Mechanism Of Action

Phenytoin limits the repetitive firing of action potentials evoked by a sustained depolarization. This effect is mediated by a slowing of the rate of recovery of voltage-activated Na+ channels from inactivation. At therapeutic concentrations, the effects on Na+ channels are selective, without changes in spontaneous activity or in responses to GABA or glutamate. At concentrations five- to tenfold higher, other effects of phenytoin include reduction of spontaneous activity and enhancement of responses to GABA that may underlie some of the toxicity associated with high levels of phenytoin.

PHARMACOKINETIC PROPERTIES Phenytoin is available in rapid-release and extended-release oral forms; once-daily dosing is possible only with extended-release formulations. Due to differences in dissolution and other formulation-dependent factors, the plasma phenytoin level may change upon conversion from one formulation to the other. Different formulations can include either phenytoin or phenytoin sodium; therefore, comparable doses can be approximated by considering "phenytoin equivalents," but serum level monitoring is necessary to assure therapeutic safety.

Phenytoin is extensively (-90%) bound to serum proteins, mainly albumin. Small variations in the bound fraction dramatically affect the absolute amount of free (active) drug; increased proportions of free drug are evident in the neonate, in patients with hypoalbuminemia, and in uremic patients. Some agents (e.g., valproic acid) can compete with phenytoin for binding sites on plasma proteins; when combined with valproate-mediated inhibition of phenytoin metabolism, marked increases in free phenytoin can result.

Phenytoin's rate of elimination varies as a function of its concentration (i.e., the rate is nonlinear). The plasma t1/2 of phenytoin ranges between 6 and 24 hours at plasma concentrations <10 ug/mL but increases with higher concentrations. As a result, plasma concentration increases disproportionately as dosage is increased, even with small adjustments for levels near the therapeutic range.

Phenytoin is largely (95%) metabolized by hepatic CYPs (Table 19-2). The principal metabolite, a parahydroxyphenyl derivative, is inactive. Phenytoin metabolism is saturable, and other substrates of these CYPs can inhibit phenytoin metabolism and increase its plasma concentration. Conversely, phenytoin will reduce the degradation of other drugs that are substrates for these enzymes, such as warfarin. The addition of phenytoin to a patient receiving warfarin can lead to bleeding disorders (see Chapter 54). Other drug interactions arise from phenytoin's capacity to induce CYPs (see Chapter 3 and Table 19-2) and increase the degradation of drugs (e.g., oral contraceptives) metabolized by CYP3A4; treatment with phenytoin could enhance the metabolism of oral contraceptives and lead to unplanned pregnancy. The potential teratogenic effects of phenytoin underscore the importance of attention to this interaction. Carbamazepine, oxcarbazepine, phenobarbital, and primidone also can induce CYP3A4 and likewise might increase degradation of oral contraceptives.

The low aqueous solubility of phenytoin hindered its intravenous use. Fosphenytoin (cerebyx), a water soluble prodrug, is rapidly converted into phenytoin by phosphatases in liver and erythrocytes. Fosphenytoin is extensively (95-99%) bound to plasma proteins, primarily albumin. This binding is saturable, and fosphenytoin displaces phenytoin from binding sites. Fosphenytoin is useful for adults with partial or generalized seizures when intravenous or intramuscular administration is indicated.

324 SECTION III Drugs Acting on the Central Nervous System Table 19-2

Interactions of Antiseizure Drugs with Hepatic Microsomal Enzymes*

Induces Inhibits Inhibits Metabolized Metabolized

Drug Induces CYP UGT CYP UGT by CYP by UGT

Induces Inhibits Inhibits Metabolized Metabolized

Drug Induces CYP UGT CYP UGT by CYP by UGT

Carbamazepine

2C9;3A families

Yes

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