Drug interactions with warfarin

Drugs may interact with warfarin through pharmacodynamic or pharmacokinetic mechanisms. Examples of the former include alteration of the bioavailability of vitamin K by antibiotics, mineral oils or cholestyramine; oestrogens, diuretics and hypolipidaemic agents such as clofibrate may influence vitamin K-dependent clotting factor synthesis, and drugs which affect haemostasis, e.g. via platelet function, will enhance the anticoagulant effect of warfarin. Pharmacokinetic interactions are better understood. Few drugs have been shown to alter warfarin absorption, the importance of protein binding displacement has been exaggerated, and since warfarin is not eliminated to any extent unchanged by the kidney, the most important kinetic interactions are those due to inhibition or induction of its hepatic metabolism. Isomeric differences in metabolism form an important basis for stereoselective metabolic interactions, especially inhibition; this has been demonstrated with phenylbutazone, metronidazole and co-trimoxazole. Enzyme induction, although recognised for many years, may still pose problems in therapeutics, usually on withdrawal of the inducing agent.