Warfarin metabolism

Disulfiram inhibits several of the enzymes responsible for warfarin metabolism increased PT/INR have been noted if disulfiram is added to warfarin therapy, carefully monitor PT/INR the warfarin dose will probably have to be decreased. 

Rettie, A. E. etal. (1994). Impaired (S)-warfarin metabolism catalysed by the R144C allelic variant of CYP2C9. Pharmacogenetics, 4, 39 42. 

Asthma prophylaxis 600 mg qid, not for acute attacks inhibition of theophylline and warfarin metabolism. Hepatotoxic. 

Answer The half-life of amiodarone is 35 days. Approximately five half-Uves are required for functionally complete drug elimination. Thus, it will take approximately 6 months (5 half-lives) before the amiodarone is eliminated from the body. Since amiodarone strongly inhibits metabolism of S-warfarin (active enantiomer), it will continue to affect warfarin metabolism for 6 months following discontinuation of amiodarone. Thus, the dose of warfarin will have to be monitored approximately every month and adjusted if necessary. This monthly monitoring should be continued for at least 6 months, until the metabolism of warfarin stabilizes and a constant dose of warfarin can again be maintained. 

Griseofulvin is usually well tolerated. Headache is common with initiation of therapy. Hepatotoxicity (especially in patients with acute intermittent porphyria), dermatitis, and gastrointestinal distress also occur. Griseofulvin increases warfarin metabolism, and griseofulvin metabolism is increased by phenobarbital. 

Hansen JM, Siersback-Nielsen K, Skovsted L. Carbamazepine induced acceleration of diphenylhydantoin and warfarin metabolism in man. Clin Phannacol Ther 1979 20 519-525. 

Clopidogrel [NP] Decreased warfarin metabolism and inhibits platelet function. 

P] Inhibited warfarin metabolism displaces from protein binding. 

Sulfonamides [NE] Inhibit warfarin metabolism displace protein binding. 

Zhang Z, Fasco MJ, Huang Z, et al. Human cytochromes P4501A1 and P4501A2— R-warfarin metabolism as a probe. Drug Metab Dispos 1995 23 1339-1345. 

Ngui JS, Chen Q, Shou M, et al. In vitro stimulation of warfarin metabolism by quinidine increases in the formation of 4 - and 10-hydroxywarfarin. Drug Metab Dispos 2001 29 877-886. 

Cropp JS, Bussey HI. A review of enzyme induction of warfarin metabolism with recommendations for patient management. Pharmacotherapy 1997 17 917-928. 

Takahashi, H. et al. Population differences in S-warfarin metabolism between CYP2C9 genotype-matched Caucasian and Japanese patients. Clin Pharmacol Ther 2003, 73 253-263. 

Correct choice = A. Rifampin induces the hepatic mixed function oxidases that metabolize warfarin. Platelet inhibitors, such as aspirin, increase the anticoagulant effect of warfarin. Phenylbutazone can transiently increase the level of free warfarin by displacing it from the plasma albumin binding site. Cimetidine inhibits warfarin metabolism and causes potentiation of the anticoagulant. Disulfiram inhibits warfarin metabolism. 

PROPAFENONE ANTICOAGULANTS-ORAL Warfarin levels may be t by propafenone Propafenone seems to inhibit warfarin metabolism Monitor INR at least weekly until stable... 

Altered warfarin metabolism. CYP2C9-mediated metabolism of the more potent isomer, S-warfarin, may be induced or inhibited. The less potent... 

Analgesics. Avoid if possible, all NSAIDs including aspirin (but see p. 576, myocardial infarctionjbecause of their irritant effect on gastric mucosa and action on platelets. Paracetamol is acceptable but doses over 1.5 g/d may raise the INR. Dextropropox5q>hene inhibits warfarin metabolism and compounds that contain it, e.g. co-proxamol, should be avoided. Codeine, dihydrocodeine and combinations with paracetamol, e.g. co-dydramol, are preferred. 

Antimicrobials. Aztreonam, cefamandole, chloramphenicol, ciprofloxacin, co-trimoxazole, erythromycin, fluconazole, itraconazole, ketoconazole, metronidazole, miconazole, ofloxacin and sulphonamides (including co-trimoxazole) increase anticoagulant effect by mechanisms that include interference with warfarin or vitamin K metabolism. Rifampicin and griseofulvin accelerate warfarin metabolism (enzyme induction) and reduce its effect. Intensive broad-spectrum antimicrobials, e.g. eradication regimens for Helicobacter pylori (see p. 630), may increase sensitivity to warfarin by reducing the intestinal flora that produce vitamin K. 

Anticonvulsants. Carbamazepine, phenobarbital and primidone accelerate warfarin metabolism (enzyme induction) the effect of phenytoin is variable. Clonazepam and sodium valproate are safe. 

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