LiverTox: Clinical and Research Information on Drug-Induced Liver Injury

The calcium channel blockers act by blocking the influx of calcium ions into vascular smooth muscle and cardiac muscle cells during membrane depolarization. Because muscle contraction is largely dependent upon influx of calcium, its inhibition causes relaxation, particularly in arterial beds. Thus, the major effects of the calcium channel blockers are relaxation of vascular and arterial smooth muscle cells resulting in arterial vasodilation. The major use of the calcium channel blockers is for hypertension and angina pectoris (variant, exertional, and unstable). Some calcium channel blockers are also used for supraventricular arrhythmias and heart failure. Off label uses include migraine headaches. The major calcium channel blockers used in the United States include amlodipine, diltiazem, felodipine, isradipine, nicardipine, nifedipine, nimodipine, nisoldipine, and verapamil. While all affect the L type voltage gated calcium channel, the structure and site of interaction within the channel varies among the agents. Verapamil blocks the phenylalkylamine site and diltiazem the benzothiazepine site, while the remaining agents (exemplified by amlopidine and nifedipine) bind to the 1,4 dihydropyridine site. These agents are also commonly referred to as being first generation (verapamil, diltiazem, nifedipine) or second generation (amlopine, felodipine, isradipine, nicardipine, nimodipine and others) calcium channel blockers. Several of the calcium channel blockers are now available in generic forms and some are available as combinations with diuretics and lipid lowering agents. Many of the calcium channel blockers have been linked to rare instances of idiosyncratic drug induced liver disease. Hepatic injury from calcium channel blockers is usually mild and reversible, but rare symptomatic and severe instances have been reported. Agents most clearly linked to liver injury are verapamil, diltiazem, amlodipine and nifedipine, probably because these agents have been most widely used. The pattern of injury varies somewhat among the different agents, so that the hepatic injury appears not to be a class effect or the result of inhibition of calcium channels, but rather due to hypersensitivity (verapamil) or metabolic injury that usually results in a mixed hepatocellular-cholestatic pattern (diltiazem, amlopidine, nifedipine). These four agents have different chemical structures and interact with different sites or different calcium channels, so that different patterns of idiosyncratic adverse events and different hepatic reactions might be expected. However, repeated instances of liver injury from different calcium channel blockers have been reported, so that switching from one calcium channel blocker that has caused liver injury to another in this class should be done with caution. Several of these agents can also cause minor elevations in serum aminotransferase levels that are often transient and resolve even with continuation of the agent or can be persistent, resolving only once the agent(s) are discontinued. Common, minor class specific side effects of the calcium channel blockers include headache, dizziness, flushing, nausea, fatigue, diarrhea, peripheral edema, palpitations, bradycardia and rash. Each calcium channel blocker is discussed separately with individual clinical cases and references. The following are links to each drug record.