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Phenobarbital is a barbiturate and primidone is a deoxybarbiturate that are effective in the treatment of generalized tonic-clonic and partial seizures (Table 13-1).1,2 Phenobarbital is available as a separate agent, but is also an active metabolite produced via hepatic metabolism during primidone treatment. Because of this, and because they share a similar antiseizure spectrum, these two drugs are considered together in this chapter. The probable mechanism of action for phenobarbital is elevation of seizure threshold by interacting with γ-aminobutyric acidA (GABAA) postsynaptic receptors which potentiates synaptic inhibition.3,4 While the exact mechanism of action is not known for the antiepileptic effect of primidone, a portion of its antiseizure activity is produced by the active metabolites phenobarbital and phenylethylmalonamide (PEMA).3,4

Table 13-1 International Classification of Epileptic Seizures with Treatment Recommendations1,2

The therapeutic ranges for phenobarbital and primidone are defined by most laboratories as 15–40 μg/mL and 5–12 μg/mL, respectively. When primidone is given, sufficient doses are usually administered to produce therapeutic concentrations of both phenobarbital and primidone. At present, concentrations of the other possible active metabolite of primidone, PEMA, are not routinely measured. While animal experiments indicate that primidone has inherent antiseizure activity, some clinicians believe that phenobarbital is the predominant species responsible for the therapeutic effect of primidone in humans.5 Because phenobarbital and PEMA are produced via hepatic metabolism of primidone, it is very difficult to study the antiepileptic activity of primidone alone in patients.

The most common concentration-related adverse effects of phenobarbital involve the central nervous system: ataxia, headache, unsteadiness, sedation, confusion, and lethargy.4,6 Other concentration-related side effects are nausea, and in children, irritability and hyperactivity. At phenobarbital concentrations >60 μg/mL, stupor and coma have been reported. During long-term treatment with phenobarbital, changes in behavior, porphyria, decreased cognitive function, and osteomalacia can occur. For primidone, concentration-related side effects include nausea, vomiting, diplopia, dizziness, ...

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