Phenobarbital is useful in the treatment of focal seizures and generalized tonic-clonic seizures. Evidence-based comparisons of phenobarbital with phenytoin and carbamazepine have shown no difference in seizure control, but phenobarbital was more likely to be discontinued due to adverse effects. Phenobarbital may be useful in the treatment of myoclonic seizures, such as in juvenile myoclonic epilepsy, but it is not a drug of first choice. Phenobarbital may worsen absence seizures and infantile spasms. Long-term administration of phenobarbital leads to physical dependence such that seizure threshold is reduced upon withdrawal. The drug must be discontinued gradually over several weeks to avoid the occurrence of severe seizures or status epilepticus.
Pharmacokinetics, Therapeutic Levels, & Dosage
For pharmacokinetics, drug interactions, and toxicity of phenobarbital, see Chapter 22. The dose of phenobarbital is individualized based on clinical response. Dosing information from clinical trials is limited. Doses in the range of 60–200 mg, divided two or three times daily, are typically used. The minimally effective dose may be 60 mg/d, and the median effective dose range may be 100–150 mg/d. The accepted serum concentration reference range is 15 to 40 mcg/mL, although many patients tolerate chronic levels above 40 mcg/mL. Mean steady-state plasma phenobarbital levels with 60 and 100 mg/d dosing are 14 and 21 mcg/mL, respectively.
Primidone (2-desoxyphenobarbital) is a derivative of phenobarbital. In the early 1950s, the drug was found to have anti-seizure activity in animal models; subsequent evidence showed it to be clinically active in the treatment of epilepsy. It was widely used until the 1960s, but was then largely abandoned because of its high incidence of adverse effects. It is effective for the treatment of essential tremor and is still used for this indication.
Mechanism of Action
Primidone is metabolized to phenobarbital and phenylethylmalonamide (PEMA). All three compounds are active antiseizure agents. Although phenobarbital is roughly equally active in the MES and PTZ animal tests, primidone has greater activity in the MES test than the PTZ test, indicating that it acts more like the sodium channel-blocking antiseizure drugs than phenobarbital. Also, in animal models, primidone causes relatively less acute motor impairment than phenobarbital. With chronic treatment, phenobarbital is thought to mediate most of the antiseizure activity of primidone. Attempts to determine the relative contributions of the parent drug and its two metabolites have been conducted in newborn infants, in whom drug-metabolizing enzyme systems are very immature and in whom primidone is only slowly metabolized. In these patients, primidone is effective in controlling seizures, confirming that it has intrinsic antiseizure activity. This conclusion was reinforced by studies in older patients initiating treatment with primidone, in which seizure control was obtained before phenobarbital concentrations reached the therapeutic range.
Primidone is effective against focal seizures and generalized tonicclonic seizures, but its overall effectiveness is less than drugs such as carbamazepine and phenytoin because of a high incidence of acute toxicity on initial administration and because of chronic sedative effects at effective doses. Primidone is also used in some movement disorders (see Chapter 28).