Adverse Drug Reactions and Drug • Gender

Interactions - Females have 1.5-1.7 folds of developing ADR

than males
Adverse Drug Reaction:
- Women are prone to develop blood
• Response to a drug which is noxious,
dyscrasias with phenylbutazone &
unintended and occurs at doses used in man
chloramphenicol
for prophylaxis, diagnosis and therapy (WHO)
- Histaminoid reactions with neuromuscular
• Unwanted or harmful reaction experienced
blocking drugs
after the administration of a drug or
• Intercurrent disease
combination of drugs under normal
conditions of use and suspected to be related - Hepatic/renal disease

to drug - HIV –skin reactions with co-trimoxazole

Type of adverse reactions: - Critical illness

• Type A (Augmented) - Trauma

• Type B (Bizarre) • Race and genetic polymorphism

• Type C (Chronic) - Drug-metabolizing enzymes (poor, extensive

& ultra-rapid metabolizers)
• Type D (Delayed)
- Drug receptors
• Type E (End of use)
- Drug transporters (P-gp or MDR1)
• Type F (Therapeutic failure)

• Type G (Genetic/genomic) Mechanism of dose related (Type A)

reactions
Classification is based on…
• Different doses to produce the pharmacologic
• Dose relatedness
effect
• Time course
• Different responses to a defined dose
• Susceptibility
Pharmaceutical cause
Type A ADRs – intrinsic to the drug effects
-pharmaceutical aspects of a dosage form
Type B ADRs - idiosyncratic
Indomethacin – GI bleeding
Predisposing factors:

• Multiple drug therapy

Pharmacokinetic causes
• Age
1. Absorption –reduced efficacy
1. Elderly- hypnotics, diuretics, NSAIDS, anti-
GI motility, gastric contents, disease,
hypertensives, psychotropics, digoxin
absorption in the GI tract, first-pass
2. Adults- polypharmacy
metabolism in liver & gut wall,
3. Children- antiepileptics, cytotoxic agents, concomitant drugs
anesthetic gases, antibiotics (associated with
2. Distribution
hepatic failure), Na valproate
Plasma-protein and tissue binding
4. Neonates- chloramphenicol, morphine,
3. Metabolism
antiarrhythmics
Enzyme induction or inhibition –
Reye’s syndrome - ?
efficacy??
Hepatotoxicity – Na valproate
 Genetic variants – oxidation, hydrolysis, Mechanisms of non dose-related (Type B)
acetylation ADR:
Drugs competing for glucoronidation • Pharmaceutical causes
• Microsomal oxidation - Presence of degradation products of the
• CYP2D6 or Debrisoquine hydroxylase active constituents
polymorphism (5-10% Europeans) - Excipients
- Poor metabolizers – reduced first- • Pharmacokinetic causes
pass
- P-glycoprotein / MDR1 – found in the
- Drugs metabolized includes cells of gut wall, surface of
psychiatric, neurological and hepatocytes & renal tubular cells
cardiovascular
• Pharmacodynamic causes
- Higher incidence of extrapyramidal
-target organs – genetic, immunologic,
symptoms seen as AE of
neoplastic or teratogenic
antipsychotics metabolized by
Erythrocyte glucose-6-phosphate (G6PD) deficiency
CYP2D6
• Sex-linked inherited deficiency
• CYP2C9
• Weakened red cell membrane
-CYP2C9*1/*1 – normal metabolic
rate for warfarin • Hemolysis from primaquine, sulfonamides,
sulfones and nitrofurantoin
CYP2C9*3/*3 – lowest metabolic
clearance rate for warfarin • African type-mild, Mediterranean type-severe

• Hydrolysis • Drugs that should be avoided with G6PD

deficiency
• Pseudocholinesterase
• Dapsone
- Decreased activity in variants
leading to suxamethonium apnea • Niridazole

• Acetylation • Methylene blue (methylthioninium Cl)

• N-acetyltransferase – rapid (Japan, • Primaquine

Canadian, half of UK) & slow acetylators • Quinolones (ciprofloxacin, nalidixic acid,

• Dapsone, INH, hydralazine, phenelzine, norfloxacin, ofloxacin)

procainamide, sulfonamides • Sulfonamides (Cotrimoxazole)

• Peripheral neuropathy – INH, Hereditary methemoglobinemias

hematologic AE- dapsone, SLE – • Methemoglobin reductase - cyanosis
procainamide & hydralazine
Porphyrias
• Glucuronidation
• Inherited disorder in heme biosynthesis
• Morphine, paracetamol, ethinylestradiol
• Abdominal and neuropsychiatric
• Glucuronyltransferases disturbances
4. Elimination • Excretion of excessive amounts of porphyrin
-digoxin, ACE inhibitors, aminoglycosides precursors 5-ALA (aminolaevulinic) or
antibiotics, class I anti-arrhythmic porphobilinogen
drugs (disopyramide, flecainide) and Malignant hyperthermia
cytotoxic agents
 • Rapid rise in body temperature (at least 2 C • Pharmacokinetic
per hour) • pharmacodynamic
• Associated with anesthetics and muscle • Who are susceptible?
relaxants (succinylcholine)
• Polypharmacy
• Stiffness of skeletal muscle, hyperventilation,
• Hepatic or renal disease
acidosis, hyperkalemia, increased activity of
• Long-term therapy for chronic illness
sympathetic NS à outcome?
• Critically ill
• Associated with a sudden release of
intracellular ionized Ca • ICU patients

• Antidote: D _ _ _ _ _ _ ene • Patients who have more than one prescribing

MD
Glucocorticoid glaucoma
• Drugs with high risk of interaction
Cholestatic jaundice induced by oral contracepitves
- Concentration dependent toxicity
Immunologic reasons for abnormal response
1. Digoxin
• Features:
2. Lithium
- No relation to the unusual pharmacologic
effects of the drug 3. Aminoglycosides

- Delay between the 1st exposure to the drug 4. Cytotoxic agents

and subsequent occurrence of the ADR 5. Warfarin

- Small doses may elicit the reaction once the - Steep dose response curve
allergy is established 1. Verapamil
- Reaction disappears on withdrawal 2. Sulfonylureas
- Illness is often recognizable as a form of 3. Levodopa
immunologic reaction
- Patient dependent on therapeutic effect
Delayed adverse effects
1. Immunosuppresives (e.g. cyclosporin,
• Pigmentary retinopathy – phenothiazine tacrolimus)
• Vaginal carcinoma – stilbestrol 2. Glucocorticoids
• Malignancy – immunosuppressives and 3. Oral contraceptives
chemotherapeutic agents
4. Anti-epileptics
Adverse effects associated with drug withdrawal
5. Anti-arrhythmics
• Benzodiazepine withdrawal syndrome
6. Anti-psychotics
• Rebound hypertension – clonidine
7. Antiretrovirals
• Acute adrenal insufficiency - corticosteroids
- Saturable hepatic metabolism
DRUG INTERACTIONS:
1. Phenytoin
• Occurs when the effects of one drug are
2. Theophylline
changed by the presence of another drug,
Pharmacokinetic:
herbal medicine, or some environmental
chemical agent • Absorption

• Outcome à Good or bad or fatal 1. Changes in GI pH

Mechanism of drug interactions

 - PPIs, H2 antagonist + weak acid, • Disulfiram – halothane
itraconazole • Verapamil – Midazolam
2. Adsorption, chelation and other complexing • Tobacco smoke – theophylline
mechanism
• Cimetidine – theophylline
-tetracycline and aluminum/magnesium
• Omeprazole – Diazepam
hydroxide
• Phenytoin - Nifedipine
- kaolin/charcoal
Enzyme induction
- Colestyramine, colestipol – digoxin,
Carbamazepine, barbiturates –
propranolol, warfarin levothyroxine,
autoinduction
cyclosporin
Short-half life drugs (rifampicin) induce
3. Effects on GI motility
metabolism than long-half life drugs
Narcotics, atropine, antacids à motility?
(phenytoin)
Domperidone, metoclopramide, cisapride
Chronic alcohol use, Cigarette smoking, St.
à motility?
John’s wort (Hypericum perforatum)
Slow motility is dis/advantageous to
penicllin & levodopa
Enzyme inhibition
Rapid motility is dis/advantageous to
Grapefruit juice- caution with simvastatin,
enteric coated tablet & griseofulvin
tacrolimus, vardenafil
4. Induction or inhibition of drug transport
Caution when given with drugs with
proteins
narrow TI – theophylline, phenytoin,
Verapamil enhances digoxin
warfarin
bioavailability by inhibiting P-gp
• Elimination
• Distribution
1. Changes in urinary pH
- Dependent on ionic composition, lipid
Enhance excretion of weak acids (aspirin)
solubility, and protein-binding
at alkaline pH
characteristics
Enhance excretion of weak base
- Plasma protein binding
(paracetamol) at acidic pH
Albumin – acidic drugs (warfarin)
Strong acids and bases are not affected by
α1 acid glycoprotein – basic drugs (TCA,
pH changes
lidocaine, disopyramide &
2. Changes in active renal tubular
propranolol)
secretion
• Metabolism
- Competition with the organic anion
CYP3A4 in the intestinal wall– grapefruit
transporters- probenecid &
juice & felodipine & cyclosporine
penicillin
MAO-A in the liver & intestinal wall –
- NSAIDs, salicylates & methotrexate
tranylcypromine, phenelzine &
3. Changes in renal blood flow
tyramine (diet) à increase
norepinephrine - Prostaglandins produces renal
blood flow
• Dexamethasone – R-warfarin
- NSAIDs & lithium
• Ciprofloxacin – Imipramine
 4. Influence of proximal reabsorption in - Hydrocortisone & hydrochlorothiazide à
relation to sodium ions hyperglycemia & hypokalemia

-Thiazide, loop diuretics & lithium à - Diuretic-induced hypokalemia &

decrease renal clearance of hypomagnesemia increases risks of
lithium dysrhythmia caused by digoxin

Drugs excreted entirely by glomerular - Increase risk of ototoxicity and

filtration is unlikely to be affected nephrotoxicity from combination of
by other drugs aminoglycosides and furosemide

5. Biliary excretion and enterohepatic

shunt

Ethinylestradiol conjugates &

antibiotics

6. Drug transporter proteins

P-glycoprotein – present in renal

proximal tubule, hepatocytes,
intestinal mucosa, and blood brain
barrier

Inhibitors- verapamil, atorvastatin

Inducers- rifampicin

Pharmacodynamic

• Antagonistic

- Flumazenil and benzodiazepines

(diazepam)

- Salbutamol and b-blockers (propranolol)

- Vit K and anticoagulants

- Levodopa and dopamine antagonist

• Additive /synergistic

- Antidepressants, hypnotics,
antihistamines

- MAOI and tyramine, amphetamines,

pseudoephedrine, cough & cold medicines

- TCA, antihistamines, phenothiazines à

anticholinergic

- TCA & epinephrine

- Benzodiazepines and alcohol

- Aspirin and warfarin

- ACE inhibitor, K supplement, and K

sparing diuretic à hyperkalemia