Q3 LONG ANSWER 10M ★ High-yield

Define adverse drug reaction. Classify adverse drug reactions and describe their mechanisms. Add a note on pharmacovigilance.

Pharmacology · 2nd Professional — Para-Clinical

Definitions

The WHO defines an adverse drug reaction as any noxious, unintended response to a drug occurring at doses normally used in man for prophylaxis, diagnosis or therapy.

An adverse event is any untoward occurrence during treatment, whether or not it is caused by the drug — the distinction matters in trials and in causality assessment
Doses "normally used in man" excludes deliberate overdose and poisoning
Adverse reactions cause about 5% of hospital admissions and are a leading cause of iatrogenic death

Rawlins–thompson Classification

Type	Name	Features	Examples
Type A	Augmented (pharmacological)	Predictable from the known action; dose-related; common (about 80%); low mortality; managed by reducing the dose	Bleeding with warfarin; hypoglycaemia with insulin; bradycardia with propranolol; dry mouth with atropine; postural hypotension with prazosin
Type B	Bizarre (idiosyncratic)	Unpredictable; not dose-related; uncommon; high mortality; managed by stopping the drug	Penicillin anaphylaxis; chloramphenicol aplastic anaemia; halothane hepatitis; malignant hyperthermia; Stevens–Johnson syndrome
Type C	Chronic (continuous)	Related to cumulative dose and duration	Osteoporosis and adrenal suppression with steroids; analgesic nephropathy; tardive dyskinesia; chloroquine retinopathy
Type D	Delayed	Appear long after exposure, sometimes in the next generation	Teratogenesis (thalidomide); carcinogenesis (vaginal adenocarcinoma in daughters exposed to diethylstilboestrol); second malignancy after alkylating agents
Type E	End of treatment (withdrawal)	Occur on stopping the drug	Rebound angina and infarction after abrupt beta-blocker withdrawal; adrenal crisis after stopping steroids; withdrawal seizures after benzodiazepines; hypertensive crisis after clonidine
Type F	Failure of therapy	Unexpected lack of efficacy, often from an interaction	Oral contraceptive failure with rifampicin or an antiepileptic

CLINICAL PEARL

Types A and B differ in every practical respect, and the management follows from the difference. A type A reaction is an extension of the drug’s known action, so it is predictable and the answer is to reduce the dose. A type B reaction has nothing to do with the pharmacology, so no dose is safe and the drug must be stopped and never given again.

Types of Adverse Reaction BY Mechanism

Category	Definition	Examples
Side effect	An unwanted but pharmacologically predictable effect at therapeutic dose	Atropine causing dry mouth; morphine causing constipation
Secondary effect	An indirect consequence of the primary action	Superinfection and pseudomembranous colitis after broad-spectrum antibiotics; hypokalaemia from a diuretic precipitating digoxin toxicity
Toxic effect	Result of excessive dose or prolonged use	Aminoglycoside ototoxicity; paracetamol hepatotoxicity
Intolerance	A characteristic effect at an unusually low dose	Tinnitus after a single tablet of aspirin
Idiosyncrasy	A genetically determined abnormal response	Haemolysis with primaquine in G6PD deficiency; prolonged apnoea after succinylcholine with atypical pseudocholinesterase; malignant hyperthermia
Drug allergy (hypersensitivity)	Immunologically mediated; requires prior sensitisation; unrelated to dose	See below
Photosensitivity	Cutaneous reaction on exposure to light	Tetracyclines, sulphonamides, fluoroquinolones, amiodarone
Drug dependence	Psychological or physical	Opioids, benzodiazepines, alcohol, nicotine
Iatrogenic disease	Physician-induced disease	Steroid-induced Cushing syndrome; drug-induced parkinsonism

Drug Allergy

Gell and Coombs type	Mechanism	Timing	Examples
Type I	IgE on mast cells	Minutes	Anaphylaxis, urticaria, bronchospasm, angio-oedema — penicillin is the commonest cause
Type II	IgG or IgM against cell-bound antigen	Variable	Haemolytic anaemia (methyldopa, penicillin); thrombocytopenia (quinine, heparin); agranulocytosis
Type III	Immune complexes	7–12 days	Serum sickness; drug-induced lupus (hydralazine, procainamide, isoniazid); vasculitis
Type IV	T cell mediated	24–72 hours or longer	Contact dermatitis; maculopapular rashes; stevens–johnson syndrome and toxic epidermal necrolysis

Severe cutaneous reactions — Stevens–Johnson syndrome and toxic epidermal necrolysis are most often caused by sulphonamides, allopurinol, carbamazepine, phenytoin, lamotrigine, nevirapine and NSAIDs; mortality in toxic epidermal necrolysis exceeds 30%
HLA-B*15:02 predicts carbamazepine-induced Stevens–Johnson syndrome in South-East Asian populations, and testing is recommended before starting it

Causality Assessment and Reporting

WHO causality categories — certain, probable, possible, unlikely, conditional, unassessable; the Naranjo scale is a structured scoring system
The strongest evidence is DE-challenge (improvement on stopping) and RE-challenge (recurrence on restarting) — though deliberate re-challenge is rarely ethical
Pharmacovigilance is the science of detecting, assessing and preventing adverse effects; India runs the Pharmacovigilance Programme of India (PvPI)
Spontaneous reporting (the yellow card system) is the main method of detecting rare type B reactions, because clinical trials are far too small to find an event occurring in 1 in 10,000 patients
Under-reporting is the chief weakness — probably under 10% of reactions are reported; every clinician has a duty to report

Organ-specific Drug Toxicity

Organ	Drugs and effect
Liver	Paracetamol (dose-related necrosis), isoniazid, rifampicin, pyrazinamide, methotrexate, halothane, valproate, amiodarone, statins
Kidney	Aminoglycosides, NSAIDs, ACE inhibitors, amphotericin B, contrast media, ciclosporin, cisplatin
Ear (ototoxicity)	Aminoglycosides (vestibular with streptomycin and gentamicin, cochlear with amikacin and kanamycin), loop diuretics, quinine, cisplatin, high-dose salicylates
Bone marrow	Chloramphenicol (aplastic anaemia), cytotoxics, carbimazole and clozapine (agranulocytosis), phenytoin, co-trimoxazole, zidovudine
Eye	Ethambutol (optic neuritis and loss of colour vision), chloroquine (retinopathy), steroids (cataract and glaucoma), amiodarone (corneal deposits)
Nerve	Isoniazid, vincristine, metronidazole, nitrofurantoin, phenytoin (peripheral neuropathy)
Heart	Doxorubicin (dose-related cardiomyopathy), drugs prolonging the QT interval — quinidine, sotalol, erythromycin, antipsychotics — causing torsades DE pointes
Lung	Amiodarone, bleomycin, methotrexate, nitrofurantoin (pulmonary fibrosis)

Applied Aspects

Prevention — take a careful drug and allergy history, avoid unnecessary polypharmacy, start low and go slow in the elderly, adjust for renal and hepatic function, and anticipate interactions
Always ask what happened when a patient reports an "allergy" — most reported penicillin allergy is nausea or a non-specific rash, and wrongly labelling a patient allergic denies them the best treatment for life
Type B reactions cannot be predicted but can be recognised early — warn patients on carbimazole or clozapine to report a sore throat, and on antiepileptics to report a rash
Stop the offending drug and record the reaction prominently; the record is what protects the patient at the next admission
Post-marketing surveillance found the problem in every famous drug withdrawal — thalidomide, practolol, rofecoxib, cerivastatin — because none was detectable in pre-marketing trials
In India, self-medication and over-the-counter sale of prescription drugs are widespread, and a drug history must ask specifically about them rather than relying on what is volunteered

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