Warfarin enzyme induction

Only a small number of drug interactions have been reported with donepezil. In vitro studies show a low rate of binding of donepezil to cytochrome P-450 (CYP)3A4 or 2D6. Whether or not donepezil has the potential for enzyme induction is not known. No interactions with theophylline, cimeti-dine, warfarin, digoxin, or ketoconazole have been documented. In vitro studies show that inhibitors of CYP3A4 and 2D6 have the potential to inhibit the metabolism of donepezil. The clinical relevance of this is unknown. However, monitoring for possible increased peripheral side effects is advised... 

Vigilance for drug-drug interactions is required because of the greater number of medications prescribed to elderly patients and enhanced sensitivity to adverse effects. Pharmacokinetic interactions include metabolic enzyme induction or inhibition and protein binding displacement interactions (e.g., divalproex and warfarin). Pharmacodynamic interactions include additive sedation and cognitive toxicity, which increases risk of falls and other impairments. 

Is the drug likely to he co-prescribed with a drug of narrow therapeutic index For example, a drug for angina, cardiac failure or an antiarrhythmic agent is likely to be co-prescribed with warfarin. If there is any evidence of enzyme induction or inhibition, a clinical study with warfarin may be required. 

Problem/lnfluence of Medication. St. John s wort can cause enzyme induction, which results in an increase in the liver s ability to metabolize other medications, including warfarin. This process could result in the warfarin being metabolized too rapidly and therefore failing to reach therapeutic levels. Lack of adequate anticoagulant effects would place the patient at increased risk for subsequent thrombosis and pulmonary embolism. 

From Eq. (18) we see that AUC following an oral dose depends only on/u and CLint when all of the administered drug reaches the liver essentially intact, as happens with both warfarin and alprenolol. Accordingly, the oral AUC should decrease with enzyme induction, irrespective of whether the drug is of high or low extraction ratio, as was observed. 

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

Pharmacokinetic interaction the drugs interact remotely from the target site to alter plasma (and other tissue) concentrations so that the amount of the drug at the target site of clinical effect is altered, e.g. enzyme induction by rifampicin will reduce the plasma concentration of warfarin enzyme inhibition by ciprofloxacin will elevate the concentration of theophylline. 

Interactions. Enzyme induction of CYP 3A, e.g. by rifampicin, reduces the plasma concentration of itraconazole. Additionally, its affinity for several P450 isoforms, notably CYP 3A4, causes it to inhibit the oxidation of a number of drugs, including phenytoin, warfarin, cyclosporine, tacrolimus, midazolam, triazolam, cisapride and terfenidine (see above), increasing their intensity and/or duration of effect. 

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. 

Warfarin and Phenoharhital. Phenobarbital, by causing enzyme induction, can increase the rate of metabolism of warfarin. The result of this interaction is a decreased response to the anticoagulant and an increased risk of thrombus formation if the interaction is not recognized. 

Drug Interactions. Felbamate inhibits the clearance and increases the serum concentration of phenytoin, valproic acid, and phenobar-bital. The concentration of carbamazepine decreases in patients on concmrent therapy with felbamate secondary to enzyme induction however, the concentration of the 10,11 -epoxide metabolite increases. It is recommended that the dose of phenytoin, carbamazepine, and valproic acid be decreased by about 30% when felbamate is added. Felbamate does not appear to interact with either gabapentin or 1am-otrigine. Phenytoin and carbamazepine are enzyme inducers and have been shown to increase the clearance of felbamate. Interactions with warfarin also have been reported. ... 

Enzyme induction Drug induces increased activity of enzymes Alcohol induces enzymes that metabolize warfarin... 

The average prothrombin time of 10 patients stabilised on warfarin was 20.9 seconds before, 20.4 seconds during, and 19.6 seconds after taking methaqualone 300 mg at bedtime for 4 weeks. The plasma warfarin levels of another patient were unaffected by methaqualone, although there was some evidence that enzyme induction had occurred. Methaqualone has some enzyme-inducing effects so that any small changes in prothrombin times reflect a limited increase in the metabolism and clearance of warfarin, but these appear to be too small to be of clinical significance. No special precautions seem to be necessary. 

Propoxyphene interacts with several drugs. The use of sedatives in combination with propoxyphene can be fatal. In addition, the metabolism of the drug is increased in smokers due to induction of liver enzymes. Thus, smokers may require a higher dose of the drug for pain relief. Propoxyphene enhances the effects of both warfarin and carbamazepine and may increase the toxicity associated with both drugs, such as bleeding and sedation, respectively. 

Barbiturates and rifampin cause a marked decrease of the anticoagulant effect by induction of the hepatic enzymes that transform racemic warfarin. Cholestyramine binds warfarin in the intestine and reduces its absorption and bioavailability. 

Pharmacokinetics. Carbamazepine is extensively metabolised one of the main products, an epoxide (a chemically reactive form), has anticonvulsant activity similar to that of the parent drug but may also cause some of its adverse effects. The t) of carbamazepine falls from 35 h to 20 h over the first few weeks of therapy due to induction of hepatic enzymes that metabolise it as well as other drugs, including corticosteroids (adrenal and contraceptive), theophylline and warfarin. Cimetidine and valproate inhibit its metabolism. There are complex interactions with other antiepilepsy drugs, which constitute a reason for monodrug therapy. 

---