What are examples of medications that are hepatotoxic?

Common Hepatotoxic Medications

Acetaminophen, isoniazid (INH), pyrazinamide (PZA), rifampin, carbamazepine, valproic acid, and diclofenac are among the most significant hepatotoxic medications that can cause severe liver injury and should be used with caution in patients with underlying liver disease. 1, 2, 3

First-Line Antituberculosis Medications

Pyrazinamide (PZA)

• Among first-line TB agents, PZA is considered the most hepatotoxic 1
• Requires careful monitoring of liver function during treatment
• Should be avoided in patients with pre-existing liver disease
• Maximum daily dose should not exceed 2.0 g (20 mg/kg/day) 1

Isoniazid (INH)

• Well-documented cause of hepatotoxicity
• Risk factors for INH hepatotoxicity include:
  • Advanced age
  • Pre-existing liver disease
  • Concurrent use of other hepatotoxic medications
  • History of previous INH-associated liver injury 1

Rifampin

• Can cause hepatotoxicity, particularly when combined with INH or PZA
• Used in combination regimens for TB treatment 1

NSAIDs

Diclofenac

• Associated with significant risk of hepatotoxicity
• In clinical trials, approximately 4% of patients showed meaningful elevations of ALT/AST 2
• Can cause severe hepatic reactions including:
  • Liver necrosis
  • Jaundice
  • Fulminant hepatitis
  • Liver failure (some cases resulting in death or liver transplantation) 2
• Risk increases with:
  • Female gender
  • Doses ≥150 mg
  • Duration >90 days 2

Anticonvulsants

Carbamazepine

• Can cause dose-related hepatotoxicity
• Requires baseline and periodic liver function monitoring
• Should be discontinued if evidence of liver dysfunction develops 3
• Induces hepatic enzymes (CYP3A4, CYP1A2, CYP2B6, CYP2C8/9/19) 3

Valproic Acid

• Known hepatotoxic potential, especially in certain risk groups
• Risk factors for valproic acid hepatotoxicity include:
  • Young age
  • Polytherapy
  • Developmental delays
  • Metabolic disorders 4, 5

Antibiotics

Amoxicillin-Clavulanic Acid

• One of the most frequently implicated causes of drug-induced liver injury worldwide 6, 7
• Typically causes cholestatic pattern of injury
• Risk increases with age and repeated courses

Over-the-Counter Medications

Acetaminophen (Paracetamol)

• Dose-dependent hepatotoxicity
• Can cause hepatotoxicity even at standard doses (4g/day) in vulnerable populations 8
• Risk factors include:
  • Fasting
  • Alcohol use
  • Older age
  • Concurrent use of enzyme-inducing drugs
  • Recent dose escalation from PRN to scheduled dosing 8

Monitoring Recommendations

For patients on hepatotoxic medications:

• Baseline liver function tests before starting therapy
• Regular monitoring of serum aminotransferases and bilirubin
• Immediate discontinuation if:
  • ALT >5x upper limit of normal in asymptomatic patients
  • Any elevation of ALT with symptoms of hepatitis
  • Elevated bilirubin 1, 2

Risk Mitigation Strategies

1. Avoid concurrent use of multiple hepatotoxic medications
2. Use lowest effective dose for shortest duration possible
3. Educate patients about warning signs of hepatotoxicity:
   • Nausea
   • Fatigue
   • Lethargy
   • Jaundice
   • Right upper quadrant tenderness
   • "Flu-like" symptoms 2
4. Consider alternative medications in patients with pre-existing liver disease

Understanding the hepatotoxic potential of commonly prescribed medications is essential for preventing drug-induced liver injury and optimizing patient outcomes.