Pharmacovigilance

Pharmacovigilance

1. Scope, definitions and conceptual hierarchy

• Pharmacovigilance (PV) — "the science and activities relating to the detection, assessment, understanding and prevention of adverse effects or any other drug-related problems" (WHO 2002 definition, adopted verbatim by virtually every national PV programme). (KDT 8e Ch.6, p.93; Padmaja 7e Ch.4, p.65; Atkinson 4e Ch.26, p.499)
  • Goal: ensure safe and rational use of medicines across the entire life-cycle of a drug — the safety profile of a marketed drug is not fixed at approval and must be reassessed continuously. (G&G 14e Ch.8, p.145)
  • Domain extends beyond ADRs to medication errors, drug quality problems, off-label use, counterfeit/substandard products, drug interactions, drug abuse/misuse, and lack of efficacy. (Atkinson 4e Ch.26, p.499; KDT 8e Ch.6, p.93)
• Adverse drug reaction (ADR) — "any response to a drug that is noxious and unintended and that occurs at doses normally used in man for prophylaxis, diagnosis or therapy" (WHO). (Padmaja 7e Ch.4, p.60; KDT 8e Ch.6, p.92; B&B Ch.9, p.113)
  • Edwards & Aronson (2000) refinement: "an appreciably harmful or unpleasant reaction, resulting from an intervention related to the use of a medicinal product, which predicts hazard from future administration and warrants prevention or specific treatment, or alteration of dosage regimen or withdrawal of the product." (Atkinson 4e Ch.26, p.500)
  • Excludes trivial expected side effects, overdose, and accidental exposure. (KDT 8e Ch.6, p.92)
• Adverse drug event (ADE) — "any untoward medical occurrence that may present during treatment with a medicine, but which does not necessarily have a causal relationship with the treatment". ADE is the broader umbrella; ADR is a subset of ADE with established causality. (KDT 8e Ch.6, p.92; Atkinson 4e Ch.26, p.500)
• Side effect — minor, predictable, dose-related, pharmacodynamic effect at therapeutic dose (e.g. atropine dry mouth, prazosin postural hypotension). Used to keep ADR statistics undiluted by trivial events. (B&B Ch.9, p.113; KDT 8e Ch.6, p.94)
• Secondary effect — indirect consequence of a primary drug action (e.g. tetracycline-induced Clostridium difficile superinfection; thiazide hypokalaemia precipitating digoxin toxicity; corticosteroid-induced reactivation of latent tuberculosis). (KDT 8e Ch.6, p.94; B&B Ch.9, p.113)
• Toxic effect — excessive pharmacological action from absolute or relative overdose; "the dose distinguishes a drug from a poison" — Paracelsus c. 1500. Manifestations are predictable and dose-related (e.g. coma with barbiturates, complete AV block with digoxin, bleeding with heparin, respiratory failure with morphine overdose, hepatic necrosis with paracetamol). (KDT 8e Ch.6, p.95; R&D 10e Ch.58)
• Intolerance — characteristic toxic effect at therapeutic dose; the patient sits at the extreme left of the Gaussian sensitivity curve (e.g. dystonia after a single dose of triflupromazine in a child; ataxia after a few doses of carbamazepine; cinchonism after one tablet of quinine). (KDT 8e Ch.6, p.95; B&B Ch.9, p.113)
• Idiosyncrasy — genetically determined qualitatively abnormal reactivity to a drug; the drug interacts with a unique feature of the individual (e.g. primaquine-induced haemolysis in G6PD deficiency; chloramphenicol-induced aplastic anaemia; succinylcholine apnoea in atypical pseudocholinesterase carriers; malignant hyperthermia after halothane in RYR1 mutation carriers). (KDT 8e Ch.6, p.96; B&B Ch.9, p.113; KDT 8e Ch.5, p.76)
• Drug allergy (hypersensitivity) — immunologically mediated, stereotyped response unrelated to pharmacodynamic profile, requires prior sensitisation, occurs in only a small proportion of recipients. (KDT 8e Ch.6, p.96)
• Iatrogenic disease — physician-induced; functional disturbance caused by a drug that persists after the offending drug is withdrawn and largely eliminated (e.g. NSAID/corticosteroid-induced peptic ulcer; phenothiazine-induced parkinsonism; isoniazid-induced hepatitis; hydralazine-induced SLE). (KDT 8e Ch.6, p.101)
• Pharmacoepidemiology — application of epidemiological methods to study drug effects (use, beneficial, adverse) in populations; the foundational discipline that supplies PV with quantitative tools (cohort, case-control, real-world database studies). (B&B Ch.9, p.114; Atkinson 4e Ch.26, p.509)
• Pharmacogenomics — use of inherited genomic variation to predict drug response and adverse-reaction susceptibility; an increasingly integrated tool of modern PV. (G&G 14e Ch.8, p.152; KDT 8e Ch.5, p.75)
• The whole field rests on a single recognition: a drug that has passed the safety threshold required for marketing is not "safe" — the critical safety experiment begins after marketing. (G&G 14e Ch.8, p.147)