What medications should be avoided in liver injury?

Medications to Avoid in Liver Injury

In patients with liver injury, acetaminophen, NSAIDs, rifampin plus pyrazinamide, methotrexate, and certain antibiotics should be avoided or used with extreme caution due to their potential to worsen liver damage. 1

High-Risk Medications to Avoid

Acetaminophen

• Limit to less than 3g per day in patients with liver disease 2
• Consider complete avoidance in severe liver injury 3
• FDA recommends limiting daily intake to maximum of 4g and imposes a limit of 325mg per tablet in prescription products 2
• Avoid combination products containing acetaminophen to prevent excess dosing 2
• Risk factors for hepatotoxicity: chronic alcohol use, fasting, malnutrition 1

NSAIDs

• Avoid in patients with GFR <30 ml/min/1.73 m² 2
• Not recommended for prolonged therapy in patients with GFR <60 ml/min/1.73 m² 2
• Should be used with caution or avoided in patients with liver disease due to risk of gastrointestinal bleeding and renal toxicity 2
• Increased risk of bleeding in patients with liver disease due to potential coagulopathy 4
• Risk of hepatotoxicity is higher in patients with rheumatoid arthritis compared to those with osteoarthritis 5

Antimicrobials

• Amoxicillin-clavulanate, trimethoprim-sulfamethoxazole, and azithromycin are most likely to cause chronic liver injury 1, 6
• Cefazolin can lead to liver injury 1-3 weeks after exposure to a single infusion 6
• Nitrofurantoin can cause liver injury after years of treatment and lead to acute liver failure or autoimmune-like reaction 6

Antituberculosis Drugs

• Rifampin plus pyrazinamide combination has extremely high risk of severe liver injury and death 2, 1
• CDC and American Thoracic Society recommend against using this combination for latent TB treatment 2
• Pyrazinamide is considered the most hepatotoxic among first-line TB agents 2
• Isoniazid can cause liver injury, especially in patients with pre-existing liver disease 2

Other High-Risk Medications

• Methotrexate: Reduce dose when GFR <60 ml/min/1.73 m², avoid if possible when GFR <15 ml/min/1.73 m² 2
• Valproic acid: Can cause life-threatening liver injury 1
• Statins: Generally safe in liver disease but monitor liver enzymes 1
• Opioids: Reduce dose when GFR <60 ml/min/1.73 m², use with caution in GFR <15 ml/min/1.73 m² 2

Monitoring and Management Guidelines

For Patients with Existing Liver Injury

1. Baseline Assessment:

   • Obtain baseline liver function tests (LFTs) before starting potentially hepatotoxic medications 1
   • Essential tests include ALT, AST, ALP, and total bilirubin 1

2. Monitoring Schedule:

   • High-risk medications: Weekly monitoring for first 6-8 weeks, then every 1-3 months 1
   • Increase monitoring frequency with abnormal results or dose increases 1

3. LFT Interpretation and Action:

   • ALT/AST <2× ULN: Repeat LFTs in 2-4 weeks 1
   • ALT/AST 2-3× ULN: Consider dose reduction and close monitoring 1
   • ALT/AST 3-5× ULN: Consider temporary discontinuation or dose reduction 1
   • ALT/AST >5× ULN: Discontinue medication 2, 1

4. For Immune Checkpoint Inhibitor-Related Liver Injury:

   • Grade I (AST/ALT ≤3× ULN): Monitor liver enzymes, continue medication if asymptomatic 2
   • Grade II (AST/ALT 3-5× ULN): Hold medication, consider oral prednisone 2
   • Grade III-IV (AST/ALT >5× ULN): Discontinue medication permanently, start IV methylprednisolone 2

Prevention Strategies

1. Patient Education:

   • Advise against alcohol consumption 2, 1
   • Educate about avoiding over-the-counter medications containing acetaminophen 2
   • Instruct patients to report symptoms of liver injury immediately (jaundice, abdominal pain, fatigue) 4

2. Medication Management:

   • Avoid concomitant use of multiple hepatotoxic drugs 1
   • Consider alternative medications with less hepatotoxic potential 2
   • For necessary medications, use lowest effective dose for shortest duration 1

3. Risk Assessment:

   • Identify patients with pre-existing risk factors: alcohol use, obesity, diabetes, advanced age 1
   • Consider genetic factors affecting drug metabolism 1
   • Note that medications used continuously for more than 1-2 years without liver problems are unlikely to cause new liver damage 2

Common Pitfalls and Caveats

1. Acetaminophen Misconceptions:

   • Despite concerns, acetaminophen can be used safely in stable chronic liver disease at reduced doses (≤3g/day) 7
   • The greatest risk is with acute overdose or in alcoholic patients 7

2. NSAID Considerations:

   • Risk of NSAID-induced liver injury is relatively low compared to other adverse effects (GI bleeding, kidney injury) 5
   • Sulindac has higher hepatotoxic risk compared to other NSAIDs 5

3. Unexpected Hepatotoxins:

   • Even common over-the-counter medications like diphenhydramine can rarely cause severe liver injury 8
   • Herbal and dietary supplements can cause significant liver injury and should be thoroughly evaluated 2

4. Drug Interactions:

   • Medications that inhibit or induce cytochrome P450 enzymes can alter metabolism of hepatotoxic drugs 1
   • Monitor for drug-drug interactions that may increase hepatotoxicity risk 1

By carefully selecting medications, monitoring appropriately, and educating patients, the risk of drug-induced liver injury can be significantly reduced in patients with existing liver disease.