Phenobarbital and Primidone Mysoline

Phenobarbital and primidone are quite similar both chemically and pharmacologically, and much of the an-ticonvulsant activity of primidone may be ascribed to its metabolic conversion to phenobarbital. As would be expected in such a case, the clinical indications for the two compounds are very similar. There is some indication that primidone may be more effective in the treatment of partial seizures with complex symptoms, but the evidence is not compelling.

The primary mechanism of action of phenobarbital is related to its effect of facilitating GABA inhibition. By binding to an allosteric site on the GABA-benzodi-azepine receptor, hence by prolonging the opening of the chloride channels, phenobarbital enhances GABA's inhibitory activity. At somewhat higher concentrations, phenobarbital can block sodium channels, similar to drugs previously discussed, and may block excitatory glutamate responses.

Phenobarbital is effective orally and is distributed widely throughout the body. It is metabolized by microsomal drug-metabolizing enzymes, but up to 50% of the parent drug is excreted unchanged by the kidneys. Primidone is metabolized to phenobarbital and phenyl-ethylmalonamide. The latter metabolite has anticonvul-sant activity, but most of the anticonvulsant efficacy of primidone is due to the phenobarbital that is produced.

The major untoward effect of phenobarbital and primidone, when used as anticonvulsants, is sedation. Another side effect of considerable importance, particularly in children, is a possible disturbance in cognitive function. Even when the serum concentration is within the therapeutic range, apparently the ability to concentrate and perform simple tasks is decreased.

At present, phenobarbital and primidone are considered as alternative drugs for the treatment of partial seizures and for generalized tonic-clonic epilepsy. They are judged to be less effective than carbamazepine and phenytoin.

Phenobarbital and primidone are classic agents capable of inducing microsomal drug-metabolizing enzymes (See Chapter 4), and this fact must be considered when using either drug singly or in combination with other agents. Consequently, many interactions can occur between phenobarbital and primidone and a variety of other drugs, and it is necessary, therefore, to monitor drug blood concentrations to ensure that therapeutic levels of all administered agents are being maintained. Phenobarbital and primidone are known to alter blood phenytoin levels. If valproic acid is administered with either phenobarbital or primidone, striking increases in phenobarbital blood levels are frequently observed.

Two other barbiturates, mephobarbital (Mebaral) and metharbital (Gemonil) continue to be marketed as anticonvulsant drugs, but they are infrequently used.

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