Effect of Phenobarbital and Glutethimide on Biological Half-Life of Warfarin

Corn, Milton

doi:10.1055/s-0038-1655648

Cited by 33 publications

(14 citation statements)

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“…Amobarbital 112 , phenobarbital 107 , secobarbital 107 has also been reported to diminish pharmacological activity of warfarin. A number of other hypnosedatives and anticonvulsant drugs such as gluthethimide 107,113,114 , carbamazepine 115,116,117,118 and phenytoin 119 induce metabolism of warfarin. Benzodiazepines do not interact significantly with warfarin 1 .…”

Section: Drugs Causing Enzyme Inductionmentioning

confidence: 99%

Interactions of Warfarin

Rehulková¹

2001

Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub

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In this article, the author reviews and updates the basis of interactions with warfarin, illustrated with appropriate examples. The interactions with drugs, medicinal herbs and foods are summarised. 28Cholestyramine binds vitamin K in the gut, thus preventing its absorption 18 . It also decreases the absorption and may interrupt the enterohepatic recirculation of warfarin, resulting in a reduced anticoagulant effect 19,20 .Colestipol does not affect the absorption of warfarin. When colestipol is administered with warfarin, no depressant effects on blood levels are seen 21 . Drugs affecting receptor sensitivityEstrogens increase the synthesis of various clotting factors and may thus reduce the effect of anticoagulants 22, 23 . Oral contraceptives increase clotting factor concentrations and inhibit warfarin metabolism. The net effect depends on balance between these factors. Oral contraceptives are generally contraindicated in most patients taking warfarin since they are trombogenic 1, 24 .Steroids with anabolic or androgenic properties, such as oxymetholone 25, 26, 27 , stanozolol 28, 29 and danazol 30, 31, 32 , may potentiate the action of warfarin allegedly by reducing clotting factor synthesis. The 17-alpha-alkylated steroids appear to be more likely to induce this reaction than the non-substituted steroids 25, 26, 27, 33 . However, there has been a report of topically applied testosterone, which does not have 17-alpha-alkyl substituent, enhancing warfarin 34 .Diuretics may antagonise the action of warfarin by two pharmacodynamic mechanisms 18 : (a) patients in cardiac failure have impaired clotting factor synthesis due to hepatic congestion -correction of this state leads to increased clotting factor synthesis; (b) diuretics also reduce the plasma volume producing an increased concentration of clotting factors which may alter the anticoagulant effect of warfarin 35 . Chlorthalidone 36 and spironolactone 35 have both been associated with a reduction of warfarin activity probably as a consequence of diuresis concentrating the circulating clotting factors. Bumetanide, furosemide and thiazides appear to have no effect on warfarin 23 .Certain cephalosporines, such as cefotetan, cefamandole, cefoperazone, or moxalactam may cause marked hypoprothrombinemia and/or prolonged bleeding time at concurrent use with warfarin 38, 39, 40, 41 . The main mechanism of interaction consists in decreasing synthesis of vitamin K-dependent clotting factors.Clofibrate may potentiate warfarin action, probably by altering receptor sensitivity 23, 37 . Although clofibrate displaces warfarin from albumin binding sites this does not appear to be a principal mechanism of the interaction 42 .Drugs altering thyroid function may affect anticoagulant control, since rates of synthesis and degradation of clotting factors are dependent on thyroid function 7 . Thyroid compounds do enhance the activity of oral anticoagulants by increased metabolism of clotting factors 12 . Dextrothyroxine increases the anticoagulant effect of warfarin ...

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Section: Drugs Causing Enzyme Inductionmentioning

confidence: 99%

Interactions of Warfarin

Rehulková¹

2001

Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub

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“…It is probably that all barbiturates can induce the metabolism of all the coumarin anticoagulants. Time for significant induction varies but can be as short as 1 or 2 days (Corn, 1966). After withdrawal of the barbiturate, some weeks are often required for return of normal metabolic rates (MacDonald and Robinson, 1968).…”

Section: Metabolismmentioning

confidence: 99%

Clinical Pharmacokinetics of Oral Anticoagulants

Kelly

O’Malley

1979

Clinical Pharmacokinetics

112

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Warfarin is clinically the most widely used oral anticoagulant and its properties have been extensively studied. Assay method for these compounds have until recently been relatively nonspecific. The advent of chromatographically based techniques has enabled re-evaluation of the pharmacokinetics of oral anticoagulants, but most work continues to involve warfarin. The most important recent work has concerned the different anticoagulant potencies and metabolic pathways of the optical isomers of some of these drugs. The effects of age and some diseases on pharmacokinetics of warfarin have been examined but much remains to be done, especially with oral anticoagulants other than warfarin. There are several well established pharmacokinetic drug interactions with warfarin. There is a wide awareness of the drugs most likely to reduce anticoagulant effects by enzyme induction and alternative drugs can be used. Mechanisms of some interactions have been re-investigated. In vivo drug displacement interactions are complicated by the correlation between hepatic clearance of these drugs and the size of the unbound fraction in plasma. The interactions between phenylbutazone and warfarin and metronidazole and warfarin, resulting in potentiation of anticoagulant effect have been suggested to be due mainly to an inhibition of the metabolism of the more potent S isomer of warfarin.

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“…In normal subjects, Udall (1975) found significant alteration in anticoagulant activity after adding phenobarbitone in 9 out of 10 cases. Corn (1966) showed that the warfarin half-life falls in 13 out of 21 patients after treatment with phenobarbitone.…”

Section: Induction Of Drug Biotransformationmentioning

confidence: 99%

“…Besides barbiturates, glutethimide shortens the half-life of warfarin (Corn, 1966) and also alters the anticoagulant activity to a clinically significant extent (Udall, 1975),…”

Section: Induction Of Drug Biotransformationmentioning

confidence: 99%

Drug Interactions and Clinical Pharmacokinetics

Kristensen

1976

Clinical Pharmacokinetics

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Some drugs influence the gastro-intestinal absorption, distribution , metabolism or renal excretion of other drugs, i.e., processes involved in pharmacokinetic interactions. The clinical consequences of pharmacokinetic drug-drug interactions will be either an increase or a decrease in known therapeutic or toxic effects of the interacting drug. In order to evaluate the importance of drug interaction affecting gastro-intestinal absorption, it is necessary to distinguish between interactions which alter the rate of absorption of another drug and those which alter the amount of drug absorbed. Many drugs displace other drugs from their protein binding sites in vitro. This may cause an increase in the pharmacological effect of the displaced drug. However, much discrepancy exists between in vitro findings. In some cases, the enhanced effect only seems to be a temporary phenomenon. The degree of protein binding and the size of apparent volume of distribution (Vd) must also be taken into consideration. Perhaps the importance of interaction involving protein binding has been overemphasized. Barbiturates, glutethimide, rifampicin and phenytoin increase the rate of drug metabolism in man. The most important interactions reported are between oral anti-coagulants and barbiturates. After withdrawal of these hepatic microsomal enzyme inducing drugs, it takes 2 to 3 weeks before the rate of drug metabolism reaches the pretreatment level. In this period, risk of haemorrhage exists. Induction seems to be dose-dependent, but not all persons are inducible. Many drugs compete for the drug metabolising enzyme system in the liver and consequently some drugs inhibit the biotransformation of other drugs. The time course of these interactions depends on the pharmacokinetic properties of the drug involved, and these interactions also seem to be dose-dependent. The most important of such interactions, clinically involved the oral sulphonylurea hypoglycaemic drugs and the antiepilepic drug phenytoin. Drugs are eliminated by urinary excretion through three mechanisms: glomerular filtration, tubular reabsorption, and active tubular secretion. The most important interactions seem to be those involving competition for tubular secretion.

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Effect of Phenobarbital and Glutethimide on Biological Half-Life of Warfarin

Cited by 33 publications

References 0 publications

Interactions of Warfarin

Interactions of Warfarin

Clinical Pharmacokinetics of Oral Anticoagulants

Drug Interactions and Clinical Pharmacokinetics

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