High-Yield Terms to Learn

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

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 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.

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 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.

Carbamazepine

Carbamazepine induces formation of liver drug-metabolizing enzymes that increase metabolism of the drug itself and may increase the clearance of many other anticonvulsant drugs including clonazepam, lamotrigine, and valproic acid. Carbamazepine metabolism can be inhibited by other drugs (eg, propoxyphene, valproic acid). A related drug, oxcarbazepine, is less likely to be involved in drug interactions.

Valproic Acid

In addition to competing for phenytoin plasma protein binding sites, valproic acid inhibits the metabolism of carbamazepine, ethosuximide, phenytoin, phenobarbital, and lamotrigine. Hepatic biotransformation of valproic acid leads to formation of a toxic metabolite that has been implicated in the hepatotoxicity of the drug.

Other Drugs

Gabapentin, pregabalin, levetiracetam, and vigabatrin are unusual in that they are eliminated by the kidney, largely in unchanged form. These agents have virtually no drug-drug interactions. Topiramate and zonisamide undergo both hepatic metabolism and renal elimination of intact drug. Lamotrigine is eliminated via hepatic glucuronidation.

Mechanisms of Action

The general effect of antiseizure drugs is to suppress repetitive action potentials in epileptic foci in the brain. Different mechanisms are involved in achieving this effect. In some drugs, many mechanisms may contribute to their antiseizure activities. Some of the recognized mechanisms are described next.

Sodium Channel Blockade

At therapeutic concentrations, phenytoin, carbamazepine, lamotrigine, and zonisamide block voltage-gated sodium channels in neuronal membranes. This action is rate-dependent (ie, dependent on the frequency of neuronal discharge) and results in prolongation of the inactivated state of the Na+ channel and the refractory period of the neuron. Phenobarbital and valproic acid may exert similar effects at high doses.

GABA-Related Targets

As described in Chapter 22, benzodiazepines interact with specific receptors on the GABA A receptor-chloride ion channel macromolecular complex. In the presence of benzodiazepines, the frequency of chloride ion channel opening is increased; these drugs facilitate the inhibitory effects of GABA. Phenobarbital and other barbiturates also enhance the inhibitory actions of GABA but interact with a different receptor site on chloride ion channels that results in an increased duration of chloride ion channel opening.

GABA aminotransaminase (GABA-T) is an important enzyme in the termination of action of GABA. The enzyme is irreversibly inactivated by vigabatrin at therapeutic plasma levels and can also be inhibited by valproic acid at very high concentrations. Tiagabine inhibits a GABA transporter (GAT-1) in neurons and glia prolonging the action of the neurotransmitter. Gabapentin is a structural analog of GABA, but it does not activate GABA receptors directly. Other drugs that may facilitate the inhibitory actions of GABA include felbamate, topiramate, and valproic acid.

Calcium Channel Blockade

Ethosuximide inhibits low-threshold (T type) Ca2+

Stay updated, free articles. Join our Telegram channel

Join