Potassium-sparing diuretics (mineralocorticoid receptor antagonists)
ATC code: C03DA01 (Spironolactone)
Competitive aldosterone antagonist at the distal nephron – reduces sodium reabsorption and potassium secretion. Produces potassium-sparing diuresis, modest BP lowering, and reduces cardiovascular mortality in HFrEF and resistant hypertension. Has antiandrogen activity (gynecomastia in men). Active metabolites canrenone and 7α-thiomethylspironolactone provide a long duration of action.
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.
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.
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. 2024 lists spironolactone as a class I recommendation, level of evidence A. NG136 and / 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.
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.
Spironolactone is a potassium-sparing diuretic. Supplemental potassium or potassium-containing salt substitutes sharply raise hyperkalemia risk, especially in CKD. Monitor plasma K regularly; limit potassium-containing supplements.
Source: ESC: 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure (2021)
6 pairs found. Sorted from critical to minor.
Mechanism
Same as the ACE-inhibitor/spironolactone pair: the ARB blocks AT1 receptors and lowers aldosterone synthesis, while spironolactone blocks the mineralocorticoid receptor. Dual potassium-sparing action causes hyperkalemia, especially in older patients with CKD or diabetes.
Management
Justified in HFrEF ( 2024 guidelines). Start spironolactone at 12.5–25 mg. Monitor potassium and creatinine on the same schedule as for ACE inhibitors. If K+ exceeds 5.5 mmol/L, reduce the dose or discontinue.
Sources
Mechanism
Aspirin's NSAID effect reduces prostaglandin-dependent renal perfusion and blunts the diuretic and natriuretic action of spironolactone. Antiplatelet doses of 75–100 mg barely affect renal prostaglandin synthesis. Analgesic and antipyretic doses of 500–1000 mg and above suppress renal prostaglandin synthesis systemically – similar to ibuprofen and naproxen. HF patients may decompensate. Additionally, additive GI bleeding risk (synergistic gastrotoxicity from COX inhibition plus the erosive action of aspirin).
Management
In HF, low antiplatelet aspirin doses of 75–100 mg are acceptable – clinically meaningful diuretic blunting is unlikely. Analgesic and antipyretic doses of 500–1000 mg and above are contraindicated in HF NYHA II–IV and/or eGFR below 60 mL/min ( 2016 and HF 2024 guidelines) – replace with paracetamol. For worsening edema or a 2 kg or greater weight gain over 3 days, check creatinine and seek medical review.
Mechanism
Dual blockade of the renin-angiotensin-aldosterone system. Enalapril reduces aldosterone synthesis while spironolactone blocks the aldosterone receptor – synergistic potassium retention. Risk of severe hyperkalemia (above 6.0 mmol/L) with arrhythmias, particularly in patients over 75, with CKD (eGFR below 45 mL/min), diabetes, or dehydration.
Management
The combination is indicated in HFrEF with LVEF below 35 % (mortality benefit – RALES, EMPHASIS-HF) but requires strict monitoring. Start spironolactone at 12.5–25 mg. Check potassium and creatinine on day 3–5, at 1, 2, 4 weeks, then monthly. If K+ exceeds 5.5 mmol/L, reduce the dose or stop spironolactone. Do not combine with potassium supplements or potassium-containing salt substitutes.
Sources
Mechanism
Spironolactone moderately inhibits P-glycoprotein – digoxin concentration rises by 20–30 %. In addition, spironolactone interferes with immunoassay measurements of digoxin (falsely elevated values).
Management
Check digoxin concentration 2–3 weeks after starting spironolactone, guided by clinical status rather than the level alone. The target in HF is 0.5–0.9 ng/mL. Reduce the digoxin dose by 25 % if needed.
Sources
Mechanism
Opposing effects on potassium: furosemide depletes potassium, spironolactone retains it. A target combination in HF and resistant hypertension. The potassium balance depends on the dose ratio and renal function – in CKD and diabetes, spironolactone dominates and hyperkalemia risk rises.
Management
Check potassium and creatinine 3–7 days after initiation or dose change, then every 1–3 months. Target potassium is 4.0–5.0 mmol/L. If K+ > 5.5 mmol/L, reduce the spironolactone dose.
Sources
Mechanism
Opposing effects on potassium: thiazide depletes, spironolactone retains. The combination is used in resistant hypertension and ascites. In CKD or diabetes, spironolactone dominates – with hyperkalemia risk.
Management
Check potassium, sodium, and creatinine at 7–14 days after initiation, then every 1–3 months. Target potassium is 4.0–5.0 mmol/L. For hyponatremia (Na+ < 130 mmol/L), reassess therapy.
Sources
FDA category D. Antiandrogenic action may impair sexual differentiation of a male fetus. Contraindicated in pregnancy.
Active metabolite canrenone is excreted in breast milk. Not recommended during breastfeeding.
spironolactone is evaluated for the following indications with varying evidence strength: Primary aldosteronism (evidence tier A), Resistant arterial hypertension (evidence tier A), Heart failure (evidence tier A). See the full indication matrix with dosing and citations above on this page.
Common side effects of spironolactone (≥ 1 in 100): Hyperkalemia, Gynecomastia, breast tenderness in men, Menstrual irregularities in women, Nausea, diarrhea, Dizziness. See the Safety section for uncommon and serious reactions.
FDA category D. FDA category D. Antiandrogenic action may impair sexual differentiation of a male fetus. Contraindicated in pregnancy.
Active metabolite canrenone is excreted in breast milk. Not recommended during breastfeeding.
spironolactone is contraindicated in: Hyperkalemia (potassium above 5.0 mmol/L); Severe renal impairment (eGFR below 30); Addison's disease; Concurrent use with eplerenone; Pregnancy. Full list in the Safety section.