Key Facts

ADRs are a major cause of morbidity, mortality, and healthcare cost. The majority are preventable with careful prescribing, monitoring, and patient education. Recognition and reporting are essential for improving drug safety.

Epidemiology

• ~6.5% of hospital admissions attributable to ADRs in UK (Pirmohamed et al., BMJ 2004)
• ~2–5% of in-hospital patients experience ADRs
• ADRs are the 4th leading cause of death in developed countries
• ~70% of ADR-related admissions are potentially preventable
• Cost to NHS: ~£500 million–£1 billion/year

Classification (Rawlins-Thompson)

• Type A (Augmented): dose-dependent, predictable from pharmacology; common; rarely fatal; manageable with dose reduction — e.g. hypotension with antihypertensives, bleeding with anticoagulants
• Type B (Bizarre): dose-independent, unpredictable, often immune-mediated; uncommon but may be fatal — e.g. anaphylaxis, SJS/TEN, DRESS, hepatotoxicity
• Type C (Chronic): related to cumulative dose/duration — e.g. osteoporosis (steroids), analgesic nephropathy
• Type D (Delayed): delayed onset after exposure — e.g. secondary malignancy (cytotoxics), teratogenicity
• Type E (End-of-use): withdrawal reactions — e.g. seizures (benzodiazepines), rebound hypertension (clonidine, beta-blockers)

Pathophysiology

• Type A: extension of pharmacological action — dose-dependent; related to PK (altered absorption, metabolism, excretion) and PD (receptor sensitivity)
• Type B: immune-mediated (Types I–IV hypersensitivity) or pharmacogenetic — e.g. HLA associations, enzyme deficiencies (G6PD, TPMT)
• Risk factors: polypharmacy, extremes of age, renal/hepatic impairment, genetic polymorphisms, female sex, previous ADR history

Common Type A ADRs

• GI bleeding: NSAIDs, aspirin, anticoagulants
• Hypoglycaemia: insulin, sulfonylureas
• Hypotension: antihypertensives, diuretics
• Bradycardia: beta-blockers, digoxin, rate-limiting CCBs
• Bleeding: warfarin, DOACs, heparin
• Sedation: opioids, benzodiazepines, antihistamines

Common Type B ADRs

• Anaphylaxis: penicillins, NSAIDs, neuromuscular blockers — IgE-mediated (Type I)
• SJS/TEN: anticonvulsants, allopurinol, antibiotics — T-cell mediated (Type IV)
• DRESS: anticonvulsants, allopurinol, antibiotics — T-cell mediated with eosinophilia
• Hepatotoxicity: isoniazid, flucloxacillin, statins, paracetamol
• Agranulocytosis: carbimazole, clozapine, sulfasalazine
• Aplastic anaemia: chloramphenicol, carbamazepine, NSAIDs

Red Flags

• Anaphylaxis: stridor, hypotension, urticaria — IM adrenaline 500 mcg immediately
• Drug-induced liver injury (DILI): jaundice, raised ALT >10× ULN — stop drug, hepatology referral
• SJS/TEN: mucosal erosions, epidermal detachment — dermatology/burns unit emergency
• Agranulocytosis: sore throat + fever on carbimazole/clozapine — URGENT FBC

Acute Assessment

• Full drug history: timeline of all drugs vs symptom onset — essential
• Naranjo probability scale: systematic assessment of ADR likelihood
• FBC: agranulocytosis, eosinophilia, thrombocytopenia
• U&Es, LFTs: renal and hepatic drug toxicity
• Coagulation screen: anticoagulant-related bleeding
• Mast cell tryptase: within 1–6 hours of suspected anaphylaxis
• ECG: QT prolongation, arrhythmia

Specialist Investigation

• Skin prick testing/specific IgE: drug allergy (penicillin) — allergy clinic
• Drug provocation testing: graded challenge to confirm or exclude allergy — specialist only
• Patch testing: delayed drug eruptions
• HLA typing: before high-risk drugs (HLA-B5701/abacavir, HLA-B5801/allopurinol)
• Pharmacogenomic testing: CYP2D6, TPMT, DPYD — if genetic susceptibility suspected

Reporting

• MHRA Yellow Card: report ALL suspected ADRs for ▼ (black triangle/newly licensed) drugs; serious ADRs for all drugs
• Online, paper form, or via app

Immediate

• Stop or reduce the suspected drug — most important step
• Supportive care: based on presentation (fluids, oxygen, monitoring)
• Antidotes: where available — naloxone (opioids), N-acetylcysteine (paracetamol), flumazenil (benzodiazepines — with caution), vitamin K/PCC (warfarin)

Type A ADR Management

• Dose reduction: may be sufficient
• Drug substitution: switch to alternative with fewer side effects
• Adding protective medication: PPI with NSAID, laxative with opioid

Type B ADR Management

• Immediate withdrawal of suspected drug
• Lifelong avoidance of causative drug and structurally related agents
• Treat reaction: adrenaline for anaphylaxis, ciclosporin for SJS/TEN, corticosteroids for DRESS
• Document allergy: patient notes, GP letter, allergy alert card/bracelet

Prevention

• Prescribe only when necessary: clear indication for every drug
• Use lowest effective dose: especially in elderly, renal/hepatic impairment
• Check interactions: BNF interactions checker
• Pharmacogenomic testing: where available and indicated
• Monitor: TDM for narrow TI drugs; regular blood tests where indicated
• Patient education: recognise symptoms of ADRs; when to seek help

Referral Criteria

• Allergy clinic: suspected drug allergy — formal testing and documentation
• Clinical pharmacology: complex ADR assessment, pharmacogenomics
• Hepatology: drug-induced liver injury
• Dermatology: severe cutaneous adverse reactions (SJS/TEN, DRESS)

• Type A ADRs: usually reversible with dose reduction or drug withdrawal; rarely fatal
• Type B ADRs: potentially fatal (anaphylaxis, SJS/TEN, agranulocytosis); require immediate drug withdrawal
• DRESS mortality: ~5–10%
• TEN mortality: ~25–30%
• Drug-induced liver injury: ~10% of acute liver failure in UK; mortality varies
• Prevention: majority of serious ADRs are preventable — careful prescribing reduces risk
• ADR reporting (Yellow Card): contributes to drug safety — has led to withdrawal of drugs (rofecoxib, cisapride)

ADR Classification Summary

Pirmohamed Study (BMJ 2004)