Mechanism of action
Spironolactone is a synthetic 17-spirolactone steroid that acts as a competitive antagonist at the cytosolic mineralocorticoid receptor in the principal cells of the distal convoluted tubule and collecting duct.
Normally, aldosterone binds this receptor, translocates to the nucleus, and increases transcription of epithelial sodium channels (ENaC) and Na+/K+-ATPase, promoting sodium reabsorption in exchange for potassium and hydrogen ion secretion. By blocking this receptor, spironolactone:
- Reduces sodium reabsorption (mild natriuretic/diuretic effect)
- Reduces potassium and hydrogen secretion, so it spares potassium and can cause hyperkalemia
- Produces only a weak diuretic effect on its own, since only 2-3% of filtered sodium is handled distally; it is often combined with a loop or thiazide diuretic
Spironolactone also has significant off-target steroid receptor activity that explains many of its adverse effects:
- Antiandrogenic effect (blocks androgen receptors and inhibits androgen synthesis)
- Weak progestogenic effect
Beyond diuresis, aldosterone antagonism blunts the pathologic cardiac and vascular remodeling (fibrosis, hypertrophy) driven by chronic aldosterone excess in heart failure, which is why it improves mortality independent of its diuretic action.
Eplerenone is a related, more selective mineralocorticoid receptor antagonist with less affinity for androgen and progesterone receptors, so it causes less gynecomastia.
- Potassium-sparing diuretic that antagonizes the mineralocorticoid (aldosterone) receptor in the collecting duct
- Causes hyperkalemia, the opposite effect of loop and thiazide diuretics which cause hypokalemia
- Reduces mortality in heart failure via anti-fibrotic/anti-remodeling effects, not just diuresis
- Gynecomastia and sexual dysfunction result from antiandrogenic and progestogenic activity
- Contraindicated in hyperkalemia, significant renal impairment, and Addison disease
- Combination with ACE inhibitors/ARBs/NSAIDs/potassium supplements raises hyperkalemia risk significantly
- Active metabolite canrenone contributes to its prolonged duration of action
- Eplerenone is a more selective mineralocorticoid antagonist with fewer antiandrogenic side effects
Indications
- Heart failure with reduced ejection fraction (NYHA class II-IV), as part of guideline-directed medical therapy
- Resistant/refractory hypertension, especially when aldosterone-mediated
- Primary hyperaldosteronism (Conn syndrome), both as diagnostic/medical management and pre-surgical treatment
- Ascites and edema due to cirrhosis (often first-line diuretic in cirrhotic ascites, combined with furosemide)
- Edema from nephrotic syndrome
- Hirsutism and acne in women (off-label, due to antiandrogenic activity)
- Hormone therapy for transgender women (off-label, androgen suppression)
Dosing follows the product label; titration is guided by serum potassium and renal function.
Pharmacokinetics
| Parameter | Detail |
|---|---|
| Absorption | Well absorbed orally; food increases bioavailability |
| Metabolism | Extensive hepatic metabolism to active metabolites, most notably canrenone |
| Active metabolite | Canrenone has a long half-life and accounts for much of the sustained effect |
| Onset | Diuretic/antihypertensive effect delayed, often takes days (maximal effect may take up to 2 weeks) |
| Elimination | Renal and biliary excretion of metabolites |
The delayed onset relates to its mechanism: it blocks new receptor-mediated protein synthesis rather than acting on channels already inserted in the membrane, so effect depends on the turnover of existing ENaC/Na+/K+-ATPase units.
Adverse effects
Common
- Hyperkalemia (can be severe, especially with renal impairment or concurrent ACE inhibitors/ARBs/potassium supplements)
- Gynecomastia and mastodynia in men (antiandrogenic/progestogenic effect, dose-related)
- Menstrual irregularities, breast tenderness in women
- Decreased libido, erectile dysfunction
- Hirsutism or voice changes (rare)
- Gastrointestinal upset
Serious
- Severe hyperkalemia with cardiac arrhythmia, particularly in renal insufficiency or with other potassium-raising drugs
- Metabolic acidosis
Unlike older rodent carcinogenicity signals noted historically in product labeling, clinical significance in humans at therapeutic doses is not established, but the label does carry a tumorigenicity warning based on animal data; this is a point sometimes tested conceptually rather than clinically acted upon.
Contraindications and warnings
- Hyperkalemia (baseline) or significant renal impairment (contraindicated or requires caution per label, since drug cannot be cleared and potassium cannot be excreted)
- Addison disease (adrenal insufficiency) — contraindicated, since blocking aldosterone receptor worsens mineralocorticoid deficiency
- Concurrent use with other potassium-sparing diuretics or potassium supplements generally avoided
- Anuria
- Pregnancy: antiandrogenic activity raises theoretical concern for feminization of a male fetus; used only if benefit clearly outweighs risk, and avoided when possible, particularly in the first trimester
- Lactation: caution, as metabolites are excreted in breast milk
Monitor serum potassium and renal function at baseline and periodically, especially after initiation or dose changes and in patients on ACE inhibitors, ARBs, or NSAIDs.
Drug interactions
- ACE inhibitors, ARBs, direct renin inhibitors: additive hyperkalemia risk (classic triple-threat combination tested on exams)
- Potassium supplements or salt substitutes (often contain KCl): additive hyperkalemia
- NSAIDs: reduce renal blood flow and diuretic effect, and increase hyperkalemia risk
- Trimethoprim: additional hyperkalemia risk (acts like a potassium-sparing diuretic itself)
- Digoxin: spironolactone and its metabolites can interfere with certain digoxin immunoassays, and may alter renal clearance; monitor levels
- Lithium: reduced renal clearance of lithium, risk of toxicity
- CYP-related interactions are minor since spironolactone is not a major substrate of concern for most CYP enzymes, but it does have some mild inducing effects on hepatic metabolism of other drugs
Clinical pearls
- Remember spironolactone as the "K+-sparing" diuretic that causes hyperkalemia, opposite of loop/thiazide diuretics which cause hypokalemia
- In heart failure, spironolactone (and eplerenone) reduce mortality through anti-fibrotic, anti-remodeling effects on the myocardium, not primarily through diuresis
- First-line diuretic in cirrhotic ascites, often combined with furosemide in a fixed ratio to maintain normokalemia
- Used diagnostically and therapeutically in primary hyperaldosteronism (Conn syndrome)
- Antiandrogenic effects make it useful off-label for hirsutism/acne in women and as part of feminizing hormone therapy, but cause gynecomastia in men
- Eplerenone is the more receptor-selective alternative when gynecomastia or sexual side effects from spironolactone are intolerable
- Always check potassium and renal function before and after starting, especially with ACE inhibitors/ARBs
SPIRONOLACTONE = "Saves Potassium, Inhibits aldosteRONe" — spares K+ by blocking aldosterone receptor, unlike loop/thiazide diuretics that waste potassium.
Practice questions
1. A 58-year-old man with NYHA class III heart failure and an ejection fraction of 30% is already on a beta-blocker, an ACE inhibitor, and a loop diuretic. His physician adds a low-dose aldosterone receptor antagonist to reduce mortality risk. Three weeks later, routine labs show a serum potassium of 6.2 mEq/L. Which mechanism best explains this finding?
2. A 34-year-old woman is being evaluated for resistant hypertension and hypokalemia. Plasma aldosterone is elevated and plasma renin is suppressed. A CT scan reveals a unilateral adrenal adenoma. Prior to surgery, which drug is most appropriate to control her blood pressure and potassium?
3. A 45-year-old man started on spironolactone for cirrhotic ascites returns after two months complaining of bilateral breast tenderness and enlargement. He is otherwise asymptomatic and his labs are unremarkable. Which property of spironolactone best explains this finding?
Frequently asked questions
How does spironolactone work?
Spironolactone works by competitively blocking the mineralocorticoid (aldosterone) receptor in the kidney's collecting duct. This prevents aldosterone from increasing sodium reabsorption and potassium/hydrogen secretion, leading to mild sodium loss and potassium retention. It also has antiandrogenic activity at other steroid receptors, which explains additional effects like reduced acne and hirsutism, but also gynecomastia in men.
What are the side effects of spironolactone?
The most important side effect is hyperkalemia, which can be serious in patients with kidney impairment or those taking ACE inhibitors or ARBs. Other common effects include gynecomastia and decreased libido in men due to antiandrogenic activity, menstrual irregularities in women, and gastrointestinal upset. Regular monitoring of potassium and kidney function is recommended.
Is spironolactone a controlled substance?
No, spironolactone is not a controlled substance. It is a prescription-only aldosterone receptor antagonist with no abuse potential or psychoactive effects, so it is not scheduled under controlled substances regulations in the US or similarly regulated markets.
Spironolactone vs eplerenone — what is the difference?
Both are mineralocorticoid receptor antagonists used in heart failure and hypertension, but spironolactone also binds androgen and progesterone receptors, causing gynecomastia, menstrual changes, and sexual side effects. Eplerenone is more selective for the mineralocorticoid receptor, so it causes far less gynecomastia and sexual dysfunction, though it is generally considered somewhat less potent and is more expensive.
Can spironolactone cause hyperkalemia?
Yes, hyperkalemia is the signature adverse effect of spironolactone because it blocks aldosterone-driven potassium excretion in the kidney. Risk increases with renal impairment, higher doses, and concurrent use of ACE inhibitors, ARBs, NSAIDs, or potassium supplements. Serum potassium should be monitored before starting and periodically during treatment.
Conditions it is used for
Related drugs
Sources and further reading
DailyMed (FDA labels)StatPearls (NCBI Bookshelf)MedlinePlusWHO ATC/DDD index: C03DA01
Educational content for medical students, prepared by the WhiteCoat Pro editorial team with AI assistance; every page is reviewed by a second AI model for factual errors. It is not medical advice and does not replace the product label, local guidelines or a clinician.