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.
The drug is promoted for these uses outside international guidelines. Each entry below is analyzed against AEMPS, FDA, EMA, Cochrane and major RCTs.
Not recommended
Spironolactone is a potassium-sparing diuretic and aldosterone antagonist. It is prescribed for primary aldosteronism, heart failure, and resistant hypertension ( 2024). Spironolactone is actively prescribed to women for acne, hirsutism, and androgenic alopecia, citing its antiandrogen effect (the AEMPS Ficha Técnica does not include these indications; 2024 and 2023 consider spironolactone an off-label option as second- or third-line for female acne). For mild acne or anti-aging hair in women, clinical studies of prophylactic use are limited. The drug has specific risks: hyperkalemia (especially in older adults, renal impairment, or with ACE inhibitor/ARB), gynecomastia and mastodynia in men and women, erectile dysfunction in men, menstrual disturbances, and teratogenicity in male fetuses. If spironolactone was prescribed for dermatology or anti-aging without a discussion of risks, consider seeking a second opinion.
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: ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure (2021)
20 pairs found. Sorted from critical to minor.
Mechanism
Both drugs are mineralocorticoid receptor antagonists. Concurrent use produces dual aldosterone blockade; renal potassium excretion stops. Severe hyperkalaemia (K+ above 6.5 mmol/L) develops with risk of fatal arrhythmia.
Symptoms
Muscle weakness, paresthesia, bradycardia. ECG shows peaked T waves, QRS widening; in severe cases asystole.
Management
Combination contraindicated. For resistant heart failure choose one: spironolactone if renal function is preserved, or eplerenone if gynaecomastia developed on spironolactone. Check potassium at weeks 1, 2 and 4, then monthly.
Mechanism
Both are potassium-sparing diuretics. Combined use produces dual potassium retention and severe hyperkalaemia with risk of fatal arrhythmia.
Symptoms
K+ above 6.5 mmol/L, muscle weakness, arrhythmia, ECG peaked T waves.
Management
Combination contraindicated. Choose one potassium-sparing diuretic.
Mechanism
Trimethoprim blocks ENaC in collecting ducts – potassium retention. With spironolactone dual aldosterone blockade. Sudden death increase reported in the elderly.
Symptoms
Hyperkalaemia within 3-7 days.
Management
Combination contraindicated in patients over 65. In younger patients check K+ at 3-5 days.
Mechanism
Aspirin suppresses renal prostaglandin synthesis that maintains glomerular perfusion. Diuretic and natriuretic effects of spironolactone diminish and potassium accumulates.
Symptoms
Oedema, weight gain, rising blood pressure. Weakness, paraesthesia, and arrhythmias from hyperkalaemia. Reduced diuretic effect emerges within 1–2 weeks of starting aspirin.
Management
At low aspirin doses (75–100 mg for cardioprotection), the clinical effect is minimal; co-prescription is acceptable with potassium and creatinine monitoring. At full anti-inflammatory doses, the diuretic response drops markedly – titrate spironolactone clinically.
Sources
Mechanism
Captopril (ACE-I) reduces aldosterone synthesis, while spironolactone directly blocks aldosterone receptors. Both retain potassium. In chronic kidney disease and older patients, severe hyperkalaemia risk reaches 10–15% in the first weeks.
Symptoms
Muscle weakness, paraesthesia in the limbs, slowed pulse, arrhythmias. ECG shows peaked T waves and widened QRS. Severe cases progress to cardiac arrest. Symptoms typically appear within 1–2 weeks of starting the combination.
Management
The combination is appropriate in heart failure. Check potassium and creatinine 1 week after start, then monthly. If potassium exceeds 5.5 mmol/L, reduce the spironolactone dose; above 6.0 mmol/L, stop one of the drugs.
Sources
Mechanism
Trimethoprim in co-trimoxazole blocks epithelial sodium channels in renal collecting ducts via the same mechanism as amiloride. Combined with spironolactone this produces dual potassium retention. In the elderly and in chronic kidney disease cohort studies show increased sudden death rates with the combination.
Symptoms
Hyperkalaemia within 1–2 weeks: weakness, paresthesia, arrhythmia. Detected on labs; symptoms appear late.
Management
Switch to an alternative antibiotic when possible (amoxicillin, cefalexin for urinary tract infection). If co-trimoxazole is required, check potassium and creatinine on days 3–5 and at end of course. Avoid the combination in patients over 65 with eGFR below 60 mL/min/1.73 m².
Mechanism
Enalapril (an angiotensin-converting enzyme inhibitor, ACE-I) reduces aldosterone synthesis, while spironolactone directly blocks aldosterone receptors. Both retain potassium; hyperkalaemia develops in renal impairment or diabetes.
Symptoms
Muscle weakness, paraesthesia in the limbs, slowed pulse, arrhythmias. ECG shows peaked T waves and widened QRS. Severe cases progress to cardiac arrest. Symptoms typically appear within 1–2 weeks of starting the combination.
Management
The combination is appropriate in heart failure with reduced ejection fraction – a standard regimen. Check potassium and creatinine 1 week after start, then monthly. If potassium exceeds 5.5 mmol/L, stop spironolactone or cut its dose; above 6.0 mmol/L, review both agents.
Sources
Mechanism
Losartan (angiotensin II receptor blocker, ARB) suppresses the renin-angiotensin-aldosterone system and reduces aldosterone release. Spironolactone directly blocks aldosterone receptors. Both retain potassium.
Symptoms
Muscle weakness, paraesthesia in the limbs, slowed pulse, arrhythmias. ECG shows peaked T waves and widened QRS. Severe cases progress to cardiac arrest. Symptoms typically appear within 1–2 weeks of starting the combination.
Management
The combination is appropriate in heart failure. Check potassium and creatinine 1 week after start, then monthly. If potassium exceeds 5.5 mmol/L, reduce the dose of one agent; above 6.0 mmol/L, stop one of them.
Mechanism
Spironolactone retains potassium via aldosterone receptor blockade. Tacrolimus reduces renal potassium secretion via a distal tubular inhibitory effect. Additive hyperkalaemia.
Symptoms
Muscle weakness, paraesthesia, slowed pulse, arrhythmias. ECG: peaked T waves, widened QRS. Severe cases progress to cardiac arrest.
Management
Avoid the combination in transplant patients. Alternative diuretics: furosemide (loop, removes potassium) or hydrochlorothiazide. If spironolactone is needed, check potassium and creatinine every 1–2 weeks.
Mechanism
Additive hyperkalaemia. Both drugs retain potassium: spironolactone directly blocks aldosterone receptors; telmisartan (ARB) reduces aldosterone synthesis.
Symptoms
Muscle weakness, paraesthesia, slowed pulse, arrhythmias. ECG: peaked T waves, widened QRS. Severe cases progress to cardiac arrest.
Management
The combination is appropriate in heart failure with reduced ejection fraction. Check potassium and creatinine 1 week after start, then monthly. If potassium exceeds 5.5 mmol/L, reduce the dose of one agent.
Sources
Mechanism
Valsartan (ARB) suppresses the RAAS, while spironolactone blocks aldosterone receptors. Dual aldosterone blockade raises hyperkalaemia risk.
Symptoms
Muscle weakness, paraesthesia in the limbs, slowed pulse, arrhythmias. ECG shows peaked T waves and widened QRS. Severe cases progress to cardiac arrest. Symptoms typically appear within 1–2 weeks of starting the combination.
Management
The combination is appropriate in heart failure with reduced ejection fraction. Check potassium and creatinine 1 week after start, then monthly. If potassium exceeds 5.5 mmol/L, reduce the spironolactone dose.
Sources
Mechanism
No direct pharmacokinetic interaction. In chronic kidney disease, spironolactone causes hyperkalaemia and apixaban exposure rises (partly renally cleared). Cumulative adverse event risk in reduced renal function.
Symptoms
Weakness, fatigue, arrhythmia (from hyperkalaemia), bleeding and bruising without trauma (from apixaban). Symptoms are more pronounced with creatinine clearance below 50 mL/min.
Management
With normal renal function, no dose change needed. At creatinine clearance 30–50 mL/min, check potassium and creatinine every 2–4 weeks. In severe CKD (clearance below 30 mL/min), stop spironolactone or switch to eplerenone with careful potassium monitoring.
Mechanism
Standard combination in heart failure with reduced ejection fraction – additive antihypertensive effect. Spironolactone retains potassium, reducing arrhythmia risk on a beta-blocker.
Symptoms
Lower blood pressure, postural dizziness, fatigue. Older patients: fall risk.
Management
Standard combination. Check potassium and creatinine 1 week after start, then monthly. If potassium exceeds 5.5 mmol/L, reduce spironolactone.
Sources
Mechanism
Spironolactone is a weak P-glycoprotein inhibitor and may slightly raise colchicine levels. Clinically significant toxicity is described in chronic kidney disease and on long-term combination.
Symptoms
Nausea, vomiting, diarrhoea, muscle weakness, paraesthesias. With severe toxicity: myopathy, neuropathy, bone marrow suppression.
Management
With normal renal function, no dose adjustment needed. With creatinine clearance below 50 mL/min, halve the colchicine dose. Check creatinine, CK, and CBC every 3 months. In gout flares, a short colchicine course (0.5 mg 2–3 times daily for 1–3 days) is better tolerated than long-term use.
Mechanism
Spironolactone moderately inhibits P-glycoprotein; digoxin levels rise by 20–30%. Spironolactone metabolites cross-react with immunoassays and falsely elevate digoxin readings.
Symptoms
Nausea, vomiting, loss of appetite, confusion, yellow-green halos around lights, arrhythmia (bigeminy, AV block). Symptoms appear earlier in older patients and chronic kidney disease.
Management
On spironolactone start, shift the target digoxin concentration toward the lower end of the range. Check potassium and creatinine every 2–4 weeks for the first 3 months. With toxicity signs, reduce digoxin by 25%.
Sources
Mechanism
Spironolactone moderately inhibits P-glycoprotein; digoxin levels rise by 20–30%. Spironolactone metabolites also cross-react with immunoassay measurements of digoxin, falsely elevating reported values.
Symptoms
Nausea, vomiting, loss of appetite, confusion, yellow-green halos around lights, arrhythmia (bigeminy, AV block). Symptoms appear earlier in older patients and chronic kidney disease.
Management
On spironolactone start, reinterpret target digoxin concentration (rather than 0.5–0.9 ng/mL, aim for the lower boundary). Check potassium and creatinine every 2–4 weeks for the first 3 months. With toxicity signs, reduce digoxin by 25%.
Sources
Mechanism
Opposing effects on potassium: furosemide depletes it via the loop of Henle, spironolactone retains it by blocking aldosterone in collecting ducts. Target combination in heart failure, resistant hypertension, and ascites.
Symptoms
With a balanced combination, no specific symptoms. In chronic kidney disease, hyperkalaemia may occur: Weakness, fatigue, paraesthesias, arrhythmia. Symptoms develop at potassium above 5.5 mmol/L; life-threatening above 6.5 mmol/L.
Management
Check potassium and creatinine at 1 and 4 weeks after starting, then every 3 months. With creatinine clearance below 30 mL/min, do not prescribe spironolactone, or cap at 25 mg every other day. In dehydration, temporarily stop both until volume is restored.
Sources
Mechanism
Opposing effects on potassium: thiazide depletes it, spironolactone retains it. Combination in resistant hypertension and ascites. In CKD, hyperkalaemia risk rises.
Symptoms
With a balanced combination, no specific symptoms. Weakness, fatigue, paraesthesias, arrhythmia. Symptoms develop at potassium above 5.5 mmol/L; life-threatening above 6.5 mmol/L.
Management
Check potassium and creatinine at 2 and 4 weeks after starting, then every 3 months. With creatinine clearance below 30 mL/min, do not prescribe spironolactone. In older patients, watch for dehydration, especially in heat or acute illness.
Sources
Mechanism
No direct interaction. Mild additive hypotension and fall risk in older patients during hypovolaemia or on starting the combination.
Symptoms
Possible mild morning hypotension and sedation. In older patients: fall risk.
Management
No dose adjustment needed. In older patients, start alprazolam at 0.125 mg at bedtime. In dehydration or acute illness, temporarily stop spironolactone.
Mechanism
No direct interaction. Additive orthostatic hypotension possible in older patients during hypovolaemia: spironolactone via diuresis, amitriptyline via α1-blockade.
Symptoms
Possible postural dizziness, fatigue. In older patients: fall risk.
Management
Begin amitriptyline at 10 mg at bedtime. In older patients, do not exceed 25 mg/day. Check standing/sitting BP at 1–2 weeks. With pronounced orthostatic hypotension, consider neuropathic-pain alternatives: gabapentin or pregabalin.
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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.
Reference information, not a clinical decision. Discuss feeding pauses or changes with your physician or an IBCLC.
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.