What are the medications known to have hepatotoxic effects?

Comprehensive List of Hepatotoxic Medications

Medications with known hepatotoxic potential should be carefully monitored, as drug-induced liver injury can lead to significant morbidity and mortality, with some agents requiring permanent discontinuation after severe reactions. 1

First-Line Antitubercular Drugs

• Isoniazid (INH): Major hepatotoxin that can cause severe liver injury
• Pyrazinamide (PZA): Most hepatotoxic among first-line TB agents
• Rifampin: Less hepatotoxic alone but enhances isoniazid hepatotoxicity
• Rifampin-Pyrazinamide (RZ) combination: Associated with severe liver injury and death (hospitalization rate 3.0 per 1,000 treatment initiations; mortality rate 0.9 per 1,000) 2

NSAIDs

• Diclofenac: Can cause marked elevations in transaminases (>8 times ULN in about 1% of patients) 3
• Bromfenac: Withdrawn due to hepatotoxicity
• COX-2 inhibitors: Both preferential and selective inhibitors have hepatotoxic potential 4

Anticonvulsants

• Carbamazepine: Associated with hepatocellular tumors in animal studies; can cause granulomatous hepatitis 5, 6
• Valproic acid: Can cause severe hepatotoxicity, especially in patients with risk factors 4
• Phenytoin: Known hepatotoxin 4

Antimicrobials

• Amoxicillin-clavulanic acid: One of the most frequently implicated causes of drug-induced liver injury worldwide 7
• Macrolide antibiotics (Clarithromycin, Azithromycin): Can cause hepatitis 1

Antiretroviral Medications

• Nevirapine: Can cause severe clinical hepatitis in up to 12% of female patients 2, 1
• Lopinavir-ritonavir: ALT may increase to >5× ULN in 5% of patients 1
• Protease inhibitors: Associated with liver enzyme abnormalities that can occur at any time during treatment 2

Antimalarial Medications

• Chloroquine and Hydroxychloroquine: Both have likelihood score D (possible rare cause of clinically apparent liver injury) 2, 1

Antidiabetic Agents

• Acarbose, Gliclazide, Metformin: Implicated in causing liver injury 4
• Troglitazone: Withdrawn due to hepatotoxicity 4

Lipid-Lowering Agents

• Statins: Can cause transaminase elevations in approximately 1% of patients 1
• Niacin: Can cause hepatitis and elevations in liver enzymes 1
• Lomitapide: May cause elevations in liver transaminases 1

Antihypertensive Agents

• Methyldopa: Known hepatotoxin (though rarely prescribed now) 4
• Angiotensin receptor blockers and ACE inhibitors: Increasingly reported to cause liver injury 4

Psychotropic Drugs

• Clozapine: Requires regular monitoring of liver function tests 1
• Selective serotonin reuptake inhibitors (SSRIs): Associated with liver injury 4

Immunomodulators

• Methotrexate: Requires liver biopsy monitoring at high cumulative doses 1
• Immune checkpoint inhibitors: Can cause immune-mediated hepatitis 1

Antiasthmatic Medications

• Montelukast and Zafirlukast: Can cause reversible hepatitis and rarely irreversible hepatic failure 1
• Zileuton: Can cause elevation of liver enzymes 1

Antiviral Medications

• Remdesivir: Can cause mild ALT elevation to >2× ULN 1

Over-the-Counter Medications

• Acetaminophen: Major cause of drug-induced liver injury 8
• Diphenhydramine: Can rarely cause severe liver injury 1

Monitoring Recommendations

For patients taking hepatotoxic medications:

1. Baseline liver function tests before starting therapy

2. Regular monitoring schedule:

   • For anti-TB drugs: Every 2 weeks for first 2 months, then monthly 9
   • For immune checkpoint inhibitors: Before each infusion 1
   • For clozapine: Monthly for first 6 months, then every 1-3 months 1

3. Action based on liver enzyme elevations:

   • <2× ULN: Continue medication, repeat testing in 2-4 weeks
   • ≥2× but <3× ULN: Consider dose reduction
   • ≥3× but <5× ULN: Consider temporary discontinuation

   • 5× ULN: Discontinue medication and consider hepatology consultation 1

High-Risk Patients

Patients with the following factors require closer monitoring:

• Pre-existing liver disease
• Alcohol consumption
• Obesity
• Diabetes
• Advanced age
• Concomitant use of multiple hepatotoxic drugs 1

Patient Education

Patients taking hepatotoxic medications should be instructed to:

• Avoid alcohol consumption
• Avoid over-the-counter medications containing acetaminophen
• Report symptoms like fatigue, nausea, right upper abdominal discomfort, dark urine, or jaundice immediately 1

This comprehensive list highlights the most common hepatotoxic medications across various drug classes, with monitoring recommendations to minimize the risk of serious liver injury.