Many other drugs potentiate the anticoagulant effect of warfarin by inhibiting its clearance through stereoselective or nonselective pathways. Stereoselective interactions may affect the oxidative metabolism of either the S-isomer or R-isomer of warfarin.
The inhibition of S-warfarin metabolism is more important clinically, because this isomer is five times more potent than the R-isomer as a VKA. Phenylbutazone, sulfinpyrazone, metronidazole and trimethoprim-sulfamethoxazole inhibit the clearance of S-warfarin, and each potentiates the effect of warfarin on the PT. In contrast, drugs such as cimetidine and omeprazole, which inhibit the clearance of the R-isomer, potentiate the PT only modestly in patients who have been treated with warfarin. Amiodarone is a potent inhibitor of the metabolic clearance of both the S-isomer and the R-isomer, and potentiates warfarin anticoagulation. The anticoagulant effect is inhibited by drugs like barbiturates, rifampin, and carbamazepine, which increase hepatic clearance. Long-term alcohol consumption has a similar potential to increase the clearance of warfarin, but ingestion of even relatively large amounts of wine has little influence on PT in subjects who have been treated with warfarin. The effect of enzyme induction on warfarin therapy has been discussed in more detail in a critical review (Table 3).
Drugs may also influence the pharmacodynamics of warfarin by inhibiting the synthesis of or increasing the clearance of vitamin K-dependent coagulation factors or by interfering with other pathways of hemostasis. The anticoagulant effect of warfarin is augmented by second-generation and third-generation cephalosporins, which inhibit the cyclic interconversion of vitamin K, by thyroxine, which increases the metabolism of coagulation
Table 2—Drug and Food Interactions With Warfarin by Level of Supporting Evidence and Direction of Interaction
| Level of Evidence | Potentiation | Inhibition | No Effect |
| I | Alcohol (if concomitant liver disease) | Barbiturates, carbamazepine, | Alcohol, antacids, atenolol, |
| amiodarone anabolic steroids, | chlordiazepoxide, cholestyramine, | bumetadine, enoxacin, famotidine, | |
| cimetidine,t clofibrate, | griseofulvin, nafcillin, rifampin, | fluoxetine, ketorolac, metoprolol, | |
| cotrimoxazole erythromycin, | sucralfate, high vitamin K content | naproxen, nizatidine, psyllium, | |
| fluconazole, isoniazid (600 mg daily), metronidazole, miconazole, omeprazole, phenylbutazone, piroxicam, propafenone, propranolol, t sulfinpyrazone (biphasic with later inhibition) | foods/enteral feeds, large amounts
of avocado |
ranitidine j | |
| II | Acetaminophen, chloral hydrate, ciprofloxacin, dextropropoxyphene, disulfiram, itraconazole, quinidine, phenytoin (biphasic with later inhibition), tamoxifen, tetracycline, flu vaccine | Dicloxacillin | Ibuprofen, ketoconazole |
| III | Acetylsalicylic acid, disopyramide, fluorouracil, ifosphamide, ketoprofen, lovastatin, metozalone, moricizine, nalidixic acid, norfloxacin, ofloxacin, propoxyphene, sulindac, tolmetin, topical salicylates | Azathioprine, cyclosporine, etretinate, trazodone | |
| IV | Cefamandole, cefazolin, gemfibrozil, heparin, indomethacin, sulfisoxazole | Diltiazem tobacco vancomycin |