Is Cardizem (Diltiazem) Damaging to the Liver?
Diltiazem is not typically hepatotoxic in standard clinical use, but the FDA label warns of rare instances of acute hepatic injury with significant enzyme elevations that are reversible upon discontinuation. 1
Direct Hepatotoxicity Risk
Diltiazem carries a low but documented risk of liver injury:
- The FDA explicitly warns that "in rare instances, significant elevations in enzymes such as alkaline phosphatase, LDH, SGOT, SGPT, and other phenomena consistent with acute hepatic injury have been noted." 1
- These reactions are reversible when the drug is stopped, though the relationship to diltiazem is "uncertain in most cases, but probable in some." 1
- The FDA recommends monitoring liver function tests at regular intervals during prolonged use, particularly in patients with pre-existing hepatic impairment. 1
Hepatic Metabolism Considerations
Diltiazem's relationship with the liver is primarily metabolic rather than toxic:
- Diltiazem is extensively metabolized by the liver and requires dose adjustments in patients with hepatic dysfunction to minimize adverse effects. 2, 1
- The drug has a high hepatic extraction ratio, meaning its clearance depends primarily on hepatic blood flow, which decreases with age and liver disease. 2
- In patients with liver cirrhosis, diltiazem elimination is impaired (half-life increases from 5.3 to 7.2 hours), leading to higher drug levels and increased risk of adverse effects. 3
Clinical Context: When Liver Damage Occurs
The evidence suggests liver injury from diltiazem occurs in specific circumstances:
- Hypoxic hepatitis can develop when diltiazem causes hypotension in patients with pre-existing liver disease (chronic alcohol use, liver congestion from heart failure), though this represents indirect injury from hemodynamic instability rather than direct drug toxicity. 4
- In animal toxicity studies, high doses (125 mg/kg in rats, 20 mg/kg in dogs) produced reversible histological liver changes, but these doses far exceed therapeutic human dosing. 1
- Interestingly, research shows diltiazem may actually be protective against certain hepatotoxins (acetaminophen, carbon tetrachloride) by reducing liver calcium accumulation and lipid peroxidation, though this requires high doses. 5, 6
Monitoring Recommendations
Based on FDA guidance and clinical guidelines:
- Monitor liver function tests if clinically indicated, particularly in patients with pre-existing hepatic disease or those on prolonged therapy. 7, 1
- Watch for signs of hepatic injury: jaundice, right upper quadrant pain, unexplained fatigue, or dark urine. 1
- Use caution and consider dose reduction in patients with hepatic dysfunction, as diltiazem clearance is impaired. 2, 1
- If enzyme elevations occur, discontinue diltiazem promptly—the injury is reversible. 1
Key Clinical Pitfall
The most important caveat is that diltiazem-induced hypotension can precipitate hypoxic hepatitis in patients with underlying liver disease or right heart dysfunction. 4 This represents a greater practical risk than direct hepatotoxicity. Monitor blood pressure closely during initiation and titration, especially in patients with compromised hepatic blood flow from heart failure or cirrhosis. 7, 4