Verapamil is a first generation calcium channel blocker used for treatment of hypertension, angina pectoris and superventricular tachyarrhythmias. Verapamil has been linked to a low rate of serum enzyme elevations during therapy and to rare instances of clinically apparent acute liver injury.
Verapamil (ver ap' a mil) belongs to the phenylalkylamine class of calcium channel blockers and is used to treat hypertension and angina pectoris as well as atrial tachyarrhythmias. Like other calcium channel blockers, verapamil acts by blocking the influx of calcium ions into vascular smooth muscle and cardiac muscle cells during membrane depolarization. This action causes relaxation of vascular and arterial smooth muscle cells, resulting in arterial vasodilation and a decrease in cardiac work and oxygen consumption. Verapamil also decreases the rate of the sinus node pacemaker and slows atrial-ventricular conduction, making it effective in controlling some superventricular tachyarrhythmias (an action not shared by all calcium channel blockers). Verapamil was the first calcium channel blocker approved in the United States (1981) and it remains in wide use with more than eight million prescriptions filled yearly. Several generic formulations are available in tablet sizes of 40, 80 or 120 mg; specific commercial names include Calan, Isoptin, Apo-, Novo-, or Nu-Verap, and Verelan. For hypertension and angina pectoris, the recommended dose in adults is 120 to 480 mg daily in three divided doses. Chronic therapy is typical. Extended release formulations are available for once-daily dosing and intravenous formulations for treatment of atrial fibrillation or flutter. Like other calcium channel blockers, verapamil is generally well tolerated and side effects are largely due to its vasodilating activities and can include headache, flushing, dizziness, fatigue, nausea, diarrhea, palpitations, peripheral edema and skin rash.
Chronic therapy with verapamil is associated with a low rate of serum aminotransferase elevations that are usually mild and may resolve even with continuation of therapy. Clinically apparent liver injury with jaundice or symptoms from verapamil is uncommon and usually presents with fatigue, weakness with or without jaundice 2 to 8 weeks after starting the drug. The pattern of injury is usually mixed or cholestatic. Acute presentation can include fever, rash, arthralgias and eosinophilia, but these immunoallergic features are rarely prominent. Rapid recurrence with rechallenge has been reported. Autoantibodies are usually not present. Most cases have been mild and self-limited. Recovery is prompt with stopping verapamil and no cases of chronic hepatitis or vanishing bile duct syndrome have been attributed to its use. At least a dozen instances of acute liver injury attributed to verapamil have been published and the nature of the reaction is probably an idiosyncratic and immunologic.
Likelihood score: B (Likely cause of clinically apparent liver injury).
Mechanism of Injury
The mechanism of clinically apparent hepatotoxicity from verapamil is probably hypersensitivity. Verapamil is a derivative of papaverine which also causes an allergic form of hepatitis. Verapamil is metabolized by multiple cytochrome P450 enzymes including CYP 3A4 and is susceptible to drug-drug interactions with agents that are subtrates of CYP 3A4 as well as with inducers and inhibitors of the enzyme.
Outcome and Management
The severity of liver injury from verapamil ranges from mild and transient serum enzyme elevations to mild-to-moderate, but self-limited jaundice. Complete recovery is expected after stopping the drug and recovery is usually rapid (2 to 6 weeks) depending upon the severity. Rechallenge leads to recurrence and should be avoided. There is little information on cross sensivity of liver injury with other calcium channel blockers.
Case 1. Asymptomatic elevations in serum enzymes during verapamil therapy.
[Modified from a case in the database of the Drug Induced Liver Injury Network.]
A 54 year old woman with migraine headaches was started on verapamil in a dose of 80 mg daily, which was increased to 120 mg daily 3 weeks later. On routine testing 6 months later, she was found to have marked elevations in serum alkaline phosphatase and moderate increases in serum ALT and AST without jaundice (Table). Previous liver test results had been normal. She denied all symptoms and had no history of exposure to hepatitis, toxins or alcohol. She had a complex medical history and was also taking estrogens for menopausal symptoms, rabeprazole for acid reflux, valacyclovir for recurrent genital herpes, zolpidem for insomnia, fexofenadine for allergic rhinnitis, aspirin for coronary prophylaxis, and acetaminophen intermittently at low dosage for miscellaneous muscular-skeletal complaints. Tests for acute hepatitis A, B and C as well as autoimmune markers were negative. An abdominal ultrasound showed a heterogenous texture to the liver, but no gallstones or evidence of bile duct abnormalities. Verapamil was discontinued and laboratory test results returned to normal except for minimal elevations in alkaline phosphatase. Her other medications were continued.
|Medication:||Verapamil, 80-120 mg daily|
|| Cholestatic (R=0.6)
||1+ (never jaundiced, never hospitalized)
|Latency:||Five to six months |
|Recovery:||Near complete within 2 months|
|Other medications:||Rabeprazole, valacyclovir, zolpidem, fexofenadine, aspirin, intermittent acetaminophen
|Time After Starting
||Time After Stopping
||Alk P (U/L)
||Verapamil started at a dose of 80 mg/day
||Dose 120 mg/day
||Verapamil stopped after 26 weeks
This patient was asymptomatic of liver disease, but was found to have serum enzyme abnormalities on routine blood testing after she had been on verapamil for six months. Serum alkaline phosphatase was markedly elevated (~10-20 fold) while serum aminotransferase levels were only moderately increased (~4-6 fold). Serum bilirubin levels had increased, although not into the abnormal range. There were no features that suggested hypersensitivity (rash, fever or eosinophilia). Evaluation for other causes of liver disease was unrevealing, and stopping verapamil was followed by a rapid improvement. The latency of 5 to 6 months was unusual for verapamil, most published cases arising within 2 to 8 weeks of starting. However, the cholestatic pattern of serum enzymes, absence of other obvious causes of liver disease and the improvement with drug withdrawal were compatible with verapamil induced hepatotoxicity.
REPRESENTATIVE TRADE NAMES
Verapamil – Generic, Calan®
Product labeling at DailyMed, National Library of Medicine, NIH
||CAS REGISTRY NO
References updated: 11 January 2017
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