What are the indications, recommended dosing and titration, monitoring requirements, contraindications, adverse effects, and alternative agents for spironolactone?

Spironolactone: Clinical Overview

Primary Indications

Spironolactone is indicated for heart failure with reduced ejection fraction (NYHA class III-IV), resistant hypertension, edema from cirrhosis, primary hyperaldosteronism, and hormonal acne in women. 1, 2

Heart Failure with Reduced Ejection Fraction

• Recommended for patients with LVEF ≤35-40% and moderate to severe symptoms (NYHA III-IV) on optimal therapy with ACE inhibitor/ARB and beta-blocker to reduce mortality and hospitalizations. 1
• The RALES trial demonstrated a 30% reduction in mortality when spironolactone 12.5-50 mg was added to ACE inhibitors and loop diuretics in advanced heart failure. 1, 3
• Both progressive heart failure death and sudden cardiac death were reduced. 1

Resistant Hypertension

• Effective at doses of 25-50 mg daily, particularly in low-renin and salt-sensitive hypertension. 4
• For essential hypertension, initial dosing is 25-100 mg daily, titrated at two-week intervals; doses >100 mg/day generally provide no additional blood pressure reduction. 2

Other Indications

• Edema in cirrhosis: 100 mg daily (range 25-200 mg), initiated in hospital setting with slow titration. 2
• Primary hyperaldosteronism: 100-400 mg daily for surgical preparation or long-term maintenance. 2
• Hormonal acne in women: 50-200 mg daily, typically combined with oral contraceptives to minimize menstrual irregularities. 5

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Dosing and Titration

Heart Failure Initiation Protocol

Start with 25 mg once daily in patients with serum potassium ≤5.0 mEq/L and eGFR >50 mL/min/1.73 m². 1, 2

• Check renal function and electrolytes at baseline, then at 1 week and 4 weeks after initiation. 1
• After 4-8 weeks, if tolerated, increase to target dose of 50 mg once daily. 1
• For eGFR 30-50 mL/min/1.73 m², consider initiating at 25 mg every other day due to hyperkalemia risk. 2
• If hyperkalemia develops on 25 mg daily, reduce to 25 mg every other day. 1, 2

Ongoing Monitoring Schedule

• Recheck electrolytes and renal function at 1,2,3, and 6 months after achieving maintenance dose, then every 6 months thereafter. 1
• More frequent monitoring needed when combined with other drugs causing hyperkalemia or in patients with impaired renal function. 2

Dose Adjustments for Adverse Effects

• If potassium rises to >5.5 mmol/L: Halve the dose (e.g., 25 mg on alternate days) and monitor closely. 1
• If potassium rises to ≥6.0 mmol/L: Stop spironolactone immediately and treat hyperkalemia. 1
• If creatinine rises to >220 μmol/L (2.5 mg/dL): Halve the dose and monitor closely. 1
• If creatinine rises to >310 μmol/L (3.5 mg/dL): Stop spironolactone immediately. 1

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Contraindications

Absolute contraindications include: 5, 2

• Pregnancy (Category C - risk of feminization of male fetuses) 5
• Hyperkalemia 5, 2
• Anuria 5
• Acute renal failure 5
• Significant renal impairment 5
• Addison's disease 5
• Concomitant use with eplerenone or triamterene 5

Avoid the routine triple combination of ACE inhibitor + ARB + aldosterone antagonist due to excessive hyperkalemia risk. 1

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Adverse Effects

Hyperkalemia (Most Serious)

• The most critical adverse effect, particularly when combined with ACE inhibitors/ARBs or in patients with renal impairment. 2
• Real-world incidence can be as high as 24% (compared to 2% in clinical trials), with half having potassium >6 mEq/L. 1
• A population-based study showed hospitalization for hyperkalemia increased from 2.4 to 11 per 1000 patients after widespread spironolactone adoption. 1
• Stop potassium supplementation when initiating spironolactone and counsel patients to avoid high-potassium foods and NSAIDs. 1

Hormonal Side Effects

• Gynecomastia occurs in approximately 9-10% of men at doses of 25-26 mg daily, increasing to 52.2% at ≥150 mg/day (compared to 6.9% at 50 mg/day). 1, 6, 2
• Onset varies from 1-2 months to over a year; usually reversible upon discontinuation. 2
• Decreased libido is frequent, particularly in men, due to potent anti-androgenic effects (inhibition of testosterone and DHT binding to androgen receptors). 6
• In women: menstrual irregularities (15-30%, dose-dependent), breast tenderness (3-5%). 5

Other Common Side Effects

• Dizziness (3-4%), nausea (2-4%), headache (2%), polyuria and fatigue (1-2%). 5
• Hyponatremia, hypomagnesemia, hypocalcemia, hypochloremic alkalosis, hyperglycemia, and asymptomatic hyperuricemia. 2

Hypotension and Renal Dysfunction

• Excessive diuresis can cause symptomatic dehydration, hypotension, and worsening renal function, especially in salt-depleted patients or those on ACE inhibitors/ARBs. 2
• Monitor volume status and renal function periodically. 2

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Alternative Agents

Eplerenone

Eplerenone is a more selective mineralocorticoid receptor antagonist with reduced affinity for androgen and progesterone receptors, resulting in significantly fewer sexual side effects and gynecomastia. 1, 6, 7

• Dosing: Start 25 mg once daily, titrate to target of 50 mg once daily within 4 weeks. 7
• Demonstrated 15% reduction in mortality in post-MI heart failure patients. 1
• Hyperkalemia risk is similar to spironolactone; same monitoring requirements apply. 7
• Less potent than spironolactone but much better tolerated. 7
• Primary indication for eplerenone is in men with breast discomfort/enlargement caused by spironolactone. 1

Potassium Canrenoate

• May reduce gynecomastia and sexual side effects compared to spironolactone. 6
• Less commonly used in clinical practice. 3

Other Potassium-Sparing Diuretics

• Amiloride or triamterene are generally prescribed as fixed-dose combinations with hydrochlorothiazide for essential hypertension. 4
• Do not have the aldosterone-blocking benefits for heart failure mortality reduction. 4

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Key Clinical Pitfalls and Cautions

Real-World vs. Trial Populations

Clinical trial populations are highly selected; toxicity increases dramatically when applied to general populations. 1

• The Ontario population study showed a tripling of spironolactone prescriptions led to a nearly 5-fold increase in hyperkalemia hospitalizations and a 7-fold increase in associated mortality. 1

High-Risk Situations for Hyperkalemia

• Elderly patients, those with diabetes, hypertension, chronic kidney disease, or on medications affecting renal/adrenal/hepatic function require more intensive monitoring. 5
• Volume depletion from gastroenteritis or other causes can precipitate hyperkalemia during chronic therapy. 1
• Avoid NSAIDs and COX-2 inhibitors, which worsen renal function and increase hyperkalemia risk. 1

Combining with Thiazide Diuretics

In resistant hypertension, combining spironolactone with adequate doses of thiazide or thiazide-like agents (e.g., chlorthalidone) maximizes efficacy and reduces hyperkalemia risk. 4

Special Populations

• Women of childbearing age: Must use effective contraception; spironolactone is pregnancy category C. 5
• For acne treatment in women: Combine with oral contraceptives (including drospirenone-containing COCs) to minimize menstrual irregularities without increasing hyperkalemia risk. 5
• Cirrhosis patients: Initiate therapy in hospital setting with slow titration. 2

Potassium Supplementation

• Generally discontinued after starting spironolactone. 1
• Exception: Patients with previous ventricular arrhythmias from hypokalemia may need continued supplementation at lower doses. 1
• Supplementation required during aggressive diuresis is often unnecessary once maintenance fluid balance is achieved. 1

Dosing for Minimizing Side Effects

Start with the lowest effective dose; for acne, 75-100 mg daily is as effective as 150-300 mg daily but with substantially fewer sexual side effects. 6, 5