Phenobarbital

PHENOBARBITAL

Aside from the bromides, phenobarbital is the oldest of the currently available antiseizure drugs. Although it has long been considered one of the safest of the antiseizure agents, the use of other medications with lesser sedative effects has been urged. Many consider the barbi-turates the drugs of choice for seizures only in infants.

Chemistry

The four derivatives of barbituric acid clinically useful as antisei-zure drugs are phenobarbital, mephobarbital, metharbital, and primidone. The first three are so similar that they are considered together. Metharbital is methylated barbital, and mephobarbital is methylated phenobarbital; both are demethylated in vivo. The pK_as of these three weak acid compounds range from 7.3 to 7.9. Slight changes in the normal acid-base balance, therefore, can cause significant fluctuation in the ratio of the ionized to the non-ionized species. This is particularly important for phenobarbital, the most commonly used barbiturate, whose pK_a is similar to the plasma pH of 7.4.

The three-dimensional conformations of the phenobarbital and N-methylphenobarbital molecules are similar to that of phe-nytoin. Both compounds possess a phenyl ring and are active against partial seizures.

Mechanism of Action

The exact mechanism of action of phenobarbital is unknown, but enhancement of inhibitory processes and diminution of excitatory transmission probably contribute significantly. Recent data indicate that phenobarbital may selectively suppress abnormal neurons, inhibiting the spread and suppressing firing from the foci. Like phenytoin, phenobarbital suppresses high-frequency repetitive fir-ing in neurons in culture through an action on Na⁺ conductance, but only at high concentrations. Also at high concentrations, barbi-turates block some Ca²⁺ currents (L-type and N-type). Phenobarbital binds to an allosteric regulatory site on the GABA_A receptor, and it enhances the GABA receptor-mediated current by prolonging the openings of the Cl^– channels . Phenobarbital can also decrease excitatory responses. An effect on glutamate release is probably more significant than blockade of AMPA responses . Both the enhancement of GABA-mediated inhibition and the reduction of glutamate-mediated excitation are seen with therapeutically relevant concentrations of phenobarbital.

Clinical Uses

Phenobarbital is useful in the treatment of partial seizures and generalized tonic-clonic seizures, although the drug is often tried for virtually every seizure type, especially when attacks are difficult to control. There is little evidence for its effectiveness in general-ized seizures such as absence, atonic attacks, and infantile spasms; it may worsen certain patients with these seizure types.Some physicians prefer either metharbital (no longer readily available) or mephobarbital (especially the latter) to phenobarbital because of supposed decreased adverse effects. Only anecdotal data are available to support such comparisons.

Pharmacokinetics, Therapeutic Levels, & Dosage

For pharmacokinetics, drug interactions, and toxicity of pheno-barbital.The therapeutic levels of phenobarbital in most patients range from 10 mcg/mL to 40 mcg/mL. Documentation of effectiveness is best in febrile seizures, and levels below 15 mcg/mL appear inef-fective for prevention of febrile seizure recurrence. The upper end of the therapeutic range is more difficult to define because many patients appear to tolerate chronic levels above 40 mcg/mL.