Spironolactone

Potassium-sparing diuretics, aldosterone antagonists

ATC code: C03DA01 (Spironolactone)

Mechanism of action

Competitive mineralocorticoid receptor antagonist. Blocks aldosterone action on renal collecting tubules, reducing sodium reabsorption and potassium retention. Beyond its diuretic effect, it has antiandrogenic activity – blocks androgen receptors and suppresses testosterone synthesis. This antiandrogenic effect accounts for some adverse reactions as well as additional indications.

Indications

Heart failure

First line

Spironolactone 25-50 mg daily is a cornerstone of HFrEF therapy. The RALES trial showed a 30% mortality reduction when spironolactone was added to standard treatment (ACEi + loop diuretic). Prescribed when potassium is below 5.0 mmol/L and eGFR above 30. Monitor potassium and creatinine one week after initiation and with each dose change.

HFrEF (LVEF 35% or below), NYHA class II-IV.

Primary aldosteronism

First line

Spironolactone is the drug of choice for primary aldosteronism when surgery is not feasible or the patient declines operation. Doses are typically higher than in HF – 100-400 mg daily. In bilateral adrenal hyperplasia, medical therapy with spironolactone is the primary treatment.

Resistant arterial hypertension

First line

First-line fourth agent for resistant hypertension. The PATHWAY-2 trial (Lancet 2015, 335 patients) demonstrated spironolactone 25–50 mg daily reduced home SBP by 8.7 mmHg more than placebo and significantly outperformed both doxazosin and bisoprolol. Subsequent meta-analyses replicated the effect. ESC/ESH 2024 lists spironolactone as a class I recommendation, level of evidence A. NICE NG136 and AHA/ACC 2017 support the same position.

Target population – patients on maximally tolerated triple therapy (ACEi/ARB + CCB + diuretic) with BP above target. Spironolactone is used as the fourth agent.

Hypertension

Adjunct

In the general hypertensive population, spironolactone is not a first-line agent. Therapy is built on ACEi/ARB, calcium channel blockers, and thiazide-like diuretics. Spironolactone is considered as the fourth agent in resistant forms (see separate indication) and as the therapy of choice in primary aldosteronism.

In the general hypertensive population, spironolactone is not a first-line agent. Its place is in resistant forms and in primary aldosteronism.

Practical notes

Monitoring

Check potassium and creatinine 3-7 days after initiation, then at 1 month, then every 3 months. If potassium rises above 5.5 mmol/L, reduce dose or discontinue. Hyperkalemia risk is increased with concurrent ACEi/ARB, potassium supplements, and in patients with reduced eGFR. Do not combine with other potassium-sparing diuretics.

Special situations

In men, doses above 50 mg daily frequently cause gynecomastia and breast tenderness – a dose-dependent antiandrogenic effect. In women, menstrual irregularities may occur. If side effects are significant, consider switching to eplerenone – it is more selective for mineralocorticoid receptors, lacks antiandrogenic activity, but costs more.

Safety

Contraindications

Hyperkalemia (potassium above 5.0 mmol/L)
Severe renal impairment (eGFR below 30)
Addison's disease
Concurrent use with eplerenone
Pregnancy

Serious adverse effects

Severe hyperkalemia with cardiac arrhythmias
Hyponatremia
Acute renal failure (with hypovolemia or in combination with nephrotoxic agents)

Common adverse effects

Hyperkalemia
Gynecomastia, breast tenderness in men
Menstrual irregularities in women
Nausea, diarrhea
Dizziness

PregnancyFDA D

FDA category D. Antiandrogenic action may impair sexual differentiation of a male fetus. Contraindicated in pregnancy.

Breastfeeding

Active metabolite canrenone is excreted in breast milk. Not recommended during breastfeeding.