: Morrison JC, Pollack IP, editors. Glaucoma: science and practice.
New York (NY): Thieme; 2003.
21. Brubaker RF, Schoff EO, Nau CB et al. Effects of AGN 192024, a new ocular hypotensive agent, on aqueous
dynamics. Am J Ophthalmol 2001;131(1):19-24.
22. Johnstone MA. Hypertrichosis and increased pigmentation of eyelashes and adjacent hair in the region of the
ipsilateral eyelids of patients treated with unilateral topical latanoprost. Am J Ophthalmol 1997;124(4):544-7.
23. Butler P, Mannschreck M, Lin S et al. Clinical experience with the long-term use of 1% apraclonidine.
Incidence of allergic reactions. Arch Ophthalmol 1995;113(3):293-6.
24. Blondeau P, Rousseau JA. Allergic reactions to brimonidine in patients treated for glaucoma Can J Ophthalmol
2002;37(1):21-6.
25. Serle JB et al. Adrenergic agonists. In: Morrison JC, Pollack IP, editors. Glaucoma: science and practice. New
York (NY): Thieme; 2003.
26. Derick RJ. Cholinergic agonists. In: Morrison JC, Pollack IP, editors. Glaucoma: science and practice. New York
(NY): Thieme; 2003.
27. Strohmaier K, Snyder E, DuBiner H et al. The efficacy and safety of the dorzolamide-timolol combination
versus the concomitant administration of its components. Dorzolamide-Timolol Study Group. Ophthalmology
1998;105(10):1936-44.
28. Craven ER, Walters TR, Williams R et al. Brimonidine and timolol fixed-combination therapy versus
monotherapy: a 3-month randomized trial in patients with glaucoma or ocular hypertension. J Ocul Pharmacol
Ther 2005;21(4):337-48.
29. Higginbotham EJ, Feldman R, Stiles M et al. Latanoprost and timolol combination therapy vs monotherapy:
one-year randomized trial. Arch Ophthalmol 2002;120(7):915-22.
30. Schuman JS, Katz GJ, Lewis RA et al. Efficacy and safety of a fixed combination of travoprost 0.004%/timolol
0.5% ophthalmic solution once daily for open-angle glaucoma or ocular hypertension. Am J Ophthalmol
2005;140(2):242-50.
31. Stamper RL et al. Carbonic anhydrase inhibitors. In: Becker-Shaffer’s diagnosis and therapy of the glaucomas.
7th ed. St. Louis (MO): Mosby; 1999.
32. Zimmerman TJ, Kooner KS, Kandarakis AS et al. Improving the therapeutic index of topically applied ocular
drugs. Arch Ophthalmol 1984;102(4):551-3.
33. Abelson MB et al. Antiallergic therapies. In: Zimmerman TJ et al., editors. Textbook of ocular pharmacology.
Philadelphia (PA): Lippincott-Raven; 1997.
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Page 310
e-Therapeutics+ : Therapeutics : Eye Disorders: Red Eye Page 1 of 10
Therapeutic Choice
Print Close
Eye Disorders: Red Eye
Date Prepared: February 2007

Sueda Akkor, MD, FRCSC
Red eye is common in a wide variety of ocular conditions, some of which have serious consequences and require immediate
referral to an ophthalmologist.
Goals of Therapy
Preserve eyesight
Control infection
Control inflammation
Provide symptomatic relief
Investigations (Figure 1 - Management of Red Eye)
The first step is to differentiate the major/serious causes from the minor causes (Table 1). The presence of one or more warning
signs requires referral to an ophthalmologist (Table 2).
Table 1: Etiology of Red Eye
Cause Examples
Infection Conjunctivitis/keratitis (bacterial, viral, other), lacrimal system infection
Allergy
Dry eyes (keratoconjunctivitis sicca) Sjögren's syndrome, vitamin A deficiency, other
Blepharitis and secondary

conjunctivitis/keratitis
Toxic/chemical/other irritants Topical drugs, contact lens solutions, acids/alkalis, smoke, wind, UV light (e.g.,
tanning bed, welder's arc)
Traumatic injury Corneal abrasions, foreign bodies, hyphema (bleeding into the anterior chamber),
heat exposure, other
Ocular inflammation Iritis, episcleritis, scleritis
Glaucoma Acute angle-closure glaucoma
Other Pterygium, subconjunctival hemorrhage
Table 2: Warning Signs for Ophthalmologist Referral
Limbal/ciliary injection (redness dominant at the corneoscleral junction)

Pain not relieved by test dose of topical anesthetic drop (proparacaine, tetracaine)
Pupil abnormalities (miotic or mid-dilated and fixed)
Signs and symptoms of acute angle-closure glaucoma such as red painful eye with raised intraocular pressure, blurred
vision, headache, vomiting or coloured halos around lights
History of iritis/angle-closure glaucoma
Recent trauma to eye
Therapeutic Choices (Figure 1 - Management of Red Eye)
Instruct patient to:
Stop wearing contact lenses until the problem is resolved

Avoid makeup, smoke, wind and other irritants
Apply cold wet compresses for allergic or viral conjunctivitis
Apply hot wet compresses for blepharitis/styes
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Therapeutic Choice
Practise lid hygiene for blepharitis:
warm water compresses applied to closed eyelids for 5 to 10 minutes, followed by gentle scrubbing of lid margins with
warm water, a commercial eyelid scrub or a few drops of baby shampoo in a small amount of warm water
repeat daily at bedtime
Choice depends on underlying cause (see Table 3). Once the major/serious conditions are ruled out, treatment can be initiated.
In general, if no improvement is seen after one week, refer.
For symptomatic relief (decreased redness, edema) of allergic or viral conjunctivitis or minor eye irritation,
ophthalmic vasoconstrictors should be reserved for occasional and short-term use (e.g., ≤ 3–4 times per month
and ≤ 3 days in a row). Overuse may cause rebound hyperemia. Useful Info?
Therapeutic Tips
Most topically administered eye drops used in therapy are themselves capable of causing irritation or toxicity.
Corticosteroids or antibiotic/corticosteroid combinations may worsen herpetic/fungal keratitis and should not be used
indiscriminately.
Long-term use of topical corticosteroids may cause glaucoma and/or cataracts.
Topical decongestants/vasoconstrictors may provoke angle-closure glaucoma in those predisposed (see Eye Disorders:
Glaucoma).
Some patients may react to preservatives in artificial tears. In those who use drops more than four to five times daily and
who experience irritation, nonpreserved lubricants may be preferable.
Figure 1- Management of Red Eye
Page 312
Therapeutic Choice
a.
Corneal staining with fluorescein strip indicates corneal involvement.
b.
Used rarely to prevent secondary bacterial infection.
Table 3: Ophthalmic Medications for Red Eye
a
Class Drug Indications Dose Adverse Effects Cost
Vasoconstrictors/ naphazoline Alleviation of redness 1–2 drops Q3– Minor stinging on $

Decongestants, Albalon, Naphcon Forte, and/or eyelid edema in 4H PRN × instillation; pupillary
ophthalmic Refresh Redness Relief, allergic or viral 3–4 days dilation and angle-
generics conjunctivitis, minor closure glaucoma in
irritation (smoke, dust, predisposed persons,
wind, chlorinated e.g., elderly white or
pool). Asian females who are
significantly hyperopic,
Page 313
Therapeutic Choice
a
have a positive family
history and have not had
a therapeutic or
prophylactic iridectomy.
Ophthalmic
vasoconstrictors are
meant for occasional
and short-term use.
Overuse may cause
rebound hyperemia.
Vasoconstrictors/ oxymetazoline Alleviation of redness 1–2 drops Q6H Minor stinging on $

Decongestants, Claritin Eye Allergy and/or eyelid edema in PRN × instillation; pupillary
ophthalmic Relief, Visine Workplace allergic or viral 3–4 days dilation and angle-
conjunctivitis, minor closure glaucoma in
a therapeutic or
Ophthalmic
and short-term use.
Overuse may cause
rebound hyperemia.
Vasoconstrictors/ phenylephrine Alleviation of redness 1–2 drops QID Minor stinging on $

Decongestants, Mydfrin, generics and/or eyelid edema in PRN × instillation; pupillary
ophthalmic allergic or viral ≤ 3 days dilation and angle-
a therapeutic or
Ophthalmic
and short-term use.
Overuse may cause
rebound hyperemia.
Vasoconstrictors/ tetrahydrozoline Alleviation of redness 1–2 drops BID- Minor stinging on $

Decongestants, Visine, others and/or eyelid edema in QID instillation; pupillary
ophthalmic allergic or viral dilation and angle-
a therapeutic or
Ophthalmic
and short-term use.
Overuse may cause
rebound hyperemia.
Page 314
Therapeutic Choice
a
Antibacterials, besifloxacin Bacterial conjunctivitis. 1 drop in Antibacterials: Chronic $$

ophthalmic Besivance affected eye(s) use may cause corneal
TID for 7 days epithelial toxicity;
allergy.
Antibacterials, chloramphenicol Bacterial 1 drop, or 1 Antibacterials: Chronic $

ophthalmic Pentamycetin, generics conjunctivitis/keratitis; cm ointment use may cause corneal
blepharitis/styes; Q3H × 48 h, epithelial toxicity;
prophylactically in then frequency allergy.
corneal epithelial may decrease. Chloramphenicol:
disorders such as dry Controversial/theoretical
eyes, exposure, lid risk of blood dyscrasias
malpositions; choose with ophthalmic use of
broad-spectrum agent chloramphenicol; in
first, guided by patient patients at increased
allergies. risk, consider using
other broad-spectrum
ophthalmic
antibacterials such as
fusidic acid or
framycetin.
Antibacterials, ciprofloxacin Bacterial Drops: 1–2 Antibacterials: Chronic $

ophthalmic Ciloxan, generics conjunctivitis/keratitis; drops Q2H use may cause corneal
blepharitis/styes; while awake × epithelial toxicity;
prophylactically in 2 days then 2 allergy.
corneal epithelial drops Q4H
disorders such as dry while awake ×
eyes, exposure, lid 5 days
malpositions; choose Ointment: 1.25
broad-spectrum agent cm TID ×
first, guided by patient 2 days then
allergies. BID × 5 days
Fluoroquinolones
should be reserved for
serious infections such
as Pseudomonas.
Antibacterials, erythromycin Bacterial Ointment: 1.25 Antibacterials: Chronic $

ophthalmic generics conjunctivitis/keratitis; cm 2–6 use may cause corneal
blepharitis/styes; times/day epithelial toxicity;
prophylactically in allergy.
corneal epithelial
disorders such as dry
eyes, exposure, lid
malpositions; choose
broad-spectrum agent
first, guided by patient
allergies.
Antibacterials, framycetin Bacterial Drops: 1–2 Antibacterials: Chronic Drops: $

ophthalmic Soframycin conjunctivitis/keratitis; drops Q1–2H × use may cause corneal Ointment:
blepharitis/styes; 2–3 days then epithelial toxicity;
prophylactically in 1–2 drops TID- allergy. $$
corneal epithelial QID
disorders such as dry Ointment: 1.25
eyes, exposure, lid cm BID-TID, or
malpositions; choose at bedtime if
broad-spectrum agent drops used
first, guided by patient during the day
allergies.
Antibacterials, fusidic acid Bacterial 1 drop Q12H × Antibacterials: Chronic $

ophthalmic Fucithalmic conjunctivitis/keratitis; 7 days use may cause corneal
blepharitis/styes; epithelial toxicity;
corneal epithelial
eyes, exposure, lid
Page 315
Therapeutic Choice
a
allergies.
Due to its broad
spectrum and BID
dosing, fusidic acid is
especially useful in
children and elderly
patients.
Antibacterials, gatifloxacin Bacterial First 2 days: 1 Antibacterials: Chronic $$

ophthalmic Zymar conjunctivitis/keratitis; drop in use may cause corneal
blepharitis/styes; affected eye(s) epithelial toxicity;
prophylactically in Q2H while allergy.
corneal epithelial awake, up to 8
disorders such as dry times daily.
eyes, exposure, lid Days 3 to 7: 1
malpositions; choose drop QID
allergies.
Fluoroquinolones
as Pseudomonas.
Antibacterials, gentamicin Bacterial Drops: 1–2 Antibacterials: Chronic $

ophthalmic Garamycin Ophthalmic conjunctivitis/keratitis; drops Q2–4H use may cause corneal
blepharitis/styes; Ointment: 1.2 epithelial toxicity;
Drops/ Ointment,
prophylactically in cm BID-TID, or allergy.
generics
corneal epithelial up to Q3–4H
eyes, exposure, lid
allergies.
Antibacterials, moxifloxacin Bacterial 1 drop TID × 7 Antibacterials: Chronic $$

ophthalmic Vigamox conjunctivitis/keratitis; days use may cause corneal
corneal epithelial
eyes, exposure, lid
allergies.
Antibacterials, ofloxacin Bacterial 1–2 drops Q2– Antibacterials: Chronic $

ophthalmic Ocuflox, generics conjunctivitis/keratitis; 4H x 2 days use may cause corneal
blepharitis/styes; then QID × 5 epithelial toxicity;
prophylactically in days allergy.
corneal epithelial
eyes, exposure, lid
allergies.
Fluoroquinolones
as Pseudomonas.
Page 316
Therapeutic Choice
a
Antibacterials, polymyxin Bacterial Initially 1–3 Antibacterials: Chronic $

ophthalmic B/trimethoprim conjunctivitis/keratitis; drops Q1H, use may cause corneal
Polytrim, generics blepharitis/styes; gradually epithelial toxicity;
prophylactically in decreasing to 1 allergy.
corneal epithelial –2 drops 4–6
disorders such as dry times daily
eyes, exposure, lid
allergies.
Antibacterials, polymyxin B ± bacitracin Bacterial Drops: initially Antibacterials: Chronic $

ophthalmic ± gramicidin ± conjunctivitis/keratitis; 1–3 drops use may cause corneal
neomycin blepharitis/styes; Q1H, gradually epithelial toxicity;
Neosporin Eye and Ear prophylactically in decreasing to 1 allergy.
Solution, Polysporin corneal epithelial –2 drops 4–6
disorders such as dry times daily
Eye/Ear Drops,
eyes, exposure, lid Ointment:
Polysporin Ophthalmic malpositions; choose apply 2–5
Ointment, generics broad-spectrum agent times daily
allergies.
Antibacterials, sulfacetamide Bacterial 1–2 drops Q2– Antibacterials: Chronic $

ophthalmic Sodium Sulamyd conjunctivitis/keratitis; 3H use may cause corneal
corneal epithelial
eyes, exposure, lid
allergies.
Antibacterials, tobramycin Bacterial Drops: 1–2 Antibacterials: Chronic $

ophthalmic Tobrex, generics conjunctivitis/keratitis; drops Q4H use may cause corneal
blepharitis/styes; Ointment: 1.25 epithelial toxicity;
prophylactically in cm BID-TID allergy.
corneal epithelial
eyes, exposure, lid
allergies.
Antivirals, trifluridine Herpes simplex; not 1 drop Q2H Chronic use may cause $$$
ophthalmic Viroptic, generics for herpes zoster while awake, corneal epithelial
infections. maximum 9 toxicity.
drops per day,
until lesion re-
epithelialized,
then 1 drop
Q4H, maximum
5 drops per
day, × 7 days
Antivirals, systemic acyclovir Herpes zoster, herpes Herpes zoster: GI upset (uncommon); $$$$
Zovirax Oral, generics simplex. 800 mg po well tolerated.
5 times/day
× 7 days
Herpes
simplex:
200 mg po QID
× 2 wk
Antivirals, systemic famciclovir Herpes zoster, herpes Herpes zoster: GI upset (uncommon); $$$$
Famvir, generics simplex. 500 mg po TID well tolerated.
Page 317
Therapeutic Choice
a
× 7 days
Antivirals, systemic valacyclovir Herpes zoster, herpes Herpes zoster: GI upset (uncommon); $$$$
Valtrex, generics simplex. 1 g po TID × 7 well tolerated.
days
Antihistamines/Mast sodium cromoglycate Ocular allergies; 1–2 drops 4–6 Minor stinging on $
Cell Stabilizers, Opticrom, generics contact lens wear- times/day instillation.
ophthalmic related giant papillary
conjunctivitis (a
hypersensitivity
disorder seen in
patients with contact
lenses or artificial
eyes; family
practitioners may
suspect it in patients
complaining of itch
and ropy whitish
discharge, but
diagnosis requires slit
lamp exam by an
ophthalmologist).
Antihistamines/Mast emedastine Ocular allergies. 1 drop up to Minor stinging on $$

Cell Stabilizers, Emadine QID instillation.
ophthalmic
Antihistamines/Mast ketotifen fumarate Ocular allergies. 1 drop Q8–12H Minor stinging on $$$
Cell Stabilizers, Zaditor instillation.
ophthalmic
Antihistamines/Mast lodoxamide Ocular allergies. 1–2 drops QID Minor stinging on $$

Cell Stabilizers, Alomide instillation.
ophthalmic
Antihistamines/Mast levocabastine Ocular allergies. 1 drop QID for Minor stinging on $$$
Cell Stabilizers, Livostin up to 2 wk instillation.
ophthalmic
Antihistamines/Mast nedocromil Ocular allergies. 1–2 drops BID Minor stinging on $$$
Cell Stabilizers, Alocril instillation.
ophthalmic
Antihistamines/Mast olopatadine Ocular allergies. 1–2 drops Minor stinging on $$$

Cell Stabilizers, Patanol Q6–8H instillation.
ophthalmic
Antihistamines/Mast antazoline/naphazoline Ocular allergies. 1–2 drops Minor stinging on $

Cell Stabilizers, Albalon-A Liquifilm, Q3–4H instillation.
ophthalmic Refresh Eye Allergy
Relief, generics
Antihistamines/Mast pheniramine/naphazoline Ocular allergies. 1–2 drops up Minor stinging on $

Cell Stabilizers, Diopticon A , Naphcon- to QID instillation.
ophthalmic A, Opcon-A
Ocular Lubricants carboxymethylcellulose Dry eyes, exposure, lid 1–2 drops Preservative toxicity, $
Celluvisc, Refresh malpositions, TID-QID filmy vision.
Liquigel, Refresh Plus, blepharitis, minor
Refresh Tears irritations.
Ocular Lubricants dextran Dry eyes, exposure, lid 1–2 drops TID- Preservative toxicity, $
70 /hypromellose malpositions, QID filmy vision.
(hydroxypropyl blepharitis, minor
methylcellulose) irritations.
Bion Tears, Tears
Naturale, Tears Naturale
Free, Tears Naturale II
Ocular Lubricants hypromellose Dry eyes, exposure, lid 1–2 drops TID- Preservative toxicity, $
(hydroxypropyl malpositions, QID filmy vision.
methylcellulose) blepharitis, minor
Genteal, Isopto Tears irritations.
Page 318
Therapeutic Choice
a
Ocular Lubricants polysorbate Dry eyes, exposure, lid 1–2 drops Preservative toxicity, $
Dioptears, Tears Encore malpositions, TID-QID filmy vision.
blepharitis, minor
irritations.
Ocular Lubricants polyvinyl alcohol Dry eyes, exposure, lid 1–2 drops Preservative toxicity, $
Hypotears Ophthalmic malpositions, TID-QID filmy vision.
Solution, Refresh, blepharitis, minor
generics irritations.
Ocular Lubricants mineral oil/petrolatum Dry eyes, exposure, lid Ointment: Preservative toxicity, $
Duolube, Hypotears Eye malpositions, 0.6 cm to filmy vision.
Ointment, Lacri-Lube blepharitis, minor inside of lower
S.O.P., generics irritations. lid as needed
Ocular Lubricants propylene Dry eyes, exposure, lid 1–2 drops as Preservative toxicity, $
glycol/polyethylene malpositions, needed filmy vision.
glycol-400 blepharitis, minor
Systane irritations.
Ocular Lubricants sodium hyaluronate Dry eyes, exposure, lid With Preservative toxicity, $
Eyestil malpositions, preservative: 1 filmy vision.
blepharitis, minor drop up to
irritations. QID;
preservative-
free drops can
be used more
frequently as
needed
Corticosteroids, dexamethasone Episcleritis, iritis, Drops: 2 drops Minor stinging on $

ophthalmic Maxidex, generics scleritis, some Q1H during the instillation; may worsen
keratitis, ocular day and Q2H herpetic/fungal keratitis;
allergy. during the long-term use may
night; cause glaucoma,
gradually ↓ to cataracts.
Q3–4H then to
TID-QID
Ointment:
small amount
to conjunctival
sac TID-QID
Corticosteroids, fluorometholone Episcleritis, iritis, 1–2 drops Minor stinging on $

ophthalmic FML, FML Forte, Flarex, scleritis, some BID-QID; may instillation; may worsen
generics keratitis, ocular be used more herpetic/fungal keratitis;
allergy. frequently long-term use may
during initial cause glaucoma,
48 h if needed cataracts.
Corticosteroids, loteprednol 0.2% Seasonal allergic 1 drop in Minor stinging on $$$

ophthalmic Alrex conjunctivitis. affected eye(s) instillation; may worsen
QID for up to herpetic/fungal keratitis;
14 days long-term use may
cause glaucoma,
cataracts.
Corticosteroids, prednisolone Episcleritis, iritis, 1–2 drops Q1H Minor stinging on $$

ophthalmic Pred Mild/Forte, scleritis, some during the day instillation; may worsen
generics keratitis, ocular and Q2H at herpetic/fungal keratitis;
allergy. night until long-term use may
favourable cause glaucoma,
response, then cataracts.
1 drop Q4H
Corticosteroids, rimexolone Inflammation following Postoperative Minor stinging on $$

ophthalmic Vexol ocular surgery; inflammation: instillation; may worsen
anterior uveitis. 1–2 drops QID herpetic/fungal keratitis;
× 2 wk, long-term use may
beginning
Page 319
Therapeutic Choice
a
24 h post-op cause glaucoma,
Uveitis: cataracts.
1–2 drops Q1H
while awake ×
1 wk, then
Q2H while
awake × 1 wk,
then QID ×
1 wk, then TID
× 4 days, then
BID × 3 days
NSAIDs, ophthalmic diclofenac Episcleritis, minor 1 drop Minor stinging on $$

Voltaren Ophtha corneal abrasions; as 4–5 times daily instillation.
an adjunct to topical
corticosteroids in
scleritis, iritis.
NSAIDs, ophthalmic ketorolac Episcleritis, minor 1 drop QID Minor stinging on $

Acular, generics corneal abrasions; as instillation.
an adjunct to topical
corticosteroids in
scleritis, iritis.
a.
Cost of smallest available pack size or 7-day supply of oral medications; includes drug cost only.
Legend: $ < $10 $$ $10–20 $$$ $20–30 $$$$ > $30
Suggested Readings
Abnormal eye appearances. In: Frith P. The eye in clinical practice. 2nd ed. Oxford (UK): Blackwell Science; 2001. p. 57-84.
Canadian Ophthalmological Society. Self-directed learning modules. Assessment of the red eye. Available from:
http://www.eyesite.ca/7modules/Module2/html/Mod2_TOC.html Accessed Jan 16, 2007.
Chern, Kenneth C, editor. Emergency ophthalmology : a rapid treatment guide. New York (NY): McGraw-Hill; 2002. p. 85-128.
Maclean, Hunter. The eye in primary care : a symptom-based approach. Oxford (UK): Butterworth-Heinemann; 2002. p. 96-114.
Trobe, Jonathan D; American Academy of Family Physicians. The physician's guide to eye care. 2nd ed. San Francisco (CA):
American Academy of Ophthalmology; 2001. p. 41-67.
Page 320
e-Therapeutics+ : Therapeutics : Fluid and Electrolyte Disorders: Dehydration in Children Page 1 of 7
Therapeutic Choice
Print Close
Fluid and Electrolyte Disorders: Dehydration in Children
Gary I. Joubert, MD, FRCPC
Goals of Therapy
Treat shock/impending shock

Treat dehydration using an appropriate fluid and route
Treat electrolyte imbalances
Prevent complications (seizures or edema)
Fluids in Infants and Children
Newborn and young children have a much higher water content than adolescents and adults (Table 1) and are more
+ +
prone to both water and salt (sodium [Na ] and potassium [K ]) loss during illness.
Table 1: Age vs Percentage of Body Water
Age % Body Water
Newborn 75–80
Child ≤ 1 y 70–75
Child 1–12 y 60–70
Adolescent/adult 55–60
Investigations

underlying cause(s): vomiting and/or diarrhea or other excessive fluid loss
frequency and amount of loss
frequency and amount of urinary output
Physical examination including a full set of vital signs to assess clinical manifestations and degree of
1
dehydration
Laboratory tests: electrolytes, BUN, creatinine, glucose, serum bicarbonate (HCO3), blood gases and urinalysis
as indicated clinically
The assessment of dehydration in infants and children is challenging (Table 2). This difficulty is related to a child's
ability to maintain adequate blood pressure in the face of moderate to severe dehydration.
Table 2: Estimation of Dehydration
Extent of
Dehydration Mild Moderate Severe
Weight loss– 5% 10% 15%

Infants
(under 1 y)
Weight loss– 3–4% 6–8% 10%

Children
(over 1 y)
History decreased intake decreased intake very decreased intake
decreased urine output marked decreased urine anuria

output
Page 321
Therapeutic Choice
Extent of
Dehydration Mild Moderate Severe
normal activity listless, weight loss obtunded
inquire about frequency inquire about frequency of inquire about frequency of vomiting
of vomiting and vomiting and diarrhea and diarrhea
diarrhea longer duration of illness
Pulse normal slightly increased rapid
Blood pressure normal normal to orthostatic, orthostatic to shock

> 10 mm Hg change
Behaviour normal irritable hyperirritable to lethargic
Thirst slight moderate intense
Mucous normal dry parched

a
membranes
Tears present decreased absent, sunken eyes
Anterior normal normal to sunken sunken

fontanelle
External jugular visible when supine not visible except with not visible even with supraclavicular
vein supraclavicular pressure pressure
Skin a capillary refill < 2 sec slowed capillary refill (2–4 significant delayed capillary refill
(less useful in sec), decreased turgor (> 4 sec) and tenting; skin cool,
children > 2 y) acrocyanotic or mottleda
Urine specific > 1.020 > 1.020, oliguria oliguria or anuria

gravity
(SG)
Lab values normal BUN/creatinine increased BUN/creatinine +++

increased BUN/creatinine,
increased Hgb, low glucose
a.
These signs are less prominent in patients who have hypernatremia.
Therapeutic Choices
Treatment of dehydration involves replacing fluid deficits, then maintaining normal hydration.
Shock must be treated aggressively using isotonic saline (0.9% NaCl).
The calculation of the fluid deficit for a given degree of dehydration can be based on historical or objective
information (e.g., predehydrational and present dehydrated weight). When the predehydrational weight is known:
Deficit litres (L) = predehydrational weight (kg) – present weight (kg).
Predehydrational body weight can be estimated by:
Body weight (kg) = 3(age) + 7. This gives an estimated weight at or about the 50th percentile for age and can be
2
used for children up to 10 years of age.
Maintenance fluid (Table 4) is the amount of fluid required to maintain normal hydration. Maintenance fluids are
linked to caloric requirements and take into account insensible losses.
Dehydration is classified into three types depending on serum Na+ concentration (Table 3).
Table 3: Types of Dehydration
Page 322
Therapeutic Choice
+
Type of Dehydration Serum Na Serum Osmolality
(frequency) (mmol/L) (mOsm/kg)
Isonatremic (80%) 130–150 Normal: 280–295 mOsm/kg

Equal water and salt loss
Hypernatremic (15%) > 150 Elevated: 295 mOsm/kg

Water loss > salt loss
Hyponatremic (5%) < 130 ↓ or normal or ↑ serum osmolality

Must determine subgroup (see text)
Isonatremic dehydration (Figure 1 - Management of Isonatremic Dehydration) is the most common form of
dehydration, with loss of both K+ and Na+. K+ can be added to the iv mixture following establishment of urinary
output. K+ administration should not exceed 4 mmol/kg/day.3 Higher K+ concentrations can be used in life-
threatening hypokalemia.
Hypernatremic dehydration usually develops slowly and is corrected slowly to prevent cerebral edema and seizures.
Shock is treated aggressively by administering iv 0.9% NaCl until urinary output is re-established, then 0.45% NaCl
+
+ D5W is used to correct dehydration states and restore Na to normal levels.
+
The goal of therapy is to reduce serum Na by 10 to 15 mmol/L/day and to restore hydration to normal in no less
than 48 hours. If the serum concentration drops rapidly (i.e., > 10 to 15 mmol/day or > 1 mmol every two hours),
change the iv solution to 0.9% NaCl + D5W.
Hyponatremic dehydration is classified into three subgroups:
excessive water
Na+ depletion
fictitious lowering of serum Na+ concentration due to increased glucose, electrolytes, lipids and proteins
+ +
Symptomatic hyponatremia is usually related to the degree of serum Na depletion. Children with serum Na > 120
+
mmol/L rarely demonstrate any clinical manifestations. When serum Na drops below 120 mmol/L, neurologic
manifestations (e.g., seizures) are common. Children who are symptomatic require aggressive replacement using
+
hypertonic saline (3% NaCl) to achieve a serum Na > 125 mmol/L.
+
Serum Na deficit can be calculated as follows:
[Na+] deficit = ([Na+] desired – [Na+] actual) × body weight (kg) × total body water (L/kg)
After initial elevation of Na+ to > 125 mmol/L, the remaining deficit can be replaced over 24 to 48 hours.
Remember that children who are dehydrated and continue to have ongoing fluid losses need to have those fluid
losses replaced. Those replacements need to be considered in addition to their estimated deficit plus maintenance
fluids. The replacement of ongoing fluid losses usually occurs in a ratio of 1 mL of replacement to each 1 mL of
4
fluid lost. Fluid loss replacement is in excess of the usual sensible and insensible losses (i.e., secondary to high
urinary output in a diabetic, nasogastric losses, or excessive ongoing vomiting and/or diarrhea). Adjust fluid for
electrolyte losses as well.5
Table 4: Maintenance Fluid and Electrolyte Requirements in Children
Weight
(kg) Daily Fluid Requirement Hourly Rate Daily Electrolytes
0–10 100 mL/kg 4 mL/kg Na+: 2.5–3 mmol/ 100 mL

fluid/day
11–20 1000 mL + (50 mL/kg × each kg 40 mL/h + (2 mL/kg × each kg
> 10) > 10)
Page 323
Therapeutic Choice
Weight
(kg) Daily Fluid Requirement Hourly Rate Daily Electrolytes
> 20 1500 mL + (20 mL/kg × each kg 60 mL/h + (1 mL/kg × each kg

> 20) > 20)
Table 5: Calculation of Maintenance Fluid Requirements
Using information from Table 4:

Example: For a 15 kg child use information for 11–20 kg.
Fluids Daily Fluid Rate Hourly Fluid Rate

(quick calculation)
For the first 10 10 kg × 100 mL/kg = 1000 mL 10 kg × 4 mL/kg = 40 mL

kg
For the next 5 5 kg × 50 mL/kg = 250 mL 5 kg × 2 mL/kg = 10 mL

kg
Total 1250 mL or 52 mL/h Total 50 mL/h
Electrolytes: Na+ K+
1250 mL × 3 mmol/100 mL = 37.5 mmol 1250 mL × 2 mmol/100 mL = 25 mmol

( 37.5 mmol/1250 mL or 30 mmol/L) (25 mmol/1250 mL or 20 mmol/L)
Suggested commercially available solution best meeting the needs would be 0.2% NaCl/D5W + 20 mmol KCl/L.
Table 6: Calculation of Fluid Deficit and Replacement for Isonatremic Dehydration
Example: For a 15 kg child who has 10% isonatremic dehydration

Fluids: Total fluid replacement equals deficit replacement plus maintenance. Fluid deficit in 10% dehydration is
100 mL/kg; in 5% dehydration 50 mL/kg
(i) Deficit replacement calculation = 15 kg × 10% (100 mL/kg) or 1500 mL

Need to replace 50% or 750 mL over first 8 h at a rate of 94 mL/h
(ii) Maintenance = 52 mL/h (using calculation from Table 5)
(iii) Total = 146 mL/h (94 mL/h + 52 mL/h) for first 8 h, then reduce to 100 mL/h for next 16 h (replace
remaining deficit of 750 mL + maintenance over 16 h [47 mL/h + 52 mL/h ≈ 100 mL/h])
+ +
Electrolytes: Na loss would be approximately 120 mmol (8–10 mmol/kg/day) and K loss would be
approximately 120 mmol (8–10 mmol/kg/day).a
a.
Using a rehydration solution of 0.45% NaCl + D5W at the above rate will replace 115 mmol of Na+. K+ 40 mmol/L (not to
exceed 4 mmol/kg/day) will replace 60 mmol of total loss. Replacement of K+ will make up losses over the next 2 days.
Oral Rehydration Therapy (ORT)
Oral rehydration is the treatment of choice in children with mild to moderate dehydration. It can be
used in all types of dehydration provided that hypo- and hypernatremic dehydration are not at the
extremes of the spectrum.
The fluid deficit is calculated and the rate of replacement is based upon the degree of dehydration.
In the child who is mildly to moderately dehydrated, the rate of replacement is 50 mL/kg over the first
4 hours; for the child who is moderately to severely dehydrated, the rate of replacement is 100 mL/kg
over the first 4 hours. The rehydration phase may last from 4 to 12 hours depending upon the degree
Page 324
Therapeutic Choice
of dehydration as well as the ability of the child to tolerate oral rehydration. After the first 4 hours,
replace the remainder of the deficit over the next 6 to 8 hours.
Useful Info?
+
The fluid should be a balanced electrolyte solution acceptable to the gastrointestinal tract and should facilitate Na
transport. Ideal solutions for ORT contain Na+ 45 to 75 mmol/L, K+ 20 mmol/L and glucose 20 to 24 g/L; 100 to
150 mL/kg/day is given to the child. Remember in infants less than six months of age, after the oral rehydration
6
phase is completed, restart the child on breast milk or half-strength formula.
Table 7: Oral Replacement Solutions
Product Composition Costa
Dextrose K+ Na+
g/L mmol/L mmol/L
Cl– mmol/L
17.8 20 60 60 $
Gastrolyte
25 20 45 35 $$
Pedialyte
20 20 45 35 $$
Pediatric Electrolyte
a.
Cost per litre; includes drug cost only
Legend: $ < $5 $$ $5–10

Commercially available preparations (Table 7) may be used to rehydrate the child with observation in an
ambulatory/emergency room setting or at home.
Children who have been started on iv replacement therapy can be switched to ORT at any point. It is important to
ensure that no contraindications (shock or impending shock, high diarrheal purge rates, intractable vomiting, altered
sensorium) are present.
Another option in the child failing ORT secondary to vomiting is to place an NG tube and use the fluid regimen per
hour as described above.
Therapeutic Tips
Absolute indications for admission to hospital are:

shock
hypo/hypernatremia
intractable vomiting/diarrhea
Possible indications for admission to hospital are:
serum HCO3 < 15 mmol/L at onset of therapy
poor response to ORT and ongoing requirement for iv therapy
Clinical signs of dehydration are often not present until at least 5% of a child’s body weight is lost.
Serum electrolytes should be measured before, at the time of and after starting iv fluids.
Figure 1-Management of Isonatremic Dehydration
Page 325
Therapeutic Choice
a.
Replacement therapy after bolus should contain 50–60 mmol/L Na+ plus a source of glucose (e.g., D5W) plus appropriate K+.
An ideal solution is 0.33% NaCl (Na+ 51.3 mmol/L) + D3.3W (3.3 g glucose/100 mL) + appropriate K+. K+ should not exceed 4
+
mmol/kg/day and replenishment should be done gradually over 2 days. No urine output, no K .
Abbreviations: BP = blood pressure; NS = normal saline, 0.9% NaCl; ORT = oral replacement therapy; RL = Ringer's lactate
Suggested Readings
Boineau FG, Lewy JE. Estimation of parenteral fluid requirements. Pediatr Clin North Am 1990;37(2):257-64.
Kallen RJ. The management of diarrheal dehydration in infants using parenteral fluids. Pediatr Clin North Am
1990;37(2):265-86.
Rice HE, Caty MG, Glick PL. Fluid therapy for the pediatric surgical patient. Pediatr Clin North Am 1998;45(4):719-
27.
Steiner MJ, DeWalt DA, Byerley JS. Is this child dehydrated? JAMA 2004;291(22):2746-54.
References
1. Cairns J. Paediatr Child Health 2001;6(2):69.

2. Luscombe M, Owens B. Weight estimation in resuscitation: is the current formula still valid? Arch Dis
Childhood 2007;92:412–415.
3. Kallen RJ. The management of diarrheal dehydration in infants using parenteral fluids. Pediatr Clin North Am
1990;37(2):265-86.
4. Rice HE, Caty MG, Glick PL. Fluid therapy for the pediatric surgical patient. Pediatr Clin North Am 1998;45
(4):719-27.
Page 326
Therapeutic Choice
5. Boineau FG, Lewy JE. Estimation of parenteral fluid requirements. Pediatr Clin North Am 1990;37(2):257-64.
6. Casteel HB, Fiedorek SC. Oral rehydration therapy. Pediatr Clin North Am 1990;37(2):295-311.
Page 327
e-Therapeutics+ : Therapeutics : Fluid and Electrolyte Disorders: Edema Page 1 of 12
Therapeutic Choice
Print Close
Fluid and Electrolyte Disorders: Edema
Tammy M. Keough-Ryan, MD, MSc, FRCPC
Edema is a sign of an underlying disorder that should be identified and treated prior to initiation of therapy. It results
from altered sodium homeostasis that leads to increased extracellular fluid volume (ECFV). Therapy must be
individualized.
Peripheral edema is swelling in a dependent area that is palpable on physical examination. Anasarca is gross,
generalized edema.
Common conditions that are associated with edema include heart failure (HF), liver failure including hepatic cirrhosis
and renal failure including nephrotic syndrome. The main focus of this chapter is peripheral edema. For edema
associated with specific conditions, see Cardiovascular Disorders: Heart Failure and Gastrointestinal Disorders:
Chronic Liver Diseases.
Goals of Therapy
Decrease fluid overload

Manage diuretic resistance
Investigations
History:
conditions associated with pitting edema:
general conditions: renal dysfunction, HF, liver dysfunction, pregnancy
localized conditions: lymphatic or venous obstruction, infection
salt intake
drugs that may cause or exacerbate edema, e.g., NSAIDs, calcium channel blockers, corticosteroids,
thiazolidinediones or drugs that may interact with diuretic agents
Physical exam:
generalized edema
localized edema:
pitting or nonpitting – nonpitting edema, consider lymphatic obstruction or myxedema
symmetric or asymmetric – asymmetric edema, consider lymphedema from lymphatic obstruction, deep
vein thrombosis (DVT) or infection
location of edema:
legs if ambulatory
sacrum if recumbent
weight, blood pressure, heart rate, respiratory rate
signs of fluid overload: jugular venous distention, pulmonary edema, ascites
+ + - - ++ ++
electrolytes (including Na , K , Cl , HCO3 , Ca , Mg ), uric acid, urea, creatinine
urinalysis
liver function tests
chest x-ray
other: TSH, glucose and lipids, albumin, 24-hour urine collection to quantify proteinuria and sodium if
symptoms/signs are suggestive of primary renal disorder
Therapeutic Choices (Figure 1 - Management of Edema)
Sodium: decrease sodium intake to <100 mmol/day (2.4 g Na+ or 6 g NaCl).1 , 2

2
Fluid: decrease fluid intake to 1 L/day.
Posture: supine position improves cardiac output; elevate legs.
Stockings: consider supportive compression stockings.
Paracentesis for ascites under direction of a specialist.
Ultrafiltration therapy: if renal insufficiency is significant, consider referral to a specialist for this therapy.
Page 328
Therapeutic Choice
Consider if nonpharmacologic actions do not significantly reduce the symptoms related to edema and treatment of
underlying disorder has been implemented.
Diuretic Therapy (Table 1)
Peripheral edema, in the absence of respiratory/cardiac effect, is not life threatening and fluid removal must be slow.
3
The maximum recommended rate of weight loss is 1 kg/day. Diuretics are not effective if lymphatic or venous
drainage obstruction is the underlying problem. Diuretics should not be prescribed in pregnancy (see Choices during
Pregnancy and Breastfeeding).
Diuretics decrease sodium reabsorption at various sites in the nephron by interfering with carrier proteins or
channels. Diuretics increase sodium and water losses; this decreases ECFV and improves the edema. Closely monitor
+ - ++ ++ -
for electrolyte imbalances (K , Cl , Ca , Mg , HCO3 ) and prerenal azotemia (urea, creatinine) to avoid significant
alterations.
Loop Diuretics
The loop diuretics, furosemide, ethacrynic acid, bumetanide and torsemide (not available in Canada) are potent
diuretic agents that act in the loop of Henle in the nephron. The onset and duration of action are short. Loop diuretics
are particularly useful in the presence of moderate to severe renal insufficiency (ClCr ≤50 mL/min). If there is no
response with the maximum dose, switching to an alternate loop diuretic will not be effective.
Bumetanide and torsemide have no clear advantages over furosemide despite differing sites of metabolism and more
predictable bioavailability. Ethacrynic acid is reserved for use in patients with sulfa allergy that contraindicates the
4 ,
use of the other loop diuretics. There are reports of ototoxicity with all the loop diuretics including ethacrynic acid.
5 , 6
Potassium-sparing Diuretics
Spironolactone and eplerenone are aldosterone receptor antagonists. Spironolactone is the first-line agent in
3
hepatic disease because of the secondary hyperaldosteronism that leads to sodium and water retention.
Spironolactone can also be effective adjunctive therapy for edema of NYHA Class III or IV HF (see Cardiovascular
Disorders: Heart Failure) associated with high aldosterone levels. Eplerenone is more selective for aldosterone which
may limit the side effect of gynecomastia, but it has not been as well studied as spironolactone in heart failure or in
7
combination regimes.
Amiloride and triamterene are other effective potassium-sparing diuretics that act independently of aldosterone in
the collecting duct. They are useful in combination therapy with loop diuretics in resistant edema or if hypokalemia
complicates the initial diuretic therapy used.
Thiazides
Thiazide diuretics are useful first-line agents if the creatinine clearance is >50 mL/min.3,8 Thiazides
work in the distal convoluted tube of the nephron and have a longer duration of action than the loop
diuretics. They are effective antihypertensive agents and are useful adjuncts to loop diuretic therapy for
resistant edema. Hyponatremia, as a complication of diuretic therapy, is more common with thiazide
diuretics.2 Alternate thiazides have no advantage over hydrochlorothiazide.1 Useful Info?
Management of Resistant Edema
Sodium restriction
+
emphasize adherence to ≤100 mmol/day (2.4 g Na or 6 g NaCl)
check 24-hour urine sodium to assess compliance
Fluid restriction (especially with hyponatremia)
2
emphasize adherence to ≤1 L/day
Page 329
Therapeutic Choice
Bed rest
supine position and leg elevation can increase glomerular filtration rate by 40%1
Ensure adherence to prescribed diuretic regime
Dosing of furosemide
increase the dose incrementally until diuresis is achieved by doubling the dose every 2–3 days
secretion of the diuretic into the tubular lumen of the nephron can be impaired in severe hypoalbuminemia
or decreased renal perfusion states such as renal failure or HF, resulting in ineffective diuresis with initial
doses
if unable to maintain an acceptable duration of effective diuresis, increase the frequency of dosing to 2–3
times per day
1
double the dose if switching from intravenous dose to oral dose
consider intravenous dosing if the gastrointestinal tract is edematous or in decreased cardiac output states
8
that can lead to impaired absorption of oral drug
9
consider continuous intravenous infusion
monitor clinical status carefully, including weight, to ensure daily weight loss does not exceed 1 kg
monitor for electrolyte disturbances and prerenal azotemia
Combination Diuretic Therapy
A thiazide added to a loop diuretic blocks a second distal site of sodium reabsorption to improve diuresis. If
the thiazide is given orally with intravenous furosemide, administer 30–60 minutes prior to the loop diuretic. If
both diuretics are taken orally, administer at the same time.
Potassium-sparing agents can be added to further block sodium reabsorption, particularly if the patient is
hypokalemic. As life-threatening hyperkalemia can result, exercise caution and monitor electrolytes frequently if
the patient has renal failure, diabetes mellitus or is taking any of the following medications: ACE inhibitors,
angiotensin receptor blockers, beta-blockers, cyclosporine, NSAIDs, pentamidine, tacrolimus or trimethoprim.
Spironolactone is an effective adjunctive agent in the presence of neurohumoral activation, e.g., hepatic
disease, HF or nephrotic syndrome.
Carbonic anhydrase inhibitors such as acetazolamide may occasionally be added on the advice of a
specialist if diuresis is ineffective using a combination of other diuretic agents or if diuresis is complicated by
metabolic alkalosis.
If all above measures fail, a specialist may consider other options such as ultrafiltration in renal failure or
paracentesis in cirrhosis.
Idiopathic Edema
This condition occurs most often in postpubertal, young to middle-aged, obese females. It is a diagnosis of exclusion
when physical exam and laboratory investigations fail to define an underlying cause (cardiac, hepatic or renal) for
edema. In 80% of cases, the edema is orthostatic, that is, the edema develops in the standing position and is more
evident at the end of the day. The edema usually presents in the lower extremities but can also present in the face,
hands and breasts, particularly in the morning. This can be demonstrated by weight gains of 0.7–1 kg/day from
10
morning to evening weight. An altered homeostatic response to an upright position promotes the retention of
sodium and water.
Consider nonpharmacologic measures such as restriction of sodium and fluid intake, recumbent position,
avoidance of prolonged periods of standing and use of supportive compression stockings.
Consider discontinuation of diuretic therapy.
Reassess fluid-restricted diet if rebound edema persists when diuretics are stopped. Sodium retention due to
neurohormonal adaptation may persist for 1–3 weeks before spontaneous induction of diuresis.
Consider intermittent daily diuretic use only when nonpharmacologic measures fail.
Future Directions
Antidiuretic hormone receptor antagonists (e.g., tolvaptan [not available in Canada]) and natriuretic peptides (e.g.,
10 , 11
nesiritide) may have future roles in management of edema.
Patients who are pregnant should be referred to a specialist. Diuretics are usually not recommended so as to avoid
intravascular contraction and potential negative effects on placental perfusion. For breastfeeding mothers,
hydrochlorothiazide and spironolactone can be used since their excretion in breast milk is very low and no
adverse effects have been documented in babies. However, intense diuresis should be avoided as, in theory, diuretics
may compromise milk production by depleting intravascular volume.
Page 330
Therapeutic Choice
Therapeutic Tips
Investigate unilateral edema for venous obstruction or infection.

Refer pregnant or lactating patients to a specialist.
Monitor electrolytes and renal function closely when initiating diuretic therapy, increasing the dose, using
combination therapy and/or the patient is clinically unwell.
Avoid prescribing potassium-sparing agents for patients with renal failure as these agents may cause life-
threatening hyperkalemia.
Avoid using combination products as dosing is more difficult to titrate or decrease if changes in volume status
occur.
Identify overdiuresis in patients by monitoring for clinical signs of weakness, hypotension and/or laboratory
evidence of prerenal azotemia, hypokalemia and/or metabolic alkalosis. Consider holding diuretics,
antihypertensives and/or gentle hydration and referral of these patients to a specialist.
Page 331
Therapeutic Choice
Figure 1-Management of Edema
1 , 2 , 4 , 8 , 13 , 14 , 15 , 16 , 17
Table 1: Diuretic Agents for Treatment of Edema
a
Adverse Drug Cost
Loop bumetanide Individualize Volume Aminoglycosides, Diuresis within 30 $-$$$

Diuretics Burinex dose according depletion. cisplatin: ↑ –60 min following
to patient Electrolyte ototoxicity. oral
response disturbances: Thiazide diuretics: administration.
hypochloremia, ↑ diuresis and
Page 332
Therapeutic Choice
a
Adverse Drug Cost
0.5–2 mg po as a hypokalemia electrolyte Monitor
single dose; (evident during abnormalities; monitor electrolytes, BUN,
maximum daily first 1–2 wk), for dehydration and creatinine and
dose 10 mg hyponatremia, electrolyte daily weight.
hyperuricemia abnormalities when
If diuretic (usually used in Bumetanide 1 mg
response is not asymptomatic). combination. produces a
adequate with 1 diuretic response
mg, a 2nd and Azotemia, Digoxin: similar to
3rd dose may be increase in hypokalemia and furosemide 40 mg
given at a 4–5 h serum hypomagnesemia in healthy
interval creatinine. may lead to patients; in renal
arrhythmias failure,
May dose BID. Hyperglycemia. bumetanide 2 mg
Evening dose Lithium: reduced produces a
appears to have Dizziness, renal clearance of diuretic response
a greater diuretic hypotension. lithium resulting in similar to
effect than lithium toxicity; furosemide 40
morning dose Acute monitor lithium mg.
interstitial levels and adjust
Maintenance: nephritis. dose as needed. Caution in
lowest effective patients with sulfa
daily dose Ototoxicity. NSAIDs: ↑ risk of allergy.
renal failure
Impaired hepatic Myalgias development Contraindications:
function: use (common with secondary to ↓ renal hepatic coma,
minimum high doses of blood flow resulting states of severe
effective dose; bumetanide). from prostaglandin electrolyte
maximum daily inhibition; monitor depletion.
dose 5 mg Allergy (sulfa). for ↓ diuretic and
natriuretic response.
Loop ethacrynic acid Individualize Volume Aminoglycosides, May be $$$

Diuretics Edecrin dose according depletion. cisplatin: ↑ considered in
to patient Electrolyte ototoxicity. individuals with
response disturbances: Thiazide diuretics: sulfonamide
Initial: 50 mg as hypochloremia, ↑ diuresis and hypersensitivity or
single dose after hypokalemia electrolyte in cases of
a meal (evident during abnormalities; severe, refractory
first 1–2 wk), monitor for edema.
Titrate up hyponatremia, dehydration and Onset of diuresis:
gradually in hyperuricemia electrolyte po 30 min; iv 5
increments of (usually abnormalities when min.
25–50 mg daily asymptomatic). used in
until desired combination. Duration of
response; may Azotemia, action: po 6–8 h;
require up to 200 increase in Digoxin: iv 2 h.
mg BID in serum hypokalemia and
severe, refractory creatinine. hypomagnesemia Monitor
cases of edema may lead to electrolytes, BUN,
Hyperglycemia. arrhythmias creatinine and
Maintenance: daily weight.
lowest effective Dizziness, Lithium: reduced
daily dose hypotension. renal clearance of Similar in potency
lithium resulting in to furosemide.
When adding to Acute lithium toxicity;
another diuretic, interstitial monitor lithium IV route used
start low (i.e., 25 nephritis. levels and adjust when oral intake
mg daily) and dose as needed. is not viable or in
titrate up as Ototoxicity. urgent situations
necessary NSAIDs: ↑ risk of such as
Myalgias renal failure pulmonary
(common with development edema.
Page 333
Therapeutic Choice
a
Adverse Drug Cost
high doses of secondary to ↓ renal
bumetanide). blood flow resulting
from prostaglandin
Allergy (sulfa). inhibition; monitor
for ↓ diuretic and
May be natriuretic response.
associated with
severe
ototoxicity.
Can be used in
sulfa-allergic
patients.
Loop furosemide Individualize Volume Aminoglycosides, Half-life: 1.5–2 h $–$$

Diuretics Lasix, Lasix dose according depletion. cisplatin: ↑ and prolonged in
to patient Electrolyte ototoxicity. kidney
Special, generics
response disturbances: Thiazide diuretics: insufficiency.
Initial: 20–80 mg hypochloremia, ↑ diuresis and
po as a single hypokalemia electrolyte Extent and rate of
dose preferably (evident during abnormalities; monitor absorption varies
in a.m. If desired first 1–2 wk), for dehydration and between patients
response has not hyponatremia, electrolyte depending on
been achieved, ↑ hyperuricemia abnormalities when concomitant
by 20–40 mg Q6– (usually used in disease states.
8H; maximum asymptomatic). combination.
single dose Effectiveness
dependent on Azotemia, Digoxin: diminishes in the
disease state and increase in hypokalemia and presence of gut
renal function; ↑ serum hypomagnesemia wall edema.
dose if initial dose creatinine. may lead to
fails to produce arrhythmias Onset of diuresis:
adequate increase Hyperglycemia. po 30–60 min; iv
in urinary output Lithium: reduced 5 min.
within 4–6 h of Dizziness, renal clearance of
dose hypotension. lithium resulting in Duration of
lithium toxicity; action: po 4–8 h,
IV dose: 20–40 Acute monitor lithium iv 2 h.
mg as a single interstitial levels and adjust
injection, may nephritis. dose as needed. Monitor
repeat Q2H. If no electrolytes, BUN,
response, may ↑ Ototoxicity. NSAIDs: ↑ risk of creatinine and
dose in 20 mg renal failure daily weight.
increments Myalgias development
(common with secondary to ↓ renal Furosemide 500
Continuous high doses of blood flow resulting mg tablet: for
infusion: 3–20 bumetanide). from prostaglandin patients with GFR
mg/h titrated to inhibition; monitor 5–20 mL/min who
patient’s Allergy (sulfa). for ↓ diuretic and have not
response natriuretic response. responded to
conventional
Maintenance: doses.
lowest effective
dose taken daily, May use in
BID or combination with
intermittently on thiazides for
alternate days synergy.
Severe edema: Caution in

can use 250–500 patients with sulfa
mg tablet po allergy.
under direction
of a specialist
Page 334
Therapeutic Choice
a
Adverse Drug Cost
Thiazide chlorthalidone Individualize Usually well Loop diuretics: ↑ Half-life: 24–55 $

Diuretics generics dose according tolerated. diuresis and h.
to patient Orthostatic electrolyte
response hypotension. abnormalities; Onset: 2–6 h,
50–100 mg once monitor for persists for 24–72
daily; can be Electrolyte dehydration and h.
given every other abnormalities: electrolyte
day hyperuricemia abnormalities when Contraindications:
(usually used in severe renal or
Maintain on asymptomatic), combination. hepatic failure,
lowest effective hyponatremia Digoxin: hypercalcemia,
dose (common), hypokalemia and refractory
hypochloremia, hypomagnesemia hypokalemia or
Ineffective as hypokalemia may lead to hyponatremia,
monotherapy in (evident during arrhythmias. symptomatic
patients with first 1–2 wk). hyperuricemia.
GFR <50 mL/min Antidiabetic
Headache, medications:
When adding to vertigo, thiazides may ↑
another diuretic, dizziness, blood sugar—seen at
start low and asthenia, higher doses.
titrate up as muscle cramps. Monitor blood
necessary glucose and adjust
Volume dose of antidiabetic
depletion. medications as
necessary.
Acute
interstitial Lithium: ↓ renal
nephritis. clearance of lithium
resulting in toxicity;
Thiazides can monitor lithium
exacerbate levels and adjust
gout. dose as needed.
NSAIDs: may
negate the diuretic
effect and ↑ risk of
NSAID-induced
renal dysfunction.
Thiazide hydrochlorothiazide Individualize Usually well Loop diuretics: ↑ Half-life: 2.5 h, $

Diuretics dose according tolerated. diuresis and prolonged in renal
Apo-Hydro, to patient Orthostatic electrolyte insufficiency.
other generics response hypotension. abnormalities; monitor Onset: 2 h with
Initial: 25–100 for dehydration and duration of 6–12
mg daily or Electrolyte electrolyte h.
divided BID or abnormalities: abnormalities when
TID hyperuricemia used in Used in
(usually combination. combination with
Can also be asymptomatic), Digoxin: furosemide for
given on hyponatremia hypokalemia and synergistic effect.
alternate days (common), hypomagnesemia
hypochloremia, may lead to
Ineffective as hypokalemia arrhythmias.
monotherapy in (evident during
patients with first 1–2 wk). Antidiabetic
GFR <50 mL/min medications:
Headache, thiazides may ↑
When adding to a vertigo, blood sugar—seen
loop diuretic, dizziness, at higher doses.
Page 335
Therapeutic Choice
a
Adverse Drug Cost
start low and asthenia, Monitor blood
titrate up as muscle cramps. glucose and adjust
necessary dose of antidiabetic
Volume medications as
depletion. necessary.
Acute Lithium: ↓ renal

interstitial clearance of
nephritis. lithium resulting in
toxicity; monitor
Thiazides can lithium levels and
exacerbate adjust dose as
gout. needed.
↑ fasting blood NSAIDs: may

glucose may be negate the diuretic
dose-related as effect and ↑ risk of
not seen with NSAID-induced
doses renal dysfunction.
<12.5 mg.
Thiazide indapamide Individualize Usually wellLoop diuretics: ↑ Half-life: 15–25 $

Diuretics Lozide, generics dose according tolerated. diuresis and h. Take with food
to patient Orthostatic electrolyte or milk to
response hypotension.abnormalities; decrease GI side
Initial: 2.5 mg monitor for effects.
once daily; may Electrolyte dehydration and Monitor
↑ to 5 mg daily if
abnormalities: electrolyte electrolytes in
no response hyperuricemia abnormalities when patients who may
within 1 wk (usually used in be at increased
asymptomatic), combination. risk of
When adding to a hyponatremia Digoxin: hypokalemia,
loop diuretic, (common), hypokalemia and e.g., patients on
start low and hypochloremia, hypomagnesemia digoxin, patients
titrate up as hypokalemia may lead to with cardiac
necessary (evident during arrhythmias. arrhythmias.
first 1–2 wk).
Ineffective as Antidiabetic Contraindications:
monotherapy in Headache, medications: progressive and
patients with vertigo, thiazides may ↑ severe oliguria,
GFR <50 mL/min dizziness, blood sugar—seen at hepatic coma.
asthenia, higher doses.
muscle cramps. Monitor blood
glucose and adjust
necessary.
Acute
NSAIDs: may
negate the diuretic
NSAID-induced
renal dysfunction.
Page 336
Therapeutic Choice
Adverse Drug Costa

Thiazide metolazone Individualize Usually well

Loop diuretics: ↑ Diuresis and $-$$
Diuretics Zaroxolyn dose according tolerated.diuresis and saluresis begin
to patient Orthostatic
electrolyte within 1 h and
response hypotension.
abnormalities; persist for 12–24
Single daily dose monitor for h, depending on
is recommended;Electrolyte dehydration and dose.
start low and abnormalities: electrolyte May be given for
titrate up hyperuricemia abnormalities when a limited time
(usually used in period initially.
2.5–20 mg Q24H asymptomatic), combination.
hyponatremia Digoxin: May be given
Ineffective as (common), hypokalemia and indefinitely to
monotherapy in hypochloremia, hypomagnesemia patients who
patients with hypokalemia may lead to remain volume-
GFR <50 mL/min (evident during arrhythmias. expanded, based
first 1–2 wk). on target weight.
Antidiabetic
Headache, medications: Contraindications:
vertigo, thiazides may ↑ hepatic coma,
dizziness, blood sugar—seen at sulfa allergy.
asthenia, higher doses.
muscle cramps. Monitor blood
glucose and adjust
necessary.
Acute
NSAIDs: may
negate the diuretic
NSAID-induced
renal dysfunction.
Potassium amiloride Individualize Hyperkalemia— ACEI and ARBs: ↑ Contraindications: $–$$

-sparing dose according common if + significant renal
Apo-Amiloride, K levels; monitor
Diuretics other generics to patient used as renal function and function
response monotherapy; potassium levels impairment,
Initial: 5 mg incidence when used in hyperkalemia.
daily; ↑ to 10 mg greater in combination,
daily if necessary patients with especially in
renal patients with renal
If persistent impairment, impairment and
hypokalemia is elderly and in type 2 diabetes
present, may ↑ to diabetes. mellitus; adjust
15 mg, then 20 mg Headache, dose as needed.
daily with careful impotence. Potassium
monitoring of
preparations: ↑ K+;
electrolytes Hyponatremia,
avoid combination
hypochloremia
unless documented
ClCr 10–50 when used in
hypokalemia;
mL/min: combination
administer 50% with other monitor K+ levels.
of normal dose diuretics.
Tacrolimus,
+
cyclosporine: ↑ K
levels.
Page 337
Therapeutic Choice
Adverse Drug Costa

NSAIDs: may
negate the diuretic
NSAID-induced
renal dysfunction.
Potassium spironolactone Individualize Hyperkalemia— ACEI and ARBs: ↑ Contraindications: $

-sparing dose according common if + significant renal
Aldactone, K levels; monitor
Diuretics generics to patient used as renal function and function
response; 25– monotherapy; potassium levels impairment,
200 mg daily incidence when used in hyperkalemia.
↑ 25–50 mg Q 5 greater in combination,
days patients with especially in
renal patients with renal
Continue initial impairment, impairment and
dose for ≥5 elderly and in type 2 diabetes
days, then titrate diabetes. mellitus; adjust
accordingly Headache, dose as needed.
impotence. Potassium
If adequate
preparations: ↑ K+;
diuresis has not Hyponatremia,
avoid combination
occurred, add a hypochloremia
unless documented
2nd diuretic when used in
hypokalemia;
which acts combination
proximally in with other monitor K+ levels.
nephron for diuretics.
additive effects Tacrolimus,
+
Gynecomastia. cyclosporine: ↑ K
ClCr 10–50 levels.
mL/min:
administer Q12– NSAIDs: may
24H negate the diuretic
ClCr <10 NSAID-induced
mL/min: avoid renal dysfunction.
Digoxin: ↑ plasma
levels due to ↓ renal
tubular secretion;
spironolactone may
interfere with digoxin
radioimmunoassay,
resulting in falsely
↑ digoxin levels.
Salicylates: may
result in sodium
retention; monitor
sodium levels and
blood pressure.
Mitotane:
antagonism of
mitotane activity;
avoid combination.
a.
Page 338
Therapeutic Choice
Abbreviations: ACEI=ACE inhibitor; ARB=angiotensin receptor blocker; GFR=glomerular filtration rate; NSAID=nonsteroidal
anti-inflammatory drug
Legend: $ < $20 $-$$ < $20–40 $$ $20-40 $-$$$ < $20– > 40 $$$ > $40
Suggested Readings
Andreoli TE. Edematous states: an overview. Kidney Int Suppl 1997;59:S2-10.
Brater DC. Diuretic therapy. N Engl J Med 1998;339(6):387-95.
Brater DC. Pharmacology of diuretics. Am J Med Sci 2000;319(1):38-50.
Morrison RT. Edema and principles of diuretic use. Med Clin North Am 1997;81(3):689-704.
O'Brien JG, Chennubhotla SA, Chennubhotla RV. Treatment of edema. Am Fam Physician 2005;71(11):2111-7.
Streeten DH. Idiopathic edema. Pathogenesis, clinical features, and treatment. Endocrinol Metab Clin North Am
1995;24(3):531-47.
Wilcox CS. Metabolic and adverse effects of diuretics. Semin Nephrol 1999;19(6):557-68.
References
1. Rose BD. Diuretics. Kidney Int 1991;39(2):336-52.

2. Wilcox CS. Metabolic and adverse effects of diuretics. Semin Nephrol 1999;19(6):557-68.
3. Rasool A, Palevsky PM. Treatment of edematous disorders with diuretics. Am J Med Sci 2000;319(1):25-37.
4. Greenberg A. Diuretic complications. Am J Med Sci 2000;319(1):10-24.
5. Ellison DH. Diuretic resistance: physiology and therapeutics. Semin Nephrol 1999;19(6):581-97.
6. Wang DJ, Gottlieb SS. Diuretics: still the mainstay of treatment. Crit Care Med 2008;36(1 Suppl):S89-94.
7. Sica DA. Edema mechanisms in the patient with heart failure and treatment options.Heart Fail Clin 2008;4
(4):511-8.
8. Brater DC. Diuretic therapy. N Engl J Med 1998;339(6):387-95.
9. Salvador DR, Rey NR, Ramos GC et al. Continuous infusion versus bolus injection of loop diuretics in
congestive heart failure. Cochrane Database Syst Rev 2005;(3):CD003178.
10. Streeten DH. Idiopathic edema. Pathogenesis, clinical features, and treatment. Endocrinol Metab Clin North Am
1995;24(3):531-47.
11. Goebel JA, Van Bakel AB. Rational use of diuretics in acute decompensated heart failure. Curr Heart Fail Rep
2008;5(3):153-62.
12. Gines P, Cardenas A. The management of ascites and hyponatremia in cirrhosis. Semin Liver Dis 2008;28(1):43
-58.
13. Bleich M, Greger R. Mechanism of action of diuretics. Kidney Int Suppl 1997;59:S11-5.
14. Brater DC. Pharmacology of diuretics. Am J Med Sci 2000;319(1):38-50.
15. Andreucci M, Russo D, Fuiano G et al. Diuretics in renal failure. Miner Electrolyte Metab 1999;25(1-2):32-8.
16. Capasso G, Pica A, Saviano C et al. Clinical complications of diuretic therapy. Kidney Int Suppl 1997;59:S16-
20.
17. Dormans TP, Gerlag PG, Russel FG et al. Combination diuretic therapy in severe congestive heart failure. Drugs
1998;55(2):165-72.
Page 339
e-Therapeutics+ : Therapeutics : Fluid and Electrolyte Disorders: Hypercalcemia Page 1 of 10
Therapeutic Choice
Print Close
Fluid and Electrolyte Disorders: Hypercalcemia

Walter Watral, BScPharm, PharmD
Goals of Therapy
Normalize serum calcium levels

correct extracellular fluid (ECF) volume contraction and dehydration
enhance renal excretion of calcium
inhibit accelerated bone resorption
Alleviate signs and symptoms of hypercalcemia, e.g., depressed level of consciousness, thirst, polyuria
Diagnose and treat underlying disorder
Investigations
Initiating treatment immediately will not interfere with diagnostic tests (see Pharmacologic Choices: General
Measures)
History and physical examination,1 , 2 with special attention to:
onset and duration of symptoms (anorexia, nausea, vomiting, constipation, altered mental status, malaise,
drowsiness, bone pain and muscle weakness are usually symptoms associated with acute hypercalcemia)
chronic hypercalcemia is usually asymptomatic
Laboratory evaluation:2 , 3
serum ionized calcium (preferred where available) or serum calcium and albumin (see Table 1 to calculate
calcium corrected for low albumin)
serum intact parathyroid hormone (PTH) level
24-hour urine creatinine and calcium (if familial hypocalciuric hypercalcemia or milk-alkali syndrome is
suspected), serum phosphate, alkaline phosphatase, total protein, serum creatinine and BUN
If hypercalcemia is acute or chronic and PTH is high, consider hyperparathyroidism.
If hypercalcemia is acute and PTH is low, consider malignancy. Perform a more complete clinical evaluation.
If hypercalcemia is chronic and PTH is low, consider granulomatous diseases, familial disorders, milk-alkali
syndrome, drug-induced (e.g., lithium, thiazide diuretics, excess vitamin A or D, derivatives and analogues of
vitamin A, estrogens, antiestrogens, progestins, androgens, parenteral nutrition, ingestion of > 3 g elemental
calcium per day), adrenal insufficiency or hyperthyroidism.
Specialists may order other tests (e.g., skeletal survey, bone scan) based on history or physical findings of
hypercalcemia-associated conditions, as required. Consider referral to endocrinologist for a complete endocrine
assessment to evaluate the possibility of multiple endocrine neoplasia (MEN) syndrome.
Therapeutic Choices (Figure 1 - Management of Hypercalcemia)
Aggressiveness of initial interventions depends on the rapidity of onset and severity of the hypercalcemia.
Definitive therapy for long-term control of hypercalcemia requires diagnosis and treatment of the underlying
condition.
Table 1: Serum Calcium Correction (mmol/L) for Low Serum Albumina
Albumin Albumin
(g/L) (g/L)
Correction (add to measured Ca++) Correction (add to measured Ca++)
10 0.6 23 0.34
11 0.58 24 0.32
12 0.56 25 0.3
13 0.54 26 0.28
Page 340
Therapeutic Choice
Albumin Albumin
(g/L) (g/L)
Correction (add to measured Ca++) Correction (add to measured Ca++)
14 0.52 27 0.26
15 0.5 28 0.24
16 0.48 29 0.22
17 0.46 30 0.2
18 0.44 31 0.18
19 0.42 32 0.16
20 0.4 33 0.14
21 0.38 34 0.12
22 0.36 35 0.1
a. Corrected Ca++ value = (40 – measured albumin) (0.02) + measured Ca++.
Mobilize2 , 3 , 4
Hypercalcemia is exacerbated by immobilization. Ambulation helps to reduce bone resorption and normalize serum
calcium.
Diet2 , 3 , 4
Dietary changes rarely correct hypercalcemia. Patients with sarcoidosis and other granulomatous causes of
hypercalcemia or those who have vitamin D-mediated hypercalcemia may benefit from dietary calcium restriction.
Excessive use of vitamin D supplements, calcium supplements or calcium-containing antacids should be curtailed in
all patients.
Hemodialysis2 , 4 , 5
If available and able to be instituted promptly, hemodialysis (zero or low calcium bath) provides rapid correction of
severe hypercalcemia. It is of particular value in those with severe hypercalcemia and severe renal impairment or
heart failure who could not safely tolerate hydration.
General Measures
Stop Offending Agents
If possible, discontinue offending agents (see Investigations) and replace with agents that do not exacerbate
hypercalcemia.
Hydrate
Patients with hypercalcemia are often dehydrated as a result of a renal water-concentrating defect induced by
hypercalcemia and by decreased fluid intake resulting from nausea and vomiting. Expansion of intravascular volume
enhances renal calcium clearance. Hydration alone usually reduces serum calcium by ≤ 0.6 mmol/L. This effect is
present only during hydration.2 , 3 , 4 Serum magnesium and potassium may also decrease and should be monitored
Page 341
Therapeutic Choice
and replaced as needed.
Patients with mild to moderate asymptomatic hypercalcemia should drink 3 L per day of noncaffeinated beverages to
achieve and maintain euvolemia. Patients with moderate to severe symptomatic hypercalcemia should receive
normal saline (0.9% NaCl) intravenously, typically at 250–500 mL/hour, if safe to do so, until euvolemic, and then
the infusion rate should be reduced to maintain normal intravascular volume. Volume correction may require 2–3 L
of fluid within the first 8 hours. Patients with a significant volume deficit may need 3–5 L of fluid in the first 24
hours and 2–3 L per 24 hours thereafter until a good urine output (≥ 0.5–1 mL/kg/hour) has been established.5 , 6 ,
7 , 8 , 9 Renal dysfunction is common among hypercalcemic patients. Careful monitoring of hydration is essential,
especially in elderly patients and those with pre-existing renal insufficiency or left ventricular systolic dysfunction as
fluid overload can develop. Refer to Figure 1 - Management of Hypercalcemia for further information on the
management of mild, moderate and severe hypercalcemia.
Use a loop diuretic (i.e., furosemide, ethacrynic acid) to treat fluid overload and heart failure, as needed, but
only after volume contraction is corrected. Thiazide diuretics are contraindicated because they impair calcium
excretion.10 , 11
Normalize Serum Phosphate
Hypophosphatemia, seen mostly in primary hyperparathyroidism and malignancy-associated hypercalcemia,

exacerbates hypercalcemia by increasing renal synthesis of 1,25-dihydroxyvitamin D, which consequently reduces
bone formation, increases bone resorption and increases intestinal absorption of dietary calcium. Oral phosphates
(1–2 g elemental phosphate per day) can be given safely in all patients, except those with renal insufficiency, to
increase serum phosphate to the low normal range (0.8–1 mmol/L). Though rare, calcium phosphate can precipitate
and cause serious organ damage (heart, kidney, lungs, blood vessels) if phosphate levels are increased to
> 1 mmol/L or if iv phosphate is administered.2
Specific Measures (Table 2)
Primary Hyperparathyroidism (PH)
Surgery remains arguably the first-line measure for control of PH in all patients.1 , 6 , 9 , 12 , 13 , 14 Medical
management is used for patients who refuse surgery, who are not candidates for surgery or who have had an
unsuccessful parathyroid surgery.3 Oral phosphate therapy can also be used if the dose is titrated to normalize
serum calcium, and appropriate monitoring is provided.8 , 9 Bisphosphonate therapy is usually reserved for
patients with moderate to severe hypercalcemia or those who exhibit osteopenia.13
Cinacalcet is the first calcimimetic approved for the reduction of hypercalcemia in patients with parathyroid
carcinoma and for the reduction of clinically significant hypercalcemia in patients with PH for whom
parathyroidectomy is not clinically appropriate or is contraindicated.16 , 17 Cinacalcet is also indicated for treatment
of secondary hyperparathyroidism in patients with chronic kidney disease on dialysis.
Malignancy
Antineoplastic therapy aimed at the underlying malignancy is the key to long-term calcium control, although not
all patients are candidates. Bisphosphonates are first-line drugs if effective antineoplastic therapy is not available
or appropriate, if the patient has severe hypercalcemia ( > 3.5 mmol/L with or without symptoms) or if the patient
has multiple myeloma. For acute management, parenteral pamidronate, clodronate or zoledronic acid may be
used.18 , 19 Two hour iv infusion of pamidronate and clodronate is convenient for outpatient therapy (Table 2).
Additionally, clodronate can be administered by a subcutaneous infusion, useful in the palliative setting.20
Zoledronic acid can be infused over 15 minutes in most patients.21 Response to treatment with an iv
bisphosphonate is generally seen within 24–48 hours so they are usually given in conjunction with saline or
calcitonin. For patients who respond, serum calcium levels can be maintained at acceptable levels for up to 5 weeks
before re-treatment is required.19 , 22 , 23 Patients with multiple myeloma benefit from reduced bone pain,
decreased skeletal morbidity and prevention of hypercalcemia recurrence with prolonged therapy.18 There is
insufficient information about the use of other bisphosphonates (e.g., alendronate, risedronate) for serum calcium
control.24 Calcitonin rapidly reduces serum calcium levels in severe hypercalcemia, however, the response tends to
abate within 48 hours20.
Page 342
Therapeutic Choice
Granulomatous Diseases
Excess production of 1,25-dihydroxyvitamin D is characteristic of granulomatous diseases (e.g., sarcoidosis).

Therapy includes restricting vitamin D and calcium intake and avoiding excessive exposure to sunlight.
Corticosteroids may be used in acutely ill patients.8 , 13
Therapeutic Tips
Overly aggressive use of loop diuretics can aggravate hypercalcemia by depleting extracellular fluid
volume. Routine prescription of a loop diuretic with hydration therapy is
discouraged.25 Useful Info?
To reduce serum calcium rapidly, i.e., within 6–12 hours in severe hypercalcemia of malignancy, use calcitonin
plus hydration. Serum calcium usually declines 0.8 mmol/L at 12–24 hours following combined therapy. To
augment and prolong serum calcium control, use definitive therapy, e.g., antineoplastic therapy, for the
underlying cause. If antineoplastic therapy is not an option, use a bisphosphonate when dehydration is
corrected and adequate urine output is achieved—preferably within 24 hours of hypercalcemia diagnosis.
Premedication with acetaminophen 650 mg can prevent bisphosphonate-induced fever in patients with
hypercalcemia of malignancy.
Adjunctive glucocorticoid therapy, e.g., prednisone 40–100 mg/day or equivalent for up to 1 week, is useful in
patients with lymphoma, myeloma, lymphoid leukemia and breast cancer in situations where hypercalcemic
flares are caused by hormonal treatment.
Figure 1- Management of Hypercalcemia
Page 343
Therapeutic Choice
Table 2: Treatment of Hypercalcemia
Antiparathyroid calcitonin Initial: 4 IU/kg Q12H sc Nausea, vomiting Used for rapid $55/
Hormone salmon or im (dose dependent), early effect, i.e., 400 IU
Calcimar, If unsatisfactory response flushing of face and within 6 h. vial
Caltine, after 1–2 days, may ↑ to hands. Duration: 1–4
generics 8 IU/kg Q12H. May ↑ to a Hypersensitivity days.
maximum of 8 IU/kg Q6H reaction.
Generally use for a
short term.
Tachyphylaxis
develops in 2–7
days; combining
with
glucocorticoids
may ↑ efficacy and
↓ tachyphylaxis.
Use with
bisphosphonate
lowers serum
calcium levels
more rapidly than
with either agent
alone.
Perform skin test

to rule out
systemic
sensitivity; if
marked erythema
and/or wheal
formation does not
occur within 15
min after
administration,
therapy can begin.
Bisphosphonates clodronate, Treatment: Establish Mild infusion site Onset: 2 days; $65/
IV and maintain adequate toxicity, vomiting. maximal effect: 6 300 mg
hydration Osteonecrosis of the days. vial
Bonefos
Single infusion: 1500 mg jaw. (See Comments.) Duration of
iv over 4 h diluted in 500 normocalcemia:
mL of NS or D5W variable, 2–3 wk in
hypercalcemia of
Multiple infusion: 300 mg malignancy.
iv over 2–6 h diluted in
500 mL of NS or D5W Fatal acute renal
failure reported
Do not dilute with Ca++- from infusion < 2
containing solutions or h.
give as bolus injections
Monitor renal
Maintenance: 1600– function (serum
2400 mg po given once creatinine and/or
daily or BID (2 h AC or 2 BUN), evaluate
h PC) within 1 wk after
infusion and just
Maximum daily dose is prior to next
3200 mg. Ensure scheduled dose.
adequate fluid
Page 344
Therapeutic Choice
rehydration Osteonecrosis of
the jaw: regular
dental exam,
especially prior to
therapy or within 3
mo if possible, as
well as good oral
hygiene.
Bisphosphonates clodronate, Maintenance: 1600– Nausea, vomiting, Concomitant intake $1.25/

oral 2400 mg po given once anorexia, diarrhea, of oral iron, 400 mg
daily or BID (2 h AC or 2 muscle cramps. calcium, capsule
Bonefos,
h PC) magnesium,
Clasteon Maximum daily dose is aluminum, e.g.,
3200 mg. Ensure antacids, may
adequate fluid prevent absorption
rehydration of oral clodronate.
Do not take with
or within 1 h
before or after
food or milk.
Reintroduce iv
clodronate if
elevated serum
calcium present
during oral
clodronate
treatment.
Bisphosphonates pamidronate Tumor-induced Local infusion site Onset: 4–72 h; ↓ $275/

hypercalcemia: reactions, febrile in calcium levels 90 mg
Aredia, Adequate hydration with reaction within seen in 24–48 h; vial
generics normal saline necessary 24–48 h of infusion— maximum lowering
before treatment may be accompanied occurs in 3–7
30–90 mg depending on by malaise, rigor, days.
serum Ca++ fatigue and flushes.26 Duration: 3–4 wk.
Rare: posterior
Consult product uveitis.27 Repeat infusion if
monograph for details calcium level does
Osteonecrosis of the not ↓ within 2 days
Not to exceed 90 mg in jaw. (See Comments.) or if hypercalcemia
250 mL administered recurs.
over 2–4 h
Monitor renal
Total dose can be given function (serum
as a single infusion or creatinine and/or
multiple infusions spread BUN), evaluate
over 2–4 consecutive within 1 wk after
days infusion and just
prior to next
Do not dilute with Ca++- scheduled dose.
containing solutions or
give as bolus injections Case reports of
safe and effective
use, without
dosage
modification, in
patients on
hemodialysis.
Page 345
Therapeutic Choice
Osteonecrosis of
the jaw: regular
dental exam,
especially prior to
therapy or within 3
mo if possible, as
well as good oral
hygiene.
Bisphosphonates zoledronic acid Tumor-induced Febrile reactions, Onset: 24–48 h. $580/

hypercalcemia: nausea, vomiting, flu- Duration: 4–5 wk. 4 mg
Aclasta, Establish and maintain like syndrome, local vial
adequate hydration infusion site Monitor renal
Zometa
4 mg in patients with reactions, mild function, evaluate
Concentrate albumin-corrected serum hypomagnesemia, within 1 wk after
calcium ≥ 3.0 mmol/L hypokalemia and infusion and just
given as a single dose iv hypophosphatemia.26 prior to next
infusion over 15 min19 Osteonecrosis of the scheduled dose.
jaw. (See Comments.)
Retreatment: 8 mg as a More potent than
single dose over 15 min. pamidronate.
In patients demonstrating
complete or partial Renal function
response without deterioration
normalization of Ca++ reported with
levels. Only for patients infusion < 15 min.
who can tolerate standard
rehydration procedures ( Osteonecrosis of
3–5 L fluids and > 400 the jaw: regular
mEq of NaCl per day) dental exam,
especially prior to
therapy or within 3
Do not dilute with Ca++-
mo if possible, as
containing solutions or
well as good oral
give as bolus injections
hygiene.
Corticosteroids, hydrocortisone 200–300 mg iv daily for Slow onset. $5/

systemic sodium 3–5 days Potential for 500 mg
diabetes mellitus, vial
succinate
osteoporosis, ↑
Solu-Cortef, susceptibility to
generics infection.
Corticosteroids, prednisone 40–60 mg daily for 5–10 Slow onset. $3 for

systemic generics days Potential for 100
diabetes mellitus, tabs of
osteoporosis, ↑ 5 mg
susceptibility to
infection.
Calcimimetics cinacalcet Dialysis Patients: Nausea, vomiting, Inhibits CYP2D6; $20/

Sensipar diarrhea, myalgia, dose adjustments 60 mg
Initial: 30 mg once daily; hypocalcemia. may be required tablet
titrate every 2–4 wk to a for concomitant
maximum dose of 180 CYP2D6-
mg once daily to achieve metabolized drugs
Page 346
Therapeutic Choice
a target parathyroid with narrow

hormone (PTH) level therapeutic index,
Primary e.g., TCAs,
Hyperparathyroidism: flecainide.
↑ the sensitivity of
Initial: 30 mg twice the calcium-
daily; titrate every 2–4 sensing receptor to
wk to 60 mg, then 90 mg circulating serum
twice daily to reduce calcium, thereby ↓
serum calcium levels the secretion of
Moderate to severe PTH.
hepatic impairment ↑
drug concentrations by Onset: PTH level ↓
approximately 2- to 4- within 2–6 h after
fold; dosage modification a dose.
may be required
Food ↑
bioavailability.
Monitor serum
calcium, serum
phosphate and
PTH.
Crystalloids sodium Initial: 200–300 mL/h Onset: 24–48 h. $7/

chloride 0.9% Dependent on Can be given ± 1000
(normal saline, concomitant disease other electrolytes. mL bag
NS) states and extent of
generics hypercalcemia Contraindications:
renal insufficiency,
congestive heart
failure.
Diuretics, loop furosemide Initial: 40–80 mg iv Q1– Electrolyte Given following $3/ 40
generics 4H after volume abnormalities, e.g., aggressive mg vial
expansion hypokalemia, rehydration
orthostatic restoring
hypotension. intravascular
volume.
Prevents fluid
overload and
inhibits calcium
reabsorption in the
distal renal tubule.
a. Drug cost only.
Suggested Readings
Ariyan CE, Sosa JA. Assessment and management of patients with abnormal calcium. Crit Care Med 2004;32(4
Suppl):S14654.
Page 347
Therapeutic Choice
Bilezikian JP, Silverberg SJ. Clinical practice. Asymptomatic primary hyperparathyroidism.N Engl J Med 2004;350
(17):174651.
Bushinsky DA, Monk RD. Electrolyte quintet: calcium. Lancet 1998;352(9124):306-11.
Jacob TP, Bilezikian JP. Clinical review: Rare causes of hypercalcemia. J Clin Endocrinol Metab 2005;90(11):631622.
Stewart AF. Clinical practice. Hypercalcemia associated with cancer. N Engl J Med 2005;352(4):373-9.
References
1. Carroll MF, Schade DS. A practical approach to hypercalcemia. Am Fam Physician 2003;67(9):1959-66.
2. Stewart AF. Clinical practice. Hypercalcemia associated with cancer. N Engl J Med 2005;352(4):373-9.
3. Kaye TB. Hypercalcemia. How to pinpoint the cause and customize treatment. Postgrad Med 1995;97(1):153-
5, 159-60.
4. Deftos LJ. Hypercalcemia: mechanisms, differential diagnosis, and remedies. Postgrad Med 1996;100(6):119-
21,125-6.
5. Nakashima L. Guidelines for the treatment of hypercalcemia associated with malignancy. J Oncol Pharm
Practice 1997;3:31-7.
6. Ralston SH, Coleman R, Fraser WD et al. Medical management of hypercalcemia. Calcif Tissue Int 2004;74
(1):1-11.
7. Chisholm MA, Mulloy AL, Taylor AT. Acute management of cancer-related hypercalcemia. Ann Pharmacother
1996;30(5):507-13.
8. Davis KD, Attie MF. Management of severe hypercalcemia. Crit Care Clin 1991;7(1):175-90.
9. Bilezikian JP. Clinical review 51: Management of hypercalcemia. J Clin Endocrinol Metab 1993;77(6):1445-9.
10. Potts JT. Hyperparathyroidism and other hypercalcemic disorders. Adv Intern Med 1996;41:165-212.
11. Strong P, Jewell S, Rinker J. Thiazide therapy and severe hypercalcemia in a patient with hyperparathyroidism.
West J Med 1991;154(3):338-40.
12. [No authors listed]. NIH conference. Diagnosis and management of asymptomatic primary
hyperparathyroidism: consensus development conference statement. Ann Intern Med 1991;114(7):593-7.
13. Bushinsky DA, Monk RD. Electrolyte quintet: calcium. Lancet 1998;352(9124):306-11.
14. Levine MA. Primary hyperparathyroidism: 7,000 years of progress. Cleve Clin J Med 2005;72(12):1084-5,
1088, 1091-2.
15. Grey AB, Stapleton JP, Evans MC et al. Effect of hormone replacement therapy on bone mineral density in
postmenopausal women with mild primary hyperparathyroidism. A randomized, controlled trial. Ann Intern
Med 1996;125(5):360-8.
16. Silverberg SJ, Rubin MR, Faiman C et al. Cinacalcet hydrochloride reduces the serum calcium concentration in
inoperable parathyroid carcinoma. J Clin Endocrinol Metab 2007;92(10):3803-8.
17. Peacock M, Bilezikian JP, Klassen PS et al. Cinacalcet hydrochloride maintains long-term normocalcemia in
patients with primary hyperparathyroidism. J Clin Endocrinol Metab 2005;90(1):135-41.
18. Lacy MQ, Dispenzieri A, Gertz MA. Mayo Clinic consensus statement for the use of bisphosphonates in multiple
myeloma. Mayo Clinic Proceedings 2006;81(3):1047-53.
19. Major P, Lortholary A, Hon J et al. Zoledronic acid is superior to pamidronate in the treatment of
hypercalcemia of malignancy: a pooled analysis of two randomized, controlled clinical trials. J Clin Oncol
2001;19(2):558-67.
20. Berenson JR. Treatment of hypercalcemia of malignancy with bisphosphonates. Semin Oncol 2002;29(6 Suppl
21):12-8.
21. Berenson J, Hirschberg R. Safety and convenience of a 15-minute infusion of zoledronic acid. Oncologist
2004;9(3):319-29.
22. Watters J, Gerrand G, Dodwell D. The management of malignant hypercalcaemia. Drugs 1996;52(6):837-48.
23. Perry CM, Figgitt DP. Zoledronic acid: a review of its use in patients with advanced cancer. Drugs 2004;64
(11):1197-211.
24. Lteif AN, Zimmerman D. Bisphosphonates for treatment of childhood hypercalcemia. Pediatrics 1998;102(4 Pt
1):990-3.
25. LeGrand SB, Leskuski D, Zama I. Narrative review: furosemide for hypercalcemia: an unproven yet common
practice. Ann Intern Med 2008;149(4):259-63.
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26. Woo SB, Hellstein JW, Kalmar JR. Narrative [corrected] review: bisphosphonates and osteonecrosis of the
jaws. Ann Intern Med 2006 May 16;144(10):753-61.
27. Haverbeke G, Pertile G, Claes C et al. Posterior uveitis: an under-recognized adverse effect of pamidronate: 2
case reports. Bull Soc Belge Ophtalmol 2003;(290):71-6.
Page 349
e-Therapeutics+ : Therapeutics : Fluid and Electrolyte Disorders: Hypovolemia Page 1 of 6
Therapeutic Choice
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Fluid and Electrolyte Disorders: Hypovolemia
Peter J. McLeod, MD, FRCPC, FACP
Hypovolemia is a generic term encompassing volume depletion and dehydration.1 Volume depletion is the loss of
salt and water from the intravascular space. It is more frequently associated with hypotension and tachycardia than
is dehydration. Dehydration, such as from excess sweating, implies loss of water from both extracellular
(intravascular and interstitial) and intracellular spaces and leads to elevated plasma sodium and osmolality.
Goals of Therapy
Restore normal volume to relieve symptoms and prevent organ damage
Investigations
History:
symptoms of hypovolemia include thirst, fatigue and postural lightheadedness
causes of hypovolemia include: hemorrhage; volume losses from GI tract, kidneys, skin, respiratory tract;
fluid sequestration or third-space losses
Physical exam:
determine the presence and severity of hypovolemia
pulse: heart rate (HR) increase of more than 30 beats/min after 1 minute of standing from recumbent
position is the most accurate sign of volume depletion.1 The pulse should be counted for 30 seconds and
doubled to determine the number of beats per minute. Supine tachycardia is insensitive
blood pressure: postural decline of systolic pressure of more than 20 mm Hg suggests volume depletion.1
Severe volume loss may lead to persistently low blood pressure, even while supine
low jugular venous pressure (JVP) is suggestive of volume depletion. Dry axillae support the diagnosis of
hypovolemia.1 Moist mucous membranes and axillae argue against hypovolemia. Skin turgor, capillary refill
time and eyeball tension are late signs and are insensitive in adults2
Laboratory tests:
blood: in hypovolemia, hematocrit and albumin concentrations increase and urea increases
disproportionately to creatinine. Sodium concentration may be normal, low or high and is dependent on the
type and amount of fluid consumed by the patient in response to thirst.
urine: hypovolemia is suggested if urine volume is <0.5 mL/kg/h, if Na+ is <20 mmol/L or if osmolality is
>450 mOsm/kg. 3 Urine specific gravity (SG) is less accurate but SG >1.015 suggests concentrated urine
and may indicate hypovolemia
Therapeutic Choices (Figure 1 - Management of Suspected Hypovolemia, Table 1)
Therapy is designed to restore volume while replacing ongoing losses. Concurrent fluid and electrolyte disorders will
influence choice of fluid used.
Hypovolemia suspected but uncertain: consider an IV fluid challenge of 250–500 mL of normal saline over 30
minutes. Closely monitor HR and BP to determine if low cardiac output is due to hypovolemia.
Mild hypovolemia (<5% of body weight): oral therapy is usually adequate. Water, juices, soft drinks or soup
broth with extra salt or a commercially available electrolyte solution (see Fluid and Electrolyte Disorders:
Dehydration in Children) may be used.4 Rice-based oral solutions have proven effective for diarrheal conditions
in developing countries.
Moderate (5–10% of body weight) or severe (>10% of body weight) hypovolemia or inability to ingest oral
fluids: IV therapy is required and 4 types of solutions are used:
dextrose 5% in water (D5W) distributes throughout total body water and is useful for intracellular
volume loss (dehydration). It is a poor plasma volume expander as very little remains in the intravascular
space and therefore it is not useful for managing acute hypotension or tachycardia.
sodium chloride 0.9% (normal saline or NS) is the fluid of choice for initial treatment of acute
hypotension and tachycardia associated with volume depletion. Like other crystalloid solutions, it
distributes to extracellular fluid. For every litre infused, about 250 mL remains in the intravascular space
and the remainder goes to the interstitial space.4
colloid solutions, including albumin, gelatins (not available in Canada) and starch compounds, are better
Page 350
Therapeutic Choice
intravascular volume expanders than NS because they remain in the intravascular space longer than
crystalloids. Their cost is high, and the duration of benefit is relatively short; their use as the primary fluid
is not justified in most hypovolemic states.
blood is an excellent intravascular expander. Packed red blood cells with normal saline is indicated for
hemorrhagic hypovolemia.
Determining Fluid Requirements
There is no precise formula since disease, age, source and rate of fluid loss influence fluid requirements. In severe
and less severe hypovolemia with obvious hemodynamic compromise, give at least 1 L of NS over 30
minutes and a second litre over the next hour. Closely monitor HR, BP and JVP, watching for
improvement or fluid overload. In less severe hypovolemia, give 250–500 mL/hour of NS. A
randomized controlled trial has demonstrated the safety and efficacy of 500 mL of normal saline given
over 30 minutes to patients with suspected sepsis and a systolic blood pressure of
<90 mm Hg.5 Useful Info?
Colloid solutions may be needed if NS is ineffective but there are no data indicating that colloid use will provide
better outcomes in critically ill patients.6 , 7 Fluid resuscitation with 4% albumin or normal saline resulted in similar
outcomes, including 28-day mortality, in ICU patients.8
Maintenance fluids must be added to those given to correct the deficit. In adults, maintenance is possible with
approximately 30 mL/kg/day or 2000–2500 mL/day containing 75 mmol of Na+ and 50 mmol of K+ in a 24-hour
period.
Other commercially available crystalloid solutions are more costly and, aside from dextrose 3.3% with sodium
chloride 0.3% (2/3–1/3) or dextrose 5% with sodium chloride 0.45% (D5-1/2 NS), they play very little role in
managing volume depletion. Users of other crystalloids must be aware of their contents. For example, Ringer's
lactate contains calcium, potassium and lactate in addition to sodium and may not be suitable for some patients,
e.g., those with renal dysfunction.
Therapeutic Tips
If presence of hypovolemia is uncertain, consider a fluid challenge.

Normal saline is the fluid of first choice for patients with hypotension and tachycardia associated with volume
depletion. Dextrose in water is a poor plasma volume expander.
Additional potassium may be required for fluid loss associated with diarrhea, vomiting or over-diuresis with
diuretics.
Colloid solutions are usually reserved as second-line plasma volume expanders; burns and other volume losses
containing protein may require additional colloid.
Figure 1- Management of Suspected Hypovolemia
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Therapeutic Choice
a. Dehydration refers to loss of intracellular water leading to elevated plasma sodium and osmolality. Patients with dehydration
may or may not have hypotension and tachycardia. Volume depletion results from loss of salt and water from the extracellular
space. Volume-depleted patients exhibit circulatory instability.
Table 1: Intravenous Solutions for Hypovolemia
Crystalloids sodium chloride Initial treatment of Fluid overload; peripheral IV solutions with Na+
0.9%, normal saline hypovolemia. edema. concentrations that
or NS Dilutional coagulopathy. approximate normal
(Na+ 154 mmol/L) serum Na+ cause more
generics Hyperchloremic metabolic intravascular and
acidosis with infusion of large interstitial expansion than
amounts of NS do D5W solutions.
(usually >3 L).
Hypernatremia.
Crystalloids Ringer’s lactate Initial treatment of Fluid overload; peripheral Contains 1.4 mmol/L
(Na+ 130 mmol/L) hypovolemia. edema. Ca++, 4 mEq K+/L; 109
Lactated Ringer's Dilutional coagulopathy. mEq Cl -/L; 28 mEq
Injection, generics lactate/L.
Hyponatremia.
May aggravate pre-existing

hyperkalemia.
Crystalloids dextrose 5% with Hypovolemia and Fluid overload; peripheral IV solutions with Na+
sodium chloride dehydration. edema. concentrations that
0.9%, D5W-NS Dilutional coagulopathy. approximate normal
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Therapeutic Choice
(usually >3 L). Compared to NS or

Ringer’s lactate, D5W
Hypernatremia. results in comparatively
small changes in plasma
volume because it
distributes throughout the
total body water space,
including the intracellular
space.
Crystalloids dextrose 5% in Dehydration; poor Water is distributed to

water, D5W plasma volume both intracellular fluid
generics expander. and extracellular fluid
after dextrose
metabolism.
Crystalloids sodium chloride Maintenance fluids. Fluid overload; peripheral IV solutions with Na+
0.45%, half-normal edema. concentrations that
saline or 1/2 NS Dilutional coagulopathy. approximate normal
(usually >3 L).
Hypernatremia.
Crystalloids dextrose 3.3% with Maintenance fluids. Fluid overload; peripheral IV solutions with Na+
sodium chloride edema. concentrations that
0.3%, 2/3–1/3 Dilutional coagulopathy. approximate normal
(usually >3 L).
Hypernatremia.
Crystalloids dextrose 5% with Maintenance fluids. Fluid overload; peripheral IV solutions with Na+
sodium chloride edema. concentrations that
0.45%, D5-1/2NS Dilutional coagulopathy. approximate normal
(usually >3 L).
Hypernatremia.
Colloids albumin Volume expander, Rare: Albumin 5% is iso-oncotic

Alburex, Plasbumin- useful for anaphylactoid/anaphylaxis. (does not pull fluid into
5, Plasbumin-25, hypoproteinemic Fluid overload. the intravascular space)
generics hypovolemia. with normal plasma; IV
Used to replace or infusion will expand
in conjunction with circulating blood volume
crystalloids. by an amount
approximately equal to
Volume remains the amount infused; does
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Therapeutic Choice
within the not aggravate tissue

extracellular dehydration; concomitant
compartment. use of crystalloids may be
necessary to maintain
Contraindicated in fluid balance.
patients at risk of Albumin 25% is used in
circulatory overload situations of oncotic
such as those with deficit, e.g., blood loss
history of HF, renal due to surgery or trauma;
insufficiency or may be used when
stabilized chronic treatment of shock has
anemia. been delayed. IV infusion
will expand plasma
volume 3–4 times the
volume infused. May be
used in patients with
clinical evidence of both
edema and hypovolemia,
i.e., is normally hydrated
or interstitial edema is
present. May be used in
combination with
crystalloids.
Colloids hetastarch 6% in Volume expander, Bleeding. Hetastarch exhibits

lactated electrolyte alternative to Macroamylase formation may comparable plasma
Hextend blood. lead to incorrect diagnosis of expansion with respect to
pancreatitis because of 5% albumin solution.
possibility of increase in Contraindicated in
blood amylase. patients at risk of
circulatory overload such
Fluid overload. as those with history of
HF, renal insufficiency or
stabilized chronic anemia.
Colloids pentastarch 6% or Volume expander. May induce coagulopathy if Commonly used in

10% in normal >28 mL/kg is given over a crystalloid refractory
saline 24-hour period though this is patients in critical care
Pentaspan extremely rare and usually areas but there is no
not clinically significant. evidence of clinical
Hyperchloremic acidosis. superiority compared to
crystalloids.
Colloids dextrans Volume expander. Aggravation of bleeding; Not used as plasma

generics interfere with blood expanders as frequently
coagulation. as albumin and starch
Anaphylaxis with higher compounds.
molecular weight solutions.
Colloids blood Packed cells with Fluid overload. Replaces or increases

saline indicated for oxygen-carrying capacity
hemorrhage. but only if not stored
for >3–5 days.
Suggested Readings
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Therapeutic Choice
Brenner BM, Rector FC, editors. Brenner and Rector's the kidney. 6th ed. Philadelphia (PA): W.B. Saunders; 2000.
Halperin ML, Goldstein MB. Fluid, electrolyte, and acid-base physiology a problem-based approach. 2nd ed.
Philadelphia (PA): Saunders; 1994.
Maxwell MH, Kleeman CR, Narins RG. Maxwell & Kleeman's clinical disorders of fluid and electrolyte metabolism. 5th
ed. New York (NY): McGraw-Hill, Health Professions Division; 1994.
McGee S, Abernethy WB, Simel DL. The rational clinical examination. Is this patient hypovolemic? JAMA 1999;281
(11):1022-9.
References
1. McGee S, Abernethy WB, Simel DL. The rational clinical examination. Is this patient hypovolemic? JAMA
1999;281(11):1022-9.
2. Webb AR. Recognizing hypovolaemia. Minerva Anesthesiol 2001;67(4):185-9.
3. Sterns RH. Renal function and disorders of water and sodium balance. In: Scientific American medicine. New
York (NY): WebMD Professional Publishing; 2002.
4. Boldt J. Volume replacement in the surgical patient--does the type of solution make a difference? Br J Anaesth
2000;84(6):783-93.
5. Rivers E, Nguyen B, Havstad S et al. Early goal-directed therapy in the treatment of severe sepsis and septic
shock. N Engl J Med 2001;345(19):1368-77.
6. Webb AR. The appropriate role of colloids in managing fluid imbalance: a critical review of recent meta-
analytic findings. Crit Care 2000;4(Suppl 2):S26-32.
7. Perel P, Roberts I. Colloids versus crystalloids for fluid resuscitation in critically ill patients. Cochrane
8. Finfer S, Bellomo R, Boyce N et al. A comparison of albumin and saline for fluid resuscitation in the intensive
care unit. N Engl J Med 2004;350(22):2247-56.
Page 355
e-Therapeutics+ : Therapeutics : Fluid and Electrolyte Disorders: Potassium Disturbances Page 1 of 13
Therapeutic Choice
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Fluid and Electrolyte Disorders: Potassium Disturbances
Date Prepared: September 2010
Jean Ethier, MD, FRCPC
Potassium, the major intracellular cation in the human body, is found in abundance in fruits (e.g., tomatoes,
cucumbers), vegetables (e.g., leafy greens) and meats. The average dietary daily intake is 100 mEq. Normal
potassium concentration is 3.5–5 mmol/L.
Hypokalemia, defined as a plasma potassium concentration of less than 3.5 mmol/L, can be mild (3–3.5 mmol/L),
moderate (2.5–3 mmol/L) or severe (<2.5 mmol/L). Hyperkalemia, defined as a plasma concentration of greater
than 5 mmol/L, can be mild (5.5–6 mmol/L), moderate (6.1–6.9 mmol/L) or severe (>7 mmol/L). Hypokalemia and
hyperkalemia are associated with potentially fatal cardiac arrhythmias.
Goals of Therapy
Prevent life-threatening cardiac arrhythmias and improve neuromuscular conductivity

Re-establish normal body stores of potassium (K+) and prevent undue losses or accumulations
Identify and correct underlying causes
Investigations
History with attention to possible etiology (see Table 1)

Physical examination to assess cardiac rhythm, paresis, muscle weakness, paresthesias, blood pressure
(consider hyperaldosteronism in the presence of hypokalemia and high blood pressure)
ECG when clinically necessary
Laboratory tests may be useful in assessing hypokalemia or hyperkalemia, if not already evident:
urea, creatinine, Na+, K+, Cl –, glucose
arterial or venous blood gases or total CO2
spot urine for Na+, K+, Cl – and osmolality to calculate the transtubular K+ concentration gradient (TTKG)
and the potassium-creatinine ratio and, in select cases, 24-hour urine collection for Na+, K+ and creatinine
aldosterone, cortisol, renin, screening tests for adrenal disease, TSH for thyrotoxicosis, renal artery
imaging in select cases
magnesium in refractory hypokalemia, especially when patient is at risk for hypomagnesemia, e.g., taking
diuretics or cisplatin, diarrhea
rule out pseudohyperkalemia (possible with thrombocytosis, severe leukocytosis, in vitro hemolysis or
forearm contraction)1
Table 1: Causes of Potassium Disturbances
Hyperkalemia Hypokalemia
Drug-induced: ACE inhibitors, aminocaproic acid, angiotensin II Diarrhea, vomiting

receptor blockers (ARBs), beta-blockers, cyclosporine, digoxin Inadequate dietary intake
overdose, drospirenone, heparin, K+ supplements, K+-sparing Drug-induced: aminoglycosides,
diuretics, ketoconazole, NSAIDs, penicillin G potassium, amphotericin B, antipseudomonal penicillins,
pentamidine, succinylcholine, tacrolimus, trimethoprim or beta2-agonists, caffeine, foscarnet, insulin,
TMP/SMX (high-dose or in susceptible patients, i.e., elderly, renal laxatives, licorice, long-term corticosteroid
failure), some herbal and nutritional supplements (e.g., alfalfa, therapy, loop and thiazide diuretics,
nettle) especially in the presence of renal failure theophylline, tocolytic agents
Renal failure, diabetes, adrenal insufficiency, hyporeninemic Familial history (Bartter's or Gitelman’s
hypoaldosteronism syndrome)
Familial history of hyperkalemia Mineralocorticoid excess (e.g., primary
Acidosis aldosteronism)
Crush injury, trauma, hemolysis, tumor lysis, massive transfusions Renovascular disease
Metabolic alkalosis
Osmotic diuresis (diabetes)
Hypomagnesemia
Increased sweat loss
Dialysis/Plasmapheresis
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Abbreviations: ACE=angiotensin converting enzyme; TMP/SMX=trimethoprim/sulfamethoxazole
Hyperkalemia
Therapeutic Choices
Therapeutic Tips
Therapeutic Choices (Figure 1 - Management of Hyperkalemia)
Stop K+ supplements and/or drugs inducing hyperkalemia (see Table 1). If necessary, resume K+ supplements at
a reduced dose once the hyperkalemia is resolved.
Reduce dietary K+ intake to ≤60 mmol/day.
In mild hyperkalemia (plasma K+ = 5.5–6 mmol/L) these measures are usually sufficient. Increasing K+, ongoing K+
load or renal failure require further measures, e.g., hemodialysis.
Do not rely only on the plasma K+ or ECG to determine the urgency of treatment. Changes in the ECG are a poor
diagnostic test and have an uncertain prognostic significance. Cardiac toxicity depends not only on the level of plasma
K+ but also on the rate of increase, chronicity of hyperkalemia, levels of other electrolytes (hypocalcemia,
hyponatremia and acidosis increase cardiotoxicity) and cardiac irritability. Consider all these factors.
In severe hyperkalemia (K+ >6.5–7 mmol/L) or when significant or advanced ECG changes are present (loss of P
waves or widening of QRS complexes), continuous cardiac monitoring should accompany treatment. Give iv calcium
promptly and begin insulin. Initiate K+ removal simultaneously (Figure 1 - Management of Hyperkalemia, Table 2).
In less severe situations, K+ removal with or without redistribution agents (e.g., insulin) may be sufficient. Estimate
renal function and ongoing gain of K+ in extracellular fluid. Initiate treatment early and more aggressively when renal
failure is present or there is rapid and severe input of K+ (e.g., rhabdomyolysis, tumor lysis syndrome) than when
there is slow or no input (e.g., hyperkalemia induced by K+-sparing diuretics).
Membrane Antagonists
Calcium gluconate or calcium chloride antagonize the adverse cardiac effects of potassium and should be used in
the presence of ECG changes since it is fast acting. Calcium iv has a rapid onset but relatively short duration of action
and should be administered simultaneously with other treatments.
Redistribution Agents
These agents act for a longer period than membrane antagonists as they facilitate reuptake of potassium into cells.
Insulin should be the first choice since it is the most effective and reliable agent. Insulin must be administered iv.2
Glucose (40–50 g per 10 units insulin) is given to avoid hypoglycemia, but avoid bolus administration because an
acute increase in plasma tonicity can induce a rise in plasma K+. Expect a 1–1.5 mmol/L fall in potassium in 60
minutes.
Sodium bicarbonate (NaHCO3) is usually reserved for hyperkalemia associated with significant metabolic acidosis.
It has a synergistic effect with insulin in the presence of mild acidosis.3 In the absence of low serum bicarbonate
concentration or pH, sodium bicarbonate has a smaller effect.4 To avoid an acute increase in K+ induced by an
osmolality change, hypertonic NaHCO3 solutions should not be used.5 The correction of acidosis in hypocalcemic
patients may induce tetany. Insulin administration is faster, more reliable and more effective than sodium
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Therapeutic Choice
bicarbonate.2
The beta2-agonist salbutamol is effective in lowering plasma K+. Its effect is similar to insulin, but the mechanism is
different; concurrent administration of insulin and salbutamol has a synergistic effect.6 High doses of nebulized
salbutamol have a similar effect to iv salbutamol; however, up to 50% of renal failure patients are resistant to this
therapy.7 Reserve salbutamol for young patients or life-threatening situations when other therapies have failed,
because it is arrhythmogenic and has the potential to exacerbate angina.
Potassium Removal
In patients with volume contraction and oliguria (prerenal disease), volume repletion should be implemented to
quickly improve renal potassium excretion.
The administration of loop diuretics in patients with sufficient renal function can significantly increase renal K+
excretion. Provide enough fluid with the diuretic to avoid volume contraction.
If large amounts of K+ must be removed rapidly, hemodialysis is the technique of choice. Because time is required to
prepare the equipment and to insert a catheter, other treatments must be initiated while preparing for dialysis.
Peritoneal dialysis is far less efficient in acutely reducing plasma K+.
Cation-exchange resins (sodium polystyrene sulfonate, calcium polystyrene sulfonate) promote the exchange of
Na+ and Ca++ for K+, respectively, in the bowel; they also bind calcium and magnesium. Despite their theoretical
value and their widespread clinical use with apparent efficacy, the K+-lowering effect of single-dose resin-cathartic
therapy is subject to debate.8 , 9 , 10 , 11 The addition of resins does not seem to increase bowel K+ removal above
the effect of the diarrhea induced by the simultaneous administration of osmotic or secretory cathartics.12 Because
cation-exchange resins are constipating, it is suggested that they are given with a laxative.
Resins have serious side effects. The Na+ released in exchange for K+ may lead to volume overload. Rectal ulceration
or colonic necrosis has been described when sodium polystyrene sulfonate mixed in sorbitol is given orally or by
enema.13 Necrosis may be caused by sorbitol rather than by resins.14 , 15 The duration of drug contact with the
mucosa may be a risk factor. A cleansing enema (sodium-free) is recommended to reduce this risk. Do not use
sorbitol when the resin is administered by enema, especially in postoperative patients.
Given the potential problems with cation-exchange resins some recommend trying all other alternatives for managing
hyperkalemia first.10 Others feel that resins should continue to be used when indicated, preferably administered in
water.11 Resins in sorbitol should not be used in the immediate postsurgical period, or in patients with compromised
gastrointestinal function.11
Therapeutic Tips
Focus the treatment of chronic hyperkalemia on the cause or pathophysiological mechanism (Table 1). The
treatments are similar to those used in acute hyperkalemia (diuretics, NaHCO3, resins).
The mineralocorticoid 9-alpha-fludrocortisone may be used in patients with hypoaldosteronism or renal
resistance to mineralocorticoids.
Closely monitor potassium after introducing or changing the dose of any medication that could
induce hyperkalemia such as ACE inhibitors, ARB, K+-sparing diuretics, in particular in patients at
risk of hyperkalemia, e.g., renal failure, elderly, cardiac insufficiency. Monitoring is even more
important when a combination of these medications is prescribed (ACE + ARB + spironolactone). In
this case measure potassium 3 and 7 days after the introduction of these medications and after any
change in the dose.16 In addition, measure creatinine and potassium at least monthly for 3 months17
and, if stable, every 3 months thereafter. Useful Info?
Hypokalemia
Therapeutic Choices
Therapeutic Tips
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Therapeutic Choice
Therapeutic Choices
If clinically appropriate reduce or stop medication leading to K+ loss.

Determine and treat the etiology (Table 1).
If the deficit is slight (plasma K+ = 3– 3.5 mmol/L) and there are no ongoing losses or clinical conditions
warranting prompt treatment, dietary intake of potassium-rich foods should be adequate. If there are still
unusual losses, K+ supplements or K+-sparing diuretics will be needed.
Pharmacologic Choices (Table 3, Table 4)
The appropriate pharmacologic approach is determined by:
Relative urgency for treatment.

The estimated total body deficit for an adult with plasma K+ of 3 mmol/L is approximately 200–400 mmol and
for plasma K+ of 2 mmol/L, approximately 500–700 mmol. Note: The true deficit will be larger with an
extracellular shift of potassium (e.g., acidosis or insulin deficit) and smaller with an intracellular shift of
potassium, (e.g., periodic paralysis or hyperadrenergic state).
Ongoing losses must be added to the deficit when replacement therapy is planned. Renal losses can be
estimated based on urine K+ levels and the volume excreted per hour.
In the presence of renal failure the treatment should be more cautious.
Potassium Salts (Table 3)
In most cases potassium chloride (KCl) is the salt of choice, and oral administration is the preferred route. If there
is no paralytic ileus or suspected absorption problem, oral administration of KCl can rapidly increase plasma K+
(40–60 mmol of a liquid preparation will increase plasma K+ by 1–1.5 mmol/L).
Reserve potassium bicarbonate or potassium citrate for hypokalemic patients with metabolic acidosis (e.g.,
renal tubular acidosis, diarrhea). Potassium phosphate is used when severe hypophosphatemia is present.
Reserve iv administration of potassium for patients requiring urgent treatment (e.g., respiratory muscle weakness,
cardiac arrhythmias especially if digitalis is present, hepatic encephalopathy) or those unable to take oral
supplements (e.g., postsurgery, paralytic ileus). To avoid sclerosis, iv potassium should be administered via a large
peripheral vein at a maximum concentration of 40–60 mmol/L. Administer higher concentrations via a central line
with the catheter positioned away from the right atrium or ventricle. In patients with severe hypokalemia, administer
K+ in a dextrose-free solution to avoid stimulating insulin secretion and subsequent intracellular K+ shift.18
Administering potassium iv rather than po is more likely to result in hyperkalemia. Thrombophlebitis and pain at site
of injection are other risks.
The rate of administration depends on the urgency to treat (Table 3). Protocols for the treatment of hypokalemia in
the hospital setting have been proposed.19 , 20
Potassium-sparing Diuretics (Table 4)
If renal K+ losses are involved in the pathogenesis of hypokalemia (e.g., hyperaldosteronism, concomitant use of
other diuretics), K+-sparing diuretics may be used to decrease these losses; they also prevent or decrease
magnesium losses. Amiloride, spironolactone and triamterene (triamterene is available only in combination
with hydrochlorothiazide in Canada) are equally effective but differ in side effects. Use spironolactone in patients
with primary or secondary hyperaldosteronism. The most frequent and serious side effect is hyperkalemia.
Avoid K+-sparing diuretics in patients with renal or adrenal insufficiency, the elderly, patients with diabetes and
patients taking other drugs that may increase plasma K+ (Table 1).
Therapeutic Tips
Avoid the use of K+ supplements and K+-sparing diuretics together as the risk of hyperkalemia is
greatly increased. Combined use may be required temporarily at the beginning of replacement
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Therapeutic Choice
therapy if renal K+ losses are very high; however, frequent monitoring of plasma K+ is mandatory,
and one of the drugs should be stopped when plasma K+ reaches 3–3.5 mmol/L. Useful Info?
Treat hypomagnesemia if present.
Figure 1- Management of Hyperkalemia
a. Loss of P waves, widening of QRS complexes or more severe changes are considered significant. Isolated peaked T waves may
not be significant. Note that ECG changes have uncertain prognostic significance.
b. Plasma potassium level is given as a guide; therapy should not rely on the plasma level alone.
Table 2: Drugs for Treatment of Hyperkalemia
Beta2- salbutamol 10–20 mg by nebulizer Reserved for life-threatening cases when

adrenergic Ventolin Onset: 30 min other treatments have failed; risk of
Agonists Nebules P.F., arrhythmia or angina; variable response.
generics Duration of action: 2–4 h
Cation- sodium Oral: 15–60 g in 50–100 mL of Effectiveness seriously questioned. Laxative

exchange polystyrene 20% sorbitol Q4–6H PRN; usual alone might be as effective.
Resins sulfonate dose: 30 g. Do not mix with orange Constipating; risk of colonic ulceration or
Kayexalate, juice or other fruit juices with high necrosis with hypertonic enema.
generics potassium content
Onset: 1–2 h Cleansing enema before pr use
recommended. Cleansing enema after pr
Rectal: 30–50 g in 100–200 mL of use to be given after evacuation of the
water or 10% dextrose Q4–6H PRN; resins or after retention for 1–6 h.
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Therapeutic Choice
retain at least 30–60 min

Available as powder and rectal suspension.
Onset: 30–60 min
Sodium overload may be a concern.
Duration of action: 4–6 h
Cation- calcium Oral: 15 g 3 or 4 times a day. May Effectiveness seriously questioned. Laxative
exchange polystyrene mix resin into a paste with alone might be as effective.
Resins sulfonate sweetened vehicle. Do not mix with Constipating; risk of colonic ulceration or
Resonium orange juice or other fruit juices necrosis with hypertonic enema.
Calcium with high potassium content
Rectal: 30 g in 100 mL of 2% Cleansing enema before pr use
methylcellulose and 100 mL of recommended. Cleansing enema after pr
water as a daily retention enema; if use to be given after evacuation of the
possible, enema should be retained resins or after retention for 1–6 h.
for 9 h
Available as powder and rectal suspension.
Use if sodium overload is a concern.
Avoid concomitant administration of

sorbitol with calcium polystyrene sulfonate
as use has been associated with colonic
necrosis and intestinal obstruction.
Diuretics furosemide 40–250 mg po/iv depending on Risk of volume depletion; transient

Lasix, generics renal function ototoxicity with high-dose furosemide.
Onset: 30–60 min
Duration of action: to end of

increased diuresis (about 4–6 h)
Electrolytes calcium 10 mL iv over 2–5 min; may repeat Continuous ECG monitoring required;
gluconate 10% once after 5 min (depending on infuse more slowly in patients on digoxin
generics ECG) because of risk of ↑ digoxin toxicity;
Onset: 1–3 min incompatible with NaHCO3-containing
solutions (precipitation).
Duration of action: 30–60 min 1 g calcium gluconate = 93 mg elemental
calcium = 4.6 mEq elemental calcium = 2.3
mmol elemental calcium.
Electrolytes calcium 5–10 mL iv over 2–5 min; may Continuous ECG monitoring required;
chloride repeat once after 5 min (depending infuse more slowly in patients on digoxin
generics on ECG) because of risk of ↑ digoxin toxicity;
Onset: 1–3 min incompatible with NaHCO3-containing
solutions (precipitation).
Duration of action: 30–60 min 1 g calcium gluconate = 93 mg elemental
calcium = 4.6 mEq elemental calcium = 2.3
Recommended in cardiac arrest in the

presence of hyperkalemia or hypocalcemia
or magnesium toxicity.
May cause tissue necrosis if extravasation
Page 361
Therapeutic Choice
occurs.
1 g calcium chloride = 270 mg elemental

calcium = 14 mEq elemental calcium = 7
Electrolytes sodium 50–100 mmol iv over 5 min; repeat Variable response; risk of tetany if
bicarbonate Q10–15 min (depending on ECG) hypocalcemia present (give calcium first);
Onset: variable, within 1 h watch for Na+ overload. Can induce
bicarbonaturia with an ↑ in renal K+
Duration of action: 2 h excretion. Hypertonic NaHCO3 solutions
should not be used.
Insulin insulin with Bolus: 5–10 units iv with 25–50 g The most reliable medication for
glucose of dextrose over 5 min. If less redistribution of K+. Risk of hypoglycemia.
urgent, infuse 10 units insulin in Avoid bolus administration of glucose
500 mL of 10% dextrose at the rate because acute increase in plasma tonicity
of 50–100 mL/h can induce ↑ K+ in plasma.
Onset: 30 min
Duration of action: 4–6 h
Abbreviations: NaHCO3 =sodium bicarbonate
Table 3: Potassium Supplements Used in the Management of Hypokalemia
Adverse Costa
Class Drug Indication Dose Effects Comments
Potassium potassium Urgent Urgent (immediate Sclerosis: Doses >40 mmol/h $$

Supplements, salts, (immediate treatment Administer via have been given in
intravenous treatment required): a large life-threatening
intravenous
generics
required): 20–40 mmol in peripheral vein hypokalemia.23
Severe the first hour with at a maximum Potassium (20–40
hypokalemia continuous ECG concentration mmol) can be
(plasma K+ <2.5 monitoring and of 40–60 diluted in 100 mL
mmol/L) frequent serum K+ mmol/L. of NaCl 0.9% if
measurements to administered via a
Symptomatic adjust further rate central vein. A
hypokalemia of administration. maximum
(respiratory When plasma K+ concentration of 10
muscle weakness = 3 mmol/L, mmol in 100 mL of
or paresis, correct the NaCl 0.9% can be
paralysis) remaining deficit administered in a
more slowly. large peripheral
Cardiac vein; however, it
arrhythmia or could induce pain
conduction Less urgent and sclerosis of the
disturbances (prompt treatment vein.
required):
Less urgent 10–20 mmol over Measure serum K+
(prompt one hour (↑ serum frequently when a
Page 362
Therapeutic Choice
Adverse Costa
treatment K+ by 0.25–0.5 large dose is

required): mmol/L)21 , 22 administered.
with ECG Measure each time
Plasma K+ = 2.5– monitoring if >10 after the
3 mmol/L mmol/h. Should administration of
be repeated 20–40 mmol.
Hypokalemia with according to
digitalis toxicity, resulting serum
myocardial K+. Correct the
infarction or remaining deficit
ischemia more slowly.
Hypokalemia with
diabetic
ketoacidosis (risk
of insulin-
induced life-
threatening
hypokalemia)
Hypokalemia with
hepatic
insufficiency (risk
of hepatic
encephalopathy)
Potassium potassium Not urgent: Initially, 40–60 Unpleasant Salt of choice, $-$$
Supplements, chloride, oral Plasma K+ >3– mmol/day taste, especially in
oral 3.5 mmol/L (divided 2–4 times aftertaste, alkalotic patients.
liquid or
daily), is usually nausea, Rapid absorption,
powder sufficient heartburn. good
K-10 (20 bioavailability.
mEq K+ /15
mL), Avoid use with
generics potassium-sparing
diuretics because of
↑ risk of severe
hyperkalemia. If
combination
therapy is required,
frequent monitoring
(at least every day)
of plasma K+ is
mandatory;
discontinue one of
the drugs when
plasma K+ reaches
3–3.5 mmol/L.
Salt substitutes also
contain potassium
chloride.
Potassium potassium Not urgent: Initially, 40–60 GI symptoms, Salt of choice, $

Supplements, + mmol/day though less especially in
chloride, oral Plasma K >3–
oral 3.5 mmol/L (divided doses), is frequent than alkalotic patients.
wax matrix
usually sufficient with liquid, GI Rapid absorption,
tablet ulceration good
Slow-K (8 (rare). bioavailability.
mEq K+/tab),
Page 363
Therapeutic Choice
Adverse Costa
generics Avoid use with

potassium-sparing
↑ risk of severe
hyperkalemia. If
combination
frequent monitoring
of plasma K+ is
mandatory;
discontinue one of
the drugs when
plasma K+ reaches
3–3.5 mmol/L.
contain potassium
chloride.
Avoid in patients
with delayed GI
transit or impaired
esophageal or
intestinal motility.
Empty wax matrix
may appear in
stool.
Potassium potassium Not urgent: Initially, 40–60 May be less Salt of choice, $
Supplements, chloride, oral Plasma K+ >3– mmol/day ulceration than especially in
oral 3.5 mmol/L (divided doses), is with wax alkalotic patients.
micro-
usually sufficient matrix. Rapid absorption,
encapsulated good
capsule bioavailability.
K-Dur (20
mEq Avoid use with
K+/cap), potassium-sparing
generics diuretics because of
Micro-K ↑ risk of severe
hyperkalemia. If
Extencaps (8
combination
mEq K+/cap) therapy is required,
frequent monitoring
of plasma K+ is
mandatory;
discontinue one of
the drugs when
plasma K+ reaches
3–3.5 mmol/L.
contain potassium
chloride.
Avoid in patients
with delayed GI
transit or impaired
esophageal or
intestinal motility.
Page 364
Therapeutic Choice
Adverse Costa
Potassium potassium Not urgent: Initially, 40–60 Unpleasant Avoid use with $$
Supplements, citrate, oral Plasma K+ >3– mmol/day taste, potassium-sparing
oral 3.5 mmol/L (divided doses), is aftertaste, diuretics because of
effervescent
usually sufficient nausea, ↑ risk of severe
tablets heartburn. hyperkalemia. If
K-Lyte (25 combination
mEq K+/tab) therapy is required,
frequent monitoring
of plasma K+ is
mandatory;
discontinue one of
the drugs when
plasma K+ reaches
3–3.5 mmol/L.
Useful for patients
with metabolic
acidosis. More
convenient for
transport. Useful
for hypokalemia
secondary to
thiazides given for
kidney stones. ↑
urinary citrate
excretion.
Potassium potassium Not urgent: Initially, 40–60 Unpleasant Avoid use with $
Supplements, citrate, oral Plasma K+ >3– mmol/day taste, potassium-sparing
oral 3.5 mmol/L (divided doses), is aftertaste, diuretics because of
tablets
usually sufficient nausea, ↑ risk of severe
K-Citra
heartburn. hyperkalemia. If
combination
frequent monitoring
of plasma K+ is
mandatory;
discontinue one of
the drugs when
plasma K+ reaches
3–3.5 mmol/L.
Useful for patients
with metabolic
acidosis. More
convenient for
transport. Useful
for hypokalemia
secondary to
thiazides given for
kidney stones. ↑
urinary citrate
excretion.
Also contains 10
mEq of bicarbonate
per 5 mL of oral
solution.
Page 365
Therapeutic Choice
Adverse Costa
Potassium potassium Not urgent: Initially, 40–60 Unpleasant Salt of choice, $

Supplements, gluconate, Plasma K+ >3– mmol/day taste, especially in
oral 3.5 mmol/L (divided doses), is aftertaste, alkalotic patients.
oral liquid
usually sufficient nausea, Rapid absorption,
generics
heartburn. good
bioavailability.
Avoid use with

potassium-sparing
↑ risk of severe
hyperkalemia. If
combination
frequent monitoring
of plasma K+ is
mandatory;
discontinue one of
the drugs when
plasma K+ reaches
3–3.5 mmol/L.
contain potassium
chloride.
Useful in patients
with acidosis.
a. Cost of 30-day supply of a 20 mmol/day dose; includes drug cost only.
Legend: $ <$10 $-$$ <$10–20 $$ $10–20
Table 4: Potassium-sparing Diuretics Used in the Management of Hypokalemia
Costa
Diuretics, spironolactone 25–200 mg/day (in Hyperkalemia, Avoid NSAIDs, ACE $

potassium- Aldactone, single or divided doses). gynecomastia, inhibitors, angiotensin
sparing generics Up to 400 mg/day in androgen-like side II receptor blockers,
patients with effects, breast potassium
hyperaldosteronism tenderness, supplements: may
gastrointestinal cause severe
symptoms. hyperkalemia.
Diuretics, amiloride 5–20 mg/day Hyperkalemia, muscle Avoid NSAIDs, ACE $–$$
potassium- Midamor, Apo- cramps, headaches, inhibitors, angiotensin
sparing gastrointestinal II receptor blockers,
Amiloride, other
symptoms (rare). potassium
generics
supplements: may
cause severe
hyperkalemia.
Abbreviations: NSAIDs=nonsteroidal anti-inflammatory agents; ACE=angiotensin converting enzyme
Page 366
Therapeutic Choice
Legend: $ <$20 $-$$ <$20–40 $$ $20–40
Suggested Readings
Cohn JN, Kowey PR, Whelton PK et al. New guidelines for potassium replacement in clinical practice: a
contemporary review by the National Council on Potassium in Clinical Practice. Arch Intern Med 2000;160(16):2429-
36.
Perazella MA. Drug-induced hyperkalemia: old culprits and new offenders. Am J Med 2000;109(4):307-14.
Rastegar A, Soleimani M. Hypokalaemia and hyperkalaemia. Postgrad Med J 2001;77(914):759-64.
References
1. Smellie WS. Spurious hyperkalaemia. BMJ 2007;334(7595):693-5.

2. Blumberg A, Weidmann P, Shaw S et al. Effect of various therapeutic approaches on plasma potassium and
major regulating factors in terminal renal failure. Am J Med 1988;85(4):507-12.
3. Kim HJ. Combined effect of bicarbonate and insulin with glucose in acute therapy of hyperkalemia in end-
stage renal disease patients. Nephron 1996;72(3):476-82.
4. Blumberg A, Weidmann P, Ferrari P. Effect of prolonged bicarbonate administration on plasma potassium in
terminal renal failure. Kidney Int 1992;41(2):369-74.
5. Conte G, Dal Canton A, Imperatore P et al. Acute increase in plasma osmolality as a cause of hyperkalemia in
patients with renal failure. Kidney Int 1990;38(2):301-7.
6. Allon M, Copkney C. Albuterol and insulin for treatment of hyperkalemia in hemodialysis patients. Kidney Int
1990;38(5):869-72.
7. Allon M, Dunlay R, Copkney C. Nebulized albuterol for acute hyperkalemia in patients on hemodialysis. Ann
Intern Med 1989;110(6):426-9.
8. Kamel KS, Wei C. Controversial issues in the treatment of hyperkalaemia. Nephrol Dial Transplant 2003;18
(11):2215-8.
9. Mahoney BA, Smith WA, Lo DS et al. Emergency interventions for hyperkalaemia. Cochrane Database Syst Rev
2005;(2):CD003235.
10. Sterns RH, Rojas M, Bernstein P et al. Ion-exchange resins for the treatment of hyperkalemia: are they safe
and effective? J Am Soc Nephrol 2010;21(5):733-5.
11. Watson M, Abbott KC, Yuan CM. Damned if you do, damned if you don't: potassium binding resins in
hyperkalemia. Clin J Am Soc Nephrol 2010;5(10):1723-6.
12. Gruy-Kapral C, Emmett M, Santa Ana CA et al. Effect of single dose resin-cathartic therapy on serum
potassium concentration in patients with end-stage renal disease. J Am Soc Nephrol 1998;9(10):1924-30.
13. McGowan CE, Saha S, Chu G et al. Intestinal necrosis due to sodium polystyrene sulfonate (Kayexalate) in
sorbitol. South Med J 2009;102(5):493-7.
14. Lillemoe KD, Romolo JL, Hamilton SR et al. Intestinal necrosis due to sodium polystyrene (Kayexalate) in
sorbitol enemas: clinical and experimental support for the hypothesis. Surgery 1987;101(3):267-72.
15. Romolo JL, Williams GM. Effect of kayexalate and sorbitol on colon of normal and uremic rats. Surg Forum
1979;30:369-70.
16. Palmer BF. Managing hyperkalemia caused by inhibitors of the renin-angiotensin-aldosterone system. N Engl J
Med 2004;351(6):585-92.
17. Hunt SA. ACC/AHA 2005 guideline update for the diagnosis and management of chronic heart failure in the
adult: a report of the American College of Cardiology/American Heart Association Task Force on Practice
Guidelines (Writing Committee to Update the 2001 Guidelines for the Evaluation and Management of Heart
Failure). J Am Coll Cardiol 2005;46(6):e1-82.
18. Kunin AS, Surawicz B, Sims EA. Decrease in serum potassium concentrations and appearance of cardiac
arrhythmias during infusion of potassium with glucose in potassium-depleted patients. N Engl J Med
1962;266:228-33.
19. Chapman SA, Kaufenberg AJ, Anderson P et al. Safety and effectiveness of a modification diet in renal disease
equation-based potassium replacement protocol. Ann Pharmacother 2009;43(3):436-43.
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Therapeutic Choice
20. Todd SR, Sucher JF, Moore LJ et al. A multidisciplinary protocol improves electrolyte replacement and its
effectiveness. Am J Surg 2009;198(6):911-5.
21. Hamill RJ, Robinson LM, Wexler HR et al. Efficacy and safety of potassium infusion therapy in hypokalemic
critically ill patients. Crit Care Med 1991;19(5):694-9.
22. Kruse JA, Carlson RW. Rapid correction of hypokalemia using concentrated intravenous potassium chloride
infusions. Arch Intern Med 1990;150(3):613-7.
23. Gennari FJ. Hypokalemia. N Engl J Med 1998;339(7):451-8.
Page 368
e-Therapeutics+ : Therapeutics : Gastrointestinal Disorders: Chronic Liver Diseases Page 1 of 13
Therapeutic Choice
Print Close
Gastrointestinal Disorders: Chronic Liver Diseases

Mark G. Swain, MD, MSc, FRCPC
This chapter discusses hepatic encephalopathy, ascites, spontaneous bacterial peritonitis, cholestatic disease
(including symptom management), autoimmune chronic hepatitis, alcoholic liver disease (including alcoholic
hepatitis), hemochromatosis and Wilson's disease. Management of esophageal varices is discussed in
Gastrointestinal Disorders: Upper Gastrointestinal Bleeding. Management of viral hepatitis is discussed in
Gastrointestinal Disorders: Viral Hepatitis.
Goals of Therapy
Manage symptoms associated with chronic liver conditions

Treat complications of chronic disease, e.g., infection
Prevent recurrence
Delay or prevent disease progression
Decrease liver-related mortality
Ascites (Portal Hypertension)
Investigations
Investigations
Thorough history with special attention to documented liver disease; rule out other causes of ascites
Physical examination for features of chronic liver disease (e.g., cutaneous stigmata), hepatosplenomegaly,
degree of ascites accumulation (shifting dullness, abdominal protuberance, eversion of umbilicus), signs of
portal hypertension (caput medusae, venous hum) or other features of liver failure and related complications
(gastrointestinal bleeding, asterixis)
Laboratory tests:
ascitic tap (all patients) for neutrophil count, culture, protein/albumin, amylase, lactate dehydrogenase,
glucose
1
calculate serum-ascites albumin gradient (SAAG)
Therapeutic Choices (Figure 1 - Management of Ascites Secondary to Portal Hypertension,

Table 1)
High plasma aldosterone levels in patients with ascites result in sodium and fluid retention; thus, spironolactone
(a specific aldosterone antagonist) is the diuretic of choice. Furosemide should be added to enhance diuresis
and/or control serum potassium levels. Metolazone can be added if ascites is refractory to spironolactone and
furosemide. The combination of furosemide and metolazone can produce profound diuresis, causing volume
depletion and electrolyte abnormalities. Start with low doses and titrate up. Amiloride can be substituted for
spironolactone if intolerable side effects develop.
Spontaneous Bacterial Peritonitis (SBP)
Investigations
Investigations
History of fever, abdominal pain or clinical deterioration

Physical examination, other than to confirm the presence of ascites, is often unhelpful
Page 369
Therapeutic Choice
Laboratory tests: culture and polymorphonuclear (PMN) cell count of ascitic fluid; repeat after treatment to
ensure resolution of the infection
Therapeutic Choices (Table 2)

9
If the ascitic fluid PMN cell count is >0.25 × 10 /L (250 cells/µL), treat with a third-generation cephalosporin (e.g.,
cefotaxime or ceftriaxone) for 5 days and commence intravenous infusion of albumin (1.5 g/kg of body weight
at the time of diagnosis and 1.0 g/kg on day 3 of treatment).
Use prophylactic antibiotics only after a patient has experienced one episode of SBP. A patient with
one episode of SBP has a 69% chance of recurrence within one year. Treatment with
2 3
sulfamethoxazole/trimethoprim (cotrimoxazole) or norfloxacin decreases the rate of SBP recurrence,
but does not improve survival. Due to overall cost, sulfamethoxazole/trimethoprim is the drug of
choice. Prophylactic antibiotics should be started after the completion of intravenous antibiotic therapy
for the acute episode and continue until resolution of ascites, transplantation or death. Useful Info?
Hepatic Encephalopathy
See Figure 2 - Management of Hepatic Encephalopathy and Table 3.
Cholestatic Disease
Goals of Therapy
Investigations
Therapeutic Choices
Goals of Therapy
Improve or prevent progression of disease

Improve symptoms, e.g., fatigue, pruritus
Improve survival and reduce the need for liver transplantation
Manage fat-soluble vitamin deficiencies
Investigations
Clinical/biochemical evidence of cholestasis (↑ alkaline phosphatase and gamma glutamyl transferase [GGT], and
later bilirubin) with:
for primary biliary cirrhosis (PBC): positive antimitochondrial antibody (> 95% of cases); can be confirmed
by liver biopsy, although this is not absolutely required if a patient has a positive antimitochondrial
antibody test and a cholestatic biochemical profile
for primary sclerosing cholangitis (PSC): ductular abnormalities (strictures, beading, etc.) on endoscopic
retrograde cholangiopancreatography (ERCP) or magnetic resonance imaging (MRCP).
Identify vitamin deficiencies by:
prothrombin time (↑ if vitamin K deficient)
serum calcium and 25(OH)-vitamin D levels
serum vitamin A and/or carotene levels
Therapeutic Choices (Figure 3 - Management of Cholestatic Symptoms, Table 4)
Primary Biliary Cirrhosis (PBC) and Primary Sclerosing Cholangitis (PSC)
Ursodeoxycholic acid (UDCA) 13 to 15 mg/kg/day improves serum liver biochemical tests in patients with PBC4 , 5 ,
6
and PSC. It appears to have limited efficacy in preventing disease progression in PSC although high-dose UDCA
7 , 8
(20 to 30 mg/kg/day) may be of benefit. In PBC, a combined analysis of three trials suggested that UDCA
significantly reduced the probability of transplantation and/or death after a median of nearly four years. It slows
Page 370
Therapeutic Choice
disease progression but is not curative.9 Its effect on symptoms (i.e., fatigue, pruritus) is controversial but likely
minimal. Episodes of cholangitis require treatment with appropriate antibiotics (e.g., oral ciprofloxacin in
outpatients for early mild episodes; intravenous ampicillin + gentamicin + metronidazole for hospitalized patients).
Vitamin Deficiencies
Vitamin A, D or K supplements may be required to treat deficiencies (usually only in chronic cholestasis). The
need for vitamin E supplements in adults has not been assessed in well-designed clinical trials.
Management of Pruritus
Rule out local cutaneous causes of pruritus, e.g., eczema. Cholestyramine will benefit about 90% of patients; it
must be continued as long as pruritus is present. Antihistamines (e.g., hydroxyzine) are of no proven benefit, but
10 11
their sedative properties may help. For patients who do not respond, naltrexone or rifampin may be tried.
Numerous other therapies have been evaluated, but all are investigational.
Autoimmune Chronic Active Hepatitis
Investigations
Investigations
Marked ↑ in serum transaminases and hypergammaglobulinemia; antinuclear antibody (ANA) is present in about
70% of patients (Type I autoimmune hepatitis)
Diagnosis confirmed by liver biopsy
The classic patient is a young woman who presents with either an acute or chronic illness characterized by lethargy,
arthralgia, oligomenorrhea, fluctuating jaundice, and who has a cushingoid appearance with striae, hirsutism and
acne.
Therapeutic Choices (Drugs Used in Autoimmune Chronic Active Hepatitis and Alcoholic Hepatitis)
Immunosuppression with glucocorticoids, with or without azathioprine, prolongs life, decreases symptoms,
improves serum biochemical abnormalities and diminishes hepatic inflammation on liver biopsy. The goal is to
induce remission, defined as a decrease in serum aminotransferase levels to within the normal range, but at least to
≤ 2 × the upper limit of normal, and a follow-up liver biopsy that is normal or shows only chronic persistent
hepatitis. Most patients will require therapy for up to two years before attempts at discontinuing prednisone should
be considered; the majority will require lifelong therapy. If the dose of prednisone cannot be decreased below 10
mg/day, azathioprine may be added to the regimen. The combination of mycophenolate mofetil (up to 1 g po
BID) and prednisone may be used in patients resistant to or intolerant of azathioprine.12
Alcoholic Liver Disease
Investigations
Therapeutic Choices
Investigations
An AST to ALT ratio ≥ 2:1 and GGT ≥ 2 × the upper limit of normal strongly suggests alcohol abuse
Chronic Alcohol-related Liver Disease
Page 371
Therapeutic Choice
There is no universally accepted medical therapy except abstention from alcohol. Long-term treatment with
13 , 14
propylthiouracil or colchicine has been studied but results have not been encouraging.
Alcoholic Hepatitis
Corticosteroids 15 and pentoxifylline 16 improve short-term survival in patients with severe biopsy-proven
alcoholic hepatitis. Severe alcoholic hepatitis can be documented by calculating the Maddrey discriminant function:
17
values > 32 denote severe alcoholic hepatitis with a mortality rate approaching 50%. Corticosteroid therapy for
severe alcoholic hepatitis has been examined in numerous studies with variable results, whereas the beneficial
17
effects of pentoxifylline have been documented in a single study (reviewed by Haber et al).
Hemochromatosis
Investigations
Investigations
Elevated serum ferritin (> 300 µg/L for males; > 200 µg/L for females), fasting percent transferrin saturation
index (serum iron level/total iron binding capacity) > 60% for males or > 50% for females
Confirmed iron overload on liver biopsy or positive C282Y (most commonly) genetic test.
The classic patient is a middle-aged man who presents with hyperpigmentation, fatigue, abdominal pain, joint
pain, diminished libido, loss of body hair and diabetes mellitus
Reduce dietary iron intake. Phlebotomy (500 mL of whole blood weekly or biweekly as tolerated) will ultimately
normalize body iron stores: when repeated weekly, this may take up to two years. If the patient is unable to tolerate
phlebotomy due to other causes of iron overload (e.g., transfusions for thalassemia), chelation with deferoxamine
can be tried.
Wilson's Disease
Investigations
Investigations
Hepatic presentations include fulminant hepatitis, chronic active hepatitis and cirrhosis. The diagnosis is
confirmed by liver biopsy with hepatic copper concentrations and/or a positive genetic test. Genetic testing is
positive in only about 65% of patients
Laboratory tests: ↑ aminotransferase, ↓ serum ceruloplasmin and total copper, ↑ 24 h urinary copper excretion (> 100
µg/day)
Family history; most patients are diagnosed before age 30
Copper chelating agents (penicillamine or trientine) are the treatment of choice for Wilson's disease, and
treatment is lifelong. Trientine may be better tolerated, but is only available through the Special Access Programme;
thus, penicillamine is the first–line agent in Canada. Pyridoxine, 25 mg daily, should be given with penicillamine to
counteract its antipyridoxine effect. Twenty-four hour urinary copper excretion and serum free copper levels can be
monitored to ensure adequate removal of copper. Trientine may be used in patients intolerant of penicillamine.
Elemental zinc is an option in patients intolerant of penicillamine and trientine. Foods high in copper should be
avoided (e.g., peanuts, chocolate, liver, shellfish, mushrooms).
Figure 1-Management of Ascites Secondary to Portal Hypertension
Page 372
Therapeutic Choice
a.
Aim for weight loss of 1–1.5 kg/day in patients with peripheral edema, and 0.5–1 kg/day in patients without edema.
b.
If side effects occur (e.g., painful gynecomastia) switch to another potassium-sparing diuretic (e.g., amiloride).
c.
Spironolactone and furosemide can be started simultaneously, which often provides more predictable diuresis with better
electrolyte balance.
Give diuretics as single morning doses. Use the lowest effective dose to achieve adequate diuresis and monitor serum
electrolytes,
BUN and creatinine before therapy, weekly until stabilized, then monthly. Doses can be reduced after diuresis is initiated.
Abbreviations: TIPS = transjugular intrahepatic portosystemic shunt
Page 373
Therapeutic Choice
Figure 2-Management of Hepatic Encephalopathy
Figure 3-Management of Cholestatic Symptoms
Page 374
Therapeutic Choice
Specific therapies refer to those directed at the possible cause of pruritus, whereas nonspecific therapies cause sedation.
Table 1: Drugs Used to Treat Ascites
a
Drug Cost
Diuretics Initial: Hyperkalemia, gynecomastia, + $$$

amiloride ↑ serum K when
Apo-Amiloride, 5 mg/day muscle cramps, hyperchloremic combined with ACE
other generics May ↑ to 20 mg/day metabolic acidosis. +
inhibitors or K
supplements.
Page 375
Therapeutic Choice
a
Drug Cost
Diuretics spironolactone Initial: Hyperkalemia, hyperchloremic + $$$

↑ serum K when
100–200 mg/day metabolic acidosis, combined with ACE
Aldactone, ↑ Q5–7 days to gynecomastia and mastalgia in
inhibitors or K+
generics 400 mg/day men.
supplements.
Diuretics furosemide Initial: Nausea, anorexia, fatigue, ↑ ototoxicity of $

40 mg/day + - + aminoglycosides; ↑
Lasix, generics weakness, ↓ serum Na , Cl , K ,
↑ by 20–40 mg/day to ++ digoxin toxicity
Mg , hyperuricemia,
achieve diuresis (up (hypokalemia).
hyperglycemia, volume
to 160 mg/day)
depletion, metabolic acidosis,
ototoxicity (high doses), rash.
Diuretics metolazone Initial: Nausea, anorexia, fatigue, ↑ digoxin toxicity $$

2.5 mg/day + - + (hypokalemia).
Zaroxolyn weakness, ↓ serum Na , Cl , K ,
May increase up to ++
Mg , hyperuricemia,
10 mg/day
hyperglycemia, volume
depletion, metabolic acidosis,
ototoxicity (high doses), rash.
a.
Legend: $ < $10 $$ $10–20 $$$ $20–30
Table 2: Drugs Used for Spontaneous Bacterial Peritonitis
a
Cost
Drug Class Drug Dose Adverse Effects Drug Interactions
Cephalosporins, cefotaxime Treatment: GI disturbances, $$$$

rd 2 g iv Q8H × hypersensitivity.
3 generation Claforan
5 days
Cephalosporins, ceftriaxone Treatment: GI disturbances, Do not reconstitute or mix $$$

3rd generation Rocephin, generics 2 g iv Q24H hypersensitivity, with calcium-containing
× 5 days biliary solutions.
pseudolithiasis Do not administer
(sludging). simultaneously with calcium
-containing iv solutions via
a Y-site. Administration may
be done sequentially
provided the infusion lines
are thoroughly flushed
between infusions.
Sulfonamide sulfamethoxazole / Prophylaxis: Nausea, vomiting, ↑ effect of sulfonylureas and $

Combinations trimethoprim 1 DS tablet fever, warfarin. ↑ phenytoin levels. ↑
5 × weekly hypersensitivity nephrotoxicity of cyclosporine.
generics
reactions (may be
severe), blood
dyscrasias.
Page 376
Therapeutic Choice
Costa
Fluoroquinolones norfloxacin Prophylaxis: GI disturbances, CNS Absorption ↓ by antacids, $$

generics 400 mg/day effects, skin rash. calcium and iron (separate
administration).
↑ theophylline levels.
a.
Cost of 30-day supply unless specified otherwise; includes drug cost.
Legend: $ < $10 $$ $10–50 $$$ $50–250 $$$$ $250–350
Table 3: Drugs Used to Treat Hepatic Encephalopathy
a
Cost
Hyperosmotic lactulose 30 mL 1–4 × daily; Bloating, $$

Agents Apo- titrate to produce 2 flatulence, cramps,
–3 loose BM/day diarrhea.
Lactulose,
other generics
Nitroimidazole metronidazole 250– GI disturbances, Disulfiram-like reaction with $

Antibiotics Flagyl, 500 mg TID headache, metallic alcohol: ↑ INR with warfarin;
generics taste. barbiturates, phenytoin may ↑
metabolism.
a.
Legend: $ < $15 $$ $15–50
Table 4: Drugs Used to Treat Cholestatic Liver Disease
a
Adverse Drug Cost
Drug Class Drug Dose Effects Interactions
Bile Acid cholestyramine Cholestatic pruritus: Constipation, May bind other $$$$
Sequestrants generics Initial: 4 g before breakfast; ↑ in 4 g heartburn, drugs given
increments first after breakfast, then nausea, concurrently;
at night and then at lunch vomiting. separate doses
(1 h before or 4–
6 h after resin).
Opiate naltrexone Cholestatic pruritus: Nausea, Precipitates $$$$$

Receptor ReVia 50 mg daily × 4 weeks vomiting, opioid
Antagonists headache, withdrawal in
insomnia, dependent
dysphoria. patients.
Vitamins, fat vitamin K Deficiency in patients with chronic Antagonizes $$

-soluble cholestasis: warfarin (↓ INR);
10 mg im monthly mineral oil ↓
absorption.
Vitamins, fat vitamin A Deficiency in patients with chronic mineral oil ↓ $

-soluble cholestasis: absorption.
Page 377
Therapeutic Choice
Adverse Drug Costa

Drug Class Drug Dose Effects Interactions
5000–10 000 IU/day po (aqueous).
Use the minimum effective dose.
Vitamins, fat vitamin D Deficiency in patients with chronic $

-soluble cholestasis:
1000 IU Q2 day po (with 2–3 g
elemental calcium/day)
Bile Acids ursodiol Primary biliary cirrhosis: Occasional Do not give with $$$$$
(ursodeoxycholic 13– diarrhea, antacids. b
acid) 15 mg/kg/day in 2–4 divided doses leukopenia,
Urso, generics rash.
a.
Cost of 30-day supply unless specified otherwise; includes drug cost only.
b.
Based on 750 mg/day × 30 days.
Legend: $ < $10 $$ $10–30 $$$ $30–80 $$$$ $80–110 $$$$$ $110–150
Table 5: Drugs Used in Autoimmune Chronic Active Hepatitis and Alcoholic Hepatitis
a
Drug Cost
Drug Class Drug Dose Adverse Effects Interactions
Corticosteroids prednisone Autoimmune chronic Fluid/electrolyte ↑ GI ulceration with $

generics active hepatitis: imbalance, suppression NSAID; ↓ efficacy
60 mg/day × 1 wk, of pituitary-adrenal with barbiturates,
then 40 mg/day × 1 function, hyperglycemia, phenytoin,
wk, then 30 mg/day peptic ulcer, behavioural rifampin; ↓ effect
× 2 wk, then disturbances, ocular of vaccines.
20 mg/day cataracts, glaucoma,
cushingoid syndrome,
Gradually taper from aseptic necrosis of hip.
20 mg/day over
weeks to months
using serum
aminotransferase
levels and clinical
status as a guide
Alcoholic hepatitis:
40 mg/day x 28
days. Taper over 2
wk
Xanthines pentoxifylline Alcoholic hepatitis: Dizziness, headache, Cimetidine and $$

Trental, 400 mg TID × 4 wk nausea, vomiting, quinolones ↑
generics heartburn, chest pain, pentoxifylline levels;
rash, tremor, flushing. ↑ theophylline
levels.
Page 378
Therapeutic Choice
Drug Costa
Drug Class Drug Dose Adverse Effects Interactions
Immunosuppressants azathioprine Autoimmune ↓ appetite, leukopenia, ↑ toxicity with $$

Imuran, hepatitis: thrombocytopenia allopurinol.
generics 50–150 mg/day (monitor CBC monthly),
infection, biliary stasis,
hypersensitivity
reactions, rash, rare veno
-occlusive disease,
nausea, vomiting.
Immunosuppressants mycophenolate Autoimmune Anemia, leucopenia, Antacids, iron $$$

mofetil hepatitis: thrombocytopenia. and
Cellcept 500–1000 mg BID cholestyramine ↓
absorption.
a.
Cost of 30-day supply unless specified otherwise; includes drug cost only.
Legend: $ < $10 $$ $10–50 $$$ $ >200
Table 6: Drugs Used in Iron Overload in Hemochromatosis
a
Drug Cost
Chelating b 1–4 g sc by Allergic reactions, Loss of consciousness with $800–

deferoxamine
Agents Desferal, minipump over auditory/ocular toxicity, prochlorperazine; cardiac 3500
12 h, adjusted tachycardia, flushing, impairment with vitamin C
generics
on an individual abdominal discomfort, pain at (> 500 mg/day).
basis injection site, hypotension,
skin rash, convulsions.
a.
b.
Phlebotomy is the preferred treatment for iron overload in hemochromatosis. Chelation with deferoxamine can be tried in
patients unable to tolerate phlebotomy.
Table 7: Drugs Used in Wilson's Disease
Drug Costa
Chelating penicillamine 1–2 g/day in 4 Proteinuria, hematologic effects, ↓ effect with antacids, $$
Agents divided doses on positive ANA, mouth ulcers, diarrhea, iron, zinc; ↓ levels of
Cuprimine an empty ↓ taste sense, ↓ appetite, nausea, digoxin.
stomach vomiting, hypersensitivity.
Chelating trientine 1–2 g/day in 4 Anemia. ↓ effect with iron. b

Agents Syprine divided doses
Chelating zinc GI disturbances. ↓ levels of quinolones, $

Agents generics 50 mg (elemental tetracycline,
zinc) TID penicillamine.
between meals
a.
b.
Available through the Special Access Programme, Therapeutic Products Directorate, Health Canada.
Page 379
Therapeutic Choice
Abbreviations: ANA=antinuclear antibody
Legend: $ < $15 $$ $100–200
Suggested Readings
Adams PC. Review article: the modern diagnosis and management of haemochromatosis. Aliment Pharmacol Ther
2006;23(12):1681-91.
Ala A, Walker AP, Ashkan K et al. Wilson's disease. Lancet 2007;369(9559):397-408.
Arroyo V, Colmenero J. Ascites and hepatorenal syndrome in cirrhosis: pathophysiological basis of therapy and
current management. J Hepatol 2003;38(Suppl 1):S69-89.
Czaja AJ, Freese DK; American Association for the Study of Liver Disease. Diagnosis and treatment of autoimmune
hepatitis. Hepatology 2002;36(2):479-97.
Das SK, Ray K. Wilson’s disease: an update. Nat Clin Pract Neurol 2006;2(9):482-93.
Heathcote EJ. Management of primary biliary cirrhosis. The American Association for the Study of Liver Diseases
practice guidelines. Hepatology 2000;31(4):1005-13.
McCullough AJ, O’Connor JF. Alcoholic liver disease: proposed recommendations for the American College of
Gastroenterology. Am J Gastroenterol 1998;93(11):2022-36.
References
1. Runyon BA, Montano AA, Akriviadis EA et al. The serum-ascites albumin gradient is superior to the exudate-
transudate concept in the differential diagnosis of ascites. Ann Intern Med 1992;117(3):215-20.
2. Singh N, Gayowski T, Yu VL et al. Trimethoprim-sulfamethoxazole for the prevention of spontaneous bacterial
peritonitis in cirrhosis: a randomized trial. Ann Intern Med 1995;122(8):595-8.
3. Gines P, Rimola A, Planas R et al. Norfloxacin prevents spontaneous bacterial peritonitis recurrence in
cirrhosis: results of a double-blind, placebo-controlled trial. Hepatology 1990;12(4 Pt 1):716-24.
4. Heathcote EJ, Cauch-Dudek K, Walker V et al. The Canadian Multicenter Double-blind Randomized Controlled
Trial of ursodeoxycholic acid in primary biliary cirrhosis. Hepatology 1994;19(5):1149-56.
5. Lindor KD, Dickson ER, Baldus WP et al. Ursodeoxycholic acid in the treatment of primary biliary cirrhosis.
Gastroenterology 1994;106(5):1284-90.
6. Poupon RE, Balkau B, Eschwege E et al. A multicenter, controlled trial of ursodiol for the treatment of primary
biliary cirrhosis. UDCA-PBC Study Group. N Engl J Med 1991;324(22):1548-54.
7. Harnois DM, Angulo P, Jorgensen RA et al. High-dose ursodeoxycholic acid as a therapy for patients with
primary sclerosing cholangitis. Am J Gastroenterol 2001;96(5):1558-62.
8. Mitchell SA, Bansi DS, Hunt N et al. A preliminary trial of high-dose ursodeoxycholic acid in primary
sclerosing cholangitis. Gastroenterology 2001;121(4):900-7.
9. Poupon RE, Lindor KD, Pares A et al. Combined analysis of the effect of treatment with ursodeoxycholic acid
on histologic progression in primary biliary cirrhosis. J Hepatol 2003;39(1):12-6.
10. Wolfhagen FH, Sternieri E, Hop WC et al. Oral naltrexone treatment for cholestatic pruritus: a double-blind,
placebo-controlled study. Gastroenterology 1997;113(4):1264-9.
11. Bachs L, Pares A, Elena M et al. Effects of long-term rifampicin administration in primary biliary cirrhosis.
12. Richardson PD, James PD, Ryder SD. Mycophenolate mofetil for maintenance of remission in autoimmune
hepatitis in patients resistant to or intolerant of azathioprine. J Hepatol 2000;33(3):371-5.
Page 380
Therapeutic Choice
13. Rambaldi A, Gluud C. Colchicine for alcoholic and non-alcoholic liver fibrosis and cirrhosis. Cochrane
14. Rambaldi A, Gluud C. Propothiouracil for alcoholic liver disease. Cochrane Database Syst Rev 2005;
(4):CD002800.
15. Ramond MJ, Poynard T, Rueff B et al. A randomized trial of prednisolone in patients with severe alcoholic
hepatitis. N Engl J Med 1992;326(8):507-12.
16. Akriviadis E, Botla R, Briggs W et al. Pentoxifylline improves short-term survival in severe acute alcoholic
hepatitis: a double-blind, placebo-controlled trial. Gastroenterology 2000;119(6):1637-48.
17. Haber PS, Warner R, Seth D et al. Pathogenesis and management of alcoholic hepatitis. J Gastroenterol
Hepatol 2003;18(12):1332-44.
Page 381
e-Therapeutics+ : Therapeutics : Gastrointestinal Disorders: Constipation in Adults Page 1 of 11
Therapeutic Choice
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Gastrointestinal Disorders: Constipation in Adults
Hugh Chaun, MA, BM, FRCP, FRCP(Ed), FRCPC, FACG
Constipation is a symptom, not a disease. Establishing the cause, if any, and correcting it is the primary objective of
treatment.
Constipation may be defined on the basis of the frequency of defecation (< 3/week) and/or on the presence of other
symptoms as outlined in Table 1.
1
Table 1: Diagnostic Criteria for Constipation
The presence of 2 or more of the following symptoms for at least 12 weeks, which need not be consecutive, during
the last 12 months :
• < 3 defecations per week
• Straining in > 25% of defecations
• Lumpy or hard stools in > 25% of defecations
• A sensation of incomplete evacuation in > 25% of defecations
• A sensation of anorectal obstruction or blockade in > 25% of defecations
• Manual manoeuvres to facilitate > 25% of defecations, e.g., digital evacuation, support of the pelvic floor
Loose stools (including laxative-induced) are not present and the criteria for irritable bowel syndrome are not met
(see Gastrointestinal Disorders: Irritable Bowel Syndrome)
Adapted with permission from Longstreth GF, Thompson WG, Chey WD et al. Functional bowel disorders. Gastroenterology
2006;130:1480-91.
Goals of Therapy
Establish regular bowel function

Abolish the need to strain and prevent the adverse effects of straining, e.g., hernia, coronary and cerebrovascular
dysfunction in the elderly, gastroesophageal reflux, rectal prolapse, aggravation of bladder or uterine prolapse in
females
Prevent complications, e.g., hemorrhoids, anal fissure, rectal prolapse, stercoral ulcer, fecal impaction, fecal
incontinence
Treat complications, e.g., fecal impaction, intestinal obstruction
Prevent adverse effects of laxative dependence, e.g., cathartic colon
Determine “normal” bowel routine for each patient, e.g., some patients may feel a bowel movement every day is
a sign of normal health, but this may not be “normal” for everyone
Investigations

duration of constipation
the most distressing features of constipation: infrequency, straining, hard stool, unusual toilet postures to
facilitate stool expulsion, digital manipulation, feeling of incomplete bowel evacuation, bloating, pain
previous laxative use
dietary fibre and fluid
physical inactivity or immobilization
drugs with constipating effects (see Table 2)
neuropsychiatric disorders (including depression in the elderly)
symptoms of obstructive disease (colonic neoplasm or stricture, anal stricture), painful hemorrhoid or
fissure, pregnancy, neurologic disease, endocrine disorder (hypothyroidism, diabetes mellitus), collagen
vascular disease (progressive systemic sclerosis)
Table 2: Drugs with Constipating Effects
Anticholinergic agents Calcium channel blockers (e.g., verapamil)
Page 382
Therapeutic Choice
Anticonvulsant agents Diuretics that cause hypokalemia
Antiparkinsonian agents Iron supplements
Antipsychotic agents Opioids (e.g., codeine, morphine)
Antacids containing aluminum or calcium Resins (e.g., cholestyramine, colestipol)
Bismuth preparations Sucralfate
abdominal/perineal/rectal examination looking for abdominal and rectal masses, rectal fissures and
hemorrhoids
Laboratory tests:
CBC
serum electrolytes and creatinine
thyroid-stimulating hormone
fecal occult blood
Sigmoidoscopy
Colonoscopy or double contrast barium enema or on rare occasions CT colonography if: recent onset in patients
over 50 years old;2 severe symptoms; symptoms do not resolve with simple measures; the cause of rectal
bleeding is not demonstrated on sigmoidoscopy; alarm features are present (e.g., weight loss, anemia,
unexplained positive fecal occult blood test); family history of colorectal cancer. Routine use of colonoscopy is
otherwise not recommended
Psychological assessment when appropriate
3 4 5
Transit studies (radiopaque markers, defecography, anorectal manometry ) and anorectal and pelvic floor tests
in selected (usually < 5%) patients
Therapeutic Choices (Figure 1 - Management of Constipation in Adults)
When possible, discontinue drugs with constipating effects (see Investigations ).

Encourage dietary fibre (20–30 g/day),6 , 7 flax seed, psyllium, unprocessed bran, whole grains, fruits and
vegetables. Increase the daily amount gradually to minimize side effects such as flatulence, bloating and
unpleasant taste.
Lactose-containing dairy products (milk, yogurt, young cheese) are an effective and natural cathartic in patients
with lactase deficiency.8
Increase fluid intake (at least 8 glasses of water or other liquids per day).
Recommend prune juice, stewed prunes or figs.
Encourage regular scheduled time for toilet use, for example, after breakfast, to develop a conditioned
gastrocolic reflex.
Advise patients not to ignore the urge to defecate.
Advise avoidance of prolonged straining.
9
Encourage physical exercise.
For constipation due to defecatory disorders, recommend relaxation exercises for the pelvic floor and external
10 , 11
anal sphincter muscles in conjunction with biofeedback.
Digital manipulation of the anal sphincter may help in patients with motility problems, e.g., those with spina
bifida.
In general, use drug therapy only when nonpharmacologic approaches have failed. Moreover, nonpharmacologic
therapy should be continued and reinforced when drug therapy is initiated.
Bulk-forming agents can be safely used for long-term therapy, but must be taken with adequate fluids.
Use osmotic and stimulant laxatives as sparingly as possible to reduce side effects and avoid dependence12
(short-term intermittent therapy, on an as-needed basis, once or twice weekly at most).
At times, a more expensive agent such as polyethylene glycol 3350 is required,13 , 14 and if necessary,
electrolyte lavage solutions.
Seek the patient's understanding and cooperation regarding general principles of therapy, and monitor laxative
tolerance.
To discontinue chronic laxative use, gradually reduce the frequency of use over 3–4 weeks, while optimizing
nonpharmacologic approaches; use an osmotic laxative (e.g., lactulose) intermittently until bowel regularity is
achieved.
Page 383
Therapeutic Choice
Start patients with a narcotic prescription on a stimulant laxative or lactulose at the same time to prevent opioid-
induced constipation.
Methylnaltrexone, a µ-opioid antagonist, is indicated for the treatment of opioid-induced constipation in
patients receiving palliative care. It is used as adjunctive treatment when response to laxatives has been
insufficient; however, more data is needed to determine its place in therapy.15
Choices During Pregnancy and Lactation
Constipation and Pregnancy/Postpartum Period
Constipation is a common condition during pregnancy; a greater prevalence is observed during the first 2 trimesters
relative to the third trimester and the postpartum period.16 , 17 In late pregnancy, constipation is attributed to
18 , 19
increased circulating progesterone which reduces gastrointestinal motility. Constipation in pregnancy is
commonly associated with symptoms of straining, hard stools and incomplete evacuation but not infrequent
defecation.16 Iron supplementation during pregnancy may cause constipation.
Management of Constipation during Pregnancy

17 , 20
Offer lifestyle choices such as adequate water (> 8 glasses/day) and dietary fibre (20–35 g/day) intake.
Because they are not systemically absorbed, bulk-forming agents containing psyllium and methylcellulose are
considered first-line.20 They increase defecation frequency and soften the stools.21 If constipation persists, especially
as heartburn is frequent during the third trimester, the laxative effect of a magnesium-containing liquid antacid
may be helpful. Stimulant laxatives such as senna and bisacodyl may be recommended short-term.20 There is
limited human data for cascara sagrada; intermittent use, and not regular use, is preferred.20 A Cochrane review
concluded that stimulant laxatives are more effective than fibre; however, they may be considered as an alternative to
fibre due to their side effect profile.21
Lactulose and polyethylene glycol may be considered if constipation is refractory to dietary fibre and stimulant
20
laxatives.
Avoid castor oil because it can induce premature uterine contractions. Chronic use of emollient laxatives such as
20
mineral oil can interfere with absorption of fat-soluble vitamins.
Docusate, a stool softener, reduces surface tension which allows the bowel to retain water by osmotic effects. It
may be used as adjunct therapy especially if hemorrhoids are present.20
Management of Constipation in Breastfeeding Women
As in pregnancy, offer lifestyle choices in breastfeeding women.
Bulk-forming agents are preferred as they are not systemically absorbed, have a lower cost and a favourable side
effect profile. Magnesium hydroxide may be considered as second-line. The American Academy of Pediatrics lists
22
senna and cascara sagrada as “usually compatible” with breastfeeding; however, stimulant laxatives are
recommended only for short-term use. Docusate may be used as adjunct, if needed.
There is a paucity of data regarding transfer of other laxatives into breast milk.
Therapeutic Tips
Careful history to determine cause, if any, and whether colonic investigation is indicated.
Encourage optimum dietary and supplementary fibre, increased daily fluid intake and regular physical exercise.
Use laxatives wisely to prevent laxative dependence.
Figure 1-Management of Constipation in Adults
Page 384
Therapeutic Choice
a.
Do not use bulk-forming agents in patients with inadequate fluid intake or those unable to express thirst, e.g., cognitively
impaired, bedbound.
Table 3: Drugs Used in Constipation
Onset
of
a
Class Drug Adult Dose Action Adverse Effects Comments Cost
Bulk-forming psyllium 3.4 g po daily to 12–72 Bloating, Increases stool $

Agents hydrophilic TID h flatulence, weight and
mucilloid abdominal consistency,
Metamucil, discomfort, allergic decreases GI transit
generics reactions (rare), time and increases
esophageal and the frequency of
colonic obstruction defecation.
(rare). Take with plenty of
fluids (at least 250
mL) to prevent
esophageal
obstruction and/or
fecal impaction.
Page 385
Therapeutic Choice
Onset
of
a
Can be used long

term.
Advise patients to
not take psyllium
within 2 hours of
taking any other
medications.
Bulk-forming polycarbophil 1250 mg (2 12–72 Bloating, Increases stool $-$$

Agents calcium caplets) po daily h flatulence, weight and
Prodiem Caplets to QID, not to abdominal consistency,
exceed 8 discomfort, allergic decreases GI transit
caplets/24 h reactions (rare), time and increases
mL) to prevent
esophageal
obstruction and/or
fecal impaction.
Can be used long

term.
Advise patients to
not take psyllium
within 2 hours of
taking any other
medications.
Bulk-forming sterculia gum One 7 g sachet 12–72 Bloating, Increases stool $

Agents Normacol daily to BID h flatulence, weight and
abdominal consistency,
discomfort, allergic decreases GI transit
reactions (rare), time and increases
mL) to prevent
esophageal
obstruction and/or
fecal impaction.
Can be used long

term.
Advise patients to
not take psyllium
within 2 hours of
taking any other
medications.
Hyperosmotic glycerin 2.6 g pr daily to 15 min Rectal discomfort Stimulates $

Agents Glycerin BID or PRN –1 h or burning. peristalsis.
Page 386
Therapeutic Choice
Onset
of
a
Suppositories, Insert high into
generics rectum and retain for
15 min if possible
Hyperosmotic lactulose 15–30 mL po daily 24–48 Bloating, Induces bowel water $

Agents Apo-Lactulose, to BID h flatulence, cramps, retention, improves
other generics diarrhea. stool consistency
and increases the
frequency of
defecation.
Lubricants mineral oil 15–45 mL po daily po: 6–8 Lipoid pneumonia Use the oral dosage Oral:$;
Fleet Enema Enema: 120 mL as h if aspirated. form with extreme Enema:
Mineral Oil, a single dose Enema: Seepage from caution because of $$$$
Lansoyl, 2–15 rectum causing the risk of aspiration
generics min pruritus and pneumonia.
irritation. Stool softeners
increase absorption
of mineral oil (do
not use together).
Use only for short

periods.
↓ absorption of fat-
soluble vitamins.
Osmotic magnesium 3.75–7.5 g (75– 30 min Hypermagnesemia Osmotic agents: $-$$

Agents citrate 150 mL) po daily. –6 h in renal dysfunction stimulate peristalsis.
Follow doses with ++ Useful for rapid
Citro-Mag, (Mg salts).
generics 250 mL water response (e.g.,
colonoscopy,
preoperatively).
Magnesium-
containing agents:
avoid in renal failure
(risk of
hypermagnesemia);
↓ absorption of
quinolones and
tetracyclines
(administer at
separate times).
Osmotic magnesium 2.4–4.8 g (30–60 30 min Hypermagnesemia Osmotic agents: $

Agents hydroxide mL) once daily or –6 h in renal dysfunction stimulate peristalsis.
in divided doses ++ Useful for rapid
Milk of (Mg salts).
Magnesia, response (e.g.,
generics colonoscopy,
preoperatively).
Magnesium-
containing agents:
(risk of
hypermagnesemia);
↓ absorption of
quinolones and
tetracyclines
(administer at
separate times).
Page 387
Therapeutic Choice
Onset
of
a
Osmotic magnesium 10–30 g 30 min Hypermagnesemia Osmotic agents: $

Agents sulfate (dissolved in 240 –6 h in renal dysfunction stimulate peristalsis.
mL water or juice) ++ Useful for rapid
Epsom Salts, (Mg salts).
generics once daily or response (e.g.,
divided doses colonoscopy,
preoperatively).
Magnesium-
containing agents:
(risk of
hypermagnesemia);
↓ absorption of
quinolones and
tetracyclines
(administer at
separate times).
Osmotic polyethylene 17 g po daily 1–2 h Common: nausea, May require $

Agents glycol 3350 cramping, diarrhea, treatment for 2–4
Lax-A-Day, Rare: hives, skin days to produce a
Pegalax, rash. bowel movement.
Restoralax
Add powder to 250
mL of water, juice,
soda, coffee, tea and
stir until completely
dissolved.
PEG is not absorbed.
May consider in
patients with renal or
cardiac dysfunction
as does not contain
electrolytes.
Osmotic sodium 120 mL (26.4 g) 2–15 Hyperphosphatemia Osmotic agents: $

Agents phosphates, pr as a single min in patients with stimulate peristalsis.
enema dose renal dysfunction. Useful for rapid
Fleet Enema, response (e.g.,
generics colonoscopy,
preoperatively).
Avoid in renal failure
(risk of
hyperphosphatemia).
Osmotic sodium 20 mL po daily 30 min Hyperphosphatemia Osmotic agents: $$

Agents phosphates, oral Dilute in 120 mL –6 h in patients with stimulate peristalsis.
cool water or clear renal dysfunction. Useful for rapid
generics liquid. Follow 240 response (e.g.,
mL cool water or Risk of arrhythmias colonoscopy,
clear liquid. if exceed preoperatively).
recommended daily Associated with
dose. decline in GFR in the
23
elderly.
Use as bowel
cleanser not
24
recommended.
Page 388
Therapeutic Choice
Onset
of
a
Avoid in renal failure
(risk of
hyperphosphatemia).
Stimulant bisacodyl 5–10 mg po daily po: 6– Abdominal pain, Stimulate colonic Tablet:$
Agents Dulcolax, or PRN 12 h cramps, cathartic peristalsis. Supp: $
Carters Little Suppository: 10 Rectal: colon. Usually short-term
mg pr daily or 15 min Rectal microscopic use only but long-
Pills, generics
PRN –1 h mucosal changes term use may be
with suppository necessary and is
and enema. suitable in patients
on long-term opioid
therapy, e.g., cancer
patients.
Stimulant castor oil 1–3 h Abdominal pain, Stimulate colonic $-$$$

Agents generics 15–60 mL po daily cramps. peristalsis.
Usually short-term
use only but long-
term use may be
necessary and is
suitable in patients
on long-term opioid
patients.
Stimulant senna 16.2–32.4 mg 6–12 h Abdominal pain, Stimulate colonic $

Agents Senokot (2–4 tablets) at cramps, cathartic peristalsis.
Preparations, bedtime (max 8 colon. Usually short-term
others tablets/day) Melanosis coli use only but long-
(anthraquinone term use may be
derivatives). necessary and is
suitable in patients
on long-term opioid
patients.
Some senna
preparations have
high sugar content.
Stool docusate sodium 100 mg po daily 12–72 Act as surfactants. $

Softeners Colace, generics to BID h Often used as 'stool
softeners' after rectal
surgery and in long-
term opioid users,
but there are no
documented
beneficial effects.
Stool docusate calcium 240 mg po daily 12–72 Act as surfactants. $

Softeners generics to BID h Often used as 'stool
softeners' after rectal
surgery and in long-
term opioid users,
but there are no
Page 389
Therapeutic Choice
Onset
of
a
documented
beneficial effects.
Lavage electrolyte 1000–4000 mL po 30 min Retching, nausea, Contain mainly $$$$

Solutions solutions prior to –1 h abdominal fullness sodium sulfate and
PegLyte, Colyte, gastrointestinal and bloating. polyethylene glycol.
Klean-Prep, examinations or Excellent cleansing
generics procedures for colonoscopy.
Klean-Prep is
available as 4 × 1 L
sachets.
Lavage picosulfate 2 sachets po: < 3–6 Retching, nausea, Excellent cleansing $$$$
Solutions sodium / taken on day h abdominal fullness for colonoscopy.
magnesium before procedure and bloating. Better tolerated.
oxide / citric acid given at 8:00 am
Pico-Salax and then between
2:00 pm and 4:00
pm
µ-opioid methylnaltrexone 38–< 62 kg: 4h Abdominal pain, For the treatment of $40
Receptor Relistor nd flatulence, nausea, opioid-induced
8 mg sc every 2
Antagonists day increased body constipation in
62–< 114 kg: temperature, patients with
12 mg sc every dizziness. advanced illness
nd receiving palliative
2 day
care.
a.
Cost per day; includes drug cost only.
Legend: $ < $1 $-$$ < $1–2 $$ $1–2 $-$$$ < $1–3 $$$ $2–3 $$$$ > $3
Suggested Readings
American College of Gastroenterology Chronic Constipation Task Force. An evidence-based approach to the
management of chronic constipation in North America. Am J Gastroenterol 2005;100(Suppl 1):S1-4.
Brandt LJ, Prather CM, Quigley EM et al. Systematic review on the management of chronic constipation in North
America. Am J Gastroenterol 2005;100(Suppl 1):S5-21.
Lembo A, Camilleri M. Chronic constipation. N Engl J Med 2003;349(14):1360-8.
Wilson JA. Constipation in the elderly. Clin Geriatr Med 1999;15(3):499-510.
References
1. Thompson WG, Longstreth GF, Drossman DA et al. Functional bowel disorders and functional abdominal pain.
Gut 1999;45(Suppl 2):II43-7.
2. Locke GR, Pemberton JH, Phillips SF. American Gastroenterological Association medical position statement:
guidelines on constipation. Gastroenterology 2000;119(6):1761-6.
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3. Hinton JM, Lennard-Jones JE, Young AC. A new method for studying gut transit times using radioopaque
markers. Gut 1969;10(10):842-7.
4. Shorvon PJ, McHugh S, Diamant NE et al. Defecography in normal volunteers: results and implications. Gut
1989;30(12):1737-49.
5. Barnett JL, Hasler WL, Camilleri M. American Gastroenterological Association medical position statement on
anorectal testing techniques. American Gastroenterological Association. Gastroenterology 1999;116(3):732-60.
6. Cummings JH. Constipation, dietary fibre and the control of large bowel function. Postgrad Med J 1984;60
(709):811-9.
7. Badiali D, Corazziari E, Habib FI et al. Effect of wheat bran in treatment of chronic nonorganic constipation. A
double-blind controlled trial. Dig Dis Sci 1995;40(2):349-56.
8. Adolfsson O, Meydani SN,.Russell RM. Yogurt and gut function. Am J Clin Nutr 2004;80(2):245-56.
9. De Schryver AM, Keulemans YC, Peters HP et al. Effects of regular physical activity on defecation pattern in
middle-aged patients complaining of chronic constipation. Scand J Gastroenterol 2005;40(4):422-9.
10. Chiarioni G, Salandini L, Whitehead WE. Biofeedback benefits only patients with outlet dysfunction, not
patients with isolated slow transit constipation. Gastroenterology 2005;129(1):86-97.
11. Chiarioni G, Whitehead WE, Pezza V et al. Biofeedback is superior to laxatives for normal transit constipation
due to pelvic floor dyssynergia. Gastroenterology 2006;130(3):657-64.
12. Velio P, Bassotti G. Chronic idiopathic constipation: pathophysiology and treatment. J Clin Gastroenterol
1996;22(3):190-6.
13. Andorsky RI, Goldner F. Colonic lavage solution (polyethylene glycol electrolyte lavage solution) as a treatment
for chronic constipation: a double-blind, placebo-controlled study. Am J Gastroenterol 1990;85(3):261-5.
14. Corazziari E, Badiali D, Habib FI et al. Small volume isosmotic polyethylene glycol electrolyte balanced solution
(PMF-100) in treatment of chronic nonorganic constipation. Dig Dis Sci 1996;41(8):1636-42.
15. McNicol ED, Boyce D, Schumann R et al. Mu-opioid antagonists for opioid-induced bowel dysfunction.
16. Bradley CS, Kennedy CM, Turcea AM et al. Constipation in pregnancy: prevalence, symptoms, and risk factors.
Obstet Gynecol 2007;110(6):1351-7.
17. Derbyshire E, Davies J, Costarelli V et al. Diet, physical inactivity and the prevalence of constipation throughout
and after pregnancy. Matern Child Nutr 2006;2(3):127-34.
18. Lawson M, Kern F, Everson GT. Gastrointestinal transit time in human pregnancy: prolongation in the second
and the third trimesters followed by postpartum normalization. Gastroenterology 1985;89(5):996-9.
19. Wald A, Van Thiel DH, Hoechstetter L et al. Effect of pregnancy on gastrointestinal transit. Dig Dis Sci 1982;27
(11):1015-8.
20. American College of Gastroenterolgy. Pregnancy in gastrointestinal disorders. Bethesda (MD): ACG; 2007.
Available from: www.gi.org/physicians/pdfs/PregnancyMonograph.pdf. Accessed December 14, 2009.
21. Jewell DJ, Young G. Interventions for treating constipation in pregnancy. Cochrane Database Syst Rev 2001;
(2):CD001142.
22. American Academy of Pediatrics Committee on Drugs. The transfer of drugs and other chemicals into human
milk. Pediatrics 2001;108(3):776-89.
23. Khurana A, McLean L, Atkinson S et al. The effect of oral sodium phosphate drug products on renal function in
adults undergoing bowel endoscopy. Arch Intern Med 2008;168(6):593-7.
24. Health Canada. Health Canada warns that use of oral sodium phosphate products for bowel cleansing may lead
to kidney injury. Ottawa (ON): Health Canada; March 5, 2009. Available from: www.hc-sc.gc.ca/ahc-
asc/media/advisories-avis/_2009/2009_37-eng.php. Accessed December 14, 2009.
Pharmacoeconomic Considerations: Constipation

Date of preparation: June 2007
Epidemiology
Country (Year) Prevalence (%)

1 27.2% of adults self-reported constipation within the previous 3 months.
Canada (2000)
Prevalence in women was twice that in men.
Canada, United Kingdom, 10–15%

United States2 30–40% of those aged > 65 years
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Country and Year of

Estimate Direct Costsa Indirect Costsb
United States4 Not reported 13.7 million days of restricted activity

3.42 million days of bed disability
United States6 US $2253 per nursing home resident Not reported
Commentary
Constipation is an economic burden for patients, health care providers and society. Constipation is more common
1 3 , 4
in females, and increases in prevalence with increasing age (30–40% in those over age 65). Direct costs are
largely those associated with over-the-counter and prescription drugs and physician consultations. Indirect costs of
4
constipation are associated with days of restricted activity and bed disability days. In long-term care or nursing
homes, reductions in the frequency and severity of complications of constipation can lead to a decrease in
7
pharmacy expenditures. Complications of constipation (impaction, pain, incontinence and perforation) may incur
direct and indirect medical costs.
Quality of life is impaired in patients with constipation when compared to nonconstipated individuals. Drug
2
treatments for constipation improve quality of life. Medications for constipation are typically not the largest cost
drivers.
There have been few formal economic analyses published for treatments associated with the care of
constipation.8 , 9 , 10 All studies showed that the cost drivers for the studies were not medications but rather the
cost of physician consultations or visits.
a.
Direct costs include those associated with physician services, nursing care, diagnostic procedures, drugs and hospitalization.
b.
Indirect costs include those associated with lost productivity and days off work due to morbidity or premature mortality.
1. Pare P, Ferrazzi S, Thompson WG et al. An epidemiological survey of constipation in Canada: definitions,

rates, demographics and predictors of health care seeking. Am J Gastroenterol 2001;96(11):3130-7.
2. Dennison C, Prasad M, Lloyd A et al. The health-related quality of life and economic burden of constipation.
Pharmacoeconomics 2005;23(5):461-76.
3. Stewart RB, Moore MT, Marks RG et al. Correlates of constipation in an ambulatory elderly population. Am J
Gastroenterol 1992;87(7):859-64.
4. Sonnenberg A, Koch TR. Epidemiology of constipation in the United States. Dis Colon Rectum 1989;32(1):1-8.
5. Passmore AP. Economic aspects of pharmacotherapy for chronic constipation. Pharmacoeconomics 1995;7
(1):14-24.
6. Frank L, Schmier J, Kleinman L et al. Time and economic cost of constipation in nursing homes. J Am Med Dir
Assoc 2002;3(4):215-23.
7. Hull C, Greco RS, Brooks DL. Alleviation of constipation in the elderly by dietary fiber supplementation. J Am
Geriatr Soc 1980;28(9):410-4.
8. Christie AH, Culbert P, Guest JF. Economic impact of low dose polyethylene glycol 3350 plus electrolytes
compared with lactulose in the management of idiopathic constipation in the UK. Pharmacoeconomics 2002;20
(1):49-60.
9. Lederle FA, Busch DL, Mattox KM et al. Cost-effective treatment of constipation in the elderly: a randomized
double-blind comparison of sorbitol and lactulose. Am J Med 1990;89(5):597-601.
10. Passmore AP, Wilson-Davies K, Stoker C et al. Chronic constipation in long stay elderly patients: a comparison
of lactulose and a senna-fibre combination. BMJ 1993;307(6907):769-71.
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e-Therapeutics+ : Therapeutics : Gastrointestinal Disorders: Diarrhea Page 1 of 14
Therapeutic Choice
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Gastrointestinal Disorders: Diarrhea

Richard N. Fedorak, MD, FRCPC
Anna M. Borowiec, MD
Clinically, diarrhea is present when an alteration in a normal bowel habit occurs; it is characterized by a decrease in
consistency to soft or liquid and an increase in frequency to ≥3 stools/day. Increased loss of fecal water and
electrolytes occurs with the increased excretion of fecal matter. Patients who have other gastrointestinal symptoms,
such as fecal incontinence or fecal urgency or who notice a change in stool consistency, may refer to it as
“diarrhea.” These symptoms will need to be ruled out before a diagnosis of “true diarrhea” is given.
Diarrhea may be acute (<14 days in duration), persistent (>14 days in duration) or chronic (>30 days in duration).
Acute diarrhea may be caused by infections, medications, food intolerance and intestinal disease (see Table 1).
Causes of persistent and chronic diarrhea include post-infectious episode of irritable bowel syndrome and persistent
and/or repeated infections.
Goals of Therapy
Reduce symptoms and re-establish normal fecal weight (volume)

Prevent and treat complications, i.e., dehydration, electrolyte depletion, nutrient malabsorption, hemorrhoids,
rectal prolapse
Remove or eradicate the cause of diarrhea where applicable
, 2 , 3
Investigations1
Key Questions Prior to Treatment:
What is the patient’s history? Obtain a thorough history that includes the following clinical and epidemiologic
features:
when and how the illness began (duration of symptoms; abrupt or gradual onset)
stool characteristics (watery, bloody, mucousy, greasy)
frequency of bowel movements and quantity of stool produced
symptoms of volume depletion (thirst, tachycardia, orthostatic hypotension, decreased urination, lethargy,
decreased skin turgor)
associated systemic symptoms and their frequency and intensity (nausea, vomiting, abdominal pain,
cramps, headache, fever, myalgias, altered sensorium)
changes in diet
medication history including use of prescription and over-the-counter drugs, herbal or “natural” products
and dietary supplements
recent travel history (see Infectious Diseases: Travellers' Diarrhea), locale of employment and residence
and other family members or co-workers that have a similar illness
Is this true diarrhea? Many people who complain of diarrhea actually have a motility disturbance, e.g., irritable
bowel syndrome. They experience an increased frequency of very small bowel movements, but the 24-hour
stool weight does not exceed normal amounts. When clinically indicated, measuring fecal fat, osmolarity and
bile acid levels can also help determine specific etiologies.
Is the diarrhea acute or chronic? In the absence of fever, dehydration or bloody stools, the management of
acute diarrhea should alleviate symptoms rather than provide a specific diagnosis or therapy. Acute diarrhea
(Figure 1 - Evaluation of Acute Diarrhea, Figure 2 - Management of Antibiotic-associated Diarrhea, Table 1) is
frequently caused by viral agents, drugs or food toxins for which there is no specific therapy, and usually remits
spontaneously within less than 1 week. Acute infectious diarrhea of a bacterial or parasitic etiology should be
identified early to permit early successful intervention. Evaluate chronic diarrhea as in Figure 3 - Evaluation of
Chronic Diarrhea.
Acute Diarrhea
Critical to disease therapy and prevention is discerning the etiology of acute diarrhea as presented in Table 1.
Table 1: Etiology of Acute Diarrhea

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Etiology Examples
Infectious Bacterial Shigella, Salmonella (typhi, enteritidis), Campylobacter, Yersinia, Escherichia coli
(EHEC 0157:H7, ETEC, EPEC), Clostridium (difficile, perfringens) Vibrio (cholerae,
parahaemolyticus), Staphylococcus aureus, Bacillus cereus
Viral Norovirus (Norwalk virus), rotavirus, adenovirus, cytomegalovirus, herpes simplex

virus
Parasitic Cryptosporidium, Microsporidia, Entamoeba histolytica, Giardia lamblia, Cyclospora
Medications Antibiotics, colchicine, laxatives, magnesium-containing antacids
Food Intolerance Lactose
Intestinal Disease Celiac disease, inflammatory bowel disease (ulcerative colitis, Crohn’s disease)
(acute episode)
Infectious Diarrhea3 (Figure 1 - Evaluation of Acute Diarrhea)
Proctitis can be diagnosed with sigmoidoscopy. Involvement of only the distal 15 cm suggests herpes virus,
gonococcal, chlamydial or syphilitic infection. Colitis extending more proximally suggests Campylobacter,
Shigella, Clostridium difficile or chlamydial (LGV serotype) infection.
An inflammatory etiology (e.g., invasive colitis due to Salmonella, Shigella or Campylobacter; C. difficile colitis,
inflammatory bowel disease) can be suspected on the basis of fever, tenesmus or bloody stools. Microscopy for
fecal leukocytes or fecal lactoferrin testing may confirm inflammation. A meta-analysis and a recent review of
the diagnostic test accuracy for fecal leukocytes demonstrated a sensitivity of only 70% and a specificity
ranging from 50–84%.1 , 3 Fecal lactoferrin has a higher sensitivity and specificity of 90% and 79%,
respectively, but is not widely available.4
Consider tests for parasitic causes of diarrhea including fluorescence and enzyme immunoassay for Giardia and
Cryptosporidium and acid-fast stains for Cryptosporidium, Cyclospora, Isospora or Mycobacterium species.
Any diarrheal illness accompanied by fever, bloody stools, systemic illness, recent use of antibiotics, daycare
centre attendance, hospitalization or dehydration should prompt evaluation of a fecal specimen, including stool
cultures plus other investigations as noted below and in Figure 1 - Evaluation of Acute Diarrhea. In patients
who do not appear unwell or do not have the above symptoms, the necessity of documenting a pathogen is
often not needed, since acute diarrheal episodes are generally self-limiting and resolve within several days.
Selective fecal testing can improve the yield and usefulness of stool testing and should be adopted whenever
possible using the following guidelines:
consider E. coli 0157 in persons with a history of undercooked red meat ingestion and acute bloody
diarrhea or hemolytic uremic syndrome, as well as those with marked abdominal pain and bloody diarrhea
but without high fever
consider Vibrio parahaemolyticus in persons who have ingested shellfish within the 3 days before the illness
began
consider Yersinia enterocolitica in fall or winter and in certain at-risk populations (e.g., Asians and African-
American infants), as well as those with persistent abdominal pain and fever
consider a C. difficile toxin assay in hospitalized patients and those who have taken antimicrobial agents
within the last 8 weeks
immunocompromised patients or those with significant comorbidities that increase the risk for
complications
patients with inflammatory bowel disease in whom distinction between a flare and superimposed infection
is critical
fecal specimens from patients with diarrhea that develops after 3 days of hospitalization have a very low
yield when cultured for standard bacterial pathogens (Campylobacter, Salmonella, Shigella, etc.) or
examined for ova and parasites
consider Norwalk virus (a norovirus) in patients with nausea, vomiting, intense cramping and watery
diarrhea. The disease is self-limited and usually lasts 48–72 hours. The virus is spread by ingestion of
feces-contaminated water (including that in swimming pools) or food, contact with contaminated
environments or individuals with the illness. The virus is shed in vomitus and the stool for at least 24–48
hours after the onset of illness. Given the classic clinical presentation and rapid recovery, the specific viral
diagnosis is not necessary in adult gastroenteritis.
Ask patients about potential epidemiologic risk factors for particular diarrheal diseases or for their spread:
travel to a developing country (see Infectious Diseases: Travellers' Diarrhea)
daycare centre attendance or employment
visitation or employment in acute-care or long-term care facilities
ingestion of unsafe foods (e.g., raw meats, eggs or shellfish; unpasteurized milk or juices)
swimming in or drinking untreated water
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visiting a farm or petting zoo or having contact with pets with diarrhea
knowledge of other ill family members or co-workers
recent antibiotic use
underlying medical conditions predisposing to infectious diarrhea (e.g., AIDS, immunosuppressive
therapies, previous gastrectomy, extremes of age)
where appropriate, receptive anal intercourse or oral-anal sexual contact
occupation as a food-handler or caregiver
3
For persons with AIDS, a modified algorithm for the investigation and management of diarrhea is available.
Antibiotic-associated Diarrhea (Figure 2 - Management of Antibiotic-associated Diarrhea)
Antibiotic-associated diarrhea is diarrhea that occurs during or shortly after administration of an antibiotic. The
use of any antibiotic can alter the commensal gastrointestinal microflora and lead to diarrhea in approximately 5
5
–35% of patients. Most cases of antibiotic-associated diarrhea are mild and resolve spontaneously. The
pathogenesis of antibiotic-associated diarrhea can vary and includes accelerated gastrointestinal motility (e.g.,
erythromycin), osmotic diarrhea due to decreased carbohydrate metabolism by colonic anaerobes or
opportunistic infections, alterations in intestinal absorption and/or secretion, bacterial overgrowth syndromes
and C. difficile infection.
C. difficile infection is the most common bacterium responsible for antibiotic-associated infectious diarrhea.
Other rare infections described include S. aureus, Salmonella, C. perfringens and Candida species.
The spectrum of symptoms associated with C. difficile infection range from no symptoms (carrier state) through
watery diarrhea to toxic megacolon.
Diagnosis consists of detection of C. difficile toxin in the stool or presence of characteristic pseudomembranous
colitis on endoscopy. Since pseudomembranes can be limited to the right side of the colon a full colonoscopy is
recommended.
Persistent and Chronic Diarrhea (Figure 3 - Evaluation of Chronic Diarrhea)
For information on diarrhea related to irritable bowel syndrome and inflammatory bowel disease, see
Gastrointestinal Disorders: Irritable Bowel Syndrome and Gastrointestinal Disorders: Inflammatory Bowel Disease.
Therapeutic Choices
Nonpharmacologic Choices2
Discontinue medications that cause diarrhea (e.g., laxatives, antacids containing magnesium, antibiotics,
diuretics, theophylline, cholinergic drugs, promotility agents, prostaglandins, acarbose, orlistat, fluorouracil,
irinotecan).
Stop ingestion of poorly absorbed carbohydrates (e.g., dietetic candies and jams containing sorbitol, mannitol
or xylitol, beverages and foods containing fructose, or lactose-containing dairy products). If the history is
compatible with lactose intolerance, a 2-week trial of a lactose-restricted diet can avoid costly diagnostic work-
ups.
Reduce food intake for 12–24 hours. This will improve the symptoms of acute diarrhea. Maintenance of
adequate fluid and electrolyte intake is important and a bland diet (low fat, low carbohydrate including, for
example, bananas, rice, unsweetened applesauce, clear soup) can be reintroduced once bowel motions have
subsided.
Prevent C. difficile spread via direct contact. Prevention of spread consists of education of patients and health
care providers, good hand hygiene (frequent handwashing) and patient isolation in hospital setting (until
symptom free for 48 hours post initiation of treatment), protective clothing (gowns and gloves) and
6
environmental control (cleaning of medical equipment).
In the case of Norwalk virus, identifying the causative agent allows for institution of appropriate control
measures:
frequent handwashing with soap
wearing of protective barriers such as gloves
careful washing of all fruits and vegetables
appropriate disposal of vomitus (in toilet) and disinfection of potentially contaminated surfaces
infected persons should not prepare foods while they are symptomatic and for 3 days after they have
recovered
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Therapeutic Choice
Acute Diarrhea
Infectious Diarrhea
Oral rehydration therapy (ORT, see Fluid and Electrolyte Disorders: Dehydration in Children) prevents
dehydration and electrolyte loss in both acute and chronic diarrhea. Oral rehydration solutions should have a
balanced sodium-to-glucose ratio. Excess glucose, for example in Jell-O and soda pop, or excess sodium, for
example in Gatorade or other “sports drinks,” may aggravate diarrhea as a consequence of their osmotic effect.
Early use of ORT is essential for young children and the elderly.
Balanced electrolyte oral rehydration solutions are available commercially without prescription (e.g., Gastrolyte,
Pedialyte). If necessary, a similar solution can be made by adding 1 level teaspoon (5 mL) of salt and 8 teaspoons
7
(40 mL) of sugar to 1 litre of water.
Aside from travellers' diarrhea (see Infectious Diseases: Travellers' Diarrhea), empiric antibiotic treatment is not
generally recommended for acute diarrhea because of the self-limiting nature of most illnesses, the cost of
treatment, the potential for promoting antimicrobial resistance and the possibility of adverse drug reactions.7 , 8
Bismuth subsalicylate has been shown to be effective, in small cohort studies, in the treatment of idiopathic
diarrhea and diarrhea caused by microscopic colitis. Although frequently used in acute diarrheas, there is no firm
evidence for its efficacy. The salicylate component can cause gastric and duodenal mucosal damage, particularly in
patients who are also using ASA or NSAIDs. At high doses, the calcium carbonate in the tablet formation can cause
hypercalcemia, hypercalciuria and associated metabolic symptoms. Bismuth-related encephalopathy can result from
the use of doses 10 times those recommended, or after years of use. Black stools due to bismuth may be confused
with melena.
Available opioids include naturally occurring preparations (opium alkaloids) and synthetic preparations (codeine,
diphenoxylate and loperamide). These agents are very effective for symptomatic use in both acute and chronic
diarrhea; however, side effects limit their acute use and tolerance usually occurs with chronic use. Antimotility
effects are not desired if the diarrhea is caused by microorganisms because gastrointestinal stasis may enhance their
7 , 9
invasion. Diphenoxylate and loperamide have fewer CNS side effects than other opioids. Diphenoxylate is
combined with atropine to limit its potential for abuse. Loperamide has the lowest incidence of side effects and
abuse potential, is available without prescription and is effective in patients with radiotherapy- and chemotherapy-
induced diarrhea and in patients with ileo-rectal pouch incontinence. Combining loperamide with simethicone
provides faster and more complete relief of acute diarrhea associated with gas-related abdominal discomfort.10
Consider codeine if sedation or analgesia is also desired.
Probiotics (see Table 3) are nonpathogenic bacteria that, when present in the gut, improve intestinal microbial
balance. Multiple clinical trials have looked at the use of probiotics in the prevention and treatment of
gastrointestinal infections in adults and children. Not all probiotics have the same therapeutic effect and the strains
and mixtures described in clinical trials should be used.
In children, probiotics are effective in reducing the severity and duration of acute rotavirus-induced and
antibiotic-associated diarrhea.11
11
In adults, probiotics are effective in reducing the severity and duration of non-C. difficile-associated diarrhea.
There is no conclusive evidence for the effectiveness of probiotics in the management of traveller’s diarrhea.
Antibiotic-associated Diarrhea
Management of C. difficile-associated diarrhea consists of the following key steps: prompt diagnosis, prevention of
spread, cessation of causative antibiotic, supportive measures in severe cases (hospitalization, rehydration,
correction of electrolyte imbalances) and eradication of C. difficile infection (Figure 2 - Management of Antibiotic-
associated Diarrhea).
Eradication therapy is required in patients with symptoms and confirmed diagnosis of C. difficile infection. Therapy
may be initiated in the absence of a firm diagnosis and in the presence of high suspicion and severe symptoms.
There are no recommendations at this time for treatment of asymptomatic patients (carrier state).
Metronidazole and oral vancomycin are the antibiotics used to treat C. difficile-antibiotic associated diarrhea.
12
Metronidazole is considered first-line therapy. Oral vancomycin is reserved for patients with severe disease, who
13
have failed metronidazole or are unable to take metronidazole (see Table 2). Relapse or reinfection occurs in 10–
25% of patients and should be managed by repeating the first line of therapy used (usually metronidazole).14 , 15
Subsequent relapses should be investigated for other causes of diarrhea and if C. difficile is confirmed treat with oral
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Therapeutic Choice
vancomycin (see Table 2).14 For recurrent C. difficile infections consult a specialist. Vancomycin tapering regimens
and vancomycin pulse regimens extending over 6 weeks, and vancomycin plus Saccharomyces boulardii
16
combinations are advocated for recurrent C. difficile infections.
Two systematic reviews showed there is no role for probiotics alone in the acute treatment of C.
difficile infections in adults and children,17,18 however, some probiotics effectively prevent
C. difficile recurrence. The probiotic Saccharomyces boulardii may be used in conjunction with
antibiotic treatment to prevent C. difficile recurrence.16,19 (See Table 2) Useful Info?
Antimotility agents such as loperamide are not used in symptomatic C. difficile infection because its use increases
20
the risk of toxin retention and precipitation of toxic megacolon.
Though there is no strong evidence advocating its use, cholestyramine's ability to bind luminal C. difficile toxins
has led to its adjunctive use in combination with antibiotic therapy for refractory C. difficile infection.
Persistent and Chronic Diarrhea
See Oral Rehydration Therapy and Opioids discussion in the Acute Diarrhea section.
Hydrophilic Bulking Agents
Psyllium is a hydrophilic agent that increases fecal water-holding capacity and may reduce nonspecific diarrheal
symptoms. In some cases it has been used to bind bacterial-mediated toxins (C. difficile toxin), but its role in the
management of diarrhea is limited. Many psyllium-containing products are mixed with laxatives; avoid these
products in patients with diarrhea.
Cholestyramine resin, in addition to its hydrophilic action, has the ability to bind bile acids. Thus, it is useful in
treating bile acid–induced diarrhea due to malabsorption of bile acids in diseased ileum (e.g., Crohn’s disease) or in
some cases of irritable bowel syndrome where rapid transit results in loss of bile acids into the colon.
Alpha2-adrenergic Agonists
Clonidine may be effective for opioid-withdrawal diarrhea and diarrhea associated with diabetic autonomic
21
neuropathy. Unfortunately, the dose required to achieve an antidiarrheal effect is often associated with sedation,
dry mouth and symptomatic orthostatic hypotension.
Somatostatin Analogues
Somatostatin analogues can be administered sc daily (octreotide) or by im injection monthly (octreotide

acetate, lanreotide acetate). These have been used to control diarrhea caused by neuroendocrine tumors
(VIPoma, carcinoid, medullary carcinoma of the thyroid). Octreotide has also been shown to limit idiopathic and
infant secretory diarrhea, as well as diarrhea associated with ileostomy, short bowel syndrome, diabetic neuropathy,
chemotherapy, bone marrow transplant, cryptosporidia, graft versus host disease and HIV disease.
Somatostatin has a short half-life and requires continuous iv infusion, which limits its role in the management of
diarrhea.
Probiotics
In adults, probiotics have no role in induction or remission maintenance in Crohn’s disease; however, in acute
ulcerative colitis certain preparations (E. coli Nissle) have been shown to be equivalent to low-dose 5-aminosalicylic
acid. In small open trials, certain probiotic preparations (VSL#3) have been shown to decrease the occurrence and
22
severity of post-radiation diarrhea.
Public Health Considerations
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Therapeutic Choice
Food-handlers in the food service industry and health care workers with direct patient contact and diarrhea
should be tested for parasitic and bacterial pathogens due to their potential to transmit the infections to large
numbers of persons
Similarly, daycare attendees and employees, or residents of an institutional facility (nursing home, psychiatric
hospital, prison) with diarrhea should be tested for bacterial, parasitic or viral pathogens since the diarrhea may
be an indicator of an endemic outbreak
Physicians who suspect an endemic diarrheal disease outbreak should report the concern to public health
authorities and, in conjunction with these authorities, initiate appropriate diagnostic testing to facilitate
identification of the pathogenic agent and to define the extent of the outbreak.
Follow-up testing is not generally recommended. However, since food-handlers and health care workers can
transmit bacterial and parasitic diseases even if they are asymptomatic, it is recommended that before returning
to their jobs these persons have 2 consecutive negative stool samples taken 24 hours apart and at least 48
hours after resolution of symptoms.
Therapeutic Tips
Infectious diarrhea can be prevented by following simple rules of personal hygiene and safe food preparation.
Handwashing with soap is an effective step in preventing spread of the illness and should be emphasized for
both patients and their caregivers.
The importance of a balanced electrolyte oral rehydration solution in preventing dehydration and the inability
of nonbalanced electrolyte solutions to achieve rehydration is critical for patients to understand.
Repeated diarrheal illnesses in young children can lead to malnutrition and physical and cognitive growth
impairment.
Specific vaccines are available for prevention of diarrhea due to cholera (V. cholerae) and enterotoxigenic E.
coli in adults and children (see Infectious Diseases: Travellers' Diarrhea), typhoid fever (S. typhi) in adults and
children, and rotavirus in infants.
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Therapeutic Choice
Figure 1- Evaluation of Acute Diarrhea
Figure 2- Management of Antibiotic-associated Diarrhea
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Therapeutic Choice
a.
Mild = <5 stools/day and + abdominal pain.
b.
In patients >65 y and/or with comorbidities, consider more aggressive management (e.g., earlier hospitalization).
c.
Moderate = febrile, ++ abdominal pain and signs of dehydration (dry mucous membranes, tachycardia and ↓ urine output).
d.
Severe = febrile, +++ abdominal pain (or peritonitis), signs of sepsis (e.g., confusion, ↓ blood pressure).
e.
In severe cases, antibiotics should be started even in the absence of confirmed C. difficile infection.
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Therapeutic Choice
Figure 3- Evaluation of Chronic Diarrhea
Table 2: Drugs Used to Treat Diarrhea
Adverse Drug
a
Class Drug Dose Effects Interactions Comments Cost
Antibacterial metronidazole Mild to Nausea, Metronidazole may $

Agents Flagyl, Moderate C. headache, potentiate
generics difficile anorexia, dry warfarin; monitor
diarrhea; 500 mouth, metallic INR when
mg TID po × taste in mouth. metronidazole is
10 days added or
discontinued and
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Therapeutic Choice
Adverse Drug
a
Recurrence of adjust warfarin
C. difficile dose accordingly.
diarrhea; 500 Disulfiram-like
mg TID po × reaction with
10 days ± S. alcohol: avoid
boulardii (see alcohol intake
Table 3) during treatment
Severe C. and for 48 h after
difficile treatment.
diarrhea; 500
mg TID iv in
combination
with
vancomycin
vancomycin Severe C. Bitter taste, Minimal with oral Vancomycin is $$$

Vancocin, difficile nausea, administration. poorly
generics diarrhea; 125 vomiting, absorbed after
mg QID po × stomatitis, oral
14 days ± chills, drug administration.
metronidazole fever,
Second eosinophilia.
recurrence of
mild to
moderate C.
difficile
diarrhea; 250
mg TID po ×
14 days then
tapering or
pulse dosing
(given 3 out of
7 days) × 6
wk, in
combination
with S.
boulardii (see
Table 3)
Bismuth bismuth 30 mL Salicylate ↓ absorption of $

subsalicylate (17.6 mg toxicity, black doxycycline and
Pepto-Bismol BSS/mL) Q30 tongue, black tetracycline.
Liquid, Pepto- min po to a stool, bismuth-
Bismol with maximum of induced
InstaCool, 8 doses/day encephalopathy.
generics
Bismuth bismuth 2 tablets Salicylate ↓ absorption of $

subsalicylate (262 mg toxicity, black doxycycline and
with calcium BSS/tab) Q30 tongue, black tetracycline.
carbonate po min to a stool, bismuth-
Pepto-Bismol maximum of induced
Chewable 8 doses/day encephalopathy.
Tablets Hypercalcemia,
hypercalciuria.
Hydrophilic psyllium 1 teaspoon (5– Inhalation of Take with $

Bulking hydrophilic 6 g) Q12H po psyllium powder fluids.
Agents mucilloid may cause Avoid
Metamucil combinations
with laxatives.
Page 402
Therapeutic Choice
Adverse Drug
a
Preparations, allergic
generics reactions.
Hydrophilic cholestyramine 4 g Q12H po Nausea, fat May bind drugs, Take with $
Bulking resin soluble vitamin e.g., digoxin, in fluids.
Agents Olestyr, deficiency with GI tract; do not
generics long-term use, take within 1 h
constipation. before or 4–6 h
after other
medications.
Opioids loperamide 2 mg po after Sedation, $

Imodium each loose nausea,
Caplets, bowel abdominal
movement cramps.
Imodium Oral
(maximum of Lowest addiction
Solution, 16 mg/day) potential of all
Imodium Quick opioids.
Dissolve, Riva-
Loperamide,
generics
Opioids diphenoxylate 5 mg po Sedation, Additive The elderly are $

with atropine initially then nausea, anticholinergic more
sulfate 2.5 mg po abdominal effects with other susceptible to
Lomotil after each cramps, dry skin anticholinergic the
loose bowel and mucous agents. antimuscarinic
movement membranes effects of
(maximum of (from atropine), atropine, e.g.,
20 mg/day) some addiction agitation,
potential. drowsiness, ↑
intraocular
pressure.
Opioids codeine 30–60 mg Q4H Sedation, Additive CNS $

generics PRN po nausea, depression with
tolerance, CNS depressants.
potentially
addictive.
Alpha2- clonidine 0.1–0.6 mg Centrally Additive effects $

adrenergic Catapres, Q12H po mediated with drugs that
Agonists generics sedation and cause
hypotension. hypotension.
Somatostatin octreotide 50–500 µg Pain at injection May ↓ insulin $$$

Analogues Sandostatin, Q12H sc site, nausea, resistance; ↑ risk of
generics mild diarrhea. low blood sugar
with concurrent
use of
antihyperglycemic
agents.
Somatostatin octreotide 10–30 mg Pain at injection $1325–

Analogues acetate monthly im site, nausea, $2195/mo
Sandostatin mild diarrhea.
LAR
Somatostatin lanreotide 60 mg monthly Pain at injection $1105/mo

Analogues acetate im site, nausea,
Somatuline mild diarrhea.
autogel
a.
Cost of 1-day supply except Sandostatin LAR and Somatuline autogel; includes drug cost only.
Abbreviations: BM=bowel movement; BSS=bismuth subsalicylate; IBS=irritable bowel syndrome; INR =international
Page 403
Therapeutic Choice
normalized ratio; LAR =long-acting release
Legend: $ <$5 $$ $5–15 $$$ $15–80
Table 3: Probiotic Products Used to Treat Diarrhea
Adverse Drug Costa

Probiotics Saccharomyces 1 capsule (250 mg) Constipation, A yeast; There have been $$
boulardii contains 5 billion bloating. therefore, do rare reports of
Florastor organisms not administer fungemia in
1 capsule BID po × 3–5 with antifungal patients with a
days, maximum 3 agents. central venous
capsules per day catheter.
In combination with
metronidazole, for
recurrence of
C. difficile- associated
diarrhea: 2 capsules
BID po × 14–21 days
In combination with
vancomycin for second
recurrence of C. difficile
diarrhea: 2 capsules
BID po × 12 mo
Probiotics Lactobacillus 1 capsule contains at ~ 2% of A bacterium; May contain $$

GG least 10 billion bacteria patients report therefore, do traces of casein
Culturelle Adults: 1–2 capsules bloating and not administer or whey. Does
daily po gas for a few with antibiotics. not ferment
days. lactose;
unhelpful for
lactose
intolerance.
Probiotics lactic acid Packets contain 450 × No evidence of A mixture of Has been studied $$
bacterial 9 adverse health bacteria; in patients with
10 freeze-dried lactic
mixture acid bacteria effects. therefore, do radiation-induced
VSL#3 (Bifidobacterium breve, not administer diarrhea, Crohn’s
B. longum, B. infantis, with antibiotics. disease,
L. acidophilus, L. ulcerative colitis,
plantarum, L. casei, L. ileal pouch
bulgaricus, anastomosis and
Streptococcus IBS.
thermophilus) in a
defined ratio.
The dose is based on
the frequency of BM
Adults: 1–2 packets/day
po if <5 BM; 2–4
packets/day po if 5–8
BM; 4 packets/day po if
>8 BM
a.
Cost of 1-day supply.
Abbreviations: BM =bowel movement; IBS =irritable bowel syndrome
Legend: $ <$5 $$ $5–15
Suggested Readings
Aranda-Michel J, Giannella RA. Acute diarrhea: a practical review. Am J Med 1999;106(6):670-6.
Page 404
Therapeutic Choice
Fedorak RN. Anti-diarrheal therapy. In: Friedman G, Jacobson ED, McCallum RW, editors. Gastrointestinal
pharmacology and therapeutics. Philadelphia (PA): Lippincott-Raven; 1997. p. 175-93.
Fine KD, Schiller LR. AGA technical review on the evaluation and management of chronic diarrhea. Gastroenterology
1999;116(6):1464-86.
Theilman NM, Guerrant RL. An algorithmic approach to the workup and management of HIV-related diarrhea. J Clin
Outcomes Manag 1997;4:36-47.
Thielman NM, Guerrant RL. Clinical practice. Acute infectious diarrhea. N Engl J Med 2004;350(1):38-47.
References
1. DuPont HL. Guidelines on acute infectious diarrhea in adults. The Practice Parameters Committee of the
American College of Gastroenterology. Am J Gastroenterol 1997;92(11):1962-75.
2. Schiller LR. Chronic diarrhea. Gastroenterology 2004;127(1):287-93.
3. Thielman NM, Guerrant RL. Clinical practice. Acute infectious diarrhea. N Engl J Med 2004;350(1):38-47.
4. Kane SV, Sandborn WJ, Rufo PA et al. Fecal lactoferrin is a sensitive and specific marker in identifying
intestinal inflammation. Am J Gastroenterol 2003;98(6):1309-14.
5. McFarland LV. Antibiotic-associated diarrhea: epidemiology, trends and treatment. Future Microbiol
2008;3:563-78.
6. Vonberg RP, Kuijper EJ, Wilcox MH et al. Infection control measured to limit the spread of Clostridium
difficile. Clin Microbiol Infect 2008;14(Suppl 5):2-20.
7. Committee to Advise on Tropical Medicine and Travel (CATMAT). Statement on travellers' diarrhea. Can
Commun Dis Rep 2001;27(ACS-3):1-12. Available from: www.phac-aspc.gc.ca/publicat/ccdr-
rmtc/01vol27/27sup/acs3.html. Accessed June 2, 2010.
8. Sirinavin S, Garner P. Antibiotics for treating salmonella gut infections. Cochrane Database Syst Rev 2000;
(2):CD001167.
9. Molbak K, Mead PS, Griffin PM. Antimicrobial therapy in patients with Escherichia coli O157:H7 infection.
JAMA 2002;288(8):1014-6.
10. Hanauer SB, DuPont HL, Cooper KM et al. Randomized, double-blind, placebo-controlled clinical trial of
loperamide plus simethicone versus loperamide alone and simethicone alone in the treatment of acute
diarrhea with gas-related abdominal discomfort. Curr Med Res Opin 2007;23(5):1033-43.
11. NASPGHAN Nutrition Report Committee; Michail S, Sylvester F et al. Clinical efficacy of probiotics: review of
the evidence with focus on children. J Pediatr Gastroenterol Nutr 2006;43(4):550-7.
12. Zar FA, Bakkanagari SR, Moorthi KM et al. A comparison of vancomycin and metronidazole for the treatment
of Clostridium difficile-associated diarrhea, stratified by disease severity. Clin Infect Dis 2007;45(3):302-7.
13. Nelson R. Antibiotic treatment for Clostridium difficile-associated diarrhea in adults. Cochrane Database Syst
Rev 2007;(3):CD004610.
14. Halsey J. Current and future treatment modalities for Clostridium difficile-associated disease. Am J Health Syst
Pharm 2008;65(8):705-15.
15. Kelly CP, Pothoulakis C, LaMont JT. Clostridium difficile colitis. N Engl J Med 1994;330(4):257-62.
16. Surawicz CM, McFarland LV, Greenberg RN et al. The search for a better treatment for recurrent Clostridium
difficile disease: use of high-dose vancomycin combined with Saccharomyces boulardii. Clin Infect Dis
2000;31(4):1012-7.
17. Pillai A, Nelson R. Probiotics for treatment of Clostridium difficile-associated colitis in adults. Cochrane
18. Johnston BC, Supina AL, Ospina M et al. Probiotics for the prevention of pediatric antibiotic-associated
diarrhea. Cochrane Database Syst Rev 2007;(2):CD004827.
19. McFarland LV, Surawicz CM, Greenberg RN et al. A randomized placebo-controlled trial of Saccharomyces
boulardii in combination with standard antibiotics for Clostridium difficile disease. JAMA 1994;271(24):1913-
8.
20. Fekety R. Guidelines for the diagnosis and management of Clostridium difficile-associated diarrhea and colitis.
American College of Gastroenterology, Practice Parameters Committee. Am J Gastroenterol 1997;92(5):739-
50.
21. Fedorak RN, Field M. Antidiarrheal therapy. Prospects for new agents. Dig Dis Sci 1987;32(2):195-205.
Page 405
Therapeutic Choice
22. Delia P, Sansotta G, Donato V et al. Prevention of radiation-induced diarrhea with the use of VSL#3, a new
high-potency probiotic preparation. Am J Gastroenterol 2002;97(8):2150-2.
Page 406
e-Therapeutics+ : Therapeutics : Gastrointestinal Disorders: Gastroesophageal Reflux Dise... Page 1 of 10
Therapeutic Choice
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Gastrointestinal Disorders: Gastroesophageal Reflux Disease

Date Revised: October 2010
Eldon A. Shaffer, MD, DABIM, FACP, FRCPC
Gastroesophageal reflux disease (GERD) refers to symptoms (commonly heartburn and/or regurgitation) resulting
from excessive reflux of caustic, primarily acidic gastric secretions from the stomach into the esophagus. Reflux may
lead to inflammation termed reflux or peptic esophagitis. Hence, reflux esophagitis is a subset of GERD with
endoscopic or histopathologic evidence of esophageal inflammation. GERD with no demonstrable esophageal
disease (i.e., a normal esophagus at endoscopy while not on any treatment) is termed nonerosive reflux disease
(NERD) or endoscopic-negative reflux disease (ENRD).
Goals of Therapy
Relieve symptoms, particularly heartburn, and improve quality of life

Promote healing of esophagitis
Prevent complications (stricture formation, bleeding or progression to Barrett's epithelium)
Prevent recurrences
a
Table 1: Classification of Symptom Severity
Severity of GERD Criteria
Trivial to mild Reflux symptoms infrequent (< 3 times/wk)

Symptoms of low intensity and short duration
Not nocturnal
Do not interfere with daily activity
Pain (retrosternal heartburn) severity rated as modest (e.g., 1–3 out of 10)
No major complications
Severe Reflux symptoms more frequent and intense; greater impact on quality of life
present for > 6 mo
regularly interfere with daily activity
can awaken patient at night
more severe retrosternal pain (e.g., 7–10 out of 10)
Takes patient to physician
Complications arise from the acidic refluxate
a.
Classification does not necessarily correspond to histological severity. Prevalence of esophagitis is low: the majority of patients
with GERD (55% to 80%) have no erosive disease on endoscopy. The severity of symptoms and esophageal mucosal injury
1
correlate with the total time the esophageal mucosa is in direct contact with acid (at pH < 4) per 24-hour period.
Investigations
History — identify:
common symptoms of GERD: heartburn, regurgitation of acid or bile, or hypersalivation (water brash). The
history is usually sufficient for diagnosis. Heartburn or acid regurgitation has a high specificity (89% and
95%, respectively), but a low sensitivity (38% and 6%) for GERD2
noncardiac extraesophageal manifestations: chest pain, aspiration (cough, asthma, pneumonia),
oropharyngeal symptoms (globus sensation, hoarseness) or ulceration, dental caries, burning mouth
syndrome
complications: dysphagia from a stricture, or peptic ulceration causing GI bleeding or pain on swallowing
(odynophagia)
predisposing/associated conditions: pregnancy, obesity, scleroderma
Endoscopy is indicated in patients with heartburn refractory to optimal therapy with a proton pump inhibitor
(Figure 1 - Management of GERD) or “alarm features” such as:
dysphagia, especially for solids
vomiting
Page 407
Therapeutic Choice
odynophagia
atypical noncardiac chest pain
GI bleeding, anemia
extraesophageal symptoms (respiratory, oropharyngeal)
weight loss > 5%
Ambulatory 24-hour pH monitoring is indicated in patients with atypical reflux symptoms, for those who fail
standard medical therapy (but have a normal endoscopy), and as preoperative evaluation (especially with
ENRD) before antireflux surgery
Helicobacter pylori infection does not play a causative role in the pathogenesis of GERD. Testing for H. pylori is
not necessary. H. pylori does not alter the effectiveness of PPI therapy nor does it influence reflux symptoms
Therapeutic Choices (Figure 1 - Management of GERD)
There is little evidence to support the effectiveness of lifestyle changes, except as initial therapy in mild cases.
However, recommending them provides broad health care benefits and carries no risk.
Dietary modifications (avoid chocolate, caffeine, acidic citrus juices, large fatty meals)
Weight loss if obese (BMI > 25 to 30 kg/m2)
No snacks within 3 hours before bedtime
No lying down after meals
Reduce alcohol intake
Elevate legs under the head of the bed on 10 to 15 cm blocks
Stop smoking (see Psychiatric Disorders: Smoking Cessation)
Avoid tight clothing
Pharmacologic Choices (Table 2, Table 3 and Table 4)
When possible, eliminate drugs that impair esophageal motility and lower esophageal sphincter tone (e.g., calcium
channel blockers, theophylline, tricyclic antidepressants, beta-blockers, anticholinergic agents).
Trivial-to-Mild GERD
Most people with mild symptoms do not seek medical attention and will obtain symptomatic relief with antacids,
alginates or nonprescription strength H2-receptor antagonists (H2RAs). Additional therapy becomes necessary if
GERD severity increases.
Moderate-to-Severe GERD
Antacids or nonprescription strength H2RAs alone are not effective. The most effective and common approach in
treating either reflux esophagitis or nonerosive reflux disease is to reduce acid secretion with a proton pump
inhibitor (PPI). The goal is to raise the intragastric pH > 4, the level above which any reflux is unlikely to elicit
1
symptoms or cause esophageal damage.
H2-receptor Antagonists
Cimetidine, famotidine, nizatidine and ranitidine are equally effective. Twice daily doses relieve symptoms in
60% and heal histologically mild esophagitis in over 40% of patients. Their safety profile is excellent. Their efficacy
is limited by the rapid development of tachyphylaxis and the inability to properly suppress meal-related acid
secretion.
This class of drugs is inefficient for severe esophagitis, being best reserved for GERD when symptoms are mild and
infrequent (< 3 times per week). Step-down therapy, where H2RAs are instituted after symptomatic relief has been
3
achieved with PPIs, can be successful without adversely affecting quality of life and reduces costs.
When initial therapy is beneficial, maintenance will be necessary if/when symptoms recur and cannot be controlled
by nonpharmacologic means. Use the lowest dose possible to control symptoms and prevent complications. This is
usually effective in mild GERD.
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Therapeutic Choice
Proton Pump Inhibitors (PPIs)
PPIs are superior to H2RAs for the reduction of heartburn and healing of esophagitis. PPIs heal all
grades of esophagitis in most patients (up to 90% by 12 weeks).1 PPIs provide more rapid relief of
1,4,5
symptoms and twice the healing rates compared to H2RAs, which makes PPIs more cost effective
3
as initial therapy. Therefore, PPIs are the drug of choice in most GERD patients with or without
mucosal injury and for extraesophageal manifestations. Useful Info?
H2RAs may be instituted after achieving symptomatic relief with PPIs. Such step-down therapy begins with potent
antisecretory agents (PPIs) to achieve rapid symptom control. The intensity of acid suppressive therapy is then
gradually decreased until breakthrough symptoms occur, which indicates the extent of therapy necessary to control
ongoing symptoms.
Though PPIs heal ulceration they do not reverse epithelial changes in patients with Barrett's esophagus.
Tachyphylaxis is not a problem, but acid rebound occurs with discontinuation.
6
For ENRD, PPIs are clearly superior to H2RAs in relieving symptoms. Generally, therapy aims at controlling
symptoms.
7 , 8
At equivalent doses, available PPIs offer similar symptom relief, mucosal healing, tolerability and safety.
Apparent differences in bioavailability and antisecretory potency upon initial dosing have no apparent clinical
importance in most settings. However, the results of a meta-analysis suggest that esomeprazole may confer a
modest advantage over other agents for severe erosive esophagitis.9 Consider cost in the initial selection of a PPI.10
Less clear is the effectiveness of substituting one PPI for another in patients who have been stabilized on therapy.
More important is optimal dosing: PPIs should be ingested ½ hour before meals for the most effective acid
suppression.
11
Helicobacter pylori infection does not cause and has little impact on GERD. Testing for H. pylori is not necessary.
H. pylori eradication has only modest effects on GERD symptoms, resulting in a slight worsening in patients with
corpus-predominant gastritis and improvement in those with antral-predominant gastritis.
Table 2: Efficacy of Drugs Used to Treat GERD
Acute Treatment
Symptoms Esophagitis Prevention of Recurrences
Antacids + – –
Alginates/antacids + – –
H2-receptor antagonists ++ + ±
Proton pump inhibitors +++ +++ +++
+ Drug of proven value (controlled trials)
– Not established (negative trial or not tested)
Prokinetic Agents
Although the basis for acid reflux is incompetence of the antireflux barrier, impaired esophageal clearance of acid
and delayed gastric emptying, no effective motility agent is available at this time.
Maintenance Therapy for Severe GERD
The recurrence rate following discontinuation of successful therapy is extremely high (75% to 90%), particularly for
12 12 , 13
erosive/severe esophagitis. PPIs maintain remission far more effectively than H2RAs and are cost-effective.
Maintenance therapy for such severe disease appears to be long term.
Page 409
Therapeutic Choice
On-demand (intermittent) medical therapy is the daily intake of a drug for a period of time sufficient to achieve
resolution of the reflux symptoms at which time the patient discontinues the drug. PPIs frequently can be so
discontinued, with a subsequent drug-free remission lasting for months,14 particularly in patients with ENRD.
Conversely, many patients take their medication prophylactically to prevent occurrence of reflux symptoms. Such
periodic therapy is less successful in severe erosive esophagitis.
Use of low-dose or half-dose PPIs is less effective than standard doses. Patients should be maintained on the lowest
dose that provides symptom relief. The safety record of PPIs is excellent, even with long-term use over many years.
Potential concerns relate to the development of nosocomial pneumonia, C. difficile diarrhea, hip fractures and
malabsorption of vitamin B12.
Management of the Refractory Patient
PPIs, though potent antisecretory agents, may not provide symptomatic relief or heal esophagitis in all patients. PPI
failure may relate to:
incorrect diagnosis, e.g., esophageal hypersensitivity (visceral hyperalgesia), functional dyspepsia, achalasia
other causes of esophagitis: alkali (bile) reflux, eosinophilic esophagitis, pill esophagitis
inadequate acid suppression (twice-daily dosing is sometimes necessary)
improper use
nonadherence
taking PPI with meals or in combination with H2RAs (PPI bioavailability is highest with secretion of gastric
acid)
genetic rapid metabolism via CYP2C19 (less common)
gastric acid hypersecretion (less common)
Additional investigations such as endoscopy with biopsies, 24-hour pH monitoring, or esophageal motility studies
may be warranted to identify the cause of refractory esophagitis
Nocturnal acid breakthrough with gastric pH < 4, and symptoms can occur in up to 70% of patients on twice daily
PPI therapy. Supplementary bedtime H2RA therapy may temporarily improve symptoms, but tolerance limits its use,
15
making such therapy no better than placebo. Another option for patients refractory to a PPI, though not completely
16
substantiated, is to switch to another PPI as some individuals may be more responsive to one PPI or another.
Antireflux Surgery
Failure of optimal medical therapy suggests intuitively that refractory patients would benefit from surgery to restore
the physiological equivalent of the lower esophageal sphincter. In fact, complete response to medical therapy is the
best predictor of surgical success. Antireflux surgery is effective for reflux control in well-selected cases. Indications
include intractable reflux esophagitis (particularly in a young person) despite medical therapy, or complications such
as severe erosive esophagitis, stricture formation or recurrent lung disease (e.g., aspiration pneumonia). Long-term
outcome studies show little difference in surgically versus medically treated patients.17 In fact, drug therapy may be
less expensive than surgery.18 , 19 Laparoscopic approaches and natural orifice transluminal endoscopic surgery
20
(NOTES) have not been critically assessed.
Therapeutic Tips
For patients with mild symptomatic GERD, nonprescription H2RAs yield only modest acid reduction and
symptom control.
PPIs are superior to H2RAs for reduction of heartburn and healing of esophagitis in patients with moderate to
severe GERD. H2RAs may be instituted after achieving symptomatic relief with PPIs.
The recurrence rate of GERD is extremely high and long term maintenance therapy is often necessary. PPIs
maintain remission far more effectively than H2RAs. On-demand (intermittent) therapy with PPIs may be
effective in select patients.
Figure 1-Management of GERD
Page 410
Therapeutic Choice
a.
b.
For suspected GERD, an empiric trial of PPI BID for 2 weeks also can be diagnostic.
c.
May be able to step down to H2RAs in some with nonerosive GERD.
d.
For those on long-term PPI, indicating severe GERD, it is reasonable to evaluate for the presence of Barrett's epithelium (a
premalignant lesion) and assess for erosive esophagitis (which requires PPIs) vs a normal esophagus (the "hypersensitive"
esophagus), which sometimes can be controlled with H2RAs
Abbreviations: PPI = proton pump inhibitor
Table 3: Nonprescription Drugs Used in Gastroesophageal Reflux Disease
a
Adverse Drug Cost
Antacids aluminum Constipation, ↓ bioavailability of Some antacids $

hydroxide/magnesium 30 mL diarrhea. digoxin, contain
hydroxide (regular tetracycline, significant
combinations strength) 1 h quinolone amounts of
PC and QHS antibiotics; sodium.
separate dosing
by 2 h.
Alginates alginate (sodium 10–20 mL PC Flatulence, ↓ bioavailability Alginates and $-$$

salt)/aluminum and QHS, eructation. of digoxin, some antacids
hydroxide followed by tetracycline, contain
Gaviscon Liquid, glass of water quinolone significant
generics antibiotics; amounts of
sodium.
Alginates alone
Page 411
Therapeutic Choice
Adverse Drug Costa

separate dosing have limited
by 2 h. value.
Alginates alginic acid/magnesium 2–4 tablets Flatulence, ↓ bioavailability of Alginates and $-$$
carbonate (chewed) PC eructation. digoxin, some antacids
Gaviscon Tablets, and QHS, tetracycline, contain
generics followed by quinolone significant
glass of water antibiotics; amounts of
separate dosing sodium.
by 2 h. Alginates alone
have limited
value.
H2- famotidine Diarrhea, Comparable $-$$

antagonists Pepcid AC, generics 10 mg BID constipation, efficacy to
headache, antacids.
fatigue,
confusion (most
likely in elderly
and those with
poor renal
function),
cardiac effects,
rash.
H2- ranitidine Diarrhea, Comparable $-$$

antagonists Zantac/Zantac 75 mg BID constipation, efficacy to
headache, antacids.
Maximum Strength
150 mg BID fatigue,
Non-Prescription, confusion (most
generics likely in elderly
and those with
poor renal
function),
cardiac effects,
rash.
a.
Cost of 30-day supply.
Legend: $ < $15 $-$$ < $15–20 $$ >$20
Table 4: Prescription Drugs Used in Gastroesophageal Reflux Disease
Costa
H2- cimetidine Diarrhea, Cimetidine ↓ CYP450- $

antagonists various generics 600 mg constipation, mediated metabolism
BID headache, fatigue, of several agents (e.g.,
confusion (most warfarin, phenytoin,
likely in elderly theophylline) — use
and those with another H2RA.
poor renal
function), cardiac
effects, rash. Also
gynecomastia,
impotence (rare).
Page 412
Therapeutic Choice
Costa
H2- famotidine Diarrhea, $$

antagonists Pepcid, 20 mg BID constipation,
generics headache, fatigue,
confusion (most
likely in elderly
and those with
poor renal
function), cardiac
effects, rash.
H2- nizatidine Diarrhea, $

antagonists Axid, generics 150 mg constipation,
BID headache, fatigue,
confusion (most
likely in elderly
and those with
poor renal
function), cardiac
effects, rash.
H2- ranitidine Diarrhea, Minor decrease in $

antagonists Zantac, 150 mg constipation, CYP450-mediated
BID headache, fatigue, metabolism of several
generics
confusion (most agents (e.g., warfarin,
likely in elderly phenytoin,
and those with theophylline) —
poor renal monitor.
function), cardiac
effects, rash.
Proton dexlansoprazole 30–60 mg Abdominal pain, PPI use may reduce Can be given $$$$
Pump Dexilant once daily diarrhea, 21 without regard
clopidogrel efficacy.
Inhibitors po headache. Monitor for ↓ efficacy of to food.
drugs requiring an acid Giving half the
medium for absorption usual dose may
from the stomach be useful for
(e.g., itraconazole, maintenance of
atazanavir, indinavir). some patients
with less severe
symptoms or
who have gone
into remission
on standard
dosages.
Proton esomeprazole 20–40 mg Abdominal pain, PPI use may reduce Commonly used $$$$
Pump Nexium once daily diarrhea, clopidogrel efficacy.21 at 40 mg daily.
Inhibitors ½ hour headache. Monitor for ↓ efficacy of
before drugs requiring an acid
food medium for absorption
from the stomach
(e.g., itraconazole,
atazanavir, indinavir).
Proton lansoprazole 30 mg Abdominal pain, PPI use may reduce If partial or no $

Pump Prevacid, once daily diarrhea, 21 response, give
Inhibitors generics ½ hour headache. Monitor for ↓ efficacy of usual dose BID
before drugs requiring an acid AC so total daily
food medium for absorption dose is doubled.
from the stomach Giving half the
usual dose may
Page 413
Therapeutic Choice
a
Cost
(e.g., itraconazole, be useful for
atazanavir, indinavir). maintenance of
some patients
with less severe
symptoms or
who have gone
into remission
on standard
dosages.
Proton omeprazole Usual: Abdominal pain, PPI use may reduce If partial or no $$
Pump Losec Capsules, 20 mg nausea, headache. 21 response, give
Inhibitors Losec Tablets, once daily Monitor for ↓ efficacy of usual dose BID
generics ½ hour drugs requiring an acid AC so total daily
before medium for absorption dose is doubled.
b Giving half the
food from the stomach
(e.g., itraconazole, usual dose may
atazanavir, indinavir). be useful for
maintenance of
Omeprazole may some patients
interfere with with less severe
cytochrome symptoms or
P450-metabolized who have gone
agents (e.g., into remission
diazepam, warfarin, on standard
phenytoin). When dosages.
omeprazole is added
or removed, these
drugs may require
dosage adjustment.
Proton pantoprazole 40 mg Diarrhea, PPI use may reduce Can be given $$

Pump magnesium once daily headache, 21 without regard
Inhibitors Tecta po dizziness, pruritus. Monitor for ↓ efficacy of to food.
drugs requiring an acid
medium for absorption
from the stomach
(e.g., itraconazole,
atazanavir, indinavir).
Proton pantoprazole 40 mg Diarrhea, PPI use may reduce If partial or no $

Pump sodium once daily headache, 21 response, give
Inhibitors Pantoloc, ½ hour dizziness, pruritus. Monitor for ↓ efficacy of usual dose BID
generics before drugs requiring an acid AC so total daily
maintenance of
some patients
with less severe
symptoms or
who have gone
into remission
on standard
dosages.
Page 414
Therapeutic Choice
Costa
Proton rabeprazole 20 mg Diarrhea, PPI use may reduce If partial or no $

Pump Pariet, generics once daily headache. clopidogrel efficacy.21 response, give
Inhibitors ½ hour Monitor for ↓ efficacy of usual dose BID
before drugs requiring an acid AC so total daily
maintenance of
Digoxin levels may some patients
increase moderately in with less severe
some patients. symptoms or
who have gone
into remission
on standard
dosages.
a.
Cost of 30-day supply, includes drug cost only.
b.
Not to exceed 20 mg/day in hepatic impairment.
Legend: $ < $15 $$ $15–30 $$$ $30–60 $$$$ $60–80
Suggested Readings
Armstrong D, Marshall JK, Chiba N et al. Canadian Consensus Conference on the management of gastroesophageal
reflux disease in adults - update 2004. Can J Gastroenterol 2005;19(1):15-35.
DeVault KR, Castell DO. Updated guidelines for the diagnosis and treatment of gastroesophageal reflux disease. Am
J Gastroenterol 2005;100(1):190-200.
Fass R. Towards a consensus in symptomatic gastroesophageal reflux disease. Am J Gastroenterol 2003;98(3 Suppl
1):S1-S55.
Moayyedi P, Talley NJ. Gastro-oesophageal reflux disease. Lancet 2006;367(9528):2086-100.
Wo JM, Mendez C, Harrell S et al. Clinical impact of upper endoscopy in the management of patients with
gastroesophageal reflux disease. Am J Gastroenterol 2004;99(12):2311-6.
References
1. Hunt RH. Importance of pH control in the management of GERD. Arch Intern Med 1999;159(7):649-57.
2. Klauser AG, Schindlbeck NE, Muller-Lissner SA. Symptoms in gastro-oesophageal reflux disease. Lancet
1990;335(8683):205-8.
3. Inadomi JM, Jamal R, Murata GH et al. Step-down management of gastroesophageal reflux disease.
4. Chiba N, De Gara CJ, Wilkinson JM et al. Speed of healing and symptom relief in grade II to IV
gastroesophageal reflux disease: a meta-analysis. Gastroenterology 1997;112(6):1798-810.
5. van Pinxteren B, Numans ME, Lau J et al. Short-term treatment of gastroesophageal reflux disease. J Gen
Intern Med 2003;18(9):755-63.
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e-Therapeutics+ : Therapeutics : Gastrointestinal Disorders: Gastroesophageal Reflux Di... Page 10 of 10
Therapeutic Choice
6. Richter JE, Campbell DR, Kahrilas PJ et al. Lansoprazole compared with ranitidine for the treatment of
nonerosive gastroesophageal reflux disease.Arch Intern Med 2000;160(12):1803-9.
7. Vakil N, Fennerty MB. Direct comparative trials of the efficacy of proton pump inhibitors in the management of
gastro-oesophageal reflux disease and peptic ulcer disease. Aliment Pharmacol Ther 2003;18(6):559-68.
8. FDC Reports. Pharmaceutical Approvals Monthly 2001;6:34.
9. Gralnek IM, Dulai GS, Fennerty MB et al. Esomeprazole versus other proton pump inhibitors in erosive
esophagitis: a meta-analysis of randomized clinical trials. Clin Gastroenterol Hepatol 2006;4(12):1452-8.
10. Nelson WW, Vermeulen LC, Geurkink EA et al. Clinical and humanistic outcomes in patients with
gastroesophageal reflux disease converted from omeprazole to lansoprazole. Arch Intern Med 2000;160
(16):2491-6.
11. Raghunath AS, Hungin AP, Wooff D et al. Systematic review: the effect of Helicobacter pylori and its
eradication on gastro-oesophageal reflux disease in patients with duodenal ulcers or reflux esophagitis.
Aliment Pharmacol Ther 2004;20(7):733-44.
12. Harris RA, Kuppermann M, Richter JE. Prevention of recurrences of erosive reflux esophagitis: a cost-
effectiveness analysis of maintenance proton pump inhibition. Am J Med 1997;102(1):78-88.
13. Vigneri S, Termini R, Leandro G et al. A comparison of five maintenance therapies for reflux esophagitis. N
Engl J Med 1995;333(17):1106-10.
14. Talley NJ, Lauritsen K, Tunturi-Hihnala H et al. Esomeprazole 20 mg maintains symptom control in endoscopy-
negative gastro-oesophageal reflux disease: a controlled trial of 'on-demand' therapy for 6 months. Aliment
Pharmacol Ther 2001;15(3):347-54.
15. Orr WC, Harnish MJ. The efficacy of omeprazole twice daily with supplemental H2 blockade at bedtime in the
suppression of nocturnal oesophageal and gastric acidity.Aliment Pharmacol Ther 2003;17(12):1553-8.
16. Hatlebakk JG. Am J Gastroenterol 1998;93:1636.
17. Spechler SJ, Lee E, Ahnen D et al. Long-term outcome of medical and surgical therapies for gastroesophageal
reflux disease: follow-up of a randomized controlled trial. JAMA 2001;285(18):2331-8.
18. Myrvold HE, Lundell L, Miettinen P et al. The cost of long term therapy for gastro-oesophageal reflux disease:
a randomised trial comparing omeprazole and open antireflux surgery. Gut 2001;49(4):488-94.
19. Romagnuolo J, Meier MA, Sadowski DC. Medical or surgical therapy for erosive reflux esophagitis: cost-utility
analysis using a Markov model. Ann Surg 2002;236(2):191-202.
20. Wallace MB. Take NOTES (Natural Orifice Transluminal Endoscopic Surgery). Gastroenterology 2006;131
(1):11-2.
2009;180(7):699-700
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e-Therapeutics+ : Therapeutics : Gastrointestinal Disorders: Inflammatory Bowel Disease Page 1 of 13
Therapeutic Choice
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Gastrointestinal Disorders: Inflammatory Bowel Disease

Brian G. Feagan, MD, FRCPC
The idiopathic inflammatory bowel diseases consist of Crohn’s disease, ulcerative colitis and ulcerative proctitis. Crohn’s disease may
involve any part of the gastrointestinal tract while ulcerative colitis is restricted, with a variable extent of involvement, to the colon.
Ulcerative proctitis is a variant of ulcerative colitis, involving less than 30 cm of the distal colon.
Investigations
History:
diarrhea, abdominal pain, rectal bleeding and weight loss are the most important symptoms
presence of nocturnal diarrhea usually indicates “organic” pathology in distinction to functional disorders such as irritable bowel
syndrome
extraintestinal manifestations, e.g., aphthous ulcers, arthritis, erythema nodosum, iritis, perianal disease, fever
genetics: increased risk in patients with a family history, Ashkenazi Jews, and those with the NOD-2\CARD 15 gene (patients with
Crohn’s disease), the first susceptibility gene identified for inflammatory bowel disease
previous endoscopic/radiologic test results
previous medical (e.g., drugs, dose, duration) or surgical treatment (e.g., type and number of surgeries)
Physical examination: weight, abdominal tenderness, presence of abdominal mass, malnutrition, perianal disease (fistulae, abscess)
growth failure in children (chart height and weight, growth curve Tanner stage)
extraintestinal manifestations
Precise diagnosis and extent of disease:
colonoscopy or upper gastrointestinal endoscopy
barium radiocontrast studies
biopsy/histopathology, small bowel x-rays
presence of small bowel involvement; granulomata are pathognomonic for Crohn’s disease
10% of cases with colonic disease cannot be classified and are termed indeterminate colitis
A definitive diagnosis is important since:
colectomy cures ulcerative colitis; Crohn’s disease recurs after surgery
the conditions respond differently to drug therapy (especially aminosalicylates)
Precise anatomic localization is necessary for selecting drug therapy and planning surgery
Laboratory tests:
measures of inflammation (WBC, Hgb, ESR, C-reactive protein, albumin)
stool cultures, C. difficile toxin assay
Goals of Therapy
Relieve symptoms and improve patients’ quality of life

Improve nutritional status and growth (children/adolescents)
Prevent disease recurrence
Prevent development of cancer of the colon, which is associated with ulcerative colitis and colonic Crohn’s disease
Identify and treat extraintestinal manifestations (e.g., arthritis, arthralgia, iritis, uveitis)
Therapeutic Choices
Therapy is determined by the site and extent of disease, and by the severity of symptoms. Patients with mild to moderate disease activity
are managed as outpatients, whereas those with severe symptoms may require hospitalization. Therapy is sequential in first inducing and
then maintaining remission.
Pharmacologic management of inflammatory bowel disease includes the use of aminosalicylates, corticosteroids, immunosuppressives,
antidiarrheals, antibiotics and, to a limited degree, opioid analgesics. In selecting therapy consider, in addition to efficacy, the route of
administration (oral, iv, rectal) and potential adverse events.
Aminosalicylates
Preparations containing 5-aminosalicylic acid (5-ASA) are formulated to release the drug at specific sites in the gastrointestinal tract,
since efficacy is dependent on luminal concentration. Salofalk, Mesasal and Pentasa release 5-ASA in the small bowel. Sulfasalazine,
olsalazine and Asacol release 5-ASA primarily in the colon.
All 5-ASA compounds are highly effective for the treatment of ulcerative colitis. However, sulfasalazine has only modest efficacy in active
1 , 2
Crohn’s disease (approximately 40% efficacy for induction of remission versus 30% with placebo ) and is generally used in patients
with mild disease. Pentasa and Asacol have been evaluated in active Crohn’s disease with equivocal results, and their widespread use for
both induction and maintenance of remission is coming under increasing scrutiny. Although these compounds are often used
interchangeably in clinical practice, evidence favours use of sulfasalazine for mildly active colonic Crohn’s disease.1 , 2 Sulfasalazine has
the least-favourable adverse effect profile, which includes nausea, headache, rash, hemolytic anemia and hepatotoxicity. However, many of
these effects are minor and dose related. The majority of these events (> 90%) are related to the sulfapyridine moiety which is not present
in 5-ASA preparations. Reversible oligospermia has been reported with sulfasalazine, but has not been associated with 5-ASA.
Page 417
Therapeutic Choice
Corticosteroids
Patients with a moderately severe exacerbation of Crohn’s disease or ulcerative colitis are treated initially with oral prednisone 40 to 60
2
mg/day. In those with severe disease, hospitalization and treatment with iv corticosteroids (e.g., hydrocortisone, methylprednisolone)
may be necessary. Patients who respond to iv therapy are switched to prednisone once stabilized. Taper the prednisone dose as
2 , 3
improvement occurs (total duration of therapy is 12 to 16 weeks for Crohn’s disease; 8 to 12 weeks for ulcerative colitis).
Long-term use of glucocorticoids should be avoided and is restricted to patients unresponsive to other drugs. Make patients aware of the
possible side effects and obtain informed consent. Osteoporosis is a concern with long-term therapy. Supplemental calcium and vitamin D
intake, smoking cessation, exercise and, in select individuals, treatment with bisphosphonates are useful interventions. Use of
glucocorticoids is also associated with avascular necrosis of the femoral head.
Budesonide is rapidly inactivated in the liver, resulting in lower systemic bioavailability and a reduced effect on the hypothalamic-
pituitary-adrenal axis. It is available as an oral controlled-release capsule for the treatment of terminal ileal/right-sided colonic Crohn’s
4 , 5
disease and as an enema for treatment of ulcerative colitis. In clinical trials, response rates for oral budesonide are marginally lower
than those for prednisone in patients with active Crohn’s disease (50 to 60% versus 70%). An important advantage of budesonide over
6
prednisone is that the manifestations of Cushing's syndrome occur less frequently. Budesonide enemas are as effective as other steroid
enemas and have a lower incidence of side effects, but are more costly.7
Immunosuppressive Agents
Azathioprine, 6-mercaptopurine (6-MP) or methotrexate are used in patients with refractory Crohn’s disease to control
symptoms or to reduce the dose of prednisone.8,9,10 All immunosuppressive drugs have important side effects (e.g., bone
marrow suppression, cytopenias and infections). Hypersensitivity pneumonitis and hepatotoxicity are the most important
adverse effects of methotrexate. Coadministration of folic acid is recommended with methotrexate (1 mg daily).
11
Pancreatitis occurs in approximately 3% of patients treated with azathioprine or 6-MP. Development of lymphoma is an
uncommon complication of treatment with purine antimetabolites, whereas no strong evidence exists to support a similar
relationship with methotrexate. Useful Info?
Biologic Response Modifiers
Antibodies directed towards tumor necrosis factor-alpha (TNF-α) are effective in patients with inflammatory bowel disease. The first such
agent, infliximab, a chimeric (murine/human) antibody, is effective for induction of remission12 , 13 and closure of fistulas14 in patients
with active Crohn’s disease refractory to other treatments, and in patients with active ulcerative colitis who do not respond to conventional
therapy.15 Infliximab is given intravenously and can provoke minor (headache, flushing, lightheadedness) or major (manifestations of
anaphylaxis) infusion reactions. Adalimumab is a recombinant human anti-TNF-α antibody that is administered subcutaneously.
Adalimumab induces and maintains disease remission in patients with moderate to severe Crohn's disease unresponsive to corticosteroids
and/or immunosuppressants.16 , 17 Adalimumab is also effective in patients refractory or intolerant of infliximab.18
Formation of anti-nuclear antibodies, a rare lupus-like syndrome, lymphoma and worsening of heart failure are important concerns
associated with anti-TNF-α therapies. Opportunistic infections and tuberculosis have occurred during treatment. Screen for tuberculosis
prior to treatment by obtaining a history of exposure and a chest x-ray, and by performing tuberculin skin testing. Manage patients who
are infected with tuberculosis in collaboration with an infectious disease physician.
Antibiotics
Short courses (two to four weeks) of metronidazole and/or ciprofloxacin are useful as a treatment for patients with Crohn’s disease and
perianal fistulae.19 Metronidazole has a potent disulfiram-like activity if alcohol is ingested and neuropathy may occur with long-term use.
Avoid the use of metronidazole in pregnant patients.
Antidiarrheals
Use antidiarrheals with caution and avoid in severe disease because of the risk of toxic megacolon. Diphenoxylate with atropine is a
combination of an opiate and an anticholinergic drug which can cause CNS side effects. Loperamide acts on both cholinergic and opiate
receptors, but has a lower incidence of adverse effects than diphenoxylate.
Patients who develop diarrhea after extensive bowel resection often respond well to resins that bind bile salts (e.g., cholestyramine).
Opiate Analgesics
Opiates decrease gastrointestinal motility. Chronic use may lead to narcotic bowel syndrome, the risk for habituation is high and, in some
individuals, may worsen symptoms.
Codeine is useful for pain control and decreasing the number of bowel movements (although approximately 10% of patients may not
respond to the drug because of a genetic polymorphism, see the section on analgesics in Musculoskeletal Disorders: Rheumatoid Arthritis).
Avoid use of morphine or meperidine; restrict use to short-term treatment in select patients.
Crohn's Disease
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Therapeutic Choice
Therapeutic Choices
Therapeutic Tips
Pharmacoeconomic Considerations
Therapeutic Choices (Figure 1 - Management of Crohn's Disease)
Encourage the patient to stop smoking (limited evidence suggests smoking worsens Crohn’s disease).20
Advise patients not to arbitrarily limit food groups. The goal is to ensure an adequate caloric intake. Nutritional supplements or
parenteral nutrition may be necessary in select patients who are malnourished.
Surgery may be necessary to treat strictures, abscesses, fistulae or for patients refractory to medical management. Recurrence after
surgery is almost universal, so conservative surgical management with resection of a minimum amount of bowel is favoured.
Psychological and social support is important, especially for adolescents.
See the previous general discussion of pharmacologic choices in inflammatory bowel diseases.
Corticosteroids are most effective for the induction of remission (70% response rate). Prednisone (40 to 60 mg/day for 12 to 16
2
weeks) is the most commonly used drug.
Chronic low-dose corticosteroid therapy is ineffective for the maintenance of remission.21 However, some patients with chronically
active disease may require continuous low-dose prednisone (10 to 15 mg/day) to suppress their symptoms.
Sulfasalazine (6 to 8 g/day) is only marginally effective for the induction of remission (approximately 40% response rate versus
30% with placebo in patients with mild disease).2 It is not clear whether 5-ASA is effective for treatment of active disease.22
The value of 5-ASA as a maintenance therapy for Crohn’s disease is controversial (in contrast to its status in ulcerative colitis). A
recent synthesis of available data concluded that maintenance therapy provided no benefit.23
24
Patients who receive purine antimetabolites and methotrexate should use effective contraception as these drugs may be teratogenic.
In pregnancy, methotrexate is absolutely contraindicated and purine antimetabolites are often discontinued (although this is
controversial). Despite earlier concerns regarding a potential risk of kernicterus, sulfasalazine has been used in pregnancy with
24
relative safety. Aminosalicylates and corticosteroids are considered to be safe and may be continued in pregnancy if indicated.
Infliximab 12 and adalimumab 16 are effective for patients who are refractory to antimetabolite therapy. Infliximab is considered to
14 , 25
be a primary therapy for patients with moderate to severe disease with fistulae. There is less evidence that adalimumab is
effective in this setting and the drug is not indicated for treatment of fistulizing disease. Most gastroenterologists coadminister
antimetabolites to prevent the development of antibodies to infliximab and potentially to enhance efficacy. This is unnecessary with
24
adalimumab. Limited experience supports the use of infliximab in pregnancy. Infusions should not be given late in the third
trimester since the antibody is actively transported across the placenta, resulting in measurable concentrations of infliximab in the
neonate.
Therapeutic Tips
A rare hypersensitivity reaction to 5-ASA preparations can worsen symptoms.

5-ASA does not have a corticosteroid-sparing effect.
Bile salt–induced diarrhea may occur in patients who have had resection of their terminal ileum. This usually responds to
cholestyramine or antidiarrheals. Vitamin B12 deficiency may occur in this setting.
Infusion reactions from infliximab may require treatment with epinephrine, antihistamines and corticosteroids.
NSAIDs may exacerbate symptoms and should be avoided.
Perform colonoscopy to screen for colon cancer according to published guidelines.26
Ulcerative Colitis
Therapeutic Choices
Therapeutic Tips
Therapeutic Choices (Figure 2 - Management of Ulcerative Colitis)
Page 419
Therapeutic Choice
Maintain a well-balanced diet with supplements. Total parenteral nutrition may be necessary in a minority of patients with severe
disease.
Surgery (colectomy) may be used to treat patients who are refractory to medical therapy or who have cancerous changes in the colon.
Colonoscopic surveillance programs in patients at high risk for cancer (early age of onset, extensive disease, long disease duration,
concomitant sclerosing cholangitis) is recommended starting seven years from the time of diagnosis.24
Although colectomy "cures" ulcerative colitis, pouchitis, a chronic inflammatory condition which occurs after ileal-anal reservoir
construction, can be troublesome.19 Symptoms of pouchitis include tenesmus, diarrhea and bleeding.
See the previous general discussion of pharmacologic choices in inflammatory bowel diseases.
Aminosalicylates are highly effective for inducing and maintaining remission in patients with ulcerative colitis compared with placebo.
Sulfasalazine is the least expensive preparation available and is well tolerated by most patients. Although the newer 5-ASA products are
better tolerated than sulfasalazine, they do not possess superior efficacy. Only 20% of patients will be unable to tolerate sulfasalazine.
Continuous use of corticosteroids, immunosuppressive agents or infliximab is reserved for patients with refractory disease who
decline surgery. Use the lowest possible dose of prednisone to control disease activity.
The efficacy of the purine antimetabolites in ulcerative colitis is less well established than in Crohn’s disease. Methotrexate is not
27
effective for the treatment of ulcerative colitis. High-dose iv cyclosporine may be effective in up to 80% of patients with severe
ulcerative colitis, but is associated with a 1% one-year mortality rate.28 It should only be offered to patients who refuse surgery and are
informed of the potential for toxicity. Recent studies have confirmed the efficacy of infliximab for the treatment of refractory ulcerative
colitis.15 , 29
Therapeutic Tips
Use extreme caution when prescribing narcotics and anticholinergic drugs for patients with active ulcerative colitis due to the risk of
toxic megacolon. Use these drugs only when all other alternatives have failed.
Weak evidence suggests that folate supplementation and high compliance with aminosalicylate maintenance therapy may reduce the
risk of colon cancer.30 , 31
Patients with severe colitis often will not tolerate tube feeds due to diarrhea.
NSAIDs may exacerbate symptoms or precipitate relapse and should be avoided.
Ulcerative Proctitis
Therapeutic Choices
Therapeutic Tips
Therapeutic Choices (Figure 3 - Management of Ulcerative Proctitis)
Given the limited extent of the inflammation (rectum/sigmoid colon), the focus is on topical therapy. 5-ASA preparations (suppositories,
enemas) administered at bedtime are the initial treatment of choice. Alternatively, topical corticosteroids can be used. If a response is
not achieved with one of these strategies, switching to the other is advised. Suppositories are effective only for proctosigmoiditis, whereas
enemas can be used to treat disease in the descending colon and rectum from the splenic flexure distally.
If a remission is not induced within two to four weeks, oral 5-ASA can be added. Limited data suggest that there is an additive benefit of
combined oral and topical 5-ASA induction therapy. Switch patients unresponsive to these measures to prednisone or (rarely) iv
corticosteroids. Patients who are brought into remission easily after a first episode (i.e., within four to eight weeks) should have all
medications discontinued. Follow-up is essential; patients with a recurrence of symptoms should receive chronic maintenance therapy with
5-ASA. Most patients prefer oral maintenance therapy, although in practice many will require prolonged topical 5-ASA therapy.
Patients brought into remission with difficulty should continue on long-term oral or topical 5-ASA preparations or corticosteroid enemas,
without an attempt to discontinue therapy.
Patients rarely require chronic treatment with low-dose prednisone or purine antimetabolites. Colectomy may be necessary in some
patients despite the limited extent of the disease. Infliximab has not been specifically evaluated in this group of patients, although it may
be considered before surgery is recommended.
Therapeutic Tips
Topical therapy is preferred.

In patients who are difficult to manage, perform a repeat sigmoidoscopy to ensure that the inflammation is still confined to the lower
bowel and has not developed into more extensive colitis.
Page 420
Therapeutic Choice
Figure 1-Management of Crohn's Disease
Abbreviations: TPN = total parenteral nutrition
Figure 2-Management of Ulcerative Colitis
Page 421
Therapeutic Choice
Abbreviation: 5-ASA = 5-aminosalicylic acid
Figure 3-Management of Ulcerative Proctitis
Page 422
Therapeutic Choice
Abbreviation: 5-ASA = 5-aminosalicylic acid
Table 1: Drugs Used for the Treatment of Inflammatory Bowel Disease
a
Cost
Corticosteroids, hydrocortisone 300–400 mg/day iv Acne, glucose Cyclosporine: $$$

systemic sodium succinate intolerance, weight although
gain, hypertension, corticosteroids and
Solu-Cortef,
hypokalemia, cyclosporine are often
generics
osteoporosis, used concurrently,
aseptic necrosis of both are metabolized
femoral head, by CYP3A4; be alert
adrenal insufficiency to ↑ response to both
with sudden drugs.
cessation. Antidiabetic agents:
glucocorticoids may ↑
blood glucose.
NSAIDs: may ↑ the

risk of GI ulceration.
Thiazide and loop

diuretics also deplete
potassium.
Corticosteroids, methylprednisolone 40–60 mg/day iv Acne, glucose Cyclosporine: No advantage $$

systemic sodium succinate intolerance, weight although over
gain, hypertension, corticosteroids and
Page 423
Therapeutic Choice
a
Cost
Solu-Medrol, hypokalemia, cyclosporine are often hydrocortisone.
generics osteoporosis, used concurrently,
aseptic necrosis of both are metabolized
femoral head, by CYP3A4; be alert
with sudden drugs.
blood glucose.
NSAIDs: may ↑ the

risk of GI ulceration.
Thiazide and loop

potassium.
Corticosteroids, prednisone 30–60 mg po (QAM) Acne, glucose Cyclosporine: Useful in $

systemic generics intolerance, weight although moderately
gain, hypertension, corticosteroids and severe and
hypokalemia, cyclosporine are often severe UC and
osteoporosis, used concurrently, CD. No role in
aseptic necrosis of both are metabolized maintenance
femoral head, by CYP3A4; be alert therapy.
with sudden drugs.
blood glucose.
NSAIDs: may ↑ the risk

of GI ulceration.
Thiazide and loop

potassium.
Corticosteroids, budesonide, oral Acute exacerbation: Acne, glucose Cyclosporine: Controlled- $

systemic Entocort Capsules 9 mg/day po intolerance, weight although release capsule
Maintenance: gain, hypertension, corticosteroids and for treating CD
3–6 mg/day po hypokalemia, cyclosporine are often in the ileum
osteoporosis, used concurrently, and/or
aseptic necrosis of both are metabolized ascending
femoral head, by CYP3A4; be alert colon. Rapidly
adrenal insufficiency to ↑ response to both metabolized,
with sudden drugs. somewhat fewer
cessation. Antidiabetic agents: adverse effects
glucocorticoids may ↑ than
blood glucose. conventional
corticosteroids.
NSAIDs: may ↑ the risk
of GI ulceration.
Thiazide and loop

potassium.
Corticosteroids, hydrocortisone, 80–100 mg QHS as Topical therapy, in Enemas $$

topical enema enema general, has less effective in UP.
Corticosteroids, Cortenema, severe adverse Useful in UC;
topical Cortifoam, Hycort effects than systemic role in CD not
therapy. well
established.
Corticosteroids, betamethasone, 5 mg QHS as enema Topical therapy, in $$

topical enema general, has less
Betnesol severe adverse
effects than systemic
therapy.
Corticosteroids, budesonide, enema 2 mg QHS as enema Topical therapy, in $$

topical Entocort Enema general, has less
severe adverse
Page 424
Therapeutic Choice
a
Cost
effects than systemic
therapy.
Aminosalicylates sulfasalazine Activeb: Dose-related Sulfasalazine may ↓ All $

Salazopyrin, ≥ 4 g/day divided adverse effects: GI absorption of aminosalicylates
generics nausea, vomiting, digoxin. It is are equally
Maintenancec:
diarrhea, anorexia, unknown whether 5- effective in UC.
2–3 g/day divided
headache. ASA also ↓ digoxin
Hypersensitivity absorption.
reaction (rash,
fever), aplastic
anemia,
oligospermia
(reversible).
Aminosalicylates olsalazine Activeb: > 1 g/day Diarrhea; may be $

Dipentum divided minimized by
increasing dose
Maintenancec:
gradually.
1 g/day divided
Aminosalicylates 5-aminosalicylic b Rare hypersensitivity Sulfasalazine may ↓ All $

Asacol – Active :
acid (5-ASA) > 1.6 g/day divided. reactions, including GI absorption of aminosalicylates
Asacol, Asacol c pneumonitis, digoxin. It is are equally
Maintenance :
800, Mesasal, hepatitis and unknown whether 5- effective in UC.
0.8–1.6 g/day divided
worsening of colitis. ASA also ↓ digoxin The value of 5-
Pentasa, Salofalk
Abdominal pain, absorption. ASA as
Tablets, generics cramps or maintenance
b
Mesasal – Active : discomfort as well therapy in CD is
> 1.5 g/day divided as rash, pruritus and controversial.
Maintenancec: anal irritation can Best evidence
1–1.5 g/day divided occur with rectal for Asacol
administration. 2.4 g/day and
Pentasa
Pentasa – Activeb: 3 g/day.
> 2 g/day divided
Maintenancec:
1.5–2 g/day divided
b
Salofalk – Active :
3–4 g/day divided
c
Maintenance :
1–2 g/day divided
Aminosalicylates 5-aminosalicylic Enema: 1–4 g/day Rare hypersensitivity Enemas and $

acid, rectal Suppositories: reactions, including suppositories
Pentasa, 0.5–1 g/day pneumonitis, effective in UP.
Salofalk Enema, hepatitis and
worsening of colitis.
Salofalk
Abdominal pain,
Suppositories cramps or
discomfort as well
as rash, pruritus and
anal irritation can
occur with rectal
administration.
Immunosuppressives azathioprine 2.5 mg/kg/day po Major adverse Allopurinol may ↑ Not for use in $
Imuran, generics effects: cytopenias azathioprine toxicity; pregnant
and rarely, dosage adjustment women.
pancreatitis, may be necessary Metabolism of
hepatotoxicity. (1/4 of regular dose); azathioprine
Common adverse similar interaction and
effects: nausea, with mercaptopurine. mercaptopurine
stomatitis, GI ACE inhibitors may ↑ is influenced by
discomfort, the likelihood of a genetic
arthralgias diarrhea, neutropenia when polymorphism.
anorexia, increased combined with
risk of opportunistic azathioprine or
infection. mercaptopurine.
Page 425
Therapeutic Choice
a
Cost
Immunosuppressives 6-mercaptopurine 100 mg/day po Major adverse Oral anticoagulants: Not for use in $$
effects: blood mercaptopurine may pregnant
Purinethol dyscrasias, and inhibit women.
rarely pancreatitis, hypoprothrombinemic Metabolism of
hepatotoxicity. response to warfarin azathioprine
Common adverse and possibly other and
effects: nausea, anticoagulants. mercaptopurine
stomatitis, GI Allopurinol may ↑ is influenced by
discomfort, azathioprine toxicity; a genetic
arthralgias diarrhea, dosage adjustment polymorphism.
anorexia, increased may be necessary
risk of opportunistic (1/4 of regular dose);
infection. similar interaction
with mercaptopurine.
ACE inhibitors may ↑
the likelihood of
neutropenia when
combined with
azathioprine or
mercaptopurine.
Immunosuppressives methotrexate 25 mg im weekly Nausea, flu-like Alcohol restriction Methotrexate is $$

generics aches, headache, may minimize potentially
oral ulcers, bone hepatotoxicity. hepatotoxic.
marrow and liver NSAIDs may ↑ MTX Oral
toxicity, serum concentrations methotrexate
pneumonitis, (probably not has not been
immunosuppression, significant with low evaluated in
lymphoma. once-weekly MTX controlled trials.
doses). Some Not for use in
penicillins may ↓ MTX pregnant
clearance. women.
Metabolism of
azathioprine
and
mercaptopurine
is influenced by
a genetic
polymorphism.
Immunosuppressives cyclosporine 4 mg/kg/day iv Renal toxicity, Metabolized by Not for use in $$$$
Sandimmune hypertension, cytochrome P450: pregnant
hypertrichosis, many possible drug women.
cytopenia, gum interactions (e.g., Metabolism of
hyperplasia, erythromycin, azathioprine
electrolyte ketoconazole, and
imbalances, nausea, rifampin, St. John's mercaptopurine
diarrhea. Seizures. wort). is influenced by
Opportunistic a genetic
infection. polymorphism.
Biologic Response infliximab Induction: Crohn's Common:nausea, Patients should not Evaluate $$$$
Modifiers Remicade disease (luminal) or infusion or injection receive live vaccines patients for risk
ulcerative colitis: site reactions. during treatment. of tuberculosis
5 mg/kg iv x 1, 2 or Rare: before starting
3 doses tuberculosis, therapy. Co-
Fistulizing Crohn's opportunistic administration
disease: 5 mg/kg iv x infections, of
3 at wks 0, 2 and 6 reactivation of antimetabolites
Maintenance: hepatitis B infection, may potentiate
5 mg/kg iv every 8 formation of the response
wks. antinuclear and reduce
antibodies, formation of
reversible lupus-like anti-infliximab
syndrome, antibodies.
worsening heart
failure, lymphoma,
CNS demyelinating
disorders.
Page 426
Therapeutic Choice
a
Cost
adalimumab Crohn's Common:nausea, Patients should not Evaluate $$$$

Humira disease:Induction: infusion or injection receive live vaccines patients for risk
160 mg (4 injections) site reactions. during treatment. of tuberculosis
sc at wk 0, then Rare: before starting
80 mg (2 injections) tuberculosis, therapy.
sc at wk 2 opportunistic
Maintenance: infections,
40 mg sc every other reactivation of
wk beginning at wk hepatitis B infection,
4. formation of
antinuclear
antibodies,
reversible lupus-like
syndrome,
worsening heart
failure, lymphoma,
CNS demyelinating
disorders.
a.
Cost of 1-day supply for 70 kg person; includes drug cost only.
b.
Active dose is for CD and UC.
c.
Maintenance dose is for UC only.
Abbreviations: UC=ulcerative colitis; CD=Crohn's disease; UP=ulcerative proctitis
Legend: $ < $5 $$ $5–10 $$$ $10–15 $$$$ > $15
Suggested Readings
Baumgart DC, Carding SR. Inflammatory bowel disease: cause and immunobiology. Lancet 2007;369:1627–40.
Baumgart DC, Sandborn WJ. Inflammatory bowel disease: clinical aspects and established and evolving therapies. Lancet 2007;369:1641–
57.
Collins P, Rhodes J. Ulcerative colitis: diagnosis and management. BMJ 2006;333(7563):340-3.
Hanauer SB. Inflammatory bowel disease: epidemiology, pathogenesis, and therapeutic opportunities. Inflamm Bowel Dis 2006:12(Suppl
1):S3-9.
Lichtenstein GR, Abreu MT, Cohen R et al. American Gastroenterological Association Institute medical position statement on
corticosteroids, immunomodulators, and infliximab in inflammatory bowel disease. Gastroenterology 2006;130(3):935-9.
Mahadevan U, Kane S. American Gastroenterological Association Institute medical position statement on the use of gastrointestinal
medications in pregnancy. Gastroenterology 2006;131(1):278-82.
Su C, Lewis JD, Goldberg B, Brensinger C et al. A meta-analysis of the placebo rates of remission and response in clinical trials of active
ulcerative colitis. Gastroenterology 2007;132(2):516-26.
References
1. Malchow H, Ewe K, Brandes J et al. European Cooperative Crohn's Disease Study (ECCDS): results of drug treatment.
2. Summers RW, Switz DM, Sessions JT et al. National Cooperative Crohn's Disease Study: results of drug treatment. Gastroenterology
1979;77(4 Pt 2):847-69.
3. Jani N, Regueiro MD. Medical therapy for ulcerative colitis. Gastroenterol Clin North Am 2002;31(1):147-66.
4. Greenberg GR, Feagan BG, Martin F et al. Oral budesonide for active Crohn's disease. Canadian Inflammatory Bowel Disease Study
Group. N Engl J Med 1994;331(13):836-41.
5. Rutgeerts P, Lofberg R, Malchow H et al. A comparison of budesonide with prednisolone for active Crohn's disease. N Engl J Med
1994;331(13):842-5.
6. Kane SV, Schoenfeld P, Sandborn WJ et al. The effectiveness of budesonide therapy for Crohn's disease. Aliment Pharmacol Ther
2002;16(8):1509-17.
7. Hanauer SB, Robinson M, Pruitt R et al. Budesonide enema for the treatment of active, distal ulcerative colitis and proctitis: a dose-
ranging study. U.S. Budesonide enema study group. Gastroenterology 1998;115(3):525-32.
8. Candy S, Wright J, Gerber M et al. A controlled double blind study of azathioprine in the management of Crohn's disease. Gut
1995;37(5):674-8.
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Therapeutic Choice
9. Feagan BG, Rochon J, Fedorak RN et al. Methotrexate for the treatment of Crohn's disease. The North American Crohn's Study Group
Investigators. N Engl J Med 1995;332(5):292-7.
10. Pearson DC, May GR, Fick GH et al. Azathioprine and 6-mercaptopurine in Crohn disease. A meta-analysis. Ann Intern Med 1995;123
(2):132-42.
11. Present DH, Meltzer SJ, Krumholz MP et al. 6-Mercaptopurine in the management of inflammatory bowel disease: short- and long-
term toxicity. Ann Intern Med 1989;111(8):641-9.
12. Hanauer SB, Feagan BG, Lichtenstein GR et al. Maintenance infliximab for Crohn's disease: the ACCENT I randomised trial. Lancet
2002;359(9317):1541-9.
13. Targan SR, Hanauer SB, van Deventer SJ et al. A short-term study of chimeric monoclonal antibody cA2 to tumor necrosis factor
alpha for Crohn's disease. Crohn's Disease cA2 Study Group. N Engl J Med 1997;337(15):1029-35.
14. Present DH, Rutgeerts P, Targan S et al. Infliximab for the treatment of fistulas in patients with Crohn's disease. N Engl J Med
1999;340(18):1398-405.
15. Rutgeerts P, Sandborn WJ, Feagan BG et al. Infliximab for induction and maintenance therapy for ulcerative colitis. N Engl J Med
2005;353(23):2462–76.
16. Hanauer SB, Sandborn WJ, Rutgeerts P et al. Human anti-tumor necrosis factor monoclonal antibody (adalimumab) in Crohn's
disease: the CLASSIC-I trial. Gastroenterology 2006;130(2):323–33.
17. Sandborn WJ, Hanauer SB, Rutgeerts P et al. Adalimumab for maintenance treatment of Crohn's disease: results of the CLASSIC II
trial. Gut 2007;56:1232–9.
18. Sandborn WJ, Rutgeerts P, Enns R et al. Adalimumab induction therapy for Crohn disease previously treated with infliximab. Ann
Intern Med 2007;146(12)829–38.
19. Shen B, Achkar JP, Lashner BA et al. A randomized clinical trial of ciprofloxacin and metronidazole to treat acute pouchitis. Inflamm
Bowel Dis 2001;7(4):301-5.
20. Sutherland LR, Ramcharan S, Bryant H et al. Effect of cigarette smoking on recurrence of Crohn's disease. Gastroenterology 1990;98
(5 Pt 1):1123-8.
21. Steinhart AH, Ewe K, Griffiths AM et al. Corticosteroids for maintenance of remission in Crohn's disease. Cochrane Database Syst Rev
2003;(4):CD000301.
22. Hanauer SB, Stromberg U. Oral Pentasa in the treatment of active Crohn's disease: a meta-analysis of double-blind, placebo-
controlled trials. Clin Gastroenterol Hepatol 2004;2(5):379-88.
23. Akobeng AK, Gardener E. Oral 5-aminosalicylic acid for maintenance of medically-induced remission in Crohn's Disease. Cochrane
24. Mahadevan U, Kane S. American Gastroenterological Association Institute technical review on the use of gastrointestinal medications
in pregnancy. Gastroenterology 2006;131(1):283-311.
25. Lichtenstein GR, Abreu MT, Cohen R et al. American Gastroenterological Association Institute technical review on corticosteroids,
immunomodulators, and infliximab in inflammatory bowel disease. Gastroenterology 2006;130(3):940-87.
26. Winawer S, Fletcher R, Rex D et al. Colorectal cancer screening and surveillance: clinical guidelines and rationale. Update based on
new evidence. Gastroenterology 2003;124(2):544-60.
27. Oren R, Arber N, Odes S et al. Methotrexate in chronic active ulcerative colitis: a double-blind, randomized, Israeli multicenter trial.
28. Lichtiger S, Present DH, Kornbluth A et al. Cyclosporine in severe ulcerative colitis refractory to steroid therapy. N Engl J Med
1994;330(26):1841-5.
29. Feagan BG, Reinisch W, Rutgeerts P et al. The effects of infliximab therapy on health-related quality of life in ulcerative colitis
patients. Am J Gastroenterol 2007;102:794–802.
30. Bernstein CN, Eaden J, Steinhart AH et al. Cancer prevention in inflammatory bowel disease and the chemoprophylactic potential of 5
-aminosalicylic acid. Inflamm Bowel Dis 2002;8(5):356-61.
31. Lashner BA, Heidenreich PA, Su GL et al. Effect of folate supplementation on the incidence of dysplasia and cancer in chronic
ulcerative colitis. A case-control study. Gastroenterology 1989;97(2):255-9.
Pharmacoeconomic Considerations: Inflammatory Bowel Disease

Epidemiology
Country Incidence and Prevalence (%)
Canada (1987-1996)1 Ulcerative colitis: 15.6 cases per 100 000 person-years
Crohn’s disease: 15.6 cases per 100 000 person-years
United States (1990)2 US $0.4 to $0.6 billion US $1.4 to $2.0 billion
Commentary
Inflammatory bowel disease (IBD) refers collectively to ulcerative colitis (UC) and Crohn's disease (CD). Wages lost from UC and CD are
significant, and are more than double the direct costs of treatment.2 In one study from the United Kingdom, lost wages accounted for
£230 to £299 per patient over a six-month period.3
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Therapeutic Choice
4
Although hospitalization for IBD is not common, it accounted for almost 50% of the overall costs associated with IBD over six months
in a university hospital setting, while medications accounted for less than 25% of the remainder.2 Surgery accounts for a significant
portion (40% to 60%) of the costs associated with hospitalization.5 , 6
7
In terms of therapeutic choices, infliximab is more expensive than methotrexate, but reduces costs associated with hospitalizations.
Infliximab is cost-effective when combined with methotrexate for the episodic management of CD, but long-term maintenance therapy
8 , 9 , 10
exceeds conventional benchmarks for cost-effectiveness. Economic evaluations of infliximab have generally considered patients
refractory to standard therapies with few other treatment options. However, direct head-to-head comparative trials of infliximab with
other biological agents are not yet available and would be helpful in determining with greater certainty the place of infliximab in the
management of IBD.8
a.
b.
1. Blanchard JF, Bernstein CN, Wajda A et al. Small-area variations and sociodemographic correlates for the incidence of Crohn’s
disease and ulcerative colitis. Am J Epidemiol 2001;154(4):328-35.
2. Hay JW, Hay AR. Inflammatory bowel disease: costs of illness. J Clin Gastroenterol 1992;14(4):309-17.
3. Bassi A, Dodd S, Williamson P et al. Cost of illness of inflammatory bowel disease in the UK: a single centre retrospective study.
Gut 2004;53(10):1471-8.
4. Feagan BG, Vreeland MG, Larson LR et al. Annual cost of care for Crohn’s disease: a payor perspective. Am J Gastroenterol 2000;95
(8):1955-60.
5. Bernstein CN, Papineau N, Zajaczkowski J et al. Direct hospital costs for patients with inflammatory bowel disease in a Canadian
tertiary care university hospital. Am J Gastroenterol 2000;95(3):677-83.
6. Cohen RD, Larson LR, Roth JM et al. The cost of hospitalization in Crohn’s disease. Am J Gastroenterol 2000;95(2):524-30.
7. Jewell DP, Satsangi J, Lobo A et al. Infliximab use in Crohn’s disease: impact on health care resources in the UK. Eur J
Gastroenterol Hepatol 2005;17(10):1047-52.
8. Jaisson-Hot I, Flourie B, Descos L et al. Management for severe Crohn’s disease: a lifetime cost-utility analysis. Int J Technol Assess
Health Care 2004;20(3):274-9.
9. Bodger K. Economic implications of biological therapies for Crohn’s disease: review of infliximab. Pharmacoeconomics 2005;23
(9):875-88.
10. Marshall JK, Blackhouse G, Goeree R et al. Clinical and economic assessment: infliximab for the treatment of Crohn's disease. Ottawa
(ON): Canadian Coordinating Office for Health Technology Assessment; 2002. Technology overview no 8.
Page 429
e-Therapeutics+ : Therapeutics : Gastrointestinal Disorders: Irritable Bowel Syndrome Page 1 of 8
Therapeutic Choice
Print Close
Gastrointestinal Disorders: Irritable Bowel Syndrome

W. Grant Thompson, MD, FRCPC
The irritable bowel syndrome (IBS) is a collection of symptoms attributed to the intestine, related to defecation and
unpredictable bowel habit (Table 1). Since there is no known pathology or pathophysiology, IBS can only be
recognized by its characteristic pattern of abdominal pain and discomfort, which is relieved by defecation or
associated with a change in bowel habit.1 , 2 A substantial number of IBS patients date the onset of their symptoms
to an attack of bacterial enteritis.3 While subgroups have been proposed according to whether constipation, diarrhea
or both are present, these are intermittent and it is very common for the predominant bowel habit to change from
time to time.
4
In Canadian adults, the one-year prevalence is about 12%, and females with IBS outnumber males 4:1. Because
the symptoms come and go, the lifetime prevalence is much higher. Most people who have these symptoms do not
consult physicians. Nevertheless, IBS accounts for 30% of gut complaints in primary care (2% of all adult patients),
and the few that are referred to specialists are about 20% of a gastroenterologist's practice. While the syndrome
2 , 5
occurs at all ages, more young IBS sufferers see physicians. IBS is the ninth most costly gastrointestinal (GI)
disorder, and in the year 2000, US direct and indirect expenditure was over $1.5 billion.
Goals of Therapy
Establish caring doctor-patient relationship

Conduct a thorough interview and examination to establish the diagnosis and rule out serious pathology
Reassure the patient through a confident diagnosis. Address fears of serious disease
Alleviate symptoms while establishing realistic expectations. Patients may expect greater benefit from lifestyle
modification than drugs6
Promote coping and normal social and occupational functioning
Treat psychosocial comorbidity if present
Investigations
Thorough history with particular attention to abdominal pain and its relationship with diet, defecation and altered
stool frequency and form (Table 1). Pelvic pain (actually lower abdominal pain) may be due to IBS rather than a
7
gynecologic cause. However, potential gynecologic causes of pain must be ruled out. Physical findings or alarm
symptoms as shown in Table 2, such as rectal bleeding, anemia, fever or profound weight loss, are not explained by
IBS. The history should also explore the patient's psychosocial circumstances and the reasons that the patient has
chosen to consult a physician. A recent history of bacterial gastroenteritis may explain self-limiting IBS-like
symptoms. Difficult, chronic constipation or persistent diarrhea are not likely due to IBS, and raise different
diagnostic and treatment issues that are discussed elsewhere (see Symptom Control: Constipation in Adults and
Symptom Control: Diarrhea).
Table 1: Diagnostic Criteria (Rome III)a , b , c for IBS1
d
Recurrent abdominal pain or discomfort at least 3 days per month in the last 3 months associated with 2 or more
of the following:
1. Improvement with defecation
2. Onset associated with a change in frequency of stool
3. Onset associated with a change in form (appearance) of stool
a.
Criteria fulfilled for the last 3 months with symptom onset at least 6 months prior to diagnosis.
b.
Supportive symptoms that are not part of the diagnostic criteria include abnormal stool frequency (a) fewer than 3 bowel
movements per week, or (b) greater than 3 bowel movements per day; abnormal stool form (c) lumpy/hard stool, or (d)
loose/watery stool; (e) defecation straining; (f) urgency, or also feeling of incomplete bowel movement, passing mucus and
bloating.
c.
In the absence of structural or metabolic abnormalities to explain the symptoms.
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Therapeutic Choice
d.
“Discomfort" means an uncomfortable sensation not described as pain.
Tests may be unnecessary in a young person with chronic and typical symptoms of IBS (Table 1), no alarm
7 , 8
symptoms and no family history of colon cancer, inflammatory bowel disease (IBD) or celiac disease (Table 2) .
If the patient is over the age of 50 years, and/or has risk factors for cancer or recent onset of atypical symptoms,
9 , 10 , 11 , 12
colon investigation with a barium enema or colonoscopy is recommended.
Table 2: Alarm Symptoms That Cannot be Explained by IBS
Fever
Anemia
Bleeding from the gut
Significant weight loss
Family history of cancer, IBD or celiac disease
Recent consistent change in bowel habit
Persistent, daily diarrhea or constipation
Abnormal physical findings, for example, abdominal mass or malnutrition
Abbreviations: IBD = inflammatory bowel disease; IBS = irritable bowel syndrome
Discuss the diagnosis and prognosis with the patient.

Address the patient’s fears and provide reassurance.
13 14
A good doctor-patient relationship maximizes placebo effects and improves long-term outcomes.
6
Patients generally derive more benefit from lifestyle modification than drug therapy.
Encourage consumption of a healthy diet (Canada's Food Guide to Healthy Eating)8 and sufficient fluid intake.
Avoid food fads, excessive caffeine, alcohol, sorbitol (in gums and candies) and fructose (in preserves).
Encourage the patient to keep a diary of foods that trigger or relieve symptoms and to note any stressors.
Many treatments proposed by alternative practitioners or the media have no proven efficacy. Some diets may be
nutritionally unsound.
Be alert to gut symptoms that may be caused by adverse effects of drugs or alternative health products, for
example, herbal medicines.
If constipated, ensure sufficient dietary fibre.
Lifestyle adjustment: stress management, relaxation advice, quiet time for eating and defecation.
15 15 16 , 17
Treat comorbid conditions: depression, anxiety, panic, life stress.
Psychological treatments may require the involvement of a mental health professional, and the benefits in
18
patients with IBS are difficult to prove. The following may help in refractory cases, or when psychopathology
19 20 21
is evident: psychopharmacotherapy, individual or group psychotherapy, cognitive-behavioural therapy,
hypnosis22 (if available) and stress management or relaxation techniques including audio and video tapes.
Avoid inappropriate referral and unnecessary surgery. IBS symptoms are sometimes mistaken for gynecologic or
gallbladder diseases.
No one drug is effective for the entire IBS symptom complex.

For the purposes of treatment, patients are grouped by their predominant bowel habit: IBS with constipation,
IBS with diarrhea or IBS alternating between constipation and diarrhea. Since this may change from time to
time, laxatives and antidiarrheal agents should be used cautiously and the effects monitored.
When nonpharmacologic measures fail, target the most troublesome symptom (Table 3).
23
The Bristol Stool Form Scale (Figure 1 - Bristol Stool Form Scale) can be used to identify patients who suffer
6 , 24
from constipation or diarrhea. Selection of pharmacotherapy depends largely upon the predominant
symptom.
For IBS patients with predominant diarrhea (Bristol Stool Form Scale type 6 or 7): loperamide
25
PRN may be recommended, especially if the patient is concerned about
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Therapeutic Choice
incontinence.26Diphenoxylate with atropine may also be used and rarely, a patient may improve on
cholestyramine. For IBS patients with predominant constipation (pellety stools, Bristol Stool Form
Scale type 1): recommend two to four tablespoonsful of raw bran or psyllium daily with plenty of
fluids. Calcium polycarbophil may also be used.27 If this fails, osmotic laxatives such as magnesium
hydroxide or lactulose may be tried. If the constipation is intractable, the patient has something
other than IBS (see Symptom Control: Constipation in Adults). Useful Info?
28
For patients with chronic abdominal pain that impairs normal functioning: amitriptyline or desipramine
21 , 28
may be useful, and may be effective in lower-than-antidepressant doses.29
Lubiprostone, a chloride channel activator, is approved in the United States for chronic constipation and IBS
with constipation. There are no data comparing this drug’s efficacy with other laxatives. Side effects include
transient dyspnea, diarrhea, nausea and abdominal pain. Lubiprostone may be used in IBS patients who are
constipated and have not responded to laxatives. Should the stools become loose or watery (Bristol types 6 or
7), the dose should be lowered or the drug withdrawn.
There is much interest in the use of probiotics for IBS, but the quality and viability of most individual products is
unknown and the supporting evidence is meagre. Promising results were demonstrated using Bifidobacterium infantis
in a small study of IBS patients where symptomatic improvement after 8 weeks correlated with normalization of the
30 , 31
IL-10/IL-12 ratio (an indicator of a pro-inflammatory state that was elevated at baseline).
Bacterial overgrowth is a supposed cause of IBS, but is likely not an important factor for many IBS patients. A
consensus questions the evidence for this hypothesis and recommends against the use of antibiotics with their
6
attendant potential for harm.
Prognosis32
Usually recurrent and lifelong; no effect upon life expectancy.

The bowel habit may change from time to time.
If the diagnosis of IBS is carefully made, there is a low risk of missing underlying structural disease.
There is no predisposition to structural disease such as diverticular disease, cancer or IBD.
The Difficult-to-Treat Patient
Complicated patients that tend to be referred to specialists often have comorbid conditions such as depression, or a
history of serious emotional trauma such as sexual abuse. Such patients are best managed with regularly scheduled
33
visits for a sympathetic discussion. If necessary, a gastroenterology consultation may support the primary care
34
physician's diagnosis and management plan, and reduce future IBS-related costs. A mental health professional
may assist with a severe comorbid psychological disorder. Long-term cure is unlikely, particularly in severely
affected patients, so the emphasis should be on coping and normal occupational and social functioning.
Table 3: Management of Irritable Bowel Syndrome (IBS)
Diagnosis: It is essential to make a positive diagnosis, rather than a diagnosis of exclusion, and to convincingly
convey this to the patient
Education/reassurance: explain the pathophysiology and natural history of IBS
Physiological abnormalities include altered intestinal motility and visceral hypersensitivity

IBS can be precipitated by a previous enteric infection
Diet has no causal role, but may exacerbate IBS
Emotional stress does not cause IBS, but psychosocial factors may exacerbate the symptoms and/or
contribute to the distress they cause
Validate symptoms. The symptoms are real, not imagined. Gut and brain interact to alter motility (muscle
contractions) and/or increase bowel sensation
IBS is a chronic, relapsing, but benign disorder
Healthy lifestyle: provide advice regarding the importance of a balanced diet, exercise and time for toilet each
morning
Diet
Follow Canada’s Food Guide to Healthy Eating (www.hc-sc.gc.ca/fn-an/food-guide-aliment/index-eng.php)

Limit intake of alcohol, caffeine, fat and sorbitol. They do not cause IBS, but may exacerbate the symptoms
Restrict lactose consumption in patients who seem to improve with a trial of lactose restriction
Refer problem eaters to a dietitian
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Therapeutic Choice
Psychosocial issues: explore in select patients
“Indicators” of difficulty coping with IBS:

Poor insight
Inability to express emotions
Comorbid conditions
History of physical or sexual abuse or other major life stresses
Multiple somatic complaints or abnormal illness behaviour
“Catastrophizing” symptoms, e.g., “First sign of pain means my day is ruined”
Poor coping mechanisms
Inadequate social supports
A 2-week symptom diary may assist select patients to connect diet and stress with aggravation of symptoms
Consider cognitive-behavioural therapy or hypnosis and relaxation therapy for patients with severe IBS
Drug Therapy
Most patients will not require drug therapy

No single drug has been shown to be beneficial for the IBS symptom complex
Specific IBS symptoms may be amenable to drug therapy (Table 4)—first identify the predominant symptom
(Figure 1 - Bristol Stool Form Scale)
Adapted with permission from Paterson WG et al. CMAJ 1999;161(2):154-60.
Therapeutic Tips
35 , 36 , 37
The efficacy of many drugs proposed for IBS is unproven or varies greatly. “Colonic spasm” does not
explain IBS symptoms and therefore drugs that “relieve spasm” are unlikely to be helpful. So-called
antispasmodic drugs approved by Health Canada for IBS include dicyclomine, pinaverium and trimebutine.
Hyoscine is not indicated for IBS. If used at all, these drugs should only be taken for a few weeks at a time.
This author endorses none of them. These drugs differ from those approved in other countries, reflecting a lack
of agreement about efficacy among regulatory authorities.32
No medication has proven beneficial for bloating.
Figure 1- Bristol Stool Form Scale
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Therapeutic Choice
Reproduced with permission from Thompson WG, Heaton KW. Fast facts: irritable bowel syndrome. 2nd edition. Oxford:
Health Press Limited; 2003.
Table 4: Drugs Used for the Management of Irritable Bowel Syndrome
Adverse Drug Costb

Drug Class Drug Dose Effects Interactions Comments
Antidiarrheals loperamide For diarrhea: Abdominal For short-term $-$$

Imodium, 2– 4 mg as cramps, control of
Riva- needed (max 12 dizziness, diarrhea.
mg/day) dry mouth. Nonprescription.
Loperamide,
other
generics
Bulk-forming calcium For Cramps, Advise patients Take with fluids. $

a polycarbophil constipation: bloating, not to take within Nonprescription.
Agents
625 mg caplets: 2 flatulence. 3 h of other drugs
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Therapeutic Choice
Adverse Drug Costb

Prodiem Fibre caplets daily to to minimize
Therapy QID, not to interference with
exceed 8 absorption.
caplets/24 h
Bulk-forming psyllium For Cramps, Advise patients Take with fluids. $

Agentsa hydrophilic constipation: bloating, not to take within Nonprescription.
mucilloid 15 g BID with flatulence. 3 h of other drugs
Metamucil meals, then to minimize
Preparations, adjust (varies interference with
generics with product) absorption.
Tricyclic amitriptyline For abdominal Drowsiness, Possible CNS Use low doses for $
Antidepressants generics pain: 25– dry mouth, excitation with select patients
100 mg QHS headache. serotonergic with intractable
agents. pain.
Avoid combined Numerous other
use with other agents are
agents that available.
prolong QTc.
Tricyclic desipramine For abdominal Drowsiness, Possible CNS Use low doses for $
Antidepressants generics pain: 25– dry mouth, excitation with select patients
100 mg QHS headache. serotonergic with intractable
agents. pain.
Avoid combined Numerous other
use with other agents are
agents that available.
prolong QTc.
a.
Information on laxatives can be found in Symptom Control: Constipation in Adults.
b.
Cost per day includes drug cost only.
Legend: $ < $1 $-$$ < $1–2 $$ $1–2
Suggested Readings
American College of Gastroenterology Task Force on Irritable Bowel Syndrome, Brandt LJ, Chey WD et al. An
evidence-based position statement on the management of irritable bowel syndrome. Am J Gastroenterol 2009;104
(Suppl 1):S1-35.
Longstreth GF, Thompson WG, Chey WD et al. Functional bowel disorders. Gastroenterology 2006;130(5):1480-91.
Thompson WG. The placebo effect in health: combining science & compassionate care. Amherst (NY): Prometheus
Books; 2005.
Thompson WG. Understanding the irritable gut: the functional gastrointestinal disorders. McLean (VA): Degnon
Associates; 2008.
References
Page 435
Therapeutic Choice
1. Longstreth GF, Thompson WG, Chey WD et al. Functional bowel disorders. Gastroenterology 2006;130
(5):1480-91.
2. Thompson WG. Understanding the irritable gut: the functional gastrointestinal disorders. McLean (VA): Degnon
Associates; 2008.
3. Spiller R, Garsed K. Postinfectious irritable bowel syndrome. Gastroenterology 2009;136(6):1979-88.
4. Thompson WG, Irvine EJ, Pare P et al. Functional gastrointestinal disorders in Canada: first population-based
survey using Rome II criteria with suggestions for improving the questionnaire. Dig Dis Sci 2002;47(1):225-
35.
5. Drossman DA. The functional gastrointestinal disorders and the Rome III process. Gastroenterology 2006;103
(5):1377-90.
6. Whitehead WE, Levy RL, Von Korff M et al. The usual medical care for irritable bowel syndrome. Aliment
Pharmacol Ther 2004;20(11-12):1305-15.
7. Thompson WG, Heaton KW, Smyth GT et al. Irritable bowel syndrome in general practice: prevalence,
characteristics, and referral. Gut 2000;46(1):78-82.
8. Paterson WG, Thompson WG, Vanner SJ et al. Recommendations for the management of irritable bowel
syndrome in family practice. IBS Consensus Conference Participants. CMAJ 1999;161(2):154-60.
9. Winawer S, Fletcher R, Rex D et al. Colorectal cancer screening and surveillance: clinical guidelines and
rationale-Update based on new evidence. Gastroenterology 2003;124(2):544-60.
10. Winawer SJ, Fletcher RH, Miller L et al. Colorectal cancer screening: clinical guidelines and rationale.
11. U.S. Preventive Services Task Force. Screening for colorectal cancer: U.S. Preventive Services Task Force
recommendation statement. Ann Intern Med 2008;149(9):627-37.
12. Leddin D, Hunt R, Champion M et al. Canadian Association of Gastroenterology and the Canadian Digestive
Health Foundation: guidelines on colon cancer screening. Can J Gastroenterol 2004;18(2):93-9.
13. Thompson WG. Placebos: a review of the placebo response. Am J Gastroenterol 2000;95(7):1637-43.
14. Owens DM, Nelson DK, Talley NJ. The irritable bowel syndrome: long-term prognosis and the physician-
patient interaction. Ann Intern Med 1995;122(2):107-12.
15. Tollefson GD, Tollefson SL, Pederson M et al. Comorbid irritable bowel syndrome in patients with generalized
anxiety and major depression. Ann Clin Psychiatry 1991;3215-222.
16. Craig TK, Brown GW. Goal frustration and life events in the aetiology of painful gastrointestinal disorder. J
Psychosom Res 1984;28(5):411-21.
17. Creed F. Life events and appendicectomy. Lancet 1981;1(8235):1381-5.
18. Talley NJ, Owen BK, Boyce P et al. Psychological treatments for irritable bowel syndrome: a critique of
controlled treatment trials. Am J Gastroenterol 1996;91(2):277-83.
19. Potter WZ, Rudorfer MV, Manji H. The pharmacologic treatment of depression. N Engl J Med 1991;325(9):633-
42.
20. Guthrie E, Creed F, Dawson D et al. A randomised controlled trial of psychotherapy in patients with refractory
irritable bowel syndrome. Br J Psychiatry 1993;163:315-21.
21. Drossman DA, Toner BB, Whitehead WE et al. Cognitive-behavioral therapy versus education and desipramine
versus placebo for moderate to severe functional bowel disorders. Gastroenterology 2003;125(1):19-31.
22. Gonsalkorale WM, Houghton LA, Whorwell PJ. Hypnotherapy in irritable bowel syndrome: a large-scale audit
of a clinical service with examination of factors influencing responsiveness. Am J Gastroenterol 2002;97
(4):954-61.
23. Heaton KW, O'Donnell LJ. An office guide to whole-gut transit time. Patients' recollection of their stool form. J
Clin Gastroenterol 1994;19(1):28-30.
24. Thompson WG, Heaton KW. Fast facts: irritable bowel syndrome. 2nd ed. Oxford (UK): Health Press; 2003.
25. Thompson WG. Nonulcer dyspepsia. Can Med Assoc J 1984;130(5):565-9.
26. Read M, Read NW, Barber DC et al. Effects of loperamide on anal sphincter function in patients complaining of
chronic diarrhea with fecal incontinence and urgency. Dig Dis Sci 1982;27(9):807-14.
27. Toskes PP, Connery KL, Ritchey TW. Calcium polycarbophil compared with placebo in irritable bowel
syndrome. Aliment Pharmacol Ther 1993;7(1):87-92.
28. Jackson JL, O'Malley PG, Tomkins G et al. Treatment of functional gastrointestinal disorders with
antidepressant medications: a meta-analysis. Am J Med 2000;108(1):65-72.
29. Halpert A, Dalton CB, Diamant NE et al. Clinical response to tricyclic antidepressants in functional bowel
disorders is not related to dosage. Am J Gastroenterol 2005;100(3):664-71.
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Therapeutic Choice
30. O'Mahony L, McCarthy J, Kelly P et al. Lactobacillus and bifidobacterium in irritable bowel syndrome:
symptom responses and relationship to cytokine profiles. Gastroenterology 2005;128(3):541-51.
31. Breener DM, Moeller MJ, Chey WD et al. The utility of probiotics in the treatment of irritable bowel syndrome:
a systematic review. Am J Gastroenterol 2009;104(4):1033-49.
32. Thompson WG. The treatment of irritable bowel syndrome. Aliment Pharmacol Ther 2002;16(8):1395-406.
33. Drossman DA. Struggling with the "controlling" patient. Am J Gastroenterol 1994;89(9):1441-6.
34. Ilnyckyj A, Graff LA, Blanchard JF et al. Therapeutic value of a gastroenterology consultation in irritable bowel
syndrome. Aliment Pharmacol Ther 2003;17(7):871-80.
35. Akehurst R, Kaltenthaler E. Treatment of irritable bowel syndrome: a review of randomised controlled trials.
Gut 2001;48(2):272-82.
36. Klein KB. Controlled treatment trials in the irritable bowel syndrome: a critique. Gastroenterology 1988;95
(1):232-41.
37. Quartero AO, Meineche-Schmidt V, Muris J et al. Bulking agents, antispasmodic and antidepressant medication
for the treatment of irritable bowel syndrome. Cochrane Database Syst Rev 2005;(2):CD003460.
Page 437
e-Therapeutics+ : Therapeutics : Gastrointestinal Disorders: Peptic Ulcer Disease Page 1 of 9
Therapeutic Choice
Print Close
Gastrointestinal Disorders: Peptic Ulcer Disease
A.B.R. Thomson, MD, PhD, FRCPC, FACG
Dyspepsia, defined as pain or discomfort in the upper abdomen, is one of the most common complaints bringing
patients to consult their family physician. The most common causes of dyspepsia include nonulcer dyspepsia (NUD),
gastroesophageal reflux disease (GERD) (Gastrointestinal Disorders: Gastroesophageal Reflux Disease), duodenal
ulcer (DU) and gastric ulcer (GU). DU and GU are considered to be two of the Helicobacter pylori-associated
diseases, and both are components of the gastroenteropathy associated with nonsteroidal anti-inflammatory drugs
(NSAIDs).
Goals of Therapy
Relieve dyspepsia and heal the ulcer

Prevent complications, e.g., bleeding, perforation
Prevent recurrence
Investigations
History and physical examination

exclude nongastrointestinal sources of pain or discomfort in the upper abdomen, e.g., ischemic heart
disease
inquire into possible alarm symptoms (vomiting, bleeding, dysphagia, anemia or weight loss) and confirm
patient age (potential risk factor for cancer)
determine the character of the dyspeptic symptoms to establish if heartburn and/or regurgitation are
predominant symptoms:
— ulcer-like (pain, relief with food)
— reflux-like (heartburn, regurgitation) (See Gastrointestinal Disorders: Gastroesophageal Reflux
Disease GERD)
— dysmotility-like (bloating, fullness)
take a drug history for NSAID/ASA use, including low-dose ASA for cardioprotection, as well as other
medications that may cause or aggravate dyspepsia, e.g., bisphosphonates, tetracyclines, calcium channel
blockers
physical examination will usually be normal. Epigastric tenderness is a common but nonspecific finding; an
abdominal mass is an alarm sign
H. pylori infection
14 13 13
C or C urea breath test (UBT) in selected individuals (Figure 1). The C (nonradioactive) UBT is
1
recommended for use in children and women of child-bearing age.
Serology is appropriate if there is no access to UBT or endoscopy. If the serology is negative, the patient is
truly H. pylori negative, but if serology is positive, there is about a 20% risk that the test is falsely positive.
Serology is not useful for confirming eradication.
Esophagogastroduodenoscopy (or endoscopy): Investigation of choice in patients with: dyspepsia over the age
of 50, alarm symptoms (such as vomiting, bleeding, anemia, weight loss, dysphagia), GU reported on an upper
GI series (to obtain biopsies to exclude gastric cancer); also following 8 to 12 weeks' treatment of a GU to
confirm healing, or to diagnose an H. pylori infection when UBT is not available.
Prompt endoscopy: the most sensitive and specific means to diagnose the cause of dyspepsia is endoscopy. It
permits the diagnosis of erosive esophagitis, Barrett's epithelium, GU or DU, gastric or duodenal erosions,
H. pylori infection and gastric or esophageal cancer. The patient and physician will be reassured as to the cause
of dyspepsia, and future use of medications and health care resources may be lessened.
The disadvantages of prompt endoscopy are self-evident. In many Canadian communities, the average waiting
time to consult a gastroenterologist to arrange for an endoscopy is at least eight weeks and may be as long as
six months. Time is lost from work, the procedure is expensive to the health care system (total cost
approximately $500), and there is a very small but real risk of a complication (about 1 per 5000 procedures)
such as aspiration or perforation.
Upper GI Barium Study: The upper GI series has an approximately 20% false-positive and false-negative rate
for ulcer disease and is generally not recommended. However, barium studies are often more available than
UBT or endoscopy and are still used to reassure the physician that nothing serious has been missed as a cause
of the dyspepsia. Because of the relatively low sensitivity and specificity of the upper GI series, perform
2
endoscopy if the patient is over 50 or has alarm features, rather than performing a barium study. An upper GI
Page 438
Therapeutic Choice
series should not be performed in the patient with bleeding from the upper GI tract as this may obscure the
diagnosis when endoscopy is performed.
Therapeutic Choices (Figure 1 - Management of Suspected Peptic Ulcers2 )
Bland diets are no longer prescribed. A simple rule of thumb is to use moderation if a food or beverage makes
dyspepsia worse. Common offenders are coffee, orange juice, spicy foods, fatty foods, large meals or eating on
the run.
Smoking cessation improves ulcer healing and reduces recurrence of ulcers not related to H. pylori infection.
See Psychiatric Disorders: Smoking Cessation for more information on smoking cessation.
Management of PUD
If the patient has dyspepsia with suspected ulcer (i.e, dyspepsia where heartburn and regurgitation are not the
3
predominant symptoms), the following are commonly used approaches:
Empiric therapy – treat with a proton pump inhibitor (PPI) once a day before breakfast or an
H2-receptor antagonist (H2RA) twice a day for four to eight weeks. This duration is sufficient to heal the erosive
esophagitis present in about 50% of all patients with uninvestigated dyspepsia.4 However, PPIs are much
superior.5 See the patient in follow-up, and for those who remain symptomatic, consider switching to another
PPI or dosing with twice daily PPI. If dyspepsia persists, or if there are frequent recurrences, investigate with a
UBT for H. pylori infection, or with prompt endoscopy. The patient should not have taken a PPI or H2RA for at
least one week before performing the UBT, since these may suppress the growth of the H. pylori sufficiently to
render the UBT falsely negative. Noninvasive testing for H. pylori is as safe and effective as endoscopy and
more comfortable and less distressing for the patient,6 although fewer patients are satisfied with their
7
treatment. Most patients with dyspepsia and an abnormal endoscopy will have erosive esophagitis (45%), and
far fewer (5%) will have DU or GU.
The advantage of empiric therapy is that it is an office-based approach that does not require initial
investigations such as UBT or endoscopy. The disadvantage is that some patients continue with dyspepsia, or
the symptoms recur and there is no diagnosis.
Test-and-treat – a diagnostic test is performed for H. pylori, and a positive test result is treated with triple
therapy (Table 1). This approach assumes that if the patient's dyspepsia is caused by DU/GU, they will be
positive for H. pylori. About 90% of DU and 70% of GU may be H. pylori-positive, although the association may
be less striking in community practice, or in patients with a past history of an ulcer complicated by bleeding.
The advantage of this approach is that the investigations needed to diagnose H. pylori, when available in the
community, can be readily used by the family physician and the results are rapidly available. The disadvantage
is that serology and UBT are not universally available in all communities in Canada, and the cost of these tests
is not usually covered by provincial health care plans.
Note that in dyspeptic nonulcer patients with an H. pylori infection, the benefit of eradication is small (7% to
8 , 9 , 10
15% symptom resolution).
Modest Acid Inhibition
Over-the-counter (OTC) therapy with antacids or H2 RAs are commonly used by patients before seeking medical
advice. They provide moderate benefit for mild symptoms of dyspepsia.
Prescription doses of H2 RAs may be used for symptom relief but are much less effective for pain relief or ulcer
healing than PPIs, and must be used twice a day and for longer periods (4 to 8 weeks for duodenal ulcer and 8 to 12
weeks for gastric ulcer). Tachyphylaxis (loss of effectiveness over time) may develop quickly, and the H2 RAs have
no role to play in the approved regimens used to eradicate H. pylori.
Extensive Acid Inhibition
The duration of use of PPI needed to heal a DU is shortened to one week when triple therapy is used to eradicate an
11
associated H. pylori infection. For those individuals with a DU or GU not associated with either H. pylori infection
or use of NSAIDs, once in the morning PPI should be used for two to four weeks, and maintenance therapy must be
Page 439
Therapeutic Choice
considered on an individualized basis. Patients with a GU must have a follow-up endoscopy to prove ulcer healing in
order to avoid the rare initial misdiagnosis of a gastric cancer.
As a class of medications, the five PPIs available in Canada are all very effective. There are minor pharmacokinetic
and pharmacodynamic differences, but the variations in healing rates are only about 5% (NNT, 20). A recent
12
Canadian Consensus Conference suggested that there were no clinically significant differences between the PPIs.
Note that some PPIs are as much as 40% less costly than others.
Maintenance Therapy
Continuous use of acid inhibition, preferably with a PPI, may be needed in selected patients with DU/GU not
associated with H. pylori infection, especially when the ulcer is complicated by bleeding or perforation, or when the
patient suffers from frequent recurrences of dyspepsia.
It is controversial whether some ulcer patients cured of their H. pylori infection may develop de novo reflux-like
dyspepsia, and require intermittent or continuous PPI. Some high-risk patients requiring continuous use of NSAIDs
may need to be maintained on PPIs to reduce the risk of recurrent GU/DU.
Eradication of H. pylori Infection (Table 1)
Eradication of H. pylori infection is more cost-effective than maintenance therapy with acid-lowering medications
and reduces the risk of developing gastric cancer or mucosa-associated lymphoid tissue (MALT) lymphoma.
Treatment regimens approved by the Canadian Helicobacter Study Group achieve a minimum eradication rate (on an
intention-to-treat basis) of at least 80%. First-line therapy includes triple therapy PPI plus two antibiotics
(clarithromycin and either amoxicillin or metronidazole) twice daily for one week (Table 1). Quadruple therapy
is also considered first-line treatment.1 Ranitidine bismuth citrate, which was previously recommended, is no longer
available in Canada. Because the prevalence of metronidazole resistance in Canada is about 20% and resistance to
1
amoxicillin is less than 1%, increasing use is made of the amoxicillin-containing regimen. Prepacked combinations
of triple therapy are available.
Table 1: H. pylori Eradication Regimens
a
Regimen Dosage Treatment Period Cost
Triple Therapy
PPI BID 7 days $$$

clarithromycin 500 mg BID
amoxicillin 1 g BID
Hp-PAC Losec 1-2-3 A
PPI BID 7 days $$$

clarithromycin 250 mg BID
metronidazole 500 mg BID
Losec 1-2-3 M
Quadruple Therapy
PPI BID 7 days $$$

bismuth subsalicylate 2 tabs QID
metronidazole 250 mg QID
tetracycline 500 mg QID
a.
Cost per treatment period; includes drug cost only.
Legend: $ < $20 $$ $20–40 $$$ $40–60

Abbreviations: PPI = proton pump inhibitor
Page 440
Therapeutic Choice
If the patient fails one triple-therapy regimen, repeat treatment with a different antibiotic combination, or treat for
two weeks rather than one, or use quadruple therapy (PPI, bismuth, metronidazole plus tetracycline). After
successful H. pylori eradication, the risk of reinfection is only about 1% per year.
Repeated testing by UBT or endoscopic biopsies to prove eradication is necessary in patients with a complicated
ulcer (bleeding or perforation) to ensure healing and prevent recurrence. In the occasional patient who experiences
recurrent dyspepsia after the use of an approved eradication regimen, it may be necessary to prove successful
eradication before looking for new causes of dyspepsia.
NSAID-associated Ulcers
Unlike H. pylori-associated ulcers, GU/DU caused by ASA or NSAIDs are more likely to be painless, and patients
often present for the first time with a complication such as bleeding or perforation.13 , 14 Over a one-year interval,
about 3% of NSAID users will develop a GU/DU. Controversy exists regarding the extent to which COXIBs may
reduce the risk of serious GI events, but the risk is not eliminated by use of these drugs.15 , 16 , 17 Recent reports
of cardiovascular complications with use of COXIBs have limited their use and challenged their safety.
The risk of developing an NSAID ulcer is greater in persons over the age of 65, and with use of more than one
NSAID, higher doses of NSAID, concomitant use of steroids or anticoagulants, a past history of ulcer disease and
coexisting ischemic heart disease. Patients taking ASA with an NSAID are also at higher risk of ulcer complications.
Discuss the risk of NSAID-induced gastric complications with patients, including signs and symptoms associated
with GI bleed, e.g., dyspepsia, coffee ground emesis, melena. At-risk patients may be offered gastric protective
therapy with standard doses of PPI. Alternatively, misoprostol 200 µg QID may be offered, but use may be limited
18
by GI adverse effects.
An NSAID-induced ulcer should be treated like a non-NSAID-induced ulcer. Whenever possible, the NSAID should
be stopped.
There is an additive effect between H. pylori infection and NSAID use on the development of peptic ulcer and ulcer
19
bleeding. For this reason, many experts recommend that persons beginning long-term NSAIDs should be screened
1
for H. pylori and treated if found to be positive.
Figure 1-Management of Suspected Peptic Ulcers2
Page 441
Therapeutic Choice
a.
Treat symptoms; lifestyle changes, diet, short courses (no more than 4 wks) of OTC antacids/H2-receptor antagonist (H2RA)
and therapeutic doses of H2RA, or preferentially a proton pump inhibitor.
Adapted with permission from Thomson AB. A suggested approach to patients with dyspepsia. Can J Gastroenterol 1997;11
(2):135-40.
Table 2: Drugs Used for Peptic Ulcer Disease
a
Cost
H2- cimetidine Treatment: 300 mg BID Diarrhea, constipation, Cimetidine ↓ $

antagonistsb generics Maintenance: headache, fatigue, cytochrome P450
400 mg Q pm confusion (most likely metabolism of several
in elderly or in poor agents (e.g., warfarin,
renal function), cardiac phenytoin,
effects, rash, theophylline). Use
gynecomastia, another H2-
impotence (rare). antagonist; ranitidine
or famotidine have
minor effect.
H2- ranitidine Treatment: 150 mg BID Diarrhea, constipation, $$

antagonistsb Zantac, Maintenance: 150 mg Q headache, fatigue,
generics pm confusion (most likely
in elderly and those
with poor renal
function), cardiac
effects, rash.
Page 442
Therapeutic Choice
Costa
H2- famotidine Treatment: 20 mg BID Diarrhea, constipation, $$

b Maintenance: 20 mg Q headache, fatigue,
antagonists Pepcid,
generics pm confusion (most likely
with poor renal
function), cardiac
effects, rash.
H2- nizatidine Treatment: 150 mg BID Diarrhea, constipation, $$

antagonistsb Axid, generics Maintenance: 150 mg Q headache, fatigue,
pm confusion (most likely
with poor renal
function), cardiac
effects, rash.
Proton Pump omeprazole Abdominal pain, Monitor for ↓ efficacy of $$

Inhibitors Losec 20 mg daily AC breakfast nausea, headache. drugs requiring an acid
Capsules, medium for absorption
Losec from the stomach
(e.g., itraconazole).
MUPS,Losec
Omeprazole may
Tablets, interfere with
generics cytochrome P450-
metabolized agents
(e.g., diazepam,
warfarin, phenytoin).
When omeprazole is
added or removed,
these drugs may
require dosage
adjustment.
Proton Pump esomeprazole Treatment: 40 mg daily Abdominal pain, Metabolized via $$$$
Inhibitors Nexium AC breakfast diarrhea, headache. cytochrome P450. No
Maintenance: significant drug
20 mg daily AC breakfast interactions with
warfarin, phenytoin or
diazepam.
Proton Pump lansoprazole Treatment: 30 mg daily Diarrhea, abdominal Metabolized via $$$
Inhibitors Prevacid AC breakfast pain, headache. cytochrome P450. No
Maintenance: significant interactions
15 mg daily AC breakfast with warfarin, ASA,
phenytoin,
prednisone, antacids,
diazepam.
Proton Pump pantoprazole 40 mg daily AC breakfast Diarrhea, headache, Metabolized via $$$
Inhibitors Pantoloc dizziness, pruritus. cytochrome P450. No
interactions with
diazepam, phenytoin,
nifedipine,
theophylline, warfarin,
digoxin, oral
contraceptives or
antacids.
Proton Pump rabeprazole 20 mg daily AC breakfast Diarrhea, headache. Metabolized via $$

Inhibitors Pariet cytochrome P450. No
clinically significant
drug interactions with
drugs metabolized by
the CYP450 system.
Page 443
Therapeutic Choice
Costa
Mucosal misoprostol Treatment: 200 µg QID Diarrhea (dose- $$

Protective generics related), abdominal
Agents cramps, flatulence.
Contraindicated in
pregnancy –
abortifacient.
a.
Cost of 30-day (treatment dosages) supply; includes drug cost only.
b.
Duration of treatment for DU is 4–8 wk. Duration of treatment for GU is 8–12 wk.
Legend: $ < $20 $-$$ < $20–40 $$ $20–40 $$$ $40–60 $$$-$$$$ $40–80 $$$$ $60–80
Suggested Readings
Huang JQ, Sridhar S, Hunt RH. Role of Helicobacter pylori infection and non-steroidal anti-inflammatory drugs in
peptic-ulcer disease: a meta-analysis. Lancet 2002;359(9300):14-22.
Hunt R, Thomson AB. Canadian Helicobacter pylori consensus conference. Canadian Association of Gastroenterology.
Can J Gastroenterol 1998;12(1):31-41.
Lassen AT, Pedersen FM, Bytzer P, Schaffalitzky de Muckadell OB. Helicobacter pylori test-and-eradicate versus
prompt endoscopy for management of dyspeptic patients: a randomised trial. Lancet 2000;356(9228):455-60.
References
1. Hunt R, Fallone C, Veldhuyzan van Zanten S et al. Canadian Helicobacter Study Group Consensus Conference:
Update on the management of Helicobacter pylori – an evidence-based evaluation of six topics relevant to
clinical outcomes in patients eradicated for H pylori infection. Can J Gastroenterol 2004;18(9):547-54.
2. Veldhuyzen van Zanten SJ, Flook N, Chiba N et al. An evidence-based approach to the management of
uninvestigated dyspepsia in the era of Helicobacter pylori. CMAJ 2000;162(12 Suppl):S3-23.
3. Spiegel BM, Vakil NB, Ofman JJ. Dyspepsia management in primary care: a decision analysis of competing
strategies. Gastroenterology 2002;122(5):1270-85.
4. Thomson AB, Barkun AN, Armstrong D et al. The prevalence of clinically significant endoscopic findings in
primary care patients with uninvestigated dyspepsia: the Canadian Adult Dyspepsia Empiric Treatment -
Prompt Endoscopy (CADET-PE) study. Aliment Pharmacol Ther 2003;17:1481-91.
5. Edwards SJ, Lind T, Lundell L. Systematic review of proton pump inhibitors for the acute treatment of reflux
oesophagitis. Aliment Pharmacol Ther 2001;15(11):1729-36.
6. McColl KE, Murray LS, Gillen D et al. Randomised trial of endoscopy with testing for Helicobacter pylori
compared with non-invasive H pylori testing alone in the management of dyspepsia. BMJ 2002;324(7344):999
-1002.
7. Lassen AT, Pedersen FM, Bytzer P, Schaffalitzky de Muckadell OB. Helicobacter pylori test-and-eradicate
versus prompt endoscopy for management of dyspeptic patients: a randomised trial. Lancet 2000;356
(9228):455-60.
8. Chiba N, Van Zanten SJ, Sinclair P et al. Treating Helicobacter pylori infection in primary care patients with
uninvestigated dyspepsia: the Canadian adult dyspepsia empiric treatment-Helicobacter pylori positive (CADET
-Hp) randomized controlled trial. BMJ 2002 324(7344):1012-6.
9. Moayyedi P, Deeks J, Talley NJ et al. An update of the Cochrane systematic review of Helicobacter pylori
eradication therapy in nonulcer dyspepsia: resolving the discrepancy between systematic reviews. Am J
Gastroenterol 2003;98(12):2621-6.
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Therapeutic Choice
10. Moayyedi P, Soo S, Deeks J et al. Pharmacological interventions for non-ulcer dyspepsia. Cochrane Database
Syst Rev 2003;(1):CD001960.
11. Hunt R, Thomson AB. Canadian Helicobacter pylori consensus conference. Canadian Association of
Gastroenterology. Can J Gastroenterol 1998;12(1):31-41.
12. Armstrong D, Marshall JK, Chiba N et al. Canadian Consensus Conference on the management of
gastroesophageal reflux disease in adults – update 2004. Can J Gastroenterol 2005;19(1):15-35.
13. Laine L. Approaches to nonsteroidal anti-inflammatory drug use in the high-risk patient. Gastroenterology
2001;120(3):594-606.
14. Hawkey CJ. Nonsteroidal anti-inflammatory drug gastropathy. Gastroenterology 2000;119(2):521-35.
15. Wright JM, Perry TL, Bassett KL et al. Reporting of 6-month vs 12-month data in a clinical trial of celecoxib.
JAMA 2001;286(19):2398-400.
16. McCormack JP, Rangno R. Digging for data from the COX-2 trials. CMAJ 2002;166(13):1649-50.
17. Chan FK, Hung LC, Suen BY et al. Celecoxib versus diclofenac and omeprazole in reducing the risk of recurrent
ulcer bleeding in patients with arthritis. N Engl J Med 2002;347(26):2104-10.
18. Rostom A, Dubé C, Jolicoeur E, Boucher M, Joyce J. Gastroduodenal ulcers associated with the use of non-
steroidal anti-inflammatory drugs: a systematic review of preventative pharmacological interventions. Ottawa
(ON): Canadian coordinating Office for Health Technology Assessment; 2004. Technology overview No 12.
19. Huang JQ, Sridhar S, Hunt RH. Role of Helicobacter pylori infection and non-steroidal anti-inflammatory drugs
in peptic-ulcer disease: a meta-analysis. Lancet 2002;359(9300):14-22.
Pharmacoeconomic Considerations: Peptic Ulcer Disease

Epidemiology

1 An estimated 6 730 000 Americans have peptic ulcer disease
United States (1998)
United States (1998)1 US $3.1 million US $0.2 million
Commentary
Outpatient physician office visits account for the majority (70%) of direct medical costs associated with peptic
2
ulcer disease (PUD). PUD is associated with significant lost work productivity; 42% of patients miss work
2
because of physician visits and sick days or are less productive because of PUD. Some authors have speculated
that economic losses due to indirect costs, namely lost productivity, are almost as large as the direct medical
2
costs of PUD.
3 , 4
Screening for Helicobacter pylori and eradication with antibiotics is cost-effective. In terms of symptomatic
treatment for PUD, there are few direct comparative trials for histamine (H2) receptor antagonists (H2 RAs) and
proton pump inhibitors. A meta-analysis found proton pump inhibitors to be more effective than placebo for
dyspeptic symptoms.5 Because H2 RAs can be purchased over-the-counter, the cost is borne by the patient. In
contrast, proton pump inhibitors are prescription-only medicines and thus the cost may be covered by third-party
payers.
a.
b.
1. Sandler RS, Everhart JE, Donowitz M et al. The burden of selective digestive disease in the United States.
2. Henke CJ, Levin TR, Henning JM et al. Work loss costs due to peptic ulcer disease and gastroesophageal
reflux disease in a health maintenance organization. Am J Gastroenterol 2000;95(3):788-92.
3. Mason J, Axon AT, Forman D et al. The cost-effectiveness of population Helicobacter pylori screening and
treatment: a Markov model using economic data from a randomized controlled trial. Aliment Pharmacol Ther
2002;16(3):559-68.
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Therapeutic Choice
4. Ford AC, Delaney BC, Forman D et al. Eradication therapy in Helicobacter pylori positive peptic ulcer disease:
systematic review and economic analysis. Am J Gastroenterol 2004;99(9):1833-55.
5. Shiau JY, Shukla VK, Dube C. The efficacy of proton pump inhibitors in adults with functional dyspepsia.
Ottawa (ON): Canadian Coordinating Office for Health Technology Assessment; 2002. Technology report no
22.
Page 446
e-Therapeutics+ : Therapeutics : Gastrointestinal Disorders: Upper Gastrointestinal Bleeding Page 1 of 5
Therapeutic Choice
Print Close
Gastrointestinal Disorders: Upper Gastrointestinal Bleeding
A.B.R. Thomson, MD, PhD, FRCPC, FACG
Upper gastrointestinal bleeding (UGIB) is a common medical emergency, with a mortality rate of about 7%,
especially in older persons with comorbid conditions. Common causes include duodenal ulcer (DU), gastric ulcer
(GU), gastric or esophageal erosions and esophageal varices. Rarely, bleeding may result from an eroded gastric
blood vessel (Dieulafoy’s lesion) or, less commonly, from a tear of the gastroesophageal junction (Mallory-Weiss
tear).1
Goals of Therapy
Resuscitate and save the patient's life

Prevent hypoxia-related damage to other organs
Heal the underlying lesion
Prevent recurrences of UGIB
Investigations
History and physical examination:

resuscitate immediately to ensure the patient is breathing and to restore circulating blood volume, while
quickly taking a focused history and performing a physical examination
cause of bleeding may be suggested by history: ulcer disease – present history of pain, past history of
ulcer, use of ASA/NSAIDs; varices – signs of liver disease (jaundice, ascites, hepatosplenomegaly,
coagulopathy, skin changes suggestive of liver disease) in patients at risk (e.g., alcohol abuse, infectious
hepatitis B or C); retching or vomiting followed by bleeding is suggestive of a Mallory-Weiss tear
prognosis is usually worse if the patient is vomiting fresh red blood or passing red blood per rectum, or
has tachycardia or hypotension
coffee-ground emesis or melena stools imply slower loss of a smaller volume of blood, but may still be
dangerous in the older patient or one with comorbidities such as COPD or coronary artery disease
Draw venous blood for “stat” type and cross match (usually four units of packed red blood cells or more
depending on the severity of bleeding), hemoglobin concentration or hematocrit, electrolytes, renal function
(creatinine or BUN) and coagulation studies (platelet count, INR and PTT)
Rapid estimate of blood loss can be made at the bedside: 50% loss of blood volume is suggested by systolic
pressure < 100 mm Hg, pulse rate > 100 BPM and Hgb < 10 g/dl
Nasogastric lavage:
if the patient is observed, or previously witnessed, to vomit blood there is no need to pass a nasogastric
(NG) tube
in patients with melena or hematochezia, the discovery of fresh, red blood in the NG tube aspirate indicates
more severe bleeding and points to the cause being in the upper GI tract
absence of fresh blood in the NG tube aspirate may be a false negative finding if the tip of the NG tube has
not been placed in the pool of blood in the stomach or duodenum, or if the source of bleeding is beyond a
closed pylorus
An electrocardiogram is useful in older patients with suspected or possible ischemic heart disease
Barium swallow. An upper GI series must not be performed in the patient with UGIB. The diagnostic accuracy is
poor in this setting, it may obscure a clear field for subsequent esophagogastroduodenoscopy (EGD), and
endoscopic hemostatic therapy (EHT) cannot be performed if the field of vision is obscured by barium
Esophagogastroduodenoscopy
all patients with UGI bleeding should be referred for EGD after they are stabilized. The timing will depend
on the suspected severity of bleeding, the likely cause and the patient's general condition
use of a prokinetic (iv erythromycin 250 mg) 20 to 90 minutes prior to EGD clears blood from the
stomach, which improves the field of vision
prompt EGD will identify the lesion in about 90% of patients. Inability to make a diagnosis is usually due to
profuse bleeding. Tc-labelled red blood cell scanning, angiography, or repeat EGD after saline lavage of the
stomach may be necessary
prognosis may be established at the time of EGD. If there is a clean-based ulcer in an otherwise healthy
person with reliable and available family support, the stable patient may be discharged home from the
emergency room after endoscopy
biopsies for H. pylori: obtain two biopsies from the gastric antrum, plus two biopsies from the gastric body
in the patient who has recently been on acid suppression therapy
Page 447
Therapeutic Choice
Therapeutic Choices (Figure 1 - Management of Acute Upper GI Bleeding1 , Table 1)
Protect the airway, provide supplementary nasal oxygen and place at least two large bore (#18 or larger) iv lines.
Fluid resuscitation and hemodynamic stability are essential before attempting endoscopy.
Endoscopic Treatment
In the more serious lesions seen in EGD, such as an ulcer with an adherent clot, visible vessel or active bleeding,
2
EHT must be used. EHT involves coaptive thermal coagulation, injection of epinephrine or a sclerosing agent
1
and/or a mechanical technique (banding, clips, staples, sutures).
In nonvariceal bleeding, injection therapy, thermal therapy or a combination of the two may be used, although
combination therapy is recommended.1
Gastric and duodenal ulcers are the most common lesions in Canadian patients with nonvariceal UGIB. After EHT,
3
the rates of rebleeding, surgery and mortality are reported to be 14.1%, 6.5% and 5.4%, respectively.
In bleeding esophageal varices, endoscopic variceal band ligation or sclerotherapy are both highly effective in
4 , 5
stopping bleeding and preventing rebleeding; band ligation is preferred because there are fewer complications.
For bleeding gastric varices, the tissue adhesive cyanoacrylate, (e.g., Krazy Glue) may be carefully applied.
Nonvariceal UGIB
Optimal therapy for nonvariceal UGIB includes early EGD (within 24 hours of the initial bleeding episode), EHT
(depending on the nature of the bleeding site) and acid inhibition with an iv proton pump inhibitor (PPI) to
stabilize the clot and to reduce ulcer bleeding. Use of oral or iv H2-receptor antagonists is not recommended.
PPIs significantly reduce rebleeding and the need for surgery in patients with nonvariceal UGIB. PPI use is
associated with significant reductions in mortality when used with EHT in patients with high-risk stigmata (active
bleeding or a nonbleeding visible vessel).6 , 7 , 8 , 9 Oral PPIs may be as effective as iv PPIs in nonvariceal UGIB,
although this is controversial.10
Pantoprazole and omeprazole are the most extensively studied parenteral PPIs for UGIB, but iv omeprazole is not
approved in Canada. IV pantoprazole is administered by continuous infusion (see Table 1). After two to three days
of iv therapy, switch to an oral PPI to heal the associated ulcer or esophagitis. Where EHT or iv PPIs are not
available, oral omeprazole 40 mg (or the equivalent dose of another oral PPI) may be administered twice daily.
Most episodes of recurrent bleeding occur during the first three days.10
If the patient is H. pylori-negative, treat them with a PPI for four weeks. If the ulcer is associated with H. pylori or
use of ASA or NSAIDs, continue PPI maintenance therapy for life to reduce the risk of rebleeding.
Bleeding Esophageal Varices
For bleeding esophageal varices, EHT (banding/sclerotherapy) may be supplemented with pharmacologic agents
aimed at reducing portal pressure. The long-acting somatostatin analogue, octreotide, reduces portal pressure and
11
bleeding, and is given intravenously for up to two days after the bleeding stops. Vasopressin reduces splanchnic
blood flow and portal pressure, but causes vasoconstriction in other vascular beds. Thus, caution is advised in
patients with myocardial ischemia or peripheral vascular disease. Where octreotide or banding/sclerotherapy are not
available, vasopressin may be used. IV nitroglycerin mitigates the adverse vasoconstrictive effects of vasopressin.
Prevention of Variceal Bleeding
Page 448
Therapeutic Choice
Nonselective beta-blockers (e.g., propranolol, nadolol) may be used to prevent an initial bleed or to
reduce the risk of recurrent bleeding in patients with portal hypertension and esophageal varices.
However, beta-blockers do not prevent the development of varices in patients with cirrhosis.12
Prophylaxis must be continued indefinitely as the risk of hemorrhage returns to that of an untreated
13
patient if beta-blocker therapy is stopped. In patients with high-risk (large) esophageal varices,
endoscopic ligation of the varices is more effective than propranolol for the primary prevention of
14
variceal bleeding. Useful Info?
Therapeutic Tips
Rapid diagnosis of UGIB using EGD is important to institute appropriate therapy. Patients with UGIB should be
hemodynamically stable prior to EGD.
Bleeding associated with gastric or duodenal ulcers should be treated empirically with a PPI.
The patient should be assessed for H. pylori and treated with triple therapy for one week if indicated. A follow-
up urea breath test (not serology) is essential in this setting to prove successful eradication of H. pylori and
thereby reduce the risk of ulcer recurrence and recurrent bleeding.
1
Figure 1-Management of Acute Upper GI Bleeding
Page 449
Therapeutic Choice
a.
Avoid normal saline in patients with suspected liver disease because of the risk of precipitating ascites.
b.
Antral biopsies may be taken at endoscopy to determine H. pylori status.
If not done initially, wait two weeks after stopping PPI before repeating endoscopy for biopsy.
If H. pylori positive, treat, repeat H. pylori testing and retreat if necessary.
If bleeding DU not associated with H. pylori or NSAIDuse, offer PPI maintenance therapy
to minimize risk of recurrent DU and bleeding.
Patient with GU, biopsy to rule out gastric cancer.
Abbreviations: EHT=endoscopie hemostatic therapy; PPI=proton pump inhibitor.
Table 1: Parenteral Drugs Used in the Management of Upper Gastrointestinal Bleeding
a
Cost
Class Drug Indication Dose Adverse Effects Comments
Proton Pump pantoprazole Nonvariceal 80 mg bolus over 2 h Abdominal pain, Metabolized via $100
Inhibitors Panto IV bleeding then 4–8 mg/h chest pain, rash, the cytochrome
continuous infusion x 1 pruritus, P-450 system.
–3 daysb anaphylaxis. Switch to oral
PPI as soon as
possible.
Somatostatin octreotide Bleeding 50–100 µg bolus in Abdominal pain, May inhibit $300
Analogues Sandostatin esophageal 0.9% NaCl, then nausea, diarrhea, morphine
varices 25–50 µg/h infusion for hyperglycemia, analgesia.
up to 2 days after headache, flushing.
bleeding stops (mix
500 µg in 500 mL 0.9%
NaCL and infuse at 50
mL/h)
Vasopressin vasopressin Bleeding 20 units in 20 mL D5W Tremor, sweating, Consider use of $1200
Receptor Pressyn, esophageal bolus over 20 minutes vertigo, nausea, iv nitroglycerin
Agonists Pressyn AR, varices then 0.2–0.4 units/min anaphylaxis, water to minimize
generics infusion for up to 2 intoxication (early ischemia.
days signs are Ganglionic
drowsiness, blocking
listlessness, agents may
headache). Vascular increase
disease patients sensitivity to
may experience pressor effects.
angina or even
myocardial
infarction.
a.
Cost for bolus and 48 h infusion.
b.
May be infused over 15 minutes.
Suggested Readings
Barkun A, Bardou M, Marshall JK et al. Consensus recommendations for managing patients with nonvariceal upper
gastrointestinal bleeding. Ann Intern Med 2003;139(10):843-57.
Barkun A, Fallone CA, Chiba N et al. A Canadian clinical practice algorithm for the management of patients with
nonvariceal upper gastrointestinal bleeding. Can J Gastroenterol 2004;18(10):605-9.
Barkun A, Sabbah S, Enns R et al. The Canadian Registry on Nonvariceal Upper Gastrointestinal Bleeding and
Endoscopy (RUGBE): Endoscopic hemostasis and proton pump inhibition are associated with improved outcomes in
a real-life setting. Am J Gastroenterol 2004;99(7):1238-46.
Page 450
Therapeutic Choice
Dallal HJ, Palmer KR. ABC of the upper gastrointestinal tract: Upper gastrointestinal haemorrhage. BMJ 2001;323
(7321):1115-7.
Sharara AI, Rockey DC. Gastroesophageal variceal hemorrhage. N Engl J Med 2001;345(9):669-81.
References
1. Dallal HJ, Palmer KR. ABC of the upper gastrointestinal tract: Upper gastrointestinal haemorrhage. BMJ
2001;323(7321):1115-7.
2. Lau JY, Sung JJ, Lam YH et al. Endoscopic retreatment compared with surgery in patients with recurrent
bleeding after initial endoscopic control of bleeding ulcers. N Engl J Med 1999;340(10):751-6.
3. Barkun AN, Thomson A, Marshall J et al. Response to "Potentially flawed interpretation of data by Andriulli et
al." Am J Gastroenterol 2005;100(9):2133.
4. Sharara AI, Rockey DC. Gastroesophageal variceal hemorrhage. N Engl J Med 2001;345(9):669-81.
5. Ferguson JW, Tripathi D, Hayes PC. Review article: the management of acute variceal bleeding. Aliment
Pharmacol Ther 2003;18(3):253-62.
6. Andriulli A, Annese V, Caruso N et al. Proton-pump inhibitors and outcome of endoscopic hemostasis in
bleeding peptic ulcers: a series of meta-analyses. Am J Gastroenterol 2005;100(1):207-19.
7. Bardou M, Toubouti Y, Benhaberou-Brun D et al. Meta-analysis: proton-pump inhibition in high-risk patients
with acute peptic ulcer bleeding. Aliment Pharmacol Ther 2005;21(6):677-86.
8. Khuroo MS, Yattoo GN, Javid G et al. A comparison of omeprazole and placebo for bleeding peptic ulcer. N
Engl J Med 1997;336(15):1054-8.
9. Leontiadis GI, Sharma VK, Howden CW. Proton pump inhibitor treatment for acute peptic ulcer bleeding.
10. Lau JY, Sung JJ, Lee KK et al. Effect of intravenous omeprazole on recurrent bleeding after endoscopic
treatment of bleeding peptic ulcers. N Engl J Med 2000;343(5):310-6.
11. Gotzsche PC, Hrobjartsson A. Somatostatin analogues for acute bleeding oesophageal varices. Cochrane
12. Groszmann RJ, Garcia-Tsao G, Bosch J et al. Beta-blockers to prevent gastroesophageal varices in patients
with cirrhosis. New Engl J Med 2005;353(21):2254-61.
13. Abraczinkas DR, Ookubo R, Grace ND et al. Propranolol for the prevention of first esophageal variceal
hemorrhage: a lifetime commitment? Hepatology 2001;34(6):1096-102.
14. Garcia-Tsao G. Portal hypertension. Curr Opin Gastroenterol 2002;18(3):351-9.
Page 451
e-Therapeutics+ : Therapeutics : Gastrointestinal Disorders: Viral Hepatitis Page 1 of 15
Therapeutic Choice
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Gastrointestinal Disorders: Viral Hepatitis

Kevork M. Peltekian, MD
Geralynn Hirsch, RN-NP, MSN
Hepatitis A virus (HAV), hepatitis B virus (HBV), hepatitis C virus (HCV), hepatitis D virus (HDV) and hepatitis E virus
1
(HEV) cause 95% of acute viral hepatitis cases observed in North America (Table 1). Other causes of viral hepatitis
include adenovirus, Coxsackie virus, cytomegalovirus, Epstein-Barr virus and, rarely, herpes simplex virus or parvovirus
B19 infection.
Table 1: Characteristics of Hepatitis Viruses
HAV HBV HCV HDV a HEV
Virus type RNA DNA RNA RNA RNA
Incubation (days) 15–45 30–180 15–60 21–140 15–65
Transmission Fecal-oral Percutaneous, Percutaneous, Percutaneous, Fecal-oral

venereal, perinatal perinatal venereal, perinatal
(uncommon)
Acute hepatitis No Adults 2–7%, 70–80% In superinfection; No

progressing to preschoolers 25%, rare in co-infection
chronic disease neonates 90%
Prevention Pre/post- Pre/post-exposure Blood donor HBV immunization Ensure safe

exposure immunization screening, risk prevents HDV drinking
immunization behaviour infection water
modification
a.
requires coexisting HBV infection
Abbreviations: HAV=hepatitis A virus; HBV=hepatitis B virus; HCV=hepatitis C virus; HDV=hepatitis D virus; HEV=hepatitis E
virus
This chapter focuses on the prevention of acute viral hepatitis and the management of chronic viral hepatitis, which may
lead to the development of liver cirrhosis, hepatocellular carcinoma and liver failure requiring liver transplantation if
untreated. The abbreviations used in the text are defined in Table 2.
Goals of Therapy
General
Prevent spread of infection

Improve quality of life
Minimize liver damage, prevent cirrhosis, hepatic failure and hepatocellular carcinoma
Specific
2
Sustained suppression of viral replication and induction of HBe seroconversion in patients with chronic hepatitis B.
Eradicate the virus in the case of acute or chronic hepatitis C infection.3 The desired outcome in chronic hepatitis C
is sustained virologic response (SVR), defined as undetectable serum HCV RNA ( < 50 IU/mL ) 24 weeks after the
end of treatment.
Table 2: Abbreviations Used in Viral Hepatitis
HAV = Hepatitis A virus HBIg = Hepatitis B immune globulin

HBV = Hepatitis B virus HCV = Hepatitis C virus
HBV DNA = Hepatitis B DNA Anti-HCV = Antibody to HCV
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Therapeutic Choice
HBe = Hepatitis B e HCV RNA = Hepatitis C RNA
HBeAg = Hepatitis B e Antigen HDV = Hepatitis D (delta) virus
Anti-HBe = Antibody to HBeAg HEV = Hepatitis E virus
HBsAg = Hepatitis B surface antigen HIV = human immunodeficiency virus
Anti-HBs = Antibody to HBsAg RVR = rapid virologic response
Anti-HBc = Antibody to hepatitis B core antigen SVR = sustained virologic response
Prevention of Viral Hepatitis
Specific vaccines are available for hepatitis A and B viruses but not for hepatitis C, D or E viruses. HDV is a defective
RNA virus that requires HBsAg for entry into and exit from hepatocytes; thus, vaccination against HBV confers immunity
against co-infection with HBV and HDV.
Individuals at high risk of contracting hepatitis A or B should be vaccinated (Table 3). Hepatitis A immunoglobulin and
hepatitis B immunoglobulin provide immediate short-term passive immunity against HAV and HBV, respectively. Active
and passive immunizing agents used for hepatitis A and B are presented in Table 5.
Hepatitis A vaccine (inactivated) is the preferred agent for pre-exposure prophylaxis. It is very effective (up to 10
years) and is recommended for high-risk groups. Detectable antibody is present at one month in 96 to 100% of
recipients after the first dose and in 100% after the booster dose, given 6 to 12 months later. Hepatitis A vaccines are
well tolerated and safe.
Hepatitis A immune globulin with or without hepatitis A vaccine protects against HAV when administered before
exposure or during the incubation period. It can be given with the vaccine to persons at risk of contracting HAV before
adequate anti-HAV antibody titres are achieved.
Table 3: Recommendations for Hepatitis A and B Vaccinations4
Hepatitis A Hepatitis B
Vaccine Vaccine
Persons with end-stage renal disease or recipients of hemodialysis x
Persons with clotting factor disorders x x
Persons with HIV infection x
Persons with chronic liver disease including HCV x x
Health care and emergency service workers who have exposure to blood in the x
workplace
Persons handling HAV-infected primates or involved in research on HAV x
Persons in training in schools of dentistry, laboratory technology, medicine, x

nursing and other allied health professions
Users of illicit drugs, e.g., snorting cocaine, injection drug use x
Persons with multiple sex partners and all clients in STI clinics x
Men who have sex with men x x
Household and sexual contacts of persons with chronic HBV x
Staff and inmates of long-term correctional facilities ? x
Clients and staff of institutions for the developmentally challenged ? x
International travellers to HAV- or HBV-endemic areas x x
Abbreviations: HAV=hepatitis A virus; HBV=hepatitis B virus; HCV=hepatitis C virus; HIV=human immunodeficiency

virus; STI=sexually transmitted infection
Legend: x=Highly recommended; ?=Recommended when there is evidence for sustained HAV transmission.
Hepatitis B vaccines induce anti-HBs production. Antibody response in general decreases with age. Children between
2 and 19 years of age have the highest response rate (99%). The response rate for those older than 60 years is 70%. In
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Therapeutic Choice
most preparations, the antigen is adsorbed onto aluminum hydroxide with thimerosal as a preservative. A preparation of
Recombivax HB without thimerosal is recommended for immunization of infants at birth. Hepatitis B vaccines are well
tolerated and safe.
Hepatitis B immune globulin (HBIg) is prepared from pooled human plasma from select donors who have a high
level of anti-HBs and are seronegative for bloodborne infections. It provides immediate short-term passive immunity.
HBIg administered concurrently with the vaccine, but at a different site, does not interfere with the antibody response to
the vaccine.
Acute Viral Hepatitis
Investigations
Therapeutic Choices
Acute viral hepatitis is a systemic viral infection that, by definition, has been present for less than six months and
causes inflammatory necrosis of the liver. Most cases are asymptomatic; however, fulminant hepatitis occurs in 1% of
patients (higher in pregnant women).5 Patients with a prolonged INR, jaundice and encephalopathy should be referred
immediately to a liver transplantation centre since massive necrosis may lead to liver failure and death.
Investigations (Figure 1 - Treatment of Acute Viral Hepatitis)
Check for risk factors such as injection drug use, high-risk sexual behavior, travel history or daycare exposure.
Rule out drug-induced hepatitis, including that caused by acetaminophen or herbal products, autoimmune hepatitis
and Wilson’s disease (especially in children and young adults).
Identify hepatitis viruses by the presence of serologic markers.
The presence of antibodies to hepatitis B core antibody (IgM) may indicate acute HBV, although it is often
impossible to distinguish a flare-up of chronic HBV infection from an acute case. Only time will identify the chronic
carriers.
Acute hepatitis C can be identified by a positive HCV RNA test as early as 2 to 3 weeks after infection. Anti-HCV
antibodies may not be detected for up to 20 weeks after exposure to the virus.
Monitor liver transaminases (ALT, AST) and liver function tests (total bilirubin, serum albumin and INR).
Therapeutic Choices
In most cases specific antiviral therapy is not indicated (Figure 1 - Treatment of Acute Viral Hepatitis). Provided with
appropriate supportive care, the majority of patients with acute hepatitis A or B recover completely and do not
experience chronic complications. Unfortunately, this is not the case with hepatitis C: most patients with acute hepatitis
C become chronic carriers.
Avoid alcohol for at least three months or until complete normalization of liver enzymes and hepatic function.
No dietary restrictions are necessary.
No restraint of physical activities is needed.
Stop all hepatotoxic drugs. For patients with a prolonged INR, administer vitamin K 10 mg subcutaneously (avoid
frozen plasma unless there is active bleeding). If the patient develops encephalopathy heralding fulminant liver failure,
start lactulose to achieve two to three loose bowel movements per day.
Effective and specific antiviral therapy is available only for acute hepatitis C (see the discussion of peginterferon alfa in
the section on chronic hepatitis C and in Table 8). Most cases of acute HCV infection are asymptomatic and are usually
diagnosed under three circumstances—documented seroconversion, known exposure (e.g., needle-stick exposure) and
acute clinical hepatitis with jaundice.
Women, younger patients and icteric patients are more likely to clear the virus than other patients with acute hepatitis
C. A single negative HCV RNA test result is insufficient to confirm viral clearance in a patient with acute hepatitis C, and
the test should be repeated at least once. If HCV RNA persists beyond 12 weeks, antiviral treatment should be
considered. Treatment is most effective if started by 24 weeks. SVR rates of > 90% have been obtained with
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Therapeutic Choice
peginterferon monotherapy. Patients infected with HCV genotypes 2 or 3 should be treated for 12 weeks; those infected
with other genotypes should be treated for 24 weeks.6
Chronic Viral Hepatitis
Investigations
Therapeutic Choices
Investigations
Therapeutic Choices
Viral hepatitis is chronic when present for six months or longer. It can progress to cirrhosis, decompensation (liver
failure) and hepatoma (primary liver cancer). HBV and HCV are the most common causes.
Chronic Hepatitis B
HBV infection becomes chronic in less than 5% of healthy individuals who are infected as adults (but up to 90% of
those infected as children). Among those with chronic hepatitis B, one percent will seroconvert spontaneously each year
from an HBsAg-positive to an anti-HBs-positive state (i.e., become immune).
Investigations
Persistence of detectable levels of HBsAg for more than six months implies chronic hepatitis B infection.
Since HBV and HIV are acquired by the same transmission routes, patients with HBV should be tested for HIV co-
infection, especially when considering nucleos(t)ide analogues for HBV.
Check for HDV co-infection in patients with elevated ALT levels but low serum HBV DNA concentrations especially
in those who may have become infected through injection drug use or if they are from endemic areas for HDV, i.e.,
sub-Saharan Africa, Romania, Central Asia, Eastern Mediterranean and the Amazon.
Check HBeAg and anti-HBe and serum transaminase (ALT, AST) values to determine the replicative state of HBV.
The presence of HBeAg indicates a high rate of viral replication (potentially treatable with antiviral agents).
Measurement of HBV DNA virus in serum is not routinely available but is helpful when transaminase levels are high
in HBeAg-negative and anti-HBe-positive patients. It is recommended that HBV DNA levels be monitored every
2
three to six months.
Liver biopsy is recommended, especially in those older than 40 years with normal liver enzymes.
Advise against all but modest alcohol consumption (less than four drinks weekly).
Peginterferon alfa
Peginterferon alfa is used to treat patients with chronic hepatitis B who are persistently HBeAg-positive and have
elevated serum transaminase values. It promotes seroconversion from an HBeAg-positive to anti-HBe-positive state,
which is associated with normalization of serum transaminases. Due to the reduced frequency of administration (i.e.,
once weekly) and documented efficacy, peginterferon alfa is recommended instead of standard interferon alfa, which
7
must be administered at least thrice weekly, for the management of chronic hepatitis B.
Most patients with hepatitis D co-infection relapse after peginterferon alfa therapy. HIV-positive and other
immunosuppressed patients with chronic hepatitis B respond poorly to peginterferon alfa.
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Therapeutic Choice
Nucleos(t)ide Analogues
Nucleoside analogues effectively inhibit replication of HBV in patients who are HBeAg-positive or HBeAg-negative and
should be given only to patients who have ongoing hepatitis (persistent ALT and HBV DNA elevations). Inhibition of
HBV replication with nucleoside analogues is associated with significant reductions in hepatic necroinflammation and
increased rates of HBe seroconversion.
Resistance to nucleos(t)ide analogues is an important issue. Among these agents, lamivudine is associated with the
highest rates of resistance and entecavir is associated with the lowest rates of resistance. Lamivudine-resistant HBV is
cross-resistant to telbivudine and emtricitabine (an antiretroviral agent with activity against HBV). Mutations that confer
resistance to lamivudine do not by themselves confer resistance to entecavir; however, they are a prerequisite for the
development of entecavir resistance, and entecavir resistance rates are considerably higher when the drug is initiated in
patients with lamivudine-refractory or -resistant strains of HBV. Adefovir has activity against lamivudine-resistant HBV.
Conversely, both lamivudine and entecavir have activity against adefovir-resistant HBV.
After three years of treatment with lamivudine the HBeAg seroconversion rate is reported to be 40%.8 Lamivudine-
resistant HBV emerges in about 15 to 25% of patients after one year of treatment and in up to 70% after five years of
therapy.9 Lamivudine improves outcomes in patients with decompensated cirrhosis and may be used to prevent disease
flares in patients on immunosuppressive therapy.
Adefovir dipivoxil has activity against wild-type, precore mutant and lamivudine-resistant HBV. The expected HBeAg
seroconversion rate is 12% after one year.10 Adefovir dipivoxil in high doses is associated with nephrotoxicity.
Monitoring of liver function tests may be necessary immediately after discontinuation since severe acute exacerbations
of hepatitis have been reported in patients stopping treatment.
11 , 12 13
Entecavir and telbivudine produce significantly greater reductions in HBV DNA levels than lamivudine in
both HBeAg-positive and HBeAg-negative patients. HBeAg seroconversion was reported in 21% of entecavir-treated
3
patients and 22% of telbivudine-treated patients after one year (similar to lamivudine). The HBeAg seroconversion rate
after three years of treatment with entecavir was 39%.3 Among nucleoside-naïve patients the rate of resistance was <
14
1% after three years of treatment with entecavir. Limited data are as yet available for telbivudine, but preliminary
reports suggest that the rate of resistance may be as high as 20% after two years (vs. 30% with lamivudine).13
Tenofovir is a nucleotide analogue that is active against HIV and HBV, and against lamivudine-resistant HBV. It has
been approved as monotherapy for chronic hepatitis B, based on studies in both HBeAg-positive and HBeAg-negative
15
adults. It has also been studied in patients with HIV-HBV co-infection receiving combination antiretroviral regimens.
Chronic Hepatitis C
Over 80% of acute infections with HCV become chronic (the rate is lower in children). HCV is acquired most frequently
through illicit drug use (e.g., snorting cocaine, injection drug use), blood transfusion (prior to 1992), tattooing and
needle-stick injuries. Risk factors for progressive fibrosis in patients with chronic hepatitis C are male gender, age > 40
years at acquisition, alcohol consumption > 50 g daily and co-infection with HIV or immune suppression.
Investigations
Anti-HCV is a marker of infection, not immunity; tests are false-positive in less than 4% of patients, but may be
false-negative in up to 40% of immunocompromised individuals (in this group the presence of HCV may be
detected only by HCV RNA assay).
HCV RNA by PCR to confirm the diagnosis.
Liver biopsy to determine inflammatory grade and fibrosis stage is preferred but may not be necessary in all
patients prior to initiation of treatment.
Measure HCV RNA viral load (quantitation) and genotype prior to starting treatment.
Therapeutic Choices
Advise against all but modest alcohol consumption (less than four drinks weekly).
Cannabis may accelerate fibrosis in patients with chronic hepatitis and use should be discouraged.
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Therapeutic Choice
The pharmacologic management of patients with chronic hepatitis C is outlined in Table 7. An overview of the properties
of antiviral agents used for chronic hepatitis C is provided in Table 8. SVR is associated with clinically significant
outcomes including improvements in liver histology and health-related quality of life, reductions in liver-related
morbidity and mortality, and is durable.16
Combination Peginterferon plus Ribavirin
The combination of peginterferon alfa plus ribavirin is the recommended treatment for chronic hepatitis C
in Canada.3 Pegylation reduces the clearance of interferon and allows for once-weekly administration.
Peginterferon alfa monotherapy is significantly less effective than combination therapy and is appropriate
only for patients who have a contraindication to ribavirin and those who cannot tolerate ribavirin.
Ribavirin monotherapy is ineffective, thus ribavirin should never be administered alone. The duration of
therapy and dose of ribavirin depend on the viral genotype (Table 7, Table 8). Patients most likely to have
an SVR are those infected with genotype 2 or 3, individuals with a low baseline HCV RNA level and those
without advanced hepatic fibrosis. Useful Info?
For patients infected with HCV genotypes 2 or 3, the standard duration of treatment has traditionally been 24 weeks and
the standard dose of ribavirin is 800 mg/day. For patients infected with HCV genotype 1, the standard duration of
treatment has traditionally been 48 weeks and the standard dose of ribavirin is 1000 or 1200 mg/day.
Ideally, HCV RNA should be tested at week 4 and week 12 of therapy. Patients with a rapid virologic response (RVR),
defined as negative HCV RNA (< 50 IU/mL by qualitative PCR) at week 4, have a very high chance of achieving an SVR,
3
and the duration of therapy may be abbreviated in these select individuals.
Consideration may be given to shortening the duration of treatment from 24 to 16 weeks for genotype 2 or 3 patients
who have an RVR. Similarly, the duration of treatment may be shortened from 48 to 24 weeks in genotype 1 patients
who have an RVR.3 , 17 Abbreviated regimens are most effective in patients with low baseline HCV RNA levels
( < 400 000 IU/mL). A 36-week abbreviated regimen is as effective as a 48-week regimen in patients with minimal
fibrosis and low baseline HVC RNA levels who are infected with genotype 4.3
If HCV RNA is detectable at week 4, treatment should be continued until week 12, at which point serum HCV RNA is
reassessed by quantitative assay. Patients without a ≥ 2-log10 drop in HCV RNA relative to baseline or undetectable HCV
RNA at week 12 are very unlikely to achieve an SVR, thus treatment may be discontinued.
Genotype 1 and 4 patients with undetectable HCV RNA at week 12 should complete 48 weeks of combination therapy.
Genotype 1 patients with a ≥ 2-log10 drop but detectable HCV RNA at week 12 should continue to week 24, at which
time HCV RNA is reassessed by qualitative HCV RNA assay. If HCV RNA is still detectable, treatment should be stopped
because of the low probability of SVR. If HCV RNA is undetectable at week 24, continue for 48 weeks and give
consideration to prolonging treatment for up to 72 weeks (if funding is available). Preliminary data has shown better
3
outcomes with prolonged treatment in individuals who are “late” responders.
All patients who complete treatment must be advised to return 24 weeks after completion of therapy for a qualitative
HCV RNA test to determine SVR status.
Patients who have not responded or who have relapsed after treatment with standard interferon alone or in combination
with ribavirin may be retreated successfully with peginterferon plus ribavirin. However, the lack of a virologic response
3
at week 12, as outlined above, indicates a very low likelihood of an SVR, and treatment should be stopped.
Expected SVR rates with the recommended regimens for genotypes 1, 2 and 3 are shown in Table 4. Infection with
genotypes other than 1–3 are much less common and outcomes are less well defined. SVR rates in these individuals are
more similar to genotype 1 than 2 or 3, thus they should be managed in a manner similar to genotype 1.
Table 4: Expected SVR Rates in Patients with Chronic Hepatitis C After Treatment with Peginterferon alfa Plus Ribavirin
Genotype Patients Duration of Treatment SVR Rate
Genotype 1 Unselected 48 weeks 42–52%18 , 19 , 20
RVR 24 weeks 21 , 22
88–89%
No RVR 72 weeks 44%23
Genotype 2 or 3 Unselected 24 weeks 18 , 19 , 20

72–80%
RVR 12–16 weeks 82–85%24 , 25
Page 457
Therapeutic Choice
Abbreviations: RVR=rapid virologic response; SVR=sustained virologic response
Therapeutic Tips
Avoid immunosuppressive drugs, including prednisone. Fifty per cent of hepatitis B carriers experience a flare-up
upon withdrawal of immunosuppressive drugs with a rise in serum transaminases and conversion from an anti-HBe
to HBeAg-positive state. This is especially a problem in those undergoing cancer chemotherapy. Short-term
lamivudine use is recommended in this setting.11
Safe sex is recommended for those with multiple sexual partners. The precise sexual transmission rate is unknown,
but the prevalence of anti-HCV in partners of HCV-infected patients is only 1.5% (most partners have other risk
26 27
factors). Presence of HIV co-infection appears to increase the probability of sexual transmission of HCV.
Nucleoside analogues should not be used as monotherapy for HBV in HIV-positive patients because of the potential
for development of resistant HIV strains.
Treatment of HBV and HCV in patients with decompensated cirrhosis or post–liver transplantation should be
handled by transplant hepatologists only.
In patients with addiction problems, delay treatment of HCV until appropriate interventions have been initiated by
addiction medicine specialists.
Co-infection with HCV and/or HBV in HIV-positive patients should be handled by infectious disease specialists.28
Adherence is very important.
Depression is a side effect of peginterferon alfa, but antidepressants are effective for peginterferon-induced
depression. Monitor patients for depression and treat proactively.
Hemolytic anemia is a common and dose-limiting side effect of ribavirin that is managed by dose reductions. As
dose reductions reduce the likelihood of achieving an SVR, erythropoietin is advocated by some as a means of
29
maintaining the dose of ribavirin (see Blood Disorders: Common Anemias).
Figure 1-Treatment of Acute Viral Hepatitis
a.
Note: co-infection with HDV does not change treatment course, but is generally more severe.
Abbreviations: ALT = alanine transaminase; Anti-HBe = antibody to HBeAg; Anti-HBs = antibody to hepatitis B
surface antigen; Anti-HCV = antibody to HCV; AST = aspartate transaminase; HAV IgM = hepatitis A IgM;
HBeAg = hepatitis B e antigen; HBsAg = hepatitis B surface antigen; HCV = hepatitis C virus;
HCV RNA = hepatitis C virus RNA; HDV = hepatitis D (delta) virus; INR = international normalized ratio;
ISG = immune serum globulin; OC = oral contraceptive; PegIFN = peginterferon alfa.
Page 458
Therapeutic Choice
Table 5: Hepatitis A and Hepatitis B Immunizing Agents
Class Vaccine Dose Costa
Viral Vaccines, hepatitis A vaccine Avaxim: Adults and children aged ≥ 12 y: 0.5 $–$$
single component Avaxim, Avaxim-Pediatric, mL (160 AU) im × 2 at 0 and 6–12 months
Havrix 1440, Havrix 720 Avaxim-Pediatric: Children aged 1 to 15 y: 0.5
mL (80 AU) im × 2 at 0 and 6–12 months
Junior, Vaqta, Vaqta pediatric
Havrix 1440: Adults aged ≥ 19 y: 1.0 mL (1440
ELISA units) im × 2 at 0 and 6–12 months
Havrix 720 Junior: Children 1 to 18 y: 0.5 mL
(720 ELISA units) im at time 0 and 6–12 mo
Vaqta: Adults aged ≥ 18 y: 1.0 mL (50 units) im
× 2 at 0 and 6 months
Vaqta pediatric: Children aged 1 to 17 y: 0.5
mL (25 units) im × 2 at 0 and 6–18 months
Viral Vaccines, hepatitis B vaccine Engerix-B: Energix-B: $

single component Engerix-B, Recombivax HB Adults aged ≥ 20 y: 1.0 mL (20 μg HBsAg) im × 3 Recombivax
at 0, 1 and 6 months or × 4 at 0, 1, 2 and 12 HB
months, or 0, 7, 21 and 365 days
Adults: $$$
Adults (dialysis ≥ 16 y): 2.0 mL (40 μg HBsAg)
im × 4 at 0, 1, 2 and 6 months Pediatric: $
Children aged 0 to 19 y: 0.5 mL (10 μg HBsAg)

im × 3 at 0, 1 and 6 months or × 4 at 0, 1, 2 and
12 months
Adolescents aged 11 to 15 y (alternative 2

dose schedule): 1.0 mL (20 μg HBsAg) im × 2 at 0
and 6 months
Immunocompromised patients: 2.0 mL (40 μg

HBsAg) im. Monitor anti-HBsAg titre annually and
give boosters as needed
Recombivax HB:
Adults aged ≥ 20 y: 1.0 mL (10 μg HBsAg) im × 3
at 0, 1 and ≥ 2 months
Adults (predialysis or dialysis): 1.0 mL (40 μg

HBsAg) im × 3 at 0, 1 and 6 months
Adolescents aged 11 to 19 y: 0.5 mL (5 μg

HBsAg) im × 3 at 0, 1 and ≥ 2 months
Infants and children aged 0 to < 11 y: 0.25 mL

(2.5 μg HBsAg) im × 3 at 0, 1 and ≥ 2 months
Adolescents aged 11 to 15 y (alternative 2

dose schedule): 1.0 mL (10 μg HBsAg) im × 2 at 0
and 4–6 months
Viral Vaccines, combined hepatitis A and B Adults aged ≥ 19 y: 1.0 mL (720 ELISA units plus $$
combinations Twinrix 20 μg HBsAg) im × 3 at 0, 1 and 6 months or × 4 at
0, 7, 21 and 365 days
Children aged 1 to 18 y: 0.5 mL (360 ELISA units
plus 10 μg HBsAg) im × 3 at 0, 1 and 6 months
Page 459
Therapeutic Choice
a
Class Vaccine Dose Cost
Adolescents aged 1 to 15 y (alternative 2 dose
schedule): 1.0 mL (720 ELISA units plus 20 μg
HBsAg) im × 2 at 0 and 6–12 months
Viral Vaccines, combined hepatitis A and Adults aged ≥ 16 y: 1.0 mL (160 AU plus 25 μg S. $$$
combinations Salmonella Typhi typhi Vi capsular polysaccharide) im × 2 at 0 and 6–
Vivaxim 12 months
Passive hepatitis B immune globulin Post-exposure prophylaxis for hepatitis B: 0.06 b

$$$$
Immunizing Hyperhep B S/D mL/kg im
Agents
Passive hepatitis A immune globulin Post-exposure prophylaxis for hepatitis A b

$$
Immunizing GamaSTAN S/D within 2 weeks of exposure (If exposure is
Agents continuous, repeat in 5 mo):
Adults: 0.08–0.12 mL/kg im
Children: 0.02–0.04 mL/kg im
a.
Vaccine cost only.
b.
Available through Canadian Blood Services.
Legend: $ < $25 $$ $25–50 $–$$ < $25–50 $$$ $50–75 $$$$ > $75
Abbreviations: Anti-HBsAg=antibody toHBsAg; AU=antigen units; ELISA=enzyme-linked immunosorbent assay; HBsAg=hepatitis
B surface antigen
Table 6: Management of Chronic Hepatitis B2
HBV Serum Markers
HBV
Anti- Anti- ALT DNA,
a
Patient Characteristics HBs HBsAg HBe Status IU/mL Recommended Management
Immune + − + ↔ − Antiviral therapy is not indicated
Low-replicating − + +/− ↔ < 1000 No antiviral therapy. Monitor ALT Q6

months
Immune- HBeAg(+) − + − ↔ > 10 000 No antiviral therapy. Monitor ALT Q3

tolerant months × 1 year, then Q6–12 months
thereafter
High- Wild type − + − ↑ > 10 000 Consider peginterferon or nucleoside

replicating analogue therapy (adefovir, entecavir,
lamivudine, telbivudine). The goal is to
suppress HBV DNA replication below the
limit of detection until HBe seroconversion
occurs
Precore − + + ↑ > 1000 Consider long-term nucleoside analogue

mutant therapy: adefovir, entecavir or lamivudine
Lamivudine- − + +/− ↑ > 10 000 Switch to entecavir 1 mg/day; or continue

resistantb lamivudine and add either adefovir or
tenofovir
Decompensated cirrhosis − + +/− ↑ > 100 Lamivudine
Post–liver transplant − + +/− ↔/↑ + Lamivudine plus HBIgc
Page 460
Therapeutic Choice
a.
Where more than one nucleoside analogue is presented, the presentation is alphabetical and does not imply the order of choice.
Drug doses are presented in Table 8.
b.
HBV species with mutations in the tyrosine-methionine-aspartate-aspartate (YMDD) locus of the HBV-RNA-dependent DNA
polymerase resulting in resistance to lamivudine.
c.
HBIg is generally given during the anhepatic phase (10 000 IU iv bolus), then daily during the first week to ensure an anti-HBs
titre > 100 IU/mL, and then either at a dose of 5 mL im monthly or adjusted to maintain an anti HBs titre > 100 IU/mL.
Legend: +=positive (marker is present); –=negative (marker is absent); ↔=not elevated above the upper limit of normal; ↑=elevated above
the upper limit of normal; HBIg=hepatitis B immune globulin
Table 7: Management of Chronic Hepatitis C3
Patient Anti- HCV Serum HCV Fibrosis on

Characteristics HCV RNA ALT Genotype Liver Biopsy Recommended Management
Chronic hepatitis C + + ↔/↑ 1,4,5,6 + PegIFN + ribavirin × 24 to 72

weeks
+ + ↔/↑ 2,3 +/− PegIFN + ribavirin × 16 to 24

weeks
Extrahepatic + + ↔/↑ 1-6 +/− Same as for chronic disease

diseasea according to HCV genotype
b + + ↔/↑ 1-6 +/− PegIFN monotherapy × at least

Renal failure
48 weeks
No viremia + − ↔c 1-6 +/− Antiviral therapy is not

indicated
a.
Mixed cryoglobinemia, membranoproliferative glomerulonephritis.
b.
Ribavirin is contraindicated in patients with renal failure.
c.
May be elevated due to other causes.
Abbreviations: ALT=alanine transaminase; Anti-HCV=antibody to HCV; HCV=hepatitis C virus; HCV RNA=hepatitis C virus
RNA; PegIFN=peginterferon
Table 8: Drugs Used in Viral Hepatitis
a
Indication Cost
Class Drug and Dose Adverse Effects Comments
Nucleoside Analogues adefovir dipivoxil Chronic Elevated Do not use $$$

Hepsera hepatitis B: transaminase nucleoside
10 mg po levels, analogues as
daily nephrotoxicity monotherapy for
(increased serum HBV in patients
creatinine). with HIV co-
infection: can
select resistant
HIV variants.
Acute
exacerbations of
HBV disease
evidenced by
marked ALT
elevations have
occurred after
discontinuing
nucleoside
analogues.
Nucleoside Analogues entecavir Chronic Elevated Do not use $$$

Baraclude hepatitis B: transaminase nucleoside
Nucleoside- levels. analogues as
naïve monotherapy for
patients: 0.5 HBV in patients
mg po daily with HIV co-
Page 461
Therapeutic Choice
a
Indication Cost
infection: can
Lamivudine- select resistant
experienced HIV variants.
patients: 1 Acute
mg po daily exacerbations of
HBV disease
evidenced by
marked ALT
elevations have
occurred after
discontinuing
nucleoside
analogues.
Nucleoside Analogues lamivudine Chronic Elevated Do not use $

Heptovir hepatitis B: transaminase nucleoside
100 mg po levels. analogues as
daily monotherapy for
HBV in patients
with HIV co-
infection: can
select resistant
HIV variants.
Acute
exacerbations of
HBV disease
evidenced by
marked ALT
elevations have
occurred after
discontinuing
nucleoside
analogues.
Nucleoside Analogues telbivudine Chronic Elevated Do not use $$$

Sebivo hepatitis B: transaminase nucleoside
600 mg po levels. Elevated analogues as
daily creatine kinase monotherapy for
levels. Peripheral HBV in patients
neuropathy if with HIV co-
given with infection: can
peginterferon select resistant
HIV variants.
Acute
exacerbations of
HBV disease
evidenced by
marked ALT
elevations have
occurred after
discontinuing
nucleoside
analogues.
Nucleoside Analogues tenofovir disoproxil Chronic Renal toxicity. Do not use $$

fumarate hepatitis B: Monitor renal nucleoside
Viread 300 mg po function and analogues as
daily serum monotherapy for
phosphorus. Lactic HBV in patients
acidosis and with HIV co-
severe infection: can
hepatomegaly select resistant
with steatosis HIV variants.
have been Acute
reported. exacerbations of
HBV disease
evidenced by
Page 462
Therapeutic Choice
a
Indication Cost
marked ALT
elevations have
occurred after
discontinuing
nucleoside
analogues.
Immuno-modulatory Agents peginterferon alfa-2a Chronic Flu-like syndrome, Neutropenia (< $$$$
Pegasys hepatitis B: fatigue, fever, 9
0.75 × 10 /L) and
180 µg sc muscle aches, thrombocytopenia
once/wk for asthenia, weight 9
(< 50 × 10 /L)
48 wk loss, headaches,
are managed by
irritability,
dose reductions.
depression, hair
Neutropenia
loss, soreness and
associated with
redness at
peginterferon does
injection site,
not appear to
neutropenia and
increase
thrombocytopenia.
susceptibility to
infection.30
Contraindications
include
pregnancy,
decompensated
liver disease,
severe cardiac
disease, solid
organ transplant
(except liver),
ongoing/untreated
alcohol abuse or
injection drug use,
severe/untreated
major depression
or psychosis,
3
renal failure
Combination Nucleoside ribavirin/peginterferon Chronic Ribavirin: Monotherapy with $$$$

Analogues/Immunomodulatory alfa-2a hepatitis C Hemolytic anemia peginterferon b
Agents Pegasys RBV peginterferon (reduce dose), should only be
alfa-2a rash. used in patients
180 µg sc Flu-like syndrome, with
once/wk with fatigue, fever, contraindications
ribavirin: muscle aches, or intolerance to
asthenia, weight ribavirin.
(Genotype 1, loss, headaches, Contraindicated in
4, 5, 6:) irritability, pregnancy
depression, hair (teratogenic);
• 1000 loss, soreness and effective
mg/day if redness at contraception
< 75 kg; injection site, during treatment
neutropenia and is mandatory.
• 1200 thrombocytopenia.
mg/day BID if Anemia (Hgb <
≥ 75 kg 100 g/L) is
managed by dose
(Genotype 2 reductions.
or 3:)
Neutropenia (<
• 800 mg/day 0.75 × 109/L) and
thrombocytopenia
Give BID with
(< 50 × 109/L)
food
are managed by
dose reductions.
Neutropenia
associated with
Page 463
Therapeutic Choice
a
Indication Cost
peginterferon does
not appear to
increase
susceptibility to
30
infection.
Contraindications
include
pregnancy,
decompensated
liver disease,
severe cardiac
disease, solid
organ transplant
(except liver),
ongoing/untreated
alcohol abuse or
injection drug use,
severe/untreated
major depression
or psychosis,
renal failure3
Combination Nucleoside ribavirin/peginterferon Chronic Ribavirin: Monotherapy with $$$$

Analogues/Immunomodulatory alfa-2b hepatitis C Hemolytic anemia peginterferon b
Agents Pegetron peginterferon (reduce dose), should only be
alfa-2b rash. used in patients
1.5 µg/kg sc Flu-like syndrome, with
once/wk with fatigue, fever, contraindications
ribavirin muscle aches, or intolerance to
13.5 mg/kg asthenia, weight ribavirin.
(600– loss, headaches, Contraindicated in
1200 mg/day) irritability, pregnancy
depression, hair (teratogenic);
Give BID with loss, soreness and effective
food. redness at contraception
injection site, during treatment
neutropenia and is mandatory.
thrombocytopenia.
Anemia (Hgb <
100 g/L) is
managed by dose
reductions.
Neutropenia (<
0.75 × 109/L) and
thrombocytopenia
(< 50 × 109/L)
are managed by
dose reductions.
Neutropenia
associated with
peginterferon does
not appear to
increase
susceptibility to
30
infection.
Contraindications
include
pregnancy,
decompensated
liver disease,
severe cardiac
disease, solid
Page 464
Therapeutic Choice
a
Indication Cost
organ transplant
(except liver),
ongoing/untreated
alcohol abuse or
injection drug use,
severe/untreated
major depression
or psychosis,
renal failure3
a.
b.
Ribavirin is sold only in combination with peginterferon alfa-2a or peginterferon alfa-2b.
Abbreviations: ALT=alanine transaminase; HBV=hepatitis B virus; HIV=human immunodeficiency virus
Legend: $ < $250 $$ $250–750 $$$ $750–1250 $$$$ $1250–1750
Suggested Readings
Hoofnagle JH, Seeff LB. Peginterferon and ribavirin for chronic hepatitis C. N Engl J Med 2006;355(23):2444-51.
Koziel MJ, Peters MG. Viral hepatitis in HIV infection. N Engl J Med 2007;356(14):1445-54.
Lok AS, McMahon BJ. Chronic hepatitis B. Hepatology 2007;45(2):507-39.
National Advisory Committee on Immunization. Canadian immunization guide. 7th ed. Ottawa (ON): Public Health
Agency of Canada; 2006. Available from: http://www.phac-aspc.gc.ca/publicat/cig-gci/pdf/cig-gci-2006_e.pdf.
Accessed November 17, 2008.
Scott JD Gretch DR. Molecular diagnostics of hepatitis C virus infection: a systematic review. JAMA 2007;297(7):724-
32.
References
1. Alter MJ, Mast EE. The epidemiology of viral hepatitis in the United States. Gastroenterol Clin North Am 1994;23
(3):437-55.
2. Sherman M, Shafran S, Burak K et al. Management of chronic hepatitis B: consensus guidelines. Can J
Gastroenterol 2007;21(Suppl C):5C-24C.
3. Sherman M, Shafran S, Burak K et al. Management of chronic hepatitis C: consensus guidelines. Can J
Gastroenterol 2007;21(Suppl C):25C-34C.
4. National Advisory Committee on Immunization. Canadian immunization guide. 7th ed. Ottawa (ON): Public Health
Agency of Canada; 2006. Available from: http://www.phac-aspc.gc.ca/publicat/cig-gci/pdf/cig-gci-2006_e.pdf.
Accessed November 17, 2008.
5. Ryder SD, Beckingham IJ. ABC of diseases of liver, pancreas, and biliary system: acute hepatitis. BMJ 2001;322
(7279):151-3.
6. Irving WL. Acute hepatitis C virus infection: a neglected disease? Gut 2006;55(8):1075-7.
7. Coffin CS, Lee SS. Chronic hepatitis B–who should be treated? MedGenMed 2006;8(1):75.
8. Leung NW, Lai CL, Chang TT et al. Extended lamivudine treatment in patients with chronic hepatitis B enhances
hepatitis B e antigen seroconversion rates: results after 3 years of therapy. Hepatology 2001;33(6):1527-32.
9. Lai CL, Chien RN, Leung NW et al. A one-year trial of lamivudine for chronic hepatitis B. Asia Hepatitis
Lamivudine Study Group. N Engl J Med 1998;339(2):61-8.
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Therapeutic Choice
10. Marcellin P, Chang TT, Lim SG et al. Adefovir dipivoxil for the treatment of hepatitis B e antigen-positive chronic
hepatitis B. N Engl J Med 2003;348(9):808-16.
11. Chang TT, Gish RG, de Man R et al. A comparison of entecavir and lamivudine for HBeAg-positive chronic
hepatitis B. N Engl J Med 2006;354(10):1001-10.
12. Lai CL, Shouval D, Lok AS et al. Entecavir versus lamivudine for patients with HBeAg-negative chronic hepatitis B.
N Engl J Med 2006;354(10):1011-20.
13. Dienstag J, Easley C,.Kirkpatrick P. Telbivudine. Nat Rev Drug Discov 2007;6(4):267-8.
14. Colonno RJ, Rose R, Baldick CJ et al. Entecavir resistance is rare in nucleoside naive patients with hepatitis B.
Hepatology 2006;44(6):1656-65.
15. Viread product monograph (tenofovir). Mississauga (ON): Gilead Sciences Canada, Inc.; August 14, 2008.
16. Dienstag JL, McHutchison JG. American Gastroenterological Association technical review on the management of
hepatitis C. Gastroenterology 2006;130(1):231-64.
17. Manns MP, Wedemeyer H, Cornberg M. Treating viral hepatitis C: efficacy, side effects, and complications. Gut
2006;55(9):1350-9.
18. Manns MP, McHutchison JG, Gordon SC et al. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b
plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. Lancet 2001;358(9286):958-65.
19. Fried MW, Shiffman ML, Reddy KR et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection.
N Engl J Med 2002;347(13):975-82.
20. Hadziyannis SJ, Sette H, Morgan TR et al. Peginterferon-alpha2a and ribavirin combination therapy in chronic
hepatitis C: a randomized study of treatment duration and ribavirin dose. Ann Intern Med 2004;140(5):346-55.
21. Jensen DM, Morgan TR, Marcellin P et al. Early identification of HCV genotype 1 patients responding to 24 weeks
peginterferon alpha-2a (40 kd)/ribavirin therapy. Hepatology 2006;43(5):954-60.
22. Zeuzem S, Buti M, Ferenci P et al. Efficacy of 24 weeks treatment with peginterferon alfa-2b plus ribavirin in
patients with chronic hepatitis C infected with genotype 1 and low pretreatment viremia. J Hepatol 2006;44(1):97
-103.
23. Sanchez-Tapias JM, Diago M, Escartin P et al. Peginterferon-alfa2a plus ribavirin for 48 versus 72 weeks in
patients with detectable hepatitis C virus RNA at week 4 of treatment. Gastroenterology 2006;131(2):451-60.
24. Mangia A, Santoro R, Minerva N et al. Peginterferon alfa-2b and ribavirin for 12 vs. 24 weeks in HCV genotype 2
or 3. N Engl J Med 2005;352(25):2609-17.
25. von Wagner M, Huber M, Berg T et al. Peginterferon-alpha-2a (40KD) and ribavirin for 16 or 24 weeks in patients
with genotype 2 or 3 chronic hepatitis C. Gastroenterology 2005;129(2):522-7.
26. Alter MJ. The epidemiology of acute and chronic hepatitis C. Clin Liver Dis 1997;1(3):559-68, vi-vii.
27. Filippini P, Coppola N, Scolastico C et al. Does HIV infection favor the sexual transmission of hepatitis C? Sex
Transm Dis 2001;28(12):725-9.
28. Adeyemi OM. Hepatitis C in HIV-positive patients–treatment and liver disease outcomes. J Clin Gastroenterol
2007;41(1):75-87.
29. Sherman M, Cohen L, Cooper MA et al. Clinical recommendations for the use of recombinant human erythropoietin
in patients with hepatitis C virus being treated with ribavirin. Can J Gastroenterol 2006;20(7):479-85.
30. Cooper CL, Al-Bedwawi S, Lee C et al. Rate of infectious complications during interferon-based therapy for
hepatitis C is not related to neutropenia. Clin Infect Dis 2006;42(12):1674-8.
Page 466
e-Therapeutics+ : Therapeutics : Genitourinary Disorders: Lower Urinary Tract Symptoms ... Page 1 of 8
Therapeutic Choice
Print Close
Genitourinary Disorders: Lower Urinary Tract Symptoms and Benign Prostatic Hyperplasia

Richard W. Norman, MD, FRCSC
Goals of Therapy
Improve or abolish lower urinary tract symptoms (LUTS)

Prevent or delay clinical progression of benign prostatic hyperplasia (BPH)
Reduce the risk of surgical intervention
Prevent the sequelae of long-term bladder outlet obstruction (urinary tract infections, bladder stones,
hydronephrosis)
Investigations

voiding (weak/interrupted stream, dribbling, hesitancy, straining) and storage (nocturia, frequency,
urgency) symptoms
onset and progression of LUTS and degree of inconvenience or bother to the patient (International Prostate
Symptom Score is recommended — available at www.cpcn.org/ipss.pdf)
details of urethral infection, injury or instrumentation
episodes of urinary tract infection, hematuria or urinary retention
abdomen (bladder distention, flank tenderness)
external genitalia (phimosis, meatal stenosis, urethral mass/induration)
digital rectal examination (DRE) (document prostate size, consistency, symmetry and tenderness)
Laboratory tests:
urinalysis (and urine culture if pyuria)
serum creatinine
prostate specific antigen (PSA); optional but recommended when a diagnosis of prostate cancer would alter
treatment in otherwise healthy men between 50 and 70 years of age with a life expectancy of at least 10
years; start obtaining annual PSA levels at age 45 when there is a positive family history and/or patient is
1
of African descent; PSA can be used as a surrogate marker of prostate size in benign disease. Canadian
Cancer Society recommends patients should discuss the potential benefits and harms of PSA testing for
2
prostate cancer with their family physician
Other diagnostic tests are occasionally required when the history is not clear, there are abnormalities of the
physical examination or laboratory tests or the response to treatment is unsatisfactory:
cystourethroscopy
urodynamic studies
renal/bladder/transrectal ultrasonography
iv urography
CT abdomen
Therapeutic Choices (Figure 1 - Management of Benign Prostatic Hyperplasia)
Manage minimal symptoms with reassurance and active surveillance (regular reassessment).
Advise patients with problematic nocturia to avoid caffeine-containing beverages and alcohol in the evening and
to elevate legs prior to retiring if pedal edema.
The alpha1-adrenergic blockers, alfuzosin, doxazosin, tamsulosin and terazosin, and the 5-alpha-reductase
inhibitors, dutasteride and finasteride, are all useful in improving symptoms.
Alpha1-adrenergic Blocking Agents
Page 467
Therapeutic Choice
Alfuzosin, doxazosin, tamsulosin and terazosin are the agents most commonly used to block alpha1-adrenergic
receptors that mediate muscular activity in the bladder neck, prostate and prostatic capsule, reducing the dynamic
component of bladder outlet obstruction. Over a period of days to weeks, this may improve urinary flow rates by 1–
3 mL/sec and symptom scores by 1–3 points. The effectiveness of the alpha1-adrenergic blockers is not influenced
by prostate size.
To avoid first-dose syncope, doxazosin and terazosin must be started at a low dosage and gradually increased until
symptomatic improvement or intolerance occurs. Dose titration is not necessary with alfuzosin and tamsulosin
because of their greater selectivity for the alpha1A-receptor subtype which predominates in the prostate, bladder
neck and urethra.
Side effects of alpha-blockers include dizziness (10–20%), headaches (15%), asthenia (5–15%) and nasal
congestion (5–10%). Retrograde ejaculation develops in 5–10% of men taking tamsulosin. These drugs may
potentiate other antihypertensive medications, and caution should be used when they are added to an ongoing
regimen, particularly in the elderly. Doxazosin and sildenafil, taken within hours of each other, may result in an
undesirable hypotensive effect in some patients.3 Alfuzosin and tamsulosin have fewer systemic side effects because
of their greater selectivity for the alpha1A-receptor subtype, and because their administration with meals produces
more constant serum drug concentrations. Side effects of terazosin and doxazosin may be reduced by taking them at
bedtime.
Alpha-blockers, especially tamsulosin, have been linked to intraoperative floppy iris syndrome (IFIS). Patients
4
taking any of these drugs should inform their ophthalmologist if they require cataract surgery.
Terazosin and doxazosin may cause a small decrease in total cholesterol and low-density lipoprotein fraction. The
clinical importance of this is unknown.
Although there are differences in the adverse event profiles of these agents, all 4 have equal clinical effectiveness.
Choice of agent should depend upon the side effect profile and on the patient’s comorbidities and individual
tolerance. Provincial drug coverage may also play a role in this decision. In patients with no significant
cardiovascular or cerebrovascular disease and with the ability to understand and carry out dose titration, terazosin
and doxazosin are cost-effective alpha1-blockers.
5-Alpha-reductase Inhibitors
Finasteride inhibits the type II and dutasteride the type I and II isoenzymes of 5-alpha-reductase, which blocks
the metabolism of testosterone to dihydrotestosterone. The net effect is a decrease in intraprostatic
dihydrotestosterone and a progressive reduction in prostatic volume. This reduces the static component of bladder
outlet obstruction over a period of several months to years and may be accompanied by an improvement in urinary
flow rates of 1–2 mL/sec and symptom scores of 1–2 points.
5-alpha-reductase inhibitors work best in men with a large prostate.5 Because of their site specificity, there is a low
incidence of side effects (e.g., 3–4% sexual dysfunction) and little risk of significant drug interactions. Within 6
months of initiation, these drugs decrease serum PSA levels by approximately 50% in men with BPH and may
partially suppress serum PSA in men with prostate cancer.
BPH patients who are concerned about prostate cancer may be counselled on the proven benefits (beyond reducing
symptoms and progression of BPH) of using a 5-alpha-reductase inhibitor for reduction of overall prostate cancer
6
risk.
Combination Alpha-blocker and 5-Alpha-reductase Inhibitor Therapy
The combination of an alpha1-adrenergic receptor blocker and a 5-alpha-reductase inhibitor is an

appropriate and effective treatment for patients with LUTS associated with demonstrable prostatic
enlargement. Useful Info?
Give patients who are successfully treated with combination therapy the option of discontinuing the alpha-blocker
7
after 6–12 months. If symptoms recur, the alpha-blocker should be restarted.
Phytotherapeutic Agents
Saw palmetto is the most popular and studied plant extract used to reduce symptoms related to BPH.
Some patients report a favourable response but published trials fail to show any benefit greater than
Page 468
Therapeutic Choice
placebo.8,9 Identification and pharmacokinetics of active ingredients are often unclear in

phytotherapeutic mixtures. Until more information regarding their mode of action and long-term
10
efficacy and safety becomes available in quality studies, their use cannot be recommended.
Useful Info?
Procedures (Table 2)
While transurethral resection of the prostate (TURP) and retropubic prostatectomy are traditional means of dealing
with an enlarged and obstructing prostate gland, transurethral incision of the prostate (TUIP) and various forms of
laser prostatectomy are useful in some patients. Long-term catheter drainage or clean intermittent catheterization
are appropriate options for patients who are not candidates for any other intervention.
Therapeutic Tips
Patients with minimal symptoms that do not interfere with their normal activities should be managed by active
surveillance and regular follow-up.
Patients starting to develop progressive symptoms or who are moderately inconvenienced or bothered by them
are candidates for pharmacologic intervention.
Continue drug therapy indefinitely since symptoms recur when medication is stopped.
Complicating factors or unexpected (or lack of) response to any intervention are indications for urologic
consultation.
Avoid decongestants and other drugs with alpha-adrenergic activity because they can stimulate smooth muscle
in the bladder neck and prostate, and increase obstruction.
Drugs with anticholinergic activity may reduce detrusor contractility. Use these agents with caution in patients
with symptoms of bladder outlet obstruction. Although they may not be as much of a problem as previously
thought in patients with symptoms of bladder outlet obstruction, these agents should be used with caution.11
Figure 1- Management of Benign Prostatic Hyperplasia
Page 469
Therapeutic Choice
Abbreviations: DRE = digital rectal examination; PSA = prostate specific antigen
Table 1: Drugs Used in Benign Prostatic Hyperplasia
Page 470
Therapeutic Choice
a
Adverse Cost
Alpha1- terazosin 1–10 mg Dizziness, Possible additive Maximal $

blockers, Hytrin, QHS headaches, hypotension when combined response seen
nonselective generics Dose titrated asthenia and with beta-blockers. Monitor in weeks.
weekly to nasal blood pressure.
desired congestion May precipitate hypotension
response (5–20%); in conjunction with
syncope phosphodiesterase type 5
(< 1%). inhibitors (e.g., sildenafil).
Alpha1- doxazosin 1–12 mg Dizziness, Possible additive Maximal $-$$

blockers, Cardura, QHS headaches, hypotension when combined response seen
nonselective generics Dose titrated asthenia and with beta-blockers. Monitor in weeks.
weekly to nasal blood pressure.
desired congestion May precipitate hypotension
response (5–20%); in conjunction with
syncope phosphodiesterase type 5
(< 1%). inhibitors (e.g., sildenafil).
Alpha1A- alfuzosin 10 mg daily Vertigo (2%). Possible additive Shown to have $$

blockers, Xatral, after the hypotension when combined a role in
selective generics same meal with beta blockers. Monitor management of
each day blood pressure. acute urinary
Avoid combination with retention.
potent CYP3A4 inhibitors,
e.g., ketoconazole,
ritonavir. Excessive
hypotension may occur.
Alpha1A- tamsulosin 0.4 mg once Retrograde No known clinically Swallow tablets $

blockers, controlled- daily at the ejaculation significant drug interactions. whole; do not
selective release same time (5–10%). crush or chew.
Flomax CR, each day,
generics with or
without food
5-Alpha- dutasteride 0.5 mg daily Sexual Combination with strong Blocks types I $$$$
reductase Avodart dysfunction (3 CYP3A4 inhibitors, e.g., and II
Inhibitors –4%). ketoconazole, ritonavir, may isoenzymes.
increase serum Reduces
concentration of dutasteride. prostate-
Monitor for increased specific antigen
adverse reactions, e.g., (PSA). Maximal
impotence, decreased libido. response seen
in 6 mo.
5-Alpha- finasteride 5 mg daily Sexual No known clinically Blocks type II $$

reductase Proscar, dysfunction (3 significant drug interactions. isoenzymes.
Inhibitors generics –4%). Reduces
prostate-
specific antigen
(PSA). Maximal
response seen
in 6 mo.
Page 471
Therapeutic Choice
a.
Legend: $ < $15 $-$$ < $15–30 $$ $15–30 $-$$$ < $15–45 $$-$$$ $15–45 $$$ $30–45 $$$$ >
$45
Table 2: Procedures for BPH
Procedure Description/Efficacy Adverse Effects Comments
Transurethral 1–2 days in hospital; gold Retrograde ejaculation For moderately enlarged
resection of standard for efficacy (85–90% (50–95%), urethral prostates.
prostate (TURP) reduction in symptoms). strictures (3%), bladder
neck contracture (3–
10%), re-resection (3–
8%).
Retropubic Open surgery; 3–5 days in Retrograde ejaculation For very enlarged prostates
prostatectomy hospital; similar efficacy to TURP. (80–90%); bladder neck or when required to correct
contraction (2–3%). other bladder pathology.
Transurethral Outpatient; 80% reduction in Retrograde ejaculation (6 Useful for smaller

incision of symptoms. –55%). prostates.
prostate (TUIP)
Laser 1-day hospital stay; 80% Little or no bleeding. Preferred technique for
prostatectomy reduction in symptoms. patients requiring
(various types) anticoagulants or with
uncorrected
coagulopathies; long-term
data awaited.
Transurethral Outpatient; 30–40% reduction in Prolonged postoperative Variable patient responses;

microwave symptoms. catheterization and risk of not reimbursed or widely
thermotherapy infection. available.
(TUMT)
Urethral stents Temporary or permanent Encrustation, migration, Biodegradable stents (and

(various types and procedure for poor surgical breakage, stress indications for stents in
compositions) candidates. incontinence. general) under
investigation.
Transurethral Outpatient; intraprostatic Temporary postoperative Long-term data awaited;

needle ablation of placement of needle electrodes urinary retention (13– not reimbursed or widely
prostate (TUNA) causes heating and necrosis of 42%); irritative voiding available.
tissue; 60% reduction in symptoms (40%); re-
symptoms. operation (14%).
Suggested Readings
Andriole GL, Grubb RL, Buys SS et al. Mortality results from a randomized prostate-cancer screening trial.N Engl J
Med 2009;360(13):1310-9.
Burnett AL,Wein AJ. Benign prostatic hyperplasia in primary care: what you need to know. J Urol 2006;175(3 Pt
2):S19-24.
Carson CC. Combination of phosphodiesterase-5 inhibitors and alpha-blockers in patients with benign prostatic
hyperplasia: treatments of lower urinary tract symptoms, erectile dysfunction, or both? BJU Int 2006;97(Suppl
2):39-43.
Fitzpatrick JM. The natural history of benign prostatic hyperplasia. BJU Int 2006;97(Suppl 2):3-6.
Reich O, Gratzke C, Stief CG. Techniques and long-term results of surgical procedures for BPH. Eur Urol 2006;49
(6):970-8.
Schoder FH, Hugosson J, Roobol MJ et al. Screening and prostate cancer mortality in a randomized European Study.
N Engl J Med 2009;360(13):1320-8.
Page 472
Therapeutic Choice
References
1. Nickel JC, Herschorn S, Corcos J et al. Canadian guidelines for the management of benign prostatic
hyperplasia. Can J Urol 2005;12(3):2677-83.
2. Canadian Cancer Society. Understanding the pros and cons of prostate cancer testing. Available from:
www.cancer.ca/Canada-wide/Prevention/Get%20screened/Understanding%20the%20pros%20and%20cons%
20of%20prostate%20testing.aspx?sc_lang=en. Accessed September 29, 2009.
3. Pfizer. Viagra (sildenafil citrate) tablets. New York (NY): Pfizer Labs; October 2007. Available from:
pfizer.com/pfizer/download/uspi_viagra.pdf. Accessed September 29, 2009.
4. Chaga DF, Braga-Mele R, Mamalis N et al. ASCRS White Paper: clinical review of intraoperative floppy-iris
syndrome. J Cataract Refract Surg 2008;34(12):2153-62.
5. McConnell JD, Roehrborn CG, Bautista OM et al. The long-term effect of doxazosin, finasteride, and
combination therapy on the clinical progression of benign prostatic hyperplasia. N Engl J Med 2003;349
(25):2387-98.
6. Klotz L, Saad F; PCPT-MTOPS Consensus Panel. PCPT, MTOPS and the use of 5-ARIs: a Canadian consensus
regarding implications for clinical practice. Can Urol Assoc J 2007;1(1):17-21.
7. Baldwin KC, Ginsberg PC, Roehrborn CG et al. Discontinuation of alpha-blockade after initial treatment with
finasteride and doxazosin in men with lower urinary tract symptoms and clinical evidence of benign prostatic
hyperplasia. Urology 2001;58(2):203-9.
8. Tacklind J, MacDonald R, Rutks I et al. Serenao repens for benign prostatic hyperplasia. Cochrane Database
Syst Rev 2009;(2):CD001423.
9. Bent S, Kane C, Shinohara K et al. Saw palmetto for benign prostatic hyperplasia. N Engl J Med 2006;354
(6):557-66.
10. Dedhia RC, McVary KT. Phytotherapy for lower urinary tract symptoms secondary to benign prostatic
hyperplasia. J Urol 2008;179(6):2119-25.
11. Blake-James BT, Rashidian A, Ikeda Y et al. The role of anticholinergics in men with lower urinary tract
symptoms suggestive of benign prostatic hyperplasia: a systematic review and meta-analysis. BJU Int
2007;99(1):85-96.
Pharmacoeconomic Considerations: Benign Prostatic Hyperplasia

Epidemiology
Country Prevalence (%)

1 50% of men aged ≥ 50 years in the general population
Worldwide
Country and Year of Estimate a

Direct Costs
United Kingdom (1990)2 £62–91 million
Commentary
2 , 4
The symptoms of benign prostatic hyperplasia (BPH) interfere with activities of daily living. Direct costs
associated with this condition are dependent on the management choice for BPH, namely surgery or medical. With
respect to surgery or transurethral prostatectomy (TURP), length of stay is the major cost driver.3
3 , 4
In general, medical management is more cost-effective than surgical management. Patient preference is
4
important, with most men preferring medical over surgical management. Surgery is associated with higher
indirect costs than medical management.5
A number of economic evaluations for the management of BPH have been conducted but the results are
inconsistent. Terazosin and finasteride, reported to be equivalent in terms of efficacy, have both been shown to
be more cost-effective than TURP (with and without complications).6 Other studies have indicated that the costs
per patient treated were similar for terazosin and placebo (i.e., a strategy of watch and wait), but the lower
Page 473
Therapeutic Choice
medication costs in the watch and wait group were offset by higher inpatient costs in the terazosin group.6
Tamsulosin is reported to be more cost-effective than finasteride, but comparable to surgical management.7 A
simple decision analytic model comparing tamsulosin, doxazosin and terazosin reported that tamsulosin was more
cost-effective than the comparators.8
A number of non-drug treatments for BPH, including photoselective vaporization and high intensity focused
ultrasound, exist for patients who may not be eligible for surgery. The costs of photoselective vaporization are
9
comparable to surgery (TURP) but sustainable and economic benefit have not yet been demonstrated.
a.
1. Napalkov P, Maisonneuve P, Boyle P. Worldwide patterns of prevalence and mortality from benign prostatic
hyperplasia. Urology 1995;46(3 Suppl A):41-6.
2. Drummond MF, McGuire AJ, Black NA et al. Economic burden of treated benign prostatic hyperplasia in the
United Kingdom. Br J Urol 1993;71(3):290-6.
3. Manyak MJ, Ackerman SJ, Blute ML et al. Cost effectiveness of treatment for benign prostatic hyperplasia: an
economic model for comparison of medical, minimally invasive, and surgical therapy. J Endourol 2002;16
(1):51-6.
4. Cockrum PC, Finder SF, Ries AJ et al. A pharmacoeconomic analysis of patients with symptoms of benign
prostatic hyperplasia. Pharmacoeconomics 1997;11(6):550-65.
5. Lowe FC, McDaniel RL, Chmiel JJ et al. Economic modeling to assess the costs of treatment with finasteride,
terazosin and transurethral resection of the prostate for men with moderate to severe symptoms of benign
prostatic hyperplasia. Urology 1995;46(4):477-83.
6. Plosker GL, Goa KL. Terazosin. A pharmacoeconomic evaluation of its use in benign prostatic hyperplasia.
Pharmacoeconomics 1997;11(2):184-97.
7. Nickel JC, Herschorn S, Corcos J et al. Canadian guidelines for the management of benign prostatic
hyperplasia. Can J Urol 2005;12(3):2677-83.
8. Oshfeldt RL, Kreder KJ, Klein RW et al. Cost-effectiveness of tamsulosin, doxazosin, and terazosin in the
treatment of benign prostatic hyperplasia. J Manag Care Pharm 2004;10(5):412-22.
9. Ruszat R, Sulser T, Seifert HH et al. Photoselective vaporisation (PVP) vs. transurethral electroresection of the
prostate (TURP): a comparing cost analysis. Eur Urol Suppl 2006;5(2):271.
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e-Therapeutics+ : Therapeutics : Genitourinary Disorders: Urinary Incontinence in Adults Page 1 of 9
Therapeutic Choice
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Genitourinary Disorders: Urinary Incontinence in Adults

R. E. Grymonpre, PharmD
Stress incontinence is the loss of urine due to an increase in intra-abdominal pressure (e.g., cough, exercise) and is more common in
women. Urethral hypermobility and/or intrinsic sphincter deficiency (ISD) are commonly present and often have been caused by
weakness in pelvic musculature (e.g., due to childbirth, abdominal obesity) or postmenopausal urogenital atrophy. Urge incontinence,
often referred to synonymously as (or as a symptom of) overactive bladder, involves leakage of moderate to large amounts of urine due
to inability to delay voiding when an urge is perceived. Causes include bladder wall hyperactivity or instability and CNS disorders (e.g.,
parkinsonism, stroke). Overflow incontinence involves leakage of urine due to an overdistended bladder, commonly resulting from
outlet obstruction (e.g., prostatic hyperplasia) or neurogenic causes (e.g., diabetic neuropathy, multiple sclerosis). Functional
incontinence is the loss of urine caused by the inability to get to a toilet. Causes include physical constraints (e.g., restricted mobility,
difficulty removing clothing), cognitive factors (e.g., depression, dementia) and environmental barriers (distance to toilet, positioning).
Goals of Therapy
Relieve urinary symptoms

Increase functional capacity of the bladder
, 2 , 3
Investigations1
Screening questions:
Do you ever lose urine when you don’t want to?

Do you ever leak urine when you cough, laugh or exercise?
Do you ever leak urine on the way to the bathroom?
Do you ever use pads, tissue or cloth in your underwear to catch urine?
Do you ever feel that you are unable to completely empty your bladder?
If positive:

possible causes such as diabetes, depression, mobility or cognitive limitations, previous bladder surgeries or neurologic
conditions such as multiple sclerosis, stroke or spinal cord injury
modifiable risk factors (Table 1)
bladder diary to determine frequency, timing and amount of voiding and urine leakage
cough test (to detect stress incontinence)
urinalysis (to rule out infection, glucosuria, hematuria)
pelvic examination (to rule out pelvic masses, organ prolapse, latent stress incontinence)
Supplemental investigations:
renal function tests (BUN, serum creatinine, glucose and calcium) if renal dysfunction suspected or polyuria present
urodynamic testing to measure detrusor compliance and contractility, postvoid residual volume and bladder capacity
Table 1: Modifiable Risk Factors for Urinary Incontinence in Adults
Caffeine intake
Bowel problems (constipation, fecal impaction)
Fluid intake (1.5–2 L/day is considered appropriate)
Morbid obesity
Smoking
High-impact physical activities
Medications (diuretics, anticholinergics, alpha-agonists, alpha-antagonists, psychotropics, alcohol)
Restricted mobility (includes dexterity in clothing removal, accessibility to toilets)
Stress Incontinence
Therapeutic Choices
Therapeutic Choices (Figure 1 - Management of Urinary Incontinence in Adults, Table 3)
Page 475
Therapeutic Choice
When secondary causes have been ruled out or treated, initiate behavioural therapy:4
Bladder training (timed voiding): maintain a voiding schedule ( e.g., one-hour voiding interval) which is gradually (e.g., weekly)
increased to a reasonable interval (e.g., voiding every two to three hours) with minimal incontinence episodes
Pelvic floor muscle training (also known as Kegel exercises): a daily minimum of 30 to 45 pelvic floor muscle contractions (goal of
10 seconds for each contraction); done in two or three sets; may take six to eight weeks to see results
Biofeedback and/or electrical stimulation therapy: stimulation that teaches the patient to isolate and control pelvic floor muscles
Surgical options depend on the etiology. For urethral hypermobility in females, retropubic suspension is superior to anterior vaginal
repair.5 For ISD in females, sling procedures (including tension-free vaginal tape) or urethral bulking injections can be done. For males
postprostatectomy, urethral bulking injections or artificial sphincters are available.
Due to limited evidence of pharmacologic efficacy, surgery may be recommended first-line.2 , 6 The current literature on estrogen
therapy in the treatment of postmenopausal stress incontinence is inconclusive, although long-term oral therapy is not
7 , 8 , 9 , 10 , 11
recommended. A Cochrane review determined that three to six months of unopposed estrogen therapy resulted in a 43%
perceived cure/improvement of stress incontinence symptoms compared to a 27% placebo response, with reduced efficacy when
estrogen was opposed with progesterone.9 In contrast, a secondary analysis of the Women’s Health Initiative trial10 found an increased
risk of stress incontinence with opposed and unopposed estrogen. Vaginal estrogen for women with postmenopausal urogenital
atrophy may be a viable option as an adjunct to behavioural or pharmacologic treatment in stress incontinence.11
Useful Info? The decision to use estrogen therapy must be discussed with the patient in the context of her individual health needs and
risk factors (e.g., cancer, DVT, MI).
Few well-designed studies have evaluated the efficacy of imipramine, and evidence supporting its role in the management of stress
incontinence is not strong.8 , 12
The efficacy of pseudoephedrine in stress incontinence has been extrapolated from studies involving phenylpropanolamine, an agent
that has been withdrawn from the Canadian market due to concerns of cerebral hemorrhage. There is no direct evidence supporting the
use of pseudoephedrine in the management of stress incontinence.
Duloxetine, a serotonin-norepinephrine reuptake inhibitor awaiting approval from Health Canada for the treatment of stress
incontinence, influences the micturition reflex centrally.13
Urge Incontinence
Therapeutic Choices
When secondary causes have been ruled out or treated, initiate behavioural therapy:4
Bladder training (timed voiding): as described under stress incontinence

Pelvic floor muscle training: as described under stress incontinence.
Biofeedback training: as described under stress incontinence
Maintaining vigilance in the management of urge incontinence is critical to minimizing associated adverse sequelae, especially in older
adults. One study found an increased risk of falling and nonvertebral fractures in older women experiencing weekly or more frequent
urge incontinence episodes.14
Consider surgical options only after failure of noninvasive treatments, including pharmacotherapy.
Anticholinergics such as oxybutynin and tolterodine are recommended as first-line treatment as they have been shown to increase
bladder capacity and diminish frequency of uninhibited detrusor contractions.2 , 12 , 15 Both are now available as once-daily, controlled
-release tablets, and oxybutynin is available as a transdermal patch; these dosage forms may reduce side effects and improve
8 , 12 , 16 , 17 , 18 , 19
adherence. As a nonselective muscarinic antagonist, tolterodine may be a useful alternative in patients
experiencing dry mouth or constipation from oxybutynin, which has more M3 receptor selectivity compared to tolterodine, although the
newly available dosage forms of oxybutynin minimize this advantage.2 , 16 , 19 , 20 Darifenacin, solifenacin and trospium are
anticholinergics now available in Canada. Darifenacin and solifenacin are both M3 selective agents; trospium is a nonselective
quaternary ammonium compound. There is insufficient evidence to substantiate any advantage of these agents over previously available
therapies for urge incontinence.19 , 21 , 22 , 23
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Therapeutic Choice
A Cochrane review determined that anticholinergic therapy resulted in a 56% perceived cure/improvement of incontinence symptoms
compared to 41% placebo response. The treatment group reported four fewer leakage episodes and five fewer voids per week
25
compared to the placebo group. The clinical significance of these benefits has been questioned.
The current literature on estrogen therapy in the treatment of postmenopausal urge incontinence is inconclusive, although long-term
8 , 9 , 10 , 11
oral therapy is not recommended. A Cochrane review determined that three to six months of unopposed estrogen therapy
resulted in a 57% perceived cure/improvement of urge incontinence symptoms compared to a 28% placebo response, with reduced
9
efficacy when estrogen was opposed with progesterone. A reduction in leakage/micturition episodes was also reported (two fewer
9 10
episodes per 24 hours compared to placebo). In contrast, a secondary analysis of the Women’s Health Initiative trial found an
increased risk of urge incontinence with opposed and unopposed estrogen. Vaginal estrogen for women with postmenopausal
urogenital atrophy may be a viable option as an adjunct to behavioural or pharmacologic treatment.11 The decision to use estrogen
therapy must be discussed with the patient in the context of her individual health needs and risk factors (e.g., cancer, DVT, MI).
The direct smooth muscle relaxant flavoxate has limited efficacy.8 , 12 , 15 Tricyclic antidepressants (e.g., imipramine, doxepin,
desipramine, nortriptyline) should be reserved for patients with concurrent depression or those unresponsive to first-line
2 , 8 , 12 , 15 26
therapies. Doxepin has strong anticholinergic side effects and is not recommended in older adults.
Overflow Incontinence
Therapeutic Choices
Overflow incontinence due to acontractile bladder is poorly responsive to behavioural or surgical therapy.27
Surgery is the treatment of choice in many men with moderate to severe overflow incontinence due to benign prostatic hyperplasia
27
(see Genitourinary Disorders: Lower Urinary Tract Symptoms and Benign Prostatic Hyperplasia).
Table 2: Drugs that May Cause or Aggravate Urinary Retention28
Antiarrhythmics Antiparkinsonian Agents Sympathomimetics (alpha-agonists)

disopyramide amantadine ephedrine
procainamide benztropine phenylephrine
quinidine bromocriptine pseudoephedrine
Anticholinergics levodopa Sympathomimetics (beta-agonists)
flavoxate trihexyphenidyl isoproterenol
oxybutynin Antipsychotics orciprenaline
scopolamine chlorpromazine terbutaline
Antidepressants prochlorperazine Miscellaneous
amitriptyline thioridazine carbamazepine
doxepin Muscle Relaxants indomethacin
imipramine baclofen nifedipine
Antihistamines cyclobenzaprine
chlorpheniramine Sedative/Hypnotics
diphenhydramine diazepam
hydroxyzine flurazepam
Catheterization is associated with urinary tract infections (UTIs) and sepsis and should only be used for well-documented
indications. For individuals who are either waiting for surgery or are not surgical candidates, catheterization may be a temporary or
permanent option:
intermittent catheterization (use clean technique for all except immunocompromised patients; use sterile technique for elderly
and immunocompromised patients)
indwelling catheter: for terminally ill patients or patients with pressure ulcers requiring short-term treatment
Discontinue drugs reported to induce or aggravate urinary retention (Table 2) if at all possible.
8 , 27
Overflow incontinence due to acontractile bladder is poorly responsive to pharmacologic therapy. For management of BPH, see
Genitourinary Disorders: Lower Urinary Tract Symptoms and Benign Prostatic Hyperplasia.
Therapeutic Tips
Treat all secondary causes (e.g., UTI, lifestyle factors, medications or poor mobility) either before or concurrently with other
management strategies.
Page 477
Therapeutic Choice
Several weeks of therapy may be required to achieve maximum effect. If no subjective improvement occurs after four to six weeks,
increase the drug dose or switch/discontinue the drug.
Provide patient education regarding management alternatives (risks, benefits, realistic outcomes), determine patient expectations
and involve the patient in the decision-making process.
As initial therapy, recommend the strategy that is the least invasive, is reversible and has the fewest side effects.
For various reasons (physical or cognitive impairment, medications), many individuals will never achieve complete bladder control.
Scheduled toileting (at fixed times every two to four hours, based on individual toilet habits), habit training (toileting based on
individual voiding patterns) and prompted voiding (checking for dryness, regular reminders and praising) are toileting assistance
strategies that will help to keep chronically incontinent patients drier.
Protective products such as pads that absorb and contain leaked urine, or devices such as vaginal pessaries that support the
bladder neck and prevent leakage, may be useful at different stages of management. Stress the importance of using absorbent
products designed specifically for bladder problems, as they reduce odour and prevent skin breakdown. They should not be
considered first-line management but rather as a supportive adjunct to other treatment measures. A thorough assessment is the
mainstay of continence care.
Be attentive to medication nonadherence. The anticholinergic side effect of dry mouth is a common cause of patient-initiated
dosage reduction or drug discontinuation.
Figure 1-Management of Urinary Incontinence in Adults
a.
In most circumstances it is appropriate to initiate treatment without referral for urologic testing.
b. 3
In the management of stress incontinence, surgery may be recommended first-line due to limited efficacy of pharmacotherapy.
c.
In the management of urge incontinence, surgical options should only be considered after failure with noninvasive treatments, including
pharmacotherapy.
Abbreviations: PVR=postvoid residual; UA=urinalysis; DM=diabetes mellitus; TCA=tricyclic antidepressant; TVT=tension-free vaginal tape.
Adapted with permission from Culligan PJ. Urinary incontinence in women: evaluation and management. Am Fam Physician 2000;62(11):2433-
44,2447,2452.
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Therapeutic Choice
Table 3: Drug Therapy for Stress Incontinence
a
Cost
Estrogens, estradiol-17β, One 2 mg ring Breast tenderness, Systemic absorption Short-term studies $$$$
vaginal vaginal ring inserted nausea, headache, variable; no serious suggest low dose
Estring Q 3 mo (delivers bloating; possible interactions reported. micronized estradiol-
7.5 µg daily) increase in 17β has minimal effects
endometrial and on endometrial tissue;
breast CA, MI, for other vaginal
CVA, VTE; estrogen preparations,
although systemic continuous or
estrogen intermittent progestin is
absorption occurs, recommended;
the incidence of regardless of
adverse effects is formulation, routine
dose, drug and endometrial surveillance
duration is recommended.29
dependent.
Estrogens, estradiol-17β, 1 tablet pv daily Breast tenderness, Systemic absorption Short-term studies $$$
vaginal vaginal tablet × 2 wk then 1 nausea, headache, variable; no serious suggest low dose
25 µg tablet pv bloating; possible interactions reported. micronized estradiol-
Vagifem twice weekly increase in 17β has minimal effects
endometrial and on endometrial tissue;
breast CA, MI, for other vaginal
dependent.
Estrogens, conjugated 1.25–2.5 mg Breast tenderness, Systemic absorption Short-term studies $$-
vaginal estrogens, (2–4 g cream) pv nausea, headache, variable; no serious suggest low dose $$$
vaginal cream daily, 3 wk on / 1 bloating; possible interactions reported. micronized estradiol-
0.625 mg/g wk off increase in 17β has minimal effects
Premarin endometrial and on endometrial tissue;
Vaginal Cream breast CA, MI, for other vaginal
dependent.
Tricyclic imipramine 25–100 mg HS Orthostatic Potential additive $

Antidepressants Tofranil, hypotension, anticholinergic effects
generics dizziness, with other drugs; mania,
arrhythmias, excitation, hyperpyrexia
cognitive with MAOIs; enzyme
impairment. inducers (e.g.,
barbiturates,
carbamazepine,
dexamethasone,
phenytoin, rifampin) may
↓ TCA levels/efficacy;
enzyme inhibitors (e.g.,
amiodarone, cimetidine,
erythromycin, fluconazole,
itraconazole,
ketoconazole, quinidine,
ritonavir, SSRIs) may ↑
TCA levels/effects.
a.
Legend: $ < $5 $$ $5–20 $$-$$$ $5–50 $$$ $20–50 $$$$ $50–75
Page 479
Therapeutic Choice
Abbreviations: CA=carcinoma; MI=myocardial infarction; CVA=cerebrovascular accident; VTE=venous thromboembolism; TCA=tricyclic
antidepressant
Table 4: Drug Therapy for Urge Incontinence
Costa
Anticholinergics darifenacin, 7.5 mg daily; Primarily Potential additive Avoid in patients $$$
extended- after 2 weeks, anticholinergic anticholinergic effects with with severe hepatic
release may increase to effects (dry other drugs. insufficiency.
Enablex 15 mg daily if mouth, Do not exceed 7.5 mg daily
necessary constipation, with potent inhibitors of
cognitive CYP3A4 such as erythromycin,
dysfunction, itraconazole, ketoconazole,
tachycardia). nelfinavir, ritonavir.
Caution with other substrates

of CYP2D6 that have narrow
therapeutic indices (e.g., TCAs
as their clearance may be ↓.
Anticholinergics oxybutynin, 2.5–5 mg BID- Primarily Potential additive In older adults, $$-
immediate- QID anticholinergic anticholinergic effects with prescribe the lowest $$$
release effects (dry other drugs. recommended
Ditropan, mouth, starting dose; when
generics constipation, switching from
cognitive immediate-release
dysfunction, to extended-release
tachycardia). formulation, use
closest equivalent
dose.
Anticholinergics oxybutynin, 5–30 mg daily Primarily Potential additive In older adults, $$$$-
extended- anticholinergic anticholinergic effects with prescribe the lowest $$$$$
Ditropan XL, mouth, starting dose; when
Uromax constipation, switching from
cognitive immediate-release
dysfunction, to extended-release
tachycardia). formulation, use
closest equivalent
dose.
Extended-release
formulation must
not be divided,
chewed or crushed.
Anticholinergics oxybutynin, 1 patch applied Primarily Potential additive In older adults, $$$$
transdermal twice weekly anticholinergic anticholinergic effects with prescribe the lowest
patch (alternating effects (dry other drugs. recommended
Oxytrol sites); delivers mouth, starting dose.
3.9 mg per day constipation,
cognitive
dysfunction,
tachycardia).
Anticholinergics solifenacin 5 mg daily; may Primarily Potential additive Avoid in patients $$$$
VESIcare ↑ to 10 mg daily anticholinergic anticholinergic effects with with severe hepatic
if tolerated effects (dry other drugs. insufficiency.
mouth, Do not exceed 5 mg daily with
constipation, potent CYP3A4 inhibitors, e.g.,
cognitive erythromycin, itraconazole,
dysfunction, nelfinavir, ritonavir.
tachycardia).
Anticholinergics tolterodine, 1–2 mg BID Primarily Potential additive In older adults, $$$$
immediate- anticholinergic anticholinergic effects with prescribe the lowest
Detrol mouth, CYP3A4 metabolism becomes starting dose.
constipation, significant in CYP2D6 poor
cognitive metabolizers — maximum dose
dysfunction, of 2 mg per day in patients
tachycardia). taking potent inhibitors of
Page 480
Therapeutic Choice
Costa
CYP3A4 (e.g., erythromycin,
itraconazole, ketoconazole,
nelfinavir, ritonavir).
Anticholinergics tolterodine, 2–4 mg once Primarily Potential additive In older adults, $$$$
extended- daily anticholinergic anticholinergic effects with prescribe the lowest
Detrol LA mouth, CYP3A4 metabolism becomes starting dose.
constipation, significant in CYP2D6 poor
cognitive metabolizers — maximum dose
dysfunction, of 2 mg per day in patients
tachycardia). taking potent inhibitors of
CYP3A4 (e.g., erythromycin,
nelfinavir, ritonavir).
Coadministration of Detrol LA
with antacid results in ↑Cmax of
tolterodine and the potential
for 'dose-dumping.' It is not
known whether a similar
interaction exists with
concurrent use of acid-
suppressing agents.30
Anticholinergics trospium 20 mg BID on an Primarily Potential additive $$$$

Trosec empty stomach anticholinergic anticholinergic effects with
or 1 h before effects (dry other drugs.
meals mouth,
In older patients constipation,
an initial dose of cognitive
20 mg HS is dysfunction,
recommended. tachycardia).
Smooth Muscle flavoxate 200–400 mg TID GI: nausea, Potential additive Limited efficacy. $$$$-
Relaxants Urispas, Apo -QID vomiting. anticholinergic effects with $$$$$
-Flavoxate, CNS: nervousness, other drugs.
other vertigo, headache,
generics drowsiness.
Ocular: blurred
vision, increased
ocular tension.
Anticholinergic:
dry mouth,
tachycardia.
TCAs imipramine 10–100 mg HS CV: orthostatic Potential additive In older adults, $

Tofranil, hypotension, anticholinergic effects with desipramine and
generics tachycardia, other drugs; mania, excitation, nortriptyline have a
quinidine-like hyperpyrexia with MAOIs; lower incidence of
cardiotoxicity. enzyme inducers (e.g., adverse effects than
CNS: dizziness, barbiturates, carbamazepine, other TCAs and are
cognitive dexamethasone, phenytoin, preferable; however,
impairment. rifampin) may ↓ TCA they may also be
Anticholinergic: levels/efficacy; enzyme inhibitors less effective than
see oxybutynin, (e.g., amiodarone, cimetidine, imipramine.
immediate- erythromycin, fluconazole,
release. itraconazole, ketoconazole,
quinidine, ritonavir, SSRIs)
may ↑ TCA levels/effects.
TCAs doxepin 10–100 mg HS CV: orthostatic Potential additive In older adults, $-$$
Sinequan, hypotension, anticholinergic effects with desipramine and
Apo- tachycardia, other drugs; mania, excitation, nortriptyline have a
hyperpyrexia with MAOIs; lower incidence of
Page 481
Therapeutic Choice
a
Cost
Doxepin, quinidine-like enzyme inducers (e.g., adverse effects than
other cardiotoxicity. barbiturates, carbamazepine, other TCAs and are
generics CNS: dizziness, dexamethasone, phenytoin, preferable; however,
cognitive rifampin) may ↓ TCA they may also be
impairment. levels/efficacy; enzyme inhibitors less effective than
Anticholinergic: (e.g., amiodarone, cimetidine, imipramine.
see oxybutynin, erythromycin, fluconazole,
immediate- itraconazole, ketoconazole,
release. quinidine, ritonavir, SSRIs)
TCAs desipramine 10–100 mg HS CV: orthostatic Potential additive In older adults, $$-
generics hypotension, anticholinergic effects with desipramine and $$$
tachycardia, other drugs; mania, excitation, nortriptyline have a
TCAs nortriptyline 10–100 mg HS CV: orthostatic Potential additive In older adults, $$-
Aventyl, hypotension, anticholinergic effects with desipramine and $$$
generics tachycardia, other drugs; mania, excitation, nortriptyline have a
a.
Legend: $ < $5 $-$$ < $5–20 $$ $5–20 $$-$$$ $5–50 $$$ $20–50 $$$$ $50–75 $$$$-$$$$$ $50– > $75 $$$$$ >
$75
Abbreviations: TCA=tricyclic antidepressant
Suggested Readings
Corcos J, Gajewski J, Heritz D et al. Canadian Urological Association guidelines on urinary incontinence. Can J Urol 2006;13(3):3127-
38.
Geneva Foundation for Medical Education and Research. For access to up-to-date guidelines and reviews on urinary incontinence:
Urogynecology, urinary and fecal incontinence. Available from:
http://www.gfmer.ch/Guidelines/Urogynecology_urinary_and_fecal_incontinence/Urogynecology_urinary_and_fecal_incontinence.htm.
Accessed December 9, 2008.
Khan IJ, Tariq SH. Urinary incontinence: behavioral modification therapy in older adult. Clin Geriatr Med 2004;20(3):499-509.
Schuessler B, Baessler K. Pharmacologic treatment of stress urinary incontinence: expectations for outcome. Urology 2003;62(4 Suppl
1):31-8.
Scottish Intercollegiate Guidelines Network. Management of urinary incontinence in primary care: a national clinical guideline.
Edinburgh, Scotland: SIGN; 2004.
References
Page 482
Therapeutic Choice
1. Association of Women’s Health, Obstetric and Neonatal Nurses. Evidence-based clinical practice guideline: continence for women.
Washington (DC): AWHONN; 2000.
2. The Canadian Continence Foundation. Canadian Consensus Conference on Urinary Incontinence: clinical practice guidelines for
adults; 2001. Available from: http://www.continence-fdn.ca/health-profs/clinicalpractice.html. Accessed December 9, 2008.
3. Farrell SA, Epp A, Flood C et al. The evaluation of stress incontinence prior to primary surgery. J Obstet Gynaecol Can 2003;25
(4):313-24.
4. Khan IJ, Tariq SH. Urinary incontinence: behavioral modification therapy in older adult. Clin Geriatr Med 2004;20(3):499-509.
5. Hendrix SL. Urinary incontinence and menopause: an evidence-based treatment approach. Dis Mon 2002;48(10):622-36.
6. Alhasso A, Glazener CMA, Pickard R, N'Dow J. Adrenergic drugs for urinary incontinence in adults. Cochrane Database Syst
Rev2005;(3):CD001842.
7. Al-Badr A, Ross S, Soroka D et al. What is the available evidence for hormone replacement therapy in women with stress urinary
incontinence? J Obstet Gynaecol Can 2003;25(7):567-74.
8. Andersson K-E. Pharmacological treatment of urinary incontinence. Plymouth (UK): Health Publication Ltd; 2002.
9. Moehrer B, Hextall A, Jackson S. Oestrogens for urinary incontinence in women. Cochrane Database Syst Rev 2003;
(2):CD001405.
10. Hendrix SL, Cochrane BB, Nygaard IE et al. Effects of estrogen with and without progestin on urinary incontinence. JAMA
2005;293(8):935-48.
11. DuBeau CE. Estrogen treatment for urinary incontinence: never, now, or in the future? JAMA 2005;293(8):998-1001.
12. Scottish Intercollegiate Guidelines Network. Management of urinary incontinence in primary care: a national clinical guideline.
Edinburgh, Scotland: SIGN; 2004.
13. McCormack PL, Keating GM. Duloxetine: in stress urinary incontinence. Drugs 2004;64(22):2567-73.
14. Brown JS, Vittinghoff E, Wyman JF et al. Urinary incontinence: does it increase risk for falls and fractures? Study of Osteoporotic
Fractures Research Group. J Am Geriatr Soc 2000;48(7):721-5.
15. Haeusler G, Leitich H, van Trotsenburg M et al. Drug therapy of urinary urge incontinence: a systematic review. Obstet Gynecol
2002;100(5 Pt 1):1003-16.
16. Weiss BD. Selecting medications for the treatment of urinary incontinence. Am Fam Physician 2005;71(2):315-22.
17. Thomas DR. Pharmacologic management of urinary incontinence. Clin Geriatr Med 2004;20(3):511-23.
18. Dull P. Transdermal oxybutynin (oxytrol) for urinary incontinence. Am Fam Physician 2004;70(12):2351-2.
19. Hay-Smith J, Herbison P, Ellis G et al. Which anticholinergic drug for overactive bladder symptoms in adults. Cochrane Database
Syst Rev 2005(3):CD005429.
20. Hegde SS. Muscarinic receptors in the bladder: from basic research to therapeutics. Br J Pharmacol 2006;147(Suppl 2):S80-7.
21. Guay DR. Darifenacin: another antimuscarinic for overactive bladder. Consult Pharm 2005;20(5):424-31.
22. Chapple CR, Abrams P. Comparison of darifenacin and oxybutinin in patients with overactive bladder: assessment of ambulatory
urodynamics and impact on salivary flow. Eur Urol 2005;48(1):102-9.
23. Erdem N, Chu FM. Management of overactive bladder and urge urinary incontinence in the elderly patient. Am J Med 2006;119(3
Suppl 1):29-36.
24. Corcos J, Gajewski J, Heritz D et al. Canadian Urological Association guidelines on urinary incontinence. Can J Urol. 2006;13
(3):3127-38.
25. Nabi G, Cody JD, Ellis G et al. Anticholinergic drugs versus placebo for overactive bladder syndrome in adults.Cochrane Database
Syst Rev 2006;(4):CD003781.
26. Fick DM, Cooper JW, Wade WE et al. Updating the Beers criteria for potentially inappropriate medication use in older adults:
results of a US consensus panel of experts. Arch Intern Med 2003;163(22):2716-24.
27. Johnson TM, Ouslander JG. Urinary incontinence in the older man. Med Clin North Am 1999;83(5):1247-66.
28. Curtis LA, Dolan TS, Cespedes RD. Acute urinary retention and urinary incontinence. Emerg Med Clin North Am 2001;19(3):591-
619.
29. Willhite LA, Dolan TS, Cespedes RD. Urogenital atrophy: prevention and treatment. Pharmacotherapy 2001;21(4):464-80.
30. Sathyan G, Dmochowski RR, Appell RA et al. Effect of antacid on the pharmacokinetics of extended-release formulations of
tolterodine and oxybutynin. Clin Pharmacokinet 2004;43(14):1059-68.
Page 483
e-Therapeutics+ : Therapeutics : Genitourinary Disorders: Urinary Incontinence in Children Page 1 of 5
Therapeutic Choice
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Genitourinary Disorders: Urinary Incontinence in Children
Fabian P. Gorodzinsky, MD, AAPd, FRCP
Urinary incontinence in children is defined as the repeated daytime or nighttime voiding of urine into the bed or
1
clothes at least twice per week for at least 3 consecutive months in a child who is at least 5 years of age. Most
children are successfully toilet trained by around the age of 3, with a very wide range of 0.75–5.25 years. Girls are
usually trained earlier than boys.2
Enuresis is bedwetting, or wetting during sleep (e.g., nap time), more than twice weekly beyond the age of 5 for
girls and 6 for boys. In primary enuresis, bladder control has never been achieved and in secondary enuresis, loss
of bladder control occurs after at least 6 months without bedwetting.3 Primary enuresis, which is more common in
boys, occurs in 10–15% of 5-year-olds and 6–8% of 8-year-olds and declines to <2% by age 15. There are 2
subtypes of primary enuresis: volume-dependent enuresis (associated with nocturnal polyuria; a normal nocturnal
rise in antidiuretic hormone secretion may not occur in these children) and detrusor-dependent enuresis (associated
with daytime frequency, urgency or incontinence).4 Possible causes of enuresis include developmental delay
(immaturity of CNS control over bladder contractions and/or responsiveness to bladder filling), genetics (molecular
5 , 6
linkage to chromosome 8q, 12q, 13q) and obstructive sleep apnea (very rare). Lack of sufficient antidiuretic
hormone (ADH, arginine-vasopressin or AVP) release, bladder overactivity and inability to wake can also cause
3
enuresis.
Daytime incontinence occurs in about 10% of children 4–6 years old, declining to 4% in adolescents. Girls are
affected twice as often as boys. It is considered a problem in a child 4 years or older who wets daily (primary) or
who relapses after 6 consecutive months without daytime wetting (secondary). Possible functional or organic causes
of daytime incontinence are listed in Table 1.
There is no evidence that urinary incontinence is associated with any specific behavioural or psychological
problems, yet most affected children are clearly distressed by their condition. The parents’ supportive role in
treatment is crucial; an intolerant attitude on the part of the parents predicts early drop-out from treatment.7
Table 1: Possible Causes of Daytime Incontinence
Functional Constipation
Deferral of voiding (“holding it in until the last minute”)
Fusion of labia minora
Urinary tract infection
Urge syndrome (unstable bladder; sudden attacks of uncontrollable urge to void; characteristic
squatting to avoid detrusor contractions)
Stress incontinence
Giggle incontinence
Emotional stress
Daytime frequency syndrome
Organic Neurogenic bladder

Partial urethral obstruction, e.g., posterior urethral valve, congenital strictures
Ectopic ureter
Goals of Therapy
Identify and/or manage serious causes

Minimize symptoms
Provide reassurance and guidance
Investigations
History with attention to:

family history (often present in enuresis)
Page 484
Therapeutic Choice
bowel function; constipation is frequently associated with urinary incontinence that is due to decreased
bladder capacity
pattern of wetting
history of urinary tract infections (UTI) or urologic surgery
psychological status of child and family dynamics
perineal sensation, perineal reflexes, sphincter tone (to rule out neurogenic bladder)
genitalia, particularly the urethral meatus (to rule out anatomical causes such as meatal stenosis in boys or
labial fusion in girls)
possible occult spinal dysraphism such as tethered cord (congenital spinal cord abnormality that can cause
progressive neurologic damage); signs include the presence of a hair tuft, dimple, pigmented lesion or
subcutaneous lipoma over the lower spine, or asymmetry of the gluteal cleft (refer to pediatric
neurosurgeon)
direct observation of voiding, if possible, to rule out abnormalities of urinary stream
Other investigations as indicated:
diary to record voiding pattern and/or bowel movements
urinalysis and urine culture; no other investigations are necessary for primary enuresis
voiding cystourethrogram (to detect vesicoureteral reflux, partial urethral obstruction, or neurogenic
bladder) as well as ultrasound of kidneys and bladder are recommended if history of UTI
3
if voiding cystourethrogram is abnormal, a referral to a urologist is likely indicated
Therapeutic Choices
Figure 1 - Management of Urinary Incontinence in Children depicts the management of urinary incontinence in
children. Tailor therapy to the etiologic factors. Combinations of different interventions may be useful.
In cases of daytime incontinence, advise parents to refrain from humiliating or punishing the child, and to
support the child’s efforts with positive reinforcement, e.g., reassurance, diary of dry days, facilitated access to
bathroom at home and school.
Have the child avoid excessive intake of fluids within 2 hours of bedtime and empty the bladder before going to
bed.
Encourage the child to avoid deferral of micturition.
Enuresis alarms are effective for enuresis when used properly for 3–4 months.8 Enuresis alarms, which are
highly sensitive to moisture, attach to underpants or an absorbent pad and either vibrate or produce sound at
the first sign of voiding. Because children with enuresis are usually very deep sleepers, the parent must often
be the one to wake the child when the alarm sounds. The child then completes voiding in the toilet and then
returns to sleep after changing the underwear or bedding. Alarm therapy may be effective in children with a
9
normal urine output but with small bladder capacity. Enuresis alarms work best in children 7 years or older,
require consistent parental involvement and support, and are available at medical supply stores. Relapse rates
were lower when dry bed training, reward systems or overlearning (child drinks 4–6 ounces of water in the hour
before going to bed while continuing to use the alarm) were added to alarm treatment.8
Encourage bladder training exercises for daytime incontinence, e.g., scheduled voiding routine, abdominal or
pelvic floor muscle exercises.
Table 2 lists medications used in the management of urinary incontinence in children.
Antidiuretic Hormone Analogues
Desmopressin (DDAVP), an analogue of human ADH, decreases urine production when given at bedtime and
reduces the number of wet nights in 75% of children, with complete cessation in about 50% of those who
10
respond. Desmopressin is used when a rapid response is required. There is limited evidence of long-term success
with desmopressin use.8 If successful, consider a 1-week interruption every 3 months to see if treatment is no
11
longer needed. Desmopressin may be most effective in children with a normal bladder capacity but with a large
11
urine output. Patients producing large amounts of dilute and poorly concentrated urine usually respond well to
12
desmopressin therapy. If cost is a concern, reserve desmopressin for special occasions such as overnight visits or
camp. The risk of overhydration and hyponatremia associated with desmopressin necessitates limiting excess fluid
intake to <500 mL for children >12 years and <250 mL for children <12 years within 1 hour of going to bed.
Page 485
Therapeutic Choice
Desmopressin nasal spray is no longer indicated for the management of primary enuresis because compared to oral
formulations, it is associated with a higher incidence of hyponatremia which may result in seizures and death.
Smooth Muscle Relaxants
Oxybutynin, a smooth muscle relaxant, is useful for reducing bladder contractions in children with detrusor
overactivity (e.g., urge syndrome or neurogenic bladder); efficacy was 67% in a select group of children with
10
detrusor overactivity. A combination of desmopressin and oxybutynin can be tried in children with both
detrusor overactivity and increased urine production. A combination of desmopressin and long-acting
tolterodine (an anticholinergic agent with the same mechanism of action as oxybutynin) at a dose of 4 mg once
15
daily has also been shown to be effective in cases when desmopressin monotherapy failed.
13
Reserve desmopressin plus anticholinergic combination therapy for refractory cases. A lower dose of oral
14
desmopressin (200 µg) is required when used in combination.
Other therapies
Imipramine has been used in the past but is not recommended because it is not more effective than desmopressin
and has a narrow therapeutic window.
There is no evidence of effectiveness for complementary therapies such as hypnosis, acupuncture, chiropractic,
16
faradization (electric shock to the genital area), homeopathy or diet or restricted foods.
Therapeutic Tips
Predictors of positive treatment outcome include a motivated child, supportive family and age over 10 years.
Predictors of treatment failure include developmental delay, low self-esteem, a history of behaviour problems or
multiple wetting at night, frequent daytime voiding, parental intolerance or annoyance, unstable family
17
dynamics and poor maternal education.
The cause of most cases of daytime incontinence is uncovered by noninvasive investigations (history, physical
exam, urinalysis, urine culture and ultrasound of kidney and bladder).
Relative to desmopressin, alarms are superior in that once the child achieves dryness there is less
8
chance of relapse. Useful Info? The effects of desmopressin are immediate whereas enuresis alarms take
longer to reduce bedwetting.
Figure 1- Management of Urinary Incontinence in Children
Abbreviation: UTI = urinary tract infection.
Page 486
Therapeutic Choice
Table 2: Drug Therapy for Urinary Incontinence in Children ≥5 Years of Age
Costa
Antidiuretic desmopressin Dose is individualized. Headache For enuresis. $$$–

Hormone DDAVP Melt, Tablets: 200–600 µg (transient), Used in conjunction with $$$$
Analogues DDAVP HS po (Start with abdominal pain, nonpharmacologic
200 µg 1 hour before water intoxication, treatment.
Tablets,
HS. If no response ↑ by hyponatremia-
Minirin, 200 µg increments related seizures Desmopressin should not
generics every 3 days). (rare). be used in children with
kidney disease, heart
Fast-melting failure, diabetes, ileitis or
formulation: cystic fibrosis.
120–240 µg HS sl
(Start with 120 µg 1 The fast-melting
hour before HS. If no formulation of DDAVP is
response ↑ by 120 µg 18
effective for 7–11 h.
increments every
3 days). Withhold DDAVP in the
May continue treatment case of an acute illness
for 6 mo. leading to decreased fluid
intake.
Combination therapy of
DDAVP and smooth muscle
relaxants can be used in
cases refractory to DDAVP
monotherapy.
Smooth oxybutynin Dose is individualized. Dry mouth, Available as syrup. $

Muscle generics >5 y: 5 mg tid po constipation, Combination therapy of
Relaxants flushing and DDAVP and smooth muscle
occasional mood relaxants can be used in
10 cases refractory to DDAVP
changes.
monotherapy.
tolterodine Children 6–17 y: 4 mg Dry mouth, DDAVP plus long-acting $$

long acting HS po constipation, tolterodine combination is
Detrol LA flushing and used in cases refractory to
occasional mood DDAVP monotherapy.
10
changes.
a.
Legend: $ <$30 $$ $30–60 $$$ $60–90 $$$–$$$$ $60– >90 $$$$ >$90
Suggested Readings
Bernard-Bonnin AC. Diurnal enuresis in childhood. Can Fam Physician 2000;46:1109-15.
Hjalmas K, Arnold T, Bower W et al. Nocturnal enuresis: an international evidence based management strategy. J
Urol 2004;171 (6 Pt 2):2545-61.
Management of primary nocturnal enuresis. Paediatr Child Health 2005;10(10):611-4.
Robson WL. Clinical practice. Evaluation and management of enuresis. N Engl J Med 2009;360(14):1429-36.
Page 487
Therapeutic Choice
Russell K, Kiddoo D. The Cochrane Library and nocturnal enuresis; an umbrella review. Evidence-Based Child
Health: a Cochrane Review Journal 2006;1(1):5-8.
References
1. Fritz G, Rockney R, Bernet W et al. Practice parameter for the assessment and treatment of children and
adolescents with enuresis. J Am Acad Child Adolesc Psychiatry 2004;43(12):1540-50.
2. Schulpen TW. The burden of nocturnal enuresis. Acta Paediatr 1997;86(9):981-4.
3. Bloom DA, Butler RJ, Djurhuus JC et al. Conservative management in children. In: Incontinence. First
International Consultation on Incontinence; 1998 June 28-July 1. Monaco: World Health Organization,
International Union Against Cancer (UICC); 1999.
4. Management of primary nocturnal enuresis. Paediatr Child Health 2005;10(10):611-4.
5. Alexopoulos EI, Kaditis AG, Kostadima E, Gourgoulianis K. Resolution of nocturnal enuresis in snoring
children after treatment with nasal budesonide. Urology 2005;66(1):194.
6. Basha S, Bialowas C, Ende K et al. Effectiveness of adenotonsillectomy in the resolution of nocturnal enuresis
secondary to obstructive sleep apnea. Laryngoscope 2005;115(6):1101-3.
7. Butler RJ, Redfern EJ, Forsythe I. The Maternal Tolerance Scale and nocturnal enuresis. Behav Res Ther
1993;31(4):433-6.
8. Glazener CM, Evans JH, Peto RE. Alarm interventions for nocturnal enuresis in children. Cochrane Database
Syst Rev 2005;(2):CD002911.
9. Hjalmas K, Arnold T, Bower W et al. Nocturnal enuresis: an international evidence based management
strategy. J Urol 2004;171(6 Pt 2):2545-61.
10. Butler R, Stenberg A. Treatment of childhood nocturnal enuresis: an examination of clinically relevant
principles. BJU Int 2001;88(6):563-71.
11. Hjalmas K, Hanson E, Hellstrom AL et al. Long-term treatment with desmopressin in children with primary
monosymptomatic nocturnal enuresis: an open multicentre study. Swedish Enuresis Trial (SWEET) Group. Br J
Urol 1998;82(5):704-9.
12. Neveus T. Osmoregulation and desmopressin pharmacokinetics in enuretic children. Scand J Urol Nephrol
Suppl 1999;202:52.
13. Vermandel A, de Wachter S, Wyndaele JJ. Refractory monosymptomatic nocturnal enuresis: a combined
stepwise approach in childhood and follow-up into adolescence, with attention to the clinical value of
normalizing bladder capacity. BJU Int 2005;96(4):629-33.
14. Lee T, Suh HJ, Lee HJ et al. Comparison of effects of treatment of primary nocturnal enuresis with oxybutynin
plus desmopressin, desmopressin alone or imipramine alone: a randomized controlled clinical trial. J Urol
2005;174(3):1084-7.
15. Austin PF, Ferguson G, Yan Y et al. Combination therapy with desmopressin and an anticholinergic medication
for nonresponders to desmopressin for monosymptomatic nocturnal enuresis: a randomized, double-blind,
placebo-controlled trial. Pediatrics 2008;122(5):1027-32.
16. Glazener CM, Evans JH, Cheuk DK. Complementary and miscellaneous interventions for nocturnal enuresis in
children. Cochrane Database Syst Rev 2005;(2):CD005230.
17. Moffatt ME, Cheang M. Predicting treatment outcome with conditioning alarms. Scand J Urol Nephrol Suppl
1995;173:119-22.
18. Vande Walle JG, Bogaert GA, Mattsson S et al. A new fast-melting oral formulation of desmopressin: a
pharmacodynamic study in children with primary nocturnal enuresis. BJU Int 2006;97(3):603-9.
Page 488
e-Therapeutics+ : Therapeutics : Infectious Diseases: Acute Bronchitis Page 1 of 6
Therapeutic Choice
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Infectious Diseases: Acute Bronchitis

Date Revised: May 2010
Cindy Marshall, MD, CCFP, FCFP
Wayne Putnam, MD, FCFP
Cough is one of the most common presenting symptoms in family practice. When present for less than three weeks, with or
without sputum production, it is consistent with the diagnosis of acute bronchitis.1 Acute bronchitis should be differentiated
from the common cold, acute exacerbation of chronic bronchitis, asthma and community-acquired pneumonia.2 A
3
nonbacterial cause is present in more than 90% of uncomplicated acute bronchitis (Table 1). Acute bronchitis is not a life-
1
threatening illness. It is generally self-limited and symptoms usually resolve in 10 to 14 days.
This chapter focuses on the treatment of acute bronchitis in the otherwise healthy immunocompetent adult.
2 , 4 , 5 , 6
Table 1: Etiologic Agents in Acute Bronchitis
Etiology of Frequency of
Bronchitis Causation Comments
Viral > 90 % Most common viral isolates in acute bronchitis based on age (in order of
prevalence):
< 1 y—RSV, parainfluenza, coronavirus
1–10 y—parainfluenza, enterovirus, RSV
> 10 y—influenza, RSV, parainfluenza (less commonly adenovirus, coronavirus,
rhinovirus)
Noninfectious Not well studied Includes chemical and fume inhalational exposures
Bacterial 5–10% The only isolates shown to cause acute bacterial bronchitis are Chlamydophila
pneumoniae, Mycoplasma pneumoniae, Bordetella pertussis, and Bordetella
parapertussis.
There is no evidence that Streptococcus pneumoniae, Haemophilus influenzae or
Moraxella catarrhalis cause acute bronchitis in adults in the absence of underlying
lung disease.
Abbreviations: RSV = respiratory syncytial virus.
Goals of Therapy
“First do no harm”
Rule out serious illness, e.g., pneumonia
Minimize symptoms
Limit the unnecessary use of antibiotics
Investigations (Figure 1 - Management of Acute Bronchitis)
History:
Symptoms:
primarily cough, may or may not be productive. Prolonged cough (> 3 weeks) can occur in up to 50% of cases due
5
to viral infections.
in children, the infection of the tracheobronchial tree may result in prolonged cough; consider diagnosis of reactive
airways, not acute bronchitis (see Respiratory Disorders: Asthma in Infants and Children ). Consider a diagnosis of
pertussis, especially in children, when the history of spasmodic cough is elicited or a known outbreak exists in the
area.3
other symptoms may include wheezing, tachypnea, respiratory distress and hypoxemia.
green sputum production is a function of peroxidase release from leukocytes, hence it implies only inflammation,
not necessarily infection.5 , 6
1 , 2 , 5
consider alternative diagnoses if symptoms persist longer than three weeks.
Page 489
Therapeutic Choice
Obtain vaccination history, travel history, use of cigarettes.

Physical exam is key to diagnosis:
absence of tachycardia (heart rate > 100 beats/min), tachypnea ( > 24 breaths/min), fever (oral temperature of >
38°C) and localized chest findings suggest acute bronchitis.7
Objective measurements:
no role for routine chest x-ray, viral culture, serologic assay, sputum culture or Gram stain or pulmonary function
testing/spirometry.2 , 5 , 6 , 7
Therapeutic Choices (Figure 1 - Management of Acute Bronchitis)
The nonpharmacologic approach is the mainstay of management.
Limit risk of inoculation and transmission by employing strict hand-washing techniques.5

Increased fluids and humidity may help reduce cough.5
Analgesics
Antipyretics or analgesics, such as acetaminophen or ibuprofen, may be used for symptomatic relief.1 , 6
Antitussives
Antitussives (codeine, dextromethorphan, hydrocodone) may provide short-term symptom relief but do not shorten the
1 , 7
duration of illness.
Bronchodilators
Studies in the pediatric population do not support the use of beta2-agonists (salbutamol, terbutaline) in the absence of
airflow obstruction.4 , 8 , 9 In adults, beta2-agonists may decrease symptoms, such as cough; however, the potential
benefit, which is not supported by evidence, must be weighed against potential adverse effects.8 Adults experiencing cough
with wheezing may benefit from treatment.7
Antibiotics
1 , 2 , 3 , 4 , 5 , 7
Routine antibiotic treatment in uncomplicated acute bronchitis is not recommended. Antibiotic treatment
does not have a consistent impact on the duration or severity of illness or in prevention of potential complications (e.g.,
pneumonia, otitis media) either in adult1 , 5 or pediatric populations.10
11
A Cochrane systematic review assessed nine trials involving more than 750 patients from the age of 8 to over 65 years.
Overall, patients taking antibiotics showed a modest benefit compared to placebo. The evidence suggests antibiotics may
reduce the duration of cough by half a day.11 The magnitude of this benefit, however, is offset by the potential for adverse
1 , 11
reactions to antibiotics and an increase in antibiotic resistance for treatment of a self-limited illness. Current evidence
reveals no statistical difference in the amount of sputum production, purulence of sputum, limitation of work activities or
reduction in the incidence of lower respiratory tract infections in the six months following antibiotic treatment.11
Therapeutic Tips
Treatment is only supportive in the vast majority of cases of acute bronchitis.

Patient satisfaction does not depend on receiving an antibiotic; it is related to the quality of the physician-patient
communication.1 , 3 , 6 , 12
Educate patients regarding the lack of evidence for the use of antibiotics in most circumstances. It is helpful to review
the concerns of increased antibiotic resistance, possible side effects of antibiotic use and the cost of unnecessary
treatment.13 Providing a related patient information handout may also reduce antibiotic use.
There is no evidence to support the use of inhaled/oral corticosteroids in the management of acute
3
bronchitis. Useful Info?
Page 490
Therapeutic Choice
In a documented influenza outbreak, consider neuraminidase inhibitors, which are active against both influenza A and
B. Initiate within 48 hours of onset of symptoms (see Infectious Diseases: Influenza).
Set the patient's expectations of a 10- to 14-day duration of cough.3 Most patients feel much better within the first
week.10
Mucolytic and expectorant preparations have failed to show any significant benefit in the management of acute
2
bronchitis.
If the patient has unresolved symptoms in 2–3 weeks from onset of symptoms, consider follow-up.
Annual influenza vaccine is recommended.
Figure 1-Management of Acute Bronchitis
Table 2: Drugs for the Symptomatic Management of Acute Bronchitis in Adults
Adverse Drug
a
Analgesics acetaminophen Well tolerated Use with caution $ b

Atasol, Tempra, 325–650 mg (rare GI upset, in patients with
Q4–6H PRN (do less than hepatic
Tylenol, generics
not exceed salicylates). impairment.
4000 mg/24 h) Severe hepatic
damage can
occur with
overdose.
Preferred agent
in children due
to experience
with this agent.
Analgesics ibuprofen Primarily GI ASA/anticoagulants Contraindicated $b

Advil, Motrin 300–400 mg TID (nausea, may increase risk in patients with
-QID PRN (do not of bleeding. active peptic
(Children's),
exceed ulcer disease or
Page 491
Therapeutic Choice
Adverse Drug
Motrin IB, 2400 mg/day) epigastric pain, inflammatory
generics heartburn). bowel disease.
Contraindicated
in patients who
have a history of
or are at risk of
ASA/NSAID
intolerance
(asthma,
anaphylaxis,
urticaria,
angioedema,
rhinitis).
Antitussives codeine Immediate- Sedation, Additive sedation Use with caution $ b

(many products release: nausea/vomiting, with other CNS in elderly or
contain additional Adults and constipation. depressants; use debilitated
ingredients): children > 12 y: with caution. patients.
10–20 mg Q4–6H
Benylin 2 Cold PRN; max 120
mg
and Flu with
Codeine,
CoActifed,
Dimetapp-C,
Dimetane
Expectorant-C,
Robitussin AC,
generics
Antitussives dextromethorphan 30 mg Q6–8H Rare but can Caution with CNS Not $b
Benylin DM, PRN cause nausea, depressants (can recommended in
Robitussin drowsiness, potentiate effects). patients with
dizziness. Do not use with asthma.
Preparations,
monoamine
generics
oxidase inhibitor
(MAOI) or for 2 wk
after stopping
MAOI.
Antitussives hydrocodone 5 mg Q4–6H; Lightheadedness, Additive sedation Caution in the $

Hycodan, may ↑ to dizziness, with other CNS elderly and
generics 10 mg/dose sedation, nausea depressants; use debilitated.
and vomiting, with caution.
constipation.
Inhaled salbutamol Diskus (200 Tremor, Caution with other Contraindicated Diskus:$$$
Beta2- Airomir, Ventolin µg/puff): 1 puff restlessness, sympathomimetic in patients with MDI:$$
adrenergic Diskus, Ventolin TID-QID; max palpitations, agents. arrhythmias or
Agonists, 800 µg/day dizziness, hypertrophic
HFA, generics
short- MDI: 1–2 puffs headache, obstructive
acting (100 to 200 µg) nausea. cardiomyopathy.
QID PRN; max Caution with
800 µg/day ischemic heart
disease,
vascular disease
and
hypertension.
Inhaled terbutaline 1–2 puffs TID- Tremor, Caution with other Contraindicated $$$
Beta2- Bricanyl QID PRN; restlessness, sympathomimetic in patients with
adrenergic Turbuhaler max 6 puffs/day palpitations, agents. arrhythmias or
Agonists, dizziness, hypertrophic
Page 492
Therapeutic Choice
Adverse Drug
short- headache, obstructive
acting nausea. cardiomyopathy.
Caution with
ischemic heart
disease,
vascular disease
and
hypertension.
a.
Costs are per day for oral medications and per unit for inhaled medications; includes drug cost only.
b.
Available without prescription; retail mark-up may vary.
Legend: $ < $5 $$ $5–10 $$$ $10–15
Suggested Readings
Alberta Clinical Practice Guidelines Working Group. Guideline for the management of acute bronchitis, 2008 update.
Edmonton (AB): Toward Optimized Practice (TOP) Program, Alberta Medical Association; 2008. Available from:
www.topalbertadoctors.org/informed_practice/clinical_practice_guidelines/complete%
20set/Bronchitis/acute_bronchitis_guideline.pdf. Accessed May 27, 2010.
Irwin RS, Baumann MH, Bolser DC et al. Diagnosis and management of cough: ACCP evidence-based clinical practice
guidelines. Chest 2006;129(1 Suppl):1S-292S.
Wenzel RP, Fowler AA. Clinical practice: acute bronchitis. N Engl J Med 2006;355(20):2125-30.
References
1. Snow V, Mottur-Pilson C, Gonzales R et al. Principles of appropriate antibiotic use for treatment of acute bronchitis in
adults. Ann Intern Med 2001;134(6):518-20.
2. Irwin RS, Baumann MH, Bolser DC et al. Diagnosis and management of cough executive summary: ACCP evidence-
based clinical practice guidelines. Chest 2006;129(1 Suppl):1S-23S.
3. Alberta Clinical Practice Guidelines Working Group. Guideline for the management of acute bronchitis, 2008 update.
Edmonton (AB): Toward Optimized Practice (TOP) Program, Alberta Medical Association; 2008. Available from:
www.topalbertadoctors.org/informed_practice/clinical_practice_guidelines/complete%
20set/Bronchitis/acute_bronchitis_guideline.pdf. Accessed May 27, 2010.
4. Anish EJ. Lower respiratory tract infection in outpatient adults. Clinics in Family Practice 2004;6(1):75-99.
5. Gonzales R, Bartlett JG, Besser RE et al. Principles of appropriate antibiotic use for treatment of uncomplicated acute
bronchitis: background. Ann Emerg Med 2001;37(6):720-7.
6. Knutson D, Braun C. Diagnosis and management of acute bronchitis. Am Fam Physician 2002;65(10):2039-44.
7. Braman SS. Chronic cough due to acute bronchitis: ACCP evidence-based clinical practice guidelines. Chest 2006;129
(1 Suppl):95S-103S.
8. Smucny J, Becker L, Glazier R. Beta2-agonists for acute bronchitis. Cochrane Database Syst Rev 2006;(4):CD001726.
9. Smucny JJ, Flynn CA, Becker LA et al. Are beta2-agonists effective treatment for acute bronchitis or acute cough in
patients without underlying pulmonary disease? A systematic review. J Fam Pract 2001;50(11):945-51.
10. Snow V, Mottur-Pilson C, Gonzales R et al. Principles of appropriate antibiotic use for treatment of nonspecific upper
respiratory tract infections in adults. Ann Intern Med 2001;134(6):487-9.
11. Smucny J, Fahey T, Becker L et al. Antibiotics for acute bronchitis. Cochrane Database Syst Rev 2004;(4):CD000245.
12. Phillips TG, Hickner J. Calling acute bronchitis a chest cold may improve patient satisfaction with appropriate
antibiotic use. J Am Board Fam Pract 2005;18(6):459-63.
13. Colgan R, Powers JH. Appropriate antimicrobial prescribing: approaches that limit antibiotic resistance. Am Fam
Physician 2001;64(6):999-1004.
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Therapeutic Choice
Page 494
e-Therapeutics+ : Therapeutics : Infectious Diseases: Acute Osteomyelitis Page 1 of 9
Therapeutic Choice
Print Close
Infectious Diseases: Acute Osteomyelitis

Simon Dobson, MD, FRCPC
Goals of Therapy
Cure the acute infection

Minimize morbidity, e.g., loss of limb function
Prevent recurrence and progression to chronic osteomyelitis
Investigations
History:
duration of symptoms: fever, pain, redness, swelling, limping or other loss of function or movement
any recent surgery, trauma or penetrating wound
vascular insufficiency
neuropathic ulcer of the diabetic foot
Examination:
tenderness over affected bone (often exquisite).1 No pain is elicited if advanced neuropathy of diabetic foot
range of movement in affected limb (any suggestion of septic arthritis?)
Laboratory tests:
2
complete blood count and acute-phase reactants (erythrocyte sedimentation rate, C-reactive protein) as baseline
blood culture before starting antibacterials (positive in 30 to 60%)
Aspiration:
an organism can be obtained in up to 80% of cases of acute hematogenous osteomyelitis. This may become an
increasingly important test as resistant organisms such as community-acquired methicillin-resistant
Staphylococcus aureus (CA-MRSA) play a greater role in acute osteomyelitis.3 , 4 Early consultation with an
orthopedic surgeon is recommended
culture of superficial ulcer or draining sinus may be unreliable due to the possible presence of colonizing
organisms. In addition, some true pathogens may be sufficiently fastidious that recovery from superficial culture
is difficult (e.g., anaerobes). The best specimen is bone or periosteal aspirate, obtained surgically or by
5
percutaneous biopsy through unaffected skin
Imaging:
x-ray may be normal initially; changes (e.g., periosteal reaction) are not evident for at least 10 days after onset
rarefaction of bone visible only when 50% loss of bone density (early in neonates, later in older children)
rarefaction of bone may be due to an adjacent chronic inflammatory lesion, which must be distinguished from
lytic lesions of osteomyelitis
x-ray does not rule out diagnosis in diabetic foot. Chronic osteopathy may be present
Bone scan:
imaging using technetium 99m-labelled methylene diphosphonate has improved early diagnosis. Early "blood pool
images" should be taken, as well as later bone uptake images, to help differentiate cellulitis from bone infection
a negative bone scan does not rule out osteomyelitis.6 In neonates an x-ray may be more reliable. Other causes
of enhanced bone turnover (e.g., fracture or tumor) will also give a positive result
in the neuropathic foot, small stress fractures may be difficult to detect clinically or radiographically, but still
show uptake on the bone scan. Vascular insufficiency may attenuate changes on the bone scan
Note: If the clinical findings suggest osteomyelitis, do not delay treatment until a bone scan is obtained
Probe diabetic ulcer with sterile instrument. If bone can be reached, this has high specificity and positive predictive
value for osteomyelitis (89%) but low sensitivity.7 Best initial evaluation is x-ray plus a probe for bone.5 If both are
negative, treat for soft tissue infection but repeat x-ray in two weeks (Figure 2 - Management of Diabetic Foot
Osteomyelitis)
Therapeutic Choices (Figure 1 - Management of Acute Osteomyelitis)
Surgical Drainage
Antibacterials do not penetrate well into collections of pus or into bone in which blood supply is compromised by
infection. Surgical decompression and exploration are necessary when there has been a delay in presentation or diagnosis,
when pus has been found on aspiration or when there is x-ray evidence of bone destruction. For early disease the role of
Page 495
Therapeutic Choice
1 , 6
immediate surgery has been controversial. However, if swelling, pain, tenderness and fever do not resolve within days
after starting antibacterials, consider surgical exploration, especially if initial empiric therapy did not cover MRSA.
Suspicion of osteomyelitis secondary to a penetrating injury (e.g., to the calcaneus) requires bone exploration,
débridement and culture. Osteomyelitis associated with diabetic foot infection often requires surgical débridement. This
should be aggressive and may involve amputation of the infected bone.
Table 1: Initial Empiric Antibacterial Therapy of Acute Osteomyelitisa
Usual Causative
Characteristics Organisms Empiric IV Antibacterials
Hematogenous Osteomyelitis
Most common type Neonates: group B Neonates: if MRSA unlikely, cloxacillind +

Predominant in children streptococci, gram- cefotaxime (to cover gram-negative enteric
Bloodborne bacteria lodge in bone as negative enterics, bacilli); if MRSA possible, vancomycin +
nidus of infection S. aureus cefotaxime or ceftriaxone
Possible in any bone but usually in long Children: S. aureus
Children: if MRSA unlikely, cloxacillin;d if MRSA
bones: femur 36%, tibia 33%, humerus (MSSA & MRSA b), group possible, vancomycin.
10% A streptococci Add cefotaxime (if not immunized against
Vertebral osteomyelitis not uncommon in c
Rare: H. influenzae , H. influenzae )
adults. Predisposing factors are iv drug d
S. pneumoniae , gram- Adults: cloxacillin or cefazolin
abuse, trauma, other source of infection,
negative enterics
e.g., urinary tract
Adults: S. aureus , gram-
In neonates, septic arthritis often
negative enterics
coexists
e
Spread from Contiguous Sites
Spread from head/neck S. aureus , anaerobes, Adults: clindamycin ± gentamicin

gram-negative organisms,
mixed infection
Spread from soft tissue infection S. aureus , streptococci Adults: cloxacillin or cefazolin
Spread from genitourinary system gram-negative enteric Adults: fluoroquinolone or extended-spectrum

bacilli beta-lactam (extended spectrum penicillin,
carbapenem, 3rd generation cephalosporin)
Penetrating Trauma (e.g., puncture wound of foot)
P. aeruginosa , S. aureus d
Children: cloxacillin + ceftazidime +
gentamicin
Adults: fluoroquinolone
Vascular Insufficiency
Diabetic foot infection S. aureus , streptococci, Adults: carbapenem or amoxicillin/clavulanate

gram-negative bacilli, or piperacillin/tazobactam or moxifloxacin ±
anaerobes clindamycin or metronidazole
a.
The site and origin of infection and organism responsible are largely related to age.
b.
MRSA is increasing in importance as a cause of acute osteomyelitis.
c.
H. influenzae is of decreasing importance due to success of immunization.
d.
A semisynthetic, penicillinase-resistant penicillin (e.g., cloxacillin) provides coverage against S. aureus and streptococci.
e.
Common in elderly; predisposing factors include surgery, soft tissue infection
Abbreviations: MSSA=methicillin-sensitiveS. aureus; MRSA =methicillin-resistantS. aureus
Antibacterials
While cultures are pending, start empiric iv antibacterial therapy, based on the most likely infecting organism (Table 1)
and on the prevalence in your geographical location of CA-MRSA as a cause of invasive staphylococcal infections.8 A
definitive choice can be made once the organism and sensitivities are identified (Table 2). The role of adjunctive
Page 496
Therapeutic Choice
antibacterials such as fusidic acid or rifampin has not been studied systematically. They cannot be used alone for
staphylococcal infections because resistance develops rapidly.
Mild diabetic foot infection may be treated with appropriate wound care and an oral regimen of amoxicillin/clavulanate or
5
ciprofloxacin plus clindamycin.
Duration of antibacterial therapy should be a minimum of 4 weeks; many authorities recommend 6 weeks.8 More severe
initial presentation, extensive bone involvement, and slow resolution of systemic and local signs indicate a 6-week course.
In osteomyelitis following penetrating injury, 10 to 14 days of treatment is sufficient if adequate débridement has been
performed. As home intravenous therapy programs have become more accessible to patients, this is an option to shorten
hospital stay. The type of home iv pumps used in a particular program may limit specific treatment options, especially
regarding dosing intervals. Choice of antibacterial therapy should not be compromised for the convenience of the local
home iv program.
For osteomyelitis in the setting of diabetic foot infection, the usual duration of antibacterial therapy is 4 to 6
weeks. If all infected bone is completely removed, a shorter duration of 2 to 3 weeks may be sufficient. If no
5,9,10
débridement of bone occurs, 10 to 12 weeks of antibiotic therapy has been curative. Useful Info?
Sequential Intravenous–Oral Antibacterial Therapy
Since a long course is required, a switch from the iv to oral route has many advantages including shortened hospital stay
8
and reduced complications from iv cannulae. In children, continue iv antibacterials until the patient is systemically better,
the temperature is normal and local signs of inflammation and tenderness are improved. This may take several days. Step-
down oral antibacterial therapy may also be appropriate for adults.11
Switching to oral therapy can be undertaken with the following provisos:
Patient is beyond neonatal age group and can be expected to attend for regular review
No underlying immunocompromise present
The dose of oral antibacterial is larger than that usually used for minor infections (Table 3)
Compliance is vital. For children, the taste of the oral antibacterial is the most important factor. Cloxacillin liquid
preparations are unpalatable; cephalexin has a more acceptable taste
If no organism was isolated but the patient has recovered well on the empiric iv regimen, a switch to a comparable
oral antibacterial therapy can still be made. Recurrence of symptoms while on oral step-down therapy demands
immediate reassessment and resumption of iv antibacterials. Home iv therapy is recommended when oral step-down
is not appropriate.
Some infectious disease specialists suggest obtaining blood for serum inhibitory concentration testing, in order to
assess the bioavailability of some drugs, particularly oral beta-lactams
Table 2: Definitive Antibacterial Therapy for Acute Osteomyelitis
Oral Antibacterials
(for completion of course)
Organism Initial iv Antibacterials
MSSA Cloxacillin, cefazolin or Cloxacillin, cephalexin, clindamycin or amoxicillin-

clindamycin clavulanate
Streptococcus Penicillin Penicillin, amoxicillin or clindamycin

group A
Streptococcus Penicillin In neonates, oral antibacterials are not appropriate

group B
Enteric gram- Cefotaxime In neonates, oral antibacterials are not appropriate

negative bacilli
P. aeruginosa Ceftazidime + Gentamicin Adults: ciprofloxacin

No suitable oral preparation available for children. However,
oral ciprofloxacin is sometimes used in children after careful
consideration and discussion of potential risks with child's
parents/guardians
MRSA Vancomycin CA-MRSA may be sensitive to clindamycin as an oral agent;

a
otherwise use home iv therapy
Mixed Carbapenem, moxifloxacin, Ciprofloxacin + clindamycin or amoxicillin/clavulanate

aerobic/anaerobic amoxicillin/clavulanate or
piperacillin/tazobactam
Page 497
Therapeutic Choice
a.
The microbiology laboratory must do a test (usually a “D” test) of inducible clindamycin resistance in MRSA.
Abbreviations: MSSA=methicillin-sensitiveS. aureus; MRSA=methicillin-resistantS. aureus; CA-MRSA=community-acquired

methicillin-resistantS. aureus
Follow-up
Success of treatment is judged by careful follow-up of systemic signs (i.e., fever and well-being, local signs of decreasing
inflammation and tenderness and return of full function). Erythrocyte sedimentation rate gradually returns to normal over
several weeks. The C-reactive protein returns to normal in a matter of days.
Therapeutic Tips
The consequences of treating osteomyelitis empirically with what turns out to be the wrong antibiotic can be dire. In
an era of increasing incidence of CA-MRSA, persuading a surgeon to obtain pus by aspirating the bone at the time of
presentation allows an accurate microbiologic diagnosis and tailored antibiotic therapy.
Home iv therapy or oral step-down therapy can be appropriate for many patients, reducing hospital stay and still
assuring cure.
Figure 1-Management of Acute Osteomyelitis
Page 498
Therapeutic Choice
Figure 2-Management of Diabetic Foot Osteomyelitis
Table 3: Antibacterials Used for the Treatment of Acute Osteomyelitisa
Drug
Class Antibacterial Dose Adverse Effects Interactions Costb
Penicillins amoxicillin Children: Gastrointestinal may ↓ efficacy of $

generics 100 mg/kg/day, po effects, rash, oral
divided Q8H; max eosinophilia. contraceptives;
3 g/day tetracyclines ↓ the
Adults: 0.5–1 g po Q8H effectiveness of
penicillins; ↑
methotrexate
serum levels;
some penicillins
can inactivate
aminoglycosides
if mixed.
Penicillins amoxicillin/clavulanate Children: 100 mg Gastrointestinal may ↓ efficacy of $

(amoxicillin)/kg/day po effects, diarrhea. oral contraceptives;
Clavulin, generics divided Q8H; max tetracyclines ↓ the
1750 mg effectiveness of
(amoxicillin)/day, given penicillins; ↑
as amoxicillin methotrexate serum
40 mg/mL + clavulanate levels; some
5.7 mg/mL suspension penicillins can
inactivate
aminoglycosides
Adults: (amoxicillin) if mixed.
500 mg po Q8H or
875 mg po Q12H
Penicillins cloxacillin Children: 200 mg/kg/day Rash, eosinophilia, may ↓ efficacy of Pediatric:
generics iv or 150–200 gastrointestinal oral $
mg/kg/day po divided effects. contraceptives; Adult: $$
Q6H; max 6 g/day tetracyclines ↓ the
Page 499
Therapeutic Choice
Drug
Adults: 2 g iv Q4H effectiveness of
penicillins; ↑
methotrexate serum
levels; some
penicillins can
inactivate
aminoglycosides
if mixed.
Penicillins penicillin G Children: 200 000 GI effects, may ↓ efficacy of Pediatric:

Crystapen, units/kg/day iv divided hypersensitivity, oral contraceptives; $
generics Q4–6H; max 20 million rash, drug fever, tetracyclines ↓ the Adult: $$
units/day positive Coombs' effectiveness of
Adults: 5–24 million test. Monitor K+ penicillins; ↑
units/day iv divided Q4– and Na+ when methotrexate
6H using high-dose serum levels;
parenteral penicillin some penicillins
G. can inactivate
aminoglycosides
if mixed.
Penicillins penicillin V Children: 100 mg/kg/day GI effects, may ↓ efficacy of $

generics po divided Q6H; max hypersensitivity, oral contraceptives;
3 g/day rash, drug fever, tetracyclines ↓ the
Adults: 0.75–1 g QID positive Coombs' effectiveness of
test. penicillins; ↑
methotrexate
serum levels;
some penicillins
can inactivate
aminoglycosides
if mixed.
Penicillins piperacillin/tazobactam Children: 300 mg Diarrhea, other GI may ↓ efficacy of Pediatric:

(piperacillin)/kg/day iv effects, headache, oral $$
Piperacillin/Tazobactam in divided doses Q6–8H; rash, contraceptives; Adult:
for Injection, Tazocin, max (piperacillin) hypersensitivity, tetracyclines ↓ the $$$
4 g/dose, 12 g/day phlebitis. effectiveness of
other generics
Adults: 3.375 g iv Q6H penicillins; ↑
methotrexate serum
levels; some
penicillins can
inactivate
aminoglycosides
if mixed.
Cephalosporins cefazolin Children: 100 mg/kg/day GI effects, ↑ nephrotoxic Pediatric:

Cefazolin for Injection, iv divided Q8H; max especially diarrhea. effects of $
6 g/day aminoglycosides; ↑ Adult: $$
other generics
Adult: 2 g iv Q8H INR with warfarin.
Cephalosporins cefotaxime Children: 150 mg/kg/day Phlebitis, ↑ nephrotoxic Pediatric:

Claforan iv divided Q8H; max hypersensitivity, effects of $$
10 g/day positive Coombs' aminoglycosides; Adult:
Adults: 2 g iv Q4–8H test. ↑ INR with warfarin. $$$
Cephalosporins ceftazidime , Children: 150 mg/kg/day Phlebitis, ↑ nephrotoxic Pediatric:

Fortaz, iv divided Q8H; max eosinophilia, effects of $$$
generics 6 g/day positive Coombs' aminoglycosides; ↑ Adult:
Adults: 2 g iv Q8H test, ↑ AST, INR with warfarin. $$$$
superinfections.
Page 500
Therapeutic Choice
Drug
Cephalosporins ceftriaxone Children: Phlebitis, ↑ nephrotoxic $$

Ceftriaxone for 75 mg/kg/day iv divided eosinophilia, effects of
Q12–24H; max 4 g/day positive Coombs' aminoglycosides; ↑
Injection USP,
Adults: 1–2 g/day in 1–2 test, ↑ AST, INR with warfarin.
Rocephin,
divided doses; max superinfections. Do not
other generics
4 g/day reconstitute or
mix with calcium
-containing
solutions.
Contraindicated
in neonates if a
calcium-
containing iv
solution is or will
be required
during care.
Do not
administer
simultaneously
with calcium-
containing iv
solutions via a Y-
site.
Administration
may be done
sequentially
provided the
infusion lines are
thoroughly
flushed between
infusions.
Cephalosporins cephalexin , Pediatric: Gastrointestinal ↑ nephrotoxic $

generics 100–150 mg/kg/day po effects, rash, effects of
divided Q6H; max eosinophilia, aminoglycosides; ↑
3 g/day leukopenia, positive INR with warfarin.
Adults: 1–4 g/day Coombs' test, ↑
divided Q6H aspartate
transaminase.
Fluoroquinolones ciprofloxacin Adults: 400 mg iv Q12H Abdominal pain, Absorption ↓ by iv: $$$
Cipro, generics or 750 mg po Q12H nausea, vomiting, antacids, iron salts, po: $
Children (off-label): rash, dizziness, magnesium
30 mg/kg/day po divided headache, sucralfate; ↓
Q12H; max 1500 mg/day drowsiness, theophylline and
po diarrhea. caffeine elimination.
Fluoroquinolones moxifloxacin Adult: 400 mg po or iv Abdominal pain, Absorption ↓ by iv: $$$

Avelox Q24H nausea, vomiting, antacids, iron salts, po: $
rash, dizziness, magnesium
headache, sucralfate.
drowsiness,
diarrhea.
Cases of severe
liver injury
including liver
failure have been
reported.
Page 501
Therapeutic Choice
Drug
Lincosamides clindamycin Children: Rash, neutropenia, ↓ absorption with iv: $$

Dalacin C, Dalacin C 40 mg/kg/day iv divided ↑ aspartate aluminum salts; po: $
Flavored Granules, Q6H or 30 mg/kg/day po transaminase and ↑ effects of
divided Q8H; max 2 alkaline phosphatase, anesthetic agents.
Dalacin C Phosphate
g/day pseudomembranous
Sterile Solution, Adults: 450–600 mg iv colitis.
generics or po Q8H
Aminoglycosides gentamicin Children: 6 mg/kg/day iv Nephrotoxicity ↑ toxicity with Pediatric:

generics divided Q8H usually reversible, ↑ other $
Adults: 5–7 mg/kg/day risk with dose, nephrotoxic or Adult: $$
iv divided Q8H or once duration; ototoxic drugs; ↑
daily if renal function ototoxicity often effects of
permits reversible. anesthetic
agents.
Carbapenems imipenem/cilastatin Adults: 500 mg iv Q6H Caution in beta- May cause $$$$
Primaxin lactam sensitivity; seizures with
risk of seizures if theophylline.
dose exceeded in
renal failure.
Carbapenems meropenem Adults: 500 mg iv Q6H Caution in beta- May ↓ valproate $$$$
Merrem lactam sensitivity; levels.
risk of seizures if
dose exceeded in
renal failure.
Glycopeptides vancomycin Children: 40 mg/kg/day Hypotension, ↑ toxicity with other Pediatric:

Vancocin, Vancomycin, iv divided Q6H; max flushing, red man nephrotoxic or $$
generics 4 g/day syndrome, chills, ototoxic drugs. Adult:
Adults: 1 g iv Q12H drug fever, $$$$
eosinophilia.
a.
Therapy is initiated with iv antibacterials. Patients can be stepped down to oral antibacterials under certain conditions.
b.
Cost per day (pediatric dosage based on 20 kg and adult based on 70 kg body weights); includes drug cost only.
Legend: $ < $10 $$ $10–50 $$–$$$ $10–100 $$$ $50–100 $$$$ > $100
Suggested Readings
Carek PJ, Dickerson LM, Sack JL. Diagnosis and management of osteomyelitis. Am Fam Physician 2001;63(12):2413-20.
Cunha BA. Osteomyelitis in elderly patients. Clin Infect Dis 2002;35(3):287-93.
Raasch RH. Osteomyelitis/Septic arthritis. In: Koda-Kimble M, Young LY, editors. Applied therapeutics: the clinical use of
drugs. 7th ed. Philadelphia (PA): Lippincott Williams & Wilkins; 2001. p.64.1-64.7.
References
1. Nade S. Acute haematogenous osteomyelitis in infancy and childhood. J Bone Joint Surg Br 1983;65(2):109-19.
2. Unkila-Kallio L, Kallio MJ, Eskola J et al. Serum C-reactive protein, erythrocyte sedimentation rate, and white blood
cell count in acute hematogenous osteomyelitis of children. Pediatrics 1994;93(1):59-62.
Page 502
Therapeutic Choice
3. Kaplan SL. Community-acquired methicillin-resistant Staphylococcus aureus infections in children. Semin Pediatr
Infect Dis 2006;17(3):113-9.
4. Arnold SR, Elias D, Buckingham SC et al. Changing patterns of acute hematogenous osteomyelitis and septic
arthritis: emergence of community-associated methicillin-resistant Staphylococcus aureus. J Pediatr Orthop 2006;26
(6):703-8.
5. Caputo GM, Cavanagh PR, Ulbrecht JS et al. Assessment and management of foot disease in patients with diabetes.
N Engl J Med 1994;331(13):854-60.
6. Lew DP, Waldvogel FA. Osteomyelitis. N Engl J Med 1997;336(14):999-1007.
7. Grayson ML, Gibbons GW, Balogh K et al. Probing to bone in infected pedal ulcers. A clinical sign of underlying
osteomyelitis in diabetic patients. JAMA 1995;273(9):721-3.
8. Canadian Paediatric Society, Infectious Diseases and Immunization Committee. Can J Infect Dis 1994;4:10-2.
9. Eckman MH, Greenfield S, Mackey WC et al. Foot infections in diabetic patients. Decision and cost-effectiveness
analyses. JAMA 1995;273(9):712-20.
10. Bader MS. Diabetic foot infection. Am Fam Physician 2008;78(1):71-9.
11. Daver NG, Shelburne SA, Atmar RL et al. Oral step-down therapy is comparable to intravenous therapy for
Staphylococcus aureus osteomyelitis. J Infect 2007;54(6):539-44.
Page 503
e-Therapeutics+ : Therapeutics : Infectious Diseases: Acute Otitis Media in Childhood Page 1 of 9
Therapeutic Choice
Print Close
Infectious Diseases: Acute Otitis Media in Childhood

Joseph V. Vayalumkal, MD, FRCPC
One of the most frequently encountered situations in primary care is the irritable child with a history of 2–3 days of fever, runny
nose and cough. Most children with this clinical presentation have viral infections that do not require antibiotics; however, some
will have signs of acute otitis media (AOM) evident on physical examination and may benefit from antibiotic therapy.
AOM can be caused by both viral and bacterial pathogens.1 It is often preceded by a viral upper respiratory tract infection which
may alter respiratory tract defences by disturbing the epithelium and impairing mucociliary clearance. This may subsequently lead
2 , 3
to eustachian tube dysfunction. The combination of events allows bacterial pathogens colonizing the nasopharynx to invade
the middle ear and cause acute infection. An investigation of the microbiology of acute otitis media reported that bacteria were
isolated in 92% of middle ear effusions while viruses were isolated in 70%. Co-infection was noted in 66% of patients.4
A number of prevention strategies for AOM have been assessed. Most strategies involve vaccination against AOM pathogens but
risk factor modification has also been studied.5 , 6 , 7 , 8 , 9 Exposure to tobacco smoke and exposure to other children (e.g.,
daycare) are associated with higher risk of AOM in childhood.6 , 8 , 9 Breastfeeding is protective against respiratory tract
colonization and is associated with lower rates of acute otitis media in childhood.7
Goals of Therapy
Relieve symptoms (fever, irritability, pain)

Sterilize the middle ear
Prevent complications, e.g., mastoiditis, intracranial infection, facial paralysis
Avoid inappropriate therapy which may lead to the emergence of resistant pathogens and adverse drug effects such as
antibiotic-associated diarrhea
Investigations (Figure 1 - Management of Acute Otitis Media Using a Risk Factor–Based Approach)
History
fever
nonspecific symptoms of viral upper respiratory tract infection such as cough and coryza
otalgia is a common manifestation and may be the best clue to the diagnosis; however, ear pain is not always easily
communicated by infants and toddlers (disturbed sleep, irritability, tugging the ear or rubbing the head may suggest
otalgia in young children)
focus on the head and neck region to rule out other causes of pain referred to the ear such as mastoiditis or dental
abscess
proper visual inspection of the tympanic membrane may require the following: child to be restrained by parents, proper
lighting, removal of cerumen obscuring proper view of the tympanic membrane
assess for signs of middle ear effusion and middle ear inflammation
four key features of the tympanic membrane should be evaluated: colour, position, translucency and mobility. A red,
displaced/bulging, opaque and immobile tympanic membrane indicates acute otitis media
Referral
for treatment failures or recurrences unresponsive to therapy, consider referral to an ENT specialist who can obtain
middle ear fluid for culture to identify the pathogen involved and its antibiotic susceptibility profile
children who have frequent, recurrent episodes (>3 episodes in 6 months or >4 episodes in 12 months) should be
referred to an ENT specialist for consideration of myringotomy and tympanostomy tubes
children with recurrent episodes of AOM should also have audiology assessment to determine any conductive hearing
loss
Therapeutic Choices
The strategy of watchful waiting has been recommended in many clinical practice guidelines for clinical situations in which the
child is over 2 years of age, illness is mild and uncomplicated and a parent/caregiver can easily access the physician for
communication/re-evaluation.10 , 11 , 12 , 13 , 14 More recent Canadian guidelines15 suggest a watchful waiting approach can be
used in children over 6 months of age in the first 48–72 hours provided they have:
nonsevere illness (fever <39ºC, mild otalgia)
uncomplicated AOM
no craniofacial anomalies, immunodeficiencies, cardiac or pulmonary disease, Down syndrome or history of complicated AOM
parents capable of recognizing worsening illness with ready access to medical care.
Page 504
Therapeutic Choice
Analgesics
Provide adequate analgesia in the early stages of infection. In most cases, acetaminophen 10–15 mg/kg or ibuprofen 10
mg/kg every 4–6 hours is sufficient to control the ear pain. If the pain is severe and not responding to usual pain medication, 1–
2 doses of codeine (0.5–1 mg/kg) in the first 24 hours may help but narcotic analgesics have more adverse effects than
acetaminophen or ibuprofen.
Antibiotics (Table 1, Table 2)
The primary bacterial pathogens involved in acute otitis media are Streptococcus pneumoniae, Haemophilus influenzae and
Moraxella catarrhalis. Clinical observations suggest that spontaneous resolution rates of acute otitis media caused by these 3
16
pathogens are 20%, 50% and 75%, respectively. Therefore, a wait and see approach has been proposed for a subset of
10 17 , 18
patients, which may lead to reduced number of antibiotic prescriptions. Furthermore, with the introduction of
pneumococcal conjugate vaccine the epidemiology of acute otitis media is likely to change, and treatment recommendations may
be modified in the future.19 , 20 , 21 , 22
Antibiotic resistance is common among these 3 pathogens; therefore, choosing appropriate therapy depends on understanding
the mechanisms of resistance involved. S. pneumoniae resistance to penicillin is a result of alteration of penicillin-binding cell
wall proteins leading to decreased drug affinity. Doubling the dose of amoxicillin raises the drug concentration in the middle ear
to allow effective killing of penicillin-resistant strains. For H. influenzae and M. catarrhalis, beta-lactamase production confers
resistance to amoxicillin and therefore adding a beta-lactamase inhibitor, such as clavulanate, will allow the antibiotic to work
effectively.
Standard-dose amoxicillin (40 mg/kg/day) was first-line therapy in patients without risk factors for antibiotic resistance (recent
antibiotic use, daycare attendance, recent episode of acute otitis media, treatment failure or early recurrence). Amoxicillin is most
active against S. pneumoniae, less effective for penicillin-resistant strains and is not effective against beta-lactamase-producing
strains of H. influenzae and M. catarrhalis.
Recent Canadian guidelines suggest that high-dose amoxicillin (75–90 mg/kg/day) be used in all patients irrespective of risk
15
factors for antibiotic resistance; it is effective against most penicillin-resistant strains of S. pneumoniae. Prevalence of penicillin
23
resistant S. pneumoniae has increased globally since the early 1990s. This is the primary reason for suggesting high-dose
amoxicillin as first-line therapy for AOM. However, it is not clear whether using standard-dose amoxicillin has actually caused
increasing treatment failures in Canada. Furthermore, there is ongoing debate about whether antimicrobial resistance is directly
24
related to treatment failures for various infections caused by S. pneumoniae. Based on the available evidence, standard-dose
amoxicillin is still a reasonable first-line option for AOM in children without risk factors.
Amoxicillin/clavulanate (with high-dose amoxicillin) possesses the added benefit of stability against beta-lactamases,
produced by some strains of H. influenzae and most strains of M. catarrhalis. Amoxicillin/clavulanate is effective against most
penicillin-resistant S. pneumoniae.
All other treatment options for acute otitis media are less favourable than amoxicillin or amoxicillin/clavulanate. Rates of
25 , 26 , 27
resistance to other antibiotic classes such as cephalosporins and macrolides are on the rise. However, in situations of
10 , 11 , 12 , 28 , 29
treatment failures and penicillin allergy these antibiotic classes are alternatives. It is important to differentiate
between those patients who have true type I hypersensitivity (anaphylactic) reactions and those who experience a nonspecific
adverse effect to the antibiotic. In general, parents and patients overestimate the true frequency of allergic reactions.30 , 31
Cephalosporins can be used for patients who have previously experienced a non-type I hypersensitivity reaction to penicillins.
Cefuroxime axetil and cefprozil are second-generation cephalosporins with reasonable activity against H. influenzae and M.
catarrhalis because they are less susceptible to the action of beta-lactamases than amoxicillin. However, cephalosporins are less
effective than amoxicillin against penicillin-resistant strains of S. pneumoniae. They can be used as second-line agents.
Ceftriaxone is the most effective of the cephalosporins against otitis media pathogens but is not used routinely because it is
given intravenously or intramuscularly daily for 3 days.32
Reserve azithromycin and clarithromycin for patients with type I hypersensitivity reactions to beta-lactam antibiotics.
Clindamycin is an alternative agent that can be used for patients with type I hypersensitivity reactions to beta-lactam antibiotics,
however it does not cover H. influenzae or M. catarrhalis .
Therapeutic Tips
Use of vaccines for influenza and S. pneumoniae may have a beneficial impact on the incidence of acute otitis media and
5 , 33 , 34 , 35 , 36
therefore should be encouraged for eligible patients. (See Table 3.)
Most children will have middle ear effusions after completion of therapy. There is no need to treat an abnormal-appearing
tympanic membrane in an asymptomatic child. If middle ear effusion persists over 3 months, arrange an audiology
assessment to assess hearing.
Page 505
Therapeutic Choice
Nasal and oral decongestants alone or in combination with an antihistamine have not shown efficacy in
resolving symptoms and infection or preventing complications and are not recommended for the management
1,38
of acute otitis media. Useful Info?
Figure 1-Management of Acute Otitis Media Using a Risk Factor–Based Approach
a.
Risk factors: recent antibiotic use, daycare attendance, recent episode of AOM, treatment failure or early recurrence.
b.
If treatment failure or recurrence within 1 month, consider alternative agents and repeated course of treatment or referral for
tympanocentesis.
c.
Nontoxic appearance, temperature <39°C, mild otalgia.
d.
Toxic appearance, temperature >39°C, severe otalgia.
e.
If <6 weeks old refer to emergency department. Infants >6 weeks of age require very careful assessment; other occult sources of infection
should be considered as a cause of fever.
10
Table 1: Antibiotic Treatment Recommendations for AOM
Treatment Failure
Treatment Failure Noted on Day 10–28
a
Characteristics Therapeutic Tips First Choice Noted on Day 3
Age <6 weeks Investigate for Refer to nearest emergency n/a n/a
bacteremia; acute department for further
otitis media often due assessment; symptoms such
to gram-negative as fever may be related to
bacteria sepsis in this age group.
Age <2 years Treat most cases of Standard-dose amoxicillin: High-dose amoxicillin/ High-dose amoxicillin/
No risk factors (no acute otitis media with 40 mg/kg/day divided BID or b b
clavulanate or cefprozil clavulanate or
antibiotics in prior 3 antibiotic for 10 days TID 30 mg/kg/day or cefprozil 30 mg/kg/day
months, no daycare or cefuroxime axetil or cefuroxime axetil
attendance) High-dose amoxicillin: 30 mg/kg/day or 30 mg/kg/day or
75–90 mg/kg/day divided BID ceftriaxone im/iv for ceftriaxone im/iv for
or TID 3 days 3 days
Page 506
Therapeutic Choice
Treatment Failure
Treatment Failure Noted on Day 10–28
a
Characteristics Therapeutic Tips First Choice Noted on Day 3
Age <2 years Treat most cases of High-dose amoxicillin: High-dose amoxicillin/ High-dose amoxicillin/
With risk factors acute otitis media with 75–90 mg/kg/day divided BID clavulanateb or cefprozil clavulanateb or
(received antibiotics antibiotic for 10 days or TID 30 mg/kg/day or cefprozil 30 mg/kg/day
in prior 3 months or cefuroxime axetil or cefuroxime axetil
daycare attendance) 30 mg/kg/day or 30 mg/kg/day or
ceftriaxone im/iv for 3 ceftriaxone im/iv for
days 3 days
Consider Consider
tympanocentesis tympanocentesis
Age >2 years Consider deferring Standard-dose amoxicillin: High-dose amoxicillin/ High-dose amoxicillin/
No risk factors (no treatment to see if 40 mg/kg/day divided BID or b b
clavulanate or cefprozil clavulanate or
frequent bouts AOM acute otitis media TID 30 mg/kg/day or cefprozil
and no antibiotics resolves in 48–72 h or cefuroxime axetil 30 mg/kg/day or
in prior 3 months) only if follow-up can High-dose amoxicillin: 30 mg/kg/day or cefuroxime axetil
be ensured and if 75–90 mg/kg/day divided BID ceftriaxone im/iv for 30 mg/kg/day or
antibacterial therapy or TID 3 days ceftriaxone im/iv for
can be initiated if 3 days
symptoms worsen Consider
10
Treat for 5 days tympanocentesis
Age >2 years Consider deferring High-dose amoxicillin: High-dose amoxicillin/ High-dose amoxicillin/
With risk factors treatment to see if 75–90 mg/kg/day divided BID clavulanateb or cefprozil b
clavulanate or
(received antibiotics acute otitis media or TID 30 mg/kg/day or cefprozil
in prior 3 months) resolves in 48–72 h cefuroxime axetil 30 mg/kg/day or
only if follow-up can 30 mg/kg/day or cefuroxime axetil
be ensured and if ceftriaxone im/iv for 30 mg/kg/day or
antibacterial therapy 3 days ceftriaxone im/iv for
can be initiated if Consider 3 days
symptoms worsen tympanocentesis Consider
10
Treat for 5 days tympanocentesis
Any age Verify acute otitis High-dose Ceftriaxone im/iv for High-dose amoxicillin/
Frequent bouts of media b 3 days b
amoxicillin/clavulanate clavulanate or
acute otitis media Treat acute otitis Consider cefprozil or cefuroxime
media episode for tympanocentesis axetil or ceftriaxone
≥10 days im/iv for 3 days
Consider conjugated
pneumococcal vaccine
if age <5 y
Give influenza vaccine
every year, all ages
Allergic to Verify true Clarithromycin 15 mg/kg/day Tympanocentesis Clarithromycin 15

penicillin anaphylactic-type c mg/kg/day or
or azithromycin
allergy: hives; swollen azithromycinc
lips, mouth, or throat; Consider
wheezing; ↓ BP; tympanocentesis
vomiting and diarrhea;
consider penicillin skin
testing
a.
Choose an agent not previously used for the same infection.
b.
High-dose amoxicillin/clavulanate: amoxicillin 40 mg/kg/day plus amoxicillin/clavulanate liquid (Clavulin-200 or Clavulin-400) 40 mg/kg/day
of the amoxicillin component OR amoxicillin/clavulanate liquid (Clavulin-200 or Clavulin-400) can be given at a dose of 80 mg/kg/day of the
amoxicillin component (may cause diarrhea). May be given TID rather than BID to minimize gastrointestinal side effects.
c.
Azithromycin: 10 mg/kg/day on day 1 followed by 5 mg/kg/day on days 2–5.
Abbreviations: BP=blood pressure; n/a=not applicable
Table 2: Antibiotics for Acute Otitis Media
Page 507
Therapeutic Choice
Adverse
Class Drug Dosea Effects Comments Costb
Penicillins amoxicillin Standard dose: 40 mg/kg/day po divided Excellent Most active agent $
generics BID-TID. safety profile. against pneumococci
High dose: 75–90 mg/kg/day po divided Occasionally with ↓ susceptibility to
BID-TID causes mild penicillins and
Maximum: 1.5 g/day diarrhea. cephalosporins.
For pneumococci with
Reserve standard-dose amoxicillin for the Maculopapular ↓ susceptibility to
limited number of children at low risk of rash occurs penicillins and
being infected with drug-resistant bacteria uncommonly cephalosporins,
(no daycare, no antibiotic in the prior 3- but is difficult amoxicillin is more
month period) to distinguish active than
from a cephalosporins.
concomitant
viral
exanthem.
Penicillins amoxicillin/ 75–90 mg/kg/day po amoxicillin divided Excellent Avoid the original $$
clavulanate BID-TID safety profile. formulations of
Clavulin, Maximum: 1.5 g/day amoxicillin Diarrhea amoxicillin/clavulanate
generics Best given as 2 simultaneous prescriptions occurs (Clavulin-125F and
to minimize the risk of diarrhea: one frequently. Clavulin-250F) in the
prescription of amoxicillin 40 mg/kg/day high-dose protocol
plus one prescription of 7:1 formulation because the higher
amoxicillin/clavulanate liquid (Clavulin-200 content of clavulanate
or Clavulin-400) 40 mg/kg/day of the increases the
amoxicillin component incidence of diarrhea.
Alternatively, one of the 7:1 formulations To avoid confusion
of amoxicillin/clavulanate liquid (Clavulin- when prescribing high
200 or Clavulin-400) can be given at a -dose regimens,
dose of 80 mg/kg/day of the amoxicillin confirm intention on
component, but may cause more diarrhea. the prescription (e.g.,
Some patients will tolerate these high-dose write “high dose
regimens better if doses are given 3 times amoxicillin
daily rather than twice daily intended” at the
bottom).
Active against most

bacteria likely to cause
acute otitis media.
Cephalosporins cefprozil 30 mg/kg/day (maximum 1 g/day) po Low incidence Most children like the $$$
Cefzil, divided BID of diarrhea or taste of the liquid
GI upset. formulation and it is
generics
well absorbed.
Cephalosporins ceftriaxone 50 mg/kg (maximum 1 g) Q24H im/iv for 3 Pain at Second- or third-line $$$
Ceftriaxone days injection site agent.
when May be diluted with
for Injection
administered 1% plain lidocaine to
USP, im. a final concentration
Rocephin, of 300 mg/mL to
generics minimize pain at
injection site when
given im only.
Do not reconstitute or
mix with calcium-
containing solutions.
Cephalosporins cefuroxime 30 mg/kg/day (maximum 1 g/day) po Low incidence Available as $$$

axetil divided BID of diarrhea or suspension.
Ceftin, GI upset.
generics
Page 508
Therapeutic Choice
Adverse
a b
Class Drug Dose Effects Comments Cost
Macrolides azithromycin Day 1: 10 mg/kg (maximum 500 mg) once Low incidence Most children like the $$
Zithromax, daily po of diarrhea or taste of the
generics Days 2–5: 5 mg/kg (maximum 250 mg) GI upset. suspension.
once daily Pneumococci with ↓
susceptibility to
Administer po at bedtime penicillins and
cephalosporins are
sometimes resistant to
azithromycin.
Short course may

improve compliance.
Use if true
anaphylactic-type β-
lactam allergy.
Macrolides clarithromycin 15 mg/kg/day (maximum 1000 mg/day) po Diarrhea or Pneumococci with ↓ $$$$
divided BID vomiting susceptibility to
Biaxin, Because it sometimes has a bitter (15%). penicillins and
generics aftertaste, the suspension should be taken cephalosporins are
with food and/or juice sometimes resistant to
clarithromycin.
Use if true
anaphylactic-type β-
lactam allergy.
Lincosamides clindamycin 30 mg/kg/day (maximum 1.8 g/day) po/iv Nausea, Reserve for cases of Caps: $$
Dalacin C, divided TID-QID vomiting, true anaphylactic-type Oral
Dalacin C For severe infections may increase to 40 diarrhea β-lactam allergy susp:$$$$
mg/kg/day (maximum 2.7 g/day) iv (common), and/or treatment
Flavored
divided TID-QID esophagitis, failure. IV: $120
Granules, rash, Clindamycin
Dalacin C Clostridium suspension has an
Phosphate difficile– unpleasant taste. If
Sterile associated the dose prescribed is
Solution, diarrhea. a multiple of a capsule
strength (150 mg),
generics
capsules can be
opened and mixed
with a soft solid, e.g.,
apple sauce, pudding,
chocolate sauce.
a.
Duration of treatment is 5 days for children over 2 years and 10 days if under 2 years; exceptions are ceftriaxone and azithromycin.
b.
Cost of 10-day supply based on 20 kg body weight, except 5-day supply for azithromycin, 3-day supply for ceftriaxone; includes drug cost
only.
Legend: $ < $15 $$ $15–30 $$$ $30–45 $$$$ $45–60
Table 3: Vaccines for Prevention of Acute Otitis Media
Costa
37
Vaccines, influenza vaccine, 6–35 mo: 0.25 mL im Pretreatment with acetaminophen $

viral inactivated 36 mo–8 y: 0.5 mL im may help minimize soreness and
Agriflu, Fluviral, mild flu-like symptoms.
Vaxigrip ≥9 y: 0.5 mL im Contraindicated in persons with
history of anaphylactic reaction to a
previous dose or eggs.
Page 509
Therapeutic Choice
Costa
37
Children 6 mo–8 y who have not previously
received influenza vaccine should receive a
second dose ≥4 wk after the first dose.
Vaccines, influenza vaccine, live ≥2 y: 0.2 mL intranasally given as 1 spray $

viral attenuated (0.1 mL) per nostril.
FluMist Children 2–8 y who have not previously
received influenza vaccine should receive a
second dose ≥4 wk after the first dose.
Vaccines, pneumococcal 2–6 mo: 4 doses im at 2, 4, 6 and 12–15 Pretreatment with acetaminophen $$$
bacterial vaccine, 7-valent mo may help minimize soreness at
conjugate 7–11 mo: 2 doses im given 4 wk apart plus injection site.
Prevnar a booster after the first birthday and at
least 2 mo after the last dose
12–23 mo: 2 doses im given 2 mo apart
24–59 mo: 1 dose im
conjugate 7–11 mo: 2 doses im given 1 month apart injection site.
Synflorix plus a booster after the 1st birthday and at
least 2 mo after the last dose
conjugate 7–11 mo: 2 doses im given 4 wk apart plus injection site.
Prevnar 13 a booster after the 1st birthday and at least
2 mo after the last dose
24–59 mo: 1 dose im
a.
Cost of 1 dose; includes drug cost only.
Legend: $ < $15 $$ $15–85 $$$ $85–95
Suggested Readings
American Academy of Pediatrics Subcommittee on Management of Acute Otitis Media. Diagnosis and management of acute otitis
media. Pediatrics 2004;113(5):1451-65.
Forgie S, Zhanel G, Robinson J. Management of acute otitis media. Paediatr Child Health 2009;14(7):457-64.
Neff MJ; American Academy of Pediatrics; American Academy of Family Physicians. AAP, AAFP release guideline on diagnosis and
management of acute otitis media. Am Fam Physician 2004;69(11):2713-5.
Rovers MM, Glasziou P, Appelman CL et al. Antibiotics for acute otitis media: a meta-analysis with individual patient data. Lancet
2006;368(9545):1429-35.
Rovers MM, Glasziou P, Appelman CL et al. Predictors of pain and/or fever at 3 to 7 days for children with acute otitis media not
treated initially with antibiotics: a meta-analysis of individual patient data. Pediatrics 2007;119(3):579-85.
Page 510
Therapeutic Choice
References
1. Chonmaitree T. Acute otitis media is not a pure bacterial disease. Clin Infect Dis 2006;43(11):1423-5.
2. Faden H, Stanievich J, Brodsky L et al. Changes in nasopharyngeal flora during otitis media of childhood. Pediatr Infect Dis
J 1990;9(9):623-6.
3. Sanyal MA, Henderson FW, Stempel EC et al. Effect of upper respiratory tract infection on eustachian tube ventilatory
function in the preschool child. J Pediatr 1980;97(1):11-5.
4. Ruohola A, Meurman O, Nikkari S et al. Microbiology of acute otitis media in children with tympanostomy tubes:
prevalences of bacteria and viruses. Clin Infect Dis 2006;43(11):1417-22.
5. Klein JO, Chonmaitree T, Loosmore S et al. Otitis media: a preventable disease? Proceedings of an international symposium
organized by the Marcel Merieux Foundation, Veyrier-du-Lac, France, February 13 to 16, 2000. Pediatr Infect Dis J 2001;20
(5):473-81.
6. Adair-Bischoff CE, Sauve RS. Environmental tobacco smoke and middle ear disease in preschool-age children. Arch Pediatr
Adolesc Med 1998;152(2):127-33.
7. Duffy LC, Faden H, Wasielewski R et al. Exclusive breastfeeding protects against bacterial colonization and day care
exposure to otitis media. Pediatrics 1997;100(4):E7.
8. Paradise JL, Rockette HE, Colborn DK et al. Otitis media in 2253 Pittsburgh-area infants: prevalence and risk factors during
the first two years of life. Pediatrics 1997;99(3):318-33.
9. Greenberg D, Givon-Lavi N, Broides A et al. The contribution of smoking and exposure to tobacco smoke to Streptococcus
pneumoniae and Haemophilus influenzae carriage in children and their mothers. Clin Infect Dis 2006;42(7):897-903.
10. American Academy of Pediatrics Subcommittee on Management of Acute Otitis Media. Diagnosis and management of acute
otitis media. Pediatrics 2004;113(5):1451-65.
11. Alberta Medical Association. Guideline for the diagnosis and treatment of acute otitis media in children. Edmonton (AB):
Toward Optimized Practice, Alberta Medical Association; 2008. Available from:
www.topalbertadoctors.org/informed_practice/clinical_practice_guidelines/complete%20set/Acute%20Otitis%
20Media/AOM_guideline.pdf. Accessed September 13, 2010.
12. British Columbia Medical Association, Guidelines and Protocols Advisory Committee. Acute otitis media (AOM). Victoria
(BC): BCMA; 2004. Available from: www.bcguidelines.ca/gpac/pdf/otitaom.pdf. Accessed September 13, 2010.
13. Hoberman A, Marchant CD, Kaplan SL et al. Treatment of acute otitis media consensus recommendations. Clin Pediatr
(Phila) 2002;41(6):373-90.
14. Scottish Intercollegiate Guidelines Network. Diagnosis and management of childhood otitis media in primary care: a national
clinical guideline. Edinburgh (GB): Royal College of Physicians; 2003. Available from: www.sign.ac.uk/pdf/sign66.pdf.
Accessed September 13, 2010.
15. Forgie S, Zhanel G, Robinson J. Management of acute otitis media. Paediatr Child Health 2009;14(7):457-64.
16. Klein JO. Microbiologic efficacy of antibacterial drugs for acute otitis media. Pediatr Infect Dis J 1993;12(12):973-5.
17. Rovers MM, Glasziou P, Appelman CL et al. Antibiotics for acute otitis media: a meta-analysis with individual patient data.
Lancet 2006;368(9545):1429-35.
18. Spiro DM, Tay KY, Arnold DH et al. Wait-and-see prescription for the treatment of acute otitis media: a randomized
controlled trial. JAMA 2006;296(10):1235-41.
19. Casey JR, Pichichero ME. Changes in frequency and pathogens causing acute otitis media in 1995-2003. Pediatr Infect Dis J
2004;23(9):824-8.
20. Garbutt J, St Geme JW, May A et al. Developing community-specific recommendations for first-line treatment of acute otitis
media: is high-dose amoxicillin necessary? Pediatrics 2004;114(2):342-7.
21. Garbutt J, Rosenbloom I, Wu J et al. Empiric first-line antibiotic treatment of acute otitis in the era of the heptavalent
pneumococcal conjugate vaccine. Pediatrics 2006;117(6):e1087-94.
22. Leibovitz E, Jacobs MR, Dagan R. Haemophilus influenzae: a significant pathogen in acute otitis media. Pediatr Infect Dis J
2004;23(12):1142-52.
23. Lynch JP, Zhanel GG. Streptococcus pneumoniae: epidemiology and risk factors, evolution of antimicrobial resistance, and
impact of vaccines. Curr Opin Pulm Med 2010;16(3):217-25.
24. Lynch JP, Zhanel GG. Streptococcus pneumoniae: does antimicrobial resistance matter? Semin Respir Crit Care Med
2009;30(2):210-38.
25. Doern GV, Pfaller MA, Kugler K et al. Prevalence of antimicrobial resistance among respiratory tract isolates of
Streptococcus pneumoniae in North America: 1997 results from the SENTRY antimicrobial surveillance program. Clin Infect
Dis 1998;27(4):764-70.
26. Jacobs MR, Bajaksouzian S, Zilles A et al. Susceptibilities of Streptococcus pneumoniae and Haemophilus influenzae to 10
oral antimicrobial agents based on pharmacodynamic parameters: 1997 U.S. Surveillance study. Antimicrob Agents
Chemother 1999;43(8):1901-8.
27. Jacobs MR. Increasing antibiotic resistance among otitis media pathogens and their susceptibility to oral agents based on
pharmacodynamic parameters. Pediatr Infect Dis J 2000;19(5 Suppl):S47-55.
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28. Brook I. Use of oral cephalosporins in the treatment of acute otitis media in children. Int J Antimicrob Agents 2004;24
(1):18-23.
29. Dunne MW, Latiolais T, Lewis B et al. Randomized, double-blind study of the clinical efficacy of 3 days of azithromycin
compared with co-amoxiclav for the treatment of acute otitis media. J Antimicrob Chemother 2003;52(3):469-72.
30. Langley JM, Halperin SA, Bortolussi R. History of penicillin allergy and referral for skin testing: evaluation of a pediatric
penicillin allergy testing program. Clin Invest Med 2002;25(5):181-4.
31. Langley J, Halperin S. Allergy to antibiotics in children: perception versus reality. Paediatr Child Health 2002;7(4):233-7.
32. Leibovitz E, Piglansky L, Raiz S et al. Bacteriologic and clinical efficacy of one day vs. three day intramuscular ceftriaxone
for treatment of nonresponsive acute otitis media in children. Pediatr Infect Dis J 2000;19(11):1040-5.
33. Eskola J, Kilpi T, Palmu A et al. Efficacy of a pneumococcal conjugate vaccine against acute otitis media. N Engl J Med
2001;344(6):403-9.
34. Jenson HB, Baltimore RS. Impact of pneumococcal and influenza vaccines on otitis media. Curr Opin Pediatr 2004;16(1):58
-60.
35. Ozgur SK, Beyazova U, Kemaloglu YK et al. Effectiveness of inactivated influenza vaccine for prevention of otitis media in
children. Pediatr Infect Dis J 2006;25(5):401-4.
36. Clements DA, Langdon L, Bland C et al. Influenza A vaccine decreases the incidence of otitis media in 6- to 30-month-old
children in day care. Arch Pediatr Adolesc Med 1995;149(10):1113-7.
37. National Advisory Committee on Immunization (NACI). Canadian immunization guide. 7th ed. Ottawa (ON): Public Health
Agency of Canada; 2006. Available from: www.phac-aspc.gc.ca/publicat/cig-gci/pdf/cig-gci-2006_e.pdf. Accessed
September 13, 2010.
38. Coleman C, Moore M. Decongestants and antihistamines for acute otitis media in children. Cochrane Database Syst Rev
2008;(3):CD001727.
Page 512
e-Therapeutics+ : Therapeutics : Infectious Diseases: Bacterial Meningitis Page 1 of 11
Therapeutic Choice
Print Close
Infectious Diseases: Bacterial Meningitis

Alana Rosenthal, MD, FRCPC
Lindy Samson, MD, FRCPC
Meningitis is described as inflammation of the cranial and spinal leptomeninges. Bacterial meningitis is characterized
by bacterial invasion of the cranial and spinal leptomeninges. It most often develops following bacteremia but can
also occur via extension from surrounding structures (mastoiditis, sinusitis) or direct inoculation during
neurosurgery or open head trauma. The causative pathogens in bacterial meningitis depend on age and specific host
and environmental factors (Table 1, Table 2).
Table 1: Bacterial Meningitis: Probable Pathogens and Empiric Therapy Based on Age
Age Group Bacteria Empiric Antibacterial Regimen
Infants < 6 wk Group B streptococcus Ampicillin + gentamicin

E. coli or
L. monocytogenes a
Ampicillin + cefotaxime
Other Enterobacteriaceae
Streptococcus pneumoniae (rare)
Neisseria meningitidis (rare)
Infants 6 wk–3 mo S. pneumoniae (pneumococcus) Ceftriaxone or cefotaxime

N. meningitidis (meningococcus) +
Group B streptococcus Ampicillin
b +
H. influenzae type b
E. coli (rare) Vancomycinc
L. monocytogenes (rare)
Other Enterobacteriaceae (rare)
Infants > 3 mo, children and adults S. pneumoniae Ceftriaxone or cefotaxime

N. meningitidis +
H. influenzae type bb Vancomycinc
Elderly (> 50 y) or alcoholism E. coli Ceftriaxone or cefotaxime

S. pneumoniae +
N. meningitidis Ampicillin
L. monocytogenes +
c
Vancomycin
a.
Cefotaxime is preferred over ceftriaxone in neonates because of the theoretical risk of displacement of bilirubin from albumin
and therefore of possible hyperbilirubinemia.
b.
H. influenzae type b is rare since implementation of universal vaccination.
c.
Vancomycin is included in the initial antibacterial regimen due to increasing prevalence of resistant S. pneumoniae .
Table 2: Bacterial Meningitis: Probable Pathogens and Empiric Therapy Based on Specific Host and Environmental
Factors
Empiric
Risk Factor Bacteria Antibacterials
Cerebrospinal fluid leak S. pneumoniae Ceftriaxone or

S. pyogenes cefotaxime
H. influenzae type b +
Vancomycin
Page 513
Therapeutic Choice
Empiric
Risk Factor Bacteria Antibacterials
a Staphylococcus spp. rd
Penetrating head trauma/neurosurgery 3 generation
Streptococcus spp.
cephalosporinb
E. coli
+
Klebsiella spp.
P. aeruginosa Vancomycina
Ventriculoperitoneal shunt S. epidermidis rd

3 generation
S. aureus
cephalosporinb
S. pneumoniae
+
N. meningitidis
Vancomycin
H. influenzae type b
Aerobic gram-negative bacilli (including
P. aeruginosa )
Propionibacterium acnes
Humoral immune deficiency states, e.g., S. pneumoniae Ceftriaxone or

agammaglobulinemia N. meningitidis cefotaxime
H. influenzae type b +
Vancomycin
Cellular immune deficiency states, e.g., S. pneumoniae Ceftriaxone or

chemotherapy, HIV N. meningitidis cefotaxime
L. monocytogenes +
H. influenzae type b Ampicillin
+
Vancomycin
Asplenia (anatomic or functional) S. pneumoniae Ceftriaxone or

N. meningitidis cefotaxime
Salmonella spp. +
H. influenzae type b Vancomycin
a.
Consider adding anaerobic and antifungal coverage if the wound is contaminated.
b.
Ceftazidime is the cephalosporin of choice if there is a high suspicion of P. aeruginosa infection.
There is still significant mortality and morbidity associated with bacterial meningitis. Acute complications may
include but are not limited to:
subdural effusion or empyema
brain abscess
cerebritis or ventriculitis
venous sinus thrombosis
seizures
CNS infarction, resulting in hemiparesis, quadriparesis or spinal cord infarction
brain herniation
shock and/or disseminated intravascular coagulopathy
diabetes insipidus and/or the syndrome of inappropriate antidiuretic hormone release
Neurologic sequelae may include but are not limited to:
sensorineural hearing loss
visual problems including cortical blindness
ataxia
hydrocephalus
behavioural difficulties
intellectual deficits
epilepsy
Goals of Therapy
Eradicate bacteria from the CNS
Page 514
Therapeutic Choice
Decrease mortality
Manage and minimize acute and chronic complications including permanent neurologic damage
Investigations
Clinical Presentation
The clinical presentation varies and is related to age and developmental stage. It may be acute or insidious in
onset.
infants may present with only a change in temperature (fever or hypothermia). Other signs are usually
nonspecific and may include inconsolable crying, irritability, lethargy, seizures, poor feeding, vomiting,
diarrhea, jaundice and/or a bulging anterior fontanelle. Signs of meningeal irritation such as a stiff neck are
often absent and therefore, in infants, clinicians should have a low threshold for suspecting meningitis. A
fever in a baby < 4 weeks of age warrants examination and culture of the cerebrospinal fluid (CSF) in all
circumstances.
in children and adults, symptoms usually include fever, severe headache, stiff neck or back pain and/or
photophobia. Patients often report feeling systemically unwell with associated vomiting. Neurologic signs
may include loss of balance, seizures, disorientation, confusion, altered level of consciousness, stiff neck,
positive Kernig's and Brudzinski's signs, cranial nerve palsies and/or other signs of increased intracranial
pressure, e.g., papilledema. Signs of cerebral infarction may also be present.
patients of any age can present in septic shock. Other physical exam findings may include petechia or
purpura, which are usually suggestive of meningococcal meningitis but can also be seen with S.
pneumoniae and other bacterial pathogens.
Laboratory Investigations
CSF
Examination of the CSF is essential for making the diagnosis and is warranted whenever meningitis is
suspected. Lumbar puncture (LP) is contraindicated in the presence of increased intracranial pressure (ICP),
papilledema, focal neurologic signs, deteriorating Glasgow Coma Score, shock, infection at the LP site and
bleeding disorders.1 Brain imaging may or may not be helpful in excluding increased ICP prior to lumbar
puncture. If raised ICP is strongly suspected clinically, then the LP should be deferred. Do not delay empiric
antibacterial therapy if an LP cannot be performed at the time of presentation.
Examine the CSF for cell count and differential, culture and sensitivity, and glucose and protein concentrations.
Findings consistent with bacterial meningitis include:
elevated CSF WBC count with a predominance of neutrophils is usually present; however, initially the CSF
WBC count may be considerably less elevated. It is often not possible to differentiate bacterial from viral or
other types of meningitis based purely on the CSF WBC
reduced CSF glucose ( CSF-to-serum ratio < 0.6 for infants and < 0.4 for those over 2 months of age)2
normal or elevated CSF protein (range varies according to age)
3
CSF Gram stain is positive in up to 80 to 90% of hematogenously acquired meningitis, but this varies
according to the causative pathogen.4
Culture is the gold standard for diagnosis, but may not be positive, particularly in those previously treated with
antibacterials.
Latex agglutination of the CSF in the setting of Gram stain and culture-negative meningitis is not routinely used
because of poor sensitivity and specificity.5 , 6
An elevated CSF lactate level (> 4 mmol/L) may be present in postoperative neurosurgical patients with
7
bacterial meningitis.
A repeat LP is indicated in the following situations:
failure to improve clinically
immunocompromised patients
penicillin- or cephalosporin-resistant pneumococcal meningitis
meningitis caused by enteric gram-negative bacilli or other unusual pathogens
patients who received corticosteroids for prevention of complications due to meningitis (because
corticosteroids may temporarily mask treatment failure)
meningitis caused by Group B streptococcus
some clinicians advocate a repeat LP in all cases of neonatal meningitis
Blood
Complete blood count and differential; culture and sensitivity. Draw a blood glucose level at or near the time of
the CSF glucose to enable comparison of the two values.
Page 515
Therapeutic Choice
Imaging
Imaging studies (CT or MRI of the head) are not routinely required but are indicated for those individuals with
focal neurologic signs, clinical evidence of brain herniation, decreased/fluctuating level of consciousness,
clinical deterioration, or persistent fever. In addition, some evidence suggests that CT scans should be done
prior to LP in those with underlying neurologic conditions, immunodeficiency states or in individuals > 60 years
8
of age.
Therapeutic Choices
Antibacterial Therapy
Choice of empiric antibacterial therapy is based on the most likely causative organisms, host factors such as
patient age (Table 1, Table 2) and local antimicrobial resistance patterns.
Re-evaluate and modify antibacterial therapy when results of the CSF Gram stain, culture and then sensitivity
become available (Table 3).
The duration of therapy depends on host factors and the causative pathogen. General guidelines for duration of
therapy for some common pathogens are shown in Table 3.
Doses, most common adverse effects and drug interactions are shown in Table 4.
Due to the increasing incidence of penicillin-resistant pneumococci and meningococci in Canada, penicillin G is
no longer appropriate as empiric therapy.
Use vancomycin and high-dose ceftriaxone or cefotaxime as empiric therapy for presumed pneumococcal
meningitis in all individuals > 6 weeks of age. If an infant < 6 weeks of age has a Gram stain suggestive of
pneumococcal meningitis, use vancomycin and cefotaxime, pending sensitivity results.9
For penicillin and cephalosporin-resistant pneumococci, the use of cephalosporins alone, even in high doses,
may be inadequate. The addition of vancomycin +/− rifampin to high-dose cephalosporins appears to enhance
10 , 11
bacterial eradication in the CSF.
Table 3: Antibacterial Regimens for Specific Pathogens in Uncomplicated Bacterial Meningitis
Duration of
a
Pathogen First-line Alternative Therapy
S. pneumoniae Penicillin G Ceftriaxone or cefotaxime 10–14 days

(penicillin susceptible)
S. pneumoniae Cefotaxime or Consult infectious diseases 10–14 days

(intermediate- or high-level resistance ceftriaxone specialist
to penicillin, sensitive to Consult infectious
cephalosporins) diseases specialist
S. pneumoniae Cefotaxime or Consult infectious diseases 10–14 days

(intermediate- or high-level resistance ceftriaxone specialist
rd +
to penicillin and 3 generation
cephalosporins) Vancomycin
+/−
Rifampin
Consult infectious
diseases specialist
N. meningitidis Penicillin G Cefotaxime or ceftriaxone 5–7 days

(penicillin-sensitive)
N. meningitidis Cefotaxime or 5–7 days

(penicillin-resistant) b
ceftriaxone
H. influenzae type b Ampicillin Cefotaxime or ceftriaxone 7–10 days

(beta-lactamase negative)
Page 516
Therapeutic Choice
Duration of
a
Pathogen First-line Alternative Therapy
H. influenzae type b Ceftriaxone or 7–10 days

(beta-lactamase positive) cefotaxime
Group B streptococcus Penicillin Ampicillin or cefotaxime 14–21 days

+
Gentamicin for
c
synergy
L. monocytogenes Ampicillin Sulfamethoxazole/trimethoprim At least 21 days

+
Gentamicin for
synergy
Enterobacteriaceaed Ceftriaxone or Cefepime or meropenem 1 21 days

e (Gentamicin for
cefotaxime
+/− first 7–14 days)1
f
Gentamicin
a.
These are general guidelines only; some cases may require a longer duration of therapy.
b.
Superiority over high-dose penicillin has not been proven.
c.
The addition of gentamicin provides in vitro and in vivo synergy. Gentamicin therapy should be continued for three to seven
days, but may be longer in the case of delayed sterilization of the CSF.
d.
Therapy may be different depending on suspected pathogen and susceptibilities.
e.
Ampicillin can be used if organism is susceptible.
f.
Pediatric guidelines recommend addition of gentamicin; recommended in adults only when organism is P. aeruginosa .
Adjunctive Corticosteroids
The rationale behind adjunctive therapy with dexamethasone is that it will decrease the inflammatory response in
the CNS, thereby limiting neurologic sequelae.
A theoretical concern regarding the use of dexamethasone in meningitis is the potential for delayed sterilization of
the CSF (due to altered CSF drug penetration) in individuals treated with vancomycin for resistant S. pneumoniae .
There are no large clinical studies to answer this question. The addition of rifampin to the antibacterial regimen
4 ,
should be strongly considered if resistant pneumococci are isolated in a patient who has received dexamethasone.
12
The effect of dexamethasone on long-term cognitive function remains unclear. Therefore, careful follow-up of these
patients is required.
Children
A meta-analysis of randomized controlled trials in children performed between 1988 and 1996 showed a beneficial
effect of adjunctive dexamethasone therapy in reducing severe hearing loss in children with H. influenzae type b
meningitis. In meningitis caused by S. pneumoniae, the use of dexamethasone showed a trend in protecting against
hearing loss. If dexamethasone was given before or at the time of antibacterial administration, the benefit became
significant.13
The use of adjunctive dexamethasone in children > 6 weeks of age with community-acquired bacterial meningitis
may be considered after weighing the potential benefits and risks. Consultation with an infectious diseases specialist
is warranted. The recommended dose for children is 0.6 mg/kg/day in four divided doses or 0.8 mg/kg/day in two
9
divided doses, for two to four days. This should be initiated either before or with the first dose of antibacterials.
Adults
Page 517
Therapeutic Choice
A study in adults treated with dexamethasone did not show a significant beneficial effect on neurologic sequelae
including hearing loss, but did demonstrate a reduction in unfavourable outcomes and mortality. The majority of
these study patients had pneumococcal meningitis. Benefits were not seen in subgroups with meningitis caused by
other bacteria, although patient numbers in those groups were small. In all groups, dexamethasone appeared to be
the most beneficial in patients with moderate-to-severe disease on the Glasgow Coma Scale.14 A systematic
review of adjunctive steroid therapy in adults with acute bacterial meningitis showed that steroids
significantly reduced mortality. However, the beneficial effect was statistically significant only in
pneumococcal meningitis, where the number of deaths was greatest. There was a trend toward
significant reduction in neurologic sequelae.15 For adults, the use of adjunctive dexamethasone is
recommended in cases of community-acquired bacterial meningitis where S. pneumoniae is the known
4
or suspected pathogen. Useful Info?
The dose for adults has been variable in published studies. A dose of 10 mg every six hours for four days has been
14
used. Practice guidelines from The Infectious Diseases Society of America recommend 0.15 mg/kg every six hours
for two to four days, commencing either before or with the first dose of antibacterials.4 Some experts recommend
discontinuing corticosteroids if the pathogen is determined not to be S. pneumoniae;4 however, this is
12
controversial.
Prevention
Vaccines
With the implementation in Canada of universal infant immunization programs with conjugated H. influenzae
type b, S. pneumoniae and N. meningitidis type C vaccines, the rates of bacterial meningitis have decreased
significantly. There is also evidence of the development of herd immunity (protection of unvaccinated
individuals extending from immunization of a majority of the population).
The conjugated vaccine against H. influenzae type b has led to the virtual disappearance of meningitis due to
this pathogen. The conjugated pneumococcal vaccine is > 95% effective in preventing invasive disease caused
16
by the seven serotypes included in the vaccine.
The conjugated meningococcal vaccine against N. meningitidis type C has a reported efficacy of > 90% against
17
invasive infection. In 2006, a quadrivalent conjugate meningococcal vaccine against N. meningitidis types
A,C,W,Y-135 became available in Canada for use in people over the age of 2 years. The impact of these
vaccines on the incidence of meningococcal meningitis in older children and adults is not yet clear and will need
to be evaluated if universal immunization programs are implemented.
In individuals > 2 years of age, polysaccharide vaccines are safe and efficacious for the prevention of invasive
pneumococcal and meningococcal infections. Certain high-risk individuals may benefit from receiving both
conjugated and polysaccharide vaccines; consult the Canadian Immunization Guide, seventh edition, 2006 (see
Suggested Readings).
Vaccination to prevent meningitis is recommended in Canada for certain high-risk individuals. These
recommendations are outlined in the Canadian Immunization Guide, seventh edition, 2006
( see Suggested Readings).
Intrapartum Prophylaxis
The administration of intrapartum antibacterials to prevent mother-to-child transmission significantly reduces

18
the incidence of early-onset invasive neonatal GBS infections.
, 20
Post-exposure Prophylaxis19
Those in close contact with individuals who have meningitis caused by either H. influenzae type b or
N. meningitidis are at increased risk. Post-exposure prophylaxis is recommended, for close contacts only, to
reduce the risk of transmission.
The regimen following exposure to H. influenzae type b is rifampin 20 mg/kg (maximum dose 600 mg) orally
once daily for four days.
Following exposure to N. meningitidis, the prophylactic regimen for infants ≤ 1 month is rifampin 5 mg/kg
orally every 12 hours for two days. Children > 1 month should receive rifampin 10 mg/kg (maximum 600 mg)
every 12 hours for two days or a single dose of ceftriaxone 125 mg im. For adults, options include a single dose
of ciprofloxacin 500 mg orally (if > 18 years), a single dose of ceftriaxone 250 mg im (if > 12 years) or
rifampin 600 mg orally every 12 hours for two days.
In pregnant women, ceftriaxone is recommended instead of rifampin or ciprofloxacin.
Page 518
Therapeutic Choice
In cases of meningitis involving either N. meningitidis or H. influenzae , the index patient should also receive
prophylaxis prior to discharge to eradicate bacterial carriage, unless cefotaxime or ceftriaxone was used for
treatment.
Therapeutic Tips
In the case of empiric antimicrobial therapy consisting of vancomycin and a cephalosporin, give the
cephalosporin first to ensure initial broad coverage and penetration into the CSF.
With ventriculoperitoneal shunt–associated meningitis, successful treatment should include removal of the shunt
with insertion of an external ventricular drain in addition to antimicrobial therapy.
Table 4: Intravenous Antibacterial Therapy for Bacterial Meningitis 4 , 19 , 21 , 21 , 22
a
Drug Cost
Class Antibacterial Dose Adverse Effects Interactions
Penicillins penicillin G Neonates ≤ 7 days: Rash, Tetracycline, $

generics ≤ 2 kg: 100 000 U/kg/day hypersensitivity, drug erythromycin may
divided Q12H fever, hemolytic ↓ effectiveness.
anemia, interstitial
nephritis, seizures
> 2 kg: 150 000 U/kg/day (with high doses).
divided Q8H
Group B streptococcus:
250 000–450 000 U/kg/day
divided Q8H
Neonates > 7 days:
< 1.2 kg:
100 000 U/kg/day divided
Q12H
1.2–2 kg:
Q8H
> 2 kg: 200 000 U/kg/day
divided Q6H
Q4–6H
Older infants and
children:
Q4–6H
Max: 24 million U/day
Adults: 20–24 million

U/day divided Q4–6H
Penicillins ampicillin Neonates ≤ 7 days: Rash, ↑ incidence of $$$

generics ≤ 2 kg: 100 mg/kg/day hypersensitivity, rash with
divided Q12H diarrhea, vomiting, concurrent use of
drug fever, seizures allopurinol.
(with high doses).
> 2 kg: 150 mg/kg/day
divided Q8H
200 mg/kg/day divided
Q8H
Neonates > 7 days:
< 1.2 kg: 100 mg/kg/day
divided Q12H
Page 519
Therapeutic Choice
a
Drug Cost
1.2–2 kg: 150 mg/kg/day
divided Q8H
> 2 kg: 200 mg/kg/day
divided Q6H
300–400 mg/kg/day
divided Q4–6H
Older infants and
children:
200–400 mg/kg/day
divided Q4–6H
Adults:
2 g Q4H
Max: 12 g/day
Cephalosporins cefotaxime Neonates ≤ 7 days: Hypersensitivity, $$$$$

Claforan < 2 kg: 100 mg/kg/day phlebitis, diarrhea,
divided Q12H pseudomembranous
colitis, transient
elevation in liver
≥ 2 kg: enzymes; leukopenia;
100–150 mg/kg/day neutropenia,
divided Q8–12H eosinophilia;
Neonates > 7 days: thrombocytopenia.
1.2–2 kg: 150 mg/kg/day Seizures,
divided Q8H nephrotoxicity with
large doses.
> 2 kg: 150–200

mg/kg/day divided Q6–8H
6 wk–12 y:
300 mg/kg/day divided
b
Q6H
> 12 y:
2 g Q4–6H
Max: 12 g/day
Cephalosporins ceftriaxone Infants and children: Hypersensitivity, Do not $$$$$

Rocephin 100 mg/kg phlebitis, diarrhea, reconstitute or
Q12H × 3 doses, then pseudomembranous mix with calcium-
Q24H colitis, transient containing
elevation in liver solutions as a
enzymes; leukopenia; insoluble
Adults: neutropenia, precipitate may
2 g Q12–24H eosinophilia; form.
thrombocytopenia. Contraindicated in
Max: 4 g/day Seizures, neonates if a
nephrotoxicity with calcium-
large doses. containing iv
solution is or will
be required
during care.
Page 520
Therapeutic Choice
a
Drug Cost
Do not administer
simultaneously
with calcium-
containing iv
solutions via a Y-
site.
Administration
may be done
sequentially
provided the
infusion lines are
thoroughly
flushed between
infusions.
Cephalosporins ceftazidime Neonates ≤ 7 days: Hypersensitivity, $$$$$

Ceftazidime for < 2 kg: 100 mg/kg/day phlebitis, diarrhea,
Injection USP, divided Q12H pseudomembranous
Fortaz colitis, transient
elevation in liver
≥ 2 kg: enzymes; leukopenia;
100–150 mg/kg/day neutropenia,
divided Q8–12H eosinophilia;
Infants > 7 days and thrombocytopenia.
children: Seizures,
150 mg/kg/day divided nephrotoxicity with
Q8H large doses.
Adults:
2 g Q8H
Max: 6 g/day
Aminoglycosides gentamicin Neonates ≤ 7 days: Nephrotoxicity: ↑ risk ↑ toxicity with use of $$

generics < 1.2 kg: 2.5 mg/kg Q12H with ↑ dose and amphotericin B,
duration. magnesium,
Ototoxicity. cephalosporins,
Neonates > 7 days and penicillins, loop
older children: Levels should be diuretics,
1.2–2 kg: 2.5 mg/kg closely monitored to vancomycin,
Q8–12H reduce incidence of cisplatin,
toxicity. cyclosporin and
indomethacin.
> 2 kg: 2.5 mg/kg Q8H
Adults:
1–2 mg/kg Q8H
Glycopeptides vancomycin Neonates ≤ 7 days: Flushing, hypotension May cause $$$$$

Vancocin, < 1.2 kg: 15 mg/kg Q24H with rapid iv ototoxicity,
Vancomycin infusion; phlebitis. nephrotoxicity if
Hydrochloride receiving other
USP, generics 1.2–2 kg: 10–15 mg/kg drugs with these
Q12–18H effects.
> 2 kg: 10–15 mg/kg Q8–
12H
Page 521
Therapeutic Choice
Drug Costa
Neonates > 7 days to 6
wk:
< 1.2 kg: 15 mg/kg Q24H
1.2–2 kg: 10–15 mg/kg Q8

–12H
> 2 kg: 10–15 mg/kg Q8H
Infants > 6 weeks and
children:
60 mg/kg/day divided Q6H
Adults:
500 mg Q6H or 1 g Q12H
Max: 4 g/day
a.
Cost per day based on 70 kg body weight; includes drug cost only.
b.
High-dose cefotaxime should be used for presumed resistant pneumococcal meningitis. Dose can be decreased to 200
mg/kg/day divided Q6H once it is known that the organism is susceptible to cephalosporins.
Legend: $ < $25 $$ $25–50 $$$ $50–75 $$$$ $75–100 $$$$$ $100–140
Suggested Readings
Infectious Diseases and Immunization Committee, Canadian Paediatric Society (CPS). Therapy of suspected bacterial
meningitis in Canadian children six weeks of age and older. Paediatr Child Health 2001;6(3):147-52.
Kaplan SL. Clinical presentations, diagnosis, and prognostic factors of bacterial meningitis. Infect Dis Clin North Am
1999;13(3):579-94, vi-vii.
Kaplan SL, Mason EO. Mechanisms of pneumococcal antibacterial resistance and treatment of pneumococcal
infections in 2002. Pediatr Ann 2002;31(4):250-60.
National Advisory Committee on Immunization. Canadian immunization guide 2006. 7th ed. Ottawa (ON): Public
Health Agency of Canada, Infectious Disease and Emergency Preparedness Branch; 2006. Available from:
http://www.phac-aspc.gc.ca/publicat/cig-gci/pdf/cig-gci-2006_e.pdf Accessed March 26 2007.
Quagliarello V, Scheld WM. Bacterial meningitis: pathogenesis, pathophysiology, and progress. N Engl J Med
1992;327(12):864-72.
Straus SE, Thorpe KE, Holroyd-Leduc J. How do I perform a lumbar puncture and analyze the results to diagnose
bacterial meningitis? JAMA 2006;296(16):2012-22.
Tunkel AR, Hartman BJ, Kaplan SL et al. Practice guidelines for the management of bacterial meningitis. Clin Infect
Dis 2004;39(9):1267-84.
References
1. Schaad UB. Rev Med Microbiol 1997;8:171-8.
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2. Straus SE, Thorpe KE, Holroyd-Leduc J. How do I perform a lumbar puncture and analyze the results to
diagnose bacterial meningitis? JAMA 2006;296(16):2012-22.
3. Saez-Llorens X et al. Acute bacterial meningitis beyond the newborn period. In: Long SS et al., editors.
Principles and practice of pediatric infectious diseases. 2nd ed. New York (NY): Churchill Livingstone; 2003.
4. Tunkel AR, Hartman BJ, Kaplan SL et al. Practice guidelines for the management of bacterial meningitis. Clin
Infect Dis 2004;39(9):1267-84.
5. Maxson S, Lewno MJ, Schutze GE. Clinical usefulness of cerebrospinal fluid bacterial antigen studies. J Pediatr
1994;125(2):235-8.
6. Tarafdar K, Rao S, Recco RA et al. Lack of sensitivity of the latex agglutination test to detect bacterial antigen
in the cerebrospinal fluid of patients with culture-negative meningitis. Clin Infect Dis 2001;33(3):406-8.
7. Leib SL, Boscacci R, Gratzl O et al. Predictive value of cerebrospinal fluid (CSF) lactate level versus CSF/blood
glucose ratio for the diagnosis of bacterial meningitis following neurosurgery. Clin Infect Dis 1999;29(1):69-
74.
8. Hasbum R, Abrahams J, Jekel J et al. Computed tomography of the head before lumbar puncture in adults with
suspected meningitis. N Engl J Med 2001;345(24):1727-33.
9. Infectious Diseases and Immunization Committee, Canadian Paediatric Society (CPS). Therapy of suspected
bacterial meningitis in Canadian children six weeks of age and older. Paediatr Child Health 2001;6(3):147-52.
10. Doit C, Barre J, Cohen R et al. Bactericidal activity against intermediately cephalosporin-resistant
Streptococcus pneumoniae in cerebrospinal fluid of children with bacterial meningitis treated with high doses
of cefotaxime and vancomycin. Antimicrob Agents Chemother 1997;41(9):2050-2.
11. Klugman KP, Friedland IR, Bradley JS. Bactericidal activity against cephalosporin-resistant Streptococcus
pneumoniae in cerebrospinal fluid of children with acute bacterial meningitis. Antimicrob Agents Chemother
1995;39(9):1988-92.
12. van de Beek D, de Gans J, Tunkel AR et al. Community-acquired bacterial meningitis in adults. N Engl J Med
2006;354(1):44-53.
13. McIntyre PB, Berkey CS, King SM et al. Dexamethasone as adjunctive therapy in bacterial meningitis. A meta-
analysis of randomized clinical trials since 1988. JAMA 1997;278(11):925-31.
14. de Gans J, van de Beek D et al. Dexamethasone in adults with bacterial meningitis. N Engl J Med 2002;347
(20):1549-56.
15. van de Beek D, de Gans J, McIntyre P et al. Steroids in adults with acute bacterial meningitis: a systematic
review. Lancet Infect Dis 2004;4(3):139-43.
16. Black S, Shinefield H, Fireman B et al. Efficacy, safety and immunogenicity of heptavalent pneumococcal
conjugate vaccine in children. Northern California Kaiser Permanente Vaccine Study Center Group. Pediatr
Infect Dis J 2000;19(3):187-95.
17. Balmer P, Borrow R, Miller E. Impact of meningococcal C conjugate vaccine in the UK. J Med Microbiol
2002;51(9):717-22.
18. Schrag S, Gorwitz R, Fultz-Butts K et al. Prevention of perinatal group B streptococcal disease. Revised
guidelines from CDC. MMWR Recomm Rep 2002;51(RR-11):1-22.
19. American Academy of Pediatrics. Meningococcal infections. In: Pickering LK, editor. 2000 Red book: report of
the Committee on Infectious Diseases. 25th ed. Elk Grove Village (IL): American Academy of Pediatrics; 2000.
20. American Academy of Pediatrics. Haemophilus influenzae infections. In: Pickering LK, editor. 2000 Red book:
report of the Committee on Infectious Diseases. 25th ed. Elk Grove Village (IL): American Academy of
Pediatrics; 2000.
21. Taketomo CK. Pediatric dosage handbook: including neonatal dosing, drug administration & extemporaneous
preparations. 9th ed. Hudson (OH): Lexi-Comp; 2002.
22. Wubbel L, McCracken GH. Management of bacterial meningitis: 1998. Pediatr Rev 1998;19(3):78-84.
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e-Therapeutics+ : Therapeutics : Infectious Diseases: Community-acquired Pneumonia Page 1 of 18
Therapeutic Choice
Print Close
Infectious Diseases: Community-acquired Pneumonia

Thomas J. Marrie, MD, FRCPC
Community-acquired pneumonia (CAP) is a common and a serious illness. While most (about 80%) cases are
treated at home, the mortality rate among those requiring hospitalization is 8–10% and up to 40% for those
1
requiring treatment in an intensive care unit (ICU). In general, the clinical presentation of CAP does not allow for
an etiologic diagnosis. Many microorganisms cause CAP (Table 1). Mycobacterium tuberculosis is an uncommon and
often forgotten cause of pneumonia. Consider M. tuberculosis particularly in those with pneumonia who are foreign
born, have HIV or other immune deficiencies and those who are residents of long-term care facilities. Also consider
tuberculosis in patients who do not respond to treatment.
Table 1: Pathogens in Community-acquired Pneumonia2 , a
Pneumonia treated on an ambulatory basis
Streptococcus pneumoniae
Mycoplasma pneumoniae
Haemophilus influenzae
Chlamydophila pneumoniae
Respiratory virusesb
Moraxella catarrhalis
Mycobacterium tuberculosis (uncommon)
Pneumonia requiring admission to hospital ward
Chlamydophila pneumoniae
Haemophilus pneumoniae
Legionella spp.
Aspirationc
Gram-negative bacilli (e.g., Escherichia coli, Klebsiella spp., Enterobacter spp., Serratia spp., Pseudomonas
aeruginosa)
Mixed or polymicrobial etiology (e.g., viral plus bacterial)
Respiratory virusesb
Pneumonia requiring admission to hospital intensive care unit
Staphylococcus aureus
Legionella spp.
Gram-negative bacilli (e.g., Escherichia coli, Klebsiella spp., Enterobacter spp., Serratia spp., Pseudomonas
aeruginosa)
a.
Stratification for severity of illness based on ambulatory or hospital site of care. Pathogens within each stratification are listed
in decreasing order of frequency of occurrence.
b.
Influenza A and B, adenovirus, parainfluenza, respiratory syncytial virus, human metapneumovirus. Respiratory viruses
3
account for about 15% of CAP cases.
c.
Polymicrobial; etiology depends on state of oral hygiene (e.g., periodontal disease — anaerobes; edentulous state — viridans
streptococci) and age (aerobic gram-negative bacilli in elderly persons, especially those in long-term care facilities)
Adapted from Mandell LA, Wunderink RG, Anzueto A et al. Infectious Diseases Society of America/American Thoracic Society
consensus guidelines on the management of community-acquired pneumonia in adults. Clin Infect Dis 2007;44(Suppl 2):S27-
Page 524
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72.
Each microbe can result in an illness that spans the spectrum from mild to life-threatening disease. Streptococcus
pneumoniae accounts for about 50% of all cases of CAP that require hospital admission.1
This chapter addresses treatment and prevention of community-acquired pneumonia.
Goals of Therapy
Assess severity of pneumonia. The pneumonia-specific severity of illness score guides the appropriate location
for treatment, i.e., home, hospital ward or intensive care unit (Table 2). Alternatively, consider the functional
status of the patient in the week or two prior to admission. For patients who are fully functional, walking with
assistance, wheelchair bound and bedridden, the mortality rate is 4%, 5.6%, 20% and 25%, respectively4
Eradicate infecting pathogen
Relieve symptoms such as fever, cough, pleuritic chest pain, sputum production and/or dyspnea
Promptly recognize and treat complications such as metastatic infection (meningitis, purulent pericarditis,
endocarditis, osteomyelitis), empyema, cavitation, pneumothorax, septic shock, syndrome of inappropriate
antidiuretic hormone (SIADH), respiratory failure and/or worsening of comorbid conditions (ischemic heart
disease, diabetes mellitus)
Provide compassionate end-of-life care if this emerges
Investigations
History and physical examination with particular attention to:

symptoms: cough, shortness of breath, pleuritic chest pain, hemoptysis, sputum production, fever, chills,
myalgia, headache, arthralgia, confusion (new onset may be common in the elderly)
Check patients with ongoing fever (oral temperature >37.5°C) for empyema. Perform drainage early. Drug
fever should be kept in mind and the diagnosis reconsidered if the patient is not improving.
history of recent travel and other risk factors for pneumonia such as tobacco smoking; excessive alcohol
ingestion; hobbies such as exploring old caves; recent loss of consciousness; comorbid illnesses. Some of
these risk factors may influence recovery
physical findings: general appearance, e.g., respiratory distress, well or chronically ill or acutely ill.
Crackles, wheezes, findings of consolidation of pulmonary tissue (dullness to percussion, increased tactile
and vocal fremitus, bronchial breathing, whispered pectoriloquy), pleural friction rub, altered mental status
vital signs: respiratory rate ≥30 breaths/minute is the single most sensitive and specific sign of severe
pneumonia in adults; ≥25 for patients who are <50 years of age
oxygenation status: measure oxygen saturation in all patients with CAP presenting to emergency. If oxygen
saturation <92% in a COPD patient, perform arterial blood gas
chest radiograph: posterior-anterior and lateral views. Consider a CT scan of the chest in all those who
have a negative chest radiograph but clinically suspect pneumonia
Laboratory tests for hospitalized patients:
electrolytes, glucose, BUN, creatinine, CBC and differential white blood cell count
consider blood cultures in critically ill patients: two samples drawn at separate sites. Anaerobic culture is
generally not necessary
sputum for Gram stain and culture if a good quality specimen can be obtained. Confirm sputum sample is
from the lower respiratory tract (<10 squamous epithelial cells/low power field). Special requests such as
culture for M. tuberculosis, Legionella, fungi such as Blastomyces dermatiditis or Cryptococcus are dictated
by the clinical setting. Consult a microbiologist.
urine for Legionella antigen (will only detect serogroup 1 infections), if high clinical suspicion for
Legionnaires’ disease or for patients who require ICU admission because of progressive pneumonia. If
available, use PCR test on sputum or other respiratory secretions that can amplify DNA of all Legionella
species
consider rapid or culture tests for influenza during influenza season
consider serologic studies as dictated by clinical setting, e.g., suspected Mycoplasma pneumoniae
pneumonia. Obtain an acute or a 10- to 14-day convalescent phase serum sample. If Legionnaires’ disease
is suspected, collect a convalescent phase sample 6 weeks following acute phase serum sample. Hantavirus
infection and Q fever (Coxiella burnetii) are best diagnosed serologically
for patients admitted to hospital and who undergo bronchoalveolar lavage in addition to routine testing
samples, some laboratories have the capacity to use nucleic acid amplification tests to detect nucleic acid of
Legionella spp, M. pneumoniae, Influenza A and B, respiratory syncytial virus, adenovirus, human
metapneumovirus, parainfluenza viruses, coronaviruses, rhinoviruses
Treatment of Community-acquired Pneumonia
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Therapeutic Choices
Therapeutic Choices
Successful management of pneumonia (Figure 1 - Initial Management of Community-acquired Pneumonia (CAP)) is

based on an accurate assessment of illness severity (Table 2) and selection of the most appropriate site for
2
treatment.
Table 2: Pneumonia-specific Severity of Illness (PSI) Score
Patient characteristic Points assigned
Males age (years)
Females age (years) minus 10
Nursing home resident 10
Comorbid illness
Neoplastic disease 30
Liver disease 20
Heart failure 10
Cerebrovascular disease 10
Renal disease 10
Physical examination findings
Altered mental status 20
Respiratory rate ≥30 breaths/min 20
Systolic blood pressure <90 mm Hg 20
Temperature <35°C or ≥40°C 15
Pulse ≥125 beats/min 10
Laboratory findings
Arterial pH <7.35 30
Blood urea nitrogen >11 mmol/L 20
Sodium <130 mmol/L 20
Glucose ≥14 mmol/L 10
Hematocrit <30% 10
Partial pressure of arterial oxygen <60 mm Hg 10
Pleural effusion 10
Reproduced with permission from Fine MJ, Auble TE, Yealy DM et al. A prediction rule to identify low-risk patients with community
-acquired pneumonia. N Engl J Med 1997;336(4):243-50. Copyright © 1997 Massachusetts Medical Society. All rights reserved.
The PSI score is designed to predict 30-day mortality rates among patients with CAP and is a validated tool for
determining the need for admitting patients to hospital.5 , 6 If the score is ≤90, treat as outpatient. Some patients in
this category may require hospital admission (see Figure 1 - Initial Management of Community-acquired Pneumonia
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Therapeutic Choice
(CAP)). If the PSI score is ≥91, treat in hospital. However, physician judgment is paramount in the assessment of
any patient and should always override any scoring system.
SMRT-CO is a tool that accurately predicts which patients with CAP are likely to require intensive respiratory or
vasopressor support (IRVS).7 It measures at initial patient assessment the systolic blood pressure (<90 mmHg),
multilobular chest radiography involvement, respiratory rate (≥25 breaths/min for those ≤50 years and ≥30 for
those >50 years), tachycardia (≥125 bpm), confusion and oxygenation. SMRT-CO scores ≥2, increase the likelihood
of the patient requiring IRVS (see Figure 1 - Initial Management of Community-acquired Pneumonia (CAP)). SMART-
7
COP includes the above assessments plus measurements of serum albumin and pH.
Initial empiric antibiotic therapy (Figure 1 - Initial Management of Community-acquired Pneumonia (CAP)) is based
on the likely causative pathogen after considering specific risk factors for each patient (e.g., COPD, smoking). Once
the etiology is established (Table 3), tailor the antibiotic and/or antifungal therapy paying heed to local
susceptibility patterns of bacteria (e.g., S. pneumoniae) and local epidemiologic patterns (e.g., outbreaks or
endemic foci of Legionella species and dimorphic fungi such as Histoplasma). Antibiotics used in the treatment of
CAP are described in Table 4.
Duration of Antibiotic Therapy
For patients who are well enough to be treated on an ambulatory basis, a minimum of 5 days of
2
antibiotic therapy is required. Patients who are hospitalized and who respond to treatment within 48
1
hours can be treated with 10 days of antibiotics. Specific etiologies may require longer treatment such
as 21 days for severe Legionnaires' disease, 14 days for bacteremic aerobic gram-negative bacilli
1
pneumonia and up to 21 days for pneumonia caused by Pseudomonas aeruginosa. Useful Info? Empyema
requires drainage and treatment for 14 days or longer. Prolonged therapy is necessary when a lung abscess
complicates pneumonia. Antibiotics are given intravenously until the patient has been afebrile for 72 hours and then
orally until the cavity has closed, a process that may take 12–16 weeks.
Table 3: Antibiotic Therapy for Community-acquired Pneumonia Caused by Specific Pathogens2
Penicillin nonresistant (MIC <2 mg/L)

Initial therapy: penicillin G, amoxicillin.
Alternatives: macrolide, po cephalosporins (cefprozil, cefuroxime), iv cephalosporins (cefuroxime,
a
ceftriaxone, cefotaxime), clindamycin, doxycycline, respiratory fluoroquinolones
Penicillin resistant (MIC ≥2 mg/L)
a
Initial therapy: cefotaxime, ceftriaxone, po or iv respiratory fluoroquinolone.
Alternatives: vancomycin, linezolid, high-dose amoxicillin (3 g/day for penicillin MIC ≤4 mg/L)
2nd or 3rd generation cephalosporin or amoxicillin/clavulanate, fluoroquinolones, doxycycline, azithromycin,
clarithromycin. Amoxicillin monotherapy if non-beta-lactamase producing.
Staphylococcus aureus
Methicillin-susceptible: cloxacillin, cefazolin, clindamycin
Methicillin-resistant: vancomycin, linezolid, tigecycline
Legionella species (Legionnaires' disease)

Fluoroquinolones or azithromycin, or doxycycline (alternative)
Mycoplasma pneumoniae, Chlamydophila pneumoniae

Macrolides or tetracyclines, fluoroquinolones (alternative)
Coxiella burnetii (Q fever)

Doxycycline, fluoroquinolones, macrolides (alternative—although some strains may be resistant)
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Therapeutic Choice
Aerobic gram-negative bacilli (e.g., Escherichia coli, Enterobacter spp., Klebsiella spp., Serratia spp, Proteus
spp.)
3rd generation cephalosporin, carbapenemb (some Enterobacter spp. and uncommon strains of E. coli and
Klebsiella spp. produce cephalosporinases and initial therapy should be with piperacillin/tazobactam)
Pseudomonas aeruginosa
c
Antipseudomonal beta-lactam plus ciprofloxacin or aminoglycoside OR aminoglycoside plus ciprofloxacin
(alternative)
a.
Respiratory fluoroquinolones: levofloxacin, moxifloxacin.
b.
Carbapenem: ertapenem, imipenem/cilastatin, meropenem.
c.
Antipseudomonal beta-lactam: aztreonam, cefepime, ceftazidime, imipenem, meropenem, piperacillin, ticarcillin.
Aspiration Pneumonia
Aspiration pneumonia denotes two distinct clinical entities. The first is aspiration pneumonitis, which is aspiration of
gastric contents (usually sterile as long as there is gastric acid present) into the lungs with a resultant inflammatory
response. The second is pneumonia resulting from the aspiration of oropharyngeal flora into the lung with resultant
bacterial infection. Risk factors for aspiration include altered level of consciousness, incompetent gastroesophageal
junction, elevated intragastric pressure or volume, affected swallowing mechanisms secondary to neurologic
8
diseases and interference of glottic closure because of neuromuscular diseases.
Younger patients, in general, aspirate due to altered level of consciousness (seizures, drugs, alcohol) and older
patients aspirate due to neurologic diseases that affect the swallowing mechanism. Patients with aspiration
9
pneumonia require admission to ICU more commonly than those with CAP due to other causes.
Aspiration pneumonitis does not require antibiotic therapy. Patients with aspiration pneumonia who have poor
dental hygiene or putrid sputum or who are alcoholics (anaerobic infection suspected), should be treated with
metronidazole, clindamycin, beta-lactam/beta-lactamase inhibitor combinations, carbapenems and fluoroquinolones
with established anaerobic activity (e.g., moxifloxacin). Treat patients without these specific risk factors for
anaerobic infection with standard antibiotics (Figure 1 - Initial Management of Community-acquired Pneumonia
(CAP)).
Methicillin-resistant Staphylococcus aureus (MRSA) Pneumonia10
Methicillin-resistant S. aureus, an uncommon yet emerging cause of CAP, accounts for 1 to 5% of cases. MRSA
pneumonia is more common in patients with severe pneumonia who require treatment in an intensive care unit and
among residents in long-term care facilities. S. aureus, both methicillin-sensitive (MSSA) and MRSA, is about the
third most frequent cause of bacteremic pneumonia in the community. S. aureus pneumonia has classically been
described as a secondary bacterial pathogen in the setting of a primary influenza virus upper respiratory tract
11 , 12 , 13
infection. In the setting of bacteremic S. aureus pneumonia, exclude endocarditis (often right sided),
especially if multiple rounded opacities are present on the chest radiograph (septic emboli). More recently,
community-acquired MRSA infections have been caused by strains producing the Panton-Valentine leukocidin (PVL),
known to be associated with tissue necrosis. To date, PVL S. aureus infections including pneumonia have been more
14 , 15 16
common in young patients. Vancomycin and linezolid are effective choices.
Tigecycline is a new glycylcycline, broad-spectrum, intravenous antibiotic that was not inferior to levofloxacin in
17
clinical trials of CAP. In a murine model of M. pneumoniae pneumonia, tigecycline significantly improved lung
18
histologic inflammation and reduced pulmonary cytokines and chemokines. It does have MRSA activity but its role
in the treatment of MRSA pneumonia is still unclear.19
Do not use daptomycin in MRSA pneumonia as it is inactivated by pulmonary surfactant.20
There is insufficient evidence on which to base firm recommendations for the treatment of severe PVL- producing
MRSA pneumonia. In seriously ill patients, consider blocking toxin production by using clindamycin in combination
with an anti-MRSA agent.
Influenza Pneumonia
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The last major pandemic of influenza in 1918 caused the deaths of more than 20 million persons, and made almost
1 billion people ill.21 The majority of deaths resulted from secondary bacterial pneumonia.22
Influenza A virus infection can be treated with the neuramidase inhibitors, oseltamivir and zanamivir or with
23 , 24
amantadine. (see Infectious Diseases: Influenza) The appropriate treatment will vary from year to year
depending on the susceptibilities of the season's circulating strains. Unlike uncomplicated influenza, treatment may
2
be initiated in hospitalized patients with influenza pneumonia even after 48 hours of the onset of symptoms. The
major concern is bacterial superinfection and this has to be treated immediately.
Prevention of Community-acquired Pneumonia
Vaccines
Smoking Cessation
Encourage smoking cessation (see Psychiatric Disorders: Smoking Cessation). Tobacco smoking is associated with a
25
two-fold increase in risk for invasive pneumococcal pneumonia. It is likely that cessation of tobacco smoking will
reduce the rate of pneumonia, but there are no data from clinical trials. Nevertheless, this recommendation is likely
to have many benefits, including slowing the age-related decline in lung function and reducing the risk of lung
cancer.
Vaccines
, 27
Influenza Vaccine26
Up to now standard teachings have held that: yearly influenza vaccination of the elderly reduces the rate of
28
admission to hospital for both pneumonia and heart failure ; hospitalized patients with CAP demonstrated
29
improved survival from prior vaccination ; and immunization of health care workers against influenza reduces the
30
mortality rate due to influenza in patients. However, there is a suggestion that the beneficial effects of influenza
vaccine may represent a “healthy user effect” in that a 51% reduction in mortality with influenza vaccination was
31
observed in patients who developed CAP outside the influenza season. In addition, a Cochrane review concluded
that there was no credible evidence that vaccinating health care workers protected elderly institutionalized persons
32
against influenza or its complications. Despite this, until Canadian authorities recommend otherwise, the current
guidelines for influenza vaccination should be followed (see Infectious Diseases: Influenza).
Pneumococcal Vaccine
A 23-valent capsular polysaccharide vaccine is available for use in adults.33 The most common capsular
polysaccharide types of S. pneumoniae causing bacteremic pneumonia are represented in the vaccine.33 A booster
dose given 5 years after the first dose is warranted in patients who are at increased risk of pneumococcal diseases
such as those with chronic renal failure or immunosuppressive conditions. Revaccinate patients who were <65 years
33
when they received their primary vaccination ≥5 years earlier. A polysaccharide-protein conjugate vaccine is
currently undergoing clinical trials, and may be more effective. A protein conjugate vaccine is available for use in
34
children and its widespread use has resulted in a reduction in invasive pneumococcal disease amongst adults. In
35
patients admitted to the hospital with CAP, prior pneumococcal vaccination reduced mortality and ICU admission.
Prevention of Aspiration Pneumonia
For patients at risk of aspiration, the “chin down” posture has been found to reduce the occurrence of aspiration
both before and during the swallow. This posture results in a posterior shift of the anterior pharyngeal structures,
narrowing the laryngeal entrance while widening the angle of the epiglottis to the anterior tracheal wall. The end
result is protection of the airway. Cleaning of the teeth and gingiva by caregivers after each meal reduced the
latency time of the swallowing reflex and increased substance P in the saliva of patients with dysphagia due to
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Therapeutic Choice
cerebrovascular disease. Substance P stimulates the neural pathways to improve the swallowing reflex. Elevation of
36
the head of the bed is also helpful in preventing aspiration pneumonia.
Therapeutic Tips
Administer an agent from a different therapeutic class if the patient has received antibiotics within the 3 months
prior to diagnosis of CAP.
Because of its lowered activity against H. influenzae, erythromycin monotherapy is not routinely recommended
in patients with COPD.
Switch patients from intravenous to an oral antibiotic when the following criteria are met:2 , 37 , 38 GI tract is
functioning normally (e.g., no vomiting, diarrhea or disorder compromising GI absorption); hemodynamically
stable; 2 temperature readings are normal (oral temperature < 37.5°C) over 16 hours in previously febrile
patients; normalized white blood cell count; subjective improvement in cough and shortness of breath; able to
consume oral medications. If blood cultures are positive, the duration of intravenous therapy is dictated by the
organism recovered from the blood.
Discharge the patient when the following criteria are met in addition to those above: absence of complications
from the pneumonia (e.g., empyema); absence of complications from comorbid illnesses (e.g., myocardial
infarction); absence of complications from treatment (e.g., severe adverse drug reactions); physiological
stability as indicated by an oxygen saturation of ≥92% while breathing room air at sea level for those who do
not have COPD (for patients with COPD, a return to baseline status is desirable), pulse rate of <100
2
beats/minute and respiratory rate ≤24 breaths/minute.
Prevent recurrent pneumonia in patients ≥65 years and in those suffering from recurrent episodes. A checklist
that includes a search for causes of aspiration and measures to prevent recurrent aspiration may be useful.
Review pneumococcal and influenza vaccine status and immunize if indicated.
If a pleural effusion is >1 cm on a decubitus chest film with the affected side down, aspirate and send for pH,
culture (aerobes, anaerobes, M. tuberculosis), white cell count, LDH and protein. A pH <7.2 suggests the need
for prompt drainage to avoid loculation and fibrotic pleural disease.
Perform follow-up chest radiographs for all tobacco smokers over age 35 and all patients over age 50. Two per
cent of all patients with CAP will have lung cancer and, in half of these, the cancer is not diagnosed on the
initial radiograph. Do the follow-up chest radiograph at the time of the follow-up visit, usually within 2 weeks
of presentation. If the pneumonia has not cleared, a repeat film should be done in 8 weeks; if the pneumonic
opacity is still present, further investigation such as bronchoscopy may be warranted.
Figure 1- Initial Management of Community-acquired Pneumonia (CAP)
Page 530
Therapeutic Choice
a. 1
Approximately 20% of patients in this category will require admission.
b.
Psychosocial and medical factors, e.g., can reliably take oral medications, exacerbation of underlying disease (diabetes, COPD,
heart failure), homelessness, may influence the decision to admit.
c.
Risk factors for DRSP include age <2 or >65 years, comorbid conditions, antibiotic use in the past 3 months, alcoholism,
2
immunosuppressive conditions and exposure to a child in a daycare centre.
d.
For patients who have received an antibiotic within the past 3 months, use another class of antibiotics.
e.
Respiratory fluoroquinolone: levofloxacin, moxifloxacin. Gemifloxacin is currently not approved for CAP. For hospitalized
patients, the dose of levofloxacin is 750 mg once daily for 5 days.
f.
Absolute indications for admittance into ICU: a) septic shock requiring vasopressors; b) acute respiratory failure requiring
endotracheal intubation and mechanical ventilation.
g.
Aztreonam is available through the Special Access Programme, Therapeutic Products Directorate, Health Canada
h.
Cefepime, imipenem, meropenem, piperacillin/tazobactam.
Abbreviations: CXR = chest x-ray; DRSP = drug-resistant S. pneumoniae; HD = high dose; ICU = intensive care unit; IRVS =
intensive respiratory or vasopressor support; PSI = pneumonia-specific severity of illness
Table 4: Anti-infectives for the Treatment of Pneumonia
Costa
Aminoglycosides gentamicin Conventional Nephrotoxicity, Aminoglycosides do not $

generics dosing: ototoxicity. penetrate pulmonary
1.5 mg/kg tissue very well.
Page 531
Therapeutic Choice
Costa
b Exhibits concentration-
DBW Q8H
iv dependent bacterial
Extended killing and
interval postantibiotic effect.
dosing: 4–7
b Coadministration of
mg/kg DBW
vancomycin or loop
once daily iv
diuretics may ↑ risk of
nephrotoxicity and
ototoxicity, respectively.
Coadministration of
penicillins in vivo or in
iv bags and syringes,
may result in
aminoglycoside
inactivation.
Aminoglycosides tobramycin Conventional Nephrotoxicity, Aminoglycosides do not $

generics dosing: ototoxicity. penetrate pulmonary
1.5 mg/kg tissue very well.
DBWb Q8H Exhibits concentration-
iv dependent bacterial
Extended killing and
interval postantibiotic effect.
dosing:
4–7 mg/kg Coadministration of
vancomycin or loop
DBWb once
diuretics may ↑ risk of
daily iv
nephrotoxicity and
ototoxicity, respectively.
Coadministration of
penicillins in vivo or in
iv bags and syringes,
may result in
aminoglycoside
inactivation.
Carbapenems ertapenem 1 g daily iv Anaphylaxis, ↑ seizure Indicated for S. $$$

Invanz risk (compromised renal pneumoniae (penicillin-
function, CNS susceptible strain only),
disorders, e.g., H. influenzae (beta-
history of seizures), lactamase negative
diarrhea, headache. strain only) or M.
catarrhalis.
Carbapenems imipenem/ cilastatin 500 mg Q6H Hypotension, nausea Antipseudomonal. For $$$$$
Primaxin iv with rapid infusion; patients with risk
seizure activity with factors for P.
high levels. aeruginosa.
Carbapenems meropenem 1 g Q8H iv Hypotension, nausea Antipseudomonal. For $$$$$

Merrem with rapid infusion; patients with risk
less likely than factors for P.
imipenem to cause aeruginosa.
seizures.
Cephalosporins, cefazolin 1– 2 g Q8H Anaphylaxis, rash, $-$$

first-generation Cefazolin for Injection, iv gastrointestinal
upset, renal and
other generics
hepatic dysfunction,
Page 532
Therapeutic Choice
Costa
phlebitis and pain at
site of im injection.
Cephalosporins, cefaclor 250 mg TID Anaphylaxis, rash, $

second- generics po gastrointestinal
generation upset, renal and
hepatic dysfunction.
Cephalosporins, cefprozil 500 mg BID Anaphylaxis, rash, $

second- Cefzil, generics po gastrointestinal
generation upset, renal and
Cephalosporins, cefuroxime axetil 500 mg BID Anaphylaxis, rash, Do not use for $
second- Ceftin, generics po gastrointestinal treatment of penicillin-
generation upset, renal and resistant S.
hepatic dysfunction. pneumoniae.
Cephalosporins, cefuroxime sodium 750 mg Q8H Anaphylaxis, rash, Do not use for $
second- generics iv gastrointestinal treatment of penicillin-
generation upset, renal and resistant S.
hepatic dysfunction, pneumoniae.
Cephalosporins, cefotaxime 1–2 g Q8H iv Anaphylaxis, rash, Can be used in $$-

third-generation Claforan gastrointestinal hepatobiliary disease. $$$
upset, renal and
Cephalosporins, ceftazidime 1–2 g Q8H iv Anaphylaxis, rash, $$$-

third-generation Fortaz, generics gastrointestinal $$$$$
upset, renal and
Cephalosporins, ceftriaxone 1–2 g Q24H Anaphylaxis, rash, Do not reconstitute or $$

third-generation Ceftriaxone for iv gastrointestinal mix with calcium-
upset, renal and containing solutions.
Injection USP,
hepatic dysfunction, Do not administer
Rocephin,
phlebitis and pain at simultaneously with
other generics
site of im injection. calcium-containing iv
solutions via a Y-site.
Administration may be
done sequentially
provided the infusion
lines are thoroughly
flushed between
39
infusions.
Cephalosporins, cefepime 1– 2 g Q12H Anaphylaxis, rash, Antipseudomonal; for $$

fourth- Maxipime, generics iv gastrointestinal patients with risk
generation upset, renal and factors for P.
hepatic dysfunction, aeruginosa.
Page 533
Therapeutic Choice
Costa
Fluoroquinolones ciprofloxacin po: 500– Gastrointestinal Ciprofloxacin is not a po: $

Cipro, generics 750 mg BID upset, headache, first-line agent for CAP. iv:
iv: 400 mg dizziness, Available as an oral $$$
Q12H photosensitivity, suspension.
hepatitis.
Cartilage toxicity: Ciprofloxacin-resistant
avoid in children. (MIC ≥4 mg/L) S.
pneumoniae isolates in
Canada in 2005 were
2.29%.
Concomitant antacids,
metal cations, sucralfate
↓ absorption of
fluoroquinolones.
Ciprofloxacin may ↓
theophylline or
cyclosporine
elimination; may
prolong the INR if given
with warfarin.
Fluoroquinolones levofloxacin po: 500 mg Gastrointestinal Levofloxacin 750 mg po: $

Levaquin, generics Q24H × 10 upset, headache, daily for 5 days is iv: $$
days or 750 dizziness, equivalent to 500 mg
mg Q24H × photosensitivity, 40
daily for 10 days.
5 days hepatitis. An alternative to β-
iv: 500 mg Cartilage toxicity: lactam/macrolide
once daily avoid in children. combination for patients
on hospital wards.
Can switch from iv to po

therapy while
maintaining serum
levels.
↓ absorption of
fluoroquinolones.
May ↑ warfarin effect.
Avoid in patients on
Class Ia or III
antiarrhythmics or with
prolonged QT interval.
Cases of severe liver

injury including liver
failure have been
reported.
Fluoroquinolones moxifloxacin 400 mg Gastrointestinal An alternative to β- po: $

Avelox Q24H po/iv upset, headache, lactam/macrolide iv:
dizziness, combination for patients $$$
photosensitivity, on hospital wards.
hepatitis. Can switch from iv to po
therapy while
Page 534
Therapeutic Choice
a
Cost
Cartilage toxicity: maintaining serum
avoid in children. levels.
↓ absorption of
fluoroquinolones.
Avoid in patients on
Class Ia or III
antiarrhythmics or with
prolonged QT interval.

failure have been
reported.
Glycopeptides vancomycin 1 g Q12H iv Infusion-related For MRSA-pneumonia. $$$$$

Vancocin, adverse effects occur Coadministration with
generics with shorter infusion aminoglycosides may ↑
times: intense risk of nephrotoxicity.
flushing (red man or
red neck syndrome),
hypotension.
Nephrotoxicity,
ototoxicity.
Glycylcyclines tigecycline 100 mg iv Nausea, vomiting, Contraindicated if $$$$$

Tygacil then 50 mg diarrhea, acute hypersensitivity with
Q12H pancreatitis (rare). tetracyclines as it is
structurally related.
Not indicated for severe
CAP or hospital-
acquired pneumonia
(HAP). Lower cure rates
and higher mortality has
been seen when used
for HAP.
Lincosamides clindamycin 300–450 mg Abdominal pain, Clindamycin-resistant S. $

Dalacin C, Dalacin C Q6H po nausea, vomiting, pneumoniae isolates in
Flavored Granules, 600 mg Q8H diarrhea, C. difficile Canada in 2005 was
iv colitis. 43
Dalacin C Phosphate 8%.
Solution Sterile, For suspected
aspiration; provides oral
generics
anaerobic coverage.
Macrolides, azithromycin po: 500 mg Better tolerated than Oral azithromycin given $
conventional Z-PAK, Zithromax, st erythromycin. daily × 5 days is
1 day then
generics 250 mg × Gastrointestinal equivalent to oral
4 days upset, rash, erythromycin QID ×
iv: 500 mg cholestatic hepatitis. 10 days.
daily × 7– A 5-day course of
10 days azithromycin is
adequate for mild to
moderate CAP.
Page 535
Therapeutic Choice
a
Cost
Azithromycin more
active than
clarithromycin for H.
influenzae.
Macrolides, clarithromycin Regular Better tolerated than Coadministration with $

conventional Biaxin, Biaxin XL, release: erythromycin. pimozide is
generics 500 mg BID Gastrointestinal contraindicated.
po upset, rash, Rifampin: ↓ macrolide
Extended cholestatic hepatitis. concentrations.
release:
1000 mg po May ↑ warfarin effect; ↑
once daily concentrations of
substrates of CYP3A4
(potent inhibitor) e.g.,
atorvastatin,
carbamazepine, digoxin,
lovastatin, simvastatin.
Macrolides, erythromycin 500 mg QID Gastrointestinal Coadministration with $

conventional Eryc, generics po upset, rash, pimozide is
cholestatic hepatitis. contraindicated.
Rifampin: ↓ macrolide
concentrations.
May ↑ warfarin effect; ↑

concentrations of
substrates of CYP3A4
(potent inhibitor) e.g.,
atorvastatin,
carbamazepine, digoxin,
lovastatin, simvastatin.
Use cautiously with

other drugs that cause
QTc prolongation.
Macrolides, telithromycin 800 mg po Diarrhea, nausea, Not considered first-line. $

ketolides Ketek daily × 7–10 vomiting, elevated Hepatotoxicity may be
days liver enzymes, fatal.
hepatotoxicity.41 Telithromycin ↑ levels of
atorvastatin, lovastatin,
simvastatin, digoxin,
itraconazole,
ketoconazole.
Itraconazole,
ketoconazole ↑ levels of
telithromycin.
Coadministration of
pimozide and cisapride
is contraindicated.
Coadministration with
ergot alkaloids is not
recommended.
Page 536
Therapeutic Choice
Costa
Reports of exacerbation
of myasthenia gravis
42
with telithromycin,
therefore
contraindicated.
Nitroimidazoles metronidazole 500 mg Vertigo, headache, Concomitant intake of $

Flagyl, generics po/iv Q12H ataxia, ethanol may lead to a
gastrointestinal disulfiram-like reaction;
upset, taste avoid alcohol until 48
alterations. hours after last dose of
metronidazole.
Oxazolidinones linezolid 600 mg Gastrointestinal Preferred agent for $$$$$

Zyvoxam Q12H po/iv upset, headache, MRSA-pneumonia.16 , 44
dose- and time- ↑ risk of serotonin toxicity
dependent bone with concomitant
marrow suppression, serotonergic drugs,
peripheral e.g., selective serotonin
neuropathy, optic 45 ,
reuptake inhibitors.
neuritis (rare). 46
Penicillins penicillin V potassium 300 mg TID- Hypersensitivity $

generics QID po reactions, rash,
gastrointestinal
upset, interstitial
nephritis.
Penicillins penicillin G 2 million U Hypersensitivity $

Crystapen, Q4H iv reactions, rash,
generics gastrointestinal
upset, interstitial
nephritis.
Penicillins amoxicillin 500 mg TID Hypersensitivity Consider high-dose $

generics po reactions, rash, amoxicillin if patient
gastrointestinal presents with drug-
upset, interstitial resistant
nephritis. S. pneumoniae risk
factors.
Penicillins amoxicillin/ clavulanate 500/125 mg Hypersensitivity Consider high-dose $

TID po or reactions, rash, amoxicillin/clavulanate
Clavulin, generics 875/ 125 mg gastrointestinal if patient presents with
BID upset, interstitial drug-resistant
nephritis. S. pneumoniae risk
factors.
Penicillins ampicillin 1 g Q6H iv Hypersensitivity $

generics reactions, rash,
gastrointestinal
upset, interstitial
nephritis.
Penicillins cloxacillin 1 g Q6H iv Hypersensitivity $

generics reactions, rash,
gastrointestinal
upset, interstitial
nephritis.
Penicillins piperacillin 3 g Q4H iv Hypersensitivity $$$$

generics or 4 g Q6H reactions, rash,
gastrointestinal
Page 537
Therapeutic Choice
a
Cost
iv upset, interstitial
nephritis.
Penicillins piperacillin/ tazobactam 3 g/0.375 g Hypersensitivity Antipseudomonal; for $$$

Q6H iv reactions, rash, patients with risk
Piperacillin/Tazobactam gastrointestinal factors for P.
for Injection, upset, interstitial aeruginosa.
nephritis.
Tazocin,
other generics
Penicillins ticarcillin/ clavulanate >60 kg: 3.1 Hypersensitivity, $

Timentin g Q4–6H iv gastrointestinal
<60 kg: 200 upset.
–300 mg/kg
daily iv
divided Q4–
6H
Rifamycins rifampin 300 mg BID Rash (petechial rash Should never be used as $
Rifadin, Rofact po may suggest a single agent for CAP.
thrombocytopenia), Induction of CYP
orange isozymes resulting in
discolouration of many potential
body fluids (contact interactions.
lens staining), GI
upset, liver toxicity, May ↓ levels of
hematologic effects cyclosporine,
(e.g., tacrolimus, sirolimus,
thrombocytopenia). phenytoin, warfarin and
oral contraceptives.
Adjust dose of affected

drug when rifampin is
initiated or
discontinued.
Tetracyclines doxycycline 100 mg BID Gastrointestinal Iron or antacids may ↓ $

Vibramycin, generics po 1st day upset, doxycycline absorption.
then 100 mg photosensitivity. Alcohol, barbiturates,
daily phenytoin, rifampin,
carbamazepine may ↓
doxycycline levels.
Antivirals amantadine 200 mg once Confusion, nausea, Contraindicated if $

generics daily or vomiting, loss of poorly controlled
divided BID appetite, ataxia, seizure disorders or
× 5 days insomnia, seizures past history of
≥65 y: (most likely in those neuroleptic malignant
100 mg once with pre-existing syndrome.
daily × 5 disorder). ↑ risk of CNS side effects:
days anticholinergic therapy.
↑ amantadine
concentrations:
triamterene. Monitor for
signs of toxicity.
Page 538
Therapeutic Choice
Costa
Antivirals oseltamivir 75 mg BID × Nausea, vomiting, Do not use if ClCr is $

Tamiflu 5 days. If headache. <10 mL/min.
ClCr 10–30
mL/min: 75
mg once
daily × 5
days
Antivirals zanamivir 10 mg (2 Bronchospasm has Do not use in patients $$

Relenza inhalations) been reported, with asthma or COPD
BID × 5 especially in patients due to risk of serious
days with respiratory bronchospasm.
disease.
Headache, dizziness,
cough.
a.
Cost of oral and IV medications is per 1-day supply based on 6-foot male; cost of inhaled agents is per unit; includes drug cost
only.
b.
In obese patients (>30% ideal body weight [IBW]), use dosing body weight (DBW) instead of total body weight (TBW) to
prevent overdosing. DBW = IBW + 0.4(TBW-IBW) where IBW (kg; males) = 50 + (2.3 × height in inches over 5 feet). IBW (kg;
females) = 45.5 + (2.3 × height in inches over 5 feet).
Legend: $ < $25 $-$$ < $25–50 $$ $25–50 $$-$$$ $25–75 $$$ $50–75 $$$$ $75–100 $$$-$$$$$
$50– >$100 $$$$$ > $100
Suggested Readings
Almirall J, Gonzalez CA, Balanzo X et al. Proportion of community-acquired pneumonia cases attributable to tobacco
smoking. Chest 1999;116(2):375-9.
Mandell LA, Wunderink RG, Anzueto A et al. Infectious Diseases Society of America/American Thoracic Society
consensus guidelines on the management of community-acquired pneumonia in adults. Clin Infect Dis 2007;44
(Suppl 2):S27-72.
References
1. Marrie T, Campbell G, Walker D, Low D. Pneumonia. In: Kasper DL et al. Harrison's principles of internal
medicine. 16th ed. New York (NY): McGraw-Hill; 2005. p. 1528-41.
2. Mandell LA, Wunderink RG, Anzueto A et al. Infectious Diseases Society of America/American Thoracic Society
consensus guidelines on the management of community-acquired pneumonia in adults. Clin Infect Dis
2007;44(Suppl 2):S27-72.
3. Johnstone J, Majumdar SR, Fox JD et al. Viral infection in adults hospitalized with community-acquired
pneumonia: prevalence, pathogens and presentation. Chest 2008;134(6):1141-8.
4. Marrie TJ, Wu L. Factors influencing in-hospital mortality in community-acquired pneumonia: a prospective
study of patients not initially admitted to the ICU. Chest 2005;127(4):1260-70.
5. Lin CC, Lee CH, Chen CZ et al. Value of the pneumonia severity index in assessment of community-acquired
pneumonia. J Formos Med Assoc 2005;104(3):164-7.
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Therapeutic Choice
6. Renaud B, Coma E, Labarere J et al. Routine use of the Pneumonia Severity Index for guiding the site-of-
treatment decision of patients with pneumonia in the emergency department: a multicenter, prospective,
observational, controlled cohort study. Clin Infect Dis 2007;44(1):41-9.
7. Charles PG, Wolfe R, Whitby M et al. SMART-COP: a tool for predicting the need for intensive respiratory or
vasopressor support in community-acquired pneumonia. Clin Infect Dis 2008;47(3):375-84.
8. Marik PE. Aspiration pneumonitis and aspiration pneumonia. N Eng J Med 2001;344(9):665-71.
9. Reza Shariatzadeh M, Huang JQ, Marrie TJ. Differences in the features of aspiration pneumonia according to
site of acquisition: community or continuing care facility. J Am Geriatr Soc 2006;54(2):296-302.
10. Soderquist B, Berglund C, Stralin K. Community-acquired pneumonia and bacteremia caused by an unusual
methicillin-resistant Staphylococcus aureus (MRSA) strain with sequence type 36, staphylococcal cassette
chromosome mec type IV and Panton-Valentine leukocidin genes. Eur J Clin Microbiol Infect Dis 2006;25
(9):604-6.
11. Adam H, McGeer A, Simor A. Fatal case of post-influenza, community-associated MRSA pneumonia in an
Ontario teenager with subsequent familial transmission. Can Commun Dis Rep 2007;33(4):45-8.
12. Frazee BW, Salz TO, Lambert L et al. Fatal community-associated methicillin-resistant Staphylococcus aureus
pneumonia in an immunocompetent young adult. Ann Emerg Med 2005;46(5):401-4.
13. Hageman JC, Uyeki TM, Francis JS et al. Severe community-acquired pneumonia due to Staphylococcus
aureus, 2003-04 influenza season. Emerg Infect Dis 2006;12(6):894-9.
14. Gillet Y, Issartel B, Vanhems P et al. Association between Staphylococcus aureus strains carrying gene for
Panton-Valentine leukocidin and highly lethal necrotising pneumonia in young immunocompetent patients.
Lancet 2002;359(9308):753-9.
15. Francis JS, Doherty MC, Lopatin U et al. Severe community-onset pneumonia in healthy adults caused by
methicillin-resistant Staphylococcus aureus carrying the Panton-Valentine leukocidin genes. Clin Infect Dis
2005;40(1):100-7.
16. Barton M, Hawkes M, Moore D et al. Guidelines for the prevention and management of community-associated
methicillin-resistant Staphylococcus aureus: a perspective for Canadian health care practitioners. Can J Infect
Dis Med Microbiol 2006;17(Suppl C):4C-24C.
17. McKeage K, Keating GM. Tigecycline: in community-acquired pneumonia. Drugs 2008;68(18):2633-44.
18. Salvatore CM, Techasaensiri C, Tagliabue C et al. Tigecycline therapy significantly reduces inflammatory
pulmonary cytokines and chemokines in a murine model of Mycoplasma pneumoniae pneumonia. Antimicrob
Agents Chemother 2009;53(4):1546-51.
19. Tverdek FP, Crank CW, Segreti J. Antibiotic therapy of methicillin-resistant Staphylococcus aureus in critical
care. Crit Care Clin 2008;24(2):249-60.
20. Silverman JA, Mortin LI, Vanpraagh AD et al. Inhibition of daptomycin by pulmonary surfactant: in vitro
modeling and clinical impact. J Infect Dis 2005;191(12):2149-52.
21. Cox NJ, Fukuda K. Influenza. Infect Dis Clin North Am 1998;12(1):27-38.
22. Morens DM, Taubenberger JK, Fauci AS. Predominant role of bacterial pneumonia as a cause of death in
pandemic influenza: implications for pandemic influenza preparedness. J Infect Dis 2008;198(7):962-70.
23. Penn CR. Inhibitors of influenza virus neuramidase. In: Nicholson K et al. Textbook of influenza. Oxford (UK):
Blackwell Science; 1998. p. 477-500.
24. Aoki FY. Amantadine and rimantadine. In: Nicholson K et al. Textbook of influenza. Oxford (UK): Blackwell
Science; 1998. p. 457-76.
25. Nuorti JP, Butler JC, Farley MM et al. Cigarette smoking and invasive pneumococcal disease. Active Bacterial
Core Surveillance Team. N Engl J Med 2000;342(10):681-9.
26. Voordouw BC, Sturkenboom MC, Dieleman JP et al. Annual influenza vaccination in community-dwelling
elderly individuals and the risk of lower respiratory tract infections or pneumonia. Arch Intern Med 2006;166
(18):1980-5.
27. National Advisory Committee on Immunization (NACI). Statement on influenza vaccination for the 2008-2009
season. An Advisory Committee Statement (ACS). Can Commun Dis Rep 2008;32(ACS-3):1-46.
28. Nichol KL, Nordin J, Mullooly J et al. Influenza vaccination and reduction in hospitalizations for cardiac
disease and stroke among the elderly. N Engl J Med 2003;348(14):1322-32.
29. Spaude KA, Abrutyn E, Kirchner C et al. Influenza vaccination and risk of mortality among adults hospitalized
with community-acquired pneumonia. Arch Intern Med 2007;167(1):53-9.
30. Carman WF, Elder AG, Wallace LA et al. Effects of influenza vaccination of health-care workers on mortality of
elderly people in long-term care: a randomised controlled trial. Lancet 2000;355(9198):93-7.
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31. Eurich DT, Marrie TJ, Johnstone J et al. Mortality reduction with influenza vaccine in patients with pneumonia
outside “flu” season: pleiotropic benefits or residual confounding? Am J Respir Crit Care Med 2008;178
(5):527-33.
32. Thomas RE, Jefferson T, Lasserson TJ. Influenza vaccination for healthcare workers who work with the elderly.
33. National Advisory Committee on Immunization (NACI). Canadian immunization guide. 7th ed. Ottawa (ON):
Public Health Agency of Canada, Infectious Disease and Emergency Preparedness Branch, Centre for Infectious
Disease and Control; 2006. Available from: http://www.phac-aspc.gc.ca/publicat/cig-gci/pdf/cig-gci-
2006_e.pdf. Accessed March 29, 2010.
34. Lexau CA, Lynfield R, Danila R et al. Changing epidemiology of invasive pneumococcal disease among older
adults in the era of pediatric pneumococcal conjugate vaccine. JAMA 2005;294(16):2043-51.
35. Johnstone J, Marrie TJ, Eurich DT et al. Effect of pneumococcal vaccination in hospitalized adults with
community-acquired pneumonia. Arch Intern Med 2007;167(18):1938-43.
36. Muscedere J, Dodek P, Keenan S et al. Comprehensive evidence-based clinical practice guidelines for
ventilator-associated pneumonia: prevention. J Crit Care 2008;23(1):126-37.
37. Ramirez JA, Srinath L, Ahkee S et al. Early switch from intravenous to oral cephalosporins in the treatment of
hospitalized patients with community-acquired pneumonia. Arch Intern Med 1995;155(12):1273-6.
38. Oosterheert JJ, Bonten MJ, Schneider MM et al. Effectiveness of early switch from intravenous to oral
antibiotics in severe community acquired pneumonia: multicentre randomised trial. BMJ 2006;333
(7580):1193.
39. Health Canada. Updated prescribing information for all ceftriaxone products marketed in Canada. Available
from: http://hc-sc.gc.ca/dhp-mps/alt_formats/pdf/medeff/advisories-avis/prof/2009/ceftriaxone_2_nth-aah-
eng.pdf. Accessed March 29, 2010.
40. Dunbar LM, Wunderink RG, Habib MP et al. High-dose, short-course levofloxacin for community-acquired
pneumonia: a new treatment paradigm. Clin Infect Dis 2003;37(6):752-60.
41. Clay KD, Hanson JS, Pope SD et al. Brief communication: severe hepatotoxicity of telithromycin: three case
reports and literature review. Ann Intern Med 2006;144(6):415-20.
42. Perrot X, Bernard N, Vial C et al. Myasthenia gravis exacerbation or unmasking associated with telithromycin
treatment. Neurology 2006;67(12):2256-8.
43. Canadian Bacterial Surveillance Network. Annual report: 2005. Toronto (ON): Mount Sinai Hospital,
Department of Microbiology. Available from: http://microbiology.mtsinai.on.ca/research/cbsn/cbsnnews/cbsn-
annual-report05.pdf. Accessed March 29, 2010.
44. Wunderink RG, Rello J, Cammarata SK et al. Linezolid vs vancomycin: analysis of two double-blind studies of
patients with methicillin-resistant Staphylococcus aureus nosocomial pneumonia. Chest 2003;124(5):1789-
97.
45. Lawrence KR, Adra M, Gillman PK. Serotonin toxicity associated with the use of linezolid: a review of
postmarketing data. Clin Infect Dis 2006;42(11):1578-83.
46. Clark DB, Andrus MR, Byrd DC. Drug interactions between linezolid and selective serotonin reuptake
inhibitors: case report involving sertraline and review of the literature. Pharmacotherapy 2006;26(2):269-76.
Page 541
e-Therapeutics+ : Therapeutics : Infectious Diseases: Herpesvirus Infections Page 1 of 15
Therapeutic Choice
Print Close
Infectious Diseases: Herpesvirus Infections

Fred Y. Aoki, MD
This chapter addresses treatment of herpes simplex virus (HSV) and varicella-zoster virus (VZV) infections in
immunocompetent and immunocompromised patients.
The characteristics of some herpesvirus infections, such as recurrent genital or orolabial herpes simplex virus
infection, differ when caused by HSV type 1 or 2. However, knowledge of HSV type is not of practical value in
guiding selection of drug therapy since both are similarly susceptible to available drugs. Drug choices can be based
on the nature and severity of the disease and evidence from controlled clinical trials.
In immunocompromised patients, HSV and herpes VZV infections may be more severe and resolve less rapidly than
in immunocompetent hosts. The recommended drugs are the same in both types of patients; however, dose
regimens may be different.
Herpes Simplex Virus
Orolabial Infection
Goals of Therapy
Anogenital Infection
Goals of Therapy
Eczema Herpeticum
Encephalitis
Goals of Therapy
Keratoconjunctivitis
Goals of Therapy
Orolabial Infection
Goals of Therapy
Improve symptoms
Prevent outbreaks
Primary HSV Gingivostomatitis
Primary HSV gingivostomatitis is commonly seen in children. If the child can swallow, treat mild to moderate
gingivostomatitis with acyclovir oral suspension. Acyclovir 15 mg/kg five times per day for 7 days1 or 600 mg/m2
2
QID for 10 days accelerates resolution of orolabial signs and symptoms and fever, and reduces the duration of viral
shedding. Acyclovir is well tolerated. If the severity of disease precludes ingestion of medication, iv acyclovir in
Page 542
Therapeutic Choice
pediatric doses analogous to those which are effective and safe in adults with primary genital herpes (Table 1), can
be inferred to be appropriate treatment, although no published data support this recommendation.
Recurrent Orolabial Herpes
Treat recurrent orolabial herpes in immunocompetent adults with oral antivirals (acyclovir, famciclovir and
valacyclovir) for 4 to 5 days.
Oral acyclovir 400 mg five times per day for 5 days, initiated within 1 hour of onset, reduced the duration of pain
by 0.9 days compared with placebo although no other disease parameters, such as time to healing and duration of
virus shedding, are altered.3
4
Valacyclovir is approved for 1-day treatment of cold sores in patients 12 years of age or older. Valacyclovir 2 g
BID × 2 doses, self-initiated an average of 2 hours after the earliest symptom of tingling, itching or burning,
5
reduced the duration of the episode by about 1 day compared with placebo. Valacyclovir is well tolerated.
Famciclovir 750 mg BID for 1 day or 1500 mg once, started within 1 hour of onset of cold sore prodromal
symptoms, improved a number of lesional symptoms and signs,6 reduced the duration of pain and tenderness and
the median times to healing. Median times to normal skin were 5.7 to 4.5 days with treatment compared to 7.0 days
with placebo. Famciclovir is well tolerated.
Topical antiviral creams are effective but require frequent applications and carry a risk of self-
inoculation. Topical acyclovir ointment is not effective. Acyclovir 5% cream, self-initiated within 1 hour
of the onset of a recurrent episode and applied five times daily for 4 days, reduced the duration of pain
by about one-half day compared with placebo; however, acyclovir cream did not prevent progression to
vesicles, ulcers and/or crusts.7 Provide patients with prescriptions for oral antivirals to enable them to
self-initiate therapy at the onset of symptoms Useful Info? .
For healthy persons with recurrent cold sores (> 6 times per year) daily ingestion of oral antivirals can suppress
8 9
recurrences during therapy of up to 4 months. Oral acyclovir 400 mg BID or 200 mg QID and oral valacyclovir 500
mg daily10 are comparably effective and well tolerated as suppressive therapy. Once therapy is discontinued,
however, cold sores tend to recur. The effectiveness of these regimens for periods greater than 4 months is
unknown.
For individuals in whom orolabial herpes is reactivated by exposure to sunlight, oral acyclovir 400 mg BID begun 12
hours prior to sun exposure with frequent sunscreen use prevents attacks. Prophylaxis is continued for the duration
of sun exposure.11
Otherwise healthy adults with a history of cold sores who undergo elective trigeminal nerve decompression to treat
tic douloureux may be treated with oral acyclovir 400 mg BID started on the evening prior to surgery and continued
for 5 days. This reduces the incidence of cold sore by 75%.12
Anogenital Infection
Goals of Therapy
Improve symptoms
Prevent outbreaks
Prevent acquisition of infection
Primary Episodes of Genital Herpes
First episodes of genital herpes in otherwise healthy individuals may range from inapparent to severe. Treatment is
15
effective if initiated up to 7 days after onset. For severe cases, use iv acyclovir 5 mg/kg every 8 hours for 5 to 10
13 14
days. Oral acyclovir 200 mg five times daily for 5 to 10 days is also effective. IV treatment is approximately
25% better than oral treatment overall with improved resolution of local and systemic symptoms and decreased time
15 16
to healing but no difference in viral shedding. Famciclovir 250 mg TID for 7 days and valacyclovir 500 to
Page 543
Therapeutic Choice
1000 mg BID for 10 days17 have comparable efficacy and tolerance to oral acyclovir. The simplicity of the
famciclovir and valacyclovir regimens is an advantage.
Recurrent Genital Herpes
Recurrent genital herpes in immunocompetent patients, traditionally treated for 5 to 7 days, can now be treated for
1 to 3 days using higher doses than those formerly recommended. Five days of treatment with oral acyclovir 200
mg five times daily,18 famciclovir 125 mg BID19 or valacyclovir 500 mg BID20 initiated within the first 12 hours
after symptom onset, reduced median times to pain relief and lesion healing by 1 to 2 days.
Shorter courses of therapy (1 to 3 days) appear to be as effective as 5-day treatments for episodes of recurrent
genital herpes in healthy individuals. Acyclovir 800 mg TID for 2 days was more effective than placebo;21 the
benefit was similar to that observed with 200 mg five times per day for 5 days.18 Valacyclovir 500 mg BID for 3
22
days is as effective as the same dose given for 5 days. Famciclovir 1000 mg × 2 doses beginning less than 6
23
hours after symptom onset reduced median duration of pain and median lesion healing time from 6.1 to 4.3 days.
Short courses of therapy are effective and well tolerated, though therapy needs to be initiated within hours of
symptom onset.
For individuals with frequently recurring disease (≥ 6 episodes per year), suppressive therapy is more effective than
episodic therapy. Initiate suppressive therapy in immunocompetent patients with acyclovir 200 mg TID. Acyclovir
24 25 26
200 mg five times per day, 400 mg BID and 800 mg daily is effective. If the response to acyclovir 200 mg TID
is favourable, the dose may be reduced to BID and if unfavourable, increased to 200 mg five times daily or 400 mg
27
BID. Famciclovir 250 mg BID and valacyclovir 500 mg daily (for < 9 recurrences per year) or 1000 mg daily (for
28
> 9 recurrences per year) are approved for suppressive therapy of recurrent genital herpes in healthy adults.
Valacyclovir, 500 or 1000 mg, is the only treatment approved for once-daily dosing. Valacyclovir 500 mg daily
29
appeared better than famciclovir 250 mg BID for suppression of genital herpes and associated HSV shedding. The
time to a first virologically confirmed recurrence was shorter among famciclovir recipients. Acyclovir 400 mg BID
can also be used. The safety of all the drugs has been demonstrated in placebo-controlled trials up to one year and
30
in the case of acyclovir, an uncontrolled study suggested it is safe for up to five years. Suppression should be
interrupted periodically to evaluate the need for continued treatment. One strategy is to stop every 3 to 6 months
and to await two recurrences. Only if these two recurrences are close together (maximum of 2 months apart) would
another 3- to 6-month course be appropriate. This strategy can be continued indefinitely.31
Transmission of symptomatic genital herpes disease was reduced by 77% with valacyclovir 500 mg daily in a
46
placebo-controlled trial in monogamous couples discordant for genital herpes infection. Transmission of infection,
symptomatic disease as well as asymptomatic seroconversion, was reduced by 50%.
Herpes Proctitis
Herpes proctitis acquired by anal intercourse or through oral-anal contact refers to the inflammation of the rectal
mucosa.32 Symptoms include anorectal pain and mucopurulent or bloody rectal discharge.32 Herpes proctitis can be
treated using acyclovir. Acyclovir, 400 mg five times per day initiated within 12 days of onset and continued for 10
days, reduces healing time for first-episode herpes proctitis from 14 to 5 days.33
Genital Herpes and HIV
In HIV-infected patients, first episodes of genital HSV infection may be more severe and prolonged than in non-HIV
infected patients.34 Although data from controlled trials are lacking, iv and oral regimens recommended for non-
immunocompromised patients (vide supra) are likely to be effective in HIV-infected patients. Some experts,
35 , 36
however, recommend higher doses. Oral acyclovir 400 mg three to five times daily can be continued until
healing is complete. The duration of therapy will generally exceed the 5 to 10 days used in HIV-negative patients.
Treat recurrent genital herpes in HIV-infected patients with acyclovir 200 to 400 mg five times per day,
famciclovir 500 mg BID or valacyclovir 1000 mg BID for 5 to 7 days. Controlled trials have shown that
famciclovir 500 mg BID for 7 days is as effective as acyclovir 400 mg five times per day for 7 days.37
38
Valacyclovir 1000 mg BID was as effective as acyclovir 200 mg five times per day, both for 5 days. Shorter 1-
and 3-day courses have not been tested in HIV-infected patients.
Page 544
Therapeutic Choice
In patients with frequently recurring episodes of genital herpes complicating HIV infection, valacyclovir 500 mg BID
39
reduced recurrences, was 20% more efficacious than 1000 mg daily and tended to be more efficacious than
40
acyclovir 400 mg BID. Famciclovir 500 mg BID reduced recurrences by 69% compared with placebo. All regimens
are well tolerated.
There is a significant risk that drug-resistant HSV mutants will be selected by suppressive therapy in HIV-infected
41
patients, especially among those who are severely immunocompromised. Accordingly, it is important that optimal
HAART therapy be coadministered if appropriate. If refractory mucocutaneous HSV infection appears, consultation
with an infectious diseases expert is advised. Intravenous and topical foscarnet, topical trifluorothymidine alone
or in combination with interferon alfa and cidofovir have all been reported to be effective.42 (See Infectious
Diseases: Opportunistic Infections in HIV-positive Patients)
Genital Herpes and Pregnancy

43
Genital herpes in the pregnant woman may result in neonatal herpes, a serious and potentially fatal infection.
Transmission occurs at parturition and is greater if the maternal infection develops late in pregnancy than if she has
44
been infected prior to becoming pregnant. Acyclovir, taken daily beginning at 36 weeks' gestation, reduces
recurrences, asymptomatic shedding and the need for Caesarean section because herpetic lesions are less commonly
45
observed in labour. Doses of acyclovir 200 mg QID to 400 mg TID are effective and safe. In managing genital
herpes in a pregnant woman, consultation with an infectious diseases specialist is recommended.
Eczema Herpeticum
Eczema herpeticum is an uncommon HSV infection of eczematous skin that can cause extensive disease (fever,
malaise, lymphadenopathy), presumably arising from autoinoculation from a cold sore or virus shed
asymptomatically in saliva. Complications include keratoconjunctivitis, viremia and multiorgan involvement with
meningitis and encephalitis.
Oral acyclovir 200 mg five times per day for 5 days shortened disease duration in 81% of patients in the acyclovir
group compared to 43% in the placebo group.50 Acyclovir treatment may be life saving.47 In severe cases, iv
48
acyclovir 5–10 mg/kg Q8H for 7 days is recommended for patients over 12 years of age. For younger children,
2
750 mg/m per dose intravenously TID for 7 days is recommended.
There are no published trials supporting the effectiveness and safety of valacyclovir and famciclovir in eczema
herpeticum.48
Encephalitis
Herpes simplex encephalitis (HSE) is characterized by acute onset of fever plus focal neurologic symptoms and signs
(behavioural changes, speech disturbances and, less frequently, seizures). A brain abscess is the principal
differential diagnostic possibility and antibiotic therapy should be included in the initial treatments prescribed,
preferably with the help of an infectious diseases consultant.
During therapy, diagnostic testing to demonstrate focal unilateral frontotemporal cerebritis (MRI, EEG, brain scan,
CT) and HSV etiology (by detection of HSV in brain biopsy or of HSV DNA in CSF) should be rapidly effected.
Culture of CSF for HSV is uniformly negative. Acute phase serum will contain no HSV antibody in one out of three
patients. A rise in titre demonstrated in a convalescent phase serum sample in these patients indicates primary HSV
49
infection.
Goals of Therapy
Prevent death
Prevent long-term neurologic sequelae
Page 545
Therapeutic Choice
Initiate iv acyclovir as soon as the diagnosis of HSE is considered.51 The dose is 10 mg/kg infused iv over not less
than 60 minutes to obviate obstructive nephropathy caused by formation of acyclovir crystals in the renal tubular
lumen. Repeat the dose at 8-hour intervals in persons with normal renal function. Because acyclovir is eliminated
exclusively through renal excretion by filtration and tubular secretion, dose intervals should be increased in renal
dysfunction (see Appendices: Dosage Adjustment in Renal Impairment). Duration of treatment is usually 21 days.
Rarely, relapse with virologically confirmed recrudescence occurs, necessitating prolonged therapy for 10 to 14
more days.
Valacyclovir and famciclovir have not been evaluated as treatment for HSE.
Keratoconjunctivitis
HSV can cause keratitis and/or conjunctivitis and uveitis. Because distinguishing HSV conjunctivitis from bacterial
infection can be difficult, and because of the risk of visual impairment, consultation with an ophthalmologist is
strongly advised if HSV infection is suspected. Consult with an ophthalmologist for all HSV eye infections, except
typical dendritic keratitis.
Goals of Therapy
Ameliorate symptoms
Prevent corneal injury with vision impairment
Topical trifluridine (Viroptic) and idoxuridine (Herplex-D) are similar in efficacy although idoxuridine is less well
tolerated.52 , 53
The role of oral acyclovir is controversial. Oral acyclovir 400 mg BID for 12 months in immunocompetent patients
reduced the rate of recurrent stromal keratitis, the most common serious form of HSV ocular disease, more
54
effectively than placebo.
Herpes Varicella-Zoster Virus
Chickenpox
Goals of Therapy
Acute Herpes Zoster
Goals of Therapy
Chickenpox
Goals of Therapy
Accelerate healing of skin lesions

Prevent complications, e.g., pneumonia, encephalitis
Individuals who do not have a history of chickenpox should avoid patients with chickenpox. Herpes varicella-
zoster virus (VZV) can be transmitted through the air and by direct contact from skin lesions. A person is
infectious from a couple of days prior to the development of the rash until the last lesion has crusted.
Page 546
Therapeutic Choice
Closely crop nails and use astringent soaks to avoid secondary bacterial infection associated with scratching
pruritic skin lesions.
Antivirals
55 56 57
In healthy children, adolescents and adults, the benefit of acyclovir therapy exceeds placebo effects, i.e.,
reduced number of lesions, total time to crusting and duration of fever, if initiated within 24 hours of rash onset.
The American Academy of Pediatrics does not recommend routine use of acyclovir in healthy children.58 Consider
acyclovir in healthy patients who are at increased risk of moderate to severe varicella such as those ≥ 12 years,
patients with chronic cutaneous or pulmonary disorders, patients receiving long-term salicylate treatment and in
those receiving short, intermittent or aerosolized courses of corticosteroids.
58
Adjust the dose of acyclovir according to age for children: 5 to 7 years of age, 20 mg/kg; 8 to 12 years, 15
mg/kg; 13 to 16 years, 10 mg/kg given QID for 5 to 7 days. For adults, oral acyclovir 800 mg five times daily for 5
57
days or iv acyclovir 10 mg/kg every 8 hours for 5 days accelerates healing and is well tolerated. Rare
complications such as varicella pneumonia are more common in adults than in children. It is not known whether
acyclovir prevents complications, or whether famciclovir or valacyclovir is as effective as acyclovir in the treatment
of chickenpox.
In immuncompromised patients, treat chickenpox even if more than 24 hours have elapsed since the rash began.
Data regarding antiviral efficacy in immunocompromised patients are lacking.
Vaccines (Table 6)
One dose of varicella virus vaccine is recommended in healthy children 12 months to 12 years of age. Two doses
59
of the vaccine given 4 to 8 weeks apart is recommended in adults and adolescents ≥ 13 years. Vaccinate all
susceptible adults. The varicella virus vaccine is not recommended in pregnancy.59
Acute Herpes Zoster (Shingles)
Goals of Therapy
Stop viral replication

Accelerate healing of skin lesions
Relieve acute neuritis
Prevent postherpetic neuralgia (see Neurologic Disorders: Neuropathic Pain)
Keep rash clean and dry to reduce risk of bacterial superinfection. Consult physician if fever is present.
Avoid use of topical antibiotics and dressing with adhesives as these may cause irritation and delay rash
healing.
Use sterile wet dressing to relieve discomfort in some patients.
Antivirals (Table 3)
Systemic antivirals (acyclovir, famciclovir, valacyclovir), initiated within 72 hours of rash onset, reduce the
duration of viral shedding and acute pain and the appearance of new lesions and may reduce the risk of postherpetic
60 , 61 , 62 , 63 60
neuralgia. Topical antivirals are not effective in the treatment of herpes zoster. To reduce the risk of
postherpetic neuralgia and other complications, initiate systemic antiviral therapy ≤ 72 hours after rash onset. In
patients with ocular zoster, treat even if the rash has been present for up to 7 days to prevent ocular complications.
Advanced age (patients < 50 years rarely develop postherpetic neuralgia64), severe pain and extensive disease
identify patient and zoster disease characteristics that correlate with an increased risk of postherpetic neuralgia.60 ,
64 , 65
Promptly refer patients with ocular complications to an ophthalmologist. Acyclovir, famciclovir and
Page 547
Therapeutic Choice
valacyclovir are well tolerated. Common adverse effects include nausea and headache. Famciclovir and valacyclovir
may improve patient adherence because they can be given TID.
Corticosteroids, Analgesics and Opioids
Prevention of postherpetic neuralgia using antiviral therapy is not absolute. Analgesics, opioids, tramadol,
60
gabapentin, pregabalin and corticosteroids may be used in the treatment of pain related to herpes zoster.
Corticosteroid therapy improves quality of life (resolution of acute neuritis, uninterrupted sleep and return to normal
activity) but does not accelerate healing or reduce the incidence of postherpetic neuralgia compared to acyclovir
alone.66 For more information on acute and postherpetic neuralgia, see Neurologic Disorders: Neuropathic Pain.
Vaccines (Table 6)
A live, attenuated varicella zoster vaccine (Zostavax) containing approximately 15 times more virus than varicella
virus (chickenpox) vaccines, reduced the incidence of shingles and postherpetic neuralgia by 51% and 67%,
67
respectively, compared with placebo, in healthy adults ≥ 60 years and was well tolerated. While it may be
68
valuable as an individual health measure, its cost-effectiveness as a public health measure is not clear.
Therapeutic Tips
For orolabial and genital herpes virus infections, provide patients with prescriptions enabling them to self-
initiate therapy at the onset of symptoms.
For patients with mild to moderate pain secondary to herpes zoster, a constant level of analgesia may be more
beneficial than PRN dosing.
Famciclovir 125 mg BID is recommended for treating recurrences of genital herpes whereas famciclovir 250 mg
BID is recommended for prevention and suppression of recurrences. Assess most appropriate dose case-by-
case.
Figure 1- Management of Herpes Zoster
Table 1: Antivirals for Orolabial and Mouth HSV Infections
Page 548
Therapeutic Choice
Adverse
a
Class Drug Indication/ Dose Effects Cost
Guanine acyclovir HSV gingivostomatitis in children: Not different HSV

Nucleoside Zovirax Cream, 15 mg/kg po 5 × daily × 7 days or 600 from gingivostomatitis in
Analogues 2 placebo. children:
Zovirax Oral, mg/m po QID × 10 days
po: $$
generics
250 mg/m2 Q8H iv × 5–10 days b
iv : $$$$
Recurrent orolabial HSV:

Treatment, oral: 400 mg po 5 × daily × Recurrent orolabial
5 days HSV:
Treatment, po: $
Treatment, topical: Start within 1 hour of
onset of signs or symptoms. Apply the Treatment, topical
cream five times daily during waking cream: $
hours × 4 days.
Prophylaxis:
Prophylaxis: 400 mg po BID 12 h prior to $$/30 day supply
sun exposure × duration of exposure
Suppression:
Suppression: 200 mg po QID or 400 mg $$$/30 day supply
BID up to 4 mo
Guanine famciclovir Recurrent orolabial HSV: Not different $$

Nucleoside Famvir, Treatment: 750 mg po BID × 1 day or from
Analogues generics 1500 mg po as a single dose placebo.
Guanine valacyclovir Recurrent orolabial HSV: Not different Treatment: $

Nucleoside Valtrex, generics Treatment: 2 g po BID × 1 day or 750 from Suppression: $$$/30
Analogues mg po BID × 1 day or 1500 mg po once placebo. day supply
Suppression: 500 mg po daily × 4 mo
a.
Cost per course of treatment unless otherwise specified; includes drug cost only. Cost of iv acyclovir assumes no wastage.
b.
Based on 20 kg body weight for children and 70 kg for adults.
Legend: $ < $50 $$ $50–100 $$$ $100–150 $$$$ > $150
Table 2: Antivirals for Genital and Anal HSV Infections
Adverse
a
Class Drug Indication Effects Cost
Guanine acyclovir Genital HSV infection, first Not different Genital HSV infection, first
Nucleoside Zovirax, episode: from placebo. episode:
Analogues 5 mg/kg Q8H iv × 5–10 days po: $
generics
200 mg po 5 × daily × 5–10 days b
iv : $$$$
Recurrent genital HSV infection:
Page 549
Therapeutic Choice
Adverse
a
Class Drug Indication Effects Cost
Treatment: 200 mg po 5 × daily × Recurrent genital HSV
5–7 days infection:
Treatment: $
or 800 mg po TID × 2 days
Suppression: $$-$$$/30
Suppression: 200 mg po BID up to day supply
5 × daily or 400 mg po BID or 800
mg po daily × 3–6 mo
HSV proctitis: $$
HSV proctitis:
400 mg po 5 × daily × 10 days
Guanine famciclovir Genital HSV infection, first Not different Genital HSV infection, first
Nucleoside Famvir, episode: from placebo. episode: $$$
Analogues generics 250 mg po TID × 10 days
Recurrent genital HSV
infection:
Recurrent genital HSV infection: Treatment: $
Treatment: 125 mg po BID × 5
days or Suppression: $$$$/30 day
supply
1000 mg po BID × 1 day
Suppression: 250 mg po BID × 3–

6 mo
Guanine valacyclovir Genital HSV infection, first Not different Genital HSV infection, first
Nucleoside Valtrex, episode: from placebo. episode: $$
Analogues generics 1000 mg po BID × 10 days
Recurrent genital HSV
infection:
Recurrent genital HSV infection: Treatment: $
Treatment: 500 mg po BID × 3–5
days Suppression: $$$-$$$$/30
day supply
Suppression: ≤ 9 recurrences: 500
mg po daily × 3–6 mo
> 9 recurrences: 1000 mg po daily Prevention of genital HSV
× 3–6 mo infection transmission:
$$$/30 day supply
Prevention of genital HSV infection

transmission:
500 mg po daily
a.
b.
Legend: $ < $50 $$ $50–100 $$-$$$ $50–150 $$$ $100–150 $$$-$$$$ $100– >150 $$$$ > $150
Page 550
Therapeutic Choice
Table 3: Antivirals for Herpesvirus Infections of the Skin
Adverse
a
Class Drug Indication/Dose Effects Cost
Guanine Nucleoside acyclovir Chickenpox: Not different Chickenpox:

Analogues Children: 10–20 mg/kg po QID × 5–7 from placebo. b
Zovirax, Children : $
days
generics
Adults: po: $$;
Adults: 800 mg po 5 × daily × 5 days
ivb: $$$$
or 10 mg/kg iv Q8H × 5 days
Eczema herpeticum:
Eczema
herpeticum: $
Herpes zoster: $$
Herpes zoster:
Guanine Nucleoside famciclovir Herpes zoster: Not different $$$

Analogues Famvir, 500 mg po TID × 7 days from placebo.
generics
Guanine Nucleoside valacyclovir Herpes zoster: Not different $$$

Analogues Valtrex, 1000 mg po TID × 7 days from placebo.
generics
a.
Cost per course of treatment; includes drug cost only. Cost of iv acyclovir assumes no wastage.
b.
Legend: $ < $50 $$ $50–100 $$$ $100–150 $$$$ > $150
Table 4: Antivirals for HSV Encephalitis
a
Cost
Guanine Nucleoside acyclovir 10 mg/kg iv Q8H × GI upset, lightheadedness, redness at $$$$ b

Analogues Zovirax, 21 days injection site.
generics
a.
Cost per course of treatment; includes drug cost only. Cost of iv acyclovir assumes no wastage.
b.
Legend: $$$$ > $150
Table 5: Antivirals for HSV Keratoconjunctivitis
Page 551
Therapeutic Choice
Adverse
a
Class Drug Indication/Dose Effects Cost
Guanine acyclovir Suppression of recurrent keratoconjunctivitis: Not $$$/30

Nucleoside Zovirax, 400 mg po BID up to 12 mo different day
Analogues generics from supply
placebo.
Guanine idoxuridine Treatment: 1 drop Q1H while awake and Q2H at night Burning, $/15 mL
Nucleoside 0.1% continued until definite improvement. Continue stinging.
Analogues generics treatment for 5–7 days after healing is complete to avoid
recurrence (duration of treatment should not exceed 21
days)
Guanine trifluridine Treatment: 1 drop Q2H onto cornea while awake (max 9 Burning, $$$
Nucleoside Viroptic 1.0% drops/ day) until complete re-epithelialization of cornea, stinging.
Analogues solution, then ↓ to 1 drop Q4H while awake (max 5 drops/day) ×
generics 7 days post re-epithelialization of the cornea
Store under refrigeration
a.
Legend: $ < $50 $$ $50–100 $$$ $100–150
Table 6: Vaccines for Prevention of Varicella Virus Infection and Acute Herpes Zoster
a
Cost
Vaccines, varicella virus 12 mo–12 y: one dose Not recommended in pregnancy.59 $60
viral vaccine, live sc Common side effects: local pain, swelling,
attenuated ≥ 13 y: 2 doses of the redness.
Varilrix, Varivax III vaccine given 4 to 8
weeks apart
Vaccines, zoster virus ≥ 60 y: 1 dose sc Not recommended in pregnancy or pediatrics. $150

viral vaccine, live Do not coadminister with Pneumovax 23 as
attenuated reduced immunogenicity of zoster vaccine is
Zostavax observed.
Common side effects: local pain, swelling,

redness. Rash has been observed.
a.
Cost of 1 dose; includes drug cost only.
Suggested Readings
Aoki FY. Contemporary antiviral drug regimens for the prevention and treatment of orolabial and anogenital herpes
simplex virus infection in the normal host: four approved indications and 13 off-label uses. Can J Infect Dis 2003;14
(1):17-27.
Page 552
Therapeutic Choice
Aoki FY. Genital herpes simplex virus (HSV) infections. In: Canadian guidelines on sexually transmitted infections.
2006 edition. Ottawa (ON): Public Health Agency of Canada; 2006. Available from: http://www.phac-aspc.gc.ca/std
-mts/sti_2006/pdf/sti2006_e.pdf Accessed June 12, 2007.
Corey L. Herpes simplex virus. In: Mandell GL, Bennett JE, Dolin R, editors. Mandell, Douglas and Bennett’s
Principles and practice of infectious diseases. 5th ed. Philadelphia (PA): Churchill Livingstone; 2000. p.1564-80.
Hyndiuk RA, Tabbara KF, editors. Infections of the eye. Boston (MA): Little, Brown; 1986.
Whitley RJ. Varicella-zoster virus. In: Mandell GL, Bennett JE, Dolin R, editors. Mandell, Douglas and Bennett’s
Principles and practice of infectious diseases. 5th ed. Philadelphia (PA): Churchill Livingstone; 2000. p.1580-86.
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31. Aoki FY. Contemporary antiviral drug regimens for the prevention and treatment of orolabial and anogenital
herpes simplex virus infection in the normal host: four approved indications and 13 off-label uses. Can J Inf
Dis 2003;14(1):17-27.
32. Rompalo AM. Diagnosis and treatment of sexually acquired proctitis and proctocolitis: An update. Clin Infect
Dis 1999;28(Suppl 1):S84-S90.
33. Rompalo AM, Mertz GJ, Davis LG et al. Oral acyclovir for treatment of first-episode herpes simplex virus
proctitis. JAMA 1988;259(19):2879-81.
34. Maier JA, Bergman A, Ross MG. Acquired immunodeficiency syndrome manifested by chronic primary genital
herpes. Am J Obstet Gynecol 1986;155(4):756-8.
35. Strick LB, Wald A, Celum C. Management of herpes simplex virus type 2 infection in HIV type-1 infected
persons. Clin Infect Dis 2006;43(3):347-56.
36. Drew WL, Stempien MJ, Kheraj M et al. Management of herpesvirus infections (cytomegalovirus, herpes
simplex virus and varicella-zoster virus). In: Sande MA, Volberding PA, editors. The medical management of
AIDS. 6th ed. Philadelphia (PA): Saunders; 1999. p. 444.
37. Romanowski B, Aoki FY, Martel AY et al. Efficacy and safety of famciclovir for treating mucocutaneous herpes
simplex infection in HIV-infected individuals. Collaborative Famciclovir HIV Study Group. AIDS 2000;14
(9):1211-7.
38. Schacker T. The International Valaciclovir HSV Study Group. Valaciclovir as acute treatment for recurrent
anogenital herpes in immunocompromised (HIV positive) individuals [abstract]. International Society for
Sexually Transmitted Diseases Research; Denver (CO); 1999.
39. Warren T, Harris J, and Brennan CA. Efficacy and safety of valacyclovir for the suppression and episodic
treatment of herpes simplex virus in patients with HIV. Clin Infect Dis 2004;39(Suppl 5):S258-66.
40. Schacker T, Hu HL, Koelle DM et al. Famciclovir for the suppression of symptomatic and asymptomatic herpes
simplex virus reactivation in HIV-infected persons. A double-blind, placebo-controlled trial. Ann Intern Med
1998;128(1):21-8.
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41. Levin MJ, Bacon TH, Leary JJ. Resistance of herpes simplex virus infections to nucleoside analogues in HIV-
infected patients. Clin Infect Dis 2004;39(Suppl 5):S248-57.
42. Aoki FY. Management of genital herpes in HIV-infected patients. Herpes 2001;8(2):41-5.
43. Brown ZA, Wald A, Morrow RA et al. Effect of serologic status and cesarean delivery on transmission rates of
herpes simplex virus from mother to infant. JAMA 2003;289(2);203-9.
44. Nahmias AJ, Josey WE, Naib ZM et al. Perinatal risk associated with maternal genital herpes simplex virus
infection. Am J Obstet Gynecol 1971;110(6):825-37.
45. Aoki FY. Genital herpes simplex virus (HSV) infections. In: Canadian guidelines on sexually transmitted
infections. 2006 ed. Ottawa (ON): Public Health Agency of Canada; 2006. Available from: http://www.phac-
aspc.gc.ca/std-mts/sti_2006/pdf/sti2006_e.pdf Accessed June 12, 2007.
46. Corey L, Wald A, Patel R et al. Once daily valacyclovir reduces transmission of genital herpes. N Engl J Med
2004;350:11-20.
47. Sanderson IR, Brueton LA, Savage MO et al. Eczema herpeticum: a potentially fatal disease. Br Med J (Clin Res
Ed) 1987;294(6573):693-4.
48. Wollenberg A, Wetzel S, Burgdorf WH et al. Viral infections in atopic dermatitis: pathogenic aspects and
clinical management. J Allergy Clin Immunol 2003;112(4):667-74.
49. Whitley RJ, Lakeman F. Herpes simplex virus infection of the central nervous system: therapeutic and
diagnostic considerations. Clin Infect Dis 1999;20(2):414-20.
50. Niimura M, Nishikawa T. Treatment of eczema herpeticum with oral acyclovir. Am J Med 1988;85(2A):49-52.
51. Whitley RJ, Alford CA, Hirsch MS et al. Vidarabine versus acyclovir therapy in herpes simplex encephalitis. N
Eng J Med 1986;314(3):144-9.
52. Van Bijsterveld OP, Post H. Trifluorothmidine versus adenine arabinoside in the treatment of herpes simplex
keratitis. Br J Ophthalmol 1908;64:33-6.
53. Pavan-Langston D. Major ocular viral infections. In: Galasso GH, Whitley RJ, Merigan TC, editors. Antiviral
agents and viral diseases of man. New York (NY): Raven Press; 1999. p. 183-223.
54. [No authors listed]. Acyclovir for the prevention of recurrent herpes simplex virus eye disease. Herpetic Eye
Disease Study GroupN Engl J Med 1998;339(5):300-6.
55. Dunkle LM, Arvin AM, Whitley RJ et al. A controlled trial of acyclovir for chickenpox in normal children. N Engl
J Med 1991;325(22)1539-44.
56. Balfour HH, Rothart HA, Feldman S et al. Acyclovir treatment of varicella in otherwise healthy adolescents. The
Collaborative Acyclovir Varicella Study Group. J Pediatr 1992;120(4 Pt 1):627-33.
57. Wallace MR, Bowler WA, Murray NB et al. Treatment of adult varicella with oral acyclovir. A randomized,
placebo-controlled trial. Ann Intern Med 1992;117(5):358-63.
58. American Academy of Pediatrics. Varicella-zoster infections. In: Pickering LK, Baker CJ, Long SS et al, editors.
Red book: 2006 report of the Committee on Infectious Diseases. 27th edition. Elk Grove Village (IL):
American Academy of Pediatrics; 2006. p. 711-25.
59. Public Health Agency of Canada. Canadian Immunization Guide. 2006, Ottawa, Canada.
60. Dworkin RH, Johnson RW, Breuer J et al. Recommendations for the management of herpes zoster. Clin Infect
Dis 2007;44:(Suppl 1):S1-26.
61. Beutner KR, Friedman DJ, Forszpaniak C et al. Valacyclovir compared with acyclovir for improved therapy for
herpes zoster in immunocompetent adults. Antimicrob Agents Chemother 1995;39(7):1546-53.
62. Degreef H. Famciclovir, a new oral anti herpes drug: results of the first controlled clinical study demonstrating
its efficacy and safety in the treatment of uncomplicated herpes zoster in immunocompetent patients. Int J
Antimicrob Agents 1994;4:241-6.
63. Wood, MJ, Kay R, Dworkin RH et al. Oral acyclovir accelerates pain resolution in herpes zoster: a meta-
analysis of placebo-controlled trials. Clin Infect Dis 1996;22(2):341-7.
64. Choo PW, Galil K, Donahue JG et al. Risk factors for postherpetic neuralgia. Arch Intern Med 1997;157
(11):1217-24.
65. Whitley RJ, Weiss WL, Zoong SJ et al. Herpes zoster: risk categories for persistent pain. J Inf Dis 1999;179:9-
15.
66. Whitley RJ, Weiss H, Gnann JW et al. Acyclovir with and without prednisone for the treatment of herpes
zoster. A randomized, placebo-controlled trial. The National Institute of Allergy and Infectious Diseases
Collaborative Antiviral Study Group. Ann Int Med 1996;125(5):376-83.
67. Oxman MN, Levin MJ, Johnson GR et al. A vaccine to prevent herpes zoster and post-herpetic neuralgia in
older adults. N Engl J Med 2005;352(22):2271-84.
68. Rothberg MB, Virapongse A, Smith KJ. Cost-effectiveness of a vaccine to prevent herpes zoster and
postherpetic neuralgia in older adults. Clin Infect Dis 2007;44(10):1280-8.
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Page 556
e-Therapeutics+ : Therapeutics : Infectious Diseases: HIV Infection Page 1 of 14
Therapeutic Choice
Print Close
Infectious Diseases: HIV Infection

Date Revised: April 2010
Valentina Montessori, MD, FRCPC
Marianne Harris, MD, CCFP
Julio S.G. Montaner, MD, FRCPC, FCCP
Goals of Therapy
Prolong survival
Slow disease progression
Improve quality of life
Decrease viral replication
Prevent/reverse immunologic impairment
Delay/prevent the emergence of drug-resistant strains of HIV
Investigations
Clinical history:
risk behaviours, social support and need for counselling
establish date of infection if possible based on a review of past sexual contacts, period of needle sharing, receipt of blood or
blood products, availability of a previous negative test or a history of possible seroconversion illness (e.g., mononucleosis-
like or severe flu-like illness) shortly after a high-risk exposure
general indicators: anorexia, weight loss, fatigue or malaise, lymphadenopathy
symptoms of opportunistic infections, e.g., fever, night sweats, cough, dyspnea, diarrhea, headache or skin rashes
travel history
Past medical history:
sexually transmitted diseases (syphilis, gonorrhea, chlamydia, granuloma inguinale, lymphogranuloma venereum, herpes
simplex, genital warts, pubic lice)
past history or exposure to tuberculosis (TB), hepatitis B or C
conditions that may compromise future drug therapy, e.g., kidney dysfunction, peripheral neuropathy, liver disease,
pancreatitis, cardiovascular disease, psychiatric disorders, substance abuse
allergies
immunization history
focus on signs of immune dysfunction and indications of opportunistic disease
direct specific attention to examination of the mental status, skin, visual fields, ocular fundi, oral cavity, lymph nodes,
abdomen, rectal and genital exam (including cervical Pap smear in women and referral for an anal Pap smear in men with
history of human papillomavirus infection)
HIV antibody test (repeat to rule out lab error)
plasma HIV RNA level (viral load) with the CD4 lymphocyte count is the best prognostic marker for progression to AIDS and
1
survival. Plasma viral load ranges vary according to the test employed. There is no "safe" level. The most sensitive plasma
HIV-1 RNA assays currently available have a quantitation limit of 40 copies/mL
viral drug resistance mutations become harder to detect over time. Therefore conduct a resistance test at entry into treatment
2
program even if use of antiretroviral treatment is not currently contemplated
CD4 lymphocyte count and percentage is useful in determining where a patient lies in the continuum of HIV disease and the
need for specific intervention (Table 1). Knowledge of the CD4 count can also help to narrow the differential diagnosis in a
symptomatic HIV-infected patient. In adults, a CD4 count of 430 to 1360 cells/μL (0.43 to 1.36 Giga/Litre or G/L) is
considered normal in most laboratories
2 , 3
screen all patients for the presence of the HLA-B*5701 allele before starting or restarting abacavir. A positive result
indicates a very high risk for severe allergy to abacavir and should be filed in the patient's chart
perform a tropism assay to determine the chemokine receptor status (CCR5, CXCR4 or dual-mixed tropic) if considering use
of the CCR5 inhibitor maraviroc. A plasma viral load of at least 1000 copies/mL is required to perform this test
CBC, differential and platelet count
liver (AST, ALT, GGT, LDH, CPK, alkaline phosphatase, bilirubin, INR, albumin) and renal (BUN, creatinine, electrolytes,
urinalysis) profiles
metabolic profiles (fasting glucose and lipids—total cholesterol, LDL, HDL, triglycerides)
hepatitis B, hepatitis C, syphilis, cytomegalovirus (CMV) and toxoplasmosis serologies
cultures and smears for sexually transmitted diseases as indicated
tuberculosis skin tests, sputum cultures and smears for mycobacteria as indicated
chest x-ray
Management recommendations are included in Table 1.
Page 557
Therapeutic Choice
Table 1: Management of Patients with HIV Infection
CD4 Count
(cells/μL) Action
At all levels General counselling (safer sex, nutrition, need for follow-up, importance of adherence, etc.)
History and physical examination every 3– 6 mo
Plasma viral load and CD4 count at least every 3– 4 mo
Herpes suppression if frequent recurrences (more than 4–6 episodes per year)
Syphilis serology
Pneumococcal vaccine; hepatitis A and B vaccines if appropriate; update diphtheria, tetanus and inactivated
polio vaccines as needed; consider annual influenza vaccinations
TB skin test and isoniazid prophylaxis if indicated (consider repeating skin test yearly)
< 500 Plasma viral load and CD4 count every 3– 4 mo

Clinical evaluations and laboratory investigations at least bimonthly if symptomatic, diagnosed with AIDS,
or on antiretroviral therapy
< 200 Start prophylaxis for Pneumocystis jirovecii pneumonia (PCP)
< 100 Start toxoplasmosis prophylaxis if seropositive and not on trimethoprim/sulfamethoxazole for PCP
prophylaxis
< 75 Consider MAC prophylaxis
< 50 Screen by an ophthalmologist for early CMV retinitis (repeat at 3– 6 mo intervals) or consider CMV
prophylaxis
Abbreviations: CMV = cytomegalovirus; MAC = Mycobacterium avium complex; TB = tuberculosis
Antiretroviral Therapy
Durability of the treatment effect is related to the prevention of drug resistance and this is only achieved with intense suppression of
viral replication. Long-term nonprogression of disease can be expected if the plasma viral load is maintained below the level of
detection on a long-term basis. The goal of a plasma viral load < 40 copies/mL is recommended as this is the lower limit of
quantitation common to all currently available assays (Figure 1 - Approach to Antiretroviral Therapy). As newer, more sensitive assays
become available, the goal may be revised.
An alternative, but less desirable approach, is partially suppressive therapy. This is often the only option available to patients who
have failed previous courses of therapy. Even short-term decreases in plasma viral load on the order of 0.5–1.5 log10 have been
associated with substantial (2- to 3-fold) reductions in disease progression and delayed mortality in clinical trials.4
Highly active antiretroviral therapy (HAART) is the standard of care and is defined as a combination of at least 3 drugs. HAART
regimens recommended for first-line therapy consist of 2 nucleoside (or nucleotide) reverse transcriptase inhibitors plus either a non-
nucleoside reverse transcriptase inhibitor or a ritonavir-boosted protease inhibitor (PI) (see Table 2). The integrase inhibitor
raltegravir provides a new option for first-line therapy in combination with 2 nucleoside/nucleotide reverse transcriptase inhibitors.
Other more recently introduced classes of drugs (fusion inhibitors and entry inhibitors) are reserved for use in treatment-experienced
patients with limited options due to drug resistance or intolerable adverse events.
Table 2: Highly Active Antiretroviral Therapy Regimens
Regimen Comment
2 N[t]RTIs + NNRTI Once daily dosing, lower pill burden. May not be effective in the presence of primary NNRTI resistance.
Adverse effects: rash, CNS effects (efavirenz), hepatitis.
2 N[t]RTIs + PI + low- Once or twice daily dosing. Drug interactions more likely. Adverse effects: GI intolerance, lipid
dose ritonavir abnormalities, hepatitis.
Abbreviations: CNS = central nervous system; GI = gastrointestinal; NNRTI = non-nucleoside reverse transcriptase inhibitor; N[t]RTI = nucleoside
[or nucleotide] reverse transcriptase inhibitor; PI = protease inhibitor
Page 558
Therapeutic Choice
Effective control of HIV infection with HAART reduces the incidence of opportunistic infections and certain cancers, and prolongs life.5
6
Long-term treatment with HAART is associated with metabolic complications and a small but significant increase in the incidence of
cardiovascular events.7
Antiretroviral therapy is recommended in patients with a history of an AIDS-defining illness or those with CD4 < 500 cells/μL.2
Analysis of a large, long-term observational cohort has shown a reduction in the risk of disease progression or death when HAART is
8
initiated in patients with CD4 counts between 351 and 450 cells/μL as compared to 251–350 cells/μL. Similarly, another large cohort
study demonstrated reduced mortality among patients starting HAART with a CD4 of 350–500 cells/μL as compared to those who
9
deferred treatment until their CD4 fell below the 350 cells/μL threshold. Evidence from cohort studies for a possible benefit of
initiating HAART in individuals with CD4 > 500 cells/μL is conflicting;8 , 9 however, such individuals appear to be at increased risk for
non-AIDS-associated cancers, coronary artery disease, hepatic and renal disease and other conditions due to uncontrolled viral
10
replication and chronic immune activation. HAART initiation may be appropriate regardless of current CD4 cell count in patients with
HIV-associated nephropathy, hepatitis co-infection, or those at high risk for cardiovascular disease.2
When selecting the antiretroviral regimen, use agents with additive antiviral effects and avoid those with additive toxicities. Also
consider issues of cross-resistance, adherence, convenience and cost (Table 3). Nonadherence to therapy promotes the emergence of
drug-resistant HIV strains and is the single most important remaining challenge in the management of HIV infection.11 , 12
Counselling and support are critical to ensure ongoing compliance.
Drug interactions are an important consideration whenever starting or stopping antiretrovirals or other drugs.2 In addition to toxicity,
reduced serum drug levels are an important consequence. Suboptimal antiretroviral levels not only reduce efficacy but may also
promote resistance. All protease inhibitors and non-nucleoside reverse transcriptase inhibitors are metabolized by the CYP 450
enzyme system and consequently are associated with many drug interactions. Nucleoside reverse transcriptase inhibitors are not
metabolized by CYP 450 but other interactions occur.
A confirmed rebound towards baseline in plasma viral load implies treatment failure or nonadherence. If adherence is confirmed, the
regimen should then be changed to a new 3-drug regimen, avoiding cross-resistance with previous treatments.13
If a patient experiences drug toxicity, brief cessation of all medications is recommended. Avoid decreasing the dosage
13,14
or stopping only 1 medication, as this will promote the development of resistance. Useful Info?
The risk of opportunistic infections and death was higher in patients randomized to episodic treatment interruptions based on CD4
count as compared with continuous HAART in the SMART study.15 For this reason, structured treatment interruptions (“drug holidays”)
16
are not recommended.
Postexposure Prophylaxis
For recommendations on HIV postexposure prophylaxis, visit www.cdc.gov/mmwr/preview/mmwrhtml/rr5409a1.htm plus

www.cdc.gov/mmwr/preview/mmwrhtml/mm5649a4.htm for updates.
HIV Infection and Pregnancy
Optimal management of HIV in pregnancy requires referral to specialists. Considerations during pregnancy should include optimal
therapy of the pregnant woman, risk of mother-to-child-transmission (MTCT) of HIV, changes in pharmacokinetics of antiretrovirals
and possible teratogenic and other effects of HAART on the developing fetus.17 All pregnant women should be offered HAART with a
discussion of its risks and benefits and treatment should not be withheld because of pregnancy.
Choices During Pregnancy
Among the antiretrovirals, AZT has been most extensively used in pregnancy and therefore should be included in a treatment regimen
unless contraindicated.17 , 18 , 19 The preferred HAART regimen should include AZT and 3TC plus an NNRTI or ritonavir-boosted
PI. The combination of stavudine and didanosine should be avoided because of an increased risk of lactic acidosis during pregnancy.
There are limited studies concerning use of tenofovir in human pregnancy; however, animal data suggest the potential for fetal bone
toxicity. Among the NNRTIs, efavirenz should be avoided in the first trimester because of demonstrated teratogenicity in animals, but
it may be used in the second and third trimesters. Nevirapine is the recommended NNRTI unless CD4 counts are > 250 cells/μL upon
initiation, due to an increased risk of life-threatening hepatotoxicity in this population. Delavirdine is not recommended. The preferred
PI is twice daily lopinavir-ritonavir. Other PIs are alternatives. Currently, there are insufficient data to support the use of etravirine,
darunavir, fosamprenavir, tipranavir, raltegravir and entry inhibitors during pregnancy.
Choices During Lactation
Page 559
Therapeutic Choice
Breastfeeding by HIV-positive women is contraindicated in the developed world due to the risk of HIV transmission to the child and
ready availability of infant formula. Therefore, HIV treatment recommendations for the breastfeeding mother are the same as for the
general HIV-infected population.
See also Appendix: Drug Use During Pregnancy and Appendix: Drug Use During Lactation for a discussion of the general principles.
For more detailed information on the use of specific medications in this condition during pregnancy and lactation the reader is
referred to Motherisk (www.motherisk.org/women/drugs.jsp); Briggs GG, Freeman RK, Yaffe SJ. Drugs in Pregnancy and Lactation
2008; LactMed (toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen?LACT); and Hale T. Medications and Mothers' Milk 2008.
Therapeutic Tips
Develop a long-term treatment strategy in advance to deal with drug intolerance and treatment failure due to resistance.
Poor adherence is the single most critical determinant of therapeutic failure. Promote adherence by prescribing the simplest
possible regimen that is likely to be effective.
Nonquantifiable plasma viral levels (below the detectable threshold) do not imply cure, eradication or a reason for complacency
with safer sex practices or similar safety measures.
The variability of the plasma viral load assays is approximately 0.3 to 0.5 log10. Hence, in untreated patients changes in plasma
viral load of < 0.3 to 0.5 log10 are usually not regarded as clinically significant.20
21
Intercurrent illnesses or vaccinations can transiently but substantially increase plasma viral load.
22
CD4 counts show diurnal variation, being lowest in the morning and highest in the evening. Fluctuations of up to 30% may
occur, which are not attributable to a change in disease status. Overall, it is important to monitor the trends in CD4 counts over
time rather than placing too much emphasis on one specific reading.
From a practical standpoint it is useful to consider the CD4 count as indicative of “the immunologic damage that has already
occurred” and the plasma viral load as “the damage that is about to occur.”
If the plasma viral load rebounds despite ongoing therapy, consider noncompliance and resistance as the most likely causes.13
Some antiretroviral agents have variable pharmacokinetic profiles which may lead to suboptimal therapeutic responses even in an
13
adherent patient.
Figure 1- Approach to Antiretroviral Therapy
a.
Consideration should be given to comorbidities, age, risk of disease progression, i.e., rapid decline in CD4 cell count (> 100/μL/year) and plasma
HIV-1 RNA level > 100,000 copies/mL, risk factors for CVD and other non-AIDS diseases, patient willingness/readiness for treatment and estimated
ability to adhere to long-term treatment.
Page 560
Therapeutic Choice
Table 3: Antiretroviral Medications for HIV Therapy
Drug b
Standard Cost
Class Drug Dose Adverse Effects Interactionsa Comments
Nucleoside abacavir (ABC) 600 mg once Hypersensitivity Alcohol may ↑ Screen patients $$$$
Reverse Ziagen daily reactions in abacavir plasma levels. for the
Transcriptase or patients with a presence of
Inhibitors genetic HLA-B*5701
(NRTI) 300 mg BID predisposition before
(can be severe).c starting.c Close
Potential increased early clinical
risk of myocardial monitoring.
infarction. Caution Alternate first-
in patients with line therapy.
pre-existing
serious
cardiovascular
disease.
Nucleoside didanosine (ddI) < 60 kg: GI intolerance, Tenofovir, Avoid $$-

Reverse Videx EC 250 mg once pancreatitis, ↑ uric ganciclovir ↑ ddI combined use $$$
Transcriptase daily acid, reversible levels. of ddI and
Inhibitors ≥ 60 kg: peripheral Contraindicated with stavudine or
(NRTI) 400 mg once neuropathy, ↑ lactic allopurinol or tenofovir.
daily acid, hepatic ribavirin. When used
steatosis. with tipranavir
Increased risk of separate doses
toxicity with by at least 2
stavudine. hours.
Nucleoside lamivudine (3TC) 150 mg BID Minimal toxicity, Enhanced toxic Alternate first- $$
Reverse 3TC or generally well effects with line therapy.
Transcriptase tolerated. emtricitabine. Avoid
Inhibitors 300 mg once combined use
(NRTI) daily of 3TC and
emtricitabine
(similar
resistance
profiles).
Nucleoside stavudine (d4T) < 60 kg: 30 mg Reversible Pharmacologic Avoid $$

Reverse Zerit BID peripheral antagonism with combined use
Transcriptase ≥ 60 kg: 40 mg neuropathy, ↑ lactic zidovudine. of d4T and
Inhibitors BID acid, hepatic ↑ toxicity with didanosine or
(NRTI) steatosis, didanosine. zidovudine.
pancreatitis,
lipoatrophy, Ribavirin may
dyslipidemia. enhance
hepatotoxicity of
d4T.
Nucleoside zidovudine (AZT) 300 mg BID Nausea, headache, Additive Avoid $$

Reverse Retrovir, generics or malaise, fatigue, hemotoxicity with combined use
Transcriptase rash, myositis, other agents, e.g., of AZT and
Inhibitors 200 mg TID myocarditis, anemia with stavudine.
(NRTI) anemia, ribavirin and
leukopenia, ↑ liver ganciclovir.
enzymes, ↑ lactic Pharmacologic
acid, hepatic antagonism with
steatosis, ↑ CK. stavudine.
Nucleotide tenofovir (TDF) 300 mg once Renal toxicity. TDF ↑ ddI levels. Recommended $$$$$
Reverse Viread daily Monitor renal TDF ↓ atazanavir first-line
Transcriptase function and levels, therefore therapy.
administer only in Avoid
combined use
Page 561
Therapeutic Choice
Drug b
Standard Cost
a
Inhibitors serum combination with of TDF and
(NtRTI) phosphorus. ritonavir. didanosine.
Atazanavir ↑ TDF
levels.
Non- delavirdine (DLV) 400 mg TID Rash, headache, ↑ Do not administer Not for first- $$
nucleoside Rescriptor liver enzymes. with alprazolam, line therapy:
Reverse carbamazepine, inferior
Transcriptase ergot derivatives, efficacy.
Inhibitors d
midazolam,
(NNRTI) phenobarbital,
phenytoin,
pimozide, rifampin,
St. John's wort and
triazolam.
Inhibits metabolism
of atorvastatin,
lovastatin,
maraviroc and
simvastatin.
Non- efavirenz (EFV) 600 mg once CNS toxicity, Do not administer Recommended $$$$
nucleoside Sustiva daily drowsiness, rash, with cisapride, ergot first-line
Reverse ↑ liver enzymes. derivatives, therapy.
Transcriptase Avoid in patients d
midazolam,
Inhibitors with a history of pimozide and
(NNRTI) anxiety, triazolam.
depression or Induces metabolism
psychosis. of maraviroc.
Contraindicated in St. John's wort ↓

1st trimester of levels.
pregnancy
(teratogenic in Voriconazole: EFV ↑
animals). Avoid in and voriconazole ↓;
women of child- dosage adjustments
bearing potential. needed.
Non- etravirine (TMC-125) 200 mg BID Severe skin Do not administer Reserve for $$$$$
nucleoside Intelence reactions (Stevens with carbamazepine, treatment-
Reverse -Johnson phenobarbital, experienced
Transcriptase syndrome, toxic phenytoin, rifampin, patients with
Inhibitors epidermal St. John's wort. limited
(NNRTI) necrolysis and Rifabutin not options.
erythema recommended if May be
multiforme), etravirine effective
hypersensitivity coadministered with against NNRTI-
reactions (may a ritonavir-boosted resistant HIV.
include PI due to ↓ etravirine
hepatotoxicity or levels.
hepatic failure),
nausea. Tipranavir/ritonavir
↓ etravirine exposure
(avoid combined
use).
Etravirine ↑
fosamprenavir
exposure and ↓
atazanavir exposure
(avoid combined
use).
Induces metabolism
of maraviroc.
↓ clarithromycin levels;
consider alternative
for MAC prophylaxis
and treatment.
Page 562
Therapeutic Choice
Drug b
Standard Cost
a
Non- nevirapine (NVP) 200 mg once Rash (rare severe Do not administer Alternate first- $$$
nucleoside Viramune daily for 2 wk allergic reactions). with ketoconazole, line therapy.
Reverse then ↑ liver enzymes rifampin, St. John's
Transcriptase 200 mg BID (rare cases of fatal wort.
Inhibitors Full daily dose hepatitis). ↓ clarithromycin levels;
(NNRTI) can be given Not recommended consider alternative for
once a day in liver disease, if MAC prophylaxis
starting abacavir, and treatment.
or if the baseline
CD4 count is ≥ Fluconazole
250/μL in women significantly ↑ NVP
or ≥ 400/μL in levels increasing the
men. risk of
hepatotoxicity.
Protease atazanavir (ATZ) Treatment- Hyperbilirubinemia PIs are not Recommended $$$$$
Inhibitors Reyataz experienced or in patients with a recommended in first-line
(PI) with tenofovir: genetic combination with therapy only
300 mg + RTV e ergot alkaloids, when used
predisposition.
100 mg once Rash (rare). fluticasone, with ritonavir.
daily lovastatin,
d
All PIs except midazolam,
Treatment- unboosted ATZ rifampin, sildenafil
naïve: 400 mg associated with when used for
once daily or hyperlipidemia. pulmonary arterial
300 mg + RTV hypertension,
100 mg once simvastatin, St.
daily John's wort or
triazolam. If used
with rifabutin,
monitor rifabutin
drug levels and
consider dose
reduction of
rifabutin. All PIs
except
tipranavir/ritonavir
inhibit metabolism
of maraviroc.
Do not use
atazanavir with
proton-pump
inhibitors or H2
antagonists. Do not
use
atazanavir/ritonavir
with etravirine.
Protease darunavir (TMC-114) Treatment- Diarrhea, nausea, PIs are not An option for $$$$$
Inhibitors Prezista experienced: headache, rash recommended in first-line
(PI) 600 mg + RTV (possible cross- combination with therapy.
100 mg BID sensitivity with ergot alkaloids, Approved for
sulfonamides). fluticasone, use only with
Treatment- Drug-induced lovastatin, ritonavir (do
naïve: 800 mg hepatotoxicity, in d not use as a
midazolam,
+ RTV 100 mg some cases fatal, rifampin, sildenafil sole PI).
once daily has been reported when used for
with darunavir in pulmonary arterial
combination with hypertension,
ritonavir. simvastatin, St.
John's wort or
All PIs except triazolam. If used
unboosted ATZ with rifabutin,
associated with monitor rifabutin
hyperlipidemia. drug levels and
consider dose
reduction of
rifabutin. All PIs
Page 563
Therapeutic Choice
Drug b
Standard Cost
a
except
inhibit metabolism
of maraviroc.
Protease fosamprenavir (f-APV) Treatment- Rash (19%), GI PIs are not Alternate first- $$$$
Inhibitors Telzir experienced: upset. recommended in line therapy.
(PI) 700 mg + RTV All PIs except combination with Approved for
100 mg BID unboosted ATZ ergot alkaloids, use only with
Treatment- associated with fluticasone, ritonavir (do
naïve: 700 mg hyperlipidemia. lovastatin, not use as a
+ RTV 100 mg d sole PI).
midazolam,
BID or rifampin, sildenafil
when used for
1400 mg + RTV pulmonary arterial
200 mg once hypertension,
daily simvastatin, St.
John's wort or
triazolam. If used
with rifabutin,
monitor rifabutin
drug levels and
consider dose
reduction of
rifabutin. All PIs
except
inhibit metabolism
of maraviroc. Do not
use f-APV/ritonavir
with etravirine.
Protease indinavir (IDV) 800 mg TID Liver enzyme PIs are not Avoid because $$$$$
Inhibitors Crixivan or elevations, recommended in of adverse
(PI) nephrolithiasis. combination with effects.
800 mg + RTV All PIs except ergot alkaloids, Adequate fluid
100 or 200 mg unboosted ATZ fluticasone, intake
BID associated with lovastatin, recommended
hyperlipidemia. d (at least 1.5
midazolam,
rifampin, sildenafil L/day) to
when used for reduce risk of
pulmonary arterial nephrolithiasis.
hypertension,
simvastatin, St.
John's wort or
triazolam. If used
with rifabutin,
monitor rifabutin
drug levels and
consider dose
reduction of
rifabutin. All PIs
except
inhibit metabolism
of maraviroc.
Protease lopinavir/ritonavir (LPV/RTV) Treatment- GI upset, liver PIs are not Recommended $$$$$
Inhibitors Kaletra experienced: enzyme recommended in first-line
(PI) 400/100 mg elevations. combination with therapy in
BID All PIs except ergot alkaloids, pregnancy
Treatment- unboosted ATZ fluticasone, only—
naïve: associated with lovastatin, otherwise is an
400/100 mg hyperlipidemia. d alternate
midazolam,
BID or rifampin, sildenafil therapy.
when used for Once daily
800/200 mg pulmonary arterial LPV/RTV not
once daily hypertension, recommended
simvastatin, St. in pregnancy;
With EFV or John's wort or use twice daily
NVP: 400/100 triazolam. If used regimen.
or 600/150 mg with rifabutin,
BID monitor rifabutin
drug levels and
consider dose
Page 564
Therapeutic Choice
Drug b
Standard Cost
reduction of
rifabutin. All PIs
except
inhibit metabolism
of maraviroc.
Efavirenz,
nevirapine ↓ levels.
Protease nelfinavir (NFV) 1250 mg BID Diarrhea. PIs are not Not boosted by $$$$$
Inhibitors Viracept or All PIs except recommended in ritonavir to a
(PI) unboosted ATZ combination with significant
750 mg TID associated with ergot alkaloids, extent.
hyperlipidemia. fluticasone,
lovastatin,
d
midazolam,
rifampin, sildenafil
when used for
pulmonary arterial
hypertension,
simvastatin, St.
John's wort or
triazolam. If used
with rifabutin,
monitor rifabutin
drug levels and
consider dose
reduction of
rifabutin. All PIs
except
inhibit metabolism
of maraviroc.
Protease ritonavir (RTV) 600 mg BID GI upset, diarrhea, PIs are not As a PK $$$$$
Inhibitors Norvir, Norvir Sec (sole PI). circumoral recommended in booster, low-
(PI) As a PK paresthesia, liver combination with dose RTV is a
booster, see enzyme ergot alkaloids, component of
atazanavir, elevations. fluticasone, many
darunavir, All PIs except lovastatin, regimens.
fosamprenavir, unboosted ATZ d Avoid use as a
midazolam,
indinavir, associated with rifampin, sildenafil sole PI because
saquinavir and hyperlipidemia. when used for of adverse
tipranavir pulmonary arterial effects.
hypertension,
simvastatin, St. Drug-induced
John's wort or hepatotoxicity,
triazolam. If used in some cases
with rifabutin, fatal, has been
monitor rifabutin reported with
drug levels and darunavir in
consider dose combination
reduction of with ritonavir.
rifabutin. All PIs See darunavir
except Product
tipranavir/ritonavir Monograph
inhibit metabolism
of maraviroc.
Protease saquinavir (SQV) 1000 mg + RTV ↑ liver enzymes, GI PIs are not Avoid $$$$$
Inhibitors Invirase 100 mg BID upset, headache, recommended in unboosted
(PI) QT and PR interval combination with SQV: inferior
prolongation. ergot alkaloids, efficacy.
All PIs except fluticasone, Alternate first-
unboosted ATZ lovastatin, line therapy
associated with midazolam,d when used
hyperlipidemia. rifampin, sildenafil with ritonavir.
when used for
pulmonary arterial
hypertension,
simvastatin, St.
John's wort or
triazolam. If used
Page 565
Therapeutic Choice
Drug b
Standard Cost
a
with rifabutin,
monitor rifabutin
drug levels and
consider dose
reduction of
rifabutin. All PIs
except
inhibit metabolism
of maraviroc.
Saquinavir should
not be used with
other medications
that prolong the QT
interval (e.g.,
quinidine, sotalol).
Protease tipranavir (TPV) 500 mg + RTV Hepatotoxicity, PIs are not Reserve for $$$$$
Inhibitors Aptivus 200 mg BID rash (possible recommended in treatment-
(PI) cross-sensitivity combination with experienced
with ergot alkaloids, patients with
sulfonamides). fluticasone, limited
Intracranial lovastatin, options.
hemorrhage d Approved for
midazolam,
(rare). rifampin, sildenafil use only with
All PIs except when used for ritonavir (i.e.,
unboosted ATZ pulmonary arterial do not use as a
associated with hypertension, sole PI).
hyperlipidemia. simvastatin, St.
John's wort or When used
triazolam. If used with ddI
with rifabutin, separate doses
monitor rifabutin by at least 2 h.
drug levels and
consider dose
reduction of
rifabutin. All PIs
except
inhibit metabolism
of maraviroc. Do not
use TPV/ritonavir
with etravirine.
Fusion enfuvirtide (T20) 90 mg BID sc Most patients Does not interact Reserve for $$$$$
Inhibitors Fuzeon experience with CYP isozymes. treatment-
injection site experienced
reactions (may be patients with
severe). limited
Hypersensitivity options.
reactions (< 1%).
Entry maraviroc 300 mg BID Cough, fever, ↓ levels with CYP3A4 Phenotype test $$$$$
Inhibitors Celsentri with NRTIs, upper respiratory inducers: efavirenz, required prior
tipranavir/RTV, tract infection, etravirine, rifampin. to treatment:
nevirapine rash, abdominal ↑ levels with CYP3A4 effective only
and/or other pain, muscle pain, inhibitors: PIs (except in patients with
drugs that are dizziness, tipranavir/ritonavir), CCR5 tropic
not strong hepatotoxicity. itraconazole, HIV (not
inhibitors or ketoconazole, CXCR4 or
inducers of clarithromycin, mixed-tropic
CYP3A4 telithromycin. virus).
150 mg BID
with strong
CYP3A4
inhibitors
including PIs
(except
tipranavir/RTV),
delavirdine
Page 566
Therapeutic Choice
Drug b
Standard Cost
600 mg BID
with strong
CYP3A4
inducers
including
efavirenz,
etravirine
See Drug
Interactions
Integrase raltegravir 400 mg BID Nausea, headache, Not an inhibitor or An option for $$$$$
Inhibitors Isentress 800 mg BID diarrhea, pyrexia. inducer of CYP first-line
may be isozymes. Rifampin therapy.
considered ↓ raltegravir levels
when by inducing
coadministered glucuronidation.
with rifampin2
RTI abacavir/lamivudine 600 mg/ Hypersensitivity Alcohol may ↑ Alternate first- $$$$$
Combination Kivexa 300 mg once reactions in abacavir plasma levels. line therapy.
Products daily patients with a Enhanced toxic Renal
genetic effects with impairment:
predisposition emtricitabine. combined
(can be severe).c products are
Potential increased not
risk of myocardial recommended.
infarction. Caution Use individual
in patients with products and
pre-existing adjust each
serious agent
cardiovascular accordingly.
disease.
RTI abacavir/lamivudine/zidovudine 300 mg/150 Hypersensitivity Alcohol may ↑ Renal $$$$$

Combination Trizivir mg/ 300 mg reactions in abacavir plasma levels. impairment:
Products twice daily patients with a Enhanced toxic combined
genetic effects with products are
predisposition emtricitabine. not
c recommended.
(can be severe).
Potential increased Additive Use individual
risk of myocardial hemotoxicity with products and
infarction. Caution other agents, e.g., adjust each
in patients with anemia with agent
pre-existing ribavirin and accordingly.
serious ganciclovir.
cardiovascular Pharmacologic
disease. antagonism with
stavudine.
Nausea, headache,
malaise, fatigue,
rash, myositis,
myocarditis,
anemia,
leukopenia, ↑ liver
enzymes, ↑ lactic
acid, hepatic
steatosis, ↑ CK.
RTI emtricitabine/tenofovir 200 mg/ Renal toxicity. Avoid combined use Recommended $$$$$
Combination Truvada 300 mg once Monitor renal of emtricitabine and first-line
Products daily function and lamivudine (similar therapy.
serum resistance profiles Renal
phosphorus. and enhanced impairment:
toxicity). combined
Page 567
Therapeutic Choice
Drug b
Standard Cost
TDF ↑ ddI levels. products are
TDF ↓ atazanavir not
levels, therefore recommended.
administer only in Emtricitabine is
combination with not available
ritonavir. as a single
entity product.
Atazanavir ↑ TDF
levels.
RTI lamivudine/zidovudine 150 mg/ Nausea, headache, Enhanced toxic Renal $$$$$
Combination Combivir 300 mg twice malaise, fatigue, effects with impairment:
Products daily rash, myositis, emtricitabine. combined
myocarditis, Additive products are
anemia, hemotoxicity with not
leukopenia, ↑ liver other agents, e.g., recommended.
enzymes, ↑ lactic anemia with Use individual
acid, hepatic ribavirin and products and
steatosis, ↑ CK. ganciclovir. adjust each
Pharmacologic agent
antagonism with accordingly.
stavudine.
RTI efavirenz/emtricitabine/tenofovir 600 mg/ CNS toxicity, Do not administer Recommended $$$$$
Combination Atripla 200 mg/ drowsiness, rash, with cisapride, ergot first-line
Products 300 mg once ↑ liver enzymes. derivatives, therapy.
daily Avoid in patients d Renal
midazolam,
with a history of pimozide and impairment:
anxiety, triazolam. combined
depression or Induces metabolism products are
psychosis. of maraviroc. not
recommended.
Contraindicated in St. John's wort ↓ Emtricitabine is
1st trimester of levels. not available
pregnancy as a single
(teratogenic in Voriconazole: EFV ↑ entity product.
animals). Avoid in and voriconazole ↓;
women of child- dosage adjustments
bearing potential. needed.
Renal toxicity. Avoid combined use

Monitor renal of emtricitabine and
function and lamivudine (similar
serum resistance profiles
phosphorus. and enhanced
toxicity).
TDF ↑ ddI levels.

TDF ↓ atazanavir
levels, therefore
administer only in
combination with
ritonavir.
Atazanavir ↑ TDF
levels.
a.
Many drug interactions occur among antiretroviral drugs. Those listed here are limited to more significant or relevant interactions. Always consult a
reputable drug interaction reference or the product monograph for more information.
b.
c.
Patients with the HLA-B*5701 allele, present in 5% to 8% of white patients but rare in patients of African and Asian descent, are predisposed to
23
allergic reactions. A positive test result for the allele should be recorded as an allergy to abacavir in the patient's chart.
d.
May use a single dose of parenteral midazolam with caution for monitored medical procedures.
e.
Patients with a particular polymorphism in the multidrug resistance gene 1 have higher plasma levels of atazanavir and higher bilirubin levels
during atazanavir therapy than those without this polymorphism. The risk of severe hyperbilirubinemia during atazanavir therapy is further increased
24 , 25
by the presence of distinct variants in the gene coding for UDP-glucuronosyltransferase (UGT1A).
Page 568
Therapeutic Choice
Abbreviations: CK=creatine kinase; CCR5=chemokine receptor 5; CYP=cytochrome P450; PI=protease inhibitor; PK=pharmacokinetic
Legend: $ $100–200 $$ $200–300 $$-$$$ $200–400 $$$ $300–400 $$$$ $400–500 $$$$$ > $500
Suggested Readings
Aberg JA, Kaplan JE, Libman H et al. Primary care guidelines for the management of persons infected with human immunodeficiency
virus: 2009 update by the HIV medicine association of the infectious diseases society of America. Clin Infect Dis 2009;49(5):651-81.
AIDS Education & Training Centers National Resource Center. Clinical manual for management of the HIV-infected adult. Newark (NJ):
AETC National Resource Center; 2006. Available from: www.aids-ed.org/aetc/aetc?page=cm-00-00. Accessed December 22, 2009.
Hammer SM, Eron JJ, Reiss P et al. Antiretroviral treatment of adult HIV infection: 2008 recommendations of the International AIDS
Society-USA panel. JAMA 2008;300(5):555-70.
Hatano H, Deeks SG. Drug resistant HIV. BMJ 2007;334(7604):1124-5.
Hogg RS, Yip B, Chan KJ et al. Rates of disease progression by baseline CD4 cell count and viral load after initiating triple-drug
therapy. JAMA 2001;286(20):2568-77.
Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults
and adolescents. Department of Health and Human Services. December 1, 2009. p. 1-161. Available from:
www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Accessed December 22, 2009.
Wood E, Hogg RS, Harrigan PR et al. When to initiate antiretroviral therapy in HIV-infected adults: a review for clinicians and patients.
Lancet Infect Dis 2005;5(7):407-14.
References
1. Mellors JW, Kingsley LA, Rinaldo CR et al. Quantitation of HIV-1 RNA in plasma predicts outcome after seroconversion. Ann
Intern Med 1995;122(8):573-9.
2. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected
adults and adolescents. Department of Health and Human Services. December 1, 2009. p. 1-161. Available from:
www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Accessed December 22, 2009.
3. Mallal S, Phillips E, Carosi G et al. HLA-B*5701 screening for hypersensitivity to abacavir. N Engl J Med 2008;358(6):568-79.
4. Grabar S, Le Moing V, Goujard C et al. Clinical outcome of patients with HIV-1 infection according to immunologic and virologic
response after 6 months of highly active antiretroviral therapy. Ann Intern Med 2000;133(6):401-10.
5. Palella FJ, Delaney KM, Moorman AC et al. Declining morbidity and mortality among patients with advanced human
immunodeficiency virus infection. HIV Outpatient Study Investigators. N Engl J Med 1998;338(13):853-60.
6. Morse CG, Kovacs JA. Metabolic and skeletal complications of HIV infection: the price of success. JAMA 2006;296(7):844-54.
7. Friis-Moller N, Sabin CA, Weber R et al. Combination antiretroviral therapy and the risk of myocardial infarction. N Engl J Med
2003;349(21):1993-2003.
8. When To Start Consortium, Sterne JA, May M et al. Timing of initiation of antiretroviral therapy in AIDS-free HIV-1-infected
patients: a collaborative analysis of 18 HIV cohort studies. Lancet 2009;373(9672):1352-63.
9. Kitahata MM, Gange SJ, Abraham AG et al. Effect of early versus deferred antiretroviral therapy for HIV on survival. N Engl J
Med 2009;360(18):1815-26.
10. Deeks SG, Phillips AN. HIV infection, antiretroviral treatment, ageing, and non-AIDS related morbidity. BMJ 2009;338:a3172.
11. Condra JH, Schleif WA, Blahy OM et al. In vivo emergence of HIV-1 variants resistant to multiple protease inhibitors. Nature
1995;374(6522):569-71.
12. Descamps D, Flandre P, Calvez V et al. Mechanisms of virologic failure in previously untreated HIV-infected patients from a trial
of induction-maintenance therapy. Trilege (Agence Nationale de Recherches sur le SIDA 072) Study Team). JAMA 2000;283
(2):205-11.
13. Hammer SM, Eron JJ, Reiss P et al. Antiretroviral treatment of adult HIV infection: 2008 recommendations of the International
AIDS Society-USA panel. JAMA 2008;300(5):555-70.
14. Vanhove GF, Schapiro JM, Winters MA et al. Patient compliance and drug failure in protease inhibitor monotherapy. JAMA
1996;276(24):1955-6.
15. The Strategies for Management of Antiretroviral Therapy (SMART) Study Group. CD4+ count-guided interruption of
antiretroviral treatment. N Engl J Med 2006;355(22):2283-96.
16. Ananworanich J, Hirschel B. Intermittent therapy for the treatment of chronic HIV infection. AIDS 2007;21(2):123-34.
17. Anderson BL and Cu-Uvin S. Pregnancy and optimal care of HIV-infected patients. Clin Infect Dis 2009;48(4):449-55.
18. Perinatal HIV Guidelines Working Group. Public Health Service Task Force. Recommendations for use of antiretroviral drugs in
pregnant HIV-infected women for maternal health and interventions to reduce perinatal HIV transmission in the United States.
April 29, 2009. p. 1-90. Available from: aidsinfo.nih.gov/ContentFiles/PerinatalGL.pdf. Accessed December 22, 2009.
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19. Connor EM, Sperling RS, Gelber R et al. Reduction of maternal-infant transmission of human immunodeficiency virus type 1
with zidovudine treatment. Pediatric AIDS Clinical Trials Group Protocol 076 Study Group. N Engl J Med 1994;331(18):1173-80.
20. Raboud JM, Montaner JS, Conway B et al. Variation in plasma RNA levels, CD4 cell counts, and p24 antigen levels in clinically
stable men with human immunodeficiency virus infection. J Infect Dis 1996;174(1):191-4.
21. Staprans SI, Hamilton BL, Follansbee SE et al. Activation of virus replication after vaccination of HIV-1-infected individuals. J
Exp Med 1995;182(6):1727-37.
22. Raboud JM, Haley L, Montaner JS et al. Quantification of the variation due to laboratory and physiologic sources in CD4
lymphocyte counts of clinically stable HIV-infected individuals. J Acquir Immune Defic Syndr Hum Retrovirol 1995;10(Suppl
2):S67-73.
23. Phillips EJ. Genetic screening to prevent abacavir hypersensitivity reaction: are we there yet? Clin Infect Dis 2006;43(1):103-5.
24. Lankisch TO, Moebius U, Wehmeier M et al. Gilbert's disease and atazanavir: from phenotype to UDP-glucuronosyltransferase
haplotype. Hepatology 2006;44(5):1324-32.
25. Rodriguez-Novoa S, Martin-Carbonero L, Barreiro P et al. Genetic factors influencing atazanavir plasma concentrations and the
risk of severe hyperbilirubinemia. AIDS 2007;21(1):41-6.
Page 570
e-Therapeutics+ : Therapeutics : Infectious Diseases: Infections in the Cancer Patient Page 1 of 12
Therapeutic Choice
Print Close
Infectious Diseases: Infections in the Cancer Patient

Coleman Rotstein, MD, FRCPC, FACP, FIDSA
Infections are a significant cause of morbidity and mortality in cancer patients despite progress in their recognition,
therapy and prevention. The ever expanding armamentarium of antineoplastic chemotherapeutic agents, radiation
therapy and immunotherapy has improved the survival of cancer patients, but simultaneously has rendered them more
susceptible to infections.
Goals of Therapy
Decrease morbidity associated with infection

Minimize risk of death from infection
Enhance the supportive care and quality of life of cancer patients by using prophylactic measures to prevent
infection and outpatient antibiotic management when appropriate to facilitate care and reduce length of hospital
stay
Investigations

the nature of the malignancy and associated defects in host defenses, e.g., neutropenia, B cell and/or T cell
dysfunction
the effects of cytotoxic, myelosuppressive or immunosuppressive therapy to treat the patient's cancer; note day
of onset of fever relative to the first day of the most recent cycle of chemotherapy
neutropenia (severity and expected duration)
iatrogenic procedures performed on the patient, e.g., splenectomy, placement of venous access devices or
other surgical procedures
whether the nature of the malignancy suggests obstruction of natural body passages, e.g., bronchus, bowel,
ureter, biliary tree
CNS dysfunction
occupational and travel history, and exposure to animals
Complete physical examination with particular attention to venous access sites, wounds, skin, mouth, pharynx,
sinuses, rectum and other possible sites of infection
Laboratory tests:
CBC and differential to assess the total neutrophil count
biochemical profile with attention to renal and liver function
at least 2 sets of blood cultures: ensure blood cultures are done from peripheral site as well as lumens of
venous access devices
culture of any other suspected site of infection, e.g., urine, skin, sputum
radiographic studies appropriate for suspected sites of infection, e.g., chest x-ray or CT scan of the chest for
pneumonia, CT scan or MRI of the head for encephalitis or cerebral abscess
stool for Clostridium difficile and other potential pathogens (e.g., Salmonella spp., Shigella spp., Campylobacter
spp., viruses and protozoa) if diarrhea is present
serological tests (i.e., serology or antigen assays for cytomegalovirus, Cryptococcus spp., Epstein-Barr virus,
hepatitis and Toxoplasma spp.) if indicated
when appropriate, biopsy for pathology and culture of skin lesions suspected to be infectious
Therapeutic Choices
Infection control measures such as handwashing and use of high-efficiency particulate filtration rooms for
profoundly neutropenic patients at high risk for filamentous fungal infections are mandatory.
Use specialized infection control procedures (contact precautions) for patients colonized with multiple-resistant
organisms, e.g., methicillin-resistant Staphylococcus aureus or vancomycin-resistant enterococci.
For neutropenic patients, avoid ingesting raw fruits and vegetables, and avoid fresh flowers and plants in the
patient's room.
Page 571
Therapeutic Choice
Antibacterial Therapy
Although neoplasms can cause fevers in cancer patients, seek an infectious etiology in all cases of elevated
temperature. Fever is defined as a single oral temperature ≥ 38.3°C or a temperature of ≥ 38°C for ≥ 1-hour
1
period in the absence of obvious environmental causes.
Most infections are caused by microorganisms that have colonized the patient at or near the site of infection, e.g.,
the skin, oropharynx, genitourinary tract, gastrointestinal tract or lungs.
Bacteria are the principal pathogens causing infections in cancer patients, making up > 60% of initially documented
episodes of infection.
The choice of antibacterial agents in febrile cancer patients is predicated on the neutrophil count, the patient's
clinical status and the site of infection (Figure 1 - Approach to Fever in Cancer Patients). Neutropenia is defined as
a neutrophil count ≤ 1.0 × 109/L. A more profound degree of neutropenia (< 0.5 × 109/L) confers a greater risk of
developing more severe infection. In addition, the risk of severe infection is directly related to the duration of
neutropenia. Because of the high risk of life-threatening bacterial infection and the inability to reliably distinguish
patients with bacterial infection from noninfected patients at presentation (particularly in neutropenic patients),
initiate prompt intravenous antibiotic therapy.
In selecting the initial antibiotic regimen and the site of care (the inpatient or outpatient setting), consider
concurrent comorbid medical illnesses (e.g., heart failure, renal disease, liver disease, bleeding disorders), the
control of the cancer and presence of serious medical complications.2 , 3 , 4 Outpatient antibiotic therapy may be
employed not only for non-neutropenic patients, but also for low-risk neutropenic patients who do not have the
aforementioned medical conditions or uncontrolled cancer (Figure 2 - Management of Infection in Febrile
Neutropenic Cancer Patients). Broad spectrum antibiotic therapy that ensures adequate coverage for both gram-
positive and gram-negative organisms is necessary for febrile neutropenic patients.
Vancomycin may be incorporated into the initial therapeutic regimen for patients with suspected venous access
catheter-related infection, positive blood cultures for gram-positive bacteria in groups and chains, severe mucositis,
known colonization with methicillin-resistant S. aureus , hypotension or other evidence of cardiovascular
impairment.1 Alternatively, vancomycin may be added later to the initial broad spectrum regimen once
susceptibility testing has been completed. Vancomycin should be discontinued if the infecting organism is
subsequently shown to be susceptible to other antibiotics.
Metronidazole or clindamycin may be used as part of the initial antibiotic regimen for presumed anaerobic
infection related to the gastrointestinal tract or skin.
In neutropenic patients with a suspected bacterial infection, continue antibacterial therapy until they are no longer
9
profoundly neutropenic (neutrophils ≥ 0.5 × 10 /L) and are afebrile for ≥ 48 hours. For patients with
microbiologically or clinically documented infection, continue broad spectrum antibacterial therapy for a minimum
9
of 10 to 14 days and until patients are afebrile and no longer neutropenic (neutrophils ≥ 0.5 × 10 /L).
In non-neutropenic cancer patients with a suspected bacterial infection, continue antibiotic therapy for
approximately 7 days and until the patient is afebrile for ≥ 48 hours. Alternatively, switch from intravenous
antibiotic therapy to oral therapy to complete an appropriate course of therapy directed towards the site that is
infected.
Antifungal Therapy
Non-neutropenic patients who develop oral and or esophageal candidiasis may be treated with a topical agent such
as nystatin or systemic oral agents such as fluconazole, itraconazole, posaconazole or voriconazole.
Patients with extensive lesions may require parenteral therapy with fluconazole, an amphotericin B formulation,
caspofungin, micafungin or voriconazole.
Parenteral antifungal therapy should be initiated for documented invasive or disseminated fungal infection in non-
neutropenic and neutropenic cancer patients.
Treatment of a documented or suspected fungal infection in a neutropenic patient requires parenteral antifungal
therapy with amphotericin B, most often, or with caspofungin or fluconazole in patients with renal
dysfunction.1
The lipid-based preparations of amphotericin B have equivalent efficacy but produce less nephrotoxicity and
infusion reactions than conventional amphotericin B. They may be used as salvage therapy for patients with fungal
5
infections that fail to respond to amphotericin B or for patients with amphotericin B toxicity or intolerance.
Caspofungin, micafungin or anidulafungin may be beneficial for the treatment of candidemia in neutropenic or
6
non-neutropenic patients.
Itraconazole, which is only available in an oral formulation, has enhanced activity against Aspergillus spp.
compared to fluconazole and is an alternative for oral step-down therapy after parenteral treatment for invasive
aspergillosis.
Voriconazole, available both in intravenous and oral formulations, has superior activity compared to
7
amphotericin B when used as primary therapy for invasive aspergillosis, and for infections caused by
Scedosporium spp. and Fusarium spp.
Voriconazole or caspofungin, alone or in combination or with a lipid-based formulation of amphotericin B may
8 , 9
be used in the treatment of documented invasive aspergillosis.
Posaconazole may be used for refractory invasive fungal infections.10
Page 572
Therapeutic Choice
Antiviral Therapy
There is no indication for the empirical use of antiviral drugs in the treatment of cancer patients without evidence of
1
viral disease.
Skin or mucous membrane lesions due to herpes simplex virus or varicella-zoster virus may be treated with oral or
intravenous acyclovir. Oral famciclovir or valacyclovir are better absorbed from the gastrointestinal tract than
11
acyclovir and are alternatives.
Intravenous foscarnet is available through the federal Special Access Programme for acyclovir-resistant
herpesvirus infections.
Cytomegalovirus infection in bone marrow transplant recipients may be treated with ganciclovir. Valganciclovir
is used only when oral therapy is required.
Supportive Care Measures
Granulocyte (G-CSF) and granulocyte-macrophage (GM-CSF) colony-stimulating factors may decrease the
incidence and duration of neutropenia after chemotherapy. Their use is advocated for patients who remain
profoundly neutropenic and have failed to respond to appropriate antimicrobial therapy for documented infection
1 , 12 9
such as pneumonia, severe cellulitis or sinusitis. Once neutrophil counts reach ≥ 1.0 × 10 /L, colony-
stimulating factor support should be discontinued.
Prevention of Infection in Cancer Patients
For cancer patients with pronounced T cell dysfunction, prophylaxis with oral sulfamethoxazole/trimethoprim
is recommended to prevent Pneumocystis jirovecii pneumonia. Alternative prophylactic agents are inhaled
pentamidine and dapsone.
Strategies designed to prevent bacterial infection in profoundly neutropenic cancer patients, such as those with
acute leukemia, focus on eliminating indigenous microflora and preventing acquisition of new potential pathogens.
Potential antimicrobial regimens are fluoroquinolones, sulfamethoxazole/trimethoprim or oral nonabsorbable
antibiotics (gentamicin, vancomycin and nystatin). Ciprofloxacin or levofloxacin significantly decrease
febrile morbidity, bacterial infections and mortality for patients with acute leukemia and those undergoing bone
marrow transplantation.13 Prophylaxis during the expected period of neutropenia in the first month of
chemotherapy in patients with solid tumors or lymphoma (levofloxacin 500 mg for 7 days) also reduces the rate of
febrile episodes.14 There may be a predilection for gram-positive infection when ciprofloxacin is used
prophylactically. This may be overcome by adding another antibiotic with good activity against gram-positive
organisms (e.g., a penicillin or a macrolide).15
Antifungal prophylaxis with oral fluconazole prevents invasive fungal infection in allogeneic bone marrow
16 , 17
transplant recipients and patients with acute leukemia undergoing remission-induction chemotherapy.
Itraconazole prophylaxis may be preferred for individuals at greater risk of developing invasive aspergillosis.
Posaconazole is as effective as fluconazole in preventing all invasive fungal infections, but is superior for
prevention of invasive aspergillosis in hematopoietic stem-cell transplant recipients with graft-versus-host
18
disease. In patients with acute leukemia undergoing chemotherapy, posaconazole is more effective than both
fluconazole and itraconazole for prevention of invasive fungal infections.19
20
Micafungin is effective as prophylaxis in hematopoietic stem-cell transplant recipients.
If fluconazole has been used prophylactically, it should not be used empirically or for documented
fungal infections in neutropenic cancer patients. For these situations, a parenteral amphotericin B
8
formulation or caspofungin are the drugs of choice. Useful Info?
Therapeutic Tips
Avoid aminoglycosides in patients with impaired renal function, particularly those receiving treatment with other
nephrotoxic drugs such as cisplatin, cyclosporine or amphotericin B.
In deciding on cost-effective empirical therapy, drug acquisition costs by themselves are of limited value. Also
consider the relative effectiveness, side effect profile and overall resource consumption of the available treatments.
Monotherapy with an intravenous broad spectrum antipseudomonal beta-lactam (ceftazidime,
imipenem/cilastatin, meropenem or piperacillin/tazobactam) is suitable for the treatment of febrile
neutropenic episodes.
Combination therapy for febrile neutropenia with a beta-lactam and an aminoglycoside is associated with more
adverse events (e.g., a higher incidence of nephrotoxicity, ototoxicity) than monotherapy with a beta-lactam.
Identification of low-risk patients appropriate for outpatient antibiotic management may enhance the patient's
quality of life and reduce costs.
Page 573
Therapeutic Choice
Figure 1- Approach to Fever in Cancer Patients
Figure 2- Management of Infection in Febrile Neutropenic Cancer Patients
Page 574
Therapeutic Choice
a.
Antipseudomonal combination therapy = a beta-lactam (piperacillin, piperacillin/tazobactam, ceftazidime, imipenem/cilastatin or
meropenem) plus an aminoglycoside.
b.
Cefepime, ceftazidime, imipenem/cilastatin or meropenem.
c.
Double beta-lactam therapy = ceftazidime plus either piperacillin or piperacillin/tazobactam.
Abbreviations: MRSA = methicillin-resistant S. aureus
Table 1: Drugs Used to Treat Infections in Cancer Patients
a
Cost
Penicillins amoxicillin/clavulanate One 500/125 mg Diarrhea, rash, $

tablet po TID or hypersensitivity
Clavulin, generics One 875/125 mg reactions, interstitial
tablet po BID nephritis,
neutropenia,
hemolytic anemia;
thrombocytopenia.
Page 575
Therapeutic Choice
a
Cost
Penicillins piperacillin 4 g iv Q6H Diarrhea, rash, $$$$

generics hypersensitivity
reactions, interstitial
nephritis,
neutropenia,
hemolytic anemia;
thrombocytopenia.
Penicillins piperacillin/tazobactam 12–16 g/1.5–2 g/day Diarrhea, rash, $$$

iv divided Q6–8H hypersensitivity
Tazocin reactions, interstitial
Piperacillin/Tazobactam nephritis,
neutropenia,
for Injection,
hemolytic anemia;
other generics thrombocytopenia.
Cephalosporins cefepime 2 g iv Q8H Diarrhea, rash, $$$

Maxipime, generics hypersensitivity
nephritis,
neutropenia,
hemolytic anemia;
thrombocytopenia.
Cephalosporins ceftazidime , 2 g iv Q8H Diarrhea, rash, $$$$$

Fortaz, generics hypersensitivity
nephritis,
neutropenia,
hemolytic anemia;
thrombocytopenia.
Cephalosporins ceftriaxone 1–2 g iv once daily Diarrhea, rash, Do not reconstitute $$

Rocephin hypersensitivity or mix with calcium-
Ceftriaxone for reactions, interstitial containing solutions.
nephritis, Do not administer
Injection USP,
neutropenia, simultaneously with
other generics
hemolytic anemia; calcium-containing
thrombocytopenia. iv solutions via a Y-
Pseudocholelithiasis. site. Administration
may be done
sequentially
provided the
infusion lines are
thoroughly flushed
between infusions.
Carbapenems imipenem/cilastatin 500 mg iv Q6H Diarrhea, rash, $$$$$

Primaxin hypersensitivity
nephritis,
neutropenia,
hemolytic anemia;
thrombocytopenia.
Associated with
seizures especially
with high doses
(1 g Q6H) and in
patients with renal
dysfunction.
Carbapenems meropenem 1 g iv Q8H Diarrhea, rash, $$$$$

Merrem nausea,
Page 576
Therapeutic Choice
a
Cost
hypersensitivity
reactions:
interstitial nephritis,
neutropenia,
hemolytic anemia;
thrombocytopenia.
Aminoglycosides amikacin 15–20 mg/kg once Ototoxicity (auditory Synergistic or $$$

generics daily (extended and/or vestibular), additive toxicity if
b nephrotoxicity, used with
interval regimen)
neuromuscular vancomycin and/or
paralysis (rare). platinum-derived
antineoplastics,
amphotericin B
and/or other
nephrotoxic/ototoxic
drugs.
Aminoglycosides gentamicin 5–7 mg/kg once Ototoxicity (auditory Synergistic or $

interval regimen)
antineoplastics,
amphotericin B
and/or other
drugs.
Aminoglycosides tobramycin 5–7 mg/kg once Ototoxicity (auditory Synergistic or $

interval regimen)
antineoplastics,
amphotericin B
and/or other
drugs.
Fluoroquinolones ciprofloxacin 500 or 750 mg po GI upset, rash, CNS Warfarin: ↑ INR. po:$
Cipro, generics BID toxicity. Binds with antacids, iv:$$$
400 mg iv Q12H iron, sucralfate.
Fluoroquinolones levofloxacin 500 mg po once Nausea, diarrhea, Binds with antacids, po:$
Levaquin, generics daily headache, insomnia, metal cations, iv:$$
500 mg iv once daily dizziness. sucralfate.
failure have been
reported.
Fluoroquinolones moxifloxacin 400 mg po once Nausea, diarrhea, Binds with antacids, po:$
Avelox daily headache, insomnia, metal cations, iv:
400 mg iv once daily dizziness. sucralfate. $$$
failure have been
reported.
Page 577
Therapeutic Choice
a
Cost
Fluoroquinolones ofloxacin 400 mg po BID Nausea, vomiting, Warfarin: ↑ INR. $

generics rash, headache Binds with antacids,
insomnia, dizziness. iron, sucralfate.
Glycopeptides vancomycin 15 mg/kg iv Q12H Shock after rapid iv Nephrotoxicity may $$$
Vancocin, generics infusion ( < 1 h), be enhanced if given
fever, chills, with
phlebitis, “red-neck” aminoglycosides or
syndrome, tingling other nephrotoxins.
and flushing of
head, neck, chest,
rash, transient
leukopenia or
eosinophilia,
ototoxicity.
Lincosamides clindamycin 600 mg iv Q8H Diarrhea, minor May enhance action $$

Dalacin C Phosphate reversible ↑ liver of neuromuscular
Sterile Solution, transaminases, blocking agents.
generics reversible
neutropenia,
thrombocytopenia,
pseudomembranous
colitis.
Macrolides azithromycin 500 mg iv once daily GI upset. May ↑ bioavailability of $

Zithromax, generics digoxin.
Macrolides erythromycin 1 g iv Q6H Abdominal pain, May interfere with $$$$

Erythrocin, generics nausea, vomiting, metabolism of
diarrhea; carbamazepine,
thrombophlebitis, cyclosporine,
transient hearing methylprednisolone,
loss with high theophylline,
doses. warfarin.
Nitroimidazoles metronidazole 500 mg iv Q12H GI upset, reversible Disulfiram-like $

generics neutropenia, reaction with
seizures, peripheral alcohol.
neuropathy (rare), Potentiation of
rash, metallic taste. warfarin effects and
other oral coumarin-
type anticoagulants.
Sulfonamide sulfamethoxazole / po/iv: trimethoprim Nausea, vomiting, May ↑ effect of po: $

Combinations trimethoprim 20 mg/kg/day and diarrhea; warfarin. iv: $$
sulfamethoxazole hypersensitivity
Septra Injection,
100 mg/kg/day reactions,
generics divided QID leukopenia,
thrombocytopenia,
hepatitis (rare).
Polyene amphotericin B 0.3–1.5 mg/kg iv Rigors, renal ↑ azotemia when $$–

Antifungals Fungizone Q24H dysfunction used with other $$$
(azotemia), nephrotoxic drugs.
headache,
hypokalemia,
phlebitis,
thrombocytopenia,
anemia, leukopenia
(rare), hypotension.
Page 578
Therapeutic Choice
a
Cost
Polyene amphotericin B lipid 3–5 mg/kg iv Q24H Less nephrotoxicity $$$$$

Antifungals preparations than amphotericin B.
Abelcet, AmBisome
Polyene nystatin, 3.6 million U po Q4H Nausea, vomiting, $

Antifungals ratio-Nystatin, other diarrhea.
generics
Triazole fluconazole 100–400 mg po Nausea, headache, May cause po:$

Antifungals Diflucan, generics Q24H skin rash, abdominal hepatotoxicity if iv: $$
100–400 mg iv Q24H pain, vomiting, used with other -$$$
diarrhea. potentially
hepatotoxic drugs.
Coumarin-like
drugs, cyclosporine,
phenytoin,
sulfonylureas may
require dosage
adjustment
(monitor).
Triazole itraconazole 100–200 mg po daily Nausea, rash, Coumarin-like $

Antifungals Sporanox –BID headache, reversible drugs, cyclosporine,
Sporanox Oral Solution ↑ hepatic enzymes. digoxin, phenytoin,
sulfonylureas may
require dosage
adjustment
(monitor).
Didanosine, H2-
antagonists,
phenytoin, rifampin
may ↓ itraconazole
levels; itraconazole ↑
levels of statins.
Triazole posaconazole Prophylaxis: Nausea, vomiting, Cyclosporine, $$$$$

Antifungals Posanol 200 mg po TID fever, diarrhea, dry midazolam,
Refractory invasive mouth, abdominal sirolimus, statins,
fungal infections: pain, headache. tacrolimus and vinca
400 mg po BID alkaloids require
dose adjustments
(monitor).
Cimetidine,
phenytoin, rifabutin
may ↓ posaconazole
levels.
Triazole voriconazole 200 mg po BID; 4– Visual disturbances, Coumarin-like $$$$$

Antifungals Vfend 6 mg/kg iv Q12H nausea, vomiting, drugs, cyclosporine,
rash, ↑ hepatic sulfonylureas may
enzymes. require dosage
adjustment
(monitor);
barbiturates,
carbamazepine,
phenytoin and
rifampin may ↓
voriconazole levels.
Echinocandin anidulafungin 200 mg iv loading Diarrhea, No clinically $$$$$

Antifungals Eraxis dose, then 100 mg iv hypokalemia, significant
elevated liver interactions.
Page 579
Therapeutic Choice
a
Cost
daily function tests, rash.
Echinocandin caspofungin 70 mg iv loading Fever, nausea, ↑ LFTs with $$$$$

Antifungals Cancidas dose, then 50 mg iv vomiting, phlebitis cyclosporine.
daily at the injection site, Carbamazepine,
diarrhea. dexamethasone,
efavirenz, nelfinavir,
phenytoin, rifampin
↓ caspofungin levels.
Caspofungin ↓ levels
of tacrolimus.
Echinocandin micafungin 50 mg iv daily as Headache, rash, Micafungin ↑ serum $$$$$

Antifungals Mycamine prophylaxis nausea, vomiting, levels of nifedipine
150 mg iv daily for phlebitis at the and sirolimus.
treatment of injection site.
esophageal
candidiasis
Antivirals acyclovir 5–10 mg/kg iv Q8H Phlebitis, rash, Probenecid ↓ renal $$$$$
generics hypotension, clearance; may ↑
headache, nausea, theophylline levels.
tremors, confusion,
seizures (1%), renal
dysfunction.
Antivirals famciclovir 500 mg po TID Headache, nausea, Probenecid ↓ renal $

Famvir, generics pruritus. clearance.
Antivirals ganciclovir Induction: 5 mg/kg Leukopenia, nausea, Avoid use with $$

Cytovene iv Q12H headache, zidovudine (↑
Maintenance: behavioural hematologic
6 mg/kg iv Q24H changes. toxicity).
Antivirals valganciclovir 900 mg po daily Leukopenia, nausea, Prodrug of $$

Valcyte headache, ganciclovir.
behavioural Avoid use with
changes. zidovudine (↑
hematologic toxicity).
Antivirals valacyclovir 1 g po TID Headache, nausea. Probenecid ↓ renal $

Valtrex, generics clearance.
a.
Cost of 1-day supply based on 50 kg body weight; includes drug cost only.
b.
The extended interval regimen (high-dose, once-daily administration) is thought to be associated with less toxicity. However, for
patients with uncertain or impaired renal function some clinicians prefer to use the conventional dosing method (daily dose divided
Q8H) because of more experience with this regimen in this population. Whichever regimen is used, serum levels and renal function
should be monitored and the dose and/or interval should be adjusted accordingly.
Legend: $ < $25 $$ $25–50 $$–$$$ $25–75 $$$ $50–75 $$$–$$$$ $50–100 $$$$ $75–100 $$$$$ >
$100
Suggested Readings
Page 580
Therapeutic Choice
Hughes WT, Armstrong D, Bodey GP et al. 2002 guidelines for the use of antimicrobial agents in neutropenic patients
with cancer. Clin Infect Dis 2002;34(6):730-51.
Paul M, Soares-Weiser K, Grozinsky S et al. Beta-lactam versus beta-lactam-aminoglycoside combination therapy in

cancer patients with neutropenia. Cochrane Database Syst Rev 2003;(3):CD003038.
Rotstein C, Laverdiere M, Marciniak A et al. An economic evaluation of voriconazole versus amphotericin B for the
treatment of invasive aspergillosis in Canada. Can J Infect Dis Med Microbiol 2004;15(5):277-84.
Rotstein C, Mandell LA, Goldberg N. Fluoroquinolone prophylaxis for profoundly neutropenic cancer patients: a meta-
analysis. Current Oncology 1997;4(Suppl 2):S2-S7.
Yu DT, Seger DL, Peterson JF et al. Fluconazole for empiric antifungal therapy in cancer patients with fever and
neutropenia. BMC Infect Dis 2006;6:173.
References
1. Hughes WT, Armstrong D, Bodey GP et al. 2002 guidelines for the use of antimicrobial agents in neutropenic
patients with cancer. Clin Infect Dis 2002;34(6):730-51.
2. Talcott JA, Siegel RD, Finberg R et al. Risk assessment in cancer patients with fever and neutropenia: a
prospective, two-center validation of a prediction rule. J Clin Oncol 1992;10(2):316-22.
3. Talcott JA, Whalen A, Clark J et al. Home antibiotic therapy for low-risk cancer patients with fever and
neutropenia: a pilot study of 30 patients based on a validated prediction rule. J Clin Oncol 1994;12(1):107-14.
4. Paul M, Yahav D, Fraser A et al. Empirical antibiotic monotherapy for febrile neutropenia: systematic review and
meta-analysis of randomized controlled trials. J Antimicrob Chemother 2006;57(2):176-89.
5. Walsh TJ, Finberg RW, Arndt C et al. Liposomal amphotericin B for empirical therapy in patients with persistent
fever and neutropenia. National Institute of Allergy and Infectious Diseases Mycoses Study Group. N Engl J Med
1999;340(10):764-71.
6. Mora-Duarte J, Betts R, Rotstein C et al. Comparison of caspofungin and amphotericin B for invasive candidiasis.
N Engl J Med 2002;347(25):2020-9.
7. Herbrecht R, Denning DW, Patterson TF et al. Voriconazole versus amphotericin B for primary therapy of invasive
aspergillosis. N Engl J Med 2002;347(6):408-15.
8. Walsh TJ, Teppler H, Donowitz GR et al. Caspofungin versus liposomal amphotericin B for empirical antifungal
therapy in patients with persistent fever and neutropenia. N Engl J Med 2004;351(14):1391-402.
9. Marr KA, Boeckh M, Carter RA et al. Combination antifungal therapy for invasive aspergillosis. Clin Infect Dis
2004;39(6):797-802.
10. Walsh TJ, Raad I, Ratterson JF et al. Treatment of invasive aspergillosis with posaconazole in patients who are
refractory or intolerant of conventional therapy: an externally controlled trial. Clin Infect Dis 2007;44(1):2-12.
11. [No authors listed]. Drugs for non-HIV viral infections.Med Lett Drugs Ther 2002;44(1123):9-16.
12. Ozer H, Armitage JO, Bennett CL et al. 2000 update of recommendations for the use of hematopoietic colony-
stimulating factors: evidence-based, clinical practice guidelines. American Society of Clinical Oncology Growth
Factors Expert Panel. J Clin Oncol 2000;18(20):3558-85.
13. Leibovici L, Paul M, Cullen M et al. Antibiotic prophylaxis in neutropenic patients: new evidence, practical
decisions. Cancer 2006;107(8):1743-51.
14. Cullen M, Steven N, Billingham L et al. Antibacterial prophylaxis for solid tumors and lymphomas. N Engl J Med
2005;353(14):988-98.
15. Rotstein C, Mandell LA, Goldberg N. Fluoroquinolone prophylaxis for profoundly neutropenic cancer patients: a
meta-analysis. Current Oncology 1997;4(Suppl 2):S2-S7.
16. Rotstein C, Bow EJ, Laverdiere M et al. Randomized placebo-controlled trial of fluconazole prophylaxis for
neutropenic cancer patients: benefit based on purpose and intensity of cytotoxic therapy. Clin Infect Dis 1999;28
(2):331-40.
17. Bow EJ, Laverdiere M, Lussier N et al. Antifungal prophylaxis for severely neutropenic chemotherapy recipients: a
meta analysis of randomized-controlled clinical trials. Cancer 2002;94(12):3230-46.
18. Ullmann AJ, Lipton JH, Vesole DH et al. Posaconazole versus fluconazole or itraconazole prophylaxis in severe
graft–versus–host disease. N Engl J Med 2007;356(4):335-47.
19. Cornely OA, Maertens J, Winston DJ et al. Posaconazole vs. fluconazole or itraconazole prophylaxis in patients
with neutropenia. N Engl J Med 2007;356(4):348-59.
Page 581
Therapeutic Choice
20. van Burik JA, Ratanatharathorn V, Stepan DE et al. Micafungin versus fluconazole for prophylaxis against fungal
infections during neutropenia in patients undergoing hematopoietic stem cell transplantation. Clin Infect Dis
2004;39(10):1407-16.
Page 582
e-Therapeutics+ : Therapeutics : Infectious Diseases: Infective Endocarditis—Management ... Page 1 of 13
Therapeutic Choice
Print Close
Infectious Diseases: Infective Endocarditis—Management and Prevention
Alfred Gin, BScPharm, PharmD
Infective endocarditis (IE) is a life-threatening infection of the cardiac endothelium associated with significant
morbidity and mortality. IE occurs as a result of a combination of injury or trauma to the cardiac endothelial surface
(e.g., turbulent blood flow, intravenous catheter or foreign particulate matter), fibrin deposition and bacterial
adherence. IE may involve the heart valves and surrounding tissues on either the left or right side of the heart
although bilateral involvement has been described. Metastatic infection to extra-cardiac sites may occur. Complications
include heart failure, peri-annular abscess, mycotic aneurysm and glomerulonephritis. Emboli to extra-cardiac sites
such as the brain, lung or kidney may also occur.
Goals of Therapy
Reduce morbidity and mortality associated with IE

Eradicate infection
Stabilize or normalize patient hemodynamics by pharmacologic, surgical and supportive interventions as necessary
Avoid or minimize drug toxicity
Prevent IE in patients with cardiovascular conditions at risk of severe outcome
Investigations1
The modified Duke criteria are widely accepted as the gold standard for determining the likelihood of IE in a patient.2
It classifies IE cases as definite, probable or rejected based on pathologic, clinical, laboratory and radiologic findings
1 , 2
(see Table 1 and Table 2). Due to the heterogeneous nature of IE, clinical judgment should be used in conjunction
with the modified Duke criteria.2
A systematic history and physical examination should be carried out:

history: Conduct a thorough history to document patient signs and symptoms, time course of illness and
potential risk factors (e.g., recent dental or surgical procedures, dental health, cardiac disease or
malformation, history of cardiac surgery or valve replacement, prior history of IE, intravenous drug use,
placement or manipulation of any intravascular device)
medication history: Conduct a thorough medication review. Patients receiving oral anticoagulation should be
assessed to determine anticoagulation need (e.g., temporarily stopping anticoagulants) if IE is suspected or
documented. Note whether patient is taking any antibiotics which may interfere with culture results. Document
drug allergies including antibiotic-related
symptoms: fever, chills, weakness, dyspnea, pleuritic chest pain, anorexia, weight loss, malaise, arthralgia,
night sweats, skin lesions, nausea/vomiting, headache, abdominal pain, back pain
physical findings: general appearance (e.g., respiratory distress, acute or chronic illness). Signs of IE stigmata
include splinter hemorrhages, Janeway's lesions, Osler's nodes, buccal or mucosal surface petechiae,
clubbing, Roth's spots, loss of visual acuity, conjunctival petechiae, cardiac murmurs, heart failure, pulmonary
edema, pleuritic chest rub, neurologic deficits, splenomegaly
CBC and differential, electrolytes, glucose, BUN, creatinine, liver function tests, erythrocyte sedimentation
rate, C-reactive protein
blood cultures prior to initiation of antibiotic therapy to identify the pathogen, antibiotic sensitivities and to
determine antibiotic management. At least 3 blood cultures from different venipuncture sites should be taken
3
over a 24-hour period. Alternatively, at least 3 blood cultures taken 1 hour apart has also been
recommended.4 Ensure sufficient blood volume to improve detection. Repeat blood cultures during antibiotic
therapy to confirm clearance of bacteremia
urinalysis to detect abnormalities such as hematuria, proteinuria or pyuria, etc.
culture-negative blood cultures may require serologic and/or molecular diagnostics to identify difficult to grow
pathogens such as Coxiella burnetii. Consultation with an infectious diseases specialist is encouraged
Diagnostic:
baseline ECG and chest radiograph
echocardiography in all patients with suspected or documented IE. Transthoracic echocardiography (TTE) is
commonly available and performed initially especially in patients with low suspicion or risk of IE.1
Transesophageal echocardiography (TEE) is more sensitive than TTE for detecting small extension into tissue
surrounding the valve or for assessing prosthetic heart valves.1 TEE may be used in high risk patients (e.g.,
S. aureus bacteremia) or those with moderate to high suspicion of IE. Repeat or follow-up echocardiography
may be used to assess response to antimicrobial therapy, disease progression or need for surgery
Page 583
Therapeutic Choice
Consider consultations with an infectious diseases specialist and/or cardiothoracic surgeon
Table 1: Definition of Infective Endocarditis According to the Modified Duke Criteria2
Definite Infective Endocarditis

Pathological criteria
Microorganisms demonstrated by culture or histological examination of a vegetation, a vegetation that has
embolized, or an intracardiac abscess specimen; or pathological lesions; vegetation or intracardiac abscess
confirmed by histological examination showing active endocarditis
Clinical criteria
2 major criteria; or
1 major criterion and 3 minor criteria; or
5 minor criteria
Possible Infective Endocarditis

1 major criterion and 1 minor criterion; or
3 minor criteria
Rejected Diagnosis of Infective Endocarditis

Firm alternative diagnosis explaining evidence of IE; or
Resolution of IE syndrome with antibiotic therapy for ≤4 days; or
No pathological evidence of IE at surgery or autopsy, with antibiotic therapy for ≤4 days; or
Does not meet criteria for possible IE as above
Reproduced with permission from Li JS, Sexton DJ, Mick N et al. Clin Infect Dis 2000;30(4):633-8. Published by The University of
Chicago Press. Copyright © 2000 by the Infectious Diseases Society of America. All rights reserved.
2
Table 2: Definition of Terms Used in the Modified Duke Criteria for the Diagnosis of Infective Endocarditis
Major Criteria
Blood culture positive for IE
Typical microorganisms consistent with IE from 2 separate blood cultures: Viridans streptococci, Streptococcus
bovis, HACEK group, Staphylococcus aureus; or community-acquired enterococci in the absence of a primary
focus; or
Microorganisms consistent with IE from persistently positive blood cultures defined as follows: At least 2
positive cultures of blood samples drawn >12 h apart; or all of 3 or a majority of ≥4 separate cultures of blood
(with first and last sample drawn at least 1 h apart)
Single positive blood culture for Coxiella burnetii or anti-phase 1 IgG antibody titer >1:800
Evidence of endocardial involvement
Echocardiogram positive for IE (TEE recommended for patients with prosthetic valves, rated at least “possible IE” by
clinical criteria, or complicated IE (paravalvular abscess); TTE as first test in other patients) defined as follows:
oscillating intracardiac mass on valve or supporting structures, in the path of regurgitant jets, or on implanted
material in the absence of an alternative anatomic explanation; or abscess; or new partial dehiscence of
prosthetic valve
New valvular regurgitation (worsening or changing or pre-existing murmur not sufficient)
Minor Criteria
Predisposition, predisposing heart condition, or IDU
Fever, temperature >38°C
Vascular phenomena, major arterial emboli, septic pulmonary infarcts, mycotic aneurysm, intracranial hemorrhage,
conjunctival hemorrhages and Janeway’s lesions
Immunologic phenomena: glomerulonephritis, Osler’s nodes, Roth’s spots and rheumatoid factor
Microbiological evidence: positive blood culture but does not meet a major criterion as noted abovea or serological
evidence of active infection with organism consistent with IE
Echocardiographic minor criteria eliminated
a.
Excludes single positive cultures for coagulase-negative staphylococci and organisms that do not cause endocarditis.
Abbreviations: IDU=intravenous drug use; TEE=transesophageal echocardiography; TTE=transthoracic echocardiography
Page 584
Therapeutic Choice
Reproduced with permission from Li JS, Sexton DJ, Mick N et al. Clin Infect Dis 2000;30(4):633-8. Published by The University of
Chicago Press. Copyright © 2000 by the Infectious Diseases Society of America. All rights reserved.
Treatment of Infective Endocarditis
Therapeutic Choices
Therapeutic Choices
Surgical Intervention
Surgery is indicated for patients with life-threatening heart failure secondary to valvular damage (regurgitation or
stenosis) due to IE.1 , 5 Other indications for surgical intervention include persistent emboli, embolic complication,
large vegetation (>10 mm), failure of adequate antimicrobial treatment to control infection, severe valvular failure
(abscess, dehiscence, perforation or rupture) or evidence of extension into surrounding cardiac tissues or relapsing
1 , 5
infection. The timing for the surgery should be done in consultation with the cardiothoracic surgeon.
Pharmacologic Choices (Intravenous Therapy of Infective Endocarditis)
Pathogens and Considerations for Treatment
The gram-positive bacteria staphylococci, streptococci and enterococci account for the majority of pathogens causing
IE.6 Other bacterial pathogens include gram-negative bacteria. Selection of an antibiotic regimen should be based on
patient risk factors and compliance, left versus right-sided IE, native versus prosthetic valve, cultures and antibiotic
sensitivities and likelihood of antibiotic resistance. Prosthetic valve involvement or disseminated infection (e.g.,
vertebral osteomyelitis, abscesses or septic arthritis) require a longer duration of treatment.
Staphylococci (Table 3)
S. aureus, including methicillin-sensitive (MSSA) and methicillin-resistant (MRSA) strains, or coagulase negative
staphylococci (e.g., S. epidermidis, S. lugdunensis) may occur in both native and prosthetic valve IE and together
account for approximately 40% of cases of IE. IE involving the prosthetic valve requires a longer duration of
treatment. For MSSA, cloxacillin or cefazolin should be used for primary treatment. Although gentamicin may be
added for 3–5 days, the benefit of short-course aminoglycoside has been questioned for MSSA IE.7 , 8 , 9 , 10 In
patients with right-sided, uncomplicated, MSSA IE (no renal impairment, no extra-cardiac metastatic infection), a 2-
1
week course may be used. Vancomycin is the agent of choice for the treatment of MRSA IE and in patients with a
type-1 hypersensitivity reaction to beta-lactams. For MSSA IE, beta-lactams should be used preferentially over
vancomycin. In patients with a beta-lactam type-1 hypersensitivity reaction, beta-lactam desensitization may be
considered. Daptomycin may be used to treat MSSA or MRSA right-sided IE in select patients only.
1
Table 3: Treatment of Staphylococcal Native or Prosthetic Valve Endocarditis
Suggested Regimen Duration Comments
Staphylococci—No Prosthetic Material
Methicillin-sensitive:
Page 585
Therapeutic Choice
Suggested Regimen Duration Comments
Cloxacillin or Cefazolin 6 weeks May use 2 weeks' treatment if the IE is uncomplicated a and right-sided
+/- Gentamicin First 3–5 only.
days
Methicillin-resistant:
Vancomycin 6 weeks
Staphylococci—Prosthetic Valve
Methicillin-sensitive:
Cloxacillin + Rifampin ≥6 weeks Cefazolin may be used in place of cloxacillin.

+ Gentamicin First 2 weeks
Methicillin-resistant:
Vancomycin + ≥6 weeks
Rifampin First 2 weeks
+ Gentamicin
a.
No renal impairment or metastatic infection.
Streptococci (Table 4)
Alpha-hemolytic or viridans streptococci account for 20% of IE cases.6 Viridans streptococci include S. sanguis, S.
oralis (mitis), S. salivarius, S. mutans, and Gemella morbillorum (formerly called S. morbillorum), S. anginosus group
(S. intermedius, anginosus, and constellatus) and S. bovis group (includes S. gallolyticus spp, S. infantarius spp).1
Other viridans streptococci include Abiotrophia defectiva and Granulicatella species. Most streptococci are sensitive to
1 , 11
penicillin, however, tolerance or resistance to penicillin have been reported. Depending on the penicillin
susceptibility, monotherapy with intravenous penicillin G or ceftriaxone is recommended. In selected patients,
gentamicin may be added in combination with penicillin or ceftriaxone to shorten the duration of treatment to 2
weeks. In cases of intermediate penicillin-sensitive streptococci, gentamicin must be added for the first 2 weeks of a
4-week treatment course. IE due to A. defectiva, Granulicatella species, Gemella species or viridans streptococci with
MIC >0.5 µg/mL may be difficult to treat and should be treated with antibiotic regimens used for enterococcal IE (see
Table 5).
Table 4: Treatment of Viridans Group Streptococci and S. bovis Endocarditis1
Suggested
Regimen(s) Duration Comments
a
Viridans Group Streptococci and S. bovis Sensitive to Penicillin —Native Valve
Penicillin G or 4 weeks Consider avoiding gentamicin-containing regimen in elderly patients or those at risk
Ceftriaxone of aminoglycoside toxicity. Short course (2 weeks) should not be used in IE cases
with cardiac or extra-cardiac abscesses.
or Vancomycin reserved for patients unable to tolerate beta-lactam antibiotics.
Penicillin G or 2 weeks
Ceftriaxone
+ Gentamicin
or
Vancomycin 4 weeks
b
Viridans Group Streptococci and S. bovis Relatively Resistant to Penicillin —Native Valve
Page 586
Therapeutic Choice
Suggested
Penicillin G or 4 weeks Penicillin-resistant strains MIC >0.5 µg/mL should be treated with regimens
Ceftriaxone recommended for enterococcal endocarditis.
+ Gentamicin First 2
weeks
or
Vancomycin 4 weeks Vancomycin reserved for patients unable to tolerate beta-lactam antibiotics.
Viridans Group Streptococci and S. bovis—Prosthetic Valve
Penicillin G or 6 weeks
Ceftriaxone
If penicillin MIC First 2

≤0.12: weeks
± Gentamicin
If penicillin MIC 6 weeks

>0.12:
+ Gentamicin
or
a.
Sensitive to penicillin = MIC ≤0.12 µg/mL.
b.
Relatively resistant to penicillin = MIC >0.12–≤0.5 µg/mL.
Abbreviations: IE=infective endocarditis; MIC=minimum inhibitory concentration
Enterococci (Table 5)
Enterococci (e.g., E. faecalis, E. faecium) account for approximately 10% of IE cases.6 Choice and duration of the
antibiotic regimen depends on the enterococcal species and its susceptibility to penicillin, gentamicin or
vancomycin. Patients with enterococcal IE generally require 4–6 weeks of concomitant beta-lactam and
aminoglycoside therapy. In beta-lactam-allergic patients vancomycin is the agent of choice. Vancomycin-resistant
enterococcal endocarditis is uncommon. For IE caused by enterococci resistant to penicillin, aminoglycosides and
vancomycin, a minimum of 8 weeks of therapy is recommended. Depending on the enterococcal species, combination
beta-lactam therapy, linezolid or dalfopristin/quinupristin is recommended (see Table 5). Management of multi-
drug resistant enterococcal IE, however, may be difficult and is not fully defined. Various combination regimens
including those with linezolid or daptomycin have been suggested although clinical data remain limited.12
Table 5: Treatment of Enterococci in Native or Prosthetic Valve Endocarditis1
Sensitive to Penicillin, Gentamicin and Vancomycin
Ampicillin or Penicillin G 4–6

+ Gentamicin weeks
or
+ Gentamicin
Sensitive to Penicillin, Streptomycin and Vancomycin and Resistant to Gentamicin
Ampicillin or Penicillin G
+ Streptomycin
Page 587
Therapeutic Choice
4–6 Native valve: 4-week therapy recommended for patients with symptoms of
or weeks illness <3 mo; 6-week therapy recommended for patients with symptoms >3
months.
Prosthetic valve: 6-week minimum therapy recommended. Vancomycin
Vancomycin 6 weeks reserved for patients unable to tolerate beta-lactam antibiotics.
+ Streptomycin
Sensitive to Aminoglycosides and Vancomycin, Resistant to Penicillin
Vancomycin 6 weeks
+ Gentamicin
Resistant to Aminoglycosides, Penicillin and Vancomycin
E. faecium ≥8 weeks Optimal treatment not defined.

Linezolid or
Dalfopristin/Quinupristin
E. faecalis ≥8 weeks
Imipenem/Cilastatin or
Ceftriaxone + Ampicillin
Current and past recommendations have suggested that gentamicin peak and trough concentrations be maintained at
3–4 mg/L and <1 mg/L, respectively.1 , 13 , 14 Concerns with nephrotoxicity and lack of additional efficacy with higher
15
peak levels may have led clinicians to recommend these lower gentamicin peak concentrations.
Gram-Negative Bacteria
IE due to gram-negative bacteria may account for 2% of cases.6 Identification of the gram-negative pathogen and
susceptibility to antibiotics is important in determining the antibiotic regimen and course. Gram-negative bacteria may
be divided into HACEK and non-HACEK group bacteria. HACEK group organisms are fastidious, slow growing, gram-
negative bacilli accounting for approximately 1–2% of IE. HACEK group pathogens include Haemophilus species (e.g.,
H. parainfluenzae, H. aphrophilus), Aggregatibacter (formerly Actinobacillus) actinomycetemcomitans, Cardiobacterium
hominis, Eikenella corrodens and Kingella species.1
Due to concerns with beta-lactamase production among HACEK strains, ampicillin is not recommended for treatment of
HACEK IE. Third generation or higher cephalosporins may be used to treat HACEK IE. In patients with beta-lactam
allergies, fluoroquinolones (ciprofloxacin, levofloxacin or moxifloxacin) are alternatives.
Culture-Negative IE
Blood cultures may remain negative in 8% of cases despite radiologic and clinical evidence of IE. Reasons for this may
include difficult to grow pathogens (e.g., Coxiella burnetii or Bartonella spp.), nonbacterial or unusual pathogens and
administration of antibiotic therapy prior to blood cultures. A thorough review of the patient host factors (e.g.,
immunosuppression, burn), comorbidities (e.g., diabetes), history of intravenous drug use, animal or insect exposure,
indwelling devices, prior surgical procedures, etc., should be conducted to search for possible etiologic causes of
16
culture-negative IE. Staining techniques may be used to identify potential pathogens. Molecular diagnostics may be
1
used to identify pathogens such as Coxiella burnetii, Bartonella or Chlamydia species. Select antibiotic therapy based
on the most likely pathogen after a review of available patient data. Consult with an infectious diseases specialist and
clinical microbiologist.
Outpatient Parenteral Antimicrobial Therapy of IE
Although outpatient parenteral antimicrobial therapy (OPAT) has been used to treat IE, stringent entry criteria and
close patient follow-up should be considered for patients receiving OPAT.17 , 18 In uncomplicated IE patients, OPAT
may be used to complete a 4–6 week total treatment course providing proper patient assessment and follow-up is
conducted. In general, eligible patients should have received an initial 2 weeks of intravenous antibiotic therapy
17 , 18
administered as an inpatient before initiation of OPAT. Patients should be monitored for clinical response,
Page 588
Therapeutic Choice
complications and adverse drug effects from antibiotic therapy (e.g., resulting from prolonged aminoglycoside
therapy).
Prevention of Infective Endocarditis
Concerns about bacteremia and severity of IE led to a consensus among experts over the past 50 years to recommend
antibiotic prophylaxis for patients with risk factors undergoing procedures known to cause bacteremia.19 , 20 , 21 , 22
Assumptions were made that antibiotic prophylaxis would prevent IE in patients undergoing dental, gastrointestinal
and genitourinary tract procedures. There is, however, an absence of randomized controlled trials documenting the
efficacy of antibiotic prophylaxis in preventing IE. Most cases of IE cannot be attributed to invasive procedures. Over
the past decade, there has been concern about the lack of supportive data.23 , 24 Studies suggest the benefit of
25
widespread antibiotic prophylaxis to prevent infective endocarditis is small. As a result, recent
recommendations have limited antibiotic prophylaxis to patients with underlying cardiac conditions at
highest risk of adverse outcome from IE (see Table 6).21,22 Useful Info? Despite the paradigm shift in recent
recommendations, controversy remains whether to use antibiotic prophylaxis or not.26 , 27 , 28 , 29
21
Table 6: Cardiac Conditions Associated with Highest Risk of Adverse Outcomes from Infective Endocarditis
Prosthetic cardiac valve, or prosthetic material used for cardiac valve repair
Previous infective endocarditis
Congenital heart disease (CHD)a
Unrepaired cyanotic congenital heart disease, including those with palliative shunts and conduits
Completely repaired congenital heart disease with prosthetic material or device, whether placed by surgery or
catheter intervention, during the first 6 months after the procedureb
Repaired congenital heart disease with residual defects at the site or adjacent to the site of a prosthetic patch or
prosthetic device (which inhibit endothelialization)
Cardiac transplantation recipients with cardiac valvular disease
a.
Except for the conditions above, antibiotic prophylaxis is no longer recommended for any other forms of CHD.
b.
Prophylaxis is reasonable because endothelialization of prosthetic material occurs within 6 months following the procedure.
Reprinted with permission Circulation.2007;116:1736-54 ©2007 American Heart Association, Inc.
Antibiotic prophylaxis is directed against alpha-hemolytic (viridans) streptococci for patients with underlying cardiac
conditions at highest risk of adverse outcomes undergoing procedures outlined in Table 7. The antibiotic should be
administered to provide effective serum concentrations at the time of the anticipated bacteremia and for a few hours
thereafter.
Table 7: Dental or Surgical Procedures for which Endocarditis Prophylaxis is Reasonable for Patients with Cardiac
a 21
Conditions Identified in Table 6 ,
Prophylaxis is reasonable with:

All dental procedures that involve manipulation of gingival tissue or the periapical region of teeth or
perforation of the oral mucosa
The following dental procedures and events do not need prophylaxis: routine anesthetic injections through
noninfected tissue, taking dental radiographs, placement of removable prosthodontic or orthodontic appliances,
adjustment of orthodontic appliances, placement of orthodontic brackets, shedding of deciduous teeth and
bleeding from trauma to the lips or oral mucosa
Procedures on respiratory tract involving incision or biopsy of respiratory mucosa (such as tonsillectomy or
adenoidectomy)
Use the agents recommended in Table 8. For known S. aureus infections, use an antistaphylococcal penicillin
(e.g., cloxacillin) or cephalosporin (e.g., cephalexin); use vancomycin in patients unable to take beta-lactam
antibiotics or if the strain is methicillin-resistant
Procedures in patients with infected skin, skin structures or musculoskeletal tissue
Use the agents recommended in Table 8. For patients who cannot take beta-lactam antibiotics or those with
known or suspected methicillin-resistant staphylococcus infection, use vancomycin or clindamycin
Page 589
Therapeutic Choice
a.
Antibiotic prophylaxis solely to prevent IE is no longer recommended for genitourinary or gastrointestinal tract procedures.
If the antibiotic is inadvertently not administered before the procedure, the dose may be administered up to 2 hours
after the procedure. This should be reserved only for those patients who did not receive a dose prior to the procedure.
If the patient is already taking an antibiotic that would be used for endocarditis prophylaxis, select an agent from a
different class, to avoid encountering resistant strains. Alternatively, the procedure could be delayed until 10 days or
more after completion of the antibiotic course, to allow the bacterial flora to return to its usual state.
Table 8: Antibiotic Regimens for Endocarditis Prophylaxis in Dental Proceduresa , 21
Drug Adult Doseb Pediatric Doseb , c
Standard Regimen
Amoxicillin 2 g po 50 mg/kg
Unable to Take Oral Medications
Ampicillin 2 g ime or iv 50 mg/kg ime or iv

or
Cefazolin 1 g ime or iv e
50 mg/kg im or iv
or
Ceftriaxone 1 g im or iv 50 mg/kg im or iv
Allergic to Penicillins
d 2 g po 50 mg/kg
Cephalexin
or
Clindamycin 600 mg po 20 mg/kg

or
Azithromycin 500 mg po 15 mg/kg

or
Clarithromycin 500 mg po 15 mg/kg
Allergic to Penicillins and Unable to Take Oral Medications

f e e
Cefazolin 1 g im or iv 50 mg/kg im or iv
or
f e e
Ceftriaxone 1 g im or iv 50 mg/kg im or iv
or
e
Clindamycin 600 mg im or iv 20 mg/kg ime or iv
a.
See Table 6 and Table 7.
b.
Administered 30–60 min prior to procedure.
c.
Pediatric dose should not exceed adult dose.
d.
Or other first- or second-generation oral cephalosporin in equivalent adult or pediatric dosage.
e.
Avoid im injections in anticoagulated patients.
f.
Cephalosporins should not be used in an individual with a history of anaphylaxis, angioedema or urticaria to penicillins or
ampicillin.
SOURCE: AMERICAN HEART ASSOCIATION, INC.
Page 590
Therapeutic Choice
Therapeutic Tips
Intravenous antibiotic therapy is the antimicrobial administration route of choice.

When considering the duration of treatment in IE patients with an initial positive blood culture, it is recommended
to count the required duration of treatment from the first day the blood culture is negative.1
Due to an association with colon cancer, patients with S. bovis IE or positive blood cultures should undergo a
30
colonoscopy to investigate for presence of malignancy.
Table 9: Intravenous Therapy of Infective Endocarditis
Drug Costa
Penicillins penicillin G 12–18 Rash, Use 24 million $

Crystapen, generics million hypersensitivity, units per day
Units per drug fever, for viridans
day divided interstitial streptococci
Q4-6H iv nephritis, seizure and S. bovis in
or (high dose). a prosthetic
valve IE.
24 million
Units per
day divided
Q4-6H iv
Penicillins ampicillin 2 g Q4H iv Rash, $$

generics hypersensitivity,
drug fever,
interstitial
nephritis, seizure
(high dose).
Penicillins cloxacillin 2 g Q4H iv Rash, $$

drug fever,
interstitial
nephritis, seizure
(high dose).
Cephalosporins cefazolin 2 g Q8H iv Rash, $$

drug fever,
diarrhea.
Cephalosporins ceftriaxone 2 g Q24H iv Rash, 2 g Q12H for $$

Ceftriaxone for (see hypersensitivity, vancomycin-
Comments) drug fever, resistant E.
Injection USP,
diarrhea, faecalis IE
Rocephin, other
eosinophilia, combined with
generics
thrombocytosis, ampicillin.
elevated AST
and/or ALT.
Carbapenems imipenem/cilastatin 500 mg Phlebitis, rash, Increased risk of $$$$

Primaxin Q6H iv hypersensitivity, seizures when
drug fever, nausea, used with
vomiting diarrhea; ganciclovir.
seizure (high
dose).
Aminoglycosides gentamicin 1 mg/kg Nephrotoxicity, Enhanced effects Toxicity risk $

generics Q8H iv ototoxicity. with concomitant may increase
or nephrotoxins or with prolonged
ototoxins (e.g., administration
amphotericin B, and/or
Page 591
e-Therapeutics+ : Therapeutics : Infectious Diseases: Infective Endocarditis—Manageme... Page 10 of 13
Therapeutic Choice
Drug Costa
3 mg/kg vancomycin). concomitant
once daily Increased risk of nephrotoxins or
iv/im (for respiratory ototoxins.
viridans depression with Monitor renal
streptococci neuromuscular function and
and S. blocking agents. serum
bovis) gentamicin
concentrations
especially for
prolonged
courses.
Consider
maintaining
gentamicin
trough
concentrations
≤1 mg/L to
minimize risk
of
nephrotoxicity.
For
enterococcal IE
only,
gentamicin
peak and
trough levels of
3–4 mg/L and
1 mg/L
respectively,
may be
considered.
Aminoglycosides streptomycin 7.5 mg/kg Nephrotoxicity, Enhanced effects Serum $$$$

generics Q12H iv/im ototoxicity. with concomitant concentration
nephrotoxins or assay not
ototoxins (e.g., commonly
amphotericin B, available.
vancomycin). Toxicity risk
Increased risk of may increase
respiratory with prolonged
depression with administration
neuromuscular and/or
blocking agents. concomitant
nephrotoxins or
ototoxins.
Glycopeptides vancomycin 15 mg/kg Thrombophlebitis, Increased Monitor $$$$$

Vancocin, generics Q12H iv rash, fever, incidence of vancomycin
(see anemia, nephrotoxicity troughs to
Comments) nephrotoxicity, when used with maintain
otoxicity, red man aminoglycosides. concentrations
syndrome. between 15–20
µg/mL for
S. aureus IE31
(may require
>30 mg/kg/day
dosing);
nephrotoxicity
and ototoxicity
have been
reported with
Page 592
Therapeutic Choice
a
Drug Cost
higher
dosages.
Rifamycins rifampin 300 mg Rash, orange Potent inducer of Should be used iv: b
Q8H iv/po discolouration of multiple only in po: $
body fluids (e.g., substrates— combination
contact lens evaluate when with other
staining), nausea, co-administered antibiotics.
vomiting, hepatic with other drugs
toxicity, (e.g., may ↓
thrombocytopenia. levels of
cyclosporine,
tacrolimus,
sirolimus,
phenytoin,
warfarin and oral
contraceptives).
Oxazolidinones linezolid 600 mg Diarrhea, nausea, MAO inhibitor $$$$$

Zyvoxam Q12H iv vomiting, anemia, therefore
thrombocytopenia. caution; evaluate
concomitant
agents for
potential
interaction.
Streptogramins quinupristin/ 7.5 mg/kg Diarrhea, nausea, Cytochrome b

dalfopristin Q8H iv vomiting, P450 3A4
thrombophlebitis, inhibitor
injection site therefore
pain/reaction, caution; evaluate
conjugated concomitant
hyperbilirubinemia. agents for
potential
interaction (e.g.,
increased levels
of calcium
channel
blockers,
carbamazepine,
cyclosporine,
tacrolimus,
statins).
Lipopeptides daptomycin 6 mg/kg Diarrhea, nausea, Consider Monitor $$$$$

Cubicin Q24H iv vomiting, avoiding creatinine
constipation, concomitant kinase weekly
thrombophlebitis, HMG-CoA at minimum,
injection site reductase especially in
pain/reaction, inhibitor patients with
anemia, creatinine administration as renal
kinase elevation; a precaution as impairment
myalgia, daptomycin may and/or HMG-
rhabdomyolysis. increase its CoA reductase
levels. co-
administration.
a.
Cost per day based on 70 kg body weight; includes drug cost only.
b.
Available through Health Canada’s Special Access Programme.
Page 593
Therapeutic Choice
Abbreviations: IE=infective endocarditis; MAO=monoamine oxidase inhibitor
Legend: $ < $30 $$ $30–60 $$$ $60–90 $$$$ $90–120 $$$$$ > $120
Suggested Readings
Baddour LM, Wilson WR, Bayer AS et al. Infective endocarditis: diagnosis, antimicrobial therapy, and management of
complications: a statement for healthcare professionals from the Committee on Rheumatic Fever, Endocarditis, and
Kawasaki Disease, Council on Cardiovascular Disease in the Young, and the Councils on Clinical Cardiology, Stroke,
and Cardiovascular Surgery and Anesthesia, American Heart Association: endorsed by the Infectious Diseases Society
of America. Circulation 2005;111(23):e394-434.
Wilson W, Taubert KA, Gewitz M et al. Prevention of infective endocarditis: guidelines from the American Heart
Association: a guideline from the American Heart Association Rheumatic Fever, Endocarditis, and Kawasaki Disease
Committee, Council on Cardiovascular Disease in the Young, and the Council on Clinical Cardiology, Council on
Cardiovascular Surgery and Anesthesia, and the Quality of Care and Outcomes Research Interdisciplinary Working
References
1. Baddour LM, Wilson WR, Bayer AS et al. Infective endocarditis: diagnosis, antimicrobial therapy, and
management of complications: a statement for healthcare professionals from the Committee on Rheumatic Fever,
Endocarditis, and Kawasaki Disease, Council on Cardiovascular Disease in the Young, and the Councils on
Clinical Cardiology, Stroke, and Cardiovascular Surgery and Anesthesia, American Heart Association: endorsed
by the Infectious Diseases Society of America. Circulation 2005;111(23):e394-434.
2. Li JS, Sexton DJ, Mick N et al. Proposed modifications to the Duke criteria for the diagnosis of infective
endocarditis. Clin Infect Dis 2000;30(4):633-8.
3. Haldar SM, O'Gara PT. Infective endocarditis: diagnosis and management. Nat Clin Pract Cardiovasc Med 2006;3
(6):310-7.
4. Horstkotte D, Follath F, Gutschik E et al. Guidelines on prevention, diagnosis and treatment of infective
endocarditis executive summary; the Task Force on Infective Endocarditis of the European Society of Cardiology.
Eur Heart J 2004;25(3):267-76.
5. Bonow RO, Carabello BA, Kanu C et al. ACC/AHA 2006 guidelines for the management of patients with valvular
heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice
Guidelines (writing committee to revise the 1998 Guidelines for the Management of Patients With Valvular Heart
Disease): developed in collaboration with the Society of Cardiovascular Anesthesiologists: endorsed by the
Society for Cardiovascular Angiography and Interventions and the Society of Thoracic Surgeons. Circulation
2006;114(5):e84-231.
6. Fowler VG, Miro JM, Hoen B et al. Staphylococcus aureus endocarditis: a consequence of medical progress.
JAMA 2005;293(24):3012-21.
7. Falagas ME, Matthaiou DK, Bliziotis IA. The role of aminoglycosides in combination with a beta-lactam for the
treatment of bacterial endocarditis: a meta-analysis of comparative trials. J Antimicrob Chemother 2006;57
(4):639-47.
8. Paul M, Leibovici L. Combination antimicrobial treatment versus monotherapy: the contribution of meta-
analyses. Infect Dis Clin North Am 2009;23(2):277-93.
9. Ribera E, Gomez-Jimenez J, Cortes E et al. Effectiveness of cloxacillin with and without gentamicin in short-term
therapy for right-sided Staphylococcus aureus endocarditis. A randomized, controlled trial. Ann Intern Med
1996;125(12):969-74.
10. Cosgrove SE, Vigliani GA, Fowler VG et al. Initial low-dose gentamicin for Staphylococcus aureus bacteremia
and endocarditis is nephrotoxic. Clin Infect Dis 2009;48(6):713-21.
11. Knoll B, Tleyjeh IM, Steckelberg JM et al. Infective endocarditis due to penicillin-resistant viridans group
streptococci. Clin Infect Dis 2007;44(12):1585-92.
12. Arias CA, Contreras GA, Murray BE. Management of multi-drug resistant enterococcal infections. Clin Microbiol
Infect 2010;16(6):555-62.
13. Wilson WR, Karchmer AW, Dajani AS et al. Antibiotic treatment of adults with infective endocarditis due to
streptococci, enterococci, staphylococci, and HACEK microorganisms. American Heart Association. JAMA
1995;274(21):1706-13.
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14. Bisno AL, Dismukes WE, Durack DT et al. Antimicrobial treatment of infective endocarditis due to viridans
streptococci, enterococci, and staphylococci. JAMA 1989;261(10):1471-7.
15. Geraci JE. The antibiotic therapy of bacterial endocarditis: therapeutic data on 172 patients seen from 1951
through 1957: additional observations on short-term therapy (two weeks) for penicillin-sensitive streptococcal
endocarditis. Med Clin North Am 1958;42(4):1101-40.
16. Houpikian P, Raoult D. Diagnostic methods. Current best practices and guidelines for identification of difficult-to
-culture pathogens in infective endocarditis. Cardiol Clin 2003;21(2):207-17.
17. Andrews MM, von Reyn CF. Patient selection criteria and management guidelines for outpatient parenteral
antibiotic therapy for native valve infective endocarditis. Clin Infect Dis 2001;33(2):203-9.
18. Tice AD. Safety of outpatient parenteral antimicrobial therapy for endocarditis. Clin Infect Dis 2002;34(3):419-
20.
19. Elliott TS, Foweraker J, Gould FK et al. Guidelines for the antibiotic treatment of endocarditis in adults: report of
the Working Party of the British Society for Antimicrobial Chemotherapy. J Antimicrob Chemother 2004;54
(6):971-81.
20. Embil JM, Chan KL. The American Heart Association 2007 endocarditis prophylaxis guidelines: a compromise
between science and common sense. Can J Cardiol 2008;24(9):673-5.
21. Wilson W, Taubert KA, Gewitz M et al. Prevention of infective endocarditis: guidelines from the American Heart
Association: a guideline from the American Heart Association Rheumatic Fever, Endocarditis, and Kawasaki
Disease Committee, Council on Cardiovascular Disease in the Young, and the Council on Clinical Cardiology,
Council on Cardiovascular Surgery and Anesthesia, and the Quality of Care and Outcomes Research
Interdisciplinary Working Group. Circulation 2007;116(15):1736-54.
22. Stokes T, Richey R, Wray D. Prophylaxis against infective endocarditis: summary of NICE guidance. Heart
2008;94(7):930-1.
23. Oliver R, Roberts GJ, Hooper L et al. Antibiotics for the prophylaxis of bacterial endocarditis in dentistry.
24. Van der Meer JT, Van Wijk W, Thompson J et al. Efficacy of antibiotic prophylaxis for prevention of native-valve
endocarditis. Lancet 1992;339(8786):135-9.
25. Duval X, Alla F, Hoen B et al. Estimated risk of endocarditis in adults with predisposing cardiac conditions
undergoing dental procedures with or without antibiotic prophylaxis. Clin Infect Dis 2006;42(12):e102-7.
26. Dhoble A, Vedre A, Abdelmoneim SS et al. Prophylaxis to prevent infective endocarditis: to use or not to use?
Clin Cardiol 2009;32(8):429-33.
27. Connaughton M. Commentary: Controversies in NICE guidance on infective endocarditis. BMJ 2008;336
(7647):771.
28. Ramsdale DR, Palmer ND. Featured correspondence. Comment on editorial by Ashrafian and Bogle. Heart
2007;93(6):753; author reply 753-4.
29. Ashrafian H, Bogle RG. Antimicrobial prophylaxis for endocarditis: emotion or science? Heart 2007;93(1):5-6.
30. Ballet M, Gevigney G, Gare JP et al. Infective endocarditis due to Streptococcus bovis. A report of 53 cases. Eur
Heart J 1995;16(12):1975-80.
31. Rybak M, Lomaestro B, Rotschafer JC et al. Therapeutic monitoring of vancomycin in adult patients: a consensus
review of the American Society of Health-System Pharmacists, the Infectious Diseases Society of America, and
the Society of Infectious Diseases Pharmacists. Am J Health Syst Pharm 2009;66(1):82-98.
Page 595
e-Therapeutics+ : Therapeutics : Infectious Diseases: Influenza Page 1 of 11
Therapeutic Choice
Print Close
Infectious Diseases: Influenza

Susan K. Bowles, PharmD, MSc, FCCP
Robert Strang, MD, MHSc, FRCPC
Influenza is an acute viral illness of the respiratory tract caused by influenza A or influenza B viruses. A typical
influenza season in Canada runs from mid-October to the end of April.
Influenza-like illness (ILI) is a term often used in public health surveillance programs for influenza, which refers to
any acute illness having symptoms typical of influenza. Adenovirus, parainfluenza or respiratory syncytial virus may
cause similar symptoms.
1
Influenza-like illness is defined as an acute onset of respiratory illness with fever, cough and one or more of: sore
throat, arthralgia, myalgia or prostration. Gastrointestinal symptoms may be present in children <5 years. Fever
may not be prominent in children <5 years or adults ≥65 years.
Investigations
History with particular attention to symptoms and onset of symptoms, the key to appropriate use of antiviral
agents:
healthy adolescents and adults: when influenza is known to be circulating in the community, abrupt onset
2 , 3
of fever of 38.5°C or greater and dry cough is likely to be influenza. The predictive value of these
symptoms is considerably less in the very young or the elderly
young children: can present with either a nonspecific febrile illness or with a respiratory illness resembling
4
croup, bronchitis and occasionally bronchiolitis. GI symptoms (nausea, vomiting, diarrhea) may also be
present in children <5 years
4 , 5
older adults: fever may not be prominent. When influenza is known to be circulating in the community,
have a high index of suspicion for influenza if older patients present with ≥2 symptoms of sore throat,
5
arthralgia, myalgia or prostration; this is particularly true of elderly residents of long-term care facilities
Laboratory testing:
beyond formal surveillance programs, widespread laboratory testing in the community is not necessary or
practical, but it is important to differentiate between influenza and other respiratory viruses in the event of
an outbreak of ILI in the long-term care setting
as a general guideline, nasopharyngeal swabs from ill long-term care residents should be sent for
6
laboratory testing in the event of ≥2 cases of ILI within a 72-hour period. Obtain swabs from the initial
cases as well as the next 3–5 individuals presenting with ILI. Public health officials should also be notified
contact the lab to obtain instructions on specimen collection, storage and transport. Some labs may offer
rapid tests, which tend to be less sensitive than traditional viral culture, especially in adults
to decrease the potential for a false negative result, swabs are best obtained within 24 hours of symptom
onset and should not be taken more than 48 hours after onset of symptoms
Prevention
Goals of Therapy
Therapeutic Choices
Goals of Therapy
Prevent influenza illness from occurring, especially in individuals at high risk of developing serious influenza-
related complications, e.g., pneumonia, exacerbation of cardiac or respiratory disease, death
Decrease influenza-related hospitalizations and deaths
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Therapeutic Choice
Therapeutic Choices
General measures to prevent acquisition of influenza include:
wash hands often; use hand sanitizer if water and soap are not available.
cough/sneeze into tissues (or into a sleeve if tissues are not available) and throw all used tissues into the
garbage.
if flu symptoms are present, stay home from work or school and do not visit hospitals, nursing homes or
individuals at high risk of influenza-related complications.
In the event of a cluster of ILI in the long-term care setting, implement the following to reduce the potential of
influenza spreading from ill to well residents (Figure 1 - Prevention and Control of Influenza in the Long-term Care
Setting):
promote and enhance proper hand washing by staff, ambulatory residents and visitors.
confine ill residents to their rooms until their acute symptoms have resolved.
enhance environmental controls, e.g., more frequent cleaning.
if possible, ill residents should be cared for only by staff who have received their annual influenza
immunization.
if possible, ill residents should be cared for by separate staff members who are not looking after well residents.
If this is not possible, provide care for well individuals first, with strict hand washing between each patient.
limit gatherings or activities where residents from different areas of the facility come into contact with each
other.
limit visitors when possible and exclude visits from all individuals with ILI.
staff with symptoms of ILI should not work until their acute symptoms have resolved.
Influenza Vaccine7
October to mid-November is the usual recommended time for influenza immunization; however, clinicians should
work with their local Public Health Departments to determine the best time for immunization at the local level. Table
1 addresses recommended recipients of seasonal influenza vaccine.
a , 7
Table 1: Recommended Recipients of Seasonal Influenza Immunization
Persons at high risk for influenza-related complications

adults and children ≥6 mo of age with chronic cardiac or respiratory disorders (includes asthma,
bronchopulmonary dysplasia, cystic fibrosis and COPD) requiring regular medical follow-up
all residents of nursing homes and other long-term care facilities
all persons ≥65 y of age
adults and children ≥6 mo of age with any of the following chronic disorders:
diabetes mellitus or other metabolic disorder
cancer
immunodeficiency
immunosuppression (due to underlying disease or treatment)
renal disease
anemia
hemoglobinopathies
children and adolescents (6 mo to 18 y of age) requiring chronic ASA therapy
pregnant women (all trimesters)
healthy children 6 to 23 mo
Persons capable of transmitting influenza to those at high risk of influenza-related complications

health care workers and other personnel (e.g., volunteers, housekeeping staff) who have significant contact
with those in the above-mentioned high-risk groups, regardless of the practice setting
adults and children ≥6 mo of age who are household contacts of those at high risk of influenza-related
complications. This includes household contacts of children <6 mo old who are at high risk of complications
from influenza but for whom there is no currently licensed vaccine. Pregnant women should be immunized if
they are expected to deliver during influenza season; they will become household contacts of their newborn.
those providing regular child care to children age 0 to 23 mo, whether in or out of the home
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Therapeutic Choice
Other
people who provide essential community services, e.g., police officers and fire fighters
people who are in direct contact with avian influenza-infected poultry during culling operations
Additional considerations in 2010-2011

persons who are morbidly obese (BMI ≥40)
aboriginal peoples
healthy children 2–4 y of age
a.
Healthy persons aged 5–64 years without contraindication are also encouraged to receive influenza vaccine even if they are not
in one of the priority groups.
Annual influenza vaccination of individuals at high risk of influenza-related complications (Table 1) is, and remains,
the primary strategy for the reduction of influenza-related morbidity and mortality, in both community and long-
term care settings.
Annual vaccination of individuals who have significant contact with individuals at high risk of influenza-related
complications (Table 1) or who provide essential community services is also recommended. Encourage healthy
individuals aged 5–64 years to receive influenza vaccine annually, even if they are not in the aforementioned priority
groups.
Travellers may find themselves in areas with high transmission during other months of the year, e.g., Asia, the
southern hemisphere and cruise ships. Detailed recommendations for the prevention of influenza related to travel
are outlined in the 2005 Committee to Advise on Tropical Medicine and Travel, Statement on Travel, Influenza and
Prevention—Update (www.phac-aspc.gc.ca/publicat/ccdr-rmtc/05vol31/asc-dcc-11/index.html).
Antiviral Agents
Antiviral agents can be used to prevent influenza in high-risk individuals under several circumstances (Table 2).
Their greatest utility is in the long-term care setting (see Figure 1 - Prevention and Control of Influenza in the Long-
term Care Setting).
When an influenza outbreak is identified in a long-term care setting, give antiviral prophylaxis as soon as possible
to all residents who are not yet ill, regardless of their vaccination status, as well as to nonimmunized health care
providers.
Table 2: Criteria for Prophylactic Use of Antivirals7
Administer to all residents of a long-term care facility who are not already ill, regardless of vaccination status
as soon as an influenza outbreak is identified. Duration of prophylaxis is until 8 days after onset of symptoms
of last case (covers one infectious period and one incubation period).
Administer antiviral prophylaxis for the duration of the outbreak to LTC providers who refuse immunization.
Continue prophylaxis for the duration of influenza activity in the community in non-institutionalized people at
high risk during outbreak situations when vaccine is not available, contraindicated or unlikely to be effective
due to poor match between vaccine and strain circulating in the community and as a supplement to
vaccination of those at high risk expected to have an impaired immune response to vaccine.
Continue prophylaxis for 2 weeks after vaccination (approximately the time required to mount a protective
immune response to vaccine) as an adjunct to late vaccination of those at high risk or health care workers
caring for those at high risk.
Monitoring of antiviral resistance of circulating influenza viruses has been incorporated into national surveillance.
8 , 9 , 10
Resistance has been demonstrated towards both amantadine and oseltamivir. As such, the choice of antiviral
for prophylaxis may be dependent upon resistance patterns for a particular strain of influenza in previous years.
Amantadine has been effective for prophylaxis against influenza A. If influenza A is sensitive to amantadine,
simultaneous use of amantadine for prophylaxis and treatment within a facility is not advised due to the increased
risk of developing resistance. Amantadine dose should be based on renal function to minimize adverse effects (see
Appendices: Dosage Adjustment in Renal Impairment).
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Therapeutic Choice
Neuraminidase inhibitors, oseltamivir and zanamivir, are effective for prophylaxis against influenza A and B.
Oseltamivir is the first-line agent during outbreaks of influenza A (if expected to be sensitive) or influenza B.
Zanamivir is not currently recommended in the long-term care setting due to the potential risk of bronchospasm in
persons with pre-existing respiratory disease and difficulty in using the inhaler device by some frail elderly.
In a long-term care setting, continue surveillance for new cases of ILI to establish effectiveness of antiviral
prophylaxis in controlling an influenza outbreak once post-exposure prophylaxis is initiated in a facility. Regardless
of the agent used, reports of drug specific-resistant strains of influenza A during outbreak situations demand change
in therapy.
If cases of laboratory-confirmed influenza continue to occur more than 96 hours after initiation of antiviral
prophylaxis, consider antiviral prophylaxis failure.11 Contact the local Medical Officer of Health for assistance.
Treatment
Goals of Therapy
Therapeutic Choices
Therapeutic Tips
Goals of Therapy
Relieve influenza symptoms

Reduce duration of influenza infection
Reduce the potential for influenza-related complications
Decrease influenza-related hospitalizations and deaths
Therapeutic Choices
Analgesics/Antipyretic Agents
Use acetaminophen or ibuprofen for relief of fever, headache and myalgias. To avoid overdose, caution patients
about the concurrent use of cough and cold products that contain acetaminophen or ibuprofen. Cough and cold
products contain other ingredients such as antihistamines, which may not be needed.
Children and adolescents less than 18 years of age should not take ASA due to the associated risk of Reye’s
syndrome.
Antiviral Agents
Consider antiviral agents for treatment of influenza, when it is either laboratory confirmed or strongly suspected
based on symptoms and known local circulation. The use of antiviral agents for treatment of influenza in the
community setting is illustrated in Figure 2 - Treatment of Influenza-like Illness in the Community.
The usual duration of symptoms of influenza is 4–7 days. Studies in otherwise healthy adults and children
12 , 13
demonstrated that neuraminidase inhibitors reduce the duration of symptoms by 24–60 hours. However,
there is currently insufficient evidence to support the routine use of these agents for the treatment of influenza in
these populations. Early treatment with oseltamivir may reduce influenza complications (need for antibiotics,
hospitalizations, asthma exacerbations) in high-risk adults and children.14 , 15 , 16 , 17
Amantadine is not currently recommended for treatment of influenza A due to resistance. When influenza A is
sensitive to amantadine, simultaneous use of amantadine for prophylaxis and treatment within a facility, i.e., long-
term care or nursing home, is not advised due to the increased risk of developing amantadine resistance.
Page 599
Therapeutic Choice
Treatment with any antiviral agent is best initiated within 48 hours after the onset of symptoms.18 However,
treatment can be considered later than this for persons who experience more severe illness.19
Do not continue treatment for more than 5 days. Five days is an adequate treatment period and it minimizes the risk
of resistance, a particular concern with amantadine.
Therapeutic Tips
Antivirals are not substitutes for the influenza vaccine for prevention of influenza.
Influenza surveillance information can be obtained from the FluWatch program from the Public Health Agency of
Canada (www.phac-aspc.gc.ca/fluwatch/index-eng.php). Contact local Public Health authorities to determine if
influenza is circulating in a specific community and if so, whether it is influenza A or B.
Rapid identification of influenza in the long-term care setting allows timely implementation of control measures,
thereby reducing influenza-related morbidity and mortality. Therefore, each facility should have a surveillance
program in place to identify ILI, and policies and procedures regarding laboratory testing for ill residents. Staff
should be familiar with the case definition of ILI.
Consider another antiviral if there is a history of a severe adverse effect (e.g., hallucinations, seizures) with
previous use of amantadine.
Figure 1- Prevention and Control of Influenza in the Long-term Care Setting
Page 600
Therapeutic Choice
Adapted with permission from Gomolin IH, Kathpalia RK. Influenza. How to prevent and control nursing home
outbreaks.Geriatrics 2002;57(1):30. Geriatrics is a copyrighted publication of Advanstar Communications Inc. All rights
reserved.
Abbreviations: ILI = influenza-like illness; RSV = respiratory syncytial virus
Figure 2- Treatment of Influenza-like Illness in the Community
Adapted with permission from Stiver G. The treatment of influenza with antiviral drugs. CMAJ 2003;168(1):49-56.
Page 601
Therapeutic Choice
Abbreviations: ILI = influenza-like illness
7
Table 3: Drugs Used for the Prevention and Treatment of Influenza
a
Cost
Antivirals, amantadine Dose is based on age Confusion, nausea, Simultaneous use of $

adamantane generics and renal function and vomiting, loss of amantadine for
derivatives is the same for appetite, ataxia, prophylaxis and
treatment or insomnia, seizures treatment within an LTC
prophylaxis. (most likely in those facility is not advised
Duration of therapy for with pre-existing due to the increased risk
treatment is 5 days but disorder). of developing resistance.
is variable for Role as prophylaxis in
prevention. LTC facility is dependent
upon patterns of
Treatment/Prevention: resistance to circulating
1–9 y: 5 mg/kg once strain.
daily or divided BID; Contraindicated if poorly
maximum 150 mg/day controlled seizure
disorders or past history
of neuroleptic malignant
10–64 y: 200 mg once syndrome.
daily or divided BID. If
<40 kg, use dose as ↑ risk of CNS side effects:
listed under 1–9 y. ↓ anticholinergic therapy.
dose to 100 mg once daily
in patients with seizure ↑ amantadine concentrations:
disorders. triamterene.
≥65 y: 100 mg once

daily
Dosing based on renal

function reduces the
overall rate of adverse
effects and minimizes
the need for
discontinuation in the
nursing home setting.
Antivirals, oseltamivir Treatment: Adults: Nausea, vomiting, Effective for treatment $$-
neuraminidase Tamiflu 75 mg BID × 5 days. If headache. and prevention against $$$
inhibitors ClCr 10–30 mL/min: 75 influenza A and B.
mg once daily × 5 days Treatment is best
initiated within 48 hours
20 , of symptom onset but
Treatment: Children:
21 may be started after 48
>1 y and ≤15 kg: 30 hours in those with high
mg BID × 5 days risk for influenza-related
complications and/or if
>15–23 kg: 45 mg BID 19
severely ill.
× 5 days Do not use if ClCr is <10
mL/min.
>23–40 kg: 60 mg BID
× 5 days Available as 30, 45 and
75 mg capsules. Also
>40 kg: 75 mg BID available as a suspension
× 5 days of 12 mg/mL.
Page 602
Therapeutic Choice
a
Cost
If oral suspension is not

Prevention: available the capsules
Adults and children may be opened and
≥13 y: mixed with sweetened
75 mg once daily. If liquid, such as regular or
ClCr 10–30 mL/min: 75 sugar-free chocolate
mg every other day syrup.
Prevention:
20 , 21
Children:
>1 y and ≤15 kg: 30
mg once daily
>15–23 kg: 45 mg once

daily
>23–40 kg: 60 mg once

daily
>40 kg: 75 mg once

daily
Duration of prophylaxis
is variable and is used
for the duration of the
outbreak
Antivirals, zanamivir Treatment: 10 mg (2 Bronchospasm has Effective for treatment $$$

neuraminidase Relenza inhalations) BID × 5 been reported, and prophylaxis against
inhibitors days especially in patients influenza A and B.
Prevention for ≥7 y: with respiratory Treatment is best
Household setting: 10 disease. initiated within 48 hours
mg (2 inhalations) daily Headache, dizziness, of symptom onset but
× 10 days gastrointestinal upset, may be started after
cough. 48 hours in those with
Community outbreaks: high risk for influenza-
10 mg (2 inhalations) related complications
daily × 28 days 19
and/or if severely ill.
Do not use in patients
with asthma or COPD
due to risk of serious
bronchospasm.
Should not be
reconstituted and used
for nebulization.
Vaccines, viral influenza Children 6 mo–8 y who Common: soreness at Acetaminophen after $
vaccine, have not previously injection. vaccination may help
trivalent, received influenza Mild flu-like minimize soreness and
inactivated vaccine should receive a symptoms (myalgias, mild flu-like symptoms.
Agriflu, second dose malaise, low-grade Contraindicated in
Fluviral S/F, ≥1 mo after the first fever). persons with history of
dose. anaphylactic reaction to
Influvac,
6–35 mo: 0.25 mL im Oculorespiratory a previous dose or eggs.
Vaxigrip syndrome (ORS;
Page 603
Therapeutic Choice
Costa
36 mo–8 y: 0.5 mL im bilateral red eyes, Delay vaccination in
breathing symptoms adults with an acute
≥9y: 0.5 mL im or facial swelling): febrile illness. Vaccine
not considered an can be given to those
Influvac is approved for allergic reaction. with mild upper
use in ≥18y: 0.5 mL im People who had mild respiratory tract illness.
as a single dose or moderate cases of
ORS, or severe ORS Can be used in pregnant
with non-lower 7
and nursing women.
respiratory symptoms
can be re- Case reports of elevated
22
immunized. Consult theophylline blood levels
the local Medical following immunization
Officer of Health for and increased INR in
advice on more patients taking warfarin.
severe reactions. Monitor following
vaccination.
Vaccines, viral influenza 18–59 y: 0.1 mL of 9 Common: redness Not indicated for children $
vaccine, µg/strain and soreness at or adolescents <18 y of
trivalent, ≥60 y: 0.1 mL of 15 intradermal injection age.
inactivated µg/strain site. Not publicly funded for
(intradermal) Less common: mild the 2010–2011 influenza
Intanza flu-like symptoms season.
(headache, myalgias,
malaise).
Vaccines, viral influenza 2–59 y: 0.2 mL Nasal congestion, Not indicated for children $
vaccine, live intranasally given as 1 rhinorrhea. <2 y or adults >59 y.
attenuated spray (0.1 mL) per Increased incidence Contraindicated in
FluMist nostril. of wheezing when persons with history of
Children 2–8 y who administered to anaphylactic reaction to
have not previously children <24 mo of a previous influenza
received influenza age. This was not vaccination or eggs.
vaccine should receive a observed in older
second dose children and adults. Do not use in pregnant
≥4 wk after the first or breastfeeding women,
dose. severely
immunocompromised
individuals, persons with
wheezing in the prior 7
days or severe asthma
and those <18 y who use
ASA regularly.
Not publicly funded for

the 2010–2011 influenza
season.
a.
Cost of course of adult treatment; includes drug cost only.
Dosage adjustment may be required in renal dysfunction; see Appendices: Dosage Adjustment in Renal Impairment.
Abbreviations: ClCr=creatinine clearance; COPD=chronic obstructive pulmonary disease; LTC=long-term care; NACI=National
Advisory Committee on Immunization
Page 604
Therapeutic Choice
Legend: $ < $15 $$ $15–30 $$-$$$ $15–45 $$$ $30–45
Suggested Readings
Fiore AE, Shay DK, Broder K et al. Prevention and control of influenza. Recommendations of the Advisory Committee
on Immunization Practices (ACIP), 2008. MMWR Recomm Rep 2008;57(RR-7):1-64.
Moscona A. Neuraminidase inhibitors for influenza. N Engl J Med 2005;353(13):1363-73.
National Advisory Committee on Immunization (NACI). Statement on Seasonal Trivalent Inactivated Influenza
Vaccine (TIV) for 2010-2011. An Advisory Committee Statement (ACS). Can Commun Dis Rep 2010;36(ACS-6):1-
49. Available from: www.phac-aspc.gc.ca/publicat/ccdr-rmtc/10vol36/acs-6/index-eng.php. Accessed November 4,
2010.
Stiver G. The treatment of influenza with antiviral drugs. CMAJ 2003;168(1):49-56.
Zaman K, Roy E, Arifeen SE et al. Effectiveness of maternal influenza immunization in mothers and infants. N Engl J
Med 2008;359(15):1555-64.
References
1. Public Health Agency of Canada. FluWatch. Definitions for the 2010-2011 season. Ottawa (ON): Public Health
Agency of Canada; 2010. Available from: www.phac-aspc.gc.ca/fluwatch/10-11/def10-11-eng.php. Accessed
November 4, 2010.
2. Boivin G, Hardy I, Tellier G et al. Predicting influenza infections during epidemics with use of a clinical case
definition. Clin Infect Dis 2000;31(5):1166-9.
3. Monto AS, Gravenstein S, Elliott M et al. Clinical signs and symptoms predicting influenza infection. Arch
Intern Med 2000;160(21):3243-7.
4. Cox NJ, Subbarao K. Influenza. Lancet 1999;354(9186):1277-82.
5. Govaert TM, Dinant GJ, Aretz K et al. The predictive value of influenza symptomatology in elderly people. Fam
Pract 1998;15(1):16-22.
6. Gomolin IH, Leib HB, Arden NH et al. Control of influenza outbreaks in the nursing home: guidelines for
diagnosis and management. J Am Geriatr Soc 1995;43(1):71-4.
7. National Advisory Committee on Immunization (NACI). Statement on seasonal Trivalent Inactivated Influenza
Vaccine (TIV) for 2010-2011. An Advisory Committee Statement (ACS). Can Commun Dis Rep 2010;36(ACS-
6):1-49. Available from: www.phac-aspc.gc.ca/publicat/ccdr-rmtc/10vol36/acs-6/index-eng.php. Accessed
November 4, 2010.
8. Public Health Agency of Canada. Recommendation for use of Amantadine for treatment and prevention of
influenza. Ottawa (ON): Public Health Agency of Canada; 2006. Available from: www.phac-
aspc.gc.ca/media/nr-rp/2006/20061101-amantadine-eng.php. Accessed November 17, 2010.
9. Bright RA, Medina MJ, Xu X et al. Incidence of adamantane resistance among influenza A (H3N2) viruses
isolated worldwide from 1994 to 2005: a cause for concern. Lancet 2005;366(9492):1175-81.
10. Bright RA, Shay DK, Shu B et al. Adamantane resistance among influenza A viruses isolated early during the
2005-2006 influenza season in the United States. JAMA 2006;295(8):891-4.
11. Bowles SK, Lee W, Simor AE et al. Use of oseltamivir during influenza outbreaks in Ontario nursing homes,
1999-2000. J Am Geriatr Soc 2002;50(4):608-16.
12. Jefferson T, Jones M, Doshi P et al. Neuraminidase inhibitors for preventing and treating influenza in healthy
adults. Cochrane Database Syst Rev 2010;(2):CD001265.
13. Matheson NJ, Harnden AR, Perera R et al. Neuraminidase inhibitors for preventing and treating influenza in
children. Cochrane Database Syst Rev 2007;(1):CD002744.
14. Piedra PA, Schulman KL, Blumentals WA. Effects of oseltamivir on influenza-related complications in children
with chronic medical conditions. Pediatrics 2009;124(1):170-8.
15. Orzeck EA, Shi N, Blumentals WA. Oseltamivir and the risk of influenza-related complications and
hospitalizations in patients with diabetes. Clin Ther 2007;29(10):2246-55.
Page 605
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16. Kaiser L, Wat C, Mills T et al. Impact of oseltamivir treatment on influenza-related lower respiratory tract
complications and hospitalizations. Arch Intern Med 2003;163(14):1667-72.
17. Machado CM, Boas LS, Mendes AV et al. Use of oseltamivir to control influenza complications after bone
marrow transplantation. Bone Marrow Transplant 2004;34(2):111-4.
18. Aoki FY, Macleod MD, Paggiaro P et al. Early administration of oral oseltamivir increases the benefits of
influenza treatment. J Antimicrob Chemother 2003;51(1):123-9.
19. Allen UD, Aoki FY, Stiver HG. The use of antiviral drugs for influenza: recommended guidelines for
practitioners. Can J Infect Dis Med Microbiol 2006;17(5):273-84.
20. Oo C, Barrett J, Hill G et al. Pharmacokinetics and dosage recommendations for an oseltamivir oral suspension
for the treatment of influenza in children. Paediatr Drugs 2001;3(3):229-36.
21. Oo C, Hill G, Dorr A et al. Pharmacokinetics of anti-influenza prodrug oseltamivir in children aged 1-5 years.
Eur J Clin Pharmacol 2003;59(5-6):411-5.
22. Oculo-respiratory syndrome following influenza vaccination: review of post-marketing surveillance through
four influenza seasons in Canada. Can Commun Dis Rep 2005;31(21):217-25.
Page 606
e-Therapeutics+ : Therapeutics : Infectious Diseases: Malaria Prevention Page 1 of 10
Therapeutic Choice
Print Close
Infectious Diseases: Malaria Prevention

W.L. Wobeser, MD, FRCPC
J.S. Keystone, MD, FRCPC
Malaria results in more than 1 million deaths worldwide each year. The risk of malaria for travellers is greatest in
sub-Saharan Africa and Oceania, intermediate on the Indian subcontinent and Haiti and lowest in Southeast Asia and
Latin America. There is regional and seasonal variation of risk within these areas. Each year in Canada 300–400
cases of malaria are reported along with several deaths. Since malaria is a potentially fatal disease, it is of utmost
importance that travellers take appropriate measures to prevent this infection.
Goals of Therapy
Assess risk of acquisition of malaria

Provide safe and effective chemoprophylaxis
Therapeutic Choices (Figure 1 - Malaria Prophylaxis)
Malaria transmission by the anopheline mosquito mainly occurs between dusk and dawn. The following measures
optimize protection during this time:
Use insect repellents containing diethyltoluamide (DEET) before outdoor activity during the main
hours of malarial transmission. DEET has been rarely associated with neurologic side effects in
children exposed to high concentrations (> 35%) and prolonged use. The American Academy of
Pediatrics now recommends that 30% DEET may be used in children as young as 2 months of age.1
Useful Info?
In standard formulations, 30% DEET is effective for 4–6 hours. Citronella is usually effective for less than 1
2 , 3
hour.
Use bed nets, preferably impregnated with permethrin.4
Use mosquito coils, aerosolized insecticides or electrically operated insecticide generators containing
pyrethroids.
Wear clothes covering exposed skin, weather permitting. Sleep in an air-conditioned or screened room if
possible.
Principles of Chemoprophylaxis5
Determinants of acquisition risk include malaria endemicity, season, altitude, degree of rural travel and preventive
measures for mosquito bites. Additional considerations in choosing chemoprophylaxis include antimalarial drug
resistance, side effects, concurrent medications and illnesses, contraindications, pregnancy, age and allergies. All
travellers to an endemic area require prophylaxis. Check an up-to-date source (e.g., Centers for Disease Control and
Prevention at wwwn.cdc.gov/travel/default.aspx or Public Health Agency of Canada at www.travelhealth.gc.ca )
about the location and extent of drug-resistant Plasmodium species when counselling patients about malaria
chemoprophylaxis, as recommendations may change periodically.
In Canada, chloroquine is recommended for prevention of malaria in areas where the parasite is still sensitive to
this drug (i.e., Central America except Panama, Haiti and parts of the Dominican Republic and Middle East). In areas
where chloroquine-resistant P. falciparum malaria exists, mefloquine, doxycycline or atovaquone/proguanil
are the drugs of choice. Primaquine is an effective alternative. The combination of chloroquine and proguanil
should not be used because it has limited efficacy in areas with chloroquine-resistant P. falciparum. Drugs that are
effective in chloroquine-resistant areas may also be used in chloroquine-sensitive areas. Physicians without
experience and expertise in malaria chemoprophylaxis should strongly consider referring patients to a well-
Page 607
Therapeutic Choice
recognized travel medicine clinic. Listings of travel medicine clinics can be obtained from www.phac-aspc.gc.ca/tmp
-pmv/travel/clinic_e.html.
Chloroquine and Hydroxychloroquine
Chloroquine is the drug of choice in areas where chloroquine-resistant P. falciparum malaria has not occurred.
Hydroxychloroquine is an acceptable alternative to chloroquine and shares a similar side effect profile; however a
different dose may be used. Chloroquine should be started 1–2 weeks before travelling to and continued until 4
weeks after leaving a malarious area.
, 7 , 8
Mefloquine6
Mefloquine is used to prevent malaria in travellers going to areas reporting chloroquine-resistant P. falciparum.
However, resistance to mefloquine is clinically important along the Thai–Cambodian and Thai–Myanmar borders,
Eastern Myanmar, Western Cambodia and South/Central Vietnam, and therefore it should not be used. Severe
neuropsychiatric reactions (seizures and psychosis) occur in 1:13 000 patients who use the drug at appropriate
9 , 10
prophylactic doses. Less severe, disabling, neuropsychological side effects (e.g., anxiety, nightmares,
9 , 10
depression, irritability) occur in about 1:250 to 500 users. Mefloquine is contraindicated in those with a history
of seizures, psychosis, depression or a recent anxiety disorder. Mefloquine should be started 1–2 weeks before
travelling to and continued until 4 weeks after leaving a malarious area. Since most adverse events occur during the
first 3 doses, many practitioners recommend starting the drug 4 weeks prior to departure to ensure tolerance. If a
traveller does not have 4 weeks prior to departure, a loading dose may be given; 1 tablet is given daily for 3 days
followed by weekly dosing thereafter. Should a dose be forgotten, the traveller can take the dose right away since
mefloquine has a very long half life and, therefore, mefloquine blood levels have a lower chance of dropping below
effective levels.
Doxycycline7
Doxycycline is recommended for those travelling to chloroquine-resistant areas who cannot take mefloquine and for
those travelling to mefloquine-resistant areas. Unlike mefloquine, daily dosing is required. Users are advised to
avoid prolonged sun exposure and to use a sunscreen that absorbs UVA radiation (see Skin Disorders: Sunburn).
Doxycycline should be taken with food and liberal amounts of fluids while in the upright position. Doxycycline
chemoprophylaxis should begin 1–2 days before entry to the area and continue for 4 weeks after departure from the
area. Doxycycline is contraindicated in pregnancy and children < 8 years.
, 12 , 13
Primaquine11
Primaquine is used for terminal prophylaxis, i.e., "radical cure," in long-term travellers returning from areas with P.
vivax and P. ovale, both of which have dormant liver forms (hypnozoites). Hypnozoites are not affected by
chloroquine or mefloquine. Primaquine may also be used as a prophylactic agent in areas of chloroquine-resistant P.
falciparum malaria. It is a very effective prophylactic agent but must be taken daily. It is about 5–10% less effective
than the drugs of choice (mefloquine, doxycycline, atovaquone/proguanil) for the prevention of chloroquine-
resistant falciparum malaria. Primaquine should be started 1–2 days before entry to and continue for only 3 days
after departure from the area. It is well tolerated and has few side effects when taken with food.
Primaquine is a potent oxidizing agent which can induce severe hemolytic anemia in those with G6PD deficiency. In
risk groups for this enzyme deficiency (Blacks, Mediterraneans, Asians and Southeast Asians), a G6PD level is
mandatory before primaquine is used. The drug is contraindicated in pregnancy.
, 14 , 15 , 16
Atovaquone/Proguanil6
Atovaquone/proguanil is better tolerated than mefloquine. Uncommon adverse effects include GI upset, headache,
insomnia, cough and mouth ulcers. Atovaquone/proguanil should be taken daily with food, starting 1–2 days before
entry to a malarious area and may be discontinued 1 week after departure from the area. The drug is not
17 , 18
recommended in pregnancy or infants < 5 kg.
Malaria Prevention in Special Populations
Page 608
Therapeutic Choice
Pregnancy and Infancy
Pregnant women and young children should avoid travel to areas where chloroquine-resistant malaria is endemic. If
travel is unavoidable, effective protection against mosquitoes and appropriate chemoprophylaxis is strongly
recommended. Doxycycline, atovaquone/proguanil and primaquine are contraindicated in pregnancy. Doxycycline is
contraindicated in children < 8 years old or < 11 kg. In chloroquine-sensitive areas, chloroquine is recommended
for pregnant women and young children. In chloroquine-resistant areas, mefloquine has been shown to be safe after
the first trimester of pregnancy and can be used in children > 5 kg. Limited data suggest that mefloquine may also
19
be safe in the first trimester. Azithromycin is safe in pregnant women and young children but is suboptimally
effective. There is no safe and effective chemoprophylaxis for pregnant women or children < 11 kg who travel to
mefloquine-resistant areas.
Therapeutic Tips
Mefloquine is not favoured as a prophylactic agent by some physicians in the United Kingdom and in developing
countries. Travellers may be advised by physicians and travellers from these areas that they are on a dangerous
drug. In general, such advice should be accepted politely and ignored.
No currently available regimen of malaria chemoprophylaxis is ideal and completely effective. Adhering to the
chemoprophylaxis regimen helps reduce the risk of malaria acquisition. Drug-resistant malaria continues to
spread.
Remind travellers in writing to continue taking their antimalarials even after their return from an endemic
region. All travellers in whom fever develops within 1 year (particularly within 3 months) of return from a
malaria-endemic area must be considered to have malaria, regardless of chemoprophylaxis. Consider this a
medical emergency. Request thick and thin blood films to rule out malaria. If negative, repeat them twice over
48 hours.
20
In sub-Saharan Africa, the rate of false positive blood films for malaria is at least 40%. Travellers in this area
should be warned that if they are taking an appropriate antimalarial regularly and are diagnosed with “malaria,”
they should follow the advice of local practitioners, but not stop their chemoprophylaxis.
Travellers are advised to buy their full supply of medications before departure. The sale of poor quality and
21
counterfeit antimalarials is rampant in the developing world.
Page 609
Therapeutic Choice
Figure 1-Malaria Prophylaxis
Table 1: Drugs for Malaria Chemoprophylaxis
Page 610
Therapeutic Choice
a
Cost
Quinoline chloroquine Start 1–2 wk prior to Common: nonallergic Safe to use in $

Derivatives generics exposure and generalized pruritus in pregnancy.
continue weekly for African Canadians, Retinal toxicity a
4 wk after leaving the vomiting, headache, concern with
endemic area. bitter taste. continuous use of
A loading dose of Uncommon: hair chloroquine, i.e.,
1000 mg can be used depigmentation, skin cumulative dose >
in adults if eruptions, myopathy, 100 g chloroquine
chloroquine is not reversible corneal base. Screen for
initiated 2 wk prior to opacity, partial retinal changes every
exposure. alopecia, blood 6–12 mo if taking
dyscrasias. chloroquine for > 5 y.
22 23 , 24
Children:
Rare: nail and mucous
< 6 kg: 37.5 mg membrane
base (¼ tablet) discolouration, nerve
once/wk deafness,
photophobia,
6–9.9 kg: 75 mg retinopathy,
base (½ tablet) myopathy.
once/wk
10–15.9 kg: 112.5

mg base (¾ tablet)
once/wk
16–24.9 kg: 150 mg

base (1 tablet)
once/wk
25–44.9 kg: 225 mg

base (1½ tablet)
once/wk
Adults: 500 mg (300

mg base or 2 tablets)
once/wk
Adjust dose when

ClCr < 10 mL/min.
Quinoline hydroxychloroquine Start 2 wk prior to Common: nonallergic Safe to use in $$

Derivatives Plaquenil, generics exposure and generalized pruritus in pregnancy.
continue weekly for African Canadians, Retinal toxicity a
8 wk after leaving the vomiting, headache, concern with
endemic area. bitter taste. continuous use of
An initial loading Uncommon: hair chloroquine, i.e.,
dose of 800 mg to depigmentation, skin cumulative dose >
adults or 10 mg eruptions, myopathy, 100 g chloroquine
base/kg to children in reversible corneal base. Screen for
2 divided doses 6 h opacity, partial retinal changes every
apart can be given if alopecia, blood 6–12 mo if taking
hydroxychloroquine dyscrasias. chloroquine for > 5 y.
is not initiated 23 , 24
2 wk prior to Rare: nail and mucous
exposure membrane
discolouration, nerve
Children: 6.5 mg/kg deafness,
salt (5 mg/kg base) photophobia,
once/wk. Max 400
Page 611
Therapeutic Choice
a
Cost
mg (310 mg base) retinopathy,
once/wk myopathy.
Adults: 400 mg (310

mg base) once/wk
Quinoline mefloquine Start 1 wk prior to Common: GI upset, Used in regions of $$$$$

Derivatives Lariam, generics exposure, weekly dizziness, nausea, chloroquine-resistant
during the stay in the vomiting, diarrhea, P. falciparum; does
region and weekly for headaches, sinus not prevent multidrug
4 wk after leaving the bradycardia, -resistant P.
endemic area. nightmares, insomnia, falciparum.
Administer with a mood alteration, Contraindicated in
meal and with at anxiety, irritability. patients with seizure
least 240 mL of Uncommon: hair loss, disorders, active
water. skin rash. depression, recent
history of depression
Children: Rare: seizures, episodes, anxiety
psychosis, thrombotic disorders.
5–9 kg: 31.25 mg -thrombocytopenia
base (⅛ tablet) 25 Loading dose confers
purpura.
once/wk quicker attainment of
steady state (4 days
10–19 kg: 62.5 mg as opposed to 7–9
base (¼ tablet) wk).
once/wk
Loading dose is
20–30 kg: 125 mg associated with an
base (½ tablet) increased risk of
once/wk depression. When
possible, mefloquine
31–45 kg: 187.5 mg may be started 4
base (¾ tablet) weeks prior to
once/wk departure since 70%
of severe adverse
> 45 kg: adult dose reactions occur within
the first 3 doses.
Adults: 250 mg base
once (1 tablet) Considered to be safe
once/wk nd rd
in 2 and 3
trimesters of
Loading dose: 250 pregnancy.
mg base once daily
for 3 days, then 250
mg base weekly
thereafter.
Quinoline primaquine Start 1 day prior to Common: hemolysis Used in regions of $$

Derivatives Primaquine exposure, continue with G6PD deficiency. chloroquine-resistant
daily while in the Uncommon: GI upset P. falciparum.
malarial region and (take with food). Determine G6PD
for 3 days after deficiency in all
leaving the endemic Rare: individuals prior to
area methemoglobinemia. administration.
Administer with food
Contraindicated in
Children: pregnancy because of
unknown G6PD status
of infant and
Page 612
Therapeutic Choice
Costa
Prophylaxis: 0.5 mg subsequent risk of
base/kg/day. Max 30 hemolysis.
mg base (2 tablets)
once/day Methemoglobinemia
has been precipitated
Post-exposure: 0.5 in HIV-infected
mg base/kg/day × 14 patients who are
days. Max 30 mg being treated or are
base (2 tablets) on prophylactic
once/day therapy for P. jirovecii
pneumonia, especially
Adults: if taken with
26 , 27 , 28
dapsone.
Prophylaxis: 52.6 mg
(30 mg base or 2
tablets) once/day; <
60 kg: 0.5
base/kg/day. Max 30
mg base or 2 tablets
26
once/day
Post-exposure: 52.6
mg (30 mg base or 2
tablets) once/day ×
14 days
Tetracyclines doxycycline Start 1 day prior to Common: GI upset, Used in regions of $$$$$
Vibramycin, exposure, continue photosensitivity, chloroquine-resistant
generics daily while in the staining of teeth in P. falciparum; can be
malarial region and children and fetuses, used for prevention of
for 4 wk after leaving candida vaginitis (use multidrug-resistant P.
the endemic area fluconazole for self- falciparum.
Administer with food treatment). Contraindicated in
and plenty of water. Uncommon: azotemia pregnancy and
Important not to in renal disease, children < 8 y.
recline after enterocolitis.
administration. Because of the
Rare: allergic increased risk of
Children: reactions, blood photosensitivity, use
dyscrasias, sunscreens to block
≥ 8 y: 2 mg/kg/day. esophageal UV radiation.
Max 100 mg/day ulcerations.
Adults: 100 mg
once/day
Antimalarials, atovaquone/ Start 1 day prior to Common: GI upset, Used in regions of $$$$$
combination proguanil exposure, continue headache. chloroquine-resistant
Malarone, Malarone daily while in the P. falciparum; can be
malarial region and used for prevention of
Pediatric
for 1 wk after leaving multidrug-resistant P.
the endemic area falciparum.
Administer with a Acts on pre-
meal erythrocytic hepatic
phase of malaria but it
17 does not prevent the
Children: Use
Malarone Pediatric hypnozoite formation
(62.5 mg/25 mg) by P. ovale or P.
vivax.
Page 613
Therapeutic Choice
Costa
5–8 kg: ½ tab daily Not recommended in

pregnancy.
9–10 kg: ¾ tab daily
Contraindicated in
11–20 kg: 1 tab daily patients with renal
insufficiency.
21–30 kg: 2 tabs
daily
31–40 kg: 3 tabs

daily
> 40 kg: 250 mg/100

mg daily; use
Malarone (250
mg/100 mg)
Adults: 250 mg/100

mg daily; use
Malarone (250
mg/100 mg)
ClCr < 30 mL/min:

avoid
a.
Cost of 2-week supply of adult dosage for 1 week of travel; includes drug cost only.
Legend: $ < $5 $$ $5–10 $$$ $10–15 $$$$ $15–20 $$$$$ > $20
Suggested Readings
Baird JK, Fryauff DJ, Hoffman SL. Primaquine for prevention of malaria in travelers. Clin Infect Dis 2003;37
(12):1659-67.
Chen LH, Keystone JS. New strategies for the prevention of malaria in travelers. Infect Dis Clin North Am 2005;19
(1):185-210.
Fischer PR, Bialek R. Prevention of malaria in children. Clin Infect Dis 2002;34(4):493-8.
Fradin MS. Mosquitoes and mosquito repellents: a clinician's guide. Ann Intern Med 1998;128(11):931-40.
References
1. American Academy of Pediatrics. West Nile Virus information. Follow safety precautions when using DEET on
children. Elk Grove Village (IL): American Academy of Pediatrics; 2003. Available from:
http://www.aap.org/family/wnv-jun03.htm Accessed February 28, 2007.
2. Fradin MS, Day JF. Comparative efficacy of insect repellents against mosquito bites. N Engl J Med 2002;347
(1):13-8.
3. Hill DR, Ericsson CD, Pearson RD et al. The practice of travel medicine: guidelines by the Infectious Diseases
Society of America. Clin Infect Dis 2006;43(12):1499-539.
Page 614
Therapeutic Choice
4. Nevill CG, Some ES, Mung'ala VO et al. Insecticide-treated bednets reduce mortality and severe morbidity
from malaria among children on the Kenyan coast. Trop Med Int Health 1996;1(2):139-46.
5. Kain KC, Shanks GD, Keystone JS. Malaria chemoprophylaxis in the age of drug resistance. I. Currently
recommended drug regimens. Clin Infect Dis 2001;33(2):226-34.
6. Nosten F, ter KF, Maelankiri L et al. Mefloquine prophylaxis prevents malaria during pregnancy: a double-
blind, placebo-controlled study. J Infect Dis 1994;169(3):595-603.
7. Ohrt C, Richie TL, Widjaja H et al. Mefloquine compared with doxycycline for the prophylaxis of malaria in
Indonesian soldiers. A randomized, double-blind, placebo-controlled trial. Ann Intern Med 1997;126(12):963-
72.
8. Overbosch D, Schilthuis H, Bienzle U et al. Atovaquone-proguanil versus mefloquine for malaria prophylaxis in
nonimmune travelers: results from a randomized, double-blind study. Clin Infect Dis 2001;33(7):1015-21.
9. Taylor WR, White NJ. Antimalarial drug toxicity: a review. Drug Saf 2004;27(1):25-61.
10. Palmer KJ, Holliday SM, Brogden RN. Mefloquine. A review of its antimalarial activity, pharmacokinetic
properties and therapeutic efficacy. Drugs 1993;45(3):430-75.
11. Baird JK, Lacy MD, Basri H et al. Randomized, parallel placebo-controlled trial of primaquine for malaria
prophylaxis in Papua, Indonesia. Clin Infect Dis 2001;33(12):1990-7.
12. Soto J, Toledo J, Rodriquez M et al. Primaquine prophylaxis against malaria in nonimmune Colombian
soldiers: efficacy and toxicity. A randomized, double-blind, placebo-controlled trial. Ann Intern Med 1998;129
(3):241-4.
13. Weiss WR, Oloo AJ, Johnson A et al. Daily primaquine is effective for prophylaxis against falciparum malaria
in Kenya: comparison with mefloquine, doxycycline, and chloroquine plus proguanil. J Infect Dis 1995;171
(6):1569-75.
14. Faucher JF, Binder R, Missinou MA et al. Efficacy of atovaquone/proguanil for malaria prophylaxis in children
and its effect on the immunogenicity of live oral typhoid and cholera vaccines. Clin Infect Dis 2002;35
(10):1147-54.
15. Ling J, Baird JK, Fryauff DJ et al. Randomized, placebo-controlled trial of atovaquone/proguanil for the
prevention of Plasmodium falciparum or Plasmodium vivax malaria among migrants to Papua, Indonesia. Clin
Infect Dis 2002;35(7):825-33.
16. Sukwa TY, Mulenga M, Chisdaka N et al.. A randomized, double-blind, placebo-controlled field trial to
determine the efficacy and safety of Malarone (atovaquone/proguanil) for the prophylaxis of malaria in
Zambia. Am J Trop Med Hyg 1999;60(4):521-5.
17. Boggild AK, Parise ME, Lewis LS et al. Atovaquone-proguanil: report from the CDC expert meeting on malaria
chemoprophylaxis (II). Am J Trop Med Hyg 2007;76(2):208-223.
18. Borrmann S, Faucher JF, Bagaphou T et al. Atovaquone and proguanil versus amodiaquine for the treatment of
Plasmodium falciparum malaria in African infants and young children. Clin Infect Dis 2003;37:1441-7.
19. Phillips-Howard PA, Steffen R, Kerr L et al. Safety of mefloquine and other antimalarial agents in the first
trimester of pregnancy. J Travel Med 1998;5(3):121-6.
20. Reyburn H, Mbatia R, Drakeley C et al. Overdiagnosis of malaria in patients with severe febrile illness in
Tanzania: a prospective study. BMJ 2004;329(7476):1212.
21. Dondorp AM, Newton PN, Mayxay M et al. Fake antimalarials in Southeast Asia are a major impediment to
malaria control: multinational cross-sectional survey on the prevalence of fake antimalarials. Trop Med Int
Health 2004;9(12):1241-6.
22. Chiodini P, Hill D, Lalloo D et al. Guidelines for malaria prevention in travellers from the United Kingdom.
London (UK): Health Protection Agency; January 2007. Available from:
http://www.hpa.org.uk/publications/2006/Malaria/Malaria_guidelines.pdf Accessed November 14, 2007.
23. Chen LH, Wilson ME, Schlagenhauf P. Prevention of malaria in long-term travelers. JAMA 2006;296(18):2234-
44.
24. Hughes C, Tucker R, Bannister B et al. Malaria prophylaxis for long-term travellers. Commun Dis Public Health
2003;6(3):200-8.
25. Fiaccadori E, Maggiore U, Rotelli C et al. Thrombotic-thrombocytopenic purpura following malaria prophylaxis
with mefloquine. J Antimicrob Chemother 2006;57(1):160-1.
26. Hill DR, Baird JK, Parise ME et al. Primaquine: report from CDC expert meeting on malaria chemoprophylaxis
I. Am J Trop Med Hyg 2006;75(3):402-15.
27. Sin DD, Shafran SD. Dapsone- and primaquine-induced methemoglobinemia in HIV-infected individuals. J
Acquir Immune Defic Syndr Hum Retrovirol 1996;12(5):477-81.
28. Kantor GS. Primaquine-induced methemoglobinemia during treatment of Pneumocystis carinii pneumonia. N
Engl J Med 1992;327(20):1461.
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e-Therapeutics+ : Therapeutics : Infectious Diseases: Opportunistic Infections in HIV-posit... Page 1 of 17
Therapeutic Choice
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Infectious Diseases: Opportunistic Infections in HIV-positive Patients

Edward D. Ralph, BSc, MD, FRCPC
Opportunistic infections are a major cause of mortality and morbidity in HIV-positive patients and are often the first
evidence of immunodeficiency leading to the diagnosis of acquired immunodeficiency syndrome (AIDS).
Susceptibility to specific opportunistic infections increases as the CD4 (helper T-cell) count declines. This
relationship is very useful in the differential diagnosis of various infectious syndromes, especially at CD4 counts
1
< 200/µL.
Goals of Therapy
Prevent specific infections

Treat established opportunistic infections
Reduce drug burden by discontinuing chemoprophylactic regimens and maintenance therapy when appropriate
Investigations2
The initial investigations will be predicated on whether the patient is symptomatic. If a patient is symptomatic, the
following tests establish a baseline for determining the susceptibility to various opportunistic infections. In general,
latent infections can reactivate as the CD4 count declines.
Complete blood count

Lymphocyte flow cytometry—CD4 count and percentage, CD4/CD8 ratio
HIV viral load
Tuberculin skin test or interferon gamma release assay (IGRA) (the response of both tests is affected by CD4
count)
Hepatitis A, B and C virus serology
Herpes virus serology: varicella zoster virus (VZV), cytomegalovirus (CMV)
Toxoplasma serology
Syphilis serology (screening test)
Chest x-ray
Baseline biochemistry profile (prior to initiating drug therapy)
albumin
alkaline phosphatase
aminotransferases
bilirubin
blood urea nitrogen
serum creatinine
serum electrolytes
serum amylase
creatine kinase
lactate dehydrogenase
lipid profile (fasting)
Glucose-6-phosphate dehydrogenase—in members of at-risk groups prior to treatment with oxidant medications
(sulfonamides or dapsone)
If a patient has symptoms of a specific opportunistic infection, order appropriate investigations.
Therapeutic Choices
Advise patients with HIV infection and immunosuppression that their risk of infections can be reduced by following
good hygienic practices.
Ensure thorough hand washing after contact with potentially contaminated substances (diapers, soil, uncooked
meat and produce) or handling pets
Avoid raw or uncooked meat and eggs, e.g., Caesar salad
Page 617
Therapeutic Choice
Drink from treated water sources only
Avoid handling sick animals or pet (especially cat) litter
Avoid cat scratches and do not allow cats to lick wounds
Avoid contact with reptiles
Preventive interventions are outlined in Table 1.
Consider starting antiretroviral therapy (ART) concurrently with therapy for opportunistic infections to improve
immune function. See also Immune Reconstitution Inflammatory Syndromes.
Clinical Syndromes
Respiratory Tract Syndromes
Most upper respiratory tract symptoms are caused by viruses, but bacterial superinfections (otitis media, sinusitis)
are more common in HIV-infected patients and require antibiotic treatment. Patients with pneumonia (see Infectious
Diseases: Community-acquired Pneumonia) and CD4 counts > 200/µL can be treated for community-acquired
pneumonia. As the CD4 count declines to < 200/µL, Pneumocystis jirovecii (formerly P. carinii) becomes an
increasingly important pathogen. At counts < 100/µL, Mycobacterium avium complex (MAC), CMV, Cryptococcus
neoformans and Aspergillus spp. are more frequently isolated. Empirical treatment for P. jirovecii is often started in
patients in whom the diagnosis is suspected (fever, dyspnea, chest x-ray findings). Bronchoscopy with
bronchoalveolar lavage (BAL) and transbronchial biopsy is often required to confirm the diagnosis and may reveal
the presence of other opportunistic pathogens.
Painful Mouth and Swallowing
Oral candidiasis is very common and can occur with CD4 counts > 200/µL . Treatment with azole antifungal agents
is usually very effective, but with prolonged use, especially in those with low CD4 counts, resistance can develop.
Discrete ulcerative lesions are usually caused by herpes simplex virus (HSV), CMV or aphthous ulcers. The same
pathogens can cause odynophagia, but empirical treatment for candidiasis is instituted. Failure to respond after a
week's treatment necessitates endoscopy with cultures and biopsy.
1
Table 1: Preventive Interventions for HIV-positive Patients
Indications Condition Prophylactic Therapy
Independent of CD4 count Routine immunizations Update all vaccines (no live vaccines with the possible
exception of MMR and varicella vaccines if CD4
> 200/µL)
Meningococcal disease Meningococcal conjugate vaccine
Pneumococcal infection 23–valent polysaccharide pneumococcal vaccine, repeat

once after 5 years
Influenza Annual influenza immunization
Hepatitis Hepatitis A vaccine

Hepatitis B vaccine for nonimmune individuals
Varicella Post-exposure prophylaxis with IVIG for nonimmune

adults
Consider varicella vaccine if CD4 count > 400/µL and not
immune or if between 200 and 400 cells/µL while on
stable ART
Cervical cancer (HPV) Cervical Pap smear twice in the first year after diagnosis
of HIV infection, then annually if the results are normal.
Refer women with atypical squamous cells for colposcopy
Consider HPV vaccine in women 15–26 years
Page 618
Therapeutic Choice
Indications Condition Prophylactic Therapy
Frequent oral or genital Suppressive therapy with acyclovir, famciclovir or

herpes simplex outbreaks valacyclovir (Table 4)
Sexually transmitted Patients on antiretroviral therapy can become infected

infections (STIs) with STIs including resistant HIV strains. Condom use for
personal protection is recommended
Positive PPD (≥ 5 mm) or Mycobacterium The preferred prophylactic therapy is isoniazid +

IGRA, independent of CD4 tuberculosis pyridoxine for 9 months (Table 7)
count a
Rifampin for 4 months is an alternative
CD4 < 200 cells/µL or Pneumocystis jirovecii The preferred prophylactic therapy is SMX/TMP (Table 8)
thrush pneumonia (PCP) Alternatives include dapsone (alone or combined with
pyrimethamine + leucovorin); or atovaquone; or monthly
inhaled pentamidine (Table 8)
CD4 < 100 cells/µL and Toxoplasma gondii The preferred prophylactic therapy is SMX/TMP (Table 8)
positive T. gondii serology encephalitis Alternatives include dapsone alone or combined with
pyrimethamine + leucovorin, or atovaquone alone or
combined with pyrimethamine + leucovorin (Table 8)
CD4 < 50 cells/µL Mycobacterium avium The preferred prophylactic therapy is a macrolide
complex (azithromycin once weekly or twice-daily clarithromycin)
(Table 7)
Rifabutin is an alternative (Table 7)
Cytomegalovirus Prophylaxis is not cost effective. The focus of therapy is

restoration of the immune system
Fungal infections Fluconazole may be used for persons with recurrent

thrush or prior esophageal candidiasis (Table 5)
a.
Rifampin significantly alters the pharmacokinetics of many drugs including antiretroviral agents and its use is contraindicated
with some drugs. Therefore, the regimen must be carefully reviewed, and modified if necessary, before starting and stopping
rifampin therapy.
Abbreviations: ART=antiretroviral therapy; HPV=human papillomavirus; IGRA=interferon gamma release

assay; IVIG=intravenous immune globulin; PPD=purified protein derivative (of tuberculin)
Central Nervous System Symptoms
HIV-infected patients are at increased risk for opportunistic infections of the CNS, especially as their CD4 counts
decline to < 200/µL. At CD4 counts > 200/µL the usual bacterial, mycobacterial (M. tuberculosis) and viral causes
should be suspected. Unusual causes of CNS infection, especially C. neoformans (meningitis) and T. gondii (focal
lesions) are disproportionately more common as the CD4 count falls to < 200/µL (Figure 1 - Management of Fever
and Neurologic Complaints in HIV-positive Patients). Progressive multifocal leukoencephalopathy (PML) is an
opportunistic infection caused by JC virus for which there is no effective prophylaxis or treatment and can occur
even at higher CD4 counts.
Fever of Unknown Origin (Figure 1 - Management of Fever and Neurologic Complaints in

HIV-positive Patients)
Patients with low CD4 counts may present with fever and flu-like symptoms but no specific focal symptoms to
suggest a source. Possible infectious causes to be investigated include hepatitis viruses, sinusitis, MAC,
M. tuberculosis, CMV disease, P. jirovecii pneumonia (negative chest x-ray) and HIV viremia.
Diarrhea
Page 619
Therapeutic Choice
Diarrhea is a very common symptom in HIV-positive patients, and infectious causes must be distinguished from
noninfectious causes including adverse drug effects. Acute bacterial gastroenteritis caused by the usual enteric
bacterial pathogens may be more severe, may result in bacteremia and may require prolonged antibiotic treatment.
Long-term antibiotic prophylaxis and hospitalization predisposes patients to C. difficile infection. Chronic diarrheal
syndromes in patients with CD4 counts < 150/µL may be associated with MAC or parasitic infections including
giardiasis, cryptosporidiosis, cyclosporiasis and microsporidiosis.
Immune Reconstitution Inflammatory Syndromes
Patients initiating antiretroviral therapy, especially those with low initial CD4 counts, may experience
worsening of opportunistic infections usually within 1–3 months as their CD4 count improves, despite
3,4
appropriate antimicrobial treatment. The opportunistic infections most frequently encountered in
this setting are mycobacterial (tuberculosis or MAC), cryptococcal and viral (HSV, CMV, VZV, PML)
although any opportunistic infection, as well as autoimmune conditions and malignancies, may be
exacerbated by immune reconstitution. This phenomenon has been attributed to an enhanced
inflammatory response at the site of infection and is usually self-limited. Both combination ART and
antimicrobial treatment are usually continued with the judicious use of NSAIDs and steroids in select
individuals. Useful Info?
Discontinuation of Prophylaxis
Prophylaxis for some infections can be discontinued as the immune system recovers during antiviral therapy (Table
5 , 6 , 7 , 8 , 9
2).
Table 2: Criteria for Discontinuing Prophylaxis of Opportunistic Infections in HIV-positive Patients1
Pathogen Type of Prophylaxis Criteria for Discontinuing
P. jirovecii Primary and secondary CD4 > 200 cells/µL × ≥ 3 mo
T. gondii Primary CD4 > 200 cells/µL × ≥ 3 mo
Secondary CD4 > 200 cells/µL × ≥ 6 mo
M. avium complex Primary CD4 > 100 cells/µL × ≥ 3 mo
Secondary CD4 > 100 cells/µL × ≥ 6 mo
CMV retinitis Secondary CD4 > 150 cells/µL × ≥ 6 mo

No active disease
Regular ophthalmic examination
C. neoformans Secondary CD4 > 100–200 cells/µL × ≥ 6 mo
, 2
Management of Specific HIV-associated Infections1
Candida Species
The frequency of mucosal infection increases as the CD4 count decreases. Esophageal candidiasis is usually a later
manifestation, but can occur in the absence of oral or vaginal disease. Severe discomfort or esophageal disease
requires systemic therapy (see Table 5).
For oral thrush, topical therapy can be used initially. For example, use nystatin suspension (swish and swallow) or
use miconazole or clotrimazole vaginal tablets/suppositories as oral lozenges (see Table 5). For vaginal
candidiasis, topical azole antifungal creams or tablets/suppositories are the first-line therapy (see Table 5).
Fluconazole is the first line oral systemic therapy. Itraconazole and ketoconazole are alternatives. Higher doses
of fluconazole are used for esophageal disease with tapering of the dose when symptoms improve.
Amphotericin B suspension is an alternative for less advanced disease. Intravenous amphotericin B, caspofungin
or micafungin are used in patients who do not respond to oral therapy. Lipid-based preparations of amphotericin B
are less toxic but more expensive than the conventional formulation.
Page 620
Therapeutic Choice
Cryptococcus neoformans
C. neoformans is a major cause of meningitis in the later stages of HIV infection (10% of AIDS patients). The
diagnosis requires culture of the organism or detection of cryptococcal antigen in blood or CSF.
Induction therapy usually involves 2–6 weeks of intravenous amphotericin B with or without flucytosine, then
completion of a 12-week course of oral or intravenous fluconazole 400 mg/day (see Table 5). Fluconazole may be
used exclusively for patients who are well and who are followed closely. Maintenance therapy consists of daily oral
fluconazole.
Cytomegalovirus
CMV usually occurs in patients with CD4 counts < 50 cells/µL. Retinitis with visual disturbances is the most common
manifestation; however, enteritis, colitis, pneumonitis, encephalitis, myelitis and/or neuritis can also occur. The
prognosis is poor without therapy. Ganciclovir-resistant strains of CMV have emerged and CMV that is resistant to
ganciclovir may be cross-resistant to cidofovir and foscarnet.
Induction therapy involves oral valganciclovir (a prodrug of ganciclovir), or intravenous ganciclovir, or

intravenous foscarnet for 14–21 days (see Table 6). Maintenance therapy involves daily administration of oral
valganciclovir, intravenous foscarnet or intravenous cidofovir.
Mycobacterium avium complex
MAC occurs in patients with CD4 counts < 100 cells/µL. Symptoms include fever, weight loss, fatigue, night sweats
alone or with diarrhea, anemia, lymphadenopathy and/or hepatitis. The diagnosis is made primarily by
mycobacterial blood culture or biopsy and culture of involved tissue.
Multidrug regimens are used to treat MAC (see Table 7), the basis of which is an oral macrolide (clarithromycin or
azithromycin) plus ethambutol. Additional drugs such as rifabutin (or rifampin), ciprofloxacin or
levofloxacin, or amikacin may also be used depending on the circumstances. Therapy is given for 2–4 months,
followed by maintenance therapy. Maintenance therapy consisting of clarithromycin (or azithromycin) plus
ethambutol with or without rifabutin is continued for life unless a patient has sustained immune recovery on
combination ART.
Pneumocystis jirovecii
P. jirovecci is the primary cause of pneumonia in patients with CD4 counts < 200 cells/µL. P. jirovecii pneumonia
(PCP) commonly presents as a persistent fever with progressive shortness of breath and cough, often with a normal
chest x-ray. The organism cannot be cultured. Definitive diagnosis requires histopathologic examination of induced
sputum, bronchoalveolar lavage or lung biopsy.
Standard therapy is 21 days of oral or intravenous sulfamethoxazole/trimethoprim (SMX/TMP, cotrimoxazole)

(see Table 8). For severe disease, intravenous pentamidine may be given for 21 days. Oral dapsone plus
trimethoprim is better tolerated than SMX/TMP, but is suitable only for mild or moderate disease (there is no iv
formulation). Other alternatives include oral atovaquone; clindamycin plus primaquine; and trimetrexate plus
leucovorin. In patients with severe PCP, the addition of oral prednisone decreases morbidity and the side effects
of SMX/TMP. Patients with paO2 < 70 mm Hg on room air or an alveolar-arterial O2 gradient > 35 mm Hg should
receive adjunctive prednisone 40 mg twice daily for 5 days, then 20 mg twice daily for 5 days, then 20 mg daily to
complete 21 days of treatment.
Toxoplasma gondii
Up to 50% of HIV-positive patients with antibodies to this parasite will develop toxoplasma encephalitis when their
CD4 cell count decreases to < 200 cells/µL. Patients most commonly present with a fever and focal neurologic
signs. A CT scan with contrast or MRI usually reveals multiple intracranial-enhancing lesions.
Treat patients empirically. A marked clinical response usually occurs within 7 days; if there is no response, refer to
a specialty centre. Standard therapy is pyrimethamine plus leucovorin and sulfadiazine given for 4–8 weeks
(see Table 8). Alternatives include pyrimethamine plus leucovorin and clindamycin; or oral or intravenous
Page 621
Therapeutic Choice
SMX/TMP. Patients with perilesional edema require dexamethasone. Maintenance therapy comprises
pyrimethamine plus leucovorin and sulfadiazine; or pyrimethamine plus leucovorin and clindamycin.
Choices during Pregnancy and Lactation1
Prevention and Management of Opportunistic Infections
Prior to a planned pregnancy and during pregnancy, the patient should be treated with combination ART to ensure
an undetectable viral load and to maintain the CD4 count above 200/µL. This will prevent many of the serious
opportunistic infections. Patients with a CD4 count < 200/µL are encouraged to defer pregnancy until the CD4 count
is greater than 200/µL.
During pregnancy SMX/TMP can be given to prevent PCP and toxoplasmosis, although risk versus benefit needs to
be assessed in the first trimester. Initiate treatment for PCP with SMX/TMP in any trimester (see Table 3). Preferred
agents for MAC and mucocutaneous candidiasis are azithromycin and topical antifungal drugs, respectively. For
less common opportunistic infections, consult a reference such as the Guidelines for Prevention and Treatment of
Opportunistic Infections in HIV-Infected Adults and Adolescents (see Suggested Readings) for specific regimens
approved for use in pregnancy.
In the postpartum period, the usual preventive and therapeutic regimens can be reintroduced since breast-feeding is
contraindicated because of possible transmission of HIV to the child.
Table 3: Preferred Agents during Pregnancy1
Type of Infection Prevention Treatment
PCP a a
SMX/TMP SMX/TMP
MAC 1st choice: Azithromycin Azithromycin + ethambutol ± rifampinb

2nd choice: Azithromycin + ethambutol
Toxoplasma encephalitis a referral

SMX/TMP
Mucocutaneous candidiasis none topical antifungals
CMV none valganciclovir
a.
Monitor neonate for hyperbilirubinemia and kernicterus.
b.
If rifampin is given during the last few weeks of pregnancy vitamin K is indicated to prevent postnatal hemorrhage in the
mother and neonate.
Abbreviations: CMV=cytomegalovirus; MAC=mycobacterium avium complex; PCP=Pneumocystis jirovecii

pneumonia; SMX/TMP=sulfamethoxazole/trimethoprim
See also Appendix: Drug Use During Pregnancy and Appendix: Drug Use During Lactation for a discussion of the
general principles. For more detailed information on the use of specific medications in this condition during
pregnancy and lactation the reader is referred to Motherisk (www.motherisk.org/women/drugs.jsp); Briggs GG,
Freeman RK, Yaffe SJ. Drugs in Pregnancy and Lactation: a Reference Guide to Fetal and Neonatal Risk 2008;
LactMed (toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen?LACT); and Hale T. Medications and Mothers' Milk 2008.
Therapeutic Tips
All practitioners caring for patients who are HIV-positive should be aware of and participate in preventive
interventions.
Treatment of opportunistic infections requires specialized expertise and should be done in centres experienced
with the management of HIV-infected patients.
Figure 1- Management of Fever and Neurologic Complaints in HIV-positive Patients
Page 622
Therapeutic Choice
Abbreviations: CMV = cytomegalovirus; CSF = cerebral spinal fluid; CT = computed tomography; HSV = herpes simplex virus;
LOC = level of consciousness; MAC = mycobacterium avium complex; MRI = magnetic resonance imaging; PCR = polymerase
chain reaction; TB = tuberculosis; VZV = varicella zoster virus
Table 4: Drugs for Suppression of Frequent Oral or Genital Outbreaks of Herpes Simplex Virus
Costa
Class Drug Adult Dose Adverse Effects Comments
Guanine Nucleoside acyclovir 200 mg TID or Gastrointestinal, ↑ CNS adverse effects $

Analogue Antiviral Zovirax Oral, 400 mg BID headache. when taken with AZT or
Agents generics po probenecid.
May impair renal excretion
of tenofovir.
Guanine Nucleoside famciclovir 250 mg BID Gastrointestinal, Prodrug of penciclovir. $

Analogue Antiviral Famvir, po headache.
Agents generics
Guanine Nucleoside valacyclovir 500 mg BID Gastrointestinal, Prodrug of acyclovir. $

Analogue Antiviral Valtrex, po headache. ↑ CNS adverse effects when
Agents generics taken with AZT or
probenecid.
May impair renal excretion
of tenofovir.
Page 623
Therapeutic Choice
a.
Cost per day based on dosages in this table for a 50 kg person; includes drug cost only.
Abbreviations: AZT=zidovudine
Legend: $ < $6
Table 5: Drugs for Prophylaxis and Treatment of Candida spp and Cryptococcus neoformans Infections
a
Class Drug Indication and Adult Dose Adverse Effects Comments Cost
Polyene amphotericin Oral candidiasis treatment: IV: infusion ↑ nephrotoxicity with iv:$$$$$
Antifungal 300–500 mg po suspension QID reactions (fever, other nephrotoxic b
B po:
Agents Fungizone swish and swallow chills, nausea), drugs.
Esophageal candidiasis hypotension, ↑ hemotoxicity of
treatment: 0.3–0.5 mg/kg/day nephrotoxicity, AZT.
iv × 2–3 wk then weekly after electrolyte
symptoms resolve disturbances, Consider use of a
anemia, liposomal
C. neoformans induction myelosuppression. preparation to
therapy: 0.7 mg/kg/day iv × 2–6 reduce the
wk ± flucytosine incidence of
nephrotoxicity.
Polyene amphotericin AmBisome: 3–5 mg/kg/day iv IV: infusion Lipid preparations $$$$$
Antifungal B lipid Abelcet: 5 mg/kg/day iv reactions (fever, are better
Agents preparations chills, nausea), tolerated than
hypotension, standard
Abelcet, nephrotoxicity, amphotericin B.
AmBisome electrolyte
disturbances,
anemia,
myelosuppression.
Polyene nystatin Oral candidiasis treatment: Gastrointestinal, $

Antifungal ratio- 500 000 U po suspension QID local irritation.
Agents Nystatin, swish and swallow; or 100 000 U
other vaginal tab sucked QID
generics
Pyrimidine C. neoformans induction Gastrointestinal, Amphotericin- b

flucytosine
Antifungal b therapy: 100–150 mg/kg/day neurological, induced
Agents Ancotil Q6H po × 2 wk + amphotericin B myelosuppression nephrotoxicity
iv (especially with predisposes
high serum patients to
levels). adverse effects.
↑ myelosuppression
with other
myelosuppressive
agents (e.g. AZT,
ganciclovir).
Echinocandin caspofungin Esophageal candidiasis Headache, fever, Rifampin and $$$$$

Antifungal Cancidas treatment (alt): 50 mg/day iv × elevated NNRTIs may ↓
Agents 14 days transaminase caspofungin levels.
levels.
Echinocandin micafungin Esophageal candidiasis: Headache, fever, ↑ itraconazole $$$$$

Antifungal Mycamine 150 mg/day iv x 15 days elevated levels.
Agents
Page 624
Therapeutic Choice
Class Drug Indication and Adult Dose Adverse Effects Comments Costa
transaminase
levels.
Azole fluconazole Prophylaxis for frequent Gastrointestinal, Inhibits CYP2C9 po: $$

Antifungal recurrence of oral or rash, elevated and 2C19. iv: $$$$
Agents, Diflucan, esophageal candidiasis: 100– transaminase ↑ levels of
systemic generics 200 mg/day po or 400 mg/wk po levels. cyclosporine,
Oral, esophageal or severe fentanyl,
vaginal candidiasis: 100– phenytoin,
200 mg/day po × 7–14 days for sulfonylureas,
oral or vaginal lesions; up to 400 tacrolimus and
mg/day po or iv × 14–21 days for warfarin, some
esophageal lesions HMG CoA
reductase
C. neoformans consolidation inhibitors (e.g.,
therapy: 400 mg/day po or iv to simvastatin) and
complete 12 weeks of therapy some
after amphotericin B induction benzodiazepines.
C. neoformans maintenance Rifampin ↓

therapy: 200 mg/day po fluconazole levels.
Azole itraconazole Oral, esophageal or vaginal Gastrointestinal, Absorption $

Antifungal Sporanox candidiasis: 200 mg/day po rash, headache, requires gastric
Agents, Capsules, × 7–14 days for oral or vaginal edema, acid: ↓ absorption
systemic lesions, × 14–21 days for hypokalemia. with antacids, H2-
Sporanox
esophageal lesions blockers, PPIs.
Oral Inhibits CYP3A4
Solution (many potential
interactions). ↑
levels of
cyclosporine,
digoxin, fentanyl,
warfarin, some
HMG CoA
reductase
inhibitors
(atorvastatin,
lovastatin,
simvastatin) and
some
benzodiazepines.
Carbamazepine,
phenytoin and
rifampin ↓
itraconazole levels.
Azole ketoconazole Oral, esophageal or vaginal Gastrointestinal, Absorption $

Antifungal generics candidiasis: elevated requires gastric
Agents, 200–400 mg once daily or BID po transaminase acid: ↓ absorption
systemic levels. with antacids, H2-
blockers, PPIs.
Inhibits CYP3A4
(many potential
interactions). ↑
levels of
cyclosporine,
digoxin, fentanyl,
warfarin, some
HMG CoA
reductase
inhibitors
Page 625
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Therapeutic Choice
Class Drug Indication and Adult Dose Adverse Effects Comments Costa
(atorvastatin,
lovastatin,
simvastatin) and
some
benzodiazepines.
Carbamazepine,
phenytoin and
rifampin ↓
itraconazole
levels.
Azole voriconazole Invasive aspergillosis, Hepatoxicity, Inhibits CYP 3A4: IV:

Antifungal Vfend candidemia, disseminated visual ↑ levels of $$$$$
Agents, candidiasis: 6 mg/kg Q12H iv x disturbances. cyclosporine, PO:
systemic 2 doses then 4 mg/kg Q12H iv efavirenz, HMG CoA $$$$$
or reductase
inhibitors,
400 mg Q12H po x 2 doses then phenytoin,
200 mg Q12H po (> 40 kg BW) or sirolimus,
100 mg Q12H po (< 40 kg BW) tacrolimus,
warfarin.
Only use oral
therapy in
patients with ClCr
< 50 mL/min.
Azole clotrimazole Oral candidiasis: 200 mg Local irritation. $

Antifungal Canesten vaginal tab sucked 5 times/day ×
Agents, Vaginal, 7–14 days
topical generics Topical therapy for
vulvovaginal candidiasis: 1%
cream × 6 nights; or 2% cream
and 200 mg vaginal tablet × 3
nights
Azole miconazole Oral candidiasis: 100 mg Local irritation. $

Antifungal Monistat, vaginal tab sucked 5 times/day ×
Agents, generics 7–14 days
topical Topical therapy for
vulvovaginal candidiasis: 2%
cream and/or 100 mg vaginal
ovule × 7 nights; or 4% cream
and/or 400 mg vaginal ovule × 3
nights
Azole terconazole Topical therapy for Local irritation. $

Antifungal Terazol, vulvovaginal candidiasis: 0.4%
Agents, generics cream × 7 nights; or 0.8% cream
topical and/or 80 mg vaginal ovule × 3
nights
a.
Cost per day based on dosages in this table for 50 kg person; includes drug cost only.
b.
Available through Special Access Programme, Therapeutic Products Directorate, Health Canada.
Page 626
Therapeutic Choice
Abbreviations: Alt=alternative therapy; AZT=zidovudine; BW=body weight; CYP=cytochrome P450; NNRTI=non-nucleoside

reverse transcriptase inhibitor; =; PPI =proton pump inhibitor
Legend: $ < $10 $$ $10–25 $$$ $25–50 $$$$ $50–100 $$$$$ > $100
Table 6: Drugs for Prophylaxis and Treatment of Cytomegalovirus Infection
a
Indication and Cost
Guanine ganciclovir CMV treatment: 5 Fever, gastrointestinal, ↑ AZT levels and $$$
Nucleoside Cytovene mg/kg iv Q12H × headache, confusion, hemotoxicity. ↓ renal
Analogue 14–21 days pruritus, neuropathy, excretion of tenofovir. G-
Antiviral Agents CMV myelosuppression. CSF can be used for
maintenance: neutropenia; ganciclovir-
5 mg/kg daily iv or resistant strains of CMV
6 mg/kg iv 5–7 have emerged.
times/week
Guanine valganciclovir CMV treatment: Fever, gastrointestinal, Prodrug of ganciclovir. $$$$

Nucleoside 900 mg po BID po headache, confusion, ↑ AZT levels and
Analogue Valcyte × 21 days pruritus, neuropathy, hemotoxicity. ↓ renal
Antiviral Agents CMV myelosuppression. excretion of tenofovir. G-
maintenance: CSF can be used for
900 mg/day po neutropenia; ganciclovir-
resistant strains of CMV
have emerged.
Cytidine b CMV treatment Gastrointestinal, Avoid other nephrotoxins b

cidofovir
Nucleotide Vistide (alt): 5 mg/kg iv myelosuppression, (additive
Analogue once/wk × 2 wk, ocular hypotony, nephrotoxicity).
Antiviral Agents then Q2wk nephrotoxicity.
Hydrate with NS.
Give probenecid 2 g
3 h before, and 1 g
2 h and 8 h after
each infusion
Inorganic b CMV induction Gastrointestinal, fever, Prehydrate to ↓ b

foscarnet
Pyrophosphate Foscavir (alt): 60 mg/kg headache, electrolyte nephrotoxicity. Avoid other
Analogue Q8H iv × 14–21 disturbances (may nephrotoxins (additive
Antiviral Agents days cause tetany, seizures), nephrotoxicity). More
CMV maintenance nephrotoxicity, anemia. difficult to administer
(alt): and more toxic than
90–120 mg/kg daily ganciclovir, but may
iv. Give 500 mL NS prolong survival.
before and after Ciprofloxacin ↑ seizure
each infusion potential.
a.
b.
Page 627
Therapeutic Choice
Abbreviations: Alt=alternative therapy; AZT=zidovudine; CMV=cytomegalovirus; G-CSF=granulocyte colony-stimulating

factor; NS=normal saline
Legend: $$$ $25–50 $$$$ $50–100
Table 7: Drugs for Prophylaxis and Treatment of Mycobacterium avium complex Infection and for Prophylaxis of
Mycobacterium tuberculosis Infection
a
Indication and Cost
Macrolide azithromycin MAC prophylaxis Gastrointestinal. Interchangeable with $$

Antibiotics Zithromax, (1st choice): 1200 clarithromycin for MAC
generics mg once/wk po therapy.
MAC treatment: May ↑ effect of digoxin,
500 mg/day po + warfarin, theophylline.
ethambutol ± 1–3
additional drugs
(amikacin,
ciprofloxacin or
levofloxacin, rifabutin
or rifampin) × 2–4
mo
MAC maintenance
(alt): 500 mg/day po
+ ethambutol ±
rifabutin
Macrolide clarithromycin MAC prophylaxis Gastrointestinal, Interchangeable with $

Antibiotics (1st choice): 500 abnormal taste. QTc azithromycin for MAC
Biaxin, mg BID po prolongation (rare). therapy.
generics MAC treatment: 500 Substrate and inhibitor
mg BID po + of CYP3A4 (many
ethambutol ± 1–3 potential interactions).
additional drugs
(amikacin, PIs may ↓ clearance of
ciprofloxacin or clarithromycin.
or rifampin) × 2–4 May ↑ effects of
mo carbamazepine, digoxin
and warfarin.
MAC maintenance
(1st choice): 500 Use cautiously with
mg BID po + other drugs that cause
ethambutol ± QTc prolongation.
rifabutin
Aminoglycoside amikacin MAC treatment: 10– Nephrotoxicity, ↑ nephrotoxicity with other $$$$$
Antibiotics generics 15 mg/kg/day iv × 2– ototoxicity (auditory nephrotoxic drugs.
4 mo as an optional and vestibular).
component in a
regimen containing a
macrolide +
ethambutol
Rifamycin rifabutin MAC prophylaxis Gastrointestinal, Substrate of CYP1A2 $

Antibiotics Mycobutin (alt): 300 mg/day po rash, pruritus, and 3A4; induces 3A4
MAC treatment: myelosuppression. (many potential
300 mg/day po × 2–4 Uveitis at doses > interactions). Clinically
mo as an optional 300 mg/day. significant drug
Page 628
Therapeutic Choice
Indication and Costa

component in a interactions with PIs
regimen containing a Hepatotoxicity is and NNRTIs: do not use
macrolide + rare. in combination with
ethambutol ritonavir, saquinavir,
delavirdine.
Discolours body fluids
and feces.
Rifamycin rifampin MAC treatment: Rash, pruritus, Broad-based induction $

Antibiotics Rifadin, 600 mg/day po × 2–4 hepatitis (rare). of CYP isozymes (many
mo as an optional potential interactions).
Rofact
component in a Clinically significant
regimen containing a drug interactions with
macrolide + many PIs and NNRTIs.
ethambutol Induces metabolism of
TB prophylaxis AZT.
(alt): 600 mg/day po Discolours body fluids
× 4–6 mo and feces.
Fluoroquinolone ciprofloxacin MAC treatment: 500 Headache, Absorption ↓ by antacids, $

Antibiotics – 750 mg BID po × 2 gastrointestinal, calcium and iron (separate
Cipro, –4 mo as an optional tendon rupture administration).
generics component in a (rare). Inhibits CYP1A2 and
regimen containing a 3A4 (many potential
macrolide + interactions): markedly
ethambutol ↑ theophylline and tizanidine
levels.
Fluoroquinolone levofloxacin MAC treatment: 500 Headache, Absorption ↓ by antacids, $

Antibiotics Levaquin, mg/day po × 2–4 mo gastrointestinal, calcium and iron (separate
as an optional tendon rupture administration).
generics
component in a (rare). Inhibits CYP1A2 (many
regimen containing a potential interactions).
macrolide +
ethambutol
Antimycobacterial ethambutol MAC treatment: Gastrointestinal, Absorption ↓ by aluminum $

Agents generics 15 mg/kg/day po × 2 headache, confusion, salts (separate
–4 mo + peripheral neuritis, administration).
clarithromycin or optic neuritis, rash, Patient should have
azithromycin ± 1–3 pruritus. regular eye exams and
additional drugs advised to report any
(amikacin, changes in vision.
ciprofloxacin or
or rifampin)
MAC maintenance:
15 mg/kg/day po +
clarithromycin or
azithromycin ±
rifabutin
Antimycobacterial isoniazid TB prophylaxis (1st Gastrointestinal, Absorption ↓ by antacids $

Agents generics choice): 300 mg/day hepatotoxicity, (administer separately).
po or 900 mg
Page 629
Therapeutic Choice
Indication and Costa

twice/wk × 9 mo with peripheral Inhibits metabolism of
pyridoxine 50 mg/day neuropathy. carbamazepine,
phenytoin and
theophylline.
a.
Abbreviations: Alt=alternative therapy; AZT=zidovudine; CYP=cytochrome P450; MAC=Mycobacterium

aviumcomplex; NNRTI=non-nucleoside reverse transcriptase inhibitor; PI =HIV protease inhibitor; TB=tuberculosis
Legend: $ < $10 $$ $10–25 $$$ $25–50 $$$$ $50–100 $$$$$ > $100
Table 8: Drugs for Prophylaxis and Treatment of Pneumocystis jirovecii and Toxoplasma gondii Infections
Indication and Adult Costa

Sulfonamide sulfamethoxazole / PCP, T. gondii prophylaxis Adverse reactions are Use with po: $
Combinations trimethoprim (1st choice): common, often caution in iv:
1 DS tab/day (800/160 mg) requiring alternative patients with $$$
(SMX/TMP,
is preferred; 1 SS tab/day agents. G6PD
cotrimoxazole) (400/80 mg) or 1 DS tab Nausea, vomiting and deficiency, or
Septra Injection, M/W/F are alternatives fever, impaired renal
generics PCP treatment (1st hypersensitivity or hepatic
choice): 15–20 mg/kg/day reactions (may be function.
(TMP) iv or po (divided Q6– severe), May ↑ effect of
8H) × 21 days myelosuppression, sulfonylureas and
hyperkalemia with warfarin.
T. gondii treatment (alt): high (i.e., treatment)
5– 10 mg/kg/day (TMP) iv or doses. TMP ↓ excretion
po BID × 30 days of dofetilide –
avoid
combination.
↑ hemotoxicity with
AZT.
Sulfonamide b T. gondii treatment (1st Nausea, vomiting and Use with b

sulfadiazine
Antibiotics choice): 100– fever, caution in
150 mg/kg/day po (max hypersensitivity patients with
6g/day) divided Q6H + reactions (may be G6PD
pyrimethamine + leucovorin severe), deficiency, or
× 6–8 wk myelosuppression. impaired renal
T. gondii maintenance or hepatic
(1st choice): 1 g BID po + function.
pyrimethamine + leucovorin May ↑ effect of
sulfonylureas and
warfarin.
↑ hemotoxicity with
AZT.
Page 630
Therapeutic Choice

Sulfone dapsone PCP, T. gondii prophylaxis Hypersensitivity Better tolerated $

Antibiotics Dapsone, generics (alt): 100 mg/day po alone; reactions (may be than SMX/TMP.
or 50 or 200 mg/day + severe), Clearance ↑ by
pyrimethamine + leucovorin myelosuppression, rifampin. Excretion
PCP treatment (alt): 100 hemolytic anemia, ↓ by probenecid.
mg/day po + TMP 15–20 methemoglobinemia
mg/kg/day po × 21 days (more common in TMP + dapsone
G6PD deficiency). ↑ toxicity of both
drugs. ↑
hemotoxicity with
AZT,
pyrimethamine,
primaquine,
TMP.
Antiprotozoal atovaquone PCP prophylaxis (alt): Gastrointestinal, Less effective $$$$$

Agents Mepron 1500 mg/day po headache, rash. than SMX/TMP
PCP treatment (alt): 750 for treatment of
mg BID po mild-moderate
PJP.
High fat meal ↑
absorption.
Clearance ↑ by
rifabutin,
rifampin.
Antiprotozoal primaquine PCP treatment (alt): 15– Gastrointestinal, $

Agents Primaquine, 30 mg/day po + clindamycin hemolytic anemia,
generics (300–450 mg Q6–8H po or methemoglobinemia.
600–900 mg Q8H iv)
Antiprotozoal pyrimethamine PCP prophylaxis (alt): 50 Gastrointestinal, Leucovorin ↓ $

Agents Daraprim or 75 mg once/wk po + hypersensitivity bone marrow
dapsone + leucovorin reactions (may be toxicity.
25 mg/wk po severe), ↑ hemotoxicity with
T. gondii treatment (1st myelosuppression, sulfonamides,
choice): 100 mg Q12H po × anorexia, vomiting. AZT,
2, then 50 mg/day (< 60 kg) ganciclovir.
or 75 mg/day (≥ 60 kg) +
leucovorin 10– 20 mg/day po
× 4–8 wk + sulfadiazine (or
+ clindamycin 600 mg Q6H
iv or po rather than
sulfadiazine)
T. gondii maintenance
(1st choice): 25–
50 mg/day po + leucovorin
10 mg/day po + sulfadiazine
(or with clindamycin 300 mg
Q6H po rather than
sulfadiazine)
Antiprotozoal pentamidine PCP prophylaxis (alt): Aerosol: chest pain, Aerosolized $$$$
Agents generics aerosol 300 mg/mo rash, wheezing. pentamidine is
better tolerated
Page 631
Therapeutic Choice

PCP treatment (alt for Injection: anemia, but less
severe): 4 mg/kg/day iv × arrhythmias, effective than iv
21 day dysglycemia, for PCP
hypotension, treatment. Give
nephrotoxicity, aerosol by
myelosuppression, Respirgard
pancreatitis. inhaler.
Infuse over 1 h
while
monitoring BP.
Caution with
other drugs that
cause QTc
prolongation.
↑ nephrotoxicity
with other
nephrotoxic
drugs.
a.
b.
Abbreviations: Alt=alternative therapy; AZT=zidovudine; CYP=cytochrome P450; G6PD=glucose-6-phosphate

dehydrogenase; PCP=Pneumocystis jiroveciipneumonia
Legend: $ < $10 $$ $10–25 $$$ $25–50 $$$$ $50–100 $$$$$ > $100
Suggested Readings
Aberg JA, Gallant JE, Anderson J et al. Primary care guidelines for the management of persons infected with human
immunodeficiency virus: recommendations of the HIV Medicine Association of the Infectious Diseases Society of
America. Clin Infect Dis 2004;39(5):609-29.
Kaplan JE, Benson C, Holmes KH et al. Guidelines for prevention and treatment of opportunistic infections in HIV-
infected adults and adolescents: recommendations from CDC, the National Institutes of Health, and the HIV Medicine
Association of the Infectious Diseases Society of America. MMWR Recomm Rep 2009;58(RR-4):1-207.
Lipman M, Breen R. Immune reconstitution inflammatory syndrome in HIV. Curr Opin Infect Dis 2006;19(1):20-5.
References
1. Kaplan JE, Benson C, Holmes KH et al. Guidelines for prevention and treatment of opportunistic infections in
HIV-infected adults and adolescents: recommendations from CDC, the National Institutes of Health, and the
HIV Medicine Association of the Infectious Diseases Society of America. MMWR Recomm Rep 2009;58(RR-4):1
-207.
2. Sanford JP, Gilbert DN, Moellering RC et al. The Sanford guide to HIV/AIDS therapy 2009. 17th ed. Sperryville
(VA): Antimicrobial Therapy; 2008.
3. Battegay M, Nuesch R, Hirschel B et al. Immunological recovery and antiretroviral therapy in HIV-1 infection.
Lancet Infect Dis 2006;6(5):280-87.
Page 632
Therapeutic Choice
4. Lawn SD, Bekker LG, Miller RF. Immune reconstitution disease associated with mycobacterial infections in HIV
-infected individuals receiving antiretrovirals. Lancet Infect Dis 2005;5(6):361-73.
5. Aberg JA, Williams PL, Liu T et al. A study of discontinuing maintenance therapy in human immunodeficiency
virus-infected subjects with disseminated Mycobacterium avium complex: AIDS Clinical Trial Group 393 Study
Team. J Infect Dis 2003;187(7):1046-52.
6. Ledergerber B, Mocroft A, Reiss P et al. Discontinuation of secondary prophylaxis against Pneumocystis carinii
pneumonia in patients with HIV infection who have a response to antiretroviral therapy. Eight European Study
Groups. N Engl J Med 2001;344(3):168-74.
7. Lopez Bernaldo de Quiros JC, Miro JM, Pena JM et al. A randomized trial of the discontinuation of primary and
secondary prophylaxis against Pneumocystis carinii pneumonia after highly active antiretroviral therapy in
patients with HIV infection. Grupo de Estudio del SIDA 04/98. N Engl J Med 2001;344(3):159-67.
8. Miro JM, Lopez JC, Podzamczer D et al. Discontinuation of primary and secondary Toxoplasma gondii
prophylaxis is safe in HIV-infected patients after immunological restoration with highly active antiretroviral
therapy: results of an open, randomized, multicenter clinical trial. Clin Infect Dis 2006;43(1):79-89.
9. Vibhagool A, Sungkanuparph S, Mootsikapun P et al. Discontinuation of secondary prophylaxis for
cryptococcal meningitis in human immunodeficiency virus-infected patients treated with highly active
antiretroviral therapy: a prospective, multicenter, randomized study. Clin Infect Dis 2003;36(10):1329-31.
Page 633
e-Therapeutics+ : Therapeutics : Infectious Diseases: Sepsis and Septic Shock Page 1 of 13
Therapeutic Choice
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Infectious Diseases: Sepsis and Septic Shock

Steven C. Reynolds, MD, FRCPC
Anthony W. Chow, MD, FRCPC, FACP
Goals of Therapy
Recognize sepsis early (Table 1)

Promptly initiate goal-directed resuscitative efforts to restore tissue perfusion within the first 6 hours
Eradicate causative pathogens (administer appropriate antibiotics within the first hour of recognizing sepsis)
Establish source control (eliminate potential sources of infection) through measures such as:
débridement of infected necrotic tissue
drainage of abscesses
removal of potentially infected devices or foreign bodies
Restore intravascular fluid volume
Reduce oxygen demand
Manage complications, e.g., acute renal failure, acute respiratory distress syndrome, disseminated intravascular coagulation, multiple
organ dysfunction syndrome
Prevent nosocomial infections
Prevent progression from sepsis to full septic shock
Investigations
Thorough history with special attention to underlying disease, precipitating event and possible sites of infection
Physical examination to determine the site and extent of infection, assess end-organ dysfunction and identify evidence of disseminated
intravascular coagulation or disseminated infection (e.g., skin rash, purpura, ecthyma gangrenosum, subcutaneous nodules)
Clinical monitoring of vital signs, urine output, weight, level of consciousness and total fluids in and out
Laboratory monitoring:
CBC and differential
arterial blood gases
plasma lactate
electrolytes, acid-base status
BUN and serum creatinine
liver function tests
serum ionized calcium, magnesium and phosphate
chest x-ray, ECG
coagulation status
stool for occult blood
Gram stain and cultures of: blood drawn from two separate sites (peripheral and central lines), urine, sputum and other body sites as
appropriate
imaging studies to search for the focus of infection
Note: the cardinal signs of infection, fever and leukocytosis, may not be present in sepsis
Additional investigations may be necessary to monitor cardiopulmonary status. Informal transthoracic echocardiograms by the bedside
intensivist are increasingly being performed.1 Pulmonary artery catheters provide dynamic information on cardiac output but their routine
use is not warranted2 , 3
Give serious consideration to insertion of a central venous catheter (CVC) into the superior vena cava for the measurement of central
venous oxygen saturation and central venous pressure in all patients with suspected sepsis. This facilitates rapid and appropriate
resuscitation efforts. Furthermore a CVC should be placed into the superior vena cava in all patients not responsive to initial fluid
resuscitation or those who have ongoing hemodynamic instability
Classification of Sepsis and Septic Shock
Categorize patients into 1 of 3 syndromes (Table 1).
Table 1: Classification of Sepsis, Severe Sepsis and Septic Shock4
Clinical
Staging Diagnostic Criteria
Sepsis Clinical evidence suggestive of infection plus:

Signs of a systemic inflammatory response to infection ( ≥2 of the following):
Tachypnea (>20 breaths/min or PaCO2 <32 mm Hg [<4.3 kPa])
Tachycardia (>90 beats/min)
Hyperthermia ( >38°C) or hypothermia (<36°C)
WBC >12 × 109 cells/L, or <4 × 109 cells/L, or >10% immature (band) forms
Severe sepsis Sepsis with hypotension (systolic blood pressure <90 mm Hg or a 40 mm Hg decrease from baseline in the absence of
other causes), organ dysfunction and perfusion abnormalities such as:
Oliguria: <0.5 mL/kg for at least 1 h in patients with urinary catheters
↑ plasma lactate (> normal upper limit)
Altered mental status
Page 634
Therapeutic Choice
Clinical
Staging Diagnostic Criteria
Septic shock Severe sepsis as defined above, despite adequate fluid resuscitation
Note: patients who are on pressor agents may not be hypotensive
Therapeutic Choices (Figure 1 - Early Management of Septic Shock7 )
Resuscitation and Monitoring
Meticulous monitoring of the patient's circulating volume and ventilatory status is essential, with immediate resuscitation if required. If simple
measures do not quickly restore hemodynamic stability, consider intensive care with invasive hemodynamic monitoring and aggressive
cardiovascular support.5 , 6 , 7
Early institution of mechanical ventilation and sedation helps to reduce oxygen demand and improve oxygen delivery and extraction at the
8
tissue level. Neuromuscular blockade should be avoided if possible because of the risk of prolonged muscular weakness. Sedation protocols
should include a process of daily lightening of sedation with a careful clinical evaluation. Adequate caloric intake with trace element and
vitamin supplements, preferably through the enteral route, is also important.9
A seminal study demonstrated a marked improvement in 28-day mortality in patients for whom the following goals of resuscitation were
accomplished within 6 hours of hospital admission:5
central venous pressure (CVP): 8–12 mm Hg (in a mechanically ventilated patient, the target central venous pressure should be
12–15 mm Hg due to the increased intrathoracic pressure)
mean arterial pressure (MAP) ≥65 mm Hg
urine output ≥0.5 mL/kg/hour
central venous (superior vena cava) or mixed venous oxygen saturation ≥70%
In the above study protocol, a packed red blood cell transfusion was given to achieve a hematocrit of ≥30% if fluid resuscitation did not result
in a mixed venous saturation of ≥70% despite a CVP of 8–12 mm Hg (or 12–15 mm Hg in a mechanically ventilated patient). If the hematocrit
was at or above this goal and the mixed venous saturation was not ≥70%, a dobutamine infusion was initiated to achieve the target
saturation of ≥70%.
These are reasonable goals of initial resuscitation but strict adherence to absolute values is discouraged. As an example, the absolute value of
CVP does not reflect the ability of administered fluid to increase cardiac output,10 whereas the trend is more useful. Therefore CVP should be
interpreted in the context of other indicators of patient volume status.
Transfusion Therapy
Maintaining hemoglobin above 70–80 g/L is a safe transfusion threshold for the general ICU population.11 A higher concentration, 90–100
g/L, may be required in patients with myocardial ischemia or to augment oxygen delivery in those with low mixed venous oxygen
saturation.12
Glucose Control
Despite conflicting results in recent studies, it is still prudent to maintain euglycemia in septic patients. Intravenous regular human insulin is
given by continuous infusion with a glycemic check every hour. Original data supported a glycemic goal of 4.4–6.1 mmol/L;13 however,
14 , 15
additional trials failed to demonstrate a documented benefit with an aggressive glucose control regimen. Moreover, a significant
increase in rate of hypoglycemia was observed. Therefore, many clinicians relax this goal by providing an upper limit of approximately 8.3
mmol/L. A recent large, multicentre, randomized trial showed that tight glucose control (4.5– 6 mmol/L) was associated with increased 90-
day mortality compared to a less strict glucose parameter (≤10 mmol/L).16 Although there are still some unanswered questions in the debate
over glucose control, in light of this large, well-designed trial and a recent meta-analysis17 it is reasonable to aim for glucose levels of ≤10
mmol/L in the general ICU population.
Localization and Evacuation of Loculated Infections
Plain radiographs, ultrasonography and computed tomography are invaluable for localizing the nidus of infection. Drain abscesses whenever
possible, and strongly consider removing infected foreign bodies.18
The ability of a patient to tolerate transportation away from the intensive care unit to facilitate imaging needs to be carefully considered.
Transportation imposes a small but very real risk of complications associated with moving a critically ill patient (extubation, hemodynamic
collapse, dysrhythmia).
Persistent bacteremia, despite appropriate antimicrobial therapy, suggests a valvular or endovascular infection, or the emergence of a resistant
microorganism. Intermittent bacteremias tend to be due to abscesses or localized infections which “shower” bacteria into the blood
sporadically.
Anticipation and Prevention of Complications
Page 635
Therapeutic Choice
Acute renal failure: avoid nephrotoxic drugs; monitor and dialyze as needed. Intermittent hemodialysis and continuous venovenous
hemofiltration are equally effective, although the latter may be better tolerated from a hemodynamic and fluid balance perspective.19
Acute respiratory distress syndrome (ARDS): anticipate and treat supportively (ventilatory support, inhaled beta2-agonists and
judicious use of crystalloids or colloids). Lung-protective ventilation strategies should be used in patients with acute lung injury (ALI)
or ARDS. This includes the use of low tidal volumes (6 mL/kg) and a goal of maintaining end-inspiratory pressures <30 cm of H2O.
Often, a moderate increase in arterial carbon dioxide tension (PaCO2), i.e., permissive hypercapnia, is necessary to achieve these
ventilator goals. Permissive hypercapnia may not be appropriate for patients with metabolic acidosis and is contraindicated in head
injuries. Positive end-expiratory pressure (PEEP) should be used to minimize lung injury. The level of PEEP will vary from patient to
patient but a reasonable starting point is 5–10 mm H2O.7
Aspiration: whenever possible, raise the head of the patient's bed 45 degrees to minimize the risk of passive aspiration and ventilator-
acquired pneumonia.
Electrolyte and acid-base status: correct metabolic derangements. Consider refeeding syndrome in those with poor nutrition. This
syndrome is characterized by metabolic disturbances upon reinitiation of feeding after a period of malnourishment. Advance feeds slowly
in those at risk while monitoring electrolytes carefully. Acidosis should not be routinely corrected with sodium bicarbonate unless the pH
is <7.15.7 Some advocate using a pH threshold of 7 for initiation of bicarbonate.20 The primary focus in a severely acidotic patient should
be to correct the underlying cause.
Edema, pericardial and pleural effusions: maintain adequate intravascular volume before using diuretics to mobilize extravascular fluid.
Generally, diuretics are not employed while patients are on vasopressors except in extenuating circumstances. Occasionally diuretics are
used when patients are receiving positive inotropes. Drain empyemas as soon as possible with a large-bore chest tube. Be suspicious of a
tamponade in a patient with a pericardial effusion.
Disseminated intravascular coagulation (DIC) and thrombocytopenia: although heparin will theoretically prevent further consumption of
clotting factors by reducing thrombin generation, its use in patients with bleeding is controversial. The first-line therapy for DIC is to
manage the underlying illness and treat supportively. Fresh frozen plasma should only be given to a patient with an elevated INR if an
invasive procedure is planned or if there is spontaneous bleeding. Transfuse with platelets for all cases where values are less than
5000/mm3.7 Consider transfusing in those who are at risk of bleeding and have a platelet value of 5000/mm3 to 30 000/mm3. In those
who have an invasive procedure planned, a platelet count > 50 000/mm3 is desirable.
Deep vein thrombosis: use unfractionated heparin, low molecular weight heparins or venous compression devices (see
Cardiovascular Disorders: Venous Thromboembolism) to prevent deep vein thrombosis.21 , 22
Hepatic dysfunction: be wary of toxic accumulation from medications that undergo biotransformation in the liver.
Stress ulcer prophylaxis: if the patient is not being fed orally, prophylaxis with H2-receptor blockers or proton pump inhibitors
23
reduces bleeding and improves clinical outcome. It is particularly indicated in those patients with prolonged mechanical ventilation,
21
hypotension and coagulopathy. H2-receptor blockers increase the incidence of ventilator-acquired pneumonia (VAP) and the risk and
benefits of their use must be assessed in each patient.24
Impaired gastrointestinal motility: manage slow gastric emptying with prokinetic agents such as metoclopramide or erythromycin.
Additionally, a post-pyloric feeding tube may be placed. A prokinetic agent should not be given to a patient who has high gastric residuals
secondary to a mechanical obstruction.
Central nervous system dysfunction: be vigilant for the development of delirium. Antipsychotics are typically used to manage delirium
25
although there is no good evidence supporting this practice. Indeed the benefit may lie in the discontinuation of precipitating agents
such as benzodiazepines.
Nosocomial infections: strict adherence to handwashing, aseptic technique and other infection control principles is required to minimize
the development of nosocomial infections.26 Central venous catheters, foley catheters and other invasive lines should be removed as soon
as possible. Nasogastric and nasotracheal intubation should be avoided to prevent nosocomial sinusitis. Weaning protocols that utilize
daily spontaneous breathing trials minimize the number of days on mechanical ventilation and lower the risk of ventilator-acquired
pneumonia.27
Pneumothorax: watch for pneumothoraces in patients who are mechanically ventilated.
Empiric Antimicrobial Therapy
Antimicrobial therapy remains the cornerstone of treatment for sepsis and septic shock. However, the underlying disease, comorbid conditions
and development of complications (e.g., ARDS, multi-organ dysfunction) often dictate the eventual outcome of therapy. Source control (see
Goals of Therapy) if possible, is critical for the successful treatment of infections.
Broad-spectrum antibiotics should be administered immediately, with the first dose being ordered and administered “stat.”
There is good evidence that mortality increases dramatically with each hour that appropriate antibiotic administration is
delayed in the septic patient.28 Useful Info? If feasible, all samples for microbial identification should be acquired prior to the
administration of antibiotics. Antibiotic administration should not be delayed in the critically ill patient for the sole purpose of maximizing the
microbial yield nor for initiation of imaging studies.
Initial antimicrobial therapy is empiric because gram-positive, gram-negative, mycobacterial, fungal and viral sepsis are often clinically
indistinguishable. Antibiotic selection is based on the most likely source/site of infection and hence the most likely causative microorganisms
and their anticipated susceptibility profiles (Table 2). The choice of antimicrobial agents, described in Table 3, may also be influenced by the
presence of acute renal or hepatic failure, hypersensitivity reactions, need for fluid restriction, local antimicrobial susceptibility patterns,
emergence of resistance and drug interactions. Another element that may factor into antibiotic selection is the local presence of severe
C. difficile -associated diarrhea.29
Antibiotics should be administered intravenously in critically ill patients and reassessed within 48–72 hours. Adjustments are guided by
culture results, in vitro susceptibility patterns and clinical response. Once antimicrobial sensitivities are known there are only very few cases
where double coverage with effective antibiotics is indicated. Pseudomonas is the classic example and it is standard of care to “double cover”
to prevent the development of resistance but this is not based on strong evidence.30
Candida is the fourth most common pathogen isolated in blood stream infections in the ICU, yet when to start antifungal therapy is not
entirely clear.31 , 32 In special at-risk populations such as neutropenic patients, empiric antifungal therapy should be considered. Other
patients need to be considered on a case-by-case basis for empiric antifungal therapy. Risk factors for candidemia include multiple
colonization sites, long-term broad-spectrum antibiotic therapy, hollow viscus rupture or abdominal surgery, intravenous catheters, prolonged
ICU stay and total parenteral nutrition.33
Page 636
Therapeutic Choice
Candidemia may be difficult to detect through blood cultures. Consider early or prophylactic antifungal therapy in those with hollow viscus
rupture34 or in patients who have developed unexplained fever or shock and have multiple risk factors for candidemia, particularly those in an
intensive care unit with a high prevalence of fungal infections.33 , 35 Although empiric antifungal therapy in those felt to be at risk is
33 36
advocated in guidelines, a trial randomizing high-risk patients to receive fluconazole or placebo showed no difference in outcomes. Be
33
suspicious of fungal infections when evaluating critically ill immunocompromised patients.
The most appropriate choice of empiric antifungal therapy is not entirely clear. Fluconazole, amphotericin B (liposomal or conventional) or
an echinocandin are all reasonable choices. Care must be taken to avoid and to monitor for toxicities, such as renal failure with amphotericin
B. Avoid fluconazole if the patient has received fluconazole in the recent past, has advanced septic shock (and therefore cannot tolerate even
the very small chance of infection with a fluconazole-resistant candida), is neutropenic or if there is a high local incidence of Candida glabrata
or Candida krusei (in which case an echinocandin is preferred).37
Table 2: Empiric Antimicrobial Treatment of Sepsis and Septic Shock
Source of Infection Common Pathogens Initial Antimicrobial Regimen
Community-acquired Streptococcus viridans, Streptococcus pyogenes, Streptococcus Extended-spectrum beta-lactama

pneumonia38 pneumoniae, Haemophilus influenzae, Legionella pneumophila,
(usually a 3rd generation cephalosporin
Staphylococcus aureus (MRSA or MSSA), gram-negative bacilli
is adequate)
(rarely Pseudomonas aeruginosa except in those with risk
±
factors), Mycoplasma pneumoniae, Chlamydia pneumoniae
extended-spectrum fluoroquinolone
Evaluate the potential of other pathogens based on risk factors
or
macrolide
±
vancomycinb
or
b
linezolid
Intraperitoneal/gastrointestinal Enteric gram-negative bacilli, Bacteroides fragilis, Extended-spectrum beta-lactama

39 Peptostreptococcus spp., Clostridia spp., Enterococcus spp., less Consider early empiric addition of an
tract
commonly Candida spp. anti-candidal agent (e.g., fluconazole) in
severely ill patient with a hollow viscus
33 , 34
rupture
Urinary tract40 Escherichia coli, other enteric gram-negative bacilli, Extended-spectrum beta-lactama
Staphylococcus saprophyticus, Enterococcus spp., ±
ciprofloxacin
or
aminoglycoside
Less commonly, Pseudomonas aeruginosa Ciprofloxacin

or
aminoglycoside
+
ceftazidime
or
meropenem/imipenem
or
piperacillin/tazobactam
Central nervous system41 Neisseria meningitidis, H. influenzae , S. pneumoniae, Listeria 3rd generation cephalosporin (high dose)
monocytogenes ±
vancomycin (for penicillin-resistant
pneumococcus)
±
ampicillin (for elderly, alcoholic or
young patients, in particular for Listeria
coverage)
Necrotizing skin and soft Group A streptococcus, S. aureus, Clostridia spp. Penicillin G
tissues42 +
clindamycin
±
vancomycin
Gram-negative Enterobacteriaceae and anaerobes are prominent Extended-spectrum beta-lactama

in perirectal/genital infections.
Intravascular devices- S. aureus, coagulase-negative staphylococci Vancomycin

associated43 Much less commonly, enteric gram-negative bacilli and Candida
spp.
Unknown source Piperacillin/tazobactamc

or
Page 637
Therapeutic Choice
Source of Infection Common Pathogens Initial Antimicrobial Regimen
ticarcillin/clavulanatec
a. rd th
Extended-spectrum beta-lactam = 3 or 4 generation cephalosporin, extended-spectrum penicillin with beta-lactamase inhibitor or carbapenem.
rd th
Metronidazole should be added if a 3 or 4 generation cephalosporin is selected to treat severe perirectal soft tissue infections or
intraperitoneal/gastrointestinal tract infections.
b.
If increased risk of methicillin-resistant S. aureus (MRSA).
c.
A more focused antimicrobial choice should be instituted once the nidus of infection and likely pathogens become more apparent.
Vasoactive Agents for Cardiovascular Support
Although rapid fluid administration alone may be sufficient to restore hemodynamic stability, vasopressors are often necessary to restore an
adequate mean arterial pressure (MAP) primarily by bolstering systemic vascular resistance.
Norepinephrine (0.03–1.5 μg/kg/min) is the pressor of choice in septic shock. It has peripheral vasoconstricting activity and may be
superior to dopamine in septic shock by increasing peripheral resistance and improving splanchnic perfusion.44 , 45 It is a potent
vasoconstrictor and has lesser positive inotropic and chronotropic effects. Dopamine (5– 20 µg/kg/min) has positive chronotropic, inotropic
and vasoconstrictive effects. Use of dopamine is often limited by its strong positive chronotropic effects. Low-dose dopamine does not
preserve renal function.46 Epinephrine is a second-line agent that possesses positive inotropic and vasopressor activity. A recent study
compared epinephrine to norepinephrine and dobutamine and found similar outcomes in septic shock.47 Therefore, epinephrine may be a
reasonable choice in septic shock but a combination of norepinephrine and dobutamine allows greater control over relative degree of inotropy
and vasopressor activity required. Phenylephrine (2–10 μg/kg/min) also has potent vasoconstricting properties and increases blood
pressure. It only acts peripherally and its relative lack of chronotropy makes it useful in tachyarrhythmias. It is not recommended as a first- or
second-line agent in septic shock because of its potential to reduce stroke volume.7
Occasionally, low-dose vasopressin (0.02–0.04 µg/min) is used as an adjunctive or “rescue” vasopressor. The VASST trial randomized
patients with septic shock to receive vasopressin and norepinephrine or norepinephrine alone.48 No differences were noted between the 2
groups except significantly less renal failure in the “low norepinephrine” (<15 µg/min) plus vasopressin group. This study showed that
vasopressin is safe and may be useful to “spare” high doses of norepinephrine in the septic patient who cannot tolerate tachycardia. It does
not, however, improve outcomes in the general ICU population.
Dobutamine (2–20 μg/kg/min) is a positive inotrope, but decreases systemic vascular resistance because of its vasodilatory properties.
When added to norepinephrine, it may improve splanchnic blood flow49 and it is often used in septic shock to improve oxygen delivery in a
patient who has a mixed venous value of less than 70%.
Drotrecogin alfa
Drotrecogin alfa (activated protein C) is indicated for use in adult patients with severe sepsis and an Acute Physiology and Chronic Health
Evaluation (APACHE II) score of ≥25 with multiple acute organ dysfunction. Randomized, placebo-controlled trials show a 19% relative
reduction in mortality.50 , 51 It is administered as an iv infusion at a rate of 24 μg/kg/h for a total of 96 hours. The major risk is bleeding;
hence, avoid in patients with prolonged PT or aPTT, thrombocytopenia (platelet count <30 × 109/L), bleeding at a noncompressible site,
recent surgery, risk of intracranial hemorrhage or predisposing conditions such as gastrointestinal ulceration.
There has been strong criticism of the initial PROWESS trial, which demonstrated the efficacy of activated protein C in septic shock.52 As a
result, another multicentred, randomized, placebo-controlled study is underway.
Corticosteroids
Major clinical trials in recent years have yielded conflicting recommendations.53 , 54 Corticosteroids can be life saving for a subset of patients
who require them. Conversely, there is a higher risk of super infections and new septic shock in those receiving them.55 Identifying patients in
whom the benefit is expected to outweigh risk is not straightforward. Consider administration of hydrocortisone in patients whose
7
hypotension does not adequately respond to fluids and vasopressors. The practice of using an ACTH stimulation test to identify the cohort of
7 , 55
patients who would benefit is no longer recommended. It may be prudent, however, to do a random cortisol level on all patients with
shock initially unresponsive to fluid and low-dose vasopressors to avoid missing those with profoundly low levels due to absolute adrenal
insufficiency. Absolute adrenal deficiency is characterized by an absence of endogenous production of adrenal hormones and may be seen in
bilateral adrenal infarcts, such as with Waterhouse-Fredrickson syndrome or thrombotic heparin-induced thrombocytopenia, or bilateral
adrenal infiltration, as seen in some disseminated malignancies or histoplasmosis. If a corticosteroid is needed, hydrocortisone is preferred at
a dose of no more than 300 mg daily. The addition of fludrocortisone (50 µg po daily) is recommended only if a corticosteroid without
mineralocorticoid activity is used in place of hydrocortisone. It is considered optional if hydrocortisone is used.
Immune Globulins
Immunotherapy to neutralize or remove specific exotoxins may be worthwhile if etiologic agents are identified (e.g., diphtheria, botulism,
anthrax, clostridial septicotoxemia, toxic shock syndrome). However, as specific antisera are seldom available, immunoglobulins pooled from
healthy donors are often used instead.
The use of polyclonal iv immune globulins (IVIG) is recommended in patients with hereditary or acquired immunodeficiency.56 , 57 An
58
observational study also suggested that IVIG at 2 g/kg for 1–2 doses could be useful in streptococcal toxic shock syndrome. IVIG may
improve outcome in cases of necrotizing fasciitis due to group A streptococcus (Streptococcus pyogenes) at a dose of 1 g/kg on day 1 and
59 60
then 0.5 g/kg on days 2 and 3. IVIG may also be useful in staphylococcal toxic shock syndrome.
Page 638
Therapeutic Choice
Currently there is clinical equipoise regarding the use of polyclonal IVIG in septic shock. There have been conflicting results in recent meta-
analyses, and further well-designed, multicentre, randomized, placebo-controlled trials are needed.61 , 62 Polyclonal IVIG is not recommended
for use in septic shock outside of the specific indications cited above.
Therapeutic Tips
Early recognition and treatment of sepsis is of paramount importance. Relevant antibiotics must be quickly available, ideally stored at the
point of care to avoid delays in acquisition.
When the CNS is the source of infection, consider covering with acyclovir until viral encephalitis (most commonly due to herpes simplex
virus) is ruled out or another diagnosis is apparent (e.g., obvious bacterial meningitis). Strongly consider giving dexamethasone 0.15
mg/kg iv Q6H × 2–4 days as it improves outcomes in pneumococcal meningitis.63 First dose should be administered before or
concomitantly with antibiotics. Discontinue if culture results are negative for pneumococci.
Culture-negative infections are particularly common among patients who have received partial antimicrobial therapy before cultures are
obtained, and in immunocompromised patients undergoing bone marrow or solid organ transplants.
Patients who have shock with no clear etiology must be treated for sepsis with appropriate antimicrobial therapy while further
investigations are undertaken. Distributive shock from sepsis may present concomitant with other forms of shock, such as cardiogenic,
particularly in those patients who have pre-existing chronic disease.
Biomarker assays, such as procalcitonin, are emerging as a useful adjunct in the evaluation of sepsis and may aid in determining the
optimal duration of antimicrobial therapy.64
Although sepsis typically involves low system vascular resistance, there is often some degree of myocardial suppression. Bedside
echocardiography facilitates the recognition and management of mixed shock states (low systemic vascular resistance and low cardiac
output).
Appropriate antimicrobial stewardship is challenging in the intensive care unit. The balance between ensuring the best outcome for
patients and avoiding the overuse of broad-spectrum agents can be difficult. The general principles of initial broad-spectrum therapy with
re-evaluation and de-escalation of therapy based on microbiology results after 48–72 hours should be applied in all patients.
Occasionally, de-escalation is not prudent because of ongoing severe illness.
Figure 1- Early Management of Septic Shock7
Abbreviations: ACTH = adrenocorticotropic hormone; ALI = acute lung injury; APACHE = Acute Physiology and Chronic
Health Evaluation; ARDS = acute respiratory distress syndrome
Page 639
Therapeutic Choice
Table 3: Intravenous Antimicrobials Used in Sepsis and Septic Shock
Drug Costa
Carbapenems imipenem/cilastatin 500 mg–1 g iv Usually well tolerated. Avoid concurrent May be used with $$$$$
Primaxin Q6H Gastrointestinal, use with caution in patients with
hematologic reactions, ganciclovir as non-immediate
rarely seizures. seizures have penicillin allergy.
been reported. Extended spectrum beta
Carbapenems -lactam antibiotics have
may decrease become the mainstay of
valproic acid treatment because of
levels. lack of nephrotoxicity
and broad-spectrum
Enhanced activity vs gram-
neurotoxic negative organisms.
effects may
occur with
cyclosporine.
Carbapenems meropenem 1 g iv Q8H Usually well tolerated. Carbapenems May be used with $$$–
Merrem (traditional Gastrointestinal, may decrease caution in patients with $$$$
dosing) hematologic reactions, valproic acid non-immediate
OR rarely seizures. levels. penicillin allergy.
Extended spectrum beta
500 mg iv Q6H -lactam antibiotics have
(alternative become the mainstay of
dosing)65 treatment because of
lack of nephrotoxicity
and broad-spectrum
activity vs gram-
negative organisms.
Penicillins, piperacillin/tazobactam 3.375 g iv Q6H Usually well tolerated. Tetracyclines ↓ Extended spectrum beta $$
extended- (4.5 g iv Q6H Gastrointestinal, effectiveness of -lactam antibiotics have
spectrum Tazocin, for hematologic reactions, penicillins. become the mainstay of
Piperacillin/Tazobactam Pseudomonas) rarely seizures. ↑ methotrexate treatment because of
serum levels. lack of nephrotoxicity
for Injection,
and broad-spectrum
other generics activity vs gram-
negative organisms.
Penicillins, ticarcillin/clavulanate 3.1 g iv Q4–6H Usually well tolerated. Tetracyclines ↓ Extended spectrum beta $-$$
extended- Timentin Gastrointestinal, effectiveness of -lactam antibiotics have
spectrum hematologic reactions, penicillins. become the mainstay of
rarely seizures. ↑ methotrexate treatment because of
serum levels. lack of nephrotoxicity
and broad-spectrum
activity vs gram-
negative organisms.
Experts differ on
whether
ticarcillin/clavulanate is
equivalent to
piperacillin/tazobactam.
Cephalosporins, cefotaxime 2 g iv Q6–8H Usually well tolerated. No known May be used with $$-
third generation Claforan Meningitis: 2 g Gastrointestinal, common drug caution in patients with $$$
iv Q4–6H hematologic reactions, interactions. non-immediate
rarely seizures. penicillin allergy.
-lactam antibiotics have
become the mainstay of
treatment because of
and broad-spectrum
activity vs gram-
negative organisms.
Cephalosporins, ceftazidime 2 g iv Q6H Usually well tolerated. No known May be used with $$$$$
third generation Fortaz, generics Gastrointestinal, common drug caution in patients with
hematologic reactions, interactions. non-immediate
rarely seizures. penicillin allergy.
Page 640
Therapeutic Choice
Drug Costa
and broad-spectrum
activity vs gram-
negative organisms.
Good antipseudomonal
activity, poor gram-
positive coverage.
Cephalosporins, ceftriaxone 1–2 g iv Q24H Usually well tolerated. Do not May be used with $-$$
third generation Ceftriaxone for Meningitis: 2 g Gastrointestinal, reconstitute or caution in patients with
iv Q12H hematologic reactions, mix with calcium non-immediate
Injection USP,
rarely seizures. -containing penicillin allergy.
Rocephin,
solutions. Extended spectrum beta
other generics
Do not -lactam antibiotics have
administer become the mainstay of
simultaneously treatment because of
with calcium- lack of nephrotoxicity
containing iv and broad-spectrum
solutions via a Y activity vs gram-
-site. negative organisms.
Administration
may be done
sequentially
provided the
infusion lines are
thoroughly
flushed between
infusions.
Cephalosporins, cefepime 2 g iv Q12H Usually well tolerated. No known May be used with $$
fourth Maxipime, generics If neutropenic: Gastrointestinal, common drug caution in patients with
generation 2 g iv Q8H hematologic reactions, interactions. non-immediate
rarely seizures. Associated penicillin allergy.
with hemolytic anemia. Extended spectrum beta
and broad-spectrum
activity vs gram-
negative organisms.
Excellent activity
against many resistant
gram-negative
pathogens including
Pseudomonas. Good
activity against most
gram-positive
organisms.
Aminoglycosides amikacin 7.5 mg/kg iv Nephrotoxicity, ototoxicity, Penicillins may ↓ Avoid as a first-line $$-
generics Q12H or neuromuscular blockade. serum levels. agent in septic shock $$$
15–20 mg/kg iv because of
once daily nephrotoxicity and
ototoxicity; monitor
serum drug levels to
guide dosing and avoid
toxicity.
Desired peak
40 μg/mL; desired
trough <10 μg/mL.
Aminoglycosides gentamicin 1.5 mg/kg iv Nephrotoxicity, ototoxicity, Penicillins may ↓ Avoid as a first-line $
generics Q8H or neuromuscular blockade. serum levels. agent in septic shock
toxicity.
Page 641
Therapeutic Choice
Drug Costa
Desired peak
10 μg/mL; desired
trough <2 μg/mL.
Aminoglycosides tobramycin 1.5 mg/kg iv Nephrotoxicity, ototoxicity, Penicillins may ↓ Avoid as a first-line $
generics Q8H or neuromuscular blockade. serum levels. agent in septic shock
toxicity.
Desired peak
10 μg/mL; desired
trough <2 μg/mL.
Fluoroquinolones ciprofloxacin 400 mg iv Hypersensitivity reactions, Avoid using in Oral formulations $-$$
Q8–12H lowers seizure threshold, conjunction with available for step-down
Cipro, generics
prolongs QT interval. agents or therapy; most
conditions that appropriate
prolong QT fluoroquinolone for
interval. pseudomonal
As an inhibitor of infections; emerging
CYP1A2, resistance worldwide.
ciprofloxacin can
increase serum
concentrations of
CYP1A2
substrates (e.g.,
theophylline).
Fluoroquinolones levofloxacin 500–750 mg iv Hypersensitivity reactions, Avoid using in Oral formulations $$

Levaquin, generics Q24H lowers seizure threshold, conjunction with available for step-down
prolongs QT interval. agents or therapy; effective
Hypo- or hyperglycemia. conditions that against atypical
prolong QT pathogens of
Cases of severe liver injury interval. community-acquired
including liver failure have Not metabolized pneumonia and many
been reported. by CYP enzymes. gram-positive cocci.
Fluoroquinolones moxifloxacin 400 mg iv Hypersensitivity reactions, Avoid using in Oral formulations $$

Avelox Q24H lowers seizure threshold, conjunction with available for step-down
prolongs QT interval. agents or therapy; improved
Cases of severe liver injury conditions that activity against
including liver failure have prolong QT anaerobic bacteria as
been reported. interval. well as gram-positive
Not metabolized cocci and enteric gram-
by CYP enzymes. negative bacilli;
effective against
atypical pathogens of
community-acquired
pneumonia.
Glycopeptides vancomycin 15–20 mg/kg iv Nephrotoxicity, ototoxicity, Enhanced Desired serum levels: $1900
Vancocin, generics Q8–12H phlebitis, “red man nephrotoxicity trough 15–20 µg/mL.
(monitor levels syndrome” (flushing/rash, when used with Useful if serious
and adjust dose hypotension) if infused too aminoglycosides. infection with
accordingly) rapidly (<1 h). enterococci or
coagulase-negative
staphylococci, or for
methicillin-resistant S.
aureus.
Lincosamides clindamycin 600–900 mg iv Rash, thrombophlebitis, GI May ↑ Used in necrotizing skin $$

Dalacin C Phosphate Q8H, can also effects, neuromuscular infections to reduce
Sterile Solution, be pseudomembranous blocking action endotoxin production
generics administered colitis, blood dyscrasias, ↑ of other agents. and for synergy with
Q6H liver function tests. Antagonism with beta-lactams.
erythromycin.
Page 642
Therapeutic Choice
Drug Costa
Nitroimidazoles metronidazole 500 mg iv Q8– Not common: ↑ lithium levels. Excellent anaerobic $
generics 12H thrombophlebitis, blood coverage; caution if
dyscrasias, neurological severe hepatic
disturbances. dysfunction.
Macrolides azithromycin 500 mg iv Venous May increase Used for coverage of $

Zithromax, generics Q24H irritation/thrombophlebitis, serum atypical pathogens in
prolongation of QT concentrations of community-acquired
interval. cardiac pneumonia (not
glycosides. necessary if patient is
Enhanced QT taking a
prolongation fluoroquinolone).
effect of
amiodarone.
Glycylcyclines tigecycline 100 mg Nausea and vomiting Possible Broad spectrum; active $$$$
Tygacil initially, then relatively common, increased risk of against most gram-
50 mg iv Q12H pancreatitis, injection site pseudotumor positive, gram-negative
reactions, tooth cerebri in and anaerobic bacteria.
discolouration. patients taking No activity against
isotretinoin. Pseudomonas. Active
against VRE and MRSA.
Structurally similar to
tetracyclines. Avoid in
pregnant women.
Tigecycline has been
associated with an
increased risk of
mortality compared to
other antibiotics when
used for severe
infections, particularly
ventilator-associated
pneumonia. Other
antibiotics are preferred
when susceptibilities
permit their use.
Cyclic daptomycin Skin and soft Myalgias. Occasionally, No known Effective against gram- $$$$
Lipopeptides Cubicin tissue rhabdomyolysis. Rarely, significant drug positive organisms
infections: eosinophilic pneumonia. interactions. including MRSA and
4 mg/kg iv VRE. Should not be
daily used in pneumonia
Bacteremias: because of poor lung
6 mg/kg iv penetration.
daily
Oxazolidinones linezolid 600 mg iv/po Rarely lactic acidosis. May potentiate Effective against gram- $$$$$
Zyvoxam BID Peripheral and optic the pressor positive organisms;
neuropathy, effect of 100% oral
myelosuppression. adrenergic bioavailability but do
agents. Possible not use orally in septic
serotonin patients as
syndrome when bioavailability is
used with SSRIs unreliable; may have
or MAOIs. better outcomes than
vancomycin in MRSA
pneumonia.
Azole fluconazole 400 mg iv Gastrointestinal reactions, Additive effect $$

Antifungals Diflucan, Q24H hepatic injury, exfoliative with other QT-
skin disorders. prolonging
Fluconazole Injection,
agents. ↑ levels of
other generics sulfonylureas,
phenytoin. Rifampin
↓ azole levels.
Azole voriconazole Loading dose Gastrointestinal reactions, Additive effect Use in non-neutropenic $$$$$
Antifungals Vfend of 6 mg/kg iv visual disturbances, rash, with other QT- patients only. Avoid iv
Q12H × 24 h, hepatic injury. prolonging in renal impairment
then 3–4 agents. ↑ levels of because of nephrotoxic
mg/kg iv Q12H sulfonylureas, vehicle.
Oral phenytoin. Effective against
maintenance Rifampin ↓ azole Aspergillus.
dose: levels.
<40 kg: Oral formulation
100 mg BID; available for step-down
Page 643
Therapeutic Choice
a
Drug Cost
max 150 mg therapy and is safe in
BID renal impairment.
≥40 kg:
200 mg BID;
max 300 mg
BID
Echinocandin caspofungin 70 mg iv day 1, Fever, rash, nausea, ↑ LFTs with Active against most $$$$$
Antifungals Cancidas then 50 mg iv vomiting, phlebitis at cyclosporine. candidal species and
Q24H injection site. Dexamethasone, well tolerated.
efavirenz,
nevirapine,
phenytoin,
rifampin,
carbamazepine ↓
caspofungin levels.
Echinocandin micafungin 100 mg iv Fever, rash, nausea, ↑ cyclosporine, Active against most $$$$$
Antifungals Mycamine Q24H vomiting, phlebitis at nifedipine and candidal species and
injection site. sirolimus levels. well tolerated.
Probably not
clinically
significant.
Echinocandin anidulafungin 200 mg iv Fever, rash, nausea, No clinically Active against most $$$$$
Antifungals Eraxis day 1, then 100 vomiting, phlebitis at significant candidal species and
mg iv Q24H injection site. interactions. well tolerated.
Polyene amphotericin B 0.6–1 mg/kg iv Fever, electrolyte Increased Use limited by renal $$-
Antifungals Fungizone Q24H disturbances, nephrotoxicity failure or electrolyte $$$
nausea/vomiting, with other disturbances.
nephrotoxicity, anemia, nephrotoxic
hypotension, phlebitis. drugs.
Polyene amphotericin B lipid 3–5 mg/kg iv Less nephrotoxicity than Increased $4800
Antifungals preparation Q24H standard amphotericin B. nephrotoxicity
Abelcet, AmBisome with other
nephrotoxic
drugs.
a.
Dosage adjustment required in renal impairment; see Appendices: Dosage Adjustment in Renal Impairment.
Abbreviations: LFT=liver function test; MAOI=monoamine oxidase inhibitor; MRSA=methicillin-resistantS. aureus; SSRI=selective serotonin reuptake
inhibitor; VRE=vancomycin-resistant enterococci
Legend: $ < $300 $–$$ < $300–600 $$ $300–600 $$–$$$ $300–900 $$$ $600–900 $$$-$$$$ $600–1200 $$$$ $900–1200
$$$$$ > $1200
Suggested Readings
Dellinger RP, Levy MM, Carlet JM et al. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic
shock: 2008. Crit Care Med 2008;36(1):296-327.
Green RS, Djogovic D, Gray S et al. Canadian Association of Emergency Physicians Sepsis Guidelines: the optimal management of severe
sepsis in Canadian emergency departments. CJEM 2008;10(5):443-59.
Kumar A, Roberts D, Wood KE et al. Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of
survival in human septic shock. Crit Care Med 2006;34(6):1589-96.
Rivers E, Nguyen B, Havstad S et al. Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med 2001;345
(19):1368-77.
Russell JA. Management of sepsis. N Engl J Med 2006;355(16):1699-713.
References
Page 644
Therapeutic Choice
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4. [No authors listed]. American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference: definitions for sepsis
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5. Rivers E, Nguyen B, Havstad S et al. Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med
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6. [No authors listed]. Practice parameters for hemodynamic support of sepsis in adult patients in sepsis. Task Force of the American
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7. Dellinger RP, Levy MM, Carlet JM et al. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic
shock: 2008. Crit Care Med 2008;36(1):296-327.
8. Manthous CA, Hall JB, Olson D et al. Effect of cooling on oxygen consumption in febrile critically ill patients. Am J Respir Crit Care Med
1995;151(1):10-4.
9. Cerra FB, Benitez MR, Blackburn GL et al. Applied nutrition in ICU patients. A consensus statement of the American College of Chest
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10. Osman D, Ridel C, Ray P. Cardiac filling pressures are not appropriate to predict hemodynamic response to a volume challenge. Crit
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11. Hebert PC, Wells G, Blajchman MA et al. A multicenter, randomized, controlled clinical trial of transfusion requirements in critical care.
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12. Vincent JL. Hemodynamic support in septic shock. Intensive Care Med 2001;27(Suppl 1):S80-92.
13. van den Berghe G, Wouters P, Weekers F et al. Intensive insulin therapy in critically ill patients. N Engl J Med 2001;345(19):1359-67.
14. Brunkhorst FM, Engel C, Bloos F et al. Intensive insulin therapy and pentastarch resuscitation in severe sepsis. N Engl J Med 2008;358
(2):125-39.
15. De La Rosa Gdel C, Donado JH, Restrepo AH et al. Strict glycaemic control in patients hospitalised in a mixed medical and surgical
intensive care unit: a randomised clinical trial. Crit Care 2008;12(5):R120.
16. The NICE-SUGAR Study Investigators et al. Intensive versus conventional glucose control in critically ill patients. New Engl J Med
2009;360(13):1283-97.
17. Griesdale DE, de Souza RJ, van Dam, RM et al. Intensive insulin therapy and mortality among critically ill patients: a meta-analysis
including NICE-SUGAR study data. CMAJ 2009;180(8):821-7.
18. Jimenez MF, Marshall JC; International Sepsis Forum. Source control in the management of sepsis. Intensive Care Med 2001;27(Suppl
1):S49-62.
19. Rabindranath K, Adams J, Macleod AM et al. Intermittent versus continuous renal replacement therapy for acute renal failure in adults.
20. Boyd JH, Walley KR. Is there a role for sodium bicarbonate in treating lactic acidosis from shock? Curr Opin Crit Care 2008;14(4):379-
83.
21. Perez J, Dellinger RP; International Sepsis Forum. Other supportive therapies in sepsis. Intensive Care Med 2001;27(Suppl 1):S116-27.
22. Davidson BL, Geerts WH, Lensing AW. Low-dose heparin for severe sepsis. N Engl J Med 2002;347(13):1036-7.
23. Steinberg KP. Stress-related mucosal disease in the critically ill patient: risk factors and strategies to prevent stress-related bleeding in
the intensive care unit. Crit Care Med 2002;30(6 Suppl):S362-4
24. Kahn JM, Doctor JN, Rubenfeld GD. Stress ulcer prophylaxis in mechanically ventilated patients: integrating evidence and judgement
using a decision analysis. Intensive Care Med2006;32(8):1151-8.
25. Girard TD, Pandharipande PP, Ely EW. Delirium in the intensive care unit. Crit Care 2008;12(Suppl 3):S3.
26. Huskins WC. Interventions to prevent transmission of antimicrobial-resistant bacteria in the intensive care unit. Curr Opin Crit Care
2007;13(5):572-7.
27. Esteban A, Alía I, Tobin MJ et al. Effect of spontaneous breathing trial duration on outcome of attempts to discontinue mechanical
ventilation. Spanish Lung Failure Collaborative Group. Am J Respir Crit Care Med 1999;159(2):512-8.
28. Kumar A, Roberts D, Wood KE et al. Duration of hypotension before initiation of effective antimicrobial therapy is the critical
determinant of survival in human septic shock. Crit Care Med 2006;34(6):1589-96.
29. Gould CV, McDonald LC. Bench-to-bench bedside review: Clostridium difficile colitis. Crit Care 2008;12(1):203.
30. Pier GB, Ramphal R. Pseudomonas aeruginosa. In: Mandell GL et al. Mandell, Douglas, and Bennett's principles and practice of infectious
diseases. 6th ed. Philadelphia (PA): Elsevier Churchill Livingstone; 2005. p. 2600-1.
31. Golan Y, Wolf MP, Pauker SG et al. Empirical anti-Candida therapy among selected patients in the intensive care unit: a cost-
effectiveness analysis. Ann Intern Med 2005;143(12):857-69.
32. Sarosi GA. Fungal infections and their treatment in the intensive care unit. Curr Opin Crit Care 2006;12(5):464-9.
33. Pappas PG, Kauffman CA, Andes D et al. Clinical practice guidelines for the management of candidiasis: 2009 update by the Infectious
Diseases Society of America. Clin Infect Dis 2009;48(5):503-35.
34. Shan YS, Sy ED, Wang ST et al. Early presumptive therapy with fluconazole for occult Candida infection after gastrointestinal surgery.
World J Surg 2006;30(1):119-26.
35. Piarroux R, Grenouillet F, Balvay P et al. Assessment of preemptive treatment to prevent severe candidiasis in critically ill surgical
patients. Crit Care Med 2004;32(12):2443-9.
36. Schuster MG, Edwards JE, Sobel JD et al. Empirical fluconazole versus placebo for intensive care unit patients: a randomized trial. Ann
Intern Med 2008;149(2):83-90.
37. Ostrosky-Zeichner L, Pappas PG. Invasive candidiasis in the intensive care unit. Crit Care Med 2006:34(3):857-63.
38. Mandell LA, Wunderink RG, Anzueto A et al. Infectious Diseases Society of America/American Thoracic Society consensus guidelines on
the management of community-acquired pneumonia in adults. Clin Infect Dis 2007;44(Suppl 2):S27-72.
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39. Solomkin JS, Mazuski JE, Baron EJ et al. Guidelines for the selection of anti-infective agents for complicated intra-abdominal infections.
Clin Infect Dis 2003;37(8):997-1005.
40. Wagenlehner FM, Weidner W, Naber KG. Pharmacokinetic characteristics of antimicrobials and optimal treatment of urosepsis. Clin
Pharmacokinet 2007;46(4):291-305.
41. Tunkel AR, Hartman BJ, Kaplan SL et al. Practice guidelines for the management of bacterial meningitis. Clin Infect Dis 2004;39(9):1267
-84.
42. Stevens DL, Bisno AL, Chambers HF et al. Practice guidelines for the diagnosis and management of skin and soft-tissue infections. Clin
Infect Dis 2005;41(10):1373-406.
43. Raad I, Hanna H, Maki D. Intravascular catheter-related infections: advances in diagnosis, prevention, and management. Lancet Infect
Dis 2007;7(10):645-57.
44. Martin C, Papazian L, Perrin G et al. Norepinephrine or dopamine for the treatment of hyperdynamic septic shock? Chest 1993;103
(6):1826-31.
45. Marik PE, Mohedin M. The contrasting effects of dopamine and norepinephrine on systemic and splanchnic oxygen utilization in
hyperdynamic sepsis. JAMA 1994;272(17):1354-7.
46. Bellomo R, Chapman M, Finfer S et al. Low-dose dopamine in patients with early renal dysfunction: a placebo-controlled randomised
trial. Australian and New Zealand Intensive Care Society (ANZICS) Clinical Trials Group. Lancet 2000;356(9248):2139-43.
47. Annane D, Vignon P, Renault A et al. Norepinephrine plus dobutamine versus epinephrine alone for management of septic shock: a
randomised trial. Lancet 2007;370(9588):676-84.
48. Russell JA, Walley KR, Singer J et al. Vasopressin versus norepinephrine infusion in patients with septic shock. N Engl J Med 2008;358
(9):877-87.
49. Duranteau J, Sitbon P, Teboul JL et al. Effects of epinephrine, norepinephrine, or the combination of norepinephrine and dobutamine on
gastric mucosa in septic shock. Crit Care Med 1999;27(5):893-900.
50. Siegel JP. Assessing the use of activated protein C in the treatment of severe sepsis. N Engl J Med 2002;347(13):1030-4.
51. Bernard GR, Vincent JL, Laterre PF et al. Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med
2001;344(10):699-709.
52. Opal SM, Garber GE, LaRosa SP et al. Systemic host responses in severe sepsis analyzed by causative microorganism and treatment
effects of drotrecogin alfa (activated). Clin Infect Dis 2003;37(1):50-8.
53. Annane D, Sebille V, Charpentier C et al. Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in
patients with septic shock. JAMA 2002;288(7):862-71.
54. Sprung CL, Annane D, Keh D et al. Hydrocortisone therapy for patients with septic shock. N Engl J Med 2008;358(2):111-24.
55. Marik PE, Pastores SM, Annane D et al. Recommendations for the diagnosis and management of corticosteroids insufficiency in critically
ill adult patients: consensus statements from an international task force by the American College of Critical Care Medicine. Crit Care Med
2008;36(6):1937-49.
56. Schwartz SA. Intravenous immunoglobulin treatment of immunodeficiency disorders. Pediatr Clin North Am 2000;47(6):1355-69.
57. Spector SA, Gelber RD, McGrath N et al. A controlled trial of intravenous immune globulin for the prevention of serious bacterial
infections in children receiving zidovudine for advanced human immunodeficiency virus infection. Pediatric AIDS Clinical Trials Group. N
Engl J Med 1994;331(18):1181-7.
58. Kaul R, McGeer A, Norrby-Teglund A et al. Intravenous immunoglobulin therapy for streptococcal toxic shock syndrome—a comparative
observational study. The Canadian Streptococcal Study Group. Clin Infect Dis 1999;28(4):800-7.
59. Darenberg J, Ihendyane N, Sjolin J et al. Intravenous immunoglobulin G therapy in streptococcal toxic shock syndrome: a European
randomized, double-blind, placebo-controlled trial. Clin Infect Dis 2003;37(3):333-40.
60. Darenberg J, Soderquist B, Normark BH et al. Differences in potency of intravenous polyspecific immunoglobulin G against streptococcal
and staphylococcal superantigens: implications for therapy of toxic shock syndrome. Clin Infect Dis 2004;38(6):836-42.
61. Turgeon AF, Hutton B, Fergusson DA et al. Meta-analysis: intravenous immunoglobulin in critically ill adult patients with sepsis. Ann
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62. Pildal J, Gotzsche PC. Polyclonal immunoglobulin for treatment of bacterial sepsis: a systematic review. Clin Infect Dis 2004;39(1):38-
46.
63. de Gans J, van de Beek D; European Dexamethasone in Adulthood Bacterial Meningitis Study Investigators. Dexamethasone in adults
with bacterial meningitis. N Engl J Med 2002;347(20):1549-56.
64. Becker KL, Snider R, Nylen ES. Procalcitonin assay in systemic inflammation infection and sepsis: clinical utility and limitataions. Crit
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65. Patel GW, Duquaine SM, McKinnon PS. Clinical outcomes and cost minimization with an alternative dosing regimen for meropenem in a
community hospital. Pharmacotherapy 2007;27(12):1637-43.
Page 646
e-Therapeutics+ : Therapeutics : Infectious Diseases: Sexually Transmitted Infections Page 1 of 31
Therapeutic Choice
Print Close
Infectious Diseases: Sexually Transmitted Infections

Natasha Press, MD, FRCPC
Sexually transmitted infections (STIs) can be characterized according to whether the major initial manifestations are
vaginal discharge, urethritis or cervicitis, or genital lesions. Anogenital warts and pelvic inflammatory disease, an
infection of the upper genital tract, are discussed as well.
Goals of Therapy
Treat the infection

Abolish symptoms
Decrease spread to sexual partners
Decrease vertical transmission from mother to newborn
Reduce transmission of HIV
Decrease probability of complications, such as infertility, chronic pain, sepsis
, 2
Investigations1
History:
duration of symptoms, if any
risk factors, e.g., sexual contact with person with known STI, recent new partner, more than two partners
in past year, injection drug use, commercial sex workers, non-barrier contraception
recent childbirth, intrauterine contraceptive device insertion
past history of STIs, therapy and response
Physical:
search for systemic signs of STIs, e.g., syphilis, disseminated gonococcus
inspect mucocutaneous regions including pharynx and anus
inspect external genitalia for lesions, inflammation, discharge
consider a digital rectal exam and anoscopy if perianal warts are present or if patient has rectal symptoms
or has practised receptive anal intercourse
palpate for inguinal lymphadenopathy
in women: perform speculum examination to visualize cervix and vaginal walls and to evaluate endocervical
and vaginal discharges; bimanual pelvic exam to detect uterine or adnexal masses or tenderness
in men: search for signs of urethral discharge, palpate testicles/epididymides
Laboratory tests:
3
for women: cervical swabs for chlamydia test, i.e., nucleic acid amplification tests (NAATs) and gonorrhea
culture (NAATs will not give information on antibiotic susceptibility); vaginal swab for pH test, Gram stain
and trichomoniasis wet preparation slide; culture for trichomoniasis (more sensitive than wet mount
microscopy); ultrasound if pelvic inflammatory disease (PID) suspected; consider beta-hCG to rule out
ectopic pregnancy; rectal specimens for chlamydia and lymphogranuloma venereum (LGV), as indicated
for men: urethral swab for gonorrhea culture, first-void urine for chlamydia; scrotal ultrasound if
epididymo-orchitis suspected, consider testing for LGV (culture, NAAT, serology); rectal specimens for
chlamydia and LGV, as indicated
for external lesions: swabs for herpes (use viral media), bacteria, syphilis (send fluid from lesion for
darkfield test or direct immunofluorescence test) as indicated
throat and rectal swabs for gonorrhea if indicated
consider serology for syphilis, HIV (see Infectious Diseases: HIV Infection), hepatitis B and hepatitis C (see
Gastrointestinal Disorders: Viral Hepatitis) as indicated
Infections Characterized by Vaginal Discharge
Therapeutic Choices
The three infections most frequently associated with vaginal discharge are trichomoniasis (caused by Trichomonas
vaginalis), bacterial vaginosis (caused by a replacement of the normal vaginal flora by an overgrowth of anaerobic
Page 647
Therapeutic Choice
microorganisms, mycoplasmas and Gardnerella vaginalis) and vulvovaginal candidiasis (commonly caused by
Candida albicans) (Table 1). There is an element of recurrence in these conditions. Recurrent vulvovaginal
candidiasis (≥ 4 episodes/year) requires investigation and possibly referral. Address predisposing causes if present,
e.g., use of systemic antibiotics, poorly controlled diabetes or HIV (consider testing).
Nonsexually transmitted causes of vaginitis are numerous, e.g., atrophic vaginitis, trauma, malignancy, detergents,
contraceptive chemicals, allergy to latex condoms. Candidiasis and bacterial vaginosis are not usually considered
sexually transmitted (Table 2).
Therapeutic Choices (Figure 1 - Management of Vaginitis and Cervicitis)
Pharmacologic Choices (Table 3, Table 4,Table 5 )
Treatment of trichomoniasis is necessary for all nonpregnant women, including asymptomatic women.
Pregnant women at high risk of preterm birth and with asymptomatic bacterial vaginosis can be treated with oral
antibiotics; vaginal antibiotics are ineffective in preventing preterm birth.4 Oral or vaginal antibiotics may be used
for the treatment of symptomatic bacterial vaginosis in women who are at a low risk of preterm birth.4 Treatment of
asymptomatic bacterial vaginosis is also necessary in women undergoing gynecologic surgery, therapeutic abortion,
upper tract instrumentation or prior to IUD insertion.5
Uncomplicated vulvovaginal candidiasis (VVC) can be treated by a short course of topical antifungal formulations.
Individualize therapy considering factors such as patient preference, cost, convenience, compliance, portability and
history of response or side effects to prior treatments. Vaginal nystatin is less effective than topical azoles.
Consider prophylactic fluconazole at start of antibiotic treatment in women prone to recurrent VVC secondary to
antibiotic use. Teratogenicity has been shown in the first trimester with continuous daily fluconazole doses of
≥ 400 mg. Data is lacking for single-dose use. Fluconazole may be used in recurrent VVC if benefit outweighs
potential risk (see Appendix: Drug Use During Pregnancy).
Table 1: Differential Diagnosis of Vaginal Discharge1 , 2
Candidiasis Trichomoniasis Bacterial Vaginosis
Signs/symptoms:
Pruritus + + –
Odour – + + (fishy)
Discharge white, clumpy & curdy off-white or yellow, grey or milky, thin, copious
frothy
Inflammation + + –
Simple tests:
pH < 4.5 > 4.5 > 4.5
"Whiff" testa – +/- +
Microscopic findings:
Specific budding yeast, motile trichomonads b

clue cells, predominant Gram-negative curved
psuedohyphae bacilli and coccobacilli
PMNs ++ +++ –
Lactobacilli + – –
a.
Malodour often intensified after addition of 10% potassium hydroxide (KOH).
b.
Clue cells are vaginal epithelial cells covered with numerous coccobacilli.
Abbreviations: PMNs=polymorphonucleocytes
Infections Characterized by Urethritis and Cervicitis

Page 648
Therapeutic Choice
Therapeutic Choices
The two main causes of urethritis and cervicitis are gonorrhea (caused by Neisseria gonorrhoeae) and chlamydia
(caused by Chlamydia trachomatis serovars D to K). Patients with gonorrhea are often infected with chlamydia and
should receive presumptive treatment for both.1 , 2 Test and treat sexual partners (Table 2). Because individuals
may be asymptomatic, symptoms should not be a prerequisite for screening individuals at risk for STIs. HIV
screening is recommended.
In men, symptoms include purulent discharge and severe dysuria (“drip and burn”). Complications of urethritis
include epididymitis, seminal vesiculitis, prostatitis and disseminated infection (fever, skin and joint involvement).
If epididymo-orchitis is due to sexual transmission, empiric therapy for both gonorrhea and chlamydia are required,
but the antichlamydial regimen should be given for at least 10 days and until resolution occurs. Scrotal elevation,
bedrest and analgesics are advisable. Epididymo-orchitis may require referral to rule out other diagnoses such as
testicular torsion and abscess.
In women, symptoms include copious vaginal discharge, dysuria, intermenstrual uterine bleeding and menorrhagia.
Chlamydia may be asymptomatic; therefore, high-risk women should be screened (e.g., young, sexually active
women, women with multiple sex partners or new sex partners).2 Screen all pregnant women at first prenatal visit.
Complications of cervicitis include pelvic inflammatory disease, ectopic pregnancy and infertility.
Both men and women can acquire anorectal or pharyngeal gonococcal infection.
Therapeutic Choices (Figure 1 - Management of Vaginitis and Cervicitis, Figure 2 -

Management of Urethritis and Epididymo-orchitis)
A test of cure for chlamydia is recommended if noncompliant, if an alternative treatment has been used, in
prepubertal children and in pregnancy when erythromycin or amoxicillin is used.1 , 2 Current Canadian guidelines
1
recommend repeat screening of individuals with chlamydia infection at 6 months.
A test of cure is not required for gonorrhea; retesting 3–12 months after treatment is recommended. Gonococcal
1 , 2
infections of the pharynx are more difficult to treat. Consider fluoroquinolones only if antimicrobial
susceptibility is demonstrated. If susceptibility testing is not available, a test of cure is essential if fluoroquinolones
are used.
Infections Characterized by Genital Ulcers
Therapeutic Choices
Six STIs are associated with genital ulcers. The two most common in North America are genital herpes (see
Infectious Diseases: Herpesvirus Infections) and syphilis. Syphilis is caused by Treponema pallidum, a bacterium
that penetrates broken skin or mucous membranes, usually through sexual contact.
Lymphogranuloma venereum (LGV) has recently surfaced in Canada and is caused by C. trachomatis
serovars L1, L2 and L3. These strains are more invasive; they preferentially affect the lymph tissue.1,2
LGV is transmitted through vaginal, anal or oral sexual contact. Complications include colorectal
fissures and secondary bacterial infections.1,2 Test and treat sexual partners (Table 2). Useful Info?
Individuals with genital ulcers are at an increased risk of acquiring and transmitting HIV.
Refer individuals co-infected with HIV and syphilis and those with suspected or proven tertiary syphilis.
Page 649
Therapeutic Choice
Therapeutic Choices (Figure 3 - Management of Genital Ulcers (Herpes, Lymphogranuloma
Venereum, Syphilis))
After treatment for syphilis (Table 8), patients should be followed serologically for treatment failure. For LGV (Table
9), test of cure is performed 3–4 weeks after completion of treatment.
Azithromycin for early syphilis is not standard-of-care and is not recommended at this time.6
Management of Specific Infections
Therapeutic Choices
Therapeutic Choices
Anogenital warts are caused by the human papillomavirus (HPV). No definitive evidence suggests any of the
available treatments to be superior to the others, and no single treatment is ideal for all patients or all warts. Warts
may resolve with or without treatment; however, there is a frustratingly high recurrence rate (approximately 33%)
of genital warts 1 year after apparent cure.
Patients with warts on their cervix or anal mucosa should be referred.
Therapeutic Choices (Figure 4 - Management of Anogenital Warts)
Imiquimod, podophyllum resin and podofilox (Table 10) are used to treat genital warts but should not be used
during pregnancy.
For prevention of genital warts and cervical cancer, a quadrivalent HPV vaccine has been approved for females
aged 9–26 years (Table 11). The vaccine does not prevent all strains of HPV, thus annual cytology screening (Pap
7
smear) is recommended until 2 consecutive tests are negative; then, screen every 3 years onwards to age 69.
Pelvic inflammatory disease (PID) includes endometritis, salpingitis and peritonitis. Patients with PID should be
hospitalized if they are pregnant, do not respond to or do not tolerate outpatient antibiotics, are noncompliant, have
1 , 2
a tubo-ovarian abscess or are very ill, e.g., vomiting, high fever. Test and treat sexual partners (Table 2).
Therapeutic Choices (Figure 5 - Management of Pelvic Inflammatory Disease)
Empiric antimicrobial therapy for PID should include coverage of the likely pathogens: N. gonorrhoeae, C.
trachomatis, anaerobes, gram-negative facultative bacteria and streptococci.
Therapeutic Tips
Treat sexual partner(s) (Table 2).

8 , 9 ,
Discuss consistent and correct use of latex or polyurethrane condoms for optimal risk reduction of STIs.
10 , 11 , 12
Recommend Hepatitis B immunization, if not previously immunized.

13
Discuss and counsel on HIV and STI risk of acquisition and transmission.
Page 650
Therapeutic Choice
1 , 2
Table 2: Treatment of Sexual Contacts
Disease Management of Partner
Anogenital warts (human Likelihood of transmission and duration of infectivity unknown, but condoms
papillomavirus) associated with decreased abnormal Pap smears in women
Bacterial vaginosis No treatment
Chlamydia and gonorrhea Refer all recent (< 60 days) partners for testing and empiric treatment. No sex for
patient or partner until 1 wk after initiation of treatment
Genital herpes Use condoms, be aware of asymptomatic shedding
Lymphogranuloma Refer all recent (< 60 days) partners for testing and empiric treatment
venereum
Pelvic inflammatory Refer all recent male partners (< 60 days) for examination and treatment. Treat
disease empirically for C. trachomatis and/or N. gonorrhoeae. No sex for patient or partner
until 1 wk after initiation of treatment
Syphilis, late latent Refer for testing all long-term partners and any of their children who were possibly
exposed during pregnancy
Syphilis, primary, Refer partners for empiric treatment even if seronegative. Trace-back period for
secondary and early latent primary, secondary and early latent syphilis is 3 mo, 6 mo and 1 y, respectively;
refer all partners for testing and empiric treatment
Trichomoniasis Treat partner. No sex until patient and partner finished treatment and are
asymptomatic
Vulvovaginal candidiasis No treatment. Consider treatment of sex partner(s) in women with recurrent
infections
Figure 1- Management of Vaginitis and Cervicitis
Page 651
Therapeutic Choice
a.
Chlamydial nucleic acid amplification testing, e.g., PCR, of a first voided urine specimen is an option if vaginal examination is
not possible.
b.
Malodour often intensified after addition of 10% potassium hydroxide (KOH).
c.
One sample mixed in a few drops of normal saline; second sample mixed with 10% KOH.
d.
Recurrent bacterial vaginosis may develop in ~15–30% of patients in the first 1–3 months of treatment.
Abbreviations: po = orally; pv = intravaginally
Figure 2- Management of Urethritis and Epididymo-orchitis
Page 652
Therapeutic Choice
a.
Diagnosis of gonorrhea by culture, rather than nucleic acid amplification testing is preferred, in order to allow for antimicrobial
susceptibility testing.
b.
Nucleic acid amplification testing, e.g., PCR, of a first voided urine specimen is accurate for chlamydia detection.
c.
Re-exposure; nonadherence; antimicrobial resistance; other etiologies such as urinary tract infections, prostatitis; other
microorganisms such as T. vaginalis, U. urealyticum, M. genitalium.
Abbreviations: PMNs = polymorphonucleocytes; PRN = as needed
Page 653
Therapeutic Choice
Figure 3- Management of Genital Ulcers (Herpes, Lymphogranuloma Venereum, Syphilis)
Page 654
Therapeutic Choice
Figure 4- Management of Anogenital Warts
Figure 5- Management of Pelvic Inflammatory Disease
Page 655
Therapeutic Choice
a.
If the patient has an IUCD in place, it should not be removed until after at least two doses of antimicrobial therapy have been
given.
Abbreviations: CBC = complete blood count; ESR = erythrocyte sedimentation rate; hCG = human chorionic gonadotropin;
IUCD = intrauterine contraceptive device
1 , 2
Table 3: Antibiotics for the Treatment of Trichomoniasis
a
Drug Cost
Nitroimidazoles metronidazole, Gastrointestinal Disulfiram-like Intravaginal $

oral 2 g po upset, urethral reaction with metronidazole not
× single burning, alcohol: avoid effective in
Flagyl, dose discolouration of alcohol intake trichomoniasis.
generics or urine (dark or during and for 24 h Test and treat
reddish brown). after treatment. partners.
500 mg
po BID Can be used in
×7 pregnancy—benefit
days outweighs possible
risks.
Nursing women:
withhold breast-
feeding during
treatment and for
12–24 h after last
dose.
Page 656
Therapeutic Choice
a
Drug Cost
a.
Cost for specified duration of treatment; includes drug cost only.
Legend: $ < $10
Table 4: Antibiotics for the Treatment of Bacterial Vaginosis1 , 2
Costa
Lincosamides clindamycin, Gastrointestinal Alternative treatment to $$

oral 300 mg po BID × upset, C. difficile metronidazole.
Dalacin C, 7 days colitis, diarrhea. Can be used in pregnant
Dalacin C and nursing women; retest
1 mo after completion to
Flavored
ensure effective therapy.
Granules,
generics Treatment necessary in the
following asymptomatic
cases: high-risk pregnancy,
i.e., history of preterm
delivery; prior to insertion
of intrauterine device; prior
to gynecologic surgery,
therapeutic abortion or
upper tract
instrumentation.
Coadministration of kaolin
↓ clindamycin absorption.
Lincosamides clindamycin, 2%: one Vulvovaginitis. Not recommended in high- $$$

vaginal cream applicatorful (5 g) risk pregnancy as it does
Dalacin Vaginal once daily 4
not prevent preterm birth.
Cream intravaginally QHS × Delay treatment until
7 days completion of menstrual
period.
Contains mineral oil—may

weaken latex condoms and
diaphragms.
Nitroimidazoles metronidazole, Preferred dose: 500 Gastrointestinal Preferred treatment. $

oral mg po BID × 7 days upset, urethral Can be used in pregnancy;
Alternate dose: 2 g burning, dark or nursing women: withhold
Flagyl,
po × single dose reddish brown breast-feeding during
generics discolouration of treatment and for 12–24 h
Recurrent bacterial urine, metallic after last dose; retest 1 mo
vaginosis: 500 mg taste. after completion to ensure
po BID × 14 days effective therapy.
Treatment necessary in the

following asymptomatic
cases: high-risk pregnancy
Page 657
Therapeutic Choice
Costa
(i.e., history of preterm
delivery); prior to insertion
of intrauterine device; prior
to gynecologic surgery,
therapeutic abortion or
upper tract
instrumentation.
Single dose metronidazole

is associated with higher
failure rate.
Recurrent bacterial
vaginosis: ≥ 3 episodes in
previous y.
Disulfiram-like reaction
with alcohol—avoid alcohol
intake during and for 24 h
after treatment with oral
metronidazole.
Nitroimidazoles metronidazole, Preferred dose: Vaginal discharge, Not recommended in high- $$

vaginal gel 0.75% gel: one yeast infection, risk pregnancy as it does
applicatorful (5 g) vulva/ vaginal 4
NidaGel, not prevent preterm birth.
once daily irritative symptoms,
generics
intravaginally × 7 pain and
days discomfort.
Recurrent BV:
0.75% gel: one
applicatorful (5 g)
once daily ×
10 days followed by
twice a wk × 4–6 mo
a.
Cost of preferred dose; includes drug cost only.
b.
Preferred treatment.
Legend: $ < $10 $$ $10–20 $$$ $20–30
1 , 2
Table 5: Antifungals for the Treatment of Symptomatic Vulvovaginal Candidiasis
a
Cost
Polyenes nystatin Vaginal cream Local hypersensitivity. Less effective than $

ratio-Nystatin, 100 000 units/g: 1 g pv × azoles.
other generics 14 days Follow-up required if
symptoms persist
despite treatment or
recur within 2 mo of
onset.
Page 658
Therapeutic Choice
Costa
Azoles, fluconazole 150 mg po × single dose Headache, nausea, Single dose may $
oral Diflucan-150, Recurrent vulvovaginal abdominal pain, elevate prothrombin
generics candidiasis: 150 mg po daily diarrhea, dyspepsia, time in women with
× 3 days then once weekly dizziness. chronic warfarin
(for a minimum of 6 therapy.
months). Follow-up required if
symptoms persist
If > 4 episodes/y, consider despite treatment or
referral. recur within 2 mo of
onset.
Azoles, clotrimazole 200 mg/vaginal tablet: 1 Local hypersensitivity. Also comes in $$

b Canesten tablet intravaginally × 3 combination with
topical
Vaginal, days external cream;
generics 1% vaginal cream: 1 available over the
applicatorful pv daily × 6 counter.
days Treat for 7–14 days in
pregnancy.
Follow-up required if
symptoms persist
onset.
Azoles, miconazole 2% vaginal cream: 1 Local hypersensitivity. Also comes in $$

b Monistat, applicatorful pv daily combination with
topical
generics × 7 days external cream;
4% vaginal cream: 1 available over the
applicatorful pv daily counter.
× 3 days Ovules contain
hydrogenated vegetable
100 mg/ovule: 1 ovule pv oil, mineral oil; ↓
× 7 days efficacy of latex condoms
or diaphragms.
400 mg/ovule: 1 ovule pv
× 3 days Treat for 7–14 days in
pregnancy.
1200 mg/ovule: 1 ovule pv
× single dose Follow-up required if
symptoms persist
onset.
Azoles, butoconazole 2% cream: 5 g pv × single Local hypersensitivity. Cream contains mineral $$

b Gynazole-1 dose oil; ↓ efficacy (weakens)
topical
of latex condoms or
diaphragms.
Though a 1-day
treatment, it takes a
few days for symptoms
to resolve.
symptoms persist
onset.
Page 659
Therapeutic Choice
Costa
Azoles, terconazole 0.4% vaginal cream: 1 Local hypersensitivity. Ovules contain $$$
b Terazol, applicatorful pv HS × 7 days hydrogenated vegetable
topical
generics 0.8% vaginal cream: 1 oil; ↓ efficacy of latex
applicatorful pv HS × 3 days condoms or diaphragms.
80 mg/ovule: 1 ovule pv symptoms persist
× 3 days despite treatment or
onset.
a.
Cost of treatment; includes drug cost only.
b.
Preferred treatment.
Legend: $ < $10 $$ $10–20 $$$ $20–30
Table 6: Antibiotics for the Treatment of Uncomplicated Chlamydia Infection
Adverse Drug Costa

Macrolides azithromycin Adults and Gastrointestinal May ↑ digoxin levels. Preferred $

Zithromax, children ≥ 45 upset. treatment; may
generics kg: 1 g po × especially benefit
single dose situations in
which poor
compliance is
expected.
Test and treat
partners.
Initiate empiric
gonorrhea
therapy.
Compared to
doxycycline,
azithromycin is
more expensive;
similar high cure
rates.
Can be used in
pregnant and
nursing women;
test of cure
indicated.
Repeat dose if
vomiting
< 1 h post-
administration.
Macrolides erythromycin Adults: Gastrointestinal May ↑ levels of Alternative to $

erythromycin upset. carbamazepine, doxycycline and
Eryc, base 500 mg digoxin, HMG CoA azithromycin.
po QID reductase Test and treat
generics
× 7 days; max inhibitors, e.g., partners.
Page 660
Therapeutic Choice
a
Adverse Drug Cost
2 g/day. If simvastatin,
tolerance is a protease inhibitors, Initiate empiric
concern: sildenafil, gonorrhea
erythromycin theophylline, therapy.
base 250 mg warfarin.
po QID × 14 Avoid use with Can be used in
days pimozide, pregnant and
Chlamydia cisapride, nursing women.
trachomatis in disopyramide. Erythromycin
infants, estolate is not
ophthalmia used during
neonatorum: pregnancy due to
erythromycin reports of
base 12.5 cholestatic
mg/kg QID × hepatitis. Test of
14 days, may cure indicated.
need second
course of Conjunctivitis:
treatment, use systemic
follow-up therapy since
topical treatment
not adequate.
Reports of
infantile
hypertrophic
pyloric stenosis
with
erythromycin use
in infants < 6
wk; monitor
signs and
symptoms.
Fluoroquinolones levofloxacin Gastrointestinal ↓ levels with Alternative to $$

500 mg po upset, headache. concurrent antacids, doxycycline and
Levaquin, daily × 7 days iron or didanosine azithromycin.
(buffered Use only if
generics
formulations). culture and
Monitor blood susceptibility
sugar in diabetics tests show
on oral susceptibility; if
antihyperglycemic susceptibility
agents when used tests are not
concomitantly. available, a test
of cure is
↑ risk of tendon essential.
rupture with
concomitant Test and treat
corticosteroid use. partners.
Avoid use with QTc Initiate empiric

prolongating gonorrhea
agents, e.g., Class therapy.
1A, III
antiarrhythmics— Contraindicated
may result in in pregnant and
arrhythmias. nursing women.
Safety in
children < 18 y
not established.
Page 661
Therapeutic Choice
a
Adverse Drug Cost
Fluoroquinolones ofloxacin Gastrointestinal ↓ levels with Alternative to $$

generics 300 mg po upset, headache. concurrent antacids, doxycycline and
BID × 7 days iron or didanosine azithromycin.
(buffered Use only if
formulations). culture and
Monitor blood susceptibility
sugar in diabetics tests show
on oral susceptibility; if
antihyperglycemic susceptibility
agents when used tests are not
concomitantly. available, a test
of cure is
↑ risk of tendon essential.
rupture with
concomitant Test and treat
corticosteroid use. partners.
Avoid use with QTc Initiate empiric

prolongating gonorrhea
agents, e.g., Class therapy.
1A, III
antiarrhythmics— Contraindicated
may result in in pregnant and
arrhythmias. nursing women.
Safety in
children < 18 y
not established.
Similar high cure

rate as
doxycycline and
azithromycin.
Penicillins amoxicillin Rash, May ↓ efficacy of oral May be used in $

generics 500 mg TID × gastrointestinal contraceptives. pregnant and
7 days upset. Tetracyclines may ↓ nursing women;
amoxicillin test of cure
effectiveness. indicated.
Test and treat
partners.
Tetracyclines doxycycline Adults and Gastrointestinal ↓ levels with antacids, Preferred $

Vibramycin, children ≥ 8 upset, rash, iron, barbiturates, treatment.
generics y: 100 mg po candidal bismuth, Test and treat
BID × 7 days vaginitis, carbamazepine, partners.
photosensitivity. phenytoin.
↓ effectiveness of Initiate empiric
penicillins and oral gonorrhea
contraceptives. therapy.
Similar high cure

rates to
azithromycin.
Contraindicated
in pregnant and
nursing women.
Page 662
Therapeutic Choice
a
Adverse Drug Cost
a.
Legend: $ < $10 $$ $10–20
Table 7: Antibiotics for the Treatment of Uncomplicated Gonorrhea Infection: Endocervical, Rectal, Urethral 1 , 2
Costa
Aminoglycosides spectinomycin 2 g im × single Pain at injection Not effective for pharyngeal b

dose site. infection; test of cure is
Children < 9 y or recommended.
< 45 kg: Alternative treatment if
40 mg/kg im × fluoroquinolones not
single dose; recommended, cephalosporin
max 2 g allergy or immediate/
anaphylactic penicillin allergy.
Test and treat partners.
Initiate empiric chlamydia

therapy.
Can be used in pregnant and

nursing women.
Repeat screening
recommended.
Cephalosporins, cefixime 400 mg po × Gastrointestinal Preferred treatment. $

3rd generation Suprax single dose upset, Initiate empiric chlamydia
Children < 9 y: 8 hypersensitivity therapy.
mg/kg po × reactions.
single dose; max Can be used in pregnant and
400 mg, follow- nursing women.
up culture
required Repeat screening
recommended.
Cephalosporins, ceftriaxone Gastrointestinal Cefixime is the preferred $$

rd 125 mg im × upset, treatment as it costs less and
3 generation Ceftriaxone for
single dose hypersensitivity is taken orally.
Injection USP,
Children < 9 y: reactions.
Rocephin,
125 mg im × Ophthalmia neonatorum: use
generics
single dose; systemic therapy since topical
alternative to antibiotic is ineffective.
cefixime if follow-
up not ensured Can be used in pregnant and
nursing women.
Ophthalmia
neonatorum: 25– May be mixed with 1–2 mL of
50 mg/kg iv or im 1% lidocaine, as it is
irritating.
Page 663
Therapeutic Choice
a
Cost
× single dose;
max 125 mg Do not reconstitute or mix
with calcium-containing
solutions.
Contraindicated in neonates if
a calcium-containing iv
solution is or will be required
during care.
Do not administer
simultaneously with calcium-
containing iv solutions via a Y
-site. Administration may be
done sequentially provided
the infusion lines are
thoroughly flushed between
infusions.
Cephalosporins, cefotaxime Gastrointestinal Alternative treatment $$

rd 500 mg im × upset, Ophthalmia neonatorum: use
3 generation Claforan
single dose14 hypersensitivity systemic therapy since topical
Ophthalmia reactions. antibiotic is ineffective.
neonatorum:
100 mg/kg im ×
single dose
Fluoroquinolones ciprofloxacin Gastrointestinal Alternative treatment. $

Cipro, generics 500 mg po × upset, headache. Use only if culture and
single dose susceptibility tests show
susceptibility; if susceptibility
tests are not available, a test
of cure is essential.

therapy.
Safety in children < 18 y not

established.
Contraindicated in pregnant
and nursing women.
Repeat screening
recommended.
↓ levels with concurrent use of

antacids, iron or with
didanosine (buffered
formulations).
Monitor blood sugar levels in
diabetics on oral
antihyperglycemic agents
when used concomitantly.
↑ risk of tendon rupture with

concomitant corticosteroid
use.
Page 664
Therapeutic Choice
a
Cost
Fluoroquinolones ofloxacin Gastrointestinal Alternative treatment. $

generics 400 mg po × upset, headache. Use only if culture and
single dose susceptibility tests show
susceptibility; if susceptibility
tests are not available, a test
of cure is essential.

therapy.
Safety in children < 18 y not

established.
Contraindicated in pregnant
and nursing women.
Repeat screening
recommended.
↓ levels with concurrent use of

antacids, iron or with
didanosine (buffered
formulations).
Monitor blood sugar levels in
diabetics on oral
antihyperglycemic agents
when used concomitantly.
↑ risk of tendon rupture with

concomitant corticosteroid
use.
a.
b.
Available through Special Access Programme, Therapeutic Products Directorate.
Legend: $ < $5 $$ $5–10
Table 8: Antibiotics for the Treatment of Syphilis1 , 2
Costa
Penicillins penicillin G Primary, secondary and Jarisch-Herxheimer Preferred treatment. $$$

benzathine early latent syphilis: 2.4 reaction: not a drug Can be used in
million units im × single allergy; may occur at any pregnant and nursing
Bicillin L-A
dose stage but prevalent during women; consider
Late latent syphilis, latent o penicillin
2 syphilis; fever, chills,
syphilis of unknown rigors, sweating may desensitization in
duration, cardiovascular occur; resolves within 24 pregnant women who
syphilis, tertiary syphilis h. are allergic to
not involving CNS: 2.4 penicillin.
million units im weekly Test and treat
× 3 doses partners.
Page 665
Therapeutic Choice
Costa
Secondary syphilis + > Tetracyclines may ↓

20 weeks gestation: penicillin efficacy.
2.4 million units im
weekly × 2 doses
Penicillins penicillin G Neurosyphilis: 3–4 Jarisch-Herxheimer Can be used in $$$$

million units iv Q4–6H reaction: not a drug pregnant and nursing
generics (16–24 million units allergy; may occur at any women; consider
daily) × 10–14 days stage but prevalent during penicillin
o desensitization in
2 syphilis; fever, chills,
rigors, sweating may pregnant women who
occur; resolves within 24 are allergic to
h. penicillin.
Test and treat
partners.
Tetracyclines may ↓
penicillin efficacy.
Tetracyclines doxycycline Primary, secondary and Gastrointestinal upset, Alternative treatment. $$

Vibramycin, early latent syphilis: 100 rash, candidal vaginitis, Test and treat
generics mg po BID × 14 days photosensitivity. partners.
Late latent syphilis, latent
syphilis of unknown Contraindicated in
duration, cardiovascular pregnant and nursing
syphilis, tertiary syphilis women.
not involving CNS:
100 mg po BID × 28 ↓ levels with antacids, iron,
days barbiturates, bismuth,
carbamazepine,
phenytoin.
↓ efficacy of penicillins
and oral
contraceptives.
a.
Cost for duration of treatment; includes drug cost only.
Dosage adjustment required in renal impairment; see Appendices: Dosage Adjustment in Renal Impairment
.
Legend: $ < $15 $$ $15–35 $$$ $35–250 $$$$ $250–300
1 , 2
Table 9: Antibiotics for the Treatment of Lymphogranuloma Venereum
a
Drug Cost
Macrolides azithromycin 1 g once Gastrointestinal May ↑ levels of Alternative $$

Zithromax, weekly po × upset. digoxin. treatment to
generics 21 days; doxycycline.
clinical data Test and treat
lacking partners.
Partners: 1 g
po × single
Page 666
Therapeutic Choice
Drug Costa
dose; optimal Test of cure
duration of performed 3–4 wk
treatment after completion of
unknown therapy; follow-up
until chlamydial
tests are negative.
Can be used in
pregnant and
nursing women.
Repeat dose if
vomiting < 1 h post
-administration.
Macrolides erythromycin Erythromycin Gastrointestinal May ↑ levels of Alternative $$$

base: 500 mg upset. carbamazepine, treatment to
Eryc, po QID × 21 digoxin, doxycycline.
generics days simvastatin, Test and treat
atorvastatin, partners.
lovastatin,
protease Test of cure
inhibitors, performed 3–4 wk
sildenafil, after completion of
theophylline. therapy; follow-up
until chlamydial
Avoid use with tests are negative.
pimozide,
cisapride, Can be used in
disopyramide, pregnant and
clindamycin. nursing women.
Erythromycin
estolate is not used
during pregnancy
due to reports of
cholestatic
hepatitis.
Tetracyclines doxycycline 100 mg po BID Gastrointestinal ↓ levels with Preferred treatment. $$

Vibramycin, × 21 days upset, rash, antacids, iron, Test and treat
generics Partners: 100 candidal vaginitis, barbiturates, partners.
mg po BID × 7 photosensitivity. bismuth,
days carbamazepine, Test of cure
phenytoin. performed 3–4 wk
after completion of
↓ efficacy of therapy; follow-up
penicillins and oral until chlamydial
contraceptives. tests are negative.
Contraindicated in
pregnant and
nursing women.
a.
Page 667
Therapeutic Choice
Legend: $ < $20 $$ $20–30 $$$ $30–40
Table 10: Topical Drugs for the Treatment of External Anogenital Warts
Antimitotic podofilox Self-applied Local irritation, pain, Perform initial $/3.5

Agents Condyline Apply to visible inflammation, erosion, application to mL
genital warts BID burning, bleeding, pruritus, demonstrate proper bottle
with a cotton swab × dizziness, insomnia. application and to
3 days, followed by 4 identify warts that
days without therapy should be treated.
Treatment does not
May repeat cycle up eliminate HPV
to 4 times infection; may
recur.
Total wart areas
2 May require up to 3
should be ≤ 10 cm
mo for response.
Total daily volume is
0.5 mL Do not use in
pregnancy.
Antimitotic podophyllum Office-based Systemic: urticaria, fever, Protect normal skin $

Agents resin treatment paresthesia, polyneuritis, adjacent to lesion
Podofilm Apply, with a cotton paralytic ileus, blood with petrolatum.
applicator, over no dyscrasias, coma, death. Can reapply at
2 Local: severe necrosis, weekly intervals if
more than 2 cm and
allow to dry. scarring, paraphimosis, essential.
pseudoepitheliomatous
Remove first hyperplasia. Do not use in
application with soap pregnancy.
and water after 1 h.
If no adverse local
reaction, subsequent
applications may be
washed off after 6 h.
Antimitotic dichloroacetic Office-based Inflammation, erosion, pain, Can be used in $

Agents acid (DCA) treatment burning, ulceration. pregnant and
Apply DCA (80–90%) nursing women.
sparingly.
Sprinkle after with

baby powder or
baking soda to react
with any residual
acid.
Antimitotic trichloroacetic Office-based Inflammation, erosion, pain, Can be used in $

Agents acid (TCA) treatment burning, ulceration. pregnant and
Apply TCA (80–90%) nursing women.
sparingly.
Sprinkle after with

baby powder or
baking soda to react
Page 668
Therapeutic Choice

with any residual
acid.
Immune imiquimod Self-applied Local irritation, pain, mild to Physicians: Perform $$$/12
Response Aldara Apply 3 times per wk moderate erythema, initial application to packets
Modifiers at HS for up to 16 burning. demonstrate proper
wk; rub cream in application and to
until no longer visible identify warts that
should be treated.
Wash hands before Treatment does not
and after treatment eliminate HPV
application infection; may
recur.
Wash treatment area
with soap and water May require up to 3
6–10 h after mo for response.
application
Do not use in
pregnancy.
Legend: $ < $50 $$ $50–100 $$$ $100–150
Table 11: Vaccines for the Prevention of External Anogenital Warts
Vaccines human 9–26 y: Pain, swelling, erythema and Prevention of cervical $$$/injection
papilloma administered pruritus at injection site, dysplasia, cervical
quadrivalent 0, 2, 6 mo im headache, fatigue, syncope, carcinoma, vulvar
vaccine 15 dysplastic lesions and
lymphadenopathy,
Gardasil 16 external genital warts
anaphylaxis (rare).
caused by HPV 6, 11, 16
and 18.
Annual Pap smear is
required as the vaccine
does not protect against
all HPV strains.
Not recommended in
pregnancy.
Can be used in nursing

mothers.
Legend: $$$ $100–150
1 , 2
Table 12: Antibiotic Combination Therapy for the Outpatient Management of Pelvic Inflammatory Disease (PID)
a
Adverse Drug Cost
Fluoroquinolones levofloxacin Levofloxacin: Levofloxacin: Levofloxacin: ↓ Initiate broad- $$

± ± 500 mg po gastrointestinal levels with concurrent spectrum
Nitroimidazoles once daily × upset, headache. use of antacids, antibiotics
metronidazole 14 days ± Metronidazole: iron or with covering
Metronidazole: gastrointestinal didanosine N. gonorrhoeae,
500 mg po upset, urethral (buffered C. trachomatis,
BID × 14 days burning, dark or formulations). anaerobic and
reddish brown mycoplasma
Page 669
Therapeutic Choice
a
Adverse Drug Cost
discolouration of Monitor blood bacteria due to
urine. sugar levels in multifactorial
diabetics on oral etiology of PID.
antihyperglycemic Test and treat
agents when used partners.
concomitantly.
Re-evaluate
↑ risk of tendon patients 2–3
rupture with days after
concomitant initiation of
corticosteroid use. therapy; if no
improvement,
Caution with parenteral
concomitant use therapy
of agents with QTc required.
prolongation, e.g.,
amiodarone; Levofloxacin:
assess contraindicated
risks/benefits of in pregnant and
therapy. nursing women;
safety in
Metronidazole: children < 18 y
disulfiram-like not established.
reaction with Use only if
alcohol—avoid culture and
alcohol intake susceptibility
during and for 24 tests show
h after treatment. susceptibility; if
susceptibility
tests are not
available, a test
of cure is
essential.
Metronidazole:
provides
anaerobic
coverage.
Fluoroquinolones ofloxacin Ofloxacin: 400 Ofloxacin: Levofloxacin: ↓ Initiate broad- $

± ± mg po once gastrointestinal levels with concurrent spectrum
Nitroimidazoles daily × 14 upset, headache. use of antacids, antibiotics
metronidazole days ± Metronidazole: iron or with covering
Metronidazole: gastrointestinal didanosine N. gonorrhoeae,
500 mg po upset, urethral (buffered C. trachomatis,
BID × 14 days burning, dark or formulations). anaerobic and
reddish brown Monitor blood mycoplasma
discolouration of sugar levels in bacteria due to
urine. diabetics on oral multifactorial
antihyperglycemic etiology of PID.
agents when used Test and treat
concomitantly. partners.
↑ risk of tendon Re-evaluate

rupture with patients 2–3
concomitant days after
corticosteroid use. initiation of
therapy; if no
Caution with improvement,
concomitant use parenteral
of agents with QTc therapy
prolongation, e.g., required.
Page 670
Therapeutic Choice
Adverse Drug Costa

amiodarone;
assess Ofloxacin:
risks/benefits of contraindicated
therapy. in pregnant and
nursing women;
Metronidazole: safety in
disulfiram-like children < 18 y
reaction with not established.
alcohol—avoid Use only if
alcohol intake culture and
during and for 24 susceptibility
h after treatment. tests show
susceptibility; if
susceptibility
tests are not
available, a test
of cure is
essential.
Metronidazole:
provides
anaerobic
coverage.
Cephalosporins ceftriaxone Ceftriaxone: Ceftriaxone: Ceftriaxone: ↑ Initiate broad- $$$$$

+ Tetracyclines + 250 mg im × gastrointestinal anticoagulant effect spectrum
± single dose + upset, C. difficile of warfarin. antibiotics
Nitroimidazoles doxycycline Doxycycline: colitis. ↑ levels with covering
± 100 mg po Doxycycline: probenecid. N. gonorrhoeae,
BID × 14 days gastrointestinal C. trachomatis,
metronidazole ± upset, rash, Doxycycline: ↓ anaerobic and
candidal levels with mycoplasma
Metronidazole: vaginitis, antacids, iron, bacteria due to
500 mg po photosensitivity. barbiturates, multifactorial
BID × 14 days bismuth, etiology of PID.
Metronidazole: carbamazepine, Test and treat
gastrointestinal phenytoin. partners.
upset, urethral
burning, dark or ↓ efficacy of Re-evaluate
reddish brown penicillins and oral patients 2–3
discolouration of contraceptives. days after
urine. initiation of
Metronidazole: therapy; if no
disulfiram-like improvement,
reaction with parenteral
alcohol—avoid therapy
alcohol intake required.
during and for 24
h after treatment. Doxycycline:
contraindicated
in pregnant and
nursing women.
Metronidazole:
provides
anaerobic
coverage.
Page 671
Therapeutic Choice
Adverse Drug Costa

Cephalosporins cefotaxime Cefotaxime: 1 Cefotaxime: Cefotaxime: ↑ risk Initiate broad- $$$$$

+ Tetracyclines + g im × single pruritus, of additive spectrum
± dose + diarrhea, nephrotoxicity antibiotics
Nitroimidazoles doxycycline Doxycycline: nausea, with covering
± 100 mg po vomiting. aminoglycosides, N. gonorrhoeae,
BID × 14 days Doxycycline: furosemide. C. trachomatis,
metronidazole ± gastrointestinal ↑ levels with anaerobic and
upset, rash, probenecid. mycoplasma
Metronidazole: candidal bacteria due to
500 mg po vaginitis, Doxycycline: ↓ multifactorial
BID × 14 days photosensitivity. levels with antacids, etiology of PID.
iron, barbiturates, Test and treat
Metronidazole: bismuth, partners.
gastrointestinal carbamazepine,
upset, urethral phenytoin. Re-evaluate
burning, dark or patients 2–3
reddish brown ↓ efficacy of days after
discolouration of penicillins and oral initiation of
urine. contraceptives. therapy; if no
improvement,
Metronidazole: parenteral
disulfiram-like therapy
reaction with required.
alcohol—avoid
alcohol intake Doxycycline:
during and for 24 contraindicated
h after treatment. in pregnant and
nursing women.
Metronidazole:
provides
anaerobic
coverage.
Cephalosporins cefoxitin Cefoxitin: 2 g Cefoxitin: Cefoxitin: ↑ risk of

Initiate broad- $$
+ Uricosuric + + im × single diarrhea. additive spectrum
Tetracyclines ± dose + Doxycycline: nephrotoxicity antibiotics
Nitroimidazoles probenecid Probenecid: 1 gastrointestinal with covering
+ g po × single upset, rash, aminoglycosides, N. gonorrhoeae,
dose candidal furosemide. C. trachomatis,
doxycycline vaginitis, ↑ levels with anaerobic and
± photosensitivity. probenecid. mycoplasma
Doxycycline: bacteria due to
metronidazole 100 mg po Metronidazole: Doxycycline: ↓ multifactorial
BID × 14 days gastrointestinal levels with antacids, etiology of PID.
± upset, urethral iron, barbiturates, Test and treat
burning, dark or bismuth, partners.
Metronidazole: reddish brown carbamazepine,
500 mg po discolouration of phenytoin. Re-evaluate
BID × 14 days urine. patients 2–3
↓ efficacy of days after
penicillins and oral initiation of
contraceptives. therapy; if no
improvement,
Metronidazole: parenteral
disulfiram-like therapy
reaction with required.
alcohol—avoid
alcohol intake Doxycycline:
during and for 24 contraindicated
h after treatment. in pregnant and
nursing women.
Page 672
Therapeutic Choice
a
Adverse Drug Cost
Metronidazole:
provides
anaerobic
coverage.
Probenecid not
required if renal
impairment is
present.
a.
Cost for duration of treatment; includes drug cost only.
Legend: $ < $25 $$ $25–50 $$$ $50–75 $$$$ $75-100 $$$$$ $100–125
1 , 2
Table 13: Antibiotic Combination Therapy for Inpatient Management of Pelvic Inflammatory Disease (PID)
a
Adverse Drug Cost
Cephalosporins cefoxitin Cefoxitin: 2 g Cefoxitin: Cefoxitin: ↑ risk of Initiate broad- $$$$

+ Tetracyclines + iv Q6H + diarrhea. additive spectrum
Doxycycline: nephrotoxicity antibiotics
doxycycline Doxycycline: gastrointestinal with covering
100 mg po or upset, rash, aminoglycosides, N. gonorrhoeae,
iv Q12H. candidal furosemide. C. trachomatis,
Therapy is for vaginitis, ↑ levels with anaerobic and
14 days photosensitivity. probenecid. mycoplasma
bacteria due to
Doxycycline: ↓ multifactorial
levels with etiology of PID.
antacids, iron, Test and treat
barbiturates, partners.
bismuth,
carbamazepine, Re-evaluate
phenytoin. patients 2–3 days
after initiation of
↓ efficacy of therapy; if no
penicillins and oral improvement,
contraceptives. parenteral
therapy required.
Consider
discontinuation
of iv therapy and
po stepdown
after
demonstrated
clinical
improvement;
total duration of
treatment is 14
days.
Doxycycline:
contraindicated
in pregnant and
nursing women.
Page 673
Therapeutic Choice
a
Adverse Drug Cost
Lincosamides + clindamycin Clindamycin: Clindamycin: Clindamycin: Initiate broad- $$$$

Aminoglycosides + 900 mg iv C. difficile colitis, monitor kidney spectrum b
Q8H, step diarrhea. function with antibiotics
gentamicin down to 450 Gentamicin: concomitant covering
mg po QID. ototoxicity, aminoglycoside. N. gonorrhoeae,
Therapy is for nephrotoxicity May ↓ therapeutic C. trachomatis,
14 days + (monitor kidney effect of live anaerobic and
function at typhoid vaccine. mycoplasma
Gentamicin: baseline and Administer bacteria due to
loading dose 2 during typhoid vaccine multifactorial
mg/kg iv or treatment). > 24 h after last etiology of PID.
im, then 1.5 dose of Test and treat
mg/kg Q8H clindamycin. partners.
or Gentamicin: Re-evaluate
Imidazoles ↓ levels patients 2–3 days
5 mg/kg iv after initiation of
Q24H therapy; if no
improvement,
parenteral
therapy required.
Consider
discontinuation
of iv therapy and
po stepdown
after
demonstrated
clinical
improvement;
total duration of
treatment is 14
days.
Fluoroquinolones levofloxacin Levofloxacin: Metronidazole: Levofloxacin: Initiate broad- $$$

± ± 500 mg iv Gastrointestinal monitor blood spectrum
Nitroimidazoles once daily ± upset, urethral sugar levels in antibiotics
metronidazole Metronidazole: burning, dark or diabetics on oral covering
500 mg iv reddish brown antihyperglycemic N. gonorrhoeae,
Q8H discolouration of agents when used C. trachomatis,
urine. concomitantly. anaerobic and
↑ risk of tendon mycoplasma
rupture with bacteria due to
concomitant multifactorial
corticosteroid etiology of PID.
use. Test and treat
partners.
Caution with
concomitant use Re-evaluate
of agents with patients 2–3 days
QTc prolongation, after initiation of
e.g., amiodarone; therapy; if no
assess improvement,
risks/benefits of parenteral
therapy. therapy required.
Metronidazole: Consider
disulfiram-like discontinuation
reaction with of iv therapy and
alcohol—avoid po stepdown
Page 674
Therapeutic Choice
Adverse Drug Costa

alcohol intake after
during and for 24 demonstrated
h after treatment. clinical
improvement;
total duration of
treatment is 14
days.
Levofloxacin:
contraindicated
in pregnant and
nursing women;
safety in children
< 18 y not
established
Use only if
culture and
susceptibility
tests show
susceptibility; if
susceptibility
tests are not
available, a test
of cure is
essential.
Metronidazole:
provides
anaerobic
coverage.
Macrolide + azithromycin Azithromycin: Azithromycin: Azithromycin: May Alternative

Nitroimidazole + 250 mg po gastrointestinal increase level of treatment: For
daily × 1 week upset. digoxin. patients allergic
metronidazole or 1 g po Metronidazole: Metronidazole: to cephalosporins
weekly × 2 gastrointestinal disulfiram-like and
weeks + upset, urethral reaction with fluoroquinolones.
Metronidazole: burning, dark or alcohol—avoid Metronidazole:
500 mg po reddish brown alcohol intake provides
BID × 14 days discolouration of during and for 24 anaerobic
urine. h after treatment. coverage.
a.
Cost for 1-day supply; includes drug cost only.
b.
Cost based on dosage for 50 kg person.
Legend: $ < $25 $$ $25–50 $$$ $50–75 $$$$ $75–100
Suggested Readings
Centers for Disease Control and Prevention. Sexually transmitted diseases treatment guidelines, 2006. MMWR
Recomm Rep 2006;55(RR-11):1-94. Available from: http://www.cdc.gov/std/treatment/2006/rr5511.pdf. Accessed
October 7, 2008.
Page 675
Therapeutic Choice
Hollier LM, Workowski KW. Treatment of sexually transmitted infections in pregnancy. Clin Perinatol 2005;32(3):629
-56.
Public Health Agency of Canada. Canadian guidelines on sexually transmitted infections, 2006 edition. Ottawa (ON):
Public Health Agency of Canada; 2006. Available from: http://www.phac-aspc.gc.ca/std-
mts/sti_2006/pdf/sti2006_e.pdf. Accessed October 7, 2008.
Sena AC, Miller WC, Hobbs MM et al. Trichomonas vaginalis infection in male sexual partners: implications for
diagnosis, treatment, and prevention. Clin Infect Dis 2007;44(1):13-22.
References
1. Public Health Agency of Canada. Canadian guidelines on sexually transmitted infections, 2006 edition. Ottawa
(ON): Public Health Agency of Canada; 2006. Available from: http://www.phac-aspc.gc.ca/std-
mts/sti_2006/pdf/sti2006_e.pdf. Accessed October 7, 2008.
2. Centers for Disease Control and Prevention. Sexually transmitted diseases treatment guidelines, 2006. MMWR
Recomm Rep 2006;55(RR-11):1-94. Available from: http://www.cdc.gov/std/treatment/2006/rr5511.pdf
Accessed October 7, 2008.
3. Cook RL, Hutchison SL, Ostergaard L et al. Systematic review: noninvasive testing for Chlamydia trachomatis
and Neisseria gonorrhoeae. Ann Intern Med 2005;142(11):914-25.
4. Yudin MH, Money DM. Screening and management of bacterial vaginosis in pregnancy. J Obstet Gynaecol Can
2008;30(8):702-8. Available from: http://www.sogc.org/guidelines/documents/gui211CPG0808.pdf. Accessed
October 7, 2008.
5. Public Health Agency of Canada. Vaginal discharge (bacterial vaginosis, vulvovaginal candidiasis,
trichomoniasis). In: Canadian guidelines on sexually transmitted infections, 2006 edition. Ottawa (ON): Public
Health Agency of Canada; updated January 2008. Available from: http://www.phac-aspc.gc.ca/std-
mts/sti_2006/pdf/408_Vaginal_Discharge.pdf. Accessed October 7, 2008.
6. Riedner G, Rusizoka M, Todd J et al. Single-dose azithromycin versus penicillin G benzathine for the treatment
of early syphilis. N Engl J Med 2005;353(12):1236-44.
7. National Advisory Committee on Immunization. Statement on human papillomavirus vaccine. Can Commun Dis
Rep 2007;33(ACS-2):1-32. Available from: http://www.phac-aspc.gc.ca/publicat/ccdr-rmtc/07pdf/acs33-
02.pdf. Accessed October 7, 2008.
8. Warner L, Stone KM, Macaluso M et al. Condom use and risk of gonorrhea and chlamydia: a systematic review
of design and measurement factors assessed in epidemiologic studies. Sex Transm Dis 2006;33(1):36-51.
9. Winer RL, Hughes JP, Feng Q et al. Condom use and the risk of genital human papillomavirus infection in
young women. N Engl J Med 2006;354(25):2645-54.
10. Wald A, Langenberg AG, Krantz E et al. The relationship between condom use and herpes simplex virus
acquisition. Ann Intern Med 2005;143(10):707-13.
11. Hogewoning CJ, Bleeker MC, van den Brule AJ et al. Condom use promotes regression of cervical
intraepithelial neoplasia and clearance of human papillomavirus: a randomized clinical trial. Int J Cancer
2003;107(5):811-6.
12. Bleeker MC, Hogewoning CJ, Voorhorst FJ et al. Condom use promotes regression of human papillomavirus-
associated penile lesions in male sexual partners of women with cervical intraepithelial neoplasia. Int J Cancer
2003;107(5):804-10.
13. Kamb ML, Fishbein M, Douglas JM et al. Efficacy of risk-reduction counseling to prevent human
immunodeficiency virus and sexually transmitted diseases: a randomized controlled trial. Project RESPECT
Study Group. JAMA 1998;280(13):1161-7.
14. Centers for Disease Control and Prevention. Updated recommended treatment regimens for gonococcal
infections and associated conditions—United States, April 2007. Available from:
http://www.cdc.gov/STD/treatment/2006/GonUpdateApril2007.pdf. Accessed October 7, 2008.
15. Studdiford J, Lamb K, Horvath K et al. Development of unilateral cervical and supraclavicular
lymphadenopathy after human papilloma virus vaccination. Pharmacotherapy 2008;28(9):1194-97.
16. Brotherton JML, Gold MS, Kemp AS et al. Anaphylaxis following quadrivalent human papillomavirus
vaccination. CMAJ 2008;179(6):525-33.
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e-Therapeutics+ : Therapeutics : Infectious Diseases: Sinusitis Page 1 of 9
Therapeutic Choice
Print Close
Infectious Diseases: Sinusitis

Susan R. Fryters, BScPharm, ACPR
Edith M. Blondel-Hill, MD, FRCPC
Sinusitis is defined as inflammation and/or mucosal thickening of one or more of the paranasal sinus cavities, the cause of which may be
allergic, viral, bacterial or (rarely) fungal.1 Acute sinusitis refers to sinusitis lasting four weeks or less, while recurrent sinusitis is defined as
2 , 3 , 4
four or more episodes of acute sinusitis per year, each lasting 10 days or more, with an absence of symptoms between episodes.
Chronic sinusitis refers to infections lasting 12 weeks or more with or without treatment.1 , 3 , 4 Acute sinusitis can also be superimposed on
2
chronic sinusitis. Rhinitis and rhinosinusitis, most commonly associated with a viral or allergic etiology, are often misdiagnosed and treated
as bacterial sinusitis.
Many similarities exist between sinusitis and otitis media, including histology, pathogenesis, etiologic agents and risk factors. In children, the
two diseases frequently coexist.2
The paranasal sinuses are normally sterile. Acute sinusitis is most often secondary to viral respiratory infections. Viral upper respiratory tract
5 , 6 , 7 , 8 , 9
infections (URTIs) are complicated by bacterial sinusitis in only 0.2 to 2% of cases.
This chapter addresses bacterial sinusitis in children and adults. Bacteria commonly implicated in bacterial sinusitis in children and adults are
listed in Table 2 and Table 3, respectively. The most common bacterial pathogens in acute sinusitis are Streptococcus pneumoniae and
unencapsulated strains of Haemophilus influenzae. Moraxella catarrhalis is more common in children.1 Up to 10% of cases of acute sinusitis in
adults may be due to mixtures of anaerobic bacteria; these are often associated with concurrent dental disease. The etiology of chronic
sinusitis is less clear, although anaerobes and Staphylococcus aureus are more common than in acute sinusitis.10
Goals of Therapy
Optimize the symptomatic management of sinusitis, especially drainage of congested sinuses

Eradicate infection
Prevent recurrences and complications
Reduce antibiotic use in ill-defined URTI to avoid the development of antibiotic resistance
Investigations
The diagnosis of acute bacterial sinusitis relies on history and physical examination. Differentiation of bacterial sinusitis from viral URTI is
determined by the duration and severity of the symptoms described below.8
Symptoms
Adults: Persistent symptoms of URTI without improvement after 10 to 14 days, or worsening after 5 days, with both nasal
congestion/purulent nasal discharge and facial pain, with or without fever, maxillary toothache or facial swelling. Nonspecific concurrent
symptoms include headache, halitosis, hyposmia/anosmia, ear pain/pressure, fatigue and cough.1 , 2 , 3 , 11
Children: Symptoms of acute bacterial sinusitis are similar in children but often also include irritability, lethargy, prolonged cough and
vomiting that occurs in association with gagging on mucus.1 , 2 , 3
Chronic: Patients with chronic sinusitis typically complain of purulent nasal discharge, postnasal drip and nasal obstruction accompanied
12
by facial pain. Symptoms can mimic the pain of atypical and typical migraine, dental disease and tension headaches.
Physical Examination
Physical findings of swelling and/or erythema over the symptomatic area, tenderness on palpation/percussion of paranasal sinuses,
periorbital swelling, erythema/swelling of nasal mucosa, postnasal drip.
In addition:
assess patient for changes in extraocular movements and visual acuity to look for orbital complications
look for associated dental infection by checking the maxillary teeth for tenderness
Objective measurements
Transillumination of the sinuses has limited value in adults and no diagnostic value in children as findings are not specific for bacterial
infection, and in children, the sinuses are not yet fully formed.
Nasal/nasopharyngeal cultures are not recommended due to poor correlation with sinus pathogens.
Plain sinus x-rays and CT scans are not routinely recommended in the diagnosis of sinusitis, as they will not distinguish between sinus
abnormalities associated with viral URTI and bacterial sinusitis.
MRI is not routinely recommended due to poor bone definition.
CT scans may be useful for:
complications of acute sinusitis (e.g., periorbital edema, subperiosteal abscess)2
chronic sinusitis unresponsive to treatment3
chronic progressive nasal obstruction without identified cause2
2 , 3
severe presentations where diagnosis is suspected but not clear
2 , 13
patients in whom surgery is being considered
Consider underlying risk factors, especially in recurrent and/or chronic sinusitis:
gastroesophageal reflux disease

allergic rhinitis
Page 678
Therapeutic Choice
structural abnormalities
cystic fibrosis (chronic sinusitis, children with nasal polyps)
immunodeficiency (chronic, recurrent sinusitis)
2
eosinophilic nonallergic rhinitis
Therapeutic Choices
, 3
Prevention of Sinusitis2
Limit the spread of viral infections. Handwashing is the most effective way to prevent the spread of infection.
Avoid environmental tobacco exposure.
Reduce environmental allergen exposure.
Local treatment with steam inhalation, cool mist humidifiers and/or saline irrigation/sprays may be of benefit in both acute and chronic
14 , 15
sinusitis to liquefy and soften crusting of nasal secretions to facilitate their removal, and to moisturize dry, inflamed nasal mucosa.
2
Although there are no scientific data on efficacy, the following comfort measures may be helpful in relieving symptoms in some patients:
adequate rest and hydration
warm facial packs/compresses
sleeping with the head of the bed elevated
adding pine oil or menthol preparations to steam treatments.
Surgical drainage for chronic sinusitis may be necessary, especially when it is unresponsive to medical therapy.16
Principles of Therapy in Sinusitis
Preferred initial strategy for managing symptoms in sinusitis is the use of analgesics/antipyretics and decongestants when needed.
Approximately 70% of cases of acute sinusitis will resolve without antibiotic treatment.17 , 18 , 19 , 20 , 21 , 22 However, if symptoms continue
for longer than 10 days, consider antibiotic therapy.
Symptomatic Management
Analgesics/antipyretics, such as acetaminophen or ibuprofen, can be used for control of pain and/or fever.
Nasal and oral decongestants may be beneficial in both acute and chronic infections.14 Oral decongestants should be used with caution in
patients with uncontrolled hypertension, cardiovascular disease, hyperthyroidism, diabetes, angle-closure glaucoma, urinary retention or in
conjunction with monoamine oxidase inhibitors. Topical decongestant sprays should be used with caution as extended use (> 3 to 5 days)
may result in rhinitis medicamentosa (rebound congestion/hyperemia), which may be refractory to subsequent decongestant therapy.2
13 , 23
The efficacy and safety of nasal/oral decongestants has not been well studied in pediatric patients less than 12 years old. Adverse
events resulting in emergency room visits due to the use and/or misuse of oral cough and cold preparations are highest among children less
than 6 years.24 In addition, overdosage of oral cough and cold preparations, specifically pseudoephedrine, has been associated with deaths
in several infants.25 As a result, in December 2008, Health Canada issued an advisory instructing caregivers not to give certain oral over-the-
counter cough and cold medications to children younger than 6 years.26 Although Health Canada does not recommend the use of these
products in children less than 6 years, some clinicians further advise against their use in children less than 12 years.23 Clinicians should
carefully weigh the risks and benefits of these medications before prescribing and should ask whether other cough and cold preparations are
being used so as to avoid overdose from multiple medications that contain the same ingredients, including analgesic medications.
Avoid antihistamines in acute sinusitis because of their tendency to cause excessive dryness with thickening of secretions and
crusting.27 The second-generation antihistamines may, however, have a role in chronic sinusitis where a clear allergic
14
component is demonstrated. Useful Info?
The use of nasal corticosteroid sprays in acute sinusitis is controversial.28 They may offer some benefit in patients with recurrent and/or
1
allergic rhinosinusitis. Nasal corticosteroids may also be beneficial in chronic sinusitis due to their ability to decrease nasal edema and
inflammation and thus promote drainage.2
There is no evidence that mucolytics, such as guaifenesin, are useful adjuncts in acute sinusitis.2
Antibiotic Therapy (Table 2, Table 3, Table 4, Table 5)

17 ,
Multiple clinical trials and two meta-analyses have shown that ~70% of cases of acute sinusitis will resolve without antibiotic treatment.
18 , 19 , 20 , 21 , 22
Antibiotic therapy should be reserved for those patients with bacterial sinusitis as defined by history and physical
20 ,
examination. There are no clinically significant differences in outcomes between first-line and second-line broader spectrum antibiotics.
21 , 22 , 29 , 30
1 , 2 , 3 , 4 , 16
Amoxicillin remains the antibiotic of choice for acute bacterial sinusitis for the following reasons:
Adequate coverage for organisms involved in acute sinusitis
Page 679
Therapeutic Choice
Best activity of all oral beta-lactam agents against S. pneumoniae, including strains with intermediate susceptibility to penicillin when
high-dose amoxicillin is used
No other antibiotic has been proven superior to amoxicillin in clinical trials
Lower potential to induce resistance
Relatively few adverse effects
Relatively inexpensive
Failure of First-line Therapy

3 , 4 ,
Amoxicillin-clavulanate offers the most appropriate spectrum of activity and is the agent of choice when first-line antibiotic therapy fails.
22
Antibiotic therapy (especially with macrolides or fluoroquinolones) within the previous three months may be a risk factor for multidrug
resistant S. pneumoniae . If this is the case, use an antibiotic from a different class.
Table 1: Antibiotics Not Recommended as Empiric Therapy for Acute Bacterial Sinusitis2 , 3 , 4
Antibiotic Comments
Cephalexin Poor activity against penicillin intermediate/resistant S. pneumoniae. No activity against Haemophilus or Moraxella spp.
Cefaclor No activity against penicillin intermediate/resistant S. pneumoniae. Marginal activity against H. influenzae.
Cefixime No activity against penicillin intermediate/resistant S. pneumoniae. Excellent activity against Haemophilus spp.
Ceftriaxone Routine use of this agent is not recommended in acute bacterial sinusitis due to potential for increased resistance to third-
generation cephalosporins.
May be an option in patients with severe acute bacterial sinusitis who have failed therapy. Three days of im/iv therapy is
recommended, as a single dose is not as effective in eradicating penicillin-resistant S. pneumoniae.
Clindamycin Not recommended for acute bacterial sinusitis as no activity against Haemophilus or Moraxella spp. Clindamycin can be used
as an alternative to amoxicillin-clavulanate in chronic sinusitis.
Erythromycin Poor activity against H. influenzae/Moraxella spp. Significant macrolide resistance in S. pneumoniae.
Ciprofloxacin Suboptimal coverage of S. pneumoniae.
Duration of Therapy
Duration of antibiotic therapy in acute bacterial sinusitis is not well defined. Empirically, a 10- to 14-day course of therapy is
recommended.1 , 2 Some physicians continue antibiotic therapy until the patient is free of symptoms and then for an additional 7 days to
ensure eradication of bacteria and to prevent relapse.2 , 16 However, short-course optimal dose therapy has been shown, with several different
31 32
antibiotics, to be effective in acute bacterial sinusitis (e.g., azithromycin or sulfamethoxazole/trimethoprim for 3 days, respiratory
33 34 , 35 , 36
quinolones or telithromycin for 5 days ) and has advantages in terms of less development of resistance, better adherence, faster
37
symptom resolution and lower costs. Further study is needed, however, before short course therapy can be extrapolated to all antimicrobials
used in the treatment of acute bacterial sinusitis.
Therapeutic Tips
1 , 2 ,
If patient shows no improvement after 72 hours of symptomatic therapy plus first-line antibiotic, change to a second-line antibiotic.
3 , 4 , 11
Inform patients that complete resolution of symptoms may take up to 14 days.4

If the patient deteriorates at any time, reassess for acute complications, other diagnoses and/or adherence to treatment.
Routine follow-up on completion of therapy in asymptomatic patients is not required.
If a patient has received antibiotics (especially macrolides or fluoroquinolones) within the past three months, choose an antibiotic from a
different class to treat acute bacterial sinusitis as there is a higher risk of multidrug resistant S. pneumoniae.
The presence of tenacious, thick, brown nasal secretions should heighten the suspicion of a fungal infection.
Refer to ENT specialist if a patient:3
1
fails second-line therapy
experiences four or more episodes of bacterial sinusitis per year
has chronic sinusitis that is not responding to medical therapy (symptomatic and antibiotic)
has anatomic anomalies
develops complications
Table 2: Recommended Empiric Therapy for Bacterial Sinusitis in Children3 , 4
Infection Usual Pathogens Recommended Empiric Therapy Comments
Acute Sinusitis S. pneumoniae Standard-dose amoxicillin × Refer to ENT specialist if ≥ 4 episodes/y.

(symptoms < 4 wk and ≤ M. catarrhalis 10 days or High-dose amoxicillin should be used in
3 episodes/y) H. influenzae High-dose amoxicillin × 10 days children at high risk of penicillin-resistant
Occasionally S. aureus, S. β-lactam allergy: S. pneumoniae: recent (< 3 mo)
pyogenes, anaerobes sulfamethoxazole/trimethoprim antibiotic exposure and/or daycare centre
(SMX/TMP) × 10 days attendance (extrapolated from acute otitis
media data).
S. pneumoniae resistance to SMX/TMP is
increasing. If patient is at high risk of
Page 680
Therapeutic Choice
bacterial resistance (see above) and has ß
-lactam allergy, use azithromycin or
clarithromycin.
Failure of First-line S. pneumoniae Amoxicillin/clavulanate (7:1) × Consider resistant organisms, especially

Agents: M. catarrhalis 10 days + amoxicillina × 10 days or penicillin-resistant S. pneumoniae and ß-
(No improvement or H. influenzae cefuroxime axetil × 10 days lactamase producing H. influenzae.
clinical deterioration after Occasionally S. aureus, S. β-lactam allergy: azithromycin × 3-5 If cefuroxime suspension or tablets is not
72 h of antibiotic therapy pyogenes, anaerobes tolerated, cefprozil can be considered. It
daysb or clarithromycin × 10 days
or recurrence within tastes better than cefuroxime but has
Severe presentation: iv cefuroxime
3 mo) inferior coverage of H. influenzae and
sodium × 10 days
penicillin-intermediate S. pneumoniae.
Azithromycin and clarithromycin use
should be restricted (Table 4).
Chronic Sinusitis Anaerobes Amoxicillin/clavulanate × 3 wk Longer duration of therapy may be

(symptoms ≥ 12 wk) Occasionally S. aureus, S. or required in exceptional circumstances.
pneumoniae, H. influenzae, M. clindamycin × 3 wk
catarrhalis, S. pyogenes,
Enterobacteriaceae
a.
If patient has failed high-dose amoxicillin therapy, amoxicillin/clavulanate alone is adequate to cover ß-lactamase producing organisms.
b.
Shorter durations of therapy have been shown to be effective in acute bacterial sinusitis but are not well studied in patients who have failed first-line
31 , 33 38 , 39
therapy. Use short-course therapy with caution in this patient population. If using azithromycin, consider using 20 mg/kg/day x 3 days.
Abbreviations: ENT = ear, nose, throat
Table 3: Recommended Empiric Therapy for Bacterial Sinusitis in Adults3 , 4
Acute Sinusitis S. pneumoniae Amoxicillin × 10 days Refer to ENT specialist if ≥ 4

(symptoms < 4 wk and H. influenzae β-lactam allergy: doxycycline × 10 days episodes/y.
≤ 3 episodes/y) M. catarrhalis or S. pneumoniae resistance to SMX/TMP
Occasionally S. aureus, S. sulfamethoxazole/trimethoprim (SMX/TMP) is increasing. If ß-lactam allergy and
pyogenes, anaerobes × 10 days previous antimicrobial exposure, use
azithromycin, clarithromycin,
levofloxacin or moxifloxacin.
Advise patients that symptoms are likely
to last up to 14 days. Studies have
demonstrated efficacy with shorter
courses of therapy.31 , 33
Failure of First-line S. pneumoniae Amoxicillin/clavulanate × 10 days Consider resistant organisms, especially

Agents: M. catarrhalis or penicillin-resistant S. pneumoniae and β
(Clinical deterioration H. influenzae cefuroxime axetil × 10 days -lactamase producing H. influenzae.
after 72 h of antibiotic Occasionally S. aureus, S. β-lactam allergy: azithromycin × 3–5 Cefuroxime axetil provides best
therapy or no pyogenes, anaerobes daysa or clarithromycin × 10 days or coverage of all oral cephalosporins
improvement post a against penicillin-intermediate strains of
levofloxacin × 5–10 days or
therapy) S. pneumoniae and provides good
moxifloxacin × 5–10 daysa coverage of H. influenzae ,
M. catarrhalis and S. aureus .
Macrolide and quinolone use should be
restricted (Table 5).
Chronic Sinusitis Anaerobes Amoxicillin/clavulanate × 3 wk A single prolonged (3 wk) course of

(symptoms ≥ 12 wk) Occasionally S. aureus, S. β-lactam allergy: clindamycin × 3 wk antibiotic may be of value in chronic
pneumoniae, H. influenzae, sinusitis.
M. catarrhalis, S. pyogenes, Repeated courses of antibiotics are not
Enterobacteriaceae recommended.
Refer to ENT specialist if not
responding.
a.
Shorter durations of therapy have been shown to be effective in acute bacterial sinusitis but not well studied in patients who have failed first-line therapy.
31 , 33
Use short-course therapy with caution in this patient population.
Abbreviations: ENT = ear, nose, throat
Table 4: Antibiotics for Bacterial Sinusitis in Children
Page 681
Therapeutic Choice
Drug
Class Drug Pediatric Dose Adverse Effects Interactions Comments Costa
Cephalosporins cefprozil 30 mg/kg/day po Nausea, vomiting, Alternative to $$$

Cefzil, generics divided BID; max 1 diarrhea,b cefuroxime if
g/day hypersensitivity suspension or tablets
reactions (cross- not tolerated. Cefprozil
reactivity with has a better taste than
penicillins < 2%). cefuroxime but inferior
coverage of H.
influenzae and
penicillin-intermediate
S. pneumoniae.
Cephalosporins cefuroxime axetil 30 mg/kg/day po Nausea, vomiting, If cefuroxime $$$

divided BID; diarrhea,b suspension/tablets not
Ceftin, generics max 1 g/day hypersensitivity tolerated, consider
reactions (cross- using cefprozil.
reactivity with
penicillins < 2%).
Cephalosporins cefuroxime sodium 100–150 mg/kg/day iv Nausea, vomiting, Use if severe $$$$$
generics divided Q8H; diarrhea,b presentation of acute
max 4.5 g/day hypersensitivity sinusitis.
reactions (cross-
reactivity with
penicillins < 2%).
Lincosamides clindamycin 30 mg/kg/day po Diarrhea.b Not active against capsules:

Dalacin C, Dalacin divided TID or QID; H. influenzae or $$$
C Flavored max 1.2–1.8 g/day M. catarrhalis. granules:
Alternative to $$$$
Granules, generics
amoxicillin/clavulanate
in chronic sinusitis.
Macrolides azithromycin 10 mg/kg (max 500 mg) GI irritation, nausea, May ↑ warfarin Use of azithromycin $$
Zithromax, po first day, then vomiting, diarrhea,b effect and clarithromycin
generics 5 mg/kg rash. (clarithromycin > should be restricted
(max 250 mg) po daily azithromycin). because S. pneumoniae
× 4 days (5 days total) resistance to
or macrolides is
increasing and
10 mg/kg (max 500 mg) macrolides have been
po × 3 days shown (in acute otitis
media) to be less
or efficacious than
amoxicillin/clavulanate.
30 mg/kg/day po × 1 If using azithromycin
day (max 1500 mg) in patients who
have failed first-line
therapy, consider
using 20 mg/kg/day x
3 days.38 , 39
Macrolides clarithromycin 15 mg/kg/day po GI irritation, nausea, May ↑ warfarin Use of azithromycin $$$
Biaxin, generics divided BID; vomiting, diarrhea,b effect and clarithromycin
max 1 g/day rash. (clarithromycin > should be restricted
azithromycin). because S. pneumoniae
Coadministration resistance to
with pimozide macrolides is
contraindicated. increasing and
Rifampin and macrolides have been
efavirenz ↓ shown (in acute otitis
clarithromycin media) to be less
concentrations. efficacious than
Clarithromycin may amoxicillin/clavulanate.
↑ levels of some If using azithromycin
benzodiazepines, in patients who
buspirone, have failed first-line
carbamazepine, therapy, consider
cyclosporine, using 20 mg/kg/day x
digoxin, ergot 3 days.38 , 39
alkaloids,
statins,
tacrolimus,
theophyllines.
Page 682
Therapeutic Choice
Drug
Class Drug Pediatric Dose Adverse Effects Interactions Comments Costa
Penicillins amoxicillin Standard dose: 40 Usually well tolerated. First-line treatment for $
generics mg/kg/day po divided Nausea, vomiting, bacterial sinusitis in
TID; max 1500 mg/day diarrhea,b children.
High dose: 90 hypersensitivity High-dose amoxicillin
mg/kg/day po divided reactions. should be used in
TID; max 2–3 g/day children at high risk of
resistant S.
pneumoniae: recent (<
3 months) antibiotic
exposure and/or
daycare centre
attendance.
Penicillins amoxicillin/ amoxicillin/clavulanate Nausea, vomiting, If patient has failed $$

clavulanate (7:1) 45 mg/kg/day hypersensitivity standard-dose
± additional (amoxicillin component) reactions. Diarrheab amoxicillin,
amoxicillin po divided BID-TID more common with amoxicillin/clavulanate
Clavulin, generics + additional amoxicillin amoxicillin/clavulanate should be combined
45 mg/kg/day po than with amoxicillin with amoxicillin to
divided BID-TID alone. increase the total dose
of amoxicillin while
minimizing diarrhea
due to the clavulanate.
If patient has failed
high-dose amoxicillin
therapy,
amoxicillin/clavulanate
alone is adequate to
cover ß-lactamase
producing organisms.
Sulfonamide sulfamethoxazole / 6–12 mg/kg/day (TMP Nausea, vomiting, May ↑ warfarin S. pneumoniae $
Combinations trimethoprim component) po divided diarrhea, rash. effect and resistance to SMX/TMP
BID; max 320 mg/day phenytoin levels. is increasing.
(SMX/TMP)
(TMP component) Enhanced bone
generics
marrow
suppression with
methotrexate.
a.
Costs are given for a 10-day course of treatment based on 20 kg body weight, except for azithromycin (1, 3, 5 days) and clindamycin (3 weeks); includes
drug cost only.
b.
Antibiotic-associated diarrhea/colitis is commonly associated with clindamycin and ß-lactams, but any antibiotic can cause this condition.
Abbreviations: TMP=trimethoprim
Legend: $ < $10 $$ $10–25 $$$ $25–50 $$$$ $50–100 $$$$$ > $100
Table 5: Antibiotics for Bacterial Sinusitis in Adults
a
Adverse Cost
Cephalosporins cefuroxime axetil 500 mg po Nausea, Cefuroxime axetil provides best $$$$
Ceftin, generics BID vomiting, coverage of all oral
diarrhea,b cephalosporins against penicillin-
hypersensitivity intermediate strains of S.
reactions (cross- pneumoniae and provides good
reactivity with coverage of H. influenzae, M.
penicillins catarrhalis and S. aureus.
< 2%).
Macrolides azithromycin 500 mg po GI irritation, May ↑ warfarin effect Macrolide use should be $$
Zithromax, daily × 3 nausea, (clarithromycin > restricted as
generics days or 500 vomiting, azithromycin). S. pneumoniae resistance to
mg po on diarrhea, rash. macrolides is increasing and
day 1, then macrolides have been shown (in
250 mg po acute otitis media) to be less
daily × 4 efficacious than amoxicillin/
days (5 days clavulanate.
total)
Page 683
Therapeutic Choice
a
Adverse Cost
Macrolides clarithromycin Regular: 500 GI irritation, May ↑ warfarin effect Macrolide use should be $$$$
Biaxin, Biaxin XL, mg po BID nausea, (clarithromycin > restricted as
generics or vomiting, azithromycin). S. pneumoniae resistance to
extended diarrhea, rash. Coadministration with macrolides is increasing and
release (XL): pimozide macrolides have been shown (in
1 g po daily contraindicated. acute otitis media) to be less
Rifampin and efavirenz efficacious than amoxicillin/
↓ clarithromycin clavulanate.
concentrations.
Clarithromycin may ↑
levels of some
benzodiazepines,
buspirone,
carbamazepine,
cyclosporine, digoxin,
ergot alkaloids, statins,
tacrolimus,
theophyllines.
Fluoroquinolones levofloxacin 750 mg po Usually well Antacids, sucralfate, Due to broad spectrum and $$$
tolerated. metal cations, potential for increased resistance,
Levaquin, generics daily × 5
days or 500 Headache, didanosine quinolones should be reserved
mg po daily dizziness may chewable/buffered for patients with ß-lactam allergy
occur. tablets or pediatric or those who have failed previous
Rare: tendon powder, dairy products antibiotic therapy.
rupture. ↓ levofloxacin
absorption.
Cases of severe Avoid in patients on
liver injury Class Ia or III
including liver antiarrhythmics.
failure have been
reported. May ↑ warfarin effect.
NSAIDs may ↑ risk of CNS
stimulation/seizures.
Fluoroquinolones moxifloxacin 400 mg po Usually well Antacids, sucralfate, Due to broad spectrum and $$$$
Avelox daily tolerated. metal cations, potential for increased resistance,
Headache, didanosine quinolones should be reserved
dizziness may chewable/buffered for patients with ß-lactam allergy
occur. tablets or pediatric or those who have failed previous
Rare: tendon powder, dairy products antibiotic therapy.
rupture. ↓ levofloxacin
absorption.
Cases of severe Avoid in patients on
liver injury Class Ia or III
including liver antiarrhythmics.
failure have been
reported. May ↑ warfarin effect.
NSAIDs may ↑ risk of CNS
stimulation/seizures.
No interaction with
calcium.
Lincosamides clindamycin 300 mg po Diarrhea.b Not active against H. influenzae $$$$

Dalacin C, QID or M. catarrhalis.
generics Alternative to
amoxicillin/clavulanate in chronic
sinusitis.
Penicillins amoxicillin 500 mg po Usually well First-line treatment for bacterial $

generics TID tolerated. sinusitis in adults.
Nausea,
vomiting,
diarrhea,b
hypersensitivity
reactions.
Penicillins amoxicillin/ 875 mg po Nausea, $$$

clavulanate BID or vomiting,
Page 684
Therapeutic Choice
a
Adverse Cost
Clavulin, generics 500 mg po hypersensitivity
TID reactions.
Diarrheab more
common than
with amoxicillin
alone.
Sulfonamide sulfamethoxazole / 800/160 mg Nausea, May ↑ warfarin effect and S. pneumoniae resistance to $
Combinations trimethoprim (1 DS tablet) vomiting, phenytoin levels. SMX/TMP is increasing.
po BID diarrhea, rash. Enhanced bone marrow
generics
suppression with
methotrexate. May ↑
risk of hypoglycemia
with coadministration
of rosiglitazone.
Tetracyclines doxycycline 200 mg po Nausea, May ↑ warfarin effect. May Excellent activity against sinusitis $
Vibramycin, once, then vomiting, ↑ digoxin levels. pathogens, including ß-lactamase
generics 100 mg po diarrhea, rash, Doxycycline seems to be producing H. influenzae and M.
BID photosensitivity. minimally affected by food catarrhalis; S. pneumoniae,
and dairy products as including penicillin-intermediate
compared to strains. ~ 50% less doxycycline
demeclocycline and resistance than macrolide
tetracycline. Aluminum, resistance in S. pneumoniae. Has
bismuth, iron and not been associated with causing
magnesium ↓ absorption. an increase in penicillin
Alcohol, resistance among S. pneumoniae
carbamazepine, (macrolides have). Excellent
phenytoin and pharmacokinetics/dynamics (high
phenobarbital may ↓ serum levels, concentration-
doxycycline dependent killing).
concentrations.
a.
Costs are given for a 10-day course of treatment except for azithromycin (3-5 days) and clindamycin (3 weeks); includes drug cost only.
b.
Antibiotic-associated diarrhea/colitis is commonly associated with clindamycin and ß-lactams, but any antibiotic can cause this condition.
Legend: $ < $10 $$ $10–25 $$$ $25–50 $$$$ $50–100
Suggested Readings
Desrosiers M, Frenkiel S, Hamid QA et al. Acute bacterial sinusitis in adults: management in the primary care setting. J Otolaryngol 2002;31
(Suppl 2):2S2-14.
Gwaltney JM. Sinusitis. In: Mandell GL, Bennett JE, Dolin R, editors. Mandell, Douglas and Bennett’s principles and practice of infectious
diseases. 6th ed. Philadelphia (PA): Churchill Livingstone; 2005.
Slavin RG, Spector SL, Bernstein IL et al. The diagnosis and management of sinusitis: a practice parameter update. J Allergy Clin Immunol
2005;116(6 Suppl):S13-47.
References
1. Desrosiers M, Frenkiel S, Hamid QA et al. Acute bacterial sinusitis in adults: management in the primary care setting. J Otolaryngol
2002;31(Suppl 2):2S2-14.
2. Slavin RG, Spector SL, Bernstein IL et al. The diagnosis and management of sinusitis: a practice parameter update. J Allergy Clin
Immunol 2005;116(6 Suppl):S13-47.
3. Alberta Medical Association. Diagnosis and management of acute bacterial sinusitis. Edmonton (AB): Toward Optimized Practice; 2008.
Available from: http://www.topalbertadoctors.org/informed_practice/cpgs/acute_sinusitis.html. Accessed February 24, 2010.
4. Blondel-Hill E, Fryters S. Bugs and drugs 2006. Edmonton (AB): Capital Health; 2006.
5. Hickner JM, Bartlett JG, Besser RE et al. Principles of appropriate antibiotic use for acute rhinosinusitis in adults: background. Ann
Intern Med 2001;134(6):498-505.
6. O’Brien KL, Dowell SF, Schwartz B et al. Acute sinusitis: principles of judicious use of antimicrobial agents. Pediatrics 1998;101(1
Suppl):174-7.
7. Wald ER, Chiponis D, Ledesma-Medina J. Comparative effectiveness of amoxicillin and amoxicillin-clavulanate potassium in acute
paranasal sinus infections in children: a double-blind, placebo-controlled trial. Pediatrics 1986;77(6):795-800.
8. Druce HM. Diagnosis of sinusitis in adults: history, physical examination, nasal cytology, echo, and rhinoscope. J Allergy Clin Immunol
1992;90(3 Pt 2):436-41.
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9. Fireman P. Diagnosis of sinusitis in children: emphasis on the history and physical examination. J Allergy Clin Immunol 1992;90(3 Pt
2):433-6.
10. Benninger MS, Anon J, Mabry RL. The medical management of rhinosinusitis. Otolaryngol Head Neck Surg 1997;117(3 Pt 2):S41-9.
11. Anon JB, Jacobs MR, Poole MD et al. Antimicrobial treatment guidelines for acute bacterial rhinosinusitis. Otolaryngol Head Neck Surg
2004;130(1 Suppl):1-45.
12. Richards W, Roth RM, Church JA. Underdiagnosis and undertreatment of chronic sinusitis in children. Clin Pediatr (Phila) 1991;30(2):88-
92.
13. American Academy of Pediatrics. Subcommittee on Management of Sinusitis and Committee on Quality Improvement. Clinical practice
guideline: management of sinusitis. Pediatrics 2001;108(3):798-808.
14. Poole MD. A focus on acute sinusitis in adults: changes in disease management. Am J Med 1999;106(5A):38S-47S.
15. Racicot J. Pharm Pract 2002;18:CE1-8.
16. Brook I. Microbiology and antimicrobial management of sinusitis. J Laryngol Otol 2005;119(4):251-8.
17. Gananca M, Trabulsi LR. The therapeutic effects of cyclacillin in acute sinusitis: in vitro and in vivo correlations in a placebo-controlled
study. Curr Med Res Opin 1973;1(6):362-8.
18. Stalman W, van Essen GA, van der Graaf Y et al. The end of antibiotic treatment in adults with acute sinusitis-like complaints in general
practice? A placebo-controlled double-blind randomized doxycycline trial. Br J Gen Pract 1997;47(425):794-9.
19. van Buchem FL, Knottnerus JA, Schrijnemaekers VJ et al. Primary-care-based randomised placebo-controlled trial of antibiotic treatment
in acute maxillary sinusitis. Lancet 1997;349(9053):683-7.
20. Garbutt JM, Goldstein M, Gellman E et al. A randomized, placebo-controlled trial of antimicrobial treatment for children with clinically
diagnosed acute sinusitis. Pediatrics 2001;107(4):619-25.
21. Williams JW, Aguilar C, Cornell J et al. Antibiotics for acute maxillary sinusitis. Cochrane Database Syst Rev 2003;(2):CD000243.
22. Ip S, Fu L, Balk E et al. Update on acute bacterial rhinosinusitis. Evidence Report/Technology Assessment No. 124 AHRQ Publication No.
05-E020-1. Rockville (MD): Agency for Healthcare Research and Quality; 2005. Available from:
http://www.ahrq.gov/downloads/pub/evidence/pdf/rhinoupdate/rhinoup.pdf. Accessed January 13, 2009.
23. Taverner D, Latte J. Nasal decongestants for the common cold. Cochrane Database Syst Rev 2007;(1):CD001953.
24. Schaefer MK, Shehab N, Cohen AL et al. Adverse events from cough and cold medications in children. Pediatrics 2008;121(4):783-7.
25. Centers for Disease Control and Prevention (CDC). Infant deaths associated with cough and cold medications--two states, 2005. MMWR
Morb Mortal Wkly Rep 2007;56(1):1-4.
26. Health Canada. Health Canada releases decision on the labelling of cough and cold products for children; December 18, 2008. Available
from: http://www.hc-sc.gc.ca/ahc-asc/media/advisories-avis/_2008/2008_184-eng.php. Accessed January 13, 2009.
27. Stafford CT. The clinician's view of sinusitis. Otolaryngol Head Neck Surg 1990;103(5 Pt 2):870-4.
28. Meltzer EO, Charous BL, Busse WW et al. Added relief in the treatment of acute recurrent sinusitis with adjunctive mometasone furoate
nasal spray. The Nasonex Sinusitis Group. J Allergy Clin Immunol 2000;106(4):630-7.
29. de Bock GH, Dekker FW, Stolk J et al. Antimicrobial treatment in acute maxillary sinusitis: a meta-analysis. J Clin Epidemiol 1997;50
(8):881-90.
30. Piccirillo JF, Mager DE, Frisse ME et al. Impact of first-line vs second-line antibiotics for the treatment of acute uncomplicated sinusitis.
JAMA 2001;286(15):1849-56.
31. Henry DC, Riffer E, Sokol WN et al. Randomized double-blind study comparing 3- and 6-day regimens of azithromycin with a 10-day
amoxicillin-clavulanate regimen for treatment of acute bacterial sinusitis. Antimicrob Agents Chemother 2003;47(9):2770-4.
32. Williams JW, Holleman DR, Samsa GP et al. Randomized controlled trial of 3 vs 10 days of trimethoprim/sulfamethoxazole for acute
maxillary sinusitis. JAMA 1995;273(13):1015-21.
33. Sher LD, McAdoo MA, Bettis RB et al. A multicenter, randomized, investigator-blinded study of 5- and 10-day gatifloxacin versus 10-day
amoxicillin/clavulanate in patients with acute bacterial sinusitis. Clin Ther 2002;24(2):269-81.
34. Buchanan PP, Stephens TA, Leroy B. A comparison of the efficacy of telithromycin versus cefuroxime axetil in the treatment of acute
bacterial maxillary sinusitis. Am J Rhinol 2003;17(6):369-77.
35. Luterman M, Tellier G, Lasko B et al. Efficacy and tolerability of telithromycin for 5 or 10 days vs amoxicillin/clavulanic acid for 10 days
in acute maxillary sinusitis. Ear Nose Throat J 2003;82(8):576-86.
36. Ferguson BJ, Guzzetta RV, Spector SL et al. Efficacy and safety of oral telithromycin once daily for 5 days versus moxifloxacin once
daily for 10 days in the treatment of acute bacterial rhinosinusitis. Otolaryngol Head Neck Surg 2004;131(3):207-14.
37. Poole MD, Portugal LG. Treatment of rhinosinusitis in the outpatient setting. Am J Med 2005;118(Suppl 7A):45S-50S.
38. Arrieta A, Arguedas A, Fernandez P et al. High-dose azithromycin versus high-dose amoxicillin-clavulanate for treatment of children with
recurrent or persistent acute otitis media. Antimicrob Agents Chemother 2003;47(10):3179-86.
39. Arrieta A, Singh J. Management of recurrent and persistent acute otitis media: new options with familiar antibiotics. Pediatr Infect Dis J
2004;23(2 Suppl):S115-24.
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e-Therapeutics+ : Therapeutics : Infectious Diseases: Streptococcal Sore Throat Page 1 of 7
Therapeutic Choice
Print Close
Infectious Diseases: Streptococcal Sore Throat

David P. Speert, MD
Goals of Therapy
Provide symptomatic relief

Prevent suppurative complications, e.g., mastoiditis, cervical lymphadenitis
Prevent nonsuppurative complications, e.g., acute rheumatic fever
Prevent spread of group A streptococci to contacts
Investigations
The probability of culturing group A streptococci is greatest in a child with an acute sore throat who is > 3 years
1
old, lacks signs of a viral upper respiratory infection and has signs and symptoms as listed below. However, the
diagnosis of streptococcal pharyngitis (strep throat) should be considered seriously in any child presenting with an
acute sore throat, with or without "classic" signs and symptoms.
Clinical diagnosis of streptococcal infection: adenitis and positive throat cultures are the only predictive
1
features
Although not diagnostic, signs and symptoms include:
signs: tender cervical adenopathy, erythematous pharynx and tonsils, pharyngeal exudate, excoriated
nares, scarlatiniform rash
symptoms: sore throat (in general of sudden onset), pain on swallowing, headache, abdominal pain,
nausea, vomiting, fever (see Symptom Control: Fever in Children)
Laboratory diagnosis:
throat culture is “gold standard” (results available in 24 to 48 hours). Viral throat culture rarely influences
therapy (results available in days to weeks). A partial list of etiologic agents for acute sore throat is
presented in Table 1
repeat cultures are not necessary at the end of therapy or from asymptomatic family contacts
antigen screen of throat secretions (rapid test): results available in 7 to 70 minutes but sensitivity (< 90%)
2
too low to rule out streptococcal infection in children or adolescents . If the rapid antigen detection test is
unavailable or is negative, obtain a culture and withhold antibiotics for 24 to 48 hours until the results are
available. If positive, recall and treat patients for group A streptococci. This approach does not increase the
risk of acute rheumatic fever3 but avoids the unnecessary use of antibiotics
streptococcal serology (antistreptolysin O or ASO, others): useful retrospectively in patients who have
4
possible complications of streptococcal infection (e.g., rheumatic fever) but are not useful in the diagnosis
of acute streptococcal pharyngitis
Table 1: Selected Pathogens of Acute Pharyngitis
Viruses (adenoviruses, enteroviruses, cytomegalovirus, Epstein-Barr, influenza, herpes simplex virus, and
parainfluenza viruses)
2
Group A β-hemolytic streptococci (children: 15–30%; adults: 5–10%)
Groups C and G β-hemolytic streptococci
Neisseria gonorrhoeae (consider sexual abuse if recovered from child's throat)
a
Chlamydia trachomatis a
Chlamydophila pneumoniae a , b
Corynebacterium diphtheriae
Arcanobacterium hemolyticum a
a.
Role in acute pharyngitis is controversial.
b.
Previously Chlamydia pneumoniae.
Page 687
Therapeutic Choice
Therapeutic Choices (Figure 1 - Management of Acute Sore Throat)
Strict hand-washing to prevent spread of infection.

Exclude from school or daycare for 24 hours after antimicrobial therapy is begun.
Analgesics
Acetaminophen or ibuprofen may be given for fever and pain. Lozenges and gargles may be indicated for
symptomatic treatment of sore throat.
Antibiotics
Antibiotic therapy for group A streptococcal pharyngitis can shorten the course of the acute illness and prevent both
suppurative and nonsuppurative complications if started early in the course of illness.4
Penicillin is the drug of choice for streptococcal sore throat.2 Although cephalosporins are effective,
they should not replace penicillin as the drug of choice. Useful Info?
5
Amoxicillin is often used in children requiring liquid medication due to the poor palatability of penicillin V
5
suspension. Erythromycin is the preferred alternative in patients allergic to penicillin.
Therapeutic Tips
Early institution of antibiotic therapy shortens the duration of fever, cervical adenitis and pharyngeal infection
6
and hastens the overall clinical improvement. Early treatment can hasten the return of children to school or
daycare and minimize work time lost by their parents.
Since there is no efficient way to differentiate between the acutely infected child and the carrier of group A
streptococci,1 all symptomatic patients with positive cultures should receive antistreptococcal therapy. A large
percentage of cases of acute rheumatic fever develop after mild or subclinical streptococcal infections.7
It is impossible to reliably differentiate between acute streptococcal infection and chronic carriage; a means of
eradicating chronic carriage is therefore desirable. Unfortunately, penicillin, the drug of choice for treating acute
streptococcal sore throat, often fails to eradicate pharyngeal streptococcal carriage. Some advocate the use of
clindamycin (20 mg/kg/day divided TID for 10 days; maximum 600 mg/day) or the addition of rifampin (20
mg/kg/day divided BID; maximum 600 mg/day) for the final four days of penicillin therapy to attempt to
interrupt chronic pharyngeal carriage of group A streptococci.8
Figure 1-Management of Acute Sore Throat
Page 688
Therapeutic Choice
a.
Antibiotic therapy may be safely withheld from an adult based on a negative rapid antigen test.
Table 2: Drugs for Treatment of Group A Streptococcal Pharyngitis
Costa
9
Cephalosporins cefadroxil Adults: 1 g po Hypersensitivity Use if treatment $$$

generics daily as a single (some cross- failure with
dose or divided reactivity with penicillin.
BID × 10 days penicillins).
Cephalosporins cefixime Adults and Hypersensitivity Use if treatment $$$$

Suprax children > 12 y: (some cross- failure with
400 mg po daily reactivity with penicillin.
× 10 days penicillins). Available as
Children 6 mo– suspension.
12 y: 8 mg/kg
po daily × 10
days
Cephalosporins cefprozil Adults and Hypersensitivity Use if treatment $$$$

Cefzil, generics children ≥ 13 y: (some cross- failure with
500 mg po daily reactivity with penicillin.
× 10 days penicillins). Available as
Children 6 mo– suspension.
12 y: 15 mg/kg
po daily divided
Q12H × 10
days; max 1
g/day
Page 689
Therapeutic Choice
Costa
9
Cephalosporins cefuroxime axetil Adults and Hypersensitivity Use if treatment $$

Ceftin, generics children ≥ 12 y: (some cross- failure with
250 mg po BID reactivity with penicillin.
× 10 days penicillins). Available as a
Children 3 mo– suspension. Prior to
12 y: 20 mg/kg administration, may
daily po divided add dose to milk, fruit
BID × 10 days; juice or lemonade.
max 500
mg/day
Cephalosporins cephalexin Adults: 250 mg Hypersensitivity Use if treatment $

generics po QID × 10 (some cross- failure with
days reactivity with penicillin.
Children: 25–50 penicillins). Available as
mg/kg po daily suspension.
divided QID ×
10 days; max 1
g/day
Lincosamides clindamycin Adults:2 600 mg C. difficile colitis, An alternative for $$$$

Dalacin C, Dalacin C po daily divided diarrhea (common). patients with
Flavored Granules, BID-QID × 10 erythromycin-resistant
generics days strain of group A
2 Streptococcus and
Children: 20–
who cannot tolerate β-
30 mg/kg po
lactam antibiotics.
daily divided
May be used for
TID × 10 days
treatment in
symptomatic patients
with multiple,
recurrent episodes of
2
pharyngitis.
Available as
suspension.
Macrolides azithromycin Adults: 500 mg Lower frequency of A 5-day course is $$

Z-Pak, Zithromax, po × 1 day, GI effects than effective.
generics then 250 mg po erythromycin. Available as
daily × 4 days suspension.
Children: 12
mg/kg po daily Less likely than other
× 5 days; max macrolides to interact
500 mg/day with other drugs.
Macrolides clarithromycin Adult: 250 mg Lower frequency of Available as $$

Biaxin, generics po BID × 10 GI effects than suspension.
days erythromycin. ↑ levels of atorvastatin,
Children: 15 carbamazepine, digoxin,
mg/kg po daily lovastatin, prednisone,
Page 690
Therapeutic Choice
Costa
9
divided BID × simvastatin,
10 days theophylline.
Macrolides erythromycin Adults: 1 g po Nausea, vomiting, An alternative for $$

Eryc, generics daily divided epigastric distress, penicillin-allergic
BID-QID × 10 diarrhea, elevated patients.
days liver enzymes, ↑ levels of atorvastatin,
Administer 1 cholestatic jaundice. carbamazepine,
hour before digoxin, lovastatin,
meals to prevent prednisone,
acid inactivation simvastatin,
theophylline.
Macrolides erythromycin estolate Adults: 1 g po Nausea, vomiting, Contraindicated in $$

generics daily divided epigastric distress, pregnancy. Incidence
BID-QID × 10 diarrhea, elevated of cholestatic hepatitis
days liver enzymes, greater in pregnancy.
Children: 20–40 cholestatic jaundice. An alternative for
mg/kg po daily penicillin-allergic
divided BID-TID patients
× 10 days; max
1 g/day Available as
suspension.
↑ levels of atorvastatin,
carbamazepine,
digoxin, lovastatin,
prednisone,
simvastatin,
theophylline.
Macrolides erythromycin Adults: 1 g po Nausea, vomiting, An alternative for $$

ethylsuccinate daily divided epigastric distress, penicillin-allergic
BID-QID × 10 diarrhea, elevated patients.
EES, generics
days liver enzymes, Available as
Children: 40–50 cholestatic jaundice. suspension.
mg/kg po daily
divided BID-QID ↑ levels of atorvastatin,
× 10 days; max carbamazepine, digoxin,
1 g/day lovastatin, prednisone,
simvastatin,
theophylline.
Penicillins amoxicillin 40 mg/kg po Usually well Available as chewable $$ b

generics daily divided tolerated. tablets and
BID-TID × 10 Rash, anaphylaxis suspension.
days (rare).
Penicillins penicillin V potassium Adults: 300 mg Anaphylaxis, Drug of choice. $

generics po TID or 600 gastrointestinal Oral route for
mg po BID × 10 upset, diarrhea. penicillin preferred.
days
Children: 25–50
mg/kg po daily
divided BID
Page 691
Therapeutic Choice
Costa
9
Penicillinase- amoxicillin/clavulanate 2 Diarrhea, May be used for $$

Adults: 500 mg
resistant po BID × 10 gastrointestinal treatment in
Penicillins Clavulin, generics days upset, anaphylaxis symptomatic patients
(rare). with multiple,
Children:2 40
recurrent episodes of
mg/kg po daily 2
divided TID × pharyngitis.
10 days; max Available as
dose of suspension.
amoxicillin: 750
mg/day
a.
Cost of 10-day supply of tablets for adult dosage (except 5 days for azithromycin); includes drug cost only.
b.
Legend: $ < $5 $$ $5–15 $$$ $15–25 $$$$ $25–35
Suggested Readings
Bisno AL, Gerber MA, Gwaltney JM et al. Practice guidelines for the diagnosis and management of group A
streptococcal pharyngitis. Infectious Diseases Society of America. Clin Infect Dis 2002;35(2):113-25.
Dajani A, Taubert K, Ferrieri P et al. Treatment of acute streptococcal pharyngitis and prevention of rheumatic fever:
a statement for health professionals. Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease of the
Council on Cardiovascular Disease in the Young, the American Heart Association. Pediatrics 1995;96(4 Pt 1):758-64.
Gerber MA. Diagnosis and treatment of pharyngitis in children. Pediatr Clin North Am 2005;52(3):729-47,vi.
Linder JA, Bates DW, Lee GM et al. Antibiotic treatment of children with sore throat. JAMA 2005;294(18):2315-22.
Martin JM, Green M. Group A streptococcus. Semin Pediatr Infect Dis 2006;17(3):140-8.
References
1. Wannamaker LW. Perplexity and precision in the diagnosis of streptococcal pharyngitis. Am J Dis Child
1972;124(3):352-8.
2. Bisno AL, Gerber MA, Gwaltney JM et al. Practice guidelines for the diagnosis and management of group A
streptococcal pharyngitis. Infectious Diseases Society of America. Clin Infect Dis 2002;35(2):113-25.
3. Catanzaro FJ, Stetson CA, Morris AJ et al. The role of the streptococcus in the pathogenesis of rheumatic
fever. Am J Med 1954;17(6):749-56.
4. Bisno AL. Group A streptococcal infections and acute rheumatic fever. N Engl J Med 1991;325(11):783-93.
5. Gerber MA. Diagnosis and treatment of pharyngitis in children. Pediatr Clin North Am 2005;52(3):729-47, vi.
6. Randolph MF, Gerber MA, DeMeo KK et al. Effect of antibiotic therapy on the clinical course of streptococcal
pharyngitis. J Pediatr 1985;106(6):870-5.
7. Carapetis JR, McDonald M, Wilson NJ. Acute rheumatic fever. Lancet 2005;366(9480):155-68.
8. Tanz RR, Poncher JR, Corydon KE et al. Clindamycin treatment of chronic pharyngeal carriage of group A
streptococci. J Pediatr 1991;119(1 Pt 1):123-8.
Page 692
Therapeutic Choice
9. Rosser W, Pennie R, Pilla N; Anti-infective Review Panel. Anti-infective guidelines for community-acquired
infections. Toronto (ON): MUMS Guideline Clearinghouse; 2005.
Page 693
e-Therapeutics+ : Therapeutics : Infectious Diseases: Travellers' Diarrhea Page 1 of 8
Therapeutic Choice
Print Close
Infectious Diseases: Travellers' Diarrhea

Laurence Green, MD, FRCPC
J. Dick MacLean, MD, FRCPC
Travellers' diarrhea is defined as the passage of three or more unformed stools in a 24-hour period plus at least one
symptom of enteric disease such as abdominal pain or cramps, nausea, vomiting, fever or tenesmus.1 Diarrhea
develops in 15–40% of travellers in less developed countries. In 10% of travellers, fever and/or bloody stools may
2
occur. Most cases in adults are caused by bacteria, predominantly enterotoxigenic Escherichia coli (ETEC) as well as
Campylobacter, Salmonella and Shigella.3 Other pathogens include viruses (norovirus, rotavirus) and protozoa, e.g.,
4
Giardia intestinalis. Recent studies suggest that enteroaggregative E. coli also plays a substantial role. Incubation
5
periods are short, and many patients develop diarrhea within the first week of travel. Because of this and the
frequent unavailability of reliable medical care, travellers must be prepared to institute self-therapy.
Goals of Therapy
Reduce risk of infection in travellers

Limit duration and severity of symptoms while travelling and during the immediate post-travel period
Investigations
Counsel travellers about self-diagnosis

distinguish mild symptoms (abdominal cramps, malaise, nausea and frequent bowel movements) from the
high fever and bloody and mucoid stools of more severe infection requiring urgent antibiotic therapy
Patients developing symptoms after returning home or presenting with symptoms persisting more than two
weeks after their return should be evaluated by:
history (e.g., destination and season of travel) and physical examination (signs of volume depletion,
abdominal tenderness/guarding)
stool for occult blood
consider stool cultures especially in cases of dysentery, in food handlers and in health- and childcare
workers
consider stool parasitology exams for diarrhea persisting more than two weeks after return
Prevention
Therapeutic Choices
Therapeutic Choices
“Boil it, cook it, peel it or forget it.”

Drink only boiled, bottled or carbonated beverages. Avoid bottled drinks if the cap is not sealed and intact.
6
Boil clear water for one minute at altitudes under 2000 m (three minutes above 2000 m) or sterilize water (five
drops of 2% tincture of iodine per litre of clear water, or iodine water purification tablets or iodinizing resin
filters).
Avoid ice cubes unless made from safe water.
Eat fruit (including tomatoes) only if it has been washed in safe water and peeled. Do not eat watermelon.
Avoid salads and raw vegetables.
Eat only thoroughly and recently cooked meats or fish.
Avoid leftovers and condiments in open bottles.
Page 694
Therapeutic Choice
Avoid food from street vendors.
Wash hands with soap and water before eating. Waterless hand sanitizers are also effective if hands are not
visibly dirty.
Bismuth Subsalicylate (BSS)
Prophylactic use of bismuth subsalicylate (BSS), given QID with food, decreases attack rates of travellers'
7
diarrhea from 40% to 14% when compared to placebo; twice-daily dosing is less effective. BSS may have
antibacterial activity as well as antisecretory and anti-inflammatory properties. Do not recommend BSS in travellers
taking anticoagulants or salicylates or who are allergic to salicylates. Side effects are minimal with short-term use
(less than three weeks) at recommended doses. Black stools produced by BSS may create diagnostic confusion by
simulating melena.
Antibiotics
Give antibiotic prophylaxis only for short courses, i.e., less than three weeks, to those at increased health risk (e.g.,
the chronically ill or immunocompromised patient), or for persons who undertake critical travel (e.g., diplomatic
missions) or get diarrhea every time they travel.
Fluoroquinolones (norfloxacin, ofloxacin, ciprofloxacin) effectively reduce attacks of travellers' diarrhea by up

8 , 9 10
to 90% and are relatively safe, although bacterial resistance severely limits their use in Thailand, India and
Nepal 11 and Indonesia. There is a risk, although low, of Clostridium difficile-associated diarrhea in travellers taking
antibiotic prophylaxis or antibiotics for any purpose. Sulfamethoxazole/trimethoprim and doxycycline are no
1
longer recommended due to significant bacterial resistance.
Rifaximin, a rifamycin-derived, nonabsorbable antibiotic, has shown good preventive efficacy relative to placebo
(74% relative risk reduction).13 Because it is not systemically absorbed, side effects are few and relatively mild.
Rifaximin is not available in Canada.
Vaccines
An inactivated oral cholera vaccine contains the B subunit of cholera toxin, which has significant homology with
14
the toxin of ETEC. It has protective efficacy of about 50% against ETEC and 25% against all travellers’ diarrhea.
Because of its low efficacy and the rapid response to self-treatment, the inactivated oral cholera
15
vaccine is not routinely recommended. It is recommended for travellers at unusually high risk such
16
as relief or aid workers, or health care professionals working in cholera risk zones. Immunization for
Travellers from the Public Health Agency of Canada is available at www.phac-aspc.gc.ca/publicat/cig-
gci/ Useful Info?
Probiotics
There is currently little evidence that probiotics such as Lactobacillus spp. or Saccharomyces boulardii are effective
17 , 18
in the prevention of travellers' diarrhea.
Self-Treatment
Therapeutic Choices
Therapeutic Choices (Figure 1 - Self-Management of Travellers' Diarrhea in Adults)
Page 695
Therapeutic Choice
Travellers with mild diarrhea may benefit from a clear fluid diet of carbonated, noncaffeinated beverages,
canned fruit juices, safe water, clear salty soups and salted crackers.
Oral Rehydration Salts (ORS)
Oral hydration, especially in infants, pregnant women and the frail elderly, is the cornerstone of all therapy.
Commercially available sachets of oral rehydration salts (e.g., Gastrolyte, Pedialyte) are dissolved in safe water
and the resulting liquid is consumed until thirst is quenched. The traveller should carry sufficient sachets to produce
two to four litres of oral rehydration solution.
If ORS is unavailable, an emergency but less ideal substitute can be prepared by adding 1 level teaspoon (5 mL) of
17
table salt and 6 teaspoons (30 mL) of sugar to 1 litre of safe water. Alternatively, 1/4 teaspoon (1 mL) of baking
soda, 1/8 teaspoon (0.5 mL) of salt and 1/2 teaspoon (2.5 mL) of pasteurized honey can be added to 1 cup (240
17
mL) of fruit juice. These ingredients may be harder to find.
Antimotility Agents
Do not use antimotility agents in children under three years of age (due to the risk of developing toxic megacolon
and obscuring the severity of fluid loss) or in patients with bloody diarrhea and fever (temperature > 38.5°C).
Loperamide provides relief for mild to moderate diarrhea (up to three to five loose stools per day and mild
19
cramping pain) in adults and older children. The combination of loperamide and an antibiotic is more effective
than either alone in reducing the duration of diarrhea.20 , 21 Diphenoxylate with atropine is not as effective as
loperamide and has a less favourable side effect profile. It has been shown to prolong symptoms in infection
22
secondary to Shigella.
Antibiotics
Travellers' diarrhea (commonly caused by ETEC) is usually a mild, self-limited disease that responds promptly to
appropriate therapy. Advise patients to take a one- to three-day course of antibiotics with them on their travels and
to initiate therapy with the onset of symptoms, especially in the case of severe diarrhea with cramps, bloody
diarrhea or high fever. Mild diarrhea can be managed with fluids and antimotility agents.
The fluoroquinolones (ciprofloxacin, ofloxacin or norfloxacin) effectively reduce the duration of diarrhea by
23 , 24
more than 50% relative to placebo. In Thailand, the most common cause of dysentery is Campylobacter.
Campylobacter is generally fluoroquinolone-resistant, thus azithromycin has become the travellers' diarrhea
antibiotic of choice.25 Similar recommendations exist in India, Indonesia and Nepal due to the high frequency of
fluoroquinolone-resistant Campylobacter. Despite lack of data, it is reasonable to extend this recommendation to
other Southeast Asian and Indian subcontinent countries.
Sulfamethoxazole/trimethoprim is ineffective against Campylobacter and should be used only in areas with low
rates of this infection, e.g., inland Mexico during summer.
Several clinical trials have shown the effectiveness of a single dose of antibiotic in the treatment of travellers'
diarrhea (see Table 1 for recommended doses). The addition of loperamide to a single dose of antibiotic appears to
17 , 20 , 26
be particularly effective.
Travellers' Diarrhea in Children
The management of travellers' diarrhea in children and infants is difficult because of the increased risk and rapid
onset of severe and life-threatening dehydration, different infectious agents (e.g., rotavirus in children under three)
and more limited antibiotic choices (e.g., fluoroquinolones not recommended in children). Advise parents to travel
with oral rehydration salts and educate them regarding their use. Seek medical help early. Do not use
loperamide in children under three. Use loperamide sparingly, if at all, in older children. Bismuth subsalicylate
(BSS) is contraindicated in children less than three years of age and should be used cautiously in older children.
Page 696
Therapeutic Choice
Use of sulfamethoxazole/trimethoprim in children is limited by the same resistance problems seen in adults.
Ciprofloxacin has been avoided because of concern over its potential effects on cartilage development. However,
studies in the past decade have not shown a problem with the short courses (one to three days) that are used to
27
treat travellers' diarrhea.
Therapeutic Tips
Mild travellers' diarrhea usually resolves within 24 hours with antimotility agents and fluids.
Discourage the use of over-the-counter drugs purchased abroad as they are ineffective for both prophylaxis and
treatment. Some foreign products contain chloramphenicol, which may induce aplastic anemia, or
iodochlorhydroxyquin, which can cause neurologic damage and optic atrophy with prolonged use.
Investigate symptoms persisting more than two weeks after the return home (history, physical and stool
parasitology as part of a first-line investigation). Irritable bowel disease is common. Also consider parasitic
infection, antibiotic-associated colitis, disaccharidase deficiency and bowel carcinoma. Inflammatory bowel
disease or celiac disease may be unmasked by an episode of travellers' diarrhea.
Advise patients to seek medical attention if, despite therapy, symptoms have not improved within 48 hours.
Figure 1-Self-Management of Travellers' Diarrhea in Adults
Abbreviations: BM = bowel movements
Page 697
Therapeutic Choice
Table 1: Drugs Used for the Treatment and Prevention of Travellers' Diarrhea
Adverse Costa
Class Drug Dose Effects Comments
Antiperistaltics loperamide Adults: Treatment: Abdominal Do not use in children $

Imodium, Riva- 4 mg initially, then cramping, < 3 y. Use with an
Loperamide, 2 mg after each loose rarely dizziness, antibiotic only if
other generics stool (max 16 mg/day) dry mouth, skin experiencing fever or
Children: Treatment: rash. bloody stools.
1–2 mg initially, then Prophylactic
1–2 mg after each antimotility agents
loose stool (max 3 mg have no effect in
daily for ages 3–5 y, preventing travellers'
4 mg daily for ages diarrhea.
5–8 y and 6 mg daily
for ages 8–12 y)
Fluoroquinolones ciprofloxacin Adults: Treatment: 500 Infrequent GI Not recommended in $

Cipro, generics mg BID po × 3 days or disturbance, southeast Asia and
750 mg single dose po CNS effects, Indian subcontinent.
Prophylaxis:b 500 mg skin rash.
once daily po
Children: Not
recommended
Fluoroquinolones norfloxacin Adults: Treatment: 400 Infrequent GI Avoid in children. $

generics mg BID × 3 days or disturbance,
800 mg single dose CNS effects, Not recommended in
b skin rash. southeast Asia and
Prophylaxis: 400
mg/day Indian subcontinent.
Children: Not
recommended
Fluoroquinolones ofloxacin Adults: Treatment: 200 Infrequent GI Avoid in children. $

generics –300 mg BID × 3 days disturbance,
or 400 mg as a single CNS effects, Not recommended in
dose skin rash. southeast Asia and
b Indian subcontinent.
Prophylaxis: 300 mg
daily
Children: Not
recommended
Intestinal bismuth Adults: Treatment: Blackening of Avoid in patients taking $

Adsorbants subsalicylate 524 mg (2 tablets) or stools and therapeutic doses of
Pepto-Bismol, 30 mL suspension tongue, mild salicylates or in whom
generics Q30min (max 8 tinnitus. salicylates are
doses/day) contraindicated (e.g.,
Page 698
Therapeutic Choice
a
Adverse Cost
Prophylaxis: 524 mg (2 children and pregnant
tablets) or 30 mL women).
suspension TID and BID dosing is less
QHS effective than QID
dosing in treating
Children: Treatment: travellers’ diarrhea.
Give the following
amounts of bismuth Avoid concomitant use
subsalicylate with doxycycline: ↓
17.6 mg/mL doxycycline absorption.
suspension Q30min
(max 8 doses per 24
h):
10–14 y: 15 mL
5–9 y: 7.4 mL
3–4 y: 5 mL
Macrolides azithromycin Adults: Treatment: GI disturbance Drug of choice for $$

Zithromax, 500 mg daily × 3 days infrequently. southeast Asia and
generics or 1000 mg single Indian subcontinent.
dose Can be used in children
Children: Treatment: 5 and in pregnancy.
–10 mg/kg (max 500
mg) daily × 1–3 days Available as
suspension.
Not recommended for

prophylaxis.
Sulfonamides sulfamethoxazole / Adults: Treatment: GI Available as $

trimethoprim 800/160 mg BID × 3 disturbances, suspension.
days or 1600/320 mg blood Only for regions where
generics
as a single dose dyscrasias, skin sulfamethoxazole/
b reactions, trimethoprim resistance
Prophylaxis:
800/160 mg daily Stevens- is uncommon (central
Johnson Mexico in summer);
Children ≤ 12 y: syndrome not first choice in other
Treatment: (rare). geographic areas.
sulfamethoxazole 20–
25 mg/kg +
trimethoprim 4–5
mg/kg (as pediatric
suspension) BID × 3
days
Vaccines Vibrio cholerae Prevention of Variable protection for $$$/1

whole cell/B enterotoxigenic E. coli travellers’ diarrhea. Not dose
subunit vaccine diarrhea: routinely recommended
Dukoral Adults and children ≥ due to low efficacy
2 y: Primary rates.
immunization: 2 doses. Limited protection
2nd dose administered against heat-labile
within 7–42 days after
Page 699
Therapeutic Choice
Adverse Costa
the 1st dose and at enterotoxin-producing
least 1 week before E. coli.
reaching destination.
Booster: 1 dose every

3 mo if the risk is
continuous.
Take orally on an
empty stomach (do not
take food or drink 1 h
before or 1 h after
administration of
vaccine).
a.
Cost of three-day treatment for adults unless otherwise specified; includes drug cost only.
b.
Prophylactic treatment should be started on the first day in the area of risk and continued for one or two days after return
home, to a maximum of three weeks total.
Legend: $ < $10 $$ $10–20 $$$ $20–30
Suggested Readings
Adachi JA, Ostrosky-Zeichner L, DuPont HL et al. Empirical antimicrobial therapy for traveler's diarrhea. Clin Infect
Dis 2000;31(4):1079-83.
Committee to Advise on Tropical Medicine and Travel (CATMAT). An Advisory Committee Statement (ACS).
Statement on travellers' diarrhea. Can Commun Dis Rep 2001;27:1-12.
Diemert DJ. Prevention and self-treatment of traveler’s diarrhea. Clin Microbiol Rev 2006;19(3):583-94.
Plourde PJ. Travellers’ diarrhea in children. Paediatr Child Health 2003;8(2):99-103.
References
1. Hill DR, Ericsson CD, Pearson RD et al. The practice of travel medicine: guidelines by the Infectious Diseases
Society of America. Clin Infect Dis 2006;43(12):1499-539.
2. DuPont HL. New insights and directions in traveler's diarrhea. Gastroenterol Clin North Am 2006;35(2):337-
53.
3. Black RE. Epidemiology of travelers' diarrhea and relative importance of various pathogens. Rev Infect Dis
1990;12(Suppl 1):S73-9.
4. Adachi JA, Jiang ZD, Mathewson JJ et al. Enteroaggregative Escherichia coli as a major etiologic agent in
traveler's diarrhea in 3 regions of the world. Clin Infect Dis 2001;32(12):1706-9.
5. Steffen R, van der Linde F, Gyr K et al. Epidemiology of diarrhea in travelers. JAMA 1983;249(9):1176-80.
6. Centers for Disease Control and Prevention.Travelers' health: yellow book. Atlanta (GA): CDC; 2008. Available
from: http://wwwn.cdc.gov/travel/ybToc.aspx. Accessed December 4, 2008.
7. DuPont HL, Ericsson CD, Johnson PC et al. Prevention of travelers' diarrhea by the tablet formulation of
bismuth subsalicylate. JAMA 1987;257(10):1347-50.
8. Rademaker CM, Hoepelman IM, Wolfhagen MJ et al. Results of a double-blind placebo-controlled study using
ciprofloxacin for prevention of travelers' diarrhea. Eur J Clin Microbiol Infect Dis 1989;8(8):690-4.
Page 700
Therapeutic Choice
9. Wistrom J, Norrby SR, Burman LG et al. Norfloxacin versus placebo for prophylaxis against travellers'
diarrhoea. J Antimicrob Chemother 1987;20(4):563-74.
10. Jain D, Sinha S, Prasad KN et al. Campylobacter species and drug resistance in a north Indian rural
community. Trans R Soc Trop Med Hyg 2005;99(3):207-14.
11. Shlim DR. Update in traveler's diarrhea. Infect Dis Clin North Am 2005;19(1):137-49.
12. Oyofo BA, Lesmana M, Subekti D et al. Surveillance of bacterial pathogens of diarrhea disease in Indonesia.
Diagn Microbiol Infect Dis 2002;44(3):227-34.
13. DuPont HL, Jiang ZD, Okhuysen PC et al. A randomized, double-blind, placebo-controlled trial of rifaximin to
prevent travelers' diarrhea. Ann Intern Med 2005;142(10):805-12.
14. Peltola H, Siitonen A, Kyronseppa H et al. Prevention of travellers' diarrhoea by oral B-subunit/whole-cell
cholera vaccine. Lancet 1991;338(8778):1285-9.
15. Committee to Advise on Tropical Medicine and Travel (CATMAT); National Advisory Committee on
Immunization (NACI). Statement on new oral cholera and travellers' diarrhea vaccination. Can Commun Dis
Rep 2005;31(ACS-7):1-11.
16. National Advisory Committee on Immunization. Canadian immunization guide. 7th edition. Ottawa (ON): Public
Health Agency of Canada; 2006. Available from: http://www.phac-aspc.gc.ca/publicat/cig-gci/pdf/cig-gci-
2006_e.pdf. Accessed December 4, 2008.
17. Committee to Advise on Tropical Medicine and Travel (CATMAT). An Advisory Committee Statement (ACS).
Statement on travellers' diarrhea. Can Commun Dis Rep 2001;27:1-12.
18. Adachi JA, Ostrosky-Zeichner L, DuPont HL et al. Empirical antimicrobial therapy for traveler's diarrhea. Clin
Infect Dis 2000;31(4):1079-83.
19. Johnson PC, Ericsson CD, DuPont HL et al. Comparison of loperamide with bismuth subsalicylate for the
treatment of acute travelers' diarrhea. JAMA 1986;255(6):757-60.
20. Ericsson CD, DuPont HL, Mathewson JJ et al. Treatment of traveler's diarrhea with sulfamethoxazole and
trimethoprim and loperamide. JAMA 1990;263(2):257-61.
21. Taylor DN, Sanchez JL, Candler W et al. Treatment of travelers' diarrhea: ciprofloxacin plus loperamide
compared with ciprofloxacin alone. A placebo-controlled, randomized trial. Ann Intern Med 1991;114(9):731-
4.
22. DuPont HL, Hornick RB. Adverse effect of lomotil therapy in shigellosis. JAMA 1973;226(13):1525-8.
23. DuPont HL, Ericsson CD, Mathewson JJ et al. Five versus three days of ofloxacin therapy for traveler's
diarrhea: a placebo-controlled study. Antimicrob Agents Chemother 1992;36(1):87-91.
24. Salam I, Katelaris P, Leigh-Smith S, et al. Randomised trial of single-dose ciprofloxacin for travellers'
diarrhoea. Lancet 1994;344(8936):1537-9.
25. Kuschner RA, Trofa AF, Thomas RJ et al. Use of azithromycin for the treatment of Campylobacter enteritis in
travelers to Thailand, an area where ciprofloxacin resistance is prevalent. Clin Infect Dis 1995;21(3):536-41.
26. Ericsson CD, DuPont HL, Mathewson JJ. Single dose ofloxacin plus loperamide compared with single dose or
three days of ofloxacin in the treatment of traveler's diarrhea. J Travel Med 1997;4(1):3-7.
27. Grady R. Safety profile of quinolone antibiotics in the pediatric population. Pediatr Infect Dis J 2003;22
(12):1128-32.
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e-Therapeutics+ : Therapeutics : Infectious Diseases: Tuberculosis Page 1 of 13
Therapeutic Choice
Print Close
Infectious Diseases: Tuberculosis

Victoria J. Cook, MD, FRCPC
J. Mark FitzGerald, MD, FRCPC
Goals of Therapy
Prevent latent infection from progressing to clinically active disease

Prevent person-to-person transmission by early diagnosis, appropriate infection control and initiation of treatment
Treat active disease by eradicating Mycobacterium tuberculosis from the affected organ(s) and relieve symptoms (fever,
sweats, weight loss, cough)
Achieve cure without relapse; prevent complications; prevent development of drug resistance and death
1 , 2 , 3 , 4 , 5 , 6 , 7
Investigations

risk factors for acquisition of tuberculosis (TB), e.g., country of birth/origin, occupation, TB exposure, travel,
substandard housing (high household occupancy density, poor air quality, inadequate ventilation)8
risk factors for reactivation of latent infection, e.g., HIV/AIDS, recent TB infection, skin test conversion – previous or ≤
2 years, predisposing medical conditions such as organ transplantation, end-stage renal disease, diabetes mellitus,
hematologic malignancies, malnutrition, use of immunosuppressants (e.g., systemic corticosteroids, cancer
chemotherapy), tumor necrosis-alpha (TNF-α) inhibitors, abnormal chest x-ray or silicosis
risk factors for drug resistance, e.g., previous treatment or previous drug-resistant disease, especially if not on directly
observed therapy (DOT), noncompliance, HIV/AIDS, alcohol abuse, travel to or residence in countries with high
prevalence of TB disease or high incidence of drug-resistant disease (e.g., countries of the former Soviet Union),
contact with a patient with drug-resistant disease
Mycobacterium bovis bacillus Calmette-Guérin (BCG) vaccination, previous Mantoux (recommended method for
intradermal tuberculin skin test) history and details of previous TB treatment
nutritional status, fever, choroid tubercles, abnormal breath sounds, meningeal signs, erythema nodosum, adenopathy
concomitant diseases that may affect treatment, e.g., HIV/AIDS, chronic liver disease, chronic renal insufficiency
often unrewarding, especially for pulmonary TB
Investigations:
chest x-ray (compare to old films if available)
obtain three sputum specimens (collected once daily in the morning on three consecutive days) for acid fast bacilli
(AFB) smear and mycobacterial culture; negative sputum smears do not preclude a diagnosis of active pulmonary TB
(50% of the patients with TB have negative sputum smears)
first morning-voided midstream urine for smear (usually negative) and culture if renal TB suspected
lumbar puncture with bacterial and AFB smear (usually negative) and mycobacterial cultures plus TB DNA polymerase
chain reaction (PCR) of cerebrospinal fluid if available, plus glucose, protein, white cell count and differential if
meningitis is suspected. In patients with HIV/AIDS, cryptococcal antigen studies, viral culture and Rapid Plasma Reagin
(RPR)
9
baseline platelet count, creatinine, AST, ALT, alkaline phosphatase, bilirubin
counselling and testing for HIV infection is strongly recommended for all patients; if a patient is HIV-positive,
document CD4 count and viral load after acute illness
in HIV-positive persons, blood cultures and stool samples for mycobacteria may yield positive cultures (for both
tuberculous and nontuberculous mycobacteria)
Special procedures:
serial or repeated sputum induction in an appropriately ventilated room has a higher yield than bronchoscopy, with a
lower risk of nosocomial transmission
fibre optic bronchoscopy +/- transbronchial biopsy, especially if miliary TB is a concern. A rapid diagnosis is possible
if caseating granulomas or AFB are found on biopsy
10
gastric washings (fasting morning sample) may be positive in patients unable to produce sputum (40% effective)
aspiration of pleural effusions for AFB smear (usually negative) and culture (positive in < 25% of specimens), chemical
and cytological analysis. Diagnosis often requires pleural biopsy for culture and histology (positive 60%) via needle
biopsy or video-assisted thoracic surgery (VATS)
a combination of culture and pleural biopsy improves diagnostic yield of mycobacterial cultures to 90%
nucleic acid amplification methods are commercially available to identify mycobacteria directly from sputum specimens
(95% sensitivity, 98% specificity if smear positive; 48 to 53% sensitivity, 95% specificity if smear negative, culture
positive). Confirms the diagnosis of TB but does not replace the need for routine AFB smear and culture11 , 12
PCR for detection of mycobacteria in body fluids is used in some laboratories. Major advantage is rapid diagnosis,
generally < 48 h and it is most useful in diagnosing meningeal TB
Mantoux test (tuberculin skin test or TST) has three uses: diagnosis of infection (Figure 1 - Diagnosis and Management of
Latent M. tuberculosis Infection), diagnosis of disease (Figure 2 - Diagnosis and Management of Pulmonary M. tuberculosis
Disease) and as an epidemiologic tool. It should not be performed on persons with previous severe blistering tuberculin
Page 702
Therapeutic Choice
reactions, documented active or prior history of TB, extensive burns or eczema or a history of infections or vaccinations
with live virus vaccines in the past month, e.g., mumps or measles
48 to 72 hours after intradermal inoculation, the widest transverse diameter of induration (not erythema) is measured;
routine anergy screening is not recommended
false negative tests can occur in seriously ill patients, who are often anergic, or with inappropriate technique/reading
(e.g., drawing tuberculin material up in syringes more than 20 minutes before administration, significant exposure of
tuberculin to sunlight). Patients’ recall of test results is not reliable. Test results may vary by 15% between arms and
between observers. A negative skin test should not preclude consideration of the diagnosis of TB. False negatives can
also occur at the extremes of age
false positive tests can occur in patients with a history of BCG vaccination or exposure to nontuberculous mycobacteria
and with inappropriate technique/reading. In general, a positive Mantoux > 15 years after BCG vaccination or > 15 mm
13
induration should not be attributed to the vaccine, especially if the vaccine is given in infancy. BCG vaccination
status should not preclude the diagnosis of latent TB infection in the event of contact
reactivity to tuberculin antigen can diminish to nonreactivity with age
repeat Mantoux may boost reactivity. Thus, it is important in populations who are going to have serial Mantoux (e.g.,
nursing home residents, health care workers) to perform an initial two-step test to determine those whose response
has waned over time. A second dose is administered one to three weeks after the first. Repeated skin testing will not
induce a false-positive reaction but the initial test may stimulate the patient’s ability to react to subsequent testing
an in vitro diagnostic test, QuantiFERON-TB Gold (QFT-G), a whole blood interferon γ release assay, is available to
14 , 15
identify persons with latent TB and active TB infection; guidelines for the use of QFT-G are available; the precise
role in at-risk populations (e.g., young children, HIV/AIDS) requires further evaluation. The T SPOT-TB, an enzyme-
linked immunospot assay, is under review
Maintain a high index of suspicion for TB in immunocompromised patients as manifestations of TB are atypical. Miliary
disease is common, and sputum smears are often negative
Therapeutic Choices
All patients with known or suspected TB (usually pulmonary) should be hospitalized in a single negative pressure room and
placed on respiratory precautions or isolated at home without high risk or new contacts. Discontinue isolation when consecutive
sputum smears are negative for AFB on three separate days and there is evidence of adherence to an appropriate treatment
regimen for a minimum of two weeks with clinical and radiographic response. Continue isolation in patients with pulmonary or
laryngeal multiple drug-resistant TB for duration of hospital stay or until cultures are negative.
Proper masks (which filter particles one micron in size, have a 95% filter efficiency when tested in the unloaded state and
provide a tight facial seal) should be worn when caring for patients with known or suspected TB. Surgical masks do not prevent
the inhalation of droplet nuclei but are appropriate for infectious TB patients. All patients with a chest x-ray consistent with TB
should be isolated pending results of sputum smear for AFB. The radiographic appearance of TB is variable in patients with HIV
and may be normal (12%).
Notify the local Department of Health for contact tracing. Close follow-up is mandatory (initially, monthly visits and regular
chest radiographs with a final chest x-ray at completion of treatment). Sputum smears and cultures for AFB should be followed
monthly to monitor response to treatment and determine appropriate duration of treatment. Directly observed therapy (DOT)
should be instituted. Failure to comply with therapy is the major reason for the marked increase in cases of multidrug-resistant
TB (MDR-TB).
, 6 , 7
Adequate nutrition is necessary to enhance healing and limit the chances of relapse.16
Discourage drinking of alcohol as it is a co-factor in drug-induced hepatitis.
Pharmacologic Choices (Table 1, Table 2 and Table 3)
Directly Observed Therapy (DOT)17
DOT is the standard of care in the treatment of tuberculosis and improves treatment completion rates. DOT requires health
professionals or trained individuals to watch the patients swallow the anti-TB drugs. The DOT short-course (DOTS) strategy
recommended by WHO is a national case-based strategy which consists of five components: commitment of governments to a
national tuberculosis program; case detection by at least sputum smear microscopy among symptomatic patients; a
standardized treatment regimen for confirmed sputum smear–positive cases, with DOT for at least the initial two months; a
regular, uninterrupted supply of all essential anti-TB drugs; and a standardized recording and reporting system that enables
assessment of treatment results. Successful treatment of active TB is the responsibility of the patient, clinician, local department
of health and government.
Latent Infection (Figure 1 - Diagnosis and Management of Latent M. tuberculosis Infection)18
Patients with latent TB infection (LTBI) have low numbers of tubercle bacilli in their bodies but do not have active disease.
Compared to patients with active TB, they are asymptomatic and noninfectious. However, the risk of active disease in certain
patient groups is high (e.g., HIV/AIDS, recent TB exposure, organ transplant recipients). Treatment of LTBI with a single drug
can greatly reduce this risk. Rule out active TB prior to the initiation of treatment.
Page 703
Therapeutic Choice
In general, patients with LTBI have a 10% risk of developing TB, and isoniazid (INH) can reduce this risk by over 90% in
compliant patients. Offer treatment of LTBI for contacts, HIV-infected persons, organ transplant recipients, patients on
immunosuppressive drugs and individuals with abnormal chest radiographs (e.g., apical fibrosis or granuloma) who have a
positive Mantoux skin test of ≥ 5 mm.7
For those who have a positive Mantoux test (≥ 10 mm) and are in a lower-risk group (Figure 1 - Diagnosis and Management of
Latent M. tuberculosis Infection), the risk of adverse effects from INH must be weighed against its benefit in reducing the risk of
active disease. The risk of significant hepatitis increases with age and history of pre-existing liver disease; however, the risk of
INH-related hepatitis has been overestimated and is 1 to 3 per 1000 person years.9 , 19 Asymptomatic liver enzyme
abnormalities (minor rises in transaminases 2–3 times normal) are common. For those with risk factors for reactivating dormant
infection, age should not preclude offering LTBI treatment.
Isoniazid daily or twice weekly for nine months is the regimen of choice. If the source case may have been INH resistant or if
the patient is unable to take INH, rifampin for four months may be substituted (Table 1).7 , 20 Short-course daily prophylaxis
with rifampin and pyrazinamide (PZA) for eight weeks is no longer recommended due to high rates of hospitalization and
21 , 22 , 23 , 24 , 25 21 , 22 , 23 ,
death due to liver injury. The rate of moderate to severe liver injury using this regimen is 7.3%.
24 , 25
Consultation with a TB expert is recommended if rifampin ± pyrazinamide is used in the event of contact with drug-
resistant patients.
Baseline and monthly testing of transaminases is recommended for persons at risk for liver disease (e.g., alcohol use,
HIV/AIDS).
,
Active Tuberculosis (Figure 2 - Diagnosis and Management of Pulmonary M. tuberculosis Disease)7
26 , 27 , 28 , 29
Treat active TB with multiple drugs using DOT. Treatment usually begins with an initial (bactericidal or intensive) phase of two
months to rapidly eliminate the majority of organisms and prevent emergence of drug resistance, followed by a continuation
(sterilizing) phase of four to seven months to eradicate dormant organisms (Table 2). Knowledge of the local epidemiology of
resistance is essential to appropriate treatment. Adjust therapy when susceptibility results are available (usually one to two
months into therapy). Dose adjustments may be required for some patients (e.g., low BMI, renal insufficiency). Single drug
therapy must never be used for active TB, nor should a single drug ever be added to a failing regimen. Rifampin-based short-
course treatment (Table 2) is the standard of care. Response to treatment is monitored by monthly smear and culture of sputum
specimens, which are repeated until two consecutive samples are negative. Repeat sensitivity testing is recommended if cultures
are persistently positive after three months.
The standard short-course regimen for active TB can be used for empiric therapy in areas where there is no INH resistance. The
regimen comprises a two-month intensive phase of isoniazid, rifampin and pyrazinamide followed by a four-month
continuation phase of isoniazid and rifampin. Twice-weekly DOTS with a rifampin-containing regimen can be given after an
initial daily intensive phase or after two weeks of intensive treatment in HIV-negative patients. A longer period of treatment
(minimum nine months) is recommended for patients with drug-susceptible, cavitary pulmonary TB whose sputum cultures
remain positive after two months of treatment because of an increased risk of relapse and treatment failure.29 This may reflect
poor drug penetration at the site of disease or high bacillary burden at the time of diagnosis.30 Short-course treatment (e.g., six
months) is only recommended with rifampin-based regimens that include PZA in the intensive phase of treatment.
Research into alternative treatment includes respiratory quinolones (e.g., moxifloxacin) and ethambutol as substitutes for INH in
the intensive phase of treatment and linezolid for the treatment of multidrug-resistant tuberculosis.31 , 32 Despite widespread
use of quinolones for nontuberculous respiratory infections, there is no indication at this time of resistance in M. tuberculosis
isolates.33
Treatment interruptions for > 14 days during the initial intensive phase of treatment or for > 3 months during
the continuation phase of treatment should lead to a complete re-start of the four-drug intensive phase regimen
due to concerns about resistance. Useful Info? Consultation with a local TB expert is suggested when confronted with
treatment interruptions, treatment failure or relapse, drug intolerance or adverse effects, or multiple drug resistance.
Table 1: Standard Treatment Regimens for Latent TB Infection and Active Disease
State of
TB Regimena Frequencyb and Durationc Comment
Latent TB Isoniazid (INH) Dailyd or 2 ×/wk for 9 mo Regimen of choice

Infection
Rifampin Dailyd for 4 mo For INH-resistant strains or in patients unable to
tolerate INH
Isoniazid + Rifampin DOT: 2 ×/wk for 6 months34 Regimen studied in Canadian Aboriginal
population
Page 704
Therapeutic Choice
State of
TB Regimena Frequencyb and Durationc Comment
Active TB d
Isoniazid + Rifampin + 1) daily for 2 mo, then INH + Empiric treatment given prior to sensitivity
Disease Pyrazinamide (PZA) + Rifampin daily for 4 mo or results for areas with INH resistance ≥ 4%. In
Ethambutol (EM) areas with INH resistance < 4%, INH, rifampin
2) dailyd for 2 mo, then INH +
and PZA without EM can be used pending
Rifampin 2 ×/wk for 4 mo or
sensitivity results.
3) 3 ×/wk for 6 mo
Total duration 6 mo only if culture
conversion at 2 mo, non-cavitary
disease and fully sensitive
organism.
Extend continuation phase to 7 mo
in patients with cavitation and
positive culture at 2 mo as they are
at a higher risk of relapse29
Isoniazid + Rifampin + Dailyd for 2 mo then INH + Empiric treatment given prior to sensitivity
Ethambutol Rifampin daily for 7 mo results
a.
Second-line drugs are available in the event of intolerance or multiple drug-resistant TB: cycloserine, ethionamide, p-aminosalicylic acid,
streptomycin, amikacin and capreomycin.
b.
DOT recommended for all regimens. Twice- and thrice-weekly regimens should only be used with a DOTS program.
c. 35
Completion of therapy is not determined by the duration of therapy but by the number of doses taken.
d. 29
Daily = 7 doses/wk or 5 doses/wk DOT.
Abbreviations: DOT=directly observed therapy; DOTS=directly observed therapy, short

course; EM=ethambutol; INH=isoniazid; PZA=pyrazinamide
Multidrug-resistant TB (MDR-TB) is resistant to both isoniazid and rifampin, and extensively drug-resistant TB (XDR-TB) is
resistant to isoniazid, rifampin, quinolones and at least one of the three injectable second-line drugs (capreomycin, kanamycin,
amikacin).7 XDR-TB is associated with high mortality. Using an aggressive outpatient strategy in HIV-negative patients, the cure
rate for patients with XDR-TB was comparable to those with MDR-TB.36 A longer time to culture conversion and an extended
duration of treatment was observed in those with XDR-TB.36 Patients with MDR-TB and XDR-TB should be referred to a TB
specialist.
Table 2: Treatment Regimens for Drug-Resistant Active Tuberculosis7
Drug-Resistant
Active TB Disease Regimena Frequencyb and Durationc Comment
INH-resistant Rifampin + Pyrazinamide (PZA) + 1) dailyd or 3 ×/wk of Rifampin + EM + Consult a TB

Disease Ethambutol (EM) ± a quinolone or PZA for 6 mo or expert
Streptomycin (SM) d
2) daily for 2 mo then 2 ×/wk of Rifampin
+ EM + PZA for 7 mo or
d
3) daily EM + PZA + Rifampin for 2 mo
d
then EM + Rifampin daily for 10 mo
Rifampin-resistant Isoniazid + Pyrazinamide + Ethambutol ± 1) dailyd INH + PZA + EM + quinolone for Consult a TB
Disease a quinolone or Streptomycin 2 mo then INH + EM + quinolone for 10– expert
16 mo or
d
2) daily or 3 ×/wk INH + PZA + SM for 9
mo or
3) dailyd INH + PZA + EM for 2 mo then
daily or 2 ×/wk INH + EM for 16 mo
a.
Second-line drugs are available in the event of intolerance or multiple drug-resistant TB: cycloserine, ethionamide, p-aminosalicylic acid,
amikacin and capreomycin.
b.
DOT recommended for all regimens. Twice- and thrice-weekly regimens should only be used with a DOTS program.
c. 35
Completion of therapy is not determined by the duration of therapy but by the number of doses taken.
d. 29
Daily = 7 doses/wk or 5 doses/wk DOT.
Abbreviations: DOT=directly observed therapy; DOTS=directly observed therapy, short

course; EM=ethambutol; INH=isozianid; PZA=pyrazinamide; SM=streptomycin
Page 705
Therapeutic Choice
Antituberculous Drug-Induced Hepatotoxicity37
In LTBI, drug-induced hepatotoxicity is defined as aspartate aminotransferase (AST) level > 3 times the upper limit of normal in
symptomatic patients (i.e., nausea, vomiting, abdominal pain, jaundice) or > 5 times the upper limit of normal in asymptomatic
patients. Withhold all hepatotoxic drugs and consult a local TB specialist. For active TB disease, consider reinstituting a
nonhepatotoxic regimen (e.g., ethambutol, streptomycin and a quinolone) when or as liver test results improve. Alcohol is the
38
most important co-factor in INH-induced hepatitis.
BCG Vaccine
Though used as a preventive measure against TB globally, BCG vaccine is not used generally in Canada except in some
jurisdictions for First Nations infants.7 , 13 The vaccine efficacy has been estimated to be 51% in preventing any TB disease in
newborns.39 BCG vaccine in infants has a protective effect in preventing TB meningitis and disseminated disease.39
Tuberculosis in Special Populations
, 29
Treatment During Pregnancy and Lactation7
Treatment of pregnant women with anti-TB medications should not be withheld because of the risk of TB to the fetus. The
preferred initial treatment regimen is isoniazid, rifampin and ethambutol. The risk of teratogenicity with pyrazinamide has
not been determined though it is unlikely to be teratogenic.29 Its use should be considered if resistance to one of the initial
drugs is suspected and susceptibility to pyrazinamide is likely. Streptomycin has been associated with congenital deafness and
should not be used. Therapy for nine months with isoniazid and rifampin should be adequate if ethambutol is substituted for
pyrazinamide during the first two months and the organism is fully sensitive. Breast-feeding need not be discouraged since only
small concentrations of anti-TB drugs appear in breast milk and they do not produce toxicity in the newborn.
Pediatric Tuberculosis
40 , 41
With rare exceptions (e.g., cavitary or laryngeal tuberculosis), children with TB are not contagious. Untreated children <
5 years are at increased risk of developing severe forms of TB such as miliary or meningeal TB; treatment should be initiated
promptly upon suspicion of TB. Dose anti-TB medications by weight (mg/kg) in children. Regimens recommended in children
are similar to those used in adults, except ethambutol is not recommended in children who cannot be assessed effectively for
visual toxicity. Children < 5 years who are exposed to an active case of TB and are tuberculin skin test (TST)-negative are
eligible for primary preventative therapy with INH until a repeat TST is performed in 8 to 12 weeks.7
Extrapulmonary Tuberculosis
The basic principles of management for extrapulmonary tuberculosis are similar to pulmonary TB. Prolonged treatment (≥ 12
months) is required for bone and joint, miliary and CNS tuberculosis. Prolonged treatment may be required in patients slow to
respond. In general, corticosteroids are indicated only for meningeal and pericardial TB as they have been shown to decrease
mortality.42 , 43 Corticosteroids may have a role in adrenal TB, pleural TB and drug reactions.
HIV Infection
Principles of treatment of active TB in HIV-infected adults are similar to treatment of individuals without HIV infection.44 , 45 ,
46
Twice-weekly intermittent therapy (e.g., rifabutin and isoniazid in the continuation phase) is not recommended in patients
with HIV infection and CD4 counts < 100 cells/mm3 due to concerns that it may contribute to rifamycin resistance.47 , 48 Daily
or thrice weekly DOT is strongly recommended due to high risk of resistance and relapse of infection with less frequent
administration.29
Dose adjustments may be required for anti-TB and antiretroviral agents.45 Rifamycins may substantially decrease the
concentration of protease inhibitors (PIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs). Among the rifamycins,
rifabutin is the least potent enzyme inducer and can be substituted for rifampin with similar efficacy though dose adjustments
may still be required. Initiation of antiretroviral therapy should be delayed for at least two weeks after the start of anti-TB
therapy for patients with advanced HIV disease ( CD4 < 100 cells/mm3 ) who are not already taking antiretrovirals.7 , 49 For
patients already receiving antiretrovirals, continue therapy during anti-TB treatment, especially if it has been successful. Monitor
for signs and symptoms of immune reconstitution inflammatory syndrome (fever, malaise, local reactions in organs) if anti-TB
50 , 51
therapy and antiretroviral therapy are started at the same time. Until there have been controlled trials evaluating the
optimal time to initiate antiretroviral therapy in patients with HIV-related TB, this decision is made on an individual basis.
Management of HIV-infected patients with TB requires health care workers with expertise in these areas. Consultation with a
respirologist or TB expert with experience managing HIV-related TB is strongly recommended due to possible drug interactions
and the risk of the immune reconstitution syndrome.
Page 706
Therapeutic Choice
Therapeutic Tips
Prescribe pyridoxine 25 to 50 mg/day to prevent peripheral neuropathy in all adult patients given isoniazid.52
Recommend DOT in the treatment of TB, especially in patients with a history of treatment failure, drug resistance, disease
relapse, HIV infection, substance use or psychiatric illness and in homeless patients.
Before splitting a dose or switching to a second-line agent, consider administering first-line anti-TB drugs with some food if
patients experience stomach upset.35 Evaluate patients with GI symptoms for drug-induced hepatitis.
Figure 1-Diagnosis and Management of Latent M. tuberculosis Infection
a.
If active TB disease is suspected, isolate the patient.
b.
Consider treatment for LTBI in HIV-positive patients or other severely immunocompromised patients (e.g., those on immunosuppressive
drugs) with close contact with an active case of TB, a chest radiograph consistent with old (inactive) TB or a history of positive TST without a
history of treatment for TB or LTBI. Consider primary preventive treatment in children ≤ 5 years who have had recent contact with an active
case of TB, until repeat skin testing is available.
Abbreviations: LTBI = latent tuberculosis infection; PPD = purified protein derivative; TST = tuberculin skin test;
TU = tuberculin units
Figure 2-Diagnosis and Management of Pulmonary M. tuberculosis Disease
Page 707
Therapeutic Choice
a.
50% of pulmonary TB cases will be smear negative. Therefore, with suspicious chest radiograph and clinical scenario, consider initiating
empiric anti-TB therapy.
b.
Induced sputum has higher yield, quicker turnaround and less risk to patients or health care workers than bronchoscopy.
c.
15% of pulmonary TB cases will be culture negative but diagnosis is based on clinical and radiographic response to therapy in the
appropriate clinical setting. Abbreviations: AFB = acid fast bacilli; EM = ethambutol; INH = isoniazid; MTB = Mycobacterium tuberculosis;
PZA = pyrazinamide; Rif = rifampin; SM = streptomycin
Table 3: Antibiotics for the Treatment of M. tuberculosis
a
Cost
Aminoglycosides streptomycin Active TB disease: Vestibular/ cochlear Additive toxicity with Second-line $$$$$
Adults: 15 toxicity, ataxia other neurotoxic, agent in active
generics mg/kg/day, up to 1 g (may be ototoxic or TB disease.
permanent), nephrotoxic drugs.
Page 708
Therapeutic Choice
a
Cost
im or 15 mg/kg (up nystagmus, Avoid in
to 1.5 g) im 3 ×/wk proteinuria, children:
hypersensitivity painful
> 59 y: 10 reaction with fever, injections, risk
mg/kg/day, up to 750 rash. of irreversible
mg im Hematologic auditory nerve
b damage.
effects.
Used in TB
meningitis.
Contraindicated
in pregnancy;
associated with
congenital
deafness.
Antimycobacterial ethambutol Active TB disease: Ocular toxicity: ↓ ↓ levels with First-line agent $
Agents Etibi Adults: visual acuity, central concomitant ingestion in active TB
15–25 mg/kg/day (up scotomata, red- of aluminum disease.
to 1.6 g) or DOTS: green colour hydroxide: separate Assess colour
50 mg/kg (up to 4 g)blindness due to doses by at least 4 h. vision and
2 ×/wk or 25–30 retrobulbar neuritis visual acuity at
mg/kg (up to 2.4 g) (dose-related; rare baseline and
3 ×/wk at 15 mg/kg/day). monitor every
Skin rash: Stevens- two mo in
Children: Johnson syndrome, patients
15–20 mg/kg/day (up toxic epidermal receiving
to 1 g/day) or necrolysis. ethambutol
50 mg/kg (up to (can use
2.5 g) 2 ×/wk Hematologic Ishihara-type
b 7
effects. diagrams
available
c online).
GI upset.
Neurologic effects: Can be used in

headache, pregnancy.
dizziness,
confusion,
hallucinations.
Antimycobacterial isoniazid Latent TB Asymptomatic ↑ INH ↑ serum levels of First-line agent $

Agents Isotamine, infection: hepatic carbamazepine,phenytoin, in active TB
generics Adults: 5 mg/kg/day transaminases and theophylline. disease.
(up to 300 mg/day) bilirubin (10–20%), ↑ hepatotoxicity of INH Educate
for 9 mo or DOTS: clinical hepatitis with rifampin, ethanol, patients on
900 mg 2 ×/wk for 9 (symptoms may acetaminophen. symptoms of
mo occur within weeks hepatitis (e.g.,
to months), Cross-hepatotoxicity fatigue, flu-like
Children: peripheral may occur between symptoms,
10–15 mg/kg (up to neuropathy (dose- drugs that are anorexia,
300 mg) for 9 mo or related). chemically related nausea with or
DOTS: 20–30 mg/kg Hematologic (e.g., INH and without
(up to 900 mg) 2 b pyrazinamide). Both vomiting).
effects.
×/wk for 9 mo agents should be
avoided if a reaction Can be used in
GI upset.c
Active TB disease: to one of them occurs. pregnancy.
Gynecomastia,
Daily or alternate Prescribe
seizures,
daily therapy may be pyridoxine 25–
drowsiness, drug-
initially preferable to 50 mg/day to
induced lupus,
less frequent therapy. prevent
toxic
peripheral
encephalopathy, 52
Adults: 300 mg daily neuropathy.
fever, skin rash,
or DOTS: 15 mg/kg
mood changes,
(up to 900 mg) 2
lymphadenopathy.
×/wk or DOTS:
Page 709
Therapeutic Choice
a
Cost
15 mg/kg (up to
600 mg7 3 ×/wk.
Children:
10 mg/kg/day (up to
300 mg daily) or
DOTS: 20–30 mg/kg
(up to 900 mg) 2
×/wk
Consult expert in
patients with severe
liver disease
Antimycobacterial pyrazinamide Active TB disease: Hepatotoxicity (rare Rifampin and First-line agent $$$
Agents Adults: 25 mg/kg/day with 2 mo therapy), pyrazinamide: liver in active TB
Tebrazid, (up to 2 g/day) or rash, arthralgia, ↑ injury in patients with disease.
generics DOTS: 50 mg/kg (up uric acid (acute gout latent TB infection.23
to 4 g) 2 ×/wk or 35 rarely seen), drug ↑ pyrazinamide levels:
–40 mg/kg (up to 3 fever, GI upset. concomitant
g) 3 ×/wk Hematologic administration of
b
effects. allopurinol through
Children: inhibition of xanthine
15–30 mg/kg/day (up oxidase.
to 2 g/day) or DOTS:
50 mg/kg (up to 2 g)
2 ×/wk
Rifamycins rifabutin Active TB disease: Rash, orange Avoid combination First-line agent $$$$$
Mycobutin Adults: 5 mg/kg/day discolouration of with unboosted in active TB
(up to 300 mg/day) body fluids (contact saquinavir, disease.
lens staining), GI delavirdine. Adjust
DOTS: 5 mg/kg (up upset, liver toxicity, rifabutin dose when
to 300 mg) 2 or 3 flu-like illness, combining with
×/wk; in HIV neutropenia, atazanavir, darunavir,
patients, twice leukopenia, efavirenz,
weekly rifabutin is myalgia. fosamprenavir,
not appropriate indinavir,
lopinavir/ritonavir,
nelfinavir, tipranavir
and with various
protease inhibitors
boosted with
53
ritonavir. Consult
TB/HIV expert.
Protease inhibitors: ↓
clearance of rifamycins.
Rifamycins: ↓
effectiveness of
protease inhibitors
and NNRTIs.
↓ serum concentration
of drugs due to
hepatic enzyme
induction, e.g., oral
contraceptives,
anticoagulants,
antihyperglycemic
agents, methadone.
Adjust dose of
affected drug when
Page 710
Therapeutic Choice
a
Cost
rifabutin is initiated or
discontinued.
Rifamycins rifampin Latent TB Rash (petechial Avoid in combination First-line agent $$$
Rifadin, infection: rash may suggest with atazanavir, in active TB
Adults: thrombocytopenia), amprenavir, disease.
Rofact,
10 mg/kg/day (up to orange delavirdine, etravirine, Can be used in
generics
600 mg/day) for 4 discolouration of fosamprenavir, pregnancy.
mo body fluids (contact indinavir, nelfinavir,
lens staining), GI saquinavir and
Children: upset, liver toxicity, tipranavir. 53
10–20 mg/kg/day (up flu-like illness, sub- Lopinavir/ritonavir: ↑
to 600 mg/day) for 4 clinical ritonavir dose if used
mo disseminated concomitantly with
intravascular
rifampin.53 ↑ maraviroc
Active TB disease: coagulation,
dose if used
diarrhea, urticaria,
concomitantly with
Adults: 10 mg/kg/day ataxia, confusion, 53
(up to 600 mg/day) visual disturbances, rifampin. Consult
or DOTS: 10 mg/kg acute interstitial TB/HIV expert.
(up to 600 mg/day) 2 nephritis. Protease inhibitors: ↓
or 3 ×/wk Hematologic clearance of rifamycins.
b
effects.
Children: Rifamycins: ↓
10–20 mg/kg/day (up effectiveness of protease
to 600 mg/day) or inhibitors and NNRTIs.
DOTS: 10–20 mg/kg
(up to 600 mg/day) 2 ↓ serum concentration of
×/wk drugs due to hepatic
enzyme induction,
Consult expert in e.g., oral
patients with severe contraceptives,
liver disease. anticoagulants,
antihyperglycemic
agents, methadone.
Adjust dose of
affected drug when
rifabutin is initiated or
discontinued.
Fluoroquinolones levofloxacin Active TB disease: Abdominal pain, ↓ absorption of Second-line $$$$$

Adults: 500–1000 mg nausea, vomiting, fluoroquinolones: agent in active
Levaquin, po daily photosensitivity, concomitant iron, TB disease and
generics dizziness, calcium, zinc, for drug-
headache, antacids, sucralfate, resistant
drowsiness, didanosine (buffered disease.
insomnia, diarrhea, tablets). Separate
pseudomembranous doses by 2 h.
colitis, eosinophilic Torsades de pointes is
meningitis, possible with drugs
tendonitis and that prolong QT
rupture. Cases of interval.
severe liver injury
including liver
failure have been
reported.
Fluoroquinolones moxifloxacin Active TB disease: Abdominal pain, ↓ absorption of Second-line $$$$$

Avelox Adults: 400 mg po nausea, vomiting, fluoroquinolones: agent in active
daily photosensitivity, concomitant iron, TB disease and
dizziness, calcium, zinc, for drug-
colitis, eosinophilic
Page 711
Therapeutic Choice
a
Cost
meningitis, Torsades de pointes is
tendonitis and possible with drugs
rupture. that prolong QT
Cases of severe interval.
liver injury
including liver
failure have been
reported.
Fluoroquinolones ofloxacin Active TB disease: Abdominal pain, ↓ absorption of Second-line $$$$$

generics Adults: 400 mg po nausea, vomiting, fluoroquinolones: agent in active
BID photosensitivity, concomitant iron, TB disease and
dizziness, calcium, zinc, for drug-
colitis, eosinophilic Torsades de pointes is
meningitis, possible with drugs
tendonitis and that prolong QT
rupture. interval.
a.
Cost of 30-day supply for adult dose; includes drug cost only.
b.
Hematologic effects may include any of eosinophilia, thrombocytopenia, transient leukopenia, hemolytic anemia, agranulocytosis, or
sideroblastic or aplastic anemia.
c.
Gastrointestinal upset: nausea, vomiting, poor appetite, abdominal pain; common in the first few weeks of therapy—manage by
administering with food or at bedtime; monitor AST to rule out hepatotoxicity.
Abbreviations: DOTS=directly observed therapy, short-course; INH=isoniazid; NNRTI=non-nucleoside reverse transcriptase inhibitor
Legend: $ < $25 $$ $25–50 $$$ $50–75 $$$$ $75–100 $$$$$ > $100
Suggested Readings
American Thoracic Society; Centers for Disease Control and Prevention; Infectious Diseases Society of America. American
Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America: controlling tuberculosis in
the United States. Am J Respir Crit Care Med 2005;172(9):1169-227.
Blumberg HM, Burman WJ, Chaisson RE et al. American Thoracic Society/Centers for Disease Control and Prevention/Infectious
Diseases Society of America: treatment of tuberculosis. Am J Respir Crit Care Med 2003;167(4):603-62.
Long R, Ellis E, editors. Canadian tuberculosis standards. 6th ed. Ottawa (ON): Canadian Lung Association; Canadian Thoracic
Society and Public Health Agency of Canada; 2007. Available from: http://www.phac-aspc.gc.ca/tbpc-
latb/pubs/pdf/tbstand07_e.pdf. Accessed June 8, 2009.
World Health Organization. Tuberculosis and air travel: guidelines for prevention and control. 2nd ed. Geneva (CH): WHO; 2006.
Available from: http://www.who.int/tb/publications/2006/who_htm_tb_2006_363.pdf. Accessed June 8, 2009.
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by the Council of the Infectious Diseases Society of America. (IDSA), September 1999, and the sections of this statement.
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2. [No authors listed]. Diagnostic Standards and Classification of Tuberculosis in Adults and Children. This official statement
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44. Burman WJ, Jones BE. Treatment of HIV-related tuberculosis in the era of effective antiretroviral therapy. Am J Respir Crit
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45. Dean GL, Edwards SG, Ives NJ et al. Treatment of tuberculosis in HIV-infected persons in the era of highly active
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46. FitzGerald JM, Houston S. Tuberculosis: 8. The disease in association with HIV infection. CMAJ 1999;61(1):47-51.
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Page 714
e-Therapeutics+ : Therapeutics : Infectious Diseases: Urinary Tract Infection Page 1 of 12
Therapeutic Choice
Print Close
Infectious Diseases: Urinary Tract Infection

Lindsay E. Nicolle, MD
Goals of Therapy
Ameliorate symptoms in acute infection

Prevent complications of untreated acute infection
Prevent recurrent infection
Prevent pyelonephritis in pregnancy
Investigations (Table 1)
Note: Relapse is recurrence of urinary tract infection (UTI) with the same organism due to persistence of the
organism within the urinary tract, usually in the prostate or kidneys. Reinfection is recurrent UTI with a new
organism; it generally follows ascension of microorganisms from the periurethral area into the bladder.
Table 1: Clinical Syndromes of UTI, Infecting Organisms and Criteria for Microbiologic Diagnosis
Most Common
a
Infecting Organisms Microbiologic
Syndrome Diagnosis Urine Culture
Acute Uncomplicated UTI E. coli (80–90%), Presence of any Generally not

(Cystitis) S. saprophyticus (5– quantitative count of a recommended.
Occurs in females with normal 10%), K. pneumoniae, gram-negative Culture if failure to
genitourinary tracts. P. mirabilis, group B organism or respond to empiric
These women have a genetic Streptococcus S. saprophyticus in a therapy, early (< 1
predisposition for recurrent UTI. voided urine specimen mo) recurrence
Behavioural factors promoting with pyuria. following therapy,
infection include sexual intercourse diagnostic uncertainty
and use of spermicides or diaphragm. or pregnant patient.
Usual presenting symptoms include
internal dysuria, frequency,
suprapubic discomfort and urgency.
Recurrences are common but of
variable frequency.
Acute Nonobstructive E. coli (90%), 7 b Always indicated.

≥ 10 cfu/L in voided
Pyelonephritis P. mirabilis (5%), specimen. Obtain before initiating
Occurs in women who also experience K. pneumoniae (5%) antimicrobials.
recurrent uncomplicated UTIs, but at Consider blood
lower frequency than cystitis. cultures.
Classic presentation includes fever
and flank pain with or without
associated irritative urinary
symptoms.
Patients who present with UTIs with
only lower tract symptoms or
asymptomatic bacteriuria occasionally
have associated occult renal infection.
Bacteremic infection occurs most
frequently in diabetic women or
women > 65 y.
Complicated UTI E. coli (50%), 8 b Always, before

≥ 10 cfu/L in voided
Occurs in individuals with an P. mirabilis (20%), specimen or any antimicrobial therapy.
abnormal genitourinary tract due to E. faecalis (10%),
Page 715
Therapeutic Choice
Most Common
a
Infecting Organisms Microbiologic
Syndrome Diagnosis Urine Culture
structural or functional abnormalities P. aeruginosa, quantitative count in
including indwelling catheter. P. stuartii, Citrobacter catheterized specimen.
Patients may present with cystitis spp.,
(lower tract) symptoms or Enterobacter spp.,
fever/pyelonephritis. Serratia spp., group B
Management includes search for streptococci, coagulase-
correctable anomalies; with persistent negative staphylococci
abnormalities, recurrent infection is
common (50% by 6 wk post-therapy).
c E. coli, 8 Voided urine specimen

Bacterial Prostatitis Urine culture > 10
enterobacteriaceae, before empiric
Acute: infection usually due to E. coli cfu/Lb; blood cultures
or S. aureus. Symptoms include acute P. aeruginosa, therapy.
positive; aspirate
onset chills, fever, perineal and low S. aureus, others
prostate abscess.
back pain, irritative and obstructive
voiding. The prostate is tender,
swollen, indurated and warm.
Prostatic massage is not
recommended because it may cause
bacteremia.
Chronic Bacterial: uncommon, ↑ with E. coli (80%), Klebsiella Post prostatic massage Urine culture with
age. Intermittent urinary infection spp, P. aeruginosa, (PPM) urine culture acute symptoms.
presenting as cystitis; history of Proteus spp positive with pyuria
recurrent UTI. Prostate examination is and negative mid-
usually normal. stream urine
specimen.
Asymptomatic Bacteriuria E. coli (60–70%), 8 b Screening for

≥ 10 cfu/L in
Microbiologic evidence for UTI in the P. mirabilis, group B 2 consecutive bacteriuria is not
absence of associated symptoms. streptococcus, specimens. indicated for
Asymptomatic bacteriuria is more coagulase-negative asymptomatic patients
common in women, ↑ with age. staphylococci, others unless they are
In pregnancy, screening should be pregnant or about to
performed for asymptomatic undergo an invasive
bacteriuria at 12–16 wk. urologic procedure.
a.
E. coli is the single most frequent organism causing UTI. Individuals with complicated UTI or recent exposure to antimicrobials
are more likely to have organisms other than E. coli or organisms of increased antimicrobial resistance.
b.
107 cfu/L = 104 cfu/mL; 108 cfu/L = 105 cfu/mL.
c.
Symptoms of chronic prostatitis are not considered attributable to infection in the absence of microbiologic documentation.
1
Antimicrobial therapy does not improve these symptoms when compared to placebo.
Abbreviations: cfu=colony-forming units
Therapeutic Choices (Figure 1 - Management of Recurrent Acute, Uncomplicated UTI , Table 2)
Sulfamethoxazole/trimethoprim (SMX/TMP) and Trimethoprim (TMP)
SMX/TMP and TMP are the drugs of choice for most UTIs. Both may be used as 3-day therapy for acute
uncomplicated UTI. Resistance to SMX/TMP and TMP is increasing and must be considered in individuals who have
failed empiric therapy or who have had recent prior therapy with these agents. Use of SMX/TMP is limited by sulfa
allergy (TMP alone may be used in sulfa-allergic patients).
Page 716
Therapeutic Choice
Nitrofurantoin
Nitrofurantoin, a urinary antiseptic, has been widely used to treat UTIs. It may not be as effective as SMX/TMP for
2
3-day therapy in the treatment of acute uncomplicated UTI; however, a 5-day course is effective. It is not
recommended for treatment of pyelonephritis and is contraindicated in renal failure (creatinine clearance
< 60 mL/min). Pulmonary and hepatic toxicity, though rare, may occur but are more common with long-term use.
Nitrofurantoin macrocrystals may be better tolerated than the standard formulation.
Amoxicillin and Amoxicillin/Clavulanic Acid
Resistance of E. coli to amoxicillin limits its current use. It should be reserved for UTIs with streptococci or
enterococci or when the infecting organism is known to be susceptible.
Amoxicillin is not recommended for empiric therapy of uncomplicated UTI as it will be about 20% less effective than
3
SMX/TMP.
Amoxicillin with clavulanic acid may be considered when TMP/SMX, nitrofurantoin and fluoroquinolones cannot
be used.4 Amoxcillin with clavulanic acid is associated with substantial gastrointestinal (GI) side effects (10–25%
incidence).
Fluoroquinolones
The renally excreted fluoroquinolones (norfloxacin, ciprofloxacin, ofloxacin and levofloxacin) are as effective
as SMX/TMP for 3-day treatment of acute uncomplicated UTI due to susceptible organisms, but are generally second
-line therapy because of cost and concerns about development of resistance. Fluoroquinolones could be considered
when resistance to SMX/TMP is anticipated to be > 20% in the population in which it is being prescribed.
Single-dose therapy with fluoroquinolones is not reliable for S. saprophyticus.5 In addition, single-dose therapy may
have poor patient acceptance because symptoms persist for 48–72 hours. Fluoroquinolones are important agents in
the treatment of complicated UTI, particularly for patients infected with resistant organisms. Ciprofloxacin for 7 days
is adequate therapy for less severe presentations of acute nonobstructive pyelonephritis.6 Fluoroquinolones should
not be used in children because of potential adverse effects on developing cartilage.
Table 2: Recommended Empiric Treatment of UTI
st nd
Condition 1 Line Therapy 2 Line Therapy
Acute SMX/TMP po × 3 daysa or Fluoroquinolone po × 3 daysa or

uncomplicated a Cephalexin po × 7 days
Trimethoprim po × 3 days or
UTI
Nitrofurantoin po × 5 days
b
Pyelonephritis
c Fluoroquinolone po × 7–14 days Amoxicillin/clavulanate po × 10–14
Mild to moderate
days or
SMX/TMP po × 10–14 days or
Trimethoprim po × 10–14 days
d e Fluoroquinolone iv × 10–14 days or

Severe Aminoglycoside iv ± ampicillin iv for initial therapy.
rd
Step down to oral therapy to complete 10–14 days if 3 generation cephalosporin iv ±
clinically appropriate aminoglycoside iv × 10–14 days
Complicated UTI b
Mild to moderate c Fluoroquinolone po × 7–10 days or Amoxicillin/clavulanate po × 7–10

SMX/TMP po × 7–10 days or days
Trimethoprim po × 7–10 days or Cephalexin po × 7–10 days
Nitrofurantoin po × 7–10 days Cefixime po × 7–10 days
Page 717
Therapeutic Choice
Condition 1st Line Therapy 2nd Line Therapy
Severe d Aminoglycoside iv ± ampicilline iv × 10–14 days Fluoroquinolone iv × 10–14 days or

rd
Step down to oral therapy to complete course if 3 generation cephalosporin iv
clinically indicated × 10–14 days
Prostatitis
Acute e Fluoroquinolone iv or po or
Aminoglycoside iv ± cloxacillin iv ± ampicillin iv
SMX/TMP po
Chronic, bacterial Fluoroquinolone po × 4–8 wk SMX/TMP po × 4–6 wk
a. 3
Treat for 7 days in women with symptoms lasting > 1 wk or women with recurrent infections in < 1 month. Treat for 3 days in
7,8
women ≥ 65 years.
b.
Always obtain urine culture prior to initiating therapy, and use results to step down therapy or modify empiric therapy.
c.
Hemodynamically stable, no vomiting.
d.
High fever, sepsis, vomiting.
e.
Include ampicillin if Enterococcus is a concern.
Cephalosporins
All the cephalosporins including cephalexin, cefazolin, cefaclor, cefuroxime and cefixime are effective for
treatment of UTI. They are not as well studied as SMX/TMP or fluoroquinolones and are somewhat less effective for
acute cystitis, especially with short courses of therapy. Cephalosporins may be associated with a greater likelihood
of vulvovaginal candidiasis.9 Third-generation cephalosporins such as ceftriaxone and cefotaxime are effective
agents for parenteral treatment of pyelonephritis.
Aminoglycosides
Aminoglycosides (gentamicin, tobramycin and amikacin) remain the therapy of choice for the treatment of acute
pyelonephritis requiring parenteral therapy. Most gram-negative organisms, especially in patients with community-
acquired infections, will remain susceptible to these agents. Initial parenteral therapy is switched to oral therapy as
soon as symptoms and signs have settled (72–96 hours). With such short duration of therapy, ototoxicity and
nephrotoxicity are unlikely. The aminoglycosides are usually interchangeable for the treatment of UTI. Antimicrobial
susceptibility and cost determine selection of an individual agent.
Natural Health Products
Cranberry
A systematic review concluded that cranberry juice or tablets were effective in reducing the incidence
of UTI in young women with recurrent acute uncomplicated urinary infection; however, the optimal
10
dose and method of administration have not been identified. Cranberry products are, however, much
less effective than antimicrobial prophylaxis for prevention. Large quantities of cranberry juice may
interact with warfarin.11,12 Useful Info?
Urinary Tract Infection (UTI) and Pregnancy

13
Pregnant women should be screened for asymptomatic bacteriuria early in pregnancy. Treat if asymptomatic
bacteriuria is confirmed on two consecutive cultures. If left untreated, bacteriuria in pregnancy can progress to
14
pyelonephritis and cause adverse effects to the fetus. Antibiotic treatment has been shown to reduce the incidence
13 , 15
of pyelonephritis, rate of preterm delivery and the risk of low birth weight babies.
Page 718
Therapeutic Choice
Management of UTI in Pregnant Women
Treat asymptomatic bacteriuria and symptomatic cystitis with a 3- to 7-day course of amoxicillin (if the organism
is known to be susceptible), amoxicillin/clavulanic acid, cephalexin or nitrofurantoin with appropriate follow
-up.16
Nitrofurantoin is usually avoided near term because of hemolytic anemia induction in the fetus or newborn,
17 , 18
especially in those with glucose-6-phosphate dehydrogenase deficiency; however, this toxicity is rare. Avoid
19 , 20
trimethoprim and TMP/SMX in the first trimester of pregnancy as it is associated with antifolate teratogenicity.
Avoid sulfonamides in the last 6 weeks of pregnancy as it may lead to neonatal hyperbilirubinemia. Avoid
fluoroquinolones in pregnancy. Impaired cartilage development has been reported in animal studies though there
have been no reports suggesting an increased risk of major malformations, adverse effects in the fetal
musculoskeletal system, spontaneous abortions, prematurity, intrauterine growth retardation or postnatal
disorders.21 , 22 , 23 , 24
Ceftriaxone is the preferred empiric therapy for treating pyelonephritis in pregnancy. Step down to oral therapy
25 , 26 , 27 , 28
once the patient is stabilized and urine culture results are available.
Upon completion of therapy, follow-up with a urine culture 1 or 2 weeks later, and then monthly until the baby is
born.19
Management of UTI in Breastfeeding Women
The American Academy of Pediatrics considers fluoroquinolones (ciprofloxacin, ofloxacin), nitrofurantoin and
TMP/SMX to be compatible with breastfeeding.29 Amoxicillin and cephalosporins are, in general, considered
compatible with breastfeeding.
Prevention of UTI in Pregnant and Breastfeeding Women
Antimicrobial prophylaxis is effective to prevent recurrent symptomatic or asymptomatic urinary infection in

pregnant women. Nitrofurantoin and cephalexin are preferred. The use of cranberry products is safe in pregnancy,
but efficacy to prevent infection is not known.30
Therapeutic Tips
Whenever possible, base initial selection of antimicrobial therapy on urine culture results.
Antimicrobial susceptibility in populations is dynamic and the local prevalence of susceptibility must always be
considered.
Base selection of empiric therapy in symptomatic patients on anticipated local antimicrobial susceptibilities and
an individual patient's recent antimicrobial exposure and tolerance.
For women (including those ≥ 65 years) with uncomplicated acute bacterial cystitis, 3 days of antimicrobial
7 , 8
therapy with sulfamethoxazole/trimethoprim, trimethoprim or a fluoroquinolone, is preferred.
Use parenteral therapy for patients who are septic, unable to tolerate oral medications, pregnant with
pyelonephritis or those with resistant organisms requiring parenteral therapy.
Consider prophylaxis for women with frequent recurrent uncomplicated UTI.
Without microbiologic confirmation of a bacterial infection, symptoms of chronic prostatitis are not an indication
for antimicrobial therapy.1
Figure 1- Management of Recurrent Acute, Uncomplicated UTI
Page 719
Therapeutic Choice
a.
Three-day course of treatment, self-administered on appearance of symptoms.
Table 3: Antimicrobials for the Treatment of Urinary Tract Infection
Drug Costa
Penicillins amoxicillin Hypersensitivity ↓ efficacy of oral $

generics 500 mg TID po reactions, rash, contraceptives;
nausea, vomiting, tetracyclines ↓ the
pseudomembranous effectiveness of
colitis, GI effects. penicillins; ↑
methotrexate serum
levels.
Penicillins amoxicillin/clavulanate Hypersensitivity ↓ efficacy of oral $

Clavulin, generics 500 mg TID po reactions, rash, contraceptives;
or 875 mg BID nausea, vomiting, tetracyclines ↓ the
po pseudomembranous effectiveness of
methotrexate serum
levels.
Penicillins ampicillin 1 g Q6H iv Hypersensitivity ↓ efficacy of oral $$

generics reactions, rash, contraceptives;
methotrexate serum
levels.
Penicillins piperacillin Hypersensitivity ↓ efficacy of oral $$$$

generics 3 g Q6H iv reactions, rash, contraceptives;
Page 720
Therapeutic Choice
Drug Costa
methotrexate serum
levels.
Penicillins piperacillin/ tazobactam Hypersensitivity ↓ efficacy of oral $$$$

Piperacillin/Tazobactam for 3.375 g Q6H reactions, rash, contraceptives;
Injection, Tazocin, other
generics
methotrexate
serum levels.
Penicillins ticarcillin/clavulanate Hypersensitivity ↓ efficacy of oral $$$$

Timentin 3.1 g Q4–6H iv reactions, rash, contraceptives;
methotrexate serum
levels.
Cephalosporins, cefazolin Hypersensitivity ↑ nephrotoxic effects $$

first-generation Cefazolin for Injection, 1 g Q8H iv reactions, rash, of aminoglycosides;
nausea, vomiting, ↑ INR with warfarin.
other generics
pseudomembranous
colitis, renal and
Cephalosporins, cephalexin Hypersensitivity ↑ nephrotoxic effects $

first-generation generics 500 mg QID po reactions, rash, of aminoglycosides;
pseudomembranous
colitis, renal and
Cephalosporins, cefuroxime axetil Hypersensitivity ↑ nephrotoxic effects $

second- Ceftin, generics 250 mg BID po reactions, rash, of
generation nausea, vomiting, aminoglycosides;
pseudomembranous ↑ INR with warfarin.
colitis, renal and
Cephalosporins, cefuroxime sodium Hypersensitivity ↑ nephrotoxic $$$

second- generics 750 mg Q8H iv reactions, rash, effects of
generation nausea, vomiting, aminoglycosides;
colitis, renal and
Cephalosporins, cefixime Hypersensitivity ↑ nephrotoxic effects $

third-generation Suprax 400 mg/day po reactions, rash, of aminoglycosides;
pseudomembranous
colitis, renal and
Cephalosporins, cefotaxime Hypersensitivity ↑ nephrotoxic effects $$$

third-generation Claforan 1 g Q8H iv reactions, rash, of aminoglycosides;
pseudomembranous
colitis, renal and
Safe in hepatobiliary
disease.
Page 721
Therapeutic Choice
a
Drug Cost
Cephalosporins, ceftazidime Hypersensitivity ↑ nephrotoxic effects $$$$

third-generation Fortaz, generics 1 g Q8H iv reactions, rash, of
nausea, vomiting, aminoglycosides;
colitis, renal and
Cephalosporins, ceftriaxone Hypersensitivity ↑ nephrotoxic effects $$

third-generation Ceftriaxone for Injection 1 g Q24H iv reactions, rash, of
nausea, vomiting, aminoglycosides;
USP, Rocephin,
other generics
colitis, renal and Do not
hepatic dysfunction. reconstitute or
mix with calcium-
containing
solutions.
Do not administer
simultaneously
with calcium-
containing iv
solutions via a Y-
site.
Administration
may be done
sequentially
provided the
infusion lines are
thoroughly
flushed between
infusions.
Fluoroquinolones ciprofloxacin Oral: Immediate Abdominal pain, Concomitant iron, PO: $

Cipro, Cipro XL, -release: 250– nausea, vomiting, antacids, IV:
500 mg BID po photosensitivity, sucralfate ↓ $$-
generics
Long-acting: dizziness, headache, absorption of $$$
500–1000 mg drowsiness, fluoroquinolones;
daily po insomnia, diarrhea, ↑ INR with warfarin;
IV: 200– pseudomembranous may ↓ theophylline
400 mg BID colitis. and caffeine
Potential adverse elimination.
effects on
developing
cartilage; avoid in
children and in
pregnancy.
Fluoroquinolones levofloxacin Abdominal pain, Iron, antacids, PO: $

Levaquin, generics 250 mg/day po nausea, vomiting, sucralfate ↓ IV:
or photosensitivity, absorption of $$
dizziness, headache, quinolones; ↑ INR
250 mg/day iv drowsiness, with warfarin.
insomnia, diarrhea,
pseudomembranous
colitis.
Potential adverse
effects on
developing
Page 722
Therapeutic Choice
Drug Costa
cartilage; avoid in
children and in
pregnancy.
Fluoroquinolones norfloxacin Abdominal pain, Concomitant iron, $

generics 400 mg BID po nausea, vomiting, antacids,
photosensitivity, sucralfate ↓
dizziness, headache, absorption of
drowsiness, fluoroquinolones;
insomnia, diarrhea, ↑ INR with warfarin;
pseudomembranous may ↓ theophylline
colitis. and caffeine
Potential adverse elimination.
effects on
developing
cartilage; avoid in
children and in
pregnancy.
Fluoroquinolones ofloxacin Abdominal pain, Iron, antacids, $

generics 400 mg BID po nausea, vomiting, sucralfate ↓
photosensitivity, absorption of
dizziness, headache, quinolones; ↑ INR
drowsiness, with warfarin.
insomnia, diarrhea,
pseudomembranous
colitis.
Potential adverse
effects on
developing
cartilage; avoid in
children and in
pregnancy.
Aminoglycosides amikacin Nephrotoxicity, ↑ ototoxicity with loop $$$$

15 mg/kg/day iv usually reversible, ↑ diuretics, ↑ b
generics
with dose and nephrotoxicity with
duration; other nephrotoxic
ototoxicity, often drugs; can be
reversible. inactivated if
mixed with some
penicillins.
Aminoglycosides gentamicin 3–5 mg/kg/day Nephrotoxicity, ↑ ototoxicity with $$-

generics iv usually reversible, ↑ loop diuretics, ↑ $$$ b
mixed with some
penicillins.
Aminoglycosides tobramycin 3–5 mg/kg/day Nephrotoxicity, ↑ ototoxicity with $$-

generics iv usually reversible, ↑ loop diuretics, ↑ $$$ b
mixed with some
penicillins.
Page 723
Therapeutic Choice
Drug Costa
Sulfonamide sulfamethoxazole / 800/160 mg (2 Hypersensitivity ↑ phenytoin levels, ↑ $

Combinations trimethoprim (SMX/TMP) regular-strength reactions, nausea, INR with warfarin,
tablets or 1 DS vomiting, diarrhea, hypoglycemia
generics
tablet) BID po rash, false ↑ serum with
creatinine, renal sulfonylureas, ↑
impairment, nephrotoxicity with
neutropenia, cyclosporine.
thrombocytopenia,
anemia,
agranulocytosis.
Folate trimethoprim Rash, pruritus. ↑ phenytoin levels; $

Antagonists generics 100 mg BID po ↑ myelosuppression
with methotrexate.
Nitrofuran nitrofurantoin Headache, nausea, Antacids may ↓ $

Derivatives generics 50–100 mg QID flatulence, loss of absorption.
po appetite; pulmonary
and hepatic toxicity
with long-term use;
rare acute
pulmonary toxicity.
Nitrofuran nitrofurantoin Headache, nausea, Antacids may ↓ $

Derivatives monohydrate/nitrofurantoin 100 mg BID po flatulence, loss of absorption.
macrocrystals appetite; pulmonary
MacroBID and hepatic toxicity
with long-term use;
rare acute
pulmonary toxicity.
Macrocrystal
formulation better
tolerated.
a.
Cost per day; includes drug costs only.
b.
Abbreviations: GI=gastrointestinal; INR=International Normalized Ratio
Legend: $ < $10 $$ $10–25 $$-$$$ $10–50 $$$ $25–50 $$$$ $50–75 $$$$$ > $75
Suggested Readings
Habermacher GM, Chason JT, Schaeffer AJ. Prostatitis/chronic pelvic pain syndrome. Annu Rev Med 2006;57:195-
206.
Hooton TM, Stamm WE. Diagnosis and treatment of uncomplicated urinary tract infection. Infect Dis Clin North Am
1997;11(3):551-81.
Nicolle L; AMMI Canada Guidelines Committee. Complicated urinary tract infection in adults. Can J Infect Dis Med
Microbiol 2005;16(6):349-60.
Nicolle LE, Bradley S, Colgan R et al. Infectious Diseases Society of America guidelines for the diagnosis and
treatment of asymptomatic bacteriuria in adults. Clin Infect Dis 2005;40(5):643-54.
Nicolle LE. Uncomplicated urinary tract infection in adults, including uncomplicated pyelonephritis. Urol Clin North
Am 2008;35(1):1-12.
Page 724
Therapeutic Choice
References
1. Alexander RB, Propert KJ, Schaeffer AJ et al. Ciprofloxacin or tamsulosin in men with chronic
prostatitis/chronic pelvic pain syndrome: a randomized, double-blind trial. Ann Intern Med 2004;141(8):581-
9.
2. Gupta K, Hooton TM, Roberts PL et al. Short-course nitrofurantoin of acute uncomplicated cystitis in women.
Arch Intern Med 2007;167(20):2207-12.
3. Warren JW, Abrutyn E, Hebel JR et al. Guidelines for antimicrobial treatment of uncomplicated acute bacterial
cystitis and acute pyelonephritis in women. Infectious Diseases Society of America (IDSA). Clin Infect Dis
1999;29(4):745-58.
4. Hooton TM, Scholes D, Gupta K et al. Amoxicillin-clavulanate vs ciprofloxacin for the treatment of
uncomplicated cystitis in women: a randomized trial. JAMA 2005;293(8):949-55.
5. Richard GA, Mathew CP, Kirstein JM et al. Single-dose fluoroquinolone therapy of acute uncomplicated urinary
tract infection in women: results from a randomized, double-blind, multicenter trial comparing single-dose to
3-day fluoroquinolone regimens. Urology 2002;59(3):334-9.
6. Talan DA, Stamm WE, Hooton TM et al. Comparison of ciprofloxacin (7 days) and trimethoprim-
sulfamethoxazole (14 days) for acute uncomplicated pyelonephritis pyelonephritis in women: a randomized
trial. JAMA 2000;283(12):1583-90.
7. Vogel T, Verreault R, Gourdeau M et al. Optimal duration of antibiotic therapy for uncomplicated urinary tract
infection in older women: a double-blind randomized controlled trial. CMAJ 2004;170(4):469-73.
8. American College of Obstetricians and Gynecologists. ACOG Practice Bulletin No. 91: Treatment of urinary
tract infections in nonpregnant women. Obstet Gynecol 2008;111(3):785-94.
9. MacDonald TM, Beardon PH, McGilchrist MM et al. The risks of symptomatic vaginal candidiasis after oral
antibiotic therapy. Q J Med 1993;86(7):419-24.
10. Jepson RG, Craig JC. Cranberries for preventing urinary tract infections. Cochrane Database Syst Rev 2008;
(1):CD001321.
11. Rindone JP, Murphy TW. Warfarin-cranberry juice interaction resulting in profound hypoprothrombinemia and
bleeding. Am J Ther 2006;13(3):283-4.
12. Li Z, Seeram NP, Carpenter CL et al. Cranberry does not affect prothrombin time in male subjects on warfarin.
J Am Diet Assoc 2006;106(12):2057-61.
13. Nicolle LE, Bradley S, Colgan R et al. Infectious Diseases Society of America guidelines for the diagnosis and
treatment of asymptomatic bacteriuria in adults. Clin Infect Dis 2005;40(5):643-54.
14. McDermott S, Daguise V, Mann H et al. Perinatal risk for mortality and mental retardation associated with
maternal urinary-tract infections. J Fam Pract 2001;50(5):433-7.
15. Smaill F, Vazquez JC. Antibiotics for asymptomatic bacteriuria in pregnancy. Cochrane Database Syst Rev
2007;(2):CD000490.
16. Le J, Briggs GG, McKeown A et al. Urinary tract infections during pregnancy. Ann Pharmacother 2004;38
(10):1692-1701.
17. Pritchard JA, Scott DE, Mason RA. Severe anemia with hemolysis and megaloblastic erythropoiesis. A reaction
to nitrofurantoin administered during pregnancy. JAMA 1965;194(4):457-9.
18. Bruel H, Guillemant V, Saladin-Thiron C et al. [Hemolytic anemia in a newborn after maternal treatment with
nitrofurantoin at the end of pregnancy]. Arch Pediatr 2000;7(7):745-7. French.
19. Anti-infective Review Panel. Anti-infective guidelines for community-acquired infections. Toronto (ON): MUMS
Guideline Clearinghouse; 2010.
20. Sivojelezova A, Einarson A, Shuhaiber S et al. Trimethoprim-sulfonamide combination therapy in early
pregnancy. Can Fam Physician 2003;49:1085-6.
21. Quinolones and pregnancy: worrying animal findings, few clinical data. Prescrire Int 1999;8(39):29-31.
22. Koren G. Use of the new quinolones during pregnancy. Can Fam Physician 1996;42:1097-9.
23. Berkovitch M, Pastuszak A, Gazarian M et al. Safety of the new quinolones in pregnancy. Obstet Gynecol
1994;84(4):535-8.
24. Loebstein R, Addis A, Ho E et al. Pregnancy outcome following gestational exposure to fluoroquinolones: a
multicenter prospective controlled study. Antimicrob Agents Chemother 1998;42(6):1336-9.
Page 725
Therapeutic Choice
25. Gilstrap LC, Ramin SM. Urinary tract infections during pregnancy. Obstet Gynecol Clin North Am 2001;28
(3):581-91.
26. Wing DA, Hendershott CM, Debuque L et al. A randomized trial of three antibiotic regimens for the treatment
of pyelonephritis in pregnancy. Obstet Gynecol 1998;92(2):249-53.
27. Millar LK, Wing DA, Paul RH et al. Outpatient treatment of pyelonephritis in pregnancy: a randomized
controlled trial. Obstet Gynecol 1995;86(4 Pt 1):560-4.
28. Sanchez-Ramos L, McAlpine KJ, Adair CD et al. Pyelonephritis in pregnancy: once-a-day ceftriaxone versus
multiple doses of cefazolin. A randomized, double-blind trial. Am J Obstet Gynecol 1995;172(1 Pt 1):129-33.
29. American Academy of Pediatrics Committee on Drugs. Transfer of drugs and other chemicals into human milk.
Pediatrics 2001;108(3):776-89.
30. Dugoua JJ, Seely D, Perri D et al. Safety and efficacy of cranberry (vaccinium macrocarpon) during pregnancy
and lactation. Can J Clin Pharmacol 2008;15(1):e80-6.
Page 726
e-Therapeutics+ : Therapeutics : Musculoskeletal Disorders: Chronic Fatigue Syndrome Page 1 of 7
Therapeutic Choice
Print Close
Musculoskeletal Disorders: Chronic Fatigue Syndrome

Elizabeth Mann, MD, FRCPC
Fatigue, usually short-lived, is common and is often related to some identified cause. Chronic fatigue syndrome (CFS) is
a biopsychosocial illness of persistent, prolonged and profound fatigue, which may be disabling. The prevalence is 0.2 to
2.6%, varying somewhat with the population and criteria used.1 It is found in all ages, races and socio-economic groups.
About 50% more women are affected than men. The peak prevalence is ages 40 to 49.2
Chronic fatigue syndrome is the subject of significant debate and controversy. No single factor appears etiologic in this
illness.3 Rather it is more likely an individual response to a number of potential stimuli, including infection, major illness
or life stress. Twin studies reveal a possible genetic component,4 suggesting a predisposition requiring an environmental
trigger. Approximately 50% of patients will have psychiatric complaints or prior psychiatric history, and many will
become depressed after the onset of this prolonged illness. CFS is not felt to be a solely psychologic entity.3
There are significant overlaps with other medically undefined syndromes, including fibromyalgia, idiopathic
environmental intolerances/multiple chemical sensitivities, and even irritable bowel syndrome.3 The syndrome tends to
5
improve over time, but even the best treatments available are not a cure.
The development of diagnostic criteria (Table 1) has encouraged research in this area. Results are often conflicting, both
for pathophysiology and for treatment. Many studies are unable to document defects in cognitive function despite
subjective complaints. There is some evidence of slowed cognitive processing speed in patients who complain of
cognitive dysfunction.6
Goals of Therapy
Provide the patient with a supportive treatment environment

Improve function and well-being and reduce fatigue
Educate and promote self-management including exercise
Investigations
Diagnostic criteria are presented in Table 1.7 Although the diagnosis of CFS cannot be seriously entertained before six
months of fatigue, investigations should proceed in the interim to medically evaluate the patient for other causes of
fatigue. This clinical evaluation (Table 2) must rule out other potentially treatable causes of fatigue.
As well as six months of fatigue, at least four of eight physical symptoms must occur (Table 1). Well-controlled illness,
both medical and psychiatric, does not preclude a diagnosis of CFS.7
Neither viral titres nor neuro-imaging studies are required or helpful in routine clinical practice. There are no consistent,
well-defined abnormalities in neuro-imaging studies. There are no specific findings in muscle or muscle metabolism to
explain the fatigue.
Table 1: Diagnostic Criteria for Chronic Fatigue Syndrome7
Clinically evaluated fatigue (history, physical, laboratory investigations) (Table 2)

Persistent or relapsing fatigue for ≥ 6 months
New or definite onset
Not significantly relieved by rest
Substantial, significant reduction in function (occupation, education, social or personal)
PLUS four or more of the following symptoms — concurrent, recurrent, or persistent:
Reduced short-term memory or concentration
Sore throat
Tender cervical or axillary lymph nodes
Muscle pain
Diffuse arthralgia without arthritis
New headaches
Unrefreshing sleep
Post-exercise fatigue lasting more than 24 hours
Page 727
Therapeutic Choice
Adapted with permission from Fukuda K et al. The chronic fatigue syndrome: a comprehensive approach to its definition and study.
International Chronic Fatigue Syndrome Study Group. Ann Intern Med 1994;121(12):953-9.
Table 2: Clinical Evaluation of Prolonged Fatigue7
1. History and physical exam

2. Mental status exam
3. Neurologic and psychiatric exam if indicated
4. Routine laboratory tests (CBC with differential, BUN, creatinine, electrolytes, fasting glucose, calcium,
phosphorus, ESR or CRP, urinalysis, TSH, liver enzymes, total protein, albumin, anti-tissue transglutaminase)
5. Any additional tests as indicated from 1–4 above
6. Label chronic fatigue syndrome if above negative or unhelpful AND all diagnostic criteria are met
7. Label idiopathic chronic fatigue if either duration or severity criteria are not met
Adapted with permission from Fukuda K et al. The chronic fatigue syndrome: a comprehensive approach to its definition and study.
International Chronic Fatigue Syndrome Study Group. Ann Intern Med 1994;121(12):953-9.
Therapeutic Choices
There are no specific treatments for CFS.1 , 8 Patients benefit from being given a positive diagnosis with reasonable
explanations of their symptoms. Treatment should stress nonpharmacologic approaches, attempts at symptom control, a
supportive environment and recognition of suffering.
Nonpharmacologic therapies should be utilized primarily.
Healthy diet: No specific diet or nutritional supplements have been proven to benefit this condition. Patients with
exaggerated orthostatic hypotension should ingest salt.
Regular progressive aerobic exercise: Bedrest confers no long-term benefit. Physical deconditioning prolongs
disability and prevents recovery. Gradual progressive aerobic exercise programs are of proven benefit (Table 3).9
Positive Pacing:
lifestyle issues are major. Using the excuse of pacing (“living within my limits”) to avoid gradual increases in
exercise perpetuates the disability.
wide fluctuations in physical activity are self-defeating and perpetuate the notion that exercise is to be avoided.
There should be periods of planned activity and a definite sleep routine. Graded increases in activity (Table 3)
are mandatory. It is better to be somewhat (and increasingly) active every day, than to do nothing most days
and then attempt to walk five miles.
Psychologic counselling and lifestyle management: Cognitive behavioural therapy (CBT) including counselling
regarding belief systems about chronic fatigue and illness, usually in association with progressive
exercise therapy, results in best outcomes. Randomized controlled trials of cognitive behavioural
therapy have shown improvement in 60 to 75% of patients receiving this treatment, compared with <
30% of patients receiving standard care.1 Useful Info?
Inability to access trained psychotherapists can limit formal CBT. Similar results have been obtained using patient
10
education and gradual progressive exercise with appropriate follow-up by family physicians. One trial
11
demonstrates that benefits of CBT are long lasting.
Table 3: Exercise Guidelines
Prescribe exercise
Choose walking, bicycle, treadmill, swimming, etc; any exercise patient can do
Gradual progressive aerobic exercise
Supervised, or independent with follow-up by physician/nurse
Start where patient is comfortable, e.g., five minutes per day
Increase weekly by increments, even one to two minutes per session, to 30 minutes per day
Do not miss any days, as it can delay further progression for a week
Page 728
Therapeutic Choice
Since there are no proven pharmacologic treatments for CFS, treat symptomatically (Table 4). Symptomatic
treatment usually includes medication for sleep, most often with low-dose antidepressants. There is no convincing
evidence that one agent is superior to another. Short trials of six to eight weeks are sufficient to notice benefit.
Although several short-term clinical trials have been published using standard replacement dose or low-dose
corticosteroids, there is no convincing evidence that benefit outweighs risk. Use of combined low-dose steroids
and fludrocortisone are of no benefit. Use of intravenous immunoglobulins provides mild benefit with severe side
effects and risks, and is not standard therapy.1
One short-term trial notes benefit from methylphenidate 10 mg twice daily in CFS patients with severe cognitive
complaints. This has not yet been confirmed and is not standard therapy.12
Therapeutic Tips
In several referral clinic–based studies, the prognosis for recovery was poor for severely ill patients, who may
remain ill for many years. Poor outcome is predicted by rigid beliefs in a physical cause for the illness, and
unwillingness to participate in either psychologic therapy or exercise-based treatments.5 , 13 , 14
There is no role for nystatin, fludrocortisone, rigid diets and/or megavitamin routines.
Patients experiencing pain can be offered analgesics usually starting with acetaminophen.
Table 4: Drugs for Symptomatic Management of Chronic Fatigue Syndrome
Adverse Drug Costa

Tricyclic amitriptyline Initial: Anticholinergic Combination with Use for sleep and $
Antidepressants generics 10– 25 mg/day (dry mouth, MAOIs may result mood, especially
(TCAs) b Usual: 75 mg/day blurred vision, in mania, nonrestorative
constipation, excitation, sleep. No
urinary hyperpyrexia. evidence for
hesitancy, Barbiturates, superiority of any
tachycardia, carbamazepine agent. Use side
delirium), and rifampin may effects
antihistaminergic ↓ effect. Cimetidine (anticholinergic,
(sedation, and antipsychotics weight gain) to
weight gain), may ↑ effect and guide therapy.
orthostatic toxicity. Should be taken
hypotension, Possible in the evening.
lowered seizure interaction with Only about 50%
threshold; antiarrhythmics: respond.
sexual may ↑ effect of
dysfunction. either drug; may
also ↑ risk of cardiac
arrhythmias.
May ↓
antihypertensive
effect of
clonidine. May
augment
hypotensive effect
of thiazides.
Tricyclic desipramine Initial: Anticholinergic Combination with Use for sleep and $-$$$
Antidepressants generics 10– 25 mg/day (dry mouth, MAOIs may result mood, especially
(TCAs)b Usual: 100 mg/day blurred vision, in mania, nonrestorative
constipation, excitation, sleep. No
urinary hyperpyrexia. evidence for
hesitancy, Barbiturates, superiority of any
tachycardia, carbamazepine agent. Use side
delirium), and rifampin may effects
antihistaminergic ↓ effect. Cimetidine (anticholinergic,
(sedation, and antipsychotics weight gain) to
weight gain), guide therapy.
Page 729
Therapeutic Choice
Adverse Drug Costa

orthostatic may ↑ effect and Should be taken
hypotension, toxicity. in the evening.
lowered seizure Possible Only about 50%
threshold; interaction with respond.
sexual antiarrhythmics:
dysfunction. may ↑ effect of
either drug; may
also ↑ risk of cardiac
arrhythmias.
May ↓
antihypertensive
effect of
clonidine. May
augment
hypotensive effect
of thiazides.
Selective fluoxetine Initial: Nausea, MAOIs may cause Use for sleep and $$-
Serotonin Prozac, 10– 20 mg/day nervousness, severe reaction — mood. No $$$$
Reuptake generics Usual: anorexia, tremor, agitation, evidence for
Inhibitors 20– 40 mg/day insomnia. ↑ risk hypomania, superiority of any
(SSRIs) b of GI bleeding hypertension. agent.
Drugs that inhibit Can use early in
cytochrome P450 the day for the
enzymes (e.g., hypersomnolent.
cimetidine,
clarithromycin, May be better
erythromycin, tolerated than
fluconazole, TCAs.
indinavir,
isoniazid,
itraconazole,
ketoconazole,
quinidine,
ritonavir) may ↑
SSRI levels.
All SSRIs inhibit

certain
cytochrome P450
enzymes and can
↓ the clearance of
other drugs (e.g.,
clozapine,
methadone,
phenytoin,
pimozide,
propafenone).
Inducers of
cytochrome P450
enzymes (e.g.,
carbamazepine,
phenobarbital,
phenytoin,
rifampin) can ↑ the
clearance of SSRIs.
↑ risk of GI
bleeding with
NSAIDs.
Page 730
Therapeutic Choice
Adverse Drug Costa

Selective sertraline Initial: Nausea, tremors, MAOIs may cause Use for sleep and $-$$
Serotonin Zoloft, 25– 50 mg/day diarrhea, dry severe reaction — mood. No
Reuptake generics Usual: mouth. ↑ risk of tremor, agitation, evidence for
Inhibitors 50– 100 mg/day GI bleeding. hypomania, superiority of any
(SSRIs)b hypertension. agent.
Drugs that inhibit Can use early in
cytochrome P450 the day for the
enzymes (e.g., hypersomnolent.
cimetidine,
clarithromycin, May be better
erythromycin, tolerated than
fluconazole, TCAs.
indinavir,
isoniazid,
itraconazole,
ketoconazole,
quinidine,
ritonavir) may ↑
SSRI levels.
All SSRIs inhibit

certain
cytochrome P450
enzymes and can
↓ the clearance of
other drugs (e.g.,
clozapine,
methadone,
phenytoin,
pimozide,
propafenone).
Inducers of
cytochrome P450
enzymes (e.g.,
carbamazepine,
phenobarbital,
phenytoin,
clearance of SSRIs.
↑ risk of GI
bleeding with
NSAIDs.
Serotonin- venlafaxine Initial: Nausea, Avoid combination This may be $$-

Norepinephrine Effexor XR, 37.5 mg/day drowsiness, with or use within more helpful for $$$$$
Reuptake generics Usual: nervousness, 2 wk of patients with
Inhibitors 112.5– 225 mg/day dizziness, dry discontinuation of pain/fibromyalgia
mouth, may MAOIs. type complaints.
increase BP if Drugs that inhibit
dose > cytochrome P450
300 mg/day. (e.g., cimetidine)
may increase
venlafaxine levels.
St. John's wort

may increase
sedative-hypnotic
effects.
Page 731
Therapeutic Choice
a
Adverse Drug Cost
Antidepressants, trazodone Initial: 50 mg QHS Drowsiness, May potentiate Useful for sleep. $
miscellaneous Desyrel, Usual: 50– 100 mg nausea, effects of other May be combined
generics QHS vomiting, CNS depressants with SSRI.
headache, dry and augment
mouth, priapism. hypotensive
Adverse events effects of
appear more antihypertensives.
common with
higher doses.
Analgesics b acetaminophen 325– 650 mg TID May cause Excessive alcohol $

Atasol hepatotoxicity if intake may
taken in excess increase the risk
preparations,
or by patients of hepatotoxicity.
Tylenol, with liver Warfarin:
generics diseases. increased
anticoagulant
effect with regular
use of > 2 g/day.
Analgesicsb ibuprofen 200– Peptic ulcers, Warfarin: Other NSAIDs $

Advil, Motrin 600 mg TID dyspepsia, fluid increased may be used. No
retention, anticoagulant evidence for
IB, generics
hypertension, effect. superiority of any
renal Antihypertensives: agent.
impairment, possible reduction
hypersensitivity. in hypertensive
MI, CVA, heart effect; may
failure all require additional
possible. Extent antihypertensive
of CV risk still therapy.
not completely
defined. Lithium: may
interfere with
sodium/water
balance. Monitor
lithium levels
when NSAID
added.
SSRIs may ↑ risk of

GI bleeding when
used with NSAIDs.
a.
b.
Listed drugs are examples of medications in this class.
Abbreviations: BP=blood pressure; MAOI=monoamine oxidase inhibitor; NSAIDs=nonsteroidal anti-inflammatory

drugs; SSRI=selective serotonin reuptake inhibitor; TCA=tricyclic antidepressant
Legend: $ < $20 $-$$ < $20–40 $$ $20–40 $-$$$ < $20–60 $$$ $40–60 $$-$$$$ $20–80 $$$$ $60–80
$$-$$$$$ $20– >80 $$$$$ >$80
Suggested Readings
Page 732
Therapeutic Choice
Centers for Disease Control and Prevention (US). Chronic fatigue syndrome. Atlanta (GA): CDC. Available from:
www.cdc.gov/cfs/ Accessed December 6, 2006.
Evengard B, Klimas N. Chronic fatigue syndrome: probable pathogenesis and possible treatments. Drugs 2002;62
(17):2433-46.
Fukuda K, Straus SE, Hickie I et al. The chronic fatigue syndrome: a comprehensive approach to its definition and study.
International Chronic Fatigue Study Group. Ann Intern Med 1994;121(12):953-9.
Prins JB, van der Meer JW, Bleijenberg G. Chronic fatigue syndrome. Lancet 2006;367(9507):346-55.
References
1. Reid S, Chalder T, Cleare A et al. Chronic fatigue syndrome. BMJ 2000;320(7230):292-6.

2. Jason LA, Richman JA, Rademaker AW et al. A community-based study of chronic fatigue syndrome. Arch Intern
Med 1999;159(18):2129-37.
3. Natelson BH. Chronic fatigue syndrome. JAMA 2001;285(20):2557-9.
4. Buchwald D, Herrell R, Ashton S et al. A twin study of chronic fatigue. Psychosom Med 2001;63(6):936-43.
5. Hill NF, Tiersky LA, Scavalla VR et al. Natural history of severe chronic fatigue syndrome. Arch Phys Med Rehabil
1999;80(9):1090-4.
6. Deluca J, Christodoulou C, Diamond BJ et al. Working memory deficits in chronic fatigue syndrome: differentiating
between speed and accuracy of information processing. J Int Neuropsychol Soc 2004;10(1):101–9.
7. Fukuda K, Straus SE, Hickie I et al. The chronic fatigue syndrome: a comprehensive approach to its definition and
study. International Chronic Fatigue Syndrome Study Group. Ann Intern Med 1994;121(12):953-9.
8. Whiting P, Bagnall AM, Sowden AJ et al. Interventions for the treatment and management of chronic fatigue
syndrome: a systematic review. JAMA 2001;286(11):1360-8.
9. Edmonds M, McGuire H, Price J. Exercise therapy for chronic fatigue syndrome. Cochrane Database Syst Rev 2004;
(3):CD003200.
10. Powell P, Bentall RP, Nye FJ, Edwards RH. Randomized controlled trial of patient education to encourage graded
exercise in chronic fatigue syndrome. BMJ 2001;322:1–5.
11. Deale A, Husain K, Chalder T et al. Long-term outcome of cognitive behavior therapy versus relaxation therapy for
chronic fatigue syndrome: a 5-year follow-up study. Am J Psychiatry 2001;158(12):2038-42.
12. Blockmans D, Persoons P, Van Houdenhove B et al. Does methylphenidate reduce the symptoms of chronic fatigue
syndrome? Am J Med 2006;119(2):167.e23-30.
13. Lawrie SM, Pelosi AJ. Chronic fatigue syndrome: prevalence and outcome. BMJ 1994;308(6931):732-3.
14. Bentall RP, Powell P, Nye FJ et al. Predictors of response to treatment for chronic fatigue syndrome. Br J Psychiatry
2002;181:248-52.
Page 733
e-Therapeutics+ : Therapeutics : Musculoskeletal Disorders: Fibromyalgia Page 1 of 6
Therapeutic Choice
Print Close
Musculoskeletal Disorders: Fibromyalgia

Howard Stein, MD, FRCPC
Fibromyalgia is characterized by chronic widespread pain, increased tenderness at specific sites known as “tender
points,” fatigue, headache and unrefreshing sleep. Fibromyalgia affects 2 to 4% of the general population. Of those
affected, 80 to 90% are females. In general, symptom onset occurs between the ages of 30 and 60.
Goals of Therapy
Reduce pain, fatigue, distress and sleep problems

Improve physical and emotional well-being, functioning and quality of life
Address the associated conditions
Provide education and promote self-management
Investigations (Figure 1 - Investigation of Diffuse Aches and Pains, Figure 2 - Tender Point
Examinationa )
Therapeutic Choices
Empathy and encouragement from health care providers.

A comprehensive, multidisciplinary program of education, self-management, nonpharmacologic pain reduction
techniques, graded aerobic exercises, sleep hygiene, stress management and cognitive behavioural therapy can
1
be effective.
Supervised aerobic exercise, walking programs, pool exercises and strength training can improve function,
symptoms and well-being.2
Nonpharmacologic pain reduction techniques include cold, heat, transcutaneous electrical nerve stimulation
(TENS), acupuncture, massage, and relaxation techniques such as biofeedback, meditation and hypnosis.
Patient education, such as the Arthritis Self-Help Course, can improve pain, sleep, fatigue, quality of life and the
6-minute walk. Improvement can last at least 3 to 12 months.1
Cognitive behavioural strategies performed over 6 to 14 weeks show improvement in tender points, Visual
Analogue Scale (VAS) pain scores, pain coping, pain behaviours, depression and physical function.3
Electroacupuncture reduces pain and analgesic requirements.4
Because the etiology of fibromyalgia remains unknown, drug treatments are largely empiric. Studies have been of
short duration and varying quality.
Low doses of tricyclic antidepressants (e.g., amitriptyline) at bedtime can improve sleep and reduce pain
5
somewhat. Only short-term efficacy has been shown. If taken two to three hours before bedtime the effect will
start at bedtime, and morning hangover will be lessened.
The only muscle relaxant that is somewhat effective is cyclobenzaprine, perhaps because it too is a tricyclic.6
Selective serotonin reuptake inhibitors (SSRIs) are not as helpful as tricyclics but may have a role
when used with amitriptyline in depressed patients with fibromyalgia.They are better tolerated
than tricyclics. Fluoxetine in the morning with evening amitriptyline was more effective than either
agent alone in a double-blind controlled trial in fibromyalgia sufferers.7,8 Useful Info?
Dual-action noradrenaline and serotonin reuptake inhibitors such as venlafaxine may help more individuals
9 , 10
with fibromyalgia than do tricyclics (60% vs 40%).
Analgesics such as acetaminophen and nonsteroidal anti-inflammatory drugs (NSAIDs) (especially
ibuprofen) deserve a trial but help very few patients. These drugs may not be useful for fibromyalgia because
the pain is probably a result of central sensitization rather than peripheral pain or inflammation. However,
tramadol (with or without acetaminophen) reduces pain and improves health-related quality of life in
Page 734
Therapeutic Choice
individuals with fibromyalgia.11 , 12 The use of tramadol with antidepressants may cause serotonin syndrome.
Other opioids should be avoided because of limited benefit, dependency and side effects.
Sedatives may benefit those with severe sleep dysfunction but do not provide effective reduction of pain.
Dependency and adverse effects are also concerns. Clonazepam or zopiclone might be useful intermittently
13
but studies are lacking.
Human growth hormone improved symptoms in a placebo-controlled trial, although further investigation is
14
required. It may help only those with low growth hormone levels. Expense and availability limit its use.
S-adenosyl-methionine (SAM-e) improved depression, pain, fatigue, morning stiffness and global disease
5
measures in fibromyalgia.
Treatment of peripheral pain generators by local injection (e.g., usually lidocaine 1% with or without a depot
form of corticosteroid) to myofascial trigger points may reduce the total pain burden and the perpetuation of
15
central pain sensitization.
Therapeutic Tips
The treatment of arthritis and other conditions may be complicated by concomitant fibromyalgia.
Pharmacologic agents work best when combined with nonpharmacologic modalities, ideally as part of a
1
multidisciplinary treatment program.
It is important to document not only reduced pain but also improved function.
Because patients with fibromyalgia are unduly sensitive to drug side effects, start medications at low doses and
increase slowly by small increments.
The initial improvement of fibromyalgia with drugs fades with time. Significant and sustained clinical
improvement due to drugs occurs only in a minority of patients. However, about 20% of patients experience
remission not necessarily related to any specific therapy. Conversely, there are subsets of patients who are
intolerant of and/or unresponsive to all pharmacologic therapy.
Sleep problems may need further study in a sleep disorder clinic.
Concomitant mood disorders require higher doses of antidepressants than are used for fibromyalgia.
Figure 1- Investigation of Diffuse Aches and Pains
a.
CBC, ESR, creatinine, AST, alkaline phosphatase, calcium, TSH.
b.
Associated disorders include mood disturbances, cognitive dysfunction, irritable bowel syndrome, irritable bladder syndrome,
dizziness, cold intolerance, subjective swelling, paresthesiae and temporomandibular joint syndrome. Abbreviations: CBC =
complete blood count; ESR = erythrocyte sedimentation rate; AST = aspartate transaminase; TSH = thyroid-stimulating hormone
Page 735
Therapeutic Choice
Figure 2-Tender Point Examinationa
a.
Using thumb pressure sufficient to blanch fingernail.
Table 1: Drugs Used in Fibromyalgia
a
Cost
Tricyclic Agents amitriptyline Anticholinergic (dry Combination with MAOIs $

b 5–20 mg 2–3 h mouth, blurred vision, may result in mania,
generics
before bedtime constipation, urinary excitation, hyperpyrexia;
hesitancy, tachycardia, barbiturates,
delirium), carbamazepine and
antihistaminergic rifampin may ↓ effect;
(sedation, weight cimetidine and
gain), orthostatic antipsychotics may ↑ effect
hypotension, lowered and toxicity; possible
seizure threshold; interaction with
sexual dysfunction. antiarrhythmics (may lead
to ↑ effect of either drug);
may ↓ antihypertensive effect
of clonidine; may augment
hypotensive effect of
thiazides.
Tricyclic cyclobenzaprine 10–40 mg/day Anticholinergic (dry Combination with MAOIs $-$$$
b in 2 to 4 divided mouth, blurred vision, may result in mania,
Agents generics
doses constipation, urinary excitation, hyperpyrexia;
hesitancy, tachycardia, barbiturates,
delirium), carbamazepine and
antihistaminergic rifampin may ↓ effect;
(sedation, weight cimetidine and antipsychotics
Page 736
Therapeutic Choice
Costa
gain), orthostatic may ↑ effect and toxicity;
hypotension, lowered possible interaction with
seizure threshold; antiarrhythmics (may lead
sexual dysfunction. to ↑ effect of either drug);
thiazides.
Selective fluoxetine Nausea, dry mouth, MAOIs may cause severe $$

Serotonin Prozac, 10–20 mg/day somnolence, sweating, reaction — tremor,
Reuptake generics with sexual dysfunction. ↑ agitation, hypomania,
Inhibitors b amitriptyline risk of GI bleeding. hypertension. Drugs that
inhibit cytochrome P450
enzymes (e.g., cimetidine,
clarithromycin,
indinavir, isoniazid,
quinidine, ritonavir) may ↑
SSRI levels.
All SSRIs inhibit certain
cytochrome P450
isoenzymes and can ↓ the
clearance of other drugs (e.g.,
clozapine, methadone,
mexiletine, phenytoin,
pimozide, propafenone).
Inducers of cytochrome
P450 enzymes (e.g.,
carbamazepine,
phenobarbital, phenytoin,
rifampin) can ↑ the clearance
of SSRIs.
↑ risk of GI bleeding with

NSAIDs.
Serotonin- venlafaxine 75 mg/day Nausea, sweating, Alcohol, warfarin, $$$

Norepinephrine Effexor XR, somnolence, dry clozapine, MAOIs,
Reuptake generic mouth, dizziness, tramadol. Drugs that inhibit
Inhibitors insomnia, cytochrome P450 may ↑
hypertension, abnormal venlafaxine levels.
ejaculation/orgasm.
b zopiclone Bitter taste, Alcohol, CNS depressants, $
Hypnotics
Imovane, 3.75–7.5 mg HS drowsiness. antidepressants.
Rhovane,
generics
Analgesics acetaminophen Hepatotoxicity, Excessive alcohol intake $

Tylenol, Atasol 325–1000 mg urticaria, rash. may ↑ the risk of hepatotoxicity.
Q4H Warfarin: ↑ anticoagulant
Preparations,
Max. 4 g/day effect with regular use of
genericsc > 2 g/day.
Analgesics tramadol / 1–2 tablets Q4– Somnolence, dizziness, Excessive alcohol intake $$$$$
acetaminophen 6H as needed flushing, constipation, may ↑ the risk of
Max. 8 tabs/day nausea, pruritus, hepatotoxicity.
Tramacet seizures, anaphylactoid
Page 737
Therapeutic Choice
Costa
reactions, dependence, Warfarin: ↑ anticoagulant
withdrawal syndrome. effect with regular use of
> 2 g/day.
Possible ↑ risk of seizure with

SSRI antidepressants or
anorectics, MAOIs, tricyclic
antidepressants and other
tricyclic compounds,
neuroleptics,
amphetamines, linezolid,
opioids or any drugs that
reduce the seizure
threshold. Use with SSRIs
or MAOIs may also ↑ risk of
serotonin syndrome. Use with
CNS depressants may ↑ the
risk of CNS and respiratory
depression. Carbamazepine
may ↑ the metabolism of
tramadol. Also, tramadol may
↑ the risk of seizures in patients
taking anticonvulsants.
Nonsteroidal ibuprofen Peptic ulcer, dyspepsia, Warfarin: ↑ anticoagulant $

Anti- Advil, Motrin 200–600 mg fluid retention, effect.
inflammatory c Q6H hypertension, renal Antihypertensives: possible
b IB, generics impairment, ↓ in hypertensive effect; may
Drugs
hypersensitivity. require additional
antihypertensive therapy.
Lithium: may interfere with

sodium/water balance.
Monitor lithium levels when
NSAID added.
SSRIs may ↑ risk of gi

bleeding when used with
NSAIDs.
a.
b.
c.
Available without a prescription.
Abbreviations: CNS=central nervous system; MAOIs=monoamine oxidase inhibitors
Legend: $ < $20 $$ $20-40 $-$$$ < $20–60 $$$ $40–60 $$$$ $60–80 $$$$$ > $80
Suggested Readings
Bennett RM. Rational management of fibromyalgia. Rheum Dis Clin North Am 2002;28(2):xiii-xv.
Goldenberg MD, Burckhardt C, Crofford L. Management of fibromyalgia syndrome. JAMA 2004;292(19):2388-95.
Page 738
Therapeutic Choice
Mease P. Fibromyalgia syndrome: review of clinical presentation, pathogenesis, outcome measures and treatment. J
Rheumatol Suppl 2005;75:6-21.
Puttick MP. Rheumatology: 11. Evaluation of the patient with pain all over. CMAJ 2001;164(2):223-7.
References
1. Bennett RM. Multidisciplinary group programs to treat fibromyalgia patients. Rheum Dis Clin North Am
1996;22(2):351-67.
2. Mannerkorpi K. Exercise in fibromyalgia. Curr Opin Rheumatol 2005;17(2):190-4.
3. Burckhardt CS. Nonpharmacologic management strategies in fibromyalgia. Rheum Dis Clin North Am 2002;28
(2):291-304.
4. Deluze C, Bosia L, Zirbs A et al. Electroacupuncture in fibromyalgia: results of a controlled trial. BMJ
1992;305(6864):1249-52.
5. Arnold LM, Keck PE, Welge JA. Antidepressant treatment of fibromyalgia. A meta-analysis and review.
Psychosomatics 2000;41(2):104-13.
6. Tofferi JK, Jackson JL, O’Malley PG. Treatment of fibromyalgia with cyclobenzaprine: a meta-analysis. Arthritis
Rheum 2004;51(1):9-13.
7. Goldenberg D, Mayskiy M, Mossey C et al. A randomized, double-blind crossover trial of fluoxetine and
amitriptyline in the treatment of fibromyalgia. Arthritis Rheum 1996;39(11):1852-9.
8. Arnold LM, Hess EV, Hudson JI et al. A randomized, placebo-controlled, double-blind, flexible-dose study of
fluoxetine in the treatment of women with fibromyalgia. Am J Med 2002;112(3):191-7.
9. Littlejohn GO, Guymer EK. Fibromyalgia syndrome: which antidepressant drug should we choose. Curr Pharm
Des 2006;12(1):3-9.
10. Sayar K, Aksu G, Ak I et al. Venlafaxine treatment of fibromyalgia. Ann Pharmacother 2003;37(11):1561-5.
11. Bennett RM, Kamin M, Karim R et al. Tramadol and acetaminophen combination tablets in the treatment of
fibromyalgia pain: a double-blind, randomized, placebo-controlled study. Am J Med 2003;114(7):537-45.
12. Bennett RM, Schein J, Kosinski MR et al. Impact of fibromyalgia pain on health-related quality of life before
and after treatment with tramadol/acetaminophen. Arthritis Rheum 2005;53(4):519-27.
13. Thorpy MJ. New paradigms in the treatment of restless legs syndrome. Neurology 2005;64(12 Suppl 3):S28-
33.
14. Bennett RM, Clark SC, Walczyk J. A randomized, double-blind, placebo-controlled study of growth hormone in
the treatment of fibromyalgia. Am J Med 1998;104(3):227-31.
15. Borg-Stein J. Management of peripheral pain generators in fibromyalgia. Rheum Dis Clin North Am 2002;28
(2):305-17.
Page 739
e-Therapeutics+ : Therapeutics : Musculoskeletal Disorders: Gout and Hyperuricemia Page 1 of 9
Therapeutic Choice
Print Close
Musculoskeletal Disorders: Gout and Hyperuricemia
Suneil Kapur, MD, FRCPC
Gunnar Kraag, MD, FRCPC
Gout is a disease in which monosodium urate monohydrate (MSU) crystals deposit in joints, soft tissues such as cartil
and bursa, or in renal tissues such as glomeruli, the interstitium and tubules. This can result in gouty arthritis, tophi,
or uric acid nephrolithiasis. Gouty arthritis is the most common cause of inflammatory arthritis in men older than 40 y
The mean age of onset is the fourth decade in males and the sixth decade in females. It is unusual for an attack to occ
30 in males and age 50 in females unless the patient has an inherited enzyme abnormality.
Goals of Therapy
Terminate the acute attack of arthritis

Prevent recurrence
Prevent or reverse complications
Deal with associated disorders
The four stages of gouty arthritis are asymptomatic hyperuricemia, acute gouty arthritis, intercritical gout and chronic
gout.
Asymptomatic Hyperuricemia
This refers to elevated serum urate levels without any clinical manifestations. It is defined as a level greater than 360
1
females and 420 µmol/L in men. During puberty, male serum urate levels increase by 60 to 120 µmol/L to levels of 2
360 µmol/L . These values remain sustained. Women develop increased urate levels after menopause, where values ap
of men. In 70% of patients with hyperuricemia, an underlying cause such as drugs or systemic conditions is discovere
1
and physical examination (Table 1 and Table 2). Hyperuricemia is not an indication for urate-lowering therapy. Most
hyperuricemia remain asymptomatic throughout life. The annual incidence of acute arthritis is 0.1 to 0.5% among pati
2
urate level between 420 and 540 µmol/L, and 5% when greater than 540 µmol/L . Similarly, the risk of nephrolithias
with the serum urate level and the 24-hour urinary uric acid excretion. This phase ends with the first attack of gouty a
urolithiasis, typically after 20 years of sustained hyperuricemia.
Table 1: Drugs That May Cause Hyperuricemia
Alcohol Nicotinic acid

Cyclosporine Pyrazinamide
Diuretics Salicylates, low-dose
Ethambutol
Levodopa
Table 2: Conditions Associated With Hyperuricemia
Alcohol consumption Intrinsic renal disease

Atherosclerosis Ischemic heart disease
Diabetes Myeloproliferative disorders and some cancers
Hyperlipidemia Obesity
Hypertension
Acute Gouty Arthritis
Page 740
Therapeutic Choice
Investigations
Therapeutic Choices
Therapeutic Tips
Investigations
History, physical and laboratory examinations:

abrupt onset of excruciating pain and inflammation of joint during the night or early morning
patients cannot tolerate even light pressure such as a bed sheet on the affected joint
most commonly affects joints of lower limb. There is a higher frequency of upper limb joint involvement in w
compared to men3
about 85% of first attacks are monoarticular; however, elderly patients often have a polyarticular presentatio
podagra (inflammation of first metatarsophalangeal [MTP] joint) involved in first attack > 50% of time and ev
> 90% of time; other joints involved include, in decreasing order, insteps, ankles, heels, knees, wrists, inter
joints and elbows
predilection for damaged joints with osteoarthritis
acute gouty bursitis may occur in prepatellar or olecranon bursa
attacks often resolve spontaneously over 3 to 10 days
precipitants of acute attacks include acute illness, surgery, trauma, alcohol, high purine diet and drugs (Table
definitive diagnosis by identification of intracellular monosodium urate crystals in synovial fluid
presumptive diagnosis with triad of acute monoarthritis, hyperuricemia and dramatic response to colchicine
Therapeutic Choices (Figure 1 - Treatment of Acute Gout)
Perhaps because many commonly used therapies for gout were available before the standards for clinical trials were d
there is a general absence of well-controlled trials and systematic reviews regarding gout therapy.
NSAIDs are the first choice in the treatment of acute gout. NSAIDs are started in full doses, reduced by one-half as s
improvement is noted and then withdrawn over several more days. Adverse effects are greatest in elderly patients with
dysfunction. COXIBs and/or cytoprotection with proton pump inhibitor (PPI) or misoprostol may be offered to pat
for ulcer complications (e.g., age > 65, previous GI bleed or patients receiving anticoagulants or corticosteroids).
The intra-articular injection of corticosteroids into a single joint at the time of diagnostic arthrocentesis is ideal therap
results in rapid control of inflammation and symptoms. Systemic corticosteroid therapy can be used for refractory atta
particularly polyarticular gout, or when other agents are contraindicated, e.g., some elderly patients.
Colchicine relieves pain within 24 hours in 90% of patients when treated within the first few hours. However, its role
4
due to its toxicity (Table 4). Gastrointestinal (GI) toxicity may precede clinical response in many patients. Because o
potential toxicity, the use of i.v. colchicine should be avoided and restricted to hospitalized patients when other option
exhausted.
Used in acute and prophylactic management of gout, uricase-PEG20 is a drug that dissolves uric acid, but with poten
immunogenic side effects. It is not yet available in Canada.
Therapeutic Tips
The earlier therapy is started, the quicker the attack will be resolved.
Do not start or stop urate-lowering drugs during an acute attack because symptoms may be exacerbated or prolon
Colchicine is not a good choice to treat acute gout because of the severity of side effects and the ready availability
options.
If prednisone is the best option, use high doses, e.g., 30 mg daily.
Intercritical Period and Prophylaxis
Page 741
Therapeutic Choice
Therapeutic Choices
Therapeutic Tips
The intercritical period is asymptomatic. Most patients have a second attack within 6 to 24 months. Subsequent attack
explosive but more frequent, severe and enduring. These attacks are often polyarticular with upper extremity involvem
constitutional symptoms. Erosive radiographic changes and tophi may develop during the intercritical period, especial
frequent attacks of gouty arthritis. About 12 to 58% of patients have urate crystals in synovial fluid during this phase.
Therapeutic Choices
In a large observational study it was found that higher amounts of meat and seafood consumption were associated wi
increased risk of gout.5 , 6 Total protein intake and total amount of purine-rich vegetable intake were not associated w
increased risk of gout. There was a strong inverse association between consumption of dairy products, especially thos
5 , 6 2
content, and incidence of gout. There is also a clear relationship between obesity (body mass index > 30 kg/m )
Higher consumption of beer and liquor was associated with an increased risk of gout attacks while wine consumption
5 , 6
associated with an increased risk.
Pharmacologic Choices (Figure 2 - Treatment of Hyperuricemia, Table 4)
When used for three months after attaining a serum urate concentration of < 390 µmol/L, colchicine ( 0.6 mg twice d
effectively reduces the frequency and severity of acute flares when starting allopurinol for chronic gouty arthritis; it al
7
the likelihood of recurrent flares. If it cannot be used, a low-dose NSAID (e.g., indomethacin 25 mg twice daily or
250 mg twice daily) may be substituted. Colchicine and NSAIDs should be used with caution in elderly patients with re
hepatic insufficiency.
Antihyperuricemic Drugs
The decision of when to initiate urate-lowering therapy remains controversial. One view is that the first attack is a late
8
gouty diathesis; even if further attacks do not occur, it cannot be assumed that renal damage will not. The other view
because recurrence may be delayed for many years and chronic tophaceous gout develops only in a minority, therapy
delayed until recurrence or detection of tophi. The aim of antihyperuricemic therapy is to reduce the serum urate conc
1
below 380 µmol/L, the saturation point of monosodium urate in the extracellular fluid. Therapy should be lifelong sin
arthritis occurs within six months and tophi within three years of discontinuation.
Allopurinol, a xanthine oxidase inhibitor, inhibits the production of uric acid. Full doses reduce serum urate concentr
2
normal in 80% of patients with gout. To avoid unnecessary risks and costs, reserve allopurinol for select patients (Ta
incidence of side effects is about 15%, with rash being the most common. Severe toxicity can occur: a hypersensitivit
occurs in less than 1 in 1000 cases and includes exfoliative dermatitis, vasculitis, bone marrow suppression, liver dysf
fever, eosinophilia, acute interstitial nephritis or death.2
Patients can be desensitized to allopurinol as long as reactions are not severe.9 The metabolite of allopurinol, oxypur
available in Canada through the Special Access Program. There is 50% cross-reactivity with allopurinol, but it may be
10
desensitize with oxypurinol in patients with mild allergic reactions to allopurinol.
Uricosuric agents such as probenecid and sulfinpyrazone are good substitutes for allopurinol but are not
the presence of renal insufficiency or gross over-production.2 The combination of allopurinol and a uricos
required to mobilize extensive urate deposits. Useful Info?
Table 3: Indications for Antihyperuricemic Drugs
Greater than 2 attacks/year
Page 742
Therapeutic Choice
Presence of tophaceous gout
24-hour urinary uric acid excretion > 1000 mg
Severe and persistent hyperuricemia (> 720 µmol/L)
Hypoxanthine-guanine phosphoribosyl transferase (HGPRT) deficiency or phosphoribosyl pyrophosphate (PRPP) synth
overactivity (both increase uric acid production)
Nephrolithiasis
Uric acid nephropathy
Chronic gouty arthritis with bony erosions
Prophylaxis of hyperuricemia prior to cytotoxic agents
Therapeutic Tips
Do not treat asymptomatic hyperuricemia.

Minimize the risk of acute gout during the intercritical period by protecting with a low-dose NSAID when initiating
lowering therapy.
Adjust allopurinol dosage according to creatinine clearance.
Improve compliance by explaining the objectives of therapy, e.g., allopurinol does not relieve pain and must be u
continuously.
Chronic Tophaceous Gout
1
This stage typically occurs 12 years from onset with a reported range of 3 to 42 years. Only 2% of patients develop s
crippling disease. The strongest associated risk factor for developing tophi is the serum urate level.1 Other factors inc
frequency of attacks, duration of hyperuricemia and severity of renal disease. Common locations of tophi are the syno
subchondral bone, digits of the hands and feet, olecranon bursa, Achilles tendon and helix of the ear. They can, howe
anywhere including the conduction system of the heart. Tophi themselves are painless but they can lead to destruction
deformities. Radiographic changes include paramarginal erosions with sclerotic margins and calcified tophi.1 The optim
for chronic tophaceous gout is prevention by aggressive management of acute gout and correction of hyperuricemia. T
therapy are to control pain and inflammation, typically with NSAIDs, and to decrease serum uric acid levels. After seve
therapy, resorption of urate deposits will eventually lead to disappearance of tophi.
Page 743
Therapeutic Choice
Figure 1-Treatment of Acute Gout
Page 744
Therapeutic Choice
Figure 2-Treatment of Hyperuricemia
Table 4: Drug Therapy of Gout
Adverse Drug
Class Drug Dose Effects Interactions Commen
NSAIDs b indomethacin Acute attack: (For all Warfarin: ↑ Indomethaci

generics 75 mg STAT, then NSAIDs) anticoagulant effect. naproxen are
50 mg Q6H × 2 days then GI Antihypertensives: listed as
50 mg Q8H × 1 day then disturbances; Possible ↓ in examples. Th
25 mg Q8H × 1 day other adverse antihypertensive is no good
Prophylaxis: effects effect; may require evidence to
25 mg BID uncommon with additional suggest one
short-term antihypertensive NSAID is mo
therapy but therapy. efficacious th
include fluid another.
retention, Lithium: May Suppositorie
hypertension, interfere with may be used
renal sodium/water oral route
impairment, balance. Monitor inadvisable.
hypersensitivity. lithium levels
when NSAID
added.

GI bleeding when
used with NSAIDs.
b Acute attack: (For all Warfarin: ↑ Indomethaci

NSAIDs naproxen
Naprosyn, 750 mg STAT, then NSAIDs) anticoagulant naproxen are
generics 500 mg BID × 4– 5 days GI effect. listed as
Prophylaxis: disturbances; Antihypertensives: examples. Th
other adverse Possible ↓ in is no good
Page 745
Therapeutic Choice
Adverse Drug
250 mg BID effects antihypertensive evidence to
uncommon with effect; may require suggest one
short-term additional NSAID is mo
therapy but antihypertensive efficacious th
include fluid therapy. another.
retention, Suppositorie
hypertension, Lithium: May may be used
renal interfere with oral route
impairment, sodium/water inadvisable.
hypersensitivity. balance. Monitor
lithium levels
when NSAID
added.

GI bleeding when
used with NSAIDs.
Antimitotics colchicine Acute attack: Very common: Patients receiving Low

generics 0.6 mg TID-QID until abdominal pain colchicine with benefit/toxic
relief or side effects and cramps, erythromycin or ratio in acute
occur; Usual max: 6 diarrhea, clarithromycin gout.
doses nausea and should be May be given
Prophylaxis: 0.6– vomiting. monitored for consult
1.8 mg/day ; usual: Rare: colchicine toxicity specialized
1 mg/day neuropathy, (fever, GI references.
myopathy, bone symptoms, Dosage shou
marrow leukopenia). ↓ in elderly a
suppression. renal impairm
Corticosteroids, triamcinolone Acute attack: Not usually

intra- hexacetonide Large joints: 10– significant after
articular Aristospan 20 mg intra-articular single intra-
articular
Small joints: 2– 6 mg injection.
intra-articular
Corticosteroids, methylprednisolone Acute attack: Not usually

intra- acetate Large joints: 20– significant after
articular Depo-Medrol, 80 mg intra-articular single intra-
generics articular
Medium joints: 10– injection.
40 mg intra-articular
Small joints: 4–
10 mg intra-articular
Corticosteroids, methylprednisolone Acute attack: 50– 100 mg Not usually Use when
systemic sodium succinate iv × 1 dose significant after prednisone
single injection. cannot be us
Solu-Medrol,
po.
generics
Corticosteroids, prednisone Acute attack: Except for GI Barbiturates, Doses

systemic generics 30 mg daily × 5 days disturbances phenytoin and < 20 mg/day
and glucose to be ineffec
Page 746
Therapeutic Choice
Adverse Drug
Effective dose range: 20– intolerance, not rifampin ↓ steroid Simultaneou
50 mg/day usually effect. -dose colchic
significant in or NSAID he
short-term use. prevent rebo
Long-term when steroid
effects are stopped.
numerous.
Uricosurics probenecid Starting dose: May precipitate Salicylates ↓ effect Liberal fluid
generics 250 mg BID; titrate acute attack of probenecid. intake and
gradually; max: during initial Probenecid: ↑ alkalinizing t
3 g/day phase of levels of dapsone, urine can he
therapy; renal methotrexate. prevent ston
calculi, Severe toxic
hypersensitivity Heparin activity ↑ rare.
reactions, GI by probenecid.
irritation.
Uricosurics sulfinpyrazone Starting dose: May precipitate Salicylates may ↑ Liberal fluid
generics 50 mg BID with meals; acute attack bleeding time, ↓ intake and
titrate gradually; max. during initial uricosuric effect of alkalinizing t
800 mg/day phase of sulfinpyrazone. urine can he
therapy; renal Action of oral prevent ston
calculi, hypoglycemics, Severe toxic
hypersensitivity insulin and rare.
reactions, GI anticoagulants ↑ by
irritation. sulfinpyrazone.
Xanthine allopurinol Starting dose: Skin rash, GI Half-life of May need to

Oxidase Zyloprim, generics 100 mg daily upset, azathioprine and 6 dose or comb
Inhibitors Usual: 300 mg/day hepatotoxicity, -mercaptopurine ↑ with uricosuric
titrated to urate levels: fever, severe by allopurinol. agents in chro
max. 800 mg/day hypersensitivity May ↑ toxicity of tophaceous g
syndrome, cyclophosphamide. To prevent a
↓ maintenance dose in xanthine stones attacks on
renal impairment: (rare). May Allopurinol inhibits initiation of
precipitate hepatic therapy, give
100 mg/day if ClCr 10– attack during metabolism of prophylactic
20 mL/min; initial phase of warfarin. NSAID or
therapy. colchicine fo
100 mg Q2– 3 days if ↑ incidence of rashes wk.
ClCr < 5 mL/min when used with
ampicillin or Desensitizati
Chemotherapy/irradiation: amoxicillin. allopurinol c
600– 800 mg/day × 2– achieved in s
3 days before therapy patients, but
sensitivity m
Children with recur.
malignancies or enzyme
deficiencies:
10 mg/kg/day
a.
Cost of 30-day supply; includes drug cost only
b.
Page 747
Therapeutic Choice
Legend: $ < $10 $$ $10–20 $$-$$$ $10–30 $$$ $20–30
Suggested Readings
Choi HK, Mount DB, Reginato AM. Pathogenesis of gout. Ann Intern Med 2005;143:499-516.
Rott KT, Agudelo CA. Gout. JAMA 2003;289(21):2857-60.
Schlesinger N. Management of acute and chronic gouty arthritis: present state-of-the-art. Drugs 2004;64(21):2399-41
References
1. Wortmann RL et al. Gout and hyperuricemia. In: Ruddy S et al., eds. Kelley's textbook of rheumatology. 6th ed.
(PA): WB Saunders; 2001.
2. Emmerson BT. The management of gout. N Engl J Med 1996;334(7):445-51.
3. De Souza AW, Fernandes V, Ferrari AJ. Female gout: clinical and laboratory features. J Rheumatol 2005;32 (11)
4. Ahern MJ, Reid C, Gordon TP et al. Does colchicine work? The results of the first controlled study in acute gout.
Med 1987;17(3):301-4.
5. Lee SJ, Terkeltaub RA, Kavanaugh A. Recent developments in diet and gout. Curr Opin Rheumatol 2006;18(2):1
6. Choi HK, Atkinson K, Karlson EW et al. Purine-rich foods, dairy and protein intake and the risk of gout in men. N
2004; 350(11):1093-103.
7. Borstad GC, Bryant LR, Abel MP et al. Colchicine for prophylaxis of acute flares when initiating allopurinol for ch
arthritis. J Rheumatol 2004;31(12):2429-32.
8. Fam AG. Should patients with interval gout be treated with urate lowering drugs? J Rheumatol 1995;22(9):1621
9. Fam AG, Lewtas J, Stein J et al. Desensitization to allopurinol in patients with gout and cutaneous reactions. Am
1992;93(3):299-302.
10. Earl JM, Saavedra M. Oxipurinol therapy in allopurinol-allergic patients. Am Fam Physician 1983;28(5):147-8.
Page 748
e-Therapeutics+ : Therapeutics : Musculoskeletal Disorders: Low Back Pain Page 1 of 15
Therapeutic Choice
Print Close
Musculoskeletal Disorders: Low Back Pain
Eldon Tunks, MD, FRCPC
This chapter summarizes the nonsurgical management of low back pain.
Goals of Therapy
Acute Low Back Pain (LBP)
Promote rapid/earlier recovery and reduce distress
Subacute/Recurrent LBP
Assess appropriately and prevent chronicity

Prevent or minimize work absence
Chronic LBP
Promote or restore healthy behaviour, fitness and appropriate role functions by defining and treating medical and
factors associated with persistent/recurrent pain, according to evidence-based principles
Acute LBP
Investigations
Therapeutic Choices
This section refers to the first 30 days of back pain (Figure 1 - Management of Acute Low Back Pain).
Investigations
Clinical history, relevant physical examination and neurological assessment. Identify “red flags” (Table 1);1 , 2 , 3 , 4 ,
further investigation and/or referral for consultation are indicated. Arrange diagnostic imaging and laboratory tests co
bedside examination findings.
Therapeutic Choices
For acute or recurrent back pain of less than 3 weeks, provide symptomatic relief, encourage the patient to continue o
and work as soon as tolerated and educate the patient to expect early recovery. Avoid unnecessary bedrest for uncom
pain as well as premature physical therapy. This approach results in the shortest duration of sick leave and pain.5 , 6 ,
For acute back pain with sciatica, advise patients to modify activities and otherwise continue activities according to to
physiotherapy offers slightly better functional status at 4 weeks' follow-up compared to bedrest, with no difference in
pain. There is no advantage to bedrest in acute back pain with sciatica.6 , 7
Table 1: “Red Flag” Symptoms/Signs in Assessment of Low Back Pain
Page 749
Therapeutic Choice
Condition Symptoms/Signs Investigatio
Positive SLR (leg pain at < 60°); weak dorsiflexion of

ankle (L4-5) or great toe (L5-S1 or L4-5); reduced ankle
reflex (L5-S1); reduced light touch in L4, L5 or S1
1
Herniated Nucleus dermatomes of foot/leg
Pulposus MRI of lumbar
Cancer Age > 50; previous cancer history; unexplained weight loss; Positive laboratory tests
2
failure to improve after 1 mo therapy elevated ESR, reduced h
imaging showing erosion
lesions
Spinal Osteomyelitis Intravenous drug abuse; sources of infection (e.g., skin, teeth, Positive laboratory tests
urinary tract, or indwelling catheter); fever; vertebral
3
tenderness
Spinal Age > 50, female gender, major trauma, pain and tenderness, Positive laboratory tests
Fracture/Compression 4 x-rays
and a distracting painful injury; also consider a history of
Fracture osteoporosis or corticosteroid use
Cauda Equina Syndrome Acute urinary retention or overflow incontinence; loss of anal Emergency laboratory as
sphincter tone/fecal incontinence; perineal numbness; change imaging
1
in sexual function; weakness of legs
Abbreviations: MRI = magnetic resonance imaging; SLR = straight leg raising
For acute uncomplicated low back pain, NSAIDs are effective for pain relief, particularly during the first f
10
there is no evidence that one NSAID or COX-2 anti-inflammatory is more effective than another. There
selecting an NSAID, consider tolerability, patient contraindications, and cost. There is moderate evidence
10
are not more effective than acetaminophen for back pain. Given the greater safety profile compared to
of acetaminophen, or acetaminophen with codeine is a reasonable option in acute uncomplicated back pa
Useful Info?
During the acute phase of low back pain, muscle relaxants may be effective for relief of pain and spasm during sho
5 , 11
are more prone to cause adverse effects such as drowsiness and dizziness. Muscle relaxants might include benzo
OTC preparations containing methocarbamol or orphenadrine, or prescribed cyclobenzaprine or the antispasticity
or tizanidine. A muscle relaxant may also be combined with an NSAID for relief of pain and spasm in acute back pain
Strong opioids such as morphine may be indicated in more severe acute pain, especially if NSAIDs or acetaminophe
provide insufficient relief, or in the presence of NSAID intolerance or contraindications.
Subacute and Recurrent LBP
Investigations
Therapeutic Choices
Subacute low back pain refers to pain continuing 4–12 weeks post onset. Recurrent refers to up to 6 months after ons
Management of Persistent Low Back Pain).
Page 750
Therapeutic Choice
Investigations
When there is persistent or recurrent pain and interference with vocational function, re-evaluate the patient.5 When re
present (Table 1), imaging and consultation are recommended. After the first 4–6 weeks, in addition to imaging, elect
be helpful if there are clinical findings suggestive of nerve root involvement.
One of the strongest predictors of satisfactory adjustment is vocational status, and delay in work return significantly r
likelihood of ever returning.
For recurrent back pain or persistent back pain of 3–6 months, reassessment is advised. This should include screening
complications (Table 2).5 , 9 , 12 Although compensation or litigation alone has an indefinite effect on prognosis, whe
12
levels are high or when the employee is in conflict, compensation and litigation may significantly impair prognosis.
Table 2: Factors Adversely Affecting Prognosis of Low Back Pain
Mental Status Indicators of Significant A

Psychosocial Factors Depression
Duration of work absence Insomnia or nightmares

High levels of self-reported functional disability Irritability
Self-report of extreme pain and constant pain in multiple body Withdrawal
areas Panic episodes or anxiety during the day or night
History of prolonged sick-listing after previous injuries Persistent tearfulness
Prior history of absenteeism Poor concentration
Delays/obstacles in work re-entry process Inability to enjoy (anhedonia)
Patients who believe that they will never return to work Poor appetite/weight loss
Adversarial attitude toward employer Poor libido
Long-standing history of psychiatric distress or maladjustment Thoughts that “life is not worth living”
Therapeutic Choices
If the pain and sick-listing are not resolved after the first month, early active treatment (individual patient education, w
and planned work re-entry) aimed at return to productive function has the greatest efficacy with regard to resolving pa
functional ability and successful work return.13 , 14 , 15 Setting a treatment timeline and projected date for return to w
for management. The active ingredient in successful work return, however, appears to be timely workplace interventio
the stakeholders rather than clinic treatment modalities, and if possible to avoid the patient having to cease work for t
9 , 15 , 16
Patient education at this stage should stress that low back pain usually has a favourable outcome if it is managed by a
and timely return to function and occupation, rather than expecting the pain to completely resolve first. Screen for and
psychosocial factors or refer when necessary.9 , 12 , 17
There are many potential modalities of symptomatic physical therapy, e.g., ice, heat, laser, ultrasound, massage, man
acupuncture, transcutaneous electrical nerve stimulation (TENS). Evidence for efficacy of any individual modality is pr
inadequate, with the exception that active exercise and avoidance of unnecessary bedrest improves outcomes.6 , 7 , 16
At approximately 3–6 months, the focus is on interrupting progress toward chronic pain (Figure 2 - Management of Per
Pain). If there is marked functional disability associated with pain that is recurrent or persisting for 3 months or more,
coordinated program between the primary care provider, patient, employer and compensation agency. If the coordinat
unsuccessful, identify possible psychological comorbidity, and consider timely referral to a multidisciplinary chronic p
5 , 12
clinic for intensive treatment.
Acetaminophen with codeine or failing that, opioid analgesics, are effective in some cases of chronic pain in gen
17
efficacy is limited, but strong enough to recommend a trial.
Page 751
Therapeutic Choice
There is some evidence for efficacy of muscle relaxants that may also be applicable for short-term relief of subacute
Pharmacologic Choices (), Acute Low Back Pain).
Chronic LBP
Investigations
Therapeutic Choices
Chronic low back pain refers to pain persisting 6 months or more post onset (Figure 2 - Management of Persistent Low
Investigations
Be aware of co-existing psychological and social complications which at this time are the strongest obstacles to impro
recovery (Table 2).
Therapeutic Choices
“Back school” or patient education alone tends to be ineffective at this point unless there is an active exercise and/or
15 , 16
restoration focus tied closely with the workplace for work re-entry. Patients must be engaged in goal-setting and
9 , 12
progress. Cognitive behavioural therapy or relaxation therapy are effective for pain and for behavioural outcomes
19
for chronic low back pain, but efficacy for work return is associated with conducting therapy if possible in the work
least in the context of a planned work re-entry.16 The focus should include multidisciplinary rehabilitation, cognitive b
therapy, active exercise, functional restoration, patient education and vocational counselling toward work re-entry, an
include psychosocial intervention and training in coping skills.5 , 12 , 17 , 20 Physical conditioning programs that includ
behavioural therapy can shorten sick time when compared to primary care or simple advice.20
For acupuncture alone or combined with other therapies for chronic back pain, there is limited evidence of only short-
21
pain and functional impairment. There is a lack of evidence whether patients who have failed treatment in a multidis
rehabilitation program (or chronic pain management program) will benefit from a second attempt. After treatment fail
interfered with progress must be identified and addressed. These might include, for example, an Axis I disorder (espe
depression, anxiety disorder or dysthymia), an attitude problem such as unwillingness to set goals for change, a subs
medication abuse problem, a previously undetected medical/surgical problem or obstacles to work re-entry or lack of
within the job environment.
For chronic back pain, muscle relaxants (benzodiazepines, relaxants or antispasticity drugs) are effective for short-t
relief.11 Although there is no established literature on it, there is some clinical experience that for chronic low back pa
with pain/tenderness in multiple areas, the gabapentinoids gabapentin or pregabalin may also sometimes be helpfu
There is limited evidence that tramadol is more effective than placebo for uncomplicated chronic back pain. 22
Some patients with persistent low back pain respond to opioid analgesics; they may be used if other non-opioid and
analgesic options have proven inadequate for pain control and if there are no contraindications for their use. If opioid
in more than small doses and for a longer period of time, sustained-release preparations are preferable. Consider stro
analgesics when pain is a significant barrier to function, is an unremitting source of distress, has not responded to oth
options and if there are otherwise no significant psychological or medical contraindications. If in doubt, obtain a cons
Currently, evidence is lacking regarding the efficacy of antidepressants for relief of chronic low back pain, although
23
indicated in the situation of comorbid depression and mood disorder with chronic pain.
Page 752
Therapeutic Choice
Injection therapies for chronic low back pain, such as epidural steroids, have not had statistically significant efficacy
pain relief and work disability;24 however, there is a tendency toward positive results with only minor side effects. Stu
joint injections with corticosteroid, with or without local anesthetic, have found conflicting evidence for relief compa
24
There is limited evidence for efficacy of trigger point blocks for short-term relief. At the moment there may be justif
injection therapy in patients with low back pain, provided it is well tolerated and accompanied by patient improvemen
therapy should not be done to the exclusion of other proven rehabilitation therapies.
Low Back Pain and Neck Pain in Pregnancy
More than 50% of pregnant women will experience back pain during pregnancy, usually in the lumbar and sacroiliac a
pain in pregnancy is more likely if there has been a previous history of low back pain and overweight. Contributing fac
hormonal changes, anterior displacement of the centre of gravity which accentuates lumbar lordosis, and weight gain
pregnancy. Spondylolysis or the progression of spondylolisthesis may occur. There is a small risk of disk herniation d
and, where necessary, non-contrast MRI could be performed.
Neck pain may also be somewhat exacerbated during pregnancy, although less frequently, especially if there is coexis
pain and weight gain.
Since the majority of treatment of back and neck pain is nonpharmacologic, most of the recommendations remain app
expectant mother. Ideally, a woman planning a pregnancy should address problems of weight and core fitness before
During pregnancy, a program of walking and modified exercise is recommended to strengthen abdominal and back mu
exercise and body mechanics should be modified to be consistent with the stage of pregnancy. Therapeutic aquatic ex
25
beneficial.
Transcutaneous electrical nerve stimulation (TENS) can be used over a limb during pregnancy but not over the low ba
due to the possibility of precipitation of labor.
If nonpharmacologic options are insufficient to manage pain and drug treatment is deemed necessary, the following in
serve as a guide in making an informed decision.
Acetaminophen in therapeutic doses is an appropriate choice for analgesia in the pregnant woman. Short-term NSA
second trimester may also be considered. First trimester use has been associated with spontaneous abortions and a sm
structural defects, while in the third trimester, NSAIDs are generally contraindicated due to increased risk of prematur
ductus arteriosus and neonatal pulmonary hypertension.26 Use of topical diclofenac in a dimethyl sulfoxide (DMSO) ve
recommended.
Where possible, opioid use should be avoided during pregnancy; if not feasible, the lowest effective dose should be u
shortest possible time, as high doses and use near term may result in adverse effects (opioid withdrawal syndrome, re
depression) in the neonate. Weaning from chronic therapy, where deemed desirable, should begin in the second trime
reduce the risk of spontaneous abortion or preterm labour. Dose reductions of no more than 10% of the total dose pe
27
suggested. Reducing the dose beyond 70% may require slower tapering, e.g. reducing by 5% of the total dose per w
amounts of immediate-release opioid may be required to treat transient symptoms of withdrawal during the final week
Neonatal withdrawal has also been reported after long-term tramadol treatment in the pregnant mother.28 , 29
26
Tricyclic antidepressants as a class are considered relatively safe in pregnancy, but should generally not be used
low back pain during pregnancy as evidence regarding their efficacy is lacking.
Use of muscle relaxants (baclofen, cyclobenzaprine, methocarbamol, orphenadrine) should be avoided as there are
on their safe use during pregnancy. There is a possible increased risk of congenital malformations with diazepam use
use in the pregnant mother has been associated with adverse effects in the neonate such as drug withdrawal and flopp
26
syndrome.
Page 753
Therapeutic Choice
Gabapentinoids (gabapentin, pregabalin) should be avoided as there are insufficient data available regarding their
pregnancy.
Normal saline may be used for injection of trigger points if necessary, rather than lidocaine or other local anesthetic
therapy and noninvasive techniques are equally likely to be effective.
Low Back Pain and Neck Pain during Breastfeeding
In the postpartum and breastfeeding period, about 1/3 of women will continue to experience low back pain. Risk facto
weight gain during pregnancy, lifting and carrying the infant and the ergonomics of how the mother carries and tends
During the postpartum period, a program of walking and modified exercise to strengthen abdominal and back muscles
continued. It is also important to institute appropriate diet and weight loss and to focus on good body mechanics whe
caring for the baby.
There is no contraindication to the use of TENS on the lactating mother except while the infant is actually nursing.
Acetaminophen in therapeutic doses is an appropriate choice for analgesia in the lactating mother. Ibuprofen has a
30
safely during lactation. Short-term use of most other NSAIDs is generally considered compatible with breastfeeding;
with shorter half-lives where possible.
Opioid use by the lactating mother can cause respiratory depression or lead to drug withdrawal syndrome in the newb
31
fatal morphine poisoning in an infant whose mother received codeine postpartum has been reported. Since codeine
to morphine, high-dose or prolonged use of codeine products may lead to toxicity in the newborn. Mothers who are CY
metabolizers are at higher risk of excessive morphine levels in the breast milk.32 To prevent possible accumulation of
neonates, codeine products should be avoided when possible, or prescribed for 2–3 days only, with careful follow-up,
mothers.
Small amounts of tramadol and its metabolites are excreted into breast milk, but published data of the effects on infa
Tricyclic antidepressants can cause sedation in the newborn if used in the antenatal period or during lactation.
Diazepam accumulates in the newborn during lactation and is associated with a risk of adverse effects to the infant.2
published information on the effects of most other non-benzodiazepine muscle relaxants on the lactating infant.
Limited data indicates that low levels of gabapentin appear in infant serum, but no apparent adverse effects to the b
reported.34
General Considerations
See also Appendix: Drug Use During Pregnancy and Appendix: Drug Use During Lactation for a discussion of the gene
For more detailed information on the use of specific medications in this condition during pregnancy and breastfeeding
referred to Motherisk [www.motherisk.org/women/drugs.jsp]; Briggs GG, Freeman RK, Yaffe SJ. Drugs in Pregnancy a
2008; LactMed [toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen?LACT]; and Hale T. Medications and Mothers' Milk 2008.
Therapeutic Tips
A significant minority of chronic pain sufferers have comorbid depression, anxiety or dysthymia (chronic depressi
often masked by the pain presentation. Key symptoms (Table 2) can reveal the underlying mood disorder. Comor
disorders often respond to antidepressants, which can improve coping with pain.
For back pain and chronic soft tissue pain, tricyclic or other types of antidepressants have equivocal efficacy, b
useful for their antidepressant effect.12
Some patients with back pain who have difficulty sleeping may benefit from a combination analgesic product cont
caffeine.
Page 754
Therapeutic Choice
Figure 1- Management of Acute Low Back Pain
Figure 2- Management of Persistent Low Back Pain
Table 3: Drugs Used in the Treatment of Back and Neck Pain
Adverse
Class Drug Dosage Effects Drug Interactions Comments
Analgesics, acetaminophen 325– 650 mg Q4H Hepatotoxicity Increased anticoagulant Found in man
nonopioid Atasol with acute effect of warfarin may combination
overdose or occur with use of products
Preparations,
marketed for
relief of pain,
Page 755
Therapeutic Choice
Adverse
Tylenol, chronic high > 1.3 g/day acetaminophen muscle spasm
generics doses. for > 1 wk. cold and flu,
menstrual
symptoms, et
Total intake
from all
sources not to
exceed max o
4 g/day.
NSAIDs b ibuprofen 600– 1200 mg/day See Table 2, See Table 2, No evidence
Advil, Motrin po divided Q6-8H Musculoskeletal Musculoskeletal Disorders: that one NSA
Disorders: Osteoarthritis for more is superior to
IB, generics
information. another for
Osteoarthritis for
back pain. Se
more
Table 2,
information.
Musculoskele
Disorders:
Osteoarthritis
for a listing o
other NSAIDs
b 500– 1000 mg/day See Table 2, See Table 2, No evidence
NSAIDs naproxen
Naprosyn, po divided Q8-12H Musculoskeletal Musculoskeletal Disorders: that one NSA
generics Disorders: Osteoarthritis for more is superior to
Osteoarthritis for
back pain. Se
more
Table 2,
information.
Musculoskele
Disorders:
Osteoarthritis
for a listing o
other NSAIDs
b 7.5–15 mg once See Table 2, See Table 2, No evidence
NSAIDs meloxicam
Mobicox, daily Musculoskeletal Musculoskeletal Disorders: that one NSA
generics Disorders: Osteoarthritis for more is superior to
Osteoarthritis for
back pain. Se
more
Table 2,
information.
Musculoskele
Disorders:
Osteoarthritis
for a listing o
other NSAIDs
b 100 mg BID or See Table 2, See Table 2, No evidence
NSAIDs celecoxib
Celebrex 200 mg once daily Musculoskeletal Musculoskeletal Disorders: that one NSA
Disorders: Osteoarthritis for more is superior to
Osteoarthritis for
back pain. Se
more
Table 2,
information.
Musculoskele
Disorders:
Osteoarthritis
for a listing o
other NSAIDs
Contraindicat
if sulfonamid
allergy.
Page 756
Therapeutic Choice
Adverse
NSAIDs, topical diclofenac Apply to affected Skin dryness or For external

Pennsaid area TID to QID irritation, use only.
Solution, hypersensitivity. Solution
Voltaren Serious GI contains
Emulgel toxicity has not diclofenac
been seen to sodium 1.5%
date in clinical w/w in DMSO
trials. vehicle. Gel
contains
diclofenac
diethylamine
1.16% w/w
and is availab
without
prescription.
Opioids acetaminophen 1–2 tabs QID Nausea and CNS depressants including Start low.
with codeine Max: 8 tabs/day vomiting, sedatives, tranquilizers, Titrate dosag
constipation, alcohol may increase CNS against pain
15, 30 or 60
Maximum amount sedation or depression. Potential gradually
mg of acetaminophen drowsiness, enhancement of opioid enough to
Tylenol with from all sources confusion, effects with lidocaine. manage
codeine, should not exceed urinary Avoid use with MAO adverse effec
Atasol with 4 g/day. retention, dry inhibitors because of Upper limits o
codeine, mouth, allergic enhanced CNS depressant clinically
reactions, e.g., effects. Avoid use of opioid appropriate
generics
rash. antagonists. Be cautious of dosage of
drugs that may precipitate opioids have
withdrawal reactions. not been
identified.
Consider
addition of
stimulant
laxative.
Opioids buprenorphine Initial (may be Application site CNS depressants including Has agonist-
transdermal used in opioid- skin reactions. sedatives, tranquilizers, antagonist
BuTrans naïve patients): alcohol may increase CNS activity.
5 µg/h patch depression. Potential
applied once enhancement of opioid Do not use in
weekly. Patch sites effects with lidocaine. patients
should not be Avoid use with MAO <40 kg.
reused for 3 wk. inhibitors because of
enhanced CNS depressant
effects. Avoid use of opioid
antagonists. Be cautious of
drugs that may precipitate
withdrawal reactions.
Concomitant use with
potent CYP3A4 inhibitors
e.g., cimetidine, efavirenz,
erythromycin, itraconazole,
ketoconazole or ritonavir,
may increase
buprenorphine plasma
concentrations.
Opioids fentanyl In opioid-tolerant Nausea and CNS depressants including Start low.
transdermal patients taking at vomiting, sedatives, tranquilizers, Titrate dosag
least 60 mg/day of constipation, alcohol may increase CNS against pain
Duragesic MAT,
oral morphine or sedation or depression. Potential gradually
ratio-Fentanyl, equivalent, drowsiness, enhancement of opioid enough to
other generics fentanyl confusion, effects with lidocaine. manage
Page 757
Therapeutic Choice
Adverse
25 µg/h patch can urinary Avoid use with MAO adverse effec
be substituted for retention, dry inhibitors because of Upper limits o
oral opioid. See mouth, allergic enhanced CNS depressant clinically
conversion table in reactions, e.g., effects. Avoid use of opioid appropriate
product rash. antagonists. Be cautious of dosage of
monograph. Similar to other drugs that may precipitate opioids have
Change patch opioids, possibly withdrawal reactions. not been
Q72H. less constipation Concomitant use with identified.
but more potent CYP3A4 inhibitors Consider
sweating. e.g., cimetidine, efavirenz, addition of
erythromycin, itraconazole, stimulant
ketoconazole or ritonavir, laxative.
may increase fentanyl Contraindicat
plasma concentrations. in patients wh
are opioid-
naïve. Some
patients may
require lower
starting dose
Opioids hydromorphone Initial: 3 mg Q12H Nausea and CNS depressants including Start low.
sustained- po for sustained- vomiting, sedatives, tranquilizers, Titrate dosag
release products constipation, alcohol may increase CNS against pain
release
sedation or depression. Potential gradually
Hydromorph drowsiness, enhancement of opioid enough to
Contin confusion, effects with lidocaine. manage
urinary Avoid use with MAO adverse effec
retention, dry inhibitors because of Upper limits o
mouth, allergic enhanced CNS depressant clinically
identified.
Consider
addition of
stimulant
laxative.
Opioids hydromorphone Initial: 4 mg Q24H Nausea and CNS depressants including Start low.
sustained- po vomiting, sedatives, tranquilizers, Titrate dosag
release constipation, alcohol may increase CNS against pain
Jurnista sedation or depression. Potential gradually
drowsiness, enhancement of opioid enough to
confusion, effects with lidocaine. manage
identified.
Consider
addition of
stimulant
laxative.
May be used
opioid-naïve
patients.
Preferable to
titrate with
shorter-acting
product, then
Page 758
Therapeutic Choice
Adverse
convert to 24
dose.
Opioids morphine Initial: 15 mg Nausea and CNS depressants including Start low.
sustained- Q12H po for vomiting, sedatives, tranquilizers, Titrate dosag
sustained-release constipation, alcohol may increase CNS against pain
release
products sedation or depression. Potential gradually
M-Eslon, MS drowsiness, enhancement of opioid enough to
Contin, confusion, effects with lidocaine. manage
generics urinary Avoid use with MAO adverse effec
identified.
Consider
addition of
stimulant
laxative.
Opioids morphine 20–30 mg Q24H Nausea and CNS depressants including Start low.
sustained- for sustained- vomiting, sedatives, tranquilizers, Titrate dosag
release release products constipation, alcohol may increase CNS against pain
Kadian sedation or depression. Potential gradually
identified.
Consider
addition of
stimulant
laxative.
Preferable to
titrate with
shorter-acting
product, then
convert to 24
dose.
Opioids oxycodone Initial: 10 mg Nausea and CNS depressants including Start low.
sustained- Q12H po for vomiting, sedatives, tranquilizers, Titrate dosag
release sustained-release constipation, alcohol may increase CNS against pain
OxyContin products sedation or depression. Potential gradually
identified.
Consider
Page 759
Therapeutic Choice
Adverse
addition of
stimulant
laxative.
Opioids tramadol Initial: 150 mg Respiratory Do not use if MAOIs taken

controlled- once daily. May depression, within past 14 days.
release increase at weekly sedation, ataxia, Caution with drugs that ↓
Ralivia, intervals to 200– constipation, seizure threshold, e.g., SSRIs,
400 mg/day seizures, TCAs, bupropion. Risk of
Tridural,
nausea, serotonin syndrome with
Zytram XL orthostatic SSRIs. ↑ sedation with other
hypotension. CNS depressants.
Carbamazepine may ↓
analgesic effect of tramadol.
Clearance may be ↓ by
CYP2D6 inhibitors e.g.,
fluoxetine, paroxetine,
quinidine, or by CYP3A4
inhibitors e.g.,
ketoconazole.
Opioids tramadol with 1–2 tablets Q4-6H. Respiratory Do not use if MAOIs taken 37.5 mg
acetaminophen Max: 8 tablets depression, within past 14 days. tramadol + 3
daily. Maximum sedation, ataxia, Caution with drugs that ↓ mg
Tramacet, amount of constipation, seizure threshold, e.g., SSRIs, acetaminophe
generics acetaminophen seizures, TCAs, bupropion. Risk of per tablet.
from all sources nausea, serotonin syndrome with
should not exceed orthostatic SSRIs. ↑ sedation with other
4 g /day hypotension. CNS depressants.
Carbamazepine may ↓
analgesic effect of tramadol.
Clearance may be ↓ by
CYP2D6 inhibitors e.g.,
fluoxetine, paroxetine,
quinidine, or by CYP3A4
inhibitors e.g.,
ketoconazole.
Muscle baclofen Start with 5 mg Sedation, muscle Potential additive CNS Adjust dose
Relaxants Lioresal Oral, TID; increase weakness, depression with TCAs, gradually to
generics gradually to max nausea, opioids, benzodiazepines, minimize
of 20 mg TID dizziness. antihypertensives. adverse effec
or withdrawa
symptoms.
Muscle cyclobenzaprine 5–10 mg po TID Drowsiness, dry May ↑ risk of CNS effects Structurally
Relaxants generics mouth, when used with opioids or other similar to
dizziness, CNS depressants. SSRIs TCAs. Can be
fatigue, nausea, and inhibitors of CYP1A2 given as 1
constipation. (quinolones, ketoconazole) nighttime dos
may ↓ clearance. ↑ in seizure
risk with tramadol. Do not use
with MAOIs.
Muscle methocarbamol 1 g po QID Drowsiness, dry Combination with opioids Also available
Relaxants Robaxin mouth, or other CNS depressants in
dizziness, may ↑ risk of CNS depression. combinations
fatigue, nausea, with ASA or
constipation. acetaminophe
with or witho
codeine.
Page 760
Therapeutic Choice
Adverse
Muscle orphenadrine 100–200 mg/day Drowsiness, dry Use with propoxyphene Can be given
Relaxants Norflex, po divided BID mouth, may ↑ CNS effects. as 1 nighttim
generics dizziness, dose.
fatigue, nausea,
constipation.
Muscle tizanidine Start with 2 mg Sedation, ↑ hypotensive effect with Adjust dose
Relaxants Zanaflex, BID; increase to dizziness, dry antihypertensives. ↓ gradually to
generics max of 4 mg TID mouth, clearance with oral minimize
weakness, contraceptives or TCAs. ↓ adverse effec
hypotension, clearance with CYP1A2 or withdrawa
hepatotoxicity inhibitors such as cimetidine, symptoms
(monitor liver ciprofloxacin, fluvoxamine, (e.g., reboun
function tests). ketoconazole. May ↑ hypertension)
phenytoin levels.
Benzodiazepines diazepam 2–5 mg orally BID Drowsiness, Potentiation of cognitive In acute pain
generics to QID for acute cognitive impairment when used with short-term us
pain impairment, opioids. Potentiation of as muscle
drug alcohol intoxication. relaxant. Not
dependence, recommended
falls, in the elderly
accumulation in
the elderly and
in presence of
pulmonary, liver
or kidney
disease.
Tricyclic amitriptyline Initial: Anticholinergic Do not use with MAOIs; TCAs may be
Antidepressants generics 10–25 mg QHS; (dry mouth, SSRIs ↑ serum levels of TCAs; effective for
increase by blurred vision, carbamazepine and rifampin soft tissue an
10–25 mg QHS constipation, may ↓ effect; cimetidine and chronic back
weekly until effect urinary antipsychotics may ↑ effect pain (evidenc
or side effects hesitancy, and toxicity; possible is mixed). Th
tachycardia, interaction with may also be
delirium), antiarrhythmics (may lead indicated for
antihistaminergic to ↑ effect of either drug); depression
(sedation, may ↓ antihypertensive effect associated wi
weight gain), of clonidine; may augment chronic pain.
orthostatic hypotensive effect of
hypotension, thiazides.
lowered seizure
threshold;
sexual
dysfunction.
Tricyclic desipramine Initial: Anticholinergic Do not use with MAOIs; TCAs may be
Antidepressants generics 10 mg QAM or (dry mouth, SSRIs ↑ serum levels of TCAs; effective for
QHS; increase to blurred vision, carbamazepine and rifampin soft tissue an
25– 75 mg/day constipation, may ↓ effect; cimetidine and chronic back
urinary antipsychotics may ↑ effect and pain (evidenc
hesitancy, toxicity; possible is mixed). Th
tachycardia, interaction with may also be
delirium), antiarrhythmics (may lead indicated for
antihistaminergic to ↑ effect of either drug); depression
(sedation, may ↓ antihypertensive effect associated wi
weight gain), of clonidine; may augment chronic pain.
orthostatic hypotensive effect of
hypotension, thiazides.
lowered seizure
threshold;
sexual
dysfunction.
Page 761
Therapeutic Choice
Adverse
Antiepileptic gabapentin Initial: 300–400 Sedation, ataxia, Administration with Do not

Drugs Neurontin, mg/day in divided tremor; less aluminum/magnesium- discontinue
generics doses. May commonly, GI containing antacids may ↓ treatment
increase at weekly upset, peripheral bioavailability. abruptly; tape
intervals to BID edema, vision dosage over a
then TID Max: changes. least 1 week
3600 mg/day avoid
withdrawal
effects.
Antiepileptic pregabalin Initial: 50–150 mg Sedation, ataxia, No significant known drug BID dosing is
Drugs Lyrica daily in 2 divided edema, diplopia, interactions. an advantage
doses. Increase weight gain, dry over
dose weekly by 50 mouth. gabapentin.
–150 mg/day to a
max of 600
mg/day
a.
Cost of 30-day supply or smallest available pack size, includes drug cost only.
b.
Legend: $ <$20 $-$$ <$20–40 $$ $20–40 $$$ $40–60 $$$$ $60-80 $$$$$ > $80
Suggested Readings
National Opioid Use Guideline Group. Canadian guideline for safe and effective use of opioids for chronic non-cancer p
(ON): NOUGG; 2010. Available from: http://nationalpaincentre.mcmaster.ca/opioid/documents.html Accessed July 16
Harwood MI, Smith BJ. Low back pain: a primary care approach. Clinics in Family Practice 2005;7(2):279-303.
References
1. Deyo RA, Rainville J, Kent DL. What can the history and physical examination tell us about low back pain? JAMA
(6):760-5.
2. Henschke N, Maher CG, Refshauge KM. Screening for malignancy in low back pain patients: a systematic review
2007;16(10):1673-9.
3. Waldvogel FA, Papageorgiou PS. Osteomyelitis: the past decade. N Engl J Med 1980;303(7):360-70.
4. Henschke N, Maher CG, Refshauge KM. A systematic review identifies five “red flags” to screen for vertebral frac
with low back pain. J Clin Epidemiol 2008;61(2):110-8.
5. Scientific approach to the assessment and management of activity-related spinal disorders. A monograph for cli
the Quebec Task Force on Spinal Disorders. Spine (Phila Pa 1976) 1987;12(7 Suppl):S1-59.
6. Hagen KB, Hilde G, Jamtvedt G, Winnem M. Bed rest for acute low-back pain and sciatica. Cochrane Database S
(4):CD001254.
7. Philadelphia Panel. Philadelphia Panel evidence-based clinical practice guidelines on selected rehabilitation inter
back pain. Phys Ther 2001;81(10):1641-74.
8. NHS Centre for Reviews and Dissemination, University of York. Acute and chronic low back pain. Eff Health Care
Available from: www.york.ac.uk/inst/crd/EHC/ehc65.pdf. Accessed December 2, 2009.
9. Carter JT, Birrell LN, editors. Occupational health guidelines for the management of low back pain at work: princ
recommendations. London (GB): Faculty of Occupational Medicine of the Royal College of Physicians; 2000.
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Therapeutic Choice
10. Roelofs PD, Deyo RA, Koes BW et al. Non-steroidal anti-inflammatory drugs for low back pain. Cochrane Databa
2008;(1):CD000396.
11. van Tulder MW, Touray T, Furlan AD et al. Muscle relaxants for non-specific low back pain. Cochrane Database S
(2):CD004252.
12. Tunks E et al. Natural history and efficacy of treatment of chronic pain arising from musculoskeletal injury. In: S
editor. Injury and the new world of work. Vancouver (BC): UBC Press; 2000.
13. Karjalainen K, Malmivaara A, van Tulder M et al. Multidisciplinary biopsychosocial rehabilitation for subacute low
among working age adults. Cochrane Database Syst Rev 2003;(2):CD002193.
14. Engers A, Jellema P, Wensing M et al. Individual patient education for low back pain. Cochrane Database Syst R
(1):CD004057.
15. Anema JR, Steenstra IA, Bongers PM et al. Multidisciplinary rehabilitation for subacute low back pain: graded ac
workplace intervention or both? A randomized controlled trial. Spine (Phila Pa 1976) 2007;32(3):291-8.
16. Loisel P, Abenhaim L, Durand P et al. A population-based, randomized clinical trial on back pain management. S
1976) 1997;22(24):2911-8.
17. College of Physicians and Surgeons of Ontario. Evidence-based recommendations for medical management of ch
malignant pain: reference guide for clinicians. Toronto (ON): CPSO; 2000. Available from:
www.cpso.on.ca/uploadedFiles/policies/guidelines/methadone/MedicalManagementPain.pdf. Accessed Decembe
18. Assendelft WJ, Morton SC, Yu EI et al. Spinal manipulative therapy for low back pain. Cochrane Database Syst R
(1):CD000447.
19. Ostelo RW, van Tulder MW, Vlaeyen JW et al. Behavioural treatment for chronic low-back pain. Cochrane Databa
2005;(1):CD002014.
20. Schonstein E, Kenny DT, Keating J et al. Work conditioning, work hardening and functional restoration for work
and neck pain. Cochrane Database Syst Rev 2003;(1):CD001822.
21. Furlan AD, van Tulder MW, Cherkin DC et al. Acupuncture and dry-needling for low back pain. Cochrane Databa
2005;(1):CD001351.
22. Deshpande A, Furlan AD, Mailis-Gagnon A et al. Opioids for chronic low-back pain. Cochrane Database Syst Rev
(3):CD004959.
23. Urquhart DM, Hoving JL, Assendelft WW et al. Antidepressants for non-specific low back pain.Cochrane Databas
(1):CD001703.
24. Staal JB, de Bie R, de Vet HC et al. Injection therapy for subacute and chronic low-back pain. Cochrane Databas
(3):CD001824.
25. Waller B, Lambeck J, Daly D. Therapeutic aquatic exercise in the treatment of low back pain: a systematic review
2009;23(1):3-14.
26. Briggs GG, Freeman RK, Yaffe SJ, editors. Drugs in pregnancy and lactation: a reference guide to fetal and neon
Philadephia (PA): Lippincott, Williams & Wilkins; 2008.
27. Centre for Addictions and Mental Health; Motherisk. Exposure to psychotropic medications and other substances
pregnancy and lactation: a handbook for health care providers. 1st ed. Toronto (ON): CAMH; 2007. Available fro
www.camh.net/Publications/Resources_for_Professionals/Pregnancy_Lactation/psychmed_preg_lact.pdf. Access
2009.
28. Meyer FP, Rimasch H, Blaha B et al. Tramadol withdrawal in a neonate. Eur J Clin Pharmacol 1997;53(2):159-60
29. Willaschek C, Wolter E, Buchhorn R. Tramadol withdrawal in a neonate after long-term analgesic treatment of th
Clin Pharmacol 2009;65(4):429-30.
30. American Academy of Pediatrics Committee on Drugs. Transfer of drugs and other chemicals into human milk. P
2001;108(3):776-89.
31. Koren G, Cairns J, Chitayat D et al. Pharmacogenetics of morphine poisoning in a breastfed neonate of a codein
mother. Lancet 2006;368(9536):704.
32. Madadi P, Koren G, Cairns J et al. Safety of codeine during breastfeeding: fatal morphine poisoning in the breas
mother prescribed codeine. Can Fam Physician 2007;53(1):33-5.
33. Ilett KF, Paech MJ, Page-Sharp M et al. Use of a sparse sampling study design to assess transfer of tramadol and
metabolite into transitional breast milk. Br J Clin Pharmacol 2008;65(5):661-6.
34. Drugs and Lactation Database (LactMed). Bethesda (MD): U.S. National Library of Medicine. Available from:
toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen?LACT. Accessed December 3, 2009.
Page 763
e-Therapeutics+ : Therapeutics : Musculoskeletal Disorders: Neck Pain and Whiplash Page 1 of 7
Therapeutic Choice
Print Close
Musculoskeletal Disorders: Neck Pain and Whiplash
Eldon Tunks, MD, FRCPC
Goals of Therapy
Acute phase
Reduce distress
Identify patients in need of urgent surgical intervention
1 to 4 weeks
Promote therapy to restore function
Return to normal activities as soon as possible
Subacute period (4 to 12 weeks)
Interrupt progress to chronicity
Promote active therapy while encouraging return to work
Chronic pain (6 months or more)
Multimodal therapy aimed at management of chronic pain/disability, with emphasis on restoring function and
independence
Acute Phase to 30 Days
Investigations
Therapeutic Choices
Investigations
Acute Phase (days 1 to 7)
History and physical examination. Assess for “red flags” (Table 1) and, based on history, physical and
laboratory findings, classify according to Whiplash-Associated Disorders (WAD) criteria (Table 2, Figure 1 -
1
Early Management of Whiplash Disorder Based on WAD Classification) or according to Bone and Joint Decade
2000-2010 Task Force on Neck Pain and Its Associated Disorders (Table 3).2
Decision to x-ray is based on history of severe trauma, impaired consciousness and neurological signs and
symptoms. However, neurological findings may not be present or prominent with cervical fracture, so clinical
1
judgment/experience and imaging are necessary when fracture is suspected.
Table 1: Possible Red Flags Associated with Neck Pain1
History of severe trauma Sensory or motor deficits

Impaired consciousness Lower body sensory changes
Loss of reflexes Loss of bowel or bladder function
Table 2: Whiplash-Associated Disorders (WAD) Classification1
WAD-I neck pain, stiffness or tenderness, but no physical signs/limitations
WAD-II pain and tenderness and reduced range
WAD-III pain and neurological signs; sensory or motor or reflex changes without fracture/instability
WAD-IV fracture or dislocation
Page 764
Therapeutic Choice
2 , a
Table 3: Bone and Joint Decade 2000-2010 Classification
Grade I neck pain/associated disorders without indication of major structural pathology, and either minor
interference or no interference with activities of daily living (ADL)
Grade no indication of major pathology, but major interference with ADL

II
Grade no indication of major pathology, but having neurological signs (reflexes, weakness, sensory)
III
Grade signs/symptoms of major structural pathology (may include fracture, vertebral dislocation, spinal cord
IV injury, infection, neoplasm, systemic inflammatory disease, etc.)
a.
This is applicable to all neck pain, not only WAD. Reference also recommends a separate dimension distinguishing presence of
claim for reimbursement, or wage replacement, long-term disability, permanent disability or punitive damage.
Therapeutic Choices
WAD-I to WAD-III: Provide symptomatic relief as indicated, reassure and counsel to resume normal activity as soon
1
as possible. Avoid immobilization or passive therapy.
Grade I or II neck pain: Patient education combined with urgent care improves acute whiplash outcome. Collars and
high health-care utilization may be associated with delayed recovery.3 However, when dealing with acute cervical
4
radiculopathy, there is evidence of benefit for treatment with rest and a semi-hard collar for 3–6 weeks.
WAD-IV: Urgent referral and surgical management.1
There is considerable agreement among opinion leaders that initial management is most effective if patients are
counselled to maintain activity or return to activity as soon as tolerated, avoiding collars, bedrest or immobilization
1 5
and limiting or avoiding work absence. However, most studies are of poor quality, and the evidence is conflicting.
If progress is not occurring as expected within the first month or by the end of the first month, consider the
possibility of psychosocial barriers or complications. Active exercise combined with psychosocial intervention results
1
in reduced pain in the short term and accelerates return to work.
Pharmacologic Choices (See Musculoskeletal Disorders: Low Back Pain, Table 3)
Evidence is inconclusive for use of NSAIDs in neck pain.6 However for back pain, during the first
month, NSAIDs are more effective for symptom relief than placebo, but there is no evidence that any
one NSAID is more effective for reducing pain.7 Useful Info? However, given the risks associated with use of
NSAIDs, or individual patient contraindications, acetaminophen, tramadol or codeine are appropriate
alternatives in the acute phase. A single study reported that intravenous methylprednisolone for acute whiplash of
less than 8 hours' duration led to reduced pain and sick leave in the short term but not at 6 months.8
During Second and Third Month (Subacute Period)
Investigations
Therapeutic Choices
Investigations
Page 765
Therapeutic Choice
Order plain radiographs for neck pain lasting more than a few weeks, or more detailed studies if there is nerve root
or spinal cord involvement or history of such injury.9 For those not making progress in function, or suffering
unexpected prolongation of pain, review to identify potential psychological risk factors (Table 4).
By this time, combined therapy is preferable: psychosocial, patient education and active exercise. Promote work re-
entry, with modifications if appropriate, if there has been delay.
10 , 11
Table 4: Identification of Psychological Risk Factors
Obvious psychological distress

Severe pain beyond what is expected
History of prior significant pain recurrences
Higher than expected functional impairment
Unexplained widespread pain
Pain and limitation not consistent with objective findings
Therapeutic Choices
There is evidence of efficacy of exercise over passive therapy. There is limited evidence for taking breaks during
sedentary work. There is evidence for massage added to manual therapy,3 and for manual therapy added to
12
exercise. Although there is a lack of quality evidence for the efficacy of treatment with only passive and palliative
physical therapy modalities or medications for symptom relief, they may be used in conjunction with active
measures to promote patient comfort and adherence to the active treatments.
The role of manual therapies, e.g., manipulation or mobilization of the spine, is still controversial, partly due to a
very small but real risk of vertebrobasilar stroke after manipulation.13 There is also evidence that manual therapy
alone is inadequate treatment for neck problems.1 , 12 Manipulation should be performed only by an expert therapist
with certified skills in manual therapy and with appropriate clinical screening to exclude patients with risk factors for
complications. There is limited evidence that exercise combined with manual therapy is efficacious for neck pain.12 ,
14
There is inconsistent evidence that acupuncture is associated with better short-term and long-term outcome in
3
subacute or chronic neck pain, compared to sham acupuncture or massage.
For neck pain Grade I and II, patient education focusing on self-efficacy, combined with usual medical care appears
promising. Weak evidence exists that magnetic therapy, laser or acupuncture are more effective in the short term
than alternatives. Evidence favours supervised exercise with or without manual (mobilization) therapy. There is
weak evidence that advice and exercise is better than advice alone in the short term for subacute whiplash
3
symptoms.
There is limited literature supporting efficacy of muscle relaxants in subacute and chronic neck disorders.3 , 6 (There
is somewhat better evidence for efficacy in back pain.) Expert opinion is that if patients complain of high level of
pain/tenderness in more than one area, muscle relaxants (cyclobenzaprine, baclofen, tizanidine, orphenadrine,
methocarbamol), tricyclic antidepressants, gabapentinoids (gabapentin, pregabalin), or tramadol may be
effective.
By 3 Months
If functional improvement and return to work/activity has not happened by this point, there is an increasing risk of
chronic pain and poor function. Identify psychosocial and related risk factors that may impair progress. If work
Page 766
Therapeutic Choice
return (with or without modifications) is not successful, refer to multidisciplinary rehabilitation, in liaison with
stakeholders, with the goal of return to work and function.
By 6 Months or More (Chronic Neck Pain)
Therapeutic Tips
Therapeutic Choices
With time there is increasing probability of associated psychological comorbidity.10 Assess and treat comorbid
depression, anxiety or adjustment problems. If appropriate, refer to an appropriate specialist.
For chronic musculoskeletal pain in general, there is limited evidence that intensive multimodal/multidisciplinary
treatment programs (cognitive behavioural therapy with active exercise and psychosocial intervention, programs that
include or simulate real-life work activities [work hardening] and planning for work re-entry) are effective for
15 , 16
improving function and sense of well-being. The active ingredient in successful work return, however, appears
to be timely workplace intervention including all the stakeholders rather than clinic treatment modalities.15 , 17
Expert opinion is that multidisciplinary pain management is recommended for chronic pain with impaired function
and failure to improve or failure of work return. There are few studies, of poor quality, that are insufficient to
estimate the efficacy of multidisciplinary biopsychosocial therapy for neck and shoulder pain.18 The Bone and Joint
Decade 2000-2010 Task Force found one nonrandomized study that multidisciplinary management of post-WAD pain
was associated with quicker claim closure compared with usual care. Another study did not find quicker recovery
3
with referrals to fitness training, inpatient or outpatient rehabilitation plus usual care.
In chronic pain, individual supervised active exercises (but not group exercise classes) can improve pain and
19
function. Otherwise, there is a lack of evidence of efficacy of individual physiotherapy modalities.
As for subacute widespread pain and tenderness, expert experience is that muscle relaxants, gabapentinoids
(gabapentin, pregabalin) and tramadol may be effective. There is limited published evidence that orphenadrine
and acetaminophen are associated with greater pain reduction in the short term (8 days) in patients with subacute
3 , 6
or chronic neck pain. There is weak and contradictory evidence for efficacy of NSAIDs for neck pain.
There is limited evidence for the efficacy of NSAIDs or opioids for chronic pain,7 , 16 but there is expert acceptance
16
of the use of opioids as one option.
Although amitriptyline is widely used for soft tissue pain, neuralgia, headache and depression, tricyclic
15
antidepressants have not been proven effective for mixed musculoskeletal and soft tissue pain relief. Use should
be governed by patient clinical response, absence of contraindications and tolerability.
Interventional Options
Although becoming widely used for persistent pain, there is limited evidence that botulinum toxin A for subacute
or chronic neck pain is not associated with better short-term pain and disability outcome, compared to other
6
treatment.
Several low-quality studies suggest that local infiltration of anesthetic to muscle tissue (i.e., trigger/tender points)
may afford short-term relief.6 , 16 Support is lacking for the use of injection therapy alone for management of
persistent neck pain/whiplash, and rehabilitation and work re-entry are recommended.
6
There is limited and poor quality evidence for treatment with epidural steroid and lidocaine for chronic neck pain.
Page 767
Therapeutic Choice
Cervical zygapophyseal joint corticosteroid injection has been used for post-WAD of more than 3 months. A
systematic review found that the evidence was inadequate; one placebo-controlled RCT found that there was not
greater pain reduction after 5 months compared to placebo.3
A short course of epidural or selective root injection with corticosteroid may be associated with short-term
symptomatic improvement of radicular symptoms but there is insufficient evidence to recommend radiofrequency
neurotomy for suspected zygapophyseal pain. There is no evidence that cervical root or epidural injections decrease
20
the rate of open surgery in seriously symptomatic radiculopathy.
Surgical Options
For neck pain with radicular symptoms, relatively rapid and substantial pain and impairment relief is noted following
surgical treatment of cervical radiculopathy in the 6–12 weeks after surgery, but there is absence of evidence for
long-term outcomes. Anterior cervical plating seems to reduce kyphosis progression. It is not clear that complex
open procedures including fusion, cage, or plate instrumentation, or fusion augmentation with bone morphogenic
protein, provide superior outcomes versus simple cervical decompression alone. Limited evidence suggests possible
favourable outcome with cervical disk arthroplasty for radicular symptoms, but long-term safety is unknown.20
Anterior cervical fusion or cervical disk arthroplasty for neck pain without radiculopathy or serious underlying
pathology is not supported by evidence.20
Choices in Pregnancy and Lactation
For a brief discussion of therapeutic choices during pregnancy and lactation for patients with low back or neck pain,
see Musculoskeletal Disorders: Low Back Pain.
Therapeutic Tips
Strong predictors of chronicity in neck pain problems include self-reported severe pain, pain in several body
locations, pervasive functional impairment, a history of previous occurrences of whiplash/neck pain, female
gender and older age. Identifying these factors early and referring to intensive rehabilitation with cognitive
behavioural therapy is a priority.
Page 768
Therapeutic Choice
Figure 1- Early Management of Whiplash Disorder Based on WAD Classification
Suggested Readings
International Steering Committee. The Bone and Joint Decade 2000-2010 Task Force on Neck Pain and Its
Associated Disorders. Spine (Phila Pa 1976) 2008;33(4 Suppl):S1-220.
National Opioid Use Guideline Group. Canadian guideline for safe and effective use of opioids for chronic non-cancer
pain. Hamilton (ON): NOUGG; 2010. Available from: nationalpaincentre.mcmaster.ca/opioid/documents.html.
Accessed July 16, 2010.
References
1. Spitzer WO, Skovron ML, Salmi LR et al. Scientific monograph of the Quebec Task Force on Whiplash-
Associated Disorders: redefining "whiplash" and its management. Spine (Phila Pa 1976) 1995;20(8 Suppl):1S-
73S.
2. Guzman J, Hurwitz EL, Carroll LJ et al. A new conceptual model of neck pain: linking onset, course, and care:
the Bone and Joint Decade 2000-2010 Task Force on Neck Pain and Its Associated Disorders. Spine (Phila Pa
1976) 2008;33(4 Suppl):S14-23.
3. Hurwitz EL, Carragee EJ, van der Velde G et al. Treatment of neck pain: noninvasive interventions: results of
the Bone and Joint Decade 2000-2010 Task Force on Neck Pain and Its Associated Disorders. Spine (Phila Pa
1976) 2008;33(4 Suppl):S123-52.
Page 769
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4. Kuijper B, Tans JT, Beelen A et al. Cervical collar or physiotherapy versus wait and see policy for recent onset
cervical radiculopathy: randomised trial. BMJ 2009;339:b3883.
5. Verhagen AP, Scholten-Peeters GG, van Wijngaarden S et al. Conservative treatments for whiplash. Cochrane
6. Peloso P, Gross A, Haines T et al. Medicinal and injection therapies for mechanical neck disorders. Cochrane
7. Roelofs PD, Deyo RA, Koes BW et al. Non-steroidal anti-inflammatory drugs for low back pain. Cochrane
8. Pettersson K, Toolanen G. High-dose methylprednisolone prevents extensive sick leave after whiplash injury.
A prospective, randomized, double-blind study. Spine (Phila Pa 1976) 1998;23(9):984-8.
9. Tsang I. Rheumatology: 12. Pain in the neck. CMAJ 2001;164(8):1182-7.
10. Tunks E et al. Natural history and efficacy of treatment of chronic pain arising from musculoskeletal injury. In:
Sullivan T, editor. Injury and the new world of work. Vancouver (BC): UBC Press; 2000.
11. Borghouts JA, Koes BW, Bouter LM. The clinical course and prognostic factors of non-specific neck pain: a
systematic review. Pain 1998;77(1):1-13.
12. Gross AR, Hoving JL, Haines TA et al. Manipulation and mobilisation for mechanical neck disorders. Cochrane
13. Cassidy JD, Boyle E, Cote P et al. Risk of vertebrobasilar stroke and chiropractic care: results of a population-
based case-control and case-crossover study. Spine (Phila Pa 1976) 2008;33(4 Suppl):S176-83.
14. Kay TM, Gross A, Goldsmith C et al. Exercises for mechanical neck disorders. Cochrane Database Syst Rev
2005;(3):CD004250.
15. Loisel P, Abenhaim L, Durand P et al. A population-based, randomized clinical trial on back pain management.
Spine (Phila Pa 1976) 1997;22(24):2911-8.
16. College of Physicians and Surgeons of Ontario. Evidence-based recommendations for medical management of
chronic non-malignant pain: reference guide for clinicians. Toronto (ON): CPSO; 2000. Available from:
www.cpso.on.ca/uploadedFiles/policies/guidelines/methadone/MedicalManagementPain.pdf. Accessed July 20,
2010.
17. Anema JR, Steenstra IA, Bongers PM et al. Multidisciplinary rehabilitation for subacute low back pain: graded
activity or workplace intervention or both? A randomized controlled trial. Spine (Phila Pa 1976) 2007;32
(3):291-8.
18. Karjalainen K, Malmivaara A, van Tulder M et al. Multidisciplinary biopsychosocial rehabilitation for neck and
shoulder pain among working age adults. Cochrane Database Syst Rev 2003;(2):CD002194.
19. Philadelphia Panel. Philadelphia Panel evidence-based clinical practice guidelines on selected rehabilitation
interventions for neck pain. Phys Ther 2001;81(10):1701-17.
20. Carragee EJ, Hurwitz EL, Cheng I et al. Treatment of neck pain: injections and surgical interventions: results
of the Bone and Joint Decade 2000-2010 Task Force on Neck Pain and Its Associated Disorders. Spine (Phila
Pa 1976) 2008;33(4 Suppl):S153-69.
Page 770
e-Therapeutics+ : Therapeutics : Musculoskeletal Disorders: Osteoarthritis Page 1 of 29
Therapeutic Choice
Print Close
Musculoskeletal Disorders: Osteoarthritis
Date Prepared: July 2005

Paul Davis, MD, FRCP UK, FRCPC
Angela Juby, MBChB
Osteoarthritis (OA) is the most prevalent of the rheumatic diseases and a leading cause of disability. The condition is
into primary and secondary forms. Risk factors for primary OA include advancing age, obesity and genetic susceptibili
Secondary OA may occur in younger age groups, usually as a result of previous traumatic or inflammatory damage to
joints. Originally believed to be a simple degenerative process of aging cartilage, OA is now recognized as a highly co
condition associated with biochemical changes within the cartilage matrix. Treatment is usually only initiated at the en
of the pathologic process when symptoms appear.
Goals of Therapy
Reduce joint pain

Improve joint function and mobility
Maintain normal articular and periarticular structures
Prevent (and possibly reverse) joint cartilage damage
The first three goals are achievable with currently available modalities, while the goal of cartilage protection and repa
intense research.
Investigations
OA is largely a clinical diagnosis.
History:
joint pain usually worse after exercise; improves with rest; joint and periarticular muscle stiffness (gelling) u
< 30 minutes
absence of obvious underlying inflammatory polyarthritis
joint pain in particular distribution (hips, knees, first metatarsophalangeal joint, distal interphalangeal joints,
metacarpal joint and axial skeleton)
secondary OA possible with history of trauma, prior inflammatory arthropathy, acromegaly
pain, limitation and stiffness of both passive and active movement of joint
possible crepitus, deformity and/or bony swelling
later stages may include disruption of joint architecture with ligamentous and capsular laxity and significant d
deformity
varying degrees of mild synovitis possible
Imaging:
radiographic imaging usually only serves to confirm clinical diagnosis and determine extent of damage, but a
discrepancy often exists between signs and symptoms of OA and radiographic findings. It is of particular valu
surgery is a consideration. Joint space narrowing, osteophyte formation, subchondral cysts (geodes) and bon
sclerosis are radiographic hallmarks of uncomplicated OA. Chondrocalcinosis may be seen in patients with un
metabolic disorders predisposing to secondary OA
bone scan, CT scan and MRI are of little value in routine clinical practice
Lab tests:
routine blood work is largely unhelpful in diagnosis
joint fluid analysis usually shows relatively minor inflammatory changes except when complicated by crystal-
synovitis where calcium pyrophosphate may be identified
Therapeutic Choices (Figure 1 - Treatment of Osteoarthritis)
Prevention
Primary prevention consists of appropriate physical activity and weight control. Secondary preventive interventions inc
avoidance of trauma and inappropriate mechanical stresses on predisposed joints as well as weight loss.
Page 771
Therapeutic Choice
Nonpharmacologic options should play a major role in improving quality of life of OA sufferers but are underutiliz
2
undervalued. Patient education sessions such as those designed by the Arthritis Society should be initiated. OA p
should be treated by a team including allied health professionals, e.g., occupational therapists, physiotherapists,
workers, pharmacists.
Physical therapies such as transcutaneous electrical nerve stimulation (TENS) and laser therapy may benefit some
There is no evidence that ultrasound is of benefit in knee OA.4 The statistical benefit of acupuncture remains a su
5 , 6
debate.
7
Orthotics such as wedge insoles may be helpful. Aids to daily living including canes and walkers may be suggeste
those with hip and knee OA. Bracing of affected joints may also assist patients.8
9 10
Exercise, weight loss, or exercise plus physiotherapy provide modest reductions in pain and disability.
Oral or Topical Therapy (Table 2, Table 3)
Oral analgesics and, to a lesser extent, topical analgesics are the mainstays of therapy. Compared to acetamin
11,12,13
NSAIDs are superior in controlling pain in OA but with more GI side effects. Consequently,
14
acetaminophen should be the initial choice due to its safety and tolerability. Useful Info? Two to thre
of acetaminophen at doses not exceeding 4 g/day constitutes an appropriate trial. Some clinicians feel acetamino
most efficacious in chronic noninflammatory mechanical knee pain.15 Analgesic/anti-inflammatories such as ibup
naproxen can be used at low (analgesic) dose if an appropriate trial of acetaminophen has failed.
In more symptomatically resistant patients, oral opioids such as morphine or oxycodone can be considered as a
16 14
for one to two weeks; however, opioid analgesics are not recommended for maintenance therapy and must be
lower doses in the elderly.
Topical analgesics can be used adjunctively but evidence supporting their use is limited. They may be offered to t
refusing systemic therapy. In a few small studies capsaicin was superior to placebo for pain control, but study p
were permitted to use oral analgesics.17 , 18 The burning sensation caused by capsaicin is often not well tolerated
topical diclofenac solution has recently been approved for treating the symptoms of OA of the knee. Its place in
remains to be determined but was effective in a recent trial.19
For inflammatory pain, many patients require more than simple analgesia with acetaminophen. Anti-inflammato
14
medications such as NSAIDs are recommended second-line after a failure of simple analgesics. Traditional NS
(e.g., naproxen) in low doses (or full doses if necessary) can be used for symptomatic management of OA. Side e
with NSAIDs include GI complications, fluid retention, hypertension and renal effects (Table 2).
The risk of increased cardiovascular events for both celecoxib, the only remaining COX-2 inhibitor, and nonselecti
20
NSAIDs is acknowledged by experts. The American Heart Association's statement on the use of NSAIDs conclud
risk of cardiovascular events is proportional to COX-2 selectivity and underlying patient risk. They suggest steppe
therapy guided by patient relief should start with acetaminophen, small doses of narcotics, nonacetylated salicylat
nonselective NSAIDs at the lowest effective dose for the shortest possible time.21 COX-2 inhibitors appear to be a
22
with a reduction in endoscopic ulcers compared to nonselective NSAIDs. Currently, individual patients must be
for cardiovascular and gastrointestinal risk factors before selecting a therapy.
If continuous NSAIDs must be used, especially if patients are at risk of GI complications (Table 1), add misopros
23
proton pump inhibitor (PPI) ( H2 -receptor antagonists are less effective ). Bleeding ulcers still may occur in h
24
patients receiving a COX-2 inhibitor or traditional NSAID/PPI combination. In patients with symptomatic OA req
treatment, traditional NSAIDs and COX-2 inhibitors may be offered, providing that patients are screened for poten
adverse effects (e.g., GI, cardiovascular) and are monitored for toxicity. Many clinicians prescribe simple analges
baseline therapy supplemented by NSAIDs (with gastroprotection if warranted) at times of increased symptomato
obvious inflammation.
Based on a systematic review, the alternative therapy glucosamine does not appear to have a clinica
significant effect on pain or function (depending on the scale used) when taken for two to three mon
a recent trial, chondroitin did not have a clinically important effect on pain in patients with severe ar
26
the knee but may offer a small protective effect on the joint. Concern exists about analysed conten
glucosamine and chondroitin in several commercial products; the lack of standardized quality may af
efficacy in non-trial settings.27 Useful Info?
14 , 28
Table 1: Risk Factors for Development of Upper GI Adverse Effects with NSAIDs
Page 772
Therapeutic Choice
Age ≥ 65
Comorbid medical conditions
Anticoagulants or oral glucocorticoids
History of upper GI bleeding
Presence of H. pylori infection
Intra-articular Therapies (Table 4)
Often used to complement traditional treatments, corticosteroid joint injections are of particular value in the ma
of patients with a small number of symptomatic joints associated with clinical evidence of inflammation.
The injection of hyaluronan and its derivatives has been used as viscosupplementation in the management of mild
29 , 30
moderate OA although results of studies are varied. Because of the nature of this material, the knee is the o
where it can be used on a regular basis. Other intra-articular procedures such as joint lavage and radioactive collo
not proven to be of major benefit in OA.
Surgery
Arthroplasty is presently advocated for most patients with moderate to severe OA of the knee and hip with unremitting
symptomatology despite adherence to a conservative medical program. Use of Silastic implants and spacers for smalle
the hands and feet are also effective in appropriately selected patients. Arthroscopic lavage and joint debridement are
questionable value.31 , 32
Therapeutic Tips
Patients should receive only one NSAID at a time (with the exception of low-dose cardioprotective ASA). It is not
to what extent the addition of low-dose ASA to COX-2 inhibitors decreases the GI benefits afforded by these agen
Dyspepsia with NSAIDs does not correlate with endoscopically proven ulcers or with serious upper GI complicatio
Patients treated with NSAIDs who complain of dyspepsia in the absence of risk factors (Table 1) can be switched
analgesics, offered a trial with a different class of NSAID or treated symptomatically.
Making patients aware of the GI risks involved with NSAID use has been shown to lower the incidence of acute GI
33
bleeding.
For most patients, a flexible regimen of appropriate simple analgesics supplemented by anti-inflammatory medica
together with nonpharmacologic modalities is sufficient to produce adequate relief of symptoms and functional be
As many OA sufferers are elderly, always consider drug intolerance. Start with low doses, increasing slowly to the
effect. Drug interactions are also a concern because many of these patients are being treated for other conditions
Patients presenting with unstable angina or non-ST segment elevation myocardial infarction (UA/NSTEMI) should
discontinue use of nonselective or COX-2 selective NSAIDs (except ASA) because of the increased cardiovascular
associated with these agents.34 An opioid analgesic such as morphine may be a suitable alternative for pain contr
setting.
Figure 1-Treatment of Osteoarthritis
Page 773
Therapeutic Choice
a.
Supplement with topicals, opioids, local injection, alternative therapies.
Table 2: Oral Agents Used in Osteoarthritis
Drug
Analgesics acetaminophen 650 mg Q4H – Hepatotoxicity—see Alcohol: ↑ risk of May cause

Tylenol, Atasol 1000 mg Q6H comments. hepatotoxicity with hepatitis if
Max: 4 g/24 h excessive alcohol taken in exces
Preparations,
intake or by patients
generics
( > 3 drinks/day). with liver
Warfarin: May ↑ diseases.
anticoagulant
effect of warfarin,
particularly at
doses
> 1.3 g/day for >
1 wk
Page 774
Therapeutic Choice
Drug
Analgesics morphine 2.5–15 mg QID for Sedation, nausea, Concurrent use of Useful for sho
MS-IR, Statex, short-acting vomiting, constipation. other sedating or -term
formulations constipating adjunctive
generics
medications may therapy. May b
increase these poorly tolerate
side effects. in the elderly.
Lidocaine:
potential
enhancement of
opioids' effects.
Analgesics oxycodone 5–10 mg QID for Sedation, nausea, Concurrent use of Useful for sho
Oxy-IR short-acting vomiting, constipation. other sedating or -term
generics formulations constipating adjunctive
medications may therapy. May b
increase these poorly tolerate
side effects. in the elderly.
Lidocaine:
potential
enhancement of
opioids' effects.
NSAIDs, acetic diclofenac 25–50 mg BID-TID Cardiovascular: Warfarin: ↑ All NSAIDs

acid derivatives Voltaren, or 75 mg BID hypertension, anticoagulant have equivalen
generics congestive heart effect. efficacy. When
failure, MI, CVA. Antihypertensives possible, avoid
Regulatory review of all (diuretics, beta- NSAIDs,
pertinent data blockers, ACE including COX
regarding CV risk is inhibitors, alpha- 2 inhibitors, in
ongoing. blockers): patients with a
CNS: dizziness possible reduction history of
(common with all in hypotensive peptic ulcer
salicylates, both effect; may disease, risk
acetylated and require additional factors for
nonacetylated), antihypertensive heart attack or
tinnitus, loss of therapy. stroke, renal
hearing, disorientation, failure, heart
confusion (tends to Lithium may failure or
occur with all NSAIDs interfere with asthma.
in the elderly), aseptic sodium/water
meningitis (reported balance. Monitor
with ibuprofen in lupus lithium levels
patients). CNS effects when NSAID
may be dose related added.
and respond to ↓
dosage. SSRIs may ↑ risk
of GI bleeding
Dermatologic: skin when used with
rashes, some serious NSAIDs.
(e.g., erythema
multiforme, Stevens-
Johnson syndrome).
Gastrointestinal:
dyspepsia,
nausea/vomiting,
diarrhea, gastric and
duodenal ulcers. Rare:
gastric hemorrhage,
perforation, small
bowel ulceration.
Hematologic:
antiplatelet effect,
agranulocytosis/aplastic
Page 775
Therapeutic Choice
Drug
anemia (indomethacin),
thrombocytopenia.
Hepatic: ↑ LFTs, Reye's

syndrome in children
with chickenpox and flu
(primarily ASA),
hypersensitivity
reaction (hepatitis in
adults) with all NSAIDs.
Pulmonary: asthma
(patients with ASA
hypersensitivity).
Renal: fluid
retention/edema, renal
insufficiency (problems
more common in
elderly patients),
hyperkalemia.
NSAIDs, acetic etodolac 200–300 mg BID Cardiovascular: Warfarin: ↑ All NSAIDs

acid derivatives Apo-Etodolac hypertension, anticoagulant have equivalen
congestive heart effect. efficacy. When
and respond to ↓
of GI bleeding
(e.g., erythema
Johnson syndrome).
Gastrointestinal:
dyspepsia,
nausea/vomiting,
gastric hemorrhage,
perforation, small
bowel ulceration.
Page 776
Therapeutic Choice
Drug
Hematologic:
thrombocytopenia.

(primarily ASA),
hypersensitivity
Pulmonary: asthma
(patients with ASA
hypersensitivity).
Renal: fluid
more common in
elderly patients),
hyperkalemia.
NSAIDs, acetic indomethacin 50–200 mg/day in Cardiovascular: Warfarin: ↑ All NSAIDs

acid derivatives two to three divided hypertension, anticoagulant have equivalen
generics doses congestive heart effect. efficacy. When
and respond to ↓
of GI bleeding
(e.g., erythema
Johnson syndrome).
Gastrointestinal:
dyspepsia,
nausea/vomiting,
gastric hemorrhage,
Page 777
Therapeutic Choice
Drug
perforation, small
bowel ulceration.
Hematologic:
thrombocytopenia.

(primarily ASA),
hypersensitivity
Pulmonary: asthma
(patients with ASA
hypersensitivity).
Renal: fluid
more common in
elderly patients),
hyperkalemia.
NSAIDs, acetic sulindac 150–200 mg BID Cardiovascular: Warfarin: ↑ All NSAIDs

acid derivatives generics hypertension, anticoagulant have equivalen
and respond to ↓
of GI bleeding
(e.g., erythema
Johnson syndrome).
Gastrointestinal:
dyspepsia,
nausea/vomiting,
Page 778
Therapeutic Choice
Drug
gastric hemorrhage,
perforation, small
bowel ulceration.
Hematologic:
thrombocytopenia.

(primarily ASA),
hypersensitivity
Pulmonary: asthma
(patients with ASA
hypersensitivity).
Renal: fluid
more common in
elderly patients),
hyperkalemia.
NSAIDs, oxicams piroxicam 10–20 mg daily Cardiovascular: Warfarin: ↑ All NSAIDs

generics hypertension, anticoagulant have equivalen
and respond to ↓
of GI bleeding
(e.g., erythema
Johnson syndrome).
Gastrointestinal:
dyspepsia,
Page 779
Therapeutic Choice
Drug
nausea/vomiting,
gastric hemorrhage,
perforation, small
bowel ulceration.
Hematologic:
thrombocytopenia.

(primarily ASA),
hypersensitivity
Pulmonary: asthma
(patients with ASA
hypersensitivity).
Renal: fluid
more common in
elderly patients),
hyperkalemia.
NSAIDs, oxicams tenoxicam 20–40 mg daily Cardiovascular: Warfarin: ↑ All NSAIDs

Apo- hypertension, anticoagulant have equivalen
Tenoxicam,
other generics
and respond to ↓
of GI bleeding
(e.g., erythema
Johnson syndrome).
Page 780
Therapeutic Choice
Drug
Gastrointestinal:
dyspepsia,
nausea/vomiting,
gastric hemorrhage,
perforation, small
bowel ulceration.
Hematologic:
thrombocytopenia.

(primarily ASA),
hypersensitivity
Pulmonary: asthma
(patients with ASA
hypersensitivity).
Renal: fluid
more common in
elderly patients),
hyperkalemia.
NSAIDs, oxicams meloxicam 7.5–15 mg daily Cardiovascular: Warfarin: ↑ All NSAIDs

Mobicox, hypertension, anticoagulant have equivalen
generics congestive heart effect. efficacy. When
and respond to ↓
of GI bleeding
(e.g., erythema
Page 781
Therapeutic Choice
Drug
Johnson syndrome).
Gastrointestinal:
dyspepsia,
nausea/vomiting,
gastric hemorrhage,
perforation, small
bowel ulceration.
Hematologic:
thrombocytopenia.

(primarily ASA),
hypersensitivity
Pulmonary: asthma
(patients with ASA
hypersensitivity).
Renal: fluid
more common in
elderly patients),
hyperkalemia.
NSAIDs, flurbiprofen 50–100 mg BID-TID Cardiovascular: Warfarin: ↑ All NSAIDs

propionic acid Ansaid, hypertension, anticoagulant have equivalen
derivatives generics congestive heart effect. efficacy. When
and respond to ↓
of GI bleeding
Page 782
Therapeutic Choice
Drug
(e.g., erythema
Johnson syndrome).
Gastrointestinal:
dyspepsia,
nausea/vomiting,
gastric hemorrhage,
perforation, small
bowel ulceration.
Hematologic:
thrombocytopenia.

(primarily ASA),
hypersensitivity
Pulmonary: asthma
(patients with ASA
hypersensitivity).
Renal: fluid
more common in
elderly patients),
hyperkalemia.
NSAIDs, ibuprofen 200–600 mg Q6H- Cardiovascular: Warfarin: ↑ All NSAIDs

propionic acid Advil, Motrin, Q8H hypertension, anticoagulant have equivalen
Page 783
Therapeutic Choice
Drug
and respond to ↓ SSRIs may ↑ risk
dosage. of GI bleeding
when used with
Dermatologic: skin NSAIDs.
rashes, some serious
(e.g., erythema
Johnson syndrome).
Gastrointestinal:
dyspepsia,
nausea/vomiting,
gastric hemorrhage,
perforation, small
bowel ulceration.
Hematologic:
thrombocytopenia.

(primarily ASA),
hypersensitivity
Pulmonary: asthma
(patients with ASA
hypersensitivity).
Renal: fluid
more common in
elderly patients),
hyperkalemia.
NSAIDs, ketoprofen 50–75 mg TID-QID Cardiovascular: Warfarin: ↑ All NSAIDs

propionic acid Apo-Keto, hypertension, anticoagulant have equivalen
derivatives other generics congestive heart effect. efficacy. When
Page 784
Therapeutic Choice
Drug
and respond to ↓
of GI bleeding
(e.g., erythema
Johnson syndrome).
Gastrointestinal:
dyspepsia,
nausea/vomiting,
gastric hemorrhage,
perforation, small
bowel ulceration.
Hematologic:
thrombocytopenia.

(primarily ASA),
hypersensitivity
Pulmonary: asthma
(patients with ASA
hypersensitivity).
Renal: fluid
more common in
elderly patients),
hyperkalemia.
NSAIDs, naproxen 250–500 mg BID Cardiovascular: Warfarin: ↑ All NSAIDs

propionic acid Naprosyn, hypertension, anticoagulant have equivalen
Page 785
Therapeutic Choice
Drug
and respond to ↓
of GI bleeding
(e.g., erythema
Johnson syndrome).
Gastrointestinal:
dyspepsia,
nausea/vomiting,
gastric hemorrhage,
perforation, small
bowel ulceration.
Hematologic:
thrombocytopenia.

(primarily ASA),
hypersensitivity
Pulmonary: asthma
(patients with ASA
hypersensitivity).
Renal: fluid
more common in
elderly patients),
hyperkalemia.
NSAIDs, naproxen 275–550 mg BID Cardiovascular: Warfarin: ↑ All NSAIDs

propionic acid sodium hypertension, anticoagulant have equivalen
derivatives Aleve, congestive heart effect. efficacy. When
Anaprox, failure, MI, CVA. Antihypertensives possible, avoid
generics Regulatory review of all (diuretics, beta- NSAIDs,
confusion (tends to failure or
Page 786
Therapeutic Choice
Drug
occur with all NSAIDs Lithium may asthma. Aleve
in the elderly), aseptic interfere with is available
meningitis (reported sodium/water without
with ibuprofen in lupus balance. Monitor prescription at
patients). CNS effects lithium levels a different
may be dose related when NSAID strength
and respond to ↓ added. ( 220 mg) tha
dosage. prescription
SSRIs may ↑ risk products.
Dermatologic: skin of GI bleeding
rashes, some serious when used with
(e.g., erythema NSAIDs.
Johnson syndrome).
Gastrointestinal:
dyspepsia,
nausea/vomiting,
gastric hemorrhage,
perforation, small
bowel ulceration.
Hematologic:
thrombocytopenia.

(primarily ASA),
hypersensitivity
Pulmonary: asthma
(patients with ASA
hypersensitivity).
Renal: fluid
more common in
elderly patients),
hyperkalemia.
NSAIDs, naproxen 750–1000 mg daily Cardiovascular: Warfarin: ↑ All NSAIDs

propionic acid sodium hypertension, anticoagulant have equivalen
derivatives controlled- congestive heart effect. efficacy. When
release failure, MI, CVA. Antihypertensives possible, avoid
Naprelan Regulatory review of all (diuretics, beta- NSAIDs,
Page 787
Therapeutic Choice
Drug
and respond to ↓
of GI bleeding
(e.g., erythema
Johnson syndrome).
Gastrointestinal:
dyspepsia,
nausea/vomiting,
gastric hemorrhage,
perforation, small
bowel ulceration.
Hematologic:
thrombocytopenia.

(primarily ASA),
hypersensitivity
Pulmonary: asthma
(patients with ASA
hypersensitivity).
Renal: fluid
more common in
elderly patients),
hyperkalemia.
NSAIDs, oxaprozin 600–1200 mg/day Cardiovascular: Warfarin: ↑ All NSAIDs

propionic acid Daypro, hypertension, anticoagulant have equivalen
Page 788
Therapeutic Choice
Drug
and respond to ↓
of GI bleeding
(e.g., erythema
Johnson syndrome).
Gastrointestinal:
dyspepsia,
nausea/vomiting,
gastric hemorrhage,
perforation, small
bowel ulceration.
Hematologic:
thrombocytopenia.

(primarily ASA),
hypersensitivity
Pulmonary: asthma
(patients with ASA
hypersensitivity).
Renal: fluid
more common in
elderly patients),
hyperkalemia.
NSAIDs, tiaprofenic 200–300 mg BID Cardiovascular: Warfarin: ↑ All NSAIDs

propionic acid acid hypertension, anticoagulant have equivalen
Page 789
Therapeutic Choice
Drug
and respond to ↓
of GI bleeding
(e.g., erythema
Johnson syndrome).
Gastrointestinal:
dyspepsia,
nausea/vomiting,
gastric hemorrhage,
perforation, small
bowel ulceration.
Hematologic:
thrombocytopenia.

(primarily ASA),
hypersensitivity
Pulmonary: asthma
(patients with ASA
hypersensitivity).
Renal: fluid
more common in
elderly patients),
hyperkalemia.
NSAIDs, salicylic ASA 325–650 mg Q4H Cardiovascular: Warfarin: ↑ All NSAIDs

acid derivatives Aspirin, hypertension, anticoagulant have equivalen
Bufferin,
Coated Regulatory review of all (diuretics, beta- NSAIDs,
Aspirin, pertinent data blockers, ACE including COX
Entrophen, regarding CV risk is inhibitors, alpha- 2 inhibitors, in
generics ongoing. blockers): patients with a
Page 790
Therapeutic Choice
Drug
and respond to ↓
of GI bleeding
(e.g., erythema
Johnson syndrome).
Gastrointestinal:
dyspepsia,
nausea/vomiting,
gastric hemorrhage,
perforation, small
bowel ulceration.
Hematologic:
thrombocytopenia.

(primarily ASA),
hypersensitivity
Pulmonary: asthma
(patients with ASA
hypersensitivity).
Renal: fluid
more common in
elderly patients),
hyperkalemia.
NSAIDs, salicylic diflunisal 250–500 mg BID Cardiovascular: Warfarin: ↑ All NSAIDs

acid derivatives generics hypertension, anticoagulant have equivalen
Page 791
Therapeutic Choice
Drug
and respond to ↓
of GI bleeding
(e.g., erythema
Johnson syndrome).
Gastrointestinal:
dyspepsia,
nausea/vomiting,
gastric hemorrhage,
perforation, small
bowel ulceration.
Hematologic:
thrombocytopenia.

(primarily ASA),
hypersensitivity
Pulmonary: asthma
(patients with ASA
hypersensitivity).
Renal: fluid
more common in
elderly patients),
hyperkalemia.
NSAIDs, nabumetone 1000–2000 mg daily Cardiovascular: Warfarin: ↑ All NSAIDs

naphthylalkanone generics or in 2 divided hypertension, anticoagulant have equivalen
derivatives congestive heart effect. efficacy. When
failure, MI, CVA. possible, avoid
Page 792
Therapeutic Choice
Drug
doses Regulatory review of all Antihypertensives NSAIDs,
pertinent data (diuretics, beta- including COX
regarding CV risk is blockers, ACE 2 inhibitors, in
ongoing. inhibitors, alpha- patients with a
CNS: dizziness blockers): history of
(common with all possible reduction peptic ulcer
salicylates, both in hypotensive disease, risk
acetylated and effect; may factors for
nonacetylated), require additional heart attack or
tinnitus, loss of antihypertensive stroke, renal
hearing, disorientation, therapy. failure, heart
confusion (tends to failure or
occur with all NSAIDs Lithium may asthma.
in the elderly), aseptic interfere with
meningitis (reported sodium/water
with ibuprofen in lupus balance. Monitor
patients). CNS effects lithium levels
may be dose related when NSAID
and respond to ↓ added.
dosage.
SSRIs may ↑ risk
Dermatologic: skin of GI bleeding
rashes, some serious when used with
(e.g., erythema NSAIDs.
Johnson syndrome).
Gastrointestinal:
dyspepsia,
nausea/vomiting,
gastric hemorrhage,
perforation, small
bowel ulceration.
Hematologic:
thrombocytopenia.

(primarily ASA),
hypersensitivity
Pulmonary: asthma
(patients with ASA
hypersensitivity).
Renal: fluid
more common in
elderly patients),
hyperkalemia.
Page 793
Therapeutic Choice
Drug
COX-2 Inhibitors celecoxib 100 mg BID or Usual doses do not Warfarin: ↑ All NSAIDs
Celebrex 200 mg once daily appear to have anticoagulant have equivalen
antiplatelet effects. effect. efficacy. When
Serious skin reactions Antihypertensives possible, avoid
have been reported. (diuretics, beta- NSAIDs,
Patients with history of blockers, ACE including COX
heart attack or stroke, inhibitors, alpha- 2 inhibitors, in
serious heart disease– blockers): patients with a
related chest pain or possible reduction history of
serious heart disease in hypotensive peptic ulcer
such as HF should not effect; may disease, risk
use COX-2 inhibitors. require additional factors for
Assess risk in patients antihypertensive heart attack or
with risk factors for therapy. stroke, renal
heart attack and stroke. failure, heart
Cardiovascular: Lithium may failure or
hypertension, interfere with asthma. Three
congestive heart sodium/water COX-2
failure, MI, CVA. balance. Monitor inhibitors,
Regulatory review of all lithium levels rofecoxib,
pertinent data when NSAID valdecoxib and
regarding CV risk is added. lumiracoxib,
ongoing. were removed
CNS: dizziness SSRIs may ↑ risk from the
(common with all of GI bleeding Canadian
salicylates, both when used with market becaus
acetylated and NSAIDs. of safety
nonacetylated), concerns.
tinnitus, loss of Celecoxib
hearing, disorientation, contraindicate
confusion (tends to if sulfonamide
occur with all NSAIDs allergy.
in the elderly), aseptic
meningitis (reported
with ibuprofen in lupus
patients). CNS effects
may be dose related
and respond to ↓
dosage.
Dermatologic: skin
rashes, some serious
(e.g., erythema
Johnson syndrome).
Gastrointestinal:
dyspepsia,
nausea/vomiting,
gastric hemorrhage,
perforation, small
bowel ulceration.
Hematologic:
thrombocytopenia.

Page 794
Therapeutic Choice
Drug
(primarily ASA),
hypersensitivity
Pulmonary: asthma
(patients with ASA
hypersensitivity).
Renal: fluid
more common in
elderly patients),
hyperkalemia.
Alternative chondroitin 400 mg TID None known. None known. Lack of produc
Therapies Cell-fX, standardizatio
various others
Alternative glucosamine 500 mg TID Mild GI problems. None known. Lack of produc
Therapies various standardizatio
a.
Cost of 1 week's therapy; includes drug cost only.
Legend: $ < $5 $$ $5–10 $$$ $10–15 $$$$ > $15
Table 3: Topical Agents Used in Osteoarthritis
Drug
Topical capsaicin Apply Transient burning on Avoid contact with eyes or ope
Agents Zostrix, TID- application. lesions.
generics QID
Topical methyl Apply Skin irritation. Warfarin: ↑ Avoid in ASA allergic patients.
Agents salicylate TID- anticoagulant Avoid contact with eyes and
Rub A-535, QID effect. mucous membranes.
others
Topical diclofenac, Apply Skin dryness or irritation, For external use only. Approved
Agents topical QID hypersensitivity. Serious GI for treatment regimen of not
Pennsaid toxicity has not been seen to more than 3 months' duration
date in clinical trials. (continuous or intermittent).
a.
Cost of 1 week's therapy; includes drug cost only.
Legend: $ < $5 $$ $5–10 $$$ $10–15 $$$$ > $15
Table 4: Intra-articular Agents Used in Osteoarthritis
Page 795
Therapeutic Choice
Corticosteroids, intra- methylprednisolone b No clinically Inexpensive, safe and

Large joints :
articular acetate 20–80 mg significant effective therapy for
Depo-Medrol, generics systemic effects. individual joints (esp.
Medium jointsc:
hips/knees).
10–40 mg
Maximum 3
Small jointsd: injections/joint/year.
4–10 mg
Minimize joint activity for
3 days following injection.
Benefits last 4-6 wk.
Corticosteroids, intra- triamcinolone acetonide b No clinically Inexpensive, safe and

Large joints :
articular Kenalog 10 Injection, 5–40 mg significant effective therapy for
Kenalog 40 Injection, d systemic effects. individual joints (esp.
Small joints :
generics hips/knees).
2.5–10 mg
Maximum 3
injections/joint/year.

Corticosteroids, intra- triamcinolone b No clinically Inexpensive, safe and

Large joints :
articular hexacetonide 10–20 mg significant effective therapy for
Aristospan d systemic effects. individual joints (esp.
Small joints :
hips/knees).
2–6 mg
Maximum 3
injections/joint/year.

Viscosupplementation hyaluronans 1 injection/wk No general Used in knee joint;

NeoVisc, Synvisc, given once or systemic effect. sometimes used in
OrthoVisc, Hyalgan, repeated Pseudogout. shoulder and hip (e.g.,
Durolane, Euflexxa depending on Pseudosepsis has Hyalgan).
product been reported
rarely in patients
receiving
35 , 36
Synvisc.
a.
Cost of one injection; includes drug cost only.
b.
Large joints: hips, knees, shoulders, ankles.
c.
Medium joints: elbows, wrists.
d.
Small joints: metacarpophalangeal, interphalangeal, sternoclavicular, acromioclavicular.
Legend: $ < $5 $$ $5–10
Suggested Readings
Jordan KM, Arden NK, Doherty M et al. EULAR Recommendations 2003: an evidence based approach to the manageme
osteoarthritis: Report of a Task Force of the Standing Committee for International Clinical Studies Including Therapeut
(ESCISIT). Ann Rheum Dis 2003;62(12):1145-55.
Page 796
Therapeutic Choice
Ontario Program for Optimal Therapeutics. Ontario treatment guidelines for osteoarthritis, rheumatoid arthritis and acu
st
musculoskeletal injury. 1 ed. Toronto (ON): OPOT; 2000.
Recommendations for the medical management of osteoarthritis of the hip and knee: 2000 update. American College o
Rheumatology Subcommittee on Osteoarthritis Guidelines. Arthritis Rheum 2000;43(9):1905-15.
Rostom A, Dubé C, Jolicoeur E et al. Gastroduodenal ulcers associated with the use of non-steroidal anti-inflammatory
systematic review of preventive pharmacological interventions. Ottawa (ON): Canadian Coordinating Office for Health
Technology Assessment; 2004. Technology Overview No: 12. Available from:
http://www.cadth.ca/media/pdf/261_gastro_ov_e.pdf. Accessed June 11, 2008.
References
1. Creamer P, Hochberg MC. Osteoarthritis. Lancet 1997;350(9076):503-8.

2. Superio-Cabuslay E, Ward MM, Lorig KR. Patient education interventions in osteoarthritis and rheumatoid arthrit
-analytic comparison with nonsteroidal antiinflammatory drug treatment. Arthritis Care Res 1996;9(4):292-301.
3. Osiri M, Welch V, Brosseau L et al. Transcutaneous electrical nerve stimulation for knee osteoarthritis. Cochrane
Syst Rev 2000;(4):CD002823.
4. Welch V, Brosseau L, Peterson J et al. Therapeutic ultrasound for osteoarthritis of the knee. Cochrane Database
2001;(3):CD003132.
5. Vas J, Mendez C, Perea-Milla E et al. Acupuncture as a complementary therapy to the pharmacological treatment
osteoarthritis of the knee: randomised controlled trial. BMJ 2004;329(7476):1216.
6. Berman BM, Lao L, Langenberg P et al. Effectiveness of acupuncture as adjunctive therapy in osteoarthritis of th
randomized, controlled trial. Ann Intern Med 2004;141(12):901-10.
7. Kerrigan DC, Lelas JL, Goggins J et al. Effectiveness of a lateral-wedge insole on knee varus torque in patients w
osteoarthritis. Arch Phys Med Rehabil 2002;83(7):889-93.
8. Brouwer RW, Jakma TS, Verhagen AP et al. Braces and orthoses for treating osteoarthritis of the knee. Cochrane
Syst Rev 2005;(1):CD004020.
9. van Baar ME, Assendelft WJ, Dekker J et al. Effectiveness of exercise therapy in patients with osteoarthritis of th
knee: a systematic review of randomized clinical trials. Arthritis Rheum 1999;42(7):1361-9.
10. Deyle GD, Henderson NE, Matekel RL et al. Effectiveness of manual physical therapy and exercise in osteoarthrit
knee. A randomized, controlled trial. Ann Intern Med 2000;132(3):173-81.
11. Lee C, Straus WL, Balshaw et al. A comparison of the efficacy and safety of nonsteroidal antiinflammatory agent
acetaminophen in the treatment of osteoarthritis: a meta-analysis. Arthritis Rheum 2004;51(5):746-54.
12. Zhang W, Jones A, Doherty M. Does paracetamol (acetaminophen) reduce the pain of osteoarthritis? A meta-ana
randomised controlled trials. Ann Rheum Dis 2004;63(8):901-7.
13. Wegman A, van der Windt D, van Tulder M et al. Nonsteroidal antiinflammatory drugs or acetaminophen for oste
of the hip or knee? A systematic review of evidence and guidelines. J Rheumatol 2004;31(2):344-54.
14. Recommendations for the medical management of osteoarthritis of the hip and knee: 2000 update. American Co
Rheumatology Subcommittee on Osteoarthritis Guidelines. Arthritis Rheum 2000;43(9):1905-15.
15. Miceli-Richard C, Le Bars M, Schmidely N et al. Paracetamol in osteoarthritis of the knee. Ann Rheum Dis 2004;6
-30.
16. Sachs CJ. Oral analgesics for acute nonspecific pain. Am Fam Physician 2005;71(5):913-8.
17. Altman RD et al. Semin Arthritis Rheum 1994;23(6 Suppl 3):25-33.
18. Deal CL, Schnitzer TJ, Lipstein E et al. Treatment of arthritis with topical capsaicin: a double-blind trial. Clin The
1991;13(3):383-95.
19. Bookman AA, Williams KS, Shainhouse JZ. Effect of a topical diclofenac solution for relieving symptoms of prim
osteoarthritis of the knee: a randomized controlled trial. CMAJ 2004;171(4):333-8.
20. Health Canada. Drugs & Health Products. Report of the Expert Advisory Panel on the safety of Cox-2 selective no
steroidal anti-inflammatory drugs (NSAIDs). Available from: http://www.hc-sc.gc.ca/dhp-mps/prodpharma/acti
consult/cox2/sap_report_gcs_rapport_cox2-eng.php. Accessed June 11, 2008.
21. Antman EM, Bennett JS, Daugherty A et al. Use of nonsteroidal antiinflammatory drugs: an update for clinicians
scientific statement from the American Heart Association. Circulation 2007;115(12):1634-42.
22. Rostom A, Dubé C, Jolicoeur E et al. Gastroduodenal ulcers associated with the use of non-steroidal anti-inflamm
drugs: a systematic review of preventive pharmacological interventions. Ottawa (ON): Canadian Coordinating Of
Page 797
Therapeutic Choice
Health Technology Assessment; 2004. Technology Overview No: 12. Available from:
http://www.cadth.ca/media/pdf/261_gastro_ov_e.pdf. Accessed June 11, 2008.
23. Koch M, Dezi A, Ferrario F et al. Prevention of nonsteroidal anti-inflammatory drug-induced gastrointestinal muc
injury. A meta-analysis of randomized controlled clinical trials. Arch Intern Med 1996;156(20):2321-32.
24. Chan FK, Hung LC, Suen BY et al. Celecoxib versus diclofenac and omeprazole in reducing the risk of recurrent
bleeding in patients with arthritis. N Engl J Med 2002;347(26):2104-10.
25. Towheed TE, Maxwell L, Anastassiades TP et al. Glucosamine therapy for treating osteoarthritis. Cochrane Datab
Rev 2005;(2):CD002946.
26. Michel BA, Stucki G, Frey D et al. Chondroitins 4 and 6 sulfate in osteoarthritis of the knee: a randomized, cont
trial. Arthritis Rheum 2005;52(3):779-86.
27. Adebowale AO, Cox DS, Liang Z et al. Analysis of glucosamine and chondroitin sulfate content in marketed prod
caco-2 permeability of chondroitin sulfate raw materials. J Am Nutraceutical Assoc 2000;3:37-44.
28. Hunt R, Fallone C, Veldhuyzan van Zanten S et al. Canadian Helicobacter Study Group Consensus Conference: U
the management of Helicobacter pylori--an evidence-based evaluation of six topics relevant to clinical outcomes
patients evaluated for H pylori infection. Can J Gastroenterol 2004;18(9):547-54.
29. Bellamy N, Campbell J, Robinson V et al. Viscosupplementation for the treatment of osteoarthritis of the knee. C
30. Arrich J, Piribauer F, Mad P et al. Intra-articular hyaluronic acid for the treatment of osteoarthritis of the knee: s
review and meta-analysis. CMAJ 2005;172(8):1039-43.
31. Moseley JB, O'Malley K, Petersen NJ et al. A controlled trial of arthroscopic surgery for osteoarthritis of the knee
Med 2002;347(2):81-8.
32. Felson DT, Buckwalter J. Debridement and lavage for osteoarthritis of the knee. N Engl J Med 2002;347(2):132-
33. Wynne HA, Long A. Patient awareness of the adverse effects of non-steroidal anti-inflammatory drugs (NSAIDs)
Pharmacol 1996;42(2):253-6.
34. Anderson JL, Adams CD, Antman EM et al. ACC/AHA 2007 Guidelines for the management of patients with unsta
angina/non ST-elevation myocardial infarction: executive summary. Circulation 2007;116(7):803-77. Available
http://circ.ahajournals.org/cgi/reprint/116/7/803. Accessed June 11, 2008.
35. Nesic M, Harrison B, Haziza P. Hyalgan G-F 20 (Synvisc): reported incidents of joint inflammation and pain. Can
Adverse Reaction Newsletter 2005;15(2):1. Available from: http://www.hc-sc.gc.ca/dhp-mps/medeff/bulletin/ca
bcei_v15n2-eng.php#1. Accessed June 11, 2008.
36. Altman RD, Status of hyaluronan supplementation therapy in osteoarthritis. Curr Rheumatol Rep 2003;5(1):7-14
Pharmacoeconomic Considerations: Osteoarthritis

Epidemiology
Country Prevalence
Canada (2000)1 16% (range 11.6–23.3%) of Canadians aged ≥ 15 years (3.9 million)

a b
Country and Year of Estimate Direct Costs Indirect Costs
Canada (1993)2 $2.46 billion Not reported
Canada (1997)2 Not reported $17.6 billion
Commentary
Osteoarthritis (OA) is a disabling condition that places an enormous medical and economic burden on society. In 199
1
physician visit rates for arthritis ranged from 146 to 207 per 1000 people for those aged greater than 15 years. It ha
reported that 82% of patients seeking medical advice for arthritis and arthritis related conditions made at least one v
1
primary care physician.
Nonsteroidal anti-inflammatory agents (NSAIDs), acetaminophen and cyclooxygenase-2 (COX-2) inhibitors are frequ
1
used to treat OA. COX-2 inhibitors (celecoxib and meloxicam) are more expensive than traditional NSAIDs and
acetaminophen. COX-2 inhibitors and NSAIDs have similar efficacy but different adverse event profiles; the rate of
gastrointestinal bleeding is lower in patients receiving COX-2 inhibitors than NSAIDs.3
Page 798
Therapeutic Choice
Acetaminophen is frequently used for OA and is inexpensive. However, as it is an over-the-counter agent it places an
economic burden on the patient. Economic evaluations comparing acetaminophen with NSAIDs and COX-2s show a r
in gastrointestinal adverse events at a low cost in patients at high risk of having gastrointestinal events.4
COX-2 inhibitors are generally not economically attractive in patients with “average” risk for gastrointestinal bleeds.5
Celecoxib is considered to be cost-effective relative to some traditional NSAIDs in patients who are at high risk of
gastrointestinal events (i.e., elderly patients or those with a history of gastrointestinal adverse events). In a Canadia
economic evaluation, celecoxib was more effective and less expensive than ibuprofen plus a proton pump inhibitor in
risk patients. In the same study, diclofenac was more effective and less expensive in both average-risk patients treat
5
without a proton pump inhibitor and in high-risk patients with a proton pump inhibitor. Other COX-2 inhibitors have
been shown to be cost-effective in older patients and in patients with risk factors for gastrointestinal adverse events.
a.
b.
1. Health Canada. Arthritis in Canada: an ongoing challenge. Ottawa (ON): Health Canada; 2003. Available from:
http://www.phac-aspc.gc.ca/publicat/ac/pdf/ac_e.pdf. Accessed June 11, 2008.
2. Stafinski T, Menon D. The Burden of osteoarthritis in Canada: a review of current literature. Alberta: Institute of
Economics; November 9, 2000.
3. Silverstein FE, Faich G, Goldstein JL et al. Gastrointestinal toxicity with celecoxib vs nonsteroidal anti-inflamma
drugs for osteoarthritis and rheumatoid arthritis: the CLASS study: a randomized controlled trial. Celecoxib Lon
Arthritis Safety Study. JAMA 2000;284(10):1247-55.
4. Kamath CC, Kremers HM, Vanness DJ et al. The cost-effectiveness of acetaminophen, NSAIDs, and selective CO
inhibitors in the treatment of symptomatic knee osteoarthritis. Value Health 2003;6(2):144-157.
5. Maetzel A, Krahn M, Naglie G. The cost effectiveness of rofecoxib and celecoxib in patients with osteoarthritis o
rheumatoid arthritis. Arthritis Rheum 2003;49(3):283-92.
6. Moore A, Phillips C, Hunsche E et al. Economic evaluation of etoricoxib versus non-selective NSAIDs in the trea
osteoarthritis and rheumatoid arthritis patients in the UK. Pharmacoeconomics 2004;22(10):643-60.
Page 799
e-Therapeutics+ : Therapeutics : Musculoskeletal Disorders: Osteoporosis Page 1 of 15
Therapeutic Choice
Print Close
Musculoskeletal Disorders: Osteoporosis

Date Revised: August 2010
David A. Hanley, MD, FRCPC
Goals of Therapy
Prevent fractures, disability and loss of independence

Preserve or enhance bone mass
Investigations
Evidence-based clinical practice guidelines identify four key predictors of osteoporosis-related fracture: age, history o
previous fragility fracture, low bone mineral density and family history of osteoporotic fracture, especially maternal hi
1
fracture.
Table 1 lists risk factors used to select candidates for bone density testing. After age 50 or menopause, 1 major or 2 m
factors should qualify an individual for a bone density test.1
Table 1: Risk Factors Prompting Assessment for Osteoporosis
Major Risk Factors Minor Risk Factors
Age >65 y Rheumatoid arthritis

Vertebral compression fracture Past history of clinical hyperthyroidis
Fragility fracture after age 40 Chronic anticonvulsant therapy
Family history of osteoporotic fracture (especially maternal hip fracture) Low dietary calcium intake
Systemic glucocorticoid therapy of >3 mo duration Smoker
Malabsorption syndrome Excessive alcohol intake
Primary hyperparathyroidism Excessive caffeine intake
Propensity to fall Weight <57 kg
Osteopenia apparent on x-ray film Weight loss >10% of weight at age 2
Hypogonadism Chronic heparin therapy
Early menopause (before age 45)
“2002 clinical practice guidelines for the diagnosis and management of osteoporosis in Canada” – Reprinted from CMAJ 12 Novemb
2002;167 (10 Suppl) by permission of the publisher © 2002 Canadian Medical Association.
History:
peak height as a young adult (4 cm greater than current measured height), or >2 cm height loss within past
chronic or acute back pain
endocrine diseases: hyperthyroidism, hyperparathyroidism, hypogonadism, Cushing's syndrome; renal diseas
organ transplantation, gastrointestinal disease: gastric surgery, malabsorption; chemotherapy for malignancy
medications associated with fractures: thiazolidinediones, proton pump inhibitors, SSRIs. High doses of vitam
are associated with increased risk of hip fracture. Advise patients not to take double doses of multivitamins to
increase vitamin D intake2
see Table 1 for other risk factors
kyphosis: <3 fingerbreadths (5–6 cm) between rib and iliac crest
factors increasing risk of falling: muscle weakness (inability to rise from a chair), impaired visual acuity, poo
balance or disability causing a tendency to fall
Laboratory investigations
all should be normal: CBC, calcium, alkaline phosphatase (may be elevated in acute recovery from fracture),
creatinine. Consider serum 25-OH vitamin D if the patient has an apparent increased risk of deficiency (e.g.,
malabsorption syndromes, housebound). Measure TSH if there is a clinical suspicion of thyroid disease. Seru
protein electrophoresis can be performed if there is a suspicion of secondary causes of osteoporosis
1
other more specific markers of calcium or bone metabolism are not routinely available or appropriate
Page 800
Therapeutic Choice
Diagnostic imaging
1
x-rays are mainly used for detecting fractures. If x-ray shows osteopenia (decreased bone mineral), confirm
bone density measurement
bone scans can identify new fracture activity in patients with back pain and no obvious new fracture on x-ray
Bone density measurements
bone mineral density (BMD) of the spine and hip by dual-energy x-ray absorptiometry (DXA) is the preferred
method of assessing bone mass and fracture risk, as well as monitoring response to therapy.1 Other methods
heel ultrasound) are acceptable for assessing fracture risk if DXA is not available3
recommendations for reporting DXA that combine age, BMD and epidemiologic data yield an estimated 10-ye
of osteoporotic fracture in women (Figure 1 - Use of Bone Density and Age to Predict Fragility Fracture Risk i
Womena ) and in men (Figure 2 - Use of Bone Density and Age to Predict Fragility Fracture Risk in Mena ), w
4
reported as low (<10%), moderate (10–20%) or high (>20%). This risk stratification has not yet been valid
as an osteoporosis management strategy. Nevertheless, an individual in the “low risk” category is not likely t
receive clinically meaningful fracture prevention benefit from pharmacologic therapy. Glucocorticoid therapy o
fragility fracture moves a patient to a higher risk category than that indicated by BMD and age
a WHO-commissioned panel recently introduced a 10-year osteoporotic fracture risk assessment tool, FRAX™
(available from http://www.shef.ac.uk/FRAX/).5 This tool uses a single femoral neck BMD measurement (or B
BMD is not available) and a small number of risk factors to calculate a country-specific 10-year percentage ri
major osteoporotic fracture (forearm, humerus, spine, hip). A Canadian FRAX™ model has not yet been deve
WHO recommends that the user select the calculation tool for the country that is closest geographically, but f
Canadians, the United Kingdom or Sweden calculator is probably more appropriate than the U.S. tool. At pres
Osteoporosis Canada recommends using the simpler Canadian system (Figure 1 - Use of Bone Density and Ag
a
Predict Fragility Fracture Risk in Women and Figure 2 - Use of Bone Density and Age to Predict Fragility Frac
a
Risk in Men ). However, FRAX™ can be used to give patients a rough numerical estimate of fracture risk
Therapeutic Choices
Osteoporosis therapy may be subdivided into prevention and treatment of established osteoporosis (Figure 3 - Use of
Density and Risk Factors in Osteoporosis Management). Chronic glucocorticoid therapy requires special attention for
1
preventive intervention.
Regular exercise (especially impact type).

Reduce risk of falling: minimize hazards for falling in the home (e.g., remove throw rugs, install grab bars in
bathrooms, ensure adequate lighting), assess drugs implicated in falls such as benzodiazepines and other
psychotropics; improve strength and balance.
Adequate protein, calcium and vitamin D intake (Table 2).
Facilitate smoking cessation; encourage avoidance of excessive alcohol (>2 drinks/day) and caffeine intake (>4 c
coffee per day or equivalent).
Bone is constantly remodelling, with older, weaker bone being removed by osteoclasts (resorption), which is then foll
by new bone formation. Osteoporosis develops if there is an imbalance in remodelling so that resorption exceeds form
(net bone loss). Therapies for osteoporosis manipulate the normal process of bone remodelling, either by reducing bo
resorption (antiresorptive or anticatabolic agents) or stimulating bone formation (anabolic).7 Anticatabolic is a more a
descriptive term than antiresorptive, because the so-called antiresorptive drugs do more than suppress osteoclast activ
the net effect is a change in remodelling balance and prevention of bone loss. Most approved osteoporosis drugs are
anticatabolic. By acting to reduce both the depth and rate of bone resorption while bone formation proceeds normally,
agents cause an initial increase in bone mass. This increase eventually plateaus, as bone formation slows to match the
7
reduced rate of resorption.
Anticatabolic Agents
Bisphosphonates
Bisphosphonates are the main drugs used in the treatment of osteoporosis. The large clinical trials of alendronate,
risedronate and zoledronate show a consistent reduction in relative risk of osteoporotic fracture in the range of 40–60
drugs are, for the most part, very well tolerated.
Page 801
Therapeutic Choice
Oral alendronate, risedronate and cyclical etidronate are approved for prevention and treatment of postmenopaus
bone loss, treatment of established osteoporosis and glucocorticoid-induced osteoporosis. All bisphosphonates have v
poor intestinal absorption, e.g., alendronate <1%. They must be taken on an empty stomach and only with water, as
medications or food will prevent absorption. Strict adherence to dosing instructions is mandatory.
The main side effects of bisphosphonates are minor gastrointestinal upset and allergic reactions. An important rare sid
effect of the aminobisphosphonates (alendronate and risedronate) is esophageal ulceration.
8
Etidronate taken for 2 weeks every 3 months increases bone density and prevents vertebral fractures. Safety and effic
for up to 7 years of cyclical etidronate therapy has been demonstrated.9 The dose schedule of etidronate (only 2 week
every 3 months) and its lower cost are attractive to some patients.
Didrocal provides 14 days of etidronate 400 mg followed by 76 days of elemental calcium 500 mg as calcium carbona
Additional calcium supplements may be used as needed.
Alendronate increases bone mass throughout the skeleton and reduces the risk of all fractures (including hip).10 , 11 ,
13 , 14
Risedronate, like alendronate, is associated with a reduced risk of all osteoporosis-associated fractures.
Gains in spinal bone density appear to be greater with alendronate and risedronate than with etidronate; a meta-analy
places these agents ahead of etidronate in preventing vertebral and nonvertebral fractures.15 Guidelines recognize
1
alendronate and risedronate as first-line therapies for osteoporosis.
There have been no well-designed, direct comparison trials of bisphosphonates that have been powered to look at frac
prevention. A recent randomized trial showed alendronate had a greater effect on BMD and biochemical markers of bo
16
turnover than risedronate, but fracture prevention was no different. However, an observational study suggests earlie
17
greater fracture prevention with risedronate than alendronate.
Recent case reports describe unusual fractures with some similarity to stress fractures, usually occurring in the
subtrochanteric region of the femur, in patients treated for 2–8+ years with bisphosphonates (mainly alendronate); 2
18 , 19
of case reports have reported bone biopsies showing very low bone turnover. These fractures may result from
bisphosphonates causing excessive suppression of bone turnover and repair. However, low bone turnover osteoporotic
fractures were seen before bisphosphonates were available; a recent review and large cohort study suggests they are
20
different from osteoporotic fractures. If a patient suffers a stress-like fracture, stop the bisphosphonate and conside
referral to a bone specialist for bone biopsy with histomorphometry. If severely suppressed bone turnover is identified
bisphosphonate therapy should not be restarted. An anabolic agent like teriparatide might be considered, to try to incr
bone turnover and repair.
Bisphosphonate drug holidays have been proposed because after several years of therapy, chronic suppre
of bone turnover could theoretically interfere with normal reparative processes of the skeleton. The FLEX
evaluated alendronate therapy past the 5-year mark of the Fracture Intervention Trial, randomizing patie
to placebo vs continuing alendronate for another 5 years.21 Patients in the placebo arm showed only a
moderate decrease in BMD and no increase in nonvertebral fracture risk compared to those continuing
alendronate over the second 5 years. These results have been used to support a drug holiday for patients
taking alendronate; however, the significantly increased risk of vertebral fractures in the placebo arm is
notable as such fractures are not trivial events. Also, bone biopsies from subjects who took alendronate f
years showed normal bone. While a 2–3 year drug holiday may be appropriate for patients who were
prescribed alendronate because of low BMD alone, drug holidays are not recommended for patients with
previous osteoporotic fracture as they are at higher risk for recurrence. Risedronate has a lower affinity t
bone than alendronate;22 BMD declined and bone turnover markers returned to placebo levels in the first
after the drug was discontinued in one study.23 However, fracture protection persisted in the year after
discontinuation. Notwithstanding this finding, a drug holiday is generally not recommended for patients
risedronate. Useful Info?
Intravenous bisphosphonates are used for patients who cannot tolerate the gastrointestinal side effects of the oral age
when it appears a patient is not responding to an oral agent. There are no clinical trials supporting the latter. A potent
advantage of iv bisphosphonate therapy is that adherence to therapy is less of an issue, particularly with once-yearly d
A large placebo-controlled clinical trial of zoledronate (zoledronic acid) 5 mg iv infusion once yearly in postmenop
24
women with osteoporosis showed a reduction in the incidence of all osteoporotic fractures, including hip fractures. I
another randomized, placebo-controlled trial in patients with hip fracture (without selection based on low BMD), once
Page 802
Therapeutic Choice
iv zoledronate reduced the incidence of subsequent fractures and was also associated with a 28% reduction in all-caus
25
mortality.
Although not approved in Canada for the treatment of osteoporosis, pamidronate 30 or 60 mg iv over 2–3 hours eve
months causes a similar improvement in BMD to that seen with oral bisphosphonates, and a small study suggests frac
26 , 27
prevention.
RANK Ligand Inhibitor
Denosumab, the first biologic agent approved for the treatment of osteoporosis, is a human monoclonal antibody tha
inhibits reactor activator of nuclear factor-kappa B ligand (RANKL), thus preventing binding to its receptor (RANK) on
surface of osteoclast precursors and osteoclasts. Inhibition of RANKL results in diminished osteoclast formation, funct
and survival and thus increased cortical and trabecular bone mass and strength. Denosumab has been shown to reduc
28
incidence of vertebral, nonvertebral and hip fractures in postmenopausal women with osteoporosis. It may be used
postmenopausal women with a history of osteoporotic fracture, multiple risk factors for fracture or in those who have
or are intolerant of other therapies.
Selective Estrogen Receptor Modulators
Raloxifene prevents postmenopausal bone loss,29 increasing bone density by approximately 3% and reducing new
30
vertebral fractures by 30–40%. It is an estrogen antagonist in breast and uterine tissue, but has estrogen-like activi
bone and lipid metabolism. Like estrogen, there is a modestly increased risk of deep vein thrombosis and pulmonary
embolism in postmenopausal women.30 It also significantly reduces the relative risk of estrogen receptor-positive brea
31 32
cancer by 76%. Raloxifene is not associated with increased cardiovascular risk.
Estrogen and Progesterone

1
Postmenopausal estrogen or estrogen/progesterone therapy is no longer a first choice for treatment of osteoporosis.
However, to prevent osteoporosis in women experiencing an early menopause (before age 45), it is recommended tha
1
hormone therapy (HT) be taken until normal age of menopause. For women entering menopause at the usual age, Ca
guidelines suggest HT should still be considered an option for women who wish to take an osteoporosis prevention th
1
and who are also experiencing problems with menopausal symptoms. For the treatment of established osteoporosis i
1
postmenopausal women over the age of 60, HT is now considered second-line, because the reduction in hip and othe
fractures is offset by increased risk of breast cancer and heart disease, according to the Women’s Health Initiative (WH
33
studies. It should be noted, however, that women participating in the WHI were at low risk for osteoporosis but had
incidence of obesity and hypertension, increasing their risk for breast cancer and cardiovascular disease. The risk/ben
ratio may be different for postmenopausal women with osteoporosis, and the cardiovascular risk of HT was not seen i
women under age 60 in the WHI.34
Calcitonin
Salmon calcitonin nasal spray has been shown to prevent vertebral fractures, but because of weaker clinical trial data,
calcitonin is a second-line therapy.1 , 35 Calcitonin reduces pain associated with acute vertebral fractures. The effectiv
of injectable calcitonin has not been standardized.
Anabolic Agents
Teriparatide
Teriparatide, a parathyroid hormone (PTH) analogue, is an anabolic agent that causes a steady gain in bone density an
50% reduction in osteoporotic fractures.36
The major clinical trials of teriparatide were stopped at a median of 19 months of therapy because of occurrence of
osteogenic sarcoma in teratogenicity studies in rats given lifelong treatment with very high doses. This finding is not l
to be relevant to its use in humans at a lower dose for a much shorter relative duration of therapy. Teriparatide has be
approved for 24 months' lifetime exposure.
Page 803
Therapeutic Choice
After teriparatide therapy is completed, treatment with a bisphosphonate or other anticatabolic agent is advised, as mu
the increase in BMD may be lost during the first year after stopping the drug unless an anticatabolic is started.38
Human Parathyroid Hormone (PTH)
In a large placebo-controlled, 18-month clinical trial in patients at low risk of fracture, recombinant human PTH 100 µ
daily significantly increased BMD and reduced the incidence of vertebral fractures.37 This drug is approved for osteopo
therapy in Europe, but has not been introduced for osteoporosis therapy in North America.
Strontium Ranelate
Strontium replaces calcium in bone matrix and also appears to uncouple bone remodelling, causing a modest reductio
39
bone resorption in conjunction with a similarly modest increase in bone formation. The dramatic increases in bone d
are partly explained by strontium having a higher atomic weight than calcium, and partly by the positive bone balance
The manufacturer has withdrawn its application to have strontium ranelate approved for osteoporosis in Canada. Howe
some patients are obtaining strontium ranelate from Europe, or purchasing other nonprescription strontium salts. Clin
trials of strontium ranelate have shown similar fracture prevention to that seen with bisphosphonates.39 Evidence for t
efficacy of other strontium salts is lacking. Strontium ranelate 2 g orally is taken as powder mixed with water, once pe
Side effects appear to be infrequent, but in pooling the clinical trials, an increased incidence of venous thromboembol
40
events was noted in the subjects receiving strontium ranelate. No effect of this drug on coagulation parameters has
identified, and the mechanism of this side effect remains unclear. Nervous system abnormalities (a variety of symptom
disorders, including seizures and memory loss) were also reported slightly more frequently with strontium therapy. A
serious systemic and skin reaction (Drug Rash with Eosinophilia Systemic Symptoms or DRESS syndrome) has been
reported as a rare complication of strontium ranelate therapy.41
Combination Therapy
Combining a bisphosphonate with other anticatabolic agents, estrogen or raloxifene, has additive or synergistic effects
BMD, but no fracture benefit has yet been demonstrated.42 , 43
Combining anticatabolic with anabolic therapy may seem an attractive approach, but results have been mixed. Giving a
bisphosphonate concurrently with PTH or teriparatide may actually blunt the anabolic response. However, combining
teriparatide with either estrogen or raloxifene does not interfere with the anabolic action, and may enhance it.44
After teriparatide therapy is completed, treatment with a bisphosphonate or other anticatabolic agent is advised, to pre
38
and consolidate the gains achieved with the anabolic agent.
Therapeutic Tips
A person over the age of 50 with a vertebral compression fracture, wrist fracture or hip fracture should be conside
have osteoporosis until proven otherwise. Test these individuals with bone densitometry. These patients are still
candidates for therapy if bone densitometry is not available.
In all age groups, adequate calcium and vitamin D preserves or enhances bone mass and prevents fractures in t
elderly.45 Ensure adequate intake of both of these nutrients when prescribing pharmacologic therapy for osteopor
46
Vitamin D insufficiency is a common problem in Canada, and many experts believe even the current recommend
for vitamin D supplements of 800 IU per day is too low.
For the prevention of osteoporosis in early postmenopause, if estrogen deficiency symptoms also require treatmen
estrogen or estrogen/progesterone remains a reasonable choice. If menopausal symptoms are not a problem, ralo
is an alternative, with the potential added benefit of reducing breast cancer risk.
For patients with established osteoporosis (e.g., a fragility fracture and bone density in the osteoporosis range),
bisphosphonates are recommended first-line therapy. Raloxifene is also ranked as first-line therapy but in the abs
of hip fracture prevention data, it would be considered after bisphosphonate therapy for individuals at high risk of
fracture (age >70 years with a prior fragility fracture history). Consider teriparatide for severe cases characterized
more than one fragility fracture and a very low BMD.47
For the prevention and treatment of glucocorticoid-induced osteoporosis, bisphosphonates are the agents of choic
Because of the absence of fracture prevention data, calcitriol, androgens and sodium fluoride are no longer consid
appropriate alternative therapies.
Page 804
Therapeutic Choice
While women are more frequently affected by osteoporosis, vertebral deformities (which may represent vertebral
48
fractures) occur almost as often in men as in women. Hip fractures in men are also more likely to result in deat
disability than those in women.
a
Figure 1- Use of Bone Density and Age to Predict Fragility Fracture Risk in Women
a.
Calculated 10-year absolute risk of typical osteoporotic fracture (hip, forearm, proximal humerus and symptomatic vertebral
compression) for women over age 50 who have not received osteoporosis therapy. Most therapies reduce relative risk of
fracture by 40–50%. Reprinted from Can Assoc Radiol J 2005;56(3):182 by permission of the publisher © 2005 Canadian Associa
Radiologists.
Figure 2- Use of Bone Density and Age to Predict Fragility Fracture Risk in Mena
a.
Calculated 10-year absolute risk of typical osteoporotic fracture (hip, forearm, proximal humerus and symptomatic vertebral
Page 805
Therapeutic Choice
compression) for men over age 50 who have not received osteoporosis therapy. Most therapies reduce relative risk of fra
by 40–50%. Reprinted from Can Assoc Radiol J 2005;56(3):182 by permission of the publisher © 2005 Canadian Association of
Radiologists.
Figure 3- Use of Bone Density and Risk Factors in Osteoporosis Management
a.
4 cm historical height loss; 2 cm prospective height loss.
b.
Low to moderate: 2.5–7.5 mg prednisone/day; moderate to high: >7.5 mg prednisone/day.
c.
Central DXA = spine and hip.
Abbreviations: BMD = bone mineral density; DXA = dual-energy x-ray absorptiometry
“2002 clinical practice guidelines for the diagnosis and management of osteoporosis in Canada”. Reprinted from CMAJ 12 Novembe
2002;167(10 Suppl):S7 by permission of the publisher © 2002 Canadian Medical Association.
Table 2: Drugs Used for the Management of Osteoporosis
Page 806
Therapeutic Choice
Class Drug Dose Adverse Effects Comments Co
Nutritional Supplements calcium Men <50 y, and Constipation and Doses represent $
Caltrate 600, Os- premenopausal, nausea are the most the total
pregnant or common side effects. intake from
Cal, Tums,
lactating women: Other possible side diet and
generics
1000 mg/day effects include supplements.
Men >50 y and hypercalcemia,
menopausal hypercalciuria, renal
women: calcification and renal
1500 mg/day stones.
Nutritional Supplements vitamin D 800–2000 IU daily6 Possible side effects Doses represent $
are hypercalcemia, the total
hypercalciuria, renal intake from
calcification and renal diet and
stones (usually at very supplements
high doses). in patients with
osteoporosis,
regardless of
age.
Increases
calcium
absorption.
Many
multivitamin
supplements
contain 400 IU
vitamin D and
are the most
commonly used
preparation.
Vitamin D3
(cholecalciferol)
is preferred
over vitamin D2
(ergocalciferol).
Oral Bisphosphonates etidronate Cyclic: 400 mg/day Side effects are usually Etidronate $
generics × 14 days Q3 mo, minimal: GI symptoms, should be taken
then calcium alone altered taste, nighttime on an empty
leg cramps. stomach with a
Rarely reported: acute- full glass of
phase reactions water. To aid
involving fever and compliance, it
lymphopenia, joint or is
muscle pain, skin recommended
reactions, ocular that patients
effects. take the therapy
at bedtime, at
Safety in impaired least 2 h before
renal function (ClCr or after eating.
<35 mL/min) is Calcium
unknown. supplements
should be
Although not reported separated by at
with cyclical etidronate, least 2 h before
osteonecrosis of the or after.
jaw has been reported
in cancer patients on
high-dose iv
Page 807
Therapeutic Choice

bisphosphonates and
rarely with oral doses
used for osteoporosis.
Although available
evidence does not
prove a causal link,
advise patients to
complete elective
dental work if possible
before starting oral
bisphosphonates.49
Oral Bisphosphonates alendronate Prevention: Usually minimal: GI Must be taken $

Fosamax, 5 mg/day symptoms, altered at least 30 min
Treatment: 10 taste, nighttime leg before the first
generics
mg/day or 70 mg cramps. food, beverage,
once weekly Rarely: acute-phase or medication
reactions involving with plain water
fever and lymphopenia, only.
joint or muscle pain, Retrospective
skin reactions, ocular analysis
effects. suggests
alendronate
Esophageal ulceration prevents
is a rare side effect of fractures within
aminobisphosphonates; the first year of
patient must take with therapy.
a full glass of water
and not lie down for 30
min after taking.
Safety in impaired
renal function (ClCr
<35 mL/min) is
unknown.
Osteonecrosis of the
high-dose iv
bisphosphonates and
Although available
evidence does not
advise patients to
complete elective
49
bisphosphonates.
Oral Bisphosphonates risedronate 5 mg/day; 35 mg Usually minimal: GI Risedronate $$

Actonel, generics once weekly; symptoms, altered should be taken
75 mg/day for 2 taste, nighttime leg on an empty
consecutive days cramps. stomach at
each mo; or Rarely: acute-phase least 30 min
150 mg once per reactions involving before
month fever and lymphopenia, consuming the
joint or muscle pain, first food, drink
(other than
Page 808
Therapeutic Choice

skin reactions, ocular plain water)
effects. and/or any
other
Esophageal ulceration medication.
is a rare side effect of Risedronate has
aminobisphosphonates; been shown to
patient must take with prevent
a full glass of water fractures within
and not lie down for 30 the first year of
min after taking. therapy.
Safety in impaired
<35 mL/min) is
unknown.
high-dose iv
bisphosphonates and
Although available
evidence does not
advise patients to
complete elective
49
bisphosphonates.
Oral alendronate / alendronate Usually minimal: GI Must be taken $$

Bisphosphonate/Nutritional vitamin D 70 mg plus vitamin symptoms, altered at least 30 min
Supplement Combinations D taste, nighttime leg before the first
Fosavance 2800 IU or 5600 IU cramps. food, beverage,
once weekly Rarely: acute-phase or medication
reactions involving with plain water
fever and lymphopenia, only.
joint or muscle pain, Retrospective
skin reactions, ocular analysis
effects. suggests
alendronate
Esophageal ulceration prevents
is a rare side effect of fractures within
aminobisphosphonates; the first year of
patient must take with therapy.
a full glass of water
and not lie down for 30
min after taking.
Safety in impaired
<35 mL/min) is
unknown.
high-dose iv
bisphosphonates and
Page 809
Therapeutic Choice

Although available
evidence does not
advise patients to
complete elective
49
bisphosphonates.
Oral etidronate/calcium Cyclic: Side effects are usually Etidronate $$/3

Bisphosphonate/Nutritional 400 mg/day × 14 minimal: GI symptoms, should be taken
Supplement Combinations Didrocal, generics days then calcium altered taste, nighttime on an empty
500 mg (as leg cramps. stomach with a
carbonate) on days Rarely reported: acute- full glass of
15–90 phase reactions water. To aid
involving fever and compliance, it
lymphopenia, joint or is
muscle pain, skin recommended
reactions, ocular that patients
effects. take the therapy
at bedtime, at
Safety in impaired least 2 h before
renal function (ClCr or after eating.
<35 mL/min) is Calcium
unknown. supplements
should be
Although not reported separated by at
with cyclical etidronate, least 2 h before
osteonecrosis of the or after.
high-dose iv
bisphosphonates and
Although available
evidence does not
advise patients to
complete elective
49
bisphosphonates.
Intravenous zoledronic acid 5 mg once yearly 10–20% of patients Product is ~$70

Bisphosphonates Aclasta iv; infuse over 15– experience acute-phase packaged as dose
30 min reaction 24–72 hours 5 mg/100 mL
after infusion, lasting ready-to-use
up to 3–4 days: fever infusion.
and lymphopenia, joint Patients should
or muscle pain, skin be well
reactions, ocular hydrated
effects. (500 mL of
Rare: atrial fibrillation. water) prior to
and following
Deterioration of renal administration.
function may occur
following
administration. To
minimize risk, do not
Page 810
Therapeutic Choice

use in patients with
ClCr <30 mL/min.
high-dose iv
bisphosphonates and
Although available
evidence does not
advise patients to
complete elective
before starting
49
bisphosphonates.
RANK Ligand Inhibitors denosumab 60 mg once every Eczema, serious Keep ~$35
Prolia 6 mo sc infections. refrigerated. dose
Hypocalcemia in
patients with reduced
GFR.
jaw was reported in
trials using high doses
(120 mg every month)
in oncology patients;
risk is similar to
bisphosphonates.
Selective Estrogen raloxifene Leg cramps, hot flashes May aggravate $$$
Receptor Modulators Evista, generics 60 mg/day especially in younger hot flushes;
postmenopausal should not be
women. started until
Venous menopause is
thromboembolism risk established.
similar to estrogen.
Hormone Therapy (See

Sexual Health:
Menopause)
Calcitonin Peptides calcitonin salmon, 200 IU/day Local effects such as $$$
intranasal intranasally rhinitis, nasal dryness
Miacalcin NS, with crusting,
generics nonsevere epistaxis
and sinusitis. Rarely
associated with
systemic effects such
as nausea, vomiting,
dizziness, flushing
accompanied by a
sensation of heat and,
uncommonly, polyuria
and chills.
Page 811
Therapeutic Choice
Calcitonin Peptides calcitonin salmon, 50–100 IU daily Local effects such as Not approved $$$$
subcutaneous nd rhinitis, nasal dryness for
or Q 2 day
Calcimar, Caltine or 5 days/wk sc with crusting, osteoporosis;
nonsevere epistaxis restrict to
and sinusitis. Rarely patients who
associated with fail
systemic effects such conventional
as nausea, vomiting, therapy.
dizziness, flushing Dose is not
accompanied by a standardized.
sensation of heat and,
uncommonly, polyuria
and chills.
Pain at site of injection,
nausea, facial flushing,
metallic taste,
hypersensitivity (rare).
Anabolic Agents teriparatide 20 µg/day sc for Nausea, dizziness, leg Limited data ~$80
Forteo 24 months cramps. Not to be available
(lifetime exposure) prescribed to patients concerning use
with an increased in renal or
baseline risk of hepatic
osteosarcoma. impairment.
Patients should be in a
supine or sitting
position for
administration because
of the risk of
orthostatic
hypotension.
a.
Cost of 30-day supply unless otherwise specified, includes drug cost only.
Legend: $ <$20 $$ $20–40 $$$ $40–60 $$$$ $60–80 $$$$$ >$80
Suggested Readings
Brown JP, Fortier M, Frame H et al. Canadian consensus conference on osteoporosis, 2006 update. J Obstet Gynaecol C
2006;28(2 Suppl 1):S95-S112.
Brown JP, Josse RG; Scientific Advisory Council of the Osteoporosis Society of Canada. 2002 clinical practice guidelin
the diagnosis and management of osteoporosis in Canada. CMAJ 2002;167(10 Suppl):S1-34.
Cranney A, Guyatt G, Griffith L et al. Meta-analyses of therapies for postmenopausal osteoporosis. IX: Summary of me
analyses of therapies for postmenopausal osteoporosis. Endocr Rev 2002;23(4):570-8.
Khan AA, Sandor GK, Dore E et al. Bisphosphonate associated osteonecrosis of the jaw. J Rheumatol 2009;36(3):478-
Siminoski K, Leslie WD, Frame H et al. Recommendations for bone mineral density reporting in Canada. Can Assoc Ra
2005;56(3):178-88.
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Page 812
Therapeutic Choice
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45. Chapuy MC, Arlot ME, Duboeuf F et al. Vitamin D3 and calcium to prevent hip fractures in the elderly women. N
Med 1992;327(23):1637-42.
46. Hanley DA, Davison KS. Vitamin D insufficiency in North America. J Nutr 2005;135(2):332-7.
47. Hodsman A; Scientific Advisory Council of Osteoporosis Canada; Papaioannou A et al. Clinical practice guideline
the use of parathyroid hormone in the treatment of osteoporosis. CMAJ 2006;175(1):48.
48. Khan AA, Hodsman AB, Papaioannou A et al. Management of osteoporosis in men: an update and case example.
2007;176(3):345-8.
49. Shane E, Goldring S, Christakos S et al. Osteonecrosis of the jaw: more research needed. J Bone Miner Res 200
(10):1503-5.
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e-Therapeutics+ : Therapeutics : Musculoskeletal Disorders: Polymyalgia Rheumatica and ... Page 1 of 7
Therapeutic Choice
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Musculoskeletal Disorders: Polymyalgia Rheumatica and Giant-Cell Arteritis
John G. Hanly, MD, MRCPI, FRCPC
Polymyalgia rheumatica (PMR) and giant-cell arteritis (GCA) are related conditions that affect older individuals and
may reflect 2 ends of a spectrum of the same disease. PMR is characterized by aching and stiffness in the muscle
groups of the neck, pectoral and pelvic girdles and thighs. The prevalence approaches 1% of people over the age of
1 , 2
50.
GCA is a chronic vasculitis of large and medium-sized arteries with a predominance for the cranial branches of the
arteries originating from the aortic arch. Thus, headache, jaw claudication and visual loss are common
1 , 3
presentations. It is less frequent than PMR and affects approximately 0.2% of people 50 years of age and older.
Both conditions are 2-fold more frequent in women than in men. There is a clear association between PMR and GCA.
Approximately 16–21% of patients with PMR will develop GCA concurrently or subsequent to the diagnosis of
PMR;1 , 2 , 4 conversely 40–60% of patients with GCA will develop symptoms of PMR. Although the etiology of both
conditions is unknown, PMR is characterized pathologically by low grade synovitis of the proximal joints while the
hallmark of GCA is granulomatous inflammation with giant cells of affected arterial walls. Both conditions may be
associated with systemic clinical manifestations.
Goals of Therapy
Eliminate symptoms of musculoskeletal pain and stiffness and associated malaise

Restore function
Relieve symptoms due to GCA and prevent permanent visual loss
Minimize the frequency and severity of corticosteroid toxicity
Investigations
The value of a thorough history and physical examination cannot be overemphasized. PMR and GCA are clinical
diagnoses. Other than a positive temporal artery biopsy there are no laboratory tests that are specific for either
disease.
The diagnostic approach is outlined in Table 1 and Figure 1 - Diagnostic Approach in Patients with Suspected
Polymyalgia Rheumatica (PMR) and Giant-Cell Arteritis (GCA).
History
Patients with PMR typically present with the following characteristics:
Significant proximal muscle discomfort, especially around the shoulders, across the neck, and in the buttocks
and thighs. The pain is generally severe and usually interferes with activities of daily living.
Many patients describe an acute onset and can pinpoint the start of their symptoms to a specific day.
Musculoskeletal morning stiffness lasting for hours is a prominent feature. Symptoms tend to worsen through
the night, and movement during sleep causes discomfort severe enough to wake the patient.
Systemic symptoms such as fever, malaise, anorexia and fatigue may be present in one-third of patients.7
Patients with GCA most frequently present with the following characteristics:
Headache and scalp tenderness in the temporal or occipital areas, claudication of the jaw or tongue and partial
or complete monocular visual loss which may affect the contralateral eye within 2 weeks even after starting
corticosteroid therapy.
Additional distinct clinical presentations may occur based upon the pattern of vascular involvement and the
8
degree of systemic symptoms. For example, involvement of large vessels such as the branches of the aortic
arch, similar to that seen in Takayasu’s arteritis, may occur in up to 15% of cases and is manifested by audible
bruits and upper limb claudication. The treatment and outcome is comparable to GCA without large vessel
9
involvement.
Systemic symptoms, including fever, occur in up to 50% of cases.
10
A recognized late complication of GCA is a 17-fold increase in thoracic aortic aneurysm.
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Therapeutic Choice
Patients who present with PMR should be questioned specifically about symptoms of GCA.
The physical findings in PMR are nonspecific and usually reveal a reduction in range of motion of the neck and
shoulders.
Large and small joint synovitis may be present but is unusual in locations distal to the wrist and ankle. Severe
swelling with pitting edema over the dorsum of both hands and feet may also occur and forms a distinct clinical
11 , 12
subset.
Proximal muscle tenderness may be present but muscle weakness, although difficult to assess due to pain, is
not a predominant feature of PMR.
Diminished or absent temporal artery pulsation and associated scalp tenderness, coupled with an appropriate
history, is suggestive of GCA.
Funduscopic findings related to GCA include optic neuritis with pallor and edema of the optic disc, cotton-wool
patches and small hemorrhages.
Laboratory Tests
A rapid erythrocyte sedimentation rate (ESR) and elevated levels of C-reactive protein (CRP) are usually
present. However, 5–6% of patients with PMR and GCA will have a normal ESR13 , 14 although in the majority
of such cases the CRP is elevated.13
Anemia and/or thrombocytosis may also be found in patients presenting with PMR or GCA.
Temporal artery biopsy is indicated only if there is a clinical suspicion of GCA and is not routinely recommended
in patients who present with isolated PMR. Due to patchy involvement of affected vessels, a normal biopsy does
not exclude the diagnosis. Thus, even when up to 5 cm of bilateral temporal arteries are sampled, 9% of
15 , 16 , 17 , 18
suspected cases have normal biopsies. More recent studies have suggested that performing
bilateral temporal artery biopsies increases the diagnostic yield by 1–12.7%.19 , 20 Corticosteroid therapy
should not be withheld while awaiting the result of a temporal artery biopsy. This biopsy can still show changes
21 , 22
of arteritis when performed up to 4 weeks following the commencement of corticosteroid therapy.
The diagnostic approach is outlined in Figure 1 - Diagnostic Approach in Patients with Suspected Polymyalgia
Rheumatica (PMR) and Giant-Cell Arteritis (GCA). A number of conditions must be considered in the differential
diagnosis of PMR (Table 1) although GCA can usually be readily distinguished from other forms of vasculitis.
Table 1: Differential Diagnosis of Polymyalgia Rheumatica (PMR)
Diagnosis Distinguishing Features From PMR
Myositis Muscle weakness on physical examination

↑ CPK
Abnormalities on EMG and muscle biopsy
Fibromyalgia Usually seen in younger patients

Widespread pain and tenderness at a significant number of soft tissue sites not limited to the
shoulders and hips
Normal ESR and CRP
Rheumatoid Synovitis distal to the wrist and ankle

Arthritis Seropositivity for rheumatoid factor (RF)
Consider anti-CCP antibodies if RF negative
Inadequate response to low-dose prednisone therapy
Radiographic erosions
Malignancy As directed by clinical examination, laboratory evaluation (e.g., iron deficiency anemia) and lack
of response to conventional therapy. However, the incidence of malignancy is not increased in
5 6
PMR or GCA.
Abbreviations: anti-CCP=anti-cyclic citrullinated peptide; CPK=creatine phosphokinase; CRP=C-reactive

protein; EMG=electromyography; ESR=erythrocyte sedimentation rate
Therapeutic Choices
Page 816
Therapeutic Choice
Corticosteroids
Nonsteroidal anti-inflammatory drugs (NSAIDs) are generally ineffective or provide only partial improvement of
symptoms in patients with PMR. Thus, systemic corticosteroids are the cornerstone of therapy. Prednisone 10–20
7
mg/day results in rapid and sustained clinical improvement (Table 2). Substantial, if not complete, resolution of
symptoms occurs within days. In fact, the diagnosis of PMR should be reconsidered if symptoms fail to improve
significantly after 1 week of corticosteroid therapy.
GCA requires higher doses of corticosteroids, with an initial dose of 40–60 mg of prednisone daily. Alternate-day
corticosteroid dosing to reduce the risk of adverse effects is not recommended, as it is associated with a higher
23 , 24
relapse rate. Although the infusion of large doses of methylprednisolone ( 1000 mg daily for 3 days) has
been used for the treatment of patients with impending visual loss, there is no evidence that this approach is more
25 19
effective than oral prednisone. The chances of vision loss are reduced by prompt diagnosis and treatment but
once vision loss occurs, corticosteroids will not usually reverse it. Most patients require 1–2 years of therapy,
26 , 27
although 30–50% will experience exacerbations over this period. Some patients require corticosteroids for 5–
27 , 28 29
10 years or indefinitely.
Prevention of Corticosteroid Toxicity
Since corticosteroids are associated with significant side effects, the lowest dose of corticosteroid needed to control
symptoms should be used for the shortest period of time possible in order to minimize toxicity. Treatment with
prednisone doses greater than 7.5 mg daily for more than 3 months has been associated with significant bone loss.
Bisphosphonates prevent the bone loss associated with corticosteroid use and should be prescribed in patients
30
with PMR or GCA commencing corticosteroid therapy (see Musculoskeletal Disorders: Osteoporosis). Weight-
bearing exercise, calcium (total of 1200 mg daily from diet and supplements) and vitamin D ( 800–2000 IU daily)
also reduce the risk of osteoporosis and should be prescribed in conjunction with bisphosphonates.
Immunosuppressives and Biologic Response Modifiers
Methotrexate and azathioprine have been used in the treatment of PMR and GCA primarily to minimize
corticosteroid exposure. However, studies have yielded conflicting results.31 , 32 , 33 , 34 , 35 Two out of 3 placebo-
controlled studies33 , 34 , 35 of methotrexate did not detect a statistically significant benefit in patients with GCA.
However, a meta-analysis of the data from the same 3 studies found that adjunctive therapy with methotrexate
lowered the risk of relapse and reduced exposure to corticosteroids.36 Only 1 placebo-controlled study of
37
methotrexate has shown benefit in patients with PMR. These drugs should be considered only in those patients
with significant corticosteroid toxicity, those unable to wean below 7.5 mg of prednisone daily and/or in patients
with frequent relapses.
The initial studies of anticytokine therapies such as infliximab 38 and etanercept 39 , 40 in steroid-resistant cases
provided encouraging results. However, controlled studies of infliximab did not confirm benefit in the treatment of
either PMR or GCA.41 , 42 A recent small controlled study of 17 patients suggested that the addition of etanercept in
43
the treatment of patients with GCA resulted in lower cumulative doses of corticosteroids. Consult a rheumatologist
for initiation of an immunosuppressive or anticytokine agent.
Therapeutic Tips
Prompt diagnosis and initiation of corticosteroid therapy is critical for the prevention of vision loss in patients
with giant-cell arteritis. Treatment should not be delayed while awaiting a temporal artery biopsy which can still
be positive up to 4 weeks after the initiation of corticosteroid therapy.
Two retrospective studies have suggested that use of low-dose ASA (81 mg/day) may lower the
44,45
risk of developing blindness in patients following the diagnosis of temporal arteritis.
Cytoprotection with a proton pump inhibitor or misoprostol should be considered during
concomitant therapy with prednisone and ASA to reduce the risk of gastrointestinal toxicity.46
Useful Info?
Patients may report a transient increase in musculoskeletal symptoms after each corticosteroid dose reduction.
These symptoms usually subside spontaneously over the ensuing week and do not necessarily represent a
disease flare.
Page 817
Therapeutic Choice
The ESR and CRP usually parallel disease activity in patients with PMR and GCA. These tests can be used to
confirm the clinical suspicion of a disease flare but should not be used in isolation to make treatment decisions.
Reduction in shoulder range of motion may occur in some patients with PMR due to a localized rotator cuff
tendonitis or capsulitis. This is more likely to occur when there has been a delay in diagnosis and initiation of
therapy. A local corticosteroid injection (e.g., methylprednisolone acetate, triamcinolone hexacetonide) of
the subacromial bursa or glenohumeral joint is often helpful.
Figure 1- Diagnostic Approach in Patients with Suspected Polymyalgia Rheumatica (PMR) and Giant-
Cell Arteritis (GCA)
Abbreviations: CBC = complete blood count; CPK = creatine phosphokinase; CRP = C-reactive protein; ESR = erythrocyte
sedimentation rate
Table 2: Drug Therapy of Polymyalgia Rheumatica and Giant-Cell Arteritis
a
Adverse Drug Cost
Corticosteroids prednisone PMR: 15 mg Acne, glucose Barbiturates, Avoid alternate-day $

generics daily × 2 wk. intolerance, phenytoin and corticosteroid dosing as it
Taper as weight gain, rifampin ↓ is associated with a higher
follows: 12.5 mood swings corticosteroid 23 , 24
rate of relapse.
mg daily × 2 and agitation, effect. Ensure regular clinical
wk, 10 mg cataracts, assessments to look for
daily × 4 wk, myopathy, recurrence of the original
then hypertension, symptoms while
decrease osteoporosis, concurrently checking CBC,
daily aseptic necrosis ESR and CRP during the
prednisone of large joints, prednisone taper. An
dose by 1 adrenal isolated rise in ESR or CRP
Page 818
Therapeutic Choice
Adverse Drug Costa

mg/mo until suppression, is usually not sufficient
completion increased justification to increase the
GCA: 40–60 susceptibility to dose of corticosteroids. If a
mg daily × 4 infection. disease flare does occur,
wk. Taper as increase the dose of
follows: prednisone to the lowest
decrease level that was previously
dose by 5 effective in controlling the
mg/wk until disease. Maintain at that
the dose is level for 1 mo, then taper
10 mg daily. as before.
Then taper
more Immunosuppressive agents
gradually by may be required in some
1 mg/mo cases.
until
completion
a.
Legend: $ < $ 10
Abbreviations: CBC=complete blood count; CRP=C-reactive protein; ESR=erythrocyte sedimentation rate; GCA=giant-cell
arteritis; PMR=polymyalgia rheumatica
Suggested Readings
Cantini F, Niccoli L, Nannini C et al. Diagnosis and treatment of giant cell arteritis. Drugs Aging 2008;25(4):281-97.
Dasgupta B, Borg FA, Hassan N et al. BSR and BHPR guidelines for the management of giant cell arteritis.
Dasgupta B, Borg FA, Hassan N et al. BSR and BHPR guidelines for the management of polymyalgia rheumatica.
Hernandez-Rodrıguez J, Cid MC, Lopez-Soto A et al. Treatment of polymyalgia rheumatica: a systematic review.
Arch Intern Med 2009;169(20):1839-50.
Salvarani C, Cantini F, Hunder GG. Polymyalgia rheumatica and giant-cell arteritis. Lancet 2008;372(9634):234-45.
References
1. Gonzalez-Gay MA, Vazquez-Rodriguez TR, Lopez-Diaz MJ et al. Epidemiology of giant cell arteritis and
polymyalgia rheumatica. Arthritis Rheum 2009;61(10):1454-61.
2. Salvarani C, Gabriel SE, O'Fallon WM et al. Epidemiology of polymyalgia rheumatica in Olmsted County,
Minnesota, 1970-1991. Arthritis Rheum 1995;38(3):369-73.
3. Salvarani C, Gabriel SE, O'Fallon WM et al. The incidence of giant cell arteritis in Olmsted County, Minnesota:
apparent fluctuations in a cyclic pattern. Ann Intern Med 1995;123(3):192-4.
4. Franzen P, Sutinen S, von Knorring J. Giant cell arteritis and polymyalgia rheumatica in a region of Finland:
an epidemiologic, clinical and pathologic study, 1984-1988. J Rheumatol 1992;19(2):273-6.
5. Myklebust G, Wilsgaard T, Jacobsen BK et al. No increased frequency of malignant neoplasms in polymyalgia
rheumatica and temporal arteritis. A prospective longitudinal study of 398 cases and matched population
controls. J Rheumatol 2002;29(10):2143-7.
6. Kermani TA, Schafer VS, Crowson CS et al. Malignancy risk in patients with giant cell arteritis: a population-
based cohort study. Arthritis Care Res (Hoboken) 2010;62(2):149-54.
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7. Salvarani C, Cantini F, Boiardi L et al. Polymyalgia rheumatica and giant-cell arteritis. N Engl J Med 2002;347
(4):261-71.
8. Weyand CM, Goronzy JJ. Giant-cell arteritis and polymyalgia rheumatica. Ann Intern Med 2003;139(6):505-
15.
9. Schmidt WA, Moll A, Seifert A et al. Prognosis of large-vessel giant cell arteritis. Rheumatology (Oxford)
2008;47(9):1406-8.
10. Evans JM, O'Fallon WM, Hunder GG. Increased incidence of aortic aneurysm and dissection in giant cell
(temporal) arteritis. A population-based study. Ann Intern Med 1995;122(7):502-7.
11. Oide T, Ohara S, Oguchi K et al. Remitting seronegative symmetrical synovitis with pitting edema (RS3PE)
syndrome in Nagano, Japan: clinical, radiological, and cytokine studies of 13 patients. Clin Exp Rheumatol
2004;22(1):91-8.
12. Queiro R. RS3PE syndrome: a clinical and immunogenetical study. Rheumatol Int 2004;24(2):103-5.
13. Cantini F, Salvarani C, Olivieri I et al. Erythrocyte sedimentation rate and C-reactive protein in the evaluation
of disease activity and severity in polymyalgia rheumatica: a prospective follow-up study. Semin Arthritis
Rheum 2000;30(1):17-24.
14. Salvarani C, Hunder GG. Giant cell arteritis with low erythrocyte sedimentation rate: frequency of occurrence
in a population-based study. Arthritis Rheum 2001;45(2):140-5.
15. Hall S, Persellin S, Lie JT et al. The therapeutic impact of temporal artery biopsy. Lancet 1983;2(8361):1217-
20.
16. Klein RG, Campbell RJ, Hunder GG et al. Skip lesions in temporal arteritis. Mayo Clin Proc 1976;51(8):504-10.
17. Gonzalez-Gay MA, Garcia-Porrua C, Llorca J et al. Biopsy-negative giant cell arteritis: clinical spectrum and
predictive factors for positive temporal artery biopsy. Semin Arthritis Rheum 2001;30(4):249-56.
18. Hedges TR, Gieger GL, Albert DM. The clinical value of negative temporal artery biopsy specimens. Arch
Ophthalmol 1983;101(8):1251-4.
19. Nordborg E, Nordborg C. Giant cell arteritis: strategies in diagnosis and treatment. Curr Opin Rheumatol
2004;16(1):25-30.
20. Breuer GS, Nesher G, Nesher R. Rate of discordant findings in bilateral temporal artery biopsy to diagnose
giant cell arteritis. J Rheumatol 2009;36(4):794-6.
21. Achkar AA, Lie JT, Hunder GG et al. How does previous corticosteroid treatment affect the biopsy findings in
giant cell (temporal) arteritis? Ann Intern Med 1994;120(12):987-92.
22. Ray-Chaudhuri N, Kine DA, Tijani SO et al. Effect of prior steroid treatment on temporal artery biopsy findings
in giant cell arteritis. Br J Ophthalmol 2002;86(5):530-2.
23. Bengtsson BA, Malmvall BE. An alternate-day corticosteroid regimen in maintenance therapy of giant cell
arteritis. Acta Med Scand 1981;209(5):347-50.
24. Hunder GG, Sheps SG, Allen GL et al. Daily and alternate-day corticosteroid regimens in treatment of giant
cell arteritis: comparison in a prospective study. Ann Intern Med 1975;82(5):613-8.
25. Hayreh SS, Zimmerman B. Management of giant cell arteritis. Our 27-year clinical study: new light on old
controversies. Ophthalmologica 2003;217(4):239-59.
26. Salvarani C, Macchioni PL, Tartoni PL et al. Polymyalgia rheumatica and giant cell arteritis: a 5-year
epidemiologic and clinical study in Reggio Emilia, Italy. Clin Exp Rheumatol 1987;5(3):205-15.
27. Andersson R, Malmvall BE, Bengtsson BA. Long-term corticosteroid treatment in giant cell arteritis. Acta Med
Scand 1986;220(5):465-9.
28. Bengtsson BA, Malmvall BE. Prognosis of giant cell arteritis including temporal arteritis and polymyalgia
rheumatica. A follow-up study on ninety patients treated with corticosteroids. Acta Med Scand 1981;209
(5):337-45.
29. Gonzalez-Gay MA, Blanco R, Rodriguez-Valverde V et al. Permanent visual loss and cerebrovascular accidents
in giant cell arteritis: predictors and response to treatment. Arthritis Rheum 1998;41(8):1497-504.
30. Recommendations for the prevention and treatment of glucocorticoid-induced osteoporosis: 2001 update.
American College of Rheumatology Ad Hoc Committee on Glucocorticoid-Induced Osteoporosis. Arthritis
Rheum 2001;44(7):1496-503.
31. De Silva M, Hazleman BL. Azathioprine in giant cell arteritis/polymyalgia rheumatica: a double-blind study.
Ann Rheum Dis 1986;45(2):136-8.
32. Ferraccioli G, Salaffi F, De Vita S et al. Methotrexate in polymyalgia rheumatica: preliminary results of an
open, randomized study. J Rheumatol 1996;23(4):624-8.
33. Hoffman GS, Cid MC, Hellmann DB et al. A multicenter, randomized, double-blind, placebo-controlled trial of
adjuvant methotrexate treatment for giant cell arteritis. Arthritis Rheum 2002;46(5):1309-18.
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34. Spiera RF, Mitnick HJ, Kupersmith M et al. A prospective, double-blind, randomized, placebo controlled trial of
methotrexate in the treatment of giant cell arteritis (GCA). Clin Exp Rheumatol 2001;19(5):495-501.
35. Jover JA, Hernandez-Garcia C, Morado IC et al. Combined treatment of giant-cell arteritis with methotrexate
and prednisone. a randomized, double-blind, placebo-controlled trial. Ann Intern Med 2001;134(2):106-14.
36. Mahr AD, Jover JA, Spiera RF et al. Adjunctive methotrexate for treatment of giant cell arteritis: an individual
patient data meta-analysis. Arthritis Rheum 2007;56(8):2789-97.
37. Caporali R, Cimmino MA, Ferraccioli G et al. Prednisone plus methotrexate for polymyalgia rheumatica: a
randomized, double-blind, placebo-controlled trial. Ann Intern Med 2004;141(7):493-500.
38. Salvarani C, Cantini F, Niccoli L et al. Treatment of refractory polymyalgia rheumatica with infliximab: a pilot
study. J Rheumatol 2003;30(4):760-3.
39. Tan AL, Holdsworth J, Pease C et al. Successful treatment of resistant giant cell arteritis with etanercept. Ann
Rheum Dis 2003;62(4):373-4.
40. Catanoso MG, Macchioni P, Boiardi L et al. Treatment of refractory polymyalgia rheumatica with etanercept: an
open pilot study. Arthritis Rheum 2007;57(8):1514-9.
41. Salvarani C, Macchioni P, Manzini C et al. Infliximab plus prednisone or placebo plus prednisone for the initial
treatment of polymyalgia rheumatica: a randomized trial. Ann Intern Med 2007;146(9):631-9.
42. Hoffman GS, Cid MC, Rendt-Zagar KE et al. Infliximab for maintenance of glucocorticosteroid-induced
remission of giant cell arteritis: a randomized trial. Ann Intern Med 2007;146(9):621-30.
43. Martínez-Taboada VM, Rodríguez-Valverde V, Carreno L et al. A double-blind placebo controlled trial of
etanercept in patients with giant cell arteritis and corticosteroid side effects. Ann Rheum Dis 2008;67(5):625-
30.
44. Nesher G, Berkun Y, Mates M et al. Low-dose aspirin and prevention of cranial ischemic complications in giant
cell arteritis. Arthritis Rheum 2004;50(4):1332-7.
45. Lee MS, Smith SD, Galor A et al. Antiplatelet and anticoagulant therapy in patients with giant cell arteritis.
Arthritis Rheum 2006;54(10):3306-9.
46. Lanza FL, Chan FK, Quigley EM et al. Guidelines for prevention of NSAID-related ulcer complications. Am J
Gastroenterol 2009;104(3):728-38.
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e-Therapeutics+ : Therapeutics : Musculoskeletal Disorders: Rheumatoid Arthritis Page 1 of 9
Therapeutic Choice
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Musculoskeletal Disorders: Rheumatoid Arthritis

Vivian P. Bykerk, MD, FRCPC
Rheumatoid arthritis (RA) is a systemic autoimmune disease manifesting primarily as a symmetric and erosive polyarthritis. It can cause pain, stiffness
and fatigue as well as joint destruction resulting in disability and premature mortality and can be associated with systemic manifestations including most
internal organs. The incidence is .05% per year and prevalence is 1% of the adult population. Onset can occur at any age, including childhood, but most
frequently starts at age 40–50. It affects women 3 times more frequently than men.
Erosions will be seen at the first visit in 20% of patients and will be present in up to 70% of patients at 1 year if left untreated.1 Rheumatologists
1
recommend an early optimal approach to management.
Goals of Therapy
To fully control signs and symptoms of the disease and to halt radiographic progression. All patients should reach a low disease activity state at
minimum, aiming for remission. Treatment should:
alleviate pain, stiffness and fatigue
prevent any/further joint damage and destruction
maintain function and maximize quality of life
Table 1: Evaluation of Disease Activity and Damage
Subjective
Degree of joint pain (scored /10 on ascending pain scale)
Duration of morning stiffness (in minutes or hours)
Duration of fatigue (scored /10 on ascending fatigue scale)
Limitation of function
Determine the number of actively inflamed joints
Mechanical joint problems: loss of motion, crepitus, instability, malalignment and/or deformity
Extra-articular manifestations including dry eyes, nodules, pulmonary findings
Laboratory
Erythrocyte sedimentation rate/C-reactive protein level: monitor every 1–2 months
Rheumatoid factor-titre: at baseline
Complete blood cell count: monitor during most therapies every 1–3 months
Creatinine level: monitor at least twice per year
Urinalysis at baseline and during an annual visit
Synovial fluid analysis if available: at baseline to exclude other conditions or sepsis
Other
Fatigue, pain and extent of morning stiffness at each visit
Physician and patient global assessment of disease activity at each visit
Imaging
Radiographs of hands and feet and selected involved joints annually and as indicated
Consider joint ultrasound or, if available, MRI to identify subclinical erosions if radiographs normal in the first year
Guidelines for the management of rheumatoid arthritis: 2002 update. American College of Rheumatology Subcommittee on Rheumatoid Arthritis Guidelines. Arthritis
Rheum 2002. Reprinted by permission of Wiley-Liss, Inc., a subsidiary of John Wiley & Sons Inc.
Therapeutic Choices (Figure 1 - Management of Rheumatoid Arthritis)
RA is best treated through a multidisciplinary team approach that provides patient education, emotional and psychological support and physical
rehabilitation. Advise patients regarding energy conservation, appropriate levels of activity and work roles, types of exercise, methods of pain modulation
with heat and cold applications,2 adjustments to activities of daily living and maintenance of joint range of motion and muscle strength. Recent studies
show improvement in functional ability with dynamic exercise training, which increases aerobic capacity and muscle strength without increasing disease
activity.3 Periodically evaluate patients for splints, foot orthoses, proper footwear and surgery.
Disease-Modifying Antirheumatic Drugs (DMARDs), Nonbiologic (Table 2)
Page 822
Therapeutic Choice
The diagnosis of RA should be confirmed by a rheumatologist who will start the patient on nonbiologic DMARD therapy within 2–4 weeks of disease
onset.4 Reassess patients every 3–4 months until their RA is in remission, then reduce to every 6–12 months. Adjust treatment if the patient presents
with repetitive flares, ongoing disease activity after 3 months of maximum therapy, progressive joint damage or evidence of drug toxicity.
Severity of illness, prognostic factors,5 presence of extra-articular features and comorbid conditions, potential adverse events, dosing intervals, routes of
administration, monitoring requirements, patient preferences and costs must all be considered before selecting an initial therapy. Most nonbiologic
DMARDs reach maximum effect in 3–6 months.
Frequently Used Nonbiologic DMARDs
Methotrexate (MTX) is the reference DMARD and is an anchor drug in the treatment of RA.6 An adequate trial of MTX consists of a
weekly dose of 20–25 mg (orally or parenterally) for at least 3 months. Useful Info? The minor side effects of MTX can be reduced by concurrent
use of folic or folinic acid.7
Monotherapy with hydroxychloroquine (HCQ) or sulfasalazine (SSZ) is sometimes used for early, very mild disease defined as < 2 swollen joints in
a setting of a negative or low titre rheumatoid factor (RF), normal ESR and CRP and absence of radiographic erosions in the hands or feet. Initial
combination of MTX with hydroxychloroquine and/or sulfasalazine is also recommended early for moderate to severe disease (swollen joint count ≥ 3
joints).
There is evidence of efficacy using combination therapy with MTX, HCQ and SSZ (“triple therapy”)8 or MTX with gold salts,9 leflunomide,10
azathioprine 11 or cyclosporine.12
At times rheumatologists recommend adding the DMARD leflunomide to MTX. They prefer not to discontinue MTX due to a significant risk of disease
flare when MTX is discontinued even if the patient is an incomplete responder to MTX. Leflunomide can be used in place of MTX for patients who have
contraindications to MTX. The loading dose of leflunomide often causes significant diarrhea and is thus no longer recommended. There have been
13
concerns that leflunomide may be associated with an increased risk of serious adverse events, including acute liver failure, when compared to MTX.
14
However, the FDA concluded that there is presently insufficient evidence of an increase in the risk of life-threatening events with leflunomide.
Less Frequently Used Nonbiologic DMARDs
Oral and parenteral gold, D-penicillamine, azathioprine and cyclosporine are now used less frequently and mostly in combination with other
DMARDs. They are used in patients who have failed MTX and who do not have access to biologic response modifiers.
Biologic Response Modifiers (Biologic DMARDs) (Table 3)
Biologic response modifiers target key mediators of inflammatory synovitis and bone and cartilage destruction, such as tumour necrosis factor-alpha
(TNFα), interleukin-1 (IL-1) and others. These agents improve the signs and symptoms of active RA and reduce the radiologic progression of the
disease.15
16 , 17 , 18 , 19
TNFα antagonists (adalimumab, certolizumab, etanercept, golimumab, infliximab) are most effective when used with methotrexate.
All anti-TNFα agents are thought to have comparable efficacy leading to rapid improvement in signs and symptoms, as well as laboratory parameters of
inflammation, usually within 8–12 weeks. In patients with a partial response, increasing the dose, decreasing the dosing interval (in the case of
infliximab), adding or maximizing the use of MTX or adding other nonbiologic DMARDs may provide additional improvement. All biologic agents can be
added to or substituted for previous nonbiologic DMARDs.
Anti-TNFα agents have all rarely been associated with both serious bacterial and opportunistic infections and reactivation of tuberculosis.20 If there is a
suspicion of latent TB infection, rule out active tuberculosis. Prophylactic treatment with isoniazid is warranted. Long-term safety with respect to
lymphoproliferative and other malignancies continues to be investigated.21 Post-marketing reports indicate a possible increased risk of lymphomas and
22
other malignancies in children and adolescents treated with TNFα inhibitors. Combination therapy with two biologic response modifiers is
contraindicated due to increased risk of serious infections and malignancy.23 The risk of malignancy with the use of TNFα antagonists remains low.24
Infliximab, a chimeric mouse-human monoclonal antibody to TNFα, is approved only in combination with MTX in order to reduce the immune reaction to
the murine component. In the case of inadequate response to infliximab, methotrexate doses should be maximized. If this is ineffective, infliximab should
be increased to 3–5 mg/kg every 6–8 weeks.
25 26
Etanercept monotherapy is effective in early RA; it is more effective when given with MTX in preventing radiographic damage. Etanercept can be
given subcutaneously 25 mg twice weekly25 or 50 mg once weekly.27
Adalimumab, certolizumab and golimumab also improve symptoms in patients with moderate to severe RA who are unresponsive to nonbiologic
DMARD therapy alone.28 , 29 , 30 Golimumab has also been shown to be effective in patients who have failed therapy with other TNFα inhibitors.29 , 30
Anakinra blocks the IL-1 receptor. It is indicated in patients who are not candidates for an anti-TNFα agent or who have failed this therapy. It is
associated with up to 70% chance of developing injection site reactions which are amnestic but usually resolve within a month. It may provide less
symptomatic relief than the anti-TNFα agents. It is effective in reducing radiographic damage. Anakinra appears to be associated with fewer significant
infections compared to the anti-TNFα agents.
Abatacept is a fusion protein which includes a natural inhibitor of T cell costimulation called CTLA4. This can bind to a receptor on T cells to block T cell
interaction with other antigen-presenting cells. It is used in patients who have had an inadequate response to one or more nonbiologic DMARDs and/or to
anti-TNFα agents.
Rituximab is a chimeric monoclonal antibody which effectively removes B cells, but not plasma cells, from the circulation of patients with RA. It is used
with MTX in patients who have failed or are intolerant of therapy with an anti-TNFα agent.
Tocilizumab, an interleukin-6 (IL-6) inhibitor, is a new option for patients with moderate to severe disease who do not respond to nonbiologic DMARDs
and TNFα inhibitors.
Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)
Page 823
Therapeutic Choice
Traditional NSAIDs (See Musculoskeletal Disorders: Osteoarthritis, Table 2) are believed to be effective via their inhibition of COX-2. Some adverse
reactions of NSAIDs, including gastrointestinal effects, may result from their inhibition of COX-1, whereas an increased risk of cardiovascular adverse
events may be linked to the inhibition of COX-2. COX-2 inhibitors were specifically designed to access only the COX-2 enzyme. Their efficacy is similar to
nonselective NSAIDs. Patients with heart disease should be on concurrent low-dose ASA, with appropriate gastroprotection if they are at risk of peptic
ulcer disease.31
Glucocorticoids
32 33
Glucocorticoids rapidly reduce inflammation. Chronic low doses of prednisone ≤ 10 mg/day may have disease-modifying properties. Prednisone is
the preferred oral preparation because of its moderate glucocorticoid potency, intermediate duration of action and low mineralocorticoid potency. Depot
preparations are used as bridging therapy.34 Triamcinolone is preferred for deep intra-articular injections because of low systemic absorption and long
action. Depot preparations of steroids may cause atrophy after infiltration of superficial subcutaneous soft tissues, thus methylprednisolone acetate is
recommended for small joints and tendon sheaths.
Glucocorticoids are associated with a number of serious side effects including metabolic abnormalities (e.g., hyperglycemia, hypertension, muscle
atrophy, truncal obesity), adrenal suppression, cataracts, infections and avascular necrosis. In combination with NSAIDs, glucocorticoids increase the risk
of peptic ulcer disease. Moreover, glucocorticoids will further aggravate osteoporosis and cardiovascular disease, conditions independently associated
with RA. Patients on prolonged steroid therapy should be on calcium 1500 mg/day and vitamin D 800 IU/day supplementation and an antiresorptive
agent (e.g., etidronate 400 mg daily for 2 weeks every 3 months, alendronate 5–10 mg daily or 70 mg weekly or risedronate 5 mg daily or 35 mg
weekly) to prevent the bone loss associated with corticosteroid use.35 They should also be considered for prophylactic gastroprotective therapy and
antiplatelet therapy with low-dose ASA.
Analgesia
36
RA is increasingly recognized as a chronic pain syndrome. Many adjunctive medications and alternative therapies are being used. Although controlled
trials supporting their effectiveness in RA are not available, some are compatible with the medications used to treat RA and have fewer serious side
effects than NSAIDs. Avoid propoxyphene, meperidine and pentazocine because of lack of proven efficacy, risk of accumulation and serious toxicity with
prolonged use. Also, up to 10% of the population lacks the enzyme that converts codeine to morphine. Failure to respond to codeine warrants a trial with
hydromorphone or morphine, preparations that do not require metabolic activation.
RA Treatment During Pregnancy37
Pregnancy itself has a favourable influence on disease activity. Medications can often be reduced or discontinued during pregnancy.
Glucocorticoids remain the safest therapy during pregnancy and lactation. They pose a small risk of orofacial clefts when used in the first trimester,
however, benefits often appear to outweigh risks.38
Data relating to the use of hydroxychloroquine in pregnancy is scarce. Existing data do not indicate that the drug poses significant fetal risk.38
Despite concerns regarding a potential risk of kernicterus, sulfasalazine has been used in pregnancy with relative safety.38 Because sulfasalazine is
a folic acid antagonist, folic acid supplementation should be ensured in women of reproductive age. It is still recommended to monitor for
hyperbilirubinemia in fetuses exposed to sulfasalazine close to term. Continue other DMARDs when potential benefits outweigh risks.
NSAIDs rarely pose risks in the first and second trimesters but their use in the last month of pregnancy may be of concern. Because of
antiprostaglandin effects, NSAIDs can increase risks of fetal and maternal bleeding, premature closure of the ductus arteriosus and also interfere with
labour onset or duration.
Antifolate metabolic effects of MTX may cause open neural tube defects and other CNS abnormalities, facial anomalies, growth retardation as well as
other problems. It is contraindicated in pregnancy. Women of childbearing age should use reliable contraception while taking MTX. The drug should
be stopped in both males and females at least 3 months before attempting conception. MTX also has abortifacient properties.38
Leflunomide is known to be teratogenic and is contraindicated in pregnancy. Some experts consider it prudent to avoid the use of leflunomide in
women of child-bearing potential. Women who wish to become pregnant or men who wish to father a child after taking leflunomide are advised to
undergo a drug elimination protocol consisting of cholestyramine 8 g 3 times daily for 11 days, or activated charcoal 50 g 4 times daily for 11 days
39
(not necessarily on consecutive days). Plasma concentration of leflunomide’s active metabolite is then measured on 2 separate occasions at least 2
weeks apart to confirm levels below 0.02 mg/L.39 , 40 Many laboratories do not perform this test; some manufacturers provide free measurement of
these levels via an outside laboratory upon direct request from the physician. Following the second plasma level confirmation, an additional waiting
39 40
period of 3 months before conception is recommended in men, and some experts suggest a waiting period of 1–3 menstrual cycles in women.
Without the drug elimination protocol, it could take up to 2 years for plasma levels to drop to below 0.02 mg/L, due to interindividual variation in
39 , 40
drug clearance. In the case of unplanned pregnancy or any delay of menses or other suspicion of pregnancy while taking leflunomide, women
should contact their physician immediately; rapid institution of the drug elimination protocol (outlined above) could reduce the risk to the fetus.38 ,
39
A number of registries have documented outcomes of patients who became pregnant while receiving biologic response modifiers and to date there
41
has been no reported increase in adverse outcomes. However, there are currently insufficient data to recommend the use of any biologic response
modifiers in pregnancy or during lactation.
The anti-TNFα agents are not associated with teratogenicity in animal studies. Although there are no studies in humans, it is recommended these be
discontinued if possible during pregnancy. Safety in lactation is unknown.
Therapeutic Tips
Referral to a rheumatologist and prompt institution of therapy is essential. Early, aggressive treatment is linked to a positive outcome in RA.
Comorbidities, including infections, cardiovascular disease,42 lymphoma43 and osteoporosis are common in RA patients. Routine care should include
prevention and treatment of these conditions.
Only 30% of patients have a positive RF at initial presentation. A negative RF does not exclude the possibility of rheumatoid arthritis.
Figure 1- Management of Rheumatoid Arthritis
Page 824
Therapeutic Choice
Abbreviations: CBC = complete blood count; DMARD = disease-modifying antirheumatic drug; ESR = erythrocyte sedimentation rate; HCQ = hydroxychloroquine; MCP =
metacarpal phalangeal; MTP = metatarsal phalangeal;
MTX = methotrexate; TNFα = tumour necrosis factor-alpha
Table 2: Nonbiologic Disease-Modifying Antirheumatic Drugs for Rheumatoid Arthritis
Cost
Class Drug Dose Adverse Effects Monitoring44 Drug Interactions
a
Cytotoxic Agents methotrexate Initial: Nausea, malaise, flu Baseline Alcohol restriction may Oral:
Methotrexate 7.5–15 mg po, sc or im -like aches, hepatitis B and minimize hepatotoxicity. $
Q wk, increase by headache, oral C serology and NSAIDs or ASA may ↑ MTX serum sc/im:
Tablets USP,
2.5–5 mg Q 1–4 wk ulcers, transient chest x-ray; concentrations minimally but $$-
Metoject, generics Maintenance: loose stools; rarely: CBC, LFTs, this is not clinically significant; $$$
7.5–25 mg po, sc or im bone marrow and albumin, these can be combined at low
Q wk (single dose if liver toxicity, creatinine every doses.
tolerated, or divided in 2 pneumonitis, mo × 6 mo
doses Q12H) immunosuppression, then every 2 Penicillins (e.g., amoxicillin,
For doses > 15 mg sc, malignancy. mo thereafter. cloxacillin, piperacillin) and
divided dose better Not to be used in sulfonamides (e.g.,
absorbed patients with trimethoprim/sulfamethoxazole)
hepatitis B or C, may ↓ MTX clearance.
renal insufficiency or
lung disease.
Antimalarial Agents hydroxychloroquine Initial: 400–600 mg daily Nausea, cramps, Ophthalmologic Avoid concomitant use of $
Plaquenil, generics diarrhea, rash, exam related drugs such as quinine.
Maintenance: 200–400 nightmares, Q12–18 mo
mg daily. Reduce dose if hyperpigmentation.
< 60 kg Rarely, if dosed too
high for too long,
corneal and retinal
deposition can
occur.
Page 825
Therapeutic Choice
Cost
Class Drug Dose Adverse Effects Monitoring44 Drug Interactions
a
Sulfonamides sulfasalazine Initial: Rash, marrow CBC, LFTs Sulfasalazine may ↓ $-$$
Salazopyrin, 500 mg po daily or BID, toxicity, every 3 mo. gastrointestinal absorption of
generics increase gastrointestinal digoxin.
500 mg Q wk to a intolerance. May
maintenance dose of cause sun
2–3 g po daily (divided in sensitivity. Do not
2 doses) use if sulfa allergy
or G6PD deficiency.
Immunomodulators leflunomide 10–20 mg po daily Nausea, diarrhea, Baseline Avoid alcohol because of $$$$
Arava, generics anorexia, alopecia, hepatitis B and possible ↑ risk of hepatotoxicity.
hypertension, rash. C serology; Pregnancy is contraindicated while
May cause hepatic CBC, LFTs, taking this medication. Washout
toxicity, cytopenias, creatinine Q2–8 procedure with cholestyramine 8
profound anorexia wk, LFTs Q mo g TID for 11 days recommended
and weight loss, if also on MTX. for serious toxicity or
pulmonary fibrosis, imminently planned pregnancy
interstitial lung (see RA Treatment During
disease. Pregnancy ).
Immunosuppressants azathioprine Initial: Hepatitis, drug CBC, LFTs Allopurinol may ↑ azathioprine $
Imuran, generics 50 mg po daily, increase fever, every 1–3 mo. toxicity; dosage adjustment may
by myelosuppression, be necessary (1/4 of regular
25–50 mg Q1–2 wk (dose immunosuppression, dose).
2–2.5 mg/kg/day) unconfirmed risk of
Maintenance: malignancy.
50–150 mg (divided in 1–
3 doses)
Immunosuppressants cyclosporine Initial: 2.5 mg/kg/day, Renal toxicity, Blood pressure Metabolized by cytochrome $$$$
Neoral, generics divided in 2 doses, hypertension, every mo, P450 — many possible drug
increase every 1–2 wk hypertrichosis, periodic CBC, interactions (e.g., grapefruit,
Maintenance: cytopenia, gum LFTs, erythromycin, ketoconazole,
2.5–5 mg/kg/day (divided hyperplasia. electrolytes and rifampin).
in 2 doses) drug blood
levels.
Cytotoxic Agents minocycline 100 mg po BID Hyperpigmentation, None. GI absorption impaired by iron, $$$
Minocin, generics autoimmune bismuth, aluminum and
diseases. magnesium in drugs and foods.
Separate doses by 2 h.
Heavy Metal penicillamine Initial: 125–250 mg po Proteinuria, CBC, urine Food: Since the effectiveness of $$$$
Antagonists Cuprimine daily, increase by cytopenia, dipstick Q1–2 penicillamine may be ↓ by food,
125–250 mg Q 1–3 mo autoimmune mo. administer on an empty stomach at
Maintenance: diseases. least 1 h before or 2 h after
250–750 mg po daily meals and at least 1 h apart
(single dose) from any other drug or milk.
Gold Preparations sodium Initial: 10 mg im 1st wk, Post-dose reactions CBC, dipstick $-$$
(arthralgias, for urinary
aurothiomalate 25 mg 2nd wk, then
Myochrysine, flushing, protein with
50 mg Q wk for 20 wk,
generics hypotension). every 1–2
then reduce to
Stomatitis, pruritic injections. Hold
maintenance.
dermatitis, if pruritus,
Maintenance: 50 mg im
cytopenia, mucosal ulcers,
Q2–6 wk, usually monthly
proteinuria. or > 1+
proteinuria.
a.
Cost of 4-week supply for maintenance dose based on 70 kg body weight; includes drug cost only.
Abbreviations: CBC=complete blood count; G6PD=glucose-6-phosphate dehydrogenase; LFT=liver function test; MTX=methotrexate; NSAID=nonsteroidal anti-
inflammatory drug
Legend: $ < $25 $-$$ < $25–50 $$ $25–50 $$-$$$ $25–75 $$$ $50–75 $$$$ > $75
Table 3: Biologic DMARDs (Biologic Response Modifiers) for Rheumatoid Arthritis
a
Cost
Class Drug Dose Adverse Effects Monitoring44 Contraindications
Tumour adalimumab 40 mg sc every other wk Injection site reactions; History of TB Susceptibility to or presence of $
Necrosis Factor Humira infections (including TB exposure. Baseline serious and/or recurrent
-alpha (TNFα) and opportunistic PPD and chest x-ray infection; consider lupus,
Inhibitors organisms); new-onset to assess for latent demyelinating disease or heart
psoriasis; ↑ risk of TB. failure relative
lymphoma (children and contraindications.
adolescents), leukemia and
other malignancies;
Page 826
Therapeutic Choice
Costa
Class Drug Dose Adverse Effects Monitoring44 Contraindications
autoimmune phenomena.
Tumour certolizumab 400 mg sc at weeks 0, 2 and Injection site reactions; History of TB Susceptibility to or presence of $
Necrosis Factor Cimzia 4, then 200 mg every other infections (including TB exposure. Baseline serious and/or recurrent
-alpha (TNFα) wk. May give 400 mg sc Q 4 and opportunistic PPD and chest x-ray infection; consider lupus,
Inhibitors wk as maintenance dose organisms); new-onset to assess for latent demyelinating disease or heart
adolescents), leukemia
and other malignancies;
Tumour etanercept 25 mg sc twice weekly or Injection site reactions; History of TB Susceptibility to or presence of $
Necrosis Factor Enbrel 50 mg sc once weekly infections (including TB exposure. Baseline serious and/or recurrent
adolescents), leukemia
and other malignancies;
Tumour golimumab 50 mg sc once monthly on Injection site reactions; History of TB Susceptibility to or presence of $
Necrosis Factor Simponi same date each month infections (including TB exposure. Baseline serious and/or recurrent
adolescents), leukemia and
other malignancies;
Tumour infliximab 3–5 mg/kg iv at 0, 2, 6 wk Infusion reactions, History of TB Heart failure if using $$
Necrosis Factor Remicade and Q4–8 wk thereafter infections (including TB exposure. Baseline > 5 mg/kg/infusion,
-alpha (TNFα) Always give with MTX. and opportunistic PPD and chest x-ray demyelinating disease,
Inhibitors organisms), new-onset to assess for latent susceptibility to or presence of
psoriasis, ↑ risk of TB. serious and/or recurrent
lymphoma (children and infection; lupus a relative
adolescents), leukemia contraindication.
and other malignancies,
B Cell rituximab 1 g iv × 2 doses 2 wk apart. Mild to moderate infusion CD19 counts can Susceptibility to infection. $$$$$
Depletors Rituxan Infusions are given with reactions. monitor B cell levels. Contraindicated in patients
100 mg of with known Type I
methylprednisolone; doses hypersensitivity or
can be repeated after 5–6 anaphylactic reactions to
mo. Indicated in patients murine proteins, Chinese
who have failed an anti- Hamster Ovary (CHO) cell
TNFα agent proteins or to any component
of the product.
T Cell abatacept Dosing based on weight: Rare minor infusion No cases of TB Susceptibility to infection. $$$
Costimulation Orencia < 60 kg: 500 mg iv initial reactions. documented to date.
Inhibitors infusion;
60–100 kg: 750 mg iv initial

infusion;
> 100 kg: 1 g iv initial

infusion.
After baseline dosing

administer at 2 wk, 4 wk and
then monthly. Indicated in
nonbiologic DMARD or anti-
TNFα agent failures
Interleukin-1 anakinra 100 mg sc daily Injection site reactions None recommended. Susceptibility to infection. $
(IL-1) Kineret (70%).
Inhibitors
Interleukin-6 tocilizumab 4 mg/kg IV, infused over 1 Infusion reactions, Monitor for Active infection. Screen for $
(IL-6) Actemra h, Q 4 wk; may increase to serious infections, neutropenia, latent/active TB before
Inhibitors 8 mg/kg IV Q 4 wk if gastrointestinal thrombocytopenia and initiating therapy.
response is inadequate perforation, ↓ elevated
neutrophils, ↓ platelets. transaminases 4–8 wk
after starting therapy.
Page 827
Therapeutic Choice
Costa
44
Class Drug Dose Adverse Effects Monitoring Contraindications
May ↑ CYP450 enzyme
activity—monitor
concurrent therapy
with drugs
metabolized by
CYP450.
a.
Cost of 4-week supply based on 70 kg body weight; includes drug cost only.
Abbreviations: CYP450=cytochrome P450; DMARD=disease-modifying antirheumatic drug; MTX=methotrexate; PPD=purified protein

derivative; TB=tuberculosis; TNFα=tumour necrosis factor α
Legend: $ $1000–2000 $$ $2000–4000 $$$ $4000–6000 $$$$ $6000–8000 $$$$$ $8000–10 000
Suggested Readings
American College of Rheumatology Subcommittee on Rheumatoid Arthritis Guidelines. Guidelines for the management of rheumatoid arthritis: 2002
update. Arthritis Rheum 2002;46(2):328-46.
Haraoui B, for the Subcommittee on Biologic Agents, Canadian Rheumatology Association. Position on the use of biologic agents for the treatment of
rheumatoid arthritis. Available from: http://www.rheum.ca/Resources/Pdf/Biologics_for_RA.pdf. Accessed September 10, 2009.
[No authors listed]. Guidelines for monitoring drug therapy in rheumatoid arthritis. American College of Rheumatology Ad Hoc Committee on Clinical
Guidelines. Arthritis Rheum 1996;39(5):723-31.
Scott DL, Kingsley GH. Tumor necrosis factor inhibitors for rheumatoid arthritis. N Engl J Med 2006;355(7):704-12.
Tannenbaum H, Bombardier C, Davis P et al. An evidence-based approach to prescribing nonsteroidal antiinflammatory drugs. Third Canadian Consensus
Conference. J Rheumatol 2006;33(1):140-57.
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41. British Society of Rheumatology. British Society of Rheumatology Biologics Registry; 2007.
42. Gabriel S. Heart disease in rheumatoid arthritis: changing the paradigm of systemic inflammatory disorders. J Rheumatol 2007;34(1):220-3.
43. Baecklund E, Iliadou A, Askling J et al. Association of chronic inflammation, not its treatment, with increased lymphoma risk in rheumatoid arthritis.
Arthritis Rheum 2006;54(3):692-701.
44. American College of Rheumatology Subcommittee on Rheumatoid Arthritis Guidelines. Guidelines for the management of rheumatoid arthritis: 2002
update. Arthritis Rheum 2002;46(2):328-46.
Pharmacoeconomic Considerations: Rheumatoid Arthritis

Epidemiology

1 4 million
Canada (2000)
Projected to be 6 million by 2026
Country and Year of Estimate Indirect Costsa

2 € 7217 per patient-year of lost productivity
Finland (2002)
Commentary
The direct and indirect costs of rheumatoid arthritis (RA) are significant and the disease affects health-related quality of life. Poor functioning is
3 , 4
correlated with high costs.
The main driver for overall costs of RA is lost productivity.3 , 5 , 6 Work disability is the most costly consequence of rheumatoid arthritis.7 , 8 Patients
enrolled in a randomized trial reported taking 17 days of sick leave per year and 3 days of disability leave per year.9 Predictors of work loss in patients
10
with RA include old age disability level, severity of RA and education level.
Page 829
Therapeutic Choice
10 , 11
Nonbiologic disease-modifying antirheumatic drugs (DMARDs) may reduce work disability, however, disease progression still occurs. Biologic
agents are expensive and have significantly increased the cost of care. These agents improve symptoms and slow the radiological progression of
disease, but only limited data are available on long-term outcomes. Several economic analyses, most of which were sponsored by pharmaceutical
12 , 13
manufacturers, have examined the use of biologic agents given after DMARDs. The results of these analyses suggest that the high cost of
13 , 14
biologics is offset by improved functioning in patients with moderate to severe RA.
A comprehensive pharmacoeconomic analysis in the United Kingdom concluded that the most cost-effective approach to using biologic agents is to use
them as last-line therapy in patients who do not have a satisfactory response to methotrexate.15 This review indicated that first-line use of these
agents increased the cost-effectiveness ratio.15 The cost of biologics would be beyond the means of most patients; therefore, it is essential to confirm
insurance coverage before prescribing these agents.
a.
1. Badley EM, Wang PP. The contribution of arthritis and arthritis disability to nonparticipation in the labor force: a Canadian example. J Rheumatol
2001;28(5):1077-82.
2. Puolakka K, Kautiainen H, Pekurinen M et al. Monetary value of lost productivity over a five year follow up in early rheumatoid arthritis estimated
on the basis of official register data on patients' sickness absence and gross income: experience from the FIN-RACo trial. Ann Rheum Dis 2006;65
(7):899-904.
3. Kobelt G, Eberhardt K, Jonsson L et al. Economic consequences of the progression of rheumatoid arthritis in Sweden. Arthritis Rheum 1999;42
(2):347-56.
4. Kobelt G, Jonsson L, Lindgren P et al. Modeling the progression of rheumatoid arthritis: a two-country model to estimate costs and consequences
of rheumatoid arthritis. Arthritis Rheum 2002;46(9):2310-9.
5. McIntosh E. The cost of rheumatoid arthritis. Br J Rheumatol 1996;35(8):781-90.
6. Yelin E, Wanke LA. An assessment of the annual and long-term direct costs of rheumatoid arthritis: the impact of poor function and functional
decline. Arthritis Rheum 1999;42(6):1209-18.
7. Ruof J, Hulsemann JL, Mittendorf T et al. Costs of rheumatoid arthritis in Germany: a micro-costing approach based on healthcare payer's data
sources. Ann Rheum Dis 2003;62(6):544-9.
8. Pugner KM, Scott DI, Holmes JW et al. The costs of rheumatoid arthritis: an international long-term view. Semin Arthritis Rheum 2000;29(5):305-
20.
9. Merkesdal S, Ruof J, Huelsemann JL et al. Indirect cost assessment in patients with rheumatoid arthritis (RA): comparison of data from the health
economic patient questionnaire HEQ-RA and insurance claims data. Arthritis Rheum 2005;53(2):234-40.
10. Puolakka K, Kautiainen H, Mottonen T et al. Predictors of productivity loss in early rheumatoid arthritis: a 5 year follow up study. Ann Rheum Dis
2005;64(1):130-3.
11. Puolakka K, Kautiainen H, Mottonen T et al. Impact of initial aggressive drug treatment with a combination of disease-modifying antirheumatic
drugs on the development of work disability in early rheumatoid arthritis: a five-year randomized followup trial. Arthritis Rheum 2004;50(1):55-
62.
12. Kobelt G, Lindgren P, Singh A et al. Cost effectiveness of etanercept (Enbrel) in combination with methotrexate in the treatment of active
rheumatoid arthritis based on the TEMPO trial. Ann Rheum Dis 2005;64(8):1174-9.
13. Bansback NJ, Brennan A, Ghatnekar O. Cost effectiveness of adalimumab in the treatment of patients with moderate to severe rheumatoid arthritis
in Sweden. Ann Rheum Dis 2005;64(7):995-1002.
14. Kobelt G, Eberhardt K, Geborek P. TNF inhibitors in the treatment of rheumatoid arthritis in clinical practice: costs and outcomes in a follow up
study of patients with RA treated with etanercept or infliximab in southern Sweden. Ann Rheum Dis 2004;63(1):4-10.
15. Chen YF, Jobanputra P, Barton P et al. A systematic review of the effectiveness of adalimumab, etanercept and infliximab for the treatment of
rheumatoid arthritis in adults and an economic evaluation of their cost-effectiveness. Health Technol Assess 2006;10(42):iii-xiii, 1-229.
Page 830
e-Therapeutics+ : Therapeutics : Musculoskeletal Disorders: Sports Injuries Page 1 of 9
Therapeutic Choice
Print Close
Musculoskeletal Disorders: Sports Injuries
Taryn-Lise Taylor, BKin, MSc, MD, CCFP, Dip Sport Med
The majority of sports injuries encountered by physicians involve the soft tissues, including strains, sprains and
contusions.
Goals of Therapy
To reduce acute symptoms (pain, inflammation) and recurrences

To correct contributing factors, e.g., malalignment, muscle weakness
To return the athlete's weight-bearing capability, flexibility, range of motion, strength and proprioception to
normal
To enable the athlete to participate comfortably, safely and fully in all pre-injury activities
Therapeutic Choices
For management of specific injuries, see Table 1.
Acute treatment is best summarized by the RICE protocol:
Rest the injured part.

Ice: Wrap an ice bag, cold pack or package of frozen peas in a damp, thin cloth and apply to the injured area
for 15–20 minutes at a time, at least QID for the first 48 hours (or longer if swelling continues).
Compress with an elastic bandage if there is swelling such as in an ankle sprain.
Elevation: Try to elevate the injured part above the heart.
Initial rehabilitation is directed toward allowing the injured tissues to heal. Aggravation of the injury must be
avoided, but alternative activities should be encouraged (e.g., the runner with a stress fracture of the fibula should
not run but can swim or run in deep water). The next phase is directed toward restoring and improving range of
motion, strength, endurance and proprioception. A progression toward full activity is then undertaken. Before the
patient resumes activity, any factors that may have contributed to the injury (improper shoes, poor protective
equipment) should be corrected, and sport-specific skills regained.
Oral or topical NSAIDs (including COX-2 inhibitors), if not contraindicated, can decrease swelling and discomfort
but should be used for short periods only (for more detailed information on specific drugs, see Neurologic
Disorders: Acute Pain). In the elderly, acetaminophen should be considered for initial and ongoing treatment of
persistent pain, particularly musculoskeletal pain. Elderly patients are more likely to experience adverse drug
reactions; the benefits of NSAID therapy must be weighed against their potential risks (dyspepsia, gastrointestinal
bleeding, renal impairment, blood pressure elevation).
Intra-articular or peritendinous injection of corticosteroids such as triamcinolone acetonide,

methylprednisolone acetate or betamethasone may be useful in treating specific injuries (Management
of Specific Sports Injuries). Such injections are used with some success in current practice. A
systematic review of peritendinous corticosteroid injections suggested that while there is good
evidence of short-term benefit (pain reduction) in treating tendinopathies, the effectiveness of therapy
varied with the injection site and long-term outcomes were not beneficial (higher risk of recurrence).23
Useful Info? See Musculoskeletal Disorders: Osteoarthritis, Table 4 for more information on intra-articular
corticosteroids.
The Society of Obstetricians and Gynaecologists of Canada (SOGC) and the Canadian Society for Exercise Physiology
(CSEP) recommend that, in uncomplicated pregnancies, women with or without a previously sedentary lifestyle
Page 831
Therapeutic Choice
should be encouraged to participate in aerobic and strength-conditioning exercises as part of a healthy lifestyle.24
The American College of Obstetricians and Gynecologists recommends a clinical evaluation of each pregnant woman
before recommending an exercise program, as there are both absolute (e.g., incompetent cervix, multiparity, heart
disease, bleeding) and relative (e.g., intrauterine growth retardation, poorly controlled hypertension or diabetes)
25
contraindications to exercise in pregnancy.
Glycemic control in gestational diabetes is improved by exercise.26 Participation in sports with a high risk of
contact, falling or abdominal trauma should be avoided. Supine positions should be avoided, particularly after the
first trimester, due to the potential for compression of the inferior vena cava by the gravid uterus, and the effect on
25
the maternal cardiac output. An increase in musculoskeletal injury rates during pregnancy has not been shown,
despite increased ligamentous laxity found in pregnancy, thought to be related to estrogen and relaxin. This is likely
due to decreased participation in jumping, pivoting and contact activities in the later stages of pregnancy when this
27
ligamentous laxity is greater.
24
Moderate exercise during lactation does not affect the quantity or composition of breast milk.
The same principles of injury treatment apply to both nonpregnant and pregnant or lactating athletes, with the
following exceptions:
Acetaminophen may be used if analgesia is required (see Neurologic Disorders: Acute Pain). Avoid NSAIDs,
especially in the first and third trimesters of pregnancy.
Shock wave therapy is generally considered contraindicated in pregnant patients.
Injectable corticosteroids may be considered in a pregnant patient if all other nonpharmacologic treatment
options have been used without success. Small amounts of corticosteroid plus lidocaine injections appear to
be safe in breastfeeding mothers but nonpharmacologic options remain the treatment of choice.
Therapeutic Tips
If using transdermal nitroglycerin patches to treat tendinopathy (see Table 1), patients may experience
common nitrate-related side effects such as headache, dizziness and hypotension. Coadministration of nitrates
and PDE5 inhibitors (sildenafil, tadalafil, vardenafil) is contraindicated.
Table 1: Management of Specific Sports Injuries
Injury Investigations Therapeutic Choices
Rotator Cuff Disorders History: Sudden pain if traumatic onset Rest from aggravating activities.
Tendinosis, degenerative tears, (e.g., fall), gradual onset of pain if Ice may help if acute injury.
acute tears (partial or full tendinosis. Discomfort noted with NSAIDs (oral or topical) for acute
thickness), less commonly shoulder movement (can vary with pain.
overuse inflammation (tendinitis) location of injury), especially reaching May need analgesic medication,
of the rotator cuff muscles of the overhead. Often painful at night, difficult e.g., acetaminophen ± either
shoulder. These muscles act as to find comfortable sleep position. codeine or tramadol for nighttime
movers (rotation, initial Weakness if complete or significant pain.
abduction) and stabilizers of the partial tear. Physiotherapy: strengthening of
humeral head in the glenoid. Physical Exam: Wasting may be noted scapular stabilizers, correction of
Often results in subacromial posteriorly over scapula if full thickness impaired scapulohumeral rhythm,
impingement of supraspinatus tear. Pain on active ROM and resisted addressing soft tissue tightness
(cuff muscle) and subacromial tests depending on injury type and followed by rotator cuff
bursa. location. Weakness is present with more strengthening.
significant tear. If subacromial Persistent impingement symptoms
impingement, often get “painful arc” in or bursitis may benefit from
flexion or abduction, pain with Hawkins’ subacromial corticosteroid
test (pain when shoulder placed at 90° injection (e.g., triamcinolone
of flexion and internally rotated) and acetonide 40 mg mixed with 2–
Neer’s test (pain with pronated arm 3 mL lidocaine 1%) followed by
brought into full overhead elevation). 1
resumption of exercise program.
Test for instability. Shock wave therapy by a
Imaging: X-ray if concern of bony injury physiotherapist may be considered,
(acute trauma) or osteoarthritis. 2
especially in calcific tendinopathy.
Page 832
Therapeutic Choice

Ultrasound good at detecting rotator cuff Three randomized clinical trials
tears. have shown that applying a
MRI good at detecting rotator cuff tears nitroglycerin transdermal patch
and other shoulder pathology (usually (¼ of a 0.2 mg/h patch) Q24H for 6
need MRI arthrogram or high field –8 wk directly over the site of injury
strength [3T] MRI if concern of labral enhances subjective and objective
tear). recovery of patients with tennis
Refer if: x-rays show growth plate 3 4
elbow, Achilles tendinosis and
injuries in skeletally immature patients
supraspinatus tendinosis.5
or fracture in patients >50 y.
Consider surgical intervention to
repair cuff if full thickness tear in
younger, active person. If persistent
pain and/or impingement despite
above measures, consider
debridement, acromioplasty, repair.
Lateral Epicondylosis (“Tennis History of pain at the lateral elbow or Rest from aggravating activities;
Elbow”) medial elbow usually due to overuse ice/ice massage; counter-force
Tendinosis of the common and/or faulty mechanics. brace/band.
extensor tendon at its origin at Physical examination: tenderness just NSAIDs (oral or topical) for initial
the lateral epicondyle. distal to the lateral or medial epicondyle, pain and inflammation in first 4 wk
Medial Epicondylosis painful resisted wrist extension and of condition.
(“Golfer's Elbow”) painful grip (lateral epicondylosis), wrist 6
Physiotherapy: acupuncture,
Tendinosis of the common flexion (medial epicondylosis). mobilizations, soft tissue
flexor/pronator tendon at its X-ray rarely required (only if any techniques, stretching.
origin at the medial epicondyle. concern about bony pathology, may Strengthening exercises as
confirm calcific tendinopathy). improvement occurs.
Refer if: neurologic symptoms, loss of Correction of predisposing factors:
ROM in elbow (further evaluation needed in tennis—correct poor technique
to rule out pathologies, e.g., and biomechanics, especially
osteochondritis dissecans of the backhand stroke, correct racquet
capitellum, radial tunnel syndrome, grip size, string tension to
posterior interosseous nerve maximum 50– 55 lb, lighter
compression). racquet, avoid heavy-duty or wet
balls. Suggest consultation with
teaching professional/tennis
instructor.
Work/occupation activities
important (e.g., ergonomic factors).
Gradual return to activity.
If above is unsuccessful, consider
corticosteroid injection (e.g.,
triamcinolone acetonide 20 mg)
to common extensor origin area at
lateral epicondyle or common flexor
origin at medial epicondyle.
Consider applying nitroglycerin
transdermal patch (¼ of a
0.2 mg/h patch) Q24H on elbow for
3
6–8 wk.
Consider referral to primary care
sport medicine physician or
orthopedic surgeon for PRP
autologous blood injection at the
site of the tendinosis; may reduce
7
pain and improve function.
Consider referral to radiologist for
sonographically guided
percutaneous tenotomy (dry
8
needling) at the site of tendinosis.
If still unsuccessful, consider
surgery.
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Therapeutic Choice
Patellofemoral Pain History of anterior knee pain, worse with Relief of acute symptoms: Rest from
Syndrome prolonged flexion/sitting, running, aggravating activities (emphasize
(“Runner's Knee”, stairs. alternative activities); ice, both PRN
chondromalacia patellae) Physical examination: Impairments and post-activity; NSAIDs (oral or
Anterior knee pain resulting from affecting the patellofemoral joint topical) for acute pain.
patellofemoral articulation interface may be a consequence of an Correction of contributing factors:
dysfunction. unbalanced muscle pull (weak VMO), foot overpronation—appropriate
muscle tightness (hamstring or iliotibial stability/motion control shoes with
band), malalignment between the joint good medial arch and support. If
surfaces or excessive knee valgus, i.e., severe, may require custom foot
increased Q-angle. Both pes planus with orthotic.
pronation and pes cavus with supination 9
Physiotherapy: VMO strengthening,
can be predisposing factors. e.g., closed kinetic chain exercises;
Pain with patellar pressure, painful hip abductor and external rotator
quads setting, poor flexibility, medial strengthening. Electrical muscle
quadriceps (VMO) weakness, lateral stimulation and/or biofeedback can
patellar tracking, poor control with assist.
single knee bends, pain with squat and Improve flexibility: quadriceps,
stairs. hamstrings, gastrocnemius, iliotibial
band stretches may help (no firm
X-rays (including skyline view of patella) evidence).
if trauma or bony pathology is a concern Taping techniques to correct patellar
or to assess for patellofemoral arthritis 10
malposition.
or other conditions.
Correction of training errors: in
Refer if: patient develops joint effusion.
runners, more gradual distance
increases, fewer hills. Decrease
jumping, squats; avoid resisted leg
extensions to ≥90° flexion.
Patellar stabilizing brace with
supporting buttress and/or straps
for use with activities.
Surgery (lateral release of tight
retinacula, patellar tendon transfer)
is rarely required and should be a
last resort.
Lower Leg Pain History of diffuse shin pain, usually in Rest from aggravating activities
(“Shin Splints”) inexperienced and/or inadequately (e.g., running/impact). Alternative
(Tibial periostitis, medial tibial stretched or strengthened athletes. activities: cycling, rowing,
stress syndrome) Physical examination: tenderness, swimming, skating/roller blading,
Inflammation of the tibialis usually diffuse, at medial border of tibia pool running.
posterior at its origin or of the and adjacent muscle. Ice/ice massage.
tibial periosteum. NSAIDs (oral or topical) for acute
If localized bony tenderness, rule out pain.
stress fracture. Muscle stretching and
If normal exam at rest, rule out strengthening, dynamic flexibility.
exertional compartment syndrome. Physiotherapy/massage therapy.
X-rays normal; may need bone scan to Lower legs may be taped or
differentiate from stress fracture. neoprene sleeve used to stabilize
Refer if: possible exertional and take some load off the
compartment syndrome. Lateral lower periosteum.
leg symptoms are less likely to be shin Correction of predisposing anatomic
splints. factors (e.g., with foot orthotics)
and training errors.
Gradual return to running or
activity.
Stress Fractures of the Tibia History of well-localized shin pain with Activity modification/restriction and
or Fibula pounding activities, e.g., running, rest; no pounding activities until
Result from repetitive jumping, marching. Early on, pain is pain-free and nontender at site
subthreshold loading that, over typically mild and occurs toward the end (usually 8– 12 wk).
time, exceeds the bone's intrinsic of the inciting activity. There is often a
ability to repair itself.
Page 834
Therapeutic Choice

recent change in training surface May need analgesic medication,
(density or topography). e.g., acetaminophen ± either
Intensive sustained muscular activity codeine or tramadol.
may result in bone strain and overload. Alternative low-impact activities:
This type of mechanism of injury is cycling, swimming, pool running.
common in rowers, who are prone to Long Air Cast-type brace often
stress fractures of the ribs. provides more comfort and possibly
Night pain is a frequent complaint. earlier return to pounding
Physical examination: Point tenderness 11
activities.
upon palpation or percussion of affected Address muscle weakness/strength
area. Loading the affected bone using imbalances. Adjust for structural
specific maneuvers (such as the "hop malalignments (e.g., lift for leg-
test" or the "fulcrum test") may length discrepancies) or
reproduce pain. biomechanical inefficiencies (e.g.,
X-rays usually negative until at least orthotics for excessive subtalar
2 wk after onset; may see periosteal pronation or pes cavus).
thickening. Bone scan will show discrete Correction of training errors; avoid
increased uptake at stress fracture site. excessive volume or intensity or
CT scan or MRI can help to differentiate wearing worn-out running shoes.
acute vs healing stress fracture. Runners should replace shoes every
Refer if: Beware of anterior midshaft 500–800 km to ensure adequate
tibial stress fractures (“the dreaded black midsole cushioning.
line”) which appear as a horizontal Monitor for poor bone health,
fissure extending into the cortex of the whether due to hormonal, dietary or
tibia on x-ray. They are slow to heal, pathological causes (e.g.,
often go on to non-union and should be osteoporosis, hyperparathyroidism,
assessed by an orthopedic surgeon for skeletal involvement from
possible immobilization or internal malignancy).
fixation. Gradual/progressive return to
activity when pain-free on walking
and nontender at site permits
progressively greater loading of the
affected structure.
Consider referral to a primary care
sport medicine physician or an
orthopedic surgeon for
electromagnetic bone stimulation,
which may be helpful if delayed
12
healing or non-union.
Ankle Sprain History of acute inversion of ankle Grade I & II Sprains

Partial or complete tear to ankle- (eversion less common). Initial RICE protocol.
stabilizing ligaments, most Physical examination: tenderness (most NSAIDs (oral or topical) for acute
commonly lateral (anterior and marked over injured ligament), swelling, pain and inflammation.
posterior talofibular, pain with passive inversion and plantar Gradual ↑ weight bearing; may use
calcaneofibular ligaments). flexion, positive anterior drawer test and tape/brace as support. Initiate
Grade I: No laxity, weight bears talar tilt in Grade III sprains. weight bearing as soon as pain and
without pain, minimal swelling Note: Don't forget to check for stability allow to facilitate healing
Grade II: Swelling, painful associated injury more proximally in the and proprioception.
weight bearing, possible slight leg. Early ROM exercises.
laxity X-rays: clinical decision rules for the use Stretching in dorsiflexion and
Grade III: Unstable, significant of x-rays in acute ankle sprains are plantar flexion.
laxity, complete disruption of at 13 Strengthening: ankle dorsiflexors,
outlined in the Ottawa Ankle Rules.
least 2 ligaments Refer if: Do not confuse a severe ankle plantar flexors, progress to
sprain with rupture of an Achilles or invertors and evertors.
peroneal tendon (which require Proprioception/balance retraining.
orthopedic referral). Progressive return to activity.
Grade III Sprains
Initial RICE protocol, activity
restriction.
NSAIDs for acute pain and
inflammation.
Page 835
Therapeutic Choice

Removable cast brace for 3– 6 wk
(allows for icing, physiotherapy);
then stirrup-type ankle brace. Once
stable, follow protocol for Grade I
and II sprains. Refer for orthopedic
consultation if not improved after 6
–8 wk of conservative therapy,
recurrent pain or instability, concern
of syndesmotic involvement.
Achilles Tendinitis History: Pain, often swelling, of distal Rest from aggravating activities (try
Inflammation (tendinitis) or Achilles tendon. May be acute—usually bike as alternate).
degenerative micro-tears caused by rapid increase in Ice/ice massage.
(tendinosis) of Achilles tendon training/activity (e.g., running, NSAIDs (oral or topical) for initial
mainly occurring at insertion or jumping), poor flexibility, excessive pain and inflammation in first 4 wk
distal part of tendon. In pronation or poor-fitting footwear. of condition.
tendinitis, paratenon may also be Chronic tendinosis occurs usually in Heel lift (approximately ¼").
inflamed. those over 30. Aggravated by running, Night splint (prevents plantar
jumping, walking. Sore first few steps in flexion of ankle so Achilles tendon
morning. Beware history of sudden acute remains stretched while sleeping,
pain (and occasionally feeling of “pop”), allowing healing to take place with
which may indicate tear of Achilles foot in a functional position).
tendon. Control of biomechanical factors by
Physical Exam: Occasional swelling of correcting malalignment with
distal Achilles (monitor for bursitis). appropriate shoes, using
When chronic, may have appropriate training techniques and
nodule/thickening of tendon with losing weight.
tenderness on palpation. Pain with Physiotherapy—progressive
passive ankle dorsiflexion and resisted stretching and strengthening,
plantar flexion (especially in weight eccentric calf muscle training is
bearing, painful toe raises). May have associated with a faster recovery
pes planus with pronation or pes cavus. 14 , 15
time. Extracorporeal shock
Thompson test normal if Achilles is wave therapy may be considered
intact (squeeze of calf should produce 16 , 17
(conflicting evidence).
ankle plantar flexion against gravity). If
Orthotics/arch supports if
test is not normal (no plantar flexion),
overpronates.
suspect complete tear of Achilles tendon.
Consider applying nitroglycerin
Imaging: If concern of possible
transdermal patch on Achilles
tear/rupture, ultrasound helpful.
tendon area (¼ of a 0.2 mg/h
Refer if: concern re: complete tear, 4
immediate orthopedic referral is needed. patch) Q24H for 6–8 wk.
percutaneous tenotomy of
tendinosis.8
Consider PRP autologous blood
injection at the site of the
tendinosis; may reduce pain and
improve function18 (refer to primary
care sport medicine physician or
orthopedic surgeon).
Surgery rarely required for chronic
tendinosis, but it is important to
recognize complete tear.
Plantar Fasciitis History of pain at plantar aspect of Activity modification, rest from
Microtears of the plantar fascia calcaneus, worse with first steps of the aggravating activities (e.g., bike or
and inflammation of the day upon arising in the morning, getting swim instead of run).
periosteum at its calcaneal origin up after a prolonged sit and with running NSAIDs (oral or topical) for initial
(heel bone). or prolonged walking. pain and inflammation in first 4 wk
Physical examination: Tender at plantar of condition.
fascial origin at the heel; may have pes Footwear important: cushioning
planus with pronation or pes cavus. running shoe should be worn for all
weight bearing. Custom foot
Page 836
Therapeutic Choice

X-ray not usually needed, may show orthotics, arch supports, heel pads
“spur” as a result of more chronic or gel cups may be necessary.
plantar fasciitis. Ice or ice massage (roll foot on
Refer if: Severe bruising or swelling of frozen water bottle).
the heel pad would indicate a greater Plantar massage: roll foot on soup
concern for plantar fascia rupture or can/tennis ball before weight
calcaneal stress fracture, which require bearing in morning.
referral to a specialist. Physiotherapy, including possible
extracorporeal shock wave
19
therapy.
Stretches: gastrocnemius, soleus,
20
plantar fascia, foot intrinsics.
Night splint to prevent ankle plantar
flexion while sleeping: decreases
fascial shortening and morning
21
pain.
Corticosteroid injection if not
improving with above (e.g.,
triamcinolone acetonide 20 mg
mixed with 0.5 mL lidocaine 1% to
tender area).
percutaneous tenotomy.
Nitroglycerin transdermal patch
(¼ of a 0.2 mg/h patch) Q24H on
point of maximum tenderness at the
plantar fascia insertion into the
22
calcaneus for 6–8 wk.
Consider referral to primary care
sport medicine physician or
orthopedic surgeon for PRP
autologous blood injection at the
site of the tendinosis to reduce pain
and improve function.
Surgery rarely required.
Abbreviations: NSAID=nonsteroidal anti-inflammatory drug; PRP=platelet-rich plasma; RICE=rest, ice, compression,

elevation; ROM=range of motion; VMO=vastus medialus obliquus
Suggested Readings
Brukner P, Khan K. Clinical sports medicine. 3rd ed. New York (NY): McGraw-Hill; 2007.
Crossley K, Bennell K, Green S et al. A systematic review of physical interventions for patellofemoral pain syndrome.
Clin J Sport Med 2001;11(2):103-10.
De Smedt T, de Jong A, Van Leemput W et al. Lateral epicondylitis in tennis: update on aetiology, biomechanics and
treatment. Br J Sports Med 2007;41(11):816-9.
Ellenbecker TS, Cools A. Rehabilitation of shoulder impingement syndrome and rotator cuff injuries: an evidence-
based review. Br J Sports Med 2010;44(5):319-27.
Magnussen RA, Dunn WR, Thomson AB. Nonoperative treatment of midportion Achilles tendinopathy: a systematic
review. Clin J Sport Med 2009;19(1):54-64.
References
Page 837
Therapeutic Choice
1. Koester MC, Dunn WR, Kuhn JE et al. The efficacy of subacromial corticosteroid injection in the treatment of
rotator cuff disease: a systematic review. J Am Acad Orthop Surg 2007;15(1):3-11.
2. Loew M, Daecke W, Kusnierczak D et al. Shock-wave therapy is effective for chronic calcifying tendinitis of the
shoulder. J Bone Joint Surg Br 1999;81(5):863-7.
3. Paoloni JA, Appleyard RC, Nelson J et al. Topical nitric oxide application in the treatment of chronic extensor
tendinosis at the elbow: a randomized, double-blinded, placebo-controlled clinical trial. Am J Sports Med
2003;31(6):915-20.
4. Paoloni JA, Appleyard RC, Nelson J et al. Topical glyceryl trinitrate treatment of chronic noninsertional achilles
tendinopathy. A randomized, double-blind, placebo-controlled trial. J Bone Joint Surg Am 2004;86-A:916-22.
5. Paoloni JA, Appleyard RC, Nelson J et al. Topical glyceryl trinitrate application in the treatment of chronic
supraspinatus tendinopathy: a randomized, double-blinded, placebo-controlled clinical trial. Am J Sports Med
2005;33(6):806-13.
6. Bisset L, Beller E, Jull G et al. Mobilisation with movement and exercise, corticosteroid injection, or wait and
see for tennis elbow: randomized trial. BMJ 2006;333(7575):939.
7. Peerbooms JC, Sluimer J, Bruijn DJ et al. Positive effect of an autologous platelet concentrate in lateral
epicondylitis in a double-blind randomized controlled trial: platelet-rich plasma versus corticosteroid injection
with a 1-year follow-up. Am J Sports Med 2010;38(2):255-62.
8. Housner JA, Jacobson JA, Misko R. Sonographically guided percutaneous needle tenotomy for the treatment of
chronic tendinosis. J Ultrasound Med 2009;28(9):1187-92.
9. Warden SJ, Hinman RS, Watson MA et al. Patellar taping and bracing for the treatment of chronic knee pain: a
systematic review and meta-analysis. Arthritis Rheum 2008;59(1):73-83.
10. McConnell J. The management of chondromalacia patellae: a long term solution. Aust J Physiother 1986;32
(4):215-23.
11. Swenson EJ, DeHaven KE, Sebastianelli WJ et al. The effect of a pneumatic leg brace on return to play in
athletes with tibial stress fractures. Am J Sports Med 1997;25(3):322-8.
12. Gebauer D, Mayr E, Orthner E et al. Low-intensity pulsed ultrasound: effects on nonunions. Ultrasound Med
Biol 2005;31(10):1391-402.
13. Stiell IG, Greenberg GH, McKnight RD et al. Decision rules for the use of radiography in acute ankle injuries.
Refinement and prospective validation. JAMA 1993;269(9):1127-32.
14. Wallmann H. Achilles tendinitis: eccentric exercise prescription. ACSM’s Health & Fitness Journal 2000;4(1):7-
16.
15. Alfredson H, Pietila T, Jonsson P et al. Heavy-load eccentric calf muscle training for the treatment of chronic
Achilles tendinosis. Am J Sports Med 1998;26(3):360-6.
16. Costa ML, Shepstone L, Donell ST et al. Shock wave therapy for chronic Achilles tendon pain: a randomized
placebo-controlled trial. Clin Orthop Relat Res 2005;440:199-204.
17. Rompe JD, Nafe B, Furia JP et al. Eccentric loading, shock-wave treatment, or a wait-and-see policy for
tendinopathy of the main body of tendo Achillis: a randomized controlled trial. Am J Sports Med 2007;35
(3):374-83.
18. de Vos RJ, Weir A, van Schie HT et al. Platelet-rich plasma injection for chronic Achilles tendinopathy: a
19. Gerdesmeyer L, Frey C, Vester J et al. Radial extracorporeal shock wave therapy is safe and effective in the
treatment of chronic recalcitrant plantar fasciitis: results of a confirmatory randomized placebo-controlled
multicenter study. Am J Sports Med 2008;36(11):2100-9.
20. DiGiovanni BF, Nawoczenski DA, Lintal ME et al. Tissue-specific plantar fascia-stretching exercise enhances
outcomes in patients with chronic heel pain. A prospective, randomized study. J Bone Joint Surg Am 2003;85-
A(7):1270-7.
21. Batt ME, Tanji JL, Skattum N. Plantar fasciitis: a prospective randomized clinical trial of the tension night
splint. Clin J Sport Med 1996;6(3):158-62.
22. Murrell GA. Using nitric oxide to treat tendinopathy. Br J Sports Med 2007;41(4):227-31.
23. Coombes BK, Bisset L, Vicenzino B. Efficacy and safety of corticosteroid injections and other injections for
management of tendinopathy: a systematic review of randomised controlled trials. Lancet 2010: 376
(9754):1751-67.
24. Davies GA, Wolfe LA, Mottola MF et al. Joint SOGC/CSEP clinical practice guideline: exercise in pregnancy and
the postpartum period. Can J Appl Physiol 2003;28(3):330-41.
Page 838
Therapeutic Choice
25. ACOG Committee on Obstetric Practice. ACOG Committee opinion. Number 267, January 2002: exercise during
pregnancy and the postpartum period. Obstet Gynecol 2002;99(1):171-3.
26. Dempsey JC, Butler CL, Sorensen TK et al. A case-control study of maternal recreational physical activity and
risk of diabetes mellitus. Diabetes Res Clin Pract 2004;66(2):203-15.
27. Olson D, Sikka RS, Hayman J et al. Exercise in pregnancy. Curr Sports Med Rep 2009;8(3):147-53.
Page 839
e-Therapeutics+ : Therapeutics : Neurologic Disorders: Acute Pain Page 1 of 10
Therapeutic Choice
Print Close
Neurologic Disorders: Acute Pain
Benoit Bailey, MD, MSc, FRCPC
Pain is one of the commonest symptoms. It needs to be recognized, assessed for cause and treated appropriately as
soon as possible. The absence of treatment can lead to physiological and psychological adverse effects. Treatment
should be tailored to the level of pain; an analgesic that is effective in one patient may not necessarily be helpful in
another with the same type of pain. The absence of a diagnosis should not delay measures to relieve pain.
Goals of Therapy
Recognize that the patient is experiencing pain

Relieve the pain until the cause is treated
Identify and treat the cause of pain
Investigations
Observe the patient for behavioural signs of pain, e.g., agitation, anxiety, crying, gritting of teeth, withdrawal
from activities
Solicit self-reports of the pain
Inquire about the medical history and perform a physical examination to determine the cause and severity of the
pain
Inquire about medication self-treatment history and possible allergy or adverse reactions to analgesics
Use laboratory investigations as appropriate to determine the cause of the pain
Use a pain scale to measure and assess pain
Note: The use of a pain scale is increasingly encouraged; this can help reduce oligoanalgesia (undertreatment of
1
pain). The results of this assessment should be recorded as for a vital sign. The visual analog scale (a 100 mm
horizontal line anchored by “no pain” at 0 mm and “worst pain imaginable” at 100 mm) is the pain scale used most.
It is validated in adults and in children ≥ 5–6 years. Other pain scales such as the standardized colour analog scale
or the Wong-Baker Faces Pain Rating Scale can be used in children as young as 4–5 years or 3–6 years,
respectively.2 , 3
Therapeutic Choices (Figure 1 - Management of Acute Pain)
Patients presenting with acute pain should be quickly and calmly assessed with empathy and reassurance.
Encourage patients to verbalize their pain at all stages of treatment. Initiate measures to decrease pain immediately
(e.g., immobilize a fracture, apply dressings to burns, employ cold or heat or other techniques such as relaxation,
imagery and distraction) until pharmacologic treatment is started. Do not wait until a full assessment is made to
start pharmacologic treatment.
Oral Analgesics
For mild to moderate pain, the first step should be the use of a nonopioid analgesic alone or in combination with a
weak opioid. If the pain is still present or worsening, use a weak opioid alone or in combination with a nonopioid
analgesic. Alternatively, an NSAID can be tried. If necessary, the next step is to use a stronger opioid alone or with
a nonopioid analgesic. For severe pain, starting with a strong opioid is usually more appropriate (Figure 1 -
Management of Acute Pain).
Nonopioid Analgesics
Page 840
Therapeutic Choice
Acetaminophen can be used for mild to moderate pain. Its advantages include having analgesic and antipyretic
4
onset and efficacy equal to ASA and fewer adverse reactions and drug interactions than NSAIDs. However, it has no
5 , 6
anti-inflammatory action. It can be used with opioids for additive analgesic effect.
Nonsteroidal anti-inflammatory drugs (NSAIDs) are a heterogeneous group of medications with analgesic,
antipyretic and anti-inflammatory action that can be used for mild to moderate pain. Nonselective NSAIDs are
divided into five classes: salicylates, fenamates, propionic acid derivatives, oxicams and acetic acid derivatives (see
Musculoskeletal Disorders: Osteoarthritis). COX-2 selective NSAIDs should not be used at this time for treatment of
acute pain until their adverse effects in the acute pain setting, although unlikely, are well defined.
Adverse effects associated with single (or few) doses of nonselective NSAIDs are limited and are qualitatively
similar to those of ASA. Chronic use is associated with GI effects (ulceration, bleeding and perforation) and renal
failure. ASA, unlike other NSAIDs, irreversibly inhibits platelet function for the lifetime of the platelet (8 to 10 days)
even after a single therapeutic dose. In contrast, platelet function returns to normal when other NSAIDs have been
eliminated from the body (approximately 24 hours for most NSAIDs). NSAIDs can precipitate asthma in ASA-
sensitive patients.
Avoid NSAIDs in patients with a history of peptic ulcer disease, renal failure, congestive heart failure or asthma.
Choosing an NSAID is difficult. Some patients respond well to a certain class but not to others. Also, it appears that
4 , 6 , 7
full single doses of most NSAIDs are more effective analgesics than full doses of ASA or acetaminophen.
Cost can be an important factor.
ASA can be given with opioids for additive analgesic effect.7 It should be avoided in children, particularly those less
than 16 years of age with chickenpox or flu-like symptoms, because of possible association with Reye's syndrome.
It can also precipitate asthma in ASA-sensitive patients.
Ibuprofen 200 mg is equivalent to 650 mg ASA or acetaminophen in terms of analgesia; a dose of 400 mg is
4 , 6
superior and longer acting, and provides comparable analgesia to the combination of acetaminophen/codeine. A
10 mg/kg dose of ibuprofen is as safe as a 15 mg/kg dose of acetaminophen, although GI bleeding has been
8
reported with ibuprofen.
Naproxen 250 mg is equivalent to a dose of 650 mg of ASA; a dose of 500 mg is superior. At either dose,
4
naproxen has a longer duration of action than ASA.
Opioids
Opioids can be used orally for the treatment of moderate to severe pain. However, for severe pain the parenteral
route is preferred because of its faster onset of action. Opioids may be substituted using equipotent doses.
However, the adverse effects of codeine and meperidine can limit this process. Caution should always be used when
switching among opioids, to minimize any adverse events, particularly when substituting to the highly potent
hydromorphone. Adverse effects include constipation (codeine may be the worst offender), nausea, sedation,
respiratory depression and (if used for long period of time) tolerance, dependence and withdrawal symptoms.
Codeine is frequently given concomitantly with acetaminophen or ASA for additive analgesic effect without
4 , 5
increasing the adverse effects. Approximately 6 to 10% of the general population does not possess sufficient
CYP2D6 to transform codeine to morphine, and experiences no analgesic response to codeine. Increasing the dose is
not effective. Drugs that inhibit CYP2D6 can also decrease the analgesic effect of codeine. The use of codeine,
particularly in the elderly, should be accompanied by stool softeners and/or bulk-forming laxatives.
Morphine is available in several immediate-release dosage forms and in sustained-release preparations. However,
sustained-release preparations should rarely be given for the treatment of acute pain. Because of fewer adverse
effects compared to codeine, morphine can be titrated to achieve pain-free status.
Tramadol is a unique analgesic structurally related to morphine and codeine that acts through opioid and nonopioid
9
mechanisms. Although it appears to have less abuse potential and minimal effect on respiratory function, tramadol
causes more nausea compared to other opioids and may not be as effective unless combined with another analgesic
9 , 10
such as acetaminophen. Tramadol should not be used as a first-line analgesic.
Parenteral Analgesics
Page 841
Therapeutic Choice
The intravenous route of administration is preferred to subcutaneous and intramuscular use because it is pain free
and onset of action is predictable.
NSAIDs
Ketorolac is an NSAID that can be given im or iv for the treatment of moderate to severe pain. A dose of 30 mg is
4
comparable to approximately 12 mg of morphine. Ketorolac has the same adverse effect profile as the oral
nonselective NSAIDs. The pharmacologic effect cannot be titrated but the drug can be used when opioids are
contraindicated. Ketorolac is effective for the treatment of pain associated with renal colic.
Opioids
Morphine is the standard to which other opioids are compared. Its advantages over meperidine include longer
duration of action, and metabolism not affected by liver and renal disease. It can be administered as continuous
infusion or as patient-controlled analgesia (PCA), a pump programmed to deliver a preset amount of drug by
continuous infusion or repeated boluses, as well as smaller bolus doses for breakthrough pain.
Avoid using meperidine in patients with renal failure because an active metabolite (normeperidine) will accumulate
and cause seizures in some patients. This same metabolite causes the adverse CNS effects of meperidine (tremors,
hyperreflexia, hallucinations). Meperidine should also be avoided in patients with liver disease and those who have
received MAOIs in the past 14 days. Usually, meperidine should not be given for pain that is expected to last more
than three hours, where morphine is a better choice. In some hospitals, meperidine has been removed from the
formulary because of all these concerns.
Fentanyl is a synthetic opioid which has a duration of action of only 30 to 60 minutes, making it an ideal analgesic
for brief procedures but limiting its usefulness for managing acute pain. This can be overcome by giving fentanyl by
infusion, but this offers no advantage over morphine and is much more costly. Fentanyl has almost no hemodynamic
effects and does not induce histamine release, unlike morphine and meperidine. Rapid iv administration can lead to
chest wall rigidity that could interfere with ventilation.
Topical and Local Anesthesia
Infiltrative techniques using lidocaine are the most frequently used for minor procedures. A dose of 3 to 5 mg/kg
(maximum 300 mg) can be used for direct infiltration or regional nerve block. Coadministration of epinephrine
allows an increase of lidocaine dose to 5 to 7 mg/kg, unless epinephrine is contraindicated (e.g., if tissue
vascularity is poor or if distal vasculature is involved). If allergy to amide type local anesthetics (e.g., lidocaine,
bupivacaine) is suspected, an ester (e.g., procaine, tetracaine, benzocaine) can be used because of the absence of
cross-reactivity.
For small facial lacerations, a mixture of tetracaine 0.5 to 1%, epinephrine (adrenaline) 0.25 to 0.5% and
cocaine 1 to 4% (TAC) can be applied topically (3 mL—maximum cocaine 6 mg/kg). The restricted status of
cocaine limits its usefulness. A mixture of lidocaine 0.4%, epinephrine 0.1% and tetracaine 0.05% (LET), in a dose
of 2 mL topically, is as effective as TAC.
Topical anesthetics such as eutectic mixture of local anesthetics (EMLA), amethocaine (tetracaine; Ametop) or
liposomal lidocaine (Maxilene) can be used to reduce pain associated with minor procedures such as needle
insertion on intact skin. EMLA, containing prilocaine and lidocaine, causes vasoconstriction potentially making
cannulation difficult. To be effective, a large amount should be applied for at least 45–60 minutes with an occlusive
dressing.
11
Amethocaine is superior to EMLA in preventing pain associated with needle insertion in children.
Useful Info? It requires a shorter application time than EMLA (30 minutes). Amethocaine causes vasodilation and
may induce hypersensitivity with repeated use. Liposomal lidocaine is as effective as EMLA in decreasing pain
associated with venipuncture or intravenous cannulation. It has minimal vasoactive properties and requires an
application time of 30 minutes. An occlusive dressing is not required but it is recommended in young children.
Inhalation Pain Management
Nitrous oxide (N20) at a concentration of 30 to 50% can be used as an analgesic. Advantages include rapid onset
and short duration of action. Contraindications include altered level of consciousness, severe maxillofacial injuries,
chronic obstructive pulmonary disease, acute pulmonary edema, pneumothorax, shock, decompression sickness,
Page 842
Therapeutic Choice
bowel obstruction and major chest injury. It can produce lightheadedness, drowsiness, nausea, vomiting and
excitement.
Therapeutic Tips
Choose the medication and route of administration according to the severity of the pain, the desired onset and
duration of action.
Consider sedatives as well, particularly for procedures, but their use should not replace analgesics.
For the elderly, choose the right analgesic, considering hepatic and renal function as well as concurrent
medications.
Always wait the appropriate amount of time, according to the onset of action of the analgesic, to perform a
procedure or to assess whether an analgesic was effective.
Monitor the level of consciousness and presence of adverse effects after administration of an analgesic.
Reassess the need for analgesics frequently, using a pain scale.
Avoid the use of opioids on an as-needed basis. A regular schedule of administration is more effective.
Consult specialized acute pain services as needed.
In case overdosage occurs, keep naloxone (Table 1) on hand when administering opioids parenterally.
Overdosage will not occur as long as the patient has pain.
Table 1: Treatment of Opioid-induced Respiratory Depression
Class Drug Dose
Opioid naloxone Adults and children > 5 y or > 20 kg weight: 0.4 to 2 mg iv Q2–3 min,
Antagonist Naloxone depending on response
Hydrochloride Children birth–5 y or 20 kg weight: 0.1 mg/kg Q2–3 min, depending on
Injection USP response
Maximum dose: 10 mg. Note: May need to repeat in 1 to 2 h, depending on
half-life of opioid.
Continuous infusion may be used for overdoses of long-acting opiates.
Starting dose is 2/3 of the initial dose that was effective for the patient,
administered per hour by infusion or 0.4– 0.8 mg/h in adults and 0.05–
0.15 mg/kg/h in children. Titrate to effect.
Page 843
Therapeutic Choice
Figure 1-Management of Acute Pain
Table 2: Analgesics for the Treatment of Acute Pain
Page 844
Therapeutic Choice
a
Cost
Analgesics, acetaminophen Children: 10– Hepatotoxicity in Enhanced anticoagulant $–$$

nonopioid Atasol 15 mg/kg/dose po Q4H; overdose or effect of warfarin with
oral suspension supratherapeutic regular use of > 2
Preparations,
available dosing. g/day of
Tempra, 15–20 mg/kg/dose pr acetaminophen.
Tylenol, Q4H
generics
Max: 5 doses/day
Adults: 325– 650 mg po

or pr Q4H
Max: 4 g/day
Analgesics, ASA Children: GI upset. Warfarin: ↑ anticoagulant $

nonopioid Aspirin, 10–15 mg/kg/dose po effect.
Q4H Antihypertensives
Bufferin, Coated
Max: 5 doses/day (diuretics, beta-
Aspirin, blockers, ACE
generics inhibitors, alpha-
Adults: 325–650 mg po blockers): possible
Q4H reduction in
Max: 4 g/day hypertensive effect;
may require additional
antihypertensive
therapy.
Lithium may interfere

with sodium/water
balance. Monitor
lithium levels when
NSAID added.

SSRIs.
Analgesics, ibuprofen Children: GI upset. Warfarin: ↑ anticoagulant $

nonopioid Advil, Motrin 10 mg/kg/dose po Q6– effect.
8H; oral suspension Antihypertensives
IB, Motrin
available (diuretics, beta-
(Children's), Max: 40 mg/kg/day, not blockers, ACE
generics to exceed adult dose inhibitors, alpha-
blockers): possible
reduction in
Adults: 200– 400 mg po hypertensive effect;
Q6–8H may require additional
Max: 1.2 g/day antihypertensive
therapy.

with sodium/water
balance. Monitor
lithium levels when
NSAID added.

SSRIs.
Page 845
Therapeutic Choice
Costa
Analgesics, ketorolac Children: GI upset. Warfarin: ↑ anticoagulant $$$-

nonopioid Toradol, 0.2–1 mg/kg/dose im or effect. $$$$
generics iv Q4–6H Antihypertensives
Max: 30 mg/dose (diuretics, beta-
blockers, ACE
inhibitors, alpha-
Adults: 10–30 mg im or blockers): possible
iv Q4–6H reduction in
Max: 120 mg/day hypertensive effect;
may require additional
antihypertensive
therapy.

with sodium/water
balance. Monitor
lithium levels when
NSAID added.

SSRIs.
Analgesics, naproxen Children: 5– GI upset. Warfarin: ↑ anticoagulant $

nonopioid Naprosyn, 7 mg/kg/dose po effect.
generics Q8–12H; oral Antihypertensives
suspension available (diuretics, beta-
Max: 1000 mg/day blockers, ACE
inhibitors, alpha-
blockers): possible
Adults: 500 mg initially, reduction in
then 250 mg po Q6–8H hypertensive effect;
Max: 1250 mg/day may require additional
antihypertensive
therapy.

with sodium/water
balance. Monitor
lithium levels when
NSAID added.

SSRIs.
Analgesics, morphine Titrate to effect. All opioids: sedation, All opioids: additive $–$$
opioid M.O.S., MS-IR, Immediate-release constipation. sedation with other CNS
oral: depressants, e.g.,
generics
alcohol; potential
Children: enhancement of opioid
0.2–0.5 mg/kg/dose po effects with lidocaine.
Q4–6H
Adults: 10–30 mg po
Q4–6H
Intravenous:
Page 846
Therapeutic Choice
Costa
Children: Intermittent:
0.1–0.2 mg/kg/dose
Q2–4H
Continuous infusion:
0.01–0.05 mg/kg/h
Breakthrough pain
during infusion:
0.01–0.05 mg/kg/dose
Adults: Intermittent:
2.5–10 mg iv Q2–4H
Continuous infusion:
1–10 mg/h
Breakthrough pain
during infusion:
2.5–5 mg/dose
Analgesics, codeine Children: 0.5– All opioids: sedation, All opioids: additive $
opioid generics 1 mg/kg/dose po Q4– constipation. sedation with other CNS
6H; oral liquid depressants, e.g.,
formulation available alcohol; potential
Max: 60 mg/dose enhancement of opioid
effects with lidocaine.
Codeine: ↓ analgesic
Adults: 15– 60 mg po effect with somatostatin,
Q4–6H rifampin.
Max: 60 mg/dose
Inhibitors of CYP2D6
(e.g., celecoxib,
cimetidine,
desipramine, fluoxetine,
imatinib, paroxetine,
quinidine) may
antagonize codeine’s
analgesic effect.
Analgesics, meperidine Children: 1– All opioids: sedation, All opioids: additive $-$$
opioid (pethidine) 1.5 mg/kg/dose iv constipation. sedation with other CNS
Q3–4H Seizures can occur depressants, e.g.,
Demerol
Max: 100 mg/dose when used in renal alcohol; potential
Injectable,
failure. May cause enhancement of opioid
generics
tremors, hyperreflexia, effects with lidocaine.
Adults: 50–100 mg iv hallucinations. Avoid in Meperidine: potentially
Q3–4H liver disease and those life-threatening
Max: 100 mg/dose who have received serotonin syndrome
MAOIs within the last with nonselective
14 days. MAOIs.
Analgesics, fentanyl Children: All opioids: sedation, All opioids: additive $$-
opioid generics 0.5–3 µg/kg/dose iv Q1– constipation. sedation with other CNS $$$
2H depressants, e.g.,
Adults: 50–100 µg iv Q1 alcohol; potential
–2H enhancement of opioid
Titrate to effect effects with lidocaine.
Page 847
Therapeutic Choice
Costa
Fentanyl: inhibitors of
CYP3A4 (e.g.,
cimetidine, efavirenz,
erythromycin,
itraconazole,
ketoconazole, ritonavir)
may potentiate
fentanyl’s opioid
effects.
a.
Cost per dose (based on body weights of 20 kg for children and 70 kg for adults); includes drug cost only.
Legend: $ < $0.50 $–$$ < $0.50–1.00 $$ $0.50–1.00 $$-$$$ $0.50–2.00 $$$ $1.00–2.00 $$$-$$$$
$1.00–4.00 $$$$ $2.00–4.00
Suggested Readings
Berde CB, Sethna NF. Analgesics for the treatment of pain in children. N Engl J Med 2002;347(14):1094-103.
Collège des médecins du Québec. L’analgésie à l’urgence. Lignes directrices du Collège des Médecins du Québec.
Montreal (QC): Collège des médecins du Québec, 2006. Available from
http://www.cmq.org/DocumentLibrary/UploadedContents/CmsDocuments/Lignes-analgesie-urgence-complet-
2006.pdf Assessed May 7, 2007.
Falanga IJ, Lafrenaye S, Meyer SK et al. Management of acute pain in children: safety and efficacy of a nurse-
controlled algorithm for pain relief. Acute Pain 2006;8:45-54.
[No authors listed]. Drugs for pain. Treat Guidel Med Lett 2004;2(23):47-54.
Ranji SR, Goldman LE, Simel DL et al. Do opiates affect the clinical evaluation of patients with acute abdominal
pain? JAMA 2006;296(14):1764-74.
Sachs CJ. Oral analgesics for acute nonspecific pain. Am Fam Physician 2005;71(5):913-8.
References
1. Drendel AL, Brousseau DC, Gorelick MH. Pain assessment for pediatric patients in the emergency department.
Pediatrics 2006;117(5):1511-8.
2. O'Rourke D. The measurement of pain in infants, children, and adolescents: from policy to practice. Phys Ther
2004;84(6):560-70.
3. Hain RD. Pain scales in children: a review. Palliat Med 1997;11(5):341-50.
4. [No authors listed]. Drugs for pain. Treat Guidel Med Lett 2004;2(23):47-54.
5. Moore A, Collins S, Carroll D et al. Single dose paracetamol (acetaminophen), with and without codeine, for
postoperative pain. Cochrane Database Syst Rev 2000;(2):CD001547.
6. McQuay HJ, Moore RA. An evidence-based resource for pain. Oxford (UK): Oxford University Press; 1998.
7. McQuay H, Moore A, Justins D. Treating acute pain in hospital. BMJ 1997;314(7093):1531-5.
8. Lesko SM, Mitchell AA. An assessment of the safety of pediatric ibuprofen. A practitioner-based randomized
clinical trial. JAMA 1995;273(12):929-33.
9. Grond S, Sablotzki A. Clinical pharmacology of tramadol. Clin Pharmacokinet 2004;43(13):879-923.
10. Sachs CJ. Oral analgesics for acute nonspecific pain. Am Fam Physician 2005;71(5):913-8.
Page 848
Therapeutic Choice
11. Lander JA, Weltman BJ, So SS. EMLA and amethocaine for reduction of children’s pain associated with needle
insertion. Cochrane Database Syst Rev 2006;(3):CD004236.
Page 849
e-Therapeutics+ : Therapeutics : Neurologic Disorders: Bell's Palsy Page 1 of 4
Therapeutic Choice
Print Close
Neurologic Disorders: Bell's Palsy
William Pryse-Phillips, MD, FRCP, FRCPC
Bell's palsy is a lower motor neuron paralysis of the facial nerve, often due to herpes simplex virus-1 infection,
1 2
causing inflammation and edema. It affects about 20 per 100 000 per year without gender predominance. The
incidence increases until age 40 and then remains static until late adult life when it again increases. Bell's palsy
occurs more frequently in pregnant women and in patients with diabetes or hypertension.
Up to 85% of patients achieve spontaneous complete recovery without treatment; those who will not recover cannot
3
be identified clinically, although incomplete paralysis carries a better prognosis. In < 10% of cases the palsy recurs
on either side.
Goals of Therapy
Promote complete recovery of function through prevention of denervation

Protect the eye from corneal abrasion
Alleviate pain
Investigations
The classic presentation of Bell's palsy includes abrupt onset of facial weakness affecting the upper and lower face,
ear pain and altered taste. Involvement of other cranial nerves, remote CNS signs and systemic features would
indicate further inquiry for the conditions listed in Table 1.
Table 1: Differential Diagnosis of Unilateral Bell's Palsy
Ramsay Hunt syndrome (herpes zoster infection; vesicles in the ear or throat)
Facial nerve tumors (usually painless; examine for neurofibromatosis)
Cerebellopontine angle tumors (added neurologic signs)
Parotid tumors (clinical examination)
Mastoiditis (clinical examination; deafness, discharge)
Lyme disease (skin and joint signs)
Neurosarcoidosis (chest x-ray)
Brainstem lesions such as multiple sclerosis (other neurologic signs)
Bilateral facial palsy is a feature of Guillain-Barré syndrome, Lyme disease, sarcoid and Wegener's granulomatosis,
and of even more rare conditions.
Investigations are seldom needed after a complete history and physical examination have excluded other causes of
peripheral facial palsy.
EMG and facial nerve conduction studies may help with prognosis but only after 8–10 days
Computed tomography (CT) scan is appropriate if trauma is a likely cause
Magnetic resonance imaging (MRI) is indicated in the presence of atypical features such as slow progression or
associated neurologic signs
No laboratory tests are useful
Therapeutic Choices (Figure 1 - Management of Bell's Palsy )
Eye Care
To prevent corneal abrasions in any eye that cannot be closed voluntarily:

lubricate with ophthalmic drops or ointment
Page 850
Therapeutic Choice
tape the eyelid closed at night and protect with glasses during the day
Analgesics
Ibuprofen or acetaminophen with or without codeine is occasionally required for the first day or two.
More potent opioids such as morphine are rarely needed.
Corticosteroids
4 , 5
Corticosteroids have been shown to improve rates of full recovery as well as time to complete recovery. Early
treatment (initiated within 72 hours of symptom onset) provides maximal benefit.5 Theoretically, the anti-
inflammatory action of corticosteroids minimizes nerve damage, thus improving outcomes. In addition, there is
good anecdotal evidence for a reduction in pain with early steroid therapy, and clinical experience suggests that
steroid-treated patients are less likely to develop denervation. Therefore, the following basic regimen is reasonable:
prednisone 1 mg/kg po daily for 5 days, then taper over another 5 days (see Figure 1 - Management of Bell's Palsy
and Table 2).
In the case of complete facial paralysis, corticosteroid treatment showed clinically and statistically significant
6
improvement in recovery of function, a report not cited in the American Academy of Neurology (AAN) Practice
Parameter.7 A systematic review of the use of steroids in children with Bell's palsy concluded that in cases of
complete facial paralysis, corticosteroid therapy is not advisable.8
Antivirals
Whether antivirals such as acyclovir, famciclovir or valacyclovir confer any additional benefit over corticosteroids
alone is controversial.9 , 10 Some studies have demonstrated no additional benefit4 , 5 while others show possible
11 , 12
benefit, particularly in patients with more severe facial paralysis at presentation. Antiviral therapy alone
4 , 5
provides no significant benefit over placebo in the treatment of Bell's palsy. In Ramsay Hunt syndrome (herpes
zoster infection of the VII cranial nerve), antiviral therapy seems appropriate.
Surgical Procedures
7
Reports of decompressive surgery have also been scrutinized but the quality of evidence is insufficient to allow a
recommendation.
Figure 1- Management of Bell's Palsy
a.
The addition of antiviral therapy is an option but is not routinely warranted based on current evidence.
Page 851
Therapeutic Choice
Most cases of Bell's palsy in pregnant women occur in the third trimester. The overall incidence in pregnant women
is disputed. It has been reported that the incidence is not significantly greater than expected compared to all women
of childbearing age,13 with women of reproductive age affected 2–4 times more often than men of the same age
14 15
and, contrastingly, pregnant women affected 3.3 times more often than nonpregnant women. In 1 study, among
16
1701 cases of Bell's palsy, 46 (about 3%) were pregnant. In a well-conceived study, 41 pregnant patients with
Bell's palsy were identified, the mean onset being at 35.4 weeks' gestation. Nine (22%) of these women were also
diagnosed with pre-eclampsia and 3 (7.3%) with gestational hypertension, together representing nearly a 5-fold
increase over the expected provincial/national average. Unfortunately, the prognosis for a satisfactory recovery for
women who develop a complete facial paralysis with Bell's palsy while pregnant is significantly worse than for the
general population.17 Whether this is due to differing etiologies or to a reluctance to prescribe steroids during
pregnancy has not been ascertained. While the onset of Bell's palsy during pregnancy or the puerperium might be
associated with the development of the hypertensive disorders of pregnancy, the actual effect of such individual
factors is not known.
The preferred mode of management in pregnant women remains undecided; it is usually confined to supportive
care, since the use of corticosteroids in pregnancy is controversial.
For a discussion of general principles of drug use during pregnancy and lactation see Appendix: Drug Use During
Pregnancy and Appendix: Drug Use During Lactation. For more detailed information on the use of specific
medications during pregnancy and lactation the reader is referred to Motherisk
[www.motherisk.org/women/drugs.jsp]; Briggs GG, Freeman RK, Yaffe SJ. Drugs in Pregnancy and Lactation 2008;
LactMed [toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen?LACT]; and Hale TW. Medications and Mothers' Milk 2008.
Therapeutic Tips
No treatment is needed for mild weakness that is no longer evolving.

Use prednisone as soon as possible in all other cases of Bell's palsy unless there is a potential contraindication
to steroid use, such as diabetes or peptic ulcer disease.
There is no good evidence for benefit from prednisone if it is started more than 7 days after the onset of
symptoms.
No evidence supports the use of antiviral therapy alone.
Based on available evidence, routine use of antiviral agents with prednisone for Bell's palsy cannot be
recommended, although there may be some benefit in severe cases.
Table 2: Drug Therapy for Bell's Palsy
Costa
Corticosteroids prednisone b GI upset, hyperglycemia, sodium and $

1 mg/kg daily × 5 days,
Winpred, then taper over another 5 fluid retention, hypokalemia,
generics days hypocalcemia.
Antivirals acyclovir 400 mg 5 × daily × 10 days Headache, nausea. $$$

Zovirax Oral,
generics
Antivirals famciclovir 500 mg po TID × 1 wk Headache, nausea. $$$

Famvir,
generics
Antivirals valacyclovir 1000 mg po TID × 1 wk Headache, nausea. $$$

Valtrex,
generics
a.
Cost of 1 course of treatment, based on 70 kg weight; includes drug cost only.
b.
In cases of complete facial paralysis, treat for 10 days then taper over another 5 days.
Page 852
Therapeutic Choice
Abbreviation: GI=gastrointestinal
Legend: $ < $5 $$ $5–70 $$$ $70–100
Suggested Readings
Baringer JR. Herpes simplex virus and Bell palsy. Ann Intern Med 1996;124(1 Pt 1):63-5.
Roob G, Fazekas F, Hartung HP. Peripheral facial palsy: etiology, diagnosis and treatment. Eur Neurol 1999;41(1):3-
9.
Salinas RA, Alvarez G, Ferreira J. Corticosteroids for Bell's palsy (idiopathic facial paralysis). Cochrane Database
Syst Rev 2004;(4):CD001942.
References
1. Morrow MJ. Bell's palsy and herpes zoster oticus. Curr Treat Options Neurol 2000;2(5):407-16.
2. Rowlands S, Hooper R, Hughes R et al. The epidemiology and treatment of Bell's palsy in the UK. Eur J Neurol
2002;9(1):63-7.
3. Jabor MA, Gianoli G. Management of Bell's palsy. J La State Med Soc 1996;148(7):279-83.
4. Sullivan FM, Swan IR, Donnan PT et al. Early treatment with prednisolone or acyclovir in Bell's palsy. N Engl J
Med 2007;357(16):1598-607.
5. Engstrom M, Berg T, Stjenquist-Desatnik A et al. Prednisolone and valaciclovir in Bell's palsy: a randomised,
double-blind, placebo-controlled, multicentre trial. Lancet Neurol 2008;7(11):993-1000.
6. Ramsey MJ, DerSimonian R, Holtel MR et al. Corticosteroid treatment for idiopathic facial nerve paralysis: a
meta-analysis. Laryngoscope 2000;110(3 Pt 1):335-41.
7. Grogan PM, Gronseth GS. Practice parameter: Steroids, acyclovir, and surgery for Bell's palsy (an evidence-
based review): report of the Quality Standards Subcommittee of the American Academy of Neurology.
Neurology 2001;56(7):830-6.
8. Salman MS, MacGregor DL. Should children with Bell's palsy be treated with corticosteroids? A systematic
review. J Child Neurol 2001;16(8):565-8.
9. Quant EC, Jeste SS, Muni RH et al. The benefits of steroids versus steroids plus antivirals for treatment of
Bell's palsy: a meta-analysis. BMJ 2009;339:b3354.
10. de Almeida JR, Al Khabori M, Guyatt GH et al. Combined corticosteroid and antiviral treatment for Bell palsy: a
systematic review and meta-analysis. JAMA 2009;302(9):985-93.
11. Hato N, Murakami S, Gyo K. Steroid and antiviral treatment for Bell's palsy. Lancet 2008;371(9627):1818-20.
12. Minnerop M, Herbst M, Fimmers R et al. Bell's palsy: combined treatment of famciclovir and prednisone is
superior to prednisone alone. J Neurol 2008;255(11):1726-30.
13. Vrabec JT, Isaacson B, Van Hook JW. Bell's palsy and pregnancy. Otolaryngol Head Neck Surg 2007;137
(6):858-61.
14. Cohen Y, Lavie O, Granovsky-Grisaru S et al. Bell palsy complicating pregnancy: a review. Obstet Gynecol
Surv 2000;55(3):184-8.
15. Peitersen E. Bell's palsy: the spontaneous course of 2,500 peripheral facial nerve palsies of different
etiologies. Acta Otolaryngol Suppl 2002;(549):4-30.
16. Shmorgun D, Chan WS, Ray JG. Association between Bell's palsy in pregnancy and pre-eclampsia. QJM
2002;95(6):359-62.
17. Gillman GS, Schaitkin BM, May M et al. Bell's palsy in pregnancy: a study of recovery outcomes. Otolaryngol
Head Neck Surg 2002;126(1):26-30.
18. Hato N, Matsumoto S, Kisaki H et al. Efficacy of early treatment of Bell's palsy with oral acyclovir and
prednisolone. Otol Neurotol 2003;24(6):948-51.
Page 853
e-Therapeutics+ : Therapeutics : Neurologic Disorders: Chronic Spasticity Page 1 of 5
Therapeutic Choice
Print Close
Neurologic Disorders: Chronic Spasticity
Virginia Devonshire, MD, FRCPC
Spasticity is an involuntary velocity-dependent increase in muscle tone resulting from injury to the motor pathways
in the brain or spinal cord. It is common in spinal cord injury, multiple sclerosis, stroke and cerebral palsy.
Spasticity usually occurs as part of the upper motor neuron (UMN) complex which consists of weakness, hyper-
reflexia, Babinski’s sign and slow coordination.
Spasticity can impair feeding, dressing, bowel/bladder function, hygiene and gait. It can also reduce range-of-
movement of joints, cause contractures (shortening of muscles, which can cause joint dysfunction) and result in
significant pain and skin breakdown. However, spasticity is not always impairing and can facilitate some movements
by providing posture and tone in what would otherwise be a flaccid limb. It can allow weight bearing in a plegic
limb by essentially “bracing” that limb. Further, treatment of spasticity can sometimes worsen ambulation by
unmasking limb weakness. Thus, spasticity should only be treated when it interferes with function and care, or
results in pain.
Goals of Therapy
Improve functional movements and gait

Improve range of movement and limit contracture formation
Reduce pain and spasms
Improve seating and positioning, and reduce skin breakdown
Improve care, e.g., perineal care and catheterization
Investigations
No investigations needed if seen as part of a UMN complex already diagnosed.

Spasticity in isolation needs investigation for the underlying pathology.
Therapeutic Choices (Figure 1 - Management of Chronic Spasticity)
Search for aggravating factors if spasticity has increased in a stable patient. This can include pressure areas,
infections (bladder, toenail, etc.), bladder stones, constipation and DVTs.
Physical measures should always be undertaken and include daily stretching and range-of-movement exercises.
Braces may be used to maintain a spastic limb in a reflex-inhibiting posture and prevent contractures.
Surgical treatment of spasticity tends to be reserved for the most refractory cases. Many destructive procedures such
as myelotomy and cordotomy have significant complications and are rarely performed. Selective dorsal rhizotomy
can be effective in limited patients but can affect trunk tone and sensation. Orthopedic procedures, such as
lengthening, releasing or transferring a tendon, are helpful in optimizing function and preventing contractures but
do not treat the underlying spasticity.
Oral medications remain important in the treatment of spasticity. A number of randomized clinical trials have
demonstrated efficacy of antispasticity medications, although recent reviews found the studies were limited.1 , 2
Although level I evidence is lacking, clinical experience has shown that efficacy is better in spasticity of spinal origin
(multiple sclerosis, spinal cord injury) than cerebral origin (brain injury and stroke). With the exception of
dantrolene, which acts directly on the muscle, these drugs have a central mode of action.
Baclofen is the standard initial medication for spasticity. It must be gradually titrated and the typical effective dose
is 30 to 80 mg/day. Abrupt discontinuation can result in confusion, seizures and hallucinations.
Page 854
Therapeutic Choice
Tizanidine is also a good first-line treatment,3 or it can be combined with baclofen as they have
different sites of action. Side effects of dry mouth and drowsiness can limit its use. It is best to start
with a low dose of 2 mg at night and increase gradually. Useful Info?
Dantrolene is effective in the management of spasticity, although it is used less frequently because of an
association with liver toxicity and muscle weakness. Liver function tests should be carried out before the start of
treatment and every 3 to 6 months thereafter.
Benzodiazipines such as diazepam and clonazepam can be useful for treating spasms especially if these are
problematic at night. The sedating effects of these drugs otherwise limit their use.
Gabapentin may be a useful alternative or addition in spasticity management especially if there is concurrent
neuropathic pain.4
Cannabinoids (e.g., dronabinol, nabilone, Sativex) may emerge as another option for managing spasticity.
5 , 6
Several trials have shown mixed results. Their efficacy compared with other medications requires evaluation.
Focal treatment of spastic muscles may have advantages over the global approach to spasticity control through oral
medications. Focal treatments are useful in spasticity of cerebral origin where current drug therapies are less
successful. They also reduce spasticity selectively, leaving some muscle groups with tone that is functional. Phenol
injections are used to block nerves going to specific spastic muscle groups. Injections can be uncomfortable and
need to be repeated in six months; adverse effects can include pain, dysesthesias and infection. Botulinum toxin
A injections can also be used and may be better tolerated than phenol.7 The toxin blocks the release of
acetylcholine at the neuromuscular junction, causing weakness (reduced tone) in that muscle. The effect lasts three
months, after which collateral sprouting occurs. It is a relatively safe medication with few serious side effects.
Intrathecal delivery of medication is usually indicated when oral medications fail to control spasticity or side effects
are intolerable. The medication is delivered via a programmable pump that is usually implanted in the anterior
abdominal wall. It delivers small continuous or bolus amounts of drug (usually baclofen) into the spinal fluid.
Because the drug is acting locally at the level of the spinal cord, there are minimal cognitive side effects. The effect
on spasticity can be profound, although it is more effective for lower limb tone as there is a concentration gradient
8
from lumbar to cervical levels.
Therapeutic Tips
Treat the patient, not the spasticity. The goal is improved comfort or function.
Titrate medications slowly and to a maximum tolerated dose before switching/adding.
Consider earlier referral to a neurologist/physiatrist for focal treatment if the spasticity is limited to a focal area
and/or is of cerebral origin (therefore less likely to respond to oral agents).
Muscle spasms occurring during the night can interrupt sleep. Diazepam or clonazepam can be very helpful in
reducing these nocturnal spasms.
Page 855
Therapeutic Choice
Figure 1-Management of Chronic Spasticity
Table 1: Drug Therapy for Chronic Spasticity
a
Cost
Gamma baclofen Adults: Start with 5 mg Sedation, Potential additive CNS $$$
Aminobutyric Lioresal, BID to TID; titrate up by weakness, nausea, depression with tricyclic
Acid Derivatives generics 5–15 mg per day dizziness, lowered antidepressants, opioids,
Q3–5 days to a maximum seizure threshold. benzodiazepines and
of 120 mg/day in 3–4 antihypertensives.
divided doses
Children: Same titration
as for adults, but with a
maximum of 60 mg/day
Gamma gabapentin Adults: Start with 100 mg Sedation, Antacids may ↓ absorption $$$$
Aminobutyric Neurontin, TID; titrate up by dizziness, fatigue, of gabapentin; separate
Acid Derivatives generics 100 mg per dose Q3 days weight gain. doses by at least 2 h.
to a maximum of 800 mg
Page 856
Therapeutic Choice
Costa
QID
Skeletal Muscle dantrolene Adults: Start with 25 mg Hepatoxicity Caution with other $$$
Relaxants, Direct Dantrium BID to TID; titrate up by (monitor liver hepatotoxic agents.
-acting 25 mg per day Q3–5 days function tests), Muscle weakness may be
to a maximum of muscle weakness, additive if used with
400 mg/day in 3–4 nausea, sedation. other muscle relaxants.
divided doses Additive respiratory
Children: Start with depression with
0.5 mg/kg BID; titrate up benzodiazepines,
by 0.5 mg/kg per day barbiturates, opioids.
Q3–7 days to a maximum
of 400 mg daily in 3–4
divided doses
Alpha2- tizanidine Adults: Start with 2 mg Dry mouth, ↑ hypotensive effect with $$$$
Adrenergic Zanaflex, QHS; titrate up by sedation, antihypertensives. ↓
Agonists generics 2 mg per day Q3–5 days dizziness, clearance with oral
to a maximum of hypotension, contraceptives or TCAs. ↓
36 mg/day in 3–4 divided weakness, clearance with CYP1A2
doses hallucinations, inhibitors such as
hepatotoxicity cimetidine, ciprofloxacin,
(monitor liver fluvoxamine,
function tests). ketoconazole. May ↑
phenytoin levels.
Benzodiazepines diazepam Adults: Start with 2.5 mg Sedation, ataxia, Potentiates effects of $
Valium, QHS; titrate up by 2.5 mg weakness, other CNS depressants
generics Q3–7 days to a maximum dependence. including alcohol.
of 60 mg/day in 3–4
divided doses
For nocturnal spasms:
5–10 mg QHS
Children:
0.1–0.8 mg/kg/day in 2–3
divided doses
Benzodiazepines clonazepam Adults: 0.5–2 mg QHS Sedation, ataxia, Potentiates effects of $

Rivotril, weakness, other CNS depressants
generics dependence. including alcohol.
a.
Cost of 30-day supply at the maximum dose; includes drug cost only.
Legend: $ < $25 $$ $25–75 $$$ $75–125 $$$$ $125–175
Suggested Readings
Gracies J, Elovic E, McGuire J, Simpson D. Traditional pharmacologic treatments for spasticity. Part II. General and
regional treatments. Muscle Nerve Suppl 1997;6:S92-120.
Katz RT, Campagnolo DE. Pharmacologic management of spasticity. In: Katz RT, editor. Spasticity: state of the art
review. Vol. 8. Philadelphia (PA): Hanley & Belfus;1994. p. 473-80.
Page 857
Therapeutic Choice
References
1. Shakespeare DT, Boggild M, Young C. Anti-spasticity agents for multiple sclerosis. Cochrane Database Syst
Rev 2003;(4):CD001332.
2. Taricco M, Pagliacci MC, Telaro E et al. Pharmacological interventions for spasticity following spinal cord
injury: results of a Cochrane systematic review. Eura Medicophys 2006;42(1):5-15.
3. Nance PW, Bugaresti J, Shellenberger K et al. Efficacy and safety of tizanidine in the treatment of spasticity in
patients with spinal cord injury. North American Tizanidine Study Group. Neurology 1994;44(11 Suppl 9):S44
-51
4. Cutter NC, Scott DD, Johnson JC et al. Gabapentin effect on spasticity in multiple sclerosis: a placebo-
controlled, randomized trial. Arch Phys Med Rehabil 2000;81(2):164-9.
5. Zajicek J, Fox P, Sanders H et al. Cannabinoids for treatment of spasticity and other symptoms related to
multiple sclerosis (CAMS study): multicentre randomised placebo-controlled trial. Lancet 2003;362
(9395):1517-26.
6. Petro DJ, Ellenberg C. Treatment of human spasticity with delta 9-tetrahydrocannabinol. J Clin Pharmacol
1981;21(8-9 Suppl):413S-416S.
7. Simpson DM. Clinical trials of botulinum toxin in the treatment of spasticity. Muscle Nerve Suppl 1997;6:S169
-75.
8. Coffey JR, Cahill D, Steers W et al. Intrathecal baclofen for intractable spasticity of spinal origin: results of a
long-term multicenter study. J Neurosurg 1993;78(2):226-32.
Page 858
e-Therapeutics+ : Therapeutics : Neurologic Disorders: Headache in Adults Page 1 of 17
Therapeutic Choice
Print Close
Neurologic Disorders: Headache in Adults

R. Allan Purdy, MD, FRCPC
Goals of Therapy
Relieve or abolish pain and associated symptoms such as nausea/vomiting

Prevent recurrent symptoms in primary headache disorders, e.g., migraine, tension-type and cluster
Diagnose and manage serious causes of headache, e.g., tumor, arteritis, infection, hemorrhage
Prevent complications of medication usage
Investigations (Figure 1 - Diagnosis and Initial Assessment of Headache)
1
A thorough history and physical examination are most important for a correct diagnosis. Note characteristics of the headache:
onset: sudden versus gradual
temporal profile: progressive versus self-limited
frequency/pattern of recurrence: e.g., during menses (menstrual migraine), strictly unilateral (always on the same side)
and occurring in clusters separated by months or years (episodic cluster headache)
associated symptoms: nausea, vomiting, sensitivity to light, noise or odours, systemic or other neurologic signs or
symptoms
degree of interference with activities of daily life caused by migraine
The physical examination should be normal; if any abnormalities are found (especially visual, motor, reflex, sensory, speech
or cognitive), investigation is warranted
CT/MR scans are not routine but must be done if any organic etiology is suspected (see Table 1)
Lumbar puncture if subarachnoid hemorrhage, encephalitis, high- or low-pressure headache syndromes or meningitis is
suspected
Laboratory tests (on an individual basis)
ESR for suspected temporal arteritis
endocrine, biochemical, infection work-up
search for malignancy if indicated
Facial pain may need a thorough assessment by a dental specialist familiar with headaches and facial pain and/or an ENT
specialist if sinus or other ENT disorders are suspected
Table 1: Red Flags for Serious Headache
Red Flags
Age of onset Middle-aged to elderly patient
Type of onset Severe and abrupt
Temporal sequence Progressive severity or increased frequency
Pattern Significant change in headache pattern
Neurologic signs Stiff neck, focal signs, reduced consciousness
Systemic signs Fever, appears sick, abnormal examination
Caution: If headache does not fit typical pattern, a serious diagnosis can be missed.
Therapeutic Choices
If serious structural CNS causes for headache and facial pain have been ruled out, the primary headache disorders can be managed
2 , 3
as follows.
The management of headache is as much art as science; the science is improving, but the art remains important:
after serious causes are excluded, the interaction with the patient is the first and most important therapeutic choice
communicate with patients to let them know their headache is real, and that they have a specific diagnosis
determine patients' expectations and explain management options
Advise patients to:
avoid triggers, especially in migraine, e.g., too much or too little sleep, irregular meals, lack of regular exercise, extremes
of stress or relaxation, known dietary triggers
apply ice; sleep or rest in a dark, noise-free room
Try informal psychotherapy (family physician); refer to a psychologist or psychiatrist if psychiatric comorbidity present
Page 859
Therapeutic Choice
Try biofeedback, relaxation therapy, cognitive-behavioural therapy, psychotherapy, acupuncture and/or nerve blocks,
individualized to each patient3
Refer to neurologist and/or specialized headache or pain management unit if problems too complex, such as chronic daily
headache, or require multidisciplinary approach

4 , 5
Evidence-based guidelines for symptomatic and prophylactic therapies have been published. The following therapies are used
for management of migraine with or without aura.
Symptomatic Treatment
Analgesics
Ibuprofen, naproxen, and ASA or acetaminophen with or without codeine and/or butalbital, are used with some success for
mild to moderate headache pain. Medication-overuse headache can result from overuse of analgesics, which limits their long-term
potential. To avoid medication-overuse headache, nonopioid analgesics should be used less than 15 days per month; opioids and
combination analgesics should be used less than 10 days per month. Butalbital compounds and opioids have limited use in benign
headache disorders because of the potential for dependency.
Ergot Derivatives
Ergotamine acts on serotonin receptors and is classically used for migraine and cluster headaches but use is limited by side
effects. Ergotamine is available in many formulations and routes of administration. Ergot derivatives may produce rebound
headaches if used 10 days per month or more.
Dihydroergotamine mesylate (DHE) has similar actions to the triptans but also interacts centrally with dopamine and
adrenergic receptors, accounting for some of its side effects. It can be used to treat acute intractable headache or withdrawal from
analgesics. DHE produces no dependence.
Triptans
The triptans currently available to abort migraine include almotriptan, eletriptan, frovatriptan, naratriptan, rizatriptan,
sumatriptan and zolmitriptan. All act on serotonin (5-HT) subclass 1B and 1D receptors, on extracerebral blood vessels and
neurons respectively. The supposed mechanism of action is prevention of neurogenically sterile inflammatory responses around
vessels and vasoconstriction. The newer agents may alter pain transmission centrally at the level of the trigeminal nucleus of the
medulla, an action that may or may not have clinical benefits.
Subcutaneous sumatriptan has the fastest onset of action and remains the most efficacious triptan for a severe migraine attack. It
is also useful in an acute cluster headache. Naratriptan has the slowest onset of action with maximal efficacy at 4 hours, less
headache recurrence than the other agents and near placebo rates of side effects. Naratriptan may be best for moderately severe
migraine attacks and for individuals who have low tolerance for side effects or high pain recurrence rates.
6
Overall, there is now good evidence that the available triptans are efficacious, generally well tolerated and safe.
Meta-analyses reveal that differences among the triptans are relatively small, but may be clinically meaningful to
patients.7,8 However, the benefits in individual patients may vary, as may patient preference for specific
formulations (injection, nasal spray, tablets or fast-melt tablets).9 All triptans are contraindicated in patients with
cardiac disorders, sustained hypertension, basilar and hemiplegic migraine. Useful Info?
To avoid medication-overuse headache, triptans should be used less than 10 days per month.
Others
Corticosteroids can be useful in many headache disorders, including status migrainosus, cluster headache and cerebral
neoplasms with edema (especially metastatic lesions). Corticosteroids in temporal arteritis relieve headache and may prevent
blindness.
Phenothiazines (e.g., prochlorperazine or chlorpromazine) have been used in the emergency room for treatment of migraine
and other intractable headaches.
If no success is obtained with the above treatments for acute migraine, ketorolac im may be effective. Meperidine, administered
10
iv or im, should be regarded as a treatment of last resort. Indomethacin has been found useful in chronic paroxysmal
hemicrania and related disorders.
Antinauseants (e.g., dimenhydrinate 50–100 mg po PRN) and antiemetic/prokinetic agents (e.g., metoclopramide 10 mg po
or iv and domperidone 10–20 mg po) are useful as adjunctive therapy in headache disorders associated with nausea and
vomiting, or to facilitate absorption of medications in some patients. Metoclopramide iv is also used as a primary therapeutic agent
for headache with significant nausea and vomiting.
Page 860
Therapeutic Choice
Prophylactic Therapy (Table 3)
Prophylaxis is indicated if the migraine attacks are severe enough to interfere with the patient's quality of life, or if the patient has
3 or more severe attacks per month that fail to respond adequately to symptomatic therapy.
Beta-blockers
Beta-blockers are commonly used and efficacious in migraine prophylaxis; their mechanism of action is uncertain. Effective agents
lack partial agonist activity, but CNS penetration, membrane stabilization and cardioselectivity do not influence efficacy.
11
Propranolol has been the most studied beta-blocker for migraine prophylaxis. Because they may cross the blood-brain barrier
less than other beta-blockers, nadolol and atenolol may have fewer CNS side effects.
These drugs may work by modulating neurotransmitter function rather than producing vasodilation or protecting against hypoxia.
Verapamil is useful in migraine and cluster headache prophylaxis. Flunarizine is a selective calcium entry blocker and has good
efficacy in migraine.
Tricyclic Analgesics
Amitriptyline, nortriptyline and doxepin are effective for migraine and tension-type headache, acting as analgesics at doses
lower than those required for affective disorders. They do not produce dependence and are relatively safe medications in this
setting.
Antiepileptic Drugs
Valproic acid and divalproex sodium are effective in migraine prophylaxis and may work by modulating gamma aminobutyric
12
acid (GABA) receptors in the peripheral trigeminovascular system. Guidelines for use have been published. Teratogenicity
(neural tube defects) occurs.
13
Topiramate can be helpful in the management of some patients in doses up to 100 mg or occasionally higher. It should be
avoided in patients with renal stones and can cause increased intraocular pressure that responds to drug discontinuation; one side
effect that can be beneficial in some patients is weight loss. Start topiramate at a very low dose of 25 mg and increase very slowly
14
to avoid cognitive side effects.
Gabapentin shows promise in the prophylactic management of migraine. It is generally well tolerated and has few side effects or
15
drug interactions.
Serotonin Antagonists
Methysergide is a potent prophylactic medication for migraine and cluster headaches. It has potentially serious long-term side
effects and was voluntarily removed from the Canadian market in 2009. Although less potent than methysergide, pizotifen
(pizotyline) is helpful in migraine at maximal dosage if tolerated.
Others
Oral riboflavin (400 mg/day)16 has shown some efficacy in migraine prophylaxis but more trials are needed.
Lithium 300 mg TID is useful in the prophylactic management of chronic cluster headache.17
The role of botulinum toxin in the management of migraine is under investigation.
Choices during Pregnancy and Lactation
Migraine and Pregnancy/Postpartum Period
Migraine often improves during pregnancy but in roughly 30–40% it either worsens or does not change. Postpartum migraine flares
are common. The occurrence of migraine during pregnancy does not appear to increase the risk of preterm labour, low birth weight
or congenital abnormalities. However, migraine may be associated with a higher risk of maternal complications of pregnancy such
as gestational hypertension, pre-eclampsia and pregnancy-related stroke. When treating headache during pregnancy and the
postpartum period, a high degree of suspicion is prudent to avoid missing serious causes such as cerebral venous thrombosis, pre-
eclampsia/eclampsia, intracranial hemorrhage or headaches associated with epidural anesthesia.22 , 23 , 24
Page 861
Therapeutic Choice
Women with migraine should use effective contraception if pregnancy is not desired, particularly if they are taking medications that
are contraindicated during pregnancy. Folic acid supplementation (0.4–1 mg daily) is recommended, beginning at least 2–3
months prior to conception and continuing postpartum for at least 4–6 weeks, or as long as breastfeeding is continued. Women
taking medications that can interfere with folate function (e.g., barbiturates or valproate) should take folic acid 5 mg daily
beginning at least 3 months prior to conception and continuing until 10–12 weeks postconception, at which time they can switch to
a dose of 0.4–1 mg daily. When possible, preventive and acute headache medications should be discontinued before attempting to
22 , 23 , 24 , 25
conceive; this is also a logical time to begin training in nonpharmacologic measures such as biofeedback.
Management during Pregnancy and Postpartum Period
Nonpharmacologic approaches (see Nonpharmacologic Choices ) should be used first-line; for the majority of women whose
migraine improves during pregnancy, nonpharmacologic measures supplemented with occasional use of acetaminophen may
suffice. For women with frequent disabling headaches or who experience severe nausea and vomiting leading to dehydration, the
benefits of further drug treatment may outweigh the risks. Ibuprofen and naproxen can be used during the first or second
trimester but should be avoided in the latter stages of pregnancy because they may cause constriction of the fetal ductus arteriosis.
ASA, indomethacin and barbiturates should generally be avoided during pregnancy. Opioids such as meperidine or
acetaminophen/codeine are occasionally used for severe headache, but should be avoided near term because of the risk of
respiratory depression of the fetus. Severe nausea can be managed with metoclopramide or prochlorperazine.
Ergot derivatives restrict uterine blood flow and should not be used during pregnancy. Triptans are generally avoided as well,
although evidence is beginning to support a lack of additional risk to the mother or fetus. Vasoconstricting agents such as ergots
and triptans should also be avoided in the postpartum period because of a possible increased risk of postpartum stroke or
angiopathy.
When prophylactic medication is deemed necessary during pregnancy due to frequent, severe migraine or associated severe nausea
and vomiting, propranolol is the preferred agent. Beta-blockers have been associated with intrauterine growth retardation and
reduced placental weight; neonates exposed to beta-blockers near term should be monitored for symptoms such as bradycardia,
22 , 26
hypoglycemia and other potential effects of beta-blockade. Magnesium supplementation may also be reasonable
considering its efficacy when given iv for pre-eclampsia. Other preventive medications are generally avoided.
When possible, refer patients with severe migraine during pregnancy to a specialist in gynecologic endocrinology or to a high-risk
22 , 23 , 24
pregnancy clinic.
Migraine and Lactation
Lactation may have a positive effect on migraine activity, and breast-feeding should be encouraged. As in pregnancy, use
nonpharmacologic measures first-line during lactation. When medication is required, acetaminophen is the preferred abortive
agent. Avoid ergot derivatives, barbiturates, opioids and metoclopramide. Of the triptans, sumatriptan has been the most studied
in lactation and is considered compatible with breast-feeding, although it is prudent to avoid vasoconstricting agents in the initial
postpartum period; other triptans should be used with caution. For prophylaxis, propranolol is the preferred agent. Valproic
acid/divalproex sodium is considered compatible with breast-feeding. Other prophylactic agents should be avoided or used with
appropriate caution and monitoring of the effects on the infant.22 , 23 , 24
Resources
For a discussion of general principles of drug use during pregnancy and lactation see Appendix: Drug Use During Pregnancy and
Appendix: Drug Use During Lactation. For more detailed information on the use of specific headache medications during pregnancy
and lactation the reader is referred to Motherisk (www.motherisk.org/women/drugs.jsp); Briggs GG, Freeman RK, Yaffe SJ. Drugs
in Pregnancy and Lactation 2008; LactMed (toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen?LACT); and Hale TW. Medications and Mothers'
Milk 2008.
Chronic Daily Headache and Medication-overuse Headache
Chronic headache occurs daily or almost daily for 15 days per month, for 6 months or longer. The most common causes of these
headaches are transformed migraine and chronic tension-type headache. In the former there is history of migraine attacks and over
several years the migraine attacks become more frequent. Soon the migraine characteristics give way to chronic daily headache
with a daily or near-daily background headache that often resembles a typical “tension-type headache.” People with chronic
tension-type headache may have no history of distinct migraine.
Patients with these disorders frequently use excessive amounts of abortive agents, including ergots, acetaminophen, ASA and
opioid analgesics. They can have rebound headaches as a result of medication-overuse, while some may have symptoms of
18
depression or other psychological comorbidities. Rebound headaches can also occur with the overuse of triptans. Most will
improve in days or a few weeks with the discontinuation of these medications, especially mixed analgesics.
Page 862
Therapeutic Choice
Generally, simple analgesics should be used less than 15 days per month in primary headache disorders such as migraine or
tension-type headache or they will lead to the development of medication-overuse headache and chronic daily headache.19 Further,
if chronic daily headache develops, other useful abortive and prophylactic medications usually have less efficacy.
Management includes recognition of these disorders, tapering and stopping the offending agent(s), and starting a prophylactic
medication such as amitriptyline or another agent listed in Table 3. During withdrawal, particularly in patients with transformed
migraine, use abortive agents such as DHE or a triptan for treatment of the migraine headaches that emerge. Short-term
20 , 21
admission to hospital may be required to use the Raskin protocol (using DHE) and give support. If psychological
comorbidities such as depression are present, they must be managed and treated. Consider referral to a multidisciplinary pain
management clinic for cases failing to respond to therapy.
Therapeutic Tips
Give abortive treatment, without exceeding recommended dosages, as soon as possible.

Use simple analgesics less than 15 days per month, and ergots, triptans, opioids or analgesic combinations less than 10 days
per month.
A calendar or diary of headaches is useful in follow-up assessment.
Keep a record of medications (usefulness, dosage and side effects).
If migraine that does not respond adequately to symptomatic therapy occurs more than 3–4 times per month, try prophylactic
medications for several months and then discontinue if possible, to assess ongoing need.2
Different medications may need to be tried, including different members of the same class, such as triptans.
Follow-up is most important in managing chronic headache.
Reassurance and explanation are most important to the patient in the long term.
Always offer hope to patients with chronic headache even if no cure is available; most primary headaches can be controlled.
Figure 1- Diagnosis and Initial Assessment of Headache
a.
Any headache not recognized as migraine, tension headache or known cause is in the “other” group. Investigate if no response to usual
treatments.
Abbreviations: SAH = subarachnoid hemorrhage.
Table 2: Medications for Symptomatic Treatment of Headache
Adverse Drug
a
Class Drug Dose (per attack) Effects Interactions Comments Cost
Analgesics acetaminophen 650–1300 mg Q4H × 2 Potential Alcohol: Potential Use less than 15 $
Tylenol, generics doses hepatoxicity with hepatoxicity with days/month for
chronic use of chronic use of headache; great
high doses high doses risk of rebound
(particularly in (particularly in headache; for
heavy drinkers) heavy drinkers) symptomatic
or in acute treatment only.
Page 863
Therapeutic Choice
Adverse Drug
a
or in acute overdose. May
overdose. enhance
anticoagulant
effect of
warfarin,
particularly at
doses
> 1.3 g/day for
> 1 wk
Analgesics ASA 650–1300 mg Q4H × 2 GI upset Warfarin: ↑ Use less than 15 $

Coated Aspirin, doses (usually the only anticoagulant effect. days/month for
more common Antihypertensives headache; great
Bufferin, Aspirin,
adverse effect (diuretics, beta- risk of rebound
generics when single blockers, ACE headache; for
doses are used inhibitors, alpha- symptomatic
to treat acute blockers): treatment only.
headache). possible
For a detailed reduction in
description of hypertensive
adverse effects effect; may
associated with require additional
continuous or antihypertensive
frequent NSAID therapy.
use see Table 2,
Musculoskeletal Lithium may
Disorders: interfere with
sodium/water
Osteoarthritis.
balance. Monitor
lithium levels
when NSAID
added.
↑ risk of GI bleeding
with SSRIs.
Analgesics ibuprofen 400–800 mg Q6H × 2 GI upset Warfarin: ↑ Use less than 15 $

Advil, Motrin, doses (usually the only anticoagulant effect. days/month for
generics more common Antihypertensives headache; great
adverse effect (diuretics, beta- risk of rebound
when single blockers, ACE headache; for
doses are used inhibitors, alpha- symptomatic
to treat acute blockers): treatment only.
headache). possible
use see Table 2,
sodium/water
Osteoarthritis.
balance. Monitor
lithium levels
when NSAID
added.
with SSRIs.
Analgesics ketorolac 30–60 mg im; max Pain at the Warfarin: ↑ $

Toradol IM, 120 mg/24 h injection site, anticoagulant
generics sweating, GI effect.
upset. Antihypertensives
(diuretics, beta-
blockers, ACE
inhibitors, alpha-
blockers):
Page 864
Therapeutic Choice
Adverse Drug
a
possible
reduction in
hypertensive
effect; may
require additional
antihypertensive
therapy.
Lithium may
interfere with
sodium/water
balance. Monitor
lithium levels
when NSAID
added.
↑ risk of GI
bleeding with
SSRIs.
Analgesics naproxen 250–500 mg Q2–6H; max GI upset Warfarin: ↑ Use less than 15 $
Naprosyn, 1000 mg/day (usually the only anticoagulant effect. days/month for
generics more common Antihypertensives symptomatic
adverse effect (diuretics, beta- treatment of
when single blockers, ACE headache.
doses are used inhibitors, alpha-
to treat acute blockers):
headache). possible
use see Table 2,
sodium/water
Osteoarthritis.
balance. Monitor
lithium levels
when NSAID
added.
with SSRIs.
Analgesics naproxen sodium 275–550 mg Q2–6H; max GI upset Warfarin: ↑ Use less than 15 $
1100 mg/day (usually the only anticoagulant effect. days/month for
Anaprox, generics more common Antihypertensives symptomatic
adverse effect (diuretics, beta- treatment of
when single blockers, ACE headache.
doses are used inhibitors, alpha- Useful in
to treat acute blockers): preventing
headache). possible premenstrual
For a detailed reduction in migraine attacks
description of hypertensive when taken BID
adverse effects effect; may perimenstrually
associated with require additional for 2 wk, starting
continuous or antihypertensive 7 days before
frequent NSAID therapy. 28
menses.
use see Table 2,
sodium/water
Osteoarthritis.
balance. Monitor
lithium levels
when NSAID
added.
Page 865
Therapeutic Choice
Adverse Drug
a
with SSRIs.
Analgesics, butalbital (with 50–100 mg Q4H × 2 Dependence, Additive sedation Use less than 10 $
Combination ASA, caffeine ± doses tolerance. with other CNS days/month to
codeine) depressants avoid medication
Fiorinal, (e.g., alcohol). -overuse
Fiorinal C ¼, C ½, headache.
generics
Analgesics, codeine (with ASA 15–60 mg Q4H × 2 doses Dependence, Additive sedation Use less than 10 $
Combination or acetaminophen tolerance. with other CNS days/month to
± caffeine) depressants avoid medication
222s, Atasol-8, - (e.g., alcohol); -overuse
15, -30, inhibitors of headache.
CYP2D6 (e.g.,
Tylenol No 1, 2 or
amiodarone,
3, cimetidine,
generics fluoxetine,
moclobemide,
paroxetine,
quinidine) may
antagonize
codeine's
analgesic effect.
Ergot ergotamine (± Oral: 2 mg at onset then Chest pain, See Comments. Use less than $
Derivatives belladonna 1 mg Q1H PRN × 3 doses tingling, nausea, 10 days/month to
alkaloids ± Rectal: 1 mg at onset; vomiting, avoid medication
caffeine ± max 3 mg in 24 h paresthesias, -overuse
dimenhydrinate ± cramps, headache;
phenobarbital) vasoconstriction; contraindicated
Bellergal ergot in pregnancy,
Spacetabs, dependence cardiac disorders,
producing hypertension,
Cafergot,
ergotism. sepsis, PVD,
PUD, renal or
liver disease or
in patients taking
potent inhibitors
of CYP3A4 (e.g.,
cimetidine,
clarithromycin,
efavirenz,
erythromycin,
itraconazole,
ketoconazole and
ritonavir);
caution in
elderly.
Ergot dihydroergotamine Parenteral: 0.5–1 mg sc, Same as for Use less than Not as potent a Parenteral:
Derivatives (DHE) im or iv; may repeat at 1 ergotamine but 10 days/month vasoconstrictor $
Migranal, generics h; max 4 doses/24 h less frequent to avoid as ergotamine; Nasal: $
(Administration of DHE is and less medication- mainly
preceded by prolonged; overuse venoconstrictor;
metoclopramide 10 mg iv watch for headache; same
or prochlorperazine 5 mg hypotension contraindicated contraindications
20 , 21 (rare). in pregnancy, as ergotamines;
iv) Administer iv
meds slowly. Nasal cardiac no dependence;
Nasal: 1 spray (0.5 mg) formulation: disorders, good for attacks
in each nostril; may rhinitis, nausea, hypertension, beginning in
repeat in 15 min if no taste sepsis, PVD, emergency room
effect; max 2 mg/day disturbance. PUD, renal or and in treating
liver disease or medication-
in patients taking overuse
potent inhibitors headaches.
of CYP3A4 (e.g., Nasal spray:
cimetidine, convenient,
clarithromycin, bypasses GI
efavirenz, tract.
Page 866
Therapeutic Choice
Adverse Drug
a
erythromycin,
itraconazole,
ketoconazole and
ritonavir);
caution in
elderly.
Triptans almotriptan Oral: 6.25–12.5 mg; if All triptans: See Comments. All triptans: do $$$
Axert headache returns after chest Almotriptan: not use if any
initial relief, may repeat discomfort, inhibitors of cardiac-like
in 2 h; max 2 doses/24 h fatigue, CYP3A4 (e.g., symptoms;
dizziness, cimetidine, contraindicated
paresthesias, clarithromycin, in ischemic heart
drowsiness, efavirenz, disease,
nausea, throat erythromycin, sustained
symptoms. grapefruit juice, hypertension,
itraconazole, pregnancy,
ketoconazole and basilar or
ritonavir) may hemiplegic
increase migraine,
bioavailability of ergotamine-
almotriptan. containing
products or with
MAOIs (except
eletriptan,
frovatriptan and
naratriptan);
caution with
SSRIs or SNRIs
(increased risk of
serotonin
syndrome); do
not use a triptan
within 24 h after
another triptan;
use less than
10 days/month to
avoid medication
-overuse
headache.
Second dose not
likely to be
effective if first
dose provided no
relief.
Triptans eletriptan Oral: 20–40 mg; if All triptans: See Comments. All triptans: do $$$
Relpax headache returns after chest Eletriptan: not use if any
initial relief from discomfort, contraindicated cardiac-like
20 mg dose, may take an fatigue, within 72 h of symptoms;
additional 20 mg in 2 h; dizziness, the following contraindicated
max 40 mg/24 h paresthesias, inhibitors of in ischemic heart
drowsiness, CYP3A4: disease,
nausea, throat clarithromycin, sustained
symptoms. itraconazole, hypertension,
ketoconazole, pregnancy,
nelfinavir and basilar or
ritonavir, or any hemiplegic
potent inhibitor migraine,
of CYP3A4. ergotamine-
containing
products or with
MAOIs (except
eletriptan,
frovatriptan and
naratriptan);
caution with
SSRIs or SNRIs
(increased risk of
serotonin
syndrome); do
not use a triptan
Page 867
Therapeutic Choice
Adverse Drug
a
within 24 h after
another triptan;
use less than
10 days/month to
avoid medication
-overuse
headache.
Second dose not
likely to be
effective if first
dose provided no
relief.
Triptans frovatriptan Oral: 2.5 mg; if All triptans: See Comments. All triptans: do $$$
Frova headache recurs after chest Frovatriptan: oral not use if any
initial relief, may repeat discomfort, contraceptives cardiac-like
in 4–24 h; max 5 mg/24 fatigue, and propranolol symptoms;
h dizziness, may increase contraindicated
paresthesias, frovatriptan in ischemic heart
drowsiness, serum disease,
nausea, throat concentrations by sustained
symptoms. 30–60%. hypertension,
pregnancy,
basilar or
hemiplegic
migraine,
ergotamine-
containing
products or with
MAOIs (except
eletriptan,
frovatriptan and
naratriptan);
caution with
SSRIs or SNRIs
(increased risk of
serotonin
syndrome); do
not use a triptan
within 24 h after
another triptan;
use less than
10 days/month to
avoid medication
-overuse
headache.
Second dose not
likely to be
effective if first
dose provided no
relief.
Triptans naratriptan Oral: 1–2.5 mg; if All triptans: See Comments. All triptans: do $$
Amerge, generics headache returns after chest not use if any
initial relief, may repeat discomfort, cardiac-like
dose in 4 h; max fatigue, symptoms;
5 mg/24 h dizziness, contraindicated
paresthesias, in ischemic heart
drowsiness, disease,
nausea, throat sustained
symptoms. hypertension,
Naratriptan may pregnancy,
be associated basilar or
with fewer side hemiplegic
effects than migraine,
other triptans. ergotamine-
containing
products or with
MAOIs (except
eletriptan,
Page 868
Therapeutic Choice
Adverse Drug
a
frovatriptan and
naratriptan);
caution with
SSRIs or SNRIs
(increased risk of
serotonin
syndrome); do
not use a triptan
within 24 h after
another triptan;
use less than
10 days/month to
avoid medication
-overuse
headache.
Second dose not
likely to be
effective if first
dose provided no
relief.
Triptans rizatriptan Oral: 5–10 mg; if All triptans: See Comments. All triptans: do $$$
Maxalt, Maxalt headache returns after chest Rizatriptan: use not use if any
RPD initial relief, may repeat discomfort, with caution in cardiac-like
dose in 2 h; max fatigue, patients taking symptoms;
20 mg/24 h dizziness, propranolol (↑ contraindicated
paresthesias, bioavailability of in ischemic heart
drowsiness, rizatriptan). disease,
pregnancy,
basilar or
hemiplegic
migraine,
ergotamine-
containing
products or with
MAOIs (except
eletriptan,
frovatriptan and
naratriptan);
caution with
SSRIs or SNRIs
(increased risk of
serotonin
syndrome); do
not use a triptan
within 24 h after
another triptan;
use less than
10 days/month to
avoid medication
-overuse
headache.
Second dose not
likely to be
effective if first
dose provided no
relief.
Rizatriptan:
fastmelt wafers
can be taken
without water.
Triptans sumatriptan Oral: 25–100 mg; if All triptans: See Comments. All triptans: do Oral: $$
Imitrex, Imitrex headache returns after chest not use if any SC: $$$$$
DF, generics initial relief, may repeat discomfort, cardiac-like
in 2 h; max 200 mg/24 h fatigue, symptoms; Nasal: $$$
Injectable: 6 mg sc; may dizziness, contraindicated
Page 869
Therapeutic Choice
Adverse Drug
a
repeat in 1 h; max 2 paresthesias, in ischemic heart
injections/24 h drowsiness, disease,
Nasal spray: nausea, throat sustained
5–20 mg intranasally; symptoms. hypertension,
may repeat in 2 h; max Nasal spray: pregnancy,
40 mg/24 h taste basilar or
disturbance, hemiplegic
nausea. migraine,
ergotamine-
containing
products or with
MAOIs (except
eletriptan,
frovatriptan and
naratriptan);
caution with
SSRIs or SNRIs
(increased risk of
serotonin
syndrome); do
not use a triptan
within 24 h after
another triptan;
use less than
10 days/month to
avoid medication
-overuse
headache.
Second dose not
likely to be
effective if first
dose provided no
relief.
Sumatriptan
nasal spray:
faster onset than
with oral
formulations.
Triptans zolmitriptan Oral: 2.5–5 mg; may All triptans: See Comments. All triptans: do $$$
Zomig, Zomig repeat in 2 h; max chest Maximum dose of not use if any
Rapimelt, Zomig 10 mg/24 h discomfort, zolmitriptan cardiac-like
Nasal Spray: 2.5 or fatigue, 5 mg/24 h if also symptoms;
Nasal Spray
5 mg; may repeat in 2 h; dizziness, on fluvoxamine contraindicated
max 10 mg/24 h paresthesias, or cimetidine. in ischemic heart
drowsiness, disease,
pregnancy,
basilar or
hemiplegic
migraine,
ergotamine-
containing
products or with
MAOIs (except
eletriptan,
frovatriptan and
naratriptan);
caution with
SSRIs or SNRIs
(increased risk of
serotonin
syndrome); do
not use a triptan
within 24 h after
another triptan;
use less than
10 days/month to
avoid medication
Page 870
Therapeutic Choice
Adverse Drug
a
-overuse
headache.
Second dose not
likely to be
effective if first
dose provided no
relief.
Zolmitriptan:
orally dispersible
tablets can be
taken without
water; nasal
spray available
as 2.5 or 5 mg
per dose.
a.
Cost per dose; includes drug cost only.
Abbreviations: PUD=peptic ulcer disease; PVD=peripheral vascular disease
Legend: $ < $5 $$ $5–10 $$$ $10–20 $$$$ $20–30 $$$$$ > $30
Table 3: Medications for Prophylactic Treatment of Headache
Costa
Beta1- atenolol 50–150 mg per day Fatigue, impotence, Possible bradycardia Contraindicated in $
adrenergic Tenormin, bradycardia and with dipyridamole; asthma, insulin-
Antagonists generics hypotension, GI antacids may decrease dependent diabetes or
symptoms, absorption. heart block; avoid
bronchospasm, abrupt withdrawal;
CHF, depression. consider long-acting
formulations.
Atenolol and nadolol
may have fewer CNS
side effects.
Beta1- metoprolol 100–200 mg per Fatigue, impotence, Possible bradycardia Contraindicated in $

adrenergic Lopresor, day bradycardia and with dipyridamole; asthma, insulin-
Antagonists Betaloc, hypotension, GI antacids may decrease dependent diabetes or
generics symptoms, absorption. heart block; avoid
formulations.
Beta1- nadolol 20–160 mg per day Fatigue, impotence, Possible bradycardia Contraindicated in $
adrenergic generics bradycardia and with dipyridamole; asthma, insulin-
Antagonists hypotension, GI antacids may decrease dependent diabetes or
formulations.
Nadolol and atenolol
may have fewer CNS
side effects.
Beta1- propranolol 40–240 mg per day Fatigue, impotence, Possible bradycardia Contraindicated in $
adrenergic generics bradycardia and with dipyridamole; asthma, insulin-
Antagonists hypotension, GI antacids may decrease dependent diabetes or
abrupt withdrawal;
Page 871
Therapeutic Choice
a
Cost
bronchospasm, consider long-acting
CHF, depression. formulations.
May be used in
pregnancy if deemed
necessary.
Calcium flunarizine 5–10 mg QHS Weight gain, Long latency to onset; $–$$
Channel generics extrapyramidal many patients have
Blockers effects, side effects;
drowsiness, contraindicated in
depression. hypotension, heart
failure and
arrhythmia; avoid if
severe constipation.
Do not use flunarizine
in depressed patients
or those with
extrapyramidal
disorders.
Calcium verapamil 240–320 mg per Bradycardia, Inhibits CYP3A4 and Long latency to onset; $$
Channel Isoptin SR, day hypotension, may decrease the many patients have
Blockers generics constipation. clearance of CYP3A4 side effects;
substrates (e.g., contraindicated in
lovastatin, sildenafil). hypotension, heart
failure and
arrhythmia; avoid if
severe constipation.
Do not use flunarizine
in depressed patients
or those with
extrapyramidal
disorders.
Antiepileptic topiramate Start with 25 mg CNS effects (e.g., Additive depressant May increase risk of $$
Drugs Topamax, daily, titrate slowly dizziness, ataxia, effects with other CNS nephrolithiasis;
generics to minimum tremor, sedation, depressants. maintain adequate
effective dose cognitive May ↓ effectiveness of low hydration during
(usual maintenance impairment), GI dose oral contraceptives; therapy; avoid in
range 50–100 mg symptoms (e.g., use at least 30 μg patients with renal
daily in 2 divided nausea, dyspepsia, estrogen. stones.
doses) constipation), May cause acute
weight loss (can be Inhibitors of CYP2C19 myopia, with
beneficial in some may ↑ topiramate levels consequent angle
patients). (e.g., SSRIs, isoniazid, closure glaucoma that
omeprazole, responds to drug
moclobemide). discontinuation;
advise patients to
Phenytoin and consult an
carbamazepine can ↓ ophthalmologist or
topiramate levels. emergency room
immediately if they
have acute painful/red
eyes or
decreased/blurred
vision.
Warn patients about

CNS depressant
effects; possible risk
associated with
driving, other
hazardous activities.
Antiepileptic valproic acid, Initial: Nausea, alopecia, Inhibits CYP2C9 and Do liver function tests $–$$
Drugs (valproate) 250–500 mg/day tremor, weight may ↓ the clearance of prior to initiation of
Page 872
Therapeutic Choice
a
Cost
Depakene, Usual: gain, ↑ hepatic substrates (e.g., fluoxetine, therapy and
generics 500–1500 mg/day enzymes; neural tube fluvastatin, sertraline, periodically, especially
defects can occur if verapamil, warfarin); in the 1st 6 mo of
used during avoid ASA or warfarin; therapy and if
pregnancy. carbamazepine, symptoms of hepatic
phenytoin and dysfunction occur.
phenobarbital can
significantly ↑
clearance; may ↑
depressant effect of
alcohol.
Antiepileptic divalproex Initial: Nausea, alopecia, Inhibits CYP2C9 and Do liver function tests $–$$
Drugs sodium 250–500 mg/day tremor, weight may ↓ the clearance of prior to initiation of
Epival, Usual: gain, ↑ hepatic substrates (e.g., fluoxetine, therapy and
generics 500–1500 mg/day enzymes; neural tube fluvastatin, sertraline, periodically, especially
defects can occur if verapamil, warfarin); in the 1st 6 mo of
used during avoid ASA or warfarin; therapy and if
pregnancy. carbamazepine, symptoms of hepatic
phenytoin and dysfunction occur.
phenobarbital can
significantly ↑
clearance; may ↑
depressant effect of
alcohol.
Tricyclic amitriptyline 10–150 mg QHS All TCAs: weight All TCAs: ↑ sedation All TCAs: dose can be $
Analgesics generics gain, drowsiness, with other CNS cumulative,
(TCAs) anticholinergic depressants (e.g., adjustments needed;
symptoms (e.g., alcohol). contraindicated if
dry mouth, Amitriptyline: significant cardiac
constipation), metabolized by many disease, glaucoma,
lower seizure cytochrome P450 prostate disease or
threshold, enzymes—clearance hypotension; start
confusion. may be affected by with low dosage in
inhibitors (e.g., elderly or in patients
cimetidine, sensitive to these
ciprofloxacin, agents.
clarithromycin,
diltiazem,
erythromycin,
fluoxetine,
fluvoxamine, isoniazid,
itraconazole,
ketoconazole,
paroxetine, valproic
acid), inducers (e.g.,
phenobarbital,
carbamazepine,
phenytoin, rifampin,
smoking) or other
substrates of these
enzymes.
Tricyclic doxepin 25–100 mg QHS All TCAs: weight All TCAs: ↑ sedation with All TCAs: dose can be $
Analgesics Sinequan, gain, drowsiness, other CNS depressants cumulative,
(TCAs) Apo-Doxepin, anticholinergic (e.g., alcohol). adjustments needed;
other generics symptoms (e.g., Doxepin: metabolized contraindicated if
dry mouth, by CYP2D6; clearance significant cardiac
constipation), may be altered by disease, glaucoma,
lower seizure inducers (e.g., prostate disease or
threshold, carbamazepine, hypotension; start
confusion. phenobarbital, with low dosage in
phenytoin, rifampin), elderly or in patients
inhibitors (e.g., sensitive to these
celecoxib, fluoxetine, agents.
imatinib, paroxetine,
quinidine) or other
substrates of the
enzyme.
Page 873
Therapeutic Choice
Costa
Tricyclic nortriptyline 10–150 mg QHS All TCAs: weight All TCAs: ↑ sedation with All TCAs: dose can be $
Analgesics Aventyl, gain, drowsiness, other CNS depressants cumulative,
(TCAs) generics anticholinergic (e.g., alcohol). adjustments needed;
symptoms (e.g., Nortriptyline: contraindicated if
dry mouth, metabolized by CYP1A2 significant cardiac
constipation), and CYP2D6. Clearance disease, glaucoma,
lower seizure may be affected by prostate disease or
threshold, inducers (e.g., hypotension; start
confusion. carbamazepine, with low dosage in
phenobarbital, elderly or in patients
primidone, phenytoin, sensitive to these
rifampin, smoking), agents.
inhibitors (e.g.,
celecoxib, cimetidine,
ciprofloxacin,
clarithromycin,
diltiazem,
erythromycin, ethinyl
estradiol, fluvoxamine,
isoniazid,
ketoconazole,
fluoxetine, imatinib,
paroxetine, quinidine)
or other substrates of
either enzyme.
Serotonin pizotifen Start with Drowsiness, weight Additive sedation with Consider QHS dosing $–
Antagonists Sandomigran, 0.5 mg QHS, gain. other CNS depressants at increasingly higher $$$$
Sandomigran gradually ↑ to TID; if (e.g., alcohol). doses.
DS necessary to 3 or
6 mg/day (usual
dose: 1–6 mg)
Others lithium GI upset, tremor, ACE inhibitors and Used in chronic cluster $
Carbolith, 300 mg TID polyuria, angiotensin II receptor headache;
hypothyroidism. blockers ↓ lithium contraindicated in
Lithane,
clearance; NSAIDs and renal dysfunction,
Duralith,
thiazide diuretics ↑ dehydration, CHF.
generics
lithium serum levels; a
potential effect on
lithium levels should
be considered
whenever other drugs
are started or
discontinued.
a.
Legend: $ < $20 $-$$ < $20–40 $$ $20–40 $-$$$ < $20–60 $$$ $40–60 $-$$$$ < $20– > 60 $$$$ > $60
Suggested Readings
Pryse-Phillips WE, Dodick DW, Edmeads JG et al. Guidelines for the diagnosis and management of migraine in clinical practice.
Canadian Headache Society. CMAJ 1997;156(9):1273-87.
Pryse-Phillips WE, Dodick DW, Edmeads JG et al. Guidelines for the nonpharmacologic management of migraine in clinical
practice. Canadian Headache Society. CMAJ 1998;159(1):47-54.
References
Page 874
Therapeutic Choice
1. Purdy RA. Clinical evaluation of a patient presenting with headache. Med Clin North Am 2001;85(4):847-63.
2. Pryse-Phillips WE, Dodick DW, Edmeads JG et al. Guidelines for the diagnosis and management of migraine in clinical
3. Pryse-Phillips WE, Dodick DW, Edmeads JG et al. Guidelines for the nonpharmacologic management of migraine in clinical
4. Silberstein SD. Practice parameter: evidence-based guidelines for migraine headache (an evidence-based review): report of
the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2000;55(6):754-62.
5. Snow V, Weiss K, Wall EM et al. Pharmacologic management of acute attacks of migraine and prevention of migraine
headache. Ann Intern Med 2002;137(10):840-9.
6. Dodick D, Lipton RB, Martin V et al. Consensus statement: cardiovascular safety profile of triptans (5-HT agonists) in the
acute treatment of migraine. Headache 2004;44(5):414-25.
7. Ferrari MD, Goadsby PJ, Roon KI et al. Triptans (serotonin, 5-HT1B/1D agonists) in migraine: detailed results and methods
of a meta-analysis of 53 trials. Cephalalgia 2002;22(8):633-58.
8. Ferrari MD, Roon KI, Lipton RB et al. Oral triptans (serotonin 5-HT(1B/1D) agonists) in acute migraine treatment: a meta-
analysis of 53 trials. Lancet 2001;358(9294):1668-75.
9. Dodick DW, Silberstein S, Dahlof CG. Is there a preferred triptan? Headache 2002;42(1):1-7.
10. Friedman BW, Kapoor A, Friedman MS et al. The relative efficacy of meperidine for the treatment of acute migraine: a meta-
analysis of randomized controlled trials. Ann Emerg Med 2008;52(6):705-13.
11. Linde K and Rossnagel K. Propranolol for migraine prophylaxis. Cochrane Database Syst Rev 2004;(2):CD003225.
12. Silberstein SD. Divalproex sodium in headache: literature review and clinical guidelines. Headache 1996;36(9):547-55.
13. Brandes JL, Saper JR, Diamond M et al. Topiramate for migraine prevention: a randomized controlled trial. JAMA 2004;291
(8):965-73.
14. Young WB, Hopkins MM, Shechter AL et al. Topiramate: a case series study in migraine prophylaxis. Cephalalgia 2002;22
(8):659-63.
15. Silberstein SD, Goadsby PJ. Migraine: preventive treatment. Cephalalgia 2002;22(7):491-512.
16. Schoenen J, Jacquy J, Lenaerts M. Effectiveness of high-dose riboflavin in migraine prophylaxis. A randomized controlled
trial. Neurology 1998;50(2):466-70.
17. Bussone G, Leone M, Peccarisi G et al. Double blind comparison of lithium and verapamil in cluster headache prophylaxis.
Headache 1990;30(7):411-7.
18. Limmroth V, Katsarava Z, Fritsche G et al. Features of medication overuse headache following overuse of different acute
headache drugs. Neurology 2002;59(7):1011-4.
19. Silberstein SD, Welch KM. Painkiller headache. Neurology 2002;59(7):972-4.
20. Raskin NH. Repetitive intravenous dihydroergotamine as therapy for intractable migraine. Neurology 1986;36(7):995-7.
21. Raskin NH. Modern pharmacotherapy of migraine. Neurol Clin 1990;8(4):857-65.
22. Loder E. Migraine in pregnancy. Semin Neurol 2007;27(5):425-33.
23. Menon R, Bushnell CD. Headache and pregnancy. Neurologist 2008;14(2):108-18.
24. Loder E, Silberstein SD. Headaches in women. In: Silberstein SD, Lipton RB, Dodick DW, editors.Wolff’s headache and other
head pain. 8th ed. Oxford: Oxford University Press; 2008.
25. Wilson RD, Johnson JA, Wyatt P et al. Pre-conceptional vitamin/folic acid supplementation 2007: the use of folic acid in
combination with a multivitamin supplement for the prevention of neural tube defects and other congenital anomalies. J
Obstet Gynaecol Can 2007;29(12):1003-26.
26. Briggs GG, Freeman RK, Yaffe, SJ. Drugs in pregnancy and lactation: a reference guide to fetal and neonatal risk. 8th ed.
Philadelphia (PA): Lippincott Williams and Wilkins; 2008.
27. Drugs and Lactation Database (LactMed). Bethesda (MD): U.S. National Library of Medicine. Available from:
http://toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen?LACT. Accessed October 21, 2009.
28. Sances G, Martignoni E, Fioroni L et al. Naproxen sodium in menstrual migraine prophylaxis: a double-blind placebo
controlled study. Headache 1990;30(11):705-9.
Page 875
e-Therapeutics+ : Therapeutics : Neurologic Disorders: Headache in Children Page 1 of 10
Therapeutic Choice
Print Close
Neurologic Disorders: Headache in Children
Sharon Whiting, MBBS, FRCPC
Headaches occur commonly in children and adolescents. They may occur as a primary disorder such as migraine, or accompany
systemic disorders or infectious diseases. In Canada, more than 25% of 12- to 13-year-olds experience headache at least
weekly.1 The prevalence of migraine shows an increase with age, i.e., 2.4% in 12- to 14-year-olds and 5% in 15- to 19-year-
olds.2
Migraine in children is usually associated with at least one of the following: vomiting, photophobia, family history of migraine.
Goals of Therapy
Make an accurate diagnosis of headache

Relieve or abort pain and associated symptoms
Prevent further headaches
Investigations (Figure 1 - Investigations Based on Headache Profile )
The history is the key to the diagnosis of headache and should be obtained from both parent and child with attention to:
specific questions such as where pain began, progress, duration, frequency, relieving and aggravating factors
(especially sleep loss, excitement, certain foods, relief with activity) and associated symptoms such as vomiting and
photophobia
specific neurologic symptoms such as seizures, visual disturbances, difficulty with balance, personality change,
weakness
analgesic use
degree of interference with school and social life, e.g., pedMIDAS questionnaire3
symptoms suggestive of renal, cardiac, dental or infectious disease
mother's pregnancy/labour/delivery, with respect to the child in question
child's growth and development, behaviour, academic function
Note: During the interview, observe interaction between parent and child.
blood pressure, vital signs, palpation of sinuses, examination of teeth, neck stiffness, examination of optic fundi
height, weight, head circumference
a thorough neurologic examination including cranial nerves, muscle tone, power and reflexes and coordination tests
Investigations:
sinus x-rays if sinusitis suspected
CT followed by lumbar puncture with measurement of opening pressure if pseudotumor cerebri suspected based on
history of raised intracranial pressure with a negative CT
lumbar puncture if infectious process suspected
CT and/or MRI if abnormal neurologic examination, decreased visual acuity, recent behaviour change, increasing
severity and frequency of headaches, or if headache does not fit a known pattern
The routine use of any diagnostic study is not indicated when the clinical history has no associated risk factors and the
4
child's examination is normal
Tension-type Headache
Therapeutic Choices
Therapeutic Choices
Psychological evaluation
Relaxation therapy
Biofeedback
Page 876
Therapeutic Choice
Simple analgesics (acetaminophen, ASA) and NSAIDs, such as ibuprofen or naproxen, are effective for the treatment
of acute tension-type headache (Table 1). Because of the possible association with Reye's syndrome, avoid ASA in children
and adolescents for headache or fever associated with viral illness such as influenza or chickenpox.5
Amitriptyline (Table 2) is effective as a prophylaxis in patients with a component of depression.6 Preventive therapy may
be appropriate when headaches are frequent and significantly disabling and disruptive.
Medication-overuse Headache
The occurrence of headache induced by chronic use of analgesics, such as acetaminophen and NSAIDs, is now recognized in
pediatric patients. Treatment involves education and gradual withdrawal of analgesic drugs. Consider use of a prophylactic
7
agent (Table 2).
Migraine
Therapeutic Choices
Therapeutic Choices
After exclusion of mass lesion or other causes:
Provide reassurance and information about the headache condition.

Discuss triggers of migraine, e.g., lack of sleep, too much sleep, excitement, foods, stress, menstruation.
Encourage sleep at the time of headache and medication early in the course of the headache.
Biofeedback and relaxation therapy are effective.
These can be divided into medication given at the time of the headache (symptomatic) and medication to prevent headache
8
(prophylactic).
Symptomatic Treatments (Table 1)
Analgesics
Intermittent oral analgesics, given as early in the course of the headache as feasible, are the mainstay of pharmacologic
management of childhood migraine. Acetaminophen, ibuprofen and ASA are effective at appropriate doses.9 As for tension-
type headache, avoid ASA in children and adolescents for fever or headache associated with viral illness such as varicella or
influenza. Two evaluations of the evidence for treatment of migraine in children concluded that ibuprofen and acetaminophen
8 , 10
are effective.
Combination products, such as ASA, caffeine and butalbital ± codeine (e.g., Fiorinal), play secondary roles should the initial
agents fail. These sedating drugs have abuse potential and should be reserved for adolescents (12–18 years) for brief periods
only. Take care to avoid unnecessary opioids.
Antiemetics
Nausea and vomiting occur in up to 90% of young migraine sufferers and besides being disabling, inhibit oral
administration of analgesics. Antiemetics alone (e.g., chlorpromazine, prochlorperazine, metoclopramide) are
11
surprisingly effective in relieving all symptoms including the headache. Useful Info? Chlorpromazine combined with
12
chloral hydrate to induce sleep is an effective regimen in childhood migraine.
Ergot Derivatives
Page 877
Therapeutic Choice
Ergotamine compounds have very limited use in pediatrics for the following reasons:
Auras are uncommon and inconsistent; therefore, warning indicators that trigger the time to treat with ergot are often
unreliable.
Ergots can exacerbate gastrointestinal upset.
Ergots are contraindicated in complicated migraine syndromes because of the risk of increasing vasospasm.
Oral dihydroergotamine showed no significant difference in headache improvement in a study comparing it with placebo.13 In
severe intractable headache, dihydroergotamine can be used iv in combination with an antiemetic in the emergency
department.14
Triptans
Of the 7 agents available in Canada (almotriptan, eletriptan, frovatriptan, naratriptan, rizatriptan, sumatriptan and
zolmitriptan), none are specifically approved for use in children, though several studies have demonstrated an excellent safety
profile in children age 12–18 years.15 Consider triptans for use in adolescents with moderate to severe headaches unresponsive
to conventional analgesics.16 Nasal sumatriptan is effective and should be considered for acute treatment in adolescents 12
years and older.8 , 10 , 15 Unpleasant taste is a common side effect.
Prophylactic Agents (Table 2)
A practice parameter on the pharmacologic treatment of childhood migraine examined the evidence for efficacy for several
medications.8 Although many are in current use and may be effective, only flunarizine was deemed probably effective based
on evidence. Flunarizine has been shown to significantly reduce headache frequency and severity in children.17 , 18
Although evidence of its efficacy is lacking, pizotifen (pizotyline) may be helpful.
Evidence for propranolol is conflicting, although it is commonly used and is effective in some cases.19 Propranolol is
contraindicated in reactive airway disease, diabetes mellitus and bradyarrhythmias. Symptoms of depression are an under-
reported but common side effect in adolescents.
Despite a lack of evidence of efficacy, cyproheptadine, an antihistamine with antiserotonergic and calcium channel blocking
properties, is widely used as a prophylactic agent. Its use in older children and adolescents is limited by sedation and increased
appetite/weight gain.
Amitriptyline has shown efficacy in adults; studies in children are limited.20
NSAIDs reduce headache frequency and severity in adults, presumably through prostaglandin inhibition. Although evidence of
efficacy in children is lacking, naproxen sodium can be tried in adolescents as prophylaxis (see Therapeutic Tips).
Valproic acid has been studied in children;21 however, there is insufficient evidence to recommend its use.8 Phenobarbital and
phenytoin are no longer used.
Topiramate is approved for migraine prophylaxis in adults. While not specifically approved for use in children it is used in
adolescents.22
Therapeutic Tips
There are very few controlled trials of pharmacologic management of childhood migraine; hence, anecdotal experience
prevails. Most young patients with migraine do not require daily medication but need access to reliable analgesia at home
and at school.
Children are debilitated by nausea and vomiting and benefit greatly from antiemetics. Rest and sleep are usually very
helpful.
Consider prophylactic agents for children who cycle through periods of time when they experience such frequency of
headache that their lifestyle is disrupted, or when isolated or infrequent events are severe and complex.
For prophylaxis, consider medications with the fewest side effects first. Cyproheptadine is usually used in younger children.
For adolescents, consider using propranolol, amitriptyline, naproxen sodium or flunarizine.
A period of 6–12 months is a reasonable trial of prophylactic medication, followed by very gradual tapering and
discontinuation to assess ongoing need.
Calendars/diaries are helpful in identifying triggers, headache patterns, frequency and severity and are invaluable for
management and evaluation of response to therapy.
The prognosis for children with migraine is favourable with 50% of patients reporting improvement within 6 months after
medical intervention, regardless of treatment methods used.
Most children respond to reassurance, general advice and simple remedies for attacks when they occur.
Page 878
Therapeutic Choice
Figure 1- Investigations Based on Headache Profile
Table 1: Treatment of Headache in Children
b
Adverse Drug Cost
a
Analgesics acetaminophen GI upset; liver May enhance Analgesics are the $

Atasol 10–15 mg/kg/dose toxicity in anticoagulant most commonly used
Q4H overdose. effect of warfarin, abortive medications
Preparations,
particularly with for headache. Limit
Tempra, Tylenol, doses of use to < 15 days per
generics > 1.3 g/day for mo to avoid
> 1 wk medication-overuse
headache
Analgesics ASA Age ≥ 12 y: single GI upset Warfarin: ↑ Because of the $

Aspirin, Bufferin, dose of (usually the only anticoagulant effect. concern of Reye's
500– 650 mg per more common syndrome, ASA
Coated Aspirin,
headache adverse effect should not be used in
generics when single the context of
doses are used headache or fever
to treat acute associated with a
headache). viral illness; do not
For a detailed use more frequently
description of than Q4–6H.
adverse effects
associated with
continuous or
frequent NSAID
use see Table 2,
Musculoskeletal
Disorders:
Osteoarthritis
Analgesics ibuprofen 5–10 mg/kg/dose, up GI upset Warfarin: ↑ $

Advil, Motrin to 4 times daily (usually the only anticoagulant effect.
more common
Children's, Motrin
adverse effect
IB, generics when single
doses are used
to treat acute
headache).
For a detailed
description of
Page 879
Therapeutic Choice
b
Adverse Drug Cost
a
adverse effects
associated with
continuous or
frequent NSAID
use see Table 2,
Musculoskeletal
Disorders:
Osteoarthritis
Analgesics naproxen sodium Age > 2 y: GI upset Warfarin: ↑ $

5– 7 mg/kg/dose Q8– (usually the only anticoagulant effect.
Aleve, Anaprox, 12H more common
generics adverse effect
when single
doses are used
to treat acute
headache).
For a detailed
description of
adverse effects
associated with
continuous or
frequent NSAID
use see Table 2,
Musculoskeletal
Disorders:
Osteoarthritis
Analgesics, butalbital + ASA + 1–2 tablets 4 times GI upset; Possible additive Reserved for $
combination caffeine ± codeine daily dependence and sedation with adolescents; no more
Fiorinal, Fiorinal tolerance to other CNS than 2 days/wk; risk
barbiturates and depressants, e.g., of tolerance,
C1/4, C1/2,
opioids. alcohol. addiction and misuse.
generics
Antiemetics chlorpromazine Oral/IM: Hypotension. Possible additive Can be used with $

generics 1 mg/kg to a max of sedation with chloral hydrate
25 mg Q8H other CNS 25– 50 mg/kg
IV: depressants, e.g., po Q8H.
0.1 mg/kg Q10–15 alcohol. Can cause
min prn to a max of hypotension when
30 mg given iv; used in the
emergency
department.
Antiemetics prochlorperazine Oral: Extrapyramidal Possible additive Used iv in $

generics 2.5– 5 mg twice daily dysfunction. sedation with adolescents in the
IV: 10 mg other CNS emergency
depressants, e.g., department.
alcohol.
Antiemetics metoclopramide IV: Extrapyramidal Possible enhanced Use iv in adolescents $

generics 0.1– 0.2 mg/kg dysfunction. sedative effect of in the emergency
(≤ 10 mg) alcohol. department. See also
May repeat once if dihydroergotamine.
necessary; max 20 mg
Ergot dihydroergotamine IV: 0.1–0.25 mg/dose Parenteral: Do not use with Parenteral: useful in $
Derivatives (DHE) May be repeated Q20 Flushed feeling, potent inhibitors patients with severe
Migranal, generics min × 3. Give tingling in of CYP3A4 such as and prolonged
metoclopramide extremities, cimetidine, migraine headache;
0.2 mg/kg/dose (max nausea and clarithromycin, protocol to take place
20 mg) 30 min prior vomiting. efavirenz, in hospital;
Page 880
Therapeutic Choice
b
Adverse Drug Cost
a
to iv DHE. Nasal Spray: erythromycin, contraindicated in
Nasal spray: 1 spray Nausea, taste itraconazole, complicated
into each nostril. May disturbance, ketoconazole and migraine, coronary
repeat in 15 min rhinitis. ritonavir. heart disease,
abnormal blood
pressure, abnormal
ECG.
Triptans almotriptan Oral: 6.25 mg at start Chest All triptans: Do Consider for $$$$
Axert of headache; if discomfort, not use with adolescents 12–18
headache returns, fatigue, ergotamine- years unresponsive to
dose may be repeated dizziness, containing conventional
after paresthesias, products. Caution analgesics; do not
2 h; no more than 2 drowsiness, with SSRIs. Do use if any cardiac-
doses in a 24-h period nausea, throat not use a triptan like symptoms;
symptoms. within 24 h after contraindicated in
another triptan. ischemic heart
Almotriptan: Do disease, sustained
not use with hypertension,
MAOIs. Inhibitors pregnancy, basilar or
of CYP3A4 (e.g., hemiplegic migraine;
cimetidine, use less than
clarithromycin, 10 days/mo to avoid
efavirenz, medication-overuse
erythromycin, headache.
grapefruit juice,
itraconazole,
ketoconazole and
ritonavir) may
increase
bioavailability of
almotriptan.
Triptans eletriptan Oral: 20–40 mg as Chest All triptans: Do Consider for $$$$
Relpax soon after headache discomfort, not use with adolescents 12–18
onset as possible; if fatigue, ergotamine- years unresponsive to
initial dose is 20 mg dizziness, containing conventional
and headache returns paresthesias, products. Caution analgesics; do not
after ≥ 2 h, may drowsiness, with SSRIs. Do use if any cardiac-
repeat 20 mg dose; nausea, throat not use a triptan like symptoms;
max 40 mg in a 24-h symptoms. within 24 h after contraindicated in
period another triptan. ischemic heart
Eletriptan: disease, sustained
Contraindicated hypertension,
within 72 h of the pregnancy, basilar or
following hemiplegic migraine;
inhibitors of use less than
CYP3A4: 10 days/mo to avoid
clarithromycin, medication-overuse
itraconazole, headache.
ketoconazole,
nelfinavir and
ritonavir, or any
potent inhibitor of
CYP3A4.
Triptans frovatriptan Oral: 2.5 mg; if Chest All triptans: Do Consider for $$$$
Frova headache recurs after discomfort, not use with adolescents 12–18
initial relief, may fatigue, ergotamine- years unresponsive to
repeat in 4– 24 h; max dizziness, containing conventional
5 mg/24 h paresthesias, products. Caution analgesics; do not
drowsiness, with SSRIs. Do use if any cardiac-
nausea, throat not use a triptan like symptoms;
another triptan. ischemic heart
Frovatriptan: Oral disease, sustained
contraceptives hypertension,
and propranolol pregnancy, basilar or
may increase hemiplegic migraine;
frovatriptan serum use less than
concentrations by 10 days/mo to avoid
30–60%.
Page 881
Therapeutic Choice
b
Adverse Drug Cost
a
medication-overuse
headache.
Triptans naratriptan Oral: 1 mg at start of Chest All triptans: Do Consider for $$$$
Amerge headache; if partial discomfort, not use with adolescents 12–18
response or headache fatigue, ergotamine- years unresponsive to
returns, dose may be dizziness, containing conventional
repeated once after 4 paresthesias, products. Caution analgesics; do not
h; max dose of 5 mg drowsiness, with SSRIs. Do use if any cardiac-
in a 24-h period nausea, throat not use a triptan like symptoms;
Naratriptan may another triptan. ischemic heart
be associated disease, sustained
with fewer side hypertension,
effects than the pregnancy, basilar or
other triptans. hemiplegic migraine;
use less than
10 days/mo to avoid
medication-overuse
headache.
Triptans rizatriptan Oral: Chest All triptans: Do Consider for $$$$

Maxalt, Maxalt 5–10 mg (tablet or discomfort, not use with adolescents 12–18
RPD wafer) at start of fatigue, ergotamine- years unresponsive to
headache dizziness, containing conventional
paresthesias, products. Caution analgesics; do not
Do not repeat if no drowsiness, with SSRIs. Do use if any cardiac-
st nausea, throat not use a triptan like symptoms;
relief from 1 dose; if
headache returns 2 h symptoms. within 24 h after contraindicated in
or more after partial or another triptan. ischemic heart
complete relief from Rizatriptan: Do disease, sustained
an initial 5 mg dose, not use with hypertension,
may repeat 5 mg dose MAOIs. Use with pregnancy, basilar or
(daily max 10 mg) caution in patients hemiplegic migraine;
taking propranolol use less than
(↑ bioavailability of 10 days/mo to avoid
rizatriptan). medication-overuse
headache.
Fastmelt wafers can
be taken without
water.
Triptans sumatriptan Chest All triptans: Do Consider for $$$

Imitrex Nasal 25 mg tablet or discomfort, not use with adolescents 12–18
Spray, Imitrex DF, 20 mg nasal spray at fatigue, ergotamine- years unresponsive to
generics start of headache dizziness, containing conventional
Do not repeat if no paresthesias, products. Caution analgesics; do not
relief from 1st dose; if drowsiness, with SSRIs. Do use if any cardiac-
headache returns 2 h nausea, throat not use a triptan like symptoms;
or more after 1st dose,
Nasal spray may another triptan. ischemic heart
may repeat dose (daily
cause taste Sumatriptan: Do disease, sustained
max 2 doses)
disturbance. not use with hypertension,
MAOIs. pregnancy, basilar or
hemiplegic migraine;
use less than
10 days/mo to avoid
medication-overuse
headache.
Faster onset with
nasal spray than with
oral formulations.
Triptans zolmitriptan Chest All triptans: Do Consider for $$$$

Zomig, Zomig 2.5–5 mg (tablet, discomfort, not use with adolescents 12–18
Rapimelt, Zomig orally dispersible fatigue, ergotamine- years unresponsive to
tablet or nasal spray) dizziness, containing conventional
Nasal Spray
at start of headache paresthesias, products. Caution analgesics; do not
Page 882
Therapeutic Choice
b
Adverse Drug Cost
Class Drug Dosea Effects Interactions Comments
Do not repeat if no drowsiness, with SSRIs. Do use if any cardiac-
relief from 1st dose; if nausea, throat not use a triptan like symptoms;
headache returns 2 h symptoms. within 24 h after contraindicated in
Nasal spray may another triptan. ischemic heart
or more after 1st dose,
cause taste Zolmitriptan: Do disease, sustained
may repeat dose (daily
disturbance. not use with hypertension,
max 2 doses)
MAOIs. Maximum pregnancy, basilar or
dose of hemiplegic migraine;
5 mg/24 h if also use less than
taking 10 days/mo to avoid
fluvoxamine or medication-overuse
cimetidine. headache.
Zolmitriptan orally
dispersible tablets
can be taken without
water.
a.
Not to exceed maximum adult dose.
b.
Cost per dose, based on 20 kg body weight; includes drug cost only.
Legend: $ < $1 $$ $1–5 $$$ $5–10 $$$$ > $10
Table 2: Prophylaxis of Headache in Children
Adverse Drug Costb

Class Druga Dose Effects Interactions Comments
Beta1- propranolol Oral: 0.6– Fatigue, Antacids may Contraindicated in $

adrenergic generics 1.5 mg/kg/day in bradycardia, decrease asthma, diabetes,
Antagonists divided doses hypotension, absorption. heart block,
depression. bradyarrhythmias,
pregnancy; avoid
abrupt
withdrawal.
Calcium flunarizine Oral: Bradycardia, Additive sedation May take several $$

Channel generics 5 mg/day hypotension, with other CNS weeks to be
Blockers depression, depressants. effective; do not
drowsiness. use in depressed
patients or those
with
extrapyramidal
disorders.
Antihistamines cyproheptadine Age 2– 6 y: Drowsiness, Possible additive More useful in $$$

generics 2 mg Q8– weight gain. sedation with younger children;
12H (max other CNS use in older
12 mg/day) depressants, e.g., children and
Age 7– 14 y: alcohol. adolescents
4 mg Q8– limited by
12H (max sedation and
16 mg/day) increased
appetite/weight
gain.
NSAIDs naproxen sodium For a detailed Warfarin: ↑ Used in Aleve

Aleve, Anaprox, generics 220– 550 mg description of anticoagulant effect. adolescents. OTC:
twice daily adverse effects Antihypertensives $$
associated with (diuretics, beta- Rx:
continuous blockers, ACE $$$
NSAID use, see inhibitors, alpha-
Table 2, blockers):
Musculoskeletal possible
reduction in
hypertensive
Page 883
Therapeutic Choice
b
Adverse Drug Cost
Class Druga Dose Effects Interactions Comments
Disorders: effect; may
Osteoarthritis require additional
antihypertensive
therapy.
Lithium may
interfere with
sodium/water
balance. Monitor
lithium levels
when NSAID
added.
Tricyclic amitriptyline Weight gain, Possible additive Contraindicated in $

Analgesics generics 10– 150 mg/day drowsiness; sedation with significant cardiac
(TCAs) anticholinergic other CNS disease or
symptoms such depressants, e.g., hypotension.
as dry mouth alcohol;
and metabolized by
constipation. cytochrome P450
enzyme system—
clearance may be
affected by
inhibitors (e.g.,
erythromycin,
fluoxetine,
fluvoxamine,
isoniazid,
itraconazole,
ketoconazole,
paroxetine,
valproic acid),
inducers (e.g.,
phenobarbital,
carbamazepine,
phenytoin,
rifampin) or other
substrates of
these enzymes.
Antiepileptic topiramate Start at 25 mg Most common: Avoid use with Used in $$$$
Drugs Topamax, generics daily, increase somnolence, alcohol or other adolescents.
by 25 mg daily anorexia, CNS depressants.
at weekly weight loss,
intervals to 100 paresthesias.
mg/day in 1 or 2 Less common:
divided doses psychomotor
slowing,
metabolic
acidosis.
Serotonin pizotifen Oral: 0.5– Sedation and Possible additive Start medication $$-
Antagonists Sandomigran/Sandomigran 1.5 mg/day in weight gain. sedation with slowly and $$$
DS divided doses other CNS increase over 1–
depressants 3 wk.
including alcohol.
a.
Not to exceed maximum adult dose.
b.
Abbreviations: OTC=over the counter or nonprescription; Rx=prescription product
Legend: $ < $5 $$ $5–20 $$-$$$ $5–40 $$$ $20–40 $$$$ $40–80
Page 884
Therapeutic Choice
Suggested Readings
Friedman G. Advances in paediatric migraine. Paediatr Child Health 2002;7(4):239-43.
Guidetti V, Galli F. Recent development in paediatric headache. Curr Opin Neurol 2001;14(3):335-40.
Lewis DW. Headaches in children and adolescents. Am Fam Physician 2002;65(4):625-32.
Lewis DW. Toward the definition of childhood migraine. Curr Opin Pediatr 2004;16(6):628-36.
Winner P. Pediatric headache.Curr Opin Neurol2008;21(3):316-22.
References
1. Dooley JM, Gordon KE, Wood EP. Frequent headaches in Canadian adolescents: prevalence and associated features. Eur J
Pediatr Neurol 2003;7:357-8.
2. Gordon KE, Dooley JM, Wood EP. Prevalence of reported migraine headaches in Canadian adolescents. Can J Neurol Sci
2004;31(3):324-7.
3. Hershey AD, Powers SW, Vockell AL et al. PedMIDAS: development of a questionnaire to assess disability of migraines in
children. Neurology 2001;57(11):2034-9.
4. Lewis DW, Ashwal S, Dahl G et al. Practice parameter: evaluation of children and adolescents with recurrent headaches:
report of the Quality Standards Subcommittee of the American Academy of Neurology and the Practice Committee of the
Child Neurology Society. Neurology 2002;59(4):490-8.
5. Steiner TJ, Lange R, Voelker M. Aspirin in episodic tension-type headache: placebo-controlled dose-ranging comparison
with paracetamol. Cephalalgia 2003;23(1):59-66.
6. Hershey AD, Powers SW, Bentti AL et al. Effectiveness of amitriptyline in the prophylactic management of childhood
headaches. Headache 2000;40(7):539-49.
7. Mathew NT, Kurman R, Perez F. Drug induced refractory headache--clinical features and management. Headache 1990;30
(10):634-8.
8. Lewis D, Ashwal S, Hershey A et al. Practice parameter: pharmacological treatment of migraine headache in children and
adolescents: report of the American Academy of Neurology Quality Standards Subcommittee and the Practice Committee
of the Child Neurology Society. Neurology 2004;63(12):2215-24.
9. Hamalainen ML, Hoppu K, Valkeila E et al. Ibuprofen or acetaminophen for the acute treatment of migraine in children: a
double-blind, randomized, placebo-controlled, crossover study. Neurology 1997;48(1):103-7.
10. Damen L, Bruijn JK, Verhagen AP et al. Symptomatic treatment of migraine in children: a systematic review of medication
trials. Pediatrics 2005;116(2):e295-302.
11. Iserson KV. Parenteral chlorpromazine treatment of migraine. Ann Emerg Med 1983;12(12):756-8.
12. Logan P, Lewis D. Towards evidence based emergency medicine: best BETs from the Manchester Royal Infirmary.
Chlorpromazine in migraine.Emerg Med J 2007;24(4):297-300.
13. Hamalainen ML, Hoppu K, Santavuori PR. Oral dihydroergotamine for therapy-resistant migraine attacks in children.
Pediatr Neurol 1997;16(2):114-7.
14. Linder SL. Treatment of childhood headache with dihydroergotamine mesylate. Headache 1994;34(10):578-80.
15. Ahonen K, Hamalainen ML, Rantala H et al. Nasal sumatriptan is effective in treatment of migraine attacks in children: a
randomized trial. Neurology 2004;62(6):883-7.
16. Friedman G. Advances in paediatric migraine. Paediatr Child Health 2002;7(4):239-43.
17. Sorge F, De Simone R, Marano E et al. Flunarizine in prophylaxis of childhood migraine. A double-blind, placebo-
controlled, crossover study. Cephalalgia 1988;8(1):1-6.
18. Martinez-Lage JM. Flunarizine (Sibelium) in the prophylaxis of migraine. An open, long-term, multicenter trial. Cephalalgia
1988;8(Suppl 8):15-20.
19. Ludvigsson J. Propranolol used in prophylaxis of migraine in children. Acta Neurol Scand 1974;50(1):109-15.
20. Hershey AD, Powers SW, Bentti AL et al. Effectiveness of amitriptyline in the prophylactic management of childhood
headaches. Headache 2000;40(7):539-49.
21. Caruso JM, Brown WD, Exil G et al. The efficacy of divalproex sodium in the prophylactic treatment of children with
migraine. Headache 2000;40(8):672-6.
22. Winner P, Gendolla A, Stayer C et al. Topiramate for prevention of migraine in adolescents: a pooled analysis of efficacy
and safety. Headache 2006;46:1503-10.
Page 885
e-Therapeutics+ : Therapeutics : Neurologic Disorders: Muscle Cramps Page 1 of 3
Therapeutic Choice
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Neurologic Disorders: Muscle Cramps
Virginia Devonshire, MD, FRCPC
Muscle cramps are sudden, involuntary contractions of one or more muscle groups. They are caused by
hyperexcitability of the anterior horn cells or peripheral nerves that subserve them. Cramps are common and
increase in frequency with age. They can last up to a quarter of an hour and are typically painful. They often recur
multiple times and can leave residual pain. Common cramps typically occur at rest (usually at night, involving the
calf or foot) or after overuse. Cramps are usually idiopathic but can be associated with acute extracellular volume
depletion (diarrhea, vomiting, excessive sweating; “heat cramps”), medications, metabolic disorders including
hormonal changes (pregnancy, hypothyroidism, uremia, liver disease), hereditary disorders and rarely, autoimmune
conditions (antibodies against voltage-gated potassium channels).
Goals of Therapy
Prevent and relieve cramps
Investigations
Check for contributing factors such as excessive muscle use, acute volume depletion.
Perform laboratory tests for BUN, creatinine, sodium, potassium, magnesium, calcium, thyroid, glucose and CK.
Check for iatrogenic causes: diuretics, angiotensin receptor blockers, lithium, cyclosporine, nifedipine,
cholesterol-lowering agents, salbutamol, donepezil, phenothiazines and alcohol.
Consider underlying pathology if cramps occur in unusual muscle groups or during activities, or if they occur in
the setting of weakness, muscular atrophy/fasciculations or sensory symptoms, though some may still be
benign, i.e., cramp-fasciculation syndrome.
electromyography to rule out motor neuron disease or peripheral neuropathy
Differentiate from spasms, spasticity, dystonia (co-contraction of agonist/antagonist muscles during a
movement or posture), restless legs, tetany, myalgias and contractures (originate from muscle; associated with
exercise and metabolic myopathies).
Therapeutic Choices
Patients should be reassured of the benign nature of cramps, and nonpharmacologic treatments should be the
mainstay. Most cramps can be relieved by stretching the affected muscle. For calf cramps, the patient stands two
feet from a wall and leans into the wall, stretching the Achilles tendon. Fluid imbalances can be corrected, and
regular stretching may be of benefit in preventing cramps.
Quinine sulfate has been used for decades to manage nocturnal leg cramps; its proposed mechanism of
action involves decreasing the responsiveness of the motor endpoint to nerve stimulation by increasing
the muscle refractory period. A recent report by a subcommittee of the American Academy of Neurology
1
found class I evidence of the efficacy of quinine. However, because of potentially serious side effects
and toxicity such as cardiac arrhythmias, visual or gait disturbances, tinnitus and potentially fatal
thrombocytopenia, even at the doses used to manage nocturnal leg cramps, quinine is not
recommended for the routine management of this condition. For severe symptoms when other
measures have failed, a trial of quinine may be reasonable (200–300 mg QHS for 4–6 weeks), provided
the patient is properly monitored and informed of the risks. Treatment should be interrupted every 3
2
months to assess further need. Useful Info?
There is minimal evidence for other therapies for leg cramps. A crossover trial of vitamin E failed to show any
3 4 , 5
benefit. Results for magnesium supplementation (300–900 mg per day) have been mixed. Small, randomized,
double-blind or cross-over studies have shown potential benefit of diltiazem 30 mg daily,6 vitamin B complex7 and
orphenadrine citrate.8 Open-labelled trials of gabapentin9 and verapamil 10 showed some potential benefit. These
Page 886
Therapeutic Choice
studies are of insufficient sample size to allow for recommendation of the respective therapies; therefore, risk-
benefit analysis must guide therapy for individual patients.
Therapeutic Tips
Check patient’s medication history carefully before treating cramps.

Use quinine cautiously, only if cramps are frequent and severe and nonpharmacologic measures have failed.
Regularly reassess use of quinine, as cramps can resolve spontaneously or after a short duration of therapy.
Cramps rarely need referral unless associated with other neurologic complaints or signs.
Table 1: Management of Nocturnal Leg Cramps
Costa
Cinchona quinine For patients with Headache, dizziness, May potentiate the Advise patients $
Alkaloids sulfate severe symptoms in tinnitus, gait effect of warfarin — of potential
generics whom other disturbances, visual monitor INR; may ↓ risks and
measures have impairment, cardiac digoxin clearance — monitor for
failed: trial of arrhythmias, monitor serum serious side
200–300 mg QHS × potentially fatal concentration; effects. With
4–6 wk; may thrombocytopenia. ketoconazole may ongoing use,
continue if beneficial reduce quinine withdraw
and well tolerated clearance and ↑ therapy every 3
toxicity; rifampin months to
may ↑ quinine reassess need.
clearance and reduce
effectiveness.
a.
Legend: $ $5–15
Suggested Readings
Butler JV, Mulkerrin EC, O’Keeffe ST. Nocturnal leg cramps in older people. Postgrad Med J 2002;78(924):596-8.
MedicineNet.com. Muscle cramps (of skeletal muscles). San Clemente (CA): MedicineNet. Available from:
www.medicinenet.com/muscle_cramps/article.htm. Accessed December 2, 2010.
References
1. Katzberg HD, Khan AH, So YT. Assessment: symptomatic treatment for muscle cramps (an evidence-based
review): report of the therapeutics and technology assessment subcommittee of the American Academy of
Neurology. Neurology 2010;74(8):691-6.
2. Coppin RJ, Wicke DM, Little PS. Managing nocturnal leg cramps–calf-stretching exercises and cessation of
quinine treatment: a factorial randomized controlled trial. Br J Gen Pract 2005;55(512):186-91.
3. Connolly PS, Shirley EA, Wasson JH et al. Treatment of nocturnal leg cramps. A crossover trial of quinine vs
vitamin E. Arch Intern Med 1992;152(9):1877-80.
4. Frusso R, Zarate M, Augustovski F et al. Magnesium for the treatment of nocturnal leg cramps: a crossover
randomized trial. J Fam Pract 1999;48(11):868-71.
5. Roffe C, Sills S, Crome P et al. Randomised, cross-over, placebo controlled trial of magnesium citrate in the
treatment of chronic persistent leg cramps. Med Sci Monit 2002;8(5):CR326-30.
6. Voon WC, Sheu SH. Diltiazem for nocturnal leg cramps. Age Ageing 2001;30(1):91-2.
7. Chan P, Huang TY, Chen YJ et al. Randomized, double-blind, placebo-controlled study of the safety and
efficacy of vitamin B complex in the treatment of nocturnal leg cramps in elderly patients with hypertension. J
Clin Pharmacol 1998;38(12):1151-4.
8. Latta D. An alternative to quinine in nocturnal leg cramps. Current Therapeutic Research 1989;45(5):833-7.
Page 887
Therapeutic Choice
9. Serrao M, Rossi P, Cardinali P et al. Gabapentin treatment for muscle cramps: an open-label trial. Clin
Neuropharmacol 2000;23(1):45-9.
10. Baltodano N, Gallo BV, Weidler DJ. Verapamil vs quinine in recumbent nocturnal leg cramps in the elderly.
Arch Intern Med 1988;148(9):1969-70.
Page 888
e-Therapeutics+ : Therapeutics : Neurologic Disorders: Parkinson's Disease Page 1 of 9
Therapeutic Choice
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Neurologic Disorders: Parkinson's Disease

D.A. Grimes, MD, FRCPC
Parkinson’s disease (PD) is a chronic, progressive, neurodegenerative disease whose cardinal features are tremor,
bradykinesia and rigidity. Currently available treatments significantly decrease morbidity and mortality; however, no
1
treatment to date has been shown to impact the underlying disease process. Medications providing the most benefit
are directed at replenishing dopamine within the brain.
Goals of Therapy
Improve functioning and quality of life

Minimize acute and long-term side effects of medications
Instil a positive outlook, despite the chronic, progressive nature of PD
Investigations
The clinical diagnosis of PD can be made with confidence if the classic features of a unilateral or asymmetric
resting tremor plus bradykinesia and rigidity are present. The patient’s earliest complaints may include fatigue,
general slowness, poor handwriting and a tremulous feeling in one arm, without obvious tremor.
Postural instability, autonomic dysfunction, dementia, impaired eye movements, rapid progression and poor
response to dopaminergic therapy are not features of early PD, and if present suggest a different diagnosis.
Perform imaging studies in young patients or those with atypical features. Exclude Wilson’s disease in young
patients by performing a serum ceruloplasmin, a slit-lamp examination and a 24-hour urine for copper.
Exclude drug-induced parkinsonism. The most common drug causes include first- and second-generation
antipsychotics and central dopamine-blocking antiemetics, e.g., metoclopramide and prochlorperazine.
Therapeutic Choices
Patient education via books, websites and local and national Parkinson societies (all available through the
Parkinson Society of Canada, www.parkinson.ca).
Stress importance of staying active and having a regular exercise routine.
Encourage awareness of the important roles of allied health professionals such as speech, physical and
occupational therapists.
Pharmacologic Choices (Figure 1 - Initial Pharmacologic Management of Parkinson’s

Disease)
Levodopa
Levodopa is converted to dopamine within presynaptic dopaminergic neurons. Although used alone when first
discovered, today it is combined with a dopamine decarboxylase inhibitor, carbidopa or benserazide, to minimize
acute side effects.
There has been concern that levodopa could be toxic to already damaged dopaminergic neurons through a
2
mechanism involving excess oxidative stress. There is little evidence for this in recent in vitro studies and no good
3
evidence from in vivo animal models or human studies.
Over time, many PD patients develop symptoms such as dysarthria, gait disorders, postural instability and cognitive
dysfunction that are poorly responsive to levodopa therapy. The cause is mainly disease-related degeneration of
nondopaminergic neuronal systems, and not that levodopa has become ineffective for the initial symptoms for which
it was started.2 , 3
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Therapeutic Choice
Though initially effective, levodopa therapy is eventually complicated by motor fluctuations and dyskinesia; these
4 , 5
complications develop in up to 50% of patients after 5 years. In the early stages of PD, patients enjoy a long-
lasting response following a single dose of levodopa. With disease progression and longer-term treatment, patients
begin to experience motor fluctuations, such as end-of-dose “wearing-off” of effectiveness or periods of fluctuating
response known as “on-off” phenomena, and a variety of patterns of dyskinesia such as peak-dose dyskinesia
(occurring during the peak effect of the dose), diphasic dyskinesia (occurring at the beginning and/or end of a
dosing interval) and off-period dystonia (painful spasms, usually of the feet, occurring upon morning rising or when
a dose is wearing off). The pathophysiology of these motor complications is not completely understood, but the
leading theory suggests they are related to pulsatile stimulation of dopamine receptors resulting from intermittent
5
dosing and levodopa’s short plasma half-life.
Factors shown to increase the risk of levodopa-induced dyskinesia include higher doses of levodopa, longer duration
of treatment, severity of the underlying nigral degeneration and a younger age of disease onset.5 Delaying the use
of levodopa, especially in young-onset patients, has become the standard of practice in many movement disorder
centres. Slow-release preparations of levodopa benefit patients having difficulty with “wearing-off,” although good
randomized trials are lacking;6 there is no evidence that initiating treatment with controlled-release levodopa
7
provides an advantage over immediate-release formulations. A variety of strategies can be used to help treat
patients who have developed “wearing-off” or dyskinesia (Figure 2 - Management of Levodopa-associated Motor
Complications).
Dopamine Agonists
Bromocriptine, pramipexole and ropinirole are effective as monotherapy in the early stages of the disease, and
as adjunctive therapy with levodopa for more advanced patients with motor complications.6 , 7 Pergolide was
withdrawn from the Canadian market in 2007 because of its association with cardiac valvulopathy; it is now
available through Health Canada's Special Access Programme for patients who meet specific criteria. A transdermal
patch containing rotigotine is expected to become available. Compared to levodopa, dopamine agonists are
associated with fewer motor complications in the first 5 years of the disease, but it is not known if this translates
6 , 7
into long-term benefit for patients. Although all clinical trials demonstrate a lower efficacy compared to
7 , 8
levodopa, this difference does not seem to affect quality-of-life scores in early disease. Because of the lower
incidence of motor complications, dopamine agonists are typically used as initial therapy in younger patients, then
levodopa is added in the case of poor tolerance or inadequate benefit, or later because of waning efficacy of the
dopamine agonist.
Because bromocriptine can cause pulmonary fibrosis, the newer, non-ergot dopamine agonists
9,10
(pramipexole and ropinirole) are better choices. Daytime sleepiness or sudden irresistible attacks of
sleep can occur with all of the dopamine replacement medications, including levodopa. Sudden attacks
11
of sleep seem to occur more frequently with the newer dopamine agonists. Personality changes such
as hypersexual behaviour and pathologic gambling have also been associated with these medications;
12
discuss these rare but important side effects with your patient. Additional difficulties with dopamine
agonists, compared to levodopa, include more GI upset, orthostatic hypotension and psychiatric
reactions (hallucinations and confusion); in addition, supplementary levodopa is almost always
required for supervening disability after varying periods of time. For these reasons, dopamine agonists
tend to be used less frequently in older individuals. Useful Info?
MAO-B Inhibitors
Early clinical evaluations of selegiline, an irreversible inhibitor of monoamine oxidase B (MAO-B), suggested that it
might slow the progression of PD. The weight of evidence now indicates that it does not have a substantial
neuroprotective effect, and most of the apparent benefit during the first year of treatment is likely due to its very
7
mild effects on symptoms. In addition, it does not delay the development of dyskinesia or fluctuations associated
with chronic levodopa therapy. A second, more potent, MAO-B inhibitor rasagiline is now available as initial
treatment to improve motor symptoms and for patients with more advanced disease to help with “wearing-off.”
Initial studies suggested it may slow disease progression but further evidence is needed.13
Amantadine
Amantadine provides mild-to-modest improvement in about two-thirds of early PD patients and improves levodopa
-induced dyskinesia in the later stages of the disease.6 Its exact mechanism of action is unclear but it may act by
releasing dopamine from the presynaptic terminals or by blocking its reuptake. Amantadine is an N-methyl-D-
Page 890
Therapeutic Choice
aspartate (NMDA) antagonist, which may account for some of its antiparkinsonian efficacy. NMDA receptor blockade
confers a neuroprotective effect in some animal models of parkinsonism, and it has been suggested that amantadine
improves survival in PD patients; however, this is far from proven. It is easy to use and usually well tolerated, with
leg edema, erythema and livedo reticularis (a reversible condition characterized by bluish, mottled appearance of
the skin, mainly of the lower extremities) being the most common adverse events. In patients with cognitive
deficits, amantadine can increase confusion and should not be used.
Anticholinergics
Anticholinergic drugs such as benztropine, ethopropazine, procyclidine and trihexyphenidyl have been used
in the treatment of PD for decades, since before the availability of levodopa. Their major putative effect is on
2
tremor, with little or no effect on bradykinesia; however, this has not been well studied. They can be used as
monotherapy or as adjuncts to dopaminergic therapy. Their many side effects (e.g., dry mouth, urinary retention,
constipation) limit their use, especially in the elderly.
COMT Inhibitors
COMT (catechol-O-methyl transferase), an enzyme that helps metabolize levodopa, is found in both the brain and in
the peripheral nervous system. COMT inhibitors such as entacapone and tolcapone help prevent peripheral
metabolism of levodopa, which increases its availability to the brain. They have no effect if not used in conjunction
with levodopa. Despite some studies showing additional improvement in activities of daily living, in non-fluctuating
patients their use should be limited to patients with wearing-off.6 Most of their side effects relate to increased
dopaminergic activity in the brain (e.g., dyskinesia and, less often, confusion/hallucinations). Because of this,
levodopa dosage may have to be reduced by up to 30% when a COMT inhibitor is initiated. Tolcapone was the first
COMT inhibitor to be approved, but because of associated hepatotoxicity it is now available only through the Special
Access Programme, Health Canada, for use in exceptional cases. Entacapone is not associated with liver toxicity, but
two other potential side effects are diarrhea (often weeks to months after initiation) and a harmless discolouration
of the urine that patients need to be warned about.
Surgery
Recognition that there is a limit to the medical management of PD brought about a resurgence of surgical
treatments. Two main surgical procedures have been shown to be effective — lesioning procedures and deep brain
stimulation. Surgical treatment of PD mainly targets the thalamus (improves tremor), globus pallidum (improves
dyskinesia) and the subthalamic nucleus (improves bradykinesia, tremor and dyskinesia). These are performed only
in patients with advanced disease in whom medications can no longer control symptoms. It is important for patients
to understand that these surgeries are not a cure and will only improve function to the level of their best “on” times.
Complications — Depression, Psychosis, Dementia
Depression is common in PD, but keep in mind that a lack of facial expression in a patient with PD does not
necessarily indicate sadness or depression. Selective serotonin reuptake inhibitors (SSRIs) and tricyclic
antidepressants (TCAs) have been the mainstay of therapy for depression in patients with PD, yet there is a
surprising lack of evidence to guide the choice of antidepressant.14 TCAs should be used cautiously because their
anticholinergic effects are more likely to induce delirium, especially in memory-impaired patients; they may also
aggravate orthostatic hypotension, which can increase the risk of falls.
Psychosis and dementia are also very common in PD, typically in patients with more advanced disease. All
medications used to treat the motor symptoms can contribute to psychosis in a dose-related fashion. As the disease
progresses, PD medications often need to be withdrawn because of worsening of the patient’s cognitive status.
Usually, anticholinergics are withdrawn first, then selegiline, rasagiline, amantadine and dopamine agonists, until
only levodopa remains. Review other (non-PD) medications carefully to ensure they are not also contributing to the
psychosis. The atypical antipsychotics clozapine and quetiapine can be used for patients in whom an optimum
balance cannot be found by adjusting the PD medication.14 Avoid olanzapine as it has not been shown to be
14
effective and is poorly tolerated.
Cholinesterase inhibitors (e.g., donepezil and rivastigmine) have a modest impact on improving dementia, but
14
careful observation for deterioration in motor function is required.
Therapeutic Tips
Page 891
Therapeutic Choice
In the early stage of PD when symptoms are noticed but not troublesome, symptomatic treatment is not
necessary, remembering that all drugs have potential side effects.
To minimize the acute side effects of medications it is important to start at low doses and titrate slowly,
especially in the elderly.
To minimize gastric upset or orthostatic hypotension, domperidone (10 to 20 mg ½ hr prior to each dose) can
be very helpful when starting levodopa or a dopamine agonist.
Individualize patient management based on the severity of disease, level of disability, cost, patient preference
and patient’s age.
Nonmotor difficulties (e.g., dysarthria, sleep disturbance, depression, dementia and postural instability) are
common, especially as the disease progresses. Managing these effectively with the assistance of allied health
professionals is important for maximizing a patient’s quality of life.
Figure 1- Initial Pharmacologic Management of Parkinson’s Disease
Figure 2- Management of Levodopa-associated Motor Complications
Page 892
Therapeutic Choice
Table 1: Drugs Used in the Treatment of Parkinson's Disease
a
Cost
Levodopa levodopa/carbidopa, Initial: Nausea, vomiting, First-generation $

Preparations immediate-release 50/12.5 mg BID orthostatic antipsychotics ↓ effect
Sinemet, generics Usual: 100/25 mg – hypotension, of dopaminergic
150/37.5 mg TID– dyskinesias, drugs.
QID hallucinations, Antihypertensives,
confusion. diuretics, tricyclic
antidepressants may ↑
hypotensive action.
Levodopa levodopa/carbidopa, b Nausea, vomiting, First-generation $$

Initial:
Preparations controlled-release 100/25 mg BID orthostatic antipsychotics ↓ effect
Sinemet CR, b hypotension, of dopaminergic drugs.
Usual:
generics dyskinesias, Antihypertensives,
200/50 mg QID
hallucinations, diuretics, tricyclic
confusion. antidepressants may ↑
↓ “kick” compared hypotensive action.
to Sinemet
immediate-
release; patterns
of dyskinesia may
be more complex.
Levodopa levodopa/benserazide Initial: Nausea, vomiting, First-generation $

Preparations Prolopa 50/12.5 mg BID orthostatic antipsychotics ↓ effect
Usual: 100/25 mg – hypotension, of dopaminergic drugs.
150/37.5 mg TID– dyskinesias, Antihypertensives,
QID hallucinations, diuretics, tricyclic
confusion. antidepressants may ↑
hypotensive action.
Dopamine bromocriptine Initial: Nausea, vomiting, First-generation $$-

Agonists Apo-Bromocriptine, 1.25 mg BID orthostatic antipsychotics ↓ effect $$$
other generics Usual: 5– hypotension, of dopaminergic
10 mg TID hallucinations, drugs.
psychosis, Antihypertensives,
erythromelalgia diuretics, tricyclic
(burning pain, antidepressants may ↑
warmth and hypotensive action.
redness of the
extremities),
pleural fibrosis
(do a baseline
chest x-ray before
initiating therapy).
Dopamine pramipexole Initial: Orthostatic First-generation $$$

Agonists Mirapex, generics 0.125 mg TID hypotension, antipsychotics ↓ effect
Usual: 0.5– somnolence, of dopaminergic
1 mg TID confusion, drugs.
hallucinations, Antihypertensives,
nausea, vomiting, diuretics, tricyclic
sudden sleep antidepressants may ↑
attacks; caution hypotensive action.
patients about
Page 893
Therapeutic Choice
Costa
driving or
operating
dangerous
machinery.
Dopamine ropinirole Initial: Orthostatic First-generation $$$$-

Agonists ReQuip, generics 0.25 mg TID hypotension, antipsychotics ↓ effect $$$$$
Usual: somnolence, of dopaminergic
3–6 mg TID confusion, drugs.
hallucinations, Antihypertensives,
nausea, vomiting, diuretics, tricyclic
sudden sleep antidepressants may ↑
attacks; caution hypotensive action.
patients about
driving or Ciprofloxacin ↑ levels
operating of ropinirole.
dangerous
machinery.
MAO-B rasagiline Monotherapy: 1 mg Insomnia, Avoid use with $$$$$

Inhibitors Azilect daily confusion, antidepressants such
Adjunctive therapy: hallucinations, ↑ as TCAs, MAO-A
0.5–1 mg daily dyskinesia, inhibitors, SNRIs,
autonomic SSRIs.
dysfunction. Use lower dose of 0.5
Use lower dose of mg daily in patients
0.5 mg in patients taking ciprofloxacin or
with mild hepatic other CYP1A2
impairment and inhibitors.
avoid in patients
with severe
impairment.
MAO-B selegiline (deprenyl) Insomnia, Avoid use with $-$$

Inhibitors generics 2.5 mg daily – 5 mg confusion, pseudoephedrine,
BID hallucinations, ↑ meperidine,
Give before 1 p.m. dyskinesia, dextromethorphan,
autonomic TCAs, MAO-A
dysfunction. inhibitors, SSRIs,
Use lower dose of atomoxetine,
0.5 mg in patients bupropion,
with mild hepatic dextroamphetamine.
impairment and May need to reduce
avoid in patients dose in women taking
with severe oral contraceptives.
impairment.
COMT entacapone Dyskinesia, Potentiates levodopa; $$$-

Inhibitors Comtan 200 mg with each nausea, sleep increased dyskinesia, $$$$
dose of levodopa; disorder, anorexia, psychosis.
max 8 × daily diarrhea, Avoid nonselective
hallucinations; MAOIs, isoproterenol,
urine epinephrine,
discolouration. dopamine,
dobutamine.
Anticholinergic benztropine Dry mouth, Amantadine may ↑ $

Agents generics 1 mg BID – blurred vision, anticholinergic effects.
2 mg BID constipation,
urinary retention,
Page 894
Therapeutic Choice
a
Cost
aggravation of
glaucoma,
confusion,
memory
impairment. Avoid
in elderly.
Anticholinergic ethopropazine Dry mouth, Amantadine may ↑ $

Agents Parsitan 25 mg BID – blurred vision, anticholinergic effects.
50 mg TID constipation,
urinary retention,
aggravation of
glaucoma,
confusion,
memory
impairment. Avoid
in elderly.
Anticholinergic procyclidine Dry mouth, Amantadine may ↑ $

Agents generics 5 mg TID blurred vision, anticholinergic effects.
constipation,
urinary retention,
aggravation of
glaucoma,
confusion,
memory
impairment. Avoid
in elderly.
Anticholinergic trihexyphenidyl Initial: Dry mouth, Amantadine may ↑ $

Agents generics 1 mg BID blurred vision, anticholinergic effects.
Usual: constipation,
2 mg TID urinary retention,
aggravation of
glaucoma,
confusion,
memory
impairment. Avoid
in elderly.
N-methyl-D- amantadine Usual: Nausea, Anticholinergic agents $

aspartate generics 100 mg BID constipation, dry may ↑ effects.
(NMDA) mouth, insomnia,
Receptor anxiety, impaired
Antagonists concentration,
livedo reticularis,
orthostatic
hypotension, ankle
edema. Use with
caution in elderly;
avoid in patients
with cognitive
deficits.
Levodopa/ levodopa/ carbidopa/ 50/12.5/200 mg, Nausea, vomiting, First-generation $$$-

COMT Inhibitor entacapone 100/25/200 mg or orthostatic antipsychotics ↓ effect $$$$
Combinations Stalevo 150/37.5/200 mg hypotension, of dopaminergic drugs.
TID to QID, dyskinesias, Antihypertensives,
depending on hallucinations, diuretics, tricyclic
previous confusion. antidepressants may ↑
levodopa/carbidopa Dyskinesia, hypotensive action.
and/or entacapone nausea, sleep
dose disorder, anorexia, Potentiates levodopa;
diarrhea, increased dyskinesia,
hallucinations; psychosis.
Page 895
Therapeutic Choice
Costa
urine Avoid nonselective
discolouration. MAOIs, isoproterenol,
epinephrine,
dopamine,
dobutamine.
a.
Cost of 30-day supply of usual dose; includes drug cost only.
b.
Compared to Sinemet immediate-release formulation, bioavailability of Sinemet CR is 25–30% lower and duration of action 25
–30% longer.
Dosage adjustment is required in renal impairment; see Appendices: Dosage Adjustment in Renal Impairment.
Abbreviations: MAOIs=monoamine oxidase inhibitors; SNRIs=serotonin-norepinephrine reuptake inhibitors; SSRIs=selective

serotonin reuptake inhibitors; TCAs=tricyclic antidepressants
Legend: $ < $50 $-$$ < $50–100 $$ $50–100 $$-$$$ $50–150 $$$ $100–150 $$$-$$$$ $100–200
$$$$ $150–200 $$$$-$$$$$ $150– >200 $$$$$ > $200
Suggested Readings
Lang AE, Lozano AM. Parkinson's disease. Second of two parts. N Engl J Med 1998;339(16):1130-43.
Miyasaki JM, Martin W, Suchowersky O et al. Practice Parameter: initiation of treatment for Parkinson's disease: an
evidence-based review: report of the Quality Standards Subcommittee of the American Academy of Neurology.
Neurology 2002;58(1):11-7.
Pahwa R, Factor SA, Lyons KE et al. Practice Parameter: treatment of Parkinson disease with motor fluctuations and
dyskinesia (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of
Neurology. Neurology 2006;66(7):983-95.
Suchowersky O, Gronseth G, Perlmutter J et al. Practice Parameter: neuroprotective strategies and alternative
therapies for Parkinson disease (an evidence-based review): report of the Quality Standards Subcommittee of the
American Academy of Neurology. Neurology 2006;66(7):976-82.
References
1. Suchowersky O, Gronseth G, Perlmutter J et al. Practice Parameter: neuroprotective strategies and alternative
therapies for Parkinson disease (an evidence-based review): report of the Quality Standards Subcommittee of
the American Academy of Neurology. Neurology 2006;66(7):976-82.
2. Grimes DA, Lang AE. Treatment of early Parkinson's disease. Can J Neurol Sci 1999;26(Suppl 2):S39-44.
3. Fahn S. Does levodopa slow or hasten the rate of progression of Parkinson's disease? J Neurol 2005;252
(Suppl 4):IV37-IV42.
4. Lang AE, Lozano AM. Parkinson's disease. Second of two parts. N Engl J Med 1998;339(16):1130-43.
5. Olanow CW, Agid Y, Mizuno Y et al. Levodopa in the treatment of Parkinson's disease: current controversies.
Mov Disord 2004;19(9):997-1005.
6. Pahwa R, Factor SA, Lyons KE et al. Practice Parameter: treatment of Parkinson disease with motor
fluctuations and dyskinesia (an evidence-based review): report of the Quality Standards Subcommittee of the
American Academy of Neurology. Neurology 2006;66(7):983-95.
7. Miyasaki JM, Martin W, Suchowersky O et al. Practice Parameter: initiation of treatment for Parkinson's
disease: an evidence-based review: report of the Quality Standards Subcommittee of the American Academy
of Neurology. Neurology 2002;58(1):11-7.
Page 896
Therapeutic Choice
8. Holloway RG, Shoulson I, Fahn S et al. Pramipexole vs levodopa as initial treatment for Parkinson disease: a 4
-year randomized controlled trial. Arch Neurol 2004;61(7):1044-53.
9. Baseman DG, O'Suilleabhain PE, Reimold SC et al. Pergolide use in Parkinson disease is associated with
cardiac valve regurgitation. Neurology 2004;63(2):301-4.
10. Van Camp G, Flamez A, Cosyns B et al. Treatment of Parkinson's disease with pergolide and relation to
restrictive valvular heart disease. Lancet 2004;363(9416):1179-83.
11. Hobson DE, Lang AE, Martin WR et al. Excessive daytime sleepiness and sudden-onset sleep in Parkinson
disease: a survey by the Canadian Movement Disorders Group. JAMA 2002;287(4):455-63.
12. Dodd ML, Klos KJ, Bower JH et al. Pathological gambling caused by drugs used to treat Parkinson disease.
Arch Neurol 2005;62(9):1377-81.
13. Parkinson Study Group. A controlled, randomized, delayed-start study of rasagiline in early Parkinson disease.
Arch Neurol 2004;61(4):561-6.
14. Miyasaki JM, Shannon K, Voon V et al. Practice Parameter: evaluation and treatment of depression, psychosis,
and dementia in Parkinson disease (an evidence-based review): report of the Quality Standards Subcommittee
of the American Academy of Neurology. Neurology 2006;66(7):996-1002.
Page 897
e-Therapeutics+ : Therapeutics : Neurologic Disorders: Persistent Hiccoughs Page 1 of 3
Therapeutic Choice
Print Close
Neurologic Disorders: Persistent Hiccoughs
James M. Wright, MD, PhD, CRCPC
Persistent (2–30 days) or intractable (>1 month) hiccoughs are unusual but distressing. They may cause insomnia,
weight loss or depression and are associated with metabolic causes and abnormalities of the CNS, ear, throat,
diaphragm, thorax and abdomen.
Goals of Therapy
Stop or decrease frequency or intensity of hiccoughs

Prevent recurrence
Investigations
Complete history (including medication and alcohol use) and physical examination to provide clues for further
investigations. If no abnormalities are identified, it is reasonable to do a CBC, electrolytes, creatinine and chest
x-ray
drug-induced persistent hiccoughs are uncommon; alcohol, corticosteroids and benzodiazepines are the
1
drugs most frequently implicated
Further investigations depend on findings from the history, physical and baseline investigations, e.g., upper GI
tract endoscopy, CT brain, abdominal ultrasound
If all investigations are negative or etiologic treatment is impossible, a therapeutic trial to stop the hiccoughs is
warranted.
Therapeutic Choices
Vagal stimulation (e.g., posterior pharyngeal wall stimulation with a finger, forced expiration against a closed
glottis for 10 seconds in the sitting position) is worth trying.
If gastric distention is identified as the cause, gastric aspiration is effective.
2
Digital rectal massage or acupuncture therapy has been associated with temporary or permanent relief.
Phrenic nerve disruption is reserved for cases where all else has failed.
Pharmacologic Choices (Table 1 )
The condition is rare; one randomized, controlled trial—a cross-over trial comparing baclofen with placebo (see
3
below)—was identified. Most treatment recommendations are based on case reports or open trials in small numbers
of patients.
Dopamine Antagonists
4
Chlorpromazine historically has been the drug of choice. It has been used iv (25–50 mg over 0.5–1 hour) in the
emergency room. A trial of 25–50 mg TID-QID po for 2–3 days is also reasonable but may be less effective than iv.
Haloperidol, 2–5 mg im or 2–10 mg po, has also been effective in some cases.5 , 6 Metoclopramide, 10 mg iv or
7
im followed by 5–10 mg TID-QID po, has been successful. It may act as a dopamine antagonist or by enhancing
gastric emptying. Adverse effects of dopamine antagonists include acute dystonia and postural hypotension. If
chronic therapy is required, use back-titration to find the lowest effective dose taken once daily.
Baclofen
Baclofen has been effective in intractable hiccoughs, with maintenance therapy required in at least
50% of cases. A randomized, double blind, cross-over trial in 4 patients with intractable hiccoughs
demonstrated that baclofen was unable to eliminate the hiccoughs, but did increase hiccough-free
Page 898
Therapeutic Choice
periods and decrease hiccough severity.3 Starting with 5 mg BID, the dose is increased gradually every
2–3 days to a maximum daily dose of 80 mg. If effective, baclofen should not be discontinued
suddenly. The minimum maintenance dose can be determined by gradually reducing the dose over
time. Useful Info? Since baclofen is excreted by the kidney, much lower doses are required in the presence of renal
8
failure (2.5 mg BID was effective in hemodialysis patients ). Side effects (drowsiness, weakness, nausea and
fatigue) are relatively frequent.
Other Drugs
9 10 11
In case reports or case series, many other drugs, including amantadine, amitriptyline, carbamazepine,
gabapentin,12 nifedipine13 and valproic acid,14 have been found effective.
Duration of Treatment
When a drug is effective in aborting the hiccoughs, taper the dose downwards after 3 days. If hiccoughs return, find
the lowest dose that will suppress them. If they do not return, the drug can be tapered and stopped.
Therapeutic Tips
When a drug is effective, hiccoughs generally stop abruptly within a few hours; in some cases, the frequency
and severity may slowly decrease.
Attempt to withdraw treatments gradually; maintenance therapy may be required in some cases.
Avoid benzodiazepines, as worsening of hiccoughs has been reported.
When a drug is ineffective, there is no need to continue treatment for more than 3 days.
Table 1: Drugs Used in Persistent or Intractable Hiccoughs
Drug Costa
Dopamine chlorpromazine ER: 25–50 mg iv over Anticholinergic effects, Additive sedative $

Antagonistsb generics 30–60 min extrapyramidal effects, effects with CNS
Oral: 25–50 mg TID– hypotension, sedation. depressants,
QID × 2–3 days including alcohol.
Dopamine haloperidol ER: 2–5 mg im Sedation, extrapyramidal Additive sedative im:

b Oral: 2–10 mg daily × effects. effects with CNS $$
Antagonists generics
2–3 days depressants, po: $
including alcohol.
Dopamine metoclopramide ER: 10 mg iv or im Diarrhea, abdominal Additive sedative im/iv:

Antagonistsb Oral: 5–10 mg TID- cramps, effects with CNS $$
generics QID × 2–3 days hyperprolactinemia, depressants, po: $
sedation, extrapyramidal including alcohol.
effects, headache.
Muscle baclofen Start with 5 mg BID Sedation, muscle Additive sedative $

b po; increase gradually weakness, nausea, effects with CNS
Relaxants Lioresal Oral,
generics every 2–3 days to a dizziness, lowered seizure depressants,
maximum of 80 mg threshold. including alcohol.
per day
a.
Cost per day for oral therapy, unless otherwise specified; includes drug cost only.
b.
If chronic therapy required, establish lowest effective dose using gradual back-titration.
Abbreviations: CNS=central nervous system; ER=emergency room
Page 899
Therapeutic Choice
Legend: $ <$2 $$ $2–5
Suggested Readings
Friedman NL. Hiccups: a treatment review. Pharmacotherapy 1996;16(6):986-95.
References
1. Drug-induced hiccups. Prescrire Int 1999;8(39):23.

2. Marinella MA. Diagnosis and management of hiccups in the patient with advanced cancer. J Support Oncol
2009;7(4):122-30.
3. Ramirez FC, Graham DY. Treatment of intractable hiccup with baclofen: results of a double-blind randomized,
controlled, cross-over study. Am J Gastroenterol 1992;87(12):1789-91.
4. Friedgood CE, Ripstein CB. Chlorpromazine (thorazine) in the treatment of intractable hiccups. J Am Med
Assoc 1955;157(4):309-10.
5. Korczyn AD. Hiccup. Br Med J 1971;2(5761):590-1.
6. Ives TJ, Fleming MF, Weart CW et al. Treatment of intractable hiccups with intramuscular haloperidol. Am J
Psychiatry 1985;142(11):1368-9.
7. Madanagopolan N. Metoclopramide in hiccup. Curr Med Res Opin 1975;3(6):371-4.
8. Hadjiyannacos D, Vlassopoulos D, Hadjiconstantinou V. Treatment of intractable hiccup in haemodialysis
patients with baclofen. Am J Nephrol 2001;21(5):427-8.
9. Wilcox SK, Garry A, Johnson MJ. Novel use of amantadine: to treat hiccups. J Pain Symptom Manage 2009;38
(3):460-5.
10. Peabody CA, Dewitt J, Herrin S et al. Intractable hiccups treated with amitriptyline. Am J Psychiatry 1988;145
(8):1036-7.
11. McFarling DA, Susac JO. Letter: Carbamazepine for hiccoughs. JAMA 1974;230(7):962.
12. Ong AM, Tan CS, Foo MW et al. Gabapentin for intractable hiccups in a patient undergoing peritoneal dialysis.
Perit Dial Int 2008;28(6):667-8.
13. Lipps DC, Jabbari B, Mitchell MH et al. Nifedipine for intractable hiccups. Neurology 1990;40 (3 Pt 1):531-2.
14. Jacobson PL, Messenheimer JA, Farmer TW. Treatment of intractable hiccups with valproic acid. Neurology
1981;31(11):1458-60.
Page 900
e-Therapeutics+ : Therapeutics : Neurologic Disorders: Restless Legs Syndrome Page 1 of 6
Therapeutic Choice
Print Close
Neurologic Disorders: Restless Legs Syndrome

Anne-Louise Lafontaine, MD
Restless legs syndrome (RLS) is a neurologic disorder characterized by an unpleasant sensation in the legs
accompanied by an urge to move the legs, especially at bedtime.1 In severe cases, symptoms may extend to the
arms and trunk. The prevalence of RLS in the general population is estimated to be 5-15%;1 , 2 prevalence is higher
in women and increases with age. Patients often use the following terms to describe the symptoms of RLS: a
“creepy-crawly,” “burning,” “nagging,” “aching,” “painful,” “itching-bones” or “electric-current” sensation.
Diagnostic criteria have recently been established:3
An urge to move the legs, usually accompanied or caused by unpleasant sensations in the legs.
Symptoms begin or worsen during periods of rest or inactivity such as lying or sitting.
Symptoms are partially or totally relieved by movement, such as walking or stretching, for at least as long as
the activity continues.
Symptoms are worse in the evening or at night than during the day, or occur only in the evening or at night.
Supportive clinical features include a positive family history, response to dopaminergic therapy and periodic limb
movements during wakefulness (PLM) or during sleep (PLMS).3
Intermittent RLS is defined as symptoms that are troublesome enough to require treatment but not frequent enough
to require daily therapy. Daily RLS involves symptoms that are frequent and bothersome enough to require daily
therapy. Patients with refractory RLS are those who experience inadequate response and/or intolerable side effects
and/or “augmentation” (see Goals of Therapy) not responding to more frequent dosing, while receiving dopamine
agonist therapy for daily symptoms.
Goals of Therapy
Improve the symptoms of motor restlessness and discomfort

Improve sleep
Reduce the PLMS, if disruptive
Reduce the potential for “rebound” or “augmentation”
“rebound” is the recurrence of symptoms during the night or early morning coinciding with the end-of-dose
4
wearing off of effectiveness
“augmentation” is the occurrence of symptoms earlier in the day than they occurred prior to treatment, a
shorter latency time to symptom onset when at rest, an increase in the severity of symptoms with shorter
treatment effect, and/or spread of symptoms to involve the upper extremities and trunk.5
Investigations
History from patient and partner regarding sleep and PLMS

CBC, electrolytes, BUN, creatinine, fasting glucose, serum iron, ferritin and iron saturation
Nerve conduction studies can be performed if peripheral neuropathy is suspected
Polysomnography should be performed if there is a clinical suspicion of sleep apnea or concurrent sleep
disorder
Therapeutic Choices
Mental alertness activities (playing cards or video games or doing crossword puzzles) to reduce symptoms
6
during times of boredom.
6
Abstinence from alcohol, caffeine and nicotine.
Hot baths, stretching and moderate exercise.7
Discontinuing medications that may be contributing to symptoms, e.g., antidepressants, antipsychotics,
6
dopamine-blocking antiemetics and sedating antihistamines.
Page 901
Therapeutic Choice
Iron deficiency states are a known cause of secondary RLS; iron replacement therapy is indicated in
6
the presence of low serum ferritin level or iron deficiency. Useful Info?
Dopamine agonists are considered the drugs of choice for most patients with daily RLS because of their long
8 9 , 10
elimination half-life. Efficacy has been established in controlled clinical studies for bromocriptine, pergolide,
11 12
pramipexole and ropinirole. These drugs improve sleep efficiency and decrease frequency of PLMS. Pergolide
and bromocriptine are ergoline derivatives and are more frequently associated with adverse effects. Pergolide is
being withdrawn from the Canadian market as of August 30 2007 because of its association with cardiac
valvulopathy. Patients currently taking pergolide should discuss alternative therapy with their physician. Because
abrupt discontinuation can be associated with adverse neurologic effects, pergolide should be gradually tapered over
several weeks. The drug may become available through Health Canada's Special Access Programme for patients who
meet specific criteria. Ropinirole and pramipexole are nonergoline derivatives and have a more favourable side
effect profile overall, although they have been associated with a higher incidence of sudden sleep attacks in patients
treated with higher doses for Parkinson’s disease. The starting dose of pramipexole for RLS is 0.125 mg, taken two
hours before the onset of symptoms, and can be increased every two to three days to effectiveness. The average
effective dose is 0.5 mg but doses of up to 2 mg may be required. The starting dose of ropinirole is 0.25 mg. The
average effective dose lies between 1 and 4 mg. Some patients may require a second dose in late afternoon if
symptoms arise earlier in the day. Side effects of dopamine agonists include nausea, sedation and lightheadedness.
Levodopa/carbidopa has been shown in many clinical trials to be effective for the treatment of RLS. 14 The main
limitation of levodopa/carbidopa is its short half-life, which increases the potential for rebound and augmentation.
While levodopa/carbidopa may be appropriate for the treatment of intermittent RLS, dopamine agonists are the
treatment of choice in daily RLS.
Gabapentin may be an alternative to dopamine agonists in the event of intolerability or augmentation (see Goals of
Therapy). Effectiveness of gabapentin has been demonstrated in open15 and randomized controlled trials.16 It can
be considered the drug of choice in the presence of a particularly painful RLS. Major side effects include drowsiness
and unsteady gait, especially in the elderly.
Opioids have been used since the earliest descriptions of the treatment of RLS. Clinical effectiveness has been
17
demonstrated in a few controlled as well as open clinical trials. Opioids may be effective by virtue of their strong
sedating properties rather than their effect on leg movements. Because of the potential for dependence, low-potency
opioids such as codeine are reserved for intermittent or daily RLS, and more potent agents such as oxycodone or
methadone for refractory RLS.
Benzodiazepines have been demonstrated in clinical trials to significantly improve objective sleep efficiency and
18
subjective sleep quality in both RLS and PLMS. The main limitation of this class of drugs is the potential for
dependence. Benzodiazepines are appropriate for the treatment of intermittent RLS or in refractory RLS where they
can be added to first-line therapy. Given the long half-life of clonazepam and its potential to cause morning
sedation and dizziness, consideration should be given to agents with short or intermediate duration of action in
elderly patients.
Therapeutic Tips
Always consider nonpharmacologic management.

Start with a single dose of dopamine agonist 1–2 hours prior to bedtime. Titrate to effectiveness.
In the event of symptoms beginning earlier in the day, a second dose of dopamine agonist can be prescribed in
the afternoon, and if needed in the morning.
Rebound can be avoided by prescribing dopamine agonists rather than levodopa.
Augmentation has been reported less frequently with dopamine agonists than with levodopa. This can also be
managed by alternating medications, i.e., switching between medication classes every few months as needed.
Figure 1-Management of Restless Legs Syndrome
Page 902
Therapeutic Choice
Adapted with permission from Silber MH, Ehrenberg BL, Allen RP et al. An algorithm for the management of restless legs
syndrome. Mayo Clin Proc 2004;79(7):916-22.
Table 1: Drug Therapy for Restless Legs Syndrome
Costa
Dopamine Agonists bromocriptine 7.5 mg HS Nausea, vomiting, First-generation $$

Apo- lightheadedness; antipsychotics ↓ effect
hallucinations, psychosis, of dopamine agonists.
Bromocriptine,
erythromelalgia (burning
other generics
pain, warmth and redness of
the extremities), pleural
fibrosis.
Dopamine Agonists pramipexole 0.125–2 Lightheadedness, confusion, First-generation $

Mirapex, mg per day hallucinations, nausea, antipsychotics ↓ effect
generics in 2–3 vomiting, sedation. of dopamine agonists.
divided
doses if
Page 903
Therapeutic Choice
Costa
needed
Dopamine Agonists ropinirole 0.25–4 mg Lightheadedness, confusion, First-generation $

ReQuip, per day in hallucinations, nausea, antipsychotics ↓ effect
generics 2–3 divided vomiting, sedation. of dopamine agonists.
doses if
needed
Levodopa levodopa/ 50/12.5– Nausea, vomiting, First-generation $

Preparations carbidopa 200/50 mg lightheadedness, dry mouth, antipsychotics ↓ effect
Sinemet, HS “rebound” and of levodopa.
Sinemet CR, “augmentation.” Antihypertensives,
generics diuretics, tricyclic
antidepressants may ↑
hypotensive action.
Decreased absorption
with high-protein
meals.
Antiepileptics gabapentin 300–3600 Sedation, dizziness, ataxia, No known significant $$$

Neurontin, mg daily in tremor, vision changes, interactions.
generics 2–3 divided weight gain.
doses if
needed
Opioids codeine 30–180 mg Sedation, constipation, Additive sedation with $

immediate- per day in dependence. other CNS depressants
2–3 divided such as alcohol.
release,
doses if
generics
needed
Opioids codeine 50–150 mg Sedation, constipation, Additive sedation with $$

sustained- daily dependence. other CNS depressants
divided such as alcohol.
release
Q12H
Codeine Contin
Opioids oxycodone 5–30 mg Sedation, constipation, Additive sedation with $

immediate- daily in 2– dependence. other CNS depressants
3 divided such as alcohol.
release
doses if
Oxy-IR, needed
generics
Opioids oxycodone 10–20 mg Sedation, constipation, Additive sedation with $$

sustained- at bedtime dependence. other CNS depressants
such as alcohol.
release
Oxycontin
Opioids methadone 2.5–20 mg Sedation, constipation, Additive sedation with $

Metadol, in 2 dependence. other CNS depressants
generics divided such as alcohol.
doses if
needed
Benzodiazepines clonazepam 0.25–2 mg Sedation, dizziness, Additive sedation with $

Rivotril, HS dependence. other CNS depressants
generics such as alcohol.
Page 904
Therapeutic Choice
Costa
Benzodiazepines triazolam 0.125–0.25 Sedation, dizziness, Additive sedation with $

generics mg HS dependence. other CNS depressants
such as alcohol.
Benzodiazepines temazepam 15–30 mg Sedation, dizziness, Additive sedation with $

Restoril, HS dependence. other CNS depressants
generics such as alcohol.
Nonbenzodiazepine zopiclone 3.75–7.5 Bitter metallic taste. Minimal additive $

Agonists Imovane, mg HS effects with low doses
generics of alcohol.
a.
Cost of 30-day supply of mean dose; includes drug cost only.
Legend: $ < $25 $$ $25–50 $$$ $50–75 $$$$ > $75
Suggested Readings
Comella CL. Restless legs syndrome: treatment with dopaminergic agents. Neurology 2002;58(4 Suppl 1):S87-S92.
Earley CJ. Clinical practice. Restless legs syndrome. N Engl J Med 2003;348(21):2103-9.
Silber MH, Ehrenberg BL, Allen RP et al. An algorithm for the management of restless legs syndrome. Mayo Clin Proc
2004;79(7):916-22.
References
1. Ekbom KA. Restless legs syndrome. Neurology 1960;10:868-73.

2. Lavigne GJ, Montplaisir JY. Restless legs syndrome and sleep bruxism: prevalence and associations among
Canadians. Sleep 1994;17(8):739-43.
3. Allen RP, Picchietti D, Hening WA et al. Restless legs syndrome: diagnostic criteria, special considerations,
and epidemiology. A report from the restless legs syndrome diagnosis and epidemiology workshop at the
National Institutes of Health. Sleep Med 2003;4(2);101-19.
4. Guilleminault C, Cetel M, Philip P. Dopaminergic treatment of restless legs and rebound phenomenon.
Neurology 1993;43(2):445.
5. Allen RP, Earley CJ. Augmentation of the restless legs syndrome with carbidopa/levodopa. Sleep 1996;19
(3):205-13.
6. Silber MH, Ehrenberg BL, Allen RP et al. An algorithm for the management of restless legs syndrome. Mayo
Clin Proc 2004;79(7):916-22.
7. Ryan M, Slevin JT. Restless legs syndrome. Am J Health Syst Pharm 2006;63(17):1599-612.
8. Walters AS, Hening WA, Kavey N et al. A double-blind randomized crossover trial of bromocriptine and
placebo in restless legs syndrome. Ann Neurol 1988;24(3):455-8.
9. Wetter TC, Stiasny K, Winkelmann J et al. A randomized controlled study of pergolide in patients with restless
legs syndrome. Neurology 1999;52(5):944-50.
10. Trenkwalder C, Hundemer HP, Lledo A et al. Efficacy of pergolide in treatment of restless legs syndrome: the
PEARLS Study. Neurology 2004;62(8):1391-7.
11. Montplaisir J, Nicolas A, Denesle R et al. Restless legs syndrome improved by pramipexole: a double-blind
randomized trial. Neurology 1999;52(5):938-43.
12. Adler CH, Hauser RA, Sethi K et al. Ropinirole for restless legs syndrome: a placebo-controlled crossover trial.
Neurology 2004;62:1405-7.
13. Van Camp G, Flamez A, Cosyns B et al. Treatment of Parkinson’s disease with pergolide and relation to
restrictive valvular heart disease. Lancet 2004;363(9416):1179-83.
14. Montplaisir J, Lapierre O, Warnes H et al. The treatment of the restless legs syndrome with or without periodic
leg movements in sleep. Sleep 1992;15(5):391-5.
Page 905
Therapeutic Choice
15. Happe S, Klosch G, Saletu B et al. Treatment of idiopathic restless legs syndrome (RLS) with gabapentin.
Neurology 2001;57(9):1717-19.
16. Garcia-Borreguero D, Larrosa O, de la Llave Y et al. Treatment of restless legs syndrome with gabapentin: a
double-blind, cross-over study. Neurology 2002;59(10):1573-9.
17. Ondo WG. Methadone for refractory restless legs syndrome. Mov Disord 2005;20(3):345-8.
18. Saletu M, Anderer P, Saletu-Zyhlarz G, Prause W, Semler B, Zoghlami A et al. Restless legs syndrome (RLS)
and periodic limb movement disorder (PLMD): acute placebo-controlled sleep laboratory studies with
clonazepam. Eur Neuropsychopharmacol 2001;11(2):153-61.
Page 906
e-Therapeutics+ : Therapeutics : Neurologic Disorders: Seizures and Epilepsy Page 1 of 10
Therapeutic Choice
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Neurologic Disorders: Seizures and Epilepsy

R. Mark Sadler, MD, FRCPC
Jeremy J. Moeller, MD
Goals of Therapy
Appropriately manage patients presenting with a first seizure (See Pharmacologic Choices, The First Seizure)
Prevent seizure recurrence in patients with an established diagnosis of epilepsy, i.e., patients with recurrent seizures
Prevent or minimize adverse effects of antiepileptic drugs (AEDs)
Optimize quality of life, e.g., employment, psychosocial interactions, driving
Investigations (Figure 1 - Management of Seizures and Epilepsy)
History
Most important factor in making a diagnosis is a detailed history of the patient's “spells” obtained from both the patient
and a witness (see Clinical Features).
Is there an aura? An aura signifies the onset of the seizure, and its features provide valuable clues to the anatomic site
of the seizure onset. Lack of an aura indicates partial seizures that spread very rapidly or that the seizures are of the
primary generalized variety.
Inquire about history of intracranial sepsis, head trauma, stroke, any systemic disorders that may affect the central
nervous system (e.g., malignancies, fluid and electrolyte disorders), drugs (prescribed or recreational), sleep
deprivation, symptoms of raised intracranial pressure and family history of seizures or other neurologic diseases.
, 2
Clinical Features1
Simple partial seizures:

motor or sensory features
no impairment of consciousness
usually brief (< 60 seconds)
Complex partial seizures:
focally originating seizures characterized by impaired awareness and a blank stare
duration of 1–2 minutes
frequently accompanied by motor automatisms, e.g., lip smacking and chewing movements
brief postictal confusion is common
begin with simple partial features or impaired consciousness, and are commonly misdiagnosed as absence seizures
Absence (“petit mal”):
primary generalized seizure type
last only seconds, usually 5–10
recur daily (often in clusters) in the untreated patient
no warning signs or postictal confusion
onset in childhood or adolescence (almost never begin in adulthood)
Primary or secondarily generalized tonic-clonic (“grand mal”):
fairly uniform sequence of motor features (tonic and clonic phases)
impaired consciousness
duration of 1–2 minutes
postictal stupor, confusion and headache
a careful history may reveal a partial seizure (e.g., simple partial or complex partial) that secondarily evolves to a
generalized tonic-clonic seizure
Atonic seizures:
abrupt loss of consciousness and muscle tone
no other motor features
return to awareness in seconds
occur as part of a clinical scenario in patients with childhood onset epilepsy, significant intellectual handicaps and
other seizure types
virtually never occur in otherwise intellectually and physically intact adults
Myoclonic seizures:
a generalized seizure type consisting of brief, bilateral “shock-like” jerks
multifocal asynchronous myoclonic jerks most commonly occur in the setting of a metabolic encephalopathy
Consider whether the clinical features suggest one of the entities (e.g., syncope or psychogenic nonepileptic seizures)
commonly mistaken for epileptic seizures
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Therapeutic Choice
Look for evidence of any systemic disorder that can affect the central nervous system, e.g., a malignancy
Look for focal or lateralizing findings in the neurologic examination (hemianopia, motor weakness, hemisensory
disturbance, reflex asymmetry)
Assess potential injuries sustained during a generalized tonic-clonic seizure, such as tongue laceration, shoulder
dislocation or vertebral compression fracture
Laboratory Investigations3
For the patient presenting with the first seizure, consider:

CBC, glucose, electrolytes, calcium, renal and hepatic function
chest x-ray if metastatic disease is a consideration
electroencephalogram (EEG) to support the clinical impression of seizures and to determine if the seizure is partial
(focally originating) or primary generalized. The interictal EEG may show focal spikes in patients with partial
seizures or generalized spike-waves in the primary generalized epilepsies. The EEG may also be helpful in
determining the likelihood of seizure recurrence
computed tomography (CT) head scan. Adults should have a CT scan unless the patient is otherwise well and their
EEG demonstrates generalized spike-and-wave discharges (which indicates one of the primary generalized seizure
syndromes that are not accompanied by gross structural brain abnormalities). Patients should have a CT scan before
a lumbar puncture
lumbar puncture if the presenting clinical features suggest intracranial infection (meningitis, encephalitis) or a CT-
negative subarachnoid hemorrhage
magnetic resonance imaging (MRI) scan if the patient has partial seizures of unknown etiology and negative CT scan
For the patient with known epilepsy treated with AEDs and presenting with a seizure recurrence, assess:
factors that may precipitate loss of seizure control (medication noncompliance, intercurrent illness with fever and
vomiting, sleep deprivation, alcohol and other nonprescription drug use)
the addition (or sudden withdrawal) of a drug that may promote seizures or may cause a drug interaction with AEDs
AED serum levels (phenytoin, phenobarbital, primidone, carbamazepine, valproic acid). Serum levels for other AEDs
are not available or are of limited clinical value
Therapeutic Choices
Avoid sleep deprivation.

Keep alcohol consumption to a minimum. Cocaine and amphetamines must be forbidden because of their proconvulsant
properties. The evidence for marijuana as a “pro-” or “anti-” seizure drug is inconclusive.
, 5 , 6
Pharmacologic Choices4
Deciding whether AED treatment is indicated following a first seizure is an important consideration (See The First Seizure,
below).
The choice of an AED depends on the seizure type (Table 1), potential for drug interactions and side effects (Table 3), cost
(Table 3) and physician familiarity with the drug.
There is some evidence for a drug of first choice in both partial and generalized epilepsy syndromes. In a large, multicenter
trial of “new” AEDs for patients with a partial epilepsy syndrome, lamotrigine was better tolerated than carbamazepine,
7
and was similarly effective in obtaining long-term seizure freedom. The other AEDs used in the trial, gabapentin and
topiramate, were not superior to carbamazepine.
A parallel trial for patients with generalized epilepsy syndromes showed that valproic acid was superior to lamotrigine and
8
topiramate. Valproic acid was particularly effective in maintaining long-term seizure freedom in patients with idiopathic
generalized epilepsy. However, the trial was not designed to measure pregnancy outcomes, and there is evidence that,
among the commonly used AEDs, valproic acid may pose the highest risk to the fetus in pregnant women with epilepsy.
There is no strong evidence comparing the newer AEDs (e.g., levetiracetam, oxcarbazepine) to older therapeutic options.
a , b
Table 1: Suggested Therapeutic Choices for Antiepileptic Drugs (AEDs)
First Choice Alternate Monotherapy

a a
Monotherapy or Add-on
Seizure Type
Generalized Tonic-clonic carbamazepine clobazam

lamotrigine levetiracetam
phenytoin topiramate
valproic acid
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Therapeutic Choice
First Choice Alternate Monotherapy

a a
Monotherapy or Add-on
Seizure Type
Absence ethosuximide clobazam

valproic acid lamotrigine
levetiracetam
topiramate
Myoclonic and Atonic valproic acid clobazam

lamotrigine
levetiracetam
topiramate
Partial (simple or complex) with or without 2° Generalization carbamazepine clobazam

lamotrigine gabapentin
phenytoin levetiracetam
oxcarbazepine
phenobarbital
primidone
topiramate
valproic acid
vigabatrin
a.
AEDs are listed alphabetically; the order does not reflect a preference ranking.
b.
See Pharmacologic Choices for further discussion of first-choice monotherapy.
Basic principles are:
Select a single AED.

Start the AED at a fraction of the initial target dose to minimize the risk of dose-dependent adverse effects (exceptions
are phenytoin and phenobarbital).
Inform patient of potential risks of treatment (especially hypersensitivity reactions).
Evaluate the patient after the initial target dose has been achieved. Make a small dose reduction if dose-related adverse
effects are problematic. Slowly increase the dose if seizures have recurred.
Add a second AED if the maximum tolerated dose of the first AED has failed to achieve satisfactory seizure control.
Gradually withdraw the first AED after the maintenance dose of the second drug has been achieved. Polytherapy is
usually reserved until monotherapy with 2 to 3 drugs has failed.
The First Seizure
The decision of whether or not to treat with AEDs after the first seizure can be difficult for the patient and physician and
9 , 10
must be individualized.
Most patients come to medical attention with a primary or secondarily generalized tonic-clonic seizure. At least one-third
of these patients have experienced prior unrecognized nocturnal tonic-clonic seizures and/or nonconvulsive seizures. It
is important to determine if the event was truly the first seizure. Patients with unequivocal prior seizures should
9 , 10
generally be treated, as the risk for seizure recurrence is high.
Not all patients with a single tonic-clonic seizure will have a recurrence. The overall risk of recurrence after a single
unprovoked seizure is 40% within 2 years, but the degree of risk can be stratified based on other factors. For example,
the recurrence risk over 2 years after a single idiopathic seizure with a normal EEG is 24%. In this situation most would
9 , 10
not advocate treatment.
The risks of treatment must be weighed against the likelihood of seizure recurrence. An increased risk of recurrence is
9 , 10
suggested if one or more of the following features are present:
clear, known remote cause of seizure
focally originating seizure
abnormal neurologic examination
abnormal EEG (particularly if the EEG demonstrates epileptiform discharges)
, 12
Status Epilepticus (SE)11
“Convulsive” SE was traditionally defined as recurrent primary or secondarily generalized tonic-clonic seizures lasting
> 30 minutes, or intermittent seizures lasting > 30 minutes, from which the patient does not return to consciousness.
Note: Almost all “isolated” tonic-clonic seizures last < 2 minutes. A tonic-clonic seizure lasting > 5 minutes is therefore
“different” and has been defined as “impending SE.” Impending SE should be treated aggressively in the first 30
12
minutes.
Any seizure type can evolve to “nonconvulsive” status epilepticus (absence, partial complex, simple partial).
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Therapeutic Choice
Psychogenic nonepileptic seizures (psychiatrically based behaviours that are not associated with abnormal EEG rhythms)
can be confused with convulsive SE because of some superficial similarities. Conversely, absence or partial complex SE
is often misdiagnosed as a psychiatric condition.
Convulsive SE is associated with high morbidity and mortality, related to underlying cause and the effects of seizures on
the brain. Brain injury begins at 30 to 45 minutes after onset of SE; aggressive treatment of seizures is important to
optimize outcome. Table 2 outlines a suggested treatment protocol.
Table 2: Initial Management of Convulsive Status Epilepticus
Time Management
0–5 min History, physical examination.

Oral airway, oxygen.
Consider intubation.
Venous blood (glucose, blood counts, electrolytes, calcium, renal and liver function, AED blood levels, consider
drug screen).
Arterial blood gases.
Monitor ECG, pulse oximetry, blood pressure.
5–10 min Start 2 large-bore iv saline infusions.

50 mL dextrose 50% iv.
Thiamine 50– 100 mg im.
Lorazepam 2 mg/min iv, to max dose of 0.1 mg/kg or
diazepam 5 mg/min iv, to max dose of 0.25–0.4 mg/kg.
10–30 Phenytoin 20 mg/kg iv (max rate = 50 mg/min) or

min a
phenobarbital 20 mg/kg iv (50– 75 mg/min) or
midazolam 10 mg iv bolus, then 0.05–0.4 mg/kg/h or
propofol 2–5 mg/kg iv bolus followed by infusion at 2–10 mg/kg/h.
30–60 Obtain neuroimaging (CT, MRI) if etiology of SE not known; consider lumbar puncture if a possibility of
min meningitis-encephalitis.
Admit to critical care unit, obtain expert advice, arrange EEG.
a.
Phenobarbital injection is available through Health Canada's Special Access Programme.
Abbreviations: AED = antiepileptic drug; EEG = electroencephalogram; ECG = electrocardiogram
Other General Measures
To reduce the risk of burns during seizures:

discourage smoking
encourage patients to use microwave ovens and place pots and pans on the rear burners of stoves
Showers are preferable to tub baths because of the risk of drowning.
Assess recreational activities and current/planned employment, and counsel accordingly.
Patients with active epilepsy who are caregivers for young children should not bathe them without assistance and should
not use change tables for clothing or diaper changes.
Assess driving status. Physicians should be aware of their legal obligations to local departments of transportation
(mandatory vs. discretional reporting).
Some patients may benefit from the activities of epilepsy support groups.
, 14 , 15
Choices during Pregnancy and Lactation13
There is an increased risk of oral contraceptive (OC) failure in women taking enzyme-inducing AEDs
(carbamazepine, phenytoin, phenobarbital, primidone). The estrogenic component of the OC should be ≥ 50
µg ethinyl estradiol. In addition to using systemic (hormonal) birth control, the use of a barrier method
(i.e., condoms) should be encouraged, for increased contraceptive effect and to reduce the risk of sexually
transmitted infections. However, barrier methods should not replace more effective methods of
contraception such as OCs. Useful Info?
Discuss pregnancy plans prior to conception:
is AED treatment still required?
withdraw least helpful AEDs if the patient is treated with AED polytherapy (determined by the history of which drug
seemed to be more or less helpful when added).
over 90% of women with epilepsy treated with AEDs have successful pregnancies and outcomes. AEDs confer an
increased risk of congenital malformations and other adverse effects. Current evidence does not allow selection of
Page 910
Therapeutic Choice
an AED that is “best” for this patient population, but data suggest that valproic acid is associated with the highest
risk of adverse outcomes among the commonly used AEDs.
women of childbearing potential who take AEDs should receive continuous folic acid supplementation ( 5 mg/day)
to potentially reduce the risk of teratogenic effects associated with AEDs.
During pregnancy:
follow AED levels as they may drop significantly.
obtain expert obstetrical advice on timing and type of ultrasound to detect fetal malformations.
start oral vitamin K ( 10 mg/day) in last four weeks of pregnancy.
Postpartum:
breastfeeding is generally acceptable. Babies whose mothers are taking barbiturates may be sedated; babies
exposed to barbiturates prepartum and not breastfeeding may have barbiturate withdrawal symptoms in the first
week after delivery.
follow AED levels as they may rise precipitously in the first weeks post-delivery.
Therapeutic Tips
Obtain a baseline CBC and serum liver transaminases (and repeat in 4–6 weeks) if treating with an AED that may cause a
hypersensitivity syndrome involving blood or liver. Mild elevations (< 2–3 times normal) of liver enzymes and/or modest
reductions in blood counts (e.g., neutropenia with carbamazepine; thrombocytopenia with valproic acid) are relatively
common. Neither requires discontinuation of treatment but the abnormality should be followed with serial studies.
Do not rely on serum AED levels alone to guide therapy as their validity is not established. Some patients will have
satisfactory seizure control at low AED levels, while others have dose-related toxicity below the upper end of the quoted
“therapeutic” range. A useful adage is “treat the patient, not the serum level.”
With many AEDs, drug interactions are potential problems. Drugs with hepatic enzyme-inducing properties
(carbamazepine, phenytoin, phenobarbital, primidone) may reduce the levels of concomitant medications. The presence
(or absence) of other medications should be considered when selecting an AED.
Consider epilepsy surgery for patients with medically refractory partial seizures. Refer these patients to tertiary-care
epilepsy programs for evaluation.
Figure 1-Management of Seizures and Epilepsy
Page 911
Therapeutic Choice
Abbreviations: AED=antiepileptic drug; CT=computed tomography; EEG=electroencephalogram; MRI=magnetic resonance imaging
Table 3: Antiepileptic Drugs (AEDs)
Adverse b
Cost
a
Class Drug Dose Effects Advantages Disadvantages
Iminostilbene carbamazepine Initial: Rash 5–10%; Linear Substrate of CYP3A4 $

Derivatives immediate- 100 mg BID; rarely, can be pharmacokinetics. and inducer of
release increase by very serious. ↑ CYP1A2, 3A4, 2C9,
Tegretol, 200 mg/day liver enzymes; 2C19, 2D6, 3A4 and
generics Q3–4 days transient 2C8, therefore many
Usual neutropenia potential drug
maintenance: 800– (common); interactions; may ↓
1200 mg/day in 2– aplastic anemia effectiveness of oral
4 divided doses, (extremely contraceptives;
with meals when rare); available only as oral
hyponatremia. formulations; may
worsen absence
Page 912
Therapeutic Choice
Adverse Costb
a
possible seizures; may
produce or
exacerbate
myoclonus.
Iminostilbene carbamazepine Initial: Rash 5–10%; BID dosing; linear See carbamazepine $
Derivatives controlled- 100 mg BID; rarely, can be pharmacokinetics; immediate-release.
release increase by very serious. ↑ CR preparation
Tegretol CR, 200 mg/day liver enzymes; may be better
generics Q3–4 days transient tolerated and
Usual neutropenia improve
maintenance: 800– (common); compliance.
1200 mg/day in 2 aplastic anemia
divided doses with (extremely
meals rare);
hyponatremia.
Iminostilbene oxcarbazepine Initial: 300 mg Similar to BID dosing; ↓ efficacy of oral $$$$$
Derivatives BID; ↑ by ≤ 600 carbamazepine efficacy may be contraceptives;
Trileptal, mg/day at weekly but slightly similar to available only as oral
generics intervals higher risk of carbamazepine but formulation.
Usual hyponatremia; better tolerated;
maintenance: skin rash cross- no autoinduction
1200–2400 mg/day reaction with of liver enzymes.
in 2 divided doses carbamazepine.
Benzodiazepines clobazam Initial: 5–15 Irritability, Very safe; daily or Tolerance (initial $
Frisium, mg/day, preferably depression. BID dosing; broad good response
generics at HS spectrum; rapid followed by loss of
Usual onset; few drug seizure control).
maintenance: interactions; can
20–40 mg/day in 1 be useful as “add-
or 2 divided doses on” for patients
“nearly” seizure
free; no effect on
efficacy of oral
contraceptives.
Succinimide ethosuximide Initial: 500 mg/day GI upset. Few drug For absence seizures $
Derivatives Zarontin in 1 or 2 divided interactions; no only; confers no
doses; ↑ by 250 effect on efficacy protection for
mg/day of oral generalized tonic-
Q4–7 days contraceptives. clonic seizures.
Usual
maintenance:
750–1000 mg/day
Gamma gabapentin Initial: 300 mg Tremor; vision No known TID dosing; not for $$–
Aminobutyric Neurontin, once daily, changes. significant drug 1° generalized $$$$
Acid (GABA) generics increasing by 300 interactions; well seizures; expensive
Derivatives mg daily every 5–7 tolerated; safe; at high doses; best
days up to 300 mg not metabolized; used as “add on”
TID. can use in liver drug.
Usual failure; no effect
maintenance: 900– on efficacy of oral
3600 mg/day contraceptives.
divided
Q6–8H
Gamma vigabatrin Initial: 1000 Low incidence BID dosing; well May worsen absence $$$–
Aminobutyric Sabril mg/day in 1–2 of psychosis, tolerated; few seizures, myoclonus; $$$$$
Acid (GABA) divided doses depression; drug interactions; expensive at high
Derivatives Usual irreversible no effect on doses; reports of
maintenance: 2000 visual field efficacy of oral visual field defects
–4000 mg/day in 1 problems. contraceptives; have severely limited
–2 divided doses easy to use; linear use of this drug.
pharmacokinetics;
does not exhibit
Page 913
Therapeutic Choice
Adverse Costb
a
dermatologic,
hepatic or
hematologic
adverse effects.
Barbiturates phenobarbital 90– Sedation Long t1/2; daily Potent inducer of $

generics 120 mg/day at HS prominent; skin dosing; cytochrome P450,
rash 5%; inexpensive. therefore many
depression; potential drug
diminished interactions;
libido. metabolism inhibited
by valproic acid; may
↓ effectiveness of oral
contraceptives; declining
use because of
adverse effect
profile.
Barbiturates primidone Initial: 125 mg HS Sedation Primidone Potent inducer of $

generics × 3 days, 125 mg prominent; skin metabolized to cytochrome P450,
BID × 3 days, 125 rash 5%; phenobarbital but therefore many
mg TID × 3 days depression; parent compound potential drug
Usual diminished has significant interactions;
maintenance: 500– libido. Some antiseizure metabolism inhibited
1000 mg/day in 3– patients properties. by valproic acid; may
4 divided doses intolerant of ↓ effectiveness of oral
low-dose contraceptives; declining
primidone. use because of
adverse effect
profile; QID dosing
(to maintain high
primidone/phenobarb
ratio); slow dose
titration.
Hydantoin phenytoin 300– Gingival Daily or BID Inducer of $

Derivatives Dilantin, 400 mg/day hyperplasia. dosing; parenteral cytochrome P450,
generics If used, loading Skin rash 5– form available; therefore many
doses should be 10%; rarely can inexpensive. potential drug
administered be very serious. interactions; may ↓
carefully ↑ liver enzymes. effectiveness of oral
Blood contraceptives; long-
dyscrasias. term cosmetic
Dose-related adverse effects;
encephalopathy. dosing complicated
Coarse facial by saturation
features with kinetics.
long-term use.
Carboxylic Acid valproic acid Initial: 250 mg Nausea; weight Often may use BID Inhibits hepatic $
Derivatives Depakene, BID; increase by gain; tremor; dosing; broad enzymes, therefore
generics 250 mg/day every hair loss; blood spectrum; no many potential drug
3–4 days as dyscrasias; hepatic enzyme interactions (but
necessary. hepatotoxicity induction; no does not reduce oral
Usual rarely; edema effect on efficacy contraceptive
maintenance: 750– rarely; of oral efficacy).
1000 mg/day in 2– menstrual contraceptives;
4 divided doses irregularities; very low incidence
teratogenicity. of rash; cognitive
effects generally
less than with
other older AEDs;
drug of first choice
for patients with
mixed 1°
generalized
seizures
(generalized tonic-
clonic, myoclonus,
absence).
Page 914
Therapeutic Choice
Adverse Costb
a
Carboxylic Acid divalproex Initial: 250 mg Nausea; weight Often may use BID Inhibits hepatic $
Derivatives sodium BID; increase by gain; tremor; dosing; broad enzymes, therefore
Epival, 250 mg/day every hair loss; blood spectrum; no many potential drug
generics 3–4 days as dyscrasias; hepatic enzyme interactions (but
necessary. hepatotoxicity induction; no does not reduce oral
Usual rarely; edema effect on efficacy contraceptive
maintenance: 750– rarely; of oral efficacy).
1000 mg/day in 2 menstrual contraceptives;
divided doses irregularities; very low incidence
teratogenicity. of rash; cognitive
effects generally
less than other
older AEDs; drug
of first choice for
patients with
mixed 1°
generalized
seizures
(generalized tonic-
clonic, myoclonus,
absence); GI
tolerability may be
better than with
valproic acid.
Other lamotrigine Initial: 25 mg Q2 Rash 5–10%, BID dosing; broad Very slow dose $$
Antiepileptic Lamictal, days to 50 mg/day, which rarely can spectrum; no titration; metabolism
Drugs generics depending on be very serious; enzyme induction markedly inhibited by
concurrent AED insomnia. (few interactions); valproic
therapy; after 2 wk no effect on acid/divalproex
give same dose efficacy of oral sodium and increased
BID × 2 wk, then ↑ contraceptives; by enzyme-inducing
by 100 mg/day at 1- some patients AEDs
to 2-wk intervals more “alert;” (carbamazepine,
Usual increasing phenytoin,
maintenance: 300– evidence for primidone,
400 mg/day in 2 monotherapy; phenobarbital);
divided doses increasing use for available only as oral
1° generalized formulation;
seizures. expensive at high
doses.
Other levetiracetam Initial: 1000 Sleepiness, ↓ BID dosing; broad Expensive. $$$–
Antiepileptic mg/day in 2 energy, headache, spectrum; no drug $$$$$
Drugs Keppra, divided doses; ↑ by irritability, interactions; no
generics 1000 mg/day at depression. effect on efficacy
weekly intervals of oral
Usual contraceptives;
maintenance: 1000 rapid titration.
– 3000 mg/day in
2 divided doses
Other topiramate Initial: 100 mg/day Cognitive BID dosing; broad Slow titration; ↓ $$–
Antiepileptic Topamax, in 2 divided doses problems spectrum; safe; efficacy of oral $$$
Drugs generics Usual common; few drug contraceptives;
maintenance: 200– kidney stones; interactions; expensive; cognitive
400 mg/day weight loss; potent AED with effects commonly
headache; broad spectrum of limit use.
fingers/toes activity.
paresthesias.
a.
Virtually all AEDs can produce sedation, fatigue, cognitive impairment, dizziness and ataxia in a dose-dependent fashion.
b.
Cost of 30-day supply for usual maintenance dose; includes drug cost only.
Abbreviations: AED=antiepileptic drug; CR=controlled-release; GI=gastrointestinal
Page 915
Therapeutic Choice
Legend: $ < $50 $$ $50–100 $$-$$$ $50–150 $$$ $100–150 $$–$$$$ $50–200 $$$$ $150–200 $$$–$$$$$
$100– > 200 $$$$–$$$$$ $150– > 200 $$$$$ > $200
Suggested Readings
Chen JW, Wasterlain CG. Status epilepticus: pathophysiology and management in adults. Lancet Neurol 2006;5(3):246-56.
French JA, Pedley TA. Initial management of epilepsy. N Engl J Med 2008;359(2):166-76.
Glauser T, Ben-Menachem E, Bourgeois B et al. ILAE treatment guidelines: evidence-based analysis of antiepileptic drug
efficacy and effectiveness as initial monotherapy for epileptic seizures and syndromes. Epilepsia 2006;47(7):1094-120.
Pohlman-Eden B, Behgi E, Camfield C et al. The first seizure and its management in adults and children. BMJ 2006;332
(7537):339-42.
Tomson T, Hiilesmaa V. Epilepsy in pregnancy. BMJ 2007;335(7623):769-73.
References
1. Mosewich RK, So EL. A clinical approach to the classification of seizures and epileptic syndromes. Mayo Clin Proc
1996;71(4):405-14.
2. French JA, Pedley TA. Initial management of epilepsy. N Engl J Med 2008;359(2):166-76.
3. Krumholz A, Wiebe S, Gronseth G et al. Practice Parameter: evaluating an apparent unprovoked first seizure in adults
(an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology and
the American Epilepsy Society. Neurology 2007;69(21):1996-2007.
4. Brodie MJ, Dichter MA. Antiepileptic drugs. N Engl J Med 1996;334(3):168-75.
5. Dichter MA, Brodie MJ. New antiepileptic drugs. N Engl J Med 1996;334(24):1583-90.
6. Glauser T, Ben-Menachem E, Bourgeois B et al. ILAE treatment guidelines: evidence-based analysis of antiepileptic
drug efficacy and effectiveness as initial monotherapy for epileptic seizures and syndromes. Epilepsia 2006;47(7):1094
-120.
7. Marson AG, Al-Kharusi AM, Alwaidh M et al. The SANAD study of effectiveness of carbamazepine, gabapentin,
lamotrigine, oxcarbazepine, or topiramate for treatment of partial epilepsy: an unblinded randomised controlled trial.
Lancet 2007;369(9566):1000-15.
8. Marson AG, Al-Kharusi AM, Alwaidh M et al.The SANAD study of effectiveness of valproate, lamotrigine, or topiramate
for generalised and unclassifiable epilepsy: an unblinded randomised controlled trial. Lancet 2007;369(9566):1016-26.
9. Wiebe S. An evidence based approach to the first unprovoked seizure. Can J Neurol Sci 2002;29(2):120-4.
10. Pohlman-Eden B, Behgi E, Camfield C et al. The first seizure and its management in adults and children. BMJ 2006;332
(7537):339-42.
11. Lawn ND, Wijdicks EF. Progress in clinical neurosciences: Status epilepticus: a critical review of management options.
Can J Neurol Sci 2002;29(3):206-15.
12. Chen JW, Wasterlain CG. Status epilepticus: pathophysiology and management in adults. Lancet Neurol 2006;5(3):246
-56.
13. [No authors listed]. Practice parameter: management issues for women with epilepsy (summary statement). Report of
the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 1998;51(4):944-8.
14. Tettenborn B. Management of epilepsy in women of childbearing age: practical recommendations. CNS Drugs 2006;20
(5):373-87.
15. Tomson T, Hiilesmaa V. Epilepsy in pregnancy. BMJ 2007;335(7623):769-73.
Page 916
e-Therapeutics+ : Therapeutics : Psychiatric Disorders: Attention-Deficit Hyperactivity Dis... Page 1 of 16
Therapeutic Choice
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Psychiatric Disorders: Attention-Deficit Hyperactivity Disorder

Adil Virani, BSc(Pharm), Pharm D, FCSHP
Attention-deficit hyperactivity disorder (ADHD), the most common neuropsychiatric disorder in school-aged children, is
characterized by 3 hallmark symptoms—inattention, hyperactivity and impulsivity—the presence and severity of which vary
among individuals.1 , 2 Those affected by ADHD have impairment in behavioural, cognitive, academic, emotional and/or social
functioning.3 ADHD symptoms present before the age of 7 and may persist throughout one’s life.2 , 3 There are 3 subtypes of
ADHD:3 predominantly inattentive (10–20%), predominantly hyperactive/impulsive (5–10%) and combined inattentive and
hyperactive (70–80%).3 , 4
Goals of Therapy
Eliminate or significantly decrease core ADHD symptoms

Improve behavioural and academic performance
Improve self-esteem and social functioning
Minimize adverse effects of medications
Investigations
Currently, there are no objective tests that unequivocally diagnose ADHD

The diagnosis of ADHD is based on evidence of 6 or more specific behaviours/symptoms listed in Table 1
Interview the patient, family/caregivers, teachers/assistants and psychologists (where applicable) to identify:
nature and duration of ADHD symptoms
impact of symptoms on functioning
age of onset
social interactions with family and peers
situations that exacerbate or ameliorate symptoms
symptoms suggestive of other potentially comorbid disorders such as oppositional defiant disorder, conduct disorder,
mood/anxiety disorders, tic disorders and/or learning disabilities
Various assessment/rating scales can be used to collect the above information and assess progress; see the guidelines at
5
www.caddra.ca to find the most appropriate assessment vehicles and treatment suggestions for individual patients
Physical examination/medical history to assess hearing, vision, thyroid function, neurologic status, cardiac function, history
of dysmorphic disorder (e.g., Down syndrome) or anemia
Birth/prenatal history including in utero exposure to substances and premature birth6
Baseline blood pressure, heart rate, height and weight (especially if stimulants are likely to be used)
Table 1: DSM-IV-TR Criteria for Diagnosing ADHD
A. Either (1) or (2):
(1) Six (or more) of the following symptoms of inattention have persisted for at least 6 months to a
degree that is maladaptive and inconsistent with developmental level:
a. Often fails to give close attention to details or makes careless mistakes in schoolwork, work, or
other activities.
b. Often has difficulty sustaining attention in tasks or play activities.
c. Often does not seem to listen when spoken to directly.
d. Often does not follow through on instructions and fails to finish schoolwork, chores, or duties in
the workplace (not due to oppositional behaviour or failure to understand instructions).
e. Often has difficulty organizing tasks and activities.
f. Often avoids, dislikes, or is reluctant to engage in tasks that require sustained mental effort
(such as schoolwork or homework).
g. Often loses things necessary for tasks or activities (e.g., toys, school assignments, pencils,
books, or tools).
h. Is often easily distracted by extraneous stimuli.
i. Is often forgetful in daily activities.
(2) Six (or more) of the following symptoms of hyperactivity-impulsivity have persisted for at least 6
months to a degree that is maladaptive and inconsistent with developmental level:
a. Often fidgets with hands or feet or squirms in seat.
b. Often leaves seat in classroom or in other situations in which remaining seated is expected.
Page 917
Therapeutic Choice
c. Often runs about or climbs excessively in situations in which it is inappropriate (in adolescents
or adults, may be limited to subjective feelings of restlessness).
d. Often has difficulty playing or engaging in leisure activities quietly.
e. Is often “on the go” or often acts as if “driven by a motor.”
f. Often talks excessively.
g. Often blurts out answers before questions have been completed.
h. Often has difficulty waiting for his/her turn.
i. Often interrupts or intrudes on others (e.g., butts into conversations or games).
B. Some hyperactive-impulsive or inattentive symptoms that cause impairment were present before age 7 years.
C. Some impairment from the symptoms is present in 2 or more settings (e.g., at school [or work] and at home).
D. There must be clear evidence of clinically significant impairment in social, academic, or occupational functioning.
E. The symptoms do not occur exclusively during the course of a pervasive developmental disorder, schizophrenia, or
other psychotic disorder and are not better accounted for by another mental disorder (e.g., mood disorder, anxiety
disorder, dissociative disorder or a personality disorder).
Adapted with permission from the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision. Copyright 2000.
American Psychiatric Association.
Therapeutic Choices (Figure 1 - Management of Attention-Deficit Hyperactivity Disorder9 )
Evidence suggests that a combination of pharmacologic and nonpharmacologic therapies (e.g., behaviour modification
programs) constitutes the best treatment strategy for children with ADHD.7 , 8 Stimulant medications and atomoxetine are the
most effective treatment for the core symptoms of ADHD (hyperactivity, impulsiveness and inattention).5 , 8 , 9 Behavioural
therapies play an important role in improving social interactions, self-esteem and the common behaviours seen in ADHD.8 , 10
Despite many high-quality randomized controlled trials (RCTs) supporting the role of stimulants for ADHD, and the lack of high-
level evidence for nonpharmacologic therapies, some clinicians, parents and/or patients prefer approaches such as behaviour
management, dietary changes, physical exercise, psychotherapy, neurofeedback (EEG biofeedback) and hypnosis.11 , 12 , 13
When compared to stimulants, these nonpharmacologic options are less effective at reducing the core symptoms of ADHD.4 , 8 ,
10
Behavioural therapies are designed to minimize negative behaviours and promote positive ones by teaching parents (and
2
sometimes teachers) techniques to improve a child’s behaviours. The Multimodal Treatment Study of ADHD (MTA) is one
of the largest (597 children aged 7–9 with the combined subtype of ADHD) and longest RCTs comparing behavioural
therapy with pharmacologic therapy and combined behavioural/pharmacologic therapy. This trial found that behavioural
therapy alone was inferior to pharmacologic therapy alone at reducing core ADHD symptoms.8 Combined
behavioural/pharmacologic therapy was shown to be more effective at reducing oppositional behaviours and anxiety while
improving social interactions and self-esteem when compared to either treatment strategy alone.8 Another RCT, involving
103 children aged 7–9 years, confirmed the greater benefit of stimulant medications over behavioural strategies on core
10
ADHD symptoms, and demonstrated a sustained benefit over a 2-year period.
The elimination of certain foods from the diet in an effort to minimize ADHD symptoms is not based on evidence from
clinical trials, but rather on observations that some children exhibit more severe hyperactive behaviours in association with
certain sugars, dyes or preservatives.11
Mind-body therapies such as neurofeedback or hypnosis are geared toward training the patient’s mind (by modifying
brainwave activity) to influence physical responses to ADHD symptoms.13 Though some interesting research has been
conducted in this area, well-designed trials are still required to confirm the efficacy of these strategies in reducing core
12 , 13
ADHD symptoms.
Psychostimulants
Stimulant medications (methylphenidate, dextroamphetamine, mixed salts amphetamine) have been considered first-
2 , 4 , 9
line agents for treating ADHD for decades. Their efficacy at reducing core ADHD symptoms has been demonstrated in a
5 , 9
wide range of patients aged 6 years to adult. Controlled trials consistently demonstrate that at least 70% of patients
2 , 4 , 8 , 9
receiving stimulant therapy will have a clinically significant decrease in core ADHD symptoms. Lisdexamfetamine,
an inactive prodrug of dextroamphetamine coupled with the essential amino acid L-lysine, is now available in Canada. This
stimulant becomes active as the prodrug is slowly hydrolyzed in the intestines and liver (the amino acid is cleaved off).
Page 918
Therapeutic Choice
Lisdexamfetamine has similar efficacy to other stimulants in school-aged children and may have a lower abuse potential than
14 , 15
short-acting stimulants. Stimulants have not been adequately studied in terms of important long-term outcomes such as
quality of life, employment, school completion and long-term morbidity or mortality.
No clinical predictors of who will benefit from which stimulant have been identified; therefore, the choice of agent will depend
on patient and physician preferences.9 Patients who do not tolerate or respond to one stimulant after 2–3 weeks of therapy
should be switched to an alternative stimulant.9 Currently, there are no RCTs assessing the benefits and harms of using long-
term stimulant therapy (e.g., > 2 years). Three-year follow up of the participants of the MTA study found that children given
stimulants were on average 2 cm shorter and weighed 2.7 kg less than children who were never medicated during the same 3
years.16
Though methylphenidate sustained-release tablets (e.g., Ritalin SR) and dextroamphetamine sustained-release spansules
(Dexedrine) have a longer duration of action (up to 8 hours) than their immediate-release counterparts (see Table 2), they often
require more than once-daily dosing.
Long-acting stimulant formulations such as Concerta, Biphentin and Adderall XR (see Table 2) are as effective as
9
appropriately dosed shorter-acting stimulants. These formulations have a duration of action of 8–12 hours.
Advantages of these long-acting products include single daily dosing, potential for improved adherence,
avoidance of the need for medication administration at school, decreased abuse potential and decreased risk of
rebound hyperactivity. Given these advantages, it has been recommended that long-acting agents be used as first
5
-line treatment of ADHD. Useful Info?
In 2006, Health Canada and regulatory agencies in other countries alerted us to the possible association of stimulants (and
atomoxetine) with cardiovascular risks such as sudden cardiac death in those with underlying cardiac anomalies, and with
adverse psychiatric symptoms such as hallucinations and agitation.
Though modafinil is a central nervous system stimulant that promotes wakefulness in the treatment of narcolepsy, it is less
effective than other psychostimulants in ADHD and is not often used. It is not approved for use in ADHD. There is some
evidence from double-blind trials in children and adults that modafinil (170–425 mg/day) is superior to placebo in decreasing
core symptoms of ADHD.17 , 18
Atomoxetine
Atomoxetine, a norepinephrine reuptake inhibitor not classified as a stimulant, is indicated in children ≥ 6 years of age,
adolescents and adults with ADHD. Its efficacy and tolerability have been studied in several well-designed trials.19 , 20 , 21 , 22 ,
23 , 24 , 25
Atomoxetine is not a controlled substance. RCTs confirm that after 6–12 weeks of treatment, atomoxetine reduces
core ADHD symptoms by at least 25–30% in 60–70% of individuals.20 , 23 , 25 The efficacy of atomoxetine approaches that of
psychostimulants. While some guidelines list it as a first-line option, the available evidence supports a role in therapy for those
who have either not responded to or not tolerated an adequate trial of stimulant medications. It should also be considered for
those with ADHD and comorbid substance abuse disorder or depression.9 , 26
Antidepressants
In general, antidepressants are considered less effective than stimulants in the management of ADHD in children; hence, they
are considered as second- or third-line options or as adjunctive therapy.2 , 5 , 9 Antidepressants may benefit patients with
comorbid conditions such as depression, anxiety, enuresis or tic disorders.19
Bupropion, a norepinephrine and dopamine reuptake inhibitor, has been found to be moderately effective for the treatment of
19 , 27 , 28 , 29 , 30
ADHD in both children and adults. Although there are insufficient data from RCTs to recommend its use,
some evidence suggests venlafaxine, a serotonin and norepinephrine reuptake inhibitor, may be helpful in the management of
ADHD, particularly in adults.9 , 26 , 31
Many controlled trials have examined the effects of TCAs such as desipramine, imipramine and nortriptyline in the short-
32
term treatment of ADHD. TCAs are less effective than stimulants at reducing the core symptoms of ADHD. Despite the fact that
most TCA studies have significant design flaws (e.g., open label, not randomized), the benefits of TCAs may outweigh their
6 , 9 , 19 , 32
risks in some patients who cannot take stimulants, atomoxetine or bupropion.
Alpha2-Adrenergic Agonists
2 , 9
Alpha2-adrenergic agonists, such as clonidine, are used as second- or third-line agents for ADHD. They primarily reduce
symptoms of aggression, impulsivity, overarousal and hyperactivity, and have minimal benefit on symptoms of inattention or
poor concentration. When used concurrently with stimulants, they often target sleep disruptions, aggression, impulsivity,
6 , 19
comorbid oppositional defiant disorder and tics.
Page 919
Therapeutic Choice
Antipsychotics
Some antipsychotics may negatively affect cognition in patients with ADHD. A systematic review of the role of atypical
antipsychotics (primarily risperidone) could not identify a benefit of these agents in patients with ADHD.34
Low doses of atypical antipsychotics (e.g., risperidone) may be moderately effective for the behavioural symptoms seen in
5
hyperactive and impulsive children when stimulants alone are ineffective or not tolerated; they have little effect on inattention.
Atypical antipsychotics are also sometimes initiated to decrease behaviours seen in children with comorbid conduct disorder,
oppositional defiant disorder, autistic disorders, impulse control disorders and Tourette’s syndrome.
Natural Health Products
Though evidence from well-designed randomized trials is sparse, various natural health products (e.g., herbs, vitamins or
nutritional supplements) have been tried on the basis of their traditional uses. For example, agents with possible anxiolytic,
sedative or hypnotic effects (e.g., chamomile, valerian, melatonin) have been used in children who are restless, anxious or
having sleep difficulties.11 These herbs may play a role in calming a hyperactive child or promoting sleep in children with ADHD
and insomnia. Other agents of interest include antioxidants such as blue-green algae, various B vitamins, ginkgo biloba,
pycnogenol and evening primrose oil (essential fatty acids). In general, concerns regarding efficacy and quality of natural health
products make it difficult to support their use in place of existing prescription medications; however, after evaluating potential
drug interactions and clinical risks, it may be possible to use some of these products safely in conjunction with approved
therapies.
Therapeutic Tips
When selecting an appropriate pharmacologic regimen, consider the child's daily schedule, predominant ADHD symptoms,
likelihood of adherence, patient preferences (including medication cost) and risk of adverse effects.
Cross-over trials of stimulant vs. placebo or other stimulants (“n of 1” trials) can be helpful in assessing the response to
medication in a patient for whom therapeutic benefit is uncertain.
Although more common with methylphenidate sustained-release (e.g., Ritalin SR), a small portion of patients prescribed
long-acting stimulants such as Concerta, Biphentin or Adderall XR may require additional immediate-release stimulants in
the afternoon to help with homework and control of early evening symptoms.
Sustained-release or long-acting stimulant tablets should not be crushed or chewed. Adderall XR, Dexedrine spansules and
Biphentin capsules can be opened and sprinkled on soft foods (e.g., yogurt, applesauce). This may be helpful for younger
children unable to swallow certain medications.
Children taking stimulants should be monitored for potential growth suppression by recording their weight and height at
baseline and monthly during their stimulant therapy. These measurements can be compared with established norms for a
given child’s age/gender and plotted on growth charts.
Extended “drug holidays” (e.g., several months over the summer holidays) from stimulants are generally not recommended
in children with moderate-to-severe ADHD symptoms who are doing well on the stimulant. The return of symptoms and
resultant effects on behaviour and self-esteem do not typically outweigh the risks of taking the medication. Drug holidays
(at times of low environmental stresses), may be useful when adverse effects associated with stimulants (e.g., growth
suppression or weight loss > 10% of initial body weight) are present or when attempting to assess the continued benefit of
the stimulant.
Some clinicians raise concerns about the risk of substance abuse with stimulants. Though this can occur, trials evaluating
substance abuse in those with ADHD have found that adequately treated children with ADHD have a lower risk of substance
33
abuse later in life when compared to those who are untreated.
Page 920
Therapeutic Choice
Figure 1-Management of Attention-Deficit Hyperactivity Disorder9
Table 2: Drugs Used in Attention-Deficit Hyperactivity Disorder
a
Cost
Stimulants methylphenidate Initial: Common, usually Stimulants: Avoid Last daily dose $
immediate-release 0.3 mg/kg/day transient— concurrent use with should be given
tablets Usual: 0.15–1 continue nonselective MAOIs before 4 p.m. to
Ritalin, generics mg/kg/day or therapeutic trial: (e.g., phenelzine, avoid insomnia.
10–60 mg/day in anorexia, insomnia, tranylcypromine). Doses greater
1–3 divided weight loss, Other drugs that than 60 mg/day
doses irritability, inhibit MAO (e.g., usually do not
dizziness, moclobemide) can result in
weepiness, also ↑ hypertensive additional
headache, effect of stimulant. efficacy in
abdominal pain. Concurrent use of children.
Transient—stop sibutramine may
and re-evaluate: cause hypertension Pharmacokinetics
zombie-like effects, and tachycardia. reflect wide
Page 921
Therapeutic Choice
a
Cost
psychotic reactions individual
(e.g., Concurrent use of variations; strict
hallucinations), theophylline may ↑ weight-based
agitation, risk of tachycardia, dosing may not
tachycardia, palpitations, be predictive of
hypertension, dizziness, weakness. clinical effect;
growth failure, titrate dose
rebound Methylphenidate: against
hyperactivity, May ↑ plasma levels of response.
leukopenia, blood phenytoin, TCAs,
dyscrasias. phenobarbital. Potential for
abuse; use
Overdose Carbamazepine: ↓ cautiously,
symptoms—stop plasma levels of especially in
and retitrate: methylphenidate. adolescents.
“glassy eyes,”
insomnia, ↓ metabolism of
hyperactivity. warfarin, increased
INR.
Significant:
sudden cardiac
death reported;
neurologic
symptoms;
exacerbation of
tics; avoid in
patients with a
history of
cardiovascular
conduction
disturbances,
hypertension, acute
psychotic episodes
and
hyperthyroidism.
If seizures occur,
or if frequency
increases in patient
with controlled
epilepsy, stop and
re-evaluate.
Stimulants methylphenidate 20–60 mg/day in Common, usually Stimulants: Avoid Last daily dose $
sustained-release 1 or 2 divided transient— concurrent use with should be given
tablets doses continue nonselective MAOIs before 4 p.m. to
Ritalin SR, therapeutic trial: (e.g., phenelzine, avoid insomnia.
generics anorexia, insomnia, tranylcypromine). Doses greater
weight loss, Other drugs that than 60 mg/day
irritability, inhibit MAO (e.g., usually do not
abuse; use
Page 922
Therapeutic Choice
a
Cost
“glassy eyes,”
insomnia, ↓ metabolism of May be used in
hyperactivity. warfarin, increased combination with
INR. immediate-
Significant: release
sudden cardiac formulation.
death reported;
neurologic
symptoms;
exacerbation of
tics; avoid in
patients with a
history of
cardiovascular
conduction
disturbances,
hypertension, acute
psychotic episodes
and
hyperthyroidism.
If seizures occur,
or if frequency
with controlled
epilepsy, stop and
re-evaluate.
Stimulants methylphenidate 10–60 mg once Common, usually Stimulants: Avoid Last daily dose $$
controlled-release daily in a.m. transient— concurrent use with should be given
capsules continue nonselective MAOIs before 4 p.m. to
Biphentin therapeutic trial: (e.g., phenelzine, avoid insomnia.
anorexia, insomnia, tranylcypromine). Doses greater
abuse; use
“glassy eyes,”
insomnia, ↓ metabolism of Capsule contents
hyperactivity. warfarin, increased can be sprinkled
INR. on soft food
Significant: such as
sudden cardiac applesauce, ice
death reported; cream or yogurt.
neurologic
symptoms;
Page 923
Therapeutic Choice
a
Cost
exacerbation of
tics; avoid in
patients with a
history of
cardiovascular
conduction
disturbances,
hypertension, acute
psychotic episodes
and
hyperthyroidism.
If seizures occur,
or if frequency
with controlled
epilepsy, stop and
re-evaluate.
Stimulants methylphenidate 18–54 mg once Common, usually Stimulants: Avoid Last daily dose $$$
bilayer controlled- daily in a.m. transient— concurrent use with should be given
release tablets continue nonselective MAOIs before 4 p.m. to
Concerta, generics therapeutic trial: (e.g., phenelzine, avoid insomnia.
anorexia, insomnia, tranylcypromine). Doses greater
abuse; use
“glassy eyes,”
insomnia, ↓ metabolism of Consult product
hyperactivity. warfarin, increased monograph for
INR. dosage
Significant: conversion from
sudden cardiac other
death reported; methylphenidate
neurologic formulations.
symptoms;
exacerbation of
tics; avoid in
patients with a
history of
cardiovascular
conduction
disturbances,
hypertension, acute
psychotic episodes
and
hyperthyroidism.
Page 924
Therapeutic Choice
a
Cost
If seizures occur,
or if frequency
with controlled
epilepsy, stop and
re-evaluate.
Stimulants dextroamphetamine 0.15 mg/kg/day Common, usually Stimulants: Avoid $

immediate-release or 2.5–40 transient— concurrent use with
tablets mg/day in 1–3 continue nonselective MAOIs
Dexedrine divided doses therapeutic trial: (e.g., phenelzine,
anorexia, insomnia, tranylcypromine).
weight loss, Other drugs that
irritability, inhibit MAO (e.g.,
dizziness, moclobemide) can
weepiness, also ↑ hypertensive
headache, effect of stimulant.
abdominal pain. Concurrent use of
and re-evaluate: cause hypertension
zombie-like effects, and tachycardia.
psychotic reactions
(e.g., Concurrent use of
hallucinations), theophylline may ↑
agitation, risk of tachycardia,
tachycardia, palpitations,
hypertension, dizziness, weakness.
growth failure,
rebound Methylphenidate:
hyperactivity, May ↑ plasma levels of
dyscrasias. phenobarbital.
Overdose Carbamazepine: ↓
symptoms—stop plasma levels of
and retitrate: methylphenidate.
“glassy eyes,”
INR.
Significant:
sudden cardiac Dextroamphetamine:
death reported; Acidifying agents
neurologic (e.g., fruit juices,
symptoms; ascorbic acid) can ↓
exacerbation of absorption and ↓
tics; avoid in elimination of
patients with a dextroamphetamine.
history of
cardiovascular Alkalinizing agents
conduction (e.g., sodium
disturbances, bicarbonate) can ↑
hypertension, acute absorption and ↑
psychotic episodes elimination of
and dextroamphetamine.
hyperthyroidism.
If seizures occur,
or if frequency
with controlled
epilepsy, stop and
re-evaluate.
Stimulants dextroamphetamine 0.15 mg/kg or Common, usually Stimulants: Avoid Capsule contents $$
sustained-release 10–40 mg once transient— concurrent use with can be sprinkled
continue nonselective MAOIs on soft food
therapeutic trial: (e.g., phenelzine, such as
Page 925
e-Therapeutics+ : Therapeutics : Psychiatric Disorders: Attention-Deficit Hyperactivity ... Page 10 of 16
Therapeutic Choice
a
Cost
spansules daily in a.m. anorexia, insomnia, tranylcypromine). applesauce, ice
Dexedrine weight loss, Other drugs that cream or yogurt.
irritability, inhibit MAO (e.g.,
psychotic reactions
growth failure,
Overdose Carbamazepine: ↓
symptoms—stop plasma levels of
and retitrate: methylphenidate.
“glassy eyes,”
INR.
Significant:
sudden cardiac Dextroamphetamine:
death reported; Acidifying agents
neurologic (e.g., fruit juices,
symptoms; ascorbic acid) can ↓
exacerbation of absorption and ↓
tics; avoid in elimination of
patients with a dextroamphetamine.
history of
cardiovascular Alkalinizing agents
conduction (e.g., sodium
disturbances, bicarbonate) can ↑
hypertension, acute absorption and ↑
psychotic episodes elimination of
and dextroamphetamine.
hyperthyroidism.
If seizures occur,
or if frequency
with controlled
epilepsy, stop and
re-evaluate.
Stimulants lisdexamfetamine Initial: 6-12 y: Common, usually Stimulants: Avoid May be taken $$$$
Vyvanse 30 mg daily in transient— concurrent use with with or without
a.m.; may continue nonselective MAOIs food.
increase to therapeutic trial: (e.g., phenelzine,
50 mg daily after anorexia, insomnia, tranylcypromine).
1 wk if weight loss, Other drugs that
necessary irritability, inhibit MAO (e.g.,
psychotic reactions
(e.g.,
Page 926
Therapeutic Choice
a
Cost
hallucinations), Concurrent use of
agitation, theophylline may ↑
tachycardia, risk of tachycardia,
hypertension, palpitations,
growth failure, dizziness, weakness.
rebound
hyperactivity, Methylphenidate:
leukopenia, blood May ↑ plasma levels of
dyscrasias. phenytoin, TCAs,
phenobarbital.
Overdose
symptoms—stop Carbamazepine: ↓
and retitrate: plasma levels of
“glassy eyes,” methylphenidate.
insomnia,
hyperactivity. ↓ metabolism of
warfarin, increased
Significant: INR.
sudden cardiac
death reported; Antacids and urinary
neurologic alkalinizers can
symptoms; increase
exacerbation of amphetamine levels
tics; avoid in and adverse effects.
patients with a
history of
cardiovascular
conduction
disturbances,
hypertension, acute
psychotic episodes
and
hyperthyroidism.
If seizures occur,
or if frequency
with controlled
epilepsy, stop and
re-evaluate.
Stimulants mixed salts 10–30 mg once Common, usually Stimulants: Avoid Capsule contents $$$$
amphetamine daily in a.m. transient— concurrent use with can be sprinkled
extended-release continue nonselective MAOIs on applesauce
capsules therapeutic trial: (e.g., phenelzine, and eaten
Adderall XR anorexia, insomnia, tranylcypromine). immediately
weight loss, Other drugs that without
irritability, inhibit MAO (e.g., chewing; doses
dizziness, moclobemide) can should not be
weepiness, also ↑ hypertensive divided or
headache, effect of stimulant. stored.
psychotic reactions
growth failure,
Overdose
symptoms—stop
Page 927
Therapeutic Choice
a
Cost
and retitrate: Carbamazepine: ↓
“glassy eyes,” plasma levels of
insomnia, methylphenidate.
hyperactivity.
↓ metabolism of
Significant: warfarin, increased
sudden cardiac INR.
death reported;
neurologic
symptoms;
exacerbation of
tics; avoid in
patients with a
history of
cardiovascular
conduction
disturbances,
hypertension, acute
psychotic episodes
and
hyperthyroidism.
If seizures occur,
or if frequency
with controlled
epilepsy, stop and
re-evaluate.
Norepinephrine atomoxetine Children ≤ 70 Headaches, Inhibitors of CYP2D6 Dosing based on $$

Reuptake Strattera kg: rhinorrhea, upper such as fluoxetine, patient’s weight.
Inhibitors 0.5 mg/kg/day × abdominal pain, paroxetine or Requires 3–4
10 days, then nausea, sedation, quinidine can ↑ weeks to see
0.8 mg/kg/day × vomiting, plasma levels. beneficial
10 days, then 1– decreased appetite, Some “slow effects.
1.2 mg/kg/day dizziness, fatigue, metabolizers” (e.g.,
> 70 kg: 40 emotional lability some Asian
mg/day × 10 and small increases populations) may
days, then 60 in heart rate and have extended
mg/day × 10 blood pressure. elimination half-
days, then Significant: suicidal lives.
increase to ideation, sudden
target of 80 cardiac death, liver Concurrent use of
mg/day if toxicity, salbutamol may ↑
necessary exacerbation of heart rate.
tics.
Administer as
one dose in a.m.
or 2 divided
doses in a.m.
and late
afternoon.
Max 100 mg/day
Antidepressants, bupropion Initial: Agitation, dry Inducers of CYP2D6 It may take 2–4 $
atypical Wellbutrin SR, 2–3 mg/kg/day mouth, insomnia, or CYP3A4 (e.g., weeks before
generics Usual: headache, carbamazepine, effects on ADHD
200–300 mg/day constipation, phenytoin, rifampin) symptoms are
in 2 divided nausea, vomiting, may ↓ plasma level of seen. Be vigilant
doses. Single nervousness, bupropion and ↑ level for initiation of
doses should not dizziness, of hydroxybupropion other
exceed 150 mg sweating, (active metabolite). medications that
hypertension and Plasma can decrease the
tachycardia. concentration of seizure threshold
Significant: suicidal venlafaxine or TCAs (e.g.,
ideation, seizures such as imipramine, chloroquine,
Page 928
Therapeutic Choice
a
Cost
(0.5–1% desipramine and theophylline,
incidence). Avoid nortriptyline may ↑ tramadol,
in patients with a due to inhibition of ciprofloxacin).
history of seizure CYP2D6 by
disorders, eating bupropion.
disorders or Avoid use with
significant head MAOIs; may cause
injury. Seizure risk mania, excitation,
↑ with doses hyperpyrexia.
> 300 mg/day.
Antidepressants, venlafaxine Adults: Initial: Nausea, Inhibitors of CYP2D6 Make take up to $$$
Serotonin Effexor XR, 37.5–75 mg drowsiness, or CYP3A4 (e.g., 4 weeks for
Norepinephrine generics daily for 1 week; nervousness, clarithromycin, optimal drug
Reuptake titrate gradually dizziness, dry erythromycin, effect.
Inhibitors to 150–300 daily mouth, may ↑ BP if grapefruit juice,
Maximum of 450 dose fluoxetine,
mg/day > 300 mg/day. paroxetine) may
decrease venlafaxine
clearance; avoid use
with MAOIs; caution
with other
serotonergic drugs
(serotonin
syndrome).
Antidepressants, desipramine 6–12 y: Postural Avoid with MAOIs— May require 3–4 $
Tricyclic generics 10–20 mg/day in hypotension, may cause mania, weeks to see
3–4 divided anticholinergic excitation, beneficial
doses effects (dry mouth, hyperpyrexia. effects.
Adolescents: constipation, Inducers of CYP2D6
30–50 mg/day in urinary retention), or CYP3A4 (e.g.,
3–4 divided dizziness, nausea, carbamazepine,
doses drowsiness, phenytoin, rifampin)
weakness, tremor, may ↓ effect.
Usual max weight gain,
150 mg/day asymptomatic ECG Inhibitors of CYP2D6
changes and or CYP3A4 (e.g.,
tachycardia. clarithromycin,
Significant: erythromycin,
arrhythmias grapefruit juice,
(potential for fatal fluoxetine,
arrhythmias in paroxetine) may ↑
overdose). effect and toxicity.
Where possible,
avoid in patients
with a history of
cardiovascular
conduction
disturbances,
urinary retention,
seizure disorders,
hyperthyroidism.
Antidepressants, imipramine 6–12 y: Postural Avoid with MAOIs— May require 3–4 $
Tricyclic Tofranil, generics 10–20 mg/day in hypotension, may cause mania, weeks to see
Page 929
Therapeutic Choice
a
Cost
Where possible,
avoid in patients
with a history of
cardiovascular
conduction
disturbances,
urinary retention,
seizure disorders,
hyperthyroidism.
Antidepressants, nortriptyline 6–12 y: Postural Avoid with MAOIs— May require 3–4 $
Tricyclic Aventyl, generics 10–20 mg/day in hypotension, may cause mania, weeks to see
Where possible,
avoid in patients
with a history of
cardiovascular
conduction
disturbances,
urinary retention,
seizure disorders,
hyperthyroidism.
Alpha2- clonidine Initial: Hypotension, Avoid concurrent Caution in $

adrenergic Catapres, Dixarit, 0.05–0.1 mg/day sedation and use with tricyclic patients with
Agonists generics Usual: dizziness common antidepressants. cardiovascular
3–10 µg/kg/day initially; dry Additive effects with disease or
(0.05– mouth; could other CNS depression.
0.4 mg/day), exacerbate depressants such as
once daily or in depression. ethanol.
divided doses
Antipsychotics, risperidone Initial: Weight gain, Inhibitors of CYP2D6 Oral liquid $

atypical Risperdal 0.25–0.5 mg at drowsiness, or CYP3A4 (e.g., should not be
bedtime; headache, clarithromycin, mixed with cola
Preparations,
increase at orthostatic erythromycin, or tea; may be
generics weekly intervals hypotension, grapefruit juice, mixed with
by 0.5 mg/day in dyspepsia, dose- fluoxetine, water, orange
2 divided doses related paroxetine) may ↑ juice or low-fat
as needed extrapyramidal effect and toxicity; milk.
Usual effects; inducers of these
maintenance hyperprolactinemia. isoenzymes (e.g.,
carbamazepine,
Page 930
Therapeutic Choice
a
Cost
dose phenytoin, rifampin)
0.75–1.5 mg/day may ↓ effect.
a.
Cost of 30-day supply of mean dosage; based on 35 kg body weight; includes drug cost only.
Abbreviations: TCAs=tricyclic antidepressants; MAOIs=monoamine oxidase inhibitors
Legend: $ < $30 $$ $30–60 $$$ $60–90 $$$$ $90–120
Suggested Readings
Canadian Attention Deficit Hyperactivity Disorder Resource Alliance (CADDRA). Canadian ADHD practice guidelines. Toronto
(ON): CADDRA; 2008. Available from: http://www.caddra.ca/english/2007-08_guidelines_pdfs/2007-
08_Caddra_Guidelines.pdf. Accessed March 25, 2009.
Jensen PS, Hinshaw SP, Swanson JM et al. Findings from the NIMH Multimodal Treatment Study of ADHD (MTA): implications
and applications for primary care providers. J Dev Behav Pediatr 2001;22(1):60-73.
National Collaborating Centre for Mental Health. NICE Clinical Guideline 72. Attention deficit hyperactivity disorder: diagnosis
and management in children, young people and adults. September 2008. Available from:
http://www.nice.org.uk/nicemedia/pdf/CG072NiceGuidelineV2.pdf. Accessed March 25, 2009.
Pliszka SR, Crismon ML, Hughes CW et al. The Texas Children’s Medication Algorithm Project: revision of the algorithm for
pharmacotherapy of attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry 2006;45(6):642-57.
Rappley MD. Clinical practice. Attention deficit-hyperactivity disorder. N Engl J Med 2005;352(2):165-73.
References
1. [No authors listed]. Clinical practice guideline: diagnosis and evaluation of the child with attention-deficit/hyperactivity
disorder. American Academy of Pediatrics. Pediatrics 2000;105(5):1158-70.
2. American Academy of Pediatrics. Subcommittee on Attention-Deficit/Hyperactivity Disorder and Committee on Quality
Improvement. Clinical practice guideline: treatment of the school-aged child with attention-deficit/hyperactivity disorder.
Pediatrics 2001;108(4):1033-44.
3. American Psychiatric Association. Task Force on DSM-IV. Diagnostic and statistical manual of mental disorders: DSM-IV-
TR. Washington (DC): American Psychiatric Association; 2000.
4. Rappley MD. Clinical practice. Attention deficit-hyperactivity disorder. N Engl J Med 2005;352(2):165-73.
5. Canadian Attention Deficit Hyperactivity Disorder Resource Alliance (CADDRA). Canadian ADHD practice guidelines.
Toronto (ON): CADDRA; 2008. Available from: http://www.caddra.ca/cms4/index.php?
option=com_content&view=article&id=26&Itemid=353&lang=en. Accessed February 1, 2010.
6. Linnet KM, Dalsgaard S, Obel C et al. Maternal lifestyle factors in pregnancy risk of attention deficit hyperactivity disorder
and associated behaviors: review of the current evidence. Am J Psychiatry 2003;160(6):1028-40.
7. Daley KC. Update on attention-deficit/hyperactivity disorder. Curr Opin Pediatr 2004;16(2):217-26.
8. [No authors listed]. A 14-month randomized clinical trial of treatment strategies for attention-deficit/hyperactivity
disorder. The MTA Cooperative Group. Multimodal Treatment Study of Children with ADHD. Arch Gen Psychiatry 1999;56
(12):1073-86.
9. Pliszka SR, Crismon ML, Hughes CW et al. The Texas Children’s Medication Algorithm Project: revision of the algorithm for
pharmacotherapy of attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry 2006;45(6):642-57.
10. Abikoff H, Hechtman L, Klein RG et al. Symptomatic improvement in children with ADHD treated with long-term
methylphenidate and multimodal psychosocial treatment. J Am Acad Child Adolesc Psychiatry 2004;43(7):802-11.
11. Chan E. The role of complementary and alternative medicine in attention-deficit hyperactivity disorder. J Dev Behav
Pediatr 2002;23(1 Suppl):S37-45.
Page 931
Therapeutic Choice
12. Bernard-Bonnin A. The use of alternative therapies in treating children with attention deficit hyperactivity disorder.
Canadian Paediatric Society Position Statement. Paediatrics & Child Health 2002;7(10):710-8. Available from:
http://www.cps.ca/english/statements/PP/pp02-03.htm. Accessed March 25, 2009.
13. Fox DJ, Tharp DF, Fox LC. Neurofeedback: an alternative and efficacious treatment for attention deficit hyperactivity
disorder. Appl Psychophysiol Biofeedback 2005;30(4):365-73.
14. Biederman J, Krishnan S, Zhang Y et al. Efficacy and tolerability of lisdexamfetamine dimesylate (NRP-104) in children
with attention-deficit/hyperactivity disorder: a phase III, multicentre, randomized, double-blind, forced-dose, parallel-
group study. Clin Ther 2007;29(3):450-63.
15. Jasinski DR, Krishnan S. Abuse liability and safety of oral lisdexamfetamine dimesylate in individuals with a history of
stimulant abuse. J Psychopharmacol 2009;23(4):419-27.
16. Swanson JM, Elliott GR, Greenhill LL et al. Effects of stimulant medication on growth rates across 3 years in the MTA
follow-up. J Am Acad Child Adolesc Psychiatry 2007;46(8):1015-27.
17. Biederman J, Swanson JM, Wigal SB et al. Efficacy and safety of modafinil film-coated tablets in children and adolescents
with attention-deficit/hyperactivity disorder: results of a randomized, double-blind, placebo-controlled, flexible-dose
study. Pediatrics 2005;116(6):e777-84.
18. Biederman J, Swanson JM, Wigal SB et al. A comparison of once-daily modafinil in children with attention-
deficit/hyperactivity disorder: a randomized, double-blind, and placebo-controlled study. J Clin Psychiatry 2006;67
(5):727-35.
19. Banaschewski T, Roessner V, Dittman RW et al. Non-stimulant medications in the treatment of ADHD. Eur Child Adolesc
Psychiatry 2004;13(Suppl 1):102-16
20. Michelson D, Faries D, Wernicke J et al. Atomoxetine in the treatment of children and adolescents with attention-
deficit/hyperactivity disorder: a randomized, placebo-controlled, dose-response study. Pediatrics 2001;108(5):e83.
21. Biederman J, Heiligenstein JH, Faries D et al. Efficacy of atomoxetine versus placebo in school-age girls with attention-
deficit/hyperactivity disorder. Pediatrics 2002;110(6):e75.
22. Michelson D, Allen AJ, Busner J et al. Once-daily atomoxetine treatment for children and adolescents with attention deficit
hyperactivity disorder: a randomized, placebo-controlled study. Am J Psychiatry 2002;159(11):1896-901.
23. Spencer T, Heiligenstein JH, Biederman J et al. Results from 2 proof-of-concept, placebo-controlled studies of
atomoxetine in children with attention-deficit/hyperactivity disorder. J Clin Psychiatry 2002;63(12):1140-7.
24. Michelson D, Adler L, Spencer T et al. Atomoxetine in adults with ADHD: two randomized, placebo-controlled studies. Biol
Psychiatry 2003;53(2):112-20.
25. Kelsey DK, Sumner CR, Casat CD et al. Once-daily atomoxetine treatment for children with attention-deficit/hyperactivity
disorder, including an assessment of evening and morning behavior: a double-blind, placebo-controlled trial. Pediatrics
2004;114(1):e1-8.
26. Bezchlibnyk-Butler KZ, Virani AS, editors. Clinical handbook of psychotropic drugs for children and adolescents.
Cambridge (MA): Hogrefe & Huber; 2004.
27. Casat CD, Pleasants DZ, Van Wyck Fleet J. A double-blind trial of bupropion in children with attention deficit disorder.
Psychopharmacol Bull 1987;23(1):120-2.
28. Barrickman LL, Perry PJ, Allen AJ et al. Bupropion versus methylphenidate in the treatment of attention-deficit
hyperactivity disorder. J Am Acad Child Adolesc Psychiatry 1995;34(5):649-57.
29. Kuperman S, Perry PJ, Gaffney GR et al. Bupropion SR vs. methylphenidate vs. placebo for attention deficit hyperactivity
disorder in adults. Ann Clin Psychiatry 2001 Sep;13(3):129-34.
30. Wilens TE, Spencer TJ, Biederman J et al. A controlled clinical trial of bupropion for attention deficit hyperactivity disorder
in adults. Am J Psychiatry 2001;158(2):282-8.
31. Motavalli Mukaddes N, Abali O. Venlafaxine in children and adolescents with attention deficit hyperactivity disorder.
Psychiatry Clin Neurosci 2004;58(1):92-5.
32. Spencer T, Biederman J, Wilens T et al. Pharmacotherapy of attention-deficit hyperactivity disorder across the life cycle. J
Am Acad Child Adolesc Psychiatry 1996;35(4):409-32.
33. Wilens TE, Faraone SV, Biederman J et al. Does stimulant therapy of attention-deficit/hyperactivity disorder beget later
substance abuse? A meta-analytic review of the literature. Pediatrics 2003;111(1):179-85.
34. Einarson TR, Iskedjian M. Novel antipsychotics for patients with attention-deficit hyperactivity disorder: a systematic
review. Ottawa (ON): Canadian Coordinating Office for Health Technology Assessment (CCOHTA); 2001.
Page 932
e-Therapeutics+ : Therapeutics : Psychiatric Disorders: Bipolar Disorder Page 1 of 17
Therapeutic Choice
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Psychiatric Disorders: Bipolar Disorder
Sagar V. Parikh, MD, FRCPC
1
Bipolar disorder is a complex, recurrent mood disorder that affects 1–2% of the population. It is defined as having
either a manic, hypomanic or mixed episode (see Table 1),2 and almost always includes episodes of clinical
depression.
Table 1: Description of Bipolar Disorder Episodes2
Type of Episode Features
Mania Mood: Abnormally and persistently elevated, expansive or irritable

Duration: At least 1 week, causing significant distress/disability, or requiring hospital
admission
Plus:
If mood is elevated or expansive, 3 or more of the following features must be present. If
mood is predominantly irritable, 4 or more are required.
Grandiosity
More talkative
Excessive involvement in pleasurable activities
Less need for sleep
Flight of ideas
Distractability
More goal-directed activity
Hypomania Mood: Same symptoms as for mania, but milder and not disabling; no psychotic
symptoms
Duration: 4 days or longer
Major Depressive Mood: Depressed most of the day OR markedly diminished interest or pleasure
Episode (anhedonia)
Duration: At least 2 weeks, with significant change from previous functioning
Plus:
Four or more of the following:
Insomnia or hypersomnia
Significant weight loss/gain or change in appetite
Fatigue or loss of energy
Psychomotor retardation or agitation (observable)
Worthlessness or excessive guilt
Impaired thinking, concentrating or making decisions
Recurrent thoughts of death, suicidal ideation or attempt/plan
Mixed Episode Mood: Criteria met during same time period for both a major depressive episode and a
manic episode
Duration: Nearly every day for at least 1 week or for any duration if hospitalized
Symptoms of mania include changes in mood, energy, sleep requirements and ability to concentrate, and in some
cases psychotic symptoms.
Symptoms of depression include oversleeping or profound tiredness (the most common symptom of bipolar
depression), pessimism, inability to socialize, decreased cognitive abilities and possibly suicidal or psychotic
symptoms.
Bipolar disorder is formally divided into 3 categories: bipolar I disorder, bipolar II disorder and bipolar disorder not
2
otherwise specified (Table 2). Diagnosis of bipolar disorder is often difficult as the illness is perhaps the most
complex psychiatric disorder. It has the most variable clinical presentation and is associated with the highest
number of episodes, the highest degree of comorbidity and the highest mortality of the major psychiatric conditions.
Page 933
Therapeutic Choice
When bipolar disorder is severe and psychotic symptoms are present, it resembles schizophrenia. When
accompanied by substance abuse, it mimics a pure substance abuse disorder. In a severe depression phase, it
resembles unipolar major depression. When the symptoms are mild and changing rapidly, it resembles borderline
personality disorder.
Table 2: Classification of Bipolar Disorder2
Disorder Features
Bipolar I Disorder Lifetime history of at least one clear-cut manic or mixed episode with or without
episodes of depression
Bipolar II Disorder History of hypomanic episodes and major depressive episodes, with no history of a
full manic or a mixed episode
Bipolar Disorder Not Bipolar disorder believed to be present but diagnostic criteria not strictly met
Otherwise Specified
Bipolar Spectrum Proposed category for mood conditions that appear to fall between traditional unipolar
Disorder depression and bipolar disorder, e.g., major depression in person with first-degree
relative with bipolar disorder
Cyclothymic Disorder Recurrent episodes of hypomania and mild (subthreshold) depressive symptoms
Goals of Therapy
Control symptoms of acute episode

Prevent recurrences
Provide ancillary care for comorbid psychiatric conditions such as anxiety or substance abuse or medical
conditions such as endocrine/metabolic disorders
Investigations
It is estimated that one-third of patients appearing in primary care settings with symptoms
suggestive of unipolar major depression are actually experiencing depression in the context of
bipolar illness.3 Ask all depressed patients about possible hypomanic or manic symptoms in their
past. While no screening test is ideal, the Mood Disorder Questionnaire (MDQ) is a helpful, self-
4
completed form that asks systematic yes/no questions about the symptoms of mania; an
adolescent version also has been developed.5 Two or more “yes” answers on the MDQ should
prompt a more thorough clinical review of symptoms, including questioning family/friends if
possible. Useful Info?
The diagnosis of bipolar disorder depends not just on the clinical presentation but, very importantly, on a
reliable collateral history from a friend or family member who can corroborate episodes of elevated mood,
inappropriate behaviour, decreased sleep with increased energy or grandiosity.
It is critical to determine whether the patient has a family history of mood disorders, substance abuse or bipolar
disorder itself.
depend in part on the age and acute presentation of the patient
for all patients, basic blood tests include CBC, electrolytes, renal function, liver function and thyroid
function
metabolic parameters including weight, lipid profile and fasting blood sugars at the time of initiation of any
treatment
for patients with any unusual symptoms, neurologic signs or symptoms, or a first manic or hypomanic
episode after age 50, include structural imaging of the brain such as CAT or MRI
Therapeutic Choices
Bipolar disorder is a complex illness that can only be partly managed by a sole physician; a team approach is ideal.
At a minimum, it is helpful to have access to a nurse who will provide education and coping strategies as well as
ongoing monitoring and support. The comprehensive treatment of bipolar disorder is reviewed in detail in the
1 , 6 , 7
CANMAT treatment guidelines, which are the basis for the recommendations that follow. Key additional
resources such as treatment manuals and web sites are also listed in the CANMAT guidelines.
Page 934
Therapeutic Choice
Psychoeducation consists of information about the illness as well as training in coping strategies and
recognition of episodes early in their genesis. Structured group psychoeducational programs have been shown
to substantially reduce the risk of relapse of manic, mixed and depressive episodes.8 A recommended source of
information on psychoeducation is Structured Group Psychotherapy for Bipolar Disorder (see Suggested
Readings), which is available in both English and French and provides explicit advice for effective
psychoeducation over the course of 6 treatment sessions.
To prevent an incipient manic or depressive episode from becoming a flagrant episode, conduct a “relapse
drill,” which trains patients to recognize their unique warning symptoms and respond in a specific treatment
fashion which might include:
changes in medication strategies
rapid contact with the treating physician
additional steps to regulate sleep and other behaviours
Pharmacologic therapy varies according to the type and stage of the episode being treated. Since treatment for this
condition is lifelong, engaging the patient in collaborative decision-making is critical. Except in situations where
there is a severe episode or medical emergency, discuss the pros and cons of 2 or 3 pharmacologic options to
inform and support the patient’s decision.
Manic Episodes (Figure 1 - Management of Acute Mania in Bipolar Disorder , Table 3, Table
6)
Moderate-to-severe mania is usually treated in hospital; mild mania, which by psychiatric definition is distinct from
hypomania (see Table 1), may be treated on an outpatient basis. The first step in treating mania is to assess for risk
of aggressive behaviour or violence to others, suicide, degree of insight and the ability to adhere to treatment
6
(Figure 1 - Management of Acute Mania in Bipolar Disorder ). If the patient is taking an antidepressant, it should be
discontinued. Complicating issues such as other medical conditions, particularly substance abuse problems, will
need attention.
Specific medication strategies for mania depend on whether the patient is already on maintenance therapy and is
experiencing a breakthrough episode or whether the individual is unmedicated. If the patient is already taking a first
-line agent (lithium or divalproex or an atypical antipsychotic), dosage adjustment may be sufficient after
checking blood levels where appropriate. In moderate-to-severe manic episodes, addition of another medication is
usually necessary.
In previously unmedicated patients, initiate treatment with a first-line agent (Table 3). When the episode is
particularly severe, initiate treatment with a 2-drug combination such as lithium or divalproex plus an atypical
antipsychotic. Continue treatment on any particular regimen for 2 weeks at therapeutic doses before assessing
whether a change is necessary. Various other treatment options are shown in Figure 1 - Management of Acute Mania
in Bipolar Disorder .
Depressive Episodes (Figure 2 - Management of Depressive Episodes in Bipolar Disorder,

Table 4, Table 7)
As with acute mania, first assess the patient for basic safety issues, including potential suicidality, comorbid medical
problems or substance abuse (Figure 1 - Management of Acute Mania in Bipolar Disorder ). Next, the strategy
depends on whether the patient is on medication and has had a breakthrough episode of major depression, or
whether they are medication free (Table 4). In an unmedicated patient, therapy may begin with lithium,
lamotrigine or quetiapine. If the depression is severe, therapy can be initiated with two agents, such as lithium
plus quetiapine.
Table 3: Treatment Regimens for Acute Mania in Bipolar Disordera
Place in
Therapy Drugs Comments
First-line lithium Aim for blood levels near the high end of
therapeutic range as tolerated, i.e., 1–1.2 mmol/L
Page 935
Therapeutic Choice
Place in
divalproex Loading dose is possible; aim for blood levels high

in therapeutic range
olanzapine May start with therapeutic dose of 15 mg; note

peak sedation is 3–4 hours after ingestion, so may
dose earlier in evening
risperidone Monitor regularly for orthostatic hypotension and

extrapyramidal side effects, e.g., parkinsonism,
akathisia
quetiapine Need to titrate dose rapidly; monitor for sedation,

hypotension
aripiprazole
ziprasidone Consider pretreatment ECG; usually need ≥ 120

mg/day
lithium or divalproex plus risperidone Allows lower dosing of risperidone than in

monotherapy; useful for more severe episodes;
start risperidone first × 1–3 days
lithium or divalproex plus quetiapine Allows lower dosing of quetiapine than in

start quetiapine first × 1–3 days
lithium or divalproex plus olanzapine Allows lower dosing of olanzapine than in

start olanzapine first × 1–3 days
lithium or divalproex plus aripiprazole
Second-line carbamazepine Try several first-line treatments first before going

ECT to second-line treatments
lithium plus divalproex Asenapine is available in Europe but not yet in
asenapine Canada
lithium or divalproex plus asenapine Paliperidone has reasonable efficacy but clinical
paliperidone experience is limited so it is used second-line
Third-line haloperidol Haloperidol, including iv formulation, is well

chlorpromazine tolerated in severely medically ill patients;
lithium or divalproex plus haloperidol clozapine is very useful in rapid-cycling patients
lithium plus carbamazepine
clozapine
oxcarbazepine
tamoxifen
Not Monotherapy with gabapentin, topiramate, Use of some of these agents as adjuncts may be
recommended lamotrigine, verapamil or combination appropriate, especially if initiated prior to mania for
therapy with carbamazepine plus other symptoms (e.g., using gabapentin for
risperidone or olanzapine anxiety, topiramate for alcohol craving)
a.
Treatment trials typically run 2 weeks at therapeutic doses. Adjunctive benzodiazepine use is common, e.g., clonazepam 1–2
mg BID. If patient is not on first-line agent, start first-line agent monotherapy; if more serious, consider dual therapy. If on
maintenance therapy, optimize dosing prior to adding new medication.
Abbreviations: ECT=electroconvulsive therapy
Table 4: Treatment Regimens for Acute Depression in Bipolar Disordera
Page 936
Therapeutic Choice
Place in
First-line lithium Aim for blood levels near the high end of therapeutic range as
tolerated, i.e., 1–1.2 mmol/L. May be useful for those with
high risk of suicide or self harm
lamotrigine Slow titration schedule in turn slows response but mitigates

risk of adverse effects including rash; useful for milder
episodes
quetiapine Monotherapy studies showed doses of 300 or 600 mg/day to be

equally effective; lower dose preferred if patient is medication-
naïve
lithium or divalproex Prefer shorter half-life SSRIs in case of switch to mania

plus SSRI
lithium or divalproex As with all antidepressants, watch for switch into mania
plus bupropion
lithium plus divalproex Aim for good blood levels of each mood stabilizer
olanzapine plus May have lower rates of switch into mania compared to mood
SSRI stabilizer plus SSRI
Second-line quetiapine plus SSRI Try several first-line treatments before going to second-line
lithium or divalproex options
plus lamotrigine
divalproex
adjunctive modafinil
Third-line carbamazepine Third-line choices best reserved for mood disorder specialists.
olanzapine ECT may be initial treatment in particularly severe depression
divalproex or in medically ill patients
lithium plus carbamazepine
lithium plus pramipexole
lithium plus MAOI
lithium or divalproex plus
venlafaxine
ECT
atypical antipsychotic
atypical antipsychotic plus
TCA
lithium or divalproex or
carbamazepine plus SSRI
adjunctive eicosapentaenoic
acid, riluzole or topiramate
Not monotherapy with gabapentin

recommended or aripiprazole
a.
Treatment trials typically run a minimum of 4 weeks at therapeutic doses. Response is often slower than in unipolar
depression. Avoid antidepressants if possible, or shorten duration of antidepressant treatment to prevent switch into mania.
Abbreviations: ECT=electroconvulsive therapy; MAOI=monoamine oxidase inhibitor; SSRI=selective serotonin reuptake

inhibitor; TCA=tricyclic antidepressant
Bipolar depression is difficult to treat; steps to follow if there is an inadequate response after 2–4 weeks of therapy
are outlined in Figure 2 - Management of Depressive Episodes in Bipolar Disorder. Two key emerging observations
are that specific psychosocial strategies are potentially valuable for bipolar depression, and that combining 2
traditional mood stabilizers such as lithium plus divalproex may also be of some value. Although
antidepressants can be considered in moderate-to-severe cases, there is some potential to destabilize and
Page 937
Therapeutic Choice
promote a more rapid-cycling course in susceptible individuals. Thus, the use (with caution) of short courses of
antidepressants (e.g., ≤ 3–4 months), is prudent. Intensive psychosocial interventions for acute bipolar depression
also have some efficacy, compared to brief psychosocial intervention, while usual bipolar medications are
9
maintained.
Maintenance Therapy for Bipolar Disorder (Table 5, Table 8)
When a patient recovers from an acute episode and remains well for at least 2 months, the patient is defined as
being in the maintenance phase of the illness. Unmedicated, such individuals have an approximately 70% chance of
experiencing another episode over the next year and an approximately 95% chance of having a recurrence within 5
years. To prevent relapse, interventions include psychosocial strategies such as psychoeducation, cognitive-
behavioural therapy, family therapy and interpersonal and social rhythm therapy. Key characteristics of effective
psychosocial therapies that improve medication adherence include education about the disorder (including the
likelihood of relapse), training in self-monitoring, education about how to manage side effects, development of
strategies to manage stressors and attention to the patient’s own belief system and attitude towards the illness.
Give patients the opportunity to discuss the impact of the illness on their life and their beliefs about potential effects
of long-term medication use. To facilitate longer-term compliance, repeat a brief version of psychoeducation
periodically, e.g., annually.
There is evidence of effective relapse prevention with lithium, divalproex, olanzapine and lamotrigine as
maintenance therapy (Table 5). However, with the exception of lithium, evidence for long-term therapy is limited.
Table 5: Maintenance Treatment Regimens for Bipolar Disordera
Place in
First-line lithium Blood levels can be individualized—some patients have efficacy

at lower end of normal therapeutic range; levels lower than for
acute episode
lamotrigine Effective only for prophylaxis against depressive relapses
olanzapine Equal to lithium overall in relapse prevention, but better at

preventing relapse to mixed episodes
divalproex RCT support is lacking but clinical observation suggests effective

relapse prevention
quetiapine Effective in preventing both manic and depressive relapses
lithium or divalproex plus Effective in preventing both manic and depressive relapses
quetiapine
risperidone long-acting Monotherapy or adjunctive therapy

injection
aripiprazole
adjunctive ziprasidone May be used adjunctively with other first-line agents; watch for
emergent insomnia.
Second-line carbamazepine Try several first-line treatments before going to second-line

treatments. These recommendations are based primarily on open-
lithium plus divalproex label studies. May be able to use antidepressants concurrently for
lithium plus carbamazepine a long time in some patients with clear histories of predominantly
depressive relapses.
olanzapine
lithium plus lamotrigine
olanzapine plus fluoxetine
lithium plus risperidone
Third-line adjunctive therapy with: Third-line choices best reserved for mood disorder specialists
phenytoin
Page 938
Therapeutic Choice
Place in
clozapine
ECT
topiramate
omega-3 fatty acids
oxcarbazepine
gabapentin
Not adjunctive flupenthixol; Bipolar II patients may rarely benefit from monotherapy with
recommended monotherapy with antidepressants
gabapentin, topiramate or
antidepressants
a.
While the goal is ultimately complete relapse prevention, in individuals with severe illness reduction in the frequency, duration
and intensity of relapse may be more realistic. Psychosocial interventions are critical to reduce relapse.
Abbreviations: ECT=electroconvulsive therapy; RCT=randomized controlled trial; SSRI=selective serotonin reuptake inhibitor
Bipolar Disorder in Children and Adolescents

10
Bipolar disorder typically emerges in adolescence, most often as depression. An initial depressive episode is
impossible to distinguish from unipolar depression. The existence of first-degree relatives with bipolar disorder in
an adolescent presenting with an initial depression is suggestive of an eventual bipolar diagnosis, but treatment is
usually initiated on the assumption that the teenager has unipolar depression. Other key predictors of an eventual
shift to a bipolar diagnosis include the presence of particularly severe or psychotic symptoms in a teen who is
unmistakably depressed (as opposed to someone who likely has schizophrenia). If the teen does have an initial
presentation of hypomania or mania, the presentation is often one of a mixed state, where the mood is
11
predominantly irritable and symptoms of both mania and depression are present in the same week (see Table 1).
Both mania and depression have been documented in pre-teens, therefore bipolar disorder may be reliably
diagnosed by a specialist at a very early age. ADHD presents a major differential challenge, with the key
distinguishing feature remaining the episodic nature (weeks or months) of the bipolar disorder, while ADHD
symptoms are present on a continuous daily basis. Bipolar treatment options are limited by a lack of clinical trials in
children and adolescents, but some evidence exists for the efficacy of the usual adult treatments such as lithium,
12
divalproex, quetiapine and ziprasidone. Given the various diagnostic and medication controversies associated
with children, refer to a child psychiatrist for treatment.
Bipolar Disorder in the Elderly
When bipolar disorder begins early in life, it is a lifelong illness that, if untreated, continues to manifest with more
frequent episodes and shorter periods of recovery over the decades. The illness does not typically progress to an
extremely rapid-cycling form of illness, and elderly bipolar patients usually will have major periods of euthymia. A
small number of individuals experience a first onset of bipolar illness in their sixties or later; symptoms are typical
of adult mania but irritability may be prominent.13 Often these individuals have a history of comorbid neurologic
problems and an elevated all-cause mortality rate. Clinical trials are relatively rare in the elderly, so most treatment
14
parameters are extrapolated from the adult literature. All atypical antipsychotics carry warnings about potential
elevated stroke risk and mortality in the elderly, but the significant morbidity and mortality associated with bipolar
disorder in this population compels consideration of these agents for treatment.
Since bipolar disorder often starts early in life, many women will be living with the disorder at the time they are
considering having children. Key management principles include careful risk assessment for each woman, namely
the risk of pregnancy destabilizing the illness and the possibility of severe episodes resulting in the death of either
the patient or child, or both. Untreated women with bipolar disorder are particularly susceptible to postpartum
depression, including depression with psychotic features that may result in harm to the child. Despite such cautions,
most women with bipolar disorder are able to manage pregnancy successfully. Collaborative management of the
pregnancy by a psychiatrist, an obstetrician and a family physician is recommended, including consultation with an
agency specializing in information on medications during and following pregnancy (see below). Because most
psychiatric medications pose some teratogenic risk, and many are excreted in breast milk, medication management
Page 939
Therapeutic Choice
during and following pregnancy requires extensive consideration and review with the patient.15 If medication is to
be discontinued prior to conception, it should be tapered with medical supervision.16
Creation of a “pregnancy contract” is recommended; in consultation with the doctor, a patient creates a 1-page
document that summarizes her typical symptoms in mania and in depression, and lists preferred treatment options
for each phase of illness. That document is then shared among the treatment team and the patient’s family, and
serves as a nonbinding but helpful “advance directive” should a new episode of illness arise.
For general principles of drug therapy during pregnancy and lactation, see Appendix: Drug Use During Pregnancy
and Appendix: Drug Use During Lactation. For more detailed information on the use of specific medications during
pregnancy and lactation the reader is referred to Motherisk (www.motherisk.org/women/drugs.jsp), Briggs GG,
Freeman RK, Yaffe SJ. Drugs in Pregnancy and Lactation 2008, LactMed (http://toxnet.nlm.nih.gov/cgi-
bin/sis/htmlgen?LACT) and Hale T. Medications and Mother’s Milk 2008.
Therapeutic Tips
A key feature of bipolar disorder is recurrent nonadherence to medication; including the patient in decision-
making, together with psychoeducation, promotes a strong therapeutic alliance and enhances medication
adherence.
Patients taking lithium need to maintain their usual salt and caffeine intake and monitor fluid intake and output,
making adjustments in the event of unexpected losses due to vomiting or diarrhea.
During acute manic episodes, patients may exhibit increased tolerance to lithium.
Advise patients taking antipsychotics about antipsychotic-associated body temperature dysregulation and
strategies to prevent heat stroke (e.g., hydration, sun protection).
For lithium-associated cognitive impairment, check lithium level and thyroid function. Lowering the dose or
using a slow-release formulation may improve cognitive function.
Patients who experience tremor while taking lithium may benefit from elimination of dietary caffeine, lithium
dose reduction or addition of a beta-blocker such as propranolol or atenolol.
Patients who experience diarrhea while taking slow-release lithium preparations may fare better with immediate
17 18
-release formulations, particularly the oral liquid citrate salt.
Figure 1- Management of Acute Mania in Bipolar Disorder
Page 940
Therapeutic Choice
Abbreviations: ECT = electroconvulsive therapy
Adapted with permission from Yatham LN, Kennedy SH, Schaffer A et al. Canadian Network for Mood and Anxiety Treatments
(CANMAT) and International Society for Bipolar Disorders (ISBD) collaborative update of CANMAT guidelines for the management
of patients with bipolar disorder: update 2009. Bipolar Disord 2009;11(3):225-55.
Figure 2- Management of Depressive Episodes in Bipolar Disorder
Page 941
Therapeutic Choice
a.
Or switch SSRI to another SSRI.
Abbreviations: SSRI = selective serotonin reuptake inhibitor; ECT = electroconvulsive therapy
Adapted with permission from Yatham LN, Kennedy SH, Schaffer A et al. Canadian Network for Mood and Anxiety Treatments
(CANMAT) and International Society for Bipolar Disorders (ISBD) collaborative update of CANMAT guidelines for the management
Table 6: First-line Drug Therapy for Mania in Bipolar Disorder
Costa
Mood lithium 900–2100 mg/day, Highly toxic in Toxic levels may result $
Stabilizers carbonate guided by serum overdose. Measure when adding NSAIDs,
concentrations electrolytes and do 24- ACEIs, ARBs and
immediate-
Page 942
Therapeutic Choice
a
Cost
release (target h urine for ClCr when especially thiazide
Carbolith, 1–1.2 mmol/L) starting long-term diuretics. Reduce lithium
Single daily dose treatment. Monitor dose and check serum
Lithane,
preferred thyroid and renal level if long-term
generics
function at least every treatment with these
6 mo. agents is required.
Avoid large changes in
salt or coffee intake.
Stop lithium temporarily

during acute intermittent
illnesses causing fluid
and electrolyte losses.
Mood lithium 900–2100 mg/day, Highly toxic in Toxic levels may result $
Stabilizers carbonate guided by serum overdose. Measure when adding NSAIDs,
controlled-
(target h urine for ClCr when especially thiazide
release 1–1.2 mmol/L) starting long-term diuretics. Reduce lithium
generics Single daily dose treatment. Monitor dose and check serum

Mood lithium citrate 900–2100 mg/day, Highly toxic in Toxic levels may result $
Stabilizers syrup guided by serum overdose. Measure when adding NSAIDs,
generic
(target h urine for ClCr when especially thiazide
(8 mmol/5 mL;
1–1.2 mmol/L) starting long-term diuretics. Reduce lithium
approximately
Single daily dose treatment. Monitor dose and check serum
equivalent to
300 mg lithium
carbonate/5
mL)

Mood divalproex 750–2000 mg/day, Weight gain, Avoid combining with $$

Stabilizers sodium adjusted according thrombocytopenia, carbamazepine; use
Epival, generics to serum levels polycystic ovary caution if combining with
(target range syndrome, teratogenic; lamotrigine.
350–800 mmol/L) rarely:
hyperammonemia,
hepatotoxicity.
Mood valproic acid 750–2000 mg/day, Weight gain, Avoid combining with $$
Stabilizers Depakene, adjusted according thrombocytopenia, carbamazepine; use
generics to serum levels polycystic ovary caution if combining with
(target range syndrome, teratogenic; lamotrigine.
350–800 µmol/L) rarely:
hyperammonemia,
hepatotoxicity.
Page 943
Therapeutic Choice
Costa
Antipsychotics, risperidone 3–6 mg/day Weight gain, Avoid combining with $$$$
atypical Risperdal, orthostasis, carbamazepine.
generics extrapyramidal
symptoms, metabolic
disturbances.
Antipsychotics, olanzapine 5–20 mg/day Weight gain, metabolic Fluvoxamine and $$$$$
atypical Zyprexa, disturbances, ciprofloxacin ↑ olanzapine
Zyprexa Zydis, anticholinergic side levels.
generics effects in elderly,
akathisia. Monitor
periodically for
movement disorders.
Antipsychotics, quetiapine 400–800 mg/day Weight gain, sedation, Ketoconazole $$$$$

atypical Seroquel, orthostasis, metabolic dramatically ↑ quetiapine
generics disturbances. levels. Watch for hypotension
Monitor periodically for with antihypertensives.
movement disorders,
including akathisia.
Antipsychotics, aripiprazole 15 mg/day; max 30 Akathisia, dizziness, Carbamazepine (or other $$$$$
atypical Abilify mg/day orthostatic strong inducers of
hypotension, CYP2D6 or CYP3A4 such
headache, GI as phenytoin, rifampin)
complaints, tremor, can ↓ aripiprazole levels
sedation. significantly.
Ketoconazole, quinidine,
fluoxetine or paroxetine
(or other strong
inhibitors of CYP2D6 or
CYP3A4) can ↑ levels
substantially.
Antipsychotics, ziprasidone 120–160 mg/day in Insomnia, Carbamazepine ↓ levels $$$$$

atypical Zeldox 2 divided doses, extrapyramidal side significantly; do not use
with food effects; consider ECG with other drugs that
at baseline and prolong the QT interval.
periodically to monitor
effect on QT interval.
a.
Cost of 30-day supply of mean dose; includes drug cost only.
ACEIs=angiotensin converting enzyme inhibitors; ARBs=angiotensin receptor blockers; ClCr=creatinine

clearance; NSAIDs=nonsteroidal anti-inflammatory drugs
Legend: $ < $25 $$ $25–50 $$$ $50–75 $$$$ $75–100 $$$$$ > $100
a
Table 7: First-line Drug Therapy for Depression in Bipolar Disorder
b
Cost
Mood lithium 600–1800 Highly toxic in overdose. Toxic levels may result $
Stabilizers carbonate mg/day, adjusted Measure electrolytes and when adding NSAIDs,
according to do 24-h urine for ClCr ACEIs, ARBs and
immediate-
serum levels when starting long-term especially thiazide
release (target treatment. Monitor diuretics. Reduce lithium
Carbolith, thyroid and renal dose and check serum
Page 944
Therapeutic Choice
Costb
Lithane, 1–1.2 mmol/L) function at least every 6 level if long-term
generics mo. treatment with these
agents is required.

Mood lithium 600–1800 Highly toxic in overdose. Toxic levels may result $
Stabilizers carbonate mg/day, adjusted Measure electrolytes and when adding NSAIDs,
controlled-
release (target treatment. Monitor diuretics. Reduce lithium
generics 1–1.2 mmol/L) thyroid and renal dose and check serum
function at least every 6 level if long-term
mo. treatment with these
agents is required.

Mood lithium citrate 600–1800 Highly toxic in overdose. Toxic levels may result $
Stabilizers syrup mg/day, adjusted Measure electrolytes and when adding NSAIDs,
generic
(8 mmol/5 mL;
(target treatment. Monitor diuretics. Reduce lithium
approximately
1–1.2 mmol/L) thyroid and renal dose and check serum
equivalent to
function at least every 6 level if long-term
300 mg lithium
mo. treatment with these
carbonate/5 mL)
agents is required.

Mood divalproex 750–2000 Weight gain, Avoid combining with $$

Stabilizers sodium mg/day, adjusted thrombocytopenia, carbamazepine; use
Epival, generics according to polycystic ovary caution if combining with
serum levels syndrome, teratogenic; lamotrigine.
(target range 350 rarely:
–690 umol/L) hyperammonemia,
hepatotoxicity.
Mood valproic acid 750–2000 Weight gain, Avoid combining with $$

Stabilizers Depakene, mg/day, adjusted thrombocytopenia, carbamazepine; use
generics according to polycystic ovary caution if combining with
hepatotoxicity.
Mood lamotrigine 100–300 mg/day Rash common; severe Divalproex doubles blood $$
Stabilizers Lamictal, rash rare. level of lamotrigine;
generics always initiate slowly.
Page 945
Therapeutic Choice
Costb
Antipsychotics, quetiapine Usual: 300 Weight gain, sedation, Ketoconazole $$$$$

atypical Seroquel, mg/day orthostasis, metabolic dramatically increases
Seroquel XR, Max: 600 mg/day disturbances. quetiapine levels.
generics Monitor for hypotension
with antihypertensives.
a.
Detailed information on antidepressants can be found in Psychiatric Disorders: Depression.
b.
Cost of 30-day supply for mean dose; includes drug cost only.

Legend: $ < $25 $$ $25–50 $$$ $50–75 $$$$ $75–100 $$$$$ > $100
Table 8: First-line Maintenance Therapy for Bipolar Disorder
a
Cost
Mood lithium 600–1800 Highly toxic in Toxic levels may result $

Stabilizers carbonate mg/day, adjusted overdose. Measure when adding NSAIDs,
according to electrolytes and do 24- ACEIs, ARBs and
immediate-
serum levels h urine for ClCr when especially thiazide
release (target range starting long-term diuretics. Reduce lithium
Carbolith, 0.6–1 mmol/L) treatment. Monitor dose and check serum
Lithane, thyroid and renal level if long-term
generics function at least every 6 treatment with these
mo. agents is required.
Avoid large changes in salt
or coffee intake.

illnesses causing fluid and
electrolyte losses.
Mood lithium 600–1800 Highly toxic in Toxic levels may result $

Stabilizers carbonate mg/day, adjusted overdose. Measure when adding NSAIDs,
controlled-
release (target range starting long-term diuretics. Reduce lithium
generic 0.6–1 mmol/L) treatment. Monitor dose and check serum
thyroid and renal level if long-term
function at least every 6 treatment with these
mo. agents is required.
or coffee intake.

electrolyte losses.
Mood lithium citrate 600–1800 Highly toxic in Toxic levels may result $
Stabilizers syrup mg/day, adjusted overdose. Measure when adding NSAIDs,
generic
(8 mmol/5 mL;
(target range starting long-term diuretics. Reduce lithium
approximately
treatment. Monitor dose and check serum
equivalent to
Page 946
Therapeutic Choice
a
Cost
300 mg lithium 0.6–1 mmol/L) thyroid and renal level if long-term
carbonate/5 function at least every 6 treatment with these
mL) mo. agents is required.
or coffee intake.

electrolyte losses.
Mood divalproex 750–2000 Weight gain, Avoid combining with $$

Stabilizers sodium mg/day, adjusted thrombocytopenia, carbamazepine; use
Epival, generics according to polycystic ovary caution if combining with
hepatotoxicity.
Mood valproic acid 750–2000 Weight gain, Avoid combining with $$

Stabilizers Depakene, mg/day, adjusted thrombocytopenia, carbamazepine; use
generics according to polycystic ovary caution if combining with
hepatotoxicity.
Mood lamotrigine 100–300 mg/day Rash common; severe Divalproex doubles blood $$
Stabilizers Lamictal, rash rare. level of lamotrigine;
generics always initiate dosing
slowly.
Antipsychotics, olanzapine 5–20 mg/day Weight gain, metabolic Fluvoxamine and $$$$$
atypical Zyprexa, disturbances, ciprofloxacin ↑ olanzapine
Zyprexa Zydis, anticholinergic side levels.
generics effects in elderly,
akathisia. Monitor
periodically for
movement disorders.
Antipsychotics, quetiapine Usual: 300 Weight gain, sedation, Ketoconazole dramatically $$$$$
atypical Seroquel, mg/day orthostasis, metabolic ↑ quetiapine levels. Monitor
Seroquel XR, Max: 600 mg/day disturbances. for hypotension with
generics antihypertensives.
Antipsychotics, risperidone long 25 mg im Q2 wk, Weight gain, Avoid combining with $$$$$
atypical -acting injection by deep gluteal orthostasis, carbamazepine.
im injection extrapyramidal
Risperdal Max: 50 mg Q2 symptoms, metabolic
Consta wk disturbances.
Antipsychotics, aripiprazole 15 mg/day; max Akathisia, dizziness, Carbamazepine (or other $$$$$
atypical Abilify 30 mg/day orthostatic hypotension, strong inducers of CYP2D6
headache, GI or CYP3A4 such as
complaints, tremor, phenytoin, rifampin) can ↓
sedation. aripiprazole levels
significantly.
Ketoconazole, quinidine,
fluoxetine or paroxetine
(or other strong inhibitors
Page 947
Therapeutic Choice
Costa
of CYP2D6 or CYP3A4) can
↑ levels substantially.
Antipsychotics, ziprasidone 20–80 mg BID Insomnia, Carbamazepine ↓ levels $$$$$

atypical Zeldox with food extrapyramidal side significantly; do not use with
effects; consider ECG at other drugs that prolong
baseline and the QT interval.
periodically to monitor
effect on QT interval.
a.
Cost of 30-day supply for mean dose; includes drug cost only.

Legend: $ < $25 $$ $25–50 $$$ $50–75 $$$$ $75–100 $$$$$ > $100
Suggested Readings
Bauer MS, McBride L. Structured group psychotherapy for bipolar disorder: the life goals program. 2nd ed. New York
(NY): Springer; 2003.
Yatham LN, Kennedy SH, O'Donovan C et al. Canadian Network for Mood and Anxiety Treatments (CANMAT)
guidelines for the management of patients with bipolar disorder: consensus and controversies. Bipolar Disord
2005;7(Suppl 3):5-69.
Yatham LN, Kennedy SH, O'Donovan C et al. Canadian Network for Mood and Anxiety Treatments (CANMAT)
guidelines for the management of patients with bipolar disorder: update 2007. Bipolar Disord 2006;8(6):721-39.
Yatham LN, Kennedy SH, Schaffer A et al. Canadian Network for Mood and Anxiety Treatments (CANMAT) and
International Society for Bipolar Disorders (ISBD) collaborative update of CANMAT guidelines for the management
Yonkers KA, Wisner KL, Stowe Z et al. Management of bipolar disorder during pregnancy and the postpartum period.
Am J Psychiatry 2004;161(4):608-20.
References
1. Yatham LN, Kennedy SH, O'Donovan C et al. Canadian Network for Mood and Anxiety Treatments (CANMAT)
2005;7(Suppl 3):5-69.
2. American Psychiatric Association. Diagnostic and statistical manual of mental disorders: DSM-IV-TR. 4th
edition. Washington (DC): American Psychiatric Association; 2000.
3. Berk M, Dodd S, Berk L. The management of bipolar disorder in primary care: a review of existing and
emerging therapies. Psychiatry Clin Neurosci 2005;59(3):229-39.
4. Hirschfeld RM, Williams JB, Spitzer RL et al. Development and validation of a screening instrument for bipolar
spectrum disorder: the Mood Disorder Questionnaire. Am J Psychiatry 2000;157(11):1873-5.
5. Wagner KD, Hirschfeld RM, Emslie GJ et al. Validation of the Mood Disorder Questionnaire for bipolar
disorders in adolescents. J Clin Psychiatry 2006;67(5):827-30.
6. Yatham LN, Kennedy SH, O'Donovan C et al. Canadian Network for Mood and Anxiety Treatments (CANMAT)
guidelines for the management of patients with bipolar disorder: update 2007. Bipolar Disord 2006;8(6):721-
39.
Page 948
Therapeutic Choice
7. Yatham LN, Kennedy SH, Schaffer A et al. Canadian Network for Mood and Anxiety Treatments (CANMAT) and
International Society for Bipolar Disorders (ISBD) collaborative update of CANMAT guidelines for the
management of patients with bipolar disorder: update 2009. Bipolar Disord 2009;11(3):225-55.
8. Colom F, Vieta E, Martinez-Aran A et al. A randomized trial on the efficacy of group psychoeducation in the
prophylaxis of recurrences in bipolar patients whose disease is in remission. Arch Gen Psychiatry 2003;60
(4):402-7.
9. Miklowitz DJ, Otto MW, Frank E et al. Psychosocial treatments for bipolar depression: a 1-year randomized
trial from the Systematic Treatment Enhancement Program. Arch Gen Psychiatry 2007;64(4):419-26.
10. Schapiro NA. Bipolar disorders in children and adolescents. J Pediatr Health Care 2005;19(3):131-41.
11. Kowatch RA, Youngstrom EA, Danielyan A et al. Review and meta-analysis of the phenomenology and clinical
characteristics of mania in children and adolescents. Bipolar Disord 2005;7(6):483-96.
12. Kowatch RA, DelBello MP. Pediatric bipolar disorder: emerging diagnostic and treatment approaches. Child
Adolesc Psychiatr Clin N Am 2006;15(1):73-108.
13. Al Jurdi R, Pulakhandam S, Kunik ME et al. Late-life mania: assessment and treatment of late-life manic
symptoms. Geriatrics 2005;60(10):18-20,22-3.
14. Aziz R, Lorberg B, Tampi RR. Treatments for late-life bipolar disorder. Am J Geriatr Pharmacother 2006:4
(4):347-64.
15. Yonkers KA, Wisner KL, Stowe Z et al. Management of bipolar disorder during pregnancy and the postpartum
period. Am J Psychiatry 2004;161(4):608-20.
16. Gentile S. Prophylactic treatment of bipolar disorder in pregnancy and breastfeeding: focus on emerging mood
stabilizers. Bipolar Disord 2006;8(3):207-20.
17. Vismari L, Pires MLN, Benedito-Silva AA et al. Bioavailability of immediate and controlled release formulations
of lithium carbonate. Rev Bras Psiquitr 2002;24(2):74-9.
18. Bezchlibnyk-Butler KZ, Jeffries JJ, editors. Clinical handbook of psychotropic drugs. 15th ed. [Seattle]:
Hogrefe & Huber Publishers; 2005.
Page 949
e-Therapeutics+ : Therapeutics : Psychiatric Disorders: Acute Agitation Page 1 of 5
Therapeutic Choice
Print Close
Psychiatric Disorders: Acute Agitation

Kurt Skakum, MD, FRCPC
Jeffrey P. Reiss, MD, MSc, FRCPC
1
Acute agitation is a dangerous condition, with a prevalence of 10–20% in hospitalized acutely ill patients. It is essential to the well-being and
safety of patients and staff that agitated patients be treated quickly, effectively and safely. To achieve this, the underlying cause of agitation
must be determined and treated where possible.
Acute agitation is defined as a “state of anxiety accompanied by motor restlessness.”2 Aggression, defined as a “behaviour leading to self
assertion,”2 is often mislabelled as agitation, though it can occur in association with acute agitation. Although agitation occurs in many clinical
settings, this chapter will focus on the emergency room, psychiatric and medical/surgical ward.
Agitation can be associated with delirium from any cause, including infection, neurologic conditions (e.g., trauma, seizure, stroke or tumor),
intoxication, drug withdrawal (see Psychiatric Disorders: Drug Withdrawal Syndromes), adverse drug reactions (e.g., toxicity, allergy or
akathisia), endocrine disorders, blood sugar irregularities, cardiovascular problems and electrolyte disturbances. Agitation is also frequently
associated with dementia. Psychiatric conditions that can cause agitation include psychosis, mania, depression, anxiety and personality
disorders.
Goals of Therapy
Create a safe environment for the treatment of the agitated patient and other patients
Keep the work environment safe for staff
Ameliorate the agitated state
Prevent further episodes of agitation/aggression
Investigations
Obtain history from the patient and descriptions of the patient’s behaviour from staff and other collateral sources. Include:
triggers for the behaviour
previous episodes of agitation
description of the nature of the agitation
Review medications and concomitant medical conditions
Determine whether the agitation is accompanied by other symptoms such as confusion, clouded consciousness, cognitive impairment or
physical symptoms such as fever, hypoxia or pain
Mental status examination, a complete physical examination and relevant laboratory investigations are essential to the diagnosis
Therapeutic Choices (Figure 1 - Management of Acute Agitation)
Give special attention to safety when encountering an acutely agitated/aggressive patient. This includes safety of the agitated patient and of
other patients and staff in the environment. Often, both nonpharmacologic and pharmacologic interventions will be necessary. Address patients
in a calm and reassuring yet confident tone of voice. There should be no hesitancy to have additional staff nearby. Direct patients to attempt to
control their behaviour and reassure them that the environment is safe and that they have no reason to be fearful. Ask what the problem is and
how it can be resolved. If necessary, patients can be asked to take medication to help decrease their distress.
If verbal approaches are unsuccessful, patients may need to be physically restrained or secluded. Details on the application of restraint and
seclusion are not addressed in this chapter.
Delirium
Delirium is a condition in which an acute onset of impairment in consciousness and cognition is associated with a medical/physical cause. The
impairment typically fluctuates over the course of the day.
The first step is to determine and remove the medical cause of delirium. If the cause is removed or cannot be found and agitation persists, it
may be necessary to treat the patient pharmacologically. Antipsychotics are first-line medications in these instances (Table 1). Haloperidol is
the most studied and effective medication for decreasing agitation in delirious patients. It is available orally and for intramuscular and
intravenous injection. Small, regularly scheduled doses are preferred over “as needed” dosing. The mid-potency first-generation antipsychotic
loxapine and second-generation (“atypical”) antipsychotics such as olanzapine, risperidone and quetiapine have also been used to treat
delirium.3 When used for several weeks to months, antipsychotics have been associated with an increased risk of stroke and death in elderly
patients. Accordingly, their use in the elderly for managing acute confusional states with agitation or aggression should be done only when the
4 , 5
benefits clearly outweigh the risks.
Benzodiazepines should be reserved for cases where symptoms are attributed to alcohol withdrawal (see Psychiatric Disorders: Drug
Withdrawal Syndromes).
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Therapeutic Choice
Dementia
Patients with various forms of dementia frequently exhibit agitation. These behaviours can be disruptive to the care environment and potentially
dangerous. First, document the occurrence, frequency and nature of the behavioural disturbance and any recognizable triggers. If medications
are necessary they should be prescribed following the “start low, go slow” principle.
6
Because of their more favourable side effect profile, atypical antipsychotics are being increasingly used over first-generation antipsychotics.
Risperidone has been shown in several studies7 to have a favourable effect on the agitation and other behavioural symptoms (total behaviour,
aggression and psychosis) associated with Alzheimer’s disease. Risperidone at doses of 0.5, 1 and 2 mg per day is beneficial; the higher dosage
may offer an efficacy advantage but does so at the risk of increased side effects including falls. Olanzapine 5 to 10 mg per day reduces
aggressiveness, anxiety and euphoria.7 There is little evidence on the use of quetiapine in the control of agitation and aggression in patients
with dementia. A recent large, randomized, double blind, controlled trial of atypical antipsychotics in Alzheimer’s disease showed
that the chance of benefiting from treatment is equal to the chance of being harmed by the same treatment.8 Considering the
potential increased risks of treatment (e.g., stroke, death) and the limited tolerability and benefit in many patients, the
decision to use an antipsychotic for the intermediate to long-term treatment of agitation or aggression in patients with
dementia needs to be made on an individual basis and with caregiver support and consent.5,8 Useful Info?
Haloperidol is effective in reducing aggression in patients with dementia but not in reducing other manifestations of agitation such as
wandering and crying out.9
Other medications have also been studied, including trazodone, cholinesterase inhibitors and benzodiazepines. Data on trazodone are
10
limited but it may be useful because of its sedative effects and minimal side effect profile. A recent study suggests that cholinesterase
11
inhibitors (e.g., donepezil) may reduce behavioural disturbances associated with Alzheimer’s disease. Benzodiazepines can be useful and
effective for treating acute anxiety and agitation.12 Care must be taken in prescribing this class of medications because of an increased risk of
falls and impaired cognition. Lorazepam and oxazepam are the benzodiazepines of choice in this setting because they have no active
metabolites and their metabolism is minimally affected by aging.
Brain Injury
Many medications from different classes have been used in this setting, though conclusive evidence is lacking. Give priority to minimizing the
potential side effects when choosing a treatment in these patients. A recent review of the treatment of agitation and aggression in patients with
acquired brain injury13 found that beta-adrenergic antagonists are supported by the best evidence. In studies where propranolol has been
found to be effective in reducing the incidence of aggression, high doses have been used. Antiepileptic drugs such as carbamazepine and
divalproex are also used. There is concern about paradoxical disinhibition when benzodiazepines are used in brain-injured patients.
Antipsychotics seem to have a generally anti-aggressive effect regardless of the etiology.
There have been small studies of several other medications, including tricyclic antidepressants, selective serotonin reuptake inhibitors,
amantadine, buspirone, stimulants and lithium in this patient population, though the evidence is not strong enough to recommend their
use as first-line agents.
Mental Illness–associated Agitation
Psychosis
With acutely psychotic individuals, short-acting parenteral formulations of antipsychotics either alone or in combination with a parenteral
benzodiazepine are recommended. Intramuscular olanzapine should not be combined with benzodiazepines because of the associated cardiac
and respiratory complications. Rapidly dissolving or liquid formulations of the atypical antipsychotic medications with or without
16 , 17
benzodiazepines are an effective alternative to intramuscular medications. Risperidone is available in liquid and rapidly dissolving tablet
preparations. Olanzapine is available in a rapidly dissolving wafer form. Several first-generation antipsychotics are also available in oral liquid
formulations.
Mania
The acute control of severe agitation related to patients with mania involves both short-term treatment and initiation of longer term mood
stabilizers. Initially, atypical antipsychotics (risperidone, olanzapine or quetiapine) are effective in establishing control of agitated
behaviour. If oral medications cannot be administered, intramuscular administration is an effective alternative. Either intramuscular olanzapine
18
alone or a first-generation antipsychotic with a benzodiazepine can be used. Initiation of a mood stabilizer should also be undertaken in the
acute phase of treatment (see Psychiatric Disorders: Bipolar Disorder).
Situational or Characterologic Agitation/Aggression
Agitation and aggression not attributable to any of the previously discussed causes is a common occurrence in emergency rooms. There is a
relative lack of well-studied interventions in this setting. Nonpharmacologic interventions are essential. The most common medications used are
first-generation antipsychotics along with a benzodiazepine, either by oral administration or intramuscular injection. Emerging evidence
19
supports the use of atypical antipsychotics in this setting.
Therapeutic Tips
As a general rule, use lower doses of antipsychotics in older patients.

Implement measures to prevent delirium (and any attendant agitation) in hospitalized patients (e.g., aids to remaining orientated such as
clocks and calendars, early mobilization following surgery, prevention of sleep deprivation, eyeglasses/hearing aids to optimize functioning
and communication).
Page 951
Therapeutic Choice
Figure 1-Management of Acute Agitation
Table 1: Drugs Used for the Management of Acute Agitation
Costa
First-generation haloperidol Delirium: 0.5–2.5 mg po/im BID Sedation, Additive effects with other CNS $
Antipsychotics generics Dementia: 0.5–1 mg po BID parkinsonism, depressants, antagonism of
akathisia, acute dopamine agonists.
Psychosis: 5–10 mg/day po/im dystonia, neuroleptic
malignant syndrome.
Mania: 5–10 mg/day po/im
First-generation loxapine Delirium: 12.5–50 mg/day po Sedation, Additive effects with other CNS $
Antipsychotics generics Psychosis: 25–50 mg/day po parkinsonism, depressants, antagonism of
akathisia, acute dopamine agonists.
dystonia, neuroleptic
malignant syndrome.
First-generation zuclopenthixol, Psychosis: 50–150 mg im; Sedation, Additive effects with other CNS $$$-
Antipsychotics intramuscular duration of action 2–3 days parkinsonism, depressants, antagonism of $$$$
Clopixol-Acuphase akathisia, acute dopamine agonists.
dystonia, neuroleptic
malignant syndrome.
Atypical risperidone Delirium: 0.5–2 mg/day po Akathisia, dizziness, Additive sedation with CNS $
Antipsychotics Risperdal, Risperdal M- Psychosis: 2–8 mg/day po neuroleptic malignant depressants; antagonism of
Tab, generics syndrome. dopamine agonists; may
Dementia: 0.5–2 mg/day po potentiate antihypertensive
drug effects.
Mania: 2–3 mg/day po
Atypical olanzapine, oral Delirium: 5–10 mg/day po Anticholinergic Additive sedation with CNS $–$$$
Antipsychotics Zyprexa, Zyprexa Dementia: 2.5–5 mg/day po effects, akathisia, depressants; antagonism of
Zydis, generics dizziness, neuroleptic dopamine agonists; may
Psychosis: 10–30 mg/day po malignant syndrome. potentiate antihypertensive
drug effects.
Mania: 5–20 mg/day po
Page 952
Therapeutic Choice
a
Cost
Atypical olanzapine, Delirium or mania: 2.5–10 mg Anticholinergic Additive sedation with CNS $$$-
Antipsychotics intramuscular im; repeat in 2 h and 6 h PRN to effects, akathisia, depressants; antagonism of $$$$
Zyprexa Intramuscular a max of 30 mg/24 h dizziness, neuroleptic dopamine agonists; may
Use max of 2.5 mg/dose in malignant syndrome. potentiate antihypertensive
debilitated patients, 5 mg in drug effects.
elderly Should not be administered
simultaneously with parenteral
benzodiazepines due to reports
of cardiac and respiratory
problems including deaths.
Atypical quetiapine Delirium: 25–100 mg/day po Sedation, dizziness, Additive sedation with CNS $-$$
Antipsychotics Seroquel, generics Dementia: 12.5–50 mg/day po neuroleptic malignant depressants; antagonism of
syndrome. dopamine agonists; may
Psychosis: 300–800 mg/day po potentiate antihypertensive
drug effects.
Mania: start with 100 mg/day
po; increase by 100 mg/day as
needed to 300–600 mg/day
divided BID
Benzodiazepines lorazepam Dementia: 0.5–1 mg Q6–8H Sedation, dizziness, Additive sedation and possibly $
Ativan, generics Mania/psychosis, adjunctively cognitive impairment; cardiorespiratory depression
with antipsychotics: 1–2 mg rarely, respiratory with other CNS depressants.
po/im depression can occur
in this setting.
Benzodiazepines oxazepam Dementia: 10–15 mg po TID Sedation, dizziness, Additive sedation and possibly $
generics cognitive impairment; cardiorespiratory depression
rarely, respiratory with other CNS depressants.
depression can occur
in this setting.
Benzodiazepines clonazepam Mania: 0.25–0.5 mg po BID–TID Sedation, dizziness, Additive sedation and possibly $
Rivotril, generics cognitive impairment; cardiorespiratory depression
rarely, respiratory with other CNS depressants.
in this setting.
Beta1-adrenergic propranolol Brain injury: 20–40 mg po daily; Bradycardia, Additive hypotension with other $
Antagonists generics increase by 20 mg/day hypotension, heart antihypertensives; additive
Max: 640 mg/day block, sedation. sedation with other CNS
depressants.
Monitor heart rate and blood
pressure
Antiepileptic carbamazepine Mania: 800–1200 mg/day po in Rash, cognitive Induces cytochrome P450 $
Drugs Tegretol, generics 2 to 4 divided doses impairment, sedation, enzymes; may increase
Target serum levels: 17–50 µg/L hyponatremia. clearance of many other drugs
such as oral contraceptives,
Brain injury: 200–300 mg po lovastatin, meperidine,
BID–TID morphine, nifedipine,
oxycodone, trazodone.
Antiepileptic divalproex sodium Brain injury: 250–500 mg po Nausea, tremor, Inhibits glucuronidation; may $
Drugs Epival, generics TID sedation; rarely, decrease clearance of other
Target serum level 400–700 edema. drugs such as lamotrigine and
µmol/L lorazepam.
Antidepressants trazodone Brain injury 25–50 mg po HS Sedation, nausea, May potentiate effects of other $
Desyrel, generics Max: 200 mg HS headache, dry mouth, CNS depressants and augment
priapism (rare). hypotensive effects of
Dementia (for sedation): 25–100 antihypertensives.
mg/day po
Page 953
Therapeutic Choice
a
Cost
Combination haloperidol/lorazepam Situational/characterologic Sedation, Additive effects with other CNS $/for
Therapy agitation: haloperidol 5 mg parkinsonism, depressants, antagonism of both
po/im akathisia, acute dopamine agonists.
+ dystonia, neuroleptic Additive sedation and possibly
malignant syndrome. cardiorespiratory depression
lorazepam 2 mg po/im Sedation, dizziness, with other CNS depressants.
cognitive impairment;
rarely, respiratory
in this setting.
a.
Legend: $ < $5 $–$$ < $5–15 $$ $5–15 $–$$$ < $5–25 $$$ $15–25 $$$-$$$$ $15– >25 $$$$ > $25
Suggested Readings
Marder SR. A review of agitation in mental illness: treatment guidelines and current therapies. J Clin Psychiatry 2006;67(Suppl 10):13-21.
Nassisi D, Korc B, Hahn S et al. The evaluation and management of the acutely agitated elderly patient. Mt Sinai J Med 2006;73(7):976-84.
[No authors listed]. Practice guideline for the treatment of patients with delirium. American Psychiatric Association. Am J Psychiatry 1999;156(5
Suppl):1-20.
References
1. Trzepacz PT. Delirium. Advances in diagnosis, pathophysiology and treatment. Psychiatr Clin North Am 1996;19(3):429-48.
2. Dorland WAN. Dorland's illustrated medical dictionary. 27th ed. Philadelphia (PA): Saunders; 1988.
3. American Psychiatric Association Steering Committee on Practice Guidelines. Practice guideline for treatment of patients with delirium.
1999. Available from: http://www.psych.org/psych_pract/treatg/pg/DeliriumPG_05-15-06.pdf Accessed May 24, 2007.
4. Caine ED. Clinical perspectives on atypical antipsychotics for the treatment of agitation. J Clin Psychiatry 2006;67(Suppl 10):22-31.
5. Herrmann N, Lanctot KL. Atypical antipsychotics for neuropsychiatric symptoms of dementia: malignant or maligned? Drug Saf 2006;29
(10):833-43.
6. Alexopoulos GS, Jeste DV, Chung H et al. The expert consensus guideline series. Treatment of dementia and its behavioral disturbances.
Introduction, methods, commentary, and summary. Postgrad Med 2005;Spec No:6-22.
7. Ballard C, Waite J. The effectiveness of atypical antipsychotics for the treatment of aggression and psychosis in Alzheimer's disease.
8. Schneider LS, Tariot PN, Dagerman KS et al., Effectiveness of atypical antipsychotic drugs in patients with Alzheimer’s disease. N Engl J
Med 2006;355(15):1525-38.
9. Lonergan E, Luxenberg J, Colford J. Haloperidol for agitation in dementia. Cochrane Database Syst Rev 2002;(2):CD002852.
10. Martinson-Torres G, Fioravanti M, Grimley EJ. Trazodone for agitation in dementia. Cochrane Database Syst Rev 2004;(4):CD004990.
11. Cummings JL, McRae T, Zhang R et al. Effects of donepezil on neuropsychiatric symptoms in patients with dementia and severe behavioral
disorders. Am J Geriatr Psychiatry 2006;14(7):605-12.
12. American Psychiatric Association Steering Committee on Practice Guidelines. Practice guideline for the treatment of patients with
Alzheimer’s disease and other dementias of late life. Arlington (VA): American Psychiatric Association; 1997. Available from:
http://www.psych.org/psych_pract/treatg/pg/AlzheimersPG_05-15-06.pdf Accessed May 24, 2007.
13. Fleminger S, Greenwood RJ, Oliver DL. Pharmacological management for agitation and aggression in people with acquired brain injury.
14. Battaglia J, Moss S, Rush J et al. Haloperidol, lorazepam, or both for psychotic agitation? A multicenter, prospective, double-blind,
emergency department study. Am J Emerg Med 1997;15(4):335-40.
15. Srisurapanont M, Kittiratanapaiboon P, Jarusuraisin N. Treatment for amphetamine psychosis. Cochrane Database Syst Rev 2001;
(4):CD003026.
16. American Psychiatric Association Steering Committee on Practice Guidelines. Practice guideline for the treatment of patients with
schizophrenia. Arlington (VA): American Psychiatric Association; 2004. Available from:
http://www.psych.org/psych_pract/treatg/pg/Schizophrenia2ePG_05-15-06.pdf Accessed May 24, 2007.
17. Canadian Psychiatric Association. Clinical practice guidelines. Treatment of schizophrenia. Can J Psychiatry 2005;50(13 Suppl 1):7S-57S.
18. Yatham LN, Kennedy SH, O'Donovan C et al. Canadian Network for Mood and Anxiety treatments (CANMAT) guidelines for the
management of patients with bipolar disorder: consensus and controversies. Bipolar Disord 2005;7(Suppl 3):5-69.
19. Rund DA, Ewing JD, Mitzel K et al. The use of intramuscular benzodiazepines and antipsychotic agents in the treatment of acute agitation
or violence in the emergency department. J Emerg Med 2006;31(3): 317-24.
Page 954
e-Therapeutics+ : Therapeutics : Psychiatric Disorders: Anxiety Disorders Page 1 of 12
Therapeutic Choice
Print Close
Psychiatric Disorders: Anxiety Disorders

R.P. Swinson, MD, FRCPsych, FRCPC, FCPA
Goals of Therapy
Eliminate or decrease symptomatic anxiety

Eliminate or decrease anxiety-based disability
Prevent recurrence
Treat comorbid conditions
Investigations

nature of symptoms and onset
nature and extent of disability
presence of comorbid medical or psychiatric conditions
Note: Treat comorbid mood disorders, especially depression, as the primary condition.
Interview questions assist in obtaining an accurate diagnosis (Table 1, Table 2)

Physical examination to exclude endocrine or cardiac disorders and to look for signs of substance use
Laboratory tests:
CBC, liver function tests, gamma-glutamyl transpeptidase (GGT), thyroid indices (supersensitive TSH), ECG
Note: Treat physical disorders of recent onset before making a definitive diagnosis of an anxiety disorder.
Table 1: Classification of Anxiety Disorders1
Panic disorder with or without agoraphobia

Agoraphobia without history of panic disorder
Social anxiety disorder (social phobia)
Specific phobia
Obsessive-compulsive disorder
Post-traumatic stress disorder
Acute stress disorder
Generalized anxiety disorder
Anxiety disorder due to a general medical condition
Substance-induced anxiety disorder
Anxiety disorder not otherwise specified
a
Table 2: Interview Questions to Establish Specific Anxiety Diagnosis
Questions Further Inquiry
Do you have sudden episodes of intense anxiety? Establish nature of attack.
Do you have difficulty going to places to which you used to be Inquire about crowded places, line-ups, movies, highways, distance
able to go? from home.
Do you have difficulty talking to people in authority or speaking Establish situations (one-on-one or groups).
in public?
Are you afraid of blood, small animals or heights? Establish precise feared situation.
Do you repeat actions that you feel are excessive? Ask about washing, counting, checking and hoarding.
Do you have thoughts that keep going in your mind that you can't Ask nature of thoughts (illness, harm, sex).
stop?
Have you experienced any emotionally stressful events? Establish the nature (accident, sexual, torture) and timing of the
trauma.
Do you worry a lot of the time? Ask about worries related to health, family, job and finances.
a.
The order of asking the questions can be varied. The order represented in Table 2 reflects the sequence in the Diagnostic and Statistical Manual of Mental
1
Disorders in which panic attacks are diagnosed first, followed by phobic disorders, obsessive-compulsive disorder, post-traumatic stress disorder and
generalized anxiety disorder. Anxiety disorders that do not fit into the above categories are atypical. Accurate diagnosis is recommended before instituting
treatment.
Therapeutic Choices (Figure 1 - Management of Anxiety Disorders)
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Therapeutic Choice
Relatively mild anxiety states in response to life circumstances are frequently time-limited, and many patients respond to anxiety
management strategies without medication. Support, problem-solving and relaxation techniques may be helpful as the environmental crisis
resolves. However, specific anxiety or mood disorders may develop as a consequence of the original stressor.
Caffeine or other stimulant use should be reduced and controlled.

Alcohol use should be minimal; it should not be used to control anxiety.
Reduce the “as-needed” use of short-acting benzodiazepines as much as possible; ideally, such use should not be continued for longer
than 4 days.
Stress reduction, including relaxation training and time management, is often helpful initially.
Specific cognitive behavioural therapy (CBT) may be required; a psychiatric consultation is recommended for any patient who does not
improve with trials of 2 separate antidepressants.
The role of drug therapies varies among anxiety disorders. For some, drug treatment is not standard (e.g., specific phobia) and for others,
drug therapy represents the most common intervention, especially when intensity of symptoms and disability are moderate to severe.
Panic Disorder
Antidepressants
The selective serotonin reuptake inhibitors (SSRIs) citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine and sertraline are
all effective in reducing panic attacks. Venlafaxine, a serotonin-norepinephrine reuptake inhibitor (SNRI) has also demonstrated efficacy in
repeated double-blind, placebo-controlled trials. SSRIs and SNRIs have become first-choice agents in treating panic disorder with
or without agoraphobia.2 Useful Info? There is usually a delay in response to these agents that may be accompanied by initial agitation.
Combining the SSRI or SNRI with a brief course of low-dose benzodiazepine augmentation therapy (i.e., no longer than 8 weeks) can
increase adherence to medication and produce a more rapid response than with antidepressants alone.3
The tricyclic antidepressants (TCAs) imipramine, desipramine and clomipramine have been shown to reduce the frequency and severity
4
of panic attacks and are inexpensive. The side effect profiles of TCAs and SSRIs differ and are used to guide treatment choice. Mirtazapine
has been effective in open-label trials.5 , 6 The older monoamine oxidase inhibitors (MAOIs) phenelzine and tranylcypromine are also
effective but more difficult to use.7
The dose requirements and length of treatment are the same as for major depression (see Psychiatric Disorders: Depression). However, the
initial dose should be as low as possible (e.g., 10 mg daily of the TCAs or fluoxetine) and then increased, as tolerated, to the usual
antidepressant dose range. If a higher starting dose is used, patients may become extremely agitated and discontinue treatment abruptly.
Determining the duration of drug treatment is of great importance; medication is usually required for months or years. There is evidence
that a majority of patients suffer relapse after benzodiazepines or antidepressants are discontinued.8
Benzodiazepines
Pharmacologic treatment of panic disorder is determined by the acuity of the disorder at presentation. Low doses of high-potency
benzodiazepines can be used to abort initial panic attacks and may control high-frequency attacks later in the development of the disorder.
Alprazolam 0.25 mg TID or QID or clonazepam 0.25 to 0.5 mg BID frequently makes panic attacks more manageable. Lorazepam and
diazepam can also be used.
Although there is considerable evidence for the efficacy of benzodiazepines as monotherapy for panic disorder, they are best reserved for
those cases where SSRI/SNRI treatment has not been successful or where there is need for augmentation of an antidepressant response.
Benzodiazepines are best used short term. Many patients have been maintained on stable low doses for years, and the potential benefits of
discontinuation of benzodiazepines (i.e., decreased risk of sedation/falls, dependence/withdrawal) should be weighed against the frequent
8
increase in panic frequency or severity on benzodiazepine discontinuation.
Panic Disorder with Agoraphobia
The pharmacologic treatment of panic disorder with agoraphobia is the same as for panic disorder. However, much of the disability in panic
disorder with agoraphobia arises from the avoidance behaviour rather than the panic attacks. This can be addressed with cognitive
behavioural therapy (CBT), even if medication reduces or eliminates panic attacks. CBT can be more effective alone than when it is combined
with medication.8 However, access to specialized CBT is often limited.
Social Anxiety Disorder (Social Phobia)
This excessive fear of being criticized or negatively evaluated by others presents as shyness, avoidance of social contact or difficulty dealing
with authority figures. The disorder may be present from childhood and often becomes noticeable in adolescence. It is particularly important
to rule out comorbid major depression and alcohol use. CBT or other psychotherapy may be necessary to deal with significant social anxiety,
even when medication is used.
SSRI and SNRI antidepressants are the mainstay of medical treatment for this condition. These agents are effective for generalized social
anxiety and for milder cases manifesting as stage fright or fear of public speaking. Escitalopram,9 , 10 fluvoxamine,11 , 12
Page 956
Therapeutic Choice
paroxetine,13 , 14 sertraline 15 , 16 and venlafaxine 17 have demonstrated efficacy in repeated studies. Simple stage fright or fear of
public speaking may respond to low-dose propranolol ( 10 mg) taken 30 minutes before the event, but in generalized social anxiety
disorder propranolol is usually ineffective.18 , 19
Moclobemide has shown varying results but may be effective, particularly in higher doses.20 At doses above 600 mg/day, moclobemide
loses its isoenzyme specificity for MAO-A and as such, caution is needed regarding consumption of tyramine-rich foods such as aged
cheeses, smoked meats, beer and red wine.
There is some evidence to support a trial of gabapentin 21 or pregabalin 22 in patients not responding to first-line measures.
23
Benzodiazepines, particularly clonazepam, are effective but should be used with the same restrictions as with other anxiety disorders
(i.e., short-term use of lowest effective dose).
Specific Phobia
There is usually no indication for medication to treat the specific fear of heights, animals, injections or other common triggers. As little as 6
hours of CBT is often successful in producing marked, enduring change.
Obsessive–Compulsive Disorder
A chronic disorder that often begins in childhood or adolescence, obsessive–compulsive disorder can be extremely disabling. CBT is the
psychotherapy of choice. Drug therapy is more easily available and is indicated for many patients. The SSRIs fluoxetine, fluvoxamine,
paroxetine and sertraline, in the usual antidepressant dosing range, are recommended as first-line treatment in the Canadian Clinical
Practice Guidelines for anxiety disorders.25 It may take 6–8 weeks to produce significant change in symptoms;26 a trial at full dosages for at
least 6 weeks is required to assess the effect of each SSRI used. There is no strong evidence to suggest that SSRIs vary in efficacy, but
patients may respond to or tolerate one drug better than others in the same class. Second-line options include clomipramine,
venlafaxine, citalopram and mirtazapine. SSRIs/SNRIs may be better tolerated than clomipramine, but agitation experienced early in
therapy may cause some patients to discontinue the medication.
Treatment, if successful, may continue for years. Augmentation of SSRIs with atypical antipsychotics has been shown to increase the
response in obsessive–compulsive disorder.27 There is most evidence for the use of risperidone in this setting.
Benzodiadepines alone are not usually helpful in treating obsessive–compulsive disorder.
Post-traumatic Stress Disorder
Post-traumatic stress disorder (PTSD) presents following exposure to a traumatic event in which there is overwhelming anxiety and the
threat or occurrence of injury or death to someone. PTSD may have its onset soon after the triggering event or may be delayed for years.
The primary symptoms fall into three clusters of (i) persistent re-experiencing of the trauma, (ii) avoiding reminders of the events and
numbing and (iii) persistent autonomic arousal (e.g., hypervigilance, enhanced startle reaction). Medication is one element of a multimodal
treatment program that depends on the nature, severity and frequency of the trauma.
SSRI and SNRI antidepressants have been shown to reduce the severity of all the component symptoms of PTSD. Specifically, fluoxetine,
paroxetine,28 sertraline 29 and venlafaxine 30 are first-line options. Other antidepressants with evidence of efficacy include
fluvoxamine,31 mirtazapine,32 , 33 moclobemide 34 and phenelzine.35 , 36 Additionally, the atypical antipsychotics risperidone 37 and
olanzapine 38 have been shown to be effective augmenters of antidepressants in PTSD.
Monotherapy with benzodiazepines is not recommended due to their effects on disinhibition and the high rates of substance use disorders in
those affected by PTSD.
There is some evidence that propranolol given within a few hours of an initial traumatic episode may help to prevent the onset of PTSD.
Large-scale studies have not yet confirmed these early findings. 39
Generalized Anxiety Disorder
Generalized anxiety disorder is characterized by excessive and uncontrollable worry related to everyday-life concerns, such as safety of
family members, financial and job security and health. Patients with generalized anxiety disorder frequently exhibit depressed mood and
other anxiety symptoms. CBT is the most effective psychosocial treatment but often takes 20 or more sessions to be effective.40
SSRIs and SNRIs have become established as first-line drug treatment for generalized anxiety disorder. The use of escitalopram,41 , 42
paroxetine,43 sertraline or venlafaxine 44 is supported by multiple efficacy studies. Because of its side effects and safety concerns in
overdose, imipramine, an effective agent in generalized anxiety disorder, is usually reserved for when first-line choices are not effective.
Bupropion 45 is a further choice, as is pregabalin.46 , 47
Low-dose benzodiazepines (e.g., alprazolam, bromazepam, diazepam, lorazepam) can be used for several weeks at a time for
symptom relief, but attention must be paid to the risk of dependence and discontinuation symptoms.
Buspirone, an azapirone, has low abuse potential and is less sedating than benzodiazepines. Like antidepressants, it is relatively slow to
have effect. In switching from long-term benzodiazepine therapy to buspirone, it is important not to discontinue the benzodiazepine
abruptly; because there is no cross-tolerance between benzodiazepines and buspirone, benzodiazepine withdrawal symptoms could be
precipitated.
Therapeutic Tips
Page 957
Therapeutic Choice
Short-term interventions (i.e., psychological therapies, relaxation techniques, benzodiazepines) may be effective.
If one antidepressant is not effective in adequate dosage and after adequate time, switch to another antidepressant, which can be from
the same class.
If the second antidepressant is not effective in adequate dosage and after an adequate period of time, switch to one from another class.
Restrict benzodiazepines to very short-term use (6–8 weeks) to assist with SSRI/SNRI-related agitation.
Figure 1- Management of Anxiety Disorders
Abbreviations: BDZ = benzodiazepine; CBT = cognitive behavioural therapy; SSRI = selective serotonin reuptake inhibitor;
SNRI = serotonin norepinephrine reuptake inhibitor.
Table 3: Drugs Used for the Management of Anxiety Disorders
Indication Drug Costa

Class Drug (s) Dose Adverse Effects Interactions Comments
Benzodiazepines alprazolam GAD, PD, Drowsiness (tolerance Warn patients re: Discontinue $–$$
Xanax, PDA 0.25 mg TID–QID, develops with concomitant use of gradually to
generics up to continued therapy), alcohol, other CNS avoid rebound
1 mg QID dizziness, ↓ depressants (↑ anxiety;
concentration, effect). contraindicated
retrograde amnesia, in pregnancy and
physical dependence; in patients with a
Page 958
Therapeutic Choice

rarely, paradoxical known history of
anger or hostility. abuse; dose
escalation is rare
in patients taking
benzodiazepines
for chronic
anxiety; use
lower doses in
elderly.
Benzodiazepines clonazepam GAD, PD, Drowsiness (tolerance Warn patients re: Discontinue $
Rivotril, PDA 0.25–0.5 mg BID develops with concomitant use of gradually to
generics continued therapy), alcohol, other CNS avoid rebound
dizziness, ↓ depressants (↑ anxiety;
concentration, retrograde effect). contraindicated
amnesia, physical in pregnancy and
dependence; rarely, in patients with a
paradoxical anger or known history of
hostility. abuse; dose
escalation is rare
in patients taking
benzodiazepines
for chronic
anxiety; use
lower doses in
elderly.
Antidepressants, clomipramine PD, PDA, CNS effects (agitation May ↑ effect of May take 2–3 $–$$$
tricyclic Anafranil, OCD 75–225 mg/day on initiation of anticholinergic months for
generics therapy, confusion, drugs, CNS maximum effect.
drowsiness, depressants,
headache), warfarin; do not
anticholinergic effects use MAOIs
(dry mouth, blurred concurrently.
vision, constipation,
etc.), weight gain,
nausea, cardiovascular
effects (tachycardia,
arrhythmias,
orthostatic
hypotension),
anorgasmia.
Antidepressants, desipramine, PD, PDA, CNS effects (agitation May ↑ effect of May take 2–3 $–$$$
tricyclic generics GAD 75–300 mg/day on initiation of anticholinergic drugs, months for
therapy, confusion, CNS depressants, maximum effect.
drowsiness, warfarin; do not
headache), use MAOIs
anticholinergic effects concurrently.
(dry mouth, blurred
etc.), weight gain,
arrhythmias,
orthostatic
hypotension),
anorgasmia.
Antidepressants, imipramine PD, PDA, CNS effects (agitation May ↑ effect of May take 2–3 $-$$
tricyclic Tofranil, GAD 75–300 mg/day on initiation of anticholinergic months for
generics therapy, confusion, drugs, CNS maximum effect.
drowsiness, depressants,
headache), warfarin; do not
anticholinergic effects use MAOIs
(dry mouth, blurred concurrently.
etc.), weight gain,
arrhythmias,
orthostatic
hypotension),
anorgasmia.
Selective citalopram PD, PDA, Agitation (on initiation Serotonin May take 2–3 $$–
Serotonin Celexa, OCD, 20–60 mg/day of therapy), nausea, syndrome with months for $$$
Reuptake generics PTSD, SAD anorgasmia, insomnia, MAOIs maximum effect.
Inhibitors (hypertension, Discontinue
tremor, agitation, gradually.
Page 959
Therapeutic Choice

diarrhea, ↑ risk of GI hypomania); ↑ risk
bleeding. of GI bleeding with
NSAIDs; SSRIs are
substrates and
inhibitors of
several
cytochrome P450
isoenzymes. This
may result in ↓
clearance of many
drugs (e.g.,
clozapine,
methadone,
mexiletine,
phenytoin,
pimoxide,
propafenone) or ↓
enzymatic
conversion of a
prodrug to its
active form (e.g.,
codeine,
tamoxifen)
Selective escitalopram PD, PDA, 10–20 mg/day Agitation (on initiation Serotonin May take 2–3 $$-
Serotonin Cipralex GAD of therapy), nausea, syndrome with months for $$$
Reuptake anorgasmia, insomnia, MAOIs maximum effect.
Inhibitors diarrhea, ↑ risk of GI (hypertension, Discontinue
bleeding. tremor, agitation, gradually.
hypomania); ↑ risk
of GI bleeding with
NSAIDs; SSRIs are
substrates and
inhibitors of
several
cytochrome P450
isoenzymes. This
may result in ↓
clearance of many
drugs (e.g.,
clozapine,
methadone,
mexiletine,
phenytoin,
pimoxide,
propafenone) or ↓
enzymatic conversion
of a prodrug to its
active form (e.g.,
codeine,
tamoxifen)
Selective fluoxetine PD, PDA, Agitation (on initiation Serotonin May take 2–3 $$–
Serotonin Prozac, OCD, 20–80 mg/day of therapy), nausea, syndrome with months for $$$$$
Inhibitors headache, ↓ appetite, (hypertension, Discontinue
diarrhea, ↑ risk of GI tremor, agitation, gradually.
bleeding. hypomania); ↑ risk
of GI bleeding with
NSAIDs; SSRIs are
substrates and
inhibitors of
several
cytochrome P450
isoenzymes. This
may result in ↓
clearance of many
drugs (e.g.,
clozapine,
methadone,
mexiletine,
phenytoin,
pimoxide,
propafenone) or ↓
of a prodrug to its
active form (e.g.,
Page 960
Therapeutic Choice

codeine,
tamoxifen)
Selective fluvoxamine PD, PDA, Agitation (on initiation Serotonin May take 2–3 $$–
Serotonin Luvox, OCD, 150–300 mg/day of therapy), nausea, syndrome with months for $$$$
Reuptake generics PTSD, SAD anorgasmia, MAOIs maximum effect.
Inhibitors anticholinergic effects, (hypertension, Discontinue
sedation, ↑ risk of GI tremor, agitation, gradually.
of GI bleeding with
NSAIDs; SSRIs are
substrates and
inhibitors of
several
cytochrome P450
isoenzymes. This
may result in ↓
clearance of many
drugs (e.g.,
clozapine,
methadone,
mexiletine,
phenytoin,
pimoxide,
propafenone) or ↓
of a prodrug to its
active form (e.g.,
codeine,
tamoxifen)
Selective paroxetine PD, PDA, Agitation (on initiation Serotonin May take 2–3 $$–
Serotonin immediate- OCD, 20–60 mg/day of therapy), nausea, syndrome with months for $$$
Reuptake PTSD, SAD anorgasmia, MAOIs maximum effect.
release
Paxil, generics sedation, ↑ risk of GI tremor, agitation, gradually.
of GI bleeding with
NSAIDs; SSRIs are
substrates and
inhibitors of
several
cytochrome P450
isoenzymes. This
may result in ↓
clearance of many
drugs (e.g.,
clozapine,
methadone,
mexiletine,
phenytoin,
pimoxide,
propafenone) or ↓
of a prodrug to its
active form (e.g.,
codeine,
tamoxifen)
Selective paroxetine PD, PDA, 12.5–37.5 mg/day Agitation (on initiation Serotonin May take 2–3 $$$-
Serotonin controlled- OCD, of therapy), nausea, syndrome with months for $$$$$
Reuptake PTSD, SAD anorgasmia, MAOIs maximum effect.
release
Paxil CR sedation, ↑ risk of GI tremor, agitation, gradually.
of GI bleeding with
NSAIDs; SSRIs are
substrates and
inhibitors of
several
cytochrome P450
isoenzymes. This
may result in ↓
clearance of many
drugs (e.g.,
clozapine,
methadone,
mexiletine,
phenytoin,
Page 961
Therapeutic Choice

pimoxide,
propafenone) or ↓
of a prodrug to its
active form (e.g.,
codeine,
tamoxifen)
Selective sertraline PD, PDA, Agitation (on initiation Serotonin May take 2–3 $$–
Serotonin Zoloft, OCD, 50–200 mg/day of therapy), nausea, syndrome with months for $$$
Inhibitors diarrhea, ↑ risk of GI (hypertension, Discontinue
bleeding. tremor, agitation, gradually.
hypomania); ↑ risk
of GI bleeding with
NSAIDs; SSRIs are
substrates and
inhibitors of
several
cytochrome P450
isoenzymes. This
may result in ↓
clearance of many
drugs (e.g.,
clozapine,
methadone,
mexiletine,
phenytoin,
pimoxide,
propafenone) or ↓
enzymatic
conversion of a
prodrug to its
active form (e.g.,
codeine,
tamoxifen)
Serotonin- venlafaxine GAD, SAD Nausea, insomnia, Do not use with May take 2–3 $$–
Norepinephrine extended- 37.5–225 mg/day dizziness, asthenia. MAOIs. months for $$$$$
Reuptake release maximum effect.
Inhibitors Effexor XR, Discontinue
generics gradually.
Noradrenergic mirtazapine OCD, PTSD 15–45 mg/day, at Somnolence, increased Do not use with $
and Specific Remeron,, bedtime appetite/weight gain, MAOIs; additive
Serotonergic dizziness. sedation with
Remeron RD,
Antidepressants other CNS
generics
depressants such
as alcohol,
benzodiazepines;
substrate of
CYP1A2, 2D6 and
3A4—caution with
inhibitors or
inducers of these
isoenzymes.
Monoamine phenelzine PD, PDA, Insomnia, dizziness, Concurrent use Dietary $$–
Oxidase Nardil OCD 45–90 mg/day orthostatic with restrictions $$$
Inhibitors (refractory) hypotension, edema, sympathomimetics (tyramine-
sexual dysfunction. may ↑ BP; do not containing
use with SSRIs, foods) are
TCAs; levodopa necessary.
may ↑ effects and
side effects; do not
use with meperidine
(agitation,
hyperpyrexia,
circulatory
collapse may
occur).
Monoamine tranylcypromine PD, PDA, Insomnia, dizziness, Concurrent use Dietary $–$$$
Oxidase Parnate OCD 20–60 mg/day orthostatic with restrictions
Inhibitors (refractory) hypotension, edema, sympathomimetics (tyramine-
sexual dysfunction. may ↑ BP; do not containing
use with SSRIs,
TCAs; levodopa may
Page 962
Therapeutic Choice

↑ effects and side foods) are
effects; do not use necessary.
with meperidine
(agitation,
hyperpyrexia,
circulatory
collapse may
occur).
Reversible moclobemide SAD Nausea, insomnia. Do not use with Dietary $–$$
Inhibitors of Manerix,Apo- 300–600 mg/day meperidine, TCAs, restrictions are
Monoamine SSRIs. not required at
Moclobemide,
Oxidase-A usual doses.
other generics
(RIMAs)
Azapirones buspirone GAD Nausea, headache, Avoid use with Onset of effect $$–
Buspar, 5 mg BID–TID, up dizziness, MAOIs. not as rapid as $$$$$
generics to restlessness/insomnia. with
60 mg/day benzodiazepines.
Beta1- propranolol SAD 10 mg 30 min Hypotension. Caution re: ↑ For occasional $

adrenergic generics (specific before task PRN bradycardia with use in situations
Antagonists task- amiodarone. such as public
related speaking,
anxiety) performing; not
useful in
generalized
social anxiety
disorder.
Antiepileptics gabapentin SAD Initial: 300 Somnolence, Magnesium- and Not a first-line $$-
Neurontin, mg/day dizziness, ataxia, aluminum- agent; may be $$$$$
generics Usual: 900–1800 vision changes. containing useful in patients
mg/day in 2 antacids may not responding
divided doses decrease the to first-line
absorption of measures.
gabapentin.
Antiepileptics pregabalin SAD Initial: 150 Dizziness, sedation, No known Not a first-line $$$$$
Lyrica mg/day in 2–3 peripheral edema. significant drug agent; may be
divided doses interactions. useful in patients
May be increased not responding
to 150 mg BID to first-line
after 1 wk if measures.
necessary
Antipsychotics, risperidone OCD, PTSD Initial: 1 mg Insomnia, headaches, Additive sedation Used as $-$$
atypical Risperdal, daily. Titrate weight gain, with CNS augmentation
generics gradually to orthostatic depressants; may therapy with first
desired effect, hypotension, rhinitis, potentiate -line agents in
usually 1–2 mg anxiety, dose-related antihypertensive PTSD.
daily. May need to hyperprolactinemia drug effects;
increase to a max and extrapyramidal inhibitors of
of 4 mg daily. effects. CYP3A4 (e.g.,
clarithromycin,
erythromycin,
grapefruit juice,
ketoconazole,
prednisone) may ↑
risperidone levels;
inducers of CYP3A4
(e.g.,
carbamazepine,
phenytoin,
rifampin) may ↓
risperidone levels.
Antipsychotics, olanzapine PTSD Initial: 2.5 mg Weight gain, Sedation with CNS Used as $$$-
atypical Zyprexa, daily. Titrate dizziness, sedation, depressants; may augmentation $$$$$
Zyprexa Zydis, gradually to anticholinergic effects, potentiate therapy with first
generics desired effect, hepatic transaminase antihypertensive -line agents in
usually 2.5 to 5 elevation, orthostatic drug effects; PTSD.
mg daily. May hypotension, ↑ risk of inhibitors of
need to increase diabetes and CYP1A2 or CYP2D6
to a maximum of dyslipidemia, (e.g., diltiazem,
Page 963
Therapeutic Choice

10 mg per day. extrapyramidal effects fluvoxamine,
(especially akathisia). paroxetine) may ↑
olanzapine levels;
inducers of
CYP1A2 or CYP3A4
(e.g., barbiturates,
carbamazepine,
phenytoin,
rifampin) may ↓
olanzapine levels.
a.
Abbreviations: MAOI=monoamine oxidase inhibitor; SSRI=selective serotonin reuptake inhibitor; TCA=tricyclic antidepressant; PD=panic
disorder; PDA=panic disorder with agoraphobia; GAD=generalized anxiety disorder; OCD=obsessive–compulsive disorder; PTSD=post-traumatic stress
disorder; SAD=social anxiety disorder
Legend: $ < $25 $-$$ < $25–50 $$ $25–50 $–$$$ < $25–75 $$–$$$ $25–75 $$$ $50–75 $$–$$$$ $25–100 $$$$ $75–100
$$–$$$$$ $25–>100 $$$-$$$$$ $50– >100 $$$$$ > $100
Suggested Readings
Antony MM, Swinson RP. Pharmacological and physical approaches. In: Antony MM, Swinson RP. Phobic disorders and panic in adults: a
guide to assessment and treatment. Washington (DC): American Psychological Association; 2000. p. 265-86.
Baldwin DS, Anderson IM, Nutt DJ et al. Evidence-based guidelines for the pharmacological treatment of anxiety disorders:
recommendations from the British Association for Psychopharmacology. J Psychopharmacol 2005;19(6):567-96.
Bandelow B, Zohar J, Hollander E et al. World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for the pharmacological
treatment of anxiety, obsessive-compulsive and posttraumatic stress disorders. World J Biol Psychiatry 2002;3(4):171-99.
Barlow DH, editor. Anxiety and its disorders: the nature and treatment of anxiety and panic. 2nd ed. New York (NY): Guilford Press; 2002.
Canadian Psychiatric Association. Clinical practice guidelines. Management of anxiety disorders. Can J Psychiatry 2006;51(8 Suppl 2):9S-
91S.
References
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Washington (DC): American Psychiatric Association; 2000.
2. Boyer W. Serotonin uptake inhibitors are superior to imipramine in alleviating panic attacks: a meta-analysis. In: Darcourt G, editor.
Current therapeutic approaches to panic and other anxiety disorders. New York (NY): Karger; 1994.
3. Goddard AW, Brouette T, Almai A et al.. Early coadministration of clonazepam with sertraline for panic disorder. Arch Gen Psychiatry
2001;58(7):681-6.
4. Mavissakalian MR, Perel JM. Long-term maintenance and discontinuation of imipramine therapy in panic disorder with agoraphobia.
Arch Gen Psychiatry 1999;56(9):821-7.
5. Boshuisen ML, Slaap BR, Vester-Blokland ED et al. The effect of mirtazapine in panic disorder: an open label pilot study with a single-
blind placebo run-in period. Int Clin Psychopharmacol 2001;16(6):363-8.
6. Sarchiapone M, Amore M, De Risio S et al. Mirtazapine in the treatment of panic disorder: an open-label trial. Int Clin
Psychopharmacol 2003;18(1):35-8.
7. Buigues J, Vallejo J. Therapeutic response to phenelzine in patients with panic disorder and agoraphobia with panic attacks. J Clin
Psychiatry 1987;48(2):55-9.
8. Marks IM, Swinson RP, Basoglu M et al. Alprazolam and exposure alone and combined in panic disorder with agoraphobia. A
controlled study in London and Toronto. Br J Psychiatry 1993;162:776-87.
9. Kasper S, Stein D, Loft H et al. Escitalopram in the treatment of social anxiety disorder: randomised, placebo-controlled, flexible-
dosage study. Br J Psychiatry 2005;186:222-6.
10. Lader M, Stender K, Burger V et al. Efficacy and tolerability of escitalopram in 12- and 24-week treatment of social anxiety disorder:
randomised, double-blind, placebo-controlled, fixed-dose study. Depress Anxiety 2004;19(4):241-8.
11. Davidson J, Yaryura-Tobias J, DuPont R et al. Fluvoxamine-controlled release formulation for the treatment of generalized social
anxiety disorder. J Clin Psychopharmacol 2004;24(2):118-25.
12. Westenberg HG, Stein DJ, Yang H et al. A double-blind placebo-controlled study of controlled release fluvoxamine for the treatment of
generalized social anxiety disorder. J Clin Psychopharmacol 2004;24(1):49-55.
13. Baldwin D, Bobes J, Stein DJ et al. Paroxetine in social phobia/social anxiety disorder. Randomised, double-blind, placebo-controlled
study. Paroxetine Study Group. Br J Psychiatry 1999;175:120-6.
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14. Liebowitz MR, Stein MB, Tancer M et al. A randomized, double-blind, fixed-dose comparison of paroxetine and placebo in the
treatment of generalized social anxiety disorder. J Clin Psychiatry 2002;63(1):66-74.
15. Liebowitz MR, DeMartinis NA, Weihs K et al. Efficacy of sertraline in severe generalized social anxiety disorder: results of a double-
blind, placebo-controlled study. J Clin Psychiatry 2003;64(7):785-92.
16. Van Ameringen MA, Lane RM, Walker JR et al. Sertraline treatment of generalized social phobia: a 20-week, double-blind, placebo-
controlled study. Am J Psychiatry 2001;158(2):275-81.
17. Rickels K, Mangano R, Khan A. A double-blind, placebo-controlled study of a flexible dose of venlafaxine ER in adult outpatients with
generalized social anxiety disorder. J Clin Psychopharmacol 2004;24(5):488-96.
18. Falloon IR, Lloyd GG, Harpin RE. The treatment of social phobia. Real-life rehearsal with nonprofessional therapists. J Nerv Ment Dis
1981;169(3):180-4.
19. Liebowitz MR, Schneier F, Campeas R et al. Phenelzine vs atenolol in social phobia. A placebo-controlled comparison. Arch Gen
Psychiatry 1992;49(4):290-300.
20. Stein DJ, Cameron A, Amrein R et al. Moclobemide is effective and well tolerated in the long-term pharmacotherapy of social anxiety
disorder with or without comorbid anxiety disorder. Int Clin Psychopharmacol 2002;17(4):161-70.
21. Pande AC, Davidson JR, Jefferson JW et al. Treatment of social phobia with gabapentin: a placebo-controlled study. J Clin
22. Pande AC, Feltner DE, Jefferson JW et al. Efficacy of the novel anxiolytic pregabalin in social anxiety disorder: a placebo-controlled,
multicenter study. J Clin Psychopharmacol 2004;24(2):141-9.
23. Otto MW, Pollack MH, Gould RA et al. A comparison of the efficacy of clonazepam and cognitive-behavioral group therapy for the
treatment of social phobia. J Anxiety Disord 2000;14(4):345-58.
24. Stein MB, Liebowitz MR, Lydiard RB et al. Paroxetine treatment of generalized social phobia (social anxiety disorder): a randomized
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2):9S-91S.
26. Zohar J, Judge R. Paroxetine versus clomipramine in the treatment of obsessive-compulsive disorder. OCD Paroxetine Study
Investigators. Br J Psychiatry 1996;169(4):468-74.
27. McDougle CJ, Epperson CN, Pelton GH et al. A double-blind, placebo-controlled study of risperidone addition in serotonin reuptake
inhibitor-refractory obsessive-compulsive disorder. Arch Gen Psychiatry 2000;57(8):794-801.
28. Marshall RD, Beebe KL, Oldham M et al. Efficacy and safety of paroxetine treatment for chronic PTSD: a fixed-dose, placebo-controlled
study. Am J Psychiatry 2001;158(12):1982-8.
29. Brady K, Pearlstein T, Asnis GM et al. Efficacy and safety of sertraline treatment of posttraumatic stress disorder: a randomized
30. Seedat S, Stein DJ, Ziervogel C et al. Comparison of response to a selective serotonin reuptake inhibitor in children, adolescents, and
adults with posttraumatic stress disorder. J Child Adolesc Psychopharmacol 2002;12(1):37-46.
31. Escalona R, Canive JM, Calais LA et al. Fluvoxamine treatment in veterans with combat-related post-traumatic stress disorder. Depress
Anxiety 2002;15(1):29-33.
32. Connor KM, Davidson JR, Weisler RH et al. A pilot study of mirtazapine in post-traumatic stress disorder. Int Clin Psychopharmacol
1999;14(1):29-31.
33. Davidson JR,Weisler RH, Butterfield MI et al. Mirtazapine vs. placebo in posttraumatic stress disorder: a pilot trial. Biol Psychiatry
2003;53(2):188-91.
34. Neal LA, Shapland W, Fox C. An open trial of moclobemide in the treatment of post-traumatic stress disorder. Int Clin
35. Frank JB, Kosten TR, Giller EL et al. A randomized clinical trial of phenelzine and imipramine for posttraumatic stress disorder. Am J
Psychiatry 1988;145(10):1289-91.
36. Kosten TR, Frank JB, Dan E et al. Pharmacotherapy for posttraumatic stress disorder using phenelzine or imipramine. J Nerv Ment Dis
1991;179(6):366-70.
37. Bartzokis G, Lu PH, Turner J et al. Adjunctive risperidone in the treatment of chronic combat-related posttraumatic stress disorder. Biol
Psychiatry 2005;57(5):474-9.
38. Stein MB, Kline NA, Matloff JL. Adjunctive olanzapine for SSRI-resistant combat-related PTSD: A double-blind, placebo-controlled
study. Am J Psychiatry 2002;159(10):1777-9.
39. Pitman RK, Sanders KM, Zusman RM et al. Pilot study of secondary prevention of posttraumatic stress disorder with propranolol. Biol
Psychiatry 2002;51(2):189-92.
40. Borkovec TD, Ruscio AM. Psychotherapy for generalized anxiety disorder. J Clin Psychiatry 2001;62(Suppl 11):37-42.
41. Davidson JR, Bose A, Korotzer A et al. Escitalopram in the treatment of generalized anxiety disorder: double-blind, placebo controlled,
flexible-dose study. Depress Anxiety 2004;19(4):234-40.
42. Goodman WK, Bose A, Wang Q. Treatment of generalized anxiety disorder with escitalopram: pooled results from double-blind,
placebo-controlled trials. J Affect Disord 2005;87(2-3):161-7.
43. Pollack MH, Zaninelli R, Goddard A et al. Paroxetine in the treatment of generalized anxiety disorder: results of a placebo-controlled,
flexible-dosage trial. J Clin Psychiatry 2001;62(5):350-7.
44. Davidson JR, DuPont RL, Hedges D et al. Efficacy, safety, and tolerability of venlafaxine extended release and buspirone in outpatients
with generalized anxiety disorder. J Clin Psychiatry 1999;60(8):528-35.
45. Bystritsky A, Kerwin L, Eiduson S, Vapnik T. A pilot controlled trial of bupropion vs. escitalopram in generalized anxiety disorder
(GAD). Neuropsychopharmacol 2005;30(Suppl 1):S101.
46. Rickels K, Pollack MH, Feltner DE et al. Pregabalin for treatment of generalized anxiety disorder: a 4-week, multicenter, double-blind,
placebo-controlled trial of pregabalin and alprazolam. Arch Gen Psychiatry 2005;62(9):1022-30.
47. Feltner DE, Crockatt JG, Dubovsky SJ et al. A randomized, double-blind, placebo-controlled, fixed-dose, multicenter study of
pregabalin in patients with generalized anxiety disorder. J Clin Psychopharmacol 2003;23(3):240-9.
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Page 966
e-Therapeutics+ : Therapeutics : Psychiatric Disorders: Dementia Page 1 of 12
Therapeutic Choice
Print Close
Psychiatric Disorders: Dementia

Kenneth Rockwood, MD, FRCPC
Terry Chisholm, MD, FRCPC
Dementia is a syndrome of acquired global impairment of cognitive function sufficient to interfere with normal
activities. The most common causes are Alzheimer’s disease, vascular dementia, a mixture of the two, Lewy body
dementia and frontotemporal dementia. Dementia is also recognized as a complication of Parkinson's disease.
Dementias are progressive, deteriorating illnesses in which treatment options are different at different stages of the
illness (see Stages of Dementia).
Table 1: Stages of Dementia
Corresponding
Stage Characteristics FAST ratinga
Preclinical Subjective complaints accompanied by very mild objective complaints; 3

functioning is unimpaired. This stage has considerable overlap with normal
aging and may or may not progress to dementia.
Mild Impaired instrumental activities of daily living (IADL), e.g., driving, medication 4
use, finances, use of telephone and housekeeping
Moderate In addition to IADL impairment, personal activities of daily living (PADL) such 5
as bathing, feeding, dressing and toileting can be done only with prompting
Severe PADL cannot be done even with prompting 6
Terminal Patients must be fed and become immobile and mute 7
a. 1
Included because many jurisdictions use the Functional Assessment Staging Tool (FAST) in adjudicating reimbursement for
dementia medications.
Goals of Therapy
Alter the natural disease progression to meet patients’ and caregivers’ goals
Treat cognitive, behavioural and psychological symptoms
Alleviate caregiver burden
Minimize medication side effects
Investigations
Dementia
Thorough history with attention to memory impairment and potentially reversible causes. Cognitive impairment
can be assessed using the Mini-Mental State Examination (MMSE);2 functional disability is measured with tools
such as the Disability Assessment for Dementia3 or the Functional Assessment Staging Tool (FAST)1
Medication history to rule out drug-induced cognitive impairment, e.g., anticholinergics
Physical examination to identify the cause, which is rarely reversible4
Laboratory tests: CBC, electrolytes, kidney function, TSH, calcium, blood glucose. Homocysteine is increasingly
recognized as a marker of dementia risk, but its routine assessment is not yet recommended
CT scan for young patients (< 60 years), new onset, rapid progression, post-head injury, focal or lateralizing
signs, history of cancer, use of anticoagulants, early urinary incontinence and gait disorder or unusual cognitive
symptoms
Behavioural and Psychological Symptoms (Figure 1 - Evaluation and Management of the

Elderly Patient with Behavioural Problems)
Page 967
Therapeutic Choice
Behavioural and psychological symptoms (BPS) are seen in three contexts:
they can be part of the illness. These problems usually occur predictably, according to the stage of dementia. In
Alzheimer’s disease, for example, depression and apathy often occur early, when the dementia is mild. In
contrast, psychosis and agitated behaviour tend to occur in the moderate to later stages. If agitation is seen
early, more aggressive medical investigation is warranted.
they can be related to psychiatric problems that predate the dementia, such as depression, anxiety, psychosis
and personality issues. Elicit a careful psychiatric history; psychiatric syndromes that occurred earlier in the
patient’s life may recur and can guide treatment.
5
they can have a delirium-like presentation, which usually indicates a medical and/or environmental precipitant
(Figure 1 - Evaluation and Management of the Elderly Patient with Behavioural Problems). The diagnostic
approach in the setting of delirium includes:
history of concomitant symptoms, environmental precipitants or medication changes
examination for focal or lateralizing signs or meningismus; both sets of signs will usually be absent. Toxic
or metabolic causes should be evaluated, as well as signs of infection or congestive heart failure.
laboratory tests: CBC, electrolytes, urea, creatinine, glucose, urinalysis, chest radiograph
Note: It is unusual for delusions or hallucinations to occur early. When this happens, it can indicate that the person
is suffering from Lewy body dementia, which means that antipsychotics should be avoided, as they can precipitate
an antipsychotic sensitivity syndrome.
Therapeutic Choices
Nonpharmacologic approaches are first-line therapy for behavioural symptoms of dementia, especially agitation;
they are often sufficient to make a noticeable improvement in the target symptoms. Strategies include:
clear and respectful communication
changes to the physical environment such as ensuring safe places to wander
caregiver strategies such as distraction, avoiding confrontation and providing stimulation and structure
a multidisciplinary approach with involvement of services such as Psychology and Recreation Therapy,
which can decrease agitation through activity programs and other behavioural interventions
Involve family and other caregivers in all nonpharmacologic therapy.
Before disease progression hampers competence, establish advance health care directives and durable powers
of attorney.
Because individuals with dementia are at increased risk for accidents (falls, burns), remove environmental
hazards.
Counsel patients against driving after the initial stages of disease.
Caregiver stress is common and should be anticipated. Support groups, such as those coordinated by the
Alzheimer Society of Canada (www.alzheimer.ca), can be helpful in mitigating feelings of burden.
Nonpharmacologic measures should not be considered an “either/or” option with respect to pharmacologic
6
therapy; often they allow pharmacologic therapy to be used more sparingly.
Alzheimer’s Disease
Cholinesterase Inhibitors
The cholinesterase inhibitors, donepezil, rivastigmine and galantamine, are the mainstays of treatment for
cognitive and functional symptoms, and may have a role with BPS, especially in mild-to-moderate dementia.
Although they have distinct structures and modes of action, in the absence of blinded, controlled, head-to-head
7
trials, they seem to be of equal efficacy. While clinically detectable, benefits are small to moderate on average, and
in many patients consist mainly of disease stabilization. Treatment effects and side effects can vary among
individuals—patients who do not respond to one might respond to another. For each of the drugs, higher doses have
better outcomes. The usual treatment response is that some symptoms improve, others stabilize and still others
worsen. Reduction in repetitive questioning is a common treatment goal in patients with mild-to-moderate
8
Alzheimer's disease and usually corresponds to a generally positive treatment effect.
Target symptoms must be defined and monitored. Effectiveness is considered to be either improvement or no
change in target symptoms. A strategy of setting individual goals for treatment and measuring their attainment at
Page 968
Therapeutic Choice
regular intervals has been shown to detect a range of beneficial treatment effects.8 , 9 Follow-up to detect side
effects is advised two weeks after initiating therapy or increasing dosage, then every three months to monitor
treatment effects.
10 , 11
Most trials have had double-blind conditions for only 3 to 6 months, except for two 12-month and one 24-
12
month placebo-controlled trial of donepezil. Donepezil was shown to be effective in 3- to 6-month trials in
13
patients with mild-to-moderate Alzheimer’s disease (MMSE scores 10 to 26). It has also demonstrated efficacy in
13 , 14
moderate-to-severe Alzheimer’s disease, although this indication has yet to be approved. The initial dose is
5 mg per day, often taken at night, but it can be taken in the morning if sleep disturbances occur. Generally, after
28 days try increasing the dose to 10 mg/day.
For rivastigmine, the initial dose is 1.5 mg po BID; after 30 days, the dose is doubled to 3 mg po BID, which is
the minimum effective dose.15 The maximum dose is 6 mg po BID, although a dose-response relationship has not
been demonstrated consistently. For some patients, TID dosing is most effective, with the same maximum total daily
16 17
dose of 12 mg. Rivastigmine was effective in a double-blind trial in patients with Lewy body dementia, and for
patients with dementia associated with Parkinson's disease.18
Galantamine has been shown to be effective in several studies,9 , 19 including one in patients with mixed
Alzheimer’s disease and vascular dementia.20 A Canadian multicentre trial suggests that patients treated with
9
galantamine were more likely to meet clinical treatment goals than those on placebo. Galantamine is now available
as an extended-release formulation administered once daily, not BID as the immediate-release formulation is
administered. The recommended starting dose is 8 mg/day, increasing to 16 mg/day after 30 days. The dose can be
increased to 24 mg/day if necessary.
N-methyl-D-aspartate (NMDA) Receptor Antagonists
The NMDA receptor antagonist memantine is also used to treat dementia. Its proposed mechanism of action is to
block glutamate-induced neuronal excitotoxicity, which is implicated as a final common pathway in neuronal death.
Meta-analyses suggest memantine has a small to moderately beneficial effect on cognition, ADL and behavior in
moderate-to-severe Alzheimer’s disease at 6 months.21 , 22 The Cochrane review is more guarded.23 A trial of
memantine with donepezil suggested the combination added benefit in patients with moderate-to-severe Alzheimer’s
disease.24 The generalizability of this remains unclear, and whether combination therapy has any role in mild
disease is not yet known.
If memantine is used in patients in whom a greater response is sought than has been achieved with cholinesterase
inhibitors, or when cholinesterase inhibitors are contraindicated or poorly tolerated (e.g., GI side effects), the
approach of setting target symptoms and monitoring carefully remains the best standard for individualized clinical
decision making. The initial dose of 5 mg daily should be increased by 5 mg daily at weekly intervals to a maximum
of 10 mg BID. Reduce the dose to 5 mg BID in patients with mild-to-moderate renal failure. Dosage reduction may
also be necessitated by other conditions (e.g., renal tubular acidosis, some urinary tract infections) or concomitant
drug therapy (e.g., carbonic anhydrase inhibitors), in accordance with the manufacturer's product monograph.
Other Therapies
Despite many trials, clinically significant beneficial effects of ergoloid mesylates in Alzheimer’s disease have not
been demonstrated.
Vitamin E, in a dose of 2000 IU per day of alpha-tocopherol, appeared to slow the progression of
25
dementia. Few side effects were apparent beyond an increased incidence of falls. Given more recent
data suggesting additional adverse effects or no benefit in a range of conditions, use of high-dose
vitamin E is not recommended and any supplementation might be questionable.26 Useful Info?
In the largest study of disease progression to date, selegiline proved more effective than placebo, but no more
effective than Vitamin E alone in delaying death, institutionalization and progression to severe dementia.25
Vascular Dementia
With the aim of slowing disease progression, vascular risk factors should be modified, particularly to ensure good
control of hypertension ( < 140/80 mm Hg), and it seems reasonable to use lipid-lowering agents for dyslipidemias
(see Cardiovascular Disorders: Hypertension and Cardiovascular Disorders: Dyslipidemias).
Page 969
Therapeutic Choice
Dementia with Lewy Bodies and the Dementia of Parkinson’s Disease
Patients with dementia with Lewy bodies often present with hallucinations and early parkinsonism, which can
27
precede cognitive impairment. This psychosis can be worsened by antipsychotics. Patients with dementia with
Lewy bodies have severe antipsychotic sensitivity reactions which can precipitate irreversible parkinsonism, further
impair consciousness and induce autonomic disturbances. These reactions occur in 40 to 50% of patients and
increase mortality.
17
Clinical trial data for the use of rivastigmine demonstrate that small doses can sometimes be dramatically
effective, and leave the potential for subsequent dose titration over time. Prescribing considerations are similar to
those for Alzheimer’s disease. Similarly, a placebo-controlled trial in the treatment of patients with Parkinson’s
disease who had been diagnosed with dementia found statistically significant improvement in rivastigmine-treated
18
patients for cognition, function and behaviour. The size of the treatment effect appears to be comparable with that
reported for cholinesterase inhibitors in Alzheimer’s disease.
Prevention of Dementia
Cardiovascular risk factors increase the chance of all causes of late-life dementia, including Alzheimer’s disease.
Evidence from the Syst-Eur trial suggests that the incidence of dementia can be halved in elderly patients treated for
systolic hypertension.28 Despite the failure of some recent trials, there remains some evidence that long-term use of
29
NSAIDs might be protective for Alzheimer's disease, although their routine use is not recommended due to their
associated adverse effects. There is not enough evidence to support the use of lipid-lowering agents, particularly
statins, for prevention of dementia alone.30 Prior enthusiasm for the use of estrogen, based on observational
studies, has not been sustained by the experimental evidence, which on balance suggests net harm.
Behavioural and Psychological Symptoms (BPS)
Antidepressants
Many patients in the early stages of dementia suffer from depression. Occasionally, depression can manifest with
prominent cognitive impairment. Previously known as pseudodementia, it is more commonly referred to as dementia
of depression. A significant proportion of these patients will progress to dementia.
Most experienced psychiatrists agree that antidepressants are effective in the treatment of depression of demented
31
patients. However, there are few controlled studies specifically focused on the antidepressant treatment of these
patients.
Citalopram and sertraline, both SSRIs, have been shown to be more effective than placebo in treating depression
32 , 33 , 34
in patients with dementia in large, double-blind studies. Generally, SSRIs are less likely than tricyclic
antidepressants (TCAs) to cause anticholinergic side effects or to worsen orthostatic hypotension, which are
common and problematic in this population. An increased risk of hyponatremia/SIADH, possibly potentiated by
35 , 36
concurrent thiazide use, has been reported in elderly patients taking SSRIs. Monitoring of electrolytes is
recommended in this setting, because of the effect of hyponatremia on cognitive function. If using a TCA (because
of lack of response or sensitivity to an SSRI) choose desipramine or nortriptyline. Older adults and those with
dementia often require longer exposure to antidepressants; trials can be two to three months (see Psychiatric
Disorders: Depression for dosing information). Although trials should be longer, there are often early indications
that the antidepressant is working—there may be improvement in vegetative symptoms such as sleep, appetite and
energy before improvement of mood.
There is no evidence from randomized, controlled trials that antidepressants improve nondepression-related BPS in
34
dementia, although antidepressants are commonly used for anxiety (including compulsive behaviour), aggression
and sexually inappropriate behaviour.
Antipsychotics
For BPS associated with dementia, especially if psychotic symptoms are evident, the second-generation
antipsychotics are considered first-line. As the elderly demented brain is exquisitely sensitive to antipsychotics,
initial doses should be small. Risperidone can be started at a daily dose of 0.25 mg with 1.0 mg being the optimal
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Therapeutic Choice
dose and 2 mg/day the upper limit.37 , 38 Olanzapine, started at 2.5 mg and increased to 5 to 10 mg/day, was
effective in a placebo-controlled trial in nursing home patients with Alzheimer’s disease.39 A recent review noted
34
that there have been no published RCTs of clozapine or quetiapine in the treatment of BPS of dementia,
although individual considerations sometimes dictate the use of these medications, especially if risperidone or
olanzapine have proved to be ineffective or have resulted in side effects. A Cochrane review of haloperidol for
40
agitation in dementia recommended against its routine use. Periodic reassessment of BPS is essential; even in the
absence of therapy, the natural history is gradual diminution of these problems.
Extrapyramidal side effects are more commonly seen with the first-generation antipsychotics but can occur with the
second-generation agents (especially with doses over 2 mg/day of risperidone). Tardive dyskinesia (TD), a
potentially irreversible movement disorder, is also more common with first-generation antipsychotics. In patients
41
over 60 years of age, TD occurs in 29% of patients after one year and in up to 63% after three years of use. A
shorter study found an incidence of TD of 2.6% with risperidone after nine months.42 For patients with baseline
movement disorders or those who develop EPS with other second-generation antipsychotics, quetiapine may be
the best option.
The Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study43 found that people with dementia who
received a placebo or any of the three atypical antipsychotics (risperidone, olanzapine, quetiapine) discontinued
treatment at about the same rate. In general, patients were discontinued from placebo due to lack of effect, or from
atypical antipsychotics due to adverse effects, after an average of eight weeks. The CATIE study reminds us to be
cautious about using antipsychotics in people with dementia, and especially that they should not be used for a
nonspecific complaint of agitation. A dilemma posed by the data is that psychotic symptoms will improve with
antipsychotic therapy in some patients with dementia, but which patients will respond cannot be determined in
advance. Consequently, a medication trial is needed for patients with psychotic symptoms.
The risk of serious adverse events with all antipsychotics is significant and indicates the need to reserve these drugs
for patients with severe symptoms where alternative interventions have failed. An increased risk of stroke and death
has been demonstrated with atypical antipsychotics compared to placebo, and observational comparisons suggest
the risk may be higher when first-generation antipsychotics are used.34 , 44 , 45
Trazodone for Behavioural and Sleep Disturbances
Trazodone, a serotonin agonist, is often used successfully to manage agitated behaviour although this is not
supported by randomized controlled trials.34 Start with a low dose of 25 to 50 mg (initially given at night) and
increase every few days until the desired effect is achieved (maximum dose of 400 mg/day in divided doses).
Trazodone is also used to treat disrupted sleep/wake cycles and “sun downing” (worsening of behaviour as darkness
falls).
Benzodiazepines
Data on the efficacy of benzodiazepines for BPS in dementia are conflicting. Although their use can result in
oversedation, falls and worsening cognition, benzodiazepines are sometimes indicated for severe agitation,
especially when other agents fail. Low doses of a short-acting agent without active metabolites (e.g., lorazepam
0.5 to 1 mg, oxazepam 5 to 10 mg, temazepam 15 mg) may be tried. In an acute situation, to manage severely
agitated patients, lorazepam 0.5 to 1 mg can be mixed in the same syringe with haloperidol (0.5, 1 or 1.5 mg)
and given im every eight hours for a maximum of three days. A recent review found only one placebo-controlled
34
trial, in which intramuscular lorazepam was as effective as intramuscular olanzapine.
Others
Beta-blockers (particularly pindolol), carbamazepine, divalproex, lithium and buspirone have been used
successfully in case reports, but better evidence is lacking. These agents seem to work best when the problem
behaviour mimics the psychiatric syndrome for which the drug is efficacious (e.g., lithium for cycling and manic
features).
Therapeutic Tips
Tips for monitoring treatment effects on target symptoms:

in certain provinces, drug reimbursement by the provincial formularies relies on monitoring of degrees of
improvement or worsening of target symptoms. Symptoms should be described precisely, e.g., instead of
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Therapeutic Choice
“impaired function” state “cannot carry on a conversation; will call only one or two well-known numbers;
cannot remember how often he has called.” For many symptoms, it is important to quantify how often they
occur, e.g., asks the same question up to 20 times per day
the most common target symptoms include repetitive questioning, decreased initiative (especially for social
and leisure activities and for instrumental activities of daily living), irritability, impaired recent memory and
disorientation. A web site with the most common symptoms of dementia is available
(www.dementiaguide.ca). Subscribers to the site can use a symptom tracking option to aid in
communicating with their physicians about the effects of treatment.
Tips for using antidepressants in dementia include:
start low
monitor for side effects
increase until the recommended dosage range is reached
once the lower end of the recommended dosage range has been reached, continue increasing the dose as
side effects permit until the patient benefits, or the maximum dose has been reached; effective doses will
be similar to those used to treat younger adults
maintain therapy for four to six weeks after the first indication of symptomatic improvement (e.g.,
improved mood, appetite, sleep or energy) before evaluating the success of treatment; symptoms like
sleep, appetite and energy may improve earlier in treatment but it make take six to eight weeks for
improvement in psychological symptoms such as depressed mood or anhedonia.
Tips for using antipsychotics in dementia include:
start low, go slow; keep the dose as low as possible
treat to a designated endpoint, usually an improvement in symptoms, not their complete resolution
evaluate therapy at one, three and six months, then every six months. Symptoms may subside naturally
and the antipsychotic can then be tapered
antipsychotic-induced akathisia (increased motor restlessness) may be misinterpreted as lack of drug
effect. This can initiate a cycle of increased antipsychotic use and worsening akathisia; the escalating dose
of antipsychotic can then result in extrapyramidal rigidity to the point of immobility. Beware the elderly
patient with dementia who requires large or increasing doses of antipsychotics, especially if the patient
seems even worse after their administration
beware of antipsychotic sensitivity, manifested as rigidity, autonomic dysregulation, cognitive deterioration
(including delirium, and even coma). This can be a hallmark of Lewy body dementia, and antipsychotics are
best avoided in these patients.
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Therapeutic Choice
Figure 1-Evaluation and Management of the Elderly Patient with Behavioural Problems
Table 2: Drugs Used for the Treatment of Dementia
a
Cost
Cholinesterase donepezil Initial: Cholinesterase Cholinesterase inhibitors: $$$

Inhibitors Aricept, 5 mg/day inhibitors: Theoretically, Theoretical concern regarding
Aricept RDT Target: these agents may lower antagonistic effect of combined
10 mg/day seizure threshold, therapy with cholinesterase
Adjust dose increase the risk of GI inhibitors and drugs with
after 4 wk ulceration or bleeding or anticholinergic activity, or
exacerbate COPD or additive bradycardic effects
asthma. Donepezil: > when combined with beta-
10%: headache, nausea, blockers or calcium channel
diarrhea. blockers; few reports of actual
< 10%: vomiting, interactions. Donepezil:
anorexia, fatigue, sleep Toxicity may be ↑ by inhibitors
disturbance, syncope, of CYP2D6 or CYP3A4 (e.g.,
muscle cramps, urinary paroxetine, erythromycin,
frequency. prednisone, grapefruit juice).
Effectiveness may be ↓ by
Rare: bradycardia, heart inducers of CYP2D6 or CYP3A4
block. (e.g., carbamazepine,
Page 973
Therapeutic Choice
a
Cost
Cholinesterase galantamine Initial: Cholinesterase Cholinesterase inhibitors: $$$

Inhibitors extended- 8 mg daily inhibitors: Theoretically, Theoretical concern regarding
release Target: 16– these agents may lower antagonistic effect of combined
Reminyl ER 24 mg daily seizure threshold, therapy with cholinesterase
Adjust dose at increase the risk of GI inhibitors and drugs with
4-wk intervals ulceration or bleeding or anticholinergic activity, or
exacerbate COPD or additive bradycardic effects
asthma. when combined with beta-
Galantamine: > 10%: blockers or calcium channel
nausea, vomiting, blockers; few reports of actual
diarrhea. interactions.
Galantamine: Toxicity may be ↑
< 10%: bradycardia, by inhibitors of CYP2D6 or
syncope, dizziness, CYP3A4 (e.g., paroxetine,
headache, sleep erythromycin, prednisone,
disturbance, fatigue, grapefruit juice).
abdominal pain, weight
loss, UTI, urinary Effectiveness may be ↓ by
incontinence, rhinitis. inducers of CYP2D6 or CYP3A4
(e.g., carbamazepine,
Rare: heart block, phenytoin, rifampin).
seizures, delirium.
Cholinesterase rivastigmine Initial: Cholinesterase Cholinesterase inhibitors: $$

Inhibitors Exelon, 1.5 mg BID inhibitors: Theoretically, Theoretical concern regarding
generics Target: 6– these agents may lower antagonistic effect of combined
12 mg/day seizure threshold, therapy with cholinesterase
Adjust dose increase the risk of GI inhibitors and drugs with
monthly; take ulceration or bleeding or anticholinergic activity, or
with breakfast exacerbate COPD or additive bradycardic effects
and dinner asthma. when combined with beta-
Rivastigmine: > 10%: blockers or calcium channel
headache, dizziness, blockers; few reports of actual
nausea/vomiting, interactions.
diarrhea, abdominal Rivastigmine: None reported;
pain, anorexia. not metabolized by cytochrome
P450 system.
< 10%: fatigue,
insomnia, syncope,
dyspepsia, weight loss,
UTI, rhinitis.
Rare: heart block,

delirium, seizures.
N-methyl-D- memantine Initial: 5 mg Generally well tolerated; None reported. Not affected by $$$
aspartate Ebixa daily; increase dizziness (7%), cytochrome P450 system.
(NMDA) by 5 mg daily, headache (6%), Theoretically, urinary alkalizers
Receptor at weekly confusion (6%), (e.g., carbonic anhydrase
Antagonists intervals, to 10 constipation (5%), inhibitors) may decrease the
mg BID starting nausea/vomiting (3%). clearance of memantine.
at wk 4
Antipsychotics olanzapine Initial: Extrapyramidal Toxicity may be ↑ by inhibitors of $$$-

Zyprexa, 2.5 mg/day symptoms, sedation, CYP3A4 (e.g., erythromycin, $$$$
Zyprexa Target: 5– constipation, GI upset, clarithromycin, grapefruit juice,
10 mg/day weight gain, metabolic prednisone).
Zydis,
dysregulation (type 2 Effectiveness may be ↓ by
generics
diabetes); ↑ risk of inducers of CYP3A4 (e.g.,
stroke and death
Page 974
Therapeutic Choice
Costa
carbamazepine, phenytoin,
rifampin).
Antipsychotics quetiapine Initial: Extrapyramidal Toxicity may be ↑ by inhibitors of $-$$

Seroquel, 25 mg/day symptoms, sedation, CYP2D6 (e.g., paroxetine,
generics Up to: constipation, GI upset, quinidine).
150 mg/day weight gain, metabolic Effectiveness may be ↓ by
dysregulation (type 2 inducers of CYP2D6 (e.g.,
diabetes); ↑ risk of carbamazepine, phenytoin,
stroke and death rifampin).
Antipsychotics risperidone Initial: Extrapyramidal Toxicity may be ↑ by inhibitors of $

0.25 mg/day symptoms, sedation, CYP2D6 or CYP3A4 (e.g.,
Risperdal, Target: constipation, GI upset, paroxetine, erythromycin,
Risperdal M- 1 mg/day weight gain, metabolic prednisone, grapefruit juice).
Max: 2 mg/day dysregulation (type 2 Effectiveness may be ↓ by
Tab,
diabetes); ↑ risk of stroke inducers of CYP2D6 or CYP3A4
generics and death (e.g., carbamazepine,
Serotonin trazodone Initial: 25– Drowsiness, orthostatic Toxicity may be ↑ by inhibitors of $

Agonists Desyrel, 50 mg QHS hypotension, nausea, CYP2D6 or CYP3A4 (e.g.,
generics Max: vomiting, headache, dry paroxetine, erythromycin,
400 mg/day in mouth, priapism (rare). prednisone, grapefruit juice).
divided doses Effectiveness may be ↓ by
inducers of CYP2D6 or CYP3A4
(e.g., carbamazepine,
a.
Cost of 30-day supply of target dose; includes drug cost only.
Legend: $ < $50 $-$$ < $50–100 $$ $50–100 $$$ $100–150 $$$-$$$$ $100–250 $$$$ $150–250
Suggested Readings
Gauthier S, editor. Clinical diagnosis and management of Alzheimer’s disease. 3rd ed. Boca Raton (FL): Taylor &
Francis; 2006.
Patterson CJ, Gauthier S, Bergman H et al. The recognition, assessment and management of dementing disorders:
conclusions from the Canadian Consensus Conference on Dementia. CMAJ 1999;160(12 Suppl):S1-S15.
Sink KM, Holden KF, Yaffe K. Pharmacological treatment of neuropsychiatric symptoms of dementia: a review of the
evidence. JAMA 2005;293(5):596-608.
References
1. Reisberg B. Functional assessment staging (FAST). Psychopharmacol Bull 1988;24(4):653-9.
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Therapeutic Choice
2. Folstein MF, Folstein SE, McHugh PR. “Mini-mental state”. A practical method for grading the cognitive state of
patients for the clinician. J Psychiatr Res 1975;12(3):189-98.
3. Gélinas I, Gauthier L, McIntyre M et al. Development of a functional measure for persons with Alzheimer's
disease: the disability assessment for dementia. Am J Occup Ther 1999;53(5):471-81.
4. Clarfield AM. The decreasing prevalence of reversible dementias: an updated meta-analysis. Arch Intern Med
2003;163(18):2219-29.
5. Fick DM, Agostini JV, Inouye SK. Delirium superimposed on dementia: a systematic review. J Am Geriatr Soc
2002;50(10):1723-32.
6. Fossey J, Ballard C, Juszczak E et al. Effect of enhanced psychosocial care on antipsychotic use in nursing
home residents with severe dementia: cluster randomised trial. BMJ 2006;332(7544):756-61.
7. Rockwood K. Size of the treatment effect on cognition of cholinesterase inhibition in Alzheimer’s disease. J
Neurol Neurosurg Psychiatry 2004;75(5):677-85.
8. Rockwood K, Fay S, Jarrett P et al. Effect of galantamine on verbal repetition in AD: a secondary analysis of
the VISTA trial. Neurology 2007;68(14):1116-21.
9. Rockwood K, Fay S, Song X et al. Attainment of treatment goals by people with Alzheimer's disease receiving
galantamine: a randomized controlled trial. CMAJ 2006;174(8):1099-105.
10. Mohs RC, Doody RS, Morris JC et al. A 1-year, placebo-controlled preservation of function survival study of
donepezil in AD patients. Neurology 2001;57(3):481-8.
11. Winblad B, Engedal K, Soininen H et al. A 1-year, randomized, placebo-controlled study of donepezil in
patients with mild to moderate AD. Neurology 2001;57(3):489-95.
12. Courtney C, Farrell, Gray R et al. Long-term donepezil treatment in 565 patients with Alzheimer’s disease
(AD2000): randomised double-blind trial. Lancet 2004;363(9427):2105-15.
13. Birks J, Harvey RJ. Donepezil for dementia due to Alzheimer's disease. Cochrane Database Syst Rev 2006;
(1):CD001190.
14. Winblad B, Kilander L, Eriksson S et al. Donepezil in patients with severe Alzheimer's disease: double-
blind,parallel-group, placebo-controlled study. Lancet 2006;367(9516):1057-65.
15. Birks J. Cholinesterase inhibitors for Alzheimer's disease. Cochrane Database Syst Rev 2006;(1):CD005593.
16. Feldman HH, Lane R; Study 304 Group. Rivastigmine: a placebo controlled trial of twice daily and three times
daily regimens in patients with Alzheimer's disease. J Neurol Neurosurg Psychiatry 2007;78(10):1056-63.
17. McKeith I, Del Ser T, Spano P et al. Efficacy of rivastigmine in dementia with Lewy bodies: a randomised,
double-blind, placebo-controlled international study. Lancet 2000;356(9247):2031-6.
18. Emre M, Aarsland D, Albanese A et al. Rivastigmine for dementia associated with Parkinson's disease. N Engl J
Med 2004;351(24):2509-18.
19. Loy C, Schneider L. Galantamine for Alzheimer's disease and mild cognitive impairment. Cochrane Database
Syst Rev 2006;(1):CD001747.
20. Erkinjuntti T, Kurz A, Gauthier S et al. Efficacy of galantamine in probable vascular dementia and Alzheimer's
disease combined with cerebrovascular disease: a randomised trial. Lancet 2002;359(9314):1283-90.
21. Smith M, Wells J, Borrie M. Treatment effect size of memantine therapy in Alzheimer disease and vascular
dementia. Alzheimer Dis Assoc Disord 2006;20(3):133-7.
22. Winblad B, Jones RW, Wirth Y et al. Memantine in moderate to severe Alzheimer's disease: a meta-analysis of
randomised clinical trials. Dement Geriatr Cogn Disord 2007;24(1):20-7.
23. McShane R, Areosa Sastre A, Minakaran N. Memantine for dementia. Cochrane Database Syst Rev 2006;
(2):CD003154.
24. Tariot PN, Farlow MR, Grossberg GT et al. Memantine treatment in patients with moderate to severe Alzheimer
disease already receiving donepezil: a randomized controlled trial. JAMA 2004;291(3):317-24.
25. Sano M, Ernesto C, Thomas RG et al. A controlled trial of selegiline, alpha-tocopherol, or both as treatment
for Alzheimer’s disease. The Alzheimer’s Disease Cooperative Study. N Engl J Med 1997;336(17):1216-22.
26. Bjelakovic G , Nikolova D, Gluud LL et al. Mortality in randomized trials of antioxidant supplements for
primary and secondary prevention: systematic review and meta-analysis. JAMA 2007;297(8):842-57.
27. McKeith IG , Galasko D, Kosaka K et al. Consensus guidelines for the clinical and pathologic diagnosis of
dementia with Lewy bodies (DLB): report of the consortium on DLB international workshop. Neurology
1996;47(5):1113-24.
28. Forette F, Seux ML, Staessen JA et al. The prevention of dementia with antihypertensive treatment: new
evidence from the Systolic Hypertension in Europe (Syst-Eur) study. Arch Intern Med 2002;162(18):2046-52.
29. Etminan M, Gill S, Samii A. Effect of non-steroidal anti-inflammatory drugs on risk of Alzheimer's disease:
systematic review and meta-analysis of observational studies. BMJ 2003;327(7407):128.
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30. Rockwood K. Epidemiological and clinical trials evidence about a preventive role for statins in Alzheimer's
disease. Acta Neurol Scand Suppl 2006;185:71-7.
31. Swartz M, Barak Y, Mirecki I et al. Treating depression in Alzheimer’s disease: integration of differing
guidelines. Int Psychogeriatr 2000;12(3):353-8.
32. Nyth AL, Gottfries CG. The clinical efficacy of citalopram in treatment of emotional disturbances in dementia
disorders. A Nordic multicentre study. Br J Psychiatry 1990;157:894-901.
33. Nyth AL, Gottfries CG, Lyby K. A controlled multicenter clinical study of citalopram and placebo in elderly
depressed patients with and without concomitant dementia. Acta Psychiatr Scand 1992;86(2):138-45.
34. Sink KM, Holden KF, Yaffe K. Pharmacological treatment of neuropsychiatric symptoms of dementia: a review
of the evidence. JAMA 2005;293(5):596-608.
35. Rosner MH. Severe hyponatremia associated with the combined use of thiazide diuretics and selective
serotonin reuptake inhibitors. Am J Med Sci 2004;327(2):109-11.
36. Kirby D, Harrigan S, Ames D. Hyponatraemia in elderly psychiatric patients treated with Selective Serotonin
Reuptake Inhibitors and venlafaxine: a retrospective controlled study in an inpatient unit. Int J Geriatr
Psychiatry 2002;17(3):231-7.
37. Katz IR, Jeste DV, Mintzer JE et al. Comparison of risperidone and placebo for psychosis and behavioral
disturbances associated with dementia: a randomized, double-blind trial. Risperidone Study Group. J Clin
Psychiatry 1999;60(2):107-15.
38. De Deyn PP, Rabheru K, Rasmussen A et al. A randomized trial of risperidone, placebo, and haloperidol for
behavioral symptoms of dementia. Neurology 1999;53(5):946-55.
39. Street JS, Clark WS, Gannon KS et al. Olanzapine treatment of psychotic and behavioral symptoms in patients
with Alzheimer disease in nursing care facilities: a double-blind, randomized, placebo-controlled trial. The
HGEU Study Group. Arch Gen Psychiatry 2000;57(10):968-76.
40. Lonergan E, Luxenberg J, Colford J. Haloperidol for agitation in dementia. Cochrane Database Syst Rev 2002
(2):CD002852.
41. Jeste DV. Tardive dyskinesia in older patients. J Clin Psychiatry 2000;61(Suppl 4):27-32.
42. Jeste DV, Lacro JP, Bailey A et al. Lower incidence of tardive dyskinesia with risperidone compared with
haloperidol in older patients. J Am Geriatr Soc 1999;47(6):716-9.
43. Schneider LS, Tariot PN, Dagerman KS et al. Effectiveness of atypical antipsychotic drugs in patients with
Alzheimer's disease. N Engl J Med 2006;355(15):1525-38.
44. Gill SS, Rochon PA, Herrmann N et al. Atypical antipsychotic drugs and risk of ischaemic stroke: population
based retrospective cohort study. BMJ 2005;330(7489):445.
45. Schneeweiss S, Setoguchi S, Brookhart A et al. Risk of death associated with the use of conventional versus
atypical antipsychotic drugs among elderly patients. CMAJ 2007;176(5):627-32.
Pharmacoeconomic Considerations: Dementia

Epidemiology

1 8% of the population aged ≥ 65 years
Canada (1991)
Country and Year of Estimate a

Direct Costs
2 Cost per patient with Alzheimer's disease from a societal perspective:
Canada (1996)
Mild disease: $9451
Mild-to-moderate disease: $16 054
Moderate disease: $25 724
Severe disease: $36 794
Commentary
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Therapeutic Choice
Dementia has a significant impact on society from an economic perspective. Institutionalization is the largest cost
2
component of direct and indirect care. Unpaid caregiver time accounts for more than half of the overall costs in
2
patients with mild and mild-to-moderate dementia.
A number of cholinesterase inhibitors have been approved for the treatment of dementia. There appears to be no
3
clear advantage of one agent over another. The majority of economic evaluations have considered treatment of
4
mild-to-moderate dementia and been conducted from a societal perspective. Cholinesterase inhibitors are
generally considered to be cost-effective compared with placebo in terms of delaying disease progression and the
4
need for home care. The economic benefits of treatment of mild-to-moderate dementia is relatively favourable
for choices such as donepezil, rivastigmine and galantamine for improvements in meaningful outcomes such as
delaying the progression of symptoms or improvement in cognitive impairment as rated by the Mini Mental State
Exam.
Memantine is also considered to be cost-effective in patients with moderate-to-severe dementia, in whom it
increases patient autonomy and time spent in an independent state.5 , 6
It should be noted, however, that the literature on the cost-effectiveness of cholinesterase inhibitors is dominated
by noncomparative studies sponsored by pharmaceutical manufacturers.
a.
1. [No authors listed]. Canadian study of health and aging: study methods and prevalence of dementia. CMAJ
1994;150(6):899-913.
2. Hux MJ, O'Brien BJ, Iskedjian M et al. Relation between severity of Alzheimer’s disease and costs of caring.
CMAJ 1998;159(5):457-65.
3. Perras C, Shukla VK, Lessard C et al. Cholinesterase inhibitors for Alzheimer's disease: a systematic review of
randomized controlled trials. [Technology report no 58]. Ottawa (ON): Canadian Coordinating Office for
Health Technology Assessment; 2005.
4. Loveman E, Green C, Kirby J et al. The clinical and cost-effectiveness of donepezil, rivastigmine, galantamine
and memantine for Alzheimer’s disease. Health Technol Assess 2006;10(1):1-160.
5. Francois C, Sintonen H, Sulkava R et al. Cost-effectiveness of memantine in moderately severe to severe
Alzheimer’s disease: a markov model in Finland. Clin Drug Investig 2004;24(7):373-84.
6. Feldman H, Gauthier S, Hecker J et al. Economic evaluation of donepezil in moderate to severe Alzheimer
disease. Neurology 2004;63(4):644-50.
Page 978
e-Therapeutics+ : Therapeutics : Psychiatric Disorders: Depression Page 1 of 19
Therapeutic Choice
Print Close
Psychiatric Disorders: Depression

Sidney H. Kennedy, MD, FRCPC
Sagar V. Parikh, MD, FRCPC
Sophie Grigoriadis, MD, PhD, FRCPC
Depressive disorders (Table 1) include the specific illnesses of major depressive disorder (MDD), dysthymic
disorder and depressive disorder not otherwise specified (depressive episodes deviating from the precise criteria for
MDD). Major depressive episodes may be single or, more often, recurrent. Other disorders producing depressive
symptoms include: bipolar disorder, depressed phase (distinguished by a history of a previous manic, mixed or
hypomanic episode—see Psychiatric Disorders: Bipolar Disorder); substance-induced mood disorder (caused by
substances such as alcohol or medications); and mood disorder due to a general medical condition (when the
1 , 2
depression is thought to be a direct physiological consequence of the medical disorder).
Table 1: Clinical Features of Major Depressive Episode and Dysthymic Disorder
a
Syndrome Essential Features
Major Depressive Five (or more) of the following, at least 1 of which must be depressed mood or
Episode diminished interest/pleasure, on most days for at least 2 weeks:
Depressed mood
Diminished interest or pleasure
Significant weight loss or weight gain
Psychomotor agitation or retardation
Fatigue or loss of energy
Feelings of worthlessness or excessive guilt
Diminished ability to think or concentrate, or indecisiveness
Recurrent thoughts of death/suicide or suicide attempt
Dysthymic Disorder Depressed mood for most of the day, more days than not, for at least 2 years, plus at
least 2 of the following:
Poor appetite or overeating
Low energy or fatigue
Low self-esteem
Poor concentration or difficulty making decisions
Feelings of hopelessness
a.
Not due to medically or drug-induced conditions or normal bereavement.
b.
Symptoms must be associated with impairment in social, occupational or other areas of functioning.
Adapted with permission from the Diagnostic and Statistical Manual of mental disorders: DSM-IV-TR, 4th edition, text
revision. Copyright 2000 American Psychiatric Association.
Goals of Therapy
Achieve remission of depressive symptoms

Prevent suicide
Restore optimal functioning
Prevent recurrence
Investigations
Page 979
Therapeutic Choice
The following screening questions/assessment tools are recommended for use by primary care physicians:
The Patient Health Questionnaire (PHQ-9)3 is a self-reported version of the DSM IV criteria for a major
depressive episode. Asking the first 2 questions from the PHQ-9 is a useful and rapid screening tool:4
“During the past month have you often been bothered by feeling down, depressed or hopeless?”
“During the past month have you often been bothered by little interest or pleasure in doing things?”
5
The seven-item Hamilton Depression Rating Scale (HAM-D-7) is a validated brief physician assessment
designed to assess severity and remission.
6
The Mood Disorder Questionnaire (MDQ) is a useful screening instrument for manic or hypomanic symptoms.
7
The Edinburgh Postnatal Depression Scale (EPDS) is the most widely used and well-validated tool
to screen for depressive symptoms during pregnancy and the postpartum. Useful Info?
Therapeutic Choices
The most impressive evidence for the success of antidepressant therapy and depression-specific psychological
therapies, in terms of both clinical efficacy and restoration of occupational functioning, comes from controlled trials
8 , 9
involving multifaceted health system interventions. These interventions, tested particularly in primary care
settings, involve physicians prescribing antidepressants in conjunction with another health care provider who
engages in telephone contact to provide patient education about depression and to monitor progress during
antidepressant treatment.10 , 11 Multifaceted interventions add only modest costs but provide substantial long-term
12 , 13 , 14
reductions in health care costs and increase the likelihood of returning to work.
Decades of research, as summarized by numerous meta-analyses, demonstrate the efficacy of both cognitive-
behavioural therapy (CBT) and a specific model of interpersonal therapy (IPT) in treating depression. Broadly
speaking, these psychotherapies are equivalent in efficacy to medication, but each type of intervention has subtle
advantages in specific circumstances and patient preferences are important to consider.
Pharmacotherapy is preferable in severe depression and also when comorbid personality disorders are present; IPT
may be preferable when major interpersonal issues are present. Both CBT and IPT have evolved to generate newer
versions that have particular promise, e.g., mindfulness-based CBT (mCBT), which is particularly effective in
preventing relapse into depression,15 and acceptance and commitment therapy (ACT), which has some efficacy in
16
acute depression. CBT is also available on the Internet, in some cases at no charge (e.g.,
www.moodgym.anu.edu.au/welcome and www.livinglifetothefull.com). One meta-analysis has shown web-based
CBT to be equivalent to therapist-delivered CBT.17 Encourage patients to visit these sites and to complete the
modules and simple homework exercises, in tandem with routine clinical care visits.
Motivational interviewing, another promising psychotherapy, is a strikingly effective treatment for comorbid
substance abuse when depression is also present, but its effects are primarily on the substance abuse, not on the
18
depressive symptoms.
Regardless of any specific psychotherapy, measures to enhance treatment compliance are useful; e.g., providing
psychoeducation with the following 5 simple messages is effective:19
Take medication daily
Call this number for questions about side effects or other issues
Remember that it might take 2–4 weeks to see a noticeable effect from antidepressants
Continue to take medication even if you are feeling better
Do not stop taking the antidepressant without checking with the physician
Although diagnostic criteria for MDD and dysthymic disorder differ (Table 1), there are no differences in
recommendations for the use of antidepressants. Table 2 lists first-, second- and third-line antidepressants
according to the 2009 CANMAT guidelines.21A minimum therapeutic dose should be achieved in the first 2 weeks
and if necessary increased over the next 4–6 weeks. Consider switching within the same class during this time when
a favourable response is overshadowed by intolerable side effects. Figure 1 - Pharmacologic Treatment of
Depression21 provides a summary of current psychiatric practice in the absence of a remission of symptoms. A
recent meta-analysis of head-to-head comparisons among 12 newer antidepressants identified superior efficacy for
Page 980
Therapeutic Choice
4 agents: escitalopram, mirtazapine, sertraline and venlafaxine. When acceptability, based on drop out rates, was
20
also considered, escitalopram and sertraline were the most favourably ranked.
Cautions have been issued by regulatory authorities to highlight the potential of antidepressants to increase suicidal
ideation, particularly in children and young adults. Clinicians are faced with complex decisions about when to use
CBT and/or pharmacotherapy to treat depression in younger age groups, and are advised to monitor patients
carefully for any emergent suicidal ideation or acts, particularly during the early phase of treatment.
21
Table 2: CANMAT Classification of Antidepressants
a bupropion
First-line agents
citalopram
desvenlafaxine
duloxetine
escitalopram
fluoxetine
fluvoxamine
mirtazapine
moclobemide
paroxetine
sertraline
venlafaxine
Second-line agentsa trazodone

tricyclic and tetracyclic antidepressants
quetiapine
Third-line agentsa phenelzine

tranylcypromine
a.
Within each category antidepressants are listed in alphabetical order rather than in order of preference.
Selective Serotonin Reuptake Inhibitors (SSRIs)
Greater tolerability and ease of dosing are key reasons why SSRIs are first-choice antidepressants. Both time to
onset (2–4 weeks) and rate of response (60–70%) are comparable to tricyclic antidepressants (TCAs); side effects
mainly affect gastrointestinal (GI), central nervous system (CNS) and sexual function.21 SSRI therapy can increase
the risk of GI bleeding, particularly in patients with additional risk factors such as NSAID therapy or a history of GI
bleeding. SSRIs should be used with caution in patients already at higher risk for GI bleeding.22 Unlike GI or CNS
side effects, sexual dysfunction is more likely to persist during SSRI therapy and can involve impairment of desire,
arousal and/or orgasm/ejaculation. The importance of sexual function to the patient should be considered when
prescribing an antidepressant. Some non-SSRI antidepressants cause less sexual dysfunction (e.g., bupropion,
21
mirtazapine, moclobemide) and may be used instead.
Six SSRIs are currently available in Canada (citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine
and sertraline). Escitalopram, the stereoisomer of citalopram, has a similar side effect profile but superior efficacy
23 24
to citalopram, and at least comparable efficacy to venlafaxine. Among SSRIs, discontinuation effects are
particularly prevalent with paroxetine.25
Dual Action Antidepressants

26
Bupropion is thought to exert antidepressant effects through norepinephrine and dopamine reuptake inhibition. It
27
is a first-line agent for MDD and is also indicated under a different brand name for smoking cessation. Bupropion
is contraindicated in patients with a seizure disorder or history of anorexia or bulimia nervosa, and should be used
with extreme caution where there is a history of head trauma or prior seizure. Treatment-emergent GI disturbance
and sexual dysfunction occur less frequently with bupropion compared to SSRIs.28
Trazodone is a potent postsynaptic serotonin (5HT2) receptor antagonist with weak serotonin reuptake inhibitory
effects.29 Because of severe daytime sedation, trazodone is rarely prescribed at therapeutic antidepressant doses
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Therapeutic Choice
(300–400 mg daily) but is often prescribed at lower doses (50–100 mg) as a hypnotic in combination with other
antidepressants. While a nonbenzodiazepine such as zopiclone is generally preferred for brief hypnotic use,
trazodone is a reasonable alternative in depressed patients, with potential advantages over benzodiazepines (lack of
tolerance and potential antidepressant enhancement).
Mirtazapine acts directly on the noradrenergic system and indirectly on the serotonin system. It has a low rate of
GI and sexual side effects but is associated with sedation and weight gain.30
Venlafaxine, a serotonin norepinephrine reuptake inhibitor (SNRI), has inhibitory effects on serotonin reuptake,
and at doses of ≥ 150 mg daily it inhibits norepinephrine reuptake as well. Between 6 and 10 percent higher rates
of remission have been reported with venlafaxine compared to SSRIs, although these results are mainly due to
31 , 32
venlafaxine's superiority over fluoxetine. Hypertension at doses of 225 mg and above is a rare side effect.
Duloxetine, also an SNRI, appears to exert effects on both serotonin and norepinephrine systems at the starting
dose of 60 mg daily, and has comparable efficacy to venlafaxine.33 In addition to depression, duloxetine is also
indicated for neuropathic pain and for pain associated with fibromyalgia. Isolated cases of hepatic injury have
emerged but there is no requirement for routine monitoring of liver enzymes.
A third SNRI, desvenlafaxine, is the active metabolite of venlafaxine. The recommended dose is 50 mg daily,
although safety data are available for 100 mg daily. The response and remission rates at 8 weeks are 51–63% and
31–45%, respectively. Common adverse effects include insomnia, somnolence, dizziness and nausea.34 , 35
Tricyclic Antidepressants (TCAs)
TCAs are generally reserved as second–line medications. Amitriptyline is still the most frequently prescribed TCA,
often at considerably lower doses of 25–50 mg per day for nighttime sedation or analgesia. Nortriptyline, a
metabolite of amitriptyline and a secondary amine, has been used for many years to treat depression in older
populations; clomipramine, the most serotonergic TCA, is still favoured in the treatment of obsessive compulsive
disorder. In all cases, TCA use is limited by tolerability and safety concerns, especially cardiotoxicity following
overdose.
Monoamine Oxidase Inhibitors (MAOIs)
Use of the irreversible monoamine oxidase inhibitors (MAOIs) phenelzine and tranylcypromine is generally
managed by specialized mood disorder clinics because of their association with potentially fatal food and drug
interactions (serotonin syndrome, hypertensive crisis). However, all prescribers and pharmacists should be aware of
these risks (and how to avoid them) when faced with a patient taking an irreversible MAOI. Despite the potential
risks, under careful conditions phenelzine 30–90 mg daily or tranylcypromine 20–60 mg daily may prove effective
where other antidepressants have not.
Moclobemide is a reversible and selective MAO-A inhibitor that does not require the same dietary restrictions as
irreversible MAOIs. Moclobemide is a well-tolerated alternative to SSRI or SNRI agents, particularly in patients with
a significant anxiety component to their depressive episode. Though it is often perceived as being less effective than
irreversible MAOIs, this perception is not substantiated in clinical trials.
Antipsychotics
Extended-release quetiapine, a second-generation or “atypical” antipsychotic agent, has been approved in Canada
for the treatment of depression and is considered to be a second-line option.21 , 36
Duration of Treatment—Relapse Prevention
Evidence supports the use of maintenance antidepressant therapies for a minimum period of 1 year, particularly
when the intervals between depressive episodes become briefer and the disability associated with each depressive
episode worsens. After 1 episode, treat for 1 year and after 2 or more episodes, treat for at least 2 years. CBT and
IPT may also be effective in reducing the risk of relapse.37
In general, antidepressants should be tapered slowly to minimize the risk of discontinuation emergent symptoms.
Among newer antidepressants, paroxetine and venlafaxine are most likely to produce discontinuation symptoms
such as insomnia, dizziness, nausea and diarrhea.
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Therapeutic Choice
Treatment-Resistant Depression
Antidepressants can be switched either within a medication class or to a different class. Most physicians switch out
of class (e.g., from SSRI to SNRI or TCA) when there has been no response to the first drug. Switching within class
should be considered in the presence of a favourable response but unfavourable side effects. Generally there is no
need for a washout period, and a crossover technique can be applied (i.e., tapering one agent while up-titrating the
other). Exceptions include: switching from an irreversible MAOI (phenelzine or tranylcypromine) to any other
antidepressant, where a 2-week washout is required; switching from moclobemide, where a 5-day washout is
recommended; and switching from fluoxetine to an irreversible MAOI, where a 5-week washout is recommended.
Similarly, due to its long half-life, caution should be exercised when starting other antidepressants after fluoxetine
discontinuation.
Augmentation or combination therapy is recommended when there is a partial response and favourable tolerability to
the first antidepressant. Lithium carbonate at a dose of 600–900 mg daily has been most evaluated, although
triiodothyroxine 25–50 μg daily was as effective in the large Sequenced Treatment Alternatives to Relieve
38
Depression (STAR*D) trial. Several atypical antipsychotics, including aripiprazole, olanzapine, quetiapine and
risperidone, have also proved effective in augmenting antidepressant response, particularly where insomnia and
anxiety symptoms persist.39 These augmentations are not recommended for long-term use, and close monitoring of
weight, cholesterol and glucose indices is indicated. The combination of bupropion with SSRIs is an alternative
40 , 41
option. Psychostimulant agents including modafinil and methylphenidate have enhanced motivation and
energy but not overall symptoms of depression.42
A combination of pharmacotherapy and psychotherapy (specifically IPT or CBT) is superior to either modality alone.
In mild to moderate cases, combination therapy provides little synergy to either treatment alone, but does provide
protection against early relapse compared to either treatment alone. Pharmacotherapy typically facilitates more rapid
relief of symptoms, but does not prevent relapse if the medication is stopped; both IPT and CBT reduce relapse for
up to 3 years after completion of a course of psychotherapy. For moderate to severe depression, or refractory
depression, combination therapy should be strongly considered, particularly in individuals with a history of more
than 3 previous depressions.43
Neurostimulation Therapies
Electroconvulsive therapy (ECT) is efficacious in 80–90% of depressed patients, a response rate that is superior to
any single antidepressant drug, although relapse and recurrence rates are high in the absence of other prophylactic
44 , 45
treatments.
Other neurostimulation therapies, including repetitive transcranial magnetic stimulation (rTMS), vagus nerve
stimulation (VNS) and deep brain stimulation (DBS) are emerging alternatives.46
Bipolar Disorder
Bipolar disorder has a lower prevalence (1–2%) than MDD, but individuals with this disorder experience more
depressive episodes than those with MDD.47 Patients presenting with depression should be questioned about past
manic or hypomanic episodes, as many have difficulty recalling such episodes, and treatment of bipolar disorder
differs significantly. The primary pharmacotherapy for bipolar disorder is a mood stabilizer with other medications
as needed (see Psychiatric Disorders: Bipolar Disorder).
Depression during Pregnancy
During pregnancy, symptoms of depression are common. They can be difficult to disentangle from those frequently
reported during pregnancy (i.e., fatigue, sleeplessness, appetite changes), and are highly predictive of subsequent
postpartum depression. The decision to initiate or continue treatment during pregnancy should be based on a
risk/benefit analysis that considers both the fetus and mother. Untreated maternal depression is associated with
48
untoward effects for the fetus/neonate, the mother and her partner. If symptoms are mild or if criteria for a mild
depressive episode are met, psychotherapy is the first treatment option (e.g., IPT). For episodes of moderate
severity antidepressant medication should be considered especially in women with a past history of depression.
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Therapeutic Choice
Recent evidence suggests that these medications are not major teratogens although the neonate should be
49
monitored for transient neonatal withdrawal symptoms. If antidepressants are prescribed during pregnancy, the
dose should be minimized to the lowest effective dose. When higher doses are used, consider a dose reduction near
term to decrease the risk of withdrawal symptoms in the infant, as well as monitoring of the newborn by a
pediatrician.
Postpartum Depression
Rates of postpartum depression vary according to the severity of the episode. Postpartum “blues” affects up to 80%
of women.50 Postpartum major depression occurs in up to 16% in Canada and postpartum psychosis in ≤ 0.1%.51
“The blues” is not a disorder per se, given that it is so common and symptoms are self-limited, requiring only
monitoring and supportive care. However, women with postpartum blues are at risk to develop a depressive
episode. Psychotherapy (particularly IPT and CBT) should be considered first for the treatment of postpartum
depression, particularly if the mother is breast-feeding, unless it is inadequate or inappropriate for the patient’s
severity of illness, in which case antidepressant treatment should be initiated. For breast-feeding patients, consider
paroxetine, sertraline and nortriptyline 52 which have low concentrations in breast milk.
Resources
For general principles of drug therapy during pregnancy and lactation, see Appendix: Drug Use During Pregnancy
and Appendix: Drug Use During Lactation. For more detailed information on the use of specific medications during
Freeman RK, Yaffe SJ. Drugs in Pregnancy and Lactation 2008; LactMed (toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen?
LACT); and Hale TW. Medications and Mothers' Milk 2008.
Therapeutic Tips
Choose 1 or 2 agents from several antidepressant classes and use them consistently.
Provide structured psychoeducation with the initial prescription.
Reinforce the importance of maintenance therapy beyond the acute phase.
Although serum drug concentrations are not useful with SSRIs, MAOIs and other new antidepressants, there is a
role for such monitoring with some TCAs (e.g., desipramine, imipramine, amitriptyline and nortriptyline).
Provide patients with reliable information on drug interactions and dietary restrictions for irreversible MAOI
therapy (e.g., MAO Inhibitors—Food and Drug Interactions—What You Should Know, developed by Dr. David
Gardner and Anne Marentette at Dalhousie University; available at
www.pharmacists.ca/content/PDFs/MAOI_Interactions_GardnerMarentette.pdf).
Review alcohol and drug abuse history in nonresponders.
Refer for psychiatric consultation if the patient has psychotic symptoms or acute suicidal ideation, or after
failure of 3 treatment trials.
When initiating drug discontinuation, taper slowly over 4–6 weeks. This is particularly important for paroxetine
and venlafaxine.
For patient education, consider recommending web sites such as www.canmat.org or moodgym.anu.edu.au, or
self-help books such as Mind Over Mood 53 or Feeling Good.54
Figure 1- Pharmacologic Treatment of Depression 21
Page 984
Therapeutic Choice
a.
Response definitions: Full = > 50% reduction; Partial = 25 to 50% reduction; Non = < 25% reduction.
Abbreviations: CBT = cognitive behavioural therapy; ECT = electroconvulsive therapy; IPT = interpersonal psychotherapy;
SNRI = serotonin and norepinephrine reuptake inhibitor; SSRI = selective serotonin reuptake inhibitor
Table 3: Drug Therapy for Depression
a
Cost
SSRIs citalopram b Nausea, dry mouth, Use with MAOIs may lead $$-
Initial:
Celexa, generics 10–20 mg/day somnolence, to potentially fatal $$$
sweating, sexual reaction initially
Usual:c
dysfunction, ↑ risk of presenting with tremor,
20–40 mg/day
GI bleeding. agitation, hypomania,
High:d 60 mg/day hyperthermia and/or
hypertension; ↑ risk of GI
bleeding with NSAIDs.
Drugs that inhibit
cytochrome P450 enzymes
(e.g., cimetidine,
clarithromycin,
itraconazole,
ritonavir) may ↑ SSRI
levels.

cytochrome P450
clearance of many drugs (e.g.,
pimozide, propafenone) or
↓ the enzymatic conversion
of a prodrug to its active
Page 985
Therapeutic Choice
a
Cost
form (e.g., codeine,
tamoxifen).
P450 enzymes (e.g.,
carbamazepine,
clearance of SSRIs.
SSRIs escitalopram Initial:b 10 mg/day Nausea, dry mouth, Use with MAOIs may lead $$$
Cipralex c somnolence, to potentially fatal
Usual: 10–20
sweating, sexual reaction initially
mg/day
High:d 20 mg/day GI bleeding. agitation, hypomania,
hyperthermia and/or
Drugs that inhibit
(e.g., cimetidine,
clarithromycin,
itraconazole,
levels.

cytochrome P450
tamoxifen).
P450 enzymes (e.g.,
carbamazepine,
clearance of SSRIs.
SSRIs fluoxetine b Nausea, Use with MAOIs may lead $$-

Initial:
Prozac, generics 10–20 mg/day nervousness, to potentially fatal $$$
c anorexia, insomnia, reaction initially
Usual:
sexual dysfunction, presenting with tremor,
20–40 mg/day
d ↑ risk of GI bleeding. agitation, hypomania,
High: hyperthermia and/or
60–80 mg/day hypertension; ↑ risk of GI
Drugs that inhibit
(e.g., cimetidine,
clarithromycin,
Page 986
Therapeutic Choice
a
Cost
itraconazole,
levels.

cytochrome P450
clearance of many drugs
(e.g., clozapine,
methadone, mexiletine,
phenytoin, pimozide,
propafenone) or ↓ the
enzymatic conversion of a
prodrug to its active form
(e.g., codeine, tamoxifen).
P450 enzymes (e.g.,
carbamazepine,
clearance of SSRIs.
SSRIs fluvoxamine Initial:b Nausea, drowsiness, Use with MAOIs may lead $$-
Luvox, generics 50–100 mg/day sweating, anorexia, to potentially fatal $$$
sexual dysfunction, reaction initially
Usual:c
↑ risk of GI bleeding. presenting with tremor,
150–200 mg/day
d agitation, hypomania,
400 mg/day hypertension; ↑ risk of GI
Drugs that inhibit
(e.g., cimetidine,
clarithromycin,
itraconazole,
levels.

cytochrome P450
(e.g., clozapine,
P450 enzymes (e.g.,
carbamazepine,
clearance of SSRIs.
Page 987
Therapeutic Choice
a
Cost
SSRIs paroxetine, Initial:b Nausea, drowsiness, Use with MAOIs may lead $$-
immediate- 10–20 mg/day fatigue, sweating, to potentially fatal $$$
dizziness, sexual reaction initially
release Usual:c
Paxil, generics 20–40 mg/day
d GI bleeding. agitation, hypomania,
60 mg/day hypertension; ↑ risk of GI
Drugs that inhibit
(e.g., cimetidine,
clarithromycin,
itraconazole,
levels.

cytochrome P450
(e.g., clozapine,
P450 enzymes (e.g.,
carbamazepine,
clearance of SSRIs.
SSRIs paroxetine, Initial:b 12.5–25 Nausea, drowsiness, Use with MAOIs may lead $$$$-
controlled- mg/day fatigue, sweating, to potentially fatal $$$$$
c dizziness, sexual reaction initially
release Usual: 25–50
Paxil CR mg/day
d GI bleeding. agitation, hypomania,
High: 75 mg/day hyperthermia and/or
Drugs that inhibit
(e.g., cimetidine,
clarithromycin,
itraconazole,
levels.

cytochrome P450
Page 988
Therapeutic Choice
Costa
tamoxifen).
P450 enzymes (e.g.,
carbamazepine,
clearance of SSRIs.
SSRIs sertraline Initial:b Nausea, tremors, Use with MAOIs may lead $$
Zoloft, generics 25–50 mg/day diarrhea, dry mouth, to potentially fatal
sexual dysfunction, reaction initially
Usual:c
↑ risk of GI bleeding. presenting with tremor,
50–100 mg/day
d agitation, hypomania,
150–200 mg/day hypertension; ↑ risk of GI
Drugs that inhibit
(e.g., cimetidine,
clarithromycin,
itraconazole,
levels.

cytochrome P450
(e.g., clozapine,
P450 enzymes (e.g.,
carbamazepine,
clearance of SSRIs.
Dual Action bupropion SR formulation: Agitation, insomnia, May ↑ levels of $-$$

Antidepressants Wellbutrin SR, b anorexia; cyclophosphamide,
Initial:
75 mg/day contraindicated in ifosfamide and
Wellbutrin XL,
Usual: anorexia or bulimia orphenadrine.
generics
150–300 mg/day nervosa and seizure
d disorders.
High:
Page 989
Therapeutic Choice
Costa
375–450 mg/day
XL formulation:
b
Initial:
150 mg/day
Usual:
150–300 mg/day
d
High:
450 mg/day
Dual Action mirtazapine b Weight gain, Sedative effects may be $$

Initial:
Antidepressants Remeron, 15–30 mg/day sedation. potentiated by alcohol or
Remeron RD, Usual: diazepam.
generics 30–45 mg/day Orally disintegrating
tablets can be taken
High:d
without water.
60 mg/day
Dual Action trazodone b Drowsiness, nausea, May potentiate effects of $$-

Initial:
Antidepressants Desyrel, 150–200 mg/day headache, dry other CNS depressants $$$
generics Usual: mouth, priapism. and augment hypotensive
300–400 mg/day effects of
antihypertensives.
High:d
600 mg/day
SNRIs venlafaxine Initial:b Nausea, drowsiness, Inhibitors of CYP2D6 or $$$$

Effexor XR, 37.5–75 mg/day nervousness, CYP3A4 may ↑ venlafaxine
generics Usual: dizziness, dry levels; use with MAOIs may
112.5–225 mg/day mouth, may ↑ BP if lead to potentially fatal
dose > 300 mg/day. reaction initially
High:d
presenting with tremor,
300–375 mg/day
agitation, hypomania,
hyperthermia and/or
hypertension.
SNRIs desvenlafaxine Initial: 50 mg daily Nausea, drowsiness, Potent inhibitors of $$$$

Pristiq Usual: 50 mg daily nervousness, CYP3A4 may ↑
dizziness, dry desvenlafaxine levels; do not
High: 100 mg daily mouth, may ↑ BP if use with MAOIs.
dose > 300 mg/day.
SNRIs duloxetine Initial/Usual: 60 Nausea, drowsiness, Do not use with potent $$$$$
Cymbalta mg/day insomnia, dizziness, inhibitors of CYP1A2 (e.g.,
If necessary for dry mouth. fluvoxamine) or MAOIs.
tolerability may
start with 30
mg/day and ↑ to 60
mg in 1–2 wk
High: 120 mg/day
RIMAs moclobemide b Nausea, insomnia, Use with irreversible $$-

Initial:
Manerix, Apo- 200–300 mg/day dizziness. MAOIs may lead to $$$
Usual: potentially fatal reaction
Moclobemide,
450–600 mg/day initially presenting with
other generics
tremor, agitation,
High:d
hypomania, hyperthermia
and/or hypertension;
Page 990
Therapeutic Choice
a
Cost
900 mg/day avoid sympathomimetics,
meperidine. Caution with
opioids, antihypertensives,
antipsychotics, SSRIs,
selegiline, excessive
tyramine, alcohol. Reduce
dose with cimetidine.
TCAs amitriptyline b Anticholinergic (dry Use with MAOIs may lead $

Initial:
generics 25–50 mg/day mouth, blurred to potentially fatal
Usual: vision, constipation, reaction initially
75–200 mg/day urinary hesitancy, presenting with tremor,
d tachycardia, agitation, hypomania,
High:
delirium), hyperthermia and/or
250–300 mg/day
antihistaminergic hypertension;
(sedation, weight barbiturates,
gain), orthostatic carbamazepine and
hypotension, rifampin may ↓ effect;
lowered seizure cimetidine and
threshold; sexual antipsychotics may ↑ effect
dysfunction. and toxicity; possible
interaction with
antiarrhythmics (may lead
thiazides.
TCAs clomipramine b Anticholinergic (dry Use with MAOIs may lead $$

Initial:
Anafranil, 25–50 mg/day mouth, blurred to potentially fatal
generics Usual: vision, constipation, reaction initially
tachycardia, agitation, hypomania,
High:d
250–300 mg/day
interaction with
thiazides.
TCAs desipramine b Anticholinergic (dry Use with MAOIs may lead $$-
Initial:
generics 25–50 mg/day mouth, blurred to potentially fatal $$$
High:
250–300 mg/day
interaction with
Page 991
Therapeutic Choice
a
Cost
thiazides.
TCAs doxepin b Anticholinergic (dry Use with MAOIs may lead $-$$
Initial:
Sinequan, Apo- 25–50 mg/day mouth, blurred to potentially fatal
Doxepin, other Usual: vision, constipation, reaction initially
generics 75–200 mg/day urinary hesitancy, presenting with tremor,
High:
250–300 mg/day
interaction with
thiazides.
TCAs imipramine Initial:b Anticholinergic (dry Use with MAOIs may lead $-$$
Tofranil, 25–50 mg/day mouth, blurred to potentially fatal
High:d
250–300 mg/day
interaction with
thiazides.
TCAs nortriptyline b Anticholinergic (dry Use with MAOIs may lead $$-
Initial:
Aventyl, 25–50 mg/day mouth, blurred to potentially fatal $$$
High:
200 mg/day
interaction with
Page 992
Therapeutic Choice
Costa
thiazides.
TCAs trimipramine b Anticholinergic (dry Use with MAOIs may lead $$-
Initial:
generics 25–50 mg/day mouth, blurred to potentially fatal $$$
High:
250–300 mg/day
interaction with
to ↑ effect of either drug); may
↓ antihypertensive effect
thiazides.
Tetracyclic maprotiline Initial:b Anticholinergic (dry Use with MAOIs may lead $$$-
Antidepressants generics 75 mg/day mouth, blurred to potentially fatal $$$$
High:d
200 mg/day
interaction with
thiazides.
Antipsychotics, quetiapine Initial: 50 mg daily Sedation, dizziness, Additive sedation with $$$$
2nd generation extended- for 2 days, then 150 weight gain, CNS depressants; may
release mg daily; if orthostatic potentiate
Seroquel SR necessary can hypotension, hepatic antihypertensive drug
increase to 300 mg transaminase effects; inhibitors of
on or after day 4 elevation, headache, CYP3A4 (e.g.,
Usual: 150 mg/day anticholinergic clarithromycin,
effects, ↑ risk of erythromycin, grapefruit
High: 300 mg/day diabetes and juice, ketoconazole,
dyslipidemia, prednisone) may ↑
possible ↑ risk of quetiapine levels; inducers of
cataracts; may ↓ thyroid CYP3A4 (e.g.,
hormone levels. carbamazepine, phenytoin,
rifampin) may ↓
quetiapine levels.
Irreversible phenelzine b Edema, postural Concurrent $$

Initial:
MAOIs Nardil 15–30 mg/day hypotension, sympathomimetics may ↑
Usual: BP; use with meperidine may
cause agitation,
Page 993
Therapeutic Choice
Costa
30–75 mg/day insomnia, sexual hyperpyrexia, circulatory
High:d dysfunction. collapse and death;
90–120 mg/day SSRIs, TCAs, levodopa
may ↑ effects and side
effects; tyramine-containing
food may cause
hypertensive crisis (see
Therapeutic Tips).
Irreversible tranylcypromine b Edema, postural Concurrent $$-

Initial:
MAOIs Parnate 10–20 mg/day hypotension, sympathomimetics may ↑ $$$
Usual: insomnia, sexual BP; use with meperidine may
20–60 mg/day dysfunction. cause agitation,
hyperpyrexia, circulatory
High:d
collapse and death;
60–80 mg/day
SSRIs, TCAs, levodopa
may ↑ effects and side
effects; tyramine-containing
food may cause
hypertensive crisis (see
Therapeutic Tips).
a.
Cost of 30-day supply based on the doses of the “usual” dose range; includes drug cost only.
b.
Lower starting dose indicated where previous side effect experience or polypharmacy; often applies to elderly patients.
c.
For SSRIs, upper starting dose may be usual dose, e.g., fluoxetine 20 mg or sertraline 50 mg; otherwise, increments every 5–7
days.
d.
Higher doses often exceed upper doses in manufacturers' product monographs and usually result in more disabling side
effects. These doses should be used with caution.
Legend: $ < $20 $-$$ < $20–40 $$ $20–40 $$-$$$ $20–60 $$$ $40–60 $$$-$$$$ $40–100 $$$$
$60–100 $$$$-$$$$$ $60– >100 $$$$$ > $100
Abbreviations: SSRIs=selective serotonin reuptake inhibitors; SNRIs=serotonin-norepinephrine reuptake
inhibitors; TCAs=tricyclic antidepressants; RIMA=reversible inhibitor of MAO-A; MAOIs=monoamine oxidase inhibitors
Suggested Readings
Canadian Psychiatric Association; Canadian Network for Mood and Anxiety Treatments (CANMAT). Clinical guidelines
for the treatment of depressive disorders. Can J Psychiatry 2001;46(Suppl 1):5S-90S.
Hollon SD, Jarrett RB, Nierenberg AA et al. Psychotherapy and medication in the treatment of adult and geriatric
depression: which monotherapy or combined treatment? J Clin Psychiatry 2005;66(4):455-68.
Kennedy SH. Lam RW, Nutt DJ et al. Treating depression effectively: applying clinical guidelines. 2nd ed. London
(GB): Informa Healthcare; 2007.
Lam RW, Wan DD, Cohen NL et al. Combining antidepressants for treatment-resistant depression: a review. J Clin
Psychiatry 2002;63(8):685-93.
Yatham LN, Kennedy SH, O’Donovan C et al. Canadian Network for Mood and Anxiety Treatments (CANMAT)
2005;7(Suppl 3):5-69.
References
Page 994
Therapeutic Choice
1. American Psychiatric Association. Task Force on DSM-IV. Diagnostic and statistical manual of mental disorders:
DSM-IV-TR. Washington (DC): American Psychiatric Association; 2000.
2. Parikh SV, Lam RW; CANMAT Depression Work Group. Clinical guidelines for the treatment of depressive
disorders, I. Definitions, prevalence, and health burden. Can J Psychiatry 2001;46 (Suppl 1):13S-20S.
3. Kroenke K, Spitzer RL, Williams JB. The PHQ-9: validity of a brief depression severity measure. J Gen Intern
Med 2001;16(9):606-13.
4. Arroll B, Khin N, Kerse N. Screening for depression in primary care with two verbally asked questions: cross
sectional study. BMJ 2003;327(7424):1144-6.
5. McIntyre RS, Konarski JZ, Mancini DA et al. Measuring the severity of depression and remission in primary
care: validation of the HAMD-7 scale. CMAJ 2005;173(11):1327-34.
6. Hirschfeld RM. The mood disorder questionnaire: a simple, patient-rated screening instrument for bipolar
disorder. Prim Care Companion J Clin Psychiatry 2002;4(1):9-11.
7. Cox JL, Holden JM, Sagovsky R. Detection of postnatal depression. Development of the 10-item Edinburgh
Postnatal Depression Scale. Br J Psychiatry 1987;150:782-6.
8. Wells KB, Sherbourne C, Schoenbaum M et al. Impact of disseminating quality improvement programs for
depression in managed primary care: a randomized controlled trial. JAMA 2000;283(2):212-20.
9. Von Korff M, Goldberg D. Improving outcomes in depression. BMJ 2001;323(7319):948-9.
10. Rost K, Nutting P, Smith JL et al. Managing depression as a chronic disease: a randomised trial of ongoing
treatment in primary care. BMJ 2002;325(7370):934-7.
11. Katon W, Von Korff M, Lin E et al. Collaborative management to achieve depression treatment guidelines. J
Clin Psychiatry 1997;58(Suppl 1):20-3.
12. Simon GE, Von Korff M, Ludman EJ et al. Cost-effectiveness of a program to prevent depression relapse in
primary care. Med Care 2002;40(10):941-50.
13. Schoenbaum M, Unutzer J, McCaffrey D et al. The effects of primary care depression treatment on patients'
clinical status and employment. Health Serv Res 2002;37(5):1145-58.
14. Lave JR, Frank RG, Schulberg HC et al. Cost-effectiveness of treatments for major depression in primary care
practice. Arch Gen Psychiatry 1998;55(7):645-51.
15. Kuyken W, Byford S, Taylor RS et al. Mindfulness-based cognitive therapy to prevent relapse in recurrent
depression. J Consult Clin Psychol 2008;76(6):966-78.
16. Powers MB, Zum Vorde Sive Vording MB, Emmelkamp PM. Acceptance and commitment therapy: a meta-
analytic review. Psychother Psychosom 2009;78(2):73-80.
17. Spek V, Cuijpers P, Nyklicek I et al. Internet-based cognitive behaviour therapy for symptoms of depression
and anxiety: a meta-analysis. Psychol Med 2007;37(3):319-28.
18. Parikh SV, Segal ZV, Grigoriadis S et al. Canadian Network for Mood and Anxiety Treatments (CANMAT)
clinical guidelines for the management of major depressive disorder in adults. II. Psychotherapy alone or in
combination with antidepressant medication. J Affect Disord 2009;117(Suppl 1):S15-25.
19. Lin EH, Von Korff M, Katon W et al. The role of the primary care physician in patients' adherence to
antidepressant therapy. Med Care 1995;33(1):67-74.
20. Cipriani A, Furukawa TA, Salanti G et al. Comparative efficacy and acceptability of 12 new-generation
antidepressants: a multiple-treatments meta-analysis. Lancet 2009;373(9665):746-58.
21. Lam RW, Kennedy SH, Grigoriadis S et al. Canadian Network for Mood and Anxiety Treatments (CANMAT)
clinical guidelines for the management of major depressive disorder in adults. III . Pharmacotherapy. J Affect
Disord 2009;117(Suppl 1):S26-43.
22. Loke YK, Trivedi AN, Singh S. Meta-analysis: gastrointestinal bleeding due to interaction between selective
serotonin uptake inhibitors and non-steroidal anti-inflammatory drugs.Aliment Pharmacol Ther 2008;27(1):31-
40.
23. Wade A, Michael Lemming O, Bang Hedegaard K. Escitalopram 10 mg/day is effective and well tolerated in a
placebo-controlled study in depression in primary care. Int Clin Psychopharmacol 2002;17(3):95-102.
24. Bielski RJ, Ventura D, Chang CC. A double-blind comparison of escitalopram and venlafaxine extended release
in the treatment of major depressive disorder. J Clin Psychiatry 2004;65(9):1190-6.
25. Baldwin DS, Cooper JA, Huusom AK et al. A double-blind, randomized, parallel-group, flexible-dose study to
evaluate the tolerability, efficacy and effects of treatment discontinuation with escitalopram and paroxetine in
patients with major depressive disorder. Int Clin Psychopharmacol 2006;21(3):159-69.
26. Stahl SM. Basic psychopharmacology of antidepressants, part 1: Antidepressants have seven distinct
mechanisms of action. J Clin Psychiatry 1998;59(Suppl 4):5-14.
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27. Jorenby D. Clinical efficacy of bupropion in the management of smoking cessation. Drugs 2002;62(Suppl
2):25-35.
28. Clayton AH, Pradko JF, Croft HA et al. Prevalence of sexual dysfunction among newer antidepressants. J Clin
Psychiatry 2002;63(4):357-66.
29. Kent JM. SNaRIs, NaSSAs, and NaRIs: new agents for the treatment of depression. Lancet 2000;355
(9207):911-8.
30. Thase ME, Nierenberg AA, Keller MB et al. Efficacy of mirtazapine for prevention of depressive relapse: a
placebo-controlled double-blind trial of recently remitted high-risk patients. J Clin Psychiatry 2001;62(10):782
-8.
31. Smith D, Dempster C, Glanville J. Efficacy and tolerability of venlafaxine compared with selective serotonin
reuptake inhibitors and other antidepressants: a meta-analysis. Br J Psychiatry 2002;180:396-404.
32. Nemeroff CB, Entsuah R, Benattia I et al. Comprehensive analysis of remission (COMPARE) with venlafaxine
versus SSRIs. Biol Psychiatry 2008;63(4):424-34.
33. Perahia DG, Pritchett YL, Kajdasz DK et al. A randomized, double-blind comparison of duloxetine and
venlafaxine in the treatment of patients with major depressive disorder. J Psychiatr Res 2008;42(1):22-34.
34. Sopko MA, Ehret MJ, Grgas M. Desvenlafaxine: another “me too” drug? Ann Pharmacother 2008;42(10):1439-
46.
35. Lourenco MT, Kennedy SH. Desvenlafaxine in the treatment of major depressive disorder. Neuropsychiatr Dis
Treat 2009;5:127-36
36. Cutler AJ, Montgomery SA, Feifel D et al. Extended release quetiapine fumarate monotherapy in major
depressive disorder: a placebo- and duloxetine-controlled study. J Clin Psychiatry 2009;70(4):526-39.
37. Segal ZV, Whitney DK, Lam RW et al. Clinical guidelines for the treatment of depressive disorders. III.
Psychotherapy. Can J Psychiatry 2001;46(Suppl 1):29S-37S.
38. Fava M, Rush AJ, Trivedi MH et al Background and rationale for the sequenced treatment alternatives to relieve
depression (STAR*D) study. Psychiatr Clin North Am 2003;26(2):457-94.
39. Kennedy SH, Lam RW. Enhancing outcomes in the management of treatment resistant depression: a focus on
atypical antipsychotics. Bipolar Disord 2003;5(Suppl 2):36-47.
40. Kennedy SH, McCann SM, Masellis M et al. Combining bupropion SR with venlafaxine, paroxetine, or
fluoxetine: a preliminary report on pharmacokinetic, therapeutic, and sexual dysfunction effects. J Clin
Psychiatry 2002;63(3):181-6.
41. Zisook S, Rush AJ, Haight BR et al. Use of bupropion in combination with serotonin reuptake inhibitors. Biol
Psychiatry 2006;59(3):203-10.
42. Ravindran AV, Kennedy SH, O’Donovan MC et al. Osmotic-release oral system methylphenidate augmentation
of antidepressant monotherapy in major depressive disorder: results of a double-blind, randomized, placebo-
controlled trial. J Clin Psychiatry 2008;69(1):87-94.
43. Hollon SD, Jarrett RB, Nierenberg AA et al. Psychotherapy and medication in the treatment of adult and
geriatric depression: which monotherapy or combined treatment? J Clin Psychiatry 2005;66(4):455-68.
44. Sackeim HA, Haskett RF, Mulsant BH et al. Continuation pharmacotherapy in the prevention of relapse
following electroconvulsive therapy: a randomized controlled trial. JAMA 2001;285(10):1299-307.
45. UK ECT Review Group. Efficacy and safety of electroconvulsive therapy in depressive disorders: a systematic
review and meta-analysis. Lancet 2003;361(9360):799-808.
46. Kennedy SH, Giacobbe P. Treatment resistant depression–advances in somatic therapies. Ann Clin Psychiatry
2007;19(4):279-87.
47. Kusumakar V. Antidepressants and antipsychotics in the long-term treatment of bipolar disorder. J Clin
Psychiatry 2002;63(Suppl 10):23-8.
48. Bonari L, Pinto N, Ahn E et al. Perinatal risks of untreated depression during pregnancy. Can J Psychiatry
2004;49(11):726-35.
49. Lam RW, Kennedy SH, Grigoriadis S et al. Canadian Network for Mood and Anxiety Treatments (CANMAT)
clinical guidelines for the management of major depressive disorder in adults. III. Pharmacotherapy. J Affect
Disord 2009;117(Suppl 1):S26-43.
50. O'Hara MW, Swain AM. Rates and risk of postpartum depression–a meta-analysis. Int Rev Psychiatry
1996;8:37-54.
51. Sword W, Watt S, Gafni A et al. The Ontario mother and infant survey postpartum health and social service
utilization: a five-site Ontario study. Ottawa (ON): Canadian Health Services Research Foundation; 2001.
52. Weissman AM, Levy BT, Hartz AJ et al. Pooled analysis of antidepressant levels in lactating mothers, breast
milk, and nursing infants. Am J Psychiatry 2004;161(6):1066-78.
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53. Greenberger D, Padesky CA. Mind over mood: change how you feel by changing the way you think. New York
(NY): Guilford Press; 1996.
54. Burns DD. Feeling good: the new mood therapy. New York (NY): HarperCollins; 1999.
Page 997
e-Therapeutics+ : Therapeutics : Psychiatric Disorders: Drug Withdrawal Syndromes Page 1 of 8
Therapeutic Choice
Print Close
Psychiatric Disorders: Drug Withdrawal Syndromes

Date Revised: April 2009
James R. Kennedy, MD, FRCPC
Treatment of drug withdrawal syndromes requires attention to both the biological (medical) model and the
behavioural (psychosocial) model. Alcohol and benzodiazepine withdrawal can result in medically important
sequelae such as seizures and autonomic instability. Opioid withdrawal results in markedly unpleasant symptoms
without important medical sequelae. Stimulant withdrawal is almost exclusively behavioural with the most important
risks being suicidality and, less commonly, hallucinosis with amphetamines.
1
Withdrawal syndrome diagnosis requires:
The development of a substance-specific syndrome due to cessation or reduction of prolonged substance use
Clinically significant distress or impairment of functioning
The absence of a medical or other psychiatric disorder that can cause the syndrome
1
Table 1: Diagnostic Criteria for Substance-specific Withdrawal Syndromes
Alcohol Stimulants (Cocaine and Amphetamines)
Autonomic hyperactivity Fatigue

(e.g., sweating, pulse > 100 bpm) Vivid, unpleasant dreams
Increased hand tremor Insomnia or hypersomnia
Insomnia Increased appetite
Nausea/vomiting Psychomotor retardation or agitation
Transient visual, tactile or auditory Anxiety
hallucinations Depression
Psychomotor agitation Craving for stimulant
Anxiety Psychotic symptoms (amphetamines)
Grand mal seizures
Depression
Opioids Benzodiazepines
Dysphoric mood Autonomic hyperactivity

Nausea/vomiting (e.g., sweating, pulse > 100 bpm)
Muscle aches Increased hand tremor
Lacrimation, rhinorrhea Insomnia
Pupillary dilation, piloerection, sweating Nausea/vomiting
Diarrhea Transient visual, tactile or auditory hallucinations
Yawning Psychomotor agitation
Fever Anxiety
Insomnia Grand mal seizures (only after abrupt cessation of
high doses)
Goals of Therapy
Relieve symptoms
Anticipate, prevent and treat complications
Assess for and treat comorbidities (medical and psychiatric)
Facilitate definitive psychosocial/behavioural treatment
Prevent relapse
Investigations
Detailed history and physical examination to evaluate severity of abuse of the substance (amount, frequency,
duration) and comorbid medical and psychiatric (axis II, depression or psychosis) conditions
Page 998
Therapeutic Choice
Specific assessment tools such as the Clinical Institute Withdrawal Assessment for Alcohol (CIWA-Ar)2 or CIWA-
Benzo3
Laboratory tests and/or imaging to assess comorbidities/complications revealed in history and physical
(complete blood count, renal/liver function, electrolytes, magnesium, phosphorus, chest x-ray, CT of head)
Drug screening: blood alcohol or urine screen for benzodiazepines may be helpful in the trauma or emergency
patient where history is inadequate
Therapeutic Choices (Figure 1 - Management of Drug Withdrawal Syndromes)
Nonjudgmental approach to explain process, reassure and support.

Psychosocial treatment program (cognitive behavioural therapy, motivational enhancement therapy,
interpersonal therapy, 12-step, group and family therapies).4
General principles:
Monitor signs and symptoms.

Treat specific symptoms of withdrawal and associated complications and comorbidities (medical and
psychiatric).
Substitute abused drug with one of same or similar class (a cross-tolerant agonist that is less likely to be
abused, usually with longer half-life).
Substitute abused drug with one that blocks its reinforcing effects (antagonist).
Alcohol Withdrawal Syndrome
Assessment (Table 1)
The severity of the alcohol withdrawal syndrome and its complications correlate directly but inconsistently with the
intensity and duration of alcohol use. These complications can include undernutrition (e.g., thiamine deficiency),
low potassium, magnesium and phosphorus, liver disease and bleeding diathesis (increased INR, impaired platelet
function/thrombocytopenia), CNS disease (e.g., seizures, Wernicke encephalopathy, trauma), autonomic dysfunction
(hypertension, dehydration, pyrexia), infections (pneumonia, aspiration, cellulitis), and psychosis (hallucinations,
delusions). Mild withdrawal symptoms include tremor, irritability and insomnia, usually lasting 48–72 hours. Severe
symptoms, with onset around 48 hours and lasting up to about five days, include autonomic instability, seizures,
2
hallucinations, delusions and pyrexia. The CIWA-Ar is an effective assessment tool.
Management (Table 3)
Approximately two-thirds of patients with mild-to-moderate withdrawal symptoms can be treated with support and
5
monitoring, although comparison with pharmacotherapy is not described in the literature. Blunting symptoms with
low-dose, short-duration benzodiazepine therapy may be helpful and is of low risk.
Severe alcohol withdrawal syndrome always requires pharmacologic treatment, and guidelines usually recommend
the same for moderate cases. Larger than usually recommended doses of benzodiazepines (> 50 mg diazepam iv
in the first hour or > 200 mg in 3 hours) and/or addition of a different GABA-active drug like phenobarbital (130–
1430 mg, mean dose 390 mg) may be required for resistant alcohol withdrawal ( < 5% of cases), and these patients
require monitoring in a critical care area (emergency room, intensive care unit or intermediate care unit).6 , 7
Although many emergency room physicians add an antipsychotic (usually haloperidol 5–10 mg) in resistant alcohol
withdrawal, there is no good evidence to support their use, and there is risk of dystonia, akathisia and hypotension.
Patients admitted to hospital for surgical illness may have occult alcohol dependence, and appropriate prophylaxis
and management of alcohol withdrawal syndromes with benzodiazepines can prevent complications.8
Rehabilitation
Page 999
Therapeutic Choice
Cognitive therapy, group therapy and self-help groups like Alcoholics Anonymous form the mainstay of long-term
rehabilitation, and there is conflicting evidence to support the use of pharmacotherapy (e.g., naltrexone) in this
setting.9 A Cochrane review reported a modest effect on reducing the quantity of alcohol intake.10
Stimulant (Cocaine and Amphetamine) Withdrawal Syndrome
Symptoms of cocaine withdrawal include mostly psychosocial, subtle and medically unimportant symptoms and
signs, except for the risk of acute severe depression and suicidality in a small percentage of patients. The toxic state
is manifested by agitation, tachycardia and anorexia, and conversely the withdrawal state is characterized by
somnolence and increased appetite. Depression, anxiety, anhedonia and sleep disturbance may also occur, resolving
over several weeks. Suicidality is uncommon and requires direct assessment.
Amphetamine withdrawal shares most of the characteristics of cocaine withdrawal, but may include psychotic
features or a more severe depressed mood and may last longer. Drug craving replaces the withdrawal syndrome and
may last several months. After withdrawal from methamphetamine (“crystal meth”), a persistent
psychosis may occur and become permanent (uncommon) or last several weeks, usually responding
11
well to low-dose antipsychotics (for dosing information see Psychiatric Disorders: Psychoses).
Useful Info? Medical complications of stimulant use should be surveyed, including cardiomyopathy, local or
systemic abscess, endocarditis, HIV and hepatitis B and C.
Management
Evaluation of a variety of pharmacotherapy approaches both for treatment of the withdrawal syndrome and for
relapse prevention yielded inconsistent results, reflecting ineffective treatment. Dopamine agonists, such as
12 13 14
amantadine, bromocriptine and pergolide have demonstrated no significant benefit. Desipramine and
other antidepressants have little or no effectiveness for withdrawal or relapse prevention, but may have a role in
comorbid depression or anxiety. Agonist replacement therapy with sustained-release amphetamine or
methylphenidate has shown benefit in relapse prevention, but regulatory concerns may limit their use, unless
15
underlying attention deficit disorder co-exists. Making this diagnosis requires psychiatric expertise.
Rehabilitation
Although buprenorphine and methadone may offer benefit to patients with mixed opioid and stimulant
dependence, no drug therapy is consistently effective for treating pure stimulant dependence. Intensive outpatient,
abstinence-oriented psychosocial treatment, especially cognitive behavioural therapy, is the most effective treatment,
in addition to addressing the psychiatric comorbidities.
Opioid Withdrawal Syndrome
Symptoms of opioid withdrawal are not medically serious, with muscle aches, restlessness and insomnia
predominating. The acute withdrawal syndrome usually lasts about one week, but is much longer in withdrawal from
methadone, with drug craving often persisting for several months.
Management (Table 4)
Abstinence-based treatment may be desirable, but the most effective treatment by far continues to be replacement
therapy with a long-acting agonist like methadone or the partial agonist buprenorphine, which is available
through Health Canada's Special Access Programme. Methadone and buprenorphine can be initiated with the first
withdrawal symptoms. Higher maintenance doses (methadone 60–100 mg or buprenorphine 8–32 mg/day) are more
effective than lower doses. Because of methadone’s long half-life of about 30 hours, the risk of narcosis in patients
with an unknown degree of opioid tolerance is high in the first few days, and requires expertise and vigilance.
Buprenorphine is a partial agonist with a long half-life (36 hours) and generally does not cause narcosis in
overdose.16
Page 1000
Therapeutic Choice
Clonidine, an alpha-2 agonist that decreases the neuronal output of norepinephrine, can be used to blunt the
symptoms of withdrawal, but muscle aches and craving usually persist. Naltrexone, a long-acting opioid
antagonist, used to block opioid agonist effects like euphoria, is used to support long-term abstinence. However,
both of these agents are ineffective in decreasing long-term opioid use, in spite of psychosocial supportive
17
treatment.
Rehabilitation
The best long-term results are obtained with replacement therapy (methadone or buprenorphine) combined with
cognitive or group therapy, counselling and 12-step support. If methadone discontinuation is considered, the best
outcomes occur with slow tapering over many weeks.4
Benzodiazepine Withdrawal Syndrome
Assessing benzodiazepine withdrawal syndrome is associated with three challenges:
distinguishing recurrence of anxiety, panic or insomnia from the onset of withdrawal symptoms
assessing risk of seizures and autonomic hyperactivity
selecting the best treatment for the underlying psychiatric condition.
The withdrawal syndrome begins within 1–2 days of abrupt discontinuation and can be severe, with hypertension,
tachycardia and hyperreflexia progressing to seizures if there was long-term, high-dose use. In chronic anxiety and
panic disorders, chronic dosing may be very high (even > 100 mg diazepam per day), and may be associated with
alcohol overuse (i.e., sedative self-treatment). A number of factors correlate with severity of the benzodiazepine
withdrawal syndrome: high daily dose, use of agents with short half-life, long duration of use, diagnosis of panic
disorder, presence of severe Axis II disorders and concomitant alcohol or substance abuse.
Management
Replacement with a long half-life benzodiazepine and prolonged tapering of daily dose, combined with supportive
and eventually cognitive therapy for the underlying condition, form the only effective treatment for high-dose,
prolonged benzodiazepine dependence. Most Canadian experts use diazepam or clonazepam for replacement therapy
(Table 2). Initial tapering of the daily dose to 50% of the starting dose can usually occur over a 2–4 week period;
18
the last 50% frequently takes many weeks, sometimes with periods of weeks with no dosage change.
Since patients with personality disorders tolerate distress poorly, they often drop out early, and an intensive
supportive and cognitive program should coincide with benzodiazepine tapering and may include periods of
maintenance. Patients can be managed in an intensive outpatient program. Few patients (those with associated
cardiovascular disease, severe alcoholism or previous seizures) require a short hospitalization.
Table 2: Dose Equivalents of Benzodiazepines
Benzodiazepine Elimination Half-lifea Approximate Oral Dosage Equivalent19 (mg)
Clorazepate Long 10
Chlordiazepoxide Long 25
Diazepam Long 5
Flurazepam Long 15
Alprazolam Intermediate 0.5
Bromazepam Intermediate 3
Clonazepam Intermediate 0.25
Lorazepam Intermediate 1
Nitrazepam Intermediate 2.5
Page 1001
Therapeutic Choice
Benzodiazepine Elimination Half-lifea Approximate Oral Dosage Equivalent19 (mg)
Oxazepam Intermediate 15
Temazepam Intermediate 10
Triazolam Short 0.25
a.
Short = ≤ 5 h; Intermediate = 5–60 h; Long = ≥ 100 h.
Rehabilitation
The best treatment for the underlying condition (e.g., insomnia, generalized anxiety, panic disorder, mood disorder)
4 , 20
is cognitive behavioural therapy. Pharmacotherapy should be directed to the specific underlying condition and
should have a low risk for dependence; options include low-dose, low-potency antipsychotics. Insomnia can be
treated with these agents or with trazodone (25-100 mg at bedtime). Buspirone can be effective treatment for
generalized anxiety and has low abuse potential and reasonable but not dramatic efficacy.
Figure 1-Management of Drug Withdrawal Syndromes
Table 3: Pharmacologic Management of Alcohol Withdrawal
Page 1002
Therapeutic Choice
a
Cost
Class Drug Indication/Symptom Dose Comments
Vitamins thiamine (vitamin Treatment/ prevention of 50 mg daily iv or Best practice is to $$

B1) Wernicke's encephalopathy po × 3 days administer thiamine
Betaxin, to all patients with
generics alcohol withdrawal.
Benzodiazepines diazepam Autonomic hyperactivity, 5–10 mg po or iv Goal is mild $$

Diazemuls, agitation/tremor, Q10–20 min; see sedation.
Valium, generics hallucinations, seizures Comments. Mild withdrawal:
give Q1H.
Moderate
withdrawal: give
Q20–60 min.
Severe withdrawal:
give Q10–20 min.
Onset of action 1
min for diazepam
iv.
Benzodiazepines lorazepam Autonomic hyperactivity, 1–2 mg po or iv Goal is mild $$

Ativan, generics agitation/tremor, Q20–60 min sedation.
hallucinations, seizures Onset of action 5–
15 min for
lorazepam iv.
Benzodiazepines chlordiazepoxide Autonomic hyperactivity, 10–50 mg po Q10 Goal is mild $

generics agitation/tremor, –20 min sedation.
hallucinations, seizures Onset of action
1–2 h for
chlordiazepoxide
po.
Barbiturates phenobarbital 6 , Severe withdrawal 60 mg po or iv High dose may be $

7 refractory to Q20–30 min required (up to total
generics benzodiazepine therapy (> of 1000 mg).
50 mg diazepam given in 1 Should be used in a
h or > 200 mg in 3 h) critical care area.
IV available through
Special Access
Programme, Health
Canada.
Antipsychotics haloperidol Psychosis refractory to 0.5–5 mg im or May lower blood po:$

generics benzodiazepines po Q2H pressure or cause im:$$
Max: 20 mg in 24 acute dystonia.
h Continue
appropriate
benzodiazepine
dosing.
Antiepileptic phenytoin Seizures only if previous Loading dose: Measure trough po:$
Drugs Dilantin seizure history or cause of 300–400 mg po level in 3–5 days. iv:
seizure unrelated to alcohol Q2H up to 1 g in $$$
Capsules,
total, or 1 g iv. If
Page 1003
Therapeutic Choice
Costa
Class Drug Indication/Symptom Dose Comments
Dilantin Infatabs, phenytoin already
generics on board, half or
no loading dose
required.
Maintenance:
100 mg po or iv
Q8H or 300 mg
once daily po or
iv.
a.
Cost of a single administration; includes drug cost only.
Legend: $ < $1 $$ $1–5 $$$ > $5
Table 4: Pharmacologic Management of Opioid Withdrawal
a
Treatment Cost
Opioid methadone 16 Acute withdrawal symptoms in new High relapse rate without $$$-
Agonists generics patients: 10–20 mg po Q2–4H until maintenance therapy. Long half- $$$$
stable (usually 20–60 mg). If not to life (24–36 h). Higher
be continued as maintenance, taper maintenance doses (60–100 mg)
by 5 mg/day over 1–2 wk associated with better outcomes.
Maintenance: 40–100 mg/day po
Partial Opioid buprenorphine Long-term maintenance: 8–32 mg sl Start with first signs of c
Agonists Subutex daily withdrawal. Available through
Special Access Programme,
Health Canada.
Opioid naltrexone 50 mg daily or 100 mg 3 times Administer a naloxone 0.8 mg im $$$$

Antagonists ReVia weekly test dose to detect occult opioid
dependence. If withdrawal
symptoms occur, do not start
naltrexone.
Clinical trials fail to show
efficacy.
Alpha2- clonidine 0.1–0.5 mg/day Q8H po for 7 days, Blunts some withdrawal $-$$
adrenergic Catapres, then taper over 3–5 days symptoms. Use only for acute
Agonists Dixarit, generics detoxification and when patient
prefers over methadone.
Maintain fluid intake and monitor
for hypotensive effects.
a.
b.
Duration of study, not necessarily the recommended clinical treatment regimen.
c.
Available through Special Access Programme, Health Canada.
Legend: $ < $5 $-$$ < $5–15 $$ $5–15 $$$ $15–30 $$$-$$$$ $15–45 $$$$ $30–45
Suggested Readings
Page 1004
Therapeutic Choice
Practice guideline for the treatment of patients with substance use disorders. 2nd ed. American Psychiatric
Association. Am J Psychiatry 2007;164(4 Suppl):1-124.
Spies CD, Rommelspacher H. Alcohol withdrawal in the surgical patients: prevention and treatment. Anesth Analg
1999;88(4):946-54.
Voshaar RC, Couvee JE, van Balkom AJ et al. Strategies for discontinuing long-term benzodiazepine use: meta-
analysis. Br J Psychiatry 2006;189:213-20.
References
1. American Psychiatric Association. Task Force on DSM-IV. Diagnostic and statistical manual of mental disorders:
DSM-IV-TR. Washington (DC): American Psychiatric Association; 2000.
2. Sullivan JT, Sykora K, Schneiderman J et al. Assessment of alcohol withdrawal: the revised clinical institute
withdrawal assessment for alcohol scale (CIWA-Ar). Br J Addict 1989;84(11):1353-7.
3. Busto UE, Sykora K, Sellers EM. A clinical scale to assess benzodiazepine withdrawal. J Clin Psychopharmacol
1989;9(6):412-6.
4. Practice guideline for the treatment of patients with substance use disorders. 2nd ed. American Psychiatric
Association. Am J Psychiatry 2007;164(4 Suppl):1-124.
5. Naranjo CA, Sellers EM, Chater K et al. Nonparmacologic intervention in acute alcohol withdrawal. Clin
Pharmacol Ther 1983;34(2):214-9.
6. Hack JB, Hoffman RS, Nelson LS. Resistant alcohol withdrawal: does an unexpectedly large sedative
requirement identify these patient early? J Med Toxicol 2006;2(2):55-60.
7. Gold JA, Rimal B, Nolan A et al. A strategy of escalating doses of benzodiazepines and phenobarbital
administration reduce the need for mechanical ventilation in delirium tremens. Crit Care Med 2007;35(3):724-
30.
8. Spies CD, Dubisz N, Funk W et al. Prophylaxis of alcohol withdrawal syndrome in alcohol dependent patients
admitted to the intensive care unit following tumour resection. Br J Anaesth 1995;75(6):734-9.
9. Krystal JH, Cramer JA, Krol WF et al. Naltrexone in the treatment of alcohol dependence. N Engl J Med
2001;345(24):1734-9.
10. Srisurapanont M, Jarusuraisin N. Opioid antagonists for alcohol dependence. Cochrane Database Syst Rev
2005;(1):CD001867.
11. Curran C, Byrappa N, McBride A. Stimulant psychosis: systematic review. Br J Psychiatry 2004;185:196-204.
12. Weddington WW, Brown BS, Haertzen CA et al. Changes in mood, craving, and sleep during short-term
abstinence reported by male cocaine addicts: a controlled, residential study. Arch Gen Psychiatry 1990;47
(9):861-8.
13. Moscovitz H, Brookoff D, Nelson L. A randomized trial of bromocriptine for cocaine users presenting to the
emergency department. J Gen Intern Med 1993;8(1):1-4.
14. Malcolm R, Kajdasz DK, Herron J et al.. A double-blind, placebo-controlled outpatient trial of pergolide for
cocaine dependence. Drug Alcohol Depend 2000;60:161-8.
15. Grabowski J, Shearer J, Merril J et al. Agonist-like, replacement pharmacotherapy for stimulant abuse and
dependence. Addict Behav 2004;29(7):1439-64.
16. Petry NM, Bickel WK, Badger GJ. A comparison of four buprenorphine dosing regimens in the treatment of
opioid dependence. Clin Pharmacol Ther 1999;66(3):306-14.
17. Kirchmayer U, Davoli M, Verster A. Naltrexone maintenance treatment for opioid dependence. Cochrane
18. Rickels K, DeMartinis N, Rynn M et al. Pharmacologic strategies for discontinuing benzodiazepine treatment. J
Clin Psychopharmacol 1999:19(6 Suppl 2):12S-16S.
19. Bezchlibnyk-Butler KZ, Jeffries JJ, editors. Clinical handbook of psychotropic drugs. 15th ed. Ashland (OH):
Hogrefe & Huber Publishers; 2005.
20. Spiegel DA. Psychological strategies for discontinuation in benzodiazepine treatment. J Clin
Psychopharmacol1999:19(6 Suppl 2):17S-22S.
Page 1005
e-Therapeutics+ : Therapeutics : Psychiatric Disorders: Eating Disorders Page 1 of 8
Therapeutic Choice
Print Close
Psychiatric Disorders: Eating Disorders

Date Revised: August 2009
C. Laird Birmingham, MD, MHSc, FRCPC
A disturbance in the perception of body image and weight is an essential feature of both anorexia nervosa and
bulimia nervosa.
Anorexia nervosa is characterized by a deliberate loss of weight (to ≤ 85% of expected weight), refusal to maintain
a normal body weight, fear of weight gain and amenorrhea. The two subtypes, restricting and binge-eating/purging,
indicate the presence or absence of regular binge-eating or purging.
Bulimia nervosa is characterized by repeated episodes of binge-eating followed by inappropriate compensatory

behaviours such as self-induced vomiting, misuse of laxatives, diuretics, emetics or other medications, fasting or
excessive exercise. The two subtypes of bulimia nervosa are purging and nonpurging (uses inappropriate
compensatory behaviours, e.g., fasting or excessive exercise but does not regularly engage in self-induced
vomiting, misuse of laxatives).
Goals of Therapy
Assess and treat coexistent nutritional deficiencies

Assess and treat the effects of malnutrition, e.g., osteoporosis, hypoglycemia, dehydration
Improve cognitive and emotional function
Identify and treat psychiatric comorbidity, e.g., anxiety, depression, family dysfunction, self-injurious
behaviour, suicidal ideation
Treat binge and purge behaviour
Develop healthy eating habits
For anorexia nervosa, achieve and maintain a healthy weight/body mass index (BMI)
Investigations
A thorough history with special attention to:

weight, eating habits, binge and purge behaviour, menstruation (in females), body image, use of vomiting,
laxatives (oral formulations or rectal suppositories), diuretics, ipecac, fasting and excessive exercising
developmental and psychological history
depression, anxiety, suicidal ideation, family dysfunction and sexual abuse
symptoms of malnutrition including chest wall pain, palpitations, loss of consciousness, hematemesis,
seizures, abdominal pain, muscle weakness or cramping, episodes of confusion
dietary history
Physical examination for parotid hypertrophy, jugular venous pressure, edema, abnormal dentition, Russell’s
sign (scarring over the knuckles caused by using the hand to induce vomiting); for anorexia nervosa, look also
for postural hypotension, tachycardia, lanugo hair, hypercarotenemia, height, weight, measurements of body
fat, proximal myopathy, neuromuscular hyperirritability (Chvostek’s and Trousseau’s signs)1
Laboratory tests:
sodium, potassium, chloride, bicarbonate, creatinine, magnesium, calcium, phosphorus, zinc, B12, ferritin;
for anorexia nervosa, add ECG, hemoglobin, WBC count, urinalysis, RBC, folate and blood glucose (fasting
and two hours after eating)
For anorexia nervosa, a psychiatric and nutritional assessment if symptoms continue and weight does not
2
normalize after weekly follow-up and counselling
Anorexia Nervosa
Therapeutic Choices
Therapeutic Tips
Page 1006
Therapeutic Choice
Therapeutic Choices (Figure 1 - Management of Anorexia Nervosa)
Develop and maintain a rapport and therapeutic alliance.

Consider the need for and role of family intervention and treatment (especially for children and adolescents).
Set step-wise nutritional goals.
Use nutritional supplements (e.g., Ensure, Boost) to achieve weight gain if not possible through food.
Supportive nursing care at mealtime may improve success;3 tube feeding may be necessary if oral feeding fails.
Exercise should be limited. However, a supervised graded exercise plan (such as non-exercise yoga) can reduce
anxiety while not interfering with the rate of weight gain.4
Warming, by means of a warm room or warming vest, may reduce anxiety, hasten recovery and improve the
5
chances of long-term recovery.
Monitor binge and purge behaviour and set goals for normalization, e.g., a gradual tapering of laxatives.
Prokinetic Agents
Domperidone and metoclopramide usually help to reduce the feeling of fullness caused by decreased intestinal
motility during the early stages of feeding.7 Of the prokinetic agents, only cisapride has been compared to placebo
in this patient group, but it was withdrawn from the market because of its association with an increased rate of
dysrhythmia and death.
Unless the antinauseant effect of metoclopramide is needed, domperidone is preferred because it has a lower
incidence of extrapyramidal side effects. Rarely, if the feeling of fullness is limiting treatment and domperidone or
metoclopramide is ineffective, the addition of erythromycin may help.8 , 9
The potential for these drugs to cause QT prolongation should be considered, especially in patients with other risk
factors such as hypokalemia or hypoglycemia.
Other Therapies
In patients with anorexia nervosa, zinc gluconate supplementation (100 mg daily for two months)
10
increases the rate of weight gain irrespective of the serum zinc measurement. Zinc causes nausea in
about 2% of patients when taken orally, but it can be taken with food to reduce this adverse effect.
Useful Info?
Olanzapine decreases anorexic rumination resulting in improved motivation and may thereby promote weight gain,
even in chronic anorexia nervosa.11 , 12 A randomized controlled trial supports these findings and demonstrates that
the rate of weight gain is not increased in patients with anorexia nervosa (beyond the weight gain olanzapine would
be expected to cause in a person without anorexia).13 This is important in anorexia nervosa sufferers because they
would not use the medication if weight gain were rapid. Doses of 2.5 to 5 mg/day have been effective, with a
maximum dose of 20 mg/day. Because of extrapyramidal side effects it should not be used long term unless the
benefits outweigh the risks of developing a movement disorder. Usually, the appropriate duration of therapy is until
it is no longer needed for weight gain (around 3 months) and to a maximum BMI of 17 kg/m2. Beyond that, a rapid
increase in appetite and weight gain may occur if olanzapine is continued. Diabetes due to reduced insulin
sensitivity is a commonly observed adverse effect of olanzapine, but not in this patient group to date.
Cyproheptadine 4 to 16 mg at bedtime may be useful, particularly in chronic anorexia nervosa. It may cause a
14 , 15
modest weight gain and can be used as a hypnotic.
Benzodiazepines (e.g., clonazepam) can be used to treat severe anxiety. Take care to avoid dependence. Begin
with clonazepam at 0.25 to 0.5 mg BID and cautiously titrate upward if necessary, no more often than every three
days. The atypical antipsychotic quetiapine is often used instead of a benzodiazepine to manage anxiety in this
16 , 17
setting, because it is more effective and not addictive.
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Therapeutic Choice
Selective serotonin reuptake inhibitor (SSRI) antidepressants should be used only for coexistent depression
or purge behaviour, and if cardiac status is stable (e.g., QTc less than 450 milliseconds; see Bulimia Nervosa,
Antidepressants.)18
Give thiamine in a dose of 100 mg/day for five days at the beginning of feeding to prevent the development of
Wernicke-Korsakoff syndrome (encephalopathy).
19
Ondansetron is not effective in controlling the nausea or vomiting associated with eating disorders.
Therapeutic Tips
Hypoglycemia can occur after eating because liver glycogen is depleted. Blood glucose should be measured two
20
hours after meals for the first day or two of feeding and if confusion occurs.
21
Chronic laxative abuse can be treated by slowly tapering laxatives over months to years.
Normalizing body fat is necessary for psychological treatment to be effective and for cure.
22
Women with anorexia nervosa can become pregnant when amenorrheic.
23
Treatment refusal is common. A careful reassessment of the treatment plan is necessary. Family therapy is
particularly important for the treatment of children and adolescents.
Suicidality, worsening depression and/or an inability to gain weight are indications for referral to an eating
disorders specialist. Outpatient, residential or inpatient eating disorder treatment may be required.24
Figure 1-Management of Anorexia Nervosa
Bulimia Nervosa
Therapeutic Choices
Therapeutic Tips
Page 1008
Therapeutic Choice
Therapeutic Choices (Figure 2 - Management of Bulimia Nervosa)
Cognitive behavioural therapy and interpersonal therapy are helpful in addressing cognitive and emotional
2
issues and reinforcing normal eating behaviour. Follow progress.
Assess patients for suicidal ideation and depression; treat if present.
25 , 26
Psychoeducational groups addressing nutritional and psychological issues can enhance individual therapy.
Antidepressants
Two-thirds of patients taking an antidepressant experience a ≥ 50% reduction in binge episodes. There is no
correlation between the presence of comorbid depression and antibulimic effects of the antidepressant, nor is there
any evidence that one antidepressant is more effective than another.27 However, because of toxicity and poor
compliance, do not prescribe tricyclic antidepressants, MAOIs, or bupropion (which has been associated with an
increased likelihood of seizures in patients with eating disorders). SSRIs, venlafaxine or trazodone can be used;
28 , 29 , 30
fluoxetine is supported by the most evidence. Trazodone can be particularly useful in patients with
insomnia associated with bulimia nervosa.
Maintain therapy for at least six months, preferably one year. If symptoms persist after a trial of counselling and an
antidepressant, treatment by a multidisciplinary team may be necessary.
Therapeutic Tips
If effective, continue antidepressants for 6 to 12 months. Individual response to medication varies, so a series
of antidepressants may have to be tried until an effective one is found.
Treatment with more than one antidepressant at the same time has no proven advantages and has the potential
to increase adverse effects and cost.
Often during psychological treatment (e.g., when a long-suppressed traumatic event such as sexual abuse is
uncovered and addressed) or with significant life stress, a temporary worsening of binge and purge behaviour
occurs. This does not indicate a worsening in the patient’s overall condition.
Treatment of psychiatric comorbidity is necessary for long-term cure.
Figure 2-Management of Bulimia Nervosa
Page 1009
Therapeutic Choice
Table 1: Drugs Used in Anorexia Nervosa
Costa
Prokinetic domperidone 10–20 mg 30 min before Diarrhea, abdominal Opiates and $

Agents generics meals discomfort, antimuscarinics may
May also be given at hyperprolactinemia, antagonize action of
bedtime to deal with drowsiness; can domperidone in the
residual food ingested in prolong QT interval. gut.
evening. Caution with other
drugs that prolong
the QT interval.
Prokinetic metoclopramide 5–20 mg 30 min before Diarrhea, abdominal Avoid alcohol and $
Agents meals discomfort, other CNS
generics hyperprolactinemia, depressants (additive
drowsiness, sedative effects).
restlessness; can Caution with other
prolong QT interval. drugs that prolong
the QT interval.
Prokinetic erythromycin 125 mg BID Diarrhea, abdominal Inhibitor of CYP1A2 $

Agents generics discomfort, and potent inhibitor
prolonged QT of CYP3A4; may ↑
interval, dysrythmias. effect and toxicity of
substrates of these
isoenzymes such as
isotretinoin,
mirtazapine,
morphine,
oxycodone,
theophylline,
trazodone, tricyclic
antidepressants,
venlafaxine.
Caution with other
drugs that prolong
the QT interval.
Supplements, zinc gluconate 100 mg daily with meals Nausea; can cause a Zinc may reduce the $
mineral generics for 2 mo copper deficiency if serum concentration
taken in excess for and efficacy of
months. tetracycline;
tetracycline doses
should be taken 2–
3 h before zinc.
Supplements, thiamine 100 mg daily × 5 days N/A N/A $

vitamin generics at start of re-feeding
Benzodiazepines clonazepam Initial: 0.25–0.5 mg BID Sedation, ataxia, Potentiates effects of $

Rivotril, May titrate up cautiously weakness, other CNS
generics at 3-day intervals if dependence. depressants,
needed including alcohol.
Usual maximum:
2–5 mg/day
Page 1010
Therapeutic Choice
Costa
Antipsychotics, olanzapine 2.5–20 mg/day Drowsiness, Fluvoxamine may ↑ $$$

second- Zyprexa, akathisia. olanzapine serum
generation Zyprexa Zydis, concentrations; other
generics SSRIs are less likely
to exhibit this
interaction.
Antipsychotics, quetiapine 12.5–50 mg before Drowsiness, ↑ hypotension with $-$$

second- Seroquel, meals and at bedtime extrapyramidal side antihypertensives;
generation generics Used to manage severe effects, QT additive sedation with
anxiety in this setting prolongation. CNS depressants,
including alcohol;
inhibitors of CYP3A4
such as
erythromycin,
clarithromycin,
fluoxetine or
ketoconazole can
increase the effects
and toxicity of
quetiapine.
a.
Legend: $ < $15 $-$$ < $15–30 $$ $15–30 $$$ > $30
Table 2: Drugs Used in Bulimia Nervosa
a
Cost
Selective fluoxetine 20–60 mg daily Anxiety, GI Avoid use with MAOIs, L- $$–
Serotonin Prozac, discomfort tryptophan (serotonin syndrome); $$$$
Reuptake generics (common), sexual inhibits cytochrome P450
Inhibitorsb dysfunction, ↑ risk enzymes, especially CYP2D6—
of GI bleeding. may ↑ effects and toxicity of many
drugs including atomoxetine,
methamphetamine, mirtazapine,
TCAs, tramadol; ↑ risk of GI
Serotonin- venlafaxine 75–150 mg daily Nausea, Inhibitors of CYP2D6 or CYP3A4 $$

norepinephrine drowsiness, (e.g., erythromycin,
Reuptake Effexor XR, nervousness, clarithromycin, fluphenazine,
Inhibitors generics dizziness, dry ketoconazole) can ↑ effects and
mouth, toxicity of venlafaxine; do not use
hypertension at with MAOIs.
doses > 300 mg.
Serotonin trazodone 100–500 mg daily Sedation Avoid use with MAOIs; inhibitors $–$$$
Agonists Desyrel, in single or (common), of CYP3A4 such as erythromycin,
generics divided doses anticholinergic clarithromycin or ketoconazole
adverse effects can ↑ effects and toxicity of
less common than trazodone.
with other TCAs.
Page 1011
Therapeutic Choice
a.
b.
For other SSRIs see Psychiatric Disorders: Depression.
Abbreviations: TCA=tricyclic antidepressant; XR=extended-release
Legend: $ < $25 $–$$$ < $25–75 $$ $25–50 $$–$$$$ $25–100 $$$ $50–75 $$$$ $75–100
Suggested Readings
American Dietetic Association. Position of the American Dietetic Association: nutrition intervention in the treatment
of anorexia nervosa, bulimia nervosa, and other eating disorders. J Am Diet Assoc 2006;106(12):2073-82.
American Psychiatric Association. Treatment of patients with eating disorders, third edition. Am J Psychiatry
2006;163(7 Suppl):4-54.
Bacaltchuk J, Hay P. Antidepressants versus placebo for people with bulimia nervosa. Cochrane Database Syst Rev
2003;(4):CD003391.
Beumont P, Hay P, Beumont D et al. Australian and New Zealand clinical practice guidelines for the treatment of
anorexia nervosa. Aust N Z J Psychiatry 2004;38(9):659-70.
National Collaborating Centre for Mental Health; National Institute of Clinical Excellence. Eating disorders: core
interventions in the treatment and management of anorexia nervosa, bulimia nervosa and related eating disorders.
London (UK): National Institute for Clinical Excellence; 2004. Available from www.nice.org.uk/CG009NICEguideline
Accessed May 14, 2007.
References
1. Tyler I, Birmingham CL. The interrater reliability of physical signs in patients with eating disorders. Int J Eat
Disord 2001;30(3):343-5.
2. American Dietetic Association. Position of the American Dietetic Association: nutrition intervention in the
treatment of anorexia nervosa, bulimia nervosa, and other eating disorders. J Am Diet Assoc 2006;106
(12):2073-82.
3. Leichner P, Hall D, Calderon R. Meal support training for friends and families of patients with eating disorders.
Eat Disord 2005;13(4):407-11.
4. Thien V, Thomas A, Markin D et al. Pilot study of a graded exercise program for the treatment of anorexia
nervosa. Int J Eat Disord 2000;28(1):101-6.
5. Bergh C, Brodin U, Lindberg G et al. Randomized controlled trial of a treatment for anorexia and bulimia
nervosa. Proc Natl Acad Sci U S A 2002;99(14):9486-91.
6. Zhu AJ, Walsh BT. Pharmacologic treatment of eating disorders. Can J Psychiatry 2002;47(3):227-34.
7. Leung M, Birmingham CL. Food fight. Pharmacy Practice 1997;13(10):62-72.
8. Stacher G, Peeters TL, Bergmann H et al. Erythromycin effects on gastric emptying, antral motility and plasma
motilin and pancreatic polypeptide concentrations in anorexia nervosa. Gut 1993;34(2):166-72.
9. Ray WA, Murray KT, Meredith S, et al. Oral erythromycin and the risk of sudden death from cardiac causes. N
Engl J Med 2004;351(11):1089-96.
10. Su JC, Birmingham CL. Zinc supplementation in the treatment of anorexia nervosa. Eat Weight Disord 2002;7
(1):20-2.
11. La Via MC, Gray N, Kaye WH. Case reports of olanzapine treatment of anorexia nervosa. Int J Eat Disord
2000;27(3):363-6.
12. Mehler C, Wewetzer C, Schulze U et al. Olanzapine in children and adolescents with chronic anorexia nervosa.
A study of five cases. Eur Child Adolesc Psychiatry 2001;10(2):151-7.
13. Mondraty NK et al. A randomized controlled trial of olanzapine versus chlorpromazine in anorexia nervosa. Int
J Eat Disord. In press 2003.
Page 1012
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14. Halmi KA, Eckert E, LaDu TJ et al. Anorexia nervosa. Treatment efficacy of cyproheptadine and amitriptyline.
Arch Gen Psychiatry 1986;43(2):177-81.
15. Halmi KA, Eckert E, Falk JR. Cyproheptadine for anorexia nervosa. Lancet 1982;1(8285):1357-8.
16. Powers PS, Bannon Y, Eubanks R et al. Quetiapine in anorexia nervosa patients: an open label outpatient pilot
study. Int J Eat Disord 2007;40(1):21-6.
17. Sattar SP, Bhatia SC, Petty F. Potential benefits of quetiapine in the treatment of substance dependence
disorders. J Psychiatry Neurosci 2004;29(6):452-7
18. Walsh BT, Kaplan AS, Attia E et al. Fluoxetine after weight restoration in anorexia nervosa: a randomized
19. Fung SM, Ferrill MJ. Treatment of bulimia nervosa with ondansetron. Ann Pharmacother 2001;35(10):1270-3.
20. Puddicombe DM, Birmingham CL. Using the glucagon test to predict hypoglycemia in anorexia nervosa. Eat
Weight Disord 2006;11(2):e72-4.
21. Harper J, Leung M, Birmingham CL. A blinded laxative taper for patients with eating disorders. Eat Weight
Disord 2004;9(2):147-50.
22. Mehler PS. Diagnosis and care of patients with anorexia nervosa in primary care settings. Ann Intern Med
2001;134(11):1048-59.
23. Geller J, Cockell SJ, Drab DL. Assessing readiness for change in the eating disorders: the psychometric
properties of the readiness and motivation interview. Psychol Assess 2001;13(2):189-98.
24. Kaplan AS. Psychological treatments for anorexia nervosa: a review of published studies and promising new
directions. Can J Psychiatry 2002;47(3):235-42.
25. Davis R, McVey G, Heinmaa M et al. Sequencing of cognitive-behavioral treatments for bulimia nervosa. Int J
Eat Disord 1999;25(4):361-74.
26. Hay PJ, Bacaltchuk J, Stefano S. Psychotherapy for bulimia nervosa and binging. Cochrane Database Syst Rev
2004;(3):CD000562.
27. Bacaltchuk J, Hay P. Antidepressants versus placebo for people with bulimia nervosa. Cochrane Database Syst
Rev 2003;(4):CD003391.
28. Goldstein DJ, Wilson MG, Thompson VL et al. Long-term fluoxetine treatment of bulimia nervosa: Fluoxetine
Bulimia Nervosa Research Group. Br J Psychiatry 1995;166(5):660-6.
29. Romano SJ, Halmi KA, Sarkar NP et al. A placebo-controlled study of fluoxetine in continued treatment of
bulimia nervosa after successful acute fluoxetine treatment. Am J Psychiatry 2002;159(1):96-102.
30. [No authors listed]. Fluoxetine in the treatment of bulimia nervosa. A multicenter, placebo-controlled, double-
blind trial. Fluoxetine Bulimia Nervosa Collaborative Study Group. Arch Gen Psychiatry 1992;49(2):139-47.
Page 1013
e-Therapeutics+ : Therapeutics : Psychiatric Disorders: Insomnia Page 1 of 9
Therapeutic Choice
Print Close
Psychiatric Disorders: Insomnia

Jonathan A.E. Fleming, MB, FRCPC
1
Insomnia is a common symptom of a number of psychiatric, medical and sleep disorders. Primary insomnia
(chronic psychophysiological insomnia) is the focus of this chapter. Secondary insomnia (e.g., insomnia associated
with a mood disorder or chronic pain)2 usually responds to treatment of the underlying disorder.
Goals of Therapy
Promote sound and restorative sleep when external (e.g., stress, noise, jet lag) or internal (e.g., pain, anxiety)
factors disrupt natural sleep
Reduce daytime impairment (e.g., dysphoria, fatigue, decreased alertness) associated with sleep loss
Potentiate the effectiveness of behavioural interventions in managing patients with primary, chronic insomnia3
Investigations
A complete sleep history (Table 1) is essential:

to quantify current sleep performance and daytime impairment
to determine the outcome of previous interventions
to rule out other sleep pathologies including those for which hypnotics are contraindicated and potentially
4
lethal, e.g., obstructive sleep apnea
Completion of a sleep diary (Table 3) for one week, to quantify sleep performance and variability
Psychiatric work-up to rule out associated mental disorders (especially mood and anxiety disorders, drug and
alcohol use)
Medical work-up to rule out associated medical disorders (especially those associated with nocturnal discomfort
or pain such as arthritis, Parkinson's disease)
Thorough drug history including prescription and nonprescription medications, herbal or other natural remedies,
caffeine, nicotine, alcohol and recreational drugs
Self-rating scales for depression (available at http://www.mentalhealthprofessionalsinc.com/Forms/Zung%
20Depression%20Inventory.pdf ) and anxiety symptoms (available at
http://www.mentalhealthprofessionalsinc.com/Forms/Zung_Self-Rating_Anxiety_Scale.pdf ) are useful
screening tools for identifying depressive or anxiety disorders causing insomnia
(Note: insomnia can be both an early symptom and a cause of depression)
Therapeutic Choices (Figure 1 - Management of Primary Insomnia)
Instruct patient in sleep hygiene (Table 2); monitor and encourage adherence throughout treatment and follow-
up (important to success of any intervention).
Suggest relaxation exercises (available as audio recordings for home use, e.g.,
http://www.calming.org/tapes.htm).
5
Consider sleep restriction, stimulus control or other behavioural approaches, alone or with pharmacologic
interventions.
Aerobic exercise, a useful modifier of stress and dysphoric moods, also promotes deeper and more restful
sleep; encourage patients with insomnia to decrease daytime rest periods and increase exercise.
Table 1: The Sleep History
1. Time data (can also be collected as part of a sleep diary – Table 3 )

Did you nap or lie down to rest today? If yes, when and for how long?
What time did you go to bed last night?
What time did you put out the lights?
How long did it take you to fall asleep?
How many times did you awaken last night?
How long was your longest awake period; when was it? What time did you finally awaken?
Page 1014
Therapeutic Choice
What time did you get out of bed?
How many hours sleep did you get last night?
2. Questions about the sleep period

Do physical symptoms, such as pain, prevent you from falling asleep?
Do mental or emotional symptoms (e.g., worry or anxiety) prevent you from falling asleep?
When you awaken during the night, what awakens you? (Snoring? Gasping for air? Dreams/nightmares? Noise?)
When you get up for the day, do you have any symptoms? (Headache? Confusion? Sleepiness?)
3. Questions for the patient's bed partner

Does your partner snore, gasp or make choking sounds during the night?
Does your partner stop breathing during the night?
Do your partner's legs twitch, jerk or kick during the night?
Has your partner's use of alcohol, nicotine, caffeine or other drugs changed recently?
Has your partner's mood or emotional state changed recently?
What do you think is the cause of your partner's sleep problem?
Short courses (Figure 1 - Management of Primary Insomnia) of hypnotics are useful combined with good sleep
hygiene (Table 2). A comprehensive evaluation, education stressing the importance of sleep hygiene (especially
preventing extended sleeping such as naps or nocturnal sleep periods of more than eight hours) and careful
monitoring of progress are important. With these measures, the use of the preferred agents, the benzodiazepines or
nonbenzodiazepines such as zopiclone, is usually straightforward in patients with primary insomnia.
Table 2: Sleep Hygiene Guidelines
1. Keep a regular sleep–wake schedule, 7 days per week.

2. Restrict the sleep period to the average sleep time you have obtained each night over the preceding week.
3. Avoid sleeping in, extensive periods of horizontal rest or daytime napping; these activities usually affect the
subsequent night's sleep.
4. Get regular exercise every day: about 40 minutes of an activity with sufficient intensity to cause sweating. If
evening exercise prevents sleep, schedule the exercise earlier in the day.
5. Avoid caffeine, nicotine, alcohol and other recreational drugs, all of which disturb sleep. If you must smoke do
not do so after 7:00 p.m.
6. Plan a quiet period before lights out; a warm bath may be helpful.
7. Avoid large meals late in the evening; a light carbohydrate snack (e.g., crackers and warm milk) before bedtime
can be helpful.
8. Turn the clock face away and always use the alarm. Looking at the clock time on awakening can cause
emotional arousal (performance anxiety or anger) that prevents return to sleep.
9. As much as possible, keep the bedroom dark and soundproofed. If you live in a noisy area, consider ear plugs.
10. Use the bedroom only for sleep and intimacy; using the bed as a reading place, office or media centre
conditions you to be alert in a place that should be associated with quiet and sleep. If you awaken during the
night and are wide awake, get up, leave the bedroom and do something quiet until you feel drowsy-tired, then
return to bed.
Note: Pharmacologic (or any) interventions will be less effective if these guidelines are not followed. In mild
cases of insomnia, sleep hygiene guidelines, practised consistently and together, may be sufficient to reinstate a
normal sleep pattern.
Benzodiazepines (BDZs)
All BDZs have sedative and hypnotic properties, but differ significantly in potency and pharmacokinetics. All may
cause confusion and ataxia, especially in the elderly and the medically ill. For primary insomnia, BDZs that have
been studied in sleep-disturbed patients are generally preferred over other BDZs. When insomnia is secondary to
prominent anxiety symptoms, a long-acting BDZ (such as clonazepam) given at night may promote sleep and
manage daytime anxiety. It is inappropriate to use one BDZ during the day to manage anxiety and a different BDZ
as a hypnotic at night, in the same patient.
In Canada, four BDZs are officially indicated for insomnia: flurazepam, nitrazepam, temazepam and triazolam.
Because of their longer half-lives, flurazepam and nitrazepam accumulate with repeated dosing and are associated
Page 1015
Therapeutic Choice
with more hangover effects than shorter-acting BDZs. In the elderly, they cause higher cortical impairment resulting
6
in confusion and falls. Flurazepam and nitrazepam are not recommended, particularly in the elderly.
Temazepam is a good all-purpose hypnotic with a half-life sufficient to cover the sleep period without causing
hangover effects. However, few hypnotics have proven tolerability in the elderly, and temazepam may be associated
7
with falls in this population. It causes less rebound insomnia than more potent BDZs such as lorazepam.
Triazolam has a fast onset and short duration of action, making it more suitable for managing initial insomnia (first
third of the night) rather than maintenance insomnia (last third of the night). In addition to causing rebound
insomnia, it has a unique adverse event profile (confusion, agitation, and amnesia) making it unsuitable for use in
8
the elderly. A shorter treatment course (five to seven days) is recommended for triazolam.
Although the number of comparative studies is relatively small, oxazepam is as effective as the BDZs that are
officially indicated for insomnia.9 , 10 In patients with initial insomnia, oxazepam should be given 60 to 90 minutes
before bedtime because of its slow absorption. Conversely, patients who have no difficulty falling asleep but
experience maintenance insomnia can take oxazepam when getting into bed.
There are few trials studying the effects of lorazepam on insomnia. Lorazepam may cause significant rebound
11
effects such as anxiety and tension.
Benzodiazepine–Receptor Agonists
Although not a BDZ, the cyclopyrrolone zopiclone acts at the BDZ receptor and so has similar therapeutic and side
effects. Although psychomotor impairment associated with combined use of zopiclone and small amounts of alcohol
has been shown to be minor, zopiclone can have residual or hangover effects that could impair morning driving,
12
when used with or without alcohol. Compared with BDZs, tolerance to zopiclone’s hypnotic effect may be delayed
and rebound insomnia may be reduced.13 Eszopiclone, the active (S+) isomer of zopiclone, shares similar
pharmacologic properties to the racemic compound but is more potent.14 Several studies have demonstrated
efficacy in transient and chronic insomnia with one demonstrating continued efficacy over 12 months of use with no
evidence of tolerance or a withdrawal syndrome or rebound insomnia on discontinuation.15 Eszopiclone in not
available in Canada.
Indiplon is a short-acting pyrazolopyrimidine that binds to a specific site at the GABA-A receptor. Indiplon is not
16
available in Canada; preliminary data from Phase III trials show good efficacy and safety.
Other Hypnotics
The toxicity and drug interaction profile of chloral hydrate make it less safe than BDZs. Tolerance to its hypnotic
17
effect typically develops within two weeks. Its use is not recommended. Barbiturates are contraindicated in the
management of insomnia due to their unacceptable safety profile.18
The Canadian supply of L-tryptophan has not been associated with the development of the eosinophilia–myalgia
syndrome (a potentially lethal disorder) that has been described in the US. In high dosages (> 1 g), L-tryptophan
has a hypnotic effect, but it is not as predictable as that seen with traditional hypnotics.19 It may be useful when
one wishes to avoid BDZs.
20
Use of melatonin (1 to 5 mg) in primary insomnia remains controversial. More studies are required to determine
if the slow-release form has a role in maintenance insomnia of middle and old age. Ramelteon, a novel compound
with chronohypnotic properties (causing phase shifts in circadian rhythm) and high selectivity for MT1 and MT2
melatonin receptors, is available in the US but not in Canada. In various animal models, ramelteon has
demonstrated hypnotic properties with no effect on learning, memory or motor coordination. Human studies in
21 22
young adults and elderly patients show it is well tolerated, but further placebo-controlled studies are required to
confirm its role as a sleep-promoting agent.23
Therapeutic Tips
Always start hypnotics at the lowest dose and use them for the shortest possible time.
Set realistic treatment goals with the patient, mainly to minimize daytime impairment; a chronic poor sleeper
will not be turned into a good sleeper overnight.
Page 1016
Therapeutic Choice
The degree of daytime impairment directs the intervention: if there is an acute change in daytime functioning, a
short course of hypnotics may be indicated; if the daytime impairment is mild or chronic, try a behavioural
intervention (e.g., sleep restriction) first.
Sleep diaries (Table 3) are often helpful in delineating the initial complaint, monitoring progress and facilitating
withdrawal.
It is inappropriate to use the sedative side effect of another medication (e.g., diphenhydramine,
antidepressants) to avoid using a BDZ or non-BDZ agonist when the latter agents are the treatment of choice.
Self-medication with nonprescription agents is not recommended; patients should see their physician about
distressing insomnia.
Warn patients about combined effects when hypnotics are used with other CNS depressants, e.g., alcohol.
If a short course of a hypnotic has been used, plan to withdraw it at a low-stress time, e.g., a weekend. Two
nights before the planned withdrawal, the patient should shorten the sleep time (while staying on the
medication) by 20 minutes. This modest degree of sleep deprivation will promote physiological sleepiness,
which should counterbalance any sleep disruption associated with withdrawal. This shortened sleep period
should be maintained for one week.
Remain vigilant for the emergence of a mood disorder (which should always be treated with
antidepressants rather than hypnotics alone) as protracted insomnia may be the prodrome of an
affective illness. Furthermore, one year of continued sleep disturbance increases the risk of a mood
24
disorder in the subsequent year. Useful Info?
Page 1017
Therapeutic Choice
Figure 1-Management of Primary Insomnia
Table 3: Sleep Diary
Date
Daytime
Caffeine intake (what, when)
Alcohol intake (what, when)
Nicotine use (what, when)
Naps (start time, end time)
Page 1018
Therapeutic Choice
Date
Exercise (what, when)
Overall daytime functioning, on a

scale of 1 to 5 (1 = alert, energetic;
5 = fatigued, sleepy)
Nighttime
What time did you go to bed?
Did you watch television in bed?
Did you read in bed?
How long did it take to fall asleep?
For each time you woke up during

the night, record the following: 1.
time you were awake (e.g., 1:10–
2:30 a.m.) 2. what woke you up
(e.g., snoring, gasping for air, bad
dreams, pet, noise)?
What time did you wake up for the

day?
What time did you get out of bed for

the day?
How many hours of sleep did you

get?
How did you feel when you woke up

this morning, on a scale of 1 to 5 (1
= refreshed, alert; 5 = fatigued,
sleepy)
Table 4: Drugs Used to Manage Primary Insomnia
Dose
a
(nighttime) Drug Cost
Class Drug Adverse Effects Interactions Comments
Benzodiazepines lorazepam Initial: Benzodiazepines: dose- Additive sedation Widely used $

(BDZs) Ativan, 0.5 mg dependent ataxia, with CNS as a hypnotic
generics Maximum: dizziness; depressants such although not
1 mg dependence/withdrawal as alcohol. officially
symptoms. Lorazepam: indicated.
may cause more rebound
insomnia on withdrawal
than temazepam or
oxazepam; may cause
amnesia with higher
dosages.
Benzodiazepines oxazepam Initial: Benzodiazepines: dose- Additive sedation Slowly $

(BDZs) generics 15 mg dependent ataxia, with CNS absorbed;
Maximum: dizziness; depressants such onset of
30 mg dependence/withdrawal as alcohol. action is
symptoms. delayed;
should be
taken 60–
90 min
before
retiring for
initial
insomnia; no
Page 1019
Therapeutic Choice
Dose
a
hangover
effects.
Benzodiazepines temazepam Initial: Benzodiazepines: dose- Substrate of Good all- $

(BDZs) Restoril, 15 mg dependent ataxia, CYP3A4; purpose
generics Maximum: dizziness; metabolism hypnotic;
30 mg dependence/withdrawal could be does not
symptoms. increased by accumulate.
inducers (e.g.,
carbamazepine,
smoking,
phenytoin) or
decreased by
inhibitors (e.g.,
cimetidine,
clarithromycin,
efavirenz,
erythromycin,
grapefruit juice,
itraconazole,
ketoconazole,
ritonavir) of the
enzyme.
Benzodiazepines triazolam Initial: Benzodiazepines: dose- Substrate of Absence of $

(BDZs) generics 0.125 mg dependent ataxia, CYP3A4; hangover
Maximum: dizziness; metabolism effects is an
0.25 mg dependence/withdrawal could be advantage
symptoms. Triazolam: increased by (does not
anterograde amnesia inducers (e.g., affect
(especially with higher carbamazepine, daytime
dosages, concurrent use smoking, alertness).
of alcohol) and other phenytoin) or
potency and dose-related decreased by
side effects (rebound inhibitors (e.g.,
insomnia, daytime cimetidine,
anxiety) have limited its clarithromycin,
use; useful for initiating efavirenz,
sleep. erythromycin,
grapefruit juice,
itraconazole,
ketoconazole,
ritonavir) of the
enzyme.
Cyclopyrrolones zopiclone Initial: Major adverse effect is Minimal additive Does not $$$
Imovane, 3.75 mg bitter/metallic taste. effects with low accumulate;
Rhovane, (geriatric) doses of alcohol. minimal
generics Usual adult cognitive
dose: 25
effects;
7.5 mg may cause
Maximum: less rebound
7.5 mg on
withdrawal.
Serotonin L-tryptophan 1– May cause serotonin Combined Alternative to $$$$

Precursors Tryptan, 3g syndrome (shivering, therapy with BDZs and
other 20 min diaphoresis, hypomanic serotonergic non-BDZ
generics before behaviour and ataxia) drugs such as agonists;
bedtime alone or when combined triptans, SSRIs, erratic
with other serotonergic MAOIs and response.
drugs. sibutramine can
increase the risk
Page 1020
Therapeutic Choice
Dose
a
of serotonin
syndrome.
a.
Legend: $ < $2 $$ $2–5 $$$ $5–10 $$$$ > $10
Suggested Readings
Benca RM. Diagnosis and treatment of chronic insomnia: a review. Psychiatr Serv 2005;56(3):332-43.
Sateia MJ, Nowell PD. Insomnia. Lancet 2004;364(9449):1959-73.
Silber MH. Clinical practice. Chronic insomnia. N Engl J Med 2005;353(8):803-10
References
1. American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 4th ed. Text Revision.
Washington (DC): American Psychiatric Association; 2000.
2. McCrae CS, Lichstein KL. Secondary insomnia: diagnostic challenges and intervention opportunities. Sleep
Med Rev 2001;5(1):47-61.
3. Vallieres A, Morin CM, Guay B. Sequential combinations of drug and cognitive behavioral therapy for chronic
insomnia: an exploratory study. Behav Res Ther 2005;43(12):1611-30.
4. Flemons WW. Clinical practice. Obstructive sleep apnea. N Engl J Med 2002;347(7):498-504.
5. Edinger JD, Means MK. Cognitive-behavioral therapy for primary insomnia. Clin Psychol Rev 2005;25(5):539-
58.
6. Reynolds CF et al. Treatment of insomnia in the elderly. In: Salzman C, editor. Clinical geriatric
psychopharmacology. 3rd ed. Baltimore (MD): Williams and Wilkins;1998.
7. Frels C, Williams P, Narayanan S et al. Iatrogenic causes of falls in hospitalised elderly patients: a case-
control study. Postgrad Med J 2002;78(922):487-9.
8. Schneider DL. Insomnia. Safe and effective therapy for sleep problems in the older patient. Geriatrics 2002;57
(5):24-6, 29, 32.
9. Bliwise D, Seidel W, Greenblatt DJ et al. Nighttime and daytime efficacy of flurazepam and oxazepam in
chronic insomnia. Am J Psychiatry 1984;141(2):191-5.
10. Feldmeier C, Kapp W. Comparative clinical studies with midazolam, oxazepam and placebo. Br J Clin
Pharmacol 1983;16(Suppl 1):151S-155S.
11. Kales A, Bixler EO, Soldatos CR et al. Lorazepam: effects on sleep and withdrawal phenomena. Pharmacology
1986;32(3):121-30.
12. Vermeeren A. Residual effects of hypnotics: epidemiology and clinical implications. CNS Drugs 2004;18
(5):297-328.
13. Voderholzer U, Riemann D, Hornyak M et al. A double-blind, randomized and placebo-controlled study on the
polysomnographic withdrawal effects of zopiclone, zolpidem and triazolam in healthy subjects. Eur Arch
Psychiatry Clin Neurosci 2001;251(3):117-23.
14. Melton ST, Wood JM, Kirkwood CK. Eszopiclone for insomnia. Ann Pharmacother 2005;39(10):1659-66.
15. Roth T, Walsh JK, Krystal A et al. An evaluation of the efficacy and safety of eszopiclone over 12 months in
patients with chronic primary insomnia. Sleep Med 2005;6(6):487-95.
16. Neubauer DN. Indiplon: the development of a new hypnotic. Expert Opin Investig Drugs 2005;14(10):1269-
76.
17. Frankland A, Robinson MJ. Fatal chloral hydrate overdoses: unnecessary tragedies. Can J Psychiatry 2001;46
(8):763-4.
Page 1021
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18. Morgan WW. Abuse liability of barbiturates and other sedative-hypnotics. Adv Alcohol Subst Abuse 1990;9(1-
2):67-82.
19. Schneider-Helmert D, Spinweber CL. Evaluation of L-tryptophan for treatment of insomnia: a review.
Psychopharmacology (Berl) 1986;89(1):1-7.
20. Olde Rikkert MG, Rigaud AS. Melatonin in elderly patients with insomnia. A systematic review. Z Gerontol
Geriatr 2001;34(6):491-7.
21. Erman M, Seiden D, Zammit G et al. An efficacy, safety, and dose-response study of Ramelteon in patients
with chronic primary insomnia. Sleep Med 2006;7(1):17-24.
22. Roth T, Seiden D, Sainati S et al. Phase III outpatient trail of ramelteon for the treatment of chronic insomnia
in the elderly [abstract]. J Am Geriatr Soc 2005;53(Suppl 4):S25.
23. Bellon A. Searching for new options for treating insomnia: are melatonin and ramelteon beneficial? J Psychiatr
Pract 2006;12(4):229-43.
24. Ford DE, Kamerow DB. Epidemiologic study of sleep disturbances and psychiatric disorders. An opportunity
for prevention? JAMA 1989;262(11):1479-84.
25. Silva A, Collao A, Orellana M et al. Zopiclone, but not brotizolam, impairs memory storage during sleep.
Neurosci Res 2003;47(2):241-3.
Page 1022
e-Therapeutics+ : Therapeutics : Psychiatric Disorders: Psychoses Page 1 of 27
Therapeutic Choice
Print Close
Psychiatric Disorders: Psychoses
Heather Milliken, MDCM, FRCPC, CSPQ
Psychoses are brain disorders in which there is a distortion of or loss of contact with reality, affecting the ability to
think, feel, perceive and act. Psychotic symptoms include delusions, hallucinations, disorganized thinking and bizarre or
disorganized behaviour. Approximately 3% of people worldwide will experience at least one psychotic episode during
their lifetime (Table 1).
The age of onset of schizophrenia spectrum psychotic disorders is usually late adolescence/early adulthood. There is
increased emphasis on earlier detection and treatment of psychotic disorders1 , 2 , 3 because the duration of untreated
psychosis correlates with both short- and long-term outcomes.4 , 5
Table 1: Differential Diagnosis of Psychotic Episodes6
Disorder Characteristics
Schizophrenia Signs of illness for ≥ 6 mo; psychotic symptoms for ≥ 1 mo; social/occupational
dysfunction
Schizophreniform psychosis Similar to schizophrenia except duration of illness of < 6 mo
Schizoaffective disorder Symptoms of schizophrenia and mood disorder occur concurrently and ≥ 2 wk of
delusions or hallucinations in absence of prominent mood symptoms
Delusional disorder Nonbizarre delusions for ≥ 1 mo and does not meet criteria for schizophrenia
Brief psychotic disorder Psychotic symptoms for ≥ 1 day but < 1 mo; may or may not be related to marked
stressor; eventual full return to premorbid level of functioning
Substance-induced psychotic Delusions or hallucinations develop during or within 1 mo of substance intoxication or

disorder withdrawal or are etiologically related to medication use and are not better accounted
for by another psychotic disorder
Psychotic disorder due to a Delusions or hallucinations are direct physiological consequence of a medical
general medical condition condition and occur in absence of delirium
Psychotic disorder not Psychotic symptoms present but criteria for specific disorder not met or there is
otherwise specified insufficient or contradictory information
Major depression with Major depressive episode with concurrent mood-congruent (most common) or mood-
psychotic features incongruent psychotic symptoms
Bipolar disorder Manic episode with concurrent mood-congruent (most common) or mood-incongruent
psychotic symptoms
Goals of Therapy
Reduce psychotic agitation in acute episodes

Achieve remission of specific psychotic symptoms such as delusions, hallucinations, disordered thinking and
behaviour
Facilitate recovery of functioning and healthy development
Reduce risk of comorbidity, particularly suicide, depression and substance abuse
Prevent recurrence of psychotic episodes
Because they are often the initial contact for a person experiencing a first psychotic episode, family physicians
should have a high index of suspicion in any young individual who is experiencing persistent changes in behaviour,
mood and functioning, particularly in the presence of other risk factors such as substance abuse or a family history
of psychosis
Signs and symptoms of possible first-episode psychosis include:1
withdrawal from usual activities with friends and family
persistent decline in functioning in everyday activities, at school or at work
persistent dysphoria, anxiety or irritability, especially in the absence of identifiable stressors
Page 1023
Therapeutic Choice
rapid fluctuations in mood (emotional lability) or showing very little emotion or facial expression
unreasonable suspiciousness
insomnia; restlessness and pacing at night
unusual or bizarre behaviour
unusual perceptual experiences including hypersensitivity, illusions and/or brief intermittent hallucinations
difficulties in thinking such as organizing and/or expressing thoughts
problems with attention and concentration
Substance use (particularly cannabis) is common in first-episode psychosis. Individuals may therefore
be misdiagnosed with a substance-induced psychosis and not receive appropriate ongoing treatment.
Cannabis use can trigger the onset of a schizophrenia spectrum disorder in genetically vulnerable
individuals7 Useful Info?
Even in the presence of substance use, have a high index of suspicion of a functional psychosis, especially if:
symptoms precede the onset of substance use
symptoms are bizarre or there is marked thought disorder
symptoms persist beyond the period of intoxication or withdrawal
Individuals with a suspected first episode of psychosis require urgent services. If available, refer to a psychiatrist,
community mental health clinic or specialized early psychosis program8
Appropriate investigations are based on both the phase of the psychotic disorder (see Table 2) and individual
patient characteristics
In an acute psychotic episode, assess the nature and extent of psychopathology:
thorough history of presenting problems with special attention to onset and course of prodromal symptoms
onset, characteristics and severity of psychotic symptoms
changes in behaviour and functioning
history of any suicidal ideation or behaviour and/or aggressive/violent ideation or behaviour
history of substance use/abuse in relation to onset and course of psychotic symptoms
A thorough mental status examination is essential. Competency to consent to treatment needs to be assessed in all
acutely psychotic individuals
Obtain information from as many sources as possible since individuals with psychotic disorders are often poor
historians
interview family members whenever possible with the consent of the individual
A variety of clinical rating scales can be used at baseline and repeated periodically to monitor for symptomatic and
functional recovery following an acute psychotic episode
the Clinical Global Impression Scales for Severity (CGI-S)9 and for Change (CGI-C)9 and Global Assessment of
Functioning (GAF)6 are easy to use for documenting changes over time
the Brief Psychiatric Rating Scale (BPRS, available at www.priory.com/psych/bprs.htm) and the Positive and
Negative Syndrome Scale (PANSS) require training to be used reliably. Use of the semistructured interview
guide SCI-PANSS,10 however, takes approximately 30–40 minutes to complete and can be helpful in eliciting
signs and symptoms of psychopathology
Patients with only partial symptomatic and/or functional recovery following an acute psychotic episode require
diagnostic reassessment by a psychiatrist
Table 2: Investigations and Monitoring of Psychoses8 , 11
Parameter Phase of Illness, Recommended Monitoring/Frequency
Psychopathology First episode: baseline then weekly for first 4–8 wk; more
often if clinically indicated
Recurrent acute episode: baseline then weekly for first 4–8
wk; more often if clinically indicated
Stabilization phase: monthly for first 6 mo following first or
recurrent acute episode; more often if clinically indicated
Stable phase: every 3 mo for individuals with good
symptomatic and functional recovery and medication
adherence; more often for individuals with poor medication
adherence
Substance use First episode: baseline

Recurrent acute episode: baseline
Stabilization phase: at every patient visit or as clinically
indicated
Stable phase: at every patient visit or as clinically indicated
Level of functioning (activities of daily living; First episode: premorbid level of functioning; baseline
social and occupational functioning) assessment of current functioning
Recurrent acute episode: baseline assessment of current
functioning
Page 1024
Therapeutic Choice
Stabilization phase: monthly for first 6 mo following first or

acute episode
Stable phase: every 3 mo
Past psychiatric history First episode: baseline

Recurrent acute episode: baseline with focus on past
antipsychotic treatment including type of medication, dose,
side effects, response, duration of treatment and medication
adherence
Stabilization/Stable phase: N/A
Family psychiatric history First episode: baseline

Recurrent acute episode: baseline
Stabilization/Stable phase: N/A
Developmental history (mother’s obstetrical First episode: baseline

history including pre- and perinatal complications); Recurrent acute episode: N/A
developmental milestones; history of learning Stabilization/Stable phase: N/A
disabilities
Medical history (past and current conditions First episode: baseline

including treatment) Recurrent acute episode: baseline
Stable phase: yearly
Extrapyramidal signs and symptoms First episode: baseline; when dosage of antipsychotic is
(parkinsonism, dystonia, akathisia, dyskinesia) changed or new antipsychotic is started, then weekly for 2–4
wk.
Recurrent acute episode: baseline; when dosage of
antipsychotic is changed or new antipsychotic is started, then
weekly for 2–4 wk.
Stabilization phase: as clinically indicated
Stable phase: every 6 mo or more often for individuals at
higher risk
Cognitive functions (estimates of premorbid IQ, First episode: referral to a psychologist is recommended for
current IQ, attention and concentration, working neurocognitive testing within 3 mo after psychotic symptoms
memory, verbal and visual learning and memory, have remitted
executive functions such as abstract thinking, Recurrent acute episode: N/A
reasoning, problem solving, judgment) Stabilization phase: N/A
Stable phase: referral to a psychologist for neurocognitive
testing as clinically indicated (clinical evidence of ongoing
cognitive impairment that affects functioning)
Functional enquiry and physical examination First episode: baseline and then as clinically indicated;
with focus on current complaints, endocrine and weight and BMI monthly for 6 mo; baseline waist
sexual function, vital signs, weight, body mass index circumference; blood pressure at baseline and 12 wk or more
(BMI) often if clinically indicated
Recurrent acute episode: baseline and then as clinically
indicated; weight and BMI monthly for 6 mo after initiation of
a new antipsychotic; baseline waist circumference; blood
pressure at baseline and 12 wk or more often if clinically
indicated
Stable phase: as clinically indicated; weight and BMI every 3
mo when on stable antipsychotic dosage: waist circumference
annually; blood pressure annually or more often if clinically
indicated; functional enquiry (including endocrine and sexual
function) and physical exam at least yearly
Laboratory investigations (including CBC and First episode: Baseline; fasting glucose at baseline and
differential, electrolytes, kidney and liver function, repeat at 12 wk or more often as clinically indicated; fasting
fasting glucose and lipid profile, TSH, baseline lipid profile at baseline and 12 wk, and repeat as clinically
Page 1025
Therapeutic Choice
prolactin, routine urinalysis, urine drug screen if indicated

clinically indicated, tests for STIs, HIV and hepatitis if Recurrent acute episode: baseline; fasting glucose at
clinically indicated) baseline and repeat at 12 wk after initiating a new
antipsychotic or more often as clinically indicated; fasting
lipid profile at baseline and 12 wk and repeat as clinically
indicated
Stable phase: fasting glucose annually or more frequently if
gaining weight or symptomatic; fasting lipid profile annually
or every 6 mo if LDL or triglyceride levels above normal
range; other tests as clinically indicated
CT brain First episode: Recommended

Recurrent acute episode: As clinically indicated
Abbreviations: N/A=not applicable
Therapeutic Choices (Figure 1 - Management of Acute Psychotic Episodes)
Antipsychotic medications are the most effective treatment of schizophrenia and related psychotic disorders12 , 13
but need to be integrated with psychosocial interventions to optimize outcome.8
Both pharmacologic and psychosocial interventions should be tailored to the individual and to the phase of the
illness.
First Episode/Recurrent Acute Episode
Determine appropriate treatment setting (least restrictive setting possible), ensure safety and reduce environmental
stressors and stimuli.
Acutely agitated patients and those at imminent risk of harm to self or others will require hospitalization, if
necessary on an involuntary basis. Criteria for involuntary psychiatric assessment and/or admission are determined
by each province's mental health legislation.
See patient frequently (for outpatients at least weekly for first 4–6 weeks) in order to:
build rapport
provide support, practical advice and psychoeducation
promote medication adherence
monitor treatment response
Foster a collaborative therapeutic relationship between the patient, family/caregivers and treatment team.
Stabilization/Stable Phases
In schizophrenia and related psychotic disorders, recovery (stabilization phase) from an acute psychotic episode
usually occurs over 6 months but may take longer and may be incomplete.
focus on medication adherence, stress management, assessment of signs and symptoms of postpsychotic
depression and suicidality, assessment of substance use and education about early warning signs of relapse
Psychosocial interventions such as individual and family psychoeducation, cognitive-behavioural therapies (CBT),
social and vocational skills training and peer support groups have been shown to improve functional outcome and
community reintegration, and help prevent relapse.8
Maintain continuity of care with an individual clinician or multidisciplinary treatment team.
Individuals with serious ongoing illness and functional disability or comorbid problems such as substance abuse
may benefit from referral to an Assertive Community Treatment (ACT) team if available.8
Choice of Antipsychotic
Two major classes of antipsychotics are currently available in Canada:
First-generation antipsychotics (FGAs), also known as “typical” or “conventional” antipsychotics, can be classified
Page 1026
Therapeutic Choice
according to their chemical structure (e.g., phenothiazines such as fluphenazine or butyrophenones such as
haloperidol) or potency (low, intermediate, high) as determined by dopamine D2-receptor binding affinity (see
Table 5).
Second-generation antipsychotics (SGAs) or “atypical” antipsychotics (aripiprazole, clozapine, olanzapine,
paliperidone, quetiapine, risperidone and ziprasidone) have greater 5HT affinity relative to D2 affinity. The
duration of binding to D2 receptors may account for clinical differences in dosing requirements and side effect
profiles among SGAs (see Table 4).14
Aripiprazole, paliperidone and ziprasidone are now available in Canada for the treatment of schizophrenia and
related psychotic disorders.
aripiprazole and ziprasidone have slightly different binding affinities compared to other SGAs. Aripiprazole has
partial agonist activity at D2 and 5HT1A receptors and potent antagonism activity at 5HT2A receptors. It has a
long half-life (~75 hours), and steady state plasma concentrations are achieved in 14 days. It can therefore be
given as once-daily dosing with or without food, and changes in dosage should be made no more frequently
than every 14 days.
paliperidone is the active metabolite of risperidone. It is not metabolized by the liver and therefore has
minimal risk of drug-drug interactions compared to other oral antipsychotics. It is intended for once-daily
dosing with or without food (morning is recommended as it can cause insomnia).
ziprasidone has agonist activity at 5HT1A receptors and, unlike other SGAs, has antagonist activity at 5HT1D
receptors and moderate inhibition of synaptic reuptake of serotonin and norepinephrine. Ziprasidone requires
twice-daily dosing due to its short half-life (6.6 hours) and must be taken with food (at least 500 calories) to
ensure optimal absorption and therapeutic serum concentrations. Bioavailability of ziprasidone is reduced by
50% if taken in the absence of food.
All FGAs and SGAs, with the exception of clozapine, have similar efficacy in treating the positive (psychotic)
symptoms of schizophrenia and related disorders. SGAs may have advantages in first-episode psychosis,15 , 16 in
improving negative symptoms, mood and cognitive deficits17 , 18 and in preventing relapse19 and
rehospitalization.20 Clozapine is the only antipsychotic with proven efficacy in treatment-resistant schizophrenia,12
in reducing hostility and aggression21 , 22 and in reducing persistent suicidality.23
SGAs are now considered first-line treatment.17 , 18 , 24 The exception is clozapine which, because of the risk of
agranulocytosis and the need for regular blood monitoring, is reserved for treatment-resistant schizophrenia. The
major differences between the FGAs and SGAs are in side effect profiles, safety and tolerability (see Table 3).
Dosing and Duration of Treatment
Tailor treatment to the specific phase of the disorder, and to individual signs and symptoms.8 , 24
Acute Phase (see also Psychiatric Disorders: Acute Agitation)
Haloperidol im has been the most widely used treatment for psychotic agitation. Haloperidol 5 mg im combined
with lorazepam 2 mg im has been shown to be more effective than haloperidol alone.25
Olanzapine im in doses of 2.5–10 mg is as effective as haloperidol and causes less EPS.26 , 27 Do not combine
with parenteral benzodiazepines because of reports of cardiac and respiratory problems including deaths.
The rapid-dissolving oral formulations of olanzapine and risperidone are as effective as haloperidol im.28
Zuclopenthixol acetate is an injectable FGA which, because of its pharmacokinetics (peak serum level in 24–48
hours, declining to one-third of peak concentration in 72 hours), may reduce the number of injections required in
severe acute agitation and/or aggression. It should not be used in antipsychotic-naïve patients.
Patients with first-episode psychosis are more responsive to lower doses of antipsychotics,29 , 30 have a greater
rate of recovery29 and are more prone to side effects.
with the exception of ziprasidone and extended-release quetiapine, begin with a low dose of an SGA and titrate
gradually over 1–2 weeks up to the usual therapeutic range (see Table 4). Aripiprazole, olanzapine,
paliperidone, extended-release quetiapine and risperidone are usually administered once daily. Although twice-
daily dosing is recommended for immediate-release quetiapine, many patients can be maintained on a single
daily dose at bedtime.31 Ziprasidone requires twice-daily dosing with meals
ziprasidone should be started at a dose of 40 mg BID (20 mg BID for antipsychotic-naïve patients with first-
episode psychosis) and rapidly titrated in the first week up to 120–160 mg/day to avoid ziprasidone-induced
“activation” syndrome which occurs at the lower end of the dose range (20–40 mg po BID). The activation
syndrome consists of anxiety, restlessness, insomnia, increased energy and hypomanic-like symptoms which
develop soon after treatment initiation
extended-release quetiapine is usually administered once daily, preferably at bedtime. The recommended
initial dose is 300 mg daily. Dosage increases can be made rapidly at intervals as short as 1 day and in
increments of up to 300 mg/day, to a range of 400–800 mg daily.
if an FGA is used, consider an intermediate-potency agent such as loxapine (which has some “atypical”
properties) or perphenazine
benzodiazepines can be used to treat anxiety and agitation while titrating the dose of antipsychotic.
With the exception of ziprasidone and extended-release quetiapine, rapid titration and use of high doses do not
accelerate or enhance antipsychotic response and are rarely indicated. Even in patients with a chronic course, doses
in the range of 2–5 mg of haloperidol are as effective as 10–40 mg and are associated with fewer side effects and
Page 1027
Therapeutic Choice
greater tolerability.32 Only a very small subgroup of patients appear to benefit from high-dose therapy.33 Doses
exceeding the recommended daily maximum (e.g., olanzapine > 20 mg/day or quetiapine > 800 mg/day) are
sometimes required but should be used under the care of a psychiatrist.
An adequate trial of antipsychotic therapy is 4–8 weeks at a dose within the usual therapeutic range.8 , 18 , 24
Patients who fail to demonstrate even minimal response by that time are unlikely to benefit from a longer trial;
consider switching to a different antipsychotic and consulting a psychiatrist.
There is no good evidence to guide switching from one antipsychotic medication to another. Crossover medication
strategies, over 2 weeks to 3 months,34 are preferred. It is important to complete the crossover; combination
therapy with more than 1 antipsychotic medication is not supported by evidence and should be used only in
exceptional circumstances under the care of a psychiatrist. Patients successfully stabilized on clozapine have not
been shown to benefit from switching to any other antipsychotic medication.8
Stabilization/Stable Phases
During the stabilization (recovery) phase patients are vulnerable to relapse; avoid changes in antipsychotic
medication unless there are intolerable side effects or persistent residual symptoms that are distressing and/or
disabling to the patient.
Maintenance therapy is essential to prevent relapse. First-episode psychosis is associated with a 70–90% risk of
relapse within 5 years.
patients who discontinue medication are 5 times more likely to relapse.13 Recovery from recurrent acute
psychotic episodes (relapse) may take longer with each subsequent episode and the degree of recovery may
not be as great, resulting in persistent residual symptoms and functional disability13
continue maintenance pharmacotherapy for at least 1–2 years for first-episode individuals who achieve
symptom remission and functional recovery.8 , 24 Longer treatment (2–5 years) may be required for individuals
with a long duration of untreated psychosis, more severe illness, slower response, substance abuse and history
of suicidal or aggressive behaviour.8 , 24 For patients with a history of 2 or more episodes, maintenance
pharmacotherapy should continue until the patient has been stable and relapse-free for at least 5 years.8
many patients will require antipsychotic treatment indefinitely
in general, the lowest dose of antipsychotic that was effective in acute treatment should be used in
maintenance treatment.8 , 12
Consider long-acting intramuscular antipsychotics (e.g., risperidone) early in the course of treatment for individuals
with poor adherence. Poor medication adherence is common in individuals with schizophrenia and related psychotic
disorders and < 70–80% adherence is associated with significantly increased risk of relapse and hospitalization.35 ,
36
If discontinuation of medication is to be undertaken, gradually reduce the dose by not more than 20% at a time,
every 2–4 weeks, over a period of 6–12 months (first episode) and 6–24 months (2 or more episodes).8 , 12
Monitor patients closely for early signs of relapse. If these occur, the patient should be re-stabilized as quickly as
possible on the previously effective dose of antipsychotic.
Treatment of Comorbid Conditions
Depression and Suicidality
Depressive symptoms are common in the prodromal phase preceding the onset of a first episode of psychosis. In
the acute phase, particularly in multiple-episode patients, depressive symptoms usually remit along with the
positive psychotic symptoms.
SGAs may be more effective than FGAs in treating depressive symptoms37 in the acute phase; there is no
evidence to support the use of an antidepressant in the acute phase8
Major depressive episodes occur as often in individuals diagnosed with schizophrenia as in those with either
schizoaffective disorder or nonpsychotic major depression.38
patients with first-episode psychosis have a greater risk of depression compared to multiple-episode patients,
particularly in the stabilization phase (postpsychotic depression),39 and depressive symptoms tend to increase
for the first 3 months following a first episode of psychosis40
It can be difficult to differentiate between depression and ongoing negative symptoms, and rating scales such as
the HAM-D and Beck Depression Inventory have not been validated in individuals with schizophrenia. The Calgary
Depression Scale for Schizophrenia41 can be used to differentiate between negative symptoms and symptoms of
major depression.
Antidepressant medication may be useful in the treatment of major depression in the stabilization or stable
phases.40 Although there have been few studies, there is limited support for CBT.
Substance Abuse
Higher rates of substance abuse/dependence disorders are found in individuals with schizophrenia (lifetime
prevalence of 47–50%) compared to the general population. Persistent substance abuse is associated with
significantly poorer outcomes. A “harm reduction” approach incorporating motivational interviewing is
Page 1028
Therapeutic Choice
recommended for individuals with comorbid substance use problems.
Rates of smoking in individuals with schizophrenia and related psychotic disorders are extremely high (70% in
Canada),42 compared to a rate of approximately 20% in the general population (www.smoke-free.ca). Patients with
psychotic disorders are more likely to be heavy smokers and are 2–3 times more likely than nonsmokers to abuse
other substances.43
it is estimated that patients with schizophrenia have a life expectancy 20% lower than the general population,
attributable to increased rates of cardiovascular disease and dyslipidemia, for which smoking is a significant
risk factor44
because smoking induces the metabolism of some antipsychotics, (e.g., clozapine and olanzapine) smokers
require higher doses of these antipsychotics than nonsmokers, leading to increased side effects and adverse
events45 , 46
although smoking cessation success rates are low in patients with psychotic disorders (only 9% are former
smokers compared to 14–49% in the general population),42 actively encourage smoking cessation. Nicotine
replacement therapies may be helpful. Use caution with bupropion due to the risk of exacerbation of
psychosis. Varenicline is contraindicated in individuals with psychiatric disorders
The prevalence of cannabis use in individuals with psychotic disorders is higher than in the general population,
particularly in early psychosis where rates of use are as high as 86% and rates of DSM IV cannabis
abuse/dependence range from 14–28%.47 Cannabis use is associated with poor antipsychotic adherence, greater
severity and chronicity of symptoms and 4 times the risk of relapse.48
In individuals (particularly first-episode psychosis) who appear to have been using substances as a form of “self-
medication,” substance abuse may remit spontaneously with recovery from the acute episode.
Refer individuals with persistent substance abuse to a mental health program that can provide a comprehensive,
integrated approach.49
Side Effects of Antipsychotics (Table 3)
Neuroleptic Malignant Syndrome (NMS)
Neuroleptic malignant syndrome, which is a medical emergency with a high mortality rate, is a rare but serious side
effect. It is characterized by muscle rigidity, fever, autonomic disturbance, labile blood pressure, fluctuating levels
of consciousness and elevated WBC count and creatine kinase (CK).
It has been reported with all antipsychotics and can occur at any dosage and at any time. Dehydration is a risk
factor (see also Table 3).
Sedation and Cognitive Side Effects
Sedation is a very common side effect, especially after initiating a new antipsychotic or after increasing the dose; it
can be very disabling and distressing. It occurs most frequently with low-potency FGAs, clozapine, quetiapine and
to a lesser extent olanzapine.8 Risperidone may be associated with either mild sedation or insomnia.50 Paliperidone
is associated with insomnia and is therefore given in the morning. Ziprasidone may cause either insomnia or
sedation. Giving the greatest amount of the total daily dosage in either the morning or evening can reduce these
side effects. Aripiprazole can cause dose-related somnolence and to a lesser degree can also cause insomnia.
FGAs can cause a subjective cognitive “dulling” effect and do not improve cognitive deficits, whereas SGAs have
shown statistically significant improvement on a variety of cognitive measures51 , 52 but clinical significance has
not been demonstrated.
Concomitant medications such as anticholinergics (used to treat EPS) and anticonvulsants (used as mood
stabilizers) can worsen cognitive deficits.53 , 54
Cognitive deficits are correlated with functional outcomes such as social and occupational functioning and activities
of daily living.55
Extrapyramidal Side Effects
The major advantage of the SGAs is the significantly reduced risk of EPS (acute dystonia, parkinsonism, akathisia)
and tardive dyskinesia (TD) compared to FGAs12 , 17 , 18 , 56 , 57 However, higher doses of risperidone,
paliperidone and ziprasidone can cause EPS and akathisia, and higher doses of olanzapine and aripiprazole can
cause akathisia.
Parkinsonism can be associated with dysphoria, decreased concentration and slowing of cognition.
Akathisia (subjective and objective restlessness) is often misidentified as psychotic agitation which can result in an
increase in dose of the offending antipsychotic.
Tardive dyskinesia consists of repetitive, involuntary choreoathetoid movements usually involving the buccal-oral-
lingual musculature, face, trunk, extremities or respiratory muscles and can be permanent and disabling.
the incidence is 5% per year with FGAs and the cumulative risk is up to 50% even if low doses of FGAs are
used.8 The incidence is significantly less with aripiprazole, olanzapine, paliperidone, risperidone and
ziprasidone. Quetiapine and clozapine have rates of TD equivalent to placebo, and clozapine may improve
existing TD.8
Page 1029
Therapeutic Choice
inform patients of the risk of TD when initiating treatment with any antipsychotic medication, especially an
FGA.
Weight Gain, Diabetes and Dyslipidemia
Antipsychotic-induced weight gain is a serious side effect given that individuals with schizophrenia and bipolar
disorder are already at higher risk of obesity compared to the general population.
For FGAs, the risk of weight gain is greatest with low-potency agents.
With the exception of aripiprazole, ziprasidone and possibly paliperidone, the risk of weight gain with SGAs is
higher compared to FGAs, although this varies. Among SGAs, clozapine and olanzapine are associated with the
greatest weight gain followed by quetiapine, risperidone and aripiprazole.58 Ziprasidone is “weight-neutral”. In the
CATIE schizophrenia trial, ziprasidone was the only agent to show improvement in weight and metabolic
parameters following a switch from another SGA.59
Weight gain does not correlate with dosage in studies of 1 year or longer so reduction in dose is unlikely to result
in weight loss. Weight gain may be rapid in some individuals, but usually plateaus over time, although it can
continue for up to 1 year (or even longer). Weight gain is a common cause of nonadherence to treatment and of
requests to discontinue or switch antipsychotic medication.
Compared to FGAs, SGAs are associated with greater risk of glucose abnormalities including hyperglycemia, insulin
resistance, new onset type 2 diabetes, exacerbation of type 1 diabetes and diabetic ketoacidosis.60 This is a
concern because type 2 diabetes is 2–4 times more prevalent in individuals with schizophrenia compared to the
general population, and abnormal glucose tolerance and insulin resistance are also more common.61
There are different degrees of risk among SGAs for glucose abnormalities (independent of risks for weight gain);
clozapine and olanzapine have the highest risk. In Canada, all SGAs carry a warning about potential glucose
abnormalities.62
Hyperlipidemia has been associated with clozapine and olanzapine. Increased triglycerides have been reported with
quetiapine. Aripiprazole, paliperidone, risperidone and ziprasidone have not been associated with dyslipidemia.63 ,
64 Switching to ziprasidone from other agents such as olanzapine or quetiapine has demonstrated improvements in
dyslipidemia.59
Cardiovascular Side Effects
Orthostatic hypotension is the most common antipsychotic-induced cardiovascular side effect, particularly in elderly
patients or those with heart disease or diabetes. It is more common with low-potency first-generation
antipsychotics and with clozapine, but can occur with aripiprazole, olanzapine, quetiapine or risperidone.
Prolongation of the QTc interval is associated with the potentially lethal paroxysmal ventricular cardiac arrhythmia,
torsades de pointes, which can cause recurrent syncope, ventricular fibrillation and sudden cardiac death. Clinically,
a QTc interval of > 450 msec is concerning.65
QTc prolongation occurs with chlorpromazine, pimozide (particularly at doses > 8 mg/day) and haloperidol,
although the incidence is low. The SGAs olanzapine, quetiapine and risperidone cause modest QTc prolongation
(mean < 30 msec).66 Potentially clinically significant QTc prolongation is infrequent with clozapine (1/100 to
1/1000 patients)67
ziprasidone has a greater (though modest) capacity for QTc interval prolongation compared to other
antipsychotics. It is contraindicated in individuals with a known history of QTc interval prolongation, including
congenital long QTc syndrome or individuals with recent acute myocardial infarction or uncompensated heart
failure. Before initiating therapy in individuals at risk for electrolyte disturbance, particularly hypokalemia
and/or hypomagnesemia (e.g., history of kidney disease, diuretic therapy, water intoxication, eating disorders,
prolonged vomiting/diarrhea, alcoholism), measure baseline electrolytes and correct abnormalities
ziprasidone is contraindicated with any other drug that is known to prolong QTc interval or has demonstrated
QTc prolongation as a pharmacodynamic effect
Antipsychotic drugs in general confer a dose-related increase in the risk of sudden cardiac death.68
Clozapine is associated with an increased risk of myocarditis (especially in but not limited to the first month of
therapy), pericarditis, pericardial effusion, cardiomyopathy, heart failure, myocardial infarction and mitral
insufficiency. If signs and symptoms of any of these disorders appear, seek urgent assessment by a cardiologist.
Endocrine and Sexual Side Effects
Hyperprolactinemia is a common side effect of FGAs (especially high-potency agents such as haloperidol),
risperidone and paliperidone (especially at higher doses). Transient hyperprolactinemia can occur with olanzapine.
No differences in prolactin levels have been found with aripiprazole, clozapine or quetiapine compared to
placebo.69 , 70
hyperprolactinemia often causes no clinically significant effects but can be associated with menstrual
irregularities and galactorrhea in women, galactorrhea and gynecomastia in men and sexual dysfunction in
both men and women; sexual dysfunction, however, is associated with all antipsychotics independent of
prolactin elevation
Page 1030
Therapeutic Choice
reducing the antipsychotic dose is the first approach to the management of clinically significant side effects due
to hyperprolactinemia
Table 3: Antipsychotic-induced Side Effects: Assessment, Monitoring and Management 8 , 71
Side Effect Assessment, Monitoring and Management
Neuroleptic malignant Assessment: physical exam with focus on level of consciousness; vital signs (fever,
syndrome tachycardia, fluctuations in BP); look for evidence of muscle rigidity
Monitoring: rare, but can occur with any antipsychotic at any dose and at any time; risk
factors include young age, male gender, neurologic disabilities, dehydration, agitation,
exhaustion, rapid or parenteral administration of antipsychotic
Management: medical emergency; discontinue antipsychotic and provide supportive care
(hydration and cooling); other measures may include dantrolene 2–3 mg/kg TID to QID
iv (max 10 mg/kg daily) and/or bromocriptine 2.5–5 mg TID po, increasing by 2.5 mg
TID Q24H (max 60 mg daily)34
Sedation and cognitive Assessment: ask patient about daytime drowsiness, excessive sleep, cognitive “dulling”;
effects obtain collateral information from caregivers and family
Monitoring: see outpatients at least weekly for first 4–6 wk after initiating new
antipsychotic
Management: use SGAs as first-line treatment to reduce risk of cognitive side effects;
low initial dose and gradual titration based on degree of sedation (especially with
clozapine and first-episode psychosis). Give entire daily dose at HS if possible to reduce
daytime drowsiness; do not use anticholinergic antiparkinsonian agents prophylactically
and avoid prolonged use when treating acute EPS
Extrapyramidal side Assessment: rating scales such as Simpson Angus Scale, Barnes Akathisia Scale or
effects (EPS; dystonia, Extrapyramidal Syndrome Rating Scale (ESRS)72 are useful to assess EPS and the
parkinsonism, akathisia, Abnormal Involuntary Movement Scale or the ESRS is used to assess tardive dyskinesia
tardive dyskinesia, (TD)
tardive dystonia, tardive Monitoring: baseline assessment in antipsychotic-naïve first-episode patients, in
akathisia) multiple-episode patients when initiating a new antipsychotic, and in first-episode and
multiple-episode patients whenever dosage of antipsychotic is changed; assess weekly for
2–4 wk or until EPS resolves; in stable patients assess for TD every 6 mo or more often in
patients at higher risk (on FGAs, erratic medication adherence or intermittent treatment,
female, age > 55, diagnosis of an affective disorder, substance abuse, diabetes)
Management: Prevention is key—use SGAs first-line; if EPS occurs, first reduce dose;
consider switch to SGA if on FGA; prophylactic use of anticholinergics such as
benztropine, procyclidine and trihexyphenidyl is not recommended even with FGAs, and
should usually be used only on a short-term basis to treat parkinsonism associated with
FGAs;73 anticholinergics are generally not recommended with SGAs74
For akathisia, if dose reduction is not effective, beta-blockers (e.g., propranolol 10–120
mg/day) are the treatment of choice with monitoring for hypotension; benzodiazepines
also provide symptom relief; anticholinergics are ineffective
IM benztropine or diphenhydramine can be used to treat acute dystonia (acute
torticollis or oculogyric crisis), followed by reduction in dose or switch to SGA
There is no evidence-based treatment for TD—prevention is key—use SGAs first-line;
antiparkinsonian medications are not effective and may worsen symptoms; if TD occurs
suggest consultation with a psychiatrist; consider switching to an SGA; consider clozapine
trial for persistent, severe TD
Weight gain Assessment: baseline weight, body mass index (BMI) and waist circumference
Monitoring: weight and BMI monthly for 6 mo with new antipsychotic then every 3 mo
when on a stable dosage; waist circumference annually
Management: prevention is critical as weight reduction is especially difficult in
individuals with mental illness; educate about risk of weight gain and provide dietary and
exercise counselling; if weight increases > 7% over baseline, implement behavioural
weight reduction program; if unsuccessful assess risks/benefits of continuing current
antipsychotic vs. switching; no consistent evidence of efficacy of adjunctive weight loss
pharmacotherapy
Glucose Assessment: baseline fasting plasma glucose; HbA1c if difficult to obtain fasting plasma
abnormalities glucose; oral glucose tolerance test (OGTT) if evidence of impaired glucose tolerance;
obtain family history and medical history
Monitoring: enquire about signs and symptoms of emergent diabetes; fasting plasma
Page 1031
Therapeutic Choice
Side Effect Assessment, Monitoring and Management
glucose 12 wk after initiating new antipsychotic, then yearly; more frequent monitoring
required if significant weight gain or if symptomatic; OGTT if evidence of impaired glucose
tolerance
Management: educate about signs and symptoms of emergent diabetes; if diabetes is
diagnosed, follow the Canadian Diabetes Association Guidelines (www.diabetes.ca/for-
professionals/resources/2008-cpg/); consider switching to another antipsychotic
Dyslipidemias Assessment: baseline fasting lipid profile (total cholesterol, LDL, HDL, triglycerides)
Monitoring: fasting lipid profile at 12 wk after initiation of a new antipsychotic, then
annually; more frequent monitoring if significant weight gain, and every 6 mo if LDL
and/or triglycerides above the normal range
Management: change in diet; consider switching to ziprasidone59 , 75; consult clinical
guidelines for management of dyslipidemia at www.cmaj.ca and
www.nhlbi.nih.gov/guidelines/cholesterol/index.htm
Cardio- Assessment: baseline vital signs; obtain family history and medical history; ECG in
vascular side effects individuals >40 y and as clinically indicated
Monitoring: blood pressure at 12 wk then annually (monitor more frequently when
initiating clozapine, until stable dose reached); vital signs and ECG as clinically indicated
and with changes in medication; monitor QTc when affected by multiple medications
Management: educate about risks and prevention of orthostatic hypotension; if
symptoms persist, decrease dose of antipsychotic if possible or switch to another
antipsychotic
Endocrine and sexual Assessment: baseline functional inquiry including menstrual history and libido in women
side effects and libido, erectile and ejaculatory function in men; baseline prolactin level in first
episode psychosis, before initiating antipsychotic associated with hyperprolactinemia and
when clinically indicated
Monitoring: monitor monthly for 3 mo after initiating a new antipsychotic, then yearly.
Management: determine underlying cause of endocrine or sexual dysfunction and treat
accordingly; consider drugs for erectile dysfunction
For clinically significant hyperprolactinemia, first reduce dose of antipsychotic; if dose
reduction not tolerated (emergence of or increase in psychotic symptoms) consider
switching to an antipsychotic not associated with risk of hyperprolactinemia
Teratogenic effects have not been demonstrated with the use of antipsychotics during pregnancy. Their use is best
avoided during the first trimester, but risks and benefits must be carefully weighed for each patient. Hypertonia in
neonates has been noted following prepartum use of high-potency FGAs.
For a discussion of general principles of drug use during pregnancy and lactation see Appendix: Drug Use During
Pregnancy and Appendix: Drug Use During Lactation. For more detailed information on the use of specific medications
during pregnancy and lactation the reader is referred to Motherisk (www.motherisk.org/women/drugs.jsp); Briggs GG,
Freeman RK, Yaffe SJ. Drugs in Pregnancy and Lactation 2008; LactMed (http://toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen?
LACT); and Hale TW. Medications and Mothers' Milk 2008.
Therapeutic Tips
Initiate treatment before the development of a crisis such as self-harm, aggression or violence.8 , 24
Provide treatment in the least restrictive setting, considering safety issues, availability of community resources
(including both caregiver and mental health supports), the patient’s insight and competency to consent to treatment
and ability to cooperate with treatment.8 , 24
Integrate psychosocial interventions such as patient and family psychoeducation, supportive therapy and stress
management with the use of antipsychotic medications in order to promote adherence to treatment and optimize
outcomes.8 , 24
Conduct baseline and regular ongoing assessments of signs and symptoms, possible comorbid conditions, level of
functioning, response to treatment, side effects and medication adherence during all phases of the disorder. A
variety of standardized scales and semi-structured interviews facilitate these assessments.8
Page 1032
Therapeutic Choice
To ensure continuity of care, longitudinal follow-up by the same clinician or multidisciplinary team is optimal.8 , 24
Figure 1- Management of Acute Psychotic Episodes
Abbreviations: BDZ = benzodiazepines; DUP = duration of untreated psychosis; EPS = extrapyramidal symptoms; TD = tardive
dyskinesia
Table 4: Second-generation Antipsychotics
Drug Costa
Second- aripiprazole Initial: 10–15 Akathisia, Carbamazepine (or Advise $$
Page 1033
Therapeutic Choice
Drug Costa
generation Abilify mg/day po dizziness, other strong patients about

Antipsychotics Titration: if orthostatic inducers of antipsychotic-
necessary increase hypotension, CYP2D6 or CYP3A4 associated
dose after 2 wk headache, GI such as phenytoin, body
complaints, tremor, rifampin) can ↓ temperature
Max: 30 mg/day sedation. aripiprazole levels dysregulation
significantly. and
Ketoconazole, prevention of
quinidine, heat stroke
fluoxetine or (e.g.,
paroxetine (or hydration, sun
other strong protection).
inhibitors of
CYP2D6 or
CYP3A4) can ↑
levels
substantially.
Second- clozapine Initial: Agranulocytosis (< Additive sedation Advise $$$$

generation Clozaril, Gen- 12.5–25 mg/day po 1%), seizures (5%, with CNS patients about
Antipsychotics Clozapine, Titration: increase dose related), depressants; may antipsychotic-
generics by 12.5–25 mg on sedation, potentiate associated
second day and then orthostatic antihypertensive body
by 25–50 mg po hypotension, drug effects; temperature
daily depending on tachycardia, fever, inhibitors of dysregulation
tolerance nausea, weight CYP1A2 (e.g., and
gain, diltiazem, prevention of
Usual: hypersalivation, fluvoxamine, heat stroke
300–600 mg/day po urinary propranolol) or (e.g.,
incontinence; ↑ risk CYP3A4 (e.g., hydration, sun
Max: 900 mg/day of diabetes and clarithromycin, protection).
hyperlipidemia; erythromycin,
Divided in 1–3 myocarditis and grapefruit juice,
doses/day other cardiac prednisone) may ↑
effects (see clozapine levels;
Pharmacologic inducers of
Choices). CYP1A2 or CYP3A4
(e.g.,
carbamazepine,
phenytoin,
rifampin,
smoking), may ↓
clozapine levels;
respiratory
depression with
higher doses of
benzodiazepines;
avoid use with
bone marrow
suppressants and
drugs that lower
the seizure
threshold.
Second- olanzapine Initial: 5–10 Weight gain, Sedation with CNS Advise $$
generation Zyprexa, mg/day dizziness, sedation, depressants; may patients about
Antipsychotics Zyprexa Titration: increase anticholinergic potentiate antipsychotic-
by 2.5–5 mg every effects, hepatic antihypertensive associated
Zydis,
3–4 days transaminase drug effects; body
generics
elevation, inhibitors of temperature
(rapid-
Usual: 10–20 orthostatic CYP1A2 or CYP2D6 dysregulation
dissolving
mg/day hypotension, ↑ risk (e.g., diltiazem, and
oral tablets)
of diabetes and fluvoxamine, prevention of
Max: 20 mg/day dyslipidemia, EPS paroxetine) may ↑ heat stroke
(product (especially olanzapine levels; (e.g.,
Page 1034
Therapeutic Choice
Drug Costa
monograph). Doses akathisia). inducers of hydration, sun

of up to 40 mg/day CYP1A2 or CYP3A4 protection).
are used in clinical (e.g., barbiturates,
practice under care carbamazepine,
of a psychiatrist phenytoin,
rifampin, smoking)
Frequency: one may ↓ olanzapine
dose/day; higher levels.
doses may be given
in 2 divided doses
Second- olanzapine Initial: 5–10 mg im Weight gain, Sedation with CNS Advise $$$$
generation injection Usual: 10 mg im. If dizziness, sedation, depressants; may patients about
Antipsychotics Zyprexa necessary 2nd dose anticholinergic potentiate antipsychotic-
Intramuscular of 5–10 mg im may effects, hepatic antihypertensive associated
be given 2 h after transaminase drug effects; body
first injection elevation, inhibitors of temperature
orthostatic CYP1A2 or CYP2D6 dysregulation
Max: 20 mg/day hypotension, ↑ risk (e.g., diltiazem, and
(oral and im) with of diabetes and fluvoxamine, prevention of
no more than 3 dyslipidemia, EPS paroxetine) may ↑ heat stroke
injections in 24 h (especially olanzapine levels; (e.g.,
akathisia). inducers of hydration, sun
CYP1A2 or CYP3A4 protection).
(e.g., barbiturates,
carbamazepine,
phenytoin,
rifampin, smoking)
may ↓ olanzapine
levels.
Should not be
administered
simultaneously
with parenteral
benzodiazepines
due to reports of
cardiac and
respiratory
problems including
deaths.
Second- paliperidone Initial: 3–6 mg po Insomnia, Minimal risk of Advise $$

generation daily headaches, weight drug interactions patients about
Antipsychotics Invega If necessary gain, orthostatic due to lack of liver antipsychotic-
increase by 3 mg hypotension, metabolism. associated
per day at 5-day rhinitis, anxiety, Carbamazepine body
intervals dose-related may decrease temperature
hyperprolactinemia paliperidone dysregulation
Max: 12 mg daily and EPS. serum and
concentrations. prevention of
heat stroke
(e.g.,
hydration, sun
protection).
Second- quetiapine Initial: 50–100 Sedation, dizziness, Additive sedation Advise $$

generation immediate- mg/day weight gain, with CNS patients about
Antipsychotics release Titration: increase orthostatic depressants; may antipsychotic-
Seroquel, by 100 mg/day hypotension, potentiate associated
generics hepatic antihypertensive body
Usual: 600 mg/day transaminase drug effects; temperature
Page 1035
Therapeutic Choice
Drug Costa
elevation, inhibitors of dysregulation

Max: 800 mg/day headache, CYP3A4 (e.g., and
(product anticholinergic clarithromycin, prevention of
monograph). Doses effects, ↑ risk of erythromycin, heat stroke
of up to 1200 diabetes and grapefruit juice, (e.g.,
mg/day used in dyslipidemia, ketoconazole, hydration, sun
clinical practice possible ↑ risk of prednisone) may ↑ protection).
under care of a cataracts; may ↓ quetiapine levels;
psychiatrist thyroid hormone inducers of
levels. CYP3A4 (e.g.,
Divided in 1–3 carbamazepine,
doses/day phenytoin,
rifampin) may ↓
quetiapine levels.
Second- quetiapine Initial: 300 mg po Sedation, dizziness, Additive sedation Advise $$$
generation extended- QHS (200 mg for weight gain, with CNS patients about
Antipsychotics release first-episode orthostatic depressants; may antipsychotic-
Seroquel XR psychosis) hypotension, potentiate associated
Titration: May ↑ hepatic antihypertensive body
dose in increments transaminase drug effects; temperature
of ≤ 300 mg/day at elevation, inhibitors of dysregulation
intervals ≥ 1 day headache, CYP3A4 (e.g., and
anticholinergic clarithromycin, prevention of
Usual: 400–800 effects, ↑ risk of erythromycin, heat stroke
mg/day diabetes and grapefruit juice, (e.g.,
dyslipidemia, ketoconazole, hydration, sun
Given as a once- possible ↑ risk of prednisone) may ↑ protection).
daily dose, cataracts; may ↓ quetiapine levels;
generally in the thyroid hormone inducers of
evening levels. CYP3A4 (e.g.,
carbamazepine,
phenytoin,
rifampin) may ↓
quetiapine levels.
Second- risperidone Initial: Insomnia, Additive sedation Advise $

generation 0.5–1 mg/day po headaches, weight with CNS patients about
Antipsychotics Risperdal, Titration: increase gain, orthostatic depressants; may antipsychotic-
generics; 0.5–1 mg po every hypotension, potentiate associated
3–4 days rhinitis, anxiety, antihypertensive body
Risperdal M
dose-related drug effects; temperature
Tabs (rapid- Usual: hyperprolactinemia inhibitors of dysregulation
dissolving 2–6 mg/day po and EPS. CYP3A4 (e.g., and
oral tablets) clarithromycin, prevention of
Max: 8 mg/day po erythromycin, heat stroke
grapefruit juice, (e.g.,
Frequency: 1 ketoconazole, hydration, sun
dose/day, preferably prednisone) may ↑ protection).
HS risperidone levels;
inducers of
CYP3A4 (e.g.,
carbamazepine,
phenytoin,
rifampin) may ↓
risperidone levels.
Second- risperidone Initial: 25 mg im Insomnia, Additive sedation Advise $$$$

generation long-acting every 2 wk (oral headaches, weight with CNS patients about
Antipsychotics injection supplementation gain, orthostatic depressants; may antipsychotic-
Risperdal with current hypotension, potentiate associated
antipsychotic rhinitis, anxiety, antihypertensive body
Consta
required for first 3 dose-related drug effects; temperature
wk) hyperprolactinemia inhibitors of dysregulation
Page 1036
Therapeutic Choice
Drug Costa
Titration: depending and EPS. Adverse CYP3A4 (e.g., and

on response, effects may be less clarithromycin, prevention of
increase by 12.5 mg severe compared to erythromycin, heat stroke
every 4–8 wk oral risperidone grapefruit juice, (e.g.,
due to decreased ketoconazole, hydration, sun
Usual: 25–37.5 mg peak to trough prednisone) may ↑ protection).
im every 2 wk. serum fluctuations. risperidone levels;
Some patients can inducers of
be maintained on a CYP3A4 (e.g.,
dose of 12.5 mg carbamazepine,
every 2 wk phenytoin,
rifampin) may ↓
Max: 50 mg im risperidone levels.
every 2 wk
Second- ziprasidone Start with 40 mg po Orthostatic Contraindicated Administer $$$

generation Zeldox BID (20 mg BID for hypotension, EPS, with any other with meals of
Antipsychotics antipsychotic-naïve sedation. drug that prolongs ≥ 500 kcal to
first-episode Prolonged QT- the QTc interval; maximize
patients) and interval; may potentiate absorption
rapidly titrate in the contraindicated in antihypertensive and
first wk up to 120– patients with drug effects. therapeutic
160 mg/day history of QTc effect. Advise
Administer doses prolongation, patients about
with food (see recent MI, antipsychotic-
Comments) uncompensated associated
heart failure or with body
concomitant use of temperature
any other drug that dysregulation
prolongs the QTc and
prevention of
interval.
heat stroke
(e.g.,
Rapid titration is
hydration, sun
recommended to
protection).
prevent
ziprasidone-
induced “activation”
syndrome
consisting of
anxiety,
restlessness,
insomnia, increased
energy and
hypomanic-like
symptoms which
develop soon after
treatment initiation
and occur at the
lower end of the
dosage range (20–
40 mg po BID).
a. Cost of 30-day supply of mean usual dose; includes drug cost only.
Abbreviations: EPS=extrapyramidal symptoms
Page 1037
Therapeutic Choice
Legend: $ < $100 $$ $100–250 $$$ $250–375 $$$$ > $375
Table 5: First-generation Antipsychotics
Adverse Drug Costa

First- chlorpromazine Initial: First-generation First-generation Advise $$

generation generics 50–100 mg/day po antipsychotics: antipsychotics: patients about
Antipsychotics, Usual: sedation, additive effects antipsychotic-
low potency 200–400 mg/day po cardiovascular with other CNS associated
effects, depressants, body
Max: anticholinergic anticholinergics, temperature
1000–2000 mg/day po effects, weight alpha- dysregulation
gain, ↓ seizure adrenergic and
Divided in 1–3 threshold, antagonists; prevention of
doses/day photosensitivity inhibitors of heat stroke
(more common cytochrome (e.g.,
with low P450 enzymes hydration,
potency agents) (e.g., TCAs, sun
↑ prolactin, fluoxetine, protection).
EPS, NMS, fluvoxamine,
tardive paroxetine) may
movement ↑ serum levels;
disorders (more inducers of
common with cytochrome
high-potency P450 enzymes
agents), liver (e.g.,
function carbamazepine,
abnormalities. phenytoin) may
↓ serum levels;
effects of
levodopa may
be inhibited.
First- methotrimeprazine Initial: 25–75 mg/day First-generation First-generation Advise $

generation po antipsychotics: antipsychotics: patients about
Antipsychotics, Nozinan, generics Usual: 100–200 sedation, additive effects antipsychotic-
low potency mg/day po cardiovascular with other CNS associated
Max: 1000 mg/day po anticholinergic anticholinergics, temperature
effects, weight alpha- dysregulation
Divided in 1–3 gain, ↓ seizure adrenergic and
doses/day threshold, antagonists; prevention of
photosensitivity inhibitors of heat stroke
↓ serum levels;
effects of
levodopa may
be inhibited.
First- loxapine Initial: 10–20 mg/day First-generation First-generation Advise $

generation generics po antipsychotics: antipsychotics: patients about
Antipsychotics, Usual: 20–100 sedation, additive effects antipsychotic-
intermediate mg/day po cardiovascular with other CNS associated
potency effects, depressants, body
Page 1038
Therapeutic Choice
Adverse Drug Costa


↓ serum levels;
effects of
levodopa may
be inhibited.
First- perphenazine Initial: 4–12 mg/day First-generation First-generation Advise $

Antipsychotics, Usual: 12–48 mg/day sedation, additive effects antipsychotic-
intermediate po cardiovascular with other CNS associated
Max: 48–64 mg/day anticholinergic anticholinergics, temperature
po effects, weight alpha- dysregulation
Divided in 2–3 threshold, antagonists; prevention of
doses/day photosensitivity inhibitors of heat stroke
↓ serum levels;
effects of
levodopa may
be inhibited.
First- zuclopenthixol Initial: 10–20 mg/day First-generation First-generation Advise $$$

generation Clopixol po antipsychotics: antipsychotics: patients about
intermediate po cardiovascular with other CNS associated
Page 1039
Therapeutic Choice
Adverse Drug Costa


↓ serum levels;
effects of
levodopa may
be inhibited.
First- zuclopenthixol Range: 100–400 mg First-generation First-generation Advise $$

generation decanoate long- im Q2–4 wk antipsychotics: antipsychotics: patients about
Antipsychotics, acting injection Usual dose: sedation, additive effects antipsychotic-
intermediate Clopixol Depot 150–300 mg im cardiovascular with other CNS associated
potency Q2–4 wk effects, depressants, body
anticholinergic anticholinergics, temperature
threshold, antagonists; prevention of
↓ serum levels;
effects of
levodopa may
be inhibited.
First- flupenthixol Initial: 3–6 mg/day po First-generation First-generation Advise $$$$

generation Fluanxol Usual: 9–24 mg/day antipsychotics: antipsychotics: patients about
Antipsychotics, po sedation, additive effects antipsychotic-
high potency cardiovascular with other CNS associated
Max: 12–24 mg/day effects, depressants, body
po anticholinergic anticholinergics, temperature
Divided in 2 gain, ↓ seizure adrenergic and
↓ serum levels;
effects of
Page 1040
Therapeutic Choice
Adverse Drug Costa

levodopa may
be inhibited.
First- flupenthixol Range: 20–100 mg im First-generation First-generation Advise $$

generation decanoate long- Q2–3 wk antipsychotics: antipsychotics: patients about
Antipsychotics, acting injection Usual dose: 20–40 mg sedation, additive effects antipsychotic-
high potency Fluanxol Depot im Q2–3 wk cardiovascular with other CNS associated
↓ serum levels;
effects of
levodopa may
be inhibited.
First- fluphenazine Initial: 2–5 mg/day po First-generation First-generation Advise $

generation generics Usual: 2.5–10 mg/day antipsychotics: antipsychotics: patients about
Max: 20 mg/day po effects, depressants, body
Divided in 1–2 effects, weight alpha- dysregulation
doses/day gain, ↓ seizure adrenergic and
↓ serum levels;
effects of
levodopa may
be inhibited.
First- fluphenazine Range: 12.5–100 mg First-generation First-generation Advise $$$

generation decanoate long- im Q2–3 wk antipsychotics: antipsychotics: patients about
Antipsychotics, acting injection Usual dose: 25–50 mg sedation, additive effects antipsychotic-
high potency Modecate im Q2–3 wk cardiovascular with other CNS associated
Page 1041
Therapeutic Choice
Adverse Drug Costa


EPS, NMS, fluvoxamine, Though im
tardive paroxetine) may route is
movement ↑ serum levels; preferred, can
disorders (more inducers of be given sc.
↓ serum levels;
effects of
levodopa may
be inhibited.
First- haloperidol Initial: 1.5–3 mg/day First-generation First-generation Advise $

generation generics Usual: 4–12 mg/day antipsychotics: antipsychotics: patients about
↓ serum levels;
effects of
levodopa may
be inhibited.
First- haloperidol Range/usual dose: First-generation First-generation Advise $$

generation decanoate long- 50–300 mg im Q4 wk antipsychotics: antipsychotics: patients about
Antipsychotics, acting injection sedation, additive effects antipsychotic-
high potency generics cardiovascular with other CNS associated
EPS, NMS, fluvoxamine, Dose is
tardive paroxetine) may approximately
Page 1042
Therapeutic Choice
Adverse Drug Costa

movement ↑ serum levels; 10–15 × daily

disorders (more inducers of oral dose.
↓ serum levels;
effects of
levodopa may
be inhibited.
First- pimozide Initial: 2–4 mg/day po First-generation First-generation Advise $

generation Orap, Apo- Usual: 2–12 mg/day antipsychotics: antipsychotics: patients about
Antipsychotics, Pimozide, other sedation, additive effects antipsychotic-
high potency generics Max: 12 mg/day po cardiovascular with other CNS associated
Divided in 1–2 anticholinergic anticholinergics, temperature
doses/day effects, weight alpha- dysregulation
Pimozide: QTc ↓ serum levels;
prolongation effects of
with doses > 8 levodopa may
mg/day. be inhibited.
Pimozide: avoid
use with
sertraline due to
↑ risk of QTc
prolongation.
First- pipotiazine Range: 25–250 mg im First-generation First-generation Advise $$$

generation decanoate long- Q4 wk antipsychotics: antipsychotics: patients about
Antipsychotics, acting injection Usual dose: sedation, additive effects antipsychotic-
high potency Piportil L4 75–150 mg im Q4 wk cardiovascular with other CNS associated
Page 1043
Therapeutic Choice
Adverse Drug Costa


↓ serum levels;
effects of
levodopa may
be inhibited.
First- thiothixene Initial: 5–10 mg/day First-generation First-generation Advise $$

generation Navane Usual: 15–30 mg/day antipsychotics: antipsychotics: patients about
↓ serum levels;
effects of
levodopa may
be inhibited.
First- trifluoperazine Initial: 2–10 mg/day First-generation First-generation Advise $

high potency po cardiovascular with other CNS associated
↓ serum levels;
effects of
levodopa may
be inhibited.
Page 1044
Therapeutic Choice
a. Cost of 30-day supply of mean usual dose unless otherwise specified; includes drug cost only.
Legend: $ < $25 $$ $25–50 $$$ $50–75 $$$$ $75–100 $$$$$ > $100
Abbreviations: BDZs=benzodiazepines; CV=cardiovascular; EPS=extrapyramidal symptoms; NMS=neuroleptic malignant
syndrome; TCAs=tricyclic antidepressants
Suggested Readings
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Gardner DM, Baldessarini RJ, Waraich P. Modern antipsychotic drugs: a critical overview. CMAJ 2005;172(13):1703-11.
Meltzer HY, Kostakoglu AE. Treatment-resistant schizophrenia. In: Lieberman JA, Murray RM, editors. Comprehensive
care of schizophrenia: a textbook of clinical management. London (UK): Martin Dunitz; 2001. p. 181-203.
Newcomer JW, Haupt DW. The metabolic effects of antipsychotic medications. Can J Psychiatry 2006;51(8):480-91.
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Siegfried SI, Fleischhacker W, Lieberman JA. Pharmacological treatment of schizophrenia. In: Lieberman JA, Murray RM,
editors. Comprehensive care of schizophrenia: a textbook of clinical management. London (UK): Martin Dunitz; 2001. p.
59-94.
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to haloperidol. Arch Med Res 2002;33(6):562-5.
70. Knegtering H, van der Moolen AE, Castelein S et al. What are the effects of antipsychotics on sexual dysfunctions
and endocrine functioning? Psychoneuroendocrinology 2003;28(Suppl 2):109-23.
71. Cohn TA, Sernyak MJ. Metabolic monitoring for patients treated with antipsychotic medications. Can J Psychiatry
2006;51(8):492-501.
72. De Deyn PP, Wirshing WC. Scales to assess efficacy and safety of pharmacologic agents in the treatment of
behavioral and psychological symptoms of dementia. J Clin Psychiatry 2001;62(Suppl 21):19-22.
73. Stahl SM, Grady MM. A critical review of atypical antipsychotic utilization: comparing monotherapy with
polypharmacy and augmentation. Curr Med Chem 2004;11(3):313-27.
74. Serretti A, De Ronchi D, Lorenzi C et al. New antipsychotics and schizophrenia: a review on efficacy and side
effects. Curr Med Chem 2004;11(3):343-58.
75. Weiden PJ. Switching antipsychotics as a treatment strategy for antipsychotic-induced weight gain and
dyslipidemia. J Clin Psychiatry 2007;68(Suppl 4):34-9.
Pharmacoeconomic Considerations: Psychoses

Epidemiology
Canada & Worldwide1 , 2 , 3 , 4 , 5 1%
Canada (2004)5 $2.02 billion $4.83 billion
Commentary
Schizophrenia is associated with significant economic burden from a patient, health care and societal perspective.
Direct medical resources consumed in the care of patients with schizophrenia include physician visits, emergency
department visits, acute and non-acute hospitalizations and residential care facilities. Nonmedical resources include
social services and other government services, e.g., police, prisons. Lost work productivity is an important economic
impact of schizophrenia. The average annual income of employed schizophrenics is relatively low, indicating
underemployment.5 A high proportion (30–70%) of individuals with schizophrenia are unemployed.5
Intangible costs (e.g., pain, suffering) associated with schizophrenia have not been well documented but may also
have a significant impact on the overall societal costs of schizophrenia.
Newer atypical antipsychotic agents have higher acquisition costs compared with older antipsychotics. Atypical
antipsychotics may reduce noncompliance relative to older antipsychotic agents.6 In almost all published
pharmacoeconomic analyses, atypical antipsychotic agents have been found to be cost-effective when compared with
conventional antipsychotic agents, leading to reductions in hospitalization, use of other medical resources and
improvements in quality of life.6 , 7 , 8 , 9 Few economic evaluations have compared atypical antipsychotic agents
with one another, although the majority of these analyses have been sponsored by pharmaceutical manufacturers.
b. Indirect costs include those associated with lost productivity and days off work due to morbidity or premature mortality.
1. Goldner EM, Hsu L, Waraich P et al. Prevalence and incidence studies of schizophrenic disorders: a systematic
review. Can J Psychiatry 2002;47(9):833-43.
2. World Health Organization. Mental and neurological disorders. Fact sheet no. 265. Geneva (CH): WHO; December
2001.
Page 1048
Therapeutic Choice
3. Bresnahan M, Menezes P, Varma V et al. Geographical variation in incidence, course and outcome in
schizophrenia: a comparison of developing and developed countries. In: Murray R, Jones P, Susser E et al,
editors. Epidemiology of schizophrenia. New York (NY): Cambridge University Press; 2003.
4. Saha S, Chant D, Welham J et al. A systematic review of the prevalence of schizophrenia. PLoS Med 2005;2
(5):e141.
5. Goeree R, Farahati F, Burke N et al. The economic burden of schizophrenia in Canada in 2004. Curr Med Res Opin
2005;21(12):2017-28.
6. Dolder CR, Lacro JP, Dunn LB et al. Antipsychotic medication adherence: is there a difference between typical
and atypical agents? Am J Psychiatry 2002;159(1):103-8.
7. Rosenheck R, Perlick D, Bingham S et al. Effectiveness and cost of olanzapine and haloperidol in the treatment of
schizophrenia: a randomized controlled trial. JAMA 2003;290(20):2693-702.
8. Palmer CS, Revicki DA, Genduso LA et al. A cost-effectiveness clinical decision analysis model for schizophrenia.
Am J Manag Care 1998;4(3):345-55.
9. Rosenheck R, Leslie DL, Sindelar J et al. Cost-effectiveness of second-generation antipsychotics and
perphenazine in a randomized trial of treatment for chronic schizophrenia. Am J Psychiatry 2006;163(12) 2080-
9.
Page 1049
e-Therapeutics+ : Therapeutics : Psychiatric Disorders: Smoking Cessation Page 1 of 10
Therapeutic Choice
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Psychiatric Disorders: Smoking Cessation
Peter Selby, MBBS, CCFP
Tobacco use kills approximately 48 000 Canadians annually, primarily from cardiac disease, lung cancer and
respiratory diseases such as COPD.1 The toxicity of cigarette smoke is due to the inhalation of about 4000 chemicals
including 50 to 60 carcinogens.2 Cigarettes are highly addictive because of the rapid delivery of nicotine to the
mesolimbic reward pathways in the brain and development of tolerance. The short half-life of nicotine (60 to 90
minutes) forces repeated administration to maintain nicotine levels.3 Other psychoactive compounds in smoke
include MAOA and MAOB inhibitors.4 The polyaromatic hydrocarbons (PAHs) are inducers of CYP1A1, 1A2 and 2E1
enzymes that have clinical implications when smokers quit.5
Goals of Therapy8
The ultimate goal is to help smokers achieve complete and sustained remission from tobacco use and nicotine
dependence
An intermediate goal is to help them achieve complete and sustained remission from cigarette smoking and/or
other forms of tobacco products such as chewing tobacco
To help smokers understand that:
smoking cessation is a process not a singular event; helping smokers stay engaged in the process of
behaviour change is a major objective of therapy
the best odds of quitting are when behavioural and pharmacologic interventions complement each other
reduction in smoking by 50% in those unable or unwilling to quit is controversial because there is no long-
term health benefit.9 However, reduction is associated with subsequent successful quitting10
Investigations (Figure 1 - Tobacco-smoking History Questionnaire )
Figure 1 - Tobacco-smoking History Questionnaire provides a general assessment questionnaire for patients
who have not previously stopped smoking for more than 24 hours
Measures of physical dependence include the Fagerström Test of Nicotine Dependence11. A shorter version is
the Heaviness of Smoking Index, which asks about the time to first cigarette of the day and the number of
cigarettes smoked per day12
Motivation can be assessed by asking the following two questions:3
“Given everything going on in your life right now, on a scale of 1 to 10, where 10 is the most important
thing to do right now, how important is it for you to quit smoking altogether?”
“Given everything going on in your life right now, on a scale of 1 to 10, where 10 is the most confident you
have felt about anything, how confident do you feel you will be able to quit smoking altogether?”
Therapeutic Choices (Figure 2 - Management of Smoking Cessation, Table 2)
This chapter will focus on smokers who want to quit in the next 30 days.
Most smokers try to quit on several occasions though success rates over the long term are generally low. Many
methods for quitting smoking have been advocated; however, few have been demonstrated to be effective. This type
of evidence generally requires randomized controlled trials with a minimum follow-up assessment of self-reported
quit rates at six months along with supportive objective evidence, e.g., measurement of exhaled carbon monoxide
or cotinine levels in urine, saliva or serum.8 Though widely promoted, there is no evidence for the efficacy of
hypnosis or acupuncture.
The five evidence-based steps required to successfully quit include the following8
setting a target quit date

getting professional help
enlisting social support
using medication to quit smoking
using problem-solving methods of counselling to quit and remain smoke free.
Page 1050
Therapeutic Choice
There is a dose-response relationship between counselling and quit success.8 Estimated abstinence rates increase
from 13.4% with minimal counselling contact time (< 3 minutes) to an average of 22% with contact time > 10
minutes. Optimal total contact time is 91–300 minutes, yielding abstinence rates of approximately 28%.8 Smokers
who are attempting to quit should be counselled at least once prior to their quit date, the week following their quit
date and weekly thereafter as necessary to optimize therapy and to identify and manage early relapse.8 Formats that
have been shown to be effective include face-to-face (individual or group) counselling as well as contact by
telephone, Internet and mail.
The addition of pharmacotherapy increases the odds of quitting (see Table 1) and should be offered to
all patients who smoke 10 or more cigarettes per day and are attempting to quit. Pharmacotherapy can
be divided into first-line and second-line medications.8 First-line medications include all forms of
nicotine replacement therapy and bupropion. Second-line pharmacotherapies have evidence of efficacy
but are not officially indicated for smoking cessation. These include nortriptyline and
clonidine.14,15,16,17Varenicline, an alpha4beta2-nicotinic receptor partial agonist, with quit rates higher
than previously existing therapies, recently became available.18,19,20 In two comparative trials,
varenicline increased the odds of successfully quitting over bupropion and placebo at 12 weeks
(varenicline 44%, bupropion 29.5% and placebo 17.7%).21,22 However, differences at 6 months (i.e., 3
months after treatment was stopped) were smaller (varenicline 22%, bupropion 16%, placebo
8.4%). Useful Info?
Table 1: Estimated Abstinence Rates with Pharmacotherapy
Estimated 6-month Abstinence Rate (%)
Drug Drug Placebo
Nicotine replacement therapy23 17a 10
Varenicline21 , 22 22 8.4
Bupropion21 , 22 16 8.4
Nortriptyline8 30 11.7
Clonidine8 25 13.9
a. Pooled data from any form of nicotine replacement therapy
Nortriptyline can be used in otherwise healthy individuals with minimal risk for overdose or cardiac disease when
first-line therapies are either unaffordable or have not worked. Clonidine may be used in those with coexisting
hypertension. However, postural hypotension can be problematic and the drug must be tapered to prevent rebound
hypertension.
Choice of medication should depend on patient preference and absence of contraindications.
Monotherapy is the norm. There is evidence that combination therapy such as the nicotine patch combined with
either nicotine gum24, nicotine inhaler,25 nicotine spray25 or bupropion26 is better in the short term than
monotherapy. However, cost is a limiting factor and combination therapy should be reserved for those in whom
quitting immediately is essential. Varenicline has not been studied in combination with other medications and is
contraindicated in combination with nicotine replacement therapy. The nicotine lozenge, nasal spray and sublingual
tablet are not available in Canada. Rimonabant, a cannabinoid receptor 1 antagonist approved in Europe for weight
loss, has shown mixed results in two smoking cessation trials.27 , 28 It is not approved for smoking cessation in
either Europe or the United States and is not available in Canada.
Therapeutic Tips
Encourage smokers who have slips while on medication to continue medication for at least four weeks and use
behavioural interventions to help them to stop smoking.29
If smokers using the patch complain of unmanageable cravings and smoke cigarettes, add nicotine gum or
inhaler as a breakthrough medication.8
Page 1051
Therapeutic Choice
It is important to monitor for low mood and emergence of depression in smokers who quit.30
Potential weight gain following smoking cessation should be addressed before quitting and practical advice
should be offered to help the smoker avoid gaining weight, i.e., healthy diet and exercise and avoidance of
high-sugar products which the patient craves when quitting smoking.31 , 32
Create a therapeutic relationship in which the patient can report back at the first signs of a relapse to abort it as
soon as possible.
Figure 1-Tobacco-smoking History Questionnaire
Page 1052
Therapeutic Choice
Page 1053
Therapeutic Choice
Figure 2-Management of Smoking Cessation
Table 2: Pharmacologic Agents Used for Smoking Cessation
Adverse Drug Costb

Class Drug Dose Effects Interactionsa Comments
Nicotine nicotine First 6–12 wk: 1 Mild local Not a true $$
Page 1054
Therapeutic Choice
Adverse Drug Costb

Replacement, inhaler cartridge delivering irritation inhaler—the

immediate- Nicorette 4 mg nicotine, as (cough, throat nicotine is
release Inhaler needed irritation, delivered and
Encourage patient to stomatitis, absorbed
use at least 6 rhinitis) that buccally.
doses/day for the may decline “Hand–mouth”
first 3–6 wk with continued activity from
use; headache, using the
Max 12/day nausea, inhaler is
dyspepsia. preferred by
some quitters
Tapering: gradual while others
reduction in use find it to be a
over next 6–12 wk, trigger. Useful
stopping when in those with
reduced to 1–2/day poor oral
health or
dentures and
in those who
cannot chew
gum.
Nicotine nicotine 10–12 pieces/day Hiccoughs, GI Use 4 mg in $$

Replacement, polacrilex initially (2 or disturbances, heavily
immediate- gum 4 mg/piece) to max jaw pain and dependent
release Nicorette of 20 pieces/day, for orodental smokers. May
Gum 12 wk problems. be used for
Tapering: 1 temporary
piece/day each wk, abstinence,
as withdrawal e.g., to
symptoms allow comply with
smoking
restrictions on
airplanes.
Nicotine nicotine Habitrol: Skin sensitivity Start patch on $$$$

Replacement, transdermal > 20 cigarettes/day: and irritation the quit date.
sustained- patch 1 patch (most Advise not to
release Habitrol, (21 mg/24 h) daily common); smoke
Nicoderm, × 3–4 wk abnormal cigarettes
generics dreams; while using
≤ 20 cigarettes/day: insomnia; the patch,
1 patch nausea, though this is
(14 mg/24 h) daily dyspepsia. generally safe
× 3–4 wk and does not
indicate
treatment
Tapering: reduce failure.
strength of patch Educate users
(i.e., from 21 to 14 on the signs
to 7 mg/24 h) every and symptoms
3–4 wk of nicotine
Nicoderm: toxicity.
21 mg/24 h × 6 wk Habitrol:
then 14 mg/24 h × Takes longer
2 wk then 7 mg/24 h to reach peak
× 2 wk levels than
Nicoderm;
should not
If patient has use while
cardiovascular exercising;
Page 1055
Therapeutic Choice
Adverse Drug Costb

disease, weighs less major supplier

than 45 kg or of the
smokes < generic/store
½ pack/day begin brands.
with 14 mg/24 h ×
6 wk then ↓ to Nicoderm:
7 mg/24 h × 2 wk More rapid
onset and
shorter time
to peak
effects; may
be worn while
exercising;
although not
recommended
by the
manufacturer,
can be cut
without
damaging the
delivery
device.
Nicotine varenicline 0.5 mg daily for 3 Nausea (30%); Should not be Does not $$$$$
Receptor Partial days then BID for 4 can be combined with induce
Agonists Champix days then 1 mg po mitigated by nicotine cytochrome
BID for 12 wk. increasing replacement P450
Patient should quit water intake or therapy due to enzymes;
smoking 1–2 wk dosage increased risk of excreted
after starting the reduction. adverse effects. renally
medication. unchanged.
Reassess if patient is
still smoking 4 wk
after starting
medication; can be
continued for an
additional 12 wk if
patient has
benefited. No
tapering necessary
Antidepressants bupropion 150 mg daily × Usual: Clearance of Not $$$

3 days then 150 mg insomnia, dry bupropion may be recommended
Zyban, BID × 7–12 wk. mouth, ↓ by inhibitors in patients
generics Begin 1–2 wk before dizziness, (e.g., ticlopidine) with
the selected quit restlessness, or ↑ by inducers conditions
date difficulty (e.g., predisposing
concentrating. phenobarbital, to seizures,
Unusual: phenytoin, history of
hypersensitivity primidone) of seizures,
reactions, ↑ CYP2B6. May ↓ current eating
risk of seizures clearance of other disorder or
at higher substrates of severe hepatic
dosages. CYP2B6 (e.g., impairment.
cyclophosphamide, Least
ketamine, expensive of
promethazine, oral
propofol, medications
selegiline). MAOIs, officially
levodopa, indicated for
Page 1056
Therapeutic Choice
Adverse Drug Costb

amantadine may ↑ smoking

toxicity. May be cessation.
safely combined
with NRT (monitor
for treatment-
emergent
hypertension).
Antidepressants nortriptyline 25 mg/day titrated Common: dry Avoid with Caution in $$

generics to 75–100 mg/day. mouth, blurred MAOIs—may cause patients with
Quit day is usually vision, mania, excitation, cardiovascular
set between 1 and 4 constipation, hyperpyrexia. disease or
wk; medication is dizziness, Inducers of arrhythmias.
continued for 12 wk sedation. Less CYP2D6 or CYP3A4 Consider
common: (e.g., measuring
confusion, carbamazepine, serum levels
arrhythmias, phenytoin, to reach
urinary rifampin) may ↓ therapeutic
retention. effect. Inhibitors of dose.
CYP2D6 or CYP3A4
(e.g.,
clarithromycin,
erythromycin,
grapefruit juice,
fluoxetine,
paroxetine) may ↑
effect and toxicity.
Alpha2- clonidine 0.1 mg po BID Common: Avoid concurrent Monitor blood $

adrenergic Catapres, starting up to 3 days sedation, use with tricyclic pressure and
Receptor Dixarit, before or on the quit dizziness, antidepressants. heart rate
Agonists generics date. Increase by hypotension, Additive effects during
0.1 mg/day once per dry mouth. with other CNS treatment
wk if needed. Less common: depressants such initiation.
Duration of therapy anxiety, as ethanol. Taper off
ranges from 3–10 irritability, gradually to
wk memory avoid rebound
problems, hypertension
rebound when stopping
hypertension. treatment.
a. Smoking is associated with increased CYP1A1/ 1A2 and 2E1 activity. Upon smoking cessation, reduced clearance of substrates
of these enzymes (e.g., theophylline, clozapine, caffeine, fluvoxamine, haloperidol, olanzapine, lorazepam, alprazolam and
diazepam) may necessitate dose adjustments.
b. Cost of 105 pieces of gum, 42 inhalations, 28 patches or 30-day supply of tablets; includes drug cost only.
Abbreviations: CVS=cardiovascular; NRT=nicotine replacement therapy
Legend: $ < $25 $$ $25–50 $$$ $50–75 $$$$ $75–100 $$$$$ $100–120
Suggested Readings
Foulds J, Steinberg MB, Williams JM et al. Developments in pharmacotherapy for tobacco dependence: past, present
and future. Drug Alcohol Rev 2006;25(1):59-71.
Page 1057
Therapeutic Choice
George TP, editor. Medication treatments for nicotine dependence. Boca Raton (FL): CRC/Taylor & Francis; 2007.
McEwen A, Hajek P, McRobbie H et al. Manual of smoking cessation: a guide for counsellors and practitioners.
Malden (MA): Addiction Press, Blackwell; 2006.
West R. Bupropion SR for smoking cessation. Expert Opin Pharmacother 2003;4(4):533-40.
www.treatobacco.net. Database & educational resource for treatment of tobacco dependence. Available from:
www.treatobacco.net Accessed June 1, 2007.
References
1. Makomaski Illing EM, Kaiserman MJ. Mortality attributable to tobacco use in Canada and its regions, 1998. Can
J Public Health 2004;95(1):38-44.
2. Hoffmann D, Djordjevic MV, Hoffmann I. The changing cigarette. Prev Med 1997;26(4):427-34.
3. Le Houezec J. Role of nicotine pharmacokinetics in nicotine addiction and nicotine replacement therapy: a
review. Int J Tuberc Lung Dis 2003;7(9):811-9.
4. Fowler JS, Logan J, Wang GJ et al. Monoamine oxidase and cigarette smoking. Neurotoxicology 2003;24
(1):75-82.
5. Desai HD, Seabolt J, Jann MW. Smoking in patients receiving psychotropic medications: a pharmacokinetic
perspective. CNS Drugs 2001;15(6):469-94.
6. Song F, Raftery J, Aveyard P et al. Cost-effectiveness of pharmacological interventions for smoking cessation:
a literature review and a decision analytic analysis. Med Decis Making 2002;22(5 Suppl):S26-37.
7. Parrott S, Godfrey C. Economics of smoking cessation. BMJ 2004;328(7445):947-9.
8. Fiore MC, Bailey WC, Cohen SJ et al. Clinical practice guideline. Treating tobacco use and dependence.
Washington (DC): Public Health Service, US Department of Health and Human Services; 2000. Available from:
http://www.surgeongeneral.gov/tobacco/treating_tobacco_use.pdf Accessed June 1, 2007.
9. Tverdal A, Bjartveit K. Health consequences of reduced daily cigarette consumption. Tob Control 2006;15
(6):472-80.
10. Hyland A, Levy DT, Rezaishiraz H et al. Reduction in amount smoked predicts future cessation. Psychol Addict
Behav 2005;19(2):221-5.
11. Heatherton TF, Kozlowski LT, Frecker RC et al. The Fagerstrom Test for Nicotine Dependence: a revision of the
Fagerstrom Tolerance Questionnaire. Br J Addict 1991;86(9):1119-27.
12. Kozlowski LT, Porter CQ, Orleans CT et al. Predicting smoking cessation with self-reported measures of
nicotine dependence: FTQ, FTND, and HSI. Drug Alcohol Depend 1994;34(3):211-6.
13. Rollnick S, Mason P, Butler C. Health behavior change: a guide for practitioners. New York (NY): Churchill
Livingstone; 1999.
14. Hughes JR, Stead LF, Lancaster T. Antidepressants for smoking cessation. Cochrane Database Syst Rev
2007;1:CD000031.
15. Frishman WH, Mitta W, Kupersmith A et al. Nicotine and non-nicotine smoking cessation pharmacotherapies.
Cardiol Rev 2006;14(2):57-73.
16. Gourlay S, Forbes A, Marriner T et al. A placebo-controlled study of three clonidine doses for smoking
cessation. Clin Pharmacol Ther 1994;55(1):64-9.
17. Glassman AH, Stetner F, Walsh BT et al. Heavy smokers, smoking cessation, and clonidine. Results of a
double-blind, randomized trial. JAMA 1988;259(19):2863-6.
18. Keating GM, Siddiqui MA. Varenicline: a review of its use as an aid to smoking cessation therapy. CNS Drugs
2006;20(11):945-60.
19. Oncken C, Gonzales D, Nides M et al. Efficacy and safety of the novel selective nicotinic acetylcholine receptor
partial agonist, varenicline, for smoking cessation. Arch Intern Med 2006;166(15):1571-7.
20. Tonstad S, Tonnesen P, Hajek P et al. Effect of maintenance therapy with varenicline on smoking cessation: a
21. Jorenby DE, Hays JT, Rigotti NA et al. Efficacy of varenicline, an alpha4beta2 nicotinic acetylcholine receptor
partial agonist, vs placebo or sustained-release bupropion for smoking cessation: a randomized controlled
trial. JAMA 2006;296(1):56-63.
22. Gonzales D, Rennard SI, Nides M et al. Varenicline, an alpha4beta2 nicotinic acetylcholine receptor partial
agonist, vs sustained-release bupropion and placebo for smoking cessation: a randomized controlled trial.
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Therapeutic Choice
JAMA 2006;296(1):47-55.
23. Silagy C, Lancaster T, Stead L, et al. Nicotine replacement therapy for smoking cessation. Cochrane Database
Syst Rev, 2004;(3):CD000146
24. Haustein KO, Krause J, Haustein H et al. Comparison of the effects of combined nicotine replacement therapy
vs. cigarette smoking in males. Nicotine Tob Res 2003;5(2):195-203.
25. Sweeney CT, Fant RV, Fagerstrom KO et al. Combination nicotine replacement therapy for smoking cessation:
rationale, efficacy and tolerability. CNS Drugs 2001;15(6):453-67.
26. Jorenby DE, Leischow SJ, Nides MA et al. A controlled trial of sustained-release bupropion, a nicotine patch,
or both for smoking cessation. N Engl J Med 1999;340(9):685-91.
27. Foulds J, Steinberg MB, Williams JM et al. Developments in pharmacotherapy for tobacco dependence: past,
present and future. Drug Alcohol Rev 2006;25(1):59-71.
28. Henningfield JE, Fant RV, Buchhalter AR et al. Pharmacotherapy for nicotine dependence. CA Cancer J Clin
2005;55(5):281-99.
29. Mallin R. Smoking cessation: integration of behavioral and drug therapies. Am Fam Physician 2002;65
(6):1107-14.
30. Smith SS, Jorenby DE, Leischow SJ et al. Targeting smokers at increased risk for relapse: treating women and
those with a history of depression. Nicotine Tob Res 2003;5(1):99-109.
31. O'Hara P, Connett JE, Lee WW et al. Early and late weight gain following smoking cessation in the Lung Health
Study. Am J Epidemiol 1998;148(9):821-30.
32. Fagerstrom K, Balfour DJ. Neuropharmacology and potential efficacy of new treatments for tobacco
dependence. Expert Opin Investig Drugs 2006;15(2):107-16.
Page 1059
e-Therapeutics+ : Therapeutics : Respiratory Disorders: Adult Asthma Page 1 of 12
Therapeutic Choice
Print Close
Respiratory Disorders: Adult Asthma

David G. McCormack, MD, FRCPC
Asthma is a respiratory disorder characterized by:
Paroxysmal or persistent symptoms (dyspnea, chest tightness, wheezing, sputum production and cough)
Variable airflow limitation
Airway inflammation
Airway hyper-responsiveness
Goals of Therapy
Maintain normal activity levels, e.g., avoid absenteeism from work or school, able to exercise with no
limitations
Prevent daytime and nocturnal symptoms (cough, wheezing, dyspnea)
Maintain normal (or near normal) spirometry
Prevent exacerbations
Provide optimal pharmacotherapy and avoid side effects
Investigations
Thorough history with particular attention to:

symptoms, frequency and severity
pattern of symptoms (seasonal, perennial, diurnal variation, etc.)
precipitating factors (environmental allergens, occupational exposures, irritants such as smoke, exercise,
drugs such as ASA or beta-blockers, preservatives such as sulfites, viral respiratory infections, rhinitis,
sinusitis, gastroesophageal reflux)
previous hospitalizations, emergency room visits and intensive care admissions
Physical examination: wheezing, nasal polyps
Objective measurements needed to confirm diagnosis and assess severity include:
spirometry (preferred method of diagnosis): reduced expiratory flow rates
home peak flow monitoring can be used to diagnose asthma or to monitor patients with severe asthma or
poor perception of airway obstruction
bronchoprovocation challenge test, using methacholine or histamine, if diagnosis in doubt
Therapeutic Choices
Identify and avoid precipitating factors such as environmental allergens and occupational irritants.
Smoking cessation is essential 1 (see Psychiatric Disorders: Smoking Cessation). Also important is the avoidance
of second-hand smoke whenever possible.
Hyposensitization therapy to allergens generally is not useful in the management of asthma.2
Use of home air cleaners/purifiers is not supported by evidence.3
Choose the initial level of treatment with medication after an assessment of asthma severity and previous treatment
(Figure 1 - Continuum of Asthma Management).4 Review treatment every 3–6 months and if control is achieved, try
a stepwise reduction in treatment.
Inhaled therapy that maximizes delivery of drugs to the respiratory tract and minimizes systemic side effects is the
cornerstone of asthma management. Pressurized metered dose inhalers (pMDI) with spacers or dry powder inhalers
(DPI) deliver drugs as effectively as nebulized therapy. Medications include bronchodilators and anti-inflammatory
agents (Table 2).
Bronchodilators
Page 1060
Therapeutic Choice
Short-acting Inhaled Beta2-agonists (SABAs)
Salbutamol and terbutaline are selective beta2-agonists that are agents of first choice for treatment of acute
exacerbations and for prevention of exercise-induced asthma. They are best used as required rather than on a fixed
schedule. Although potent bronchodilators, they have little effect on the late (inflammatory) phase of an
exacerbation. If patients use a short-acting beta2-agonist more than 4 times per week (including any doses used to
prevent or treat exercise-induced symptoms), initiate therapy with an anti-inflammatory agent.4 Isoproterenol and
epinephrine are not recommended for the treatment of asthma because of lack of beta2-selectivity and potential for
excessive cardiac stimulation, especially at high doses.
Long-acting Inhaled Beta2-agonists (LABAs)
Salmeterol and formoterol are long-acting beta2-agonists for regular twice daily treatment of asthma. Salmeterol
has a slow onset of action and should not be used for immediate relief of bronchospasm. Formoterol is rapid acting
and can be utilized for rescue therapy. These drugs help to prevent exercise-induced bronchospasm.5 Both should
be used only in patients already taking inhaled corticosteroids and may be particularly useful for the prevention of
nocturnal symptoms. Adding long-acting beta2-agonists to inhaled corticosteroids may permit decreasing the latter’s
dose.6
Oral Beta2-agonists
Oral orciprenaline and salbutamol offer less bronchodilation, more systemic side effects and a slower onset of action
than the inhaled preparations and are therefore not recommended.
Anticholinergic Agents
Anticholinergics are not routinely indicated in asthma but may have a role in certain circumstances. Ipratropium is
a useful alternative for patients who are unusually susceptible to tremor or tachycardia from beta2-agonists.
Although the onset of action is delayed compared to beta2-agonists, the bronchodilator effect lasts longer. It may
also be useful in beta-blocker-induced bronchospasm.7 Tiotropium is an attractive alternative to ipratropium
bromide although its indications are not identical. Unlike ipratropium bromide, tiotropium should not be used for
relief of acute bronchospasm but as maintenance therapy. The advantage over ipratropium bromide is that
tiotropium is administered once a day instead of 3 or 4 times a day.
Theophylline Products
Oral theophylline and oxtriphylline are uncommonly used due to systemic toxicity and only mild bronchodilator
activity. Aminophylline is no longer available in an oral formulation. Administer carefully according to standard
regimens and monitor blood levels. In naïve patients, titrate the dose slowly to minimize side effects.
Anti-inflammatory Agents
Inhaled Corticosteroids
Inhaled beclomethasone, budesonide, ciclesonide and fluticasone are safe, effective, and cost-effective drugs
that treat the inflammatory component of asthma.8 They should be used regularly at the lowest effective dose rather
than “as needed” to maintain good asthma control. They have a higher ratio of topical to systemic activity than do
oral corticosteroids. The incidence of pharyngeal candidiasis from deposition of the inhaled corticosteroid in the
pharynx can be reduced by rinsing the mouth after use and/or using a spacer device. Dose equivalencies for inhaled
corticosteroids are listed in Table 1.
Table 1: Comparative Dose Equivalencies for Inhaled Corticosteroids9
Page 1061
Therapeutic Choice
Class Drug Dose
Inhaled Corticosteroids beclomethasone pMDI (HFA) Low: ≤ 250 µg/day

Qvar Moderate: 251–500 µg/day
High: > 500 µg/day
Inhaled Corticosteroids budesonide DPI Low: ≤ 400 µg/day

Pulmicort Turbuhaler Moderate: 401–800 µg/day
High: > 800 µg/day
Inhaled Corticosteroids budesonide nebulizer Low: ≤ 1000 µg/day

Pulmicort Nebuamp Moderate: 1001–2000 µg/day
High: > 2000 µg/day
Inhaled Corticosteroids ciclesonide pMDI Low: ≤ 200 µg/day

Alvesco Moderate: 201–400 µg/day
High: > 400 µg/day
Inhaled Corticosteroids fluticasone DPI or pMDI plus spacer Low: ≤ 250 µg/day
Flovent Diskus, Flovent HFA Moderate: 251–500 µg/day
High: > 500 µg/day
Abbreviations: pMDI=pressurized metered dose inhaler; DPI=dry powder inhaler; HFA=hydrofluoroalkane
Combination Inhaled Corticosteroids and Long-acting Bronchodilators
As long-acting beta2-agonists (LABAs) should only be given to patients already on inhaled

corticosteroids, combination products of inhaled corticosteroids and LABAs have been developed.
Fluticasone with salmeterol should be given on a regular BID schedule. Budesonide with formoterol
can be used as both maintenance and reliever medication.10,11 Useful Info?
Systemic Corticosteroids
These are useful in both preventing and treating acute exacerbations. Optimal dosage has not been established. Side
effects are significant: glucose intolerance, increased appetite, weight gain, mood alterations, fluid retention and
hypertension in the short term and adrenal axis suppression, dermal thinning, glaucoma, diabetes, osteoporosis,
hypertension, cataracts and myopathy in the long term. Reduce side effects by limiting treatment to short periods
(1–2 weeks) following an acute exacerbation. Side effects with long-term use may be minimized by using alternate-
day dosing regimens.
Leukotriene Receptor Antagonists (LTRAs)
Zafirlukast and montelukast have anti-inflammatory properties; however, evidence suggests that LTRAs are not
Page 1062
Therapeutic Choice
as effective as beclomethasone dipropionate 400 µg/day or equivalent in improving symptoms or preventing
exacerbations.12 In general, LTRAs may be considered as alternatives to increasing doses of inhaled steroids in
patients not controlled on low-moderate doses or may be used in conjunction with higher doses of inhaled steroids
to achieve control of persistent symptoms.8 Mild asthmatics who cannot take or refuse to take an inhaled
corticosteroid may be tried on an LTRA.
IgE-Neutralizing Antibody
Omalizumab, a monoclonal antibody, is indicated for patients with moderate to severe persistent asthma in those
who have had a positive skin test or in vitro reactivity to a perennial aeroallergen and whose symptoms are
inadequately controlled with inhaled corticosteroids. In these patients, it has been shown to significantly decrease
the incidence of asthma exacerbations and improve overall asthma control.
Other Therapies
Antihistamines are not useful. The place of ketotifen in the treatment of adult asthma has not been established.
Methotrexate and gold have been used in some chronic steroid-dependent asthmatics but should be limited to
centres experienced with this therapy.
Asthma and pregnancy
Pregnancy does not affect asthma in any predictable manner, with some patients noticing disease worsening and
others noting improvement in symptoms.6 Much more important is the effect of asthma on the outcome of the
pregnancy. Inadequate control of asthma during pregnancy is associated with worse outcomes, such as pre-term
birth, low birth weight, congenital anomalies, pre-eclampsia and placenta previa. Conversely, good control of
asthma during pregnancy is associated with a normal outcome.
Management of asthma during pregnancy
The best outcome for pregnancy complicated by asthma occurs with optimal management of asthma using the same
stepwise approach as in non-pregnant patients.3 Short-acting inhaled beta2-agonists, theophylline and inhaled
corticosteroids (particularly budesonide) have been used extensively and are considered safe for use in
pregnancy. However, theophylline may worsen gastroesophageal reflux and can cause nausea, so avoid if possible.
There is limited experience with the use of LTRAs and LABAs during pregnancy. The risk of using medications to
control asthma during pregnancy appears to be much less than the risk of adverse outcomes related to severe
uncontrolled asthma.13
Asthma and breastfeeding
Breastfeeding has no known effect on the severity of asthma. When asthma medication is required for a
breastfeeding mother, bronchodilators (SABAs, LABAs and anticholinergics) are considered safe. Further, both
inhaled and oral steroids are considered safe for breastfeeding mothers. Although theophylline is considered
safe for lactating patients, it is recommended to maintain blood theophylline levels in the low end of the therapeutic
range in the mother. There is no available information concerning the use of leukotriene receptor antagonist
therapy during breastfeeding, so alternate drugs for the control of asthma may be appropriate.
See also Appendix: Drug Use During Pregnancy and Appendix: Drug Use During Lactation for a discussion of the
general principles. For more detailed information on the use of specific medications in this condition during
Freeman RK, Yaffe SJ. Drugs in Pregnancy and Lactation 2008; LactMed (toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen?
LACT); and Hale, T. Medications and Mothers' Milk 2008.
Emergency Treatment (Figure 2 - Emergency Treatment of Asthma)
Priorities include oxygenation, rehydration, bronchodilation and use of anti-inflammatory medications.

Bronchodilation with a metered dose inhaler and a spacer is equivalent to nebulized therapy.14 , 15
Page 1063
Therapeutic Choice
Additional bronchodilator effect of ipratropium bromide and the beta2-agonists supports administering these 2
medications concomitantly.16
Use oral or parenteral steroids early in most patients.17
Avoid iv aminophylline in acute asthma.18 , 19
Therapeutic Tips
Avoid ASA and NSAIDs in ASA-induced asthmatics and in high-risk patients (severe asthma symptoms, nasal
polyps, urticaria or chronic rhinitis).20 Exercise caution in all patients.
Exercise caution with beta-blockers.
Treat conditions that may affect asthma control such as rhinitis, sinusitis and GERD.
Patient education about asthma symptoms and therapy is essential for optimal management.
Develop a written action plan for self-management based on peak expiratory flow rates and/or signs and
symptoms for each patient.
Review inhaler technique regularly.
Figure 1- Continuum of Asthma Management
Very mild, intermittent asthma may be treated with fast-acting beta2-agonists taken as needed. Inhaled corticosteroids (ICS)
should be introduced early as the initial maintenance treatment for asthma, even in individuals who report asthma symptoms less
than 3 times a week. Leukotriene receptor antagonists (LTRAs) are second-line monotherapy for mild asthma. If asthma is not
adequately controlled by low doses of ICS, additional therapy should be considered. A long-acting beta2-agonist (LABA) should
be considered first as add-on therapy only in combination with an ICS. Increasing to a moderate dose of ICS or addition of an
LTRA are third-line options. Theophylline may be considered as a fourth-line agent in adults. Severely uncontrolled asthma may
require additional treatment with prednisone. Omalizumab may be considered in individuals 12 years of age and over with poorly
controlled atopic asthma despite high doses of ICS and appropriate add-on therapy, with or without prednisone. Asthma
symptom control and lung function tests, inhaler technique, adherence to asthma treatment, exposure to asthma triggers in the
environment and the presence of comorbidities should be reassessed at each visit and before altering the maintenance therapy.
After achieving proper asthma control for at least a few weeks to months, the medication should be reduced to the minimum
necessary to maintain adequate asthma control.
This information was originally published in Canadian Respiratory Journal 2010;17(1):15-24.
Abbreviations: HFA = hydrofluoroalkane; IgE = immunoglobulin E; PEF = peak expiratory flow
Figure 2- Emergency Treatment of Asthma
Page 1064
Therapeutic Choice
Abbreviations: FiO2 = fraction of inspired oxygen; SaO2 = arterial oxygen percent saturation;
pMDI = pressurized metered dose inhaler
Table 2: Drugs for the Treatment of Chronic Asthma in Adults
Adverse
Class Drug Dose Effects Comments Costa
Inhaled Beta2- salbutamol pMDI 100 µg/puff: Nervousness, $

adrenergic Agonists, Airomir pMDI, 1–2 puffs TID-QID tremor,
short-acting Ventolin Diskus, PRN; maximum tachycardia,
(SABAs) 8 puffs/day palpitations.
Ventolin HFA,
Diskus: 200 µg TID-
Ventolin QID PRN; maximum
Nebules P.F., 800 µg/day
generics Nebules: 2.5–5 mg
QID PRN
Inhaled Beta2- terbutaline DPI 0.5 mg/puff: 1 Nervousness, $

adrenergic Agonists, Bricanyl puff Q4–6H PRN; tremor,
short-acting Turbuhaler maximum tachycardia,
6 puffs/day palpitations.
Inhaled Beta2- formoterol DPI 12 µg/capsule: Nervousness, Recommended only if $$

adrenergic Agonists, fumarate 1 capsule BID; tremor, confident patient will
long-acting (LABAs) Foradil maximum 48 µg/day tachycardia, use prescribed inhaled
palpitations. corticosteroid as well.
Combination
LABA/corticosteroid
product preferred.
Inhaled Beta2- formoterol DPI: 6–12 µg Q12H; Nervousness, Recommended only if $$

adrenergic Agonists, fumarate maximum 48 µg/day tremor, confident patient will
long-acting dihydrate tachycardia, use prescribed inhaled
Oxeze palpitations. corticosteroid as well.
Turbuhaler Combination
LABA/corticosteroid
product preferred.
Inhaled Beta2- salmeterol Diskhaler 50 Nervousness, Recommended only if $$$

adrenergic Agonists, Serevent µg/blister: 1 blister tremor, confident patient will
long-acting BID tachycardia, use prescribed inhaled
Diskus 50 µg/puff: 1 palpitations. corticosteroid as well.
puff BID Combination
Page 1065
Therapeutic Choice
Adverse
LABA/corticosteroid
product preferred.
Anticholinergic ipratropium pMDI 20 µg/puff: Dry mouth, $

Agents, short-acting Atrovent HFA 2 puffs Q6–8H PRN; metallic taste;
maximum mydriasis and
240 µg/day glaucoma if
Nebules: 250–500 µg released into
Q4–6H PRN eye.
Anticholinergic tiotropium DPI: 18 µg (1 Dry mouth, $$$

Agents, long-acting Spiriva capsule) inhaled metallic taste;
once daily mydriasis and
glaucoma if
released into
eye.
Anticholinergic/SABA ipratropium/ Individualize dose. Dry mouth, $

Combinations salbutamol Nebules: 2.5 mL metallic taste;
Combivent, (0.5 mg/2.5 mg) mydriasis and
generics Q6H PRN glaucoma if
released into
eye.
Nervousness,
tremor,
tachycardia,
palpitations.
Anticholinergic/SABA ipratropium/ Nebules: 4 mL Dry mouth, $

Combinations fenoterol (0.5/1.25 mg) Q6H metallic taste;
Duovent UDV PRN mydriasis and
glaucoma if
released into
eye.
Nervousness,
tremor,
tachycardia,
palpitations.
Corticosteroids, beclomethasone pMDI: 100–800 Sore mouth, Bone densitometry is $$$

inhaled Qvar µg/day divided BID sore throat, suggested in patients
dysphonia, who require high
oral thrush doses or have risk
(can be factors for
reduced by osteoporosis. Patients
rinsing mouth with personal or
or using family history of
spacer). glaucoma (and need
high-dose inhaled
corticosteroids) should
have IOP checked
soon after starting
therapy and
periodically thereafter.
Corticosteroids, budesonide DPI: 400–2400 Sore mouth, Bone densitometry is DPI:

inhaled Pulmicort µg/day divided BID sore throat, suggested in patients $$$$
Nebules: dysphonia, who require high Nebule:
0.125–2 mg/dose; oral thrush doses or have risk $
Page 1066
Therapeutic Choice
Adverse
dose is individualized (can be factors for

high-dose inhaled
have IOP checked
soon after starting
therapy and
Corticosteroids, ciclesonide pMDI: 100–800 µg Sore mouth, Bone densitometry is $$$

inhaled Alvesco daily sore throat, suggested in patients
Individualize dose; dysphonia, who require high
maximum 800 µg oral thrush doses or have risk
daily divided BID (can be factors for
high-dose inhaled
have IOP checked
soon after starting
therapy and
Corticosteroids, fluticasone pMDI/DPI: Sore mouth, Bone densitometry is $$-$$$

inhaled Flovent HFA, 200–1000 µg/day sore throat, suggested in patients
a divided BID; may ↑ dysphonia, who require high
Flovent Diskus
to 1000 µg BID if oral thrush doses or have risk
very severe (can be factors for
high-dose inhaled
have IOP checked
soon after starting
therapy and
Corticosteroid/LABA budesonide/ Maintenance therapy: Sore mouth, Fixed dose $$$

Combinations formoterol DPI 100/6 µg or sore throat, combination inhalers
fumarate 200/6 µg: 1–2 puffs dysphonia, are more convenient,
dihydrate daily-BID; maximum oral thrush enhance compliance,
Symbicort 4 puffs/day. May (can be ensure the patient
temporarily increase reduced by receives their inhaled
to 4 puffs BID for rinsing mouth corticosteroid with
worsening asthma or using their LABA, and are
Maintenance and spacer). less expensive than
reliever therapy: 1–2 Nervousness, the individual agents
puffs BID or 2 puffs tremor, combined.
once daily. Inhale 1 tachycardia,
additional puff PRN palpitations.
in response to
symptoms; if
symptoms persist
after a few min, an
Page 1067
Therapeutic Choice
Adverse
additional dose
should be taken;
maximum 6 puffs on
any single occasion;
maximum 8
puffs/day
Corticosteroid/LABA fluticasone/ pMDI 125/25 µg or Sore mouth, Fixed dose $$$$

Combinations salmeterol 250/25 µg: 2 puffs sore throat, combination inhalers
Advair pMDI, BID dysphonia, are more convenient,
Advair Diskus Diskus 100/50 µg or oral thrush enhance compliance,
250/50 µg or 500/50 (can be ensure the patient
µg: 1 puff BID reduced by receives their inhaled
rinsing mouth corticosteroid with
or using their LABA, and are
spacer). less expensive than
Nervousness, the individual agents
tremor, combined.
tachycardia, A disadvantage is a
palpitations. loss in dosing
flexibility.
Not for reliever

therapy.
Leukotriene Receptor montelukast 10 mg po QHS Headache ↓ montelukast levels: $$$

Antagonists Singulair (common), carbamazepine,
abdominal rifampin,
pain, flu-like phenobarbital,
symptoms. phenytoin.
Leukotriene Receptor zafirlukast 20 mg po BID, at Headache ASA may ↑ zafirlukast $$

Antagonists Accolate least 1 h before or 2 (common), levels. Zarfirlukast
h after meals nausea, may potentiate effect
diarrhea. of warfarin; may ↑
theophylline levels.
↓ zafirlukast levels:
carbamazepine,
erythromycin,
phenobarbital,
phenytoin, rifampin,
theophylline.
Methylxanthines oxtriphylline Initial: 200 mg QID Nausea, Monitor serum levels. $$

Choledyl elixir, Maintenance dose: vomiting, Multiple drug
generics 800–1200 mg/day po abdominal interactions: e.g.,
given in 3–4 divided cramps, phenytoin,
doses headache, carbamazepine,
palpitations, rifampin ↓ theophylline
CNS levels, whereas
stimulation. macrolides, oral
contraceptives and
quinolones ↑
Theophylline levels
may ↑ if patient stops
Page 1068
Therapeutic Choice
Adverse
smoking.
Oxtriphylline available
as elixir only.
Methylxanthines theophylline Initial: 400–600 Nausea, Monitor serum levels. $

Uniphyl, mg/day, given in 1–3 vomiting, Multiple drug
generics divided doses abdominal interactions: e.g.,
depending on cramps, phenytoin,
preparation used headache, carbamazepine,
palpitations, rifampin ↓ theophylline
CNS levels, whereas
stimulation. macrolides, oral
contraceptives and
quinolones ↑
Theophylline levels
may ↑ if patient stops
smoking.
Oxtriphylline available
as elixir only.
Extended release
tablets should not be
chewed, crushed or
dissolved.
IgE-Neutralizing omalizumab 150–375 mg sc every Injection site Store at 2–8°C. $630/vial

Antibody Xolair 2–4 weeks (based on reactions Reconstituted product
patient’s weight and (45%), viral may be stored for up
pretreatment serum infections to 8 hours at 2–8°C.
IgE level) (24%), upper Do not inject more
respiratory than 150 mg at one
tract infections site.
(19%),
headache After start of
(15%), treatment, do not use
sinusitis serum IgE for dose
(16%), adjustment.
pharyngitis
(10%). Omalizumab raises IgE
levels which may
persist for up to a year
after ending the
treatment.
a. Includes drug cost only. Cost of inhaled agents is per unit (1 inhaler, nebule or vial); cost of oral medications is per 30-day
supply.
Legend: $ < $25 $$ $25–50 $$-$$$ $25–85 $$$ $50–85 $$$$ > $85
Abbreviations: DPI=dry powder inhaler; pMDI=pressurized metered dose inhaler; IOP=intraocular pressure; LABA=long-
acting inhaled beta2-agonists; SABA=short-acting inhaled beta2-agonists
Page 1069
Therapeutic Choice
Suggested Readings
Balter MS, Bell AD, Kaplan AG et al. Management of asthma in adults. CMAJ 2009;181(12):915-22.
Boulet LP, Becker A, Berube D et al. Summary of recommendations from the Canadian Asthma Consensus Report,
1999. Canadian Asthma Consensus Group. CMAJ 1999;161(11 Suppl):1-12. Available from:
www.cmaj.ca/cgi/content/full/161/11_suppl_2/S1. Accessed August 18, 2010.
Global Initiative for Asthma. Global strategy for asthma management and prevention. Updated 2009. Available from:
www.ginasthma.com. Accessed August 18, 2010.
Lemiere C, Bai T, Balter M et al. Adult asthma consensus guidelines update 2003. Can Respir J 2004;11(Suppl
A):9A-18A.
Lougheed MD, Lemiere C, Dell SD et al. Canadian Thoracic Society Asthma Management Continuum—2010
Consensus Summary for children six years of age and over, and adults. Can Respir J 2010;17(1):15-24.
References
1. Chaudhuri R, Livingston E, McMahon AD et al. Effects of smoking cessation on lung function and airway
inflammation in smokers with asthma. Am J Respir Crit Care Med 2006;174(2):127-33.
2. Adkinson NF, Eggleston PA, Eney D et al. A controlled trial of immunotherapy for asthma in allergic children.
N Engl J Med 1997;336(5):324-31.
3. Boulet LP, Becker A, Berube D et al. Summary of recommendations from the Canadian Asthma Consensus
Report, 1999. Canadian Asthma Consensus Group. CMAJ 1999;161(11 Suppl):1-12. Available from:
www.cmaj.ca/cgi/content/full/161/11_suppl_2/S1. Accessed August 18, 2010.
4. Lougheed MD, Lemiere C, Dell SD et al. Canadian Thoracic Society Asthma Management Continuum—2010
Consensus Summary for children six years of age and over, and adults. Can Respir J 2010;17(1):15-24.
5. Nelson JA, Strauss L, Skowronski M et al. Effect of long-term salmeterol treatment on exercise-induced
asthma. N Engl J Med 1998;339(3):141-6.
6. Global Initiative for Asthma. Global strategy for asthma management and prevention. Updated 2009. Available
from: www.ginasthma.com. Accessed August 18, 2010.
7. Ind PW, Dixon CM, Fuller RW et al. Anticholinergic blockade of beta-blocker-induced bronchoconstriction. Am
Rev Respir Dis 1989;139(6):1390-4.
8. Boulet LP, Becker A, Berube D et al. Canadian asthma consensus report, 1999. Canadian Asthma Consensus
Group. CMAJ 1999;161(11 Suppl):S1-61.
9. Respiratory Review Panel. Respiratory (asthma and COPD) guidelines for family practice. Toronto (ON): MUMS
Guidelines Clearinghouse; 2007.
10. O'Byrne PM, Bisgaard H, Godard PP et al. Budesonide/formoterol combination therapy as both maintenance
and reliever medication in asthma. Am J Resp Crit Care Med 2005;171(2):129-36.
11. Scicchitano R, Aablers R, Ukena D et al. Efficacy and safety of budesonide/formoterol single inhaler therapy
versus a higher dose budesonide in moderate to severe asthma. Curr Med Res Opin 2004;20(9):1403-8.
12. Ducharme FM. Inhaled glucocorticoids versus leukotriene receptor antagonists as single agent asthma
treatment: systematic review of current evidence. BMJ 2003;326(7390):621.
13. Schatz M. Interrelationships between asthma and pregnancy: a literature review. J Allergy Clin Immunol
1999;103(2 Pt 2):S330-6.
14. Turner MO, Patel A, Ginsburg S et al. Bronchodilator delivery in acute airflow obstruction. A meta-analysis.
Arch Intern Med 1997;157(15):1736-44.
15. Cates CJ, Bara A, Crilly JA et al. Holding chambers (spacers) versus nebulizers for beta-agonist treatment of
acute asthma. Cochrane Database System Rev 2006;(3):CD000052.
16. Rodrigo GJ, Castro-Rodriguez JA. Anticholinergics in the treatment of children and adults with acute asthma: a
systematic review with meta-analysis. Thorax 2005;60(9):740-6.
17. Rowe BH, Spooner CH, Ducharme FM et al. Early emergency department treatment of acute asthma with
systemic corticosteroids. Cochrane Database System Rev 2001;(1):CD002178.
18. Littenberg B. Aminophylline treatment in severe, acute asthma. A meta-analysis. JAMA 1988;259(11):1678-
84.
19. Parameswaran K, Belda J, Rowe BH. Addition of intravenous aminophylline to beta-agonists in adults with
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acute asthma. Cochrane Database System Rev 2000;(4):CD002742.
20. Jenkins C, Costello J, Hodge L. Systematic review of prevalence of aspirin induced asthma and its implications
for clinical practice. BMJ 2004;328(7437):434-41.
Page 1071
e-Therapeutics+ : Therapeutics : Respiratory Disorders: Allergic Rhinitis Page 1 of 19
Therapeutic Choice
Print Close
Respiratory Disorders: Allergic Rhinitis

Date Revised: May 2010
D. William Moote, MD, FRCPC
Goals of Therapy
Prevent allergic reaction from occurring by avoiding exposure to allergens

Suppress and control symptoms produced by the allergic response
Avoid/minimize medication side effects including negative impact on activities of daily living, e.g., minimal
interference with school or work performance or attendance, leisure activities, sleep
Investigations
Clinical history (Table 1) with particular attention to:

symptoms, frequency and severity
duration and pattern of symptoms (intermittent, persistent)
precipitating factors, e.g., environmental allergens such as animal and pollen triggers
personal or family history of allergy
Physical examination (Table 1):
View nasal mucosa (e.g., colour, anatomy) using ordinary otoscope
Skin testing confirms allergic sensitivity, if present. There is little benefit in measuring serum IgE or eosinophils,
which do not correlate well with presence of allergic disease. In vitro measurements of specific allergen
sensitivity such as radio-allergosorbent testing (RAST) are acceptable, but more expensive. Skin testing is
generally preferred unless conditions exist that make it unsatisfactory, e.g., widespread skin disease. Discontinue
antihistamines temporarily for at least 3 days prior to skin testing. Tricyclic antidepressants and phenothiazines
as well as other drugs with antihistaminic effect (e.g., dimenhydrinate) will interfere with skin testing as well, but
should only be discontinued after discussion with the patient
Table 1: Differential Diagnosis of Rhinitis
Type Characteristics
Seasonal or perennial Nasal obstruction and rhinorrhea are common.

allergic rhinitis Often conjunctival symptoms, paroxysmal sneezing, itching of the nasal mucosa and the
oropharynx.
Seasonal patterns may be recognized, or perennial symptoms may flare up after exposure to
allergens like dust mites or animal danders.
Nasal mucosa is swollen, often pale or bluish, and moist.
Upper respiratory More episodic, often associated with sore throat or fever and not associated with itch.
infections Nasal mucosa is often red.
Vasomotor rhinitis Obstruction and rhinorrhea are prominent and other symptoms infrequent.
May be triggered by irritant exposures such as smoke, temperature changes, strong odours,
cold air and other factors such as exercise, eating hot or spicy foods.
Nasal polyps Obstruction is the main complaint.

Anosmia and reduced taste perception are almost always present. Nasal exam will usually
detect a polyp.
Therapeutic Choices (Figure 1 - Management of Allergic Rhinitis)
Avoid exposure to allergens to which a patient is sensitized. This allows for reduced medication use.1 , 2
Air conditioning reduces pollen exposure.
Removing pets from the home will reduce perennial symptoms caused by animal dander.
Page 1072
e-Therapeutics+ : Therapeutics : Respiratory Disorders: Allergic Rhinitis Page 2 of 19
Therapeutic Choice
Dust avoidance measures can reduce dust mite exposure as much as 60%.
Saline nose sprays, available over the counter, can help relieve symptoms by washing out mucus and the inhaled
allergen. Similarly, lubricant eyedrops or cold compresses can reduce conjunctival symptoms.
Antihistamines
Antihistamines help relieve most symptoms of acute allergic rhinitis, such as sneezing, rhinorrhea, nasal itch and
conjunctivitis, but are not usually recommended for the treatment of nasal congestion. Desloratadine has demonstrated
modest improvement in nasal congestion in clinical trials and is indicated for relief of nasal congestion.3 There is some
evidence to suggest similar results for fexofenadine;4 however, fexofenadine is not indicated for the relief of congestion.
Antihistamines are most effective if used prophylactically; however, onset of action is fast enough that they are also
effective when used on an as-needed basis. Once-daily dosing of the newer antihistamines is usually sufficient.
Although sedation and anticholinergic side effects are common with the older antihistamines (also known as first-
generation or sedating antihistamines), these side effects are usually not seen with newer agents (second-generation or
non-sedating antihistamines). Patients who are unaware of sedation may be impaired with respect to attention, memory,
vigilance and speed. These effects persist into the next day. Caution is advised in the elderly as they may be more
susceptible to the anticholinergic effects of the first-generation antihistamines. Patients whose occupations require
vigilance or concentration should receive only non-sedating antihistamines, as they do not affect performance and have no
anticholinergic effects.2 , 5 , 6 , 7 , 8 Of the newer antihistamines, cetirizine is more likely to cause some sedation,
especially at higher doses. Patients with hepatic impairment may be at increased risk of adverse effects, and dosage
modification may be required (see Table 2). The currently available second-generation antihistamines have not caused QT
interval prolongation.2
If an antihistamine taken at a recommended dose is not effective, little is gained from changing it to a different chemical
class. Although older studies of long-term dosing with first-generation antihistamines have demonstrated loss of
effectiveness, they are flawed by lack of evidence of compliance. No loss of effectiveness has been shown up to one year.9
Decongestants (Alpha-adrenergic Agonists)
Oral decongestants (pseudoephedrine, phenylephrine) relieve nasal obstruction; however, the effectiveness of
phenylephrine in improving nasal congestion has not been well established.10 Some individuals are intolerant of the
stimulant side effects of decongestants. Avoid oral decongestants in those receiving monamine oxidase inhibitors.
Although evidence is weak and circumstantial that use of decongestants at recommended doses is a problem in patients
with hypertension, hyperthyroidism or ischemic heart disease when the disease is controlled, it is recommended to use
them with caution.11 Use of topical nasal decongestants for more than 3–7 days may result in rhinitis medicamentosa;
thus, they should be avoided in allergic rhinitis because long-term therapy is often required.
Antihistamine–Decongestant Combinations
Antihistamines and decongestants have complementary effects. Patients taking both drugs may find combination tablets
convenient, although many combinations include first-generation antihistamines, which may be sedating. Some
combinations, e.g., cold preparations, may also contain analgesics and expectorants, which are not helpful in allergic
rhinitis.
Intranasal Therapy
Intranasal corticosteroids are the mainstay of therapy for moderate to severe rhinitis symptoms. Indeed, intranasal
corticosteroids as monotherapy have been shown to be more effective than combined use of an antihistamine and
leukotriene antagonist.10 They can be given on an as-needed basis in seasonal allergic rhinitis; however, continuous use
may be more effective in providing symptom relief. In addition, they are effective in managing ocular symptoms
associated with allergic rhinitis. Aqueous preparations generally have better intranasal deposition than dry

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Therapeutic Choices 2011

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e-Therapeutics+ : Therapeutics : Blood Disorders: Common Anemias Page 1 of 15

Blood Disorders: Common Anemias

Date Prepared: April 2007

S. Rutledge Harding, MD, FRCPC

Alleviate the signs and symptoms of anemia

Pharmacologic Choices (Table 1)

Cobalamin (Vitamin B12) Deficiency

Folic Acid Deficiency

Abstinence from alcohol may be necessary.

Pharmacologic Choices (Table 1)

Cobalamin (Vitamin B12)

Cobalamin deficiency is treated with either cyanocobalamin or hydroxocobalamin (hydroxycobalamin).

Anemias Responsive to Pharmacologic Stimulation of Erythropoiesis

Chronic renal failure

Pharmacologic Choices (Table 2)

Figure 1-Evaluation of Anemia

Figure 2-Diagnostic Algorithm for Microcytic Anemia

Figure 3-Diagnostic Algorithm for Normocytic Anemia

Figure 4-Diagnostic Algorithm for Macrocytic Anemia

Abbreviations: MCV = mean cell volume; MDS = myelodysplastic syndrome

Table 1: Drugs for the Treatment of Iron-deficiency and Megaloblastic Anemias

Iron ferrous fumarate 105–200 mg Gastrointestinal: There is no evidence that $

Absorption is ↓ by food and

Iron ferrous gluconate 105–200 mg Gastrointestinal: There is no evidence that $

Absorption is ↓ by food and

Iron ferrous sulfate 105–200 mg Gastrointestinal: There is no evidence that $

Absorption is ↓ by food and

Iron polysaccharide- 105–200 mg Gastrointestinal: There is no evidence that $$

Absorption is ↓ by food and

Vitamins cobalamin Pernicious Occasional Oral absorption is ↓ by $

Vitamins cyanocobalamin Pernicious Occasional Oral absorption is ↓ by $

Vitamins hydroxocobalamin Pernicious Occasional Oral absorption is ↓ by $

Legend: $ < $10 $$ $10–20 $$$ $20–250 $$$$ > $250

Table 2: Erythropoiesis-Stimulating Drugs

Class Drug Dose Adverse Effects Comments Cost

Class Drug Dose Adverse Effects Comments Cost

Class Drug Dose Adverse Effects Comments Cost

Therapeutic Choices. © Canadian Pharmacists Association, 2011. All rights reserved.

Cancer Chemotherapy Toxicity: Chemotherapy-induced Nausea and Vomiting

Date Prepared: March 2007

Lynne Nakashima, PharmD

A thorough history including:

Table 1: Emetogenic Potential of Chemotherapy Agentsa

High (> 60%)

carmustine cytarabine (> 500 mg/m2) lomustine

capecitabine epirubicin methotrexate (dose-dependent)

Low (< 30%)

altretamine (hexamethylmelamine) fludarabine rituximab

bevacizumab melphalan thiotepa

Therapeutic Choices (Figure 1 - Management of Chemotherapy-induced Nausea and

Pharmacologic Choices (Figure 1 - Management of Chemotherapy-induced Nausea and

Neurokinin-1 Receptor Antagonists

Figure 1- Management of Chemotherapy-induced Nausea and Vomiting (low emetogenic potential)

Figure 2- Management of Chemotherapy-induced Nausea and Vomiting (moderate/high emetogenic

Table 2: Drugs Used for Chemotherapy-induced Nausea and Vomiting

Benzamides metoclopramide Low: 10–20 mg Sedation (up to 80%), Sedating po:$

Benzodiazepines lorazepam Sedation (up to 80%). Sedating $

Butyrophenones haloperidol 1–2 mg po/im Sedation, Sedating $

Cannabinoids nabilone Sedation (4–89%), Sedating $

effects (“high”) (27%), for example, opioid

Cannabinoids dronabinol Sedation (4–89%), Sedating $b

Corticosteroids dexamethasone 4–10 mg po pre- Mood changes, $

Corticosteroids methylprednisolone 0.5–1 mg/kg po Mood changes, po:$

May also give as