อาการไม่พึงประสงค์จากการใช้ยา PDF

:
(Skin Disorder)
. . 2542
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. .(
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Pharm.D., Certificate in Nephrology Pharmacotherapy Residency
. ., M.Sc (Clinical Pharmacy)
. .(
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B.S. (Pharmacy), M.S. (Clinical Pharmacy)
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1.
1.1 Adverse event / Adverse experience
1.2 Adverse Drug Reaction
1.3 Side effect
1.4 Unexpected adverse reaction
1.5 Toxic Reaction
1.6 Hypersensitivity
antibodies
1.7 Idiosyncrasy
idiosyncrasy
enzymatic defect
1.8 Drug Interaction
2
1.9 Serious adverse reaction / adverse event
1.10 Significant adverse drug reaction
The American Society of Health-System Pharmacists (ASHP)
significant adverse drug reaction
1.
2.
3.
4.
5.
6.
2
7.
8.
9.
2.
(predisposing factors)
2.1
(race)
cholestetic jaundice
hemolytic anemia
hemolytic anemia
G6PD
acetylation
slow acetylators
peripheral neuropathy
isoniazid
fast acetylators
2.2
digoxin
agranulocytosis
heparin
phenylbutazone, chloramphenicol
aplastic anemia
chloramphenicol
3
2
3
2.3
sulphate
conjugation
microsomal oxidation
glucuronidation
chloramphenicol,barbiturates, morphine, vitamin K
benzodiazepines
tricyclic antidepressants
2.4
Stevens
Johnson Syndrome
50-80%
2.5
phenytoin , barbiturates ,
paracetamol,
phase I metabolism
phenytoin, warfarin, theophylline
clotting factors
anticoagulants, ticlopidine, NSAIDS
hepatic encephalopathy
barbiturates, narcotic drugs, chlorpromazine
NSAIDS, phenytion
glomerular filtration
ACE-inhibitors, aminoglycosides, cytotoxic agents
digoxin,
2.6
hypothyroidism
propranolol, digoxin
-
digoxin
(splanchnic circulation)
lithium
propranolol, lignocain
3.
2
1. Type A (augmented) adverse drug reactions
Type A reactions
type A reactions
type A reactions
80%)
type A reactions
(bradycardia)
-blockers
(hypoglycemia)
antidiabetics
(drawsiness)
benzodiazepines
(bruising)
warfarin
antihypertensives
5
(alopecia)
(myclosuppression)
antineoplastic agents
(bronchospasm)
nonselective
tricyclicantidepressants
broadspectrum antibiotics
antihistamines
anti-androgenic properties
cimetidine
-blockers
2. Type B (bizarre) adverse drug reactions

type B reactions
20 %)
type B reactions
type B reactions
anaphylactic shock
Steven Johnson Syndrome
agranulocytosis
hepatotoxicity
hemolytic anemia
type B reactions
penicillin G
carbamazepine
ACE-inhibitors
ticlopidine
halothane
NSAIDs
1.
2.
3.
4.
ADR
Type A
2
(Grahame-Smith D.G and Aronson J.K., 1992)
3. Type C (Chronic, continuous, long-term effects)
ADR
3
- Adaptive changes
narcotic analgesics
- Rebound phenomena
- adrenoreceptor antagonists
rebound tachycardia
myocardial ischemia,
clonidine
rebound hypertension
barbiturates
,
benzodiazepines
- Other effects
chloroquine - induced retinopathy and blindness
4. Type D (Delayed effects)
diethystiboestrol
HRT
vaginal adenocarcinoma
endometrial carcinoma,
;
cyclophosphamide
cyclophosphamide
chlorambucil
nonlymphocytic leukemias ;
azathioprine
corticosteroids
,
,
lymphomas
Wills S.
Brown D. (1999)
Rawlins & Thompson
1) Type A (augmented) reactions
2) Type B (bugs) reactions

Type A
;
normal flora
(pseudomembranous colitis)
oral thrush
steroids, cyclosporin,
Type A
3) Type C (chemical) reactions

,
4) Type D (delivery) reactions
(implants) ;
,
,
5) Type E (exit) reactions
(withdrawal reactions)
opioids,
benzodiazepines, tricyclic antidepressans, beta blockers, clonidine, nicotine
6) Type F (familial) reactions
8
phenylketonuria,
glucose-6-phosphate dehydrogenase (G6PD) deficiency, C1 esterase inhibitor deficiency,
porphyria
sickle cell anemia
G6PD deficiency
hemolysis
quinine
Type F
cytochrome p450 2D6

7) Type G (genetotoxicity)
carcinogenic
genotoxic
Type A
teratogenic
8) Type H (hypersensitivity) reactions

,
, Stevens-Johnson syndrome,
angioedema, blood dyscrasias

9) Type U (unclassified) reactions
,
simvastatin
NSAIDs
2
Type A reaction
prostaglandins
Type C reaction
Type A reaction
prostaglandin E2
prostaglandin
NSAIDs
enteric coated
non-irritant pro-drug
Wills & Brown
9
4.
4.1 Chromosome damage

mitomicin C
cisplatin
methotrexate
DNA
DNA
DNA
DAN
folic acid
inosine
purine
chromosome
4.2 Disorders of fetus and infant
4.3 Disorders of the heart
neuroleptic
sympathomimetic effect
class l antiarrhythmic effect
proarrhythmic effect
4.4 Disorders of the peripheral vascular system

type
A
sympathomimetic drugs, cyclosporin

radiographic contrast media
anaphylactic reaction
type B
10
4.5 Respiratory disorders
pulmonary
thromboembolism
4.6 Dental disorders
tetracycline
phenytoin
4.7 Gastrointestinal disorders

type A
digitalis, opiates, oestrogen, levodopa
NSAIDs
4.8 Hepatic disorders

5%
paracetamol
type A
stavudine
type B
11
4.9 Renal disorders
function
aminoglycosides
NSIADs
acute tubular necrosis

tubular
glomerulonephritis
acute interstitisal nephritis
4.10 Endocrine disorders

type A
carbimazole
thyroxine
glucocorticoids
hypertyroidism
type B
hypothyroidism
Cushings syndrome
4.11 Disorders of metabolism

corticosteroids
diuretics
4.12 Disorders of muscle ,bone and connective tissue

suxamethonium
type A
salbutamol
4.13 Skin disorders

30%
type A
type B
kinin potentiation
cotrimoxazole
10
type A
captopril eruption
type B penicillin eruption
type A
B
type B
12
4.14 Neurological disorders
lignocaine
4.15 Eye disorders
cortcosteroids
chloroquine
ocular damage
4.16 Ear, nose, and throat disorders
aminoglycosides
vestibular
4.17 Psychiatric disorders
amitryptyline
anticholinergics
antidepressants
atropine, benztropine,
4.18 Disorders of blood cells and haemostasis
13
4.19 Neoplastic disorders

Hormones, immunosuppressants
chemotherapeutic agents
cyclosporin
(lymphoma)
4.20 Disorders of temperature regultion
procainamide
4.21 Obstetrical and gynaecological disorders
estrogen
citrate
clomiphene
4.22 Drug induced sexual dysfunction and fertility

type A
clonidine,
methyldopa
5.
The Council for International Organizations of Medical Sciences (CIOMS)
1.1
1.1
Very common
Common (frequent)
Uncommon (infrequent)
Rare
Very rare
>1/10
>1/100 and <1/10
>1/1,000 and <1,000
>1/10,000 and <1,000
<1/10,000
(>10 %)
(>1 % and <10 %)
(>0.1 % and <1 %)
(>0.01 % and <0.1 %)
(<0.01 %)
14
6.
3
-
(mild, negligible, insignificant)
(moderate)
(serious)
Hartwig, Siegel
Schneider, 1992
1
2
3
1
5
6
7
15
7.
4
- Certain (definite, confirmed, highly probable) =
- Probable (likely) =
- Possible =
- Unlikely (doubtful, remote) =
Certain
1.
2.
3.
4.
Probable/Likely
1.
2.
3.
4.
Possible
1.
2.
3.
Unlikely
1.
16
2.
,
(algorithm)
(Bayesian method)
Naranjos
algorithm
1)
2)
17
1.1
-
1.2
Numbness
Headache
Fatigue
Sensation of heaviness
Inability to concentrate
Drowsiness
Nausea
Dryness of the mouth
General weakness
Flushes
36
23
10
14
14
7
9
7
5
6
out
out
out
out
out
out
out
out
out
out
of
of
of
of
of
of
of
of
of
of
72
92
57
77
92
72
92
77
57
77
=
=
=
=
=
=
=
=
=
=
50
25
18
18
15
10
10
9
8
8
%
%
%
%
%
%
%
%
%
%
3)
G6PD
slow acetylator
4)
18
type A reactions
15 30
5
5
type B reactions
5
12
aplastic anemia
5.
-
phenytoin
toxicity
digitoxin toxicity
6)
-
19
7)
1-7
algorithm
8.
8.1
3
1)
2)
3)
8.2
1)
2)
(objective paramater)
-
(parameter)
(subjective parameter)
20
3)
8.3
1)
(patient medication profile)
2)
-
1.
.
.
; 2542.
21
2.
.
:
;
.
3. American Society of Health-System Pharmacists. ASHP guidelines on adverse drug
reaction monitoring and reporting. Am J Health-Syst Pharm. 1995; 52 : 417-9.
4. Benichou C. Adverse Drug Reactions: A Practical Guide to Diagnosis and Management.
Chichester: John wiley & Sons; 1994.
5. Coe CP. The elements of quality in pharmaceutical care. Bethesda, MD: American Society
of Health-System Pharmacists; 1992. p. 39-45.
6. Grahme-Smith DG, Aronson JK. Oxford Textbook of Clinical Pharmacology and Drug
Therapy. 2nd ed. London: Oxford University Press; 1992. p.106-116.
7. Hartwig S, Seigel J, Schneider P. Preventability and severity assessment in reporting
adverse drug reactions. Am J Health-Syst Pharm. 1992; 49 : 2229-2232.
8. Koch KE. Adverse drug reactions. In: Brown TR. Handbook of Institutional Pharmacy
Practice. 3rd ed. Bethesda, MD: American Society of Hospital Pharmacists; 1992. p. 279-291.
9. Rawlins MD, Thomas SHL. Mechanisms of adverse drug reactions. In: Davies DM, Ferner
RE, de Glanville H (eds). Textbook of Adverse Drug Reactions. 5thed. London: Chapman &
Hall Medical ; 1998. p.40-64.
10. Rawlins MD, Thompson JW. Mechanisms of adverse drug reactions. In: Davies DM (ed).
Textbook of Adverse Drug Reactions. 4th ed. London: Oxford University Press; 1991. p.12-13.
11. Royer RJ. Mechanism of action of adverse drug reactions: An overview.
Pharmacoepidemiology and Drug Safety. 1997; 6 Suppl. 3:s43-s50.
12. Uppasala Monitoring Center. WHO Programme for International Drug Monitoring. Available
at : http://www.who-umc.org/defs.html. Accessed June 6, 2001.
13. Wills S, Brown D. A proposed new means of classifying adverse drug reactions to
medicines. Pharm J. 1999; 262:163 -165.
22
doxorubicin
fenfluramine
(cytotoxic agent)
dexfenfluramine
sympathomimetic
(antiarrhythmic)
(NSAIDs)
1.
(arrhythmias)
terfenadine
astemizole
(
27
2543)
cisapride
23
(
)
(proarrhythmia)
(predisposing factors)
(
ventricular tachycardia
fibrillation)
5-10%
Digoxin
digoxin
(automaticity)
digoxin
ventricular arrhythmia
digoxin
4
2
bradyarrhythmia, ventricular bigeminy
digoxin
2
/
digoxin
6
digoxin
digoxin
digitalis
2.1
2.1
digitalis
Bradycardia
Sinus bradycardia
Sinoatrial block
A-V nodal block
Marked slowing of ventricular response rate in atrial fibrillation
Supraventricular tachycardias
Paroxysmal atrial tachycardia with A-V nodal block
Non-paroxysmal A-V nodal tachycardia
Ventricular rhythms
Frequent or multifocal ventricular extrasystoles
Ventricular tachycardia/ventricular fibrillation
24
1.1 Prolonged QT interval

QT interval
wave
(ECG)
QT interval
QT interval
pointes
QT interval
2.2
Class Ia
2.2
Antiarrhythmic drugs
Group Ia
Disopyramide
Procainamide
Quinidine
Group Ib
Lignocaine*
Mexiletine*
Group Ic
Encainide
Group III
Amiodarone
Sotalol
Antihistamines
Astemizole
Terfenadine
Antibacterial
Clarithromycin
Co-trimoxazole
Erythromycin
Antifungals
Ketoconazole
Torsade de pointes
QRS complex
T
torsade de
potassium channels
torsade de pointes
prolonged QT interval
2.3
Class III
prolonged QT interval
Antimalarial
Chloroquine
Halofantrine
Antipsychotics
Amitriptyline
Chlorpromazine*
Doxepin*
Maprotiline*
Thioridazine
Antidepressant
Tricyclic antidepressant
Others
Cisapride
Pentamidine
Probucol
Terodiline
25
2.3
torsade de pointes
(
(bradycardia)
cardiac hypertrophy
Congenital long QT syndromes
QT interval
torsade de pointes
torsade de
pointes
atrial pacing
infusion
isoprenaline
isoprenaline
catecholamines
magnesium sulphate infusion

torsade de pointes
ventricular fibrillation
DC shock
(antiarrhythmic agents)
(proarrhythmic
arrhythmogenic) torsade de pointes
potential duration
class Ia
class III
torsade de pointes
quinidine
2-8%
sotalol
2-4%
action
2.2
class Ia
26
amiodarone
QT interval
torsade de pointes
proarrhythmic
proarrhythmic
11%
(psychotropic drugs)
electrophysiological effects
(prevalence)
tricyclic antidepressants, thioridazine
droperidol
msec)
ECG
(antihistamines)
. 1989
terfenadine
quinidine
QT interval
(> 456
torsade de pointes
ketoconazole
terfenadine
fexofenadine
terfenadine
macrolide (
imidazole, protease inhibitors ( ritonavir)

erythromycin
clarithromycin)
terfenadine
ventricular repolarization
grapefruit
terfenadine
astemizole
terfenadine
2
27
2543
Cisapride
Cisapride
CYP 3A4
cisapride
cisapride
gastro-esophageal reflux
cytochrome P450
cisapride
27
ventricular arrhythmias
imidazole
protease inhibitors
prolongation
macrolide
cisapride
cisapride
QT
3
QT interval
2.4
2.4
QT interval
(
)
QT interval
QT prolongation
QT interval
1
QT interval
terfenadine cisapride
grapefruit
(
1.2
(atrial fibrillation)
atrial fibrillation
400-700
(fatigue)
/
(angina)
(dyspnea)
(palpitations)
ECG
(thyrotoxicosis)
15-35%
atrial fibrillation
dilated cardiomyopathy
atrial fibrillation
tricyclic antidepressant, trazodone
serotonin reuptake
fluoxetine
28
serotonin
antidepressants
atrial fibrillation
systemic lupus
erythematosus
atrial fibrillation
electrical cardioversion
(Bradycardia)
1.3
sinus rhythm
60
2.5
2.5
Beta blockers
Carbamazepine
Clonidine
Digoxin
Diltiazem
Histamine H2-antagonists
Paclitaxel
Verapamil
sinus bradycardia
60 /
beta receptors
verapamil, diltiazem, digoxin
beta-blockers
beta blockers
beta blockers
atropine
SA node
beta blockers
atrioventricular block
atrioventricular node
verapamil/diltiazem
verapamil
(pacing)
29
ECG
2.
(cardiac failure)
2-3%
preload
(
afterload (
)
preload
(iatrogenic
cause)
carbenoxolone, NSAIDs
(edema)
fludrocortisone
NSAIDs
NSAIDs
mineralocorticoid steroids
NSAIDs 3-5%
(odds ratio 10.5)
NSAIDs
beta2 adrenoceptor agonists
(negative inotropic)
30
beta blockers
metoprolol, bisoprolol
carvedilol
amiodarone
verapamil
felodipine
(calcium channel blockers)

diltiazem
isradipine
nifedipine
angiotensin-converting enzyme
inhibitors (ACEI)
NSAIDs
2.6
2.6
Antacid (high sodium content)
Anthracycline cytotoxic drugs
Beta-blockers
Diltiazem
3.
Nifedipine
Non-steroidal anti-inflammatory drugs
Thyroxine
Verapamil
(hypertension)
140
90
adrenaline (epinephrine), dobutamie, dopamie
phenylephrine
monoamine oxidase inhibitors
sympathomimetics
tyramine
2
Ciclosporin
corticosteroid
ciclosporin
sympathomimetic
(MAOIs)
31
prostacyclin
nitric oxide
endothelin
(glomerular filtration)
dihydropyridine
nifedipine, amlodipine, isradipine
blockers
ACEI
felodipine
beta
2.7
2.7
Ciclosporin
Corticosteroids
Erythropoietin
Interferon alfa
Ketoconazole
Moclobemide
4.
Naloxone
Estrogens
Sympathomimetics
Tacrolimus
(myocardial toxicity)
(cardiomyopathy)
(myocytolysis)
anthyracycline (anthracycline cytotoxics)

anthracycline doxorubicin
30
early-onset chronic progressive
3
late-onset chronic progressive
32
(course)
(electrophysiology)
(pericarditis-myocarditis syndrome)
early-onset chronic progressive
anthracycline
restrictive cardiomyopathy
progressive
chronic dilated cardiomyopathy

anthracycline
late - onset chronic
congestive heart failure
anthracycline
60%
doxorubicin
450-550
/
doxorubicin
(mediastinal radiotherapy)
doxorubicin
oxygen free radicals
doxorubicin
catalysed
doxorubicin-iron complex
anthracycline
(echocardiograms)
dexrazoxane
anthracycline
hydrogen peroxide
anthracycline
2.8
superoxide anions
superhydroxide free radicals
33
2.8
Amsacrine
Busulfan
Carmustine
Cisplatin
Cyclophosphamide
Cytarabine
Daunorubicin
Doxorubicin
Epirubicin
Etoposide
Fluorouracil
Idarubicin
Ifosfamide
Mitomycin
Mitoxantrone
Paclitaxel
Vinca alkoloids
Interferon alfa
5-15%
interferon alfa
interferon
5.
(myocardial ischemia
infarction)
pH
(angina)
beta-blocker
unstable angina
sympathomimetic
beta receptors
beta blockers
Calcium channel blockers
receptor
beta blocker
nifedipine
reflex tachycardia
nifedipine
nifedipine
levothyroxine (thyroxine)
(hyperthyroidism)
(hypothyroidism)
34
thyroxine
ergotamine
ergotamine
total peripheral resistance

Fluorouracil
fluorouracil
. . 1969
1.6%
antimetabolite
24-68%
10%
2 3
bolus
3
48
90%
nitrates
calcium chennel blockers
2.2-13.3%
2.9
2.9
Adenosine
Amphetamines
Beta-agonists
Beta-blockers (withdrawal)
Caffeine
Dipyridamole
Ergotamine
6.
Fluorouracil
Nifedipine (short-acting)
Theophylline
Levothyroxine (thyroxine)
Verapamil
Vinblastine
Vincristine
(thromboembolic disorders)
1-2% deep
vein thrombosis (DVT)
35
(anticoagulant)
(pulmonary embolism, PE)
(collapse)
(cerebral circulation)
(stroke)
estrogen
50
estrogen
DVT
factor V Leiden mutation
DVT
norethisterone
levonorgestrel (
5-15
100,000
3
norgestimate
desogestrel
gestodene
2
2
3
desogestrel
gestodene
25
100,000
/
2)
PE
desogestrel, gestodene
norgestimate
3
(hormone replacement therapy, HRT)

2-4
100,000
HRT
16-23
)
36
DVT
PE
(antipsychotics)
clozapine
12
8
case-control
chlorpromazine
7.
thioridazine
(stroke)
cocaine, amphetamines
2.10
(thrombolytics)
phenylpropanolamine
(anticoagulant)
(antiplatelet)
2.10
Bromocriptine
Danazol
Desmopressin
Hypoglycemic agents
Oral contraceptive
Phenylpropanolamine
Tranexamic acid
hemorrhagic stroke
ischemic stroke
estrogen
ischemic stroke
37
10%
100,000
2-8
35
Bromocriptine
bromocriptine
ergot
bromocriptine
8.
(valvular disorders)
. 1988
cardiac murmurs
serotonin antagonist ergotamine
2
ergotamine tartrate
(mitral valve)
(aortic valve)
/
(tricuspid valve)
(appetite suppressants)
fenfluramine
phentermine
ergotamine
dexfenfluramine
phentermine
9.
fenfluramine
(hypotension)
vasovagal response
(
38
(antihypertensive drugs)
hydralazine
beta blocker
reflex
(
alpha adrenoceptor blockers
prazosin)
'first-dose hypotension'
prazosin
alpha adrenoceptor blockers

Thiazides, methyldopa, hydralazine, clonidine
clonidine
diagnostic test
pheochromocytoma
glyceryl trinitrate
hypotension
first dose effect

beta blockers
first dose
Vancomycin
Vancomycin
cefazoline
50%
vancomycin
3
vancomycin
(
14%
cefazoline
39
vasomotor centre
neuromuscular blocking agents
MAOI
MAOI
2
tranylcypromine
20
sedative, tranquilizers, antipsychotics,
antidepressants, opiates
levodopa
1. Chapelon C. Abnormal blood pressure. In: Benichou C. Adverse Drug Reactions: A

Practical Guide to Diagnosis and Management. Chichester: John Wiley & Sons, 1994;
p.133-150.
2. Davies CJ, Davies DM. Disorders of the peripheral vascular system. In: Davies DM, Ferner
RE, De Glanville H (eds.). Textbook of Adverse Drug Reactions 5th ed. London: Chapman &
Hall Medical, 1998; p.169-201.
3. Kearney MT, Wright DJ, Tan L-B. Cardiac disorders. In: Davies DM, Ferner RE, De
Glanville H (eds.). Textbook of Adverse Drug Reactions 5th ed. London: Chapman & Hall
Medical, 1998; p.119-168.
4. Maclean F, Lee A. Cardiovascular disorders In: Lee A. Adverse Drug Reactions. London:
Pharmaceutical Press, 2001; p.217-240.
5. Maclean F, Lee A. Adverse drug reactions: Drug-induced cardiovascular disorders. The
Pharmaceutical Journal 1999;262:133-118.
40
urine sediment
(end stage renal failure)
7%
20%
8%
3-6%
41
volume
status
increased blood urea nitrogen (BUN)
serum creatinine (Scr)
metabolic acidosis
Scr
Scr
(non-linear
gromerular filtration rate (GFR)

relationship)
GFR
40-
50%
Scr
1.
20-25%
(systemic drug
administration)
(total drug dose)

prostaglandins
42
3
2.
(secretion)
(reabsorption)
3.
4.
medulla
active transport
5.
osmotic diuretic
6.
pH
7.
8.
9.
43
3.1
renal syndrome
3.2
3.1
3.2
Prerenal/ hemodynamic
Intrarenal:
Acute tubular necrosis
Acute interstitial nephritis
Postrenal/ obstructive
Nephrotic syndrome
Fluid and electrolyte disturbances
Acid-base disorders
Cyclosporin, radiocontrast, amphotericin B,

angiotensin converting enzyme inhibitors, NSAIDs
Aminoglycosides, amphotericin B, cisplatin,
cephaloridine
Penicillins, cephalosporins, sulfonamides, rifampicin,
NSAIDs, ciprofloxacin
Acyclovir, analgesic abuse, cyclophosphamide,
indinavir, methotrexate
Lithium, analgesic abuse, cyclosporin, cisplatin
Gold, NSAIDs, penicillamine, captopril
3.5
3.6
44
1. Pseudo-renal failure
glomerular filtration rate (GFR)
BUN
Scr
3.3
3.3
Corticosteroid
Tetracycline
pseudo-renal failure
BUN
GFR CrCL
Scr
Trimethoprim
Cimetidine
Cefoxitin
Cephalothin
Cefazolin
Cefotaxime
Flucytosine
Methyldopa
Scr
proximal tubular lumen
BUN
(
ranitidine
H2 blockers
creatinine
Scr
)
Scr
creatinine
45
3
2. Hemodynamically mediated renal failure
glomerular afferent
arterioles
glomerular efferent arterioles

colloid oncotic pressure
angiotensin-converting enzyme
inhibitors (ACEIs), angiotensin II receptor antagonists
nonsteroidal anti-inflammatory drugs
(NSAIDs)
cyclosporin, tacrolimus, triamterene, propranolol, dextran,
epoietin
Cyclosporin
amphotericin
renal blood flow
glomerular perfusion
vasoconstrictors
cyclosporin
amphotericin
endothelin
thromboxane A2
NSAIDs
NSAIDs
prostaglandins
NSAIDs
volume depletion
compromise of renal perfusion

cyclooxygenase (
PGH synthase)
renal prostaglandin
preexisting renal disease

prostaglandins
vasodilator
renal perfusion
NSAIDs
prostagladins
renal blood flow
GFR
angiotensin-converting enzyme inhibitors (ACEI)-induced
acute renal failure
severe
bilateral renal artery stenosis
critical renal artery stenosis
nephrosclerosis
ACEIs
angiotensin I
angiotensin II
potent vasoconstrictor
46
3
angiotensin II
efferent arterioles
glomerulus
GFR
renal blood flow
ACEIs
acute renal failure
systemic blood pressure
transglomerular pressure
ACEIs
drug-induced hemodynamic renal insufficiency
3. Renal vasculitis, thrombosis, and cholesterol emboli
methamphetamine
, cyclosporin, mitomicin C, cisplatin, quinine
warfarin
cholesterol emboli
4. Glomerular diseases
druginduced glomerular disease

NSAIDs,
ampicillin, rifampicin, captopril, phenytoin, lithium, chronic heroin abuse, -interferon, gold, Dpenicillamine, mercury, hydralazine, interleukin-2, chlorpropamide
5. Tubular epithelial cell damage

2
5.1 Osmotic nephrosis
mannitol, low-molecular weight dextran, radiographic
contrast media, propylene glycol
47
3
osmotic nephritis
mannitol
cyclosporin
mannitol
mannitol
serum mannitol
1000
/
mOsm/kg water (
osmolal gap 20 mOsm/kg water
5.2 Acute tubular necrosis (ATN)
osmolal gap
55
)
ATN
aminoglycosides
amphotericin B
renal tubular cells
intracellular cations (K+, Mg2+)
BUN
Scr
400
cisplatin
cations
extracellular cations (Na+, Ca2+)
electrolytes
nonoliguric state (
/ )
oliguric state (
400
)
noncellular casts
tubular
tubular epithelial cells

lag time
gentamicin
prototype
48
3
Aminoglycoside-induced ATN
aminoglycoside toxicity
20%
aminoglycosides protein binding
renal cortex
cortical tubular cells
5-7
oliguria
Scr
renal magnesium and potassium wasting
BUN
Scr
noncellular casts
aminoglycoside-induced ATN
aminoglycoside
1.
glomerulus
30
3
1
2.
aminoglycoside
aminoglycoside
amphotericin B, vancomycin, diuretics
cyclosporin
3.
obstructive jaundice
aminoglycoside-induced ATN
culture & sensitivity
volume depletion
Scr, electrolytes
49
3
Amphotericin B-induced ATN
Amphotercin B
Amphotericin B-induced ATN

dose dependent nephrotoxicity
300-400
amphotericin B
drug-induced renal
diseases
80% cumulative dose
4
renal tubular function
potassium, sodium and magnesium wasting
distal renal tubular acidosis
BUN
Scr
amphotericin-induced ATN
volume depletion
rapid infusion
cumulative dose
3-5
amphotericin B
volume depletion
full sodium diet
NSS 1
/
amphotericin B(
)
calcium channel blocker
mannitol
renal tubular dysfunction
glomerular filtration
ATN
radiographic contrast media, cisplatin, pentamidine, foscarnet,

chloroform
CCl4,
6. Tubulointerstitial nephritis
tubulointerstitial cells
50
3
6.1 Acute allergic interstitial nephritis (AIN)
interstitial inflammatory cell infiltrates
systemic symptoms
active renal inflammation
non-glomerular levels of proteinuria
eosinophiluria
interstitial nephritis prototype
drug-induced AIN
cellular casts
methicillin allergic
AIN
corticosteroid
course
AIN
3.4
Methicillin-induced AIN
44 )
low level proteinuria (90%)
17 (
2(75%), eosinoplilia (80%), pyuria
hematuria (90%),
maculopapular rash (25%), oliguria (18%)
idiosyncratic hypersensitivity
reactions
slow acetylators
1
/
and extent of renal recovery
3.4
Antibiotics
Acyclovir
Aminoglycoside
Amphotericin B
Aztreonam
Cephalosporins
Ciprofloxacin
Cotrimoxazole
Erythromycin
Ethambutol
Penicillins
Rifampicin
Sulfonamides
Tetracyclines
1-4
prednisolone 0.5rate
allergic interstitial nephritis

Miscellaneous
Acetaminophen
Allopurinol
InterferonAspirin
Captopril
Cimetidine
Clofibrate
Cyclosporin
Glyburide
Gold
Methyldopa
p-Aminosalisylic acid
Phenylpropanolamine
51
3
3.4
allergic interstitial nephritis ( )
Vancomycin
Neuropsychiatric
Carbamazepine
Lithium
Phenobarbital
Phenytoin
Valproic acid
Nonsteroidal anti-inflammatory drugs
Diuretics
Acetazolamide
Amiloride
Furosemide
Triamterine
Thiazides
Propylthiouracil
Ranitidine
Sulfinpyrazone
Warfarin sodium
6.2 Chronic interstitial nephritis
cyclosporin
nephritis
interstitial cells
chronic interstitial nephritis
mesalasine, 5-aminosalicylic acid, ifosfamide
lithium
chronic interstitial
lithium
cyclosporin
chronic interstitial renal disease
therapeutic range
6.3 Papillary necrosis

tubulointerstitial nephritis
papillar
diseases
papillary necrosis
P. carinii infection
drug-induced renal
dapsone
AIDS
Analgesic nephropathy
(microscopic hematuria)
52
3
analgesic nephoropathy
1.
2.
intravenous pyelography, renal ultrasound

tomography imaging
renal mass
(bumpy contours)
3.
papillary calcification
renal computerized
NSAIDs 2
carcinoma
analgesic nephropathy
7. Obstructive nephropathy
Chemotherapy
chemotherapy
hematologic malignancies
uric acid
urine uric acid : creatinine
uric acid
pH
7.0
Alcohol, cocaine
heroin
rhabdomyolysis
1
allopurinol
drug-induced muscle necrosis

myoglobin
53
3
Lipid lowering agents
rhabdomyolysis
flu-like syndrome
CYP 3A4
analgesic-associated nephropathy
necrotic renal papillary tissue
Sulfonamides, methotrexate, acyclovir, ascorbic acid
molecular weight dextran
lowpH
Anticholinergic drugs, disopyramide phosphate, tricyclic antidepressants

bladder dysfunction
Cyclophosphamide, isophosphamide
fibrosis
hemorrhagic cystitis
mesna
cystitis
8. Nephrolithiasis
true nephrotoxicity
renal
collecting system
Triamterene
Sulfadiazine
pH
Toxoplasma gondii
7.15
54
3
Indinavir
protease inhibitors
highly active antiretoviral therapy (HAART)
indinavir
crystalluria, dysuria,
10%
AIDS
indinavir
pH
indinavir
magnesium trisilicate-aluminum hydroxide
magnesium ammonium phosphate (struvite)
ammonium urate
ammonium
fluid and volume disturbances
3.5
3.6
3.5
pH
acid-base disorders
drug-induced fluid and volume disturbances
Fluid & electrolyte

disturbances
Syndrome of inappropriate
anti-diuretic hormone
(SIADH)
Hyponatremia due to excess

ADH release, and cause excess
water retention
Chlorpropamide, clofibrate,
carbamazepine, cyclophosphamide,
vincristine, oxytocin, NSAIDs,
tricyclic antidepressants,
phenothiazines
Diabetes insipidus (DI)
Free water wasting when ADH

is not present
Phenytoin, ethanol, lithium,

demeclocycline
Volume disturbances
Dehydration, fluid overload
Sodiumcontaining drugs, diuretics
Electrolyte disturbances
Hypokalemia
Hyperkalemia
Large doses of carbenicillin

Some penicillins
3.6
drug-induced acid-base disorders
Acid-base disorders
Metabolic acidosis
Acetazolamide, amphotericin B, outdated tetracycline
Metabolic alkalosis
Excess mineralocorticoid
55
diagnostic
therapeutic pharmacologic
agents
56
1 Amphotericin B induced acute tubular necrosis

48
67
broad-spectrum
antibiotics
blood culture for fungal Torulopsis infection (sentitive amphotericin B)
amphotericin B
0.5
/
/ (0.25
/
)
3
/
WBC = 17000 / .3
BUN = 50
Scr = 4.5
hyposthenuria (impairment of urine concentrating

ability)
RBC , WBC
albumin casts
ATN
loading
sodium
amphotericin B
2 NSAIDs - induced nephrotoxicity

50
CHF
HTN
indomethacin
2
(2+)
BUN = 28
acute renal failure
Scr = 2.5
Urine output
FeNa < 1%
Urinary sediment : benign
1
2-3
57
3
3 Aminoglycoside-induced acute tubular necrosis
54
72
gentamicin
ceftazidime
sepsis
pseudomonal infection
7
Scr
BUN = 68
/
Scr = 5.0
/
WBC = 16700/ .3
Urine output
24
650
many WBC, RBC casts, granular casts, brush border cells
urine osmolality = 250 mOsm/kg
gentamicin quiniolone Scr
aminoglycoside
4 Ciprofloxacin-induced acute allergic interstitial nephritis
40
ciprofloxacin 500
2
diffuse, macular, erythematous lesion
BUN = 30
/
. Scr = 2.1
15000 / 3 eosinophil 13%
/
, many RBC & WBC, WBC casts
sodium (FeNa) = 3%
ciprofloxacin
14
3
4
2
/
WBC =
specific gravity = 1.011, protein 35

eosinophiluria
fraction excretion of
prednisolone 60
1. Abraham PA, Matzke GR. Drug-induced renal disease. In: Dipiro JT, Talbert RL, Yee GC,
Matzke GR, Wells BG, Posey LM (eds). Pharmacotherapy: A pathophysiologic approach. 4th
ed. Connecticut : Appleton & Lange; 1999. p. 822-44.
2. Bennett WM. Aminoglycoside nephrotoxicity. Nephron. 1983; 35:73-7.
58
3
3. Buckalew VMJ. Nonsteroidal anti-inflammatory drugs and the kidney. In: Greenberg A (ed.).
Primer on kidney diseases. 2nd ed. New York : Academic Press; 1998. P 291-8.
4. Coffman TM. Renal failure caused by therapeutic agents. In: Greenberg A (ed.). Primer on
kidney diseases. 2nd ed. New York : Academic Press; 1998. p. 260-5.
5. Comstock TJ. Acute renal failure. In: Koda-kimble MA, Young LY (eds.). Applied
therapeutics: The clinical use of drugs. 7th ed. New York : Lippincott Williams & Wilkins;
2001. p. 29.1 23.
6. DuBose Td, Molony DA. Nephrotoxicity of non-steroidal anti-inflammatory drugs. Lancet.
1994; 344:515-8.
7. Gardner ML, Godley PJ, Wasan SM. Sodium loading treatment for amphotericin B-induced
nephrotoxicity. DICP Ann Pharmacother. 1990; 24:940-6.
8. Knoben JE, Anderson PO. Handbook of Clinical drug data. 7th ed. Illinois : Drug
Intelligence Publications; 1994.
9. Liano F, Pascaul J, and the Madrid acute Renal Study Group. Epidemiology of acute renal
failure: A prospective, multicenter, community-based study. Kidney Int. 1996; 50:811.
10. Maddux MS, Barriere SL. A review of complications of amphotericin B therapy:
Recommendation for prevention and management. Drug Intell Clin Pharm. 1980; 14:177-81.
11. Micromedex healthcare Series : MICROMEDEX Inc., Englewood, Colorado (Edition
expires 1998).
12. Rothschild E. Acute renal failure. In: Benichou C. Adverse Drug Reactions: A Practical
Guide to Diagnosis and Management. Chichester: John Wiley & Sons, 1994; p.61-75.
13. Sabra R, Branch RA. Amphotericin B nephrotoxicity. Drug Saf. 1990; 5:94-108.
14. Schlondorff D. Renal complications of nonsteroidal anti-inflammatory drugs. Kidney
Internatl. 1993; 44:643-53.
15. Swanepoel CR, Cassidy MD. Renal disorders. In: Davies DM, Ferner RE, De Glanville H
(eds.). Textbook of Adverse Drug Reactions 5th ed. London: Chapman & Hall Medical, 1998;
p.339-78.
16. Whelton A, Hamilton CW. Nonsteroidal anti-inflammatory drugs: effects on kidney function. J
Clin Pharmacol. 1991; 31:588-98.
59
20%
1.
(Mouth)
1.1
(Taste disorders)
- Hypogeusia
- Ageusia
- Dysgeusia
hypogeusia
dysgeusia
(non-compliance)
(taste buds)
ion channel (cellular process)
60
4.1)
sulphydryl group
1)
1.1 Penicillamine
loss)
penicillamine
captopril
copper chelating agents

rheumatoid arthritis
Wilsons disease
(transient taste
(copper)
6
Wilsons disease
1.2 Captopril
1/3
(taste dysfunction)
ACE inhibitor
2-4%
metallic taste
sulphydryl group
zinc
2) Terbinafine
1%
3)
metallic taste
gold, metronidazole, metformin
4) Acetazolamide
5) ACE inhibitors, losartan, etidronate
nifedipine
4.1
Taste disturbance
ACE inhibitors
Acetazolamide
Griseofulvin
Isotretioin
Levodopa
Losartan
Penicillamine
Propylthiouracil
Terbinafine
Metallic taste
Allopurinol
Gold compounds
Lithium
Metformin
Metronidazole
Penicillamine
61
zinc
1.2
dysgeusia
(Gingival overgrowth)
(
cyclosporin
calcium channel blockers (
phenytoin, 30%
cyclosporin
10%
4.2)
phenytoin
dihydropyridine nifedipine)
50%
nifedipine
4.2
Cyclosporin
Phenytoin
gingival fibroblast
collagen
(onset of reaction)
3
(gingivectomy)
(management)
phenytoin, cyclosporin
isradipine
nifedipine
phenytoin, cycloporin
nifedipine
calcium channel blockers
dihydropyridine
62
1.3
(Pigmentation)
tetracyclines
minocycline
1.4
(Xerostomia)
(
4.3)
anticholinergic effect
(candidiasis)
tricyclic antidepressants (TCA)
anticholinergic agents, TCA, phenothiazines
CNS stimulants
(saliva substitute)
4.3
Amfebutamone
Anticholinergic agents
Antihistamines
Central nervous system stimulants (e.g. phentermine)
Phenothiazines
Tricyclic antidepressants
1.5
(Ptyalism)
cholinergic effect
clozapine
1.6
(stomatitis)
pilocarpine
Parkinsons disease
(Stomatitis and mouth ulcers)

(glossitis)
4.4
63
4.4
Aspirin
Auranofin
Barbiturates
Captopril
Cytotoxics
Griseofulvin
Interferon alfa
Isoniazid
Leflunomide
Nicorandil
NSAIDs
Penicillamine
Sulfasalazine
- Contact stomatitis
- Mouth ulcers
drugs, NSAIDs, gold compound
cytotoxic
sulfasalazine
Erythema Multiforme
Stevens Johnson Syndrome

Erythema Multiforme
Stevens Johnson Syndrome
penicillins, sulphonamides phenytoin
- Aphthous ulcers
mucous membrane
nicorandil
potassium channel activator
angina
aphthous
ulcers
1-36
1
30
2.
(Esophagus)
(gastroesophageal reflux disease)
4.5
64
4.5
Ascorbic acid
Aspirin
Bisphosphonates
Clindamycin
Doxycycline
Ferrous sulphate
Lincomycin
NSAIDs
Potassium chloride
Quinidine
Tetracycline
Theophylline
(lower
esophageal
sphincter)
calcium channel blockers, opioids
anticholinergic agents
(dysphagia)
(drug-induced oesophageal injury)

(odynophagia)
tetracycine, doxycyline,
NSAIDs,
bisphosphonates
alendronate
100
sucralfate
3.
(Nausea and vomiting)

(
opiods
potassium
4.6)
cytotoxic drugs, levodopa

iron salt,
65
4.6
/
Bromocriptine
Cytotoxics
Digoxin
Ergot alkaloids
Erythromycin
Iron salts
Levodopa
Oestrogens (high-dose)
Opioids
Selective serotonin reuptake inhibitors
Theophylline
vestibular apparatus, vomiting

center, nucleus of the tractus solitarius
5-HT receptor
4.
5-HT3 antagonist
(Stomach and duodenum)
4.1. Gastrointestinal ulcers

1. NSAIDs
endoscopy
NSAIDs
enteric-coated
(gastrointestinal endoscopy)
prostaglandin (PGs)
3
HCO
pepsin
bile salt
66
PGs
cyclooxygenase (cox)
NSAIDs
cox-1
arachidonic acid
cox-1
cox-2
cox-2
cox-2
cox-1
cox-2
cox-2 preferential inhibitors
nabumetone
cox-2
cox-2 selective inhibitors
cox-1
cox-1
cox-2
PG
(
cox-2
4.7)
NSAIDs
H.pylori
H.pylori
4.7
Age over 60 years
Previous history of gastrointestinal problems
(e.g. peptic ulcer, gastrointestinal bleeding)
High NSAIDs dosage
Hepatorenal dysfunction
NSAIDs
NSAIDs
NSAIDs
Concomitant corticosteroids
Concomitant warfarin
Serious systemic disorder
Cigarette smoking (possible)
Alcohol consumption (possible)
(Relative safety)
NSAIDs
(traditional)
Committee on Safety of Medicines
diclofenac, naproxen
ibuprofen
azapropazone
case-control studies
1994
ibuprofen
indomethacin
aspirin
67
(75
/ )
enteric-coated modified release
NSAIDs
paracetamol
inhibitor (PPI)
NSAIDs
NSAIDs
proton pump
PPI
NSAIDs (Prevention of gastrointestinal complication)

(gastric ulcer GU)
(duodenal ulcer-DU)
NSAIDs
misoprostol
Misoprostol Ulcer Complication Outcomes Safety Assessment (MUCOSA)
misoprotstol
NSAIDs
NSAID-induced complication
40%
NSAIDs
misoprostol PPI
2
DU
NSAIDS
NSAIDs
H2-blockers
GU
NSAIDs
NASIDs
NSAIDs
1
NSAIDs
65
misoprostol
proton pump
inhibitor
2. Corticosteroid
corticosteroid
steroid
3064
71
68
steroid
(0.8%)
(1.8%)
25
151
corticosteroid
1
3. Selective Serotonin Reuptuke Inhibitors (SSRIs)
(bleeding disorders)
SSRIs
UK General Practice Research Database
uptake
5-HT
SSRIs
(class effect)
SSRIs
NSAIDs
4. Clopidogrel
5.
chloroquine, gold
4.2 Paralytic ileus
Pseudo-obstruction
(
4.8)
pseudo-obstruction
4.8
Acarbose
Clozapine
Colestyramine
Laxatives (bulk-forming)
Loperamide
Opioids
Phenothiazines
Potassium salts
Vincristine
Vinorelbine
(Physical obstruction within the small bowel lumen)

(Physical obstruction from within the gut wall)
69
(Bowel dysmotility)
(autonomic nerve transmission)
peritoneal fibrosis
(obstruction from outside the gut wall as a result of vascular occlusion or peritoneal
fibrosis)
Crohns disease, carcinoma, cystic fibrosis
opioids, calcium channel blocker,
anticholinergic drugs, tricyclic antidepressant (TCA), phenothiazines
clozapine
vincristine
oral contraceptives
5.
anticholinergic effect
paralytic ileus (
mesenteric vein thrombosis
(Colon)
5.1
(Diarrhea)
6
(
36
4.9)
(antimicrobials)
25%
4.9
Acarbose
Antibiotics
Biguanides
Bile salts
Colchicine
Cytotoxics (docetaxel, idarubicin,
irinotecan, epirubicin, mitoxantrone)
Dipyridamole
Gold compounds
Iron preparations
Laxatives
Leflunomide
Magnesium-containing antacids
Misoprostol
NSAIDs
(especially mefenamic acid)
Orlistat
Ticlopidine
70
- Osmotic diarrhea :
mannitol, sorbitol
- Secretory diarrhea :
- Exudative diarrhea :
1
2
- Acute diarrhea
- Chronic diarrhea
1)
2-3
30%
Clostridium difficile
1.
2.
microflora
20%
(A
Pseudomembranous colitis
B)
osmotic
secretory
diarrhea
Pseudomembranous Colitis
5-10
71
plaques
membranes (pseudomembrane)
fibrin fragments, leukocytes, epithelial cells
Clostridium. difficile associated diarrhea
amoxycillin, cephalosporin
2
3, clindamycin
ceftriaxone
ceftriaxone
10-40%
nasogastric tube
(endoscopy)
colonic mucosa membrane
intensive care
C.difficile
3
7
metronidazole 500
oral vancomycin 125-500
7
blocking agents, narcotic analgesics
antidiarrheal drugs (loperamide)
colon distention
paralytic ileus
necrotising enterocolitis
2) Gold therapy :
gold
40-50%
3
antidiarrheal drugs
5.2
4
muscarinic
(Ischemic colitis)
ergotamine, estrogen, amphetamine, digoxin
cocaine (
4.10)
72
4.10
Amphetamines
Cocaine
Digoxin
Docetaxel
Ergotamine
Methotrexate
Methyldopa
Methysergide
5.3
NSAIDs
Oestrogens
Salicylates
Sulfasalazine
Sumatriptan
Vasopressin
Vinorelbine
(Proctocolitis)
isotretinoin
5.4
(Constipation)
anticholinergic drugs, opioids, iron salts
verapamil (
4.11)
4.11
Anion exchange resins
Anticholinergics
Antihistamines
Clozapine
Diuretics
Iron preparations
Mebeverine
Monoamine oxidase inhibitors
6.
Opioids
Peppermint oil
Phenothiazines
Sucralfate
Verapamil
Vincristine
(Pancreas)
6.1
(Pancreatitis)
(gallstones)
hyperlipidaemia, hypercalcaemia, endoscopic

retrograde cholangiopancreatography, trauma
aminosalicylates, azathioprine, cimetidine, interferon alfa, sodium valproate, estrogen
73
didanosine (
pancreatitis)
4.12)
(drug-induced
2%
HIV
amylase
sulfasalazine, mesalazine
olsalazine
sodium valproate
salicylate
azathioprine
mercaptopurine
1.3%
Crohns disease
4.12
Aminosalicylates (mesalazine, sulfasalazine)
Angiotensin-converting enzyme (ACE) Inhibitors
Azathioprine
Didanosine
Furosemide
Gemfibrozil
Histamine H2-receptor antagonists
Interferon alfa
Metronidazole
Oestrogens
Pentamidine
Propofol
Sodium valproate
Sulindac
Thiazide diuretics
62
osteoarthritis
transdermal oestradiol, calcium and vitamin D tablet, ibuprofen (400
2
alendronic acid 10
250
3
acute sinusitis
10
2-3
(oesophagitis)
3 )
amoxicillin
alendronic acid
74
alendronic acid
NSAIDs
aspirin
alendronic acid
NSAIDs
aspirin
alendronic acid
sinusitis
10
alendronic acid
cimetidine
alendronic acid
200
30
30
1. Bateman DN, Aziz EE. Gastrointestinal disorders. In: Davies DM, Ferner RE, De Glanville H
(eds.). Textbook of Adverse Drug Reactions 5th ed. London: Chapman & Hall Medical, 1998;
p.259-274.
2. Lee A, Morris J. Gastrointestinal disorders. In: Lee A. Adverse Drug Reactions. London:
Pharmaceutical Press, 2001; p. 45-75,
3. Pariente A, Danan G. Gastrointestinal disorders. In: Benichou C. Adverse Drug Reactions: A
Practical Guide to Diagnosis and Management. Chichester: John Wiley & Sons, 1994; p.7786.
75
(Hepatotoxicity)
2-5%
3-10%
15%
20%
40
10%
50
(Psychoactive agents)
40%
15-30%
10-15%
(cholestasis)
aspartate aminotransferase(AST), alanine aminotransferase(ALT), serum

alkaline phosphotase, gamma-glutamyl transferase (GGT)
bilirubin
(hepatocellular necrosis)
(fulminant hepatic
failure, FHF)
76
1.
1.
1.1
Type A
2
predictable ADR
intrinsic hepatotoxicity
direct
toxic effect
ADR
paracetamol
tetracycline, metrothexate
alcohol
metabolised
carbon tetrachloride
anabolic steroids
contraceptives
1.2 Type B
unpredictable ADR
idiosyncratic hepatotoxicity
type A
ADR
1-5
eosinophilia
chlorpromazine, erythromycin
sulfonamides
methyldopa, phenytoin,
ADR type B
1
12
eosinophilia
(rechallenge)
metabolite
5.1
(Lesion)
Intrinsic hepatotoxicity
Direct hepatotoxicity
Indirect hepatotoxicity
Cytotoxic
Cholestasis
Host idiosyncrasy
Hypersensitivity
Metabolic abnormality
Necrosis or steatosis
High
Steatosis, or necrosis
Bile casts
High
High
Hepatocellular or cholestasis
Hepatocellular or cholestasis
Low
Low
77
5.2
Direct Toxic Effect
Features
Predictable &
dose related
toxicity
Latent period
Arthralgia,
fever, rash,
eosinophilia
Liver
morphology
Idiosyncratic
Other
Carbon
Tetrachlor
ide
Acetaminophen
Halothane
Isoniazid
Chlorpromazine
Oral
Contraceptive
Agents
Short
0
Short
0
Variable
+
Variable
0
Variable
+
Variable
0
Necrosis,
fatty
Infiltratio
n
Centrilobular
Necrosis
Similar
to viral
hepatitis
Similar to
Viral
Hepatitis
Cholestasis
with
portal
inflammation
Cholestasis
without
Portal
inflammation
vascular lesions
* The drugs listed are typical samples
(latent period)
(
(
5.3)
5.4)
5.3
Suggestive
Compatible
Incompatible
Hepatocellular
Onset from starting drug
Onset after drug discontinued
5-90 days
<5 or >90 days

<15 days
Started after reaction

> 15 days unless
slowly metabolised
Cholestatic
Onset from starting drug
Onset after drug discontinued
5-90 days
<5 or >90 days

<1 month
started after reaction

>1 month
5.4
Hepatocellular
Decrease in ALT>50%
Cholestatic
Decrease in alkaline phosphatase
and/or bilirubin
Suggestive
Compatible
Incompatible
<8 days
<1 month
Decrease <50%
>50% within 6 months
< 5% within 6 months
No change
78
2.
2
2.1
3
(Steatosis)
2.2
3
(chronic hepatitis)
Buddi-chiari syndoame
Veno-occlusive disease (VOD),
2.
100,000
amoxicillin-clavulanic acid (Co-amoxiclav.)1-5

100
NSAIDs 1-10
1
isoniazid
100,000
methotrexate
5.5
Acute parenchymallcholestatic
Hepatic necrosis
Cholestatic hepatitis
Pure cholestasis
Fatty infiltration
Granulomatous infiltration
Chronic parrenchymal
Active chronic hepatitis
Hepatic fibrosis and cirrhosis
Hepatic phospholipidosis
Chronic cholestasis
Vanishing bile duct syndrome
Sclerosing cholangitis
Gallstones
Vascular
Budd-Chiari syndrome
Veno-occlusive disease
Sinusoidal lesions dilatation
- peliosis hepatitis
- perisinusoidal fibrosis
- non-cirrhotic portal hypertension
- nodular regenerative hyperplasia
Liver tumours
Adenoma
Focal nodula hyperplasia
Hepatocellular carcinoma
Angiosarcoma
Cholangiocarcinoma
79
1.
metobolised
methotrexate
(ascites)
2.
isoniazid, sulfonamides
methyldapa
flucloxacillin
azathioprine
niacin
(cirrhosis)
(hepatic encephalopathy)
halothane,
3.
valproate
sodium
(enzyme inducers)
aspirin
3
Reyes syndrome
steatosis
aspirin
juvenile arthritis
paracetamol
sulphate conjugation
paracetamol
40
isoniazid,
halothane, erythromycin,
diclofenac
4.
cytochrome P450 isoenzyme
sodium valproate
phenytoin
80
acetylators
fast acetylators
slow acetylators
acetylhydrazine
diacetylhydrazine
5.
isoniazid
slow acetylators
fast
metabolite
sodium valproate
paracetamol
isoniazid
methotrexate
rifampicin
isoniazid
6.
hyperthyroidism
tetracycline
fibrosis
methotrexate
methotrexate
halothane
paracetamol
AIDS
trimoxazole
hyperthyroidism
Coaspirin
3.
phase I metabolism (toxification)

(detoxification)
conjugation phase II metabolism
phase I-mediated cytochrome P450 oxidative metabolism
81
1) Reactive electrophiles
isoniazid
paracetamol
2) Free radicals
peroxidative
3) activated oxygen
cytochrome P450 isoenzymes
4 families
cytochrome P450
family
cytochrome P450
cytokines
conjugation
sulphate
subfamilies
glucuronide
glutathione
paracetamol
paracetamol
glutathione
paracetamol
phase Iphase- II metabolism
neutrophils
eosinophils
(RUQ)
2-3
5-30%
82
5.6
Factor
Examples of Drugs Affected
Comments
Age
Isoniazid, nitrofurantoin, halothane

Valproic acid, salicylates
Increased incidence/severity with age >60 yr

Higher incidence in children
Sex
Halothane, methyldopa,
nitrofurantoin
Flucoxacillin, azathioprine
Acetaminophen, aspirin
Higher incidence in females

Higher incidence in males
Dose
Methotrexate, vitamin A
Genetic factors
Halothane, phenytoin,
sulfonamides.
isoniazid
Valproic acid
Higher blood concentrations associated with

risk of hepatotoxicity
Total dose, frequency, and duration
Associated with hepatotoxic risk
Numerous familial cases; defective epoxide
hydrolases increase susceptibility to
phenytoin and halothane associated injury;
acetylator phenotype may predispose to
isoniazid hepatotoxicity
Familial cases, correlation with mitochondrial
enzyme abnormalities
History of other drug

reactions
Halothane, enflurane, ibuprofen

diclofenac, erythromycins,
Rare incidence of cross-sensitivity reported

between drug classes
Other drugs
Acetaminophen
Isoniazid, zidovudine may lower toxic dose

threshold for hepatotoxicity
Increased risk of hepatic veno-occlusive
disease
Other antiepileptic drugs increase risk of
Hepatotoxicity
Busulfan, azathioprine
Valproic acid
Excessive alcohol use
Other diseases
Obesity
Fasting
Renal failure
Pre-existing liver
disease
Organ transplantation
AIDS
Diabetes
Acetaminophen
Isoniazid, methotrexate
Lowered dosage threshold

Increased liver injury and enhanced fibrosis
Halothane hepatitis, methotrexate

Acetaminophen
Tetracycline, methotrexate
Niacin (nicotinamide),
methotrexate
Azathioprine, busulfan
Dapsone, trimethoprimsulfamethoxazole, oxacillin
Methotrexate

Increased risk of hepatotoxicity
Increased risk of liver injurry
Increased risk of vascular toxicity
Increased risk of liver injury; hypersensitivity
Increased risk of hepatic fibrosis
83
5.7
Type
Drug
Conditions
Zonal Necrosis
Carbon tetrachloride
Paracetamol
Halothane
Accidental, Occupational
Overdosage, Suicidal Attempt
Repeated Exposure
Microvesicular Fat
Sodium valproate
Amiodarone
Phosphorus(white)
Accidental or Suicidal
Acute Hepatitis
Methyldopa
Isoniazid
Halothane
Ketoconazole
Hypertension
Tuberculosis
Fibrosis
Metrotrexate
Vinyl chloride
Psoriasis
Occupational
Cholestasis :
- Canalicular
- Hepatocanalicular
Methyl testosterone
Estrogen
Erythromycin
Chlorpromazine
Clavulanic acid
Hepatic vein obstruction
Sex Hormones
Sclerosing Cholangitis Neoplastic :

- Focal nodular hyperplasia
- Adenoma
FUDR
Sex hormones
Sex hormones
Contraception
Psychosis
Infection
Rectal cancer
Rare
Rare
5.8
Manifestations
Allergic (rash, fever, eosinophilia)
Pseudo-mononucleosis
Example of Offending Agent

Sulindac, dapsone, phenytoin
Para-aminosalicylic acid, phenytoin, dapsone
Methyldopa, nitrofurantoin, minocycline,
Antinuclear antibodies
Antimicrosomal antibodies
Halothane, dihydralazine
Hematologic (bone marrow injury,

aplastic/hemolytic anemia, thrombocytopenia)
Renal injury
Gastrointestinal (ulcer, pancreatitis)
Phenylbutazone, phenytoin
Methoxyflurane, sulindac
Phenylbutazone, tetracycline
84
4.
4.1
3
lular)
(cholestatic)
(hepatocel(mixed)
5.9
Lesion
Syndrome
Biochemical
Markers
Clinical
Presentation
ALT/AST
ALP
A, N, V
8-200 x
3x
A, N, V, L, S
A, N, V, L, S, C, E
A, N, V, J, FG
8-200 x
25-200 x
8-25 x
Variable
<3 x
<3 x
None
N, V, E
2-5 x
-15 x
<3 x
<3 x
Obstructive jaundice
A, N, J, PR,
FV, R, P
8x
>3 x
Obstructive jaundice
PR, J, P
<15x
<3 x
Examples of
Offending Agents
Hepatocellular
Necrosis
Acute hepatitis
Sinusoidal beading
Massive
Subacute
Pseudo-mononucleosis
Acute liver failure
Prolonged hepatitis
Spotty
Steatosis, microvesicular
Subclinical
Reye-like
Cholestatic Injury
Hepatocanalicular
Bile casts + spotty
necrosis
Portal inflammation
Canalicular
Bile casts
Isoniazid, diclofenac,
halothane
Phenytoin, dapsone
Same as above
Propylthiouracil,
diclofenac
Isoniazid, diclofenac
Tetracycline
Carbamazepine,
erythromycin estolate,
Sulfonylureas
Anabolic steroids
Oral contraceptives
A, anorexia; C, coagulopathy; E, encephalopathy; FG, fatigue; FV, fever; J, jaundice; L, lymphadenopathy; N, nausea; P, pain;
PR, pruritus; S, splenomegaly; R, rash; V, vomiting.
4.1.1
1) Acute hepatocellular necrosis
centrilobular (zonal)
paracetamol, carbon tetrachloride, halothane
85
enflurane
diffuse (nonzonal)
isoniazid, ketoconazole
transaminase
ALT
AST
8 - 500 (
3
methyldopa
valproic acid, aspirin,
oxacillin
0-35
/
cholesterol
alkaline phoshatase
Drug-
induced hepatitis
toxic hepatitis
(coagulopathy)
Reyes syndrome
hepalitis
aspirin
valproic acid
mitochondria
ammonia
ammonia
3
prothrombin time
intracranial hypertension
transaminase
5.10
toxic
acute hepatocellular necrosis
Allopurinol
Aspirin
Carbamazepine
Cocaine
Cyclophosphamide
Dantrolene
Didanosine
Ecstasy (MDMA;methylene dioxymethamfetamine)
Halothane
Isoniazid
Methyldopa
Minocycline
Monoamine oxidase inhibitors
(NSAIDs),e.g.indomethacin,diclofenac
Paracetamol
Sodium valproate
Sulphonamides
2) Acute hepatitis
prothrombin
time
86
3) Steatosis
aspirin
fatty liver
microvesicular steatosis
tetracycline , sodium valproate
macrovesicular steatosis
corticosteroid, methotrexate
sodium valproate
3-15
fatty liver of pregnancy
estrogen
alcohol
ALT
AST
Reyes syndrome
fatty liver hepatitis
(leukocytosis)
fatty liver
didanosine (ddI),
zidovudine
(AZT)
5.11
acute hepatitis
Angiotensin-converting enzyme (ACE) inhibitors

Chinese herbs
Co-trimoxazole
Cyproterone
Dantrolene
Isoniazid
Ketoconazole
Methoxyflurane
Methyldopa
Monoamine oxidase inhibitors (MAOIs)
4.1.2
Nicotinamide
Nifedipine
Nitrofurantoin
Phenytoin
Pyrazinamide
Rifampicin
Sulfasalazine
Sulphonamides
Tizanidine
(Cholestasis)
2
- hepatocellular cholestasis
8
cholesterol
AST / ALT
alkaline phosphatase
3-10
87
- canalicular cholestasis
8
3
bilirubin
/
170
46.8
cholesterol
bilirubin
AST / ALT
42
/
2. 5
9.9
bilirubin
800
transaminase
3
hepatocellular cholestasis antidiabetics, phenothiazines , antithyroid , erythromycin estolate,
amoxicillin clavulanic acid
TPN
canalicular cholestasis
alkaline
phosphatase
anabolic steroid ,
cholestasis
1%
chlorpromazine
cholestasis
0.5-1%
2
4
phenothiazines
5.12
Cyclosporin
Flucloxacillin
Glibenclamide
Griseofulvin
4.1.3
Oral contraceptives
Tamoxifen
Warfarin
(Mixed injury)
88
AST
ALT
5.13
hepatocellular cholestasis
Angiotensin-converting enzyme (ACE) inhibitors

Azathioprine
Carbimazole
Chlorpropamide
Cimetidine
Clavulanic acid
Co-trimoxazole
Dextropropoxyphene
Erythromycin
Flucloxacillin
Flutamide
Fusidic acid
Gold salts
Ketoconazole
Nitrofurantoin
Penicillamine
Phenindione
Phenothiazines e.g. chlorpromazine
Phenytoin
Ranitidine
Sulphonamides
Sulphonylureas
Thiouracils
Ticlopidine
Tricylic antidepressants
antiepileptics
hydrazine antidepressants
flutamide
sants
neuroleptics
tricyclic antidepres48
niacin
4.2
5
necrosis , chronic steatosis , phospholipidosis
intrahepatic cholestosis
biliary sclerosis
chronic hepatitis, subacute hepatitis

fibrosis
cirrhosis
granulomatous
89
4.2.1
1) Chronic hepatitis
chronic active hepatitis
persistant hepatitis
chronic
autoimmune hepatitis (AIH)

autoimmune marker
hyperglobulinemia, antinuclear antibodies, antisingle-strand DNA
5.14
Lesion
Associated
Syndrome
Biochemical Markers
Examples of Offending
Agents
ALT/AST
ALP
Chronic hepatitis
3-50x
1-3x
Steatosis
Alcoholic steatosis
1-3x
1-3x
Phospholipidosis
Alcoholic hepatitis
1-5x
Variable
Nitrofurantoin, minocycline,
methyldopa
Methotrexate,
glucocorticoids
Amphophilic agents
Alcoholic hepatitis
1-5x
Variable
Amiodarone
Primary biliary
cirrhosis
1-3x
3-20x
Carbamazepine, haloperidol
Sclerosing
cholangitis
Hepatomegaly ;
hepatitis
1-5x
3-20x
Floxuridine
1-3x
3-20x
Allopurinol, carbamazepine,
hydralazine, quinine
Hepatomegaly
1-3x
<3x
Congestive
hepatopathy
Congestive
hepatopathy
Hepatomegaly
2-20x
Variable
2-20x
Variable
3x
Variable
Pyrrolizidine alkaloids,
azathioprine
Oral contraceptives
Noncirrhotic portal
HTN
1-3x
Variable
Vitamin A
Variable
Variable
Oral contracptives, anabolic

steroids
Hepatocellular
Necroinflammatory
Pseudoalcoholic
Chloestatic Injury
Cholangiodestructive
Biliary sclerosis
Granulomatous
Vascular Lesions
Peliosis
Veno-occlusive
Sinusoidal dilation
Pericellular/sinusoidal
fibrosis
Neoplasm
Adenoma, carcinoma
Asymptomatic
hepatic mass
Anabolic steroids, oral

contraceptives
Oral contraceptives
clometacin, diclofenac, fenofibrate, methyldopa,

minocycline, nitrofurantoin, oxyphenisatin, sulfonamides
ticrynafen
ecstasy
AIH
paracetamol
90
isoniazid
4
(1)
autoimmune hepatitis
5%
(2)
90%
hypergammaglobulinemia, antiorganelle antibodies
antibodies
neoantigen complex
(2)
cytochrome P450
antigen complex
globulinemia
(3)
transaminase
sulfonamides
trazodone
(4)
paracetamol
methyldopahypergamma-
(1)
marker
etretinate, lisinopril,
aspirin,
5.15
Cimetidine
Diclofenac
Etretintate
Herbal medicines
Isoniazid
Minocycline
Nitrofurantoin
Paracetamol
Phenytoin
Sulphonamides
spider angiomas
transaminase
hypoalbuminemia
4
91
2) Subacute hepatic necrosis

chronic hepatitis
acute necrosis
acute necrosis
isoniazid, methyldopa
propylthiouracil
3) Chronic steatosis
macrovesicular
antineoplastics
methotrexate
steatosis
steatosis
chronic steatosis
microvesicular
valproic acid
glucocorticoids,
glucocorticoids
methotrexate
tetracyclines
1.5
steatosis
70-80%
4) Phospholipidosis
lysosomes
phosholipids
phospholipids
amiodarone
perhexiline maleate diethylaminoethoxyhexestrol
5) Fibrosis and cirrhosis
fibrosis
fibrosis
(irreversible)
transaminase
collogen
fibrosis
chronic cholestasis,
steatohepatitis
chronic hepatitis
methotrexate
vitamin A
92
portal hypertension
fibrosis
methotrexate
methotrexate
psoriasis
arthritis
methotrexate
psoriasis
psoriasis
portal hypertension
fibrosis
methotrexate
arthritis
(arsenic)
4.2.2
1) Chronic cholestasis
primary biliary cirrhosis
chronic cholestasis
(
5.16)
5.16
Characteristics
Associated disease
Drug intake
Clinical symptoms
Laboratory Makers
Bilirubin
ALT/AST
Alkaline phosphatase
Histologic Markers
Ductopenia
Nonsuppurative cholangitis
Hepatic granulomas
Acute cholestasis
ALT
hypertension
chronic cholestasis
Drug-Induced Chronic
Cholestasis
Irrelevant
Phenothiazines, organic arsenicals
Pruritus, early severe jaundice,
xanthomas, hepatomegaly,
splenomegaly, cirrhosis
Primary Biliary Cirrhosis

Sicca syndrome
None
Pruritus, latent mild jaundice, xanthomas,
hepatomegaly, splenomegaly, meloderma,
cirrhosis
1-20 mg/dL
2-8x
3-10x
1-5 mg/dL
2-8x
3-10x
Slight
Absent
Absent
Remarkable
Present
Present
chronic cholestasis
bilirubin
xanthomatosis
vanishing bile duct syndrome
AST
portal
93
chronic cholestasis
ajmaline, carbamazepine, coamoxiclav, erythromycin,
flucloxacillin, haloperidol, imipramine, phenothiazines (chlorpromazine, prochlorperazine)
phenytoin, sulfamethoxazole trimethoprim, thiabendazloe, tolbutamide
organic arsenicals
gamma glutamyltransferase
2) Biliary sclerosis
intrahepatic arterial infusion
transaminase
4.2.3.
floxuridine (5 FUDR)
3
biliary sclerosis
formalin
(vascular lesions)
pyrrolizidine alkaloids
veno occlusive disease (VOD)
hepatic venules
connective tissue
(congestion)
transaminase
azathioprine, dactinomycin, dacorbazine, busulfan cyclophosphamide

busulfan
cyclophosphamide
veno occlusive disease
25%
heparin prophylaxis
Budd Chiari syndrome
hepatic vein
veno-occlusive dissease
94
Peliosis hepatitis
hemoperitoneum
androgen
estrogen, tamoxifen, danazol, azathioprine
Portal hypertension
sclerosis
vitamin A
arsenicals,copper sulfate
vinyl chloride
(pancytopenis)
6
hepatorenal
inorganic
esphageal varices
4.2.4. Granulomatous hepatitis

Granulomas
noncaseating
eosinophils
granulomas
granulomatous hepatitis
2-29%
10
4
15%
allopurinol, methyldopa , penicillins, phenytoin, quinidine
sulfonamides
gold salts
5.17
Allopurinol
Carbamazepine
Chlorpromazine
Gold
Hydralazine
Methyldopa
Nitrofurantoin
Penicilin
Phenylbutazone
Phenytoin
Procainamide
Quinidine
Quinine
Sulfasalazine
Sulphonamides
Sulphonylureas
4.2.5.
carcinoma
sarcomaandrogens,
95
estrogens
3
20
100
angiosarcomas
thorium dioxide
10
anabolic steroids
polyvinyl chloride
angiosarcoma
10
vinyl chloride
5.
aspartate aminotransferase,
alanine aminotransferase, alkaline phosphatase
total bilirubin
total protein, albumin
prothrombin time
gamma glutamyl transferase
conjugated bilirubin
96
1.
5.6 )
paracetmol
2.
90
niacin
1-2
cholestasis,
3
acute hepatocellular necrosis,
3
chronic hepatitis with portal fibrosis
niacin
3
2
transaminase
52%
2-3
niacin
50-
70%
6
3
digoxin, theophylline
piroxicam, diclofenac
clavulanic acid
niacin
salicylates
NSAIDs
sulindac,
erythromycin, amoxicillin
97
5.18
Isoniazid
Valproic acid
Halothane
Phenytoin
Sulfonamides
Propylthiouracil
Amiodarone
Dapsone
Trimethoprim-sulfamethoxazole
Rifampicin-isoniazid
Alcohol-acetaminophen
Amoxicillin-clavulanic acid
Acetaminophen-isoniazid
centrilobular necrosis
ecstasy
CYP 3A)
acute hepatocellular necrosis
Carbamazepine
Ofloxacin
Ketoconazole
Imipramine
Interferon-alfa
Lisinopril
Nicotinic acid
Etoposide
amphetamine
ecstasy
(
vinyl chloride
5.19)
5.19
Toxin
Arsenic
Carbon tetrachloride
Copper
Dimethyl formanide
2,4-Dichlorophenoxyacetic acid
Fluorine
Toluene
Trichloroethylene
Vinyl chloride
Group Associated With Exposure

Chemical, construction, agricultural workers
Chemical plant workers, laboratory technicians
Plumbers, Copper foundry workers
Horiculturalists, gardening enthusiasts
Chemical and agricutural workers, laboratory technicians
Printers, dye workers, cleaners, laboratory technicians
Plastics plant workers
98
5
*A partial list of environmental toxins that can cause liver injury. At lower exposure rates, these compounds may also
predispose the patient to liver injury from a drug.
2542
9
20-40
/ (
10
7-60
5-6
Jin bu huan
7 - 52
7
)
transaminase
20
20 - 50
1
12
lobular hepatitis with microvesicular steatosis
8
Pennyroyal oil
acute centrilobular necrosis
pulegone
Comfrey tea
venoocclusive
disease (VOD)
VOD
Germander
2
active chronic hepatitis
99
furono diterpenoids
glutathione
autoimmune active chronic hepatitis
Chaparral
AIDS
acute
hepatocellular necrosis
chronic hepatitis with cirrhosis

3-52
vitamin A
90%
(psoriasis)
4,000-5,000
sinusoids
50,000
2
25,000
100,000
nicotinic acid
(exfoliative dermatitis)
niacin
5.20
Herb
Comfrey
Gordolobo yerba tea
Mate tea
Chinese medicinal tea
Proposed Use
Health tonic
Toxic Ingredient
Pymolizidine alkaloids
Feature of Hepatic Injury

Veno-occlusive disease
Health tonic
Veno-occlusive disase
Jin Bu Huan
Sedative, analgesic
Tu-san-chiI
(compositae)
Lycopodium serratum
Chinese herbs
Germander (tea, capsules)
Eczema, psoriasis
Weight reduction,
health tonic
Herbal remedy
Herbal tonic, cathartic
Chaparral leaf
Mistletoe/skullcap/valerian
Margosa oil
Pennyroyal oil (squawmint)
Oil of cloves
Tonic
Abortifacient, herbal
remedy
Dental pain
Many
Teucrium chamaedrys
Larrea tridenta
Senna, podophylin,
aloin
Melia azadirachta indica
Labiatae plants
(possibly diterpenes)
Unknown
Hepatocellular injury :
hepatitis, fibrosis, steatosis
Nonspecific hepatic injury
Hepatitis : necrosis, fibrosis
Hepatic necrosis
Elevated liver function tests
Reyes syndrome
Elevated liver function tests
Dose-dependent hepatotoxin
100
3.
3
6
(
5.3)
4.
5.4 )
isoniazid
transaminase
2
rifampicin
2
3
isoniazid
2
5.
eosinophilia
type B
antibodies
trifluoroacetic acid (TFA) liver protein complex

halothane
TFA metabolite
halothane
101
6.
serology
antibodies
7.
(
5.21)
5.21
Enzyme
Abbrevation
Alkaline phosphatase
5 -Nucleotidase
-Glutamyl transferase
Aspartate aminotransferase
Alanine aminotransferase
Lactate dehydrogenase
T = < 100 % of normal; =
Necrotic
Cholestotic
Chronic
Alk Phos, AP
5-NC, 5NC
GGT, GGTP
AST, SGOT
ALT, SGPT
LDH
> 100% of normal;
= > 200% above normal.
5nucleotidase
-glutamyl transferase
centrilobular mitochondria
transaminase
aspartate aminotransferase (AST,
SGOT)
alanine aminotransferase (ALT,SGPT)
AST
ALT
bilirubin
bilirubin
102
prothrombin time
40
serum creatinine
arterial pH
bilirubin
albumin
transferrin
(overhydration)
prothrombin time
transferrin
prothrombin time
10
prothrombin time
albumin
2
isoniazid
40%
5%
4
AST, alkaline phosphatase
.
transaminase
(1)
(2) ALT
(3) AST
CPK
(1)
(2)
ALT,
bilirubin (total/conjugated)
alkaline phosphtase
1.5
gamma glutamyl transferase (GGT)
bilirubin
1
bilirubin
ALT
103
(3)
Pagets disease, bone

metastasis
.
(1)
hepatocellular, cholestatic
mixed
phosphatase
R>5
hepatocellular
-
R<2
2<R<5
cholestatic
ratio R = ALT/alkaline
ALT
(2)
-
3
3
(3)
hepatocellular
- prothrombin time
50%
asterixis
11-16
(4)
-
ALT
autoimmune chronic active hepatitis

inflamma-
tory bowel syndrome

5
negative bacillus
bilirubin
transminase
septicemia
right-side heart failure
gram-
104
left-sided heart failure

acute hypotension
cardiac output
CPK, BUN
serum creatinine
5.22
1:
(Recreational drug)
micronurtients
2
3
4
,
5
6
7
ultrasound , MRI, CT
8.
amiodarone
phospholipidosis
rhumatoid arthritis
1.5-2
methotrexate
hepatic fibrosis
methotrexate
105
methotrexate
1.5
zonal necrosis,
microvesicular fatly change, eosinophil infiltration, cholestasis, granuloma, destructive bile duct
vascular lesions
6.
1.
amoxicillin clavulanic acid, phenytoin
2.
3.
cholestyramine
4.
corticosteroid
3
6
paracetamol
5.
6.
7.
isoniazid, statins, gemfibrozil,

36
amiodarone
6
106
7.
5.23)
23
3
methotrexate
halothane
107
5.23
Name
Medications that Require Hepatic Monitoring

Liver Function Tests
Timeframe for Monitoring
Acetaminophen
LFTs
Albendazole
CBC with differential

and LFTs
Amiodarone
LFTs (eg, AST, ALT)
Azathioprine
CBC with platelets and

LFTs
LFTs should be monitored

every 2 weeks for the first 4
weeks and monthly
thereafter
Carbamazepine
LFT (eg, AST, ALT),

CBC (platelets and
reticulocytes), and
serum iron, serum
sodium and osmolality,
thyroid levels, and
complete urinalysis and
BUN
Baseline and periodicially

for blood test, urinalysis,
and LFTs.
Dapsone
CBC, platelet and

reticulocyte counts,
LFTs, urinalysis
LFTs (eg, ALT)
LFTs and urinalysis every 2

to 3 weeks for the first few
weeks
For low risk patients,
monitor ALT within 3
months of starting therapy
and repeat every 6 to 12
months. For high-risk
patients (eg.age > 60 years,
renal insufficiency, highdose or prolonged NSAID
use) (multiple drug use),
monitor ALT within the first
month of therapy and repeat
every 3 to 6 months.
Routine
Diclofenac
Efavirenz
Fenofibrate
LFTS, cholesterol
levels, and routine
blood chemistry
LFTs
Gemfibrozil
Serum lipid levels,

CBC, and LFTs
Griseofulvin
Renal, LFTs, and

hematopoietic
LFTs, renal function
test, CBC with differential and routine blood
chemistry
Indinavir
In overdose and chronic use

or overuse in patients
predisposed to liver toxicity
At beginning of each 28-day
cycle and every 2 weeks
while on therapy
Prior to initiation and every
6 months thereafter.
Periodically.
Comments
If tests are not WNL, a

subsequent treatment cycle
should not be started.
IF LFTs are > 3 times the
ULN, the dose should be
decreased or stopped
If LFTs are elevated,

testing should be repeated
frequently until values
return to normal. If values
are > 3 times the ULN, the
dose should be stopped,
CPK should be checked in
patients with persistent
myopathy. If elevations are
present the drug should be
stopped.
If ALT is > 3 times the

ULN, the drug should be
stopped.
Discontinue therapy if
LFTs>3 times ULN persist.
At least every 3 months

during the first year and
periodically thereafter.
Periodic monitoring while
on prolonged therapy
Every 2 to 4 weeks
108
5.23
Name
( )
Comments
Isoniazid
LFTs
Baseline and monthly.
Ketoconazole
LFTs (eg, GGT/Alk

phos, AST, ALT, and
bilirubin)
Prior to therapy and at

frequent intervals during
therapy
Lamivudine

test, and CBC
Periodically during therapy
Leflunomide
LFTs
At baseline and monthly

until values are stable.
Reduce dose if ALT

elevation is >2 to < 3 times
ULN. Discontinue if ALT >
3 times ULN and start
treatment with
cholestyramine.
Meloxicam
LFTs (eg, AST)
If AST shows a > 3-fold

elevation, the drug should
be stopped.
Methotrexate
LFTs
Monitor SGPT for low-risk

patients within 3 months of
starting therapy and repeat
Monitor the SGPT within
the first month of starting
treatment for high-risk
patients (eg,age>60 years,
renal insulfficiency, highdose or prolonged NSAID
therapy, multiple drug use)
and repeat every 3 to 6
months.
At baseline and every 1 to 2
months during therapy.
Methyldopa
LFTs
Nevirapine

tests, CBC, and routine
blood chemistry
LFTs periodically,
especially during the first 6
to 12 weeks of therapy, or
whenever an unexplained
fever occurs.
Periodically during therapy
Discontinue use if LFTs

are>3 to 5 times the ULN
or if patients develop signs
of hepatitis.
The drug should be stopped
if transient minor elevations
in liver enzymes occur
persistently
More frequent monitoring

may be needed during
antineoplastic therapy,
during intitial or changing
doses, or during periods of
increased methotrexate
levels. Usually, LFT
abnormalities are transient
and therapy is not modified.
LFT adnormalities that are
persistent and/or with
decreased serum albumin
require evaluation.
fever, abnormal LFTs, or
jaundice occurs.
109
5.23
Name
( )
Niacin
LFTs (eg, AST, ALT)
Prior to initiation. Every 6

to 12 weeks for the first year
and periodically thereafter
(eg, at 6-month intervals).
Oral gold
CBC with differential,

platelet count,
urinalysis, renal
function, and LFTs.
Prior to therapy: CBC with

differential, platelet count,
and urinalysis every month
during therapy.
Pioglitazone
LFTS (eg, AST, ALT)
Prior to initiation, every 2

months for the first year,
and periodically thereafter.
Pentamidine
Daily BUN and Scr,

daily blood glucose,
CBC and platelet count,
LFTs (bilirubin, alk
phos, AST, ALT),
calcium, and ECG
LFTs (eg, AST, ALT)
and uric acid levels
Prior to, during, and after

therapy.
Rafampcin
LFTs (eg, AST, ALT)
Riluzole
LFTs, urinalysis, CBC,

and routine blood
chemistry
Monitor prior to therapy and

then every 2 to 4 weeks
during therapy in patients
with impaired hepatic
function.
Every 2 months during
therapy.
Ritonavir
Serum glucose,
triglyceride and
cholesterol, LFTs (eg,
AST, ALT, GGT,
CPK), and uric acid
LFTs (eg, ALT)
Pyrazinamide
Rofecoxib
Prior to therapy and

periodically therafter
Comments
If LFT values are > 3 times
the ULN, or if associated
with nausea, fever, and/or
malaise, the drug should be
stopped. If 1 g is given
with a HMG-CoA,
periodically test CPK and
potassium.
If there are signs of

hepatocellar damage, the
drug should be stopped.
Discontinue therapy if signs
of hepatotoxicity occur.
If LFTs increase, more

frequent monitoring is
necessary. If
granulocytopenia occurs,
the drug must be stopped.
Baseline LFTs, CPK, and

uric acid and at periodic
intervals.
For low-risk patients, the
ALT should be monitored
within 3 months of starting
treatment and repeated
every 6 to 12 months. For
high-risk patients, the ALT
should be monitored within
the first month of starting
treatment and repeated
High-risk patients are > 60

years of age, have renal
insufficiency, are on high
dose or prolonged NSAID
therapy, or take multiple
drugs. If the ALT is > 3
times ULN, the drug should
be stopped
110
5.23
Name
( )
Liver Funcation Tests Timeframe for Monitoring
Rosiglitazone
LFTs (eg, AST, ALT)

and Hg/Hct
Statins
-
LFTs (eg, AST, ALT)

Atorvastatin
Carivastatin
Fluvastatin
Pravastatin
Simvastatin
Terbinafine
LFTs
Tretinoin
LFTs
Valproic acid
LFTs (eg, AST, ALT)
Zileuton
LFTs
For LFTs: prior to initiation.

every 2 months for the first
year, and periodically
thereafter. For Hg/Hct:
periodically during therapy.
Prior to initiation. Repeated
semiannually during the
first year or until 1 year
after the last dose increase.
Prior to therapy and

periodically if patient is on
drug for longer than 4 to 6
weeks
During treatment
Prior to initiation of therapy
and at frequent intervals
thereafter (especially during
the first 6 months).
ALT at baseline, monthly
for the first 3 months, every
2 to 3 months for the
remainder of the first year,
then periodically thereafter.
Comments
If LFTs are elevated, a

second test should be
performed. LFTs should be
repeated until values return
to normal. If values are > 3
times the ULN, the drug
should be stopped. If
weakness, myalgia, or
muscle tenderness is
present, CPK should be
tested. If CPK is > 10 times
the ULN, the drugs should
be stopped. Closer
monitoring is needed in
patients receiving fibric
acid derivatives, lipidlowering doses of niacin,
cyclosporin, erythromycin,
or azole antifungals
concurrently. In any acute,
serious condition
suggestive of myopathy, or
having a risk factor
predisposing the patient to
renal failure secondary to
rhabdomyolysis, the drug
should be stopped.
If liver dysfunction
develops, the drug should
be stopped
If LFT values are > 5 times
the ULN, the drug should
be temporarily stopped.
signs/symptoms of liver
toxicity occur, or for LFTs
= 5 times ULN.
111
streptomycin
sporin
ethambutol, cyclo-
capreomycin
3
3
isoniazid, rifampicin
pyrazinamide
2
isoniazid
rifampicin
6
isoniazid
(
200
tramsaminase
/ )
isoniazid
10 20%
2
0.53%
3
isoniazid
11
isoniazid
rifampicin
2.7 10%
10
isoniazid
isoniazid
acetylhydrazine
rapid acetylators
slow acetylators
isoniazid
35
HIV
rifampicin
rapid
slow acetylators
3.5%
isoniazid
rapid
slow acetylators
0.5%
1.4%
additive
synergistic
rifampicin
1%
bilirubin
12
23
112
rifampicin
isoniazid
pyrazinamide
/
60
60%
20-40
2%
pyrazinamide
3
7
1
isoniazid, rifampicin pyrazinamide

2
isoniazid
rifampicin
9
9
1.
2
4
transaminase
2.
3
3.
isoniazid
4.
hyperbilirubinaemia
hyperbilirubinaemia
bilirubin
2
5.
6.
7.
isoniazid
3
isoniazid
transaminase
rifampicin
bilirubin
rifampicin
isoniazid
Amiodarone
Amiodarone
metabolite
transaminase
30%
phospholipid
151-3%
113
acute alcoholic hepatitis

fibrosis
metabolite
amiodarone
transami-nase
pseudo alcoholic
portal hypertension
desethylamiodarone
cardiac arrhythmias
Co-amoxiclav
Amoxicillin clavulanic acid
Co-amoxiclav
beta-lactamase inhibitor clavulanic acid
cholestasis
amoxicillin
4-6
Anabolic steroids
Anabolic steroids
bone marrrow failure
transaminase
5%
cholestasis
Chlorpromazine
Chlorpramazine
chlorpromazine
1%
cholestasis
100
/
3
cholestasis
cholestasis
1-4
114
eosinophilia
leukocytosis
conjugated
hyperbilirubinemia alkaline phosphatase
transaminase
(
100-200
/ )
polymorphonuclear, eosinophilic
mononuclear leukocytes
scattered foci
4-8
cholestyramine
Erythromycin
Erythromycin
erythromycin estolate
mixed
erythromycin
(cholecystitis)
(cholangitis)
erythromycin
estolate
ethylsuccinate
lactobionate
Halothane
Halothane
25%
20-40%
viral-hepatitis-like reaction
3
7-10
eosinophilia
halothane
115
halothane
Hydroxymethylglutaryl coenzyme reductase inhibitors

Statins
mixed hepatocellular and cholestasis
statins
lovastatin, simvastatin, pravastatin, fluvastatin
1-2%
transaminase
3
centrilobular necrosis, centrilobular cholestasis
acute hepatitis like
transaminase
Methyldopa
Methyldopa
hepatitis
transaminase
viral hepatitis
chronic
metabolite
5%)
1%
20
2-3
eosinophilia
Oral contraceptives
cholesterol
estrogen
116
intrahepatic cholestasis of pregnancy

cholestasis
estrogen
cholestasis
Scanidavian, Chilean
cholestyramine
estrogen
2-3
Paracetamol
Paracetamol
7.5
150
10-15 )
paracetamol
5%
paracetamol
metabolised
sulfation
90%
5% metabolised
P-450
N-acetylparabenzoquinoneimine (NAPQI)
glutathione conjugation
paracetamol
30%
NAPQI
paracetamol
1)
glucuronidation
cytochrome
glutathione
NAPQI
0.524
2-3
2)
24-48
bilirubin
3)
prothrombin time
prothrombin time
72-96
transaminase
5%
3000 48000
4-18
90%
117
4)
4-14
3
paracetamol
4-12
24
(
nomogram
50
200
5.1)
12
4
/
/
200
2
transaminase
3-4
24-48
(
5.2)
5.1
paracetamol
paracetamol
metabolised
NAPQI
NAPQI
4
40%
cytochrome P450
glutathione
paracetamol
30%
118
60
paracetamol
paracetamol
paracetamol
100
100
15
paracetamol
activated charcoal
activated charcoal
N-acetylcysteine
15
4
activated charcoal 50
NAC
4
paracetamol
N-acetylcysteine (NAC)
paracetamol
sorbitol
glutathione
NAC
NAC
NAC
NAC
16
NAC
4
sulfation
8-10
paracetamol
16-24
NAC
NAPQI
paracetamol
24
5.2
119
paracetamol
NAC
2
paracetamol
140
1330
NAC
NAC
NAC
4
17
NAC
/
/
5%
70
68
NAC
1
NAC
NAC
NAC
NAC
domperidone
metoclopramide
NAC
5.24
urticaria,
angioedema,
anaphylactoid reaction
10%
15-60
transaminase
24-72
ALT
antihistamine
prothrombin time
AST
NAC
3
5.24
N-acetylcysteine
(
140
/
70
/
4 . 17
150
/
5% Dextrose 200 .
15
50
/
5%
Dextrose 500 .
4 .
100
/
5% Dextrose 1
16 .
140
/
5% Dextrose
1 .
70
/
5% Dextrose
1 . 4 . 12
/
1330
72
300
20-25
980
48
120
5
.
prothrombin time > 100
arterial pH <7.30
INR > 6.5 bilirubin
creatinine > 300 ,
Phenytoin
Phenytoin
eosinophilia
3-4
/
viral hepatitis like reaction
6
atypical lymphocytosis
leukocytosis
phenytoin
Sodium valproate
Sodium valproate
10
INH
sodium valproate
sodium valproate
eosinophilia
sodium valproate
Reyes syndrome
mitochondrial oxidation
metabolite
Total parenteral nutrition

Total parenteral nutrition (TPN)
cholestasis
total parenteral nutrition (TPN)
cholestasis, steatosis gallstones
steatosis
steatohepatitis
steatosis
TPN
cholestasis
121
cholelithiasis
premature neonates
Alternative medicines
Alternative medicines
Jin bu huan
veno-occlusive disease
senna, mistletoe, skullcap, gentian
hepatitis
steatosis
hepatocellular necrosis
pyrrolizidine alkaloid
xiao-chai-hu-tang, germander, chaparral,
comfrey pyrrolizidine alkaloid
5.25
Acetaminophen
Alcohol
Allopurinol
I:
Occasional
M:
Submassive or massive necrosis cholestatic or granulomatous hepatitis
Mech: Hypersensitivity
Amiodarone
I:
Uncommon
M:
Alcoholic hepatitis-like lesions, confluent and bridging necrosis; cirrhosis
Mech: Phospholipidosis
Amoxicillin-clavulanic acid
I:
Low
M:
Cholestasis; hepatocellular or mixed
Mech: Immunologic idiosyncrasy
Androgenic steroids
I:
High incidence of hepatic dysfunction; cholestatic jaundice dose related
M:
Canalicular cholestasis with minor or no portal inflammation; dilation of sinusoids; peliosis
hepatis; adenoma and carcinoma
Mech: Indirect intrinsic hepatotoxin
Aspirin and other salicylates
I:
0.1-0.5%
M:
Focal necrosis; steatosis
Mech: Intrinsic hepatotoxicity
Azathioprin
I:
Rare
M:
Cholestasis; minor hepatocellular injury; veno-occlusive disease
122
5.25
( )
Captopril
I:
M:
Rare
Mostly cholestasis; mixed hepatocellular and cholestatic injury; pure hepatocellular injuryrare
Mech: Hypersensitivity and modulation of eicosanoid metabolism by inhibition of kininase II with
increased hepatic bradykinin activity
Carbamazepine
I:
< 1%
M:
Hepatocellular, cholestatic, mixed
Mech: hypersensitivity; idiosyncrasy; toxic metabolites
Carmustine (BCNU)
I:
Dose related
M:
Cytotoxic
Mech: Intrinsic hepatotoxin
Chlorpromazine (CPZ)
I:
0.1-0.2%
M:
Cholestasis; scattered focal areas of necrosis
Mech: Hypersensitivity; idiosyncrasy
Cloxacillin
I:
Low
M:
Cholestasis
Mech: Hypersensitivity? Idiosyncrasy
Contraceptive steroids (OCs)
I:
Dose related 1:10,000 in Europe and North America; 1:4,000 in Chile and Scandinavia
M:
Cholestasis, adenoma, peliosis hepatis, Budd-Chiari syndome, carcinoma
Mech: Indirect hepatotoxin; genetic predisposition
Cyclosporin
I:
Uncommon
M:
Cholestasis
Mech: Direct toxic effect on bile secretion
Didanosine
See zidovudine
Diltiazem
I:
Rare
M:
Granulomatous
Mech: Idiosyncrasy
Erythromycin + other macrolides
I:
3.6/100,000
M:
Cholestasis; mixed cholestatic-cytotoxic injury
Fluconazole
See ketoconazole
Fluoroquinolones
I:
Rare
M:
Cholestasis; centrilobular necrosis
Mech: Idiosyncrasy?
Fluoxetine
I:
Very low
M:
Cholestatic
Mech: Hepatocelular?
Glucocorticoids
I:
Dose relaed
M:
Steatosis
Mech: Hepatotoxicity
123
5.25
Haloperidol
I:
M:
Mech:
Halothane
I:
( )
Low
Cholestasis
Hypersensitivity
1. Mild form > 25%
2. Severe 1:35,000-1:3,500
Centraxonial necrosis; steatosis; massive necrosis
Metabolic idiosyncrasy; hypersensitivity
M:
Mech:
Indinavir
See zidovudine.
Isoflurane
See halothane.
Itraconazole
See ketoconazole
Ketoconazole
I:
0.03-0.1%
M:
Hepatocellular necrosis; mixed cholestasis-hepatocellular
Mech: Metabolic idiosyncrasy
Mercaptopurine (6-MP)
I:
Dose related
M:
Cholestasis with fatty heptic necrosis
Mech: Indirect instrinsic hepatotoxin
Methimazole
I:
Rare
M:
Cholestasis
Methotrexate (MTX)
I:
Dose, frequency, and duration related
M:
Macrovesicular steatosis and portal inflammation; necrosis; chronic steatosis may lead to
fibrosis and cirrhosis
Mech: Indirect intrinsic hepatotoxin
Methyldopa
I:
Low
M:
Cytotoxic injury; subacute or bridging necrosis; rare cholestasis; chronic active hepatitis
Mech: Toxic metabolites; hypersensitivity
Monoamine oxidase inhibitors (MAOIs)
I:
1%
M:
Hepatocellular damage
Mech: Metabolic idiosyncrasy; autoimmune
Nevirapine
See zidovudine.
Niacin (Nicotinic acid)
I:
Occasional
M:
Hepatic necrosis; cholestasis
Mech: Unknown; dose related? Direct toxicity? formulation related?
Nifedipine
See diltiazem
Nonsteroidal anti-inflammatory drugs (NSAIDs)
I:
1:100,000 recipients
M:
Cholestasis, cytotoxic, or mixed
Mech: Hypersensitivity; reactive metabolites
Nitrofurantoin
I:
Rare
M:
Mixed cholestatic-cytotoxic injury; chronic active hepatitis
Mech: Hypersensitivity; reactive metabolites
124
5.25
( )
Penicillin
I:
Very rare
M:
Necrosis; granuloma; lupoid hepatitis
Phenylbutazone
I:
0.25%
M:
1. Granulomatous form
2. Severe necrosis with or without cholestasis
Mech: Hypersensitivity; intrinsic toxicity
Phenytoin
I:
<1%
M:
Submassive necrosis; lobular hepatitis; cholestatic hepatitis; granulomatous hepatitis
Mech: Hypersensitivity; idiosyncrasy; toxic metabolites
Prochlorparazine
I:
Rare
M:
Cholestasis
Mech: Hypersensitity
Propylthiouracil (PTU)
I:
Rare
M:
Hepatocellular injury; chronic active hepatitis; cholestasis; granuloma
Mech: Hypersensitivity; toxic metabolites?
Quinidine
I:
Rare
M:
Mixed hepatocellular; granulomata
Statins
I:
Very rare
M:
Mild focal hepatitis; cholestasis
Mech: Hepatocellular
Sulfamethoxazole-trimethoprim (co-trimoxazole)
I:
Very low
M:
Cholestasis; few hepatocellular
Mech: Idiosyncrasy
Sulfonamides
I:
0.5-1% cholestatic jaundice
M:
Mixed hepatocellular injury; subacute hepatic necrosis with cirrhosis; chronic active hepatitis;
Mech: Hypersensitivity; idiosyncrasy
Sulfonylurea oral hypoglycemics
I:
0.1-0.5%
M:
Mixed cholestatic-cytotoxic injury
Mech: Hypersensitivity, hepatotoxicity
Tetracyclines
I:
Low
M:
Microvesicular fat droplets in hepatocytes; fatty degeneration
Mech: Intrinsic hepatotoxicity
Tricyclic antidepressants (TCAs)
I:
Rare to infrequent
M:
Cholestasis; heptic necrosis
Mech: Hypersensitivity plus slight toxicity
Trifluoperazine
I:
Rare
M:
Cholestasis
125
5.25
( )
Valproic acid
I:
0.05-0.1%
M:
Microvesicular steatosis; focal or massive necrosis
Mech: Toxic metabolites; idiosyncrasy
Verapamil
See diltiazem.
Vitamin A
I:
Dose related
M:
Fat-storing cell hyperplasia and hypertrophy; nonspecific hepatocellular degeneration;
fibrosis; cirrrhosis
Mech: Intrinsic hepatotoxin
Zidovudine
I:
Very low
M:
Macrovesicular steatosis
Mech: Idosyncrasy?
Zileuton
I:
Low
M:
Unknown
Mech: Idiosyncrasy
63
76
co-trimoxazole
2
generalised tonio-clonic
7
valproic acid 1
8
2
ALT 66
/
AST 88
alkaline phosphatase 85
/
total bilirubin 0.8
/
1
152
5.6)
40
isoniazid, halothane,
diclofenac
valproic
acid
salicylates
3
126
nitrofurantoins, methyldopa
sulfouamides
paracetamol, isoniazid
cytochrome P450
valproic acid
3
2-4
CC :
HPI :
PMH :
SH :
Med:
PE :
LAB :
2
52
30
2542
nausea, anorexia
2-wk PTA, nausea, anorexia, fatigue, intense generalised itching
10 d. PTA, dark urine, light coloured stools, yellow pigmentation of the skin, no fever,
vomitting, abdominal pain, rash, fatty food intolerance.
NIDDM x 12 y
HTN x 4 y
Acute otitis media, amoxicillin-clavulanic acid 625
, q 8 x 10d. (1 mo. ago)
Tobacco (-ve), alcohol (-ve)
Troglitazone 400
/
; HCT 25
/ Lisinopril 10
/
GA weak and icteric
VS BP 126/80, HR 68, RR 15, T 37 o C,
ABD scratch marks and slightly tender, but normal size, liver
Elyte WNL
127
LFT- AST 430

/ , ALT 294
/ , alkaline phosphatase 1230
albumin 4.1 gm/dl, total : directed bilirubin ratio 7.25
/dl :6.2
,
/
CBC diff. WNL

Serology - Hepatitis A, Hepatitis B (-ve)
Ultrasound : normal biliary tract system, with no obstruction in bile ducts
Liver biopsy : normal liver architecture, marked centrilobular cholestasis with bile pigment in
hepatocytes and caniliculi, mild portal inflammatory Infiltrate with excess of
eosinophils
Assessment : Drug-induced hepatitis
1.
2. lente insulin 20
3. cholestyramine 4 , tid. for itching
4. daily diet, 1200 calorie with no added salt
5 : LFT- AST 85
/ , ALT 214
/ , alkaline phosphatase 288
, bilirubin T:D 2.46
/
: 1.69
/
BP 190/105 mm Hg, FBS 190
/
1.
lene insulin
blood glucose
insulin 35
/ (FBS
190
/
)
2. HCTZ 25
/
BP.
calcium channel blocker
10 : D/C Med HCTZ 25
/ Amlodipine 2.5
/ Pioglitazone 20
/
1:
1.
2.
3.
4.
LFT
128
5.
6.
rechallenge
(
)
infectious mononucleosis
serum aminotransferase
eosinophil
hyperbilirubinemia, serum alkaline phosphatase

AST
cellular damage
hepatic injury
ALT
bilirubin
cholestatic jaundice
hepatomixed cholestatic-cytotoxic
albumin
3
3
129
ultrasound
(extrahepatic obstructive jaundice)
unconjugated hyperbilirubinemia
hemolysis
ALT
AST
AST
eosinophils
alkaline
phosphatase
4
amoxicillin-clavulanic acid,
troglitazone, hydrochlorothiazide,
lisinopril
1. Hydrochlorothiazide
allergic cholestatic jaundice
thiazides
4
2. Lisinopril
angiotensin-converting enzyme inhibitors
hepatocellular injury
mixed cholestatic-cytotoxic injury
pure hepotocellular injury
lisinopril
hepatic injury
14
3. Troglitazone
mixed cholestatic-cytotoxic injury

(
4.9
)
3-9
ALT
20
18
4. Amoxicillin-clavulanic acid
inhibitor
)
media
ALT
semisynthetic penicillin
1-1.7
10,000
2-45
amoxicillin-clavalunic acid
-lactamase
(
27
acute otitis
amoxicillin clavulanic acid
130
(Rechallenge)
40-60%
1-12
cholestasis
amoxicillin-clavulante acid
2000-3000
, esophageal
hydrocortisone 1000
/
variceal bleeding
1.
2.
1200
cholestyramine
3.
amoxicillin-clavulanic acid
48
Tramal (Tramadol 50
3
)
131
(Jin Bu Huan)
2
ALT
1378
AST 1333
bilirubin 3.9
3%
(sedative)
(
5.20)
20
12
(7-52
)
transaminase
20-50
lobular
2-3
132
1.
. :
2.
(
:
2.
3.
4.
5.
6.
, 2541.
(Fulminant Hepatic Failure)
, 2543 ; 13(5) : 209-226.

,
.
.
2
3.
.
:
.
).
.
, 2543 . 16 (6) : 385-390
.
:
(
:
, 2541.
467-469.
).
(
:
, 2541.
,
:
).
341-346.
. Hepatitis. :
,
(
).
.
. ., 2539.
261-274.
7. Bass NM. Toxic and Drug-induced Liver Disease. In : Bennett JC, Plum F (Eds). Cecil
Textbook of Medicine 20 th ed., 1996. Saunders Company : Philadelphia. p.772-776.
8. Braunwald E, Fauci AS, Kasper DL, Hauser SL, Lango DL, Jamson JL (Eds.). Harrison s
Principles of Internal Medicine 15 th ed. McGraw Hill, 2000. p. 258-260, 1018-1019, 17371742.
9. Danan G. Liver test abnormalities. In : Benichou C. Adverse Drug Reactions : A Practical
Guide to Diagnosis and Management . Chichester : John Wiley & Sons, 1994. p. 3-12.
10. Davies M. Hepatic disorders. In: Davies DM, Ferner RE, De Glanville H (Eds.). Textbook
of Adverse Drug Reactions 5 th ed. Chapman & Hall Medical : London, 1998. p. 275-338.
11. Gill MA, Kirchain WR. Drug-Induced liver Disease. In : DiPiro JT, Talbert RL, Yee GC,
Matzke GR, Wells BG, Posey LM (Eds.). Pharmacotherapy 4 th ed. Appleton & Lange :
Connecticut, 1999. p.628-635.
133
12. Holt CD, Jim LK. Adverse Effects of Drug on the Liver. In : Koda-Kimble MA, Young LY
(Eds.). Applied Therapeutics 7 th ed. Lippincott Williams & Wilkin : Pennsylvania, 2001.
Chapter 28.
13. Koda-Kimble MA, Young LY (Eds.). Applied Therapeutics 7 th ed. Lippincott Williams and
Wilkins : Pennsylvania, 2001. p.2-45; 5-20,21; 59-11, 12,13; 83-9, 10.
14. Palacioz K. Monitoring for Drug-Induced Hepatotoxicity. Pharmacists Lelter, July 2001,
No. 170712.
15. Tice SA, Parry D. Medications that Require Hepatic Monitoring. Hospital Pharmacy, 2001;
36 (4) : 456-462
16. Ward F, Daly M. Hepatic disorders. In : Lee A (Ed.). Adverse Drug Reactions. Pharmaceutical
Press : London, 2001. p 77-97.
134
2
1.
2.
thyroxine, insulin
corticosteroid
amiodarone, ketoconazole cimetidine, spironolactone, methyldopa
antipsychotics
methimazole
thyroxine
hypothyroidism
hyperthyroidism
amiodarone
lithium
arrhythmia
manic-depressive
hypothyroidism
glucocorticoids
Cushings syndrome
hypothalamic-pituitary-adrenal axis
glucocorticoid
ketoconazole
steroid
adrenal insufficiency
dopaminergic
serotoninergic receptors
hyperprolactinaemia
galactorrhoea
spironolactone
gynecomastia
estrogen
augmented type A
carbamazepine
benzodiazepines
dexamethasone suppression test

NSAIDs
cortisol
phenytoin
amphetamines,
Cushings syndrome
135
1.
2.
3.
1.
1.1.
triiodothyronine (T3)
thyrotropin-releasing hormone (TRH)
pituitary-thyroid axis)
thyroxine (T4)
thyroid-stimulating hormone (TSH)
(Hypothalamic(feedback control)
3
hypothyroidism
hyperthyroidism
60-80
hypothyrodism
3
hyperthyroidism
6.1
hyperthyroidism
Amiodarone
Interferon alfa
Lithium
Radiographic contrast media (
Amiodarone
Amiodarone
400
hypothyroidism
Amiodarone
Interferon alfa
Lithium
)
37%
6-12
200136
100
TSH
T3, T4
hypothyroidism
hyperthyroidism
amiodarone
2-3
amiodarone
(Wolff-Chaikoff effect)
3-4
hypothyroidism
1-32%
thyroid antibodies
hypothyroidism
14
hypothyroidism
TSH ,
T4
amiodorone
(replacement therapy)
thyroxine
4-6
amiodarone
(1)
amiodarone
hypothyroidism
thyroxine
25-50
hyperthyroidism
autoantibodies
antibodies
1-23%
hyperthyroidism
amiodarone
(tremor)
(cardiac arrhythmia)
amiodarone
TSH
(1)
amiodarone
(2)
hypothyroidism
25-50
thyrotoxicosis
hyperthyroidism
T3, T4,
8
(2)
(antithyroid drugs)
amiodarone
propylthiouracil
methimazole
hyperthyroidism
potassium perchlorate
137
beta-blockers
prednisolone 40-60
(radioactive iodine)
corticosteroids
hyperthyroidism
Lithium
Lithium
amiodarone
lithium
10-34 %
hypothyroidism
hyperthyroidism
thyroid antibodeis
hypothyroidism
lithium
lithium
hypothyroidism 30%
2-3
T4
lithium
lithium
TSH
12
subclinical
T3
T3
T4
12
2-3
hypothyroidism
lithium
2%
hypothyroidism
lithium
lithium
50%
autoimmune
methimazole
lithium
Interferon Alfa
hyperthyroidism
antibodies
recombinant interferon alfa

7%
hypothyroidism
4%
thyroid
interferon alfa
amphetamine abuse
ketoconazole
rifampicin
138
6.2
Lithium (acute effect)
Potassium perchlorate
Adrenal suppressants
Antiarryhthmic
Antirheumatics
Antithyroid drugs
Antituberculous drugs
Sulphonamides
Miscellaneous
Amiodarone
Iodide (large doses)
aminoglutethimide, high-dose ketoconazole

amiodarone
oxyphenbutazone, phenylbutazone
carbimazole, methimazole, propylthiouracil
ethionamide, rifampicin
co-trimoxazole, sulphadiazine
chlorpromazine, pentazocine, sulphonylureas
Lithium (chronic effect)
1.2
TSH
3
T4
T3
total T4
T3
T4
0.03%
0.3%
total T3
estrogen
total T4
hyperthyroidism
thyroxine-binding globulin (TBG)

TSH
fluorouracil, methadone abuse heroin abuse
TBG
androgens
danazol
anabolic steroids
TBG
TSH
Total T4
(enzyme inducer)
cytochrome
P-450
phenytoin, carbamazepine
rifampicin
TSH
fenclofenace
NSAIDs
TBG
T4
TSH
2-4
T3
beta-blockers propranolol
nadolol
T4
euthyroid
hyperthyroxinemia
propronolol
139

3-4
14
hyperthyroidism
lipoprotein lipase
heparin
TBG
furosemide
/
100
heparin
60
free fatty acid
heparin
15
T4
heparin
free fatty acid

TBG
corticosteroids
T3
T4
TSH
80
) dexamethasone (
/ )
TSH
pituitary insufficiency
T4
,
0.5
dopamine (
/ )
octreotide (
TSH
140
Iodide-containing compounds,
contrast media, providoneiodine, kelp, tincture of
iodine, saturated solution
potassium iodide, Lugols
solution, amiodarone
No change if test
not interfered by
iodide (i.e., radio
immunoassay)
No
change
serum TBG
concentrations,
T4 clearance
Dilution of total body

iodide pools
or
or no
change
Displacement of T4 and
T3 from TBG
Phenytoin in vitro, high dose

heparin, furosemide,
salicylates (level > 15
mg/100 mL),
phenylbutazone,
fenclofenac, halofenate,
mitotane, chloral hydrate 5fluorouracil
Serotonin reuptake inhibitors
(e.g., sertraline)
or no change
or
little to
no
change
serum TBG
concentrations,
T4 to T3 conversion
TSH secretion
serum TBG
concentrations
Glucocorticoids (stress dosages)
Androgens anabolic steroids,

danazol, L-asparaginase,
nephrotic syndrome,
cirrhosis, familial TBG
serum TBG
concentrations
RT3U
Estrogens, oral contraceptives,

pregnancy, heroin,
methadone, clofibrate,
acute and chronic active
hepatitis, familial TBG
TT4
Mechanism
Drug or Disease
6.3
No
change
or no
change
No
change
No
change
No
change
141
FT4/FT4l
No
change
or no
change
TT3
I Uptake
or no
change
No change
No change
Slight
No change
131
No change
or no change
No change
No change
No change
TSH
Sertraline
reported to
cause
hypothyroidism
No change in
thyroid status
FT4//FT4l
corrects for
TBG alterations;
TSH indicates
true thyroid
status
Evaluate thyroid
status after
steroids are
stopped
FT4//FT4l
corrects TBG
alterations; TSH
indicates true
thyroid status
FT4//FT4l
corrects for
TBG changes;
TSH indicates
true thyroid
status
Comments
Normal or
No Change
Dopamine suppresses
TSH secretion
or normal
Hepatic enzyme inducer

of T4 metabolism
Impair peripheral
conversion of T4 to
T3; rT3
No change
TT4
Decrease total body iodide

pools
Mechanism
No
Change
No
change
or no
change
No
change
RT3U
( )
No
change
Normal
or
or
normal
No
change
FT4/FT4l
142
No
change
Usually
low
No
change
No
change
TT3
I Uptake
No change
No change
No change
Might be
131
TSH secretion
No change in
euthyroid
patients not on
T4 replacement
No change but
in euthroid sick
syndrome, slight
or in TSH
might occur
No change
TSH
No change in
euthyroid
patients not on
T4 replacement
Thyroid
replacement not
necessary
No change in
thyroid status
Comments
Not enough to
interfere with
diagnosis of
hyperthyroidism
Amiodarone, iopodate,
Impair pituitary and
No
Thyroid
Transient
iopanoate
peripheral conversion
Change
abnormalities
of T4 to T3
transient; should
be normal
within 3 mo; can
cause thyroid
dysfunction in
predisposed
patients
TT4, total thyroxine; T4, thyroxine; TBG, thyroxine-binding globulin; FT4, free thyroxine; FT4l, free thyroxine index; RT3U, resin T3 uptake; T4U, T4 uptake; TT3, total T3;
FT3I, free triiodothyronine index; TSH, thyrotropin-stimulating hormone; ATgA,antithyroglobulin antibody; TPO, thyroperoxidase antibody.
Propranolol, old age,

fasting, malnutrition,
acute and chronic
systemic illness (e.g.,
euthyroid sick
syndrome)
Dopamine, levodopa, highdose glucocorticoids,
bromocriptine
Strong diuresis by
furosemide, ethacrynic
acid, iodine deficiency
Phenytoin, carbamazepine,
rifampicin,
phenobarbital
Drug or Disease
6.3
2.
glucocorticoids,
aldosterone, androgens, estrogen
catecholamines
glucocorticoids
cortisol
androgens
corticotropin releasing hormone (CRH)
adrenocorticotropin hormone (ACTH)
mineralocorticoids
aldosterone
renin-angiotensin
prostaglandins, atrial natriuretic factor
dopamine
catecholamines epinephrine
neural stimuli
2.1
Glucocorticoids
Glucocorticoids
cortisol
hypothalamic-pituitary-adrenal (HPA)
2-3
Cushings syndrome
hydrocortisone
2
moon face, buffalo hump,
corticosteroids
ACTH
corticosteroids
(withdrawal syndrome)
ACTH
CRH
steroids
HPA
50
/
(adrenal hypofunction)
HPA
glucocorticoids
corticosteroids
corticosteroids
(replacement dose)
2
HPA
corticosteroids
HPA
beclomethasone diproprionate
1.5
/
HPA
fluorinated
corticosteroid
143
corticosteroids
40
/
prednisolone
corticosteroids
corticosteroids
3
adrenocortical insufficiency
18
1
(Pulse therapy)
HPA
10
glucocorticoids
cortisol
Cushings syndrome
Cushings Syndrome
HPA
Cushings syndrome
hydrocortisone
prednisolone
dexamethasone
cortisol
spironolactone
hydroxyzine
cortisol-binding globulin
urine steroid
estrogen
Ketoconazole
ketoconazole
200
urine cortisol
glucocorticoid
ketoconazole
2
ketoconazole
Cushings
itraconazole
fluconazole
144
Rifampicin
rifampicin
hypoadrenalism
steroids
rifampicin
heparin
2.2
phenytoin
warfarin
steroids
1-2
steroid
aldosterone synthesis
aldosterone
mineralocorticoids
aldosterone
renin-angiotensin
(RAS)
sympathetic
prostaglandins
aldosterone
ACTH
hyperaldosteronism lithium,
loop diuretics, oral contraceptives, spironolactone, thiazides
angiontensin-converting enzyme (ACE)
angiotensin I angiotensin II
aldosterone
angiotensinconverting enzyme inhibitors
hypoaldosteronism
hyperkalemia
hyperchloraemic metabolic acidosis
angiotensin II receptor antagonist losartan
aldosterone
heparin
2-3
hypoaldosteronism
heparin
7
heparin
acidosis
heparin
aldosterone
bromocriptine
potassium-sparing
7
beta-2 agonists
nebulised salbutamol
renin
piribedil
dopamine-1 agonist
(vasodilatation)
renin
aldosterone
dopamine-2 agonist
aldosterone
145
ibuprofen, piroxicam
renin
sympathetic tone
naproxen
NSAIDs
indomethacin,
renin
aldosterone
prostaglandin
growth hormone
aldosterone
3.
hypothalamic-pituitary-gonadal
gonadotrophin-releasing hormone (GnRH)

luteinisinghormone releasing hormone (LHRH)
follicle stimulating hormone (FSH)
luteinising hormone (LH)
FSH LH
gonads
testosterone, estrogen
progesterone
LH
testosterone
FSH
FSH
estrogen
LH
estrogen
progesterone
FSH
LH
gynecomastia,
hyperprolactinaemia, infertility
sexual dysfunction
erectile dysfunction, ejaculatory
disorders, priapism
altered libido
ketoconazole
400
testosterone
gynecomastia
danazol
testosterone
sex hormone-binding globulin
virilization
hirsutism
endometriosis
estrogen
metastatic prostatic carcinoma
hypothalamic-pituitary-gonadal cyproterone acetate
antiandrogen steroid
LH
FSH
testosterone
LHRH analogues
central
precocious puberty
medical castration
hot
flush
(osteoporosis)
3.1 Gynecomastia
3
neonatal
estrogen
puberty
70%
146
testosterone
gynecomastia
50%
spironolactone, cimetidine
gynecomastia
10-20%
ketoconazole
gynecomastia
2
estrogen
6.4
digoxin
estrogen analogue
6.4
testosterone
gynecomastia
10%
digoxin
gynecomastia
Drugs with oestrogenic activity

Clomifene
Digitalis glycosides
Oestrogens
Spironolactone
Drugs reducing testosterone synthesis or effects
Alcohol
Alkylating agents, e.g. vinblastine
Cimetidine
Cyproterone
Flutamide
Ketoconazole
Phenytoin
Spironolactone
Drugs where the mechansim is uncertain
Antipsychotics, e.g. chlorpromazine
Calcium channel blockers. e.g. verapamil, nifedipine
Isoniazid
Marijuana
Methadone
Methyldopa
Protease inhibitors (Melbourne et al., 1998)
Stavudine( Choi and Pai, 1998)
3.2 Infertility
endometriosis
hypogonadism
retrograde ejaculation
FSH
LH
147
GnRH
6.5
libido
erection
6.5
Alkylating agents (e.g. chlorambucil, cyclophosphamide,
melphalan)
Anabolic steroids
Colchicine
Diethylstillbestrol
Methotrexate
Nonsteroidal anti-inflammartory drugs

(women)
Procarbazine
Sulfasalazine (males)
Vincristine
Cytotoxic Chemotherapy
alkylating agents
cyclophosphamide, chlorambucil
(azoospermia)
methotrexate
psoriasis
vincristine
cisplatin
FSH
LH
ovarian failure
menopause
amenorrhoea
mephalan
estrogen
cyclophosphamide
amenorrhea, oligomenorrhea
progesterone
hyperprolactinaemia
prolactin
estrogen, methyldopa, metoclopramide, cimetidine, risperidone
neuroleptics
antipsychotics
prolactinsparing
clozapine, olanzapine
quetiapine
corticosteroids
, danazol,
isoniazid, spironolactone
100-200
/
amenorrhea
2
NSAIDs
148
diclofenac, naproxen
6.6
anovulation
Anabolic steroids
Danazol
Isoniazid
indomethacin
amenorrhea
Risperidone
Spironolactone
3.3 Sexual dysfunction
dopamine
testosterone
serotonin
erectile dysfunction
50-70
10%
exectile dysfunction
25%
antihypertensives, antipsychotics, antidepressants
50%
antiepileptics
Antihypertensives
sexual dysfunction
clonidine
methyldopa
libido,
ejaculatory failure
doxazosin
erection
ejaculatory failure
prazosin
ejaculatory failure
doxazosin
erection dysfunction
prazosin
priapism
ophthalmic timolol, atenolol,
propranolol
diuretics
calcium
channel blockers angiotensin-converting enzyme inhibitors
149
libido
methyldopa
libido
7-14%
spironolactone, propranolol, thiazides
calcium antagonist
methyldopa
clonidine
captopril
Psychotropics
antidepressants
prolactin
anorgasmia
antipsychotics
sexual function
(sedation), neurotransmitters
sexual dysfunction
SSRIs
MOAIs
SSRIs
libido
40%
serotonin
SSRIs
ejaculation
SSRIs, clozapine
psychotropics
risperidone
levodopa
SSRIs
anorgasmia
trazodone
priapism
libido
hypersexuality
premature
Parkinsons
lubrication
1961
SSRIs
libido
orgasm
anorgasmia
fluoxetine
antidepressants
orgasm
20
thioridazine
vaginal
. .
psychotropics
multiple spontaneous orgasma
clomipramine
olanzapine, nefazodone
mirtazapine
5-HT2 post-synaptic
sexual dysfunction
cimetidine
libido
antiandrogen activity
ranitidine
protease inhibitors
ejaculation failure
libido
150
sexual dysfunction
6.7
sexual dysfunction
Erectile dysfunction
Anabolic steroids
Antiandrogens (e.g. finasteride)
Anticholinergics
Antidepressants (tricyclics, monoamine oxidase inhibitors,
selective serotonin reuptake inhibitors)
Digoxin
Gabapentin
Methyldopa
Metoclopramide
Omeprazole
Phenothiazines
Phenytoin
Prazosin
Spironolactone
Thiazide diuretics
Benzodiazepines
Beta-blockers
Carbamazepine
Cimetidine
Priapism
Anticoagulants
Haloperidol
Hydralazine
Nifedipine
Olanzapine
Papaverine
Phenothiazines
Phentolamine
Prazosin
Risperidone
Trazodone
Antidepressants (tricyclics, monoamine oxidase inhibitors,

Selective serotonin reuptake inhibitors)
Benzodiazepines
Cimetidine
Clonidine
Gonadorelin analogues
Methyldopa
Oestrogens
Propranolol
Spironolactone
Thaizide diuretics
Trazodone
3.4
serotonin
Hyperprolactinaenia
Prolactin
prolactin
neurotransmitters
prolactin
dopamine
hyperprolactinaemia
(amenorrhea)
(impotence)
hyperprolactinaemia
3
dopamine
reserpine, methyldopa
prolactin
(galactorrhea)
(infertility)
dopamine
151
phenothiazines butyrophenones
antidepressants, SSRIs
6.8
serotonin reuptake
tricyclic
6.8
hyperprolactinaemia
Analgesics, e.g. methadone, morphine

Antidepressants, e.g. amitriptyline, imipramine, fluoxetine
Antihypertensives, e.g. reserpine, methyldopa, verapamil
Antipsychotics, e.g. haloperidol, chlorpromazine
Antiulcer drugs, e.g. cimetidine, ranitidine
Benzodiazepines
Estrogens
cimetidine
ranitidine
hyperprolactinaemia
histamine
prolactin
estrogens, morphine,
benzodiazepines
verapramil
hyperprolactinaemia
2-3
3.5 Growth hormone (GH)
Growth hormone (GH)
hypothalamic-growth hormone-releasing
hormone (GHRH)
somatostatin
glucocorticoid
androgen
estrogen
estrogen
hypothyroidism
GH
neuropeptides
levodopa
dopaminergic
GH
GH
neurotransmitters
neurotransmitters
GH
GH
apomorphine, bromocrlptine
clonidine
alpha-adrenergic
metoclopramide
dopamine antagonist
152
4. Syndrome of inappropriate secretion of antidiuretic hormone (SIADH)

antidiuretic hormone (ADH)
vasopressin
osmotic pressure
specific osmoreceptor neurons
osmolality
ADH
ADH
SIADH
(diabetes inspidus, DI)
SIADH
ADH
osmolality
ADH
extracellular fluid
SIADH
(serum sodium
125
/
SIADH 3
,
ADH
ADH
ADH
cerebrovascular accident
6.9
I. Leading to SIADH
Chemotherapeutic
Agents
Phenothiazines
Serotonin-reuptake Inhibitors
Miscellaneous
antidiuretic hormone
Cisplatin
Cyclophosphamide
Melphalan
Vinblastine
Vincristine
Fluphenazine
Thioridazine
Amitriptyline
Desipramine
Imipramine
Fluoxetine
Sertraline
Carbamazepine
Chlorpropamide
Haloperidol
Thiothixene
Vasopressin and its long-acting derivatives
II. Leading to diabetes insipidus (DI) (nephrogenic)

Democycline
Ifosfamide
Lithium Carbonate Short-Term Administration Causes Central DI)
Methoxyflurane
153
Psychotropics
SIADH
phenothiazines, tricyclic antidepressants, SSRIs
antipsychotics
SIADH
venlafaxine
ADH
ADH
Antiepileptics
SIADH
carbamazepine
SIADH
sodium valproate
22%
ADH
Cytotoxic agents
SIADH
cyclophosphamide, cisplatin, mephalan
vinorelbin
cyclophosphamide
cisplatin
SIADH
neurons
osmoreceptors
vincristine, visblastine
cystitis
electrolytes
vincristine
ADH
ADH
SIADH
125
ADH
SIADH
500-1000
/
chlorpropamide
hypertonic
sodium chloride 3-5%
48
1-2
125
/
/
48
/ /
severe hyponatremia
osmotic demyelinisation
154
bulbar palsy, paralysis, coma
hypertonic sodium chloride solution

SIADH
antipsychotics
carbamazepine
lithium
1-4
manic-depressive
thiazide
diltiazem
hyperparathyroidism
hyperplasia
PTH
adenoma
52
OD
nifedipine 20 mg
esophageal reflux
cimetidine 400 mg qid

(1)
(2)
gynecomastia
nifedipine
cimetidine
adrenal
testicular)
syndrome
tumours (
liver cirrhosis
gynecomastia
42
2
depression
erection
(1)
androgen
gynecomastia
hyperthyroidism, Cushings
fluoxetine 20
ejaculation
SSRIs
155
(2)
(3)
(4)
SSRIs
sildenafil
SSRIs
2-75%
20%
fluvoxamine
paroxetine
sertraline
Sildenafil
sexual dysfunction
fluoxetine
nefazodone
mirtazapine
cyproheptadine, yohimbine, amantadine, buspirone, granesitron,
3 . .
schizophrenia
26
haloperidol 15
SSRIs
ginkgo
chronic paranoid
7
2
pregnancy test
serum prolactin 75
/
( 5-25
/
)
(1)
. .
haloperidol
(2)
antipsychotics
amenorrhea
galactorrhea
dopamine
prolactin
antipsychotics
prolactin
galactorrhea, amenorrhea anovulation
azoospermia, impotence
gynecomastia
hyperprolactinaemia
osteoporosis
hyperprolactinaemia
pituitaing adenoma
serum prolactin
156
100
/
prolactin
haloperidol
haloperidol
haloperidol
dopamine agonist
bromocriptine 5-15
/
amantadine 200-300
15
9
dopamine agonist
risperidone
typical antipsychotic
4 . .
lithium 300
21
mania
3
10
1
(Tremor)
3
propranolol 10 mg, tid
lithium
. .
lithium
hypothyroidism
hypothyroidism
subclinical hypothyroidism
litihium
. .
thyroxine
mania
hypothyroidism
T3
T4
hypothyroidism
3-42%
lithium
lithium
lithium 7.8%
TSH
TSH
T4
hypothyroidism
litihium
157
5 . .
25
2-3
7
2
major depressive disorder
2
sertraline 50
4
3-4
sertraline
SSRIs
(1)
sertraline
2-4
(2)
drug holidays
(3)
bupropion 75-150
nefazodone mirtazapine
. .
sertraline
sertraline
bupropion
2
6
7
biloba 60
(4)
libido
ginsgko
sertraline
1-2
158
24
chronic paranoid schizophrenia

thioridazine 400
thioirdazine
antipsychotics
60%
ejaculatory dysfunction
libido, anorgasmia, impotence
priapism
alpha 2-adrenergic
calcium blockade
25%
schizophrenia
schizophrenia
300
/
sertindole
10-20%
haloperidol
ejaculatory volume
thioridazine
sertindole
1. Caterson ID, et al. Endocrine diseases. In: Speight TM, Holford NHG (eds.). Averys
Drug Traetment 4 thed. Auckland : Adis International ;1997. p.796-800.
2. Koda-Kimble MA, Young LY (eds.). Applied Therapeutics 7th ed, Pennsylvania : Lippincott
Williams & Wilkins ; 2001. p. 76-32,33,34,35; 77-15,16 ; 78-7,7,8,9,10.
3. Maclean F. Sexual dysfunction and infertility. In : Lee A.(ed.). Adverse Drug Reactions.
London : Pharmaceutical Press; 2001. p.267-283.
4. Watt J. Endocrine disorders. In: Lee A (ed.). Adverse Drug Reactions. London: Pharmaceutial
Press; 2001. p.119-135.
5. Yeung VTF, Chan WB, Cockram CS. Endocrine disorders. In: Davies DM, Ferner RE, De
Glanville H (Eds.). Daviess Textbook of Adverse Drug Reactions 5th ed. London: Chapman
& Hall Medical ; 1998. p. 381-409.
159
growth hormone, sympathomimetic

amines
corticosteroids
the Expert Committee on the Diagnosis and Classification of
3
Diabetes Mellitus
1)
200
/
(polyuria)
(11.1
/
(polydipsia)
2)
8
126
(7.0
(fasting plasma glucose)

)
3)
2
oral glucose
tolerance test
200
(11.1
75
160
2
1) Impaired fasting glucose (IFG)
/
(6.1
/ )
2) Impaired glucose tolerance (IGT)
/
(7.8
/ )
)
OGTT
fasting glucose
126
/
2
200
/
2
insulin dependent, IDDM
dependent, NIDDM
Type 1
(7.0
(11.1
110
/ )
140
/
1 (Type1)
2 (Type2)
non insulin
2
type 2
-cell
(gestational diabetes mellitus)
1)
adipose tissue
(free
fatty acid)
(ketone bodies)
(amino acids)
-cell membrane
(insulin resistance)
post receptor
insulin signalling pathways

161
(hyperglycemia)
2) Counter regulatory hormones
(glucagon)
(cortisol)
(adrenaline)
growth hormone (GH)
GH
type 1
GH
(glycogenolysis)
-adrenergic
(hepatic gluconeogenesis)
catecholamines (noradrenaline
adrenaline)
glycogen synthase
lipolysis)
catecholamines
2
cell
catecholamines
noradrenaline
(stress)
(lipogenesis)
adrenal medulla
GH
GH
insulin-like growth factor 1 (IGF-1)

GH
GH
dawn phenomenon
162
1. Hormones
1.1 Corticosteroids
case control
11,855
relative risk
2.2
odd ratio
1- 39,40-79,80-119
1.77,3.0,5.82,
10.34
120
1.2 Sex steroids
insulin,
12
(16%
8%)
2-hour post glucose load
type 2
fasting serum
progestogens
norgestrel
norethidrone
luteal phase
glycogen synthase
type 2
type 1
gestational diabetes
163
estrogen
progesterone
1.3 Growth hormone (GH)

GH
GH
carpal tunnel syndrome
2. Sympathomimetics
2.1
adrenergic agonists
sympathomimetics
betamethasone
salbutamol
(intravenous infusion)
glycerol
salbutamol
salbutamol
2.2 Theophylline
phosphodiesterase
sympathomimetic
cyclic AMP
theophylline
theophylline
metabolic acidosis
adrenergic
adrenaline
164
3. Cardiovascular drugs
-blockers
thiazide diuretics
(relative risk)
1.56 1.77
thiazides
3.1
6
1.4
-blockers
(Diuretics)
30%
indapamide
3.2
5
thiazide diuretics
relative risk
3%
24
hyperglycemic hyperosmolar nonketotic coma
indapamide, chlorthalidone, bumetanide furosemide
-Adrenergic blockers
in vitro
in vivo
type 2
glucose intolerance
3.3 Calcium channel blockers
165
nicardipine,
nifedipine
3.4
verapamil
diazoxide
clonidine
metoprolol
3.5 Antiarrhythmic agents
amiodarone
10
10
encainide
4. Psychotropic drugs
chlordiazepoxide, phenothiazines, clozapine

intraventricular
naloxone
opiate antagonist
adrenaline
lithium
nephrogenic diabetes insipidus
mianserin
prolaction
GH
lithium
(renal tubules)
5. Immunosuppressive and immunomodulating agents

11%
cyclosporin
glucose intolerance
corticosteroids
cyclosporin
45
HLA
166
6. Antimicrobials
Pentamidine
pentamidine isethionate
pentamidine mesylate
Didanosine
(pancreatitis)
7.
thiopental, phenytoin, niacin,
glycerol, isoniazid, nalidixic acid, rifampicin,
praziquantel
7.1
7.1
Drug/Class Name
Clinical
Significance
Comments
Asparaginase
++
2-Agonists
++
++
Generally resolves during or after asparaginase therapy is compleated.

Concomitant corticosteroids may increase the incidence and severity of
glucose intolerance.
Can induce maternal hyperglycemia when used as a tocolytic.
Alternative antihypertensive therapy perferred,unless the benefits
outweigh the risks (i.e., prevention of second myocardial infarction).
Cardioselective -blockers may cause fewer adverse effects than
nonselective agents.
Few case reports.
Do not appear to cause clinically significant long-term adverse effects on
carbohydrate metabolism.
One known case report.
Few case reports.
Glucose intolerance can occur within hours to days or after months of
chronic therapy. The adverse effect generally is considered dose
dependent and reversible upon discontinuation; the reversal may take
several months.
May cause hyperglycemia and require insulin therapy during long-term
therapy, whether or not concomitant corticosteroids are part of the
immunosuppressant regimen.
Calcitonin
Calcium antagonists
+
+
Carbamazepine
Cimetidine
Corticosteroids
+
+
+++
Cyclosporin
++
Didanosine
Hyperglycemia without pancreatitis possible.
167
7.1
( )
Drug/Class Name
Clinical
Significance
Comments
Diuretics
+++
Encainide
Imipramine
Isoniazid
Lithium
Megestrol acetate
Nicotinic acid
Oral contraceptives
Pentamidine
+
+
+
+
+
++
++
+++
All classes of diuretics, and in particular thiazides,have been reported to

cause diabetes mellitus or worsen glucose control in people with
diabetes; some may tolerate low doses (<25 mg hydrochlorothiazide
equivalent).
Two known reports in the biomedical literature.
Few case reports.
Few case reports.
Conflicting data in the biomedical literature
Few case reports.
Alternative agents for hyperlipidemia preferred for people with diabetes.
Appears to occur less frequently with an estrogen dose <50 ug.
Diabetes mellitus may occur days after initiation of therapy, but more
often is delayed by several weeks or even month. Initially,pentamidine
may cause hypoglycemia.
Many case reports,most involving chlorpromazine.Controlled studies
lacking.
Predisposed individuals (family history,underlying insulin resistance,
high doses) may develop hyperglycemia.Overall incidence very small.
One known case report.
Many cases of new-onset diabetes or worsening diabetes reported. Some
cases required hospitalization and were irreversible.Related to
lipodystrophy and insulin resistance.
Few case reports.
Clinically significant hyperglycemia infrequent,especially at usual doses.
May cause hyperglycemia and require insulin therapy during long-term
therapy, whether or not concomitant corticosteroids are part of the
immunosuppressant regimen.
Adverse effect at excessive doses.
Phenothiazines
Phenytoin
++
Pravastatin
Protease inhibitors
+
+++
Rifampicin
Sympathomimetics
Tacrolimus
+
++
++
Thyroid hormones
+
++
+++
Clinical significant possible. Limited or conflicting reports or studies.

Clinical significant. Primarily important under certain conditions.
Clinical significant effect of substantial prevalence and/or magnitude
50
40
20
/
autonomic
autoromic
/
50
autonomic
neuroglycopenic
neuroglycopenia
ataxia
neuroglycopenic
(hypoglycemic unawareness)
168
catecholamines
glycogenesis, glycogenolysis
glycolysis
gluconeogenesis
gluconeogenesis
1. Hypoglycemic drugs
microangiopathic
type 1
3-6
1.1 Insulin
10%
type 1
3%
1.8
the Diabetes Control and Complications Trial (DCCT)
19
62
100
169
1.6
5
type 2
type 1
type
(asymptomatic hypoglycemia)
50%
DCTT
, 36%
type 1
hypoadrenalism
hypopituitaism
DCTT
glycosylated
hemoglobin (HbA1c)
HBA1c
refractory hypoglycemia
C-peptide
1.2 Sulfonylureas
-cells
1.9-2.5
9-62
type 2
100
4-7%
glibenclamide
chlorpropamide
glipizide 2
chlorpropamide
glibenclamide
chlorpropamide
100
170
glibenclamide
III
glipizide
46
gliclazide
5.8, 16
glipizide
glipizide
1000
chlorpropamide, glibenclamide
glibenclamide
active metabolite
islets
9.1
7.2
hypoglycemia)
(iatrogenic
type 2
(pharmacokinetics)
(pharmacodynamics)
-cell
7.3)
7.2
Past history of hypoglycemia
Defect counter-regulation especially in Type I diabetic patients with long duration of disease
Hypoglycemic unawareness
Intensive insulin therapy
Overzealous glycemic control
Errors of dosage and timing
Old age
Missed meals
Exercise
Co-existing diseases-e.g. renal or liver disease
Recent weight loss
Drug interactions e.g. alcohol, -blocking agents,other antihyperglycemic agents
Increased insulin sensitivity-e.g. hypoadrenalism and hypopituitarism,post-partum state
Change of insulin perparation
Psychological problems-deliberate overdosage,manipulative behavior
171
7.3
Drug
Comment
Pharmacokinetic Drug Interactions with sulfonylureas
Drugs Increasing Sulfonylurea Effect
Antiacids
Enhanced glibenclamide absorption due to increased gastric pH. Avoid concomitant
administration.
Chloramphenicol Possible prolongation of chlorpropamide t1/2.
Clofibrate
May displace sulfonylureas form proteins, insulin resistance, renal tubular secretion of
chlorpropamide.
Doxepin
Mechanism unknown. Monitor of hypoglycemia
Fluconazole
Increased plasma concentrations. Watch for hypoglycemia.
Gemfibrozil
Possibly due to protein displacement. May need to reduce dose of sulfonylurea.
Heparin
Heparin may have significantly prolonged glipizide hypoglycemia in one unconvincing
case report. Confimation needed.
Nonsteroidal anti- - Severe fatal hypoglycemia can occur. Ibuprofen, sulindac, do not affect sulfonylurea
inflammatory
disposition.
Salicylates
Limited and indirect documentation (primarily in vitro) that salicylates may sulfonylurea
activity through protein-binding displacement or inhibition of active renal tubular secretion
Sulfonamide
Severe hypoglycemia with glibenclamide and chlopropamide reporter rarely. Sulfisoxazole
antimicrobials
also also rarely associated with chlorpropamide-induced severe hypoglycemia
Warfarin
No evidence that warfarin affects sulfonylurea disposition. Sulfonylureas do not appear to
alter patient response to the anticoagulants. Warfarin response should be monitored if
glibenclamide initiated, discontinued, or changed in dosage.
Drugs Decreasing Sulfonylurea Effect
Rifampicin
Glibenclamide metabolism, thereby T1/2 and plasma drug concentrations.
Other Drugs
Cyclosporin
May compete with glipizide for cytochrome P450 hydroxylation. Necessitated a 20-30%
dosage reduction of cyclosporin in two case reports.
Phenytion
Unknown effects on sulfonylurea.
1.3
(euglycemia)
metformin
gluconeogenesis
-
Glucosidase inhibitors
2. Alcohol
gluconeogenesis
172
(ACTH)
hypothalamic pituitary adrenal axis
type 1
type 2
triacylglycerol
refractory hypoglycemia
474
3. Aspirin
Paracetamol
indomethacin
piroxicam
prostaglandin E2
C-peptide
4. Cardiac drugs
173
4.1
Adrenergic blockers
catecholamines
(propranolol)
cross-over
selective (atenolol)
non-selective
1
atenolol
metoprolol
3
propranolol
type 1
blocker
4.2 Angiotensin converting enzyme inhibitors
captopril
7
timolol
type 1
1
ACE inhibitors
captoril
captopril
enalapril
ACE inhibitors
odds ratio
2.8
4.1
ACE inhibitors
angiotensin II
angiotensin II
ACE inhibitors
bradykinin
renin angiotensin
ACE inhibitors
angiotensin II
adrenaline
catecholamines
type 2
captopril
4.3 Antiarrhythmic drugs
Disopyramide
quinidine
sympathoadre-
nal
adrenal medulla
catecholamine
antiarrhythmic Class Ia
quinidine
174
quinine
14
4.4 Sympathomimetic drugs

ritodrine
linemic hypoglycemia
hyperinsu-adrenergic
salbutamol
5. Hormones
Octreotide
peptide
long-acting analogue
somatostatin
Coctreotide
GH
acromegaly
GH
GH
insulinoma,
acromegaly
metastaic carcinoid tumors

octreotide
polypeptide
somatostatin
6. Antimalarials
Plasmodium falciparum
hyperinsulinemic hypoglycemia
mefloquine
quinine
quinine, quinidine
cells
quinine
GH,
catecholamines
175
quinine
long acting somatostatin analogue

dextrose
quinine
octreotide
chloroquine
7. Pentamidine
leishmaniasis, trypanosomiasis
hemorrhagic pancreatitis
Pneumocystis carinii pneumonia
islet cells
50%
islet cell antibodies, insulin antibodies

acquired immune deficiency syndrome (AIDS)
hypoxia
pentamidine
8. Trimethoprim/sulfamethoxazole (co-trimoxazole)
co-trimoxazole
Preumocystis carinii
AIDS
C-peptide
-cells
9. Lithium and psychotropic drugs

adenyl cyclase
cyclic AMP
adrenaline,
176
adrenocorticotrophic hormone
Phenothiazines
thioxanthene derivatives
orphenadrine
bromperidol
imipramine
selective serotonin reuptake inhibitors
7.4
7.4
Drug/ Class Name
Anabolic steroids
Angiotensin-converting
enzyme (ACE) inhibitors
Clinical
Significance
+
+
++
2-Agonists
++
Disopyramide
++
Ethanol
+++
Insulin
+++
Pentamidine
+++
Quinine/Quinidine
++
Salicylates
++
Sulfonamides
Sulfonylureas
+
+++
+
++
+++
Comments
Complex metabolic effects. Only certain steroids studied.
May increase peripheral sensitivity to insulin effects. Two case
reports and one case-control study.
-blockers may prolong and mask the symptoms of
hypoglycemia. Cardioselective -blockers may cause less
adverse effects than nonselective agents.
Can induce hypoglycemia in the infants of mothers who
received these agents.
Elderly patients with liver and/or renal impairment appear to be
the most susceptible to this serious adverse effect.
Most often occurs in individuals chronically drinking large
amounts of ethanol. The adverse effect can follow binge
drinking and even moderate alcohol intake in fasting
individuals. Symptoms of hypoglycemia may be mistaken for
intoxication.
Injectable solution or suspension used therapeutically to
decrease glucose levels in people with diabetes.
Usually occurs several days to 2 weeks following initiation of
therapy. It can be sudden, recurrent, and life-threatening.
Pentamidine also may cause hyperglycemia.
Quinine 600-800 mg Q 8 hours for malaria may induce
hypoglycemia in 10% of patients. Doses of 300 mg for leg
cramps produce hypoglycemia infrequently.
Occurs with salicylate intoxication or anti-inflammatory doses
(4-6 g/day in adults). Low doses unlikely to cause this adverse
effect.
Rare reaction with renal failure and/or high doses.
Oral hypoglycemic agents used therapeutically to decrease
glucose levels in people with type 2 diabetes.
Clinical significant possible. Limited or conflicting reports or studies.

Clinical significant. Primarily important under certain conditions.
Clinical significant effect of substantial prevalence and/or magnitude
177
(iatrogenic hypoglycemia)
iatrogenic hypoglycemia
7.2)
20
10
dextrose 50%
2
50
2
25
1
2
1-2
type 1
-glucosidase inhibitors
/
metformin
178
blockers,sympathomimetics,corticosteroids
sex
hormones
1. So WY, Chan JCN, Cockram CS. Disorders of metabolism1. In: Davies DM,Ferner RE, De
Glanville H(eds). Textbook of Adverse Drug Reactions. 5th ed.London Chapman & Hall
Medical; 1998. p.410-441.
2. Koda Kimble MA, Carlisle BA. Diabetes Mellitus. In: Koda Kimble Ma,Young LY(eds).
Applied Therapeutics The Clinical Use of Drugs. 7thed. Pensylvania: Lippincott Williams &
Wilkins; 2001. p.48-1-48-92.
3. Techobroutsky G. Abnormal blood glucose values. In: Benichou C(ed). Adverse Drug
Reactions A Practical Guide to Diagnosis and Management. Chichester: John Wiley &
Sons;1994:p.91-103.
4. American Diabetes Association : Clinical Practice Recommendations 2001. Report of the
Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Available at:
http://www.diabetes.org/clinicalrecommendations/Supplement 101/S5.htm. Accessed April
6, 2001.
2
apoproteins
lipoproteins
lipoproteins
apoproteins
II,apo B, apo C
apo A
apo C-I, apo C-II,apo C-III
apo A-I
apo E
apo Aapoproteins
179
apoproteins
lipoproteins
Chylomicrons
apoprotein
very-lowdensity lipoproteins (VLDL)
chylomicrons
apoproteins
apo B
VLDL
intermediate-density lipoprotein (IDL)
low-density lipoprotein (LDL)
apo B
high-density lipoprotein (HDL)
apo A
apoprotein
HDL
(reverse
transport)
apo E
VLDL
chylomicrons
remnants
4
lecithin cholesterol acyltransferase
(LCAT)
apo A-I
cholesterol ester
lipoprotein lipase
chylomicrons
VLDL
glycerol
fatty acid
apo C-II
hepatic lipase
VLDL remnants
mobilizing
lipase
free fatty acids
adenyl cyclase
catecholamines, growth hormone glucocorticoids
lipoproteins
2
nascent chylomicrons
chylomicrons
lipoprotein lipase
lipoprotein
glycerol
fatty acids
triglycerides
phospholipids
cholesteryl ester)
cholesteryl ester
7.1)
surface material (apoprotein C,

HDL
remnant chylomicron
180
lipoprotein cholesterol
2
apo B-100 lipoprotein
(VLDL-C,IDL-C,
LDL-C)
apo A-I lipoprotein (HDL-C)
apo B-100 lipoprotein
apo B-100
VLDL
( 7.2)
VLDL
lipoprotein lipase
IDL
cholestery ester-rich remnants IDL
chylomicron remnants
LDL
LDL
lipoprotein
surface apoproteins
apo B-100
7.1
. FFA = free fatty acids;

HDL = high - density lipoproteins; PL=phospholipase; TG=triglycerides.
7.2
VLDL,
LDL. HTGL = Hepatic triglyceride lipase.

181
apo- A-I lipoprotein HDL

apo A-I
( 7.3)
HDL3
phospholipid apoprotein complexes
cholesteryl ester
HDL HDL3
HDL3
HDL2
2
apo B lipoproteins
HDL2
transfer protein
apoproteins
7.3
high-density lipoprotein
cholesteryl ester
HDL2
high density lipoproteins
(reverse transport). CETP = cholesteryl ester transfer protein; LCAT =

lecithin: cholesterol acyltransferase.
(Hyperlipidemia)
hyperlipoproteinemia
lipoproteins
2
2
7.5
7.6
Fredrickson (
7.5)
5
7.6
defective apolipoprotein B
familial
182
7.5 Fredrickson Classification of Lipid Disorders*

Appearance
of overnight
serum
Elevated
particles
Associated
clinical disorders
Creamy top layer
Chylomicrons
Iia
Clear
LDL
Iib
III
IV
Clear
Turbid
Turbid
IDL,VLDL
IDL
VLDL
Creamy top,
turbid bottom
Chylomicrons,
VLDL
Lipoprotein lipase deficiency,

apolipoprotein C-II deficiency
Familial hypercholesterolemia,
polygenic hypercholesterolemia,
nephrosis, hypothyroidism,
familial combined hyperlipidemia
Familial combined hyperlipidemia
Dysbetalipoproteinemia
Familial hypertriglyceridemia,
familial combined hyperlipidemia,
sporadic hypertriglyceridemia,
diabetes
Diabetes
Type
Serum
TC
Serum
TG
*IDL= intermediate - density lipoproteins ; LDL = low - density lipoproteins ; TC = total cholesterol ; TG = triglycerides ; VLDL
= very low - density lipoproteins ; = increased; = greatly increased ; = normal ;
= normal or increased.
7.6 Features of Major Genetic Lipoprotein Disorders*
Disorder
Principal plasma
abnormality
(corresponding
Fredrickson
classification)
Heterozygous familial
Hypercholesterolemia
LDL only (inherited

abnormality of the LDL
receptor)[IIa]
Familial defective
apolipoprotein B
LDL (inherited
abnormality of
apoprotein B interferes
with binding to LDL
receptor)[IIa]
1/3 : LDL only [IIa]
1/3 : VLDL only [IV]
1/3 : LDL and VLDL
[IIb]
Apo-B overproduction is
common
Familial combined
hyperlipidemia
Polygenic
LDL [IIa]
Clinical features
Estimated
Frequency
Tendinous xanthomas
Corneal arcus
Premature CAD
Family history of
hypercholesterolemia
Same clinical features as
heterozygous familial
hypercholestrerolemia
0.2% of general
population
5% of MI survivors
< 60 yr old
Autosomal dominant
Same frequency as
heterozygous familial
hypercholesterolemia
Usually>30yr old
Often overweight
Usually no xanthomas
Premature CAD
Different generations have
different lipoprotein
abnormalities
Premature CAD
No xanthomas
No family history of
0.5% of general
population
15% of MI survivors
< 60 yr old
Autosomal dominant
Unknown
183
7.6 Features of Major Genetic Lipoprotein Disorders*

Principal plasma
abnormality
(corresponding
Fredrickson
classification)
Disorder
Familial
hypertriglyceridemia
(200-1,0000
/
Severe
hypertriglyceridemia
(>1,000
/
)
Familial
hypoalphalipoproteinemia
VLDL only (high VLDL

production, decreased
lipoprotein lipase
Activity)[IV]
Chylomicrons and
VLDL
(high VLDL production,
decreased lipoprotein
lipase activity)[V]
HDL(<30
in males;<35
Clinical features
Often overweight
>30 yr old
Often diabetic
Hyperuricemic
May or may not have
Peremature CAD
Determined by family
history and HDL-C
Usually middle-aged
Often obese
Often hyperuricemic
Usually diabetic
Risk for recurrent
Pancreatitis
Premature CAD
1% of general population
5% of MI survivors
<60 yr old
Autosomal dominant
Yellow palmar creases

Palmar xanthomas
Tuberoeruptive xanthomas
Premature CAD
Uncommon
3% of MI survivors
Autosomal recessive
in females)
Dysbetalipoproteinemia
(TC:250-500
/
,
TG:250-600
(decreased apo
A-I production)
IDL, chylomicron
remnants
(defective apo E2/2)[III]
Estimated
Frequency
Unknown
1% of general population
25-30% of patients with
premature CAD
Autosomal dominant
*CAD = coronary artery disease; HDL-C = high-density lipoprotein cholesterol; IDL = intermediate density
lipoproteins; LDL = low-density lipoproteins; MI = mycardial intarction; TC = total cholesterol; TG =
triglycerides; VLDL = very-low-density lipoproteins.
nephrotic syndrome
apolipoproteins
184
1.
7.7
1.1
(Diuretics)
Thiazides
cholesterol,
total
, LDL-C
VLDL-C
50-100
/
thiazide diuretics
indapamide
lipoprotein fractions
thiazide
loop diuretics
potassium-sparing diuretics
HDL-C
apoprotein A-I
thiazides
non-cardioselective -blockers
propranolol
HDL-C
cardioselective -blockers
sympathomimetic activity (ISA) pindolol
acebutolol
A-II
1.2
atenolol
intrinsic
labetalol
propranolol
HDL2 subfraction
metoprolol
-adrenergic
1.3 Other antihypertensives

-adrenergic blockers
LDL-C
blockers
clonidine
atenolol
lipoprotein lipase
HDL-C
methyldopa
calcium channel
185
HDL-C
total cholesterol
converting enzyme inhibitors
cilazapril
angiotesin
7.7
Drug class
Cardiovascular drugs
Diuretics
Thiazide diuretics
Loop diuretics
Potassium-sparing
diuretics
Indapamide
-Blockers
ACE inhibitors
Calcium antagonists
-Blockers
Total cholesterol
LDL-cholesterol
HDL-cholesterol
Triglycerides
5 to 10
5 to 10
NC
5 to 10
5 to 10
NC
NC
NC
NC
5 to 15
5 to 10
NC
NC
NC
NC
NC
5
NC
NC
NC
NC
5
NC
5 to 20
NC
NC
2 to 5
NC
10 to 40
(?)
NC
4 to 14
HDL = high density lipoprotein; LDL= low density lipoprotein; NA=not available; NC = no change.
2. Corticosteroids
VLDL-C
LDL-C
HDL-C
VLDL-C
HDL-C
HDL-C
systemic lupus erythematosus

VLDL
HDL
lipoprotein lipase
VLDL-C
LDL
methylprednisolone
186
3. Immunosuppressants
cyclosporin, azathioprine
total cholesterol, LDL-C, HDL-C
cyclosporin
azathioprine
total cholesterol
LDL
HDL
cyclosporin
tacrolimus
cyclosporin
mycophenolate mofetil
4. Hormones
4.1 Oral contraceptives
The Framingham Study
40
HDL-C
total
LDL-C
HDL2 C subfraction
estrogen
VLDL-C
HDL2 subfractions
progesterone
HDL C
progesterone
progesterone
estrogen
subfraction HDL-C
HDL3-C
(coronary artery disease)
estrogen
lipoprotein lipase
HDL-C
hepatic triglyceride lipase
familial hyperlipidemia
estrogen
187
4.1 Danazol
endometriosis
LDL-C 10-40%
HDL-C
50%
8
4.2 Growth hormone
growth hormone
recombinant human growth hormone (somatropin)
total cholesterol, LDL-C
5. Isotretinoin
Isotretinoin
total cholesterol
LDL-C
15 %
35-144%
6. Tamoxifen
Tamoxifen
C
tamoxifen
non-steroidal estrogen antagonist

VLDL
orosomucoid
haptoglobin
lipoprotein
total cholesterol
LDLestrogen
7. Protease Inhibitors
HIV
protease inhibitors
total cholesterol 30-40%
lipodystrophy syndrome
ritonavir
200-
188
300%
32
tatal cholesterol
ritonavir
LDL-C 15-30%
indinavir
nelfinavir
0-55%
8. Antipsychotic drugs
clozapine
haloperidol
51%
clozapine
9. Alcohol
HDL-C
alcoholic liver disease
LDL-C
VLDL
VLDL
lipoprotein lipase
VLDL
VLDL
hyperchylomicronemia
10. Antiepileptics
carbamazepine
HDL-C 0-30%
phenytoin
HDL-C
hepatic microsomal CYP
total
cholesterol 0-15%
phenobarbital

valproic acid
valproic acid
total cholesterol
189
1. Mantel-Teeuwisse AK, Kloosterman JME, Maitland-van der Zee AH, Klungel OH, Porsius AJ,
De Boer A. Drug-Induced Lipid Changes a Review of the Unintended effects of Some
Commonly Used Drugs on Serum Lipid Levels. Drug Safety. 2001, 24(6): 443-456.
2. So WY, Chan JCN, Cockram CS. Disorders of Metabolism 1. In: Davies DM, Fener RE, De
Glanville H (eds). Textbook of Adverse Drug Reactions. 5 th ed London: Chapman & Hall
Medical; 1998. p 410-441.
3. The American Association of Clinical Endocrinologists Medical Guidelines for Clinical
Practice for the Diagnosis and Treatment of Dyslipidemia and Prevention of Atherogenesis.
Endocrine Practice. 2000;6 (2) : 162-213.
4. Witztum JL, Steinberg D. The Hyperlipoproteinemias. In: Bennett JC, Plum F (eds.) Cecil
Textbook of Medicine.20thed. Philadelphia: W.B. Saunders & Company; 1996. p.1086-1095.
5. Young KL, Allen JK,Kelly KM. HDL Cholesterol: Striving for Healthier Levels. Available at
:http://www.medscape.com/CPG/ClinReviews/2001/vll.n05/c1105.02.youn/c1105.02.01.
html. Accessed May 7,2001.
190
aplastic anemia, agranulocytosis, neutropenia, hemolytic anemia,

thrombocytopenia,
8.1
(%)
(
Aplastic anemia
Agranulocytosis
Hemolytic anemia
Thrombocytopenia
1.
/ )
0.5
3.1
1.6
2.7
46-50
9-32
4
3
(Hematopoiesis)
191
(stem cells)
(
1)
2)
8.1)
stem cells
stem cells
intermediate precursor cells
forming units (BFU) progenitor cells colony- forming units (CFU)
burst-
3)
glycoproteins
intermediate cells
stemcell factor (SCF), erythropoietin (EPO), granulocyte-macrophage cdony-stimulating
factor (GM-CSF), granulocyte-colony-stimulating factor (G-CSF), thrombopoietin
(TPO), ( 8.2)
8.1
(erythrocytes)
stem cells
erythropoietic growth factors
erythropoietin
(leukocytes)
5
2
stem cells
192
polymorphonuclear
granulocyte
granular
leukocytes
granules
cytoplasm
neutrophils 62%, eosinophils 23%
basophils 0-1%
granule
nongranular leukocytes
monocytes 5%
lymphocytes 30%
macrophages (histiocytes)
monocytes plasma
cells
B lymphocytes mast cells
basophils
8.2
CFU: colony forming unit; GEMM: granulocyte, erythroid, monocyte, megakaryocyte; BFU-E burst
forming unit-erythroid unit; CFU-E: colony forming unit-erythroid, Meg:megakaryocyte; Eos:
eosinophil; G: granulocyte; Mono: monocyte; Baso : basophil
(thrombocytes)
stem cells
megkaryocytes
megakaryocytes
cytoplasm
193
8.2
(
Neutrophils
Monocytes
Eosinophils
Basophils
Lymphocytes
. )
5.21 x 106
4.6 x 106
2.0 x 109
100-120
4500
(2600-7000)
300
150
40
2500
(1500-4000)
2.5 x 105
(1.5 4.0 x 105)
1.6 x 109
6-12
1.7 x 108
3
8-12
2.8 x 109
10
8.3
- Neutrophil
macrophage
- Eosinophil
- Basophil
(parasite)
histamine
(hypersensitivity reactions)
-Lymphocyte
194
2.
Anemia :
(
(Definition)
)
10%
MCV (Mean Corpuscular Volume)
Hemolytic anemia:
reticulocytosis
haptoglobin , hyperbilirubinemia
(indirect) bilirubin
serum LDH
unconjugated
serum iron
Aplastic anemia :
Pancytopenia :
(
)
Bicytopenia :
Leukopenia :
(
)
Neutropenia :
neutropenia
thrombocytopenia
anemia
)
2
3,000/
polymorphonuclear neutrophils (PMN)

1,500/ . (1.5x 109/ )
PMN
500/ . (0.5 x 109/
severe neutropenia
Severe neutropenia :
Agranulocytosis :
granulocytes (neutrophils, eosinophils
Granulocytopenia :
<1,500/
basophils)
.
100,000/
Thrombocytopenia :
(
)
Eosinophilia :
band form
eosinophils
450/
. (0.45 x 109/
eosinophils
> 5%
195
8.4
Test
2-6
6-12
11.5-15.5
11.5-15.5
Hematocrit (%)
34-40
35-45
MCV (fL)
75-87
77-95
MCHC (%)
MCH (pg/cell)
RBC (million/mm3)
Hemoglobin (g/dL)
18-49
M 13.5-17.5
F 12.0-16.0
M 41-53
F 36-46
80-100
31-37
M 13.0-16.0
F 12.0-16.0
M 37-49
F 36-46
M 78-98
F 78-102
31-37
24-30
25-33
25-35
26-34
3.9-5.3
4.0-5.2
M 4.5-5.3
M 4.5-5.9
Reticulocyte count, absolute (%)
8.3
( )
12-18
31-37
0.5-1.5
stem cells
3. Drug-induced aplastic anemia

aplastic amemia
25-50%
aplastia
196
50%
aplastic anemia
< 3,500/ .
< 55,000/ .
.
reticulocytes < 30,000/ .
severe aplastic anemia
2 3
:
neutrophils < 500/ .
< 20,000/ .
corrected reticulocyte index < 1%
(3-12
/
)
serum iron, transferin saturation, erythropoietin
ESR
marrow hypoplasia
fatty replacement
cell line
2
3
< 10.0 /
(intermittent claudication)
myelofibrosis
druginduced aplastic anemia
45
6.5
0.5-5
(> 4
<120 )
pluripotential hematopoietic stem cells (PHSCs)

committed stem cells
neutrophils
197
8.5 Chronological criteria : Aplastic anemia

Time to onset from the start of the
drug administration
- Initial treatment
- Subsequent treatment
Compatible
Inconclusive
Incompatible
> 4 days
Reaction occurred
before the 4th day of
treatment
> 120 days
all time intervals
Time to onset from the end of the drug

administration
< 120 days
Course of the reaction

- Without stopping the drug
- after stopping the drug
no change or
aggrevation
Spontaneous
recovery within 6
months : neutrophils
> 1500 and platelets
> 100,000
improvement in
pancytopenia or
bicytopenia
no change or
aggrevation or
improvement
with supportive
therapy
2
3.1. Dose-dependent (Type A) aplastic anemia
agents
synthesis
DNA replication (
mitotic mechanisms)
aplastic anemia
cell line
cytotoxic chemotherapeutic
RNA transcription, protein
aplastic anemia
chloramphenicol
>25
2-3
- Chloramphenicol
aplastic anemia
mitochondria
erythroid cell line
reticulocytes
hematocrit
reversible
/
- Ticlopidine
198
8.6 Cytotoxic agents that induce bone marrow aplasia

Actinomycin D
Azathioprine
Busulphan
Carboplatin
Carmustine (BCNU)
Chlorambucil
Cisplatin
Cyclophosphamide/ifosfamide
Cytarabine (cytosine arabinoside)

Doxorubicin (Adriamycin)
Epirubicin
Etoposide
Fludarabine
Fluorouracil
Hydroxyurea
Idarubicin
3.2 Dose independent (Type B) aplastic anemia

3.2.1 Idiosyncratic :
stem cells
Ifosfamide
Melphalan
Mercaptopurine
Methotrexate
Mitomycin
Mitozantrone
Taxols
Thioguanine
1)
1-6
2)
3)
(irreversible)
Idiosyncratic drug-induced aplastic anemia
(metabolism)
- Chloramphenicol
idiosyncratic reaction
nitrobenzene ring
nitroso
group
DNA stem cells
stem cells
stem cells
enterbocteria
dehydrometabolites 2
lymphocytes
- Phenytoin
carbamazepine
phenytoin
carbamazepine
macromolecules
stem cells
lymphocytes
- Phenylbutazone
aplastic anemia
stem cells
3.2.2 Drug or metabolite-induced immune reactions
antibodies
cytokines
immune system
stem
cells
stem cells
aplastic anemia
chloroquine
chloroquine
antibodies
199
8.7 Drugs associated with aplastic anemia

Antimicrobials
Anticonvulsants
Antidiabetics
Antihypertensives
Anti-inflammatory agents
Antimalarials
Antiplatelet agents
Antithyroid drugs
Diuretics
Tranquilizers
Vasodilators
Quinidine
Chloramphenicol, co-trimoxazole, dapsone, sulfonamides,
tetracyclines
Carbamazepine, lamotrigine, phenobarbital. phenytoin
Sulfonylureas (e.g. chlorpropamide)
Captopril, lisinopril
Aspirin, diclofenac, fenbufen, gold salts, indomethacin,
penicillamine, phenylbutazone, piroxicam, sulindac, sulfasalazine
Chloroquine, pyrimethamine
Ticlopidine
Methimazole, propylthiouracil
Acetazolamide, chlorothiazide, furosemide
Phenothiazines (e.g chlorpromazine)
Pentoxyfylline
1.
2.
3.
bleeding
aplastic anemia
45
immunosuppressive agents
Immunosuppressive agents
antithymocyte globulin (ATG),
antilymphocyte globulin (ALG), corticosteroids, cyclosporin
androgens
androgens
-
hematopoietic growth factors

neutrophils
erythropoietin
GM-CSF,G-CSF
CSFs
first-line treatment
severe aplastic anemia
200
4. Drug-induced neutropenia and agranulocytosis

Neutropenia
neutrophils
neutrophils
500/ .
1,500/
severe neutropenia
severe neutropenia
HIV
Viral infections
- HIV, Epstein-Barr virus, cytomegalovirus, rubella,

varicella
- Typhoid fever, brucellosis
- SLE, collagen diseases, rheumatoid arthritis
- Hair-cell leukemia, suppressor T-cell leukemia,
Bacterial infections
Systemic diseases
Blood disorders
myelodysplastic syndrome
Autoimmune neutropenia
Toxic agents
- Benzenes, ionizing radiations
drug-induced neutropenia
neutropenia
:
- hypocellular
regenerating granulocytic series
- precursor cells
infiltration hematopoietic
extrahematopoietic cells
neutropenia
2-6
Agranulocytosis
neutrophils
500/ .
(buccopharyngeal)
(perineal)
viral infection, lymphomas leukemia
201
agranulocytosis
16%
(bacteremia)
7-15
8.8
Chronological criteria : Neutropenia
Time to onset of the

reaction
- Initial treatment
- subsequent
treatment with or
without previous
history in the
relation to the same
drug
Course of the
reaction
- Without stopping
the drug
- After stopping
the drug
Suggestive
Compatible
Any time from

start of drug
administration
< 7 days from

start of drug
administration
> 7 days from

sart of drugs
administration
Neutrophils >
1500 within 30
days
Inconclusive
Incompatible
Occurrence within
30 days or
discovery after 30
days from end of
drug
administration
Drug taken after

onset of reaction
or occurrence
after 30 days from
end of drug
administration
Return of the
neutrophil count
to normal range
Continuing
decrease in
neutrophil
count
Neutrophils <
1500 after 30 days
Drug- induced agranulocytosis

4.1 Drug-induced immune agranulocytosis (Type I)
2
severe
neutropenia
2-3
4
1)
(adsorption)
(membrane)
neutrophils
drug-membrane complex
hapten
antibodies
antibodies
drug-membrane complex
complement activation
phagocytic system (
8.4)
202
penicillins
150
/
neutropenia
penicillins
8.4 The dug adsorption mechanism

2)
neutrophil
drug-specific antibody
complex
quinidine
8.5)
8.5 The innocent bystander mechanism

3)
plasma protein
neutrophils
antibodies antibodies
drug protein carrier-membrane complex
phagocytic system ( 8.6)
+
Antibody
formation
+Complement
activation
Drug
Cell membrane
Plasma protein
Antibody
Cell
toxicity
8.6 The protein carrier mechanism

203
4)
autoantibodies (antibodies
system ( 8.7)
neutrophil
neutrophil
)
phagocytic
8.7 The nonspecific binding of protein mechanism

4.2 Type II reaction
agranulocytosis
- Antithyroid drugs
propythiouracil
methimazole
0.3-0.6%
> 40
2
agranulocytosis
methimazole
30
/
propythiouracil
agranulocytosis
- Ticlopidine
myeloid colony
neutropenia 2.4%
severe neutropenia 0.85%
3
2
3
- Phenothiazines
chlorpromazine
2-15
4-6
> 50
- Clozapine
agranulocytosis
antipsychotics
10
6
4
2
agranulocytosis
204
8.9
Drugs associated with neutropenia and agranulocytosis
Analgesics
Antiarrhythmics
Antimicrobials
Paracetamol, pentazocine
Disopyramide, procainamide, quinidine, tocainide
Cephalosporins, chloramphenicol, clindamycin, co-trimoxazole, dapsone,
gentamicin, imipenem-cilastin, isoniazid, lincomycin, metronidazole,
penicillins, rifampicin, sodium aminosalicylic acid, streptomycin,
sulfonamides, tetracyclines, vancomycin
Carbamazepine, phenytoin
Amitriptyline, clomipramine, imipramine, mianserin
Sulfonylureas
Griseofulvin
Brompheniramine, cimetidine, ranitidine
Captopril, hydralazine, methyldopa, propranolol
Allopurinol, colchicine, gold salts, leflunomide,
NSAIDs, penicillamine, sulfasalazine
Chloroquine, pyrimethamine, quinine, sulfadoxine
Levodopa
Ticlopidine
Methimazole, propylthiouracil
Ganciclovir, zidovudine
Acetazolamide, chlorthalidone, ethacrynic acid, furosemide,
hydrochlorothiazide
Benzodiazepines, clozapine, phenothiazines,
Anticonvulsants
Antidepressants
Antidiabetics
Antifungals
Antihistamines
Antihypertensives
Ant-inflammatory drugs/
antigout preparations
Antimalarials
Antiparkinson drugs
Antiplatelet agents
Antithyroid drugs
Antivirals
Diuretics
Tranquilizers
- Neutropenia
1.
2.
3.
4.
- Agranulocytosis
1.
2.
48
neutropenia
3.
-
cultures
specimens
intravenous broad-spectrum antibiotics

vancomycin fluoroquinolone
bactericidal agents
205
4.
GM-CSF, G-CSF
neutropenia
5. Drug-induced hemolytic anemia

Hemolytic anemia
120
hemolytic anemia
hemolytic anemia
< 12 /
reticulocytosis
heptoglobin
hyperbilirubinnemia
serum LDH
serum iron
< 13
MCV
unconjugated (indirect bilirubin)
hemolytic anemia
:
2-3
serum
(asthenia)
plasma creatinine
hemolytic anemia
5.1 Drug-induced immune hemolytic anemia
hemolytic anemia
agranulocytosis
drug-induced
206
1) Hapten-induced hemolysis
immune
response
happen
drug-red cell complex
antibodies
IgG
(adsorb)
immune response
7-10
hemolytic anemia
tetracyclines
melphalan, methotrexate, cyclophosphamide
methotrexate
streptomycin
penicillins, cephalosporins
quinidine, cisplatin,
immune hemolytic anemia

24
10 /
- Positive direct Coombs test
Immune hemolytic anemia
hemolytic anemia
8.10 Drug implicated immune hemolytic anemia

Beta lactam antibiotics
Chlorpropamide
Ibuprofen
Quinidine
Quinine
Rifampicin
2) Drug-induced autoantibody production

methyldopa, levodopa, cimetidine, diclofenac
autoantibodies
Sulindac
Tetracyclines
mefenamic acid
hapten
207
immune system (T-cell)

autoantibodies
Coombs test
3-6
hemolysis
4-6
3) Immune complex mechanism

immunoglobulin
drug-membrane binding site
complex
IgM
chlorpropamide, isoniazid, melphalan, methotrexate,
quinidine, rifampicin, sulfonamides, tetracyclines
thiazides
4) Non-immunological protein absorption
cephalosporins
nonspecific proteins
albumin, IgG, IgA
fibrinogen
positive direct antiglobulin
reaction (Coombs test)
cephalosporins
1.
2.
3.
2-3
intravenous immunoglobulins
5.2 Drug-induced oxidative hemolytic anemia

oxidative hemolytic amemia
dehydrogenase (G6PD)
bin reductase
glutathione (GSH) peroxidase
glucose-6-phosphate
NADPH methemoglo-
oxygen radicals
methemoglobin
208
reduced glutathione
peroxidase
glutathione reductase
G6PD
hexose monophosphate shunt (HMPS) HMPS
reduced nicotinamide adenine dinucleotide phosphate (NADPH) NADPH
oxidative stress
NADPH
glutathione
state glutathione
antioxidant
oxidation
methemoglobin
8.8
reduced
G6PD
oxidants
oxidative stress
NADPH
oxidize
glutathione
G6PD
activated oxygen
G6PD
reduction pathways
lipid peroxidation
G6PD gene
X-chromosome
sex-linked mode
G6PD
400 variants
A-type (African)
(10%-11%)
M-type (Mediteranian)
G6PD Mahidol
hemolysis
hemolysis
oxidative stress
hemolysis
209
8.11 Drug that cause hemolytic anemia in G6PD deficiency

Ascorbic acid
Benzocaine
Chloramphenicol
Chloroquine
Dapsone
Diazoxide
Doxorubicin
Furazolidone
Glibenclamide
Methylene blue
Nalidixic acid
Nitrofurantoin
1.
2.
3.
NSAIDs
Phenazopyridine
Primaquine
Sufonamides
hemolysis
G6PD
8.12 Drug associated with hemolytic anemia

Acetaminophen
-Interferon
-Lactam antibiotics
Chlorpromazine
Chlorpropamide
Cisplatin
Hydralazine
Hydrochlorothiazide
Imipenem-cilastin
Isoniazid
Levodopa
Mefenamic acid
Melphalan
Methyldopa
NSAIDs
Omeprazole
p-Aminosalicylic acid
Penicillamine
Phenazopyridine
Probenecid
Procainamide
Quinidine
Quinine
Rifampicin
Streptornycin
Sulfonamides
Tetracyclines
Triamterene
1. Drug-induced megaloblastic anemia

Megaloblastic anemia
DNA
erythroid precursor
megaloblastic cells
DNA
nucleus
RNA
cytoplasm
nucleus
cytoplasm nucleus
immature
cytoplasm (MCH)
mean
corpuscular hemoglobin (MCH)
mean corpuscular volume (MCV)
DNA
erythroid precursor
granulocytes
myelocyte
metamyelocyte
nucleus
210
megakaryocyte
unattached lobes
granulation
megaloblastic anemia
nucleus
MCH
MCV
megaloblastic
hemopoietic cells immature

anemia
leukopenia
thrombocytopenia
neuropathy
DNA
vitamin
purine
pyrimidine bases
B12,folate
2
DNA
vitamin B12 folate
DNA
DNA replication
purine antagonists
6-thioguanine, azathioprine, 6mercaptopurine
pyrimidine antagonists 5-fluorouracil, cytosine arabinoside
DNA
DNA
hyroxyurea,
zidovudine
acyclovir
folate antagonists
methotrexate, pentamidine, trimethoprim, triamterene,
pyrimethamine
dihydrofolate reductase
dihydrofolate
tetrahydrofolate
DNA
Nitrous oxide
vitamin B12
folate
vitamin B12
phenytoin, phenobarbital
chemotherapeutic agents
cotrimoxazole
1-4
folic acid
1
phenytoin
phenobarbital
folinic acid 5-10
folic acid
211
8.13 Drug associated with megaloblastic anemia

Drugs that interfere with folate metabolism
(a) Dihydrofolate reductase inhibitors
Aminopterin
Methotrexate
Pentamidine
Pyrimethamine
Triamterene
Trimethoprim
(b) Impaired folate absorption/utilization
Alcohol
Cholestyramine
Cycloserine
Metformin
Nitrofurantoin
Oral contraceptive agents
Phenobarbital
Phenytoin
Potassium (slow-release)
Sulphasalazine
Drug that interfere with vitamin B12 metabolism

Alcohol
Colchicine
Metformin
Neomycin
Nitrous oxide (if prolonged)
Omeprazole
Sodium aminosalicylate
Vitamin C (in large doses)
Drugs that interfere with DNA synthesis directly
Acgclovir
Azathioprine
Cytarabine
Fluorouracil
Hydroxyurea
Mercaptopurine
Thioguanine
Zidovudine
Mechanism unknown
Benzene
Tetracycline
Vinblastine
Vitamin A
7. Drug-induced pure red cell aplasia

Pure red cell aplasia (PRCA)
)
myeloid
reticulocytes (
megakaryocytic lines
PRCA
5%
PRCA
phenytoin
DNA synthesis
PRCA
SLE, AIDs, autoimmune hemolysis
erythroid cells
plasma cells
8.14 Drugs reported to induce pure red blood cell aplasia

Azathioprine
Carbamazepine
Chloramphenicol
Co-trimoxazole
Dapsone
Fludarabine
Gold salts
Halothane
Isoniazid
Penicillamine
Penicillins
Phenobarbital
Phenybutazone
Phenytoin
Pyrimethamine
Sulfasalazine
Sulfonamides
Sulfonylureas
Thiamphenicol
Thiazides
Valproic acid
212
8. Drug - induced thrombocytopenia

Thrombocytopenia
(petechiae)
suggillation)
100,000/ .
(bleeding disorders)
(bruise, contusion, ecchymoses
(epistaxis, rhinorrhagia)
(conjunctival or retinal bleeding)
3
(immune-mediated suppression)
7.1
3
1)
hapten
covalent bond
complex
antibody
complex
penicillins, trimethoprim, heparin
2)
antibody
immune complex
heparin
Heparin-induced thrombocytopenia
White clot syndrome
heparin-immune complex
platelet
activation, coagulation activation
thrombin
5-12
heparin
)
threshold
(20x150x109/
deep vein
thrombosis
pulmonary embolism
low molecular weight heparins
heparin
thrombin
lepirudin
danaparoid
warfarin
venous limb
gangrene
2-3
heparin
3)
autoantibody
autoantibody
human leukocyte antigens (HLAs)
213
HLAs
gold salts, methyldopa
1)
2)
megakaryocytes
1
(
7-15
1
3)
6
(
corticosteroids)
4)
8.15 Chronological criteria : Thrombocytopenia
Very
suggestive
Suggestive
Time to onset of the

reaction
- Initial treatment
Compatible
< 1 month from

start of drug
administration
> 1 month from
start of drug
administration
- Subsequent
treatment with or
without previous
history in relation
to the same drug
< days from

start of drug
administration
Course of the
reaction
- Without stopping
the drug
- After stopping
the drug
8-30 days from

start of drug
administration
Inconclusive
Incompatible
Occurrence within
30 days or
discovery after 30
days from end of
drug
administration
Occureuce after 30 days from

end of drug administration
Continuing
decrease in
platelet counts
No recovery of
thrombocytopenia
Recovery
within 3 weeks
(with or without
corticosteroids)
Recovery after 3
weeks (with or
without
corticosteroids
Relapse of thrombocytopenia
after 3 weeks
)
-
(aplasia, blood disorders)

alcoholism
(HIV)
214
- Idiopathic thrombocytopenic purpura (ITP)

platelet associated immunoglobulins
RBC Coombs test
autoimmune disease
SLE
6
corticosteroids
corticosteroids
(direct suppression of thrombopoiesis)
thiazides, chemotherapeutic agents, -interferon, estrogens,
7.2
ganciclovir
megakaryocytes
2
(dose-related, monimmune
7.3
direct effect on circulating platelets)
heparin
heparin
heparin
electronic counters
reversible
1)
-
50,000/
bleeding time
anticoagulants, NSAIDs
severe hypertension, leiomyoma
> 75
50,000-100,000/
peptic ulcer,
215
8.16 Drugs associated with thrombocytopenia

Abciximab
Acetazolamide
Actinomycin
Allopurinol
Amiodarone
Amitriptyline
Amphotericin B
Aspirin
Carbamazepine
Cephalosporins
Chloramphenicol
Chlorpheniramine
Chlorthalidone
Cimetidine
Clozapine
Colchicine
Cyclophosphamide
Danazol
Desferrioxamine
Diazepam
Didanosine
Digoxin
Diltiazem
Disopyramide
Fluconazole
Furosemide
Ganciclovir
Gentamicin
Gold salts
Heparin
Hydrochlorothiazide
Idoxuridine
Imipenem-cilastin
Imipramine
Interferon alpha
Isoniazid
Levamisole
Methyldopa
Mianserin
Minoxidil
Morphine
Nitrofurantoin
2)
NSAIDs
Penicillins
Penicillamine
Phenothiazines
Phenylbutazone
Phenytoin
Procainamide
Quinidine
Quinine
Ranitidine
Rifampicin
Risperidone
Sodium aminosalicylic acid
Sulfonamides
Sulfonylureas
Thioguanine
Trimethoprim
Valproic acid
Vancomycin
Vitamin A (isotretinoin)
:
-
50,000/
3)
:
-
RBC phenotype
serum anti-RBC antibodies
4)
corticosteroids
vascular integrity
plasma exchange
IgG
216
9. Drug interfering with platelet functions
type A reaction
3
9.1 Cyclo-oxygenase inhibitors
NSAIDs
aspirin, ibuprofen, indomethacin, naproxen,
phenylbutazone, piroxicam
uricosuric agents
sulfinpyrazone
cyclo-oxygenase (COX-1)
prostaglandin endoperoxidases
thromboxane A2
aggregation)
aspirin
aspirin
bleeding time
1.2-2.0
bleeding time
1-4
NSAIDs
reversible
1
piroxicam
9.2 Increasing platelet C-AMP levels
adenyl cyclase
cyclic AMP
bleeding time
prostacyclin, dipyridamole, theophylline caffeine
9.3 Interfering with the platelet surface
(adhesion)
penicillins, cephalosporins, moxalactam, nitrofurantoin,
dextran
bleeding time
- Cardiovascular drugs
nitroprusside, nitroglycerine, propranolol, calcium channel
blockers (verapamil, nifedipine, diltiazem)
secretion
bleeding time
- CNS drugs
phenothiazine
halothane
bleeding time
217
- Antineoplastic drugs
mitomicin
bleeding time
daunarubicin
carmustine
secretion
- Food supplements
fish oil
bleeding time
eicosapentaenoic acid (EPA)
docosahexaenoic acid (DHA)
acid
cyclooxgenase
arachinodic
10. Adverse reactions to oral anticoagulants

warfarin
venous thrombosis,
arterial thromboembolism
replacement
myocardial infarction
factors II, VII, IX
X
, prosthetic valvular
vitamin K
co-factor inhibitor protein C
vitamin K
warfarin
warfarin
(plasma albumin)
free warfarin
218
CYP 450
- Vitamin K
-
CPY 450
8.17 Drugs that affect oral anticoagulant

Drugs that may potentiate oral anticoagulants
Amitriptyline
Cimetidine
Aspirin
Ciprofloxacin
Allopurinol
Clofibrate
Aminoglycosides
Danazol
Amiodarone
Disulfiram
Androgenic steroids
Erythromycin
Azapropazone
Fluoxetine
Bezafibrate
Glucagon
Cephalosporins
- Interferon
Chloral hydrate
Itraconazole
Chloramphenicol
Ketoconazole
Drugs that may reduce the effect of oral anticoagulants
Azathioprine
Cyclosporin
Barbiturates
Griseofulvin
Carbimazole
Haloperidol
Cholestyramine
Mercaptopurine
Cyclophosphamide
Vitamin K
Mefenamic acid
Metronidazole
Nalidixic acid
Norfloxacin
Omeprazole
Paracetamol
Piroxicam
Quinidine
Sulphonamides
Tetracyclines
Tamoxifen
Phenytoin
Rifampicin
Thiouracils
62
1
HPI: 2
PTA --> Stroke CBC --> WNL
Med.: Ticlopidine 1 x 1 Simvastatin 1/2 x 1
CBC: WBC 500 (3200-9800) RBC 3.01 (4.3-5.9)
Hb 9.4 (14-18)
Hct 27.3 (39-49)
Plt. 7000 (150,000-450,000)
219
BUN 50 (5-20)
Cr 3.2 (0.6-1.2)
Hemoculture: P. aeruginosae
Problem List :
1. CVA
2. Dyslipidemia
3. Pancytopenia
4. Sepsis --> P. aeruginosae
5. Renal fn. abnormal
Charcteristic of events :
1. Leukopenia with sepsis: WBC P. aeruginosae
:
- Viral infection: HIV, rubella, varicella, influenza
- Bacterial infection: typhoid fever
- SLE
- Rheumatoid arthritis
- Immunosuppressive treatment
- COPD
- Urinary or biliary obstruction
- Recent surgical operation
- Drug - induced
2. Anemia: Hb
:
- Blood loss
- Nutritional def
- Cancer
- Endocrine def. (pituitary, adrenal, thyroid)
- Chronic disease (renal, liver)
- Drug - induced
3. Thrombocytopenia
:
- Blood disorders
220
- Cancer
- Liver disease
- Bacterial / viral infection (HIV)
Timing
: Simvastation, Ticlopidine
Supporting literature
- Tertiary literature --> No report with simvastatin
- Primary & tertiary literature + WHO database:
reports of blood dyscrasias & liver damage
Dechallenge
Ticlopidine --> WBC, RBC, Platelet

simvastatin
Rechallenge
Conclusion Ticlopidine - induced pancytopenia
Plan 1.
2.
1-2
3.
2
lab.test
Dx: cystitis
4
Lab test :
55
(suprapubic)
Hgb 14.0 /
Hct 43.6%
WBC 7,500/ .3
Reticulocyte 0.5%
(
12-16)
(
38-48%)
(
4,000-11,000)
(
0.2-2.0%)
WBC 20-50 per HPF
moderate bacteria
benign prostatic hypertrophy
cotrimoxazole double-strength 1x2
Hgb 9.9 /
Hct 32.5%
WBC 9,100/ .3
221
Reticolocyte 11%
Total bilirubin 3.8
/
(
Direct bilirubin WBC 0-5 per HPF
<1.0)
bacteria
4+ bilirubin
urobilinogen
PE: scleral icterus mild tachycardia
Assessment
sulfamethoxazole-induced hemolysis
G6PD
- Time course : asymptomatic hemolysis
1-4
- Characteristics : Hct reticulocyte
indirect bilirubin
scleral icterus
- Cause : Cotrimoxazole
hemolysis
sulfamethoxazole
G6PD
cotimoxazole
G6PD
hemahysis
3
HCTZ
50
56
/
mild hypertension
2
1
78,000 / .3
megakaryocytes
Assessment
(thrombocytopenia)
- Time couse :
1-4
- Characteristics:
megakaryocytes
nonimmune process (direct marrow suppession)
- Cause : HCTZ
diuretics
furosemide
HCTZ
thiazide
222
HCTZ
HCTZ
4
62
PM: Osteoarthritis
Medication :
diclofenac 50
1x3
PE:
osteoarthritis
Lab.test:
Hgb 6.2 /
(12-16)
Reticulocyte 0.5% (0.2-2.0%)
WBC 1,800 / .3, neutrophil 50%
Platelet 35,000/ .3
Assesment
aplastic amemia (AA)
AA
diclofenac ASA
- Time course : AA
diclofenac
- Characteristics: RBC, WBC, neutrophil
- Cause :
diclofenac 6.8
diclofenac
diclofenac
(1:150,000)
1
6
ASA 325
prn
ASA
AA
AA
ASA
ASA
223
1.
; 2539.
1427.
2.
. Glucose-6-Phosphate Dehydrogenase (G-6-PD) deficiency. :

.
.
:
,
2542.
113122.
3.
. Megaloblastic anemia. :
.
.
:
, 2542.
101112.
4.
. Drug induced platelet disorders. :
.
.
:
, 2542.
196203.
5. Jackson GH, Cavet J and Proctor SJ. Disorders of blood cells and haemostasis Part 1
Disorders of blood cells. In : Davies DM, Ferner RE, De Glanville H. Textbook of
Adverse Drug Reactions 5th ed. London : Chapman & Hall Medical , 1998. p.732746.
6. Johns TE and Harbilas JW. Drug-Induced Hematologic Disorders. In : DiPiro JT, Talbert
RL, Yee GC, Matzke GR, Wells BG, Posey LM. (Eds). Pharmacotherapy : A
Pathophysiologic Approach 4thed. Stamford,CT : Appleton & Lange, 1999. p.1584-1596.
7. McMurray M. Blood disorders. In : Lee A. Adverse Drug Reactions. London :
Pharmaceutical Press, 2001. p.177-193.
8. Reilly JT and Cawley JC. Haematological disease. In : Oxford J (editor). Medicine.
London : Blackwell Sciences ;1996. p. 11.1-11.10.
9. Sasich LD and Sukkari SR. Drug-Induced Blood Disorders. In : Koda-Kimble MA and
Young LY. Applied Therpeutics : The Clinical Use of Drug 7th ed. Baltimore MD :
Lippincott Williams & Wilkins 2001. p. 85-1 85-21.
10. Solal-Celigny P. Abnormal hematologic values. In : Benichou C. Adverse Drug Reactions :
A Practical Guide to Diagnosis and Management. Chichester : John Wiley
& Sons, 1994. p.13-30.
11. Wood JC, Carey PJ and Proctor SJ. Disorders of blood cells and haemostasis Part 2
Disorders of haemostasis. In : Davies DM, Ferner RE, De Glanville H. Textbook of
Adverse Drug Reactions 5th ed. London : Chapman & Hall Medical , 1998. p.747757.
224
1.
pH
7.35-7.45 (
pH
fluid
pH
(arterial blood)
7.4)
pH
pH
cerebrospinal
pH
pH
pH
3
1.
2.
3.
(Buffering system)
(Respiratory compensation)
(Renal compensation)
(Buffering system)
(buffer)
pH
1. Bicarbonate buffer
pH
10-15
2
Carbonic acid/bicarbonate (H2CO3/HCO3-) buffer
225
2. Nonbicarbonate buffer
Bicarbonate buffer system

HCO3- + H+
phosphate hemoglobin
H2CO3
carbonic anhydrase
protein
CO2 (dissolved) + H2O
CO2 (gas)
Nonbicarbonate buffer system
HBuf
H+ + Buf
:
carbonic anhydrase
renal tubular cell
Bicarbonate buffer
(extracellular fluid; ECF)
(dissolved CO2)
pH
pH
Henderson-Hasselbach equation
[base]
[acid]
= pK + log [HCO3 ]
[H2CO3]
bicarbonate buffer system
pH = pK + log
pK = negative log
[HCO3- ]=
[H2CO3]=
...(1)
6.1
mEq/L
mEq/L
226
1:400)
pH
arterial partial pressure

Volatile acid
(solubility coefficient)
0.03
(PaCO2)
mmHg
mEq/L
PaCO2
[HCO3- ]
pH = 6.1 + log
0.03(PaCO2)
...(2)
[HCO3- ]
24 mEq/L
2
pH
40 mmHg
PaCO2
pH = 6.1 + log
24 mmol/L
= 7.4
0.03(40 mmHg)
pH
PaCO2
3
pK
log
[HCO
]
3
pH ~
PaCO2
...(3)
pH
7.4
PaCO2
[HCO3- ]
acidosis
metabolic alkalosis
component)
respiratory acidosis
pH
[HCO3- ]/.03 PaCO2

20:1
PaCO2
metabolic component
(primary process)
respiratory alkalosis
PaCO2
pH
metabolic
PaCO2 (respiratory
PaCO2
pH
227
(compensation process)
metabolic
PaCO2
acidosis
metabolic alkalosis
(respiratory compensation)
PaCO2
9.1
pH, HCO3
pH, HCO3-
9.1
pH
HCO3- mEq/L
PaCO2 mmHg
:
PaCO2
Primary disorder
Acidemia
Metabolic acidosis
Respiratory alkalosis
Primary disorder
Alkalemia
Metabolic alkalosis
Respiratory acidosis
7.35 - 7.45
22 - 26
35 - 45
acidemia
alkalemia
acidosis
alkalosis
(in vitro)
9.1
pH 7.5 HCO3- 22 mEq/L
PaCO2 29 mmHg
PaCO2
pH 7.25 HCO3- 26 mEq/L
PaCO2 60 mmHg
pH
acidosis
acidosis
alkalosis
pH
(mixed acid-base disorders)
(Respiratory compensation)
12-24
PaCO2
(pulmonary capillary)
alveoli
1. Peripheral chemoreceptors carotic arteries

aorta
arterial acidosis, hypercapnia / hypoxia
2. Central chemoreceptors medulla
cerebrospinal fluid
acidosis
PaCO2
228
chemoreceptors
medulla
CO2
(Renal compensation)
2
(HCO3- )
4,000 mEq
proximal tubule
1.
HCO3fluid
tubule
2.
(H+)
HCO3CO2
H2CO3
H2O
cell membrane
2ammonia
(HPO4 )
3-5
glomerular filtrations
85%
15%
H+ H2CO3
H2O
CO2
H2CO3
tubule lumen
2.
renal tubular
distal
carbonic anhydrase
renal tubule lumen
H+ + HCO3H+
hydrogen monophosphate
H+
H2PO4
ammonium (NH4+)
acidosis
alkalosis
metabolic acidosis
ketoacidosis
diabetic
metabolic alkalosis
-
(arterial blood gas; ABG)

-
229
1.
(
(gastroenteritis)
HCO3-
9.2)
CO2
metabolic acidosis
9.2
Metabolic
Acidosis
Alkalosis
Respiratory
acidosis
Alkalosis
Sepsis
,
/
methanol
ketoacidosis
carbonic anhydrase
Amphotericin B
Salicylate
230
2.
2.1
anion gap
-
24-30 mEq/L; SI unit = 24-30 mmol/L)

(Venous HCO3-)
HCO3-
total CO2
dissolved CO2
(Arterial
HCO3-)
-
anion gap (
9.1
12 + 4 mEq/L)
(unmeasured anion)
anion gap
(Na+)
(unmeasured cation)
anion gap
(measured cation)
(measured anion)
(K+)
(Cl-)
(HCO3-)
anion gap
anion gap = [Na+] - ([Cl-] + [HCO3- ])

metabolic acidosis
metabolic acidosis
elevated anion gap normal anion gap metabolic acidosis
metabolic acidosis
lactate
anion gap
MULEPAK
Methanol and other alcohols ingestion
Uremia (renal failure)
anion gap
2
elevated anion gap
lactic acid
elevated anion gap metabolic acidosis
231
Lactic acidosis
Ethylene glycol ingestion
Paraldehyde ingestion
Aspirin intoxication
Ketones (starvation, alcoholic and diabetic ketoacidosis)
normal anion gap metabolic acidosis
anion gap
Hyperchloremic metabolic acidosis
carbonic anhydrase
normal anion gap metabolic
acidosis
(Potassium-sparing diuretics)
-
(
pH HCO3-
2.2
3.5-5.0 mEq/L)
PaCO2 (
9.1)
-
pH
(mixed venous blood)
hypoperfusion
9.3
metabolic acidosis
9.4
10 mEq/L)
HCO3- 14 mEq/L (
40 mmHg
10-14 mmHg
PaCO2
26-30 mmHg
pH
7.29-7.35
PaCO2
(
2)
pH
7.17
alkalosis
PaCO2
acute respiratory disorder
chronic respiratory disorder
acute respiratory acidosis
PaCO2 60
26 mEq/L
mmHg
HCO3232
pH 7.26
chronic respiratory acidosis

32 mEq/L
HCO3PaCO2 HCO3mixed acid-base disorder
9.3
PaCO2 60 mmHg
pH 7.35
Primary Event
Metabolic Acidosis
pH ~
Metabolic Alkalosis
pH ~
Respiratory Acidosis
pH ~
Respiratory Alkalosis
pH ~
:
(
Compensation Event
[HCO3- ]
PaCO2
pH ~
[HCO3- ]
PaCO2
[HCO3- ]
PaCO2
pH ~
[HCO3- ]
PaCO2
pH ~
pH ~
pH
(
[HCO3 ]/PaCO2
9.4
[HCO3- ]
PaCO2
[HCO3- ]
PaCO2
[HCO3- ]
PaCO2
[HCO3- ]
PaCO2
)
pH
*
-
Metabolic acidosis
PaCO2
HCO3Metabolic alkalosis
PaCO2
HCO3Acute respiratory acidosis
HCO3PaCO2
Chronic respiratory acidosis HCO3PaCO2
Acute respiratory alkalosis
HCO3PaCO2
Chronic respiratory alkalosis HCO3PaCO2
*
HCO3- = 24 mEq/L
1.0 1.4 mmHg

12 24
1 mEq/L
0.5-1.0 mmHg
12 24
1 mEq/L
0.1 mEq/L
1 mmHg
0.4 mEq/L
35
1 mmHg
0.2 mEq/L
1 mmHg
0.4 0.5 mEq/L
35
1 mmHg
PaCO2 = 40 mmHg
PaCO2
10 mmHg
PaCO2
55 mmHg
HCO330 mEq/L
HCO3
45 mEq/L
HCO3
18 mEq/L
HCO3
12 mEq/L
233
3.
Metabolic acidosis
Metabolic alkalosis
Respiratory acidosis
Respiratory alkalosis
3.1. Metabolic acidosis

metabolic acidosis
pH
PaCO2
pH
acid, ketoacids)
endogenous acid (
ECF (
phosphates, sulfates)
lactic
(dilutional acidosis)
metabolic acidosis
metabolic acidosis
9.5
metabolic acidosis
2
1. normal anion gap metabolic acidosis
hyperchloremic states
ECF
(Cl- ) anion gap
cholestyramine
HCO3hypercholesteralemia cholestyramine
anion exchange resin
endogenous bicarbonate
pancreatic fistula, ureterosigmoidostomy, ileostomy, gastrointestinal disorders,
laxative abuses
renal tubular acidosis,
HCO3carbonic anhydrase inhibitors, potassium sparing diuretics
234
hydrochloric acid
ammonium chloride
2. elevated anion gap metabolic acidosis
endogenous acid
Cl
HCO3
- ketoacidosis
(
)
- lactic acidosis
metformin
phentermine
(severe anemia)
(congestive heart failure)
alcohol abuses
lactic acidosis
phentermine
0.251
1,000
metformin 10-20
. . 1970
lactic acidosis
metformin
0.010.08 (
0.03)
1,000
lactic
acidosis
50% metformin
lactic acidosis
-
methanol, ethylene glycol,

salicylate
methyl salicylate
metabolic acidosis
salicylate
hemodislysis
- myoglobinuric acute renal failure
salicylate
salicylate
metabolic acidosis
rhabdomyolysis
235
9.5
metabolic acidosis
elevated anion gap metabolic acidosis
Biguanides
: cholestyramine, laxatives,
: ethanol, methanol, ethylene
purgatives
glycol, propylene glycol, benzyl alcohol,
(type 2 renal
diethylene glycol
tubular acidosis): arginine hydrochloride,
Polyhydric sugar: fructose, sorbitol,
Xylitol
carbonic anhydrase inhibitors,
Salicylate
gentamicin, mercaptopurine, methyl-3chromone, sulphanilamide, tacrolimus,
Paracetamol
: -agonist cathecolamine,
valproic aid, tetracycline
,
sulphur, germanium, isoniazid, Lugols
(
)
(type 2 renal
iodine, nalidixic acid, niacin,
nitroprusside anolog, paraldehyde,
tubular acidosis): amiloride,
pentamidine, povidone-iodine, propionic
amphotericin, analgesic abuse,
cyclamate, cyclosporin, lithium, NSAIDs,
acid derivatives (ibuprofen
fenoprofen), verapamil
toluene
: ammonium chloride,
hydrochloric acid, L-arginine Llysine
pH
metabolic acidosis
metabolic acidosis
7.2
9.6
hyperventilation
Kussmauls respirations
acidosis
metabolic acidosis
(pH 6.8)
236
9.6
acidemia
Arteriolar dilatation, venoconstriction

Pulmonary vascular resistance
Cardiac output,
Arrhythmia, ventricular fibrillation
metabolic demands
insulin resistance
ATP
,
(anaerobic glycolysis)
Hyperkalemia
Hyperventilation, Dyspnea
metabolic acidosis
1.
acidosis
2.
metabolic
(
9.2 )
(
metabolic acidosis)
metabolic
diabetic ketoacidosis,
severe renal insufficiency
acidosis
acetone
dehydration
, uremia
3.
- pH
PaCO2
15 mEq/L
metabolic acidosis
metabolic acidosis
, renal tubular acidosis, diabetic ketoacidosis,
anhydrase
15 mEq/L
carbonic
237
anion gap
- pH
6.1
metabolic acidosis
pH
distal renal tubular acidosis
metabolic acidosis
chronic metabolic acidosis
12-20 mEq/L
pH 7.20-7.40
Shohls solution (sodium citrate/citric acid)

acute metabolic acidosis
(
7.2)
( ketoacidosis, lactic acidosis)
hypercholremic acidosis (
metabolic acidosis
1.
diabetic ketoacidosis
8 mEq/L
pH
regenerate
2
metabolic acidosis
metabolic acidosis
2.
pH
7.2
15 mEq/L
sodium bicarbonate
sodium acetate, sodium lactate, tromethamine
(THAM), carbicarb (sodium bicarbonate + sodium carbonate)
238
sodium bicarbonate
1
650
1
3
sodium bicarbonate
7.5% 1
50
7.5 % sodium bicarbonate 50-150
50-150 mEq/L
. sodium bicarbonate
.
sodium bicarbonate (NaHCO3)
NaHCO3
= (Vd *
NaHCO3
8 mEq
50 mEq
(dextrose water) 1
12-15 mEq/L
HCO3-
)(
HCO3-
mEq
HCO3Vd = 0.5
Vd
acidosis
Vd = 1.0
HCO3-
mEq/L
12-15 mEq/L
NaHCO3
sodium bicarbonate
pH
7.4
.
30
pH
7.2
sodium bicarbonate
sodium bicarbonate
1.
2.
tetany
transient hypokalemia
bicarbonate
(
pH 0.1
0.6 mEq/L
)
239
3.
4.
5.
6.
7.
acute acidosis
metabolic acid
( lactic acidosis,
diabetic ketoacidosis)
rebound metabolic alkalosis
lactate
ketone bodies
post treatment respiratory alkalosis
hyperventilation
blood brain barrier
HCO3cerebrospinal fluid
blood brain barrier
cerebrospinal fluid
HCO3cerebrospinal fluid
lactic acid
overalkalinization
affinity
hypernatremia
hyperosmolarity
ionized calcium
3.2. Metabolic alkalosis

metabolic alkalosis
pH
33-51%
HCO3HCO3-
PaCO2
-
tubular fluid
HCO3HCO3-
threshold
HCO3HCO3-
metabolic alkalosis
pH
metabolic alkalosis
chemoreceptors
6-7 mmHg
mEq/L
PaCO2
PaCO2
pH
HCO350-60 mmHg
10
240
metabolic alkalosis
HCO3HCO3-
1.
(
cisplatin
)
cation exchange resin (
sodium
polystyrene sulphonate)
mineralocorticoid
carbenicillin
mineralocorticoid carbenoxolone
2.
sodium bicarbonate
HCO3metabolic acidosis
lactate, citrate, acetate
HCO3gluconate
massive blood transfusion
plasma protein infusion
plasma protein
acetate
40-50 mEq/L
milk-alkali syndrome
3.
(refeeding)
metabolic alkalosis
3
1.
metabolic alkalosis
sensitive metabolic alkalosis)
(volume-responsive
10 mEq/L
chloride95%
(gastric drainage)
241
organic acidosis
2.
metabolic alkalosis
chloride-insensitive metabolic alkalosis)
(volume-nonresponsive
20 mEq/L
mineralocorticoid
5%
cushings
syndrome, hyperaldosteronism
3.
milk-alkali syndrome
metabolic alkalosis
metabolic alkalosis
(
[volume depletion])
(pH
7.60)
hypoventilation
(cardiac arrhythmia)
(neuromuscular irritability)
(tetany)
(ionized calcium)
metabolic alkalosis
1.
(
2.
3.
metabolic alkalosis
9.2)
metabolic alkalosis)
40-45 mEq/L
pH
PaCO2
-
PaCO2
pH, HCO3metabolic alkalosis
HCO3HCO3metabolic alkalosis
242
metabolic alkalosis
1.
9.7
9.7
HCO3(mEq/L)
(mild)
32-45
(mEq/L)
3.5-3.9
32-40
2.5-3.5
(moderate)
(severe)
2.0-2.5
40-42
pH 7.60
2.
metabolic alkalosis
metabolic alkalosis
.
4
metabolic alkalosis
H2 receptor (cimetidine 200-600
intravascular volume
glomerular filtration rate
metabolic alkalosis
0.9%
3-5
4-8
10-40 mEq/L
metabolic alkalosis
0.9% 1
citrate
gluconate
243
metabolic alkalosis
(pH
7.60),
(congestive heart
failure)
(hydrochloric acid)
oliguria)
100-200 mEq/L (0.1-0.20 N)
5%
normal saline
(central vein)
100-125
24
(catheter)
12-24
= [0. 5 / . *
(
HCO3-
35-40 mEq/L
HCO3-
( .)] [(
)]
pH
7.50
4-12
PaCO2
24
.
metabolic alkalosis
(intolerant to sodium volume loads)
acetazolamide
carbonic anhydrase tubular cell
250-375
1-2
(acid precursor)
ammonium chloride
encephalopathy
uremia
arginine
244
monohydrochloride
BUN
.
dialysis
metabolic alkalosis
.
hemodialysis
peritoneal dialysis
mineralocorticoid
corticosteroid
corticosteroid
mineralocorticoid
mineralocorticoid
.
.
spironolactone, amiloride, triamterene
3.3. Respiratory acidosis

PaCO2
pH
pH
PaCO2
1.
-
(neuromuscular abnormalities)
barbiturates, narcotics,
benzodiazepines
245
barbiturates
barbiturates
barbiturates
morphine
ventilatory drives
acidosis
heroin
hypoxic
hypercapnic
respiratory
pulmonary edema
benzodiazepines
barbiturates
trauma, stroke,
cervical cord
status epilepticus, tumors,

poliomyelitis, myastenia gravis, multiple sclerosis
hypothyroidism
2.
-
(mechanical ventilator)
dialysis
pnuemothorax, adult respiratory distress syndrome,

(severe pulmonary edema),
(severe
bronchospasm),
,
1.
2.
(acute respiratory acidosis)
(chronic respiratory acidosis)
246
1.
seizures stupor
2.
:
(increase cerebral blood flow)
, papilledema, focal paresis
,
3.
1.
2.
3.
respiratory acidosis)
pH
HCO3-
PaCO2
PaCO2
(PaCO2
80 mmHg)
(PO2 40 mmHg)
benzodiazepines
(oxygenation)
drive
metabolic alkalosis
respiratory
247
2-4
12-24
metabolic alkalosis
3.4. Respiratory alkalosis

(hypocapnia)
PCO2
pH
2
alkalosis
1-2
respiratory
6
PCO2
(hyperventilation)
hyperventilation
neurochemical
stimulation
(
)
(
)
cardiogenic, hypovolemic,
metabolic production
septic shock
PaCO2
1.
-
(central stimulation of respiration)

sepsis
catecholamine, theophylline, nicotine
salicylate
248
hyperventilation
salicylate
78%
salicylate
-
(peripheral stimulation of
respiration)
(altitude)
2.
pulmonary emboli, pulmonary shunts,

(acute respiratory alkalosis)
(chronic respiratory alkalosis)
1.
2.
PaCO2
(cardiac
arrhythmia)
1.
2.
3.
respiratory alkalosis)
pH
HCO3-
PaCO2
salicylate
249
pH
pH
(pH
7.50)
7.50
salicylate
hyperventilation
(paper bag rebreathing device)
(arrhythmia)
(oxygen therapy)
(pH 7.60)
56
10
Phenobarbital
30
Past Medical History
Social History
3
18
10
Past Surgical History

Medication History
Phenobarbital 30
Physical Examination
GEN:
VS:
BP 130/70 HR 100
60
, 188
Temp 37.1oC RR 25
250
HEENT:
EXT:
dry mucous membrane, sunken eyes, well-healed craniotomy scar

cool fingers and toes, dry skin, decrease skin turgor without tending,
slightly depressed reflexes
Results of Laboratory Tests

Na 145
Hct 53
K4
Hgb 16
Cl 107
Leucocytes 5.5*103
MCV 83
HCO3 15
BUN 27
CR 1.3
AST 18
ALT 17
LDH 150
Alk Phos 60
Alb 4.0
T Bili 0.5
Glu 90
Ca total 10
PO4 4
Mg 2
Urinalysis:
WNL
Chest X-ray: WNL
ECG:
WNL
ABGs:
pH 7.25, PO2 98, PCO2 35
Toxicology screen:
Salicylate level 45 mg/dl
Ethanol level 0.25%
Phenobarbital level 0
Urine output 15 ml/hr
Stool:
guaic-negative
Problem list
1. Metabolic acidosis
S: somnolence
O: pH 7.25, HCO3 15, PCO2 35, RR 25
A:
metabolic acidosis
positive anion gap
ethanol 0.25%)
anion gap 23 mEq/L

salicylate
lactate (
251
salicylate
lactate
3-4
stable
oxygenation
pH
7.2
hemodynamically
salicylate
lactate
metabolic alkalosis
hemodialysis
salicylate ions
hemodynamically stable
P:
activated charcoal 100

saline cathartic
300-350
20% sorbitol 30-45
arterial blood gas

3-4
1
mental status
2. Respiratory alkalosis
S:
O: PCO2 35, RR 25
A:
metabolic acidosis
salicylate
salicylate
15
lactate
pH
7.3
salicylate
oxygenation
PCO2
pH
P:
252
1. Kilroy RA. Acid-base disorders. In: Dipiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG,
Posey LM (eds). Pharmacotherapy: A pathophysiologic approach. 4th ed. Connecticut:
Appleton & Lange; 1999. p.918-937.
2. Swaminathan R. Disorder of metabolism 2. In: Davies DM, Ferner RE, De Glanville H (eds.).
Textbook of Adverse Drug Reactions 5th ed. London: Chapman & Hall Medical; 1998. p.442540.
3. McMullin ST, Hall TG, Kleiman-Wexler RL. Acid-Base Disorder. In: Koda-Kimble MA, Young
LY (eds). Applied therapeutics: The clinical use of drugs. 7th ed. Baltimore: Lippincott
Williams & Wilkins; 2001. p.9-1 9-14.
4. Fall PJ. A stepwise approach to acid-base disorders: Practical patient evaluation for
metabolic acidosis and other conditions. Postgrad Med 2000; 107(3): 279-50, 253-4, 257-8.
5.
.
. :
,
,
.
.
,
; 2533.
30-48.
253
polymorphonuclear
(bacteria flora )
Corticotrophin (ACTH)
adrenal glucocorticoids
(inflammatory process)
azathioprine
carbamazepine
penicillamine
mine
cyclosporin
phenytoin
dextrans
dapsone
pyrimetha-
clozapine
254
10
iodine
indomethacin
povidone
leucocyte
fibroblast
polymorphonuclear leukocytes
diclofenac
intralipid
lipid emulsion
chemotaxis
neutrophil leucocytes in vitro

iron dextran
dextran complexes
desferrioxamine
granulocyte
lympho-
cyte
in vitro
cimetidine
sulfamethoxazole)
thymidine
thymine
(elemental iron)
omeprazole
co-trimoxazole
co-trimoxazole (trimethoprim/
thymine
in vivo
thymine
255
10
Staphylococcal infections
(broad-spectrum antibiotics)
penicillin
penicillin
difficile
penicilloic acid
tetracyclines
- lactams
penicillinase
- lactam ring
Staphylococcus aureus
Clostridium
staphylococci
(osteomyelitis)
(parotitis)
(endocarditis)
(sepitcemia)
staphylococcal
(pneumonia)
indomethacin
patent ductus arteriosus
isotretinoin
Propioni-
bacterium acnes
Staphylococcus aureus
(folliculitis)
(furuncles)
(cellulitis)
Streptococcal infections
(agranulocytosis)
cytarabine
Streptococcus viridans
Gram-negative organisms infections
colifrom
256
10
Klebsiella spp.,Pseudomonas spp., Proteus spp.

bactcremia
Pseudomas bacteremia
ticlopidine
varicose ulcers
Ps.aeruginosa
Chlamydia infections
meta analysis
case control 29
Chlamydia trachomatis
Salmonellosis, shigellosis,
Campylobacter gastroenteritis
omeprazole
cimetidine, ranidine
omeprazole
salmonellae
shigellae
Campylobacter,
Clostridial infections
Pseudomembranous colitis
clindamycin
lincomycin
ampicillin
amoxicillin
10.1
CI.difficile colitis
cytarabine
chlorpropamide
pseudomembranous colitis
diclofenac
CI.difficile
257
10
10.1
Clostridium difficile Associated Diarrhea
Cephalosporins
Ampicillin and amoxicillin
Clindamyin
Other penicillins, including - lactamase-stable
penicillins
Erythromycin and other macrolides
Tetracyclines
Trimethoprim-sulfamethoxazole
Colitis
Choramphenicol
Metronidazole
Amphotericin B
Quinolones
Rifampin
5-Fluorouracil
Methotrexate
Doxorubicin
Cyclophosphamide
Aminoglycosides
Sulfonamides
Herpes viruses
herpes simplex, varicella-zoster, the Epstein-Barr
virus, human herpes virus type 6
cytomegalovirus
herpes simplex, herpes zoster
varicella
herpes simplex
(intrathecal)
fentanyl
(epidural)
fluoxetine
muromonab CD3 (OKT3)
Epstein - Barr virus
cytomegalovirus
cyclophosphamide
methotrexate
methotrexate
ketoprofen
methotrexate
hydroxychloroquine
folic acid
258
10
Aspergillosis
Aspergillus spp.
ACTH
ketoacidosis
pentamidine
Candidiasis
Candida
ACTH
zole
omepracandidiasis
oropharyngeal candidiasis
fluconazole
Candida
krusei
cimetidine
cimetidine 3
ranitidine
Candida albicans
nystatin
cimetidine
Candida
Candida
259
10
phenobarbital
pheobarbital
griseofulvin
griseofulvin
(chelation)
pH
isoiazid
2
fluoroquinone
3
ciprofloxacin
10.2
10.2
Interacting Drugs
Acyclovir with
Aminoglycosides
Narcotics
Probenecid
Zidovudine
Amantadine with
Anticholinergics
Adverse Effect
Increased nephrotoxicity and/or
neurotoxicity
Inceased pethidine effect
Possible increased acyclovir
toxicity
Increased neurotoxicity (profound
drowsiness and lethargy)
Hallucinations, confusion,
nightmares
Antihistamines
Increased CNS adverse reactions
CNS stimulants
Additive CNS stimulant effects
Triamterene
CNS toxicitv
Trimethoprim
CNS toxicity
Aminoglycoside andtibiotics with
Acyclovir
Increased nephrotoxicity and/or
neurotoxicity
Probable Mechanism
Mechanism not established
Decreased renal excrertion
Decreased renal excretion
Additive
Additive anticholinergic effects
Decreased renal clearance
Additive
260
10
10.2
( )
Interacting Drugs
Adverse Effect
Amphotericin B
Anticoagulants, oral
Nephrotoxicity
Potentiation of anticoagulation
effects
Increased nephrotoxicity
Increased ototoxicity
Increased renal toxicity
Probable decreased digoxin effect
with oral neomycin
Increased ototoxicity and
nephrotoxicity
Increased neuromuscular blockade
Possible decreased methotrexate
effect with oral aminoglycosides
Neuromuscular blockade
Bacitracin
Bumetanide
Carboplatin
Cephalosporins
Cisplatin
Cyclosporin
Digoxin
Ethacrynic acid
Furosemide
Magnesium sulfate
Methotrexate
Neuromuscular
blocking agents
NSAIDs
Possible aminoglycoside toxicity

in preterm infants with
indomethacin given for patent
ductus closure
Penicillins
Falsely low aminoglycoside levels
Polymyxins
Increased nephrotoxicity;
neuromuscular blockade
Tacrolimus
Vancomycin
Possible increased nephrotoxicity
and ototoxicity
Aminosalicylic acid (PAS) with
Anticoagulants,oral
Enhanced hypoprothrombinemic
effects
Ammonium chloride
Increased probability of
crystalluria
BCG vaccine
Negates BCG effect
Digoxin
Decreased digoxin effect
Diphenhydramine
Decreased effect of PAS
Ethionamide
GI distress/hepatotoxicity
Isoniazid
Increased isoniazid serum
concentrations
Probenecid
Increased PAS toxicity
Rifampin
Rifampin effectiveness may be
decreased; separate doses by 8-12
hr
Amphotericin B with
Aminoglycoside
Nephrotoxicity
antibiotics
Antineoplastics
Possible increased renal toxicity,
bronchospasm, and hypotension
Cisplatin
Colistin
Corticosteroids
Increased hypokalemia
Cyclosporin
Increased renal toxicity
Probable Mechanism
Synergism
Decreased GI absorption or synthesis
of vitamin K
Additive
Additive
Additive
Possibly additive or synergistic
Decreased absorption
Additive
Additive
Additive
Additive
In vitro inactivation
Additive
Additive
Additive
Acidification of urine
Negates immune response
Decreased absorption with time
Decreased GI absorption
Additive
Decreased metabolism
Decreased GI absorption due to
excipient bentonite
Synergism
Additive
Additive
Additive
Possible synergism
261
10
10.2
Interacting Drugs
Digitalis glycosides
Imidazole antifungals
Neuromuscular
blocking agents
Pentamidine
Polymyxins
Tacrolimus
Vancomycin
Zidovudine
Azithromycin with
Aluminum/magnesium
antacids
Digoxin
Aztreonam with
Chloramphenicol
Bacitracin with
Aminoglycosides
Anesthetics
Neuromuscular
blocking drugs
Polymyxins
Cephalosporins with
Alcohol
Aminoglycoside
antibiotics
Ampicillin
Aspirin
Chloramphenicol
Colistin
Diuretics
Ethacrynic acid
Furosemide
Heparin
Polymyxins
Probenecid
( )
Adverse Effect
Probable Mechanism
Increased digitalis toxicity

Possible antagonism in animal
models
Increased neuromuscular blocking
effect
Hypokalemia
Potential for increased
myelotoxicity and nephrotoxicity
Additive
Additive
Additive
Additive
Decreased peak
concentrations:dose not affect
overall absorption
Increased digoxin concentrations
Possible in vitro antagonism;

administer a few hours apart
Potentiation of neuromuscular
blocking effects
blocking effects
Additive
Additive
Disulfiram-like effect with

cefamandole, cefmetazole,
cefoperazone, and moxalactam
Inhibition of intermediary metabolism

of alcohol
In vitro antagonism with

ceftazidime versus group B
streptococci and Listeria
Possible increased anticoagulant
effect with moxalactam,
cefamandole, cefmetazole, or
cefoperazone
Possible increased bleeding risk
with moxalactam
In vitro antagonism
Increased nephrotoxicity with
some cephalosporins
Possible increased bleeding risk
with moxalactam
Higher and prolonged
cephalosporin
Hypokalemia
Destruction of intestinal Eubacterium

lentum in 10% of digoxin patients
Additive
Additive
Additive
Additive
Mechansim not established
Additive
Additive
Cmpetitive inhibition of tubular
secretion
262
10
10.2
Interacting Drugs
Salicylates
Vancomycin
Chloramphenicol with
Acetaminophen
(Paracetamol)
Aminoglycosides
Aztreonam
Barbiturates
Cephalosporins
Cimetidine
Cyclophosphamide
Folic acid
Hypoglycemics,
sulfonylurea
Iron
Lincomycin
Penicillins
Phenytoin
Rifampin
Vitamin B12
Chloroquine with
Ampicillin
Cholestyramine
Cimetidine
Cyclosporin
Magnesium antacids
Methotrexate
Rabies vaccine
Ritonavir
Succinylcholine
Clarithromycin with
Anticoagulant, oral
Astemizole
Benzodiazepines
Carbamazepines
Cimetidine
Cisapride
Clindamycin
( )
Adverse Effect
Probable Mechanism
Decreased cefixime concentrations

and AUCs
Displacement from protein-binding

sites
Additive
Possible decreased
chloramphenicol effect
In vitro antagonism; not seen in
vivo
Increased metabolism
Antagonism; administer
chloramphenicol separately a few
hours later
Increased barbiturate effect;
decreased chloramphenicol effect
Antagonism
Aplastic anemia
Decreased cyclophosphamide
effect
Delayed response to folic acid
Increased hypoglycemic effect
Delayed response to iron

Decreased lincomycin effect
In vitro antagonism; not seen in
vivo
Increased phenytoin toxicity
Possible increased
chloramphenicol toxicity
Decreased chloramphenicol effect
Delayed response to vitamin B12

Target site antagonism
Decreased ampicillin effect

Decreased effect
Aplastic anemia
Increased cyclosporin toxicity
Decreased efficacy
Decreased methotrexate efficacy
Decreased vaccine effect
Increased chloroquine toxicity
Decreased bioavailability
Possibly additive or synergistic
Decreased clearance
Increased clearance
Interference with the antibody response
Decreased clearance
Hypoprothrombinemia potentiated
Increased Q-T interval and
possible arrhythmias
Increased CNS toxicity
Increased carbamazepine toxicity
Decreased clarithromycin
concentrations
Increased cardiotoxicity
In vitro antagonism: not
documented clinically
Possible decreased metabolism

Decreased antihistamine metabolism
Decreased clearance
Decreased clearance
Prolonged absoption
263
10
10.2
Interacting Drugs
Corticosteroids
Cyclosporin
Digoxin
Disopyramide
Ergot alkaloids
Phenytoin
Rifampin
Ritonavir
Saquinavir
Tacrolinus
Theophylline
Zidovudine
Clindamycin with
Neuromuscular
blocking agents
Saquinavir
Clofazimine with
Dapsone
Isoniazid
Phenytoin
Rifampin
Cycloserine with
Alcohol
Ethionamide
Isoniazid
Phenytoin
Dapsone with
Clofazimine
Didanosine
( )
Adverse Effect
Increased effect and possible
toxicity of methylprednisolone
Increased digoxin effect
Increased disopyramide
concentrations. Q-T interval
prolongation and polymorphic
ventricular tachycardia
Increased ergot toxicity
Possible increased or decreased
effect
concentrations/increased
rifamycin toxicity
Increased clarithromycin toxicity
Increased saquinavir
concentrations
Increased tacrolimus toxicity
Increased theophylline effect and
possible toxicity
Decreased zidovudine
concentrations and AUCs with
clarithromycin
Probable Mechanism
Decreased excretion
Probably decreased metabolism
Decreased gut metabolism and
increased absorption

Altered metabolism
Increased/decreased metabolism
Additive
Increased clindamycin toxicity
Possible decrease or nullification

of clofazimines antiinflammatory activity
Increased clofazimine serum and
urine concentrations and
decreased skin concentrations
Decreased efficacy
Decreased rate of absorption, time
to reach peak, and AUC of
rifampin
Opposing effects on neutrophil motility

and lymphocyte transformation
Increased alcohol effect or

convulsions
Increased effect
Increased neurotoxicity
CNS effects, dizziness, drowsiness
Increased phenytoin
concentrations
Decrease in or nullification of
clofazimines antiinflammatory
effects
Increased incidence of PCP
recurrence
Opposing effects on neutrophil motility

and lymphocyte transformation in vitro

Increased phenytoin clearance

Additive
Additive
Inhibition of hepatic metablism
264
10
10.2
Interacting Drugs
Folic acid antagonists
Nitrite
Nitrofuratoin
Pyrimethamine
Primaquine
Rifampin
Saquinavir
Trimethoprim
Zidovudine
Didanosine with
Benzodiazepines
Co-trimoxazole
Dapsone
( )
Adverse Effect
Increased risk of hematologic
toxicity
Increased risk of hemolysis in G6-PD deficient patients
Increased risk of hemolysis in G6-PD deficient patients
toxicity
Increased risk of hemolysis in G6-PD
Decreased dapsone serum
concentrations
Increased dapsone toxicity
Increased dapsone serum
concentrations; increased risk of
adverse effects
toxicity
Additive
Increased confusion
Increased risk of pancreatitis
Increased incidence of PCP
recurrence

Additive
Antacids necessary for antiviral
absorption may have impeded
absorption
Antacids necessary for didanosine
administration raise gastric pH too high
for ketoconazole absorption
Additive
Concomitant antacids bind quinolones
and prevent absorption
Ganciclovir
Indinavir
Itraconazole
Ketoconazole
In vitro antiretroviral antagonism

Decreased indinavir effect
Decreased itraconazole effect
Decreased absorption;administer >
2 hr before didanosine
Pentamidine
Quinolones

Decreased absorption; decreased
serum concentration of the
quinolones
Decreased absorption; decreased
serum concentration of the
tetracyclines
Tetracyclines
Zalcitabine
Erythromycins with
Astemizole
Benzodiazepines
Bromocriptine
Carbamazepine
Cisapride
Clindamycin
Clozapine
Corticosteroids
Probable Mechanism
Cyclosporin
Digoxin
Hypoprothrombinemia potentiated
Cardiotoxicity
Increased benzodiazepine toxicity
Increased toxicity
Cardiotoxicity
Antagonism
Increased clozapine toxicity
Increased effect and possible
toxicity of methylprednisolone
Disopyramide
Ergot alkaloids
Cardiac arrhythmias
Additive
Additive
Additive
Additive
Hepatic enzyme induction
Additive
Concomitant antacids bind tetracyclines

and prevent absorption
Additive
Increased bioavailability
Target site competition
Decreased excretion
Probably decreased metabolism
265
10
10.2
Interacting Drugs
Felodipine
HMG-CoA reductase
inhibitors
Loratadine
Phenytoin
Ritonavir
Tacrolimus
Theophylline
Valproic acid
Vinblastine
Zafirlukast
Ethionamide with
Aminosalicylic acid
BCG vaccine
Cycloserine
Ethambutol
Isoniazid
Pyrazinamide
Rifampin
Fluconazole with
Amitriptyline
Amphotericin B
Astemizole
Benzodiazepines
Cimetidine
Cisapride
Cyclosporin
Dihydropyridines
HMG-CoA reductase
inhibitors
Phenytoin
Quetiapine fumarate
Rifampin
Sulfonylureas
Tacrolimus
Thiazides
Zidovudine
( )
Adverse Effect
Probable Mechanism
Increased toxicity
Increased risk of rhabdomyolysis
Decreased clearance
Increased loratadine toxicity

Possible increased or decreased
effect
Increased erythromycin toxicity
Increased theophylline effect and
possible toxicity
Increased valproic acid toxicity
Increased vinblastine toxicity
Decreased zatirlukast effect
Altered metabolism
Increased GI
distress/hepatotoxicity
Negates BCG effect
Increased ethambutol toxicity
Increased hepatotoxicity
Increased amitriptyline toxicity

Possible antagonism in animal
models
Prolonged Q-T interval and
Decreased fluconazole effect
Increased risk of cardiotoxicity
Increased cyclosporin
concentrations
Increased dihydropyridine toxicity
Increased phenytoin
concentrations
Possible increased quetiapine
concentrations
Decreased fluconazole
concentrations
Increased plasma concentrations
and decreased metabolism of
glipizide and glibenclamide
Increased fluconazole
concentrations and AUC
Increased zidovudine
concentrations

Additive
Additive
Additive
Additive
Inhibition of antihistamine metabolism

266
10
10.2
Interacting Drugs
Fluoroquinolones with
Antacids
BCG vaccine
Chloramphenicol
Cyclosporin
Didanosine
Iron
Nitrofurantoin
NSAIDs
Pirenzepine
Probenecid
Rifampin
Sucralfate
Tetracycline
Theophylline
Zinc
Foscarnet with
Acyclovir
Co-trimoxazole
Pentamidine
Probenecid
Furazolidone with
Alcohol
Antidepressants
Sympathomimetics
Ganciclovir with
Aminoglycosides
Amphotericin B
Co-trimoxazole
Cyclosporin
( )
Adverse Effect
Probable Mechanism
Decreased fluoroquinolone effect

with aluminum or magnesium
antacids
Prolonged prothrombin times
Negates BCG effect
Inhibition in vitro of norfloxacin
bactericidal activity
Increased risk of nephrotoxicity;
increased serum cyclosporin
concentrations
Decreased fluoroquinolone effect
Decreased serum fluoroquinolone
concentrations
Decreased norfloxacin activity
Possible increased risk of CNS
stimulation
Decreased rate of fluoroquinolone
absorption
Increased serum concentrations of
quinolones; prolonged AUCs
concentrations
Possible theophylline toxicity
concentrations
increased hypocalcemia
Increased foscarnet serum
concentrations; increased
possibility of adverse effects
Additive
Additive
Additive
Disulfiram-like effect
Either inhibition of aldehyde

dehydrogenase or inhibition of
monoamine oxidase
Additive
Increased norepinephrine availability
Increased adverse effects

Hypertensive crisis
replication inhibition of rapidly
dividing host cells
Replication inhibition of rapidly
dividing host cells

In vitro antagonism
Decreased tubular secretion
Decreased tubular secretion
Additive
Additive; additive
Additive
267
10
10.2
Interacting Drugs
Cytotoxic
antineoplastics
Dapsone
Didanosine
Flucytosine
Imipenem
Immunosuppressives
Nucleoside analogues
Pentamidine
Probenecid
Pyrimethamine
Tacrolimus
Zidovudine
Griseofulvin with
Alcohol
Contraceptives, oral
Phenobarbital
Hydroxychloroquine with
Digoxin
Imipenem with
Aztreonam
Cephalosporines
Chloramphenicol
Extended-spectrum
penicillins
Ganciclovir
Isoniazid with
Alcohol
Aluminum antacids
Aminosalicylic acid
Benzodiazepines
( )
Adverse Effect
Probable Mechanism

dividing host cells
dividing host cells
dividing host cells
Generalized seizures
Increased suppression of bone
marrow and immune system
dividing host cells
dividing host cells
Increased ganciclovir
concentrations; prolonged AUC
dividing host cells
Increased risk of nephrotoxicity
In vitro antiretroviral antagonism;
increased risk of hematologic
toxicity
Additive
Increased alcohol effects,

tachycardia and flushing
Decreased anticoagulant effect
Decreased contraceptive effect
Decreased griseofulvin
concentrations
Antagonism
Antagonism
Antagonism; administer a few
hours after imipenem
Antagonism
-Lactamase induction
Generalized seizures
Increased incidence of hepatitis;

decreased isoniazid effect in some
alcoholic patients
Mechanism not established;

increased metabolism
Decreased isoniazid effect

Increased isoniazid concentrations
Possible increased anticoagulant
effect
Pharmacologic effects of
benzodiazepines may be
increased; documented for
diazepam and triazolam
Reduced acetylation
Additive
Additive
Additive
Additive
Additive
Additive
Additive
Decrease in tubular secretion

Decreased absorption or hepatic
enzyme induction
268
10
10.2
Interacting Drugs
( )
Adverse Effect
BCG vaccine
Vaccine may be ineffective
Carbamazepine
Cyloserine
Disulfiram
Itraconazole
Ketoconazole
Phenytoin
Rifampin
Increased toxicity of both drugs

CNS effects, dizziness, drowsiness
Psychotic episodes, ataxia
Decreased itraconazole activity
Decreased ketoconazole effect
Possible increased isoniazid
hepatotoxicity
Itraconazole with
Amphotercin B
Antacids
Astemizole
Barbiturates
Benzodiazepines
Carbamazepine
Cisapride
Cyclosporin
Probable Mechanism
Isoniazid inhibits multiplication of
BCG
Altered metabolism
Altered dopamine metabolism
Increased metalism
Decreased concentraiton
Possible increased toxic metabolites
In vitro antagonism
Possible decreased itraconazole

bioavailability
Increased anticoagulant effect
Possible prolongation of Q-T
interval and arrhythmias
Increased CNS effects
Possible increased in cyclosporin
concentrations
Increased digoxin toxicity
Increased dihydropyridine effect
Decreased itraconazole
bioavailability
Didanosine
Digoxin
Dihydropyridines
Histamine H2
antagonists
HMG-CoA reductase
inhibitors
Omeprazole/lansoprazole Decreased itraconazole
bioavailability
Phenytoin
Rifampin
Decreased systemic bioavailability
of itraconazole
Tacrolimus
Ketoconazole with
Alcohol
Possible disultflram-like reaction
Antacids
Astemizole
Benzodiazepines
Carbamazepine
Cisapride
Corticosteroids
Increased methylprednisolone
effect
Cyclosporin
Increased concentration of
cyclosporin in blood
Didanosine
Dihydropyridines
Increased dihydropyridine effect
Donepezil
Increased cholinominetic effects
Decreased gastric acidity
Decreased metabolsim
Inhibition of antihistamine
Metabolism
269
10
10.2
Interacting Drugs
( )
Adverse Effect
Probable Mechanism
Histamine H2
antagonists
Hepatotoxic agents
HMG-CoA reductase
inhibitors
Indinavir
Isonizid
Possibe decreased antifungal

effect
Increased indinavir toxicity

Loratadine
Omeprazole/
Lansoprazole
Phenytoin
Increased loratadine concentratios

Decreased ketoconazole
bioavailability
Altered effects of one or both
drugs
Increased risk of quetiapine
toxicity
Decreased rifampin and
ketoconazole effects
Increased ketoconazole
concentrations
Increased saquinavir
concentrations
Decreased theophylline
concentrations
Increased lamivudine
concentrations
concentrations
concentrations
concentrations
Decreased clearance
Decreased mebendazole
concentrations
Decreased mebendazole
concentrations
Hepatic microsomal enzyme induction
Mild disulfiram-like symptoms
Possible inhibition of intermediary

metabolism of alcohol
Quetiapine fumarate
Rifampicin
Ritonavir
Saquinavir
Tacrolimus
Theophylline
Lamivudine with
Nelfinavir
Sulfonamides
Trimethoprim
Zidovudine
Mebendazole with
Carbamazepine
Phenytoin
Metronidazole with
Alcohol
Astemizole
Azathioprine
Barbiturates
Carbamazepine
Cimetidine
Disulfiram
Fluorouracil
Lithium

Possible prolongation of the Q-T
interval and arrhythmias
Transient neutropenia
Decreased metronidazole effect
with phenobarbital
Increased toxicity
Possible increased metronidazole
toxicity
Organic brain syndrome
Transient neutropenia
Lithium toxicity
Additive
Altered metabolism
Decreased blood concentrations
Decreased clearance
Decreased clearance
Hepatic microsomal enzyme induction
Mechanism not estabished

Probably increased metabolism
270
10
10.2
Interacting Drugs
Miconazole with
Aminoglycosides
Amphotericin B
Astemizole
Cisapride
Cyclosporin
Hypoglycemics,
sulfonylurea
Phenytoin
Nalidixic acid with
Antacids
Nevirapine with
Cimetidine
Clarithromycin
Erythromycin
Indinavir
Ketoconazole
Rifamycins
Zidovudine
Nitrofurantoin with
Antacids
Fluoroquinolones
Probenecid
Sulfinpyrazone
( )
Adverse Effect
Probable Mechanism
Possible decreased tobramycin

concentration
Possible antagonism in vitro
Severe hypoglycemia
Decreased nalidixic acid serum

concentrations
Impaired absorption
Increased nevirapine
concentrations
concentrations
concentrations
Decreased indinavir
concentrations
Incereased nevirapine
concentration
Decreased ritonavia
concentrations
concentrations
Possible decreased nitrofurantoin

effect
In vitro antagonism of quinolone
activity
Increased nitrofurantoin serum
concentrations
Increased nitrofurantoin serum
concentrations
Para-aminosalicylic acid:see
Aminosalicylic acid
Pentamidine with
Aminoglycosides
Amphotericin B
Colistin
Cisplatin
Foscarnet
Hypocalcemia
Polymyxins
Vancomycin
Piperazine with
Chlorpromazine
Seizures
Pyrantel pamoate
Decreased piperazine and pyrantel
pamoate activity

Inhibition of antihistamine metabolism
Displacement from binding sites

Inhibition of renal excretion
Inhibition of renal excretion
Additive
Additive
Additive
Additive
Additive
Additive
Antagonism
271
10
10.2
Interacting Drugs
Polymyxin B with
Aminoglycoside
antibiotics
Neuromuscular
blocking agents
Parenteral quinidine
Parenteral quinine
Vancomycin
Primaquine with
Ritonavir
Protease inhibitors
(except ritonavir) with
Astemizole
Barbiturates
Benzodiazepines
Carbamazepine
Cisapride
Clarithromycin
Dihydropyridines
Ergot derivatives
Ketoconazole
Phenytoin
Rifampicin
Ritonavir
Pyrantel pamoate with
Piperazine
Theophylline
Quinine with
Acetazolamide
Aluminum antacids
Astemizole
Cimetidine
Digoxin
Flecainide
Heparin
Mefloquine
Neuromuscular
blocking agents
Ritonavir
Sodium bicarbonate
Ribavirin with
Zalcitabine
Zidovudine
( )
Adverse Effect
Probable Mechanism
increased neuromuscular blockade
Increased neuromuscular
blockade
Additive
Increased primaquine
concentrations
Deceased metabolism
Decreased protease inhibitor effect
Decreased protease inhibitor
toxicity
Increased protease inhibitor
toxicity
toxicity
Decreased protease inhibitor effect
Decreased protase inhibitor effect
toxicity
Decreased pyrantel pamoate and

piperazine activity
Increased theophylline toxicity
Antagonism
Increased quinine serum

concentrations; increased toxicity
Decreased quinine serum
concentrations
Potentiation of
hypoprothombinemia effect
Decreased quinine clearance;
prolonged AUCs
Increased digoxin concentrations
Increased flecainide toxicity
Decreased anticoagulant effect
Increased cardiac events
blocking effects
Increased quinine toxicity
Increased quinine serum
concentrations; increased toxicity
Decreased clearance from increased

urinary pH
In vitro retroviral antagonism

In vitro retroviral antagonism

Additive
Additive
Additive
Additive
Decrased metabolism
Decreased clearance
Hepatic suppression of synthesis of

vitamin K-dependent clotting factors
Hepatic enzyme inhibition
Additive
Additive
Decreased clearance from increased
urinary pH
272
10
10.2
Interacting Drugs
Rifamycins with
Analgesics
Anticonvulsants
Barbiturates
BCG vaccine
Beta blockers
Cardiac glycosides
Chloramphenicol
Clarithromycin
Clofibrate
Contraceptives, oral
Corticosteroids
Cyclosporin
Dapsone
Delavirdine
Diazepam
Digitalis
Dihydropyridines
Disopyrimide
Doxycycline
Estrogens
Ethionamide
Fluconazole
HMG-CoA reductase
inhibitors
Hypoglycemics, oral
Indinavir
Isoniazid
Itraconazole
( )
Adverse Effect
Probable Mechanism
Possible decreased concentrations

and activity
and activity
and activity
and activity
and activity
and activity
and activity
and activity
rifamycin toxicity
and activity
and activity
and activity
and activity
and activity
Decreased delavirdine
rifamycin toxicity
and activity
Decreased digitoxin and digoxin
effect
Decreased dihydropyridine effect
and activity
Decreased doxycycline effect
Decreased estrogen concentrations
Increased hepatoxicity
Decreased fluconazole effect
Decreased HMG effect

and activity
Decreased indinavir effect
Possible increased hepatotoxicity
Additive
Possible increased toxic metabolites
273
10
10.2
Interacting Drugs
( )
Adverse Effect
Probable Mechanism
Ketoconazole

and activity
Mexiletine

and activity
and activity
Decreased nelfinavir effect
Decreased nevirapine effect

and activity
and activity
Decreased ritonavir
effect/increased rifamycin toxicity
Decreased saquinavir
effect/increased rifamycin toxicity
Decreased terbinafine effect
Decreased tacrolimus effect
and activity
and activity
concentrations/AUCs
Increased amiodarone toxicity risk

Increased hypoglycemia risk
Increased anticoagulant response

risk
Increased CNS toxicity risk
Increased beta blocker toxicity
risk
Increased seizure risk
Decreased ritonavir
efficacy/increased carbamazepine
toxicity
Increased macrolide toxicity risk
Increased risk of clozapine
toxicity
Increased cyclosporin toxicity risk
risk
Increased diltiazem toxicity risk
Increased risk of disopyramide
toxicity
Increased risk of doxorubicin
toxicity
Increased risk of macrolide
toxicity
Narcotics
Nelfinavir
Nevirapine
Progestins
Quinidine
Ritonavir
Saquinavir
Tacrolimus
Terbinafine
Theophylline
Verapamil
Zidovudine
Ritonavir with
Amiodarone
Antihypoglycemics,
oral
Astemizole
Benzodiazepines
Beta blockers
Bupropion
Carbamazepine
Cisapride
Clarithromycin
Clozapine
Cyclosporin
Dihydropyridines
Diltiazem
Disopyramide
Doxorublein
Erythromycin
274
10
10.2
Interacting Drugs
Flecainide
HMG-CoA reductase
inhibitors
Nefazodone
Nelfinavir
Phenytoin
Rifampin
Risperidone
Saquinavir
SSRI antidepressants
Tacrolimus
Tamoxifen
Theophylline
Tramadol
Tricyclic
antidepressants
Valproic acid
Verapamil
( )
Adverse Effect
Increased risk of flecainide
toxicity
Increased risk of nefazodone

toxicity
Increased risk of nelfinavir
toxicity
Decreased ritonavir
effect/increased phenytoin toxicity
Decreased ritonavir efficacy
Increased risk of risperidone
toxicity
Increased risk saquinavir toxicity
Increased risk of SSRI toxicity
Increased risk of tacolimus
toxicity
Increased risk of tamoxifen
toxicity
Decreased efficacy
Increased risk of tramadol toxicity
Increased risk of tricyclic toxicity
Decreased efficacy of valproic

acid
Increased risk of verapamil
toxicity
Increased risk of zolpidem toxicity
Increased clearance
Zolpidem
Spectinomycin with
Lithium
Increased lithium toxicity
Sulfadoxine/Pyrimethamine with
Lorazepam
Mild hepatoxicity
PABA
Decreased pyrimethamine effect
Sulfonamides
Increased toxicity
Trimethoprim
Increased toxicity
Sulfonamides with
Antibiotics
Altered action of sulfasalazine
Barbiturates
Cyclosporin
Digoxin
Folic acid
Hypoglycemics,
sulfonylurea
Iron
Lamivudine
Methotrexate
Probable Mechanism
Increased thiopental effect

Decreased cyclosporin effect with
sulfamethazine
Possible decreased digoxin effect
with sulfasalazine
Decreased absorption, metabolism,
and concentrations with
sulfasalazine
Increased hypoglycemic efffect
Decreased sulfasalazine serum
concentrations
Increased lamivudine toxicity
Possible increased methotrexate
toxicity
Decrease metabolism
Increased clearance
Interference with pyrimethamine action
Additive
Additive
Alteration of intestinal flora
Decreased metabolism and
displacement from binding sites
Decreased albumin binding
Possible increased metabolism
Decreased digoxin absorption
Inhibition of hepatic fotate metabolism,
intestinal transport of folic acid, and
jejunal brushborder folate conjugase
Chelation
Decreased renal clearance and
displacement from binding
Decreased renal clearance and
displacement from binding
275
10
10.2
Interacting Drugs
PABA
( )
Adverse Effect
Probable Mechanism
Possible antagonism of
sulfonamide action
Crystallization of sulfonamides in
the urine
Increased phenytoin effect, except
possibly with sulfisoxazole
Possible antagonism of
sulfonamide action
Competition for PABA site
Increased thiopental effect;

decreased dose necessary when
given with sulfisoxazole
Plasma protein-binding competition
Antacids, oral
Antidepressants,
tricyclic
Barbiturates
Carbamazepine
Contraceptive, oral
Decreased doxycycline effect in

alcoholic patients
In vitro antagonism; no in vivo
support
Decreased oral tetracycline effects
Localized hemosiderosis with
amitriptyline and minocycline
Decreased contraceptive effect
Digoxin
Iron, oral
Decreased tetracycline effect, but

not with doxycycline; decreased
iron effect
Decreased concentrations of
tetracyclines
Increased lithium toxicity
Possible increased risk of
methotrexate toxicity
In vitro antagonism; rare in vivo
support for this
Possible decreased doxycycline
effect
Possible theophylline toxicity
Decreased tetracycline effect
Paraldehyde
Phenytoin
Procaine
Thiopental
Tetracyclines with
Alcohol
Aminoglycosides
Kaolin/pectin
Lithium
Methotrexate
Penicillins
Phenytoin
Rifampin
Theophylline
Zinc sulfate
Thiabendazole with
Theophylline
Trimethoprim with
ACE inhibitors
Amiloride
Azathioprine
Cyclosporin
Dapsone
Digoxin
Acidification of the urine

Competition for PABA site

Decreased tetracycline absorption
Possible synergism
Possible decreased enterohepatic
circulation of estrogen
Increased theophylline toxicity
Hyperkalemia
Trimethoprim may potentiate
hyponatremia caused by
concomitant use of amiloride with
thiazide diuretics
Leukopenia
Increased dapsone toxicity
Possible increased digoxin effect
Reduced potassium clearance

Additive

Synergism
Altered clearance
Decreased renal excretion and possibly
decreased metabolism
276
10
10.2
Interacting Drugs
Methotrexate
Phenytoin
Thiazide diuretics
Vancomycin with
Aminoglycosides
Amphotericin B
Bacitracin
Cephalosporins
Cisplatin
Colistin
Digoxin
Polymyxins
Warfarin
Vidarabine with
Allopurinol
Theophylline
Zalcitabine with
Aminoglycosides
Amphotericin B
Chloramphenicol
Cimetidine
Cisplatin
Co-trimoxazole
Dapsone
Didanosine
Disulfiram
Foscarnet
Gold
Hydralazine
Metronidazole
Nitrofurantoin
Pentamidine
Phenytoin
( )
Adverse Effect
Probable Mechanism
Increased methotrexate toxicity

Increased phenytoin serum
concentrations with increased risk
of phenytoin toxicity; increased
risk of folate deficiency
Trimethoprim may potentiate
hyponatremia caused by
concomitant use of amiloride with
thiazide diuretics
Decreased clearance
Inhibition of hepatic metabolism;
additive
Possible increased nephrotoxicity

and ototoxicity
Possible decreased digoxin effect
Increased risk of bleeding
Possibly additive
Increased theophylline effect
Increased risk of peripheral

neuropathy
neuropathy
neuropathy
Increased zalcitabine toxicity
neuropathy
Increased risk pancreatitis
neuropathy
neuropathy
neuropathy
neuropathy
neuropathy
neuropathy
neuropathy
neuropathy
neuropathy
Decreased clearance of zalcitabine
Additive
Additive
Additive
Additive
Additive
Additive
Possibly decreased absorption
Additive

Additive
Decreased clearance
Additive
Additive
Additive
Additive
Additive
Additive
Additive
Additive
Additive
Additive
Additive
277
10
10.2
Interacting Drugs
Ribavirin
Vincristine
Zidovudine with
Acetaminophen
(Paracetamol)
Acyclovir
Amphotercin B
Antimycobacterials
Aspirin
Cimetidine
Clarithromycin
Cytotoxic/myelosuppre
ssive agents
Dapsone
Flucytosine
Ganciclovir
Indomethacin
Interferon alpha
Interferon beta
Lorazepam
Nephrotoxic agents
Nucleoside analogues
Probenecid
Ribavirin
Rifamycins
Valproic acid
( )
Adverse Effect
Probable Mechanism

neuropathy; in vitro antiretroviral
antagonism
neuropathy
Additive; mechanism not established
Ganulocytopenia
Neurotoxicity
Increased risk of nephrotoxicity

and hematologic toxicity
hematologic toxicity
hemotologic toxicity
concentrations and AUCs
toxicity
Increased neutropenia
In vitro antiretroviral antagonism;
increaed risk of hematologic
toxicity
Increased hematologic toxicity
Increased risk of toxicity

toxicity
Increased and prolonged
zidovudine serum concentration
Decreased zidovudine efficacy
concentrations
Additive
Possible inhibition of zidovudine

glucuronidation
glucuronidation
glucuronidation
Additive
Additive
Additive
Mechanism not established; additive
glucuronidation
Additive
Decreased glucuronidation
glucuronidation
Increased serum concentrations;
decreased clearance
Additive
Inhibition of glucuronidation and/or
reduces renal excretion
Abbreviations: ACE, Angiotensin-converting enzyme; AUC. Area under the serum or plasma concentrationtime curve; BCG, Calmete-Guerin bacillus; CNS, central nerveous system; GI. gastrointestinal; G-6-PD,
glucose-6-phosphate dehydrogenase; HMG-CoA.
3-hydroxy-3-methyl-glutaryl-coenzyme A; NSAID,
Nonsteroidal anti-inflammatory drug; PABA, para-aminobenzoic acid; PAS, para-aminosalicylic acid; PCP,
Pneumocystis carinii pneumonia; SSRI, selective serotonin reuptake inhibitor.
278
10
1. Davies DM. Effects of Drugs on Infections. In: Davies DM, Ferner RE, de Glanville (eds).
Textbook of Adverse Drug Reactions. 5thed. London : Chapman & Hall Medical; 1998.
p 758-777.
2. Cloutier MJ. Antibiotics : Mechanisms of Action and the Acquisition of Resistance When
Magic Bullets Lose Their Magic. Am J Pharm Ed. 1995; 59:167 172.
3. Thielman NM. Antibiltic Associated Colitis. In: Mandell GL, Bennett JE, Dorin R. (eds).
Principles and Practice of Infectious Disease. 5th ed. Philadelphia Churchill Livingstone;
2000. p.1111-1126.
4. Amsden GW. Tables of Antimicrobial Agent Pharmocology. In: Mandell GL, Bennett JE,
Dorin R.(eds). Principles and Practice of Infectious Disease. 5th ed. Philadelphia : Churchill
Livingstone: 2000. p.551-601.
279
ADR / Pharmacological Group

Abdomen feels bloated
Gastrointestinal agents
Laxatives
Somatotrophic hormones
Abdominal cramps
Anthelmintics
Anthraquinone glycosides
Antidiuretic hormones
Antivirals
Diagnostic agents
Docusate
Estrogen antagonist antineoplastics
Laxatives
Monobactams
Organic iodinates contrast media
Parasympathomimetics
Pilocarpine
Posterior pituitary hormones
Sweetening agents
Typhoid vaccines
Vasopressins
Abdominal discomfort
Anthelmintics
Antifungals
Antivirals
Bile acid binding resins
Calcium antagonist vasodilators
Diagnostic agents
Ergot compounds
Laxatives
Lincomycin
Lipid regulating agent
Macrolides
Medicinal enzymes
Sex hormones
Sweetening agents
Abdominal distension
Bulk laxatives
Chloral sedatives
Hypoglycaemics
Abdominal pain
4 Quinolones
ACE inhibitors
Amino acids
Analgesics and anti-inflammatory drugs
Anthelmintics
Antiandrogens
Antianginal vasodilators
Anticholinesterase parasympathomimetics
Antidepressants
Antidotes
Antiemetics
Antimalarials
Antimuscarinics
Antineoplastics
Antituberculous agents
Antiulcer agents
Antivirals
Aspartic acid
Bisphosphonates
Carbapenems
Cardiac glycosides
Catechol O-methyl transferase inhibitors
Central stimulants
Cephalosporins
Clofibrate and analogues
Colchicum alkaloids
Colony stimulating factors
Contrast media
Digitalis
Dopaminergic antiparkinsonian agents
E series prostaglandins
Ergolines
Ergot compounds
Essential amino acids
Gonad regulating hormones
HMG CoA reductase inhibitors
Hydroxyquinoline antiprotozoals
Imidazole antifungaals
Interleukins
Leukotriene inhibitors
Lipid regulating agents
Medicinal enzymes
Neuroleptics
Opioid antagonists
Oral hypoglycaemics
Oxazolidinedione antiepileptics
Pilocarpine
Prophylactic antiasthmatics
Triazole antifungals
Vasodilator antihypertensives
Vitamin E substances
Vitamins
Abnormal granulation tissue
Chlorine releasing substances
Abnormal uterine bleeding
Anabolics
Beta sympathomimetic vasodilators
Beta2 selective stimulants
Sex hormones
Abnormal weight gain
Alpha blocking antihypertensives
Anabolics
Antiandrogens
Antidepressants
Antiepileptics
Antiulcer agents
Ergot compounds
Estrogens
Flupenthixols
Fluphenazine
H1 antagonist antihistamines
280

Haloperidols
Immunosuppressants
Lithium
Neuroleptics
Norgestrels
Progestogens
Sex hormones
Skeletal muscle relaxants
Zuclopenthixols
Abnormal weight loss
ACE inhibitors
Anabolics
Antiandrogens
Antidepressants
Antiepileptics
Antifolate antineoplastics
Butyrophenone neuroleptics
Estrogens
Haloperidols
Norgestrel
Progestogens
Sex hormones
Thyroid agents
Vitamins
Abnormalities of the hair
Antiandrogens
ACE inhibitor symptom complex collagen
vascular
ACE inhibitors
Acidosis
Glycol and glycerol esters
Acne
Anabolics
Hydantoin antiepileptics
Norgestrels
Phenytoin
Progestogens
Sex hormones
Acquired hypothyroidism
Antithyroid agents
Class III antiarrhythmics
Iodides
Iodine compounds
Iodophores
Lithium
Acquired pyloric obstruction
Acute bronchitis/bronchiolitis
Antiulcer agents
Acute closed-angle glaucoma
Acute confusional state
Opioid analgesics
Acute conjunctivitis
Anthelmintics
Antivirals
Carbonic anhydrase inhibitors
Organic iodinated contrast media
Retinoic acid dermatological agents
Sedatives
Acute coronary insufficiency
Vasopressins
Acute cystitis
Nitrogen mustards
Acute hepatic failure
Antiepileptics
Xanthine oxidase inhibitors
Acute hepatitis
4 aminoquinoline antimalarials
ACE inhibitors
Antiadrogens
Antibacterial agents
Antibiotic antituberculous agents
Antifungals
Antiprotozoals
Beta lactamase inhibitors
Carbazepine antiepileptics
Chelating agents
Class I antiarrhythmics
Gold salts
Histamine H2 antagonists
Hydrazine MAOI antidepressants
Immunosuppressants
Indanedione anticoagulants
Inhalation anaesthetics
Isoxazolyl penicillins
Macrolides
Methadone and analogues
MAOIs depressants
Neuroleptics
Nitrofuran antimicrobials
Nitrofuran antiprotozoals
Oral hypoglycaemics
Phenytoin
Sex hormones
Sulphone antileprotics
281

Sulphonylurea hypoglycaemics
Thiouracil antithyroid agents
Thiourea antithyroid agents
Trimethoprim sulphonamide combinations
Uricosuric agents
Vitamin B substances
Acute laryngitis
Medicinal enzymes
Acute myocardial infarction
ACE inhibitors
Alpha blocking vasodilators
Ergot compounds
Erythropoietin
Nitrogen mustards
Serotonin and analogues
Acute myocarditis
Neuroleptics
Salicylate analgesics
Acute nasopharyngitis
Acute necrosis of liver
Antiepileptics
Beta blockers
Centrally acting antihypertensives
Ester type anaesthetics
Hydrazide antituberculous agents
Nitrogen mustards
Acute pancreatitis
ACE inhibitors
Antiepileptics
Antivirals
Coumarin anticoagulants
Diamidine antiprotozoals
Immunosuppressants
Loop diuretics
Oxytetracyclines
Sulphonamides
Tetracyclines
Thiazide diuretics
Acute pericarditis
Neuroleptics
Acute pharyngitis
Antiulcer agents
GABA related antiepileptics

Medicinal enzymes
Acute renal failure
Antineoplastics
Antiviral
Cinchona antimalarials
Immunosuppressants
Polyene antibiotics
Uricosuric agents
Acute renal tubular necrosis
4 Quinolones
Aminoglycosides
Antineoplastics
Edetates
Immunosuppressants
Polyene antibiotics
Acute respiratory infections
Lipid regulating antihistamines
Acute / subacute liver necrosis
4 Quinolones
Antiandrogens
Antidepressants
Sulphonamides
Uricosuric agents
Adult respiratory distress syndrome
Blood products
Aggression
Antiepileptics
Central stimulants
Neuroleptics
Sedatives
Agitation
4 Quinolones
Anabolics
Antidepressants
Antiepileptics
Antiulcer agents
Antivirals
Benzodiazepine antagonists
Central stimulants
Corticosteroids
Ergolines
Flupenthixols
Fluphenazine
Haloperidols
Neuroleptics
282

Pilocarpine
Sedatives
Thyroid agents
Zuclopenthixols
Agranulocytosis
4 Quinolones
ACE inhibitors
Antibacterial agent
Antibiotic antifungals
Antidepressants
Antimalarials
Antithyroid agents
Antiulcer agents
Antivirals
Carbacephems
Carbamate sedatives
Cephalosporins
Cephamycins
Flupenthixols
Fluphenazine
Haloperidols
Lincomycin
Neuroleptics
Oral hypoglycaemics
Phenytoin
Succinimide antiepileptics
Sulphonamides
Zuclopenthixols
Alcohol - toxic effect
Alcoholic disinfectants
Antineoplastics
Glycols
Alkaline phosphatase raised
Fat soluble vitamins
Vitamins
Alkalosis
Expectorants
Allergic alveolitis
Antineoplastics
Allergic arthritis
Chelating agents
Tetracyclic antidepressants
Allergic dermatitis
Alcohol metabolism modifiers
Gold salts
Allergic/hypersensitivity reaction
4 Quinolones
ACE inhibitors
Alcoholic solvents
Amide type anaesthetics
Amidinopenicillins
Amino acids
Aminoglycosides
Aminopenicillanic derivatives
Aminopenicillins
Anthelmintics
Antibiotic antineoplastics
Antidiarrhoeals
Antidotes
Antiemetics
Antifungals
Antihypertensives
Antimalarials
Antineoplastics
Antipseudomonal penicillins
Antisera
Barbiturates
Benzylpenicillin and derivatives
Bioflavonoids
Bismuth salts
Blood clotting factors
Blood products
Bulk laxatives
Carbacephems
Carbapenems
Carboxypenicillins
Cardiac inotropic agents
Cephalosporins
Cephamycins
Chloramphenicols
Colouring agents
Contrast media
Cough suppressants
Cytoprotective agents
Dermatological agents
Dextrans
Diagnostic agents
Diagnostic dyes
Dibenzoylmethanes
283

Direct acting anticoagulants
Disinfectants
Docusate
Flavouring agents
Fluorescein diagnostic dyes
Fluorocarbon blood substitutes
Formaldehyde and related compounds
Glucose tests
Glycerol
Glycerophosphates
Gold salts
Haemostatics
Heparinoids
Hyaluronic acid
Hypothalamic and pituitary hormones
Immunological agents
Immunosuppressants
Insulin
Interleukins
Iodides
Iodine compounds
Iodophores
Isothiazolinones
Laxatives
Lecithin derivatives
Lincomycin
Local anaesthetics
Low molecular weight heparins
Macrolides
Medicinal enzymes
Mercurial diuretics
Monobactams
Monoclonal antibodies
Mucolytics
Natural penicillins
Neuroleptics
Nonoxinols
Nutritional agents
Oral hypoglycaemics
Organic mercurial disinfectants
Osmotic diuretics
Oxytetracyclines
Penicillinase resistant penicillins
Permanganates
Phenothiazine antihistamines
Phenoxymethylpenicillin and derivatives
Phenoxypenicillins
Phenylmercuric salts
Poliomyelitis vaccines
Polyene antibiotics
Polymyxins
Preservatives
Promethazines
Sedatives
Streptogramins
Sulphonamides
Sunscreen agents
Tetracyclines
Thiazide diuretics
Thyrotrophic hormones
Trimethoprim and derivatives
Triphenylmethane diagnostic dyes
Triphenylmethane disinfectant dyes
Typhoid vaccines
Ureido penicillins
Uricosuric agents
Vaccines
Vasopressins
Alopecia
4 Aminoquinoline antimalarials
ACE inhibitors
Anabolics
Antiepileptics
Antineoplastics
Antiulcer agents
Antivirals
Benzimidazole anthelmintics
Biguanide antimalarials
Colchicum alkaloids
Ergot compounds
Ethyleneimine antineoplastics
Fluorouracil
Gold salts
Heparinoids
Immunosuppressants
Nitrogen mustards
Nitrosoureas
Norgestrels
Progestogens
284

Sex hormones
Sulphur mustards
Amblyopia
Antidepressants
Pilocarpine
Amenorrhoea
Anabolics
Antiepileptics
Immunosuppressants
Sex hormones
Anaemia
4 Quinolones
Antineoplastics
Antivirals
Central stimulants
Immunosuppressants
Polyene antibiotics
Anal pain
Contrast media
Laxatives
Medicinal enzymes
Anaphylactic shock
4 Quinolones
Amidinopenicillins
Aminopenicillins
Antineoplastics
Antisera
Blood products
Carbacephems
Carbapenems
Carboxypenicillins
Cephalosporins
Cephamycins
Contrast media
Corticosteroids
Corticotrophic hormones
Dextrans
Erythropoietin
Heparinoids
Hyaluronic acid
Immunostimulants
Immunosuppressants
Iron compounds
Medicinal enzymes
Natural penicillins
Norgestrels
Opioid analgesics
Parenteral anaesthetics
Phenoxypenicillins
Platelet activating factor antagonists
Polyene antibiotics
Progestogens
Promethazine
Sedatives
Sex hormones
Specific immunoglobulins
Triphenylmethane diagnostic dyes
Ureido penicillins
Angina pectoric
Antiandrogens
Central stimulants
Ergot compounds
Nitrogen mustards
Thyroid agents
Vasopressins
Angioneurotic oedema
4 Quinolones
ACE inhibitors
Amidinopenicillins
Aminopenicillins
Angiotensin inhibiting antihypertensives
Antiepileptics
Antiulcer agents
Bisphosphonates
Carboxypenicillins
285

Heparinoids
Medicinal enzymes
Natural penicillins
Nitroimidazole antiprotozoals
Phenoxypenicillins
Promethazines
Ureido penicillins
Anosmia-loss of smell sense
4 Quinolones
Disinfectants
Antibody formation
Anxiety
Anxiousness
4 Quinolones
Amphetamines
Antidepressants
Antivirals
Barbiturate antiepileptics
Central stimulants
Neuroleptics
Opioid antagonist
Sympathomimetics
Apathy
Flupenthixols
Fluphenazine
Haloperidols
Neuroleptics
Zuclopenthixols
Aplastic anaemia
Antiepileptics
Antifungals
Antiprotozoals
Antithyroid agents
Carbacephems
Cephalosporins
Cephamycins
Chloramphenicols
Neuroleptics
Oral hypoglycaemics
Phenytoin
Uricosuric agents
Apnoea
Polymyxins
Sedatives
Appetite increased
Antiandrogens
Antidepressants
Antiepileptics
Neuroleptics
Appetite loss - anorexia
4 Methanolquinoline antimalarials
4 Quinolones
Amphetamines
Anorecitics
Anthelmintics
Antidepressants
Antiemetics
Antiepileptics
Antifungals
Antimony antiprotozoals
Antineoplastics
Antiulcer agents
Antivirals
Biguanide hypoglycaemics
Cardiac glycosides
Central stimulants
Cephalosporins
Digitalis
Interleukins
286

Lithium
Opioid antagonists
Polyene antibiotics
Sympathomimetics
Thiazide diuretics
Vaccines
Vitamins
Arthropathy
Asthenia
4 Quinolones
Antihypertsensives
Antineoplastics
Antiulcer agents
Antivirals
Cephalosporins
Interleukins
Neuroleptics
Asthma
Ataxia
4 Quinolones
Antidepressants
Antiemetics
Antiepileptics
Antineoplastics
Antivirals
Lithium
Promethazines
Sedatives
Atony of bladder
Organic solvents
Atopic dermatitis and related
Atrophy of breast
Progestogens
Sex hormones
Attention / concentration difficulty
Antiemetics
Antiepileptics
Antivirals
Neuroleptics
Avascular necrosis, head-femur
Corticosteroids
Backache
ACE inhibitors
Angiotensin inhibing antihypertensives
Antiulcer agents
Progestogens
Sex hormones
Bacterial infection
Antiulcer agents
Antivirals
Corticosteroids
Immunosuppressants
Interleukins
Medicinal enzymes
Bacterial pneumonia
Antivirals
Behavioural disturbance
Antidepressants
Ergot compounds
Sedatives
Benign neoplasm male breast
Antiandrogens
Biliary stasis
4 Quinolones
Birth trauma / asphyxia / hypoxin
Oxytocic hormones
Bleeding time increased
Blistering of skin
Blocked sinuses
Blood disorders
4 Aminonquinoline antimalarials
4 Quinolones
ACE inhibitors
Aldosterone inhibitors
Antiepileptics
Antifungals
Antineoplastics
Antivirals
Benzodiazepine sedatives
Carbacephems
Carbamate sedatives
287

Carbapenems
Cephalosporins
Cephamycins
Chelating agents
Chloramphenicols
Colchicum alkaloids
Gold salts
Immunosuppressants
Monobactams
Oxacephalosporins
Polyene antibiotics
Potassium sparing diuretics
Promethazines
Thiazide diuretics
Uricosuric agents
Blood in urine haematuria
Antivirals
Haemostatics
Blood pressure changes
Blood pressure raised
Sympathomimetics
Blood urate raised
Antivirals
Immunosuppressants
Loop diuretics
Medicinal enzymes
Thiazide diuretics
Blood urea raised
4 Quinolones
ACE inhibitors
Antivirals
Erythropoietin
Immunosuppressants
Interleukin 2
Blurred vision
4 Quinolones
Anabolics
Anthelmintics
Antiandrogens
Antidepressants
Antiemetics
Antiepileptics
Antimuscarinics
Antineoplastics
Antiprotozoals
Antiulcer agents
Carbonic anthydrase inhibitors
Cardiac glycosides
Central stimulants
Cholinesterase reactivators
Corticosteroids
Diagnostic agents
Digitalis
Flupenthixols
Fluphenazine
H1 antagnist antihistamines
Haloperidols
Immunosuppressants
Interleukins
Lithium
Neuroleptics
Oral hypoglycaemics
Oxytetracyclines
Polymyxins
Progestogen
Promethazines
Sedatives
Sexhormones
Smooth muscle relaxants
Tetracyclines
Zuclopenthixols
Bone marrow suppression
ACE inhibitors
Antimalarials
Antineoplastics
Antivirals
Fluorouracil
Immunosuppressants
Interleukin 2
Loop diuretics
Nitrogen mustards
Nitrosoureas
288

Bradycardia
Alpha adrenoceptor stimulants
Antiarrhythmics
Antidotes
Antiemetics
Antimuscarinics
Antineoplastics
Benzomorphan opioid analgesics
Beta blockers
Calcium salts
Cardioselective beta blockers
Central stimulants
Diagnostic agents
Ergot compounds
I series prostaglandins
Local anaesthetics
Neuroleptics
Opioid analgesics
Opioid peptides
Pethidine and analogues
Pilocarpine
Rauwolfia antihypertensives
Respiratory stimulants
Sympathomimetics
Vasodilators
Breath-holding
Breathlessness
Antiandrogens
Antineoplastics
Bronchospasm
4 Quinolones
Anthelmintics
Antiarrhythmics
Antiemetics
Antineoplastics
Antiulcer agents
Beta blockers
Blood products
Competitive muscle relaxants
Diagnostic agents
F series prostaglandins
Medicinal enzymes
Pilocarpine
Polymyxins
Promethazines
Sulphites
Sympathomimetics
Vasodilators
Bullous eruption
Antiulcer agents
Sedatives
Burning or stinging
Antifungals
Antivirals
Corticosteroids
Dithronols
Immunosuppressants
Medicinal enzymes
Vitamin D substances
Candidal vulvovaginitis
Cephalosporins
Candidiasis mouth / oesophagus / gastrointestinal
tra
Antiulcer agents
Carbapenems
Capillary hyperpermeability
Carcinoma
Triphenylmethane disinfectant dyes
Cardiac arrest
Antiemetics
289

Class IV antiarrhythmics
Local anaesthetics
Medicinal enzymes
Peripheral and cerebral vasodilators
Cardiac conduction disorders
Antiandrogens
Antineoplastics
Cardiac dysrhythmias
ACE inhibitor
Antiandrogens
Antiarrhythmics
Antidepressants
Antiemetics
Antimalarials
Antimuscarinics
Antineoplastics
Antivirals
Beta adrenoceptor stimulants
Calcium salts
Cardiac glycosides
Central stimulants
Digitalis
Ergolines
Flupenthixols
Fluphenazine
Haloperidols
Interleukins
Iron compounds
Isoprenaline
Neuroleptics
Oxytocic hormones
Phenytoin
Polyene antibiotics
Potassium salts
Promethazines

Sympathomimetics
Theophylline
Thyroid agents
Vasodilators
Zuclopenthixols
Cardiac murmur
Antineoplastics
Cardiomyopathy
Amphetamines
Anorectics
Anthracycline antibiotic antineoplastics
Central stimulants
Cardiovascular symptoms
Antivirals
Expectorants
Immunosuppressants
Lithium
Nitrogen mustards
Cataract
Corticosteroids
Flupenthixols
Fluphenazine
Haloperidols
Neuroleptics
Phenothiazine neuroleptics
Sex hormones
Zuclopenthixols
Cellulitis or abscess at site of injection
Antineoplastics
Antivirals
Calcitonin
Carbapenems
Flupenthixols
Fluphenazine
Haloperidols
Imidazile antifungals
Insulin
Insulin zinc suspensions
Lincomycin
Neuroleptics
290

Sedatives
Vaccines
Zuclopenthixols
Cerebellar ataxia
Fluorouracil
Pyrimidine antagonist antineoplastics
Cerebrovascular disorders
Change in bowel habit
Change in voice
ACE inhibitors
Anabolics
Medicinal enzymes
Progestogens
Sex hormones
Changes in breast size
Chest pain
Antiandrogens
Antiarrhythmics
Antidotes
Antiemetics
Antimuscarinics
Antiulcer agents
Central stimulants
Ergot compounds
Opioid antagonists
Sedatives
Sympathomimetics
Vasodilators
Chest tightness
Antiemetics
Childhood hyperkinetic syndr.
Chills with fever
Antineoplastics
Antiulcer agents
Interleukins
Chloasma
Norgestrels
Estrogens
Progestogens
Sex hormones
Choking sensation
Antiarrhythmics
Vasodilators
Cholangitis
Cholesterol gall stones
Cholinegic urticaria
Pilocarpine
Choreas
Central stimulants
Choreiform movement
Ganglion blocking antihypertensives
Chronic active hepatitis
Centrally acting antihypretensives
Sulphonamides
Chronic renal failure
Cold extremities
Sympathomimetics
Colicky abdominal pain
Anthelmintics
Laxatives
Coma
Alcoholic disinfectant
Anthelmintics
Antivirals
Lithium
Complete atrioventricular block
Cardiac glycosides
Digitalis
Complete epiphyseal arrest
Anabolics
Androgens
Sex hormones
Testosterones
Confusion
4 Quinolones
Anthelmintics
291

Antidepressants
Antidotes
Antiemetics
Antiepileptics
Antifungals
Antimuscarinics
Antineoplastics
Antiulcer agents
Antivirals
Carbacephems
Carbapenems
Cardiac glycosides
Cephalosporins
Cephamycins
Digitalis
Ergolines
Ergot compounds
Immunosuppressants
Local anaesthetics
Opioid analgesics
Osmotic diuretics
Polymyxins
Sedatives
Sympathomimetics
Confunct.vasc.disord., / cysts
Conjunctival blanching
Conjunctival deposits
Flupenthixols
Fluphenazine
Haloperidols
Neuroleptics
Zuclopenthixols
Constipation
ACE inhibitors
Anorectics
Antacid gastrointestinal agents
Antidepressants
Antidiarrhoeals
Antiemetics
Antimuscarinics
Antineoplastics
Antiulcer agents
Bisphosphonates
Cephalosporins
Contrast media
Cough suppressants
Ergolines
Ferric salts
Ferrous salts
Flupenthixols
Fulphenazine
Haloperidols
Interleukins
Iron compounds
Monoamine oxidase inhibiting antidepressants
Morphinan cough suppressants
Neuroleptics
Opioid analgesics
Opioid antagonists
Opioid peptides
Oral hypoglycaemics
Thiazide diuretics
Zuclopenthixols
Contact dermatitis
Anthelmintics
Disinfectants
Flupenthixols
Fluphenazine
Haloperidols
Neuroleptics
Zuclopenthixols
Contact lens corneal oedema
Estrogens
Sex hormones
Convulsions
4 Quinolones
Anthelmintics
Antidepressants
292

Antifungals
Antivirals
Carbapenems
Central stimulants
Erythropoietin
Flupenthixols
Fluphenazine
Haloperidols
Hydrozide antituberculous agents
Immunosuppressants
Lithium
Local anaesthetics
Neuroleptics
Opioid analgesics
Polyene antibiotics
Promethazines
Sympathomimetics
Theophylline xanthines
Zuclopenthixols
Coordination disorders (dyspraxia)
Antiemetics
Antiepileptics
Lithium
Promethazines
Sedatives
Corneal deposits
Antiprotozoals
Corneal disorders
Sex hormones
Corneal opacity
Flupenthixols
Fluphenazine
Haloperidols
Hydroquinone dermatological agents
Neuroleptics
Zuclopenthixols
Coronary artery spasm
Ergot compounds
Corpus cavernosum haematoma
Papaverine and analogues
Corticoadrenal insufficiency
Cough
ACE inhibitors
Anthelmintics
Antineoplastics
Antiulcer agents
Antivirals
Cranial nerve palsy
4 Quinolones
Creatine kinase level raised
Central stimulants
Depolarising muscle relaxants
Neuroleptics
Crystalluria
4 Quinolones
Cushings syndrome
Corticosteroids
Cyanide toxic effects
Cystitis
Antineoplastics
Darkened tongue
Antidepressants
Antidiarrhoeals
Antiulcer agents
Bismuth salts
Deafness
293

Loop diuretics
Macrolides
Polyene antibiotics
Decreased sweating
Degenerative skin disorders
Heparinoids
Dehydration
Interleukins
Delayed recovery from anaesthesia
Delirium
Cardiac glycosides
Chloral sedatives
Digitalis
Neuroleptics
Dental fluorosis
Fluorine compounds
Depression
4 Quinolones
Anabolics
Anorectics
Antidotes
Antiemetics
Antiepileptics
Antineoplastics
Antiulcer agents
Antivirals
Central stimulants
Estrogens
Flupenthixols
Fluphenazine
Haloperidols
Neuroleptics
Norgestrels
Progestogens
Promethazines
Sedatives
Sex hormones
Zuclopenthixols
Dermatosis
Antiprotozoals
Desire to defaecate
Diagnostic agents
Pilocarpine
Vasopressins
Desire to micturate
Diagnostic agents
Diabetes mellitur with ketoacidosis
Antivirals
Diarrhoea
4 Quinolones
ACE inhibitor
Alpha glucosidase inhibitors
Amidinopenicillins
Amino acids
Aminopenicillins
Anabolics
Anorectics
Anthelmintics
Antiandrogens
Antiemetics
Antifungals
Antihypertensives
Antileprotics
Antimalarials
Antineoplastics
Antiulcer agents
Antivirals
Aspartic acid
Beta blockets
Bile acids and salts
Bisphosphonates
Carbacephems
Carbapenems
Carboxypenicillins
Cardiac glycosides
Cation exchange resins
Central stimulants
Cephalosporins
Cephamycins
Chloramphenicols
294

Colchicum alkaloids
Contrast media
Corticosteroids
Diagnostic agents
Digitalis
Expectorants
Ferric salts
Ferrous salts
Glucose tests
Gold salts
Haemostatics
Hydroxynaphthoquinones
Immunosuppressants
Iron compounds
Lincomycin
Lithium
Macrolides
Magnesium salts
Medicinal enzymes
Monobactams
Neuroleptics
Nutritional carbohydrates
Opioid antagonists
Oral hypoglycaemics
Oxacephalosporins
Oxytetracyclines
Phenoxypenicillins
Pilocarpine
Polyene antibiotics
Sedatives
Sulphonamides
Tetracyclines
Thiazide diuretics
Thyroid agents
Typhoid vaccines
Ureido penicillins
Vasodilators
Vitamins
Diffculty swallowing solids
Antimuscarinics
Difficulty with micturition
Alkylating antineoplastics
Antidepressants
Antimuscarinics
Beta blockers
Flupenthixols
Fluphenazine
Haloperidols
Morphinan opioid analgesics
Neuroleptics
Opioid analgesics
Opioid peptides
Opium alkaloid opioid analgesics
Opium poppy substances
Zuclopenthixols
Diplopia / double vision
Antiepileptics
Ergolines
Polyene antibiotics
Sedatives
Direct coombs test positive
Carbacephems
Carbapenems
Cephalosporins
Cephamycins
Discolouration of teeth
Fluorine compounds
Oxytetracyclines
Tetracyclines
Disorders of calcium metabol.
Phenytoin
Disorders of conjunctiva
Interleukins
Disorientation
Antiemetics
Dizziness
295

4 Quinolones
Alcoholic solvents
Aldose reductase inhibitors
Anabolics
Anorectics
Anthelmintics
Antiandrogens
Antidepressants
Antidotes
Antiemetics
Antiepileptics
Antihypertensives
Antineoplastics
Antiprotozoals
Antiulcer agents
Antivirals
Bisphosphonates
Carbacephems
Central stimulants
Cephalosporins
Cephamycins
Contrast media
Cough suppressants
Diagnostic agents
Ergolines
Ergot compounds
Haemostatics
Immunosuppressants
Neuroleptics
Opioid antagonists
Phenytoin
Pilocarpine
Progestogens
Sedatives
Sex hormones
Sympathomimetics
Tetracyclines
Thiazide diuretics
Uricosuric agents
Drowsiness
4 Quinolones
Adrenergic neurone blocking antihypertensives
Anorectics
Anthelmintics
Antiandrogens
Antidepressants
Antidiarrhoeals
Antiemetics
Antiepileptics
Antineoplastics
Antiulcer agents
Antivirals
Cardiac glycosides
Central stimulants
Cephalosporins
Cough suppressants
Diagnostic agents
Digitalis
Ergolines
Ergot compounds
Flupenthixols
Fluphenazine
Haloperidols
Lithium
Neuroleptics
Norgestrels
Opioid analgesics
Opioid peptides
296

Progestogens
Promethazines
Sedatives
Sex hormones
Sympathomimetics
Zuclopenthixols
Drug dependence
Anorectics
Central stimulants
Opioid analgesics
Opioid peptides
Sedatives
Drug induced myelopathy
Drug psychoses
Anorectics
Antiemetics
Antiprotozoals
Antivirals
Central stimulants
Ergolines
Lithium
Sympathomimetics
Dry cough
ACE inhibitors
Dry eyes
Antimuscarinics
Beta blockers
Dry hair
Vitamins
Dry mouth
Anorectics
Antidepressants
Antiemetics
Antihypertensives
Antimuscarinics
Antiulcer agents
Antivirals
Aromatics
Central stimulants
Dermatologicsl agents
Ergolines
Flupenthixols
Fluphenazine
H1 antogonist antihistamines
Haloperidols
Neuroleptics
Opioid analgesics
Opioid peptides
Promethazines
Sedatives
Sympathomimetics
Zuclopenthixols
Dry skin
Antimuscarinics
Antivirals
Vitamins
Duodenal ulcer (DU)
Dysarthria
Lithium
Dyskinesia
Carbazepine antiepilepticcs
Central stimulants
Ergolines
Flupenthixols
Fluphenazine
Haloperidols
297

Neuroleptics
Phenytoin
Zuclopenthixols
Dysmenorrhoea
Immunosuppressants
Dyspepsia
4 Quinolones
ACE inhibitors
Anabolic
Antidepressants
Antimuscarinics
Antiulcer agents
Antivirals
Cephalosporins
Corticosteroids
Ergolines
Evening primrose oil
Interleukins
Neuroleptics
Thiazide diuretics
Dysphagia
4 Quinolones
Dyspnoea
4 Quinolones
Anthelmintics
Antiarrhythmics
Antidotes
Antiemetics
Antineoplastics
Antivirals
Diagnostic agents
Ergolines
Ergot compounds
Immunosuppressants
Interleukins
Iron compounds
Neuroleptics
Vasodilators
Dysuria
Antivirals
Selective noradrenaline reuptake inhibiting
antidepressants
Ecchymoses
Hyaluronic acid
Interleukins
Ectopic beats
Ectropion
Electrocardiogram (ECG) abnormal
Flupenthixols
Fluphenazine
Haloperidols
Lithium
Neuroleptics
Zuclopenthixols
Electroencephalogram (EEG) abnormal
Flupenthixols
Fluphenazine
Haloperidols
Neuroleptics
Pulmonary surfactants
Zuclopenthixols
Electrolytes abnormal
Antimalarials
Antineoplastics
Electrolytes
Emotional instability
Antiepileptics
Encephalitis post plague vacc.
Vaccines
Encephalopathy
Antiandrogens
Antiulcer agents
Interleukin 2
Endocrine, nutritional, metabolic and immunity di
Immunosuppressants
Enteritis / colitis
Anlgesics and anti-inflammatory drugs
Gold salts
Immunosuppressants
Eosinophilia
4 Quinolones
298

Antidepressants
Antivirals
Carbacephems
Carbapenems
Cephalosporins
Cephamycins
Lincomycin
Neuroleptics
Oxacephalosporins
Sulphonamides
Epididymitis
Epigastric pain
Beta blockers
Ergolines
Ferric salts
Ferrous salts
Iron compounds
Polyene antibiotics
Epileptic seizures clonic
Anthelmintics
Erythropoietin
Epileptic seizures tonic
Erythropoietin
Epileptiform seizures
Epiphora excess lacrimation
Chelating agents
Edetates
Opioid antagonists
Pilocarpine
Epistaxis
Analgesics and anti-imflammatory drugs
Corticosteroids
Ergolines
Gols salts
Erythema
4 Quinolones
ACE inhibitors

Antiandrogens
Antifungals
Antiulcer agents
Benzimidadole anthemintics
Bisphosphonates
Carbacephems
Carbapenems
Central stimulants
Cephalosporins
Cephamycins
Chloramphenicols
Contrast media
Estrogens
Flupenthixols
Fluphenazine
Haloperidols
Hyaluronic acid
Medicinal enzymes
Neuroleptics
Oral hypoglycaemics
Oxytetracyclines
Phenytoin
Rubefacient vasodilators
Sex hormones
Sulphonamides
Tetracyclines
Thiazide diuretics
Vaccines
Zuclopenthixols
Erythema multiforme
Anitibacterial agents
Central stimulants
Erythrocyte sedimentation rate (ERS) raised
Vitamins
299

Euphoria
Anbolics
Anorectics
Antiemetics
Central stimulants
Corticosteroids
Sedatives
Exanthema
Antidepressants
Typhoid vaccines
Excessive belching
Omega 3 triglycerides
Vasopressins
Excessive flatulence
Excessive salivation
Antiepileptics
Blood products
Carbamate sedatives
Neuroleptics
Pilocarpine
Excessive sweating
Anorectics
Antidepressants
Antidotes
Central stimulants
Diphenylbutylpiperidine neuroleptics
Isoprenaline
Opioid analgesics
Opioid antagonists
Opioid peptedes
Pilocarpine
Promethazines
Sedatives
Sketetal muscle relaxants
Thyroid agents
Vitamins
Excessive thirst
Antiandrogens
Antimuscarinics
Opioid antagonists
Vitamins
Exfoliative dermatitis
Amidinopenicillins
Aminoglycosides
Aminopencillanic derivatives
Aminopenicillins
Carbapenems
Carboxypenicillins
Dithranols
Gold salts
Natural penicillins
Oxytetracyclines
Phenoxymethylpenicilline and derivatives
Phenoxypenicillins
Sulphonamides
Tetracyclines
Theophylline
Ureido penicillins
Exfoliative erythema
Extrapyramidal symptoms
Antiemetics
Antihypertensives
Flupenthixols
Fluphenazine
300

Haloperidols
Neuroleptics
Promethazines
Zuclopenthixols
Eye pain
Eye symptoms
Eyelid entropion / trichiasis
Faecal impaction
Ferric salts
Ferrous salts
Iron compounds
Faeces colour: dark
Antidiarrhoeals
Antiulcer agents
Bismuth salts
Falls
Sedatives
Fatigue
ACE inhibitors
Antiandrogens
Antidepressants
Antidotes
Antiemetics
Antiepileptics
Antineoplastics
Antivirals
Beta blockers
Cardiac glycosides
Central stimulants
Digitalis
Immunosuppressants
Neuroleptics

Opioid antagonists
Sedatives
Thiazide diuretics
Trace elements
Vaccines
Feels hot / feverish
Antineoplastics
Aromatics
Female genital organ symptoms
Gonal regulating hormones
Feminising effects
Estrogens
Sex hormones
Fertility problems
Alkyl sulphonate antineoplastics
Anabolics
Ethyleneimine antineoplastics
Nitrogen mustards
Nitrosoureas
Sulphur mustards
Triazene antineoplastics
Fever
4 Quinolones
Anthelmintics
Antineoplastics
Antithyroid agents
Antiulcer agents
Antivirals
Fibrosing alveolitis
Fibrosis of penis
Flatulence / wind
4 Quinolones
Alpha glucosidase inhibitors
Antimuscarinics
Antiulcer agents
Antivirals
Bulk laxatives
Cephalosporins
Chloral sedatives
Corticosteroids
Dichloroacetamide antiprotozoals
301

Hypoglycaemics
Laxatives
Sweetening agents
Fluid retention
Anabolics
Androgens
Antineoplastics
Antiulcer agents
Corticosteroids
Estrogens
Liquorice
Norgestrels
Progestogens
Sex hormones
Testosterones
Uricosuric agents
Fluid / electrolyte / acid-base
Neuroleptics
Flushing
ACE inhibitors
Antiandrogens
Antiarrhythmics
Antidepressants
Antidotes
Antiemetics
Antihypertensives
Antimuscarinics
Antineoplastics
Antivirals
Calcitonin
Diagnostic agents
Diamindine antiprotozoals
Ergolines
Ergot compounds
Hyaluronic acid
Iron compounds
Magnesium salts
Opioid analgesics
Opioid peptides
Opium alkaloid pioid analgesics
Progestogens
Rubefacient vasodilators
Sex hormones
Thyroid agents
Uricosuric agents
Vasodilators
Folate-deficiency anaemia
Phenytoin
Frostbite
Local anaesthetics
Fructose in urine
Full blood count abnormal
Galactorrhoe
Antiandrogens
Antiemetics
Flupenthixols
Fluphenazine
Haloperoidols
Neuroleptics
Selective serotonin reuptake inhibitng
antidepressants
Zuclopenthixols
Gall stones
302

Gallbladder disorders incl Cholestasis
ACE inhibitors
Antiandrogens
Gold salts
Immunosuppressants
Macrolides
Neuroleptics
Oral hypoglycaemics
Phenytoin
Sex hormones
Sulphonamides
Trimethoprim sulphonamide combination
Gangrene
Ergot alkaloids
Ergot compounds
Gastric ulcer (GU)
Medicinal enzymes
Gastritis
Anlgesics and anti-inflammatory drugs
Antiepileptics
Antiulcer agents
Chloral sedatives
Ergolines
Gastrointestinal disturbances
Anabolics
Anorectics
Anthelmintics
Antiandrogens
Antidepressants
Antidotes
Antiepileptics
Antineoplastics
Antiprotozoals
Antiulcer agents
Antivirals
Beta blockers
Bisphosphonates
Calcium salts
Carbamate sedatives
Central stimulants
Corticosteroids
Cough suppressants
Diagnostic agents
Ergot compounds
Expectorants
Ferric salts
Ferrous salts
Haemostatics
Immunosuppressants
Iron compounds
Lithium
Loop diuretics
Medicinal enzymes
Mercurial diuretics
Mucolytics
Neuroleptics
Norgestrels
Oral hypoglycaemics
Pilocarpine
Progestogens
Promethazines
Sedatives
Sex hormones
Sympathomimetics
Theophylline
Thiazide diuretics
Trace elements
Uricosuric agents
Gastrointestinal haemorrhage
Antivirals
Colchicum alkaloids
Uricosuric agents
Gastrojejunal ulcer (GJU)
303

Giddiness
Antileprotics
Haemostatics
Lithium
Gilles de la Tourettes disorder
Central stimulants
Gingival hyperplasia
Immunosuppressants
Phenytoin
Gingivitis
Glossitis
Gold salts
Macrolides
Sulphonamides
Glucose toletance test impaired
Goitre
Antihyroid agents
Iodides
Iodine compounds
Iodine radiopharmaceuticals
Iodophores
Lithium
Goodpastures syndrome
Chelating agents
Gout
Loop diuretics
Thiazide diuretics
Granulomatous hepatitis
Oral hypoglycaemics
Phenytoin
Sulphonamides
Griping pain
Docusate
Laxatives
Growth retardation in children
Anorectics
Central stimulants
Corticosteroids
Guillain-Barre syndrome
Medicinal enzymes
Gynaecomastia
Anorectics
Antiandrogens
Antiemetics
Antiepileptics
Antiulcer agents
Flupenthixols
Fluphenazine
Gonadotrophic hormones
Haloperidols
Immunosuppressants
Neuroleptics
Nitrogen mustards
Zuclopenthixols
Haematemesis
Haematocrit PCV low
Antivirals
Interleukins
Haematology result abnormal
Haemoglobin estimation
Haemoglobin low
Antivirals
Interleukins
Haemolysis, haemoglobinuria
Antidotes
Haemolytic anaemia
4 Quinolone
Antiandrogens
Antimalarials
Carbacephems
Cephalosporins
Cephamycins
Flupenthixols
Fluphenazine
Haloperidols
Neuroleptics
Zuclopenthixols
Haemolytic-uraemic syndrome
Immunosuppressants
304

Haemorrhage
Antidepressants
Gold salts
Heparinoids
Leech products
Sulphonamides
Haemorrhage of rectum and anus
Contrast media
Haemorrhagic bullae
4 Quinolones
Haemorrhagic cystitis
Antineoplastics
Nitrogen mustards
Haemorrhagic disorder
Medicinal enzymes
Halitosis
Hallucinations
4 Quinolones
Anlagesics and anti-inflammatory drug
Anorectics
Anthelmintics
Antidepressants
Antiemetics
Antifungals
Antimuscarinecs
Antineoplastics
Antiulcer agents
Antivirals
Cardiac glycosides
Central stimulants
Digitalis
Ergolines
Opioid analgesics
Opioid peptides
Sedatives

Has a sore throat
Antineoplastics
Has numbness
Sedatives
Headache
4 Quinolones
ACE inhibitors
Anabolics
Anorectics
Anthelmintics
Antiandrogens
Antidepressants
Antidotes
Antiemetics
Antiepileptics
Antifungals
Antihypertensives
Antileprotics
Antimuscarinics
Antineoplastics
Antiprotozoals
Antiulcer agents
Antivirals
Beta blockers
Bisphosphonates
Carbacephems
Carbapenems
Cardiac glycosides
Central stimulants
Cephalosporins
Cephamycins
Contrast media
Corticosteroids
Cough suppressants
305

Diagnostic agents
Digitalis
Ergolines
Ergot compounds
Estrogens
Haemostatics
Hyaluronic acid
Immunosuppressants
Isoprenaline
Macrolides
Mucolytics
Neuroleptics
Opioid analgesics
Opioid antagonists
Opioid peptides
Oral hypoglycaemics
Osmotic diuretics
Oxytetracyclines
Polyene antibiotics
Progestogens
Promethazines
Sedatives
Sex hormones
Sympathomimetics
Tetracyclines
Theophylline
Thiazide diuretics
Thyroid agents
Uricosuric agents
Vaccines
Vasodilators
Vitamins
Xanthines
Hearing difficulty
Chelating agents
Hearing symptoms
4 Quinolones
Heart failure
Anabolics
Anthelmintics
Antiandrogens
Antiulcer agnets
Beta blockers
Liquorice
Heartburn
Ergot compounds
Heinz-body anaemia
Hemianopia
Ergolines
Hepatic coma
Anabolics
Hepatomegaly
Antivirals
Vitamins
Hiccough
Barbiturate anaesthetics
Hirsutism
Anabolics
Corticosteroids
Immunosuppressants
Norgestrels
Phenytoin
Progestogens
Sex hormones
Hoarseness
Hyperactivity
Carbacephems
Cephalosporins
Cephamycins
Hyperaemia of confunctiva
306

Hyperaesthesia
Antivirals
Hyperammonaemia
Antiepileptics
Expectorants
Hypercalcaemia
Anabolics
Androgens
Calcium salts
Sex hormones
Testosterones
Thiazide diuretics
Vitamins
Hypercalcinuria
Vitamins
Hyperfibrinogenaemia
Hyperglycaemia
Antidepressants
Antivirals
Asparaginase antineoplastics
Glucose tests
Immunosuppressants
Loop diuretics
Neuroleptics
Progestogens
Sex hormones
Thiazide diuretics
Hyperkalaemia
ACE inhibitors
Erythropoietic
Immunosuppressants
Potassium salts
Hyperkinesia
Ergolines
Neuroleptics
Hyperphosphataemia
Electrolyte anions
Erythropoietin
Vitamins
Hyperpigmentation
Antineoplastics
Tetracyclines
Hypereflexia
Lithium
Hypertension
Anorectics
Antidepressants
Antineoplastics
Antiulcer agents
Antivirals
Central stimulants
Chelating agents
Corticosteroids
Ergot alkaloids
Ergot compounds
Erythropoietin
Immunosuppressants
Liquorice
Neuroleptics
Opioid analgesics
Oxytocic hormones
Pilocarpine
Sympathomimetics
Hypertensive encephalopathy
Erythropoietin
Hypertonic uterus
Hypertrophic cardiomyopathy
Immunosuppressants
Hypertrophy of breast
Estrogens
Sex hormones
Hypertrophy of clitoris
Progestogens
Sex hormones
Hypertrophy of salivary gland
Hyperventilation
307

Hypervitaminosis A
Hypocalcaemia
Antineoplastics
Antivirals
Bisphosphonates
Loop diuretics
Hypochloraemia
Loop diuretics
Thiazide diuretics
Hypoglycaemia
4 Quinolones
Antidepressants
Antivirals
Insulin
Oral hypoglycaemics
Hypokalaemia
Antineoplastics
Antiulcer agents
Beta blockers
Carboxypenicillins
Corticosteroids
Diphenylbutylpiperidine neuroleptics
Glucose tests
Interleukins
Liquorice
Lithium
Loop diuretics
Polyene antibiotics
Thiazide diuretics
Hypomagnesaemia
Aminoglycosides
Antineoplastics
Bisphosphonates
Cation exchange resins
Immunosuppressants
Loop diuretics
Polyene antibiotics
Thazide diuretics
Hypomania
Antidepressants
Hypoparathyroidism
Hypophosphataemia
Antineoplastics
Hyposmolality / hyponatraemia
ACE inhibitors
Antidepressants
Loop diuretics
Thiazide diuretics
Vinca alkaloid antineoplastics
Hypotension
4 Quinolones
ACE inhibitors
Anorectics
Antidiarrhoeals
Antidotes
Antiemetics
Antineoplastics
Antivirals
Central stimulants
Chelating agents
Class II antiarrhythmics
Diagnostic agents
Ergolines
Flupenthixols
Fluphenazine
Haloperidols
308

Immunosuppressants
Interleukin 2
Isoprenaline
Local anaesthetics
Loop diuretics
Medicinal enzymes
Mercurial diuretics
Neuroleptics
Opioid analgesics
Opioid peptides
Phenytoin
Pilocarpine
Promethazines
Sedatives
Sympathomimetics
Vasodilators
Zuclopenthixols
Hypothermia
Flupenthixols
Fluphenazine
Haloperidols
Neuroleptics
Opioid analgesics
Opioid peptides
Zuclopenthixols
Impotence
ACE inhibitors
Anorectics
Antiandrogens
Antidepressants
Antiulcer agents
Flupenthixols
Fluphenazine
Haloperidols
Neuroleptics
Opioid antagonists
Thiazide diuretics
Zuclopenthixols
Inappropriate ADH secretion syndrome
Antidepressants
Lithium
Incontinence of urine
Neuroleptics
Incontinent of faeces
Increased growth
Androgens
Sex hormones
Testosterones
Increased menstrual loss
Indirect Coombs test positive
Carbapenems
Induration of skin at site of injection
Carbapenems
Flupenthixols
Fluphenazine
Haloperidols
Lincomycin
Neuroleptics
Vaccines
Zuclopenthixols
Infection
Antineoplastics
Immunosuppressants
Inflammation of eyelids
Influenza like syndrome
Antiepileptics
Antiulcer agents
Antivirals
Erythropoietin
Inhibited female orgasm
Antidepressants
Inhibited male orgasm
309

Antidepressants
Opioid antagonists
Insommia
4 Quinolones
ACE inhibitors
Anabolics
Anorectics
Anthelmintics
Antiandrogens
Antidepressants
Antiemetics
Antiepileptics
Antihypertensives
Antimalarials
Antiulcer agents
Antivirals
Beta blockers
Carbacephems
Central stimulants
Cephalosporins
Cephamycins
Class III antiarrythmics
Corticosteroids
Ergolines
Ergot compounds
Flupenthixols
Fluphenazine
Haloperidols
Neuroleptics
Norgestrels
Opioid antagonists
Progestogens
Promethazines
Sex hormones
Sympathomimetics
Theophylline
Zuclopenthixols
Interstitial lung disease
Antiandrogens
Interstitial nephritis
4 Quinolones
ACE inhibitors
Amidinopenicillins
Aminopenicillins
Antiulcer agents
Carbacephems
Carboxypenicillins
Cephalosporins
Cephamycins
Immunosuppressants
Loop diuretics
Macrolides
Natural penicillins
Phenoxypenicillins
Phenytoin
Sulphonamides
Tetracyclines
Thiazide diuretics
Ureido penicillins
Interstitial pneumonia
Gold salts
Intestinal obstruction
Bulk laxatives
Hypoglycaemics
Intracerebral haemorrhage
Sympathomimetics
Intravascular coagulation
Involuntary movements
Iritis
Irritability
Anorectics
310

Antidotes
Antiepileptics
Central stimulants
Opioid antagonists
Sedatives
Ischaemic heart disease
Itching
4 Quinolones
Anthelmintics
Antifungals
Antineoplastics
Antiulcer agents
Antivirals
Central stimulants
Cephalosporins
Cough suppressants
Estrogens
Hyaluronic acid
Oral hypoglycaemics
Sex hormones
Itchy eyes
Jaundice
4 Quinolones
ACE inhibitors
Anabolics
Androgens
Antiandrogens
Antidepressants
Antiepileptics
Antifungals
Estrogens
Flupenthixols
Fluphenazine
Haloperidols
Lincomycin
Macrolides
Neuroleptics
Norgestrels
Oral hypoglycaemics
Progestogens
Retinoic acid
Sedatives
Sex hormones
Sulphonamides
Thiazide diuretics
Uricosuric agents
Zuclopenthixols
Keratitis
Ketonuria
Chloral sedatives
L eye completely blind
Lactic acidosis
Antivirals
Lactose intolerance
Lagophthalmos
Laryngeal oedema
Medicinal enzymes
Laryngospasm
Lens opacity
Antineoplastics
Leukocytosis
Antiulcer agents
Flupenthixols
Fluphenazine
Haloperidols
Neuroleptics
Zuclopenthixols
Leukopenia
4 Quinolones
Amidinopenicillins
Aminopencillins
Antidepressants
Antiepileptics
Antifungals
Antithyroid agents
311

Antiulcer agents
Antivirals
Carboxypenicillins
Central stimulants
Flupenthixols
Fluphenazine
Haloperidols
Immunosuppressants
Isoxazolyl penicillin
Natural penicillins
Neuroleptics
Oxacephalosporins
Phenoxypenicillins
Progestogens
Sex hormones
Sulphonamides
Ureido penicillins
Zuclopenthixols
Leukorrhoea
Cephalosporins
Lichenified skin
Beta blockers
Lid retraction or lag
Light-headedness
Anthelmintics
Antiarrhythmics
Antidepressants
Antivirals
Sedatives
Sex hormones
Vasodilators
Liver enzymes abnormal
4 Quinolones
Anthelmintics
Antiandrogens

Antidepressants
Antiemetics
Antimalarials
Antineoplastics
Antiulcer agents
Antivirals
Carbapenems
Central stimulants
Cephalosporins
Chelating agents
Mucolytics
Oral hypoglycaemics
Retinoic acid
Sedatives
Sex hormones
Uricosuric agents
Liver function tests abnormal
Anabolics
Anthelmintics
Antiandrogens
Antiepileptics
Antifungals
Antineoplastics
Antiulcer agents
Antivirals
Aromatics
Beta blockers
Central stimulants
Cephalosporins
Estrogens
Flupenthixols
Fluphenazine
Haloperidols
312

HMG Co A reductase inhibitors
Immunosuppressants
Interleukin 2
Laxatives
Neuroleptics
Nitrogen mustards
Opioid antogonists
Polyene antibiotics
Promethazines
antidepressants
Sex hormones
Tetracyclines
Uricosuric agents
Xanthine oxidase inhibitor
Zuclopenthixols
Liver moderately enlarges
Local irritation
4 Quinolones
Antifungals
Disinfectants
Magnesium salts
Medicinal enzymes
Podophyllums
Locomotor impairment
Promethazines
Loss of libido
Anorectics
Antiandrogens
Antidepressants
Antiemetics
Carbamate sedatives
Norgestrels
Progestogens
Sex hormone
Lung disease
Lupus erythematosus
Lymphademopathy
Anthelmintics
Antiepileptics
Lymphoedema
Antiandrogens
Lymphopenia
Bisphosphonates
Immunosuppressants
Malaise / letharhy
Anorectics
Anthelmintics
Antiandrogens
Antidotes
Antiepileptics
Antineoplastics
Antiulcer agents
Antivirals
Central stimulants
Ergolines
Opioid antagonists
Retinoic acid
Sedatives
Vaccines
Vitamins
Malignant hyperpyrexia
Flupenthixols
Fluphenazine
Haloperidols
Neuroleptics
Zuclopenthixols
Malignant neuplasm of thyroid gland
Mastodynia pain in breast
Antiandrogens
Norgestrels
313

Estrogens
Progestogens
Sex hormones
Magaloblastic anaemia
Melaena
Memory loss - amnesia
Antimuscarinics
Sedatives
Meningism
Meningitis - aseptic
Menopause
Menorrhagia
Gold salts
Menstrual disorders
Corticosteroids
Flupenthixols
Fluphenazine
Haloperidols
Neuroleptics
Norgestrels
Progestogens
Retinoic acid
Sex hormones
Zuclopenthixols
Mercury toxic effect
Inorganic mercury compounds
Mercurial dermatological agents
Metabolic acidosis
4 Quinolones
Nuritional carbohydrates
Metabolic alkalosis
Electrolyte antions
Loop diuretics
Thiazide diuretics
Methaemoglobinaemia

Antidotes
Disinfectants
Mecroangiopathic haemol.anaem.
Pyrimidine antaogonist antineoplastics
Micturition frequency
Pilocarpine
Migraine
Anbolics
Mild memory disturbance
Sedatives
Mood changes
ACE inhibitors
Benzomorphan opiod analgesics
Opioid analgesics
Opiod peptides
Ritinoic acid dermatological agents
Sedatives
Multiple pregnancy
Muscle cramps
ACE inhibitors
Anabolics
Antiulcer agents
Central stimulants
Corticosteroids
Diagnostic agents
Diuretics
Ergolines
Ergot compounds
Immunosuppressants
Loop diuretics
Sympathomimetics
Thyroid agents
Muscle hypertonia
Carbacephems
Cephalosporins
Cephamycins
Pareteral anaesthetics
Muscle hypotonia
Antiepileptics
Muscle spasm
314

Progestogens
Sex hormones
Muscle weakness
4 Quinolones
Antidepressants
Antiulcer agents
Beta blocders
Immunosuppressants
Liquorice
Lithium
Pilocarpine
Polymyxins
Sedatives
Muscular fasciculation
Pilocarpine
Muscular incoordination
Anthelminitics
Musculoskeletal pain
Antineoplastics
Antivirals
Bisphosphonates
Immunosuppressants
Opioid antagonists
Polyene antibiotics
Myalgia
4 Quinolones
Anthelmintics
Antidepressants
Antifungals
Antineoplastics
Antiulcer agents
Antivirals
Interleukins
Loop diuretics
Promethazines
Sex hormones
Myalgia / myositis
Myasthenia gravis
Myasthenic syndrome
Aminoglycosides
Chelating agents
Mycoses
Antivirals
Corticosteroids
Immunosuppressants
Myoclenus
Carbapenems
Myoglobinuria
Myopathy
Antivirals
Expectorants
Haemostatics
Immunosuppressants
Myopia
Thiazide diuretics
Nail disorders
Antineoplastics
Nasal congestion
Cough suppressants
Ergot compounds
Flupenthixols
Fluphenazine
Haemostatics
Haloperidols
Neuroleptics
Sedatives
Zuclopenthixols
Nasal symptoms
Antivirals
315

Nausea
4 Quinolones
ACE inhibitors
Amino acids
Aminopenicillins
Anabolics
Anthelmintics
Antiandrogens
Antiarrhythmics
Antidepressants
Antidiarrhoeals
Antidotes
Antiemetics
Antiepileptics
Antifungals
Antihypertensives
Antileprotics
Antimalarials
Antineoplastics
Antiprotozoals
Antithyroid agents
Antiulcer agents
Antivirals
Benzodiazepine anatogonists
Beta blockers
Bismuth salts
Bisphosphonates
Blood products
Calcitonin
Carbacephems
Carbapenems
Cardiac glycosides
Central stimulants
Cephalosporins
Cephamycins
Chloramphenicols
Colchicum alkaloids
Contrast media
Corticosteroids
Cough suppressants
Diagnostic agents
Digitalis
Ergot compounds
Estrogens
Expectorants
Ferric salts
Ferrous salts
Fluorouracil
GABA regulating hormones
Glucose tests
Haemostatics
Hydroxynaphthoquinone
Immunosuppressants
Iron compounds
Laxatives
Lincomycin
Loop diuretics
Macrolides
Medicinal enzymes
Monobactams
Neuroleptics
Nitrofuran microbials
Nitrogen mustards
Nitrosoureas
Omega 3 triglycerides
Opioid analgesics
Opioid antagonists
Opioid peptides
Oral hypoglycaemics
Oxytetracyclines
Pilocarpine
Polyene antibiotics
Progestogens
Prophylactic antiasthmitics
Retinoic acid
Sedatives
Sex hormones
316

Sulphonamides
Sulphur mustards
Sympathomimetics
Tetracyclines
Theophylline
Thiazide diuretics
Uricosuric agents
Vaccines
Vasodilators
Vasopressins
Vitamins
Neoplasms
Immunosuppressants
Nephritis, nephrosis
Nephrotic syndrome
Antithyroid agents
Chelating agents
Mercurial dermatological agents
Uricosuric agents
Nerves nervousness
4 Quinolones
ACE inhibitors
Anorectics
Antidepressants
Antimuscarinics
Antiulcer agents
Antivirals
Carbacephems
Central stimulants
Cephalosporins
Cephamycins
Dopaminegic antiparkinsonian agents
Interleukins
Neuroleptics
Opioid antagonists
Phenytoin
Progestogens
Sedatives
Sex hormones
Neurological symptoms
Antiepileptics
Antivirals
Glycols
Immunosuppressants
Neutropenia
ACE inhibitors
Antineoplastics
Antivirals
Carbapenems
Central stimulants
Chelating agents
Lincomycin
Macrolides
Monobactams
Neuroleptics
Thiazide diuretics
Newborn disseminated intravascular coagulation
Night blindness
Retinoic acid
Night terrors
Amphetamines
Anorectics
Central stimulants
Nightmares
Antivirals
Flupenthixols
Fluphenazine
Haloperidols
Neuroleptics
Sedatives
Zuclopenthixols
Non-alcoholic fatty liver
Antivirals
Sex hormones
Numbness
Nystagmus
Phenytoin
Pilocarpine
Obstetric trauma
Oxytocic hormones
Oedema
317

4 Quinolones
Anabolics
Androgens
Anthelmintics
Antiandrogens
Antidepressants
Antiepileptics
Antineoplastics
Antiulcer agents
Antivirals
Ergot compounds
Immunosuppressants
Interleukins
Lithium
Neuroleptics
Progestogens
Sex hormones
Testosterones
Oedema of eyelid
Erythropoietin
Oedema of glottis
Phenol disinfectants
Oedema of larynx
Oesophagitis
Amidinopenicillins
Antimuscarinics
Bisphosphonates
Tetracyclines
Oligospermia
Oliguria
Lithium
Onycholysis
ACE inhibitors
Optic neuritis
Chloramphenicols
Retinoic acid
Oral aphthae
Antivirals
Fluorouracil
Gold salts
Monobactams
Orofacial dyskinesia
Central stimulants
Osteomalacia
Barbiturate sedatives
Bisphosphonates
Phenytoin
Osteoporosis
Antiandrogens
Bisphosphonates
Corticosteroids
Heparinoids
Thyroid agents
Other penile inflammatory disorders
Ototoxicity deafness
Aminoglycosides
Antineoplastics
Ovarian cysts
Ovarian hyperstimulation
Sex hormones
Pain
Antivirals
Central stimulants
Interleukins
Medicinal enzymes
Pain at injection site
Antidotes
Antivirals
Contrast media
Hyaluronic acid
Leech products
Medicinal enzymes
318

Pain in joints arthralgia
4 Quinolones
Amidinopenicillins
Aminopenicillins
Anthelmintics
Antidotes
Antifungals
Antineoplastics
Antiulcer agents
Antivirals
Carbacephems
Carboxypenicillins
Central stimulants
Cephalosporins
Cephamycins
Natural penicillins
Phenoxypenicillins
Polyene antibiotics
Retinoic acid
Ureido penicillins
Vaccines
Pain in testicle
Painful extremities
Antidotes
Painful swallowing
Antineoplastics
Painful urination
Pallor
Flupenthixols
Fluphenazine
Haloperidols
Neuroleptics
Vasopressins
Zuclopenthixols
Palpitations
ACE inhibitors
Antalgesics and anti-inflammatory drugs
Anorectics
Antidepressants
Antimuscarinics
Central stimulants
Corticosteroids
Ergolines
Ergot compounds
Opioid analgesics
Opioid peptides
Promethazines
Sedatives
Sympathomimetics
Theophylline
Xanthines
Pancreatic steatorrhoea
Pancytopenia
4 Quinolones
Anitibacterial agents
Antithyroid agents
Antivirals
Papilloedema
Interleukins
Retinoic acid
Paraesthesia
4 Quinolones
ACE inhibitors
Antidepressants
Antiepileptics
319

Antimuscarinics
Antiulcer agents
Antivirals
Carbamate sedatives
Carbapenems
Central stimulants
Ergot compounds
Immunosuppressants
Interleukins
Neuroleptics
Polymyxins
Promethazines
Thiazide diuretics
Vitamim D substances
Paralysis
Chelating agents
Pilocarpine
Paralytic ileus
Antidepressants
Paronychia of finger
Retinoic acid
Paronychia of toe
Retinoic acid
Parotid swelling
Encephalitis vaccines
Influenza vaccines
Measles vaccine
Poliomyelitis vaccines
Typhoid vaccines
Vaccines
Parotitis
Paroxysmal choreo-athetosis
Central stimulants
Paroxysmal nocturnal haemogloinuria
Chloramphenicols
Paroxysmal supravent.tachycard.
Paroxysmal ventric.tachycard.
Antimalarials
Beta blockers
Partial atrioventricular block
Cardiac glycosides
Digitalis
Patches of alopecia
Antibacterial agnets
Antineoplastics
Gonad regulating agents
Interleukins
Peeling skin
Retinoic acid
Pellagea
Peptic ulcer
Antineoplastics
Corticosteroids
Uricosuric agents
Peptic ulcer symptoms
Central stimulants
Peri-op haemorrhage / haematoma
Perineal pain
4 Quinolones
Corticosteroids
Estrogens
Peripheral autonomic neuropathy
Antineoplastics
Antivirals
Peripheral enthesopathies
4 Quinolones
Interleukins
Peripheral neuritis or neuropathy
4 Quinolones
Antidepressants
320

Antineoplastics
Antivirals
Chloramphenicols
Colchicum alkaloids
Gold salts
Immunosuppressants
Phenytoin
Polyene antibiotics
Peripheral neuropathy
Vitamin B6 substances
Peripheral vascular symptoms
Beta blockers
Persistent miosis
Opioid analgesics
Opioid peptides
Pilocarpine
Persistent mydriasis
Antimuscarinics
Aromatics
Neuroleptics
Personality disorders
Acetylurea antiepileptics
Central stimulants
Dopaminergic antiparkinsinian agents
Petechiae
4 Quinolones
Organic iodinates contrast media
Phlebitis and thrombophlebitis
4 Quinolones
Antivirals
Carbapenems
Haemostatics
Immunosuppressants
Lincomycin
Macrolides
Osmotic diuretics
Sedatives
Photophobia
Neuroleptics
Photosensitiveness
4 Quinolones
Aminobenzoate sunscreen agents
Anthelmintics
Antiepileptics
Antifungals
Antineoplastics
Antiulcer agents
Disinfectants
Flupenthixols
Fluphenazine
Loop diuretics
Neuroleptics
Oxytetracyclines
Promethazines
Retinoic acid
Sunscreen agents
Tetracyclines
Thiazide diuretics
Zuclopenthixols
Pleural effusion
Ergolines
Pneumonitis
321

Antivirals
Thiazide diuretics
Pneumothorax
Antivirals
Polyarteritis nodosa
Phenytoin
Polydipsia
Lithium
Polyuria
Lithium
Uricosuric agents
Vitamins
Post operative UTI
Haemostatics
Post-operative haematoma formation
Postmenopausal bleeding
Postural hypotension
Anthelmintics
Antidepressants
Antineoplastics
Beta blockers
Ergolines
Ergot compounds
Neuroleptics
Opioid analgesics
Opioid peptides
Thiazide diuretics
Premature ejaculation
Antidepressants
Premenstrual tension syndrome
Norgestrels
Estrogens
Progestogens
Sex hormones
Priapism
Androgens
Antidepressants
Neuroleptics
Testosterones
Primary malignant neoplasm of liver
Anabolics
Primary pulmonary hypertension
Anorectics
Prolactin level increased
Antiemetics
Neuroleptics
Proteinuria
Antineoplasitcs
Antivirals
Gold salts
Prothrombin time increased
4 Quinolones
Oxacephalosporins
Proximal myopathy
Corticosteroids
Pruritus
4 Quinolones
Anabolics
Anthelmintics
Antiandrogens
Antifungals
Antimalarials
Antineoplastics
Antiulcer agents
Antivirals
Blood products
Carbacephems
Carbapenems
Central stimulants
Cephalosporins
Cephamycins
322

Gold salts
Immunosuppressants
Opioid analgesics
Opioid peptides
Prusritus ani
Pruritus of genital organs
Sex hormones
Pseudomembranous Colites Clostridium difficile
4 Quinolones
Aminoglycosides
Carbacephems
Carbapenems
Cephalosporins
Cephamycins
Lincomycin
Macrolides
Oxytetraxyclines
Sulphonamides
Tetracyclines
Psoriasiform rash
Antivirals
Lithium
Psychiatric disturbances
4 Quinolones
Anorectics
Antidepressants
Antiepileptics
Antimuscarinics
Carbapenems
Corticosteroids
Ergot compounds

Opioid analgesics
Polymyxins
Ptosis
Pulmonary eosinophilia
Pulmonary fibrosis
Analgesics ans anti-inflammatory drugs
Gold salts
Nitrogen mustards
Nitrosoureas
Pulmonary haemorrhage
Pulmonary surfactants
Pulmonary oedema
Ergot alkaloids
Ergot compounds
Haloperidols
Interleukin2
Opioid antagonists
Oxytocic hormones
Polyene antibiotics
Sympathomimetics
Thiazide diuretics
Punctate keratitis
Anthelmintics
Pyrexia
4 Quinolones
Amidinopenicillins
Aminopenicillins
Anthelmintics
Antiepileptics
Antimuscarinics
Antineoplastics
Antiulcer agents
Antivirals
323

Bisphosphonates
Carbacephems
Carbapenems
Carboxypenicillins
Central stimulants
Cephalosporins
Cephamycins
Flupenthixols
Fluphenazine
Gold salts
Haloperidols
Macrogol ethers
Natural penicillins
Neuroleptics
Norgestrels
Oral hypoglycaemics
Phenothiazine neuroleptics
Phenoxypenicillins
Phenytoin
Polyene antibiotics
Progestogens
Sex hormones
Ureido penicillins
Vaccines
Zuclopenthixols
R-eye completely blind
Raises intracranial pressure
4 Quinolones
Anthelmintics
Oxytetracyclines
Progestogens
Retinoic acid
Sex hormone
Tetracyclines
Raised intraocular pressure
Antimuscarinics
Hyaluronic acid
Rash
4 Quinolones
ACE inhibitors
Aminopenicillins
Anabolics
Anorectics
Anthelmintics
Antiandrogens
Antidepressants
Antidotes
Antiemetics
Antiepileptics
Antifungals
Antimalarials
Antineoplastics
Antithyroid agents
Antiulcer agents
Antivirals
Aromatics
Beta blockers
Bisphosphonates
Carbacephems
Carbapenems
Central stimulants
Cephalosporins
Cephamycins
Colchicum alkaloids
Corticosteroids
Cough suppressants
Ergolines
Ergot compounds
Estrogens
Flupenthixols
Fluphenazine
Haemostatics
Haloperidols
324

Hyaluronic acid
Immunosuppressants
Interleukins
Lincomycin
Loop diuretics
Macrolides
Medicinal enzymes
Monobactams
Mucolytics
Neuroleptics
Opioid antagonists
Oral hypoglycaemics
Pesticides
Polyene antibiotics
Progestogens
Promethazines
Retinoic acid
Sedatives
Sex hormones
Sulphonamides
Sympathomimetics
Tetracyclines
Thiazide diuretics
Uricosuric agents
Vaccines
Vasodilators
Zuclopenthixols
Raynauds phenomenon
Ergolines
RBCs reticulocytes present
Antivirals
Reactive confusion
Opioid analgesics
Rectal discharge
Rectal pain
Sedatives
Recurrent erosion of cornea
Recurrent manic episodes
Central stimulants
Recurrent URTI
Red blood cell aplasia and hypoplasia
Antiepileptics
Red / green colour blindness
Redness of eye
Sympathomimetics
Reduced sebum production
Antiandrogens
Reflux oesophagitis
Antivirals
Renal function tests abnormal
ACE inhibitors
Antiepileptics
Antineoplastics
Antiulcer agents
Chloral sedatives
Colchicum alkaloids
Immunosuppressants
Loquorice
Lithium
Oxytetracyclines
Polyene antibiotics
antidepressants
Tetracyclines
Thiazide diuretics
Renal stones
Antiepileptics
Antivirals
Repeated rapid eye movement sleep interruptions
Pilocarpine
Resorcinol hypothyroidism
Respiratory arrest
Respiratory depression
325

Anthelmintics
Antidiarrhoeals
Antiepileptics
Antivirals
Cough suppressants
Local anaesthetics
Opioid analgesics
Opioid peptides
Sedatives
Respiratory distress
Phenytoin
Respiratory symptoms
ACE inhibitors
Phenytoin
Restlessness
4 Quinolones
Anorectics
Antiemetics
Antivirals
Central stimulants
Diphenylbutylpiperdine neuroleptics
MAOI antidepressants
Sedatives
Sympathomimetics
Thyroid agents
Retinal damage
Retinal detachments & defects
Antivirals
Retinal exudate or deposits
Flupenthixols
Fluphenazine
Haloperidols
Neuroleptics
Zuclopenthixols
Retinopathy
Antineoplastics
Sex hormones
Retroperitoneal fibrosis
Beta blockers

Ergoline
Ergot compounds
Haloperidols
Retrosternal pain
Rhabdomyolysis
4 Quinolones
Barbiturates
Colchicum alkaloids
Fluphenazine
Hydrazine monoamine oxidase inhibiting
antidepressants
Lithium
MAOIs
Neuroleptics
Opioid analgesics
Opioid peptides
Polyene antibiotics
Promethazines
Retinoic acid
Theophylline
Rhinitis
Antineoplastics
Antiulcer agents
Ergolines
Neuroleptics
Pilocarpine
Rhinorrhoea
Rickets
Phenytoin
Right upper quadrant pain
Rigors
Ruptured uterus
Oxytocic hormones
Saliva abnormal colouration
326

Antiprotozoals
Seborrhoea
Progestogens
Sex hormones
Seborrhoeic dermatitis
Anabolics
Sedation
Antidepressants
Antifungals
Antihypertensives
Antineoplastics
Flupenthixols
Fluphenazine
Haloperidols
Neuroleptics
Zuclopenthixols
Semen sample volume
Neuroleptics
Sensory symptoms
Diagnostic agents
Serum bicarbonate abnormal
Antivirals
Serum bilirubin raised
Anthelmintics
Antivirals
Carbapenems
Serum cholesterol raised
Anabolics
Antidepressants
Antivirals
Loop diuretics
Retinoic acid
Thiazide diuretics
Serum creatinine abnormal
Cephalosporins
Serum creatinine raised
4 Quinolones
ACE inhibitors
Antivirals
Erythropoietin
Immunosuppressants
Interleukin2
Serum lipids high
Asparaginase antineoplastics
Serum sickness
Carbacephems
Cephalosporins
Cephamycins
Serum sodium level abnormal
Serum triglycerides raised
Anabolics
Antivirals
Loop diuretics
Retinoic acid
Thiazide diuretics
Severe uterine contractions
Anthelmintics
F series prestaglandins
Sexual dysfunction
Antidepressants
Opioid antagonists
Piperidine phenothiazine neuroleptics
Sexual precocity
Androgens
Testosterones
Shivering
Anabolics
Antidepressants
Antivirals
Blood products
Contrast media
Immunosuppressants
Opioid antagonists
Osmotic diuretics
Pilocarpine
Sideroblastic anaemia
Sinoatrial block
Sinus tachycardia
Skeletal hyperostosis
Interleukins
Skin and finger nail pigmentation
327

Antileprotics
Antiprotozoals
Antivirals
Flupenthixols
Fluphenazine
Haloperidols
Neuroleptics
Retinoic acid
Sulphonamides
Zuclopenthixols
Skin disorders / reactions
Antineoplastics
Bisphosphonates
Erythropoietin
Thiazide diuretics
Slin nodules
Skin pigmented over lesions
Antileprotics
Skin scaling
Skin ulceration
Pyrimidine antigonist antineoplastics
Slurred speech
Phenytoin
Polymyxins
Sneezing
Edetates
Soiling encopresis
Somnolence
Antiepileptics
Antimuscarinics
Antiulcer agents
Antivirals
Central stimulants
Neuroleptics
Sore gums
Gold salts
Sore mouth
Antineoplastics
Antivirals
Sore throat
ACE inhibitors
Anthelmintics
Antiulcer agents
Antivirals
Corticosteroids
Gold salts
Spasm of sphincter of Oddi
Opioid analgesics
Opioid peptides
Spasmodic torticollis
Speech problems
Sperm absent azoospermia
Anabilics
Androgents
Antiandrogens
Antivirals
Testosterones
Sperm morphology affected
Sperm no. / cc v.low; 0-10 mill.
Antivirals
Splenomegaly
Spontaneous bruising
Gold salts
Steroid acne
Corticosteroids
Steroid facies
Anabolics
Androgens
Corticosteroids
Estrogens
Norgestrels
Progestogens
Sex hormones
Testosterones
Steroid induced diabetes
Anabolics
Androgens
Corticosteroids
Estrogens
Norgestrels
Progestogens
Sex hormones
Testosterones
328

Steroid-induced glaucoma
Anabolics
Androgens
Corticosteroids
Norgestrels
Estrogens
Progestogens
Sex hormones
Testosterones
Stevens-Johnson syndrome
4 Quinolones
Anthelmintics
Antiepileptics
Antifungals
Antivirals
Polyene antibiotics
Sulphonamides
Stomatitis
ACE inhibitors
Antineoplastics
Antiulcer agents
Chelating agents
Expectorants
Fluorouracil
Macrolides
Medicinal enzymes
Polyene antibiotics
Striae atrophicae
Corticosteroids
Stricture of intestine
Medicinal enzymes
Stroke and cerebrovascular accident
ACE inhibitors
Ergot alkaloids
Ergot compounds
Subacute confusional state
Opioid analgesics
Subacete hepatitis-noninfect
Retinoic acid
Subarachnoid haemorrhage
Oxytocic hormones
Subcutaneous sclerotic plaques
Sudden death
Antiandrogens
Lithium
Mercurial diuretics
Suicidal
Retinoic acid
Suicidal ideation
Sulphuric acid toxic effect
Mineral acids
Supraventricular ectopic beats
Sweating
Antiulcer agents
Pilocarpine
antidepressants
Swelling at site of injection
Hyaluronic acid
Syncope
Anibiotic antituberculous agents
Antidepressants
Antiemetics
Contrast media
Ergolines
Lithium
Neuroleptics
Sedatives
Synovitis and tenosynovitis
4 Quinolones
Systemic lupus erythematosus
Neuroleptics
Sex hormones
Tetracyclines
Tachycardia
4 Quinolones
329

ACE inhibitors
Anorectics
Antidepressants
Antiemetics
Antimuscarinics
Antineoplastics
Central stimulants
Diagnostic agents
Ergolines
Ergot compounds
Flupenthixols
Fluphenazine
Haloperidols
Immunosuppressants
Haloperidols
Immunosuppressants
Interleukins
Isoprenaline
Neuroleptics
Sedatives
Sympathomimetics
Theophylline
Thyroid agents
Zuclopenthixols
Tachypnoea
Antivirals
Taste disturbance
4 Quinolones
ACE inhibitors
Anigiotensin inhibiting antihypertensives
Antifungals
Antineoplastics
Antiulcer agents
Antivirals
Bisphosphonates
Calcitonin
Carbapenems
Cephalosporins
Contrast media
Disinfectants
Gold salts
Macrolides
Monobactams
Sedatives
Telangiectasia
Temporary blindness
Temporary worsening of symptoms
Flurouracil
Sex hormones
Throat irritation
Corticosteroids
Throat pain
Chelating agents
Thrombocythaemia
Carbapenems
Erythropoietin
Thrombocytopenia
4 Quinolones
ACE inhibitors
Amidinopenicillins
Aminopenicillins
Antiandrogens
Antidepressants
Antiepileptics
330

Antifungals
Antineoplastics
Antiulcer agents
Antivirals
Carbacephems
Carbapenems
Carboxypenicilline
Central stimulants
Cephalosporins
Cephamycins
Diagnostic agents
Heparinoids
Immunosuppressants
Lincomycin
Monobactams
Natural penicillins
Opioid antagonists
Oral hypoglycaemics
Oxacephalosporins
Phenoxypenicillins
Progestogens
Retinoic acid
Sedatives
Sex hormones
Sulphonamides
Thiazide diuretics
Ureido penicillins
Vasidilator antihypertnsives
Thromboembolism
Thrombosis of arterio-venous surgical shunt
Erythropoietin
Thyroid hormone tests high
Antineoplastics
Antivirals
Interleukin 2
Thyroid hormone tests low

Antineoplastics
Antivirals
Interleukin 2
Thyroid swelling
Thyrotoxicosis
Iodides
Iodine compounds
Iodophores
Tics
Cerntral stimulants
Tightening pain
Tingling sensation
Antivirals
Beta blockers
Calcitonin
Diagnostic agents
Sympathomimetics
Tinnitus symptoms
4 Quinolones
Antineoplastics
Ergot compounds
Haemostatics
Mucolytics
Tiredness
ACE inhibitors
Alpha bolcking antihypertensives
Antiandrogens
Antidepressants
Antiepileptics
Antineoplastics
Antitivirals
Beta blockers
Bisphosphonates
Ergolines
331

Pilocarpine
Sedatives
Tissue necrosis
Antineoplastics
Class II antiarrhythmics
Fluorouracil
Immunostimulants
Immunosuppressants
Interleukin 2
Nitrogen mustards
Nitrosoureas
Sulphur mustards
Toxic encephalitis due to mercury
Toxic epidermal necrolysis
4 Quinolones
ACE inhibitors
Antiepileptics
Antifungals
Antivirals
Carbacephems
Carbapenems
Cephalosporins
Cephamycins
Sulphonamides
Thiazide diuretics
Toxic optic neuropathy
Termor
4 Quinolones
Anorectics
Anthelmintics
Antidepressants
Antiemetics
Antiepileptics
Antivirals
Central stimulants
Corticosteroids
Immunosuppressants
Isoprenaline
Lithium
Promethazines
Sedatives
Sympathomimetics
Ulcer of oesophagus
Bisphosphonates
Medicinal enzymes
Unspecified cell type leukaemia
Uraemia
Organic iodinate contrast media
Urinary retention
Antimuscarinics
Carbamate sedatives
Haemostatics
Neuroleptics
Promethazines
antidepressants
Urinary system symptoms
Urinary tract infection
Antiulcer agents
Urine abnormal colouration
4 Quinolones
Antileprotics
Antiprotozoals
Carbapenems
Urine colour abnormal
Anthelmintics
Urine looks dark
Urine protein abnormal
Anthelmintics
Urine urate raised
Antivirals
Medicinal enzymes
Urticaria
ACE inhibitors
332

Amidinopenicillins
Aminopenicillins
Anthelmintics
Antiemetics
Antifungals
Antineoplastics
Antiulcer agents
Antivirals
Carbacephems
Carbapenems
Carboxypenicillins
Central stimulants
Cephalosporins
Cephamycins
Gold salts
Heparinoids
Immunosuppressants
Laxatives
Macrolides
Medicinal enzymes
Monobactams
Mucolytics
Natural penicillins
Nireoimidazole antiprotozoals
Norgestrels
Opioid analgesics
Opioid peptides
Phenoxypenicillins
Polyene antibiotics
Progestogens
Sedatives
Sex hormones
Typhoid vaccines
Ureido penicillins
Uterus rupture in / after labour
Oxytocic hormones
Uveitis
Beta blockers
Vaginal discharge
Sex hormones
Vaginitis and vulvovaginitis
Cephalosporins
Vasculitis
Vasodilatation
Contrast media
Venous embolus / thrombus
Estrogens
Haemostatics
Sex hormones
Ventricular ectopic beats
Antimalarials
Ventricular fibrillat./flutter
Antimalarials
Beta blocker
Vertigo
Anthelmintics
Antiemetics
Antifungals
Antiulcer agents
Carbamate sedatives
Opioid analgesics
Opioid peptides
Polymyxins
Sedatives
Tetracyclines
Vitamins
Vesicles
Antifungals
Vesicular eruption
333

Vestibular disorders
Aminoglycosides
Viral / chlamydial infection
Antivirals
Corticosteroids
Immunosuppressants
Virilism
Anabolics
Androgens
Medicinal enzymes
Sex hormones
Testosterones
Visual disturbances
Antiulcer agents
Visual symptoms
Antiandrogens
Vitamin B12 deficiency anaemia
Vitamin K deficiency
Vomiting
4 Quinolones
ACE inhibitors
Alpha adrenoceptor sitmulants
Amino acids
Anabolics
Anthelmintics
Antiandrogens
Antiarrhythmics
Antidepressants
Antidiarrhoeals
Antidotes
Antiepileptics
Antifungals
Antimalarials
Antimuscarinics
Antineoplastics
Antiprotozoals
Antithyroid agents
Antiulcer agents
Antivirals
Aspartic acid
Beta blockers

Bismuth salts
Blood products
Calcitonin
Carbacephems
Carbapenems
Cardiac glycosides
Central stimulants
Cephalosporins
Cephamycins
Chloramphenicols
Colchicum alkaloids
Contrast media
Diagnostic agents
Digitalis
Ergolines
Ergot compounds
Estrogens
Expectorants
Fluorouracil
Glucose tests
Haemostatics
Immunosuppressants
Iron compounds
Laxatives
Lincomycin
Lithium
Macrolides
Medicinal enzymes
Monobactams
Neuroleptics
Nitrogen mustards
Nitrosoureas
Opioid analgesics
Opioid antagonists
Opioid peptides
Oral hypoglycaemics
Oxytetracyclines
334

Pilocarpine
Platelet activation factor antagonists
Polyene antibiotics
Sedatives
Serotonin and anaologues
Sex hormones
Sulphonamides
Sulphur mustards
Sympathomimetics
Tetracyclines
Typhoid vaccine
Uricosuric agents
Vitamins
Water intoxication
Oxytocic hormones
335

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:

. ., M.Sc (Clinical Pharmacy)

B.S. (Pharmacy), M.S. (Clinical Pharmacy)

1.2 Adverse Drug Reaction

1.3 Side effect

1.4 Unexpected adverse reaction

1.5 Toxic Reaction

2. Type B (bizarre) adverse drug reactions

2) Type B (bugs) reactions

3) Type C (chemical) reactions

4) Type D (delivery) reactions

5) Type E (exit) reactions

cytochrome p450 2D6

8) Type H (hypersensitivity) reactions

angioedema, blood dyscrasias

4.1 Chromosome damage

4.2 Disorders of fetus and infant

4.3 Disorders of the heart

4.4 Disorders of the peripheral vascular system

sympathomimetic drugs, cyclosporin

4.5 Respiratory disorders

4.7 Gastrointestinal disorders

4.8 Hepatic disorders

4.9 Renal disorders

acute tubular necrosis

4.10 Endocrine disorders

4.11 Disorders of metabolism

4.12 Disorders of muscle ,bone and connective tissue

4.13 Skin disorders

4.14 Neurological disorders

4.17 Psychiatric disorders

4.18 Disorders of blood cells and haemostasis

4.19 Neoplastic disorders

4.22 Drug induced sexual dysfunction and fertility

(mild, negligible, insignificant)

(patient medication profile)

1.1 Prolonged QT interval

magnesium sulphate infusion

imidazole, protease inhibitors ( ritonavir)

(calcium channel blockers)

anthyracycline (anthracycline cytotoxics)

chronic dilated cardiomyopathy

total peripheral resistance

factor V Leiden mutation

(hormone replacement therapy, HRT)

alpha adrenoceptor blockers

alpha adrenoceptor blockers

first dose effect

neuromuscular blocking agents

1. Chapelon C. Abnormal blood pressure. In: Benichou C. Adverse Drug Reactions: A

(end stage renal failure)

increased blood urea nitrogen (BUN)

serum creatinine (Scr)

gromerular filtration rate (GFR)

(total drug dose)

Cyclosporin, radiocontrast, amphotericin B,

glomerular efferent arterioles

compromise of renal perfusion

preexisting renal disease

druginduced glomerular disease

5. Tubular epithelial cell damage

intracellular cations (K+, Mg2+)

tubular epithelial cells