Warfarin with phenytoin

Phenytoin interacts widi many different drugp. For example isoniazid, chloramphenicol, sulfonamides, benzodiazepines, succinimides, and cimetidine all increase phenytoin blood levels. The barbiturates, rifampin, theophylline, and warfarin decrease phenytoin blood levels. When administering the hydantoins with meperidine, die analgesic effect of meperidine is decreased. 

The overall safety record of the currently marketed agents, particularly cimetidine and ranitidine, which have had extensive worldwide use, is excellent, and in practice safety issues seldom affect drug choice (1), except perhaps when it is necessary to avoid interactions with phenytoin, theophylline, or warfarin. Surveillance studies, which have been going on for a quarter of a century (including 10-year studies in many patients, mainly involving cimetidine and ranitidine), have failed to detect any serious adverse effects other than those recognized by 1980, or any adverse effect on mortality (2). 

During the hyperthyroid state, other drugs that are metabolized by the liver or eliminated renally may need to be adjusted because metabolism may be increased. Patients using drugs with a narrow therapeutic index such as digoxin, warfarin, and phenytoin should be monitored carefully because dosing adjustments will be necessary as the hyperthyroidism or hypermetabolic state resolves. 

Which one of the following drugs has been used in the management of alcohol withdrawal states and in maintenance treatment of patients with tonic-clonic or partial seizure states Its chronic use may lead to an increased metabolism of warfarin and phenytoin. 

Effects are enhanced by other diuretics. Profound hypotension occurs with other antihypertensives. Diazoxide displaces warfarin and phenytoin from albumin. 

None of these interaetions has been extensively studied nor are they well established, but what is known suggests that the use of dicoumarol with phenytoin should be avoided or monitored very closely. Serum phenytoin levels and anticoagulant control should be well monitored if acenoeou-marol, phenprocoumon or warfarin is given with phenytoin. Dosage adjustments may be needed to accommodate any interactions. Information about other anticoagulants (apart from phenindione, which had no effect... 

The manufacturers advise caution if leflunomide is given with phenytoin or tolbutamide. The reason is that the active metabolite of leflunomide (A771726) has been shown by in vitro studies to be an inhibitor of the cytochrome P450 isoenzyme CYP2C9, which is concerned with the metabolism of these two drugs. If this inhibition were to occur in vivo it could possibly lead to a decrease in their metabolism and an increase in their toxicity. Although so far there appear to be no clinical reports of an interaction, the manufacturers made a similar prediction with warfarin, another CYP2C9 substrate, which has, in isolated cases, been borne out in practice. See Coumarins + Leflunomide , p.423. 

Drug interactions anticonvulsants (phenytoin, barbiturates, carbamazepine) increase the risk of hepatotoxicity by increasing conversion of acetaminophen to toxic metabolites. Isoniazide also increases risk of acetaminophen hepatotoxicity. Acetaminophen may enhance the anticoagulant effect of warfarin with daily doses > 1.3 g for > 1 week. Phenothiazines may increase risk of severe hypothermia with acetaminophen. Cholestyramine resin may decrease the absorption of acetaminophen. 

While generally not of major concern, omeprazole may inhibit the metabolism of warfarin, diazepam, and phenytoin lansoprazole may decrease theophylline concentrations. Drug interactions with omeprazole are of particular concern in patients who are considered slow metabolizers, as are approximately 3% of the Caucasian population. Unfortunately, it is unclear which patients have the polymorphic gene variation that makes them slow metabolizers.17 The metabolism of esomeprazole may also be altered in patients with this polymorphic gene variation. Patients on potentially interacting drugs should be monitored for development of drug-related problems. 

Oral azoles are associated with significant interactions, particularly due to cytochrome P-450 isoenzymes. Medications that interact with azoles include warfarin, phenytoin, theophylline, rifampin, cyclosporine, and zidovudine. For patients receiving only a few doses, these interactions do not pose a significant risk. These interactions may pose a risk for patients receiving long-term suppressive therapy for recurrent infections. 

Highly protein-bound drugs In vivo, raloxifene did not affect the binding of warfarin, phenytoin, or tamoxifen. However, use caution when raloxifene is coadministered with other highly protein-bound drugs, such as diazepam, diazoxide, and lidocaine. 

Drugs that may be affected by HMG-CoA reductase inhibitors include oral contraceptives, diclofenac, digoxin, glyburide, phenytoin, and warfarin. Atorvastatin, lovastatin, and simvastatin are primarily metabolized by CYP3A4 they may interact with CYP3A4 inhibitors. 

Distribution - Valproic acid is rapidly distributed. Volume of distribution of total or free valproic acid is 11 or 92 L/1.73 m, respectively. Valproic acid has been detected in CSF (approximately 10% of total concentrations) and milk (about 1% to 10% of serum concentrations). Therapeutic range is commonly considered to be 50 to 100 mcg/mL of total valproate. The plasma protein binding of valproate is concentration-dependent. Protein binding of valproate is reduced in the elderly, in patients with chronic hepatic diseases, in patients with renal impairment, and in the presence of other drugs (eg, aspirin). Conversely, valproate may displace certain protein-bound drugs (eg, phenytoin, carbamazepine, warfarin, tolbutamide). 

Isoniazid inhibits cytochrome P450 enzyme function and thus can interact with drugs that are subject to cytochrome P450 mediated metabolism like warfarin and the antiepileptic agents phenytoin and car-bamazepine. 

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