What is the role of phenobarbital in the treatment of epilepsy?

Updated: Jan 28, 2020
  • Author: Juan G Ochoa, MD; Chief Editor: Selim R Benbadis, MD  more...
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Phenobarbital (PHB) is the most commonly prescribed AED of the 20th century. It is a very potent anticonvulsant with a broad spectrum of action. Currently, its use is limited because of its adverse effects. It is a free acid, relatively insoluble in water. The sodium salt is soluble in water but unstable in solution. It has a direct action on GABA-A receptors by binding to the barbiturate-binding site that prolongs the duration of chloride channel opening. It also reduces sodium and potassium conductance and calcium influx and depresses glutamate excitability.

PHB is a powerful inducer of the hepatic microsomal enzymes. It has an oral or IM bioavailability of 80-100% in adults. Time to peak plasma level is 1-3 hours, but it may be delayed after oral administration in patients with poor gastrointestinal (GI) motility. The serum peak levels after IM injection are achieved in 4 hours. Ethanol increases the rate of PHB absorption. It is absorbed mainly in the small intestine.

Plasma protein binding is 40-60%. The concentration in breast milk is approximately 40% of the serum concentration. The volume of distribution ranges from 0.42-0.75 L/kg. A change in pH causes a shift of the drug between compartments; therefore, acidosis increases the concentration of PHB in the tissue compartment.

After IV administration, PHB is distributed quickly to highly vascular organs, except the brain, and then it is distributed evenly. After 6-12 minutes, it penetrates the brain, but the brain penetration is much faster during status epilepticus because of increased blood flow and acidosis.

PHB has a very long elimination half-life (ie, 75-120 h); in infants, the half-life is much longer, up to 400 hours. In individuals older than 6 months, the half-life falls to 20-75 hours. PHB is metabolized in the liver. The major metabolite is p-hydroxy phenobarbital, which is excreted as a glucuronide conjugate. PHB has extensive urinary resorption, which is enhanced by acidification of the urine.

Metabolism of PHB is inhibited by phenytoin (PHT), valproate (VPA), felbamate, and dextropropoxyphene. Enzyme inducers, such as rifampin, decrease PHB levels. Because of the potent induction of the hepatic enzymes, PHB increases the metabolism of estrogen, steroids, warfarin, carbamazepine (CBZ), diazepam, clonazepam, and VPA. Its effect on PHT is unpredictable.

In a multicenter double-blind study, PHB was found to be as effective as PHT and CBZ in the treatment of partial and secondarily generalized seizures. The Veterans Administration (VA) cooperative study, however, which compared PHB, primidone, PHT, and CBZ, showed a significantly lower retention in patients on PHB or primidone, despite their similar efficacy, because of poorer tolerability. No statistical difference was reported between PHT and CBZ.

PHB is effective in a wide variety of seizures and is currently the cheaper AED. PHB still is a first-line drug for treatment of status epilepticus. However, because of its adverse effects (eg, sedation and cognitive slowing), it is a second-line agent in the treatment of partial onset and secondarily generalized tonic-clonic seizures. In developing countries, it is used widely because of its low cost.

PHB is available in tablets of 15 mg, 30 mg, 50 mg, 60 mg, and 100 mg; elixirs (15 mg/mL); and injections (200 mg/mL). The usual starting dose is 30-60 mg once a day. The dose can be titrated up to 240 mg/d. Slow titration is better tolerated. Therapeutic blood levels are 15-40 mg/L. Physical dependence and withdrawal seizures occur with long-term use. Therefore, very slow withdrawal over several weeks to months is recommended.

The most important adverse effects of PHB are cognitive and behavior alterations. Children are more likely than adults to exhibit behavioral changes (eg, paradoxical hyperkinesis). Sedation is prominent, particularly at the beginning of therapy, and usually subsides. Psychomotor slowing, poor concentration, depression, irritability, ataxia, and decreased libido are other effects.

Long-term use of PHB may be associated with coarsening of facial features, osteomalacia, and Dupuytren contractures. Folate deficiency, megaloblastic anemia, and idiosyncratic skin reaction are rare. Vitamin supplementation is warranted. Hepatitis has been reported secondary to an immune-mediated process.

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