Felbamate appears to have multiple mechanisms of action. It produces a use-dependent block of N-methyl-d-aspartate (NMDA) receptors, with selectivity for those containing the GluN2B (NR2B) subunit; the drug also produces a barbiturate-like potentiation of GABAA receptor responses. Oral felbamate is well absorbed (> 90%). Of the absorbed dose, 30–50% is excreted unchanged in the urine. The remainder is metabolized by CYP3A4 and CYP2E1 in the liver. The mean terminal half-life of 20 hours in monotherapy decreases to 13–14 hours in the presence of phenytoin or carbamazepine. The typical starting dose of felbamate is 400 mg three times a day. The dose may be escalated slowly to a maximum dose of 3600 mg/d, although some patients have received doses as high as 6000 mg/d. Effective plasma levels range from 30 to 100 mcg/mL. In addition to its usefulness in focal seizures, felbamate ameliorates atonic seizures as well as other seizure types in the Lennox-Gastaut syndrome. Felbamate decreases the clearance of phenytoin and valproic acid and increases their blood levels; dose reductions of these drugs may be necessary when felbamate is initiated. Felbamate reduces levels of carbamazepine but increases levels of the metabolite carbamazepine epoxide, which may be associated with adverse effects including dizziness, diplopia, or headache.
A limited number of antiseizure drugs are first-line agents in the treatment of patients who exhibit multiple generalized onset seizure types. Valproate is especially effective and is considered the first-choice treatment for such patients. However, it has various troublesome side effects and is a known human teratogen; its use is avoided in women of childbearing potential. Other drugs that may have broad activity in generalized epilepsies are topiramate and zonisamide.
Valproate is a first-line broad-spectrum antiseizure drug that is thought to offer protection against many seizure types. In addition, it is used as a mood stabilizer in bipolar disorder and as prophylactic treatment for migraine. Valproate was found to have antiseizure properties when used as a solvent in the search for other drugs effective against seizures.
Valproic acid is a short-chain branched fatty acid that is liquid at room temperature; it is formulated as an oral syrup solution or in gelatin capsules. More commonly, however, the drug is used in a coordination complex—referred to as divalproex sodium—composed of equal parts of valproic acid and the salt sodium valproate. An extended-release divalproex formulation in a hydrophilic polymer matrix allows once-a-day oral administration. Valproic acid has a pKa value of 4.56 and is therefore fully ionized at body pH; for that reason, the active form of the drug is the valproate ion, regardless of whether valproic acid or the salt of the acid is administered. Valproic acid is one of a series of fatty carboxylic acids that have antiseizure activity; this activity appears to be greatest for carbon chain lengths of five to eight atoms. The amides and esters of valproic acid are also active antiseizure agents.
Mechanism of Action
The mechanism or mechanisms whereby valproate exerts its therapeutic actions are not known. Valproate has broad-spectrum efficacy in animal models, conferring seizure protection in diverse chemoconvulsant seizure models, the MES test, and the kindling models. The time course of valproate’s antiseizure activity is poorly correlated with blood or tissue levels of the parent drug, an observation that has led to speculation regarding the active species.