Mod 3: Adverse Drug Reactions

Side Effect

An expected, well-documented, dose-dependent effect occurring at therapeutic doses due to a lack of receptor selectivity (e.g., dry mouth with Atropine).

Adverse Drug Reaction (ADR)

A noxious, unintended response occurring at doses normally used in humans for prophylaxis, diagnosis, or therapy (WHO definition).

Toxic Effect

A noxious response caused by overdose or drug accumulation above the therapeutic range (e.g., hepatotoxicity from 10 g of Paracetamol).

Idiosyncratic Reaction

An unpredictable, non-dose-dependent reaction unique to a genetically predisposed individual (e.g., hemolytic anemia from Primaquine in G6PD deficiency).

Type A (Augmented)

Predictable, dose-dependent

Exaggeration of normal pharmacology

High incidence, low mortality

Type B (Bizarre)

Unpredictable, dose-independent

Immunological or genetic basis

Low incidence, high mortality

Type C (Chronic)

Cumulative dose and time-dependent

Associated with long-term therapy

Type D (Delayed)

Becomes apparent long after drug exposure

Includes teratogenesis and carcinogenesis

Type E (End-of-Use)

Occurs during or shortly after drug withdrawal

Type F (Failure)

Unexpected failure of therapy

Often caused by drug interactions or resistance

Type A (Augmented): example

Hypoglycemia from Insulin/Glibenclamide

Bleeding from Warfarin

Bradycardia from Propranolol

Type B (Bizarre)

Anaphylaxis from Penicillin

Stevens-Johnson Syndrome (SJS) from Allopurinol or Carbamazepine

Type C (Chronic)

Adrenal suppression from chronic Glucocorticoids

Analgesic nephropathy from long-term NSAIDs

Type D (Delayed)

Phocomelia from Thalidomide

Vaginal adenocarcinoma in offspring exposed to Diethylstilbestrol (DES)

Type E (End-of-Use)

Rebound hypertension after stopping Clonidine or Propranolol

Withdrawal syndrome from Opioids

Type F (Failure)

Oral contraceptive failure due to enzyme induction by Rifampicin

Type I (Immediate / IgE-Mediated)

Onset Time: Minutes to 1 hour

Pathophysiology & Key Examples: Antigen cross-links IgE on mast cells/basophils → Histamine release.

_{^{Examples: Anaphylaxis, Urticaria from Penicillin or Cephalosporins.}}

Type II (Cytotoxic / IgG or IgM)

Onset Time: Hours to Days

Pathophysiology & Key Examples: Antibodies bind cell-surface antigens → Complement activation & cell lysis.

_{^{Examples: Methyldopa-induced hemolytic anemia; Heparin-Induced Thrombocytopenia (HIT Type II).}}

Type III (Immune Complex / IgG)

Onset Time: 1 to 3 weeks

Pathophysiology & Key Examples: Antigen-antibody complexes deposit in tissue/vessels → Complement activation.

_{^{Examples: Serum sickness from anti-venom; Hydralazine/Procainamide-induced Drug-Induced Lupus (DILE).}}

Type IV (Delayed / T-Cell Mediated)

Onset Time: 48 to 72 hours (or weeks)

Pathophysiology & Key Examples: Sensitized T-lymphocytes release cytokines → Macrophage activation.

_{^{Examples: Contact dermatitis (Poison Ivy); Stevens-Johnson Syndrome (SJS) / Toxic Epidermal Necrolysis (TEN).}}

Organ-specific toxicity patterns

HEPATOTOXICITY: Paracetamol (NAPQI), isoniazid, Halothane

NEPHROTOXICITY: Aminoglycosides, Amphotericin B, Cisplatin

Hepatotoxicity

Paracetamol (Acetaminophen)

Isoniazid (INH)

Halothane

Paracetamol (Acetaminophen)

Toxic metabolite NAPQI causes hepatic necrosis. Antidote: N-Acetylcysteine (NAC) (replenishes glutathione).

Isoniazid (INH)

Caused by toxic acetyl-hydrazine metabolite. Increased risk in slow acetylators.

Halothane

Halothane: Halothane hepatitis (bridging hepatic necrosis).

Nephrotoxicity & Ototoxicity

Aminoglycosides (Gentamicin, Amikacin)

Amphotericin B

Cisplatin

Furosemide + Aminoglycoside

Aminoglycosides (Gentamicin, Amikacin)

Accumulates in renal proximal tubules and inner ear endolymph → Acute Tubular Necrosis (ATN) and irreversible ototoxicity

Amphotericin B

Severe renal vasoconstriction ("Amphoterrible").

Mitigation: Pre-infusion normal saline hydration.

Cisplatin

Nephrotoxic and highly emetogenic.

Antidote / Protectant: Amifostine (reduces renal toxicity).

Furosemide + Aminoglycoside

Synergistic ototoxicity when combined

Cardiotoxicity

Doxorubicin / Daunorubicin

QT Prolongation / Torsades de Pointes

Doxorubicin / Daunorubicin

Free-radical generation causes dilated cardiomyopathy. Antidote / Protectant: Dexrazoxane (iron-chelating agent).

QT Prolongation / Torsades de Pointes

Terfenadine

Cisapride

Erythromycin

Sotalol

Haloperidol

Hematologic Toxicity

Chloramphenicol

Clozapine

Chloramphenicol

Dose-dependent bone marrow suppression and dose-independent Aplastic Anemia; also causes Gray Baby Syndrome (due to deficient glucuronidation in neonates).

Clozapine

Risk of Agranulocytosis (requires mandatory Absolute Neutrophil Count [ANC] monitoring).

Pulmonary Toxicity

Bleomycin & Amiodarone

Bleomycin & Amiodarone

Pulmonary fibrosis (look for dyspnea, non-productive cough, and "ground-glass" opacities on chest X-ray)

Teratogenicity

Thalidoimide

Isotretinoin

ACE Inhibitors / ARBs

Valproic Acid

Thalidoimide

Phocomelia (seal-like limbs).

Isotretinoin

Severe craniofacial, cardiac, and CNS malformations (Requires iPLEDGE program).

ACE Inhibitors / ARBs

Renal dysgenesis, oligohydramnios, skull hypoplasia

Valproic Acid

Neural tube defects (Spina Bifida)

Slow vs. Fast Acetylators

Procainamide, Hydralazine, and Isoniazid (PHI) cause Drug-Induced Lupus Erythematosus (DILE) primarily in slow acetylators (hepatic NAT2 enzyme deficiency).

HLA Testing

Screen for HLA-B*1502 before starting Carbamazepine in Asian populations due to high risk of SJS/TEN

Red Man Syndrome

Caused by rapid intravenous infusion of Vancomycin triggering direct, non-immunological histamine release from mast cells (Mitigation: Slow the infusion rate over at least 60 minutes and pre-treat with antihistamines)