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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
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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.
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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, ...