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DRUG RECORD

 

SPIRONOLACTONE

OVERVIEW
Spironolactone

 

 

 

Introduction

 

Spironolactone is an aldosterone receptor antagonist and potassium-sparing diuretic widely used in the therapy of edema particularly in patients with cirrhosis in which hyperaldosteronism appears to play a major role. Spironolactone has been linked to rare cases of clinically apparent drug-induced liver disease.

 

Background

 

Spironolactone (spir on oh lak' tone) is a competitive inhibitor of the mineralocorticoid receptor in the late distal tubule and collecting duct of the kidneys which causes a decrease in sodium reabsorption and potassium excretion in the distal tubule. As a result, spironolactone promotes a sodium diuresis but maintains body potassium levels. Spironolactone is particularly helpful in edematous states caused or exacerbated by hyperaldosteronism, which is typical of the edema and ascites caused by cirrhosis. Because of its potassium-sparing actions, spironolactone is also used in combination with thiazide or loop diuretics in an attempt to prevent hypokalemia. Chronic low dose therapy with spironolactone has also been reported to improve survival in patients with heart failure after myocardial infarction. Spironolactone was approved for use in the United States in 1960 and continues to be widely used. Spironolactone is available in 25, 50, 75 and 100 mg tablets generically and under the brand name of Aldactone. Fixed combinations of spironolactone and hydrochlorothiazide are also available under the brand name Aldactizide. The typical dose of spironolactone is 25 mg one to three times daily initially with modification of the dose based upon clinical efficacy and tolerance to maintenance doses of 75 to 450 mg daily. The major side effects of spironolactone are due to its anti-androgen-like effects and include hair growth and gynecomastia.

 

Hepatotoxicity

 

Clinically apparent liver injury from spironolactone is rare and only a few instances have been reported as isolated case reports. The liver injury typically arises after 4 to 8 weeks of therapy and the pattern of serum enzyme elevations is usually hepatocellular or mixed. Immunoallergic features (rash, fever, eosinophilia) are rare as is autoantibody formation. Recovery has occurred within 1-3 months of stopping and all cases have been mild and self-limited in course (Case 1).

 

Mechanism of Injury

 

The mechanism of spironolactone hepatic injury is unknown but is most likely due to a metabolic idiosyncrasy.

 

Outcome and Management

 

Reported cases of liver injury due to spironolactone have been mild with either no or minimal jaundice and recovery within a few months of stopping the medication. Recurrence on rechallenge has been reported but there is no information or cross-reactivity to the hepatic injury with other diuretics. Because eplerenone has a similar chemical structure, it is likely to cause a similar hepatic injury.

[References are provided in the overview on Diuretics.]

 

Drug Class:Diuretics:Potassium-Sparing Diuretics

 

Other drugs within this class:

 

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CASE REPORT
Spironolactone

 

 

Case 1. Spironolactone induced liver injury.
[Modified from: Shuck J, Shan S, Owensky L, Leftik M, Cucinell S. Spironolactone hepatitis in primary hyperaldosteronism. Ann Intern Med 1981; 95: 708-10. PubMed Citation]

 

A 53 year old woman with primary hyperaldosteronism due to an adrenal adenoma was found to have serum enzyme elevations (ALT 430 U/L, AST 130 U/L, Alk P 225 U/L) without symptoms 1 month after starting spironolactone (100 mg three times daily). Spironolactone was stopped and serum enzymes fell into the normal range within the next two months. One year later spironolactone was restarted (100 mg twice daily) and serum enzymes were again found to be abnormal one month later. She was not taking other medications and tests for hepatitis B and for autoantibodies were negative. There was no rash, fever or eosinophilia. A liver biopsy showed mild spotty hepatitis. Upon withdrawal of spironolactone, serum enzymes fell to normal within 6 weeks.

 

Key Points

 

Medication:Spironolactone (100 mg 2-3 times daily)
Pattern: Hepatocellular (R=6.7)
Severity:Mild (Enzyme elevations without symptoms or jaundice)
Latency: 4 Weeks
Recovery: 6-8 Weeks
Other medications:None

 

Laboratory Values

Time After Starting Time After Stopping ALT (U/L) Alk P (U/L) GGT  (U/L) Other
Pre Pre 15 80 10
Spironolactone (100 mg three times daily) given for 1 month
4 weeks 0 430 185 90
6 weeks 2 weeks 255 225 140
8 weeks 4 weeks 70 150 80
12 weeks 8 weeks 35 105 20
24 weeks 20 weeks 30 90
1 year 1 year 25 85 20
Spironolactone (100 mg two times daily) restarted for 1 month
4 weeks 0 140 145 45
6 weeks 2 weeks 125  
10 weeks 6 weeks 20 80 30
Normal Values <40 <110 < 40

 

 

Comment

 

This patient developed elevations in serum aminotransferases and alkaline phosphatase within a month of starting spironolactone. She was evidently asymptomatic and anicteric and the liver injury resolved rapidly upon withdrawal. The rare instances of hepatic injury reported with spironolactone use have been mild and self-limited. The recurrence of injury with the same latency and severity without immunoallergic features suggests metabolic idiosyncrasy as the cause of the hepatotoxicity.

 

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PRODUCT INFORMATION
Spironolactone

 

REPRESENTATIVE TRADE NAMES
Generic, Aldactone®

 

DRUG CLASS
Diuretics

 

COMPLETE LABELING

FDA product labeling at DailyMed, National Library of Medicine, NIH

 

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DRUG CAS REGISTRY NUMBER MOLECULAR FORMULA STRUCTURE
Spironolactone 52-01-7 C24-H32-O4-S Image of Chemical Structure

 

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OTHER REFERENCE LINKS
Spironolactone

 

 

  1. PubMed logoRecent References on Spironolactone

  2. Clinical Trials logoTrials on Spironolactone

  3. TOXLINE logoTOXLINE Citations on Spironolactone

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