Diltiazem hydrochloride is a first generation calcium channel blocker that is widely used in the therapy of hypertension and angina pectoris. Diltiazem therapy is associated with serum enzyme elevations and has been linked to rare instances of clinically apparent liver injury.
Diltiazem (dil tye' a zem) belongs to the benzothiazepine class of calcium channel blockers and is used for the treatment of hypertension, angina pectoris and superventricular tachyarrhythmias. Like other calcium channel blockers, diltiazem acts by inhibiting the transmembrane influx of calcium ions into cardiac muscle and vascular smooth muscle cells. The inhibition of calcium flux causes arterial vasodilation and decreases cardiac work and oxygen consumption. Diltiazem, like verapamil (but unlike other calcium channel blockers), also decreases the rate of the sinus node pacemaker and slows atrial-ventricular conduction accounting for its effects on superventricular tachyarrhythmias. Diltiazem was approved in the United States in 1982 and currently several million prescriptions are filled yearly. Current indications for oral forms of diltiazem include hypertension and management of chronic stable angina pectoris, Prinzmetal's or variant angina. Diltiazem is available orally in multiple generic formulations as well as under commerical names including Cardizem and Tiazac in capsules of 30, 60, 90 and 120 mg. Once daily, extended release formulations are available and now widely used (Cardizem CD, Cardizem LA, Cartia XT, Dilacor XR, Dilt-XR, Diltia XT, Taztia XT) in strengths ranging from 60 to 420 mg. The recommended oral dose of diltiazem in adults is 180 to 360 mg daily, usually starting with lower doses. Chronic therapy is typical. Diltiazem is also available in intravenous formulations which are used in therapy of atrial arrhythmias, including atrial fibrillation or flutter and superventricular tachycardia. Diltiazem, like other calcium channel blockers, is generally well tolerated and side effects are due to its vasodilating activities and can include dizziness, flushing, headaches, fatigue, nausea, diarrhea, palpitations, bradycardia, postural hypotension and rash. Rare but potentially severe adverse events include cardiac conduction defects, hypotension, hypersensitivity reactions and instances of Stevens Johnson syndrome.
Diltiazem therapy is associated with a low rate of mild and transient elevations in serum aminotransferase levels which are usually asymptomatic and often resolve even with continuation of therapy. Clinically apparent, acute liver injury with jaundice due to diltiazem is rare and only isolated case reports have been published. In large case series of drug induced liver injury, calcium channel blockers are rarely mentioned. Most cases attributed to diltiazem have been marked by a short latency period (3 to 14 days) and features of hypersensitivity with fever, rash and eosinophilia. The pattern of liver injury was ranged from cholestatic to hepatocellular. Jaundice is often absent and usually mild. Autoantibody formation has not been described. Thus, liver injury from diltiazem is likely to be idiosyncratic in nature and is typically mild and self-limited with resolution within 4 to 8 weeks of stopping. Acute hepatic injury is listened as a possible adverse event in the diltiazem product label.
Likelihood score: (C: probable but rare cause of clinically apparent liver injury).
Mechanism of Injury
The mechanism of diltiazem hepatotoxicity is not known, but most cases are probably due to hypersensitivity. Diltiazem is metabolized by the cytochrome P450 system and is an inhibitor of CYP 3A4 activity, which can lead to serious drug-drug interactions and potentiation of the hepatotoxic effects of other medications. Indeed, there have been several reports of clinically apparent liver injury or rhabdomyolysis occuring in patients on long term statins who had recently added diltiazem to their multidrug regimen, suggesting altered metabolism of the statin by the addition of a CYP 3A4 inhibitor.
Outcome and Management
Severity of liver injury from diltiazem ranges from mild and transient serum enzyme elevations to self-limited hepatitis with jaundice. Complete recovery is expected after stopping the drug and recovery is usually rapid (1 to 2 months). Diltiazem has not been implicated in cases of chronic liver injury or vanishing bile duct syndrome, but was the suspected agent in at least one published case of acute liver failure. Cross sensitivity of liver injury with other calcium channel blockers has been described, but not with diltiazem.
REPRESENTATIVE TRADE NAMES
Diltiazem – Generic, Cardizem®
Product labeling at DailyMed, National Library of Medicine, NIH
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