Warfarin Drug Interactions

Marie A. Yu, PharmD; Jolene R. Bostwick, PharmD; Ilze Sturis Hallman, MS

Disclosures

Journal for Nurse Practitioners. 2011;7(6):506-512. 

In This Article

Primidone/Warfarin Interaction

The drug interaction between primidone and warfarin is clinically significant and largely driven by primidone's phenobarbital metabolite. Phenobarbital is a broad-spectrum cytochrome P450 inducer that can impact the enzymatic activity of the CYP1A2, CYP2C9, CYP2C19, and CYP3A4 subfamilies.[9] Phenobarbital decreases INR and the anticoagulant effects of warfarin by increasing its clearance through induction of the cytochrome P450 isoenzymes by which warfarin is metabolized. Phenobarbital and other antiepileptic drugs induce the cytochrome P450 system by binding to hepatic cell receptors and signaling transcription factors to increase production of CYP enzymes.

However, induction is a slow, regulatory process. In response to the presence of the inducer, hepatic cells begin to synthesize new enzymes, and the time required depends on both the synthesis rate of new cytochrome enzymes and the time it takes for the inducing agent to reach steady state. Therefore, the effects may not be clinically appreciable until a few days after the inducer has been introduced.[10]

Similarly, de-induction or the dissipation of induction effects may take up to a few weeks after the drug is discontinued, reflecting the time required for the cellular degradation of the additional enzymes. The prolonged duration of de-induction depends on the rate of enzyme degradation, and can also be attributed to phenobarbital's long elimination half-life.[11] The intensity of the interaction depends on both the amount and the potency of the inducing agent. The proportional relationship between the intensity of enzyme induction and the dose of phenobarbital has been established.[12] Clinically, the extent and duration of phenobarbital's enzyme-inducing properties and its effect on warfarin metabolism may vary by individual. This important variability makes the warfarin dose adjustments that a specific patient needs difficult to predict. Current literature suggests differences in genetics can effect overall drug elimination and the severity of drug interactions experienced.[10]

Only a few trials have directly examined the clinical impact of phenobarbital on warfarin's anticoagulant effects. Udall's study on the interactions between warfarin and 5 different sedatives, including phenobarbital, found that the interaction did not produce appreciable changes in prothrombin time until approximately 1 week after phenobarbital initiation.[13] The study also found that the cytochrome enzyme induction effect of phenobarbital lasted approximately 3–4 weeks after discontinuation, which was consistent with previous studies.[13,14] This time course is reflected in the case study, where the patient's INR finally stabilized 19 days after the complete discontinuation of primidone.

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