Phenobarbital offers the advantage of parenteral (intravenous or intramuscular) administration. As with phenytoin, loading doses may be given, but they increase the chance of sedation depending on dose, rate, and route. Many laboratories consider the therapeutic range to be 15–40 mg/mL, although levels of 10–15 mg/mL or less may be enough to control seizures in many patients. The target level depends on the perceived risk of adverse effects, principally sedation, versus the risk and potential morbidity of another seizure. Because the volume of distribution in adults is approximately 0.5 liter/ kg, a loading dose of 2 mg/kg is needed to raise the level by 1 mg/mL.

In status epilepticus, 10–20 mg/kg can be given at up to 100 mg per minute, but again, cardiovascular depression is a significant risk, especially in the elderly. Respiratory suppression in this setting is virtually universal, particularly if benzodiazepines have been given first.

At more modest doses, sedation is the most common adverse effect, although patients with neurologic impairments can sometimes have “paradoxic” agitation, probably resulting from disinhibition of behavioral control or exacerbation of pre-existing focal or global neurologic deficits.

Discontinuation of phenobarbital, at least with chronic treatment, has been linked to withdrawal seizures.

Like phenytoin and carbamazepine, phenobarbital is a potent inducer of the hepatic P-450 enzyme system and has similar effects on the metabolism of warfarin and other drugs and on bone density.

Dose-related effects include sedation, depression, and cognitive slowing, as well as dizziness and ataxia. On average, phenobarbital is likely to have more detrimental cognitive effects than phenytoin, carbamazepine, and valproate.104,105

Chronic effects on connective tissue, such as frozen shoulder, have also been reported.

Adapted from: Bromfield, EB, and Henderson GV. Seizures and cerebrovascular disease. In: Ettinger AB and Devinsky O, eds. Managing epilepsy and co-existing disorders. Boston: Butterworth-Heinemann; 2002;269–289.
With permission from Elsevier ( 

Reviewed By: 
Steven C. Schachter, MD
Thursday, April 1, 2004