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Epilepsy comprises a group of chronic syndromes that involve the recurrence of seizures (ie, limited periods of abnormal discharge of cerebral neurons). Effective antiseizure drugs have, to varying degrees, selective depressant actions on such abnormal neuronal activity. However, they vary in terms of their mechanisms of action and in their effectiveness in specific seizure disorders.



Antiseizure drugs are commonly used for long periods of time to prevent recurrence of seizures, 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, have good bioavailability, and cross the blood-brain barrier readily. 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 antiseizure drugs 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 (prompt release) and extended-release oral forms and a parenteral form 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, valproate). 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 antiseizure drugs including carbamazepine, clonazepam, and lamotrigine. Fosphenytoin is a water-soluble prodrug form of phenytoin that is used parenterally.

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High-Yield Terms to Learn
Seizures Finite episodes of brain dysfunction resulting from abnormal discharge of cerebral neurons
Focal seizures Include simple focal seizures (consciousness is preserved; manifested as convulsive jerking, paresthesias, psychiatric symptoms, and/or autonomic dysfunction) and complex focal seizures (impaired consciousness that is preceded, accompanied, or followed by psychological symptoms); formerly called partial onset seizures
Tonic-clonic seizures, generalized Tonic phase (less than 1 min) involves abrupt loss of consciousness, muscle rigidity, and respiration arrest; clonic phase (2–3 min) involves jerking of body muscles, with lip or tongue ...

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