What is the effect of Phenobarbital (Phenobarb) on the liver?

From the Guidelines

Phenobarbital should be used with caution in patients with liver disease, as it can induce liver enzymes and potentially lead to hepatotoxicity, and its use is contraindicated with certain medications that are metabolized by the liver, as noted in studies such as 1.

Key Considerations

• Phenobarbital is primarily metabolized by the liver and can induce liver enzymes, specifically cytochrome P450 enzymes, which may increase the metabolism of other medications, as seen in 1 and 1.
• Long-term phenobarbital use may cause hepatotoxicity in some patients, though this is relatively uncommon compared to other anticonvulsants.
• Patients on phenobarbital should have periodic liver function tests to monitor for potential liver damage, especially during the initial months of therapy, with typical monitoring including checking liver enzymes (ALT, AST), bilirubin, and albumin every 3-6 months.
• If a patient develops symptoms such as jaundice, abdominal pain, nausea, or vomiting while taking phenobarbital, they should seek medical attention immediately as these could indicate liver problems.

Important Interactions

• Phenobarbital can interact with other medications that are metabolized by the liver, such as simeprevir, which is contraindicated in patients taking phenobarbital, as noted in 1 and 1.
• The use of phenobarbital with strong inducers of cytochrome P450, such as rifampin, carbamazepine, and phenytoin, may result in decreased efficacy and is not recommended, as seen in 1.

Monitoring and Precautions

• In patients with pre-existing liver disease, phenobarbital should be used cautiously with dose adjustments and more frequent monitoring.
• The drug's half-life may be prolonged in those with liver impairment, potentially leading to drug accumulation and increased side effects.
• Patients should be closely monitored for signs of liver damage, and the medication should be discontinued if liver function tests become abnormal or if symptoms of liver damage occur.

From the FDA Drug Label

Other Reported Reactions Headache; injection site reactions; hypersensitivity reactions, including but not limited to angioedema and skin rashes; fever; liver damage and megaloblastic anemia following chronic phenobarbital use. Prolonged therapy with barbiturates should be accompanied by periodic laboratory evaluation of organ systems, including hematopoietic, renal and hepatic systems Animal Data Phenobarbital sodium is carcinogenic in mice and rats after lifetime administration. In mice, it produced benign and malignant liver-cell tumors. Human Data In an epidemiological study of 9,136 patients who were treated on an anticonvulsant protocol which included phenobarbital, results indicated a higher than normal incidence of hepatic carcinoma.

Liver Effects of Phenobarbital:

• Liver Damage: Phenobarbital can cause liver damage, especially with chronic use 2.
• Hepatic Microsomal Enzymes: Phenobarbital can induce hepatic microsomal enzymes, which may increase the metabolism of other drugs 2 2.
• Hepatic Carcinoma: There is a higher than normal incidence of hepatic carcinoma in patients treated with phenobarbital, although the evidence is not sufficient to conclude that phenobarbital is carcinogenic in humans 2 2.
• Liver-Cell Tumors: Phenobarbital sodium is carcinogenic in mice and rats, producing benign and malignant liver-cell tumors 2 2.

From the Research

Phenobarbital and Liver Disease

• Phenobarbital is an antiepileptic drug that undergoes extensive hepatic metabolism 3
• It has been rarely linked to hepatotoxicity, but rather to enzyme induction 4
• In patients with chronic liver disease, the kinetics of drugs, including phenobarbital, are altered 5
• The use of antiepileptic drugs, such as phenobarbital, in patients with liver disease requires careful consideration of their pharmacokinetics and potential hepatotoxicity 6, 3

Hepatotoxicity and Phenobarbital

• Phenobarbital has been associated with elevations of serum gamma glutamyl transpeptidase activity and transient transaminase abnormalities 4
• However, liver tissue from patients treated with phenobarbital has shown no specific histopathology, suggesting that the drug does not result in hepatotoxicity but rather in enzyme induction 4
• Other antiepileptic drugs, such as valproic acid and phenytoin, have a well-recognized association with liver toxicity, but phenobarbital is not commonly associated with hepatotoxicity 6

Dose Adjustment in Liver Disease

• In patients with liver disease, the dose of phenobarbital may need to be adjusted due to altered hepatic metabolism 5, 7
• The extent of hepatic extraction of the drug can guide dose adjustment, with drugs having a high hepatic extraction requiring a reduced initial dose and maintenance dose in cirrhotic patients 7
• However, the dose adjustment of phenobarbital in patients with liver disease should be individualized and based on clinical monitoring of pharmacological effects and toxicity 7