The coumarin anticoagulants often interact with other drugs and with disease states. These interactions can be broadly divided into pharmacokinetic and pharmacodynamic effects (Table 34–2). Pharmacokinetic mechanisms for drug interaction with warfarin mainly involve cytochrome P450 CYP2C9 enzyme induction, enzyme inhibition, and reduced plasma protein binding. Pharmacodynamic mechanisms for interactions with warfarin are synergism (impaired hemostasis, reduced clotting factor synthesis, as in hepatic disease), competitive antagonism (vitamin K), and an altered physiologic control loop for vitamin K (hereditary resistance to oral anticoagulants).
The most serious interactions with warfarin are those that increase the anticoagulant effect and the risk of bleeding. The most dangerous of these interactions are the pharmacokinetic interactions with the mostly obsolete pyrazolones phenylbutazone and sulfinpyrazone. These drugs not only augment the hypoprothrombinemia but also inhibit platelet function and may induce peptic ulcer disease (see Chapter 36). The mechanisms interactions with oral anticoagulants.
1Stereoselectively inhibits the oxidative metabolism of the S-warfarin enantiomorph of racemic warfarin.
for their hypoprothrombinemic interaction are a stereoselective inhibition of oxidative metabolic transformation of S-warfarin (the more potent isomer) and displacement of albumin-bound warfarin, increasing the free fraction. For this and other reasons, neither phenylbutazone nor sulfinpyrazone is in common use in the United States. Metronidazole, fluconazole, and trimethoprimsulfamethoxazole also stereoselectively inhibit the metabolic transformation of S-warfarin, whereas amiodarone, disulfiram, and cimetidine inhibit metabolism of both enantiomorphs of warfarin (see Chapter 4). Aspirin, hepatic disease, and hyperthyroidism augment warfarin’s effects—aspirin by its effect on platelet function and the latter two by increasing the turnover rate of clotting factors. The third-generation cephalosporins eliminate the bacteria in the intestinal tract that produce vitamin K and, like warfarin, also directly inhibit vitamin K epoxide reductase.
Barbiturates and rifampin cause a marked decrease of the anticoagulant effect by induction of the hepatic enzymes that transform racemic warfarin. Cholestyramine binds warfarin in the intestine and reduces its absorption and bioavailability.
Pharmacodynamic reductions of anticoagulant effect occur with increased vitamin K intake (increased synthesis of clotting factors), the diuretics chlorthalidone and spironolactone (clotting factor concentration), hereditary resistance (mutation of vitamin K reactivation cycle molecules), and hypothyroidism (decreased turnover rate of clotting factors).
Drugs with no significant effect on anticoagulant therapy include ethanol, phenothiazines, benzodiazepines, acetaminophen, opioids, indomethacin, and most antibiotics.
Reversal of Warfarin Action