What is an example of a hepatotoxic drug?

Hepatotoxic Drug Examples

Acetaminophen is the most common and clinically significant hepatotoxic drug, serving as the leading cause of drug-induced liver failure in the United States. 1

Primary Hepatotoxic Medications

Acetaminophen (Paracetamol)

• Acetaminophen can cause fulminant hepatic failure, particularly at doses exceeding 4 grams per day, making it the most frequently encountered hepatotoxic agent in clinical practice. 2
• Even at therapeutic doses (≤4g daily), acetaminophen can cause hepatotoxicity in chronic alcohol users, though this remains controversial with mixed evidence. 2, 1
• The hepatotoxicity results from the toxic metabolite N-acetyl-p-benzoquinone imine (NAPQI), which depletes hepatic glutathione stores and causes hepatic necrosis. 3, 4

Antituberculosis Medications

• Among first-line antituberculosis agents, pyrazinamide is considered the most hepatotoxic drug. 2, 1
• Isoniazid, rifampin, and pyrazinamide all cause drug-induced liver injury, with the rifampin-pyrazinamide combination being particularly dangerous and now generally not recommended for latent TB treatment. 2, 1
• The rifampin-pyrazinamide regimen has caused severe liver injury requiring transplantation and should never be offered to patients with underlying liver disease, concurrent hepatotoxic medications, or excessive alcohol use. 2

Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)

• NSAIDs are responsible for approximately 10% of all drug-induced hepatitis cases and cause increased toxicity in patients with existing liver disease due to higher free drug concentrations. 2, 1
• NSAIDs cause multiple complications beyond hepatotoxicity, including nephrotoxicity, gastric ulcers, and hepatic decompensation in cirrhotic patients, warranting avoidance whenever possible. 2

High-Risk Populations

Patients with Increased Susceptibility

• Chronic alcohol users demonstrate increased susceptibility to acetaminophen hepatotoxicity, even at doses below 4 grams daily. 2, 1
• Patients with underlying liver disease, previous drug-induced liver injury, or those taking concurrent hepatotoxic medications face substantially elevated risk. 2, 1
• Fasting or malnourished states may increase susceptibility through glutathione depletion and cytochrome P-450 2E1 induction. 3

Clinical Recognition and Monitoring

Diagnostic Thresholds

• Drug-induced hepatitis is suspected when ALT levels reach ≥5 times the upper limit of normal in asymptomatic patients, or ≥3 times the upper limit with hepatitis symptoms. 1
• Acetaminophen overdose characteristically produces extremely high transaminase levels (AST and ALT >1000 IU/L), distinguishing it from most other causes of liver injury. 3

Management Principles

• When hepatotoxicity is suspected, immediately discontinue all potentially offending drugs and perform comprehensive causality assessment. 2, 1
• For acetaminophen overdose, N-acetylcysteine is highly effective when administered within 15 hours of ingestion and remains the standard antidote. 3, 5

Special Dosing Considerations

Patients with Liver Disease

• In cirrhotic patients, limit acetaminophen to 2-3 grams daily rather than the standard 4-gram maximum, as the half-life increases several-fold and bioavailability quadruples in hepatocellular carcinoma patients. 2
• Avoid NSAIDs entirely in patients with liver cirrhosis due to compounded risks of hepatotoxicity, nephrotoxicity, and decompensation. 2, 1