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Chapter: Modern Pharmacology with Clinical Applications: Antiepileptic Drugs

Drugs That Primarily Enhance the Action of GABA

A major effort has been directed to the search for agents that can mimic, facilitate, prolong, or enhance the actions of GABA, with the expectation that such com-pounds will likely be beneficial in the treatment of con-vulsive disorders.

Drugs That Primarily Enhance the Action of GABA

A major effort has been directed to the search for agents that can mimic, facilitate, prolong, or enhance the actions of GABA, with the expectation that such com-pounds will likely be beneficial in the treatment of con-vulsive disorders. Although there have been some dis-appointments, in general this appears to be a fruitful approach in the search for better and safer antiepileptic compounds.


Several benzodiazepines are used in the management of epileptic seizures, although only a few are approved for the treatment of seizure disorders in the United States. Since the benzodiazepines share many properties, they will be discussed as a class; individual members will be mentioned for specific indications.

The primary action of the benzodiazepines as anti-convulsants is to enhance inhibition through their inter-action with the GABAA receptor at the benzodiazepine binding site. However, there appears to be an additional action of benzodiazepines: blocking voltage-dependent sodium channels. This effect is not seen at usual doses but is likely a factor in their use in the treatment of sta-tus epilepticus (discussed later).

Benzodiazepines are well absorbed, and the oral route is preferred in most situations. In the treatment of status epilepticus, the preferred route is usually intra-venous. Benzodiazepines are extensively metabolized by the microsomal drug-metabolizing system; fre-quently an active compound is broken down to another agent that is also active pharmacologically. This is the reason for the long duration of action of several benzo-diazepines.

Drowsiness occurs readily and unfortunately is usu-ally a problem at therapeutic doses. The other limiting side effect of the benzodiazepines is the rapid develop-ment of tolerance to their anticonvulsant effects.

Although all of the benzodiazepines are similar, cer-tain ones are employed more for the treatment of seizure disorders. Clonazepam was the first benzodi-azepine approved in the United States specifically for the treatment of convulsive disorders. Clonazepam is a very long acting compound with potent anticonvulsant activity. Unfortunately, sedation and tolerance tend to limit its usefulness. Drooling and hypersalivation may be troublesome in children and in infants.

Lorazepam is the benzodiazepine of choice for emergency treatment of status epilepticus, serial seizures, and prolonged seizures and for prophylaxis of febrile seizures. The intravenous route is preferable for emer-gency treatment.

Clorazepate dipotassium is approved in the United States as an adjunct in the treatment of partial complex seizures. It appears to be useful, especially in patients with high seizure frequencies and psychic disturbances.

Other benzodiazepines have been used as AEDs but are not approved for this use in the United States. They include lorazepam (Ativan), nitrazepam (Mogadon), and clobazam (Urbanil). It is unlikely that these drugs offer any advantages over similar agents.


Tiagabine (Gabitril) blocks the reuptake of GABA into neurons and glia, thereby resulting in higher levels of GABA in the synaptic cleft. The ability to increase GABA concentrations is presumed to be involved in the effectiveness of tiagabine in the treatment of seizure disorders. It is primarily used in the treatment of partial complex seizures. Adverse effects of tiagabine adminis-tration include dizziness, somnolence, nervousness, nau-sea, and confusion.


Vigabatrin (Sabril) is a relatively specific irreversible in-hibitor of GABA-transaminase (GABA-T), the major enzyme responsible for the metabolism of GABA in the mammalian CNS. As a result of inhibition of GABA-T, there is an increase in the concentration of GABA in the brain and consequently an increase in inhibitory neuro-transmission. Vigabatrin is well absorbed orally and is distributed to all body systems. The major route of elimi-nation for vigabatrin is renal excretion of the parent com-pound; no metabolites have been identified in humans.

At present, the primary indication for vigabatrin is in the treatment of patients with partial seizures, but it appears to be an effective and generally well tolerated antiepileptic medication for other seizure types as well. It should not be used in patients with absence epilepsy or with myoclonic seizures. Vigabatrin is not approved as an AED in the United States, although it is approved in many other countries.

Phenobarbital and Primidone (Mysoline)

Phenobarbital and primidone are quite similar both chemically and pharmacologically, and much of the an-ticonvulsant activity of primidone may be ascribed to its metabolic conversion to phenobarbital. As would be ex-pected in such a case, the clinical indications for the two compounds are very similar. There is some indication that primidone may be more effective in the treatment of partial seizures with complex symptoms, but the evi-dence is not compelling.

The primary mechanism of action of phenobarbital is related to its effect of facilitating GABA inhibition. By binding to an allosteric site on the GABA-benzodi-azepine receptor, hence by prolonging the opening of the chloride channels, phenobarbital enhances GABA’s inhibitory activity. At somewhat higher concentrations, phenobarbital can block sodium channels, similar to drugs previously discussed, and may block excitatory glutamate responses.

Phenobarbital is effective orally and is distributed widely throughout the body. It is metabolized by micro-somal drug-metabolizing enzymes, but up to 50% of the parent drug is excreted unchanged by the kidneys. Primidone is metabolized to phenobarbital and phenyl-ethylmalonamide. The latter metabolite has anticonvul-sant activity, but most of the anticonvulsant efficacy of primidone is due to the phenobarbital that is produced.

The major untoward effect of phenobarbital and primidone, when used as anticonvulsants, is sedation. Another side effect of considerable importance, partic-ularly in children, is a possible disturbance in cognitive function. Even when the serum concentration is within the therapeutic range, apparently the ability to concen-trate and perform simple tasks is decreased.

At present, phenobarbital and primidone are con-sidered as alternative drugs for the treatment of partial seizures and for generalized tonic–clonic epilepsy. They are judged to be less effective than carbamazepine and phenytoin.

Phenobarbital and primidone are classic agents ca-pable of inducing microsomal drug-metabolizing en-zymes , and this fact must be considered when using either drug singly or in combination with other agents. Consequently, many interactions can oc-cur between phenobarbital and primidone and a variety of other drugs, and it is necessary, therefore, to monitor drug blood concentrations to ensure that therapeutic levels of all administered agents are being maintained. Phenobarbital and primidone are known to alter blood phenytoin levels. If valproic acid is administered with either phenobarbital or primidone, striking increases in phenobarbital blood levels are frequently observed.

Two other barbiturates, mephobarbital (Mebaral) and metharbital (Gemonil) continue to be marketed as anticonvulsant drugs, but they are infrequently used.

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