Adverse Drug Reactions & Drug Interactions

A perennially high-yield General Pharmacology topic that integrates kinetics, dynamics and clinical medicine. Examiners love the Type A vs Type B framework, the CYP450 inducer/inhibitor lists, and the classic warfarin–phenytoin–rifampicin triad. Master the cut-offs, the mnemonics and the named reactions and you secure easy marks.

Definition & basic terminology

An adverse drug reaction (ADR) is any noxious, unintended response to a drug occurring at doses normally used in man for prophylaxis, diagnosis or therapy (WHO definition). An adverse drug event is broader and includes harm from medication errors and overdose. A side effect is an unintended pharmacological effect at therapeutic dose (often predictable). The science of detecting, assessing and preventing ADRs is pharmacovigilance.

High-yield: ADRs are the commonest reason drugs are withdrawn post-marketing. Phase IV (post-marketing surveillance) detects rare/long-latency ADRs because phase III trials enrol too few patients to pick up reactions with incidence <1 in 1000.

Key reporting tools to remember:

• Spontaneous reporting / yellow card system – cornerstone of pharmacovigilance.
• PvPI – Pharmacovigilance Programme of India, coordinated by IPC (Indian Pharmacopoeia Commission), Ghaziabad.
• Naranjo algorithm – scores causality (Definite ≥9, Probable 5–8, Possible 1–4, Doubtful ≤0).
• WHO-UMC (Uppsala Monitoring Centre) causality categories: certain, probable, possible, unlikely, conditional, unclassifiable.

Classification of ADRs (Rawlins–Thompson, A–F)

The classic exam framework divides ADRs into types. The two giants are Type A and Type B.

Type	Name	Mechanism	Dose-dependent?	Predictable?	Mortality	Example
A (Augmented)	Pharmacological	Exaggerated/known action	Yes	Yes	Low	Bleeding with warfarin; hypoglycaemia with sulfonylurea; bradycardia with beta-blocker
B (Bizarre)	Idiosyncratic/immune	Unrelated to known action	No	No	High	Penicillin anaphylaxis; halothane hepatitis; malignant hyperthermia
C (Chronic/Continuous)	Dose + time related	Cumulative	—	—	—	HPA suppression with steroids; analgesic nephropathy
D (Delayed)	Lag effect	Latency	—	—	—	Teratogenesis; carcinogenesis; tardive dyskinesia
E (End-of-use)	Withdrawal	Stopping	—	—	—	Beta-blocker/opioid/clonidine withdrawal
F (Failure)	Unexpected therapeutic failure	Often interaction	—	—	—	OCP failure with rifampicin/enzyme inducer

High-yield: Type A = most common (about 80% of ADRs), dose-dependent, low mortality. Type B = rare, dose-independent, high mortality (anaphylaxis, blood dyscrasias, severe cutaneous reactions). This Type A vs B distinction is the single most asked fact in this topic.

Mnemonic for A–F: Augmented, Bizarre, Chronic, Delayed, End-of-use, Failure.

Special named immune/idiosyncratic reactions

• Type I (anaphylaxis) – IgE-mediated: penicillin, β-lactams.
• Type II (cytotoxic) – penicillin-induced haemolytic anaemia, methyldopa, quinidine (thrombocytopenia).
• Type III (immune complex / serum sickness) – sulfonamides, antitoxins.
• Type IV (delayed, cell-mediated) – contact dermatitis, drug rashes.
• DRESS (Drug Reaction with Eosinophilia and Systemic Symptoms) – allopurinol, anticonvulsants, sulfonamides; eosinophilia, fever, facial oedema, hepatitis. Long latency (2–6 weeks).
• Pharmacogenetic idiosyncrasy: G6PD deficiency → haemolysis with primaquine/dapsone/sulfa; slow acetylators → isoniazid neuropathy & lupus; succinylcholine apnoea with pseudocholinesterase deficiency.

Severe cutaneous adverse reactions (SCARs)

Feature	SJS	TEN
Body surface area detached	<10%	>30%
Mortality	~5–10%	~30%+
Common culprits	Sulfonamides, carbamazepine, lamotrigine, phenytoin, allopurinol, nevirapine, NSAIDs (oxicams)	Same group

High-yield: HLA-B*1502 predicts carbamazepine-induced SJS/TEN in Han Chinese/South-East Asians (screen before starting). HLA-B*5701 predicts abacavir hypersensitivity – mandatory screening. HLA-B*5801 predicts allopurinol SCAR.

Drug interactions — overview

A drug interaction occurs when the effect of one drug (object/affected) is altered by another (precipitant), by food, or by herbs. Outcomes: loss of efficacy, toxicity, or unexpected new effect. Mechanistically:

Drug interactions → Pharmacokinetic (ADME) OR Pharmacodynamic (receptor/effect) OR Pharmaceutical (in-vitro incompatibility).

Pharmacokinetic interactions

Alter the concentration of drug reaching the target — i.e. Absorption, Distribution, Metabolism, Excretion.

Absorption

• Chelation/complex formation: tetracyclines & fluoroquinolones bind Ca²⁺/Mg²⁺/Al³⁺/Fe²⁺ (antacids, dairy, iron) → reduced absorption.
• Gut pH: PPIs/antacids reduce absorption of ketoconazole, atazanavir, iron (need acid).
• Gut motility: metoclopramide speeds, opioids/anticholinergics slow gastric emptying.
• P-glycoprotein: verapamil/quinidine inhibit P-gp → raise digoxin levels.

Distribution — protein binding displacement

A drug with high plasma-protein binding can displace another from albumin, transiently raising free (active) fraction. Clinically important mainly for highly bound, low-volume-of-distribution, narrow-therapeutic-index drugs.

High-yield: Classic displacement pairs — sulfonamides/aspirin displace warfarin (bleeding) and sulfonylureas (hypoglycaemia); valproate displaces phenytoin; aspirin displaces methotrexate. NSAIDs displace bilirubin in neonates → kernicterus, so sulfonamides are avoided near term.

Metabolism — the CYP450 system (most tested)

Most drug metabolism interactions occur at hepatic cytochrome P450, chiefly CYP3A4 (metabolises ~50% of drugs), CYP2D6, CYP2C9, CYP1A2, CYP2C19.

• Enzyme inhibition → decreased metabolism → increased levels of the object drug → toxicity. Onset is rapid (hours–days).
• Enzyme induction → increased metabolism → decreased levels → therapeutic failure. Onset is slow (1–2 weeks, requires new enzyme synthesis) and offset is gradual.

Inducers (CRAP GPS)	Inhibitors (SICKFACES.COM)
Carbamazepine	Sodium valproate
Rifampicin	Isoniazid
Alcohol (chronic)	Cimetidine
Phenytoin / Phenobarbitone	Ketoconazole (azoles)
Griseofulvin	Fluconazole / Fluoxetine
Smoking (CYP1A2), St John's wort	Amiodarone, Acute alcohol
Glucocorticoids, Rifabutin	Ciprofloxacin, Chloramphenicol, Clarithromycin, grapefruit juice, Erythromycin, Sulfonamides, Omeprazole, Metronidazole

High-yield mnemonics: Inducers — "CRAP GPS" (Carbamazepine, Rifampicin, Alcohol-chronic, Phenytoin/Phenobarb, Griseofulvin, Pioglitazone, Smoking/St John's wort). Inhibitors — "SICKFACES.COM".

High-yield: Grapefruit juice inhibits intestinal CYP3A4 → raises levels of felodipine, statins (not pravastatin/rosuvastatin), cyclosporine. St John's wort is a potent inducer → OCP/cyclosporine/warfarin/indinavir failure.

Excretion

• Urinary pH: alkalinisation (sodium bicarbonate) speeds elimination of acidic drugs (aspirin, phenobarbitone, methotrexate); acidification speeds basic drugs (amphetamine).
• Tubular secretion competition: probenecid blocks penicillin secretion (prolongs action — exploited therapeutically); also blocks methotrexate excretion (toxicity).
• Renal transporters: NSAIDs reduce lithium clearance → lithium toxicity; diuretics affect lithium.

Pharmacodynamic interactions

Two drugs act at the same/related receptor or system without changing plasma levels.

• Additive/synergistic: alcohol + benzodiazepine (CNS depression); aminoglycoside + loop diuretic (ototoxicity); two QT-prolonging drugs.
• Antagonistic: beta-blocker blunts salbutamol; NSAIDs antagonise antihypertensives/diuretics.
• Serotonin syndrome: SSRI + MAOI/tramadol/linezolid → tremor, hyperthermia, clonus.
• Tyramine (cheese) reaction: MAOI + tyramine-rich food → hypertensive crisis.

Narrow therapeutic index (NTI) drugs — require monitoring

NTI drugs have a small gap between effective and toxic concentrations (low therapeutic index); small kinetic changes cause big clinical effects, so they are the usual victims of interactions and need therapeutic drug monitoring (TDM).

Drug	Target/therapeutic range	Monitor for
Warfarin	INR 2–3 (2.5–3.5 mechanical valve)	Bleeding
Phenytoin	10–20 µg/mL	Nystagmus→ataxia→coma (zero-order kinetics)
Digoxin	0.5–2 ng/mL (0.5–0.9 in HF)	Arrhythmia, visual halos
Lithium	0.6–1.2 mEq/L	Tremor, ataxia, seizures
Theophylline	10–20 µg/mL	Seizures, arrhythmia
Aminoglycosides	trough-guided	Nephro/ototoxicity
Cyclosporine/tacrolimus	level-guided	Nephrotoxicity, rejection
Vancomycin	trough/AUC	Nephrotoxicity

High-yield: Phenytoin shows zero-order (saturation/Michaelis-Menten) kinetics within the therapeutic range — small dose increments cause disproportionate rises in level. This non-linearity makes it a classic TDM and interaction drug.

The classic NEET PG triad — warfarin, phenytoin, rifampicin

These three appear repeatedly because they sit at the crossroads of binding, metabolism and induction.

Warfarin (object drug, NTI, highly protein bound, metabolised by CYP2C9/3A4):

• ↑ Effect (bleeding): enzyme inhibitors — amiodarone, metronidazole, fluconazole, cotrimoxazole, ciprofloxacin; displacement by aspirin/sulfonamides; antiplatelet additive effect.
• ↓ Effect (clot risk): enzyme inducers — rifampicin, carbamazepine, barbiturates, St John's wort; vitamin K-rich food.

Phenytoin (inducer AND substrate; zero-order kinetics):

• Valproate displaces phenytoin and inhibits its metabolism → raised free phenytoin/toxicity.
• Isoniazid, cimetidine, chloramphenicol inhibit → toxicity.
• Phenytoin induces metabolism of OCPs, warfarin, theophylline → failure.

Rifampicin — the most potent enzyme inducer in clinical use:

• Causes failure of OCPs (counsel additional contraception), warfarin, sulfonylureas, protease inhibitors, corticosteroids, cyclosporine, methadone, phenytoin, digoxin.

High-yield: A woman on OCPs who conceives after starting anti-TB therapy = rifampicin-induced enzyme induction → OCP failure (Type F ADR). Counsel barrier/alternative contraception. This is a recurrent single-best-answer stem.

Stepwise clinical approach to a suspected ADR

1. Recognise – temporal relationship between drug start and event.
2. Assess severity & seriousness – is it life-threatening / hospitalising?
3. Causality – apply Naranjo or WHO-UMC scale; check de-challenge (improves on stopping) and re-challenge (recurs on restart).
4. Manage – withdraw culprit, give antidote/supportive care.
5. Report – to PvPI / nearest ADR Monitoring Centre.
6. Prevent – document allergy, adjust future prescribing, pharmacogenomic screening where indicated.

Specific organ ADRs worth memorising

• Hepatotoxicity: paracetamol (overdose), INH, rifampicin, halothane, methotrexate, valproate.
• Nephrotoxicity: aminoglycosides, amphotericin B, cisplatin, NSAIDs, contrast.
• Ototoxicity: aminoglycosides, loop diuretics, cisplatin, quinine.
• Pulmonary fibrosis: bleomycin, busulfan, amiodarone, methotrexate, nitrofurantoin (mnemonic BBAMN).
• Photosensitivity: tetracyclines, fluoroquinolones, sulfonamides, amiodarone.
• Gingival hyperplasia: phenytoin, ciclosporin, nifedipine/amlodipine.
• Lupus-like syndrome: hydralazine, procainamide, isoniazid (HIPP — also phenytoin, methyldopa).

Complications & medico-legal angle

ADRs cause significant iatrogenic morbidity and prolonged hospitalisation, prescribing errors, and are a leading preventable cause of in-hospital harm. Type B reactions (anaphylaxis, SJS/TEN, agranulocytosis) carry high mortality and demand immediate withdrawal and supportive/critical care. Documented allergy lists, allergy bands and computerised prescribing reduce repeat exposure.

Key differentials / things to distinguish

• ADR vs disease progression vs new disease – use temporal correlation and de-challenge.
• Allergy (immune, Type B) vs intolerance/side effect (Type A) – allergy needs avoidance of the whole class.
• Drug interaction vs idiosyncrasy – interaction needs a precipitant drug; idiosyncrasy is host (genetic) determined.
• Serotonin syndrome vs NMS vs malignant hyperthermia – onset, triggering drug class, and rigidity pattern differ (rapid + clonus/hyperreflexia in serotonin syndrome; lead-pipe rigidity + neuroleptics in NMS; volatile anaesthetic/succinylcholine in MH).

Recently asked / exam angle

• Type A vs Type B ADR features (dose dependence, predictability, mortality) — repeatedly asked as direct match.
• Identify the enzyme inducer/inhibitor from a list (rifampicin = most potent inducer; cimetidine, azoles = inhibitors).
• OCP failure with rifampicin clinical vignette → Type F / enzyme induction.
• Warfarin interaction stems: which drug raises INR/causes bleeding (metronidazole, amiodarone) vs lowers it (rifampicin).
• HLA associations: B5701–abacavir, B1502–carbamazepine SJS, B*5801–allopurinol.
• Probenecid + penicillin mechanism (blocks tubular secretion — beneficial interaction).
• Grapefruit juice and intestinal CYP3A4; St John's wort as inducer.
• Naranjo scale for causality assessment; PvPI/IPC Ghaziabad as Indian pharmacovigilance body.
• Phenytoin zero-order kinetics and valproate displacement.
• Drug-induced lupus (HIPP), pulmonary fibrosis (BBAMN), gingival hyperplasia classic triads.

Rapid revision

1. Type A = augmented, dose-dependent, predictable, common, low mortality; Type B = bizarre, idiosyncratic, rare, high mortality.
2. Rifampicin = most potent enzyme inducer → causes OCP/warfarin/steroid failure (Type F ADR).
3. Enzyme inhibition → toxicity (fast onset); induction → therapeutic failure (slow onset, 1–2 wks).
4. Inducers = CRAP GPS; inhibitors = SICKFACES.COM; CYP3A4 metabolises ~50% of drugs.
5. Metronidazole/amiodarone/azoles raise INR (bleeding); rifampicin/carbamazepine lower INR (clot).
6. Phenytoin = zero-order kinetics; valproate displaces it → free-phenytoin toxicity.
7. Probenecid blocks penicillin tubular secretion (beneficial); blocks methotrexate excretion (toxic).
8. NTI drugs needing TDM: warfarin (INR 2–3), digoxin (0.5–2), lithium (0.6–1.2), phenytoin (10–20), theophylline (10–20).
9. HLA: B*5701–abacavir, B*1502–carbamazepine SJS/TEN, B*5801–allopurinol.
10. Naranjo ≥9 = definite; pharmacovigilance in India = PvPI under IPC, Ghaziabad.
11. Drug-induced lupus = HIPP (hydralazine, INH, procainamide, phenytoin); pulmonary fibrosis = BBAMN.
12. Grapefruit juice inhibits intestinal CYP3A4; St John's wort is a potent inducer.