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LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012-.

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LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet].

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Last Update: January 4, 2018.



Disopyramide is an oral antiarrhythmic agent that has been in wide use for several decades. Long term disopyramide therapy is associated with a low rate of serum enzyme elevations and is a rare cause of clinically apparent acute liver injury.


Disopyramide (dye" soe pir' a mide) is a pyridine derivative and has electrophysiological effects that resemble quinidine (antiarrhythmic Class IA). Disopyramide decreases cardiac automaticity, increases refractory periods and slows conduction. Disopyramide is considered a myocardial depressant and can depress contractility. It also has anticholinergic effects. Disopyramide was approved for use in the United States in 1977, and current indications include suppression of symptomatic premature ventricular contractions and life threatening ventricular tachycardia. It is also effective in conversion as well as maintenance of normal sinus rhythm in patients with atrial fibrillation or flutter, but is not approved for this indication in the United States. Disopyramide is available in capsules of 100 and 150 mg generically and under the brand name Norpace. Extended release formulations are also available. The usual maintenance dose in adults is 400 to 800 mg daily in 2 to 4 divided doses. The most common side effects include dry mouth, urinary hesitancy, fatigue, headache, dizziness and anxiety.


In clinical trials, disopyramide was associated with a low rate of serum aminotransferase and alkaline phosphatase elevations. Despite wide scale use, disopyramide has only rarely been linked to cases of clinically apparent liver injury. Two types of hepatic injury have been described. The first is an acute hepatocellular injury that arises within 1 to 3 days of starting disopyramide and resembles acute hepatic ischemia with marked early rises in serum aminotransferase levels (and LDH), with minimal increase in alkaline phosphatase and subsequent rise in serum bilirubin. The prothrombin time may be abnormal initially. The injury resolves rapidly and may relate to sudden worsening of congestive heart failure due to the myocardial depressant effects of disopyramide.

The second type of injury is a cholestatic hepatitis that arises after 1 to 3 weeks of therapy and is characterized by jaundice and pruritus, with prominent elevations in serum alkaline phosphatase and mild-to-moderate increases in serum aminotransferase levels (Case 1). This injury may be prolonged, but reported cases have been self limited. Immunoallergic and autoimmune features are rare.

Likelihood score: B (rare but likely cause of clinically apparent liver injury).

Mechanism of Injury

The mechanism by which disopyramide causes liver injury is not clear but the early, acute hepatocellular injury is probably caused by ischemia due to sudden worsening of heart failure. The more delayed cholestatic hepatitis attributed to disopyramide is an idiosyncratic reaction and may relate to hypersensitivity to a product of its metabolism by the cytochrome P450 system (CYP 3A4).

Outcome and Management

The hepatic injury caused by disopyramide ranges from asymptomatic and transient serum enzyme elevations, to acute hepatic necrosis to cholestatic hepatitis. Disopyramide has not been linked to cases of acute liver failure, chronic hepatitis or vanishing bile duct syndrome. Following the cholestatic, idiosyncratic hepatic injury due to disopyramide, recurrence with reexposure is typical and should be avoided. Withdrawal of disopyramide therapy may be associated with relapse in the arrhythmia for which it is used and is often done in the hospital under careful monitoring. There is no evidence that there is cross sensitivity to hepatic injury between disopyramide and other oral antiarrhythmic agents.

Drug Class: Antiarrhythmic Agents


Case 1. Mild cholestatic hepatitis due to disopyramide.

[Modified from: Edmonds ME, Hayler AM. A case of intra-hepatic cholestasis after disopyramide therapy. Eur J Clin Pharmacol 1980; 18: 285-6. PubMed Citation]

A 74 year old woman developed jaundice 13 days after starting disopyramide (100 mg daily) for difficult-to-control atrial fibrillation. She gave no history of liver disease, alcohol abuse or risk factors for viral hepatitis. However, she had a complex medical history which included chronic obstructive pulmonary disease, right heart failure, gout and diverticulitis. Six weeks before the onset of jaundice, she had undergone an emergency colostomy for large bowel obstruction after perforation of a sigmoid diverticulum. The surgery was carried out under general anesthesia with thiopentone, fentanyl and nitrous oxide. Postoperatively, she received several antibiotics including ampicillin, metronidazole and cefuroxime. The medications that she took chronically were digoxin (0.125 mg), furosemide (240 mg), prednisolone (3 mg/day), and allopurinol (300 mg/day). On examination, she was jaundiced but had no fever, rash or clinical evidence of heart failure. Laboratory tests showed a serum bilirubin of 2.2 mg/dL, AST 30 U/L, alkaline phosphatase 840 U/L and GGT 840 U/L (normal 4-18 U/L). These tests had been normal earlier during her prolonged hospital admission (Table). Tests for hepatitis B and serum autoantibodies were negative. Plasma levels of disopyramide had been in the normal therapeutic range. Disopyramide and the antibiotics were discontinued. Her serum bilirubin improved over the next week, but alkaline phosphatase levels rose to above 2000 U/L and then began to fall slowly. Six weeks after stopping disopyramide, all liver tests were normal.

Key Points

Medication:Disopyramide (100 mg daily)
Pattern:Cholestatic (R=0.2)
Severity:3+ (jaundice, hospitalization)
Latency:2 weeks
Recovery:6 weeks
Other medications:Ampicillin, metronidazole, cefuroxime, allopurinol, furosemide, digoxin, prednisolone, diazepam

Laboratory Values

Time After StartingTime After StoppingAST (U/L)Alk P* (U/L)Bilirubin* (mg/dL)Comment
1.5 weeks2501.3
2 weeks0308402.2Disopyramide stopped
3 weeks1 week20001.3
4 weeks2 weeks9001.0
5 weeks3 weeks2500.8
8 weeks6 weeks801.0
Normal Values <20 <100 <1.2

* Values estimated from Figure 1.


Despite the complexity of the medical history and exposure to multiple medications, the mild cholestatic hepatitis was entirely compatible with disopyramide induced liver injury which typically arises within 1-3 weeks of starting the medication and is characterized by a mild cholestatic course. Most of the other medications (except for ampicillin and metronidazole) were continued or restarted without recurrence of jaundice or liver test abnormalities.



Disopyramide – Generic, Norpace®


Antiarrhythmic Agents


Product labeling at DailyMed, National Library of Medicine, NIH


Disopyramide 3737-09-5 C21-H29-N3-O
Chemical Structure for Disopyramide


References updated: 04 January 2018

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    (Expert review of hepatotoxicity published in 1999 mentions that disopyramide has been linked to at least 10 cases of drug-induced liver disease).
  • De Marzio DH, Navarro VJ. Hepatotoxicity of cardiovascular and antidiabetic drugs. In, Kaplowitz N, DeLeve LD, eds. Drug-induced liver disease. 3rd ed. Amsterdam: Elsevier, 2013, pp. 524.
    (Review of hepatotoxicity of cadriovascular drugs including antiarrhythmics; disopyramide is not discussed).
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    (38 year old woman with recurrent atrial fibrillation developed nausea within 3 days of starting disopyramide followed by jaundice [bilirubin 5.7 mg/dL, ALT 242 U/L, Alk P 1381 U/L], resolving several months later).
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    (74 year old male with ventricular arrhythmia developed abnormal liver enzymes 3 days after starting disopyramide [ALT 6200 U/L, Alk P 125 U/L, bilirubin 4.0 mg/dL, INR 2.6], resolving in 2 weeks).
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    (2 men and 1 woman, ages 60-79 years, developed cholestatic hepatitis 10 to 15 days after starting disopyramide [bilirubin 0.9, 14.6 and 16.9 mg/dL, ALT peak 65-120 U/L, Alk P 280-300 U/L], all resolving, but two had jaundice that lasted 4 and 7 months).
  • Edmonds ME, Hayler AM. A case of intra-hepatic cholestasis after disopyramide therapy. Eur J Clin Pharmacol 1980; 18: 285-6. [PubMed: 7439249]
    (74 year old woman developed jaundice 13 days after starting disopyramide [bilirubin 2.3 mg/dL, Alk P 840 rising to 2000 U/L, AST 30 U/L], resolving 6 weeks after stopping: Case 1).
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    (2 men, ages 61 and 62 years, developed heart failure and raised serum enzymes within 1-2 days of starting disopyramide [AST 4780 and 1495 U/L, bilirubin peak 2.1 mg/dL, Alk P normal], resolving within 7-8 days).
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    (Ten patients with ventricular arrhythmias were treated with disopyramide vs propafenone vs placebo in a crossover study for 6 days each; no change in chemical parameters).
  • Jonason T, Ringqvist I, Bandh S, Nilsson G, Nilsson H, Lidell C, Bjerle P, et al. Propafenone versus disopyramide for treatment of chronic symptomatic ventricular arrhythmias. A multicenter study. Acta Med Scand 1988; 223: 515-23. [PubMed: 3291557]
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    (Concise review of drugs for arrhythmias; disopyramide can aggravate heart failure and anticholinergic effects are often prominent; no mention of adverse effects on the liver).
  • Chalasani N, Fontana RJ, Bonkovsky HL, Watkins PB, Davern T, Serrano J, Yang H, Rochon J; Drug Induced Liver Injury Network (DILIN). Causes, clinical features, and outcomes from a prospective study of drug-induced liver injury in the United States. Gastroenterology 2008; 135: 1924-34. [PMC free article: PMC3654244] [PubMed: 18955056]
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  • Chalasani N, Bonkovsky HL, Fontana R, Lee W, Stolz A, Talwalkar J, Reddy KR, et al.; United States Drug Induced Liver Injury Network. Features and outcomes of 899 patients with drug-induced liver injury: The DILIN Prospective Study. Gastroenterology 2015; 148: 1340-52.e7. [PMC free article: PMC4446235] [PubMed: 25754159]
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