Does Cigarette Smoking Require Special Warfarin Dosing in Patients With Weight Extremes?

Laura R. Lehman, PharmD, BCPS, CACP


March 05, 2009

Can cigarette smoking affect the metabolism of warfarin? I have some lower-weight patients taking higher doses, and some higher-weight patients taking lower doses to maintain therapeutic range. Could this be due to cigarettes?

Response from Laura R. Lehman, PharmD, BCPS, CACP
Clinical Coordinator, Department of Pharmacy, Carroll Hospital Center, Westminster, Maryland

Cigarette smoking has been associated with increased clearance of several drugs, but its effect on warfarin metabolism is not clearly established. Pharmacokinetic drug interactions with smoking are primarily attributed to components of tobacco smoke that induce cytochrome P450 1A2 (CYP1A2).[1] Thus, smokers may require higher doses of drugs that are substrates of this isoenzyme (eg, theophylline, clozapine, and fluvoxamine), and upon discontinuation of smoking, doses of such drugs may need to be decreased.[1]

Warfarin is a racemic mixture, and the R enantiomer is a substrate of CYP1A2. However, it is the more potent S enantiomer (a CYP2C9 substrate) that accounts for most of the clinical effect of warfarin.[2] Studies of smoking's effect on warfarin dosage requirements have produced conflicting results.[3,4] Two case reports described a delayed increase in international normalized ratios (INRs) in patients taking warfarin who stopped smoking.[5,6]

Because the effect of smoking on warfarin requirements is inconclusive, other factors that affect warfarin response should be taken into consideration. Whitley and colleagues[7] identified 2 significant predictors of weekly warfarin dose. Concomitant cytochrome P450 inducers (eg, phenytoin, carbamazepine, phenobarbital, rifampin) were associated with increased warfarin dose, and age was associated with an inverse relationship to warfarin dose. Other weak correlations noted, but not deemed statistically significant, were lower dosage requirements in women compared with men, higher dosage requirements in blacks compared with whites, and a weak positive association between body mass index and dose. No association was found between cigarette smoking and warfarin dose, but the authors note that tobacco use was not quantified in this study.

Research into the cause of variable warfarin requirements has recently focused on the pharmacogenetics of warfarin metabolism, specifically genetic variations in the CYP2C9 and vitamin K oxide reductase complex 1 (VKORC1) enzymes. In 2007, the US Food and Drug Administration required revisions to warfarin labeling, recommending consideration of lower initial doses in patients with certain variations of these enzymes.[8]

With limited information available concerning the effect of smoking on warfarin response, we cannot make a generalization that warfarin dosage requirements by body weight are affected by cigarette smoking. Rather, in a patient who changes smoking status with a subsequent change in INR, an attempt should first be made to rule out any of the other known factors that affect warfarin. Product information for Coumadin® states, "Numerous factors, alone or in combination, including changes in diet, medications, botanicals, and genetic variations in the CYP2C9 and VKORC1 enzymes may influence the response of the patient to warfarin."[9] In the absence of any other explanation for a change in warfarin requirements, we can consider case reports of increased INRs following smoking cessation.


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