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interacting drug may be either an inhibitor or an inducer of the crit- ical P450
isozymes involved in the substrate drugs metab- olism.
Metabolic drug interactions are most likely to occur in three situations: addition of
an interacting drug (inhibitor or inducer) to an existing critical substrate drug;
with- drawal of an interacting drug from a dosing regimen con- taining a substrate
drug; or addition of a substrate drug to an existing regimen containing an
interacting drug.
The addition of an interacting drug to a medication regimen containing a
substrate drug at steady-state levels will dramatically alter the concentration of
the substrate drug. If the interacting drug is an inhibitor, substrate drug
concentrations will rise as its elimination is reduced. This rise in substrate levels
may result in toxicity because of the drugs narrow therapeutic index. Conversely,
addition of an enzyme inducer will increase elimination of the sub- strate, thereby
lowering its concentration and therapeutic effect.
Withdrawal of an interacting drug from a drug regi- men containing a critical
substrate drug can also result in a drug interaction. The dosage of substrate drug
will have been titrated, in the presence of the interacting drug, to optimize
therapeutic effect and minimize adverse effects. Withdrawal of an enzyme
inhibitor will allow metabolism to return (increase) to normal levels. This
increased me- tabolism of the substrate drug will lower its levels and de- crease
therapeutic effect. In contrast, removal of an en- zyme inducer will result in an
increase in substrate drug levels and drug toxicity as metabolism of the substrate
de- creases to a normal rate.
Drug interactions that affect renal drug elimination are clinically significant only if
the parent drug or its ac- tive metabolite undergoes appreciable renal elimination.
The incidence of the syndrome is unknown, partly due to the lack of uniform
diagnostic criteria. Virtually all medica- tions that potentiate serotonergic
neurotransmission in the CNS have been reported in association with serotonin
syndrome. The antidepressant combinations most com- monly implicated have
been monoamine oxidase inhibitors (MAOIs; reversible and irreversible) and
TCAs, MAOIs and SSRIs, and MAOIs and venlafaxine.
Thus, the differential diagnosis for serotonin syndrome is similar to that for
neuroleptic malignant syn- drome (NMS) (see Neuroleptic Malignant Syndrome
subsection later in the chapter). Differentiating serotonin syndrome from NMS
can be very difficult in patients receiving both serotonergic and antipsychotic
medications.
Serotonin syndrome is often self-limited and usually resolves quickly after
discontinuation of serotonergic agents. Management includes the following basic
princi- ples: 1) provide necessary supportive care, 2) discontinue all serotonergic
agents, 3) anticipate potential complica- tions, 4) consider administering
antiserotonergic agents, and 5) reassess the need for psychopharmacological
therapy before reinstituting drug therapy (Keck and Arnold 2000). Some patients will
require admission to an inten- sive care unit, but most will show some
improvement within 24 hours with supportive care alone. There are no specific
antidotes available for the treatment of serotonin syndrome. The antihistamine
cyproheptadine is the most consistently effective serotonin antagonist reported.
The recommended adult dose is 48 mg and may be repeated every 14 hours
up to a maximum daily dose of 32 mg.
Autonomic and cardiovascular. The SSRIs and the novel/ mixed-action
antidepressants have a much safer cardio- vascular profile than the TCAs and
MAOIs. In general,
Bupropion is reported to cause hy- pertension without affecting heart rate in
some patients. In patients using transdermal nicotine, bupropion is asso- ciated
with a 6.1% incidence of hypertension (Khawaja and Feinstein 2003). Reboxetine
has also been associated with an increase in heart rate of 811 beats/minute
(Flei- shaker et al. 2001), but without any significant effect on
electrocardiography (Andreoli et al. 2002).
Gastrointestinal. Nausea is the most common adverse effect associated with the
serotonergic antidepressants.
Weight gain/loss. Weight gain is a relatively common problem during both acute
and long-term treatment with antidepressants. TCAs and MAOIs are more likely
to cause weight gain than other antidepressants, with the exception of
mirtazapine. Paroxetine may be more likely than other SSRIs to cause weight
gain during long-term treatment. Bupropion rarely causes weight gain (Fava
2000).
Abrupt discontinuation of SSRIs, especially those with short half-lives, may give
rise to a discontinuation syndrome characterized by a wide variety of symptoms,
including gastrointestinal, psychiatric, neurological, and flulike symptoms; sleep
disturbances; and headache (Had- dad 1998), usually resolving within 3 weeks.
Antidepres- sants, like all psychoactive medications, should be grad- ually
withdrawn. Discontinuation symptoms can cause misdiagnosis and inappropriate
treatment, particularly in a patient with an active medical illness, as well as erode
fu- ture compliance.
TCAs are now viewed as second-line treatments for depression because their
adverse effect profile is less benign than that of SSRIs.
TCAs are antagonists at histamine H1, adrenergic alpha1, and muscarinic
receptors and have type-1A antiarrhythmic (quinidine-like) effects as a result of
their blockade of voltage-dependent Na+-channels.
Adverse effects of the TCAs include sedation, anticholinergic effects (dry mouth,
dry eyes, constipation, urinary retention, decreased sweating, confusion, memory
impairment, tachycardia, blurred vision), and postural hypotension. Tolerance to
these effects usually develops over time.
TCAs can cause heart block, arrhythmias, palpitations, tachycardia, syncope,
and heart failure and should be used with caution in pa- tients with preexisting
cardiovascular disease or at risk of suicide.
Drug interactions. The combination of TCAs and other drugs with sedating,
hypotensive, antiarrhythmic, or sei- zure thresholdlowering properties may lead
to additive toxicity.
be transferred back to a psychiatric service only after the patient is med- ically
stable. Among patients who recover from NMS, there may be a 30% risk of
recurrent episodes following subse- quent antipsychotic rechallenge, but the
majority of pa- tients who require antipsychotic therapy can be cautiously retreated.
Autonomic and cardiovascular.
Among the atypical agents, the hierarchy for producing hypotension (from
greatest risk to least risk) is clozapine > quetiapine > risperidone > olanzapine =
ziprasidone = aripiprazole (estimated)
Other cardiac side effects. Potentially fatal myocarditis, cardiomyopathy, and
heart failure have been reported with clozapine.
2. Endocrinological and MetabolicGlucose tolerance.
Pharmacoepidemiological studies and case reports reveal an association
between the use of various atypical antipsychotics with hyperglycemia, newonset type 2 diabetes
Current limited data report that hyper- glycemia has been associated with all
marketed atypical antipsychotics.
Diabetic ketoacidosis has been reported in association with all atypical antipsychotics except for ziprasidone
Lipids. More recent studies with atypical antipsychotics have demonstrated
elevated serum triglyceride levels in patients taking clozapine, olanzapine, and
quetiapine (Domon and Cargile 2002; Gaulin et al. 1999; Meyer 2001b), usually
peaking in the first year of therapy.
Hyperprolactinemia. Hyperprolactinemia is relatively common, especially with
high-potency typical antipsy- chotics and risperidone, and can result in
amenorrhea or irregular menses, galactorrhea, gynecomastia, sexual dysfunction, and osteoporosis.
Weight gain. All currently marketed antipsychotics (with the possible exception of
molindone, ziprasidone, and aripiprazole) are associated with weight gain, which
may increase health risks (hypertension, atherosclerosis, type 2 diabetes,
cardiovascular disease, and stroke), stig- matization, noncompliance, impairment
in quality of life, and social withdrawal. The relative propensity to cause weight
gain among the atypical antipsychotics (from greatest to least) is clozapine >
olanzapine > risperidone = quetiapine = aripiprazole (estimated) > ziprasidone
(Tan- don 2002).
Syndrome of inappropriate antidiuretic hormone secre- tion. SIADH can occur
Cognitive Enhancers
Antidepressants
Antipsychotics
Psychostimulants
Mood Stabilizers
Cholinesterase Inhibitors
Complementary Medicines
Patients with chronic disease may be especially vulnerable to adverse effects
from herbal medicines because of compromised organ function and
polypharmacy with conventional agents.
Herbal preparations may contain several plant species used under a sin- gle
name (Chandler 2000) and may be adulterated with unlisted pharmacological
agents, pesticides, and heavy metals, including cadmium, lead, mercury, or
arsenic (Crone and Wise 1998). Drugs such as anti-inflammatory agents,
5. Ginseng
Purported use:Ginseng is promoted as a physical, men- tal, and sexual tonic,
immunostimulant, and mood enhancer.
Pharmacological effects and drug interactions: Ginseng possesses estrogenic
activity; it is contraindicated in pa- tients with estrogen receptorpositive breast
cancer. It may cause estrogen-related bleeding disorders (vaginal bleeding) and
breast nodules. Sympathomimetic activity may cause tachycardia, hypertension,
nervousness, agita- tion, mania, and headache.
Avoid use in patients with diabetes, hypertension, anxiety disor- ders, and bipolar
disorder or those using estrogen therapy, antiestrogen therapy, or anticoagulants.
Avoid long-term use, which may be associated with ginseng abuse syn- drome;
symptoms include hypertension, nervousness, in- somnia, skin eruptions,
diarrhea, and tremor. A with- drawal syndrome (hypotension, weakness, tremor)
may occur on discontinuation. Discontinue at least 7 days before surgery.
6. Kava Kava
Purported use. Anxiolytic; sedative
Kava kava is also hallucinogenic. Sale of kava has been banned in many
jurisdictions because of
several incidents of fatal hepatotoxicity. Discontinue at least 24 hours before
surgery.
7.Ma Huang (Ephedra)
Purported use. Weight loss, stimulant
Excessive sympathetic stimulation can lead to dizziness, headache, decreased
appetite, gastro- intestinal distress, irregular heartbeat, tachycardia, hypertension, insomnia, flushing, seizures, stroke, and death.
Discontinue at least 24 hours before surgery.
8. St. Johns Wort
Purported Use: Antidepressant for mild to moderate depression, sedative
Pharmacological effects and drug interactions.
St. Johns wort increases serotonin and norepinephrine activity, which may cause
sinus tachycardia and gastrointestinal distress and may exacerbate bipolar
disorder, causing ma- nia.
Discontinue at least 5 days before surgery.
9. Valerian
Purported use.
Sedative, short-term treatment of in-somnia, anxiolytic
Pharmacological effects and drug interactions.
Withdrawal effects are similar to benzodiazepine with- drawal and can be
managed with benzodiazepines.
10. Yohimbe, Yohimbine
Purported use. Aphrodisiac, stimulant
Adverse effects include insomnia, anxiety, panic attacks, hallucinations,
hypertension, tachycardia, nausea, and vomiting. It should be avoided in patients
with hyper- tension, sleep disorders, anxiety disorders, and psychosis.
Selected Nonherbal Nutritional Supplements
DHEA (Dehydroepiandrosterone)
Purported use. Depression, postmenopausal osteoporo- sis, systemic lupus
erythematosus, erectile dysfunction, multiple sclerosis, dementia
Pharmacological effects and drug interactions.
DHEA may cause weight gain, voice change, hirsutism, and menstrual
irregularities in females and gynecomastia and prostatic hypertrophy in males.
DHEA is contraindi- cated in patients who have liver dysfunction, prostate cancer, or hormone-dependent diseases such as estrogen- dependent breast
cancer.
S-Adenosyl-L-Methionine (SAMe)
Purported use. Depression, osteoarthritis, chronic liver
disease
Pharmacological effects and drug interactions.Adverse effects include nausea,
vomiting, and diarrhea. SAMe may increase anxiety and restlessness in patients
with depression and mania and hypomania in pa- tients with bipolar disorder.
Psychotropic Drug Use in the Medically Ill
A. Gastrointestinal Disease
1. Hepatic Disease
The dosage of psychotropics in patients with chronic hepatitis may need to be
modified depending on the severity of liver dysfunction.
When psychotropic medication is being pre- scribed for patients with impaired
hepatic function, it is prudent to reduce the initial dose and titrate more slowly for
any drug primarily metabolized by the liver, to care- fully monitor for clinical
response and side effects, and to choose drugs with a wide therapeutic index.
a. Antidepressants. Citalopram, paroxetine, sertraline, and fluoxetine have all
been used safely in patients with hepa- titis C, usually in the context of interferon treatment.
Hepatotoxicity is a known rare side effect of many an- tidepressants, but
nefazodone has a higher reported inci- dence than other current antidepressants
and thus should be avoided in patients with preexisting hepatic disease.
Elevation of aspartate transaminase (AST) or alanine transaminase (ALT) levels
of two to three times baseline or two times normal is significant, and any elevation of alkaline phosphatase (ALP) or bilirubin may be significant.
b. Antipsychotics. haloperidol remains the most commonly chosen antipsychotic
for patients with hepatic disease. Chlorpro- mazine should be avoided because
of its greater risk for hepatotoxicity. Low-potency typical antipsychotics, which are
more anticholinergic than high-potency typi- cals, may precipitate hepatic
encephalopathy in patients with cirrhosis (as described for TCAs).
c. Anxiolytics and sedative-hypnotics.
All benzodiazepines should be avoided in patients at risk for developing he- patic
encephalopathy because they may precipitate its on- set. When their use cannot
be avoided (e.g., alcohol withdrawal in a patient with cirrhosis), the benzodiazepines just mentioned are
preferred,d.
d. Mood stabilizers.
Because of the risk of hepatotoxicity, carbamazepine and valproic acid are
relatively contraindi- cated in patients with preexisting liver disease. If either of
these agents is used, reduce dose and monitor liver func- tion regularly,
especially during the first 6 months of ther- apy.
Lith- ium, although renally excreted, may require dose adjust- ment and close
2. Gastrointestinal Bleeding
Antidepressants. Recent reports have raised concern re- garding SSRIs and the
risk of gastrointestinal bleeding (Dalton et al. 2003; de Abajo et al. 1999).
Serotonin plays a role in hemostasis, and there have been cases of pro- longed
bleeding time, ecchymosis, purpura, and epistaxis, as well as gastrointestinal,
genitourinary, and intracranial bleeding, in patients receiving SSRIs.
3. Other Gastrointestinal Disorders
In general, however, orally administered drugs may be poorly absorbed in the
presence of malabsorption syndromes. In patients with delayed gastric emptying
(due to diabetes mellitus, atrophic gastritis, gastric cancer, pyloric stenosis,
pancreatitis, or gastric ulcer or drug induced), the pharmacokinetic effect may be
to slow ab- sorption rate and delay time to onset of the medication.
For non-enteric-coated preparations, increased gastric emptying is likely to
increase the rate of drug absorp- tion, and conversely, delayed gastric emptying
will slow the rate of drug absorption.
For enteric-coated preparations, however, reduced gastric acidity increases the
rate of drug absorp- tion because dissolution of the preparation will occur in the
stomach.
B. Renal Disease
most psychotropics do not require drastic dosage adjustment in renal failure
with end-stage renal disease (ESRD): many problems associated with use of
b. Antipsychotics
d. Mood Stabilizers
e.Cholinesterase Inhibitors
f. Psychostimulants
Antipsychotics
Pregnancy: Typical agentsNot associated with any evidence of
teratogenic, behavioral, emotional, or cognitive abnormalities. Low-potency drugsCan cause neonatal tachycardia,
gastrointestinal dysfunction, sedation, and hypoten- sion for a few days after
birth. Best avoided so as to minimize anticholinergic, hypotensive, and antihistaminic effects.
High-potency drugsPreferred despite the risk of fetal EPS. Incidence of fetal
EPS (hyperactivity, hy- perreflexia, abnormal movements, tremor, hand flapping,
and crying that may persist for several months) is dose related.
Breast-feeding: _____________________
Antidepressants
Pregnancy:
TCAsNot associated with evidence of teratogenic effects.
Avoid maprotiline because of increased ma- ternal seizure risk.
Neonatal TCA withdrawal symp- toms include seizures, irritability,
abdominal cramps, insomnia, tachycardia, tachypnea, and
cyanosis.
SSRIsFluoxetine not associated with teratogenic effects. Other
SSRIs do not appear to be teratogenic from limited human data.
MAOIsAvoid because of hypotensive effects and potential for
drug and food interactions.
Breast-feeding: __________________
6.