Phys · pharmacological
Adverse Drug Reactions — Classification, Recognition and Management
Also known as adverse drug reaction · ADR · drug side effect · adverse drug event · DRESS · drug reaction with eosinophilia and systemic symptoms · Stevens-Johnson syndrome · SJS · toxic epidermal necrolysis · TEN · drug-induced agranulocytosis · drug-induced liver injury · Hy's law · drug-induced interstitial lung disease · pharmacovigilance
Consultant-physician-depth guide to adverse drug reactions (ADRs): the Rawlins and Thompson ABCDEF classification, causality assessment (Naranjo), the high-yield severe reactions a physician must not miss (DRESS, SJS/TEN, drug-induced agranulocytosis and thrombocytopenia, DILI and Hy's Law, drug-induced interstitial lung disease, QT prolongation), Type E withdrawal syndromes, Type F treatment failure, Yellow Card and TGA reporting, and prevention through medication reconciliation and electronic alerts — structured for FRACP DWE and DCE preparation.
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Red flags
- Any new rash plus fever plus systemic symptoms 2 to 8 weeks after a new drug — think DRESS and check eosinophils and liver function
- Painful skin, mucosal involvement, target lesions or blistering with skin detachment after allopurinol, anticonvulsant, sulfonamide or NSAID — Stevens-Johnson syndrome or toxic epidermal necrolysis; stop all drugs and transfer to a burns unit
- Fever and sore throat in the first three months of carbimazole, clozapine or sulfasalazine — neutropenia or agranulocytosis; check urgent full blood count before the next dose
- Falling platelet count 5 to 14 days after heparin exposure, with or without new thrombosis — heparin-induced thrombocytopenia; stop all heparin and send a PF4 antibody
- ALT or AST more than three times the upper limit of normal plus bilirubin more than two times the upper limit of normal, with no other cause — Hy's law; the drug carries a 10 per cent mortality risk and must be stopped
- New dyspnoea, cough and diffuse infiltrates in a patient on amiodarone, methotrexate, nitrofurantoin, bleomycin or a checkpoint inhibitor — drug-induced interstitial lung disease; stop the drug and image
- QTc above 500 ms, or new QT prolongation in a patient on two or more QT-prolonging drugs or with hypokalaemia — risk of torsade de pointes; correct electrolytes and stop the offending agent
- Any severe or previously unrecognised reaction, especially to a new or recently marketed drug — report it to the TGA (Australia) or MHRA Yellow Card (UK)
Adverse Drug Reactions — Classification, Recognition and Management
[1]The one-minute consultant answer
An adverse drug reaction (ADR) is an appreciably harmful or unpleasant reaction resulting from the use of a medicinal product, which predicts hazard from future administration and warrants prevention, specific treatment, dose alteration, or withdrawal of the drug [1]. ADRs are common, often preventable, and account for roughly 6 to 7 per cent of all hospital admissions, with the burden concentrated in older patients on multiple medications [2][11]. The Pirmohamed BMJ study of 18,820 admissions found aspirin, diuretics, warfarin and NSAIDs were the commonest culprits, and that most reactions were definitely or possibly avoidable [2].
The conceptual anchor for the whole topic is the Rawlins and Thompson classification, refined by Edwards and Aronson, which sorts reactions into six types by their relationship to dose and time [1]:
- Type A (Augmented) — an exaggerated but otherwise normal pharmacological action; dose-dependent, predictable, common, low mortality. Examples: beta-blocker bradycardia, anticoagulant bleeding, opioid constipation.
- Type B (Bizarre) — a reaction novel to the drug's pharmacology; dose-independent, unpredictable, rare, high mortality when severe. Examples: anaphylaxis, DRESS, SJS/TEN, drug-induced agranulocytosis.
- Type C (Chronic) — cumulative dose over time. Examples: bisphosphonate osteonecrosis of the jaw, methotrexate hepatic fibrosis, amiodarone pulmonary toxicity.
- Type D (Delayed) — delayed in time, sometimes long after the drug is stopped. Examples: teratogenesis (thalidomide, isotretinoin), carcinogenesis (DES and vaginal clear-cell carcinoma).
- Type E (End-of-treatment) — withdrawal. Examples: opiate withdrawal, adrenal suppression after long-term steroids, clonidine rebound hypertension.
- Type F (Failure) — unexpected failure of therapy. Examples: oral contraceptive failure with enzyme inducers or antibiotics, warfarin failure with concurrent vitamin K. [1]
The clinical task at the bedside is threefold: recognise the reaction as drug-related, stop or substitute the offending agent, and report it. Recognition rests on a careful drug history with temporal association and the application of a causality tool such as the Naranjo scale [3]. For the severe Type B reactions — DRESS, SJS/TEN, agranulocytosis, HIT, severe DILI and DI-ILD — early recognition is the difference between recovery and death. Every severe or previously unrecognised reaction should be reported to the TGA in Australia (the Blue Card) or through the MHRA Yellow Card scheme in the UK, because pharmacovigilance depends on clinician reporting [1].
References12ShowHide
- [1]Edwards IR, Aronson JK Adverse drug reactions: definitions, diagnosis, and management Lancet, 2000.PMID 11072960
- [2]Pirmohamed M, James S, Meakin S, et al. Adverse drug reactions as cause of admission to hospital: prospective analysis of 18 820 patients BMJ, 2004.PMID 15231615
- [3]Naranjo CA, Busto U, Sellers EM, et al. A method for estimating the probability of adverse drug reactions Clin Pharmacol Ther, 1981.PMID 7249508
- [4]Cacoub P, Musette P, Descamps V, et al. The DRESS syndrome: a literature review Am J Med, 2011.PMID 21592453
- [5]Bastuji-Garin S, Fouchard N, Bertocchi M, et al. SCORTEN: a severity-of-illness score for toxic epidermal necrolysis J Invest Dermatol, 2000.PMID 10951229
- [6]Hoofnagle JH, Björnsson ES Drug-Induced Liver Injury - Types and Phenotypes N Engl J Med, 2019.PMID 31314970
- [7]Greinacher A CLINICAL PRACTICE. Heparin-Induced Thrombocytopenia N Engl J Med, 2015.PMID 26176382
- [8]Schwaiblmair M, Behr W, Haeckel T, et al. Drug induced interstitial lung disease Open Respir Med J, 2012.PMID 22896776
- [9]Alvir JM, Lieberman JA, Safferman AZ, et al. Clozapine-induced agranulocytosis. Incidence and risk factors in the United States N Engl J Med, 1993.PMID 8515788
- [10]Drew BJ, Ackerman MJ, Funk M, et al. Prevention of torsade de pointes in hospital settings: a scientific statement from the American Heart Association and the American College of Cardiology Foundation Circulation, 2010.PMID 20142454
- [11]Kongkaew C, Noyce PR, Ashcroft DM Hospital admissions associated with adverse drug reactions: a systematic review of prospective observational studies Ann Pharmacother, 2008.PMID 18594048
- [12]Boyer EW, Shannon M The serotonin syndrome N Engl J Med, 2005.PMID 15784664