Primidone is completely absorbed, usually reaching peak concentrations about 3 hours after oral administration. Primidone is only 30% bound to plasma proteins. The volume of distribution is 0.6 L/kg. As shown in the text figure, primidone is metabolized by oxidation to phenobarbital, which accumulates slowly, and by scission of the heterocyclic ring to form PEMA. Both primidone and phenobarbital also undergo subsequent conjugation and excretion. Primidone has a larger clearance than most other anti-seizure drugs (2 L/kg/d), corresponding to a half-life of 6–8 hours. PEMA clearance is approximately half that of primidone, but phenobarbital has a very low clearance (see Table 3–1). The appearance of phenobarbital corresponds to the disappearance of primidone. During chronic therapy, the phenobarbital levels derived from primidone are usually two to three times higher than the primidone levels.
Primidone is most efficacious when plasma levels are in the range of 8–12 mcg/mL. Concomitant levels of its metabolite, phenobarbital, at steady state, usually vary from 15 to 30 mcg/mL. Dosages of 10–20 mg/kg/d are necessary to obtain these levels. Primidone should be started at a low daily dose, which is then gradually escalated over several days to a few weeks to avoid prominent sedation and gastrointestinal complaints. When adjusting doses of the drug, the parent drug reaches steady state rapidly (30–40 hours), but the active metabolites phenobarbital and PEMA reach steady state much more slowly, at approximately 20 days and 3–4 days, respectively.
The dose-related adverse effects of primidone are similar to those of its metabolite, phenobarbital, except that many patients experience severe adverse effects on initial dosing including drowsiness, dizziness, ataxia, nausea, and vomiting. Tolerance to these adverse effects develops in hours to days and can be minimized by slow titration.
Felbamate is a dicarbamate that is used in the treatment of focal seizures and in the Lennox-Gastaut syndrome. It is structurally related to the sedative-hypnotic meprobamate. Felbamate is generally well tolerated; some patients report improved alertness. However, because the drug can cause both aplastic anemia and severe hepatitis, felbamate is used only for patients with refractory seizures who respond poorly to other medications. Despite the seriousness of the adverse effects, thousands of patients worldwide use this medication.