Coumarin, drug interactions

O Reilly, R. A., Studies on the coumarin anticoagulant drugs interaction of human plasma albumin and warfarin sodium. J. Clin. Invest. 46, 829-837 (1967). 

Coumarins are metabolized into inactive metabolites in the liver by cytochrome P450 enzymes, leading to numerous potential drug interactions. 

The most important drug interaction caused by displacement from plasma proteins occur with coumarin anticoagulants. Phenylbutazone displaces warfarin from its... 

Drug Interactions May enhance anticoagulant effects of coumarin-like drugs Rifampin INH Cyclosporine Phenytoin Hypoglycemic agents Terfenadine Astemizole... 

Drug interactions NSAIDs Salicylates Sulfonamides Chloramphenicol Probenecid Coumarins MAO inhibitors Beta-blockers Thiazides and other diuretics Corticosteroids Phenothiazines Thyroid products Estrogens Oral contraceptives Phenytoin Nicotinic acid Sympathomimetic Calcium channel blockers Isoniazid Miconazole... 

Weser JK, Sellers E. Drug interactions with coumarin anticoagulants. 2. N Engl J Med 1971 285(10) 547-58. 

Table 1 Important drug-drug interactions with coumarin anticoagulants ...

Watson PG, Lochan RG, Redding VJ. Drug interactions with coumarin derivative anticoagulants. BMJ (Clin Res Ed) 1982 285(6347) 1045-6. 

Wittkowsky AK. Warfarin and other coumarin derivatives pharmacokinetics, pharmacodynamics, and drug interactions. Semin Vase Med 2003 3(3) 221-30. 

Some commercially available phenotyping kits use an array of coumarin analogs designed to be relatively isozyme-specific substrates (probes) that are metabolized to products with easily measurable spectral characteristics. Other commercially available kits use microsomes from baculovirus-infected cells that overexpress individual human GYP isoforms and fluorescent substrates (Vivid substrates) that can be incorporated into 1536 well formats. These simple systems do not readily lend themselves to the in vitro study of enzyme induction, however. The prediction of xenobiotic alteration of the expression of GYP activity in vivo from in vitro experiments will be discussed more completely in the chapter on drug—drug interactions. 

Other adverse effects Barbiturates and carbamates (but not benzodiazepines, buspirone, zolpidem, or zaleplon) induce the formation of the liver microsomal enzymes that metabolize dmgs. This enzyme induction may lead to multiple drug interactions. Barbiturates may also precipitate acute intermittent porphyria in susceptible patients. Chloral hydrate may displace coumarins from plasma protein binding sites and increase anticoagulant effects. 

Drug interactions Chloramphenicol inhibits the metabolism of several drugs, including phenytoin, coumarins, and tolbutamide. 

Clinical uses and toxicity The drug is indicated for severe dermatophytoses of the skin, hair, and nails. Adverse effects include headaches, mental confusion, gastrointestinal irritation, photosensitivity, and changes in liver function. A drug interaction may enhance coumarin metabolism, resulting in decreased anticoagulant effect. 

Disturbance of the gut microbial flora often leads to decreased availability of vitamin K. with enhancement of the anticoagulant effects of coumarins. The answer is (C). (Can you name the drags in the other drug interactions listed )... 

Toxicity Adverse effects of metronidazole include gastrointestinal irritation, headache, and dark coloration of urine. More serious toxicity includes leukopenia, dizziness, and ataxia. Drug interactions with metronidazole include a disulfiram-like reaction with ethanol and potentiation of coumarin anticoagulant effects. Safety of metronidazole in pregnancy and in nursing mothers has not been established. 

The clinically used preparation of warfarin is racemic, but the enantiomers are not equipotent. In fact, (S)-warfarin is at least fourfold more potent as an anticoagulant than the (R)-warfarin. The difference in the activities and metabolism of the enantiomers is the key to understanding several stereoselective drug interactions. Similar stereochemical properties are noted for the other asymmetric coumarins (Fig. 31.5). In the case of acenocoumarol, the (R)-isomer is responsible for the majority of its activity. 

Coumarin analog Interacting drug Change in plasma concentration Pharmacokinetic mechanism of interaction Change in pharmacodynamics Ref... 

Based on this information the risk of a clinically relevant drug interaction with systemically administered drugs and these topical azoles would seem to be very small. However, for a case report of raised INR in a man taking warfarin while using miconazole cream for a groin infection, see Coumarins and related drugs + Azoles Miconazole , p.388. 

Weiner M, Siddiqui AA, Bostanci N, Dayton PG. Drug interactions the effect of combined administration on the half-life of coumarin and pyrazolone drugs in man. Fedt Proc ( 96S) 24,153. 

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