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Carbamazepine, valproate, and phenytoin enhance inactivation of voltage-gated sodium and calcium channels and limit the spread of electrical excitation by inhibiting sustained high-frequency firing of neurons.

Ethosuximide blocks a neuronal T-type Ca2+ channel (A) and represents a special class because it is effective only in absence seizures.

All antiepileptics are likely, albeit to different degrees, to produce adverse effects. Sedation, difficulty in concentrating, and slowing of psychomotor drive encumber practically all antiepileptic therapy. Moreover, cutaneous, hemato-logical, and hepatic changes may necessitate a change in medication. Phenobarbital, primidone, and phenytoin may lead to osteomalacia (vitamin D prophylaxis) or megaloblastic anemia (folate prophylaxis). During treatment with phenytoin, gingival hyperplasia may develop in ca. 20% of patients.

Valproic acid (VPA) is gaining increasing acceptance as a first-line drug; it is less sedating than other anticonvul-sants. Tremor, gastrointestinal upset, and weight gain are frequently observed; reversible hair loss is a rarer occurrence. Hepatotoxicity may be due to a toxic catabolite (4-en VPA).

Adverse reactions to carbamaze-pine include: nystagmus, ataxia, diplo-pia, particularly if the dosage is raised too fast. Gastrointestinal problems and skin rashes are frequent. It exerts an antidiuretic effect (sensitization of collecting ducts to vasopressin ^ water intoxication).

Carbamazepine is also used to treat trigeminal neuralgia and neuropathic pain.

Valproate, carbamazepine, and other anticonvulsants pose teratogenic risks. Despite this, treatment should continue during pregnancy, as the potential threat to the fetus by a seizure is greater. However, it is mandatory to administer the lowest dose affording safe and effective prophylaxis. Concurrent high-dose administration of folate may prevent neural tube developmental defects.

Carbamazepine, phenytoin, phenobarbital, and other anticonvulsants (except for gabapentin) induce hepatic enzymes responsible for drug biotransformation. Combinations between anticon-vulsants or with other drugs may result in clinically important interactions (plasma level monitoring!).

For the often intractable childhood epilepsies, various other agents are used, including ACTH and the glucocor-ticoid, dexamethasone. Multiple (mixed) seizures associated with the slow spike-wave (Lennox-Gastaut) syndrome may respond to valproate, la-motrigine, and felbamate, the latter being restricted to drug-resistant seizures owing to its potentially fatal liver and bone marrow toxicity.

Benzodiazepines are the drugs of choice for status epilepticus (see above); however, development of tolerance renders them less suitable for long-term therapy. Clonazepam is used for myoclonic and atonic seizures. Clobazam, a 1,5-benzodiazepine exhibiting an increased anticonvulsant/seda-tive activity ratio, has a similar range of clinical uses. Personality changes and paradoxical excitement are potential side effects.

Clomethiazole can also be effective for controlling status epilepticus, but is used mainly to treat agitated states, especially alcoholic delirium tremens and associated seizures.

Topiramate, derived from D-fruc-tose, has complex, long-lasting anticon-vulsant actions that cooperate to limit the spread of seizure activity; it is effective in partial seizures and as an add-on in Lennox-Gastaut syndrome.

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