What is the appropriate use and dosing of spironolactone (aldosterone antagonist) in patients with chronic liver disease?

Spironolactone in Chronic Liver Disease

Spironolactone is the first-line diuretic for ascites in cirrhosis, starting at 100 mg/day and titrating up to 400 mg/day as monotherapy for first-presentation ascites, with furosemide added only if spironolactone alone fails. 1

Initial Approach for First-Presentation Ascites

Start with spironolactone monotherapy:

• Begin at 100 mg/day as a single morning dose 1
• Increase every 3-5 days up to maximum 400 mg/day if response inadequate 1, 2
• Combine with sodium restriction to 5-6.5 grams/day 1
• Target weight loss: 0.5 kg/day without peripheral edema, or 1 kg/day with edema 1

Add furosemide only after spironolactone reaches 400 mg/day without adequate response:

• Start furosemide at 40 mg/day 1
• Increase to maximum 160 mg/day 1
• Maintain the 100:40 ratio (spironolactone:furosemide) when escalating doses 2

This sequential approach is supported by evidence showing spironolactone is more effective than loop diuretics alone in cirrhosis due to hyperaldosteronism, with one study demonstrating 95% response rate to spironolactone versus 52% to furosemide in nonazotemic cirrhotic patients 3.

Recurrent or Severe Ascites

For recurrent moderate-to-severe ascites, start combination therapy immediately:

• Spironolactone 100 mg + furosemide 40 mg daily 1
• Increase both simultaneously maintaining 100:40 ratio up to 400 mg/160 mg 1, 2
• This approach provides faster ascites resolution (76% vs 56% without dose changes) and lower treatment failure rates (24% vs 44%) compared to sequential therapy 1

Critical Monitoring Requirements

Check electrolytes and renal function at specific intervals:

• At 3 days, 1 week, then monthly for first 3 months 2
• Monitor spot urine sodium:potassium ratio (target 1.8-2.5 predicts adequate natriuresis >78 mmol/day) 1

Temporarily discontinue diuretics if:

• Sodium <125 mmol/L 1
• Potassium >5.5 mmol/L (hyperkalemia) 1, 2
• Creatinine rises significantly (>2.5 mg/dL warrants dose reduction) 2
• Hepatic encephalopathy worsens 1
• Severe muscle cramps develop 1

Absolute Contraindications

Do not use spironolactone when:

• Creatinine clearance <30 mL/min 2
• Baseline potassium >5.0 mEq/L 2
• Concurrent NSAIDs or COX-2 inhibitors 2
• Active acute kidney injury 4

The FDA label specifically warns that spironolactone can cause sudden fluid and electrolyte alterations precipitating hepatic encephalopathy and coma in cirrhotic patients, requiring hospital initiation in those with cirrhosis and ascites 5.

Why Spironolactone is Superior in Cirrhosis

Pathophysiologic rationale:

• Cirrhotic ascites results from secondary hyperaldosteronism with elevated renin-aldosterone activity 3
• Patients with higher aldosterone levels specifically fail furosemide but respond to spironolactone 300 mg/day 3
• Loop diuretics alone are not recommended as monotherapy in cirrhotic ascites 2
• The antiandrogenic effects (gynecomastia, decreased libido, erectile dysfunction in men; menstrual irregularities in women) are dose-dependent side effects to counsel patients about 4

Refractory Ascites Management

If ascites persists despite maximum doses (spironolactone 400 mg + furosemide 160 mg):

• Verify compliance by checking 24-hour urinary sodium excretion 1
• Exclude sodium-containing medications or NSAIDs 1
• Proceed to large-volume paracentesis with albumin replacement (8 g per liter removed) 1, 2
• Reinstitute diuretics 1-2 days post-paracentesis to prevent recurrence (reduces recurrence from 93% to 18%) 1, 2

Dose Reduction After Ascites Resolution

When ascites resolves:

• Reduce to lowest effective dose to prevent recurrence 1
• Taper furosemide first while maintaining spironolactone 2
• Monitor weight daily (should not lose >0.5 kg/day without edema) 2
• Check electrolytes weekly for first month during tapering 2

Common pitfall: The 2021 Gut guidelines note that maximal diuretic doses (400 mg/160 mg) are often not achieved in clinical practice, but inadequate dosing leads to treatment failure 1. Conversely, overzealous diuresis causes hypovolemic hyponatremia requiring normal saline and diuretic cessation 1.