Drug Interactions

Drug Interactions

1. Definition, scope & terminology

• A drug interaction (more precisely a drug–drug interaction, DDI) is said to occur when the effects of one drug are changed by the presence of another drug, herbal medicine, food, drink, or an environmental chemical agent (Stockley's 11e, Ch.1).
• The modification is mostly quantitative — the response is increased or decreased in intensity — but is sometimes qualitative, i.e. an abnormal or different type of response is produced (e.g. serotonin syndrome from two serotonergic drugs neither of which alone produces it) (KDT 8e Ch.71, p.987).
• Object (victim) vs precipitant (perpetrator): every interaction is analysed as a precipitant drug (the agent that causes the change) acting on an object drug (the drug whose effect or concentration is altered). Risk assessment and management are framed around protecting the object drug from the precipitant — the central analytic device of both Hansten & Horn and Stockley's (Hansten & Horn 2010, Pharmacokinetic Mechanisms PM-1).
• Sensitive substrate (regulatory definition): G&G/FDA define a perpetrator (inhibitor/inducer) as clinically significant when it produces a ≥5-fold change in the victim drug's AUC — a "sensitive substrate"; this cut-off is the basis for FDA DDI labelling and for contraindication/dose-adjustment decisions (G&G 14e Appendix II).
• Pharmaceutical incompatibilities are EXCLUDED from the formal definition of drug interaction in Stockley's — in-vitro/IV-admixture precipitation or inactivation (e.g. penicillin + gentamicin or thiopentone + suxamethonium mixed in one syringe) is an incompatibility, occurring outside the body, not a true pharmacological interaction (Stockley's 11e Ch.1; KDT 8e Ch.25; Padmaja 7e Ch.4). These are still clinically important and are covered separately (§13).
• The possibility of a DDI arises whenever a patient concurrently receives more than one drug, and the chance rises steeply with the number of drugs (KDT 8e Ch.71, p.987).
• Epidemiology / polypharmacy gradient: one hospital study found a clinically relevant interaction rate of 7% in patients taking 6–10 drugs but 40% in those taking 16–20 drugs — a disproportionate (non-linear) increase; reported incidences of clinically important interactions range up to ~8.8%, though the proportion of patients actually harmed is generally low (Stockley's 11e Ch.1).
• A loss of efficacy can be as harmful as added toxicity — e.g. rifampicin abolishing warfarin's anticoagulant effect (thrombosis), or antacids/milk abolishing tetracycline/quinolone absorption (treatment failure), or an enzyme inducer causing contraceptive failure (Stockley's 11e Ch.1).
• The responsible clinical position lies between over-anxiety and complacency — very few drug pairs must always be avoided; most interactions are manageable by dose adjustment, separation of administration, monitoring, or substitution (Stockley's 11e Ch.1).