Chapter 24: Antiseizure Drugs

INTRODUCTION

PHARMACOKINETICS

Antiseizure drugs are commonly used for long periods of time, and consideration of their pharmacokinetic properties is important for avoiding toxicity and drug interactions. For some of these drugs (eg, phenytoin), determination of plasma levels and clearance in individual patients may be necessary for optimum therapy. In general, antiseizure drugs are well absorbed orally and have good bioavailability. Most antiseizure drugs are metabolized by hepatic enzymes (exceptions include gabapentin and vigabatrin), and in some cases active metabolites are formed. Resistance to antiseizure drugs may involve increased expression of drug transporters at the level of the blood-brain barrier.

Pharmacokinetic drug interactions are common in this drug group. In the presence of drugs that inhibit antiseizure drug metabolism or displace anticonvulsants from plasma protein binding sites, plasma concentrations of the antiseizure agents may reach toxic levels. On the other hand, drugs that induce hepatic drug-metabolizing enzymes (eg, rifampin) may result in plasma levels of the antiseizure agents that are inadequate for seizure control. Several antiseizure drugs are themselves capable of inducing hepatic drug metabolism, especially carbamazepine and phenytoin.

A. Phenytoin

The oral bioavailability of phenytoin is variable because of individual differences in first-pass metabolism. Rapid-onset and extended-release forms are available. Phenytoin metabolism is nonlinear; elimination kinetics shift from first-order to zero-order at moderate to high dose levels. The drug binds extensively to plasma proteins (97–98%), and free (unbound) phenytoin levels in plasma are increased transiently by drugs that compete for binding (eg, carbamazepine, sulfonamides, valproic acid). The metabolism of phenytoin is enhanced in the presence of inducers of liver metabolism (eg, phenobarbital, rifampin) and inhibited by other drugs (eg, cimetidine, isoniazid). Phenytoin itself induces hepatic drug metabolism, decreasing the effects of other antiepileptic drugs including carbamazepine, clonazepam, and lamotrigine. Fosphenytoin is a water-soluble prodrug form of phenytoin that is used parenterally.