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Predisposing factors • Multiple drug therapy • Age == Elderly == Neonates- chloramphenicol, morphine, Reye’s syndrome - ? Hepatotoxicity – Aspirin Predisposing factors • Gender - Females have 1.5-1.7 folds of developing ADR than males - Women are prone to develop blood dyscrasias with phenylbutazone & chloramphenicol • Presence of disease - HIV –skin reactions with co-trimoxazole Predisposing factors • Race and genetic polymorphism - Drug-metabolizing enzymes (poor, extensive & ultra-rapid metabolizers) - Drug receptors - Drug transporters (P-glycoproteins, P-gp ) Mechanism of dose related (Type A) reactions • Pharmaceutical cause -pharmaceutical aspects of a dosage form Indomethacin – GI bleeding Mechanism of dose related (Type A) reactions • Pharmacokinetic causes 1. Absorption GI motility, gastric contents, disease, absorption in the GI tract, first-pass metabolism in liver & gut wall, concomitant drugs 2. Distribution Plasma-protein and tissue binding Mechanism of dose related (Type A) reactions • Pharmacokinetic causes 3. Metabolism Enzyme induction or inhibition – efficacy?? Genetic variants – oxidation, hydrolysis, acetylation Drugs competing for glucuronidation 4. Elimination -digoxin Examples of type B * Anesthetics e.g. Halothane and succinylcholine cause Malignant hyperthermia treated with dantrolene © Chronic type • paracetamol hepatotoxicity

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