Although it is marketed as both valproic acid (Depakene) and as sodium valproate (Depakote), it is the valproate ion that is absorbed from the gastrointestinal tract and is the active form.
As with several other AEDs, it is difficult to ascribe a single mechanism of action to valproic acid. This compound has broad anticonvulsant activity, both in experimental studies and in the therapeutic management of human epilepsy. Valproic acid has been shown to block voltage-dependent sodium channels at therapeutically relevant concentrations. In several experimental studies, valproate caused an increase in brain GABA; the mechanism was unclear. There is evidence that valproate may also inhibit T-calcium channels and that this may be important in its mechanism of action in patients with absence epilepsy.
Valproic acid is well absorbed from the gastrointestinal tract and is highly bound (~90%) to plasma protein, and most of the compound is therefore retained within the vascular compartment. Valproate rapidly enters the brain from the circulation; the subsequent decline in brain concentration parallels that in plasma, indicating equilibration between brain and capillary blood. A large number of metabolites have been identified, but it is not known whether they play a role in the anticonvulsant effect of the parent drug. Valproic acid inhibits the metabolism of several drugs, including phenobarbital, primidone, carbamazepine, and phenytoin, leading to an increased blood level of these compounds. At high doses, valproic acid can inhibit its own metabolism. It can also displace phenytoin from binding sites on plasma proteins, with a resultant increase in unbound phenytoin and increased phenytoin toxicity. In this instance, the dosage of phenytoin should be adjusted as required. These examples reinforce the need to determine serum anticonvulsant levels in epileptic patients when polytherapy is employed.
Valproic acid has become a major AED against several seizure types. It is highly effective against absence seizures and myoclonic seizures. In addition, valproic acid can be used either alone or in combination with other drugs for the treatment of generalized tonic-clonic epilepsy and for partial seizures with complex symptoms.
The most serious adverse effect associated with val-proic acid is fatal hepatic failure. Fatal hepatotoxicity is most likely to occur in children under age 2 years, especially in those with severe seizures who are given multiple anticonvulsant drug therapy. The hepatotoxicity is not dose related and is considered an idiosyncratic reaction; it can occur in individuals in other age groups, and therefore, valproic acid should not be administered to patients with hepatic disease or significant hepatic dysfunction or to those who are hypersensitive to it. Valproic acid administration has been linked to an increased incidence of neural tube defects in the fetus of mothers who received valproate during the first trimester of pregnancy. Patients taking valproate may develop clotting abnormalities.
Valproic acid causes hair loss in about 5% of patients, but this effect is reversible. Transient gastrointestinal effects are common, and some mild behavioral effects have been reported. Metabolic effects, including hyperglycemia, hyperglycinuria, and hyperammonemia, have been reported. An increase in body weight also has been noted. Valproic acid is not a CNS depressant, but its administration may lead to increased depression if it is used in combination with phenobarbital, primi-done, benzodiazepines, or other CNS depressant agents.
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