During long-term therapy in adults, the plasma concentration of phenobarbital averages 10 mg/mL per daily dose of 1 mg/kg; in children, the value is 5-7 mg/mL per 1 mg/kg. Although there is no precise relationship between efficacy and drug concentration, plasma concentrations of 10-35 mg/mL are usually recommended. The relationship between plasma phenobarbital concentration and adverse effects varies with the development of tolerance. Sedation, nystagmus, and ataxia usually are absent at concentrations <30 mg/mL during long-term therapy; adverse effects may be apparent for several days at lower concentrations when therapy is initiated or when dosage is increased. Concentrations >60 mg/mL may be associated with marked intoxication in the nontolerant individual.
Since significant behavioral toxicity may be present despite the absence of overt signs of toxicity, the tendency to maintain patients, particularly children, on excessively high doses of phenobarbital should be resisted. The plasma phenobarbital concentration should be increased above 30-40 mg/mL only if the increment is adequately tolerated and only if it contributes significantly to seizure control.
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