What medications can cause hepatic (liver) failure?

From the Guidelines

Drugs such as carbamazepine, methyldopa, minocycline, macrolide antibiotics, nitrofurantoin, statins, sulfonamides, terbinafine, chlorpromazine, and methotrexate can cause liver failure, and their use requires careful monitoring of liver functions. The liver metabolizes most drugs, and damage typically occurs through direct toxicity or immune-mediated reactions. Risk factors include age, genetics, existing liver disease, and taking multiple hepatotoxic medications simultaneously 1.

Key Points to Consider

• A wide variety of drugs are associated with liver disease, and the requirement for monitoring of liver functions may be necessary 1.
• Methotrexate treatment requires special care to prevent dose-dependent liver fibrosis, and non-invasive markers of fibrosis should be monitored 1.
• Statins can lead to drug-induced liver injury, but this is very rare, and studies have demonstrated they are safe in patients with pre-existing abnormal liver enzymes 1.
• Patients with pre-existing liver disease, including nonalcoholic fatty liver disease (NAFLD), may be at higher risk for complicated courses and adverse outcomes from drug-induced liver injury (DILI) 1.
• Signs of drug-induced liver injury include fatigue, nausea, abdominal pain, dark urine, and jaundice, and if these symptoms occur while taking medications, immediate medical attention is necessary to prevent progression to complete liver failure.

Management and Prevention

• Clinical judgment is necessary to determine the relative contribution of a drug or drugs alongside possible concomitant liver disease 1.
• A careful listing of all agents taken, the time period involved, and the quantity ingested is necessary to implicate a particular substance in drug-induced hepatotoxicity 1.
• The use of hepatotoxic drugs should be carefully considered in patients with pre-existing liver disease, and alternative treatments should be explored when possible.

From the FDA Drug Label

Baseline and periodic evaluations of liver function, particularly in patients with a history of liver disease, must be performed during treatment with this drug since liver damage may occur Carbamazepine should be discontinued, based on clinical judgment, if indicated by newly occurring or worsening clinical or laboratory evidence of liver dysfunction or hepatic damage, or in the case of active liver disease Concomitant use of carbamazepine and isoniazid has been reported to increase isoniazid-induced hepatotoxicity.

Drugs that may cause liver failure when used with carbamazepine include:

• Isoniazid Carbamazepine itself may also cause liver damage, and liver function should be monitored during treatment. 2 2

From the Research

Drugs that Cause Liver Failure

• Acetaminophen is a common cause of acute liver failure, with studies showing it accounts for 42% of cases in the United States 3.
• The annual percentage of acetaminophen-related acute liver failure has been increasing, from 28% in 1998 to 51% in 2003 3.
• Other analgesics, such as nonsteroidal anti-inflammatory drugs, opiates, tricyclic antidepressants, and anticonvulsants, rarely cause liver injury 4.

Risk Factors for Acetaminophen-Induced Liver Failure

• Concomitant depression, chronic pain, alcohol or narcotic use, and/or taking several preparations simultaneously increase the risk of acetaminophen-induced liver failure 3.
• Women are more likely to experience acetaminophen-induced acute liver injury or liver failure, with higher proportions of women having psychiatric disease and co-ingestion with sedating agents 5.
• Co-ingestion of sedating agents increases the odds of severe hepatic encephalopathy in women, but not in men 5.

Management and Treatment of Acetaminophen-Induced Liver Failure

• N-acetylcysteine is the standard of care for acetaminophen toxicity and can prevent progression to liver failure 4, 6.
• Liver transplantation is the only definitive therapy that will significantly increase the chances of survival for advanced acute liver failure 6.
• Understanding the mechanisms of acetaminophen-induced cell death can lead to the development of new therapeutic interventions 7.