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.
|Seizures||Finite episodes of brain dysfunction resulting from abnormal discharge of cerebral neurons|
|Partial seizures, simple||Consciousness preserved; manifested variously as convulsive jerking, paresthesias, psychic symptoms (altered sensory perception, illusions, hallucinations, affect changes), and autonomic dysfunction|
|Partial seizures, complex||Impaired consciousness that is preceded, accompanied, or followed by psychological symptoms|
|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 biting, and fecal and urinary incontinence; formerly called grand mal|
|Absence seizures, generalized||Impaired consciousness (often abrupt onset and brief), sometimes with automatisms, loss of postural tone, or enuresis; begin in childhood (formerly, petit mal) and usually cease by age 20 yrs|
|Myoclonic seizures||Single or multiple myoclonic muscle jerks|
|Status epilepticus||A series of seizures (usually tonic-clonic) without recovery of consciousness between attacks; it is a life-threatening emergency|
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 that 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.
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 ...