What is the role of spironolactone in the treatment of ascites?

Spironolactone in Ascites

Spironolactone is the first-line drug of choice for treating ascites due to cirrhosis, starting at 100 mg daily and titrating up to 400 mg daily as monotherapy for first-episode moderate ascites, or in combination with furosemide (maintaining a 100:40 mg ratio) for recurrent or severe ascites. 1, 2

Mechanism and Rationale

Spironolactone functions as an aldosterone antagonist acting on the distal renal tubules to increase sodium excretion while conserving potassium 1, 3. In cirrhotic ascites, spironolactone is superior to loop diuretics like furosemide when used alone because hyperaldosteronism drives the pathophysiology of sodium retention in these patients 1, 4. Controlled studies demonstrate that spironolactone achieves better natriuresis and diuresis than furosemide monotherapy in cirrhosis 1.

Dosing Strategy

First Episode of Moderate Ascites

• Start with spironolactone monotherapy at 100 mg daily 1, 2
• Increase in 100 mg increments every 3-5 days (due to the drug's long half-life and delayed onset of action) up to a maximum of 400 mg daily 1, 2
• This approach generates adequate response with fewer side effects and requires less dose adjustment, making it ideal for outpatient management 2, 5

Recurrent or Severe Ascites

• Begin with combination therapy: spironolactone 100 mg plus furosemide 40 mg daily 1, 2
• Maintain the 100:40 mg ratio when titrating to preserve normokalemia 1, 2
• Maximum doses: spironolactone 400 mg and furosemide 160 mg daily 1
• Combination therapy shortens time to ascites mobilization and is preferred for hospitalized patients requiring rapid diuresis 1, 2

Tense Ascites

• Perform large-volume paracentesis first with albumin infusion (8 g per liter removed), then initiate maintenance diuretic therapy 2, 4
• Paracentesis is faster and more effective than diuretics alone for tense ascites 2, 4

Monitoring Requirements

Check serum electrolytes, creatinine, and body weight within 3-5 days of initiation and weekly during dose titration 2. Critical thresholds requiring intervention:

• Stop diuretics if serum sodium drops below 120-125 mmol/L 1, 2
• Discontinue or reduce dose if serum creatinine increases >0.3 mg/dL or reaches >150 mmol/L 1, 2
• Hold or adjust if serum potassium >6 mmol/L or <3 mmol/L 2
• Target weight loss: 0.5 kg/day without peripheral edema, or up to 1 kg/day with peripheral edema 2

Over-diuresis causes intravascular volume depletion (25%), renal impairment, hepatic encephalopathy (26%), and hyponatremia (28%) 1.

Common Pitfalls and Management

Hyperkalemia

Hyperkalemia is a significant complication that frequently limits spironolactone use 1. Temporarily withhold furosemide in patients with hypokalemia (common in alcoholic hepatitis), and reduce spironolactone dose in patients with parenchymal renal disease 1.

Antiandrogenic Side Effects

Spironolactone causes decreased libido, impotence, and gynecomastia in men, and menstrual irregularity in women 1. If painful gynecomastia develops, switch to amiloride 10-40 mg daily or eplerenone 2. Tamoxifen 20 mg twice daily can manage established gynecomastia 1.

Hyponatremia Management

• For hypovolemic hyponatremia during diuretic therapy, discontinue diuretics and expand plasma volume with normal saline 1, 2
• Fluid restriction to 1-1.5 L/day should only be used for hypervolemic patients with severe hyponatremia (sodium <125 mmol/L) 1, 2
• Water restriction is inappropriate for euvolemic patients currently taking diuretics 1

Delayed Onset of Action

There is a 3-5 day lag between starting spironolactone and onset of natriuretic effect 1. Do not increase doses more frequently than every 72 hours 2.

Refractory Ascites Definition

Ascites is only considered refractory after intensive therapy with spironolactone 400 mg/day plus furosemide 160 mg/day for at least 1 week on salt restriction <5 g/day, with mean weight loss <800 g over 4 days 2. Approximately 10% of patients develop refractory ascites 1.

Before declaring refractoriness, verify:

• Patient compliance with sodium restriction (measure urinary sodium excretion) 1
• Absence of NSAIDs or other sodium-retaining drugs 1
• Adequate dietary sodium restriction (no more than 5-6.5 g or 87-113 mmol daily) 1

Drug Interactions

Avoid concomitant use with potassium supplements, salt substitutes, ACE inhibitors, ARBs, NSAIDs, or heparin due to severe hyperkalemia risk 3. NSAIDs can reduce the natriuretic effect of spironolactone 3. Spironolactone reduces renal clearance of lithium, inducing high risk of lithium toxicity 3.

Pharmacokinetic Considerations

Food increases spironolactone bioavailability by approximately 95%, so patients should establish a consistent pattern of taking spironolactone with or without meals 3. The terminal half-life is increased in patients with cirrhotic ascites 3. Spironolactone is >90% protein-bound with a mean half-life of 1.4 hours, but active metabolites (canrenone, TMS, HTMS) have half-lives of 13.8-16.5 hours 3.