What is the elimination half‑life of Cardizem (diltiazem) for immediate‑release and extended‑release formulations, and how are they affected by hepatic or renal impairment?

Cardizem (Diltiazem) Half-Life

The elimination half-life of immediate-release diltiazem is approximately 3–4 hours, while extended-release formulations have a half-life of approximately 6–7 hours; hepatic impairment significantly prolongs the half-life, but renal impairment does not require dose adjustment. 1, 2

Immediate-Release Formulation

• The elimination half-life of immediate-release diltiazem ranges from 2.7 to 3.5 hours in healthy adults with normal hepatic function. 1
• Peak plasma concentrations occur at approximately 38 minutes after oral administration of the solution form. 3
• The short half-life necessitates four-times-daily dosing (30–90 mg per dose) to maintain therapeutic plasma levels throughout the day. 4

Extended-Release Formulations

• Modified-release (extended-release) diltiazem has a significantly prolonged half-life of approximately 6.25 hours, compared to 2.69 hours for immediate-release. 1
• After intravenous infusion in patients with atrial fibrillation, the mean elimination half-life is 6.8–6.9 hours. 2
• Extended-release tablets are designed for once-daily administration (120–360 mg), providing consistent 24-hour drug delivery. 4
• The volume of distribution is large (299–411 liters), indicating extensive tissue distribution. 2

Effect of Hepatic Impairment

• Diltiazem is extensively metabolized by the liver and has a high hepatic extraction ratio, meaning its clearance depends primarily on hepatic blood flow. 5
• Hepatic dysfunction significantly impairs diltiazem clearance and prolongs the elimination half-life, requiring dose reduction. 6, 5
• In cases of massive overdose with sustained-release formulations, the half-life can extend to 28–48 hours due to saturation of hepatic metabolism. 7
• Dose adjustments are mandatory in patients with hepatic dysfunction to minimize adverse effects and prevent toxicity. 5

Effect of Renal Impairment

• Renal impairment does not significantly alter diltiazem pharmacokinetics, as the drug is primarily eliminated through hepatic metabolism rather than renal excretion. 8
• In patients with severe renal failure (GFR 0.03–0.87 mL/s/1.73 m²), diltiazem and its main metabolite desacetyldiltiazem showed a pharmacokinetic profile similar to patients with normal renal function. 8
• Peak plasma concentration, half-life, and urinary excretion remain unchanged in severe renal impairment. 8
• No dose adjustment is required for renal dysfunction, though caution is advised per guidelines. 6

Clinical Implications

• The 12-hour half-life of extended-release formulations allows for once-daily dosing, improving medication adherence compared to immediate-release formulations. 4
• Systemic clearance after intravenous administration is 31–42 L/hr, with evidence of nonlinear pharmacokinetics showing dose-dependent decreases in clearance at higher infusion rates. 2
• Absolute oral bioavailability is only 44% due to significant first-pass hepatic extraction, which is further impaired in liver disease. 3
• The principal metabolites (desacetyldiltiazem and N-desmethyldiltiazem) represent less than 15% and 10% of plasma diltiazem concentrations, respectively, and do not contribute significantly to pharmacodynamic effects. 2

Key Monitoring Considerations

• In patients with hepatic dysfunction, monitor liver function tests and consider empiric dose reduction given the drug's dependence on hepatic metabolism. 5
• The prolonged half-life in overdose situations (up to 48 hours) necessitates extended cardiovascular monitoring and aggressive supportive care. 7
• Elderly patients may have reduced hepatic blood flow, effectively prolonging the half-life even without overt liver disease. 5