Potassium-Sparing Diuretics
High-yield Verified · Oct 2026Quiet ENaC in collecting-duct principal cells — directly (amiloride, triamterene) or by blocking the mineralocorticoid receptor that makes ENaC (spironolactone, eplerenone) — so the lumen loses the negative charge that drives K⁺ and H⁺ secretion.
Nursing view → administration, monitoring and patient teaching
Compare: Antihypertensives compared — mechanism and drug choice →
Drugs
Mechanism
Potassium-sparing diuretics act at the collecting duct. Mineralocorticoid-receptor antagonists (spironolactone, eplerenone) competitively block the aldosterone receptor, while ENaC blockers (amiloride, triamterene) directly block the epithelial sodium channel. Either way, sodium reabsorption falls modestly and the lumen-negative gradient that drives potassium (and hydrogen) secretion collapses — so potassium is retained. Aldosterone blockade additionally reduces the cardiac/vascular remodeling of heart failure, giving a mortality benefit beyond diuresis.
The aldosterone-sensitive distal nephron
The aldosterone-sensitive distal nephron (ASDN) — the late distal tubule, connecting tubule and collecting duct — receives only about 10% of the filtrate, and ENaC there fine-tunes about 3% of filtered sodium. That is why these drugs are weak diuretics. (The whole-nephron map is on the loop-diuretic page.)
Two cell types matter. In principal cells, sodium enters through the apical epithelial sodium channel (ENaC), driven by the gradient the basolateral Na⁺-K⁺-ATPase creates. Because ENaC is electrogenic, sodium entry leaves the lumen negative, and that charge pulls K⁺ out of the cell through apical ROMK channels. Neighbouring α-intercalated cells respond to the same lumen-negative charge by secreting H⁺ through an H⁺-ATPase.
Aldosterone, made in the adrenal zona glomerulosa under control of angiotensin II, ACTH and potassium, binds the cytoplasmic mineralocorticoid receptor (MR) in principal cells. Aldosterone induces the kinase SGK-1, which phosphorylates the ubiquitin ligase Nedd4-2 so that ENaC is no longer tagged for degradation; more ENaC reaches the apical membrane and the basolateral Na⁺-K⁺-ATPase is activated, so sodium reabsorption — and with it K⁺ and H⁺ secretion — increases. (The RAAS cascade that produces aldosterone is on the ACE-inhibitor page.)
Two routes to the same channel
The mineralocorticoid-receptor antagonists are synthetic steroids that reach the principal cell from the blood and bind the cytoplasmic MR. They act indirectly, suppressing the aldosterone-induced proteins that make, insert and activate ENaC. The ENaC blockers are pteridine analogs that are secreted into the lumen in the proximal tubule and block ENaC directly. Both end at ENaC, so both reduce the lumen-negative charge and with it K⁺ and H⁺ secretion. Amiloride is not an aldosterone antagonist and works even without aldosterone; triamterene likewise acts directly on the tubule.
Selectivity separates the two receptor antagonists. Spironolactone also binds androgen and progesterone receptors. Eplerenone has 100- to 1000-fold lower affinity for glucocorticoid, progesterone and androgen receptors. Spironolactone’s androgen-receptor binding is why it is used off-label for acne, where it blocks dihydrotestosterone at androgen receptors; it is also used off-label for hirsutism. Eplerenone, being selective, is favored for primary aldosteronism.
Because so little sodium reaches the ASDN, natriuresis is limited. It grows when a more proximally acting diuretic delivers more sodium and aldosterone activity is high — the basis for pairing these drugs with loops or thiazides. ENaC blockers spare magnesium as well: amiloride reduces the extra urinary magnesium loss caused by thiazides and loops.
Aldosterone beyond the kidney — and aldosterone escape
Mineralocorticoid receptors are also found in nonepithelial tissues — heart, blood vessels and brain. There, aldosterone increases vascular stiffness and drives cardiac inflammation, fibrosis and remodeling, especially after a myocardial infarction. Blocking these effects is why the receptor antagonists reduce morbidity and mortality in heart failure, a benefit well beyond their weak diuresis.
Aldosterone escapes suppression during chronic ACE-inhibitor or ARB therapy, so adding a receptor antagonist protects against its effects. Spironolactone also counters secondary aldosteronism in edematous states — heart failure, cirrhosis and nephrotic syndrome — and the aldosteronism caused by volume depletion from active diuretic therapy. Spironolactone is the drug of choice to start in cirrhotic ascites.
Feedback runs the other way, too. Eplerenone produces sustained rises in plasma renin and serum aldosterone, because aldosterone’s negative feedback on renin is lost, but these higher levels do not overcome the blockade.
Acid–base and the single-gene models
Blocking ENaC stops both K⁺ and H⁺ secretion, so these drugs cause hyperkalemia with a hyperchloremic metabolic acidosis. The hyperkalemia worsens the acidosis: it impairs proximal ammonia generation and collecting-duct ammonia transport, ammonia excretion falls, and bicarbonate is used up buffering. Triamterene does not cause alkalosis, because it does not increase titratable-acid and ammonium excretion.
Two inherited conditions mirror the drugs. In Liddle syndrome (pseudohyperaldosteronism), gain-of-function ENaC mutations — commonly a truncated PY motif that escapes Nedd4-2 tagging — raise channel activity independently of aldosterone, causing hypertension, hypokalemia and metabolic alkalosis with suppressed renin and aldosterone. It does not respond to aldosterone antagonism; amiloride, which blocks the channel itself, is beneficial; its label reports no fetal harm in animal teratogenicity studies but no adequate studies in pregnant women. In primary hyperaldosteronism — an adrenal adenoma (Conn syndrome) or bilateral adrenal hyperplasia — autonomous aldosterone suppresses renin and often causes hypokalemia, and mineralocorticoid-receptor antagonists are first-line medical therapy.
Comparing the drugs
Mechanism and selectivity
| Drug | Target | Needs aldosterone to work? | Other receptors | Active metabolites |
|---|---|---|---|---|
| Spironolactone | Mineralocorticoid receptor (competitive) | Yes — it blocks aldosterone’s action | Androgen and progesterone receptors | Yes — canrenone and others |
| Eplerenone | Mineralocorticoid receptor (competitive) | Yes | Little: 100–1000-fold lower affinity than spironolactone | None identified |
| Amiloride | ENaC (direct block) | No — works without aldosterone | — | Not metabolized |
| Triamterene | ENaC (direct tubular effect) | No — not aldosterone antagonism | — | Hydroxytriamterene sulfate (levels exceed the parent) |
Both routes end at ENaC: the receptor antagonists indirectly, the channel blockers directly. — = none described in the listed sources.
Pharmacokinetics at a glance
| Drug | Oral bioavailability | Elimination | Half-life | Food |
|---|---|---|---|---|
| Spironolactone | — | Rapid, extensive metabolism; metabolites in urine, then bile | 1.4 h (metabolites 13.8–16.5 h) | Raises AUC about 95% |
| Eplerenone | 69% | CYP3A4; 67% urine, 32% feces | 3–6 h | No effect |
| Amiloride | About 50% | Unchanged: about 50% urine, 40% stool | 6–9 h (effect lasts about 24 h) | — |
| Triamterene | About 50% | Hepatic, to a sulfate conjugate | — (diuresis tapers 7–9 h) | — |
— = not stated in the listed sources. Amiloride needs the kidney (tubular secretion) and accumulates in renal dysfunction; triamterene and spironolactone need the liver.
Pharmacokinetics
- Spironolactone: short-lived parent, long-lived metabolites — spironolactone
- It is rapidly and extensively metabolized. The parent half-life is only 1.4 h, but its metabolites — canrenone, TMS and HTMS — have half-lives of 13.8–16.5 h. Peak levels come at 2.6 h for spironolactone and 4.3 h for canrenone. Food raises bioavailability about 95%, so the label asks patients to keep a routine pattern with regard to meals. Over 90% is protein-bound.
- Eplerenone and CYP3A4 — eplerenone
- Cleared mainly by CYP3A4 with no active metabolites, it has a 3–6 h half-life and 69% bioavailability, unaffected by food. It is about 50% bound, mainly to α1-acid glycoprotein. Strong CYP3A inhibitors (ketoconazole, itraconazole, clarithromycin, ritonavir and others) are contraindicated, and moderate inhibitors raise levels and hyperkalemia risk.
- Amiloride: renal, unmetabolized — amiloride
- Not metabolized: about half is excreted unchanged in urine and 40% in stool. The half-life is 6–9 h, the effect starts within 2 hours and lasts about 24 hours (once daily). Because it relies on tubular secretion and has a long half-life, it accumulates in renal dysfunction and can cause life-threatening hyperkalemia — yet it is preferred in liver disease.
- Triamterene: hepatic — triamterene
- Metabolized in the liver to hydroxytriamterene sulfate, whose plasma and urine levels exceed the parent’s. It acts in 2–4 hours, the diuresis tapers off by 7–9 hours (twice-daily dosing), and maximum effect may take several days.
- Bioavailability and time course across the class
- Amiloride and triamterene are each about 50% bioavailable, and eplerenone 69%. Amiloride and triamterene begin acting within hours (2 and 2–4 h), eplerenone reaches steady state within 2 days, and triamterene’s maximum effect may take several days.
- Dialysis
- Eplerenone is not removed by hemodialysis, though it binds extensively to charcoal.
Uses & drug choice
- Heart failure with reduced ejection fraction — mortality benefit (spironolactone, eplerenone)
- Resistant hypertension and primary hyperaldosteronism
- Cirrhotic ascites/edema — spironolactone first-line
- Preventing hypokalemia when combined with a loop or thiazide diuretic
Adverse effects
- Hyperkalemia (the boxed warning for amiloride and triamterene)
- With ENaC quiet, the lumen loses its negative charge and ROMK secretes less K⁺. Hyperkalemia disturbs the resting membrane potential of cardiac myocytes, causing arrhythmias and conduction defects — and the rate of rise matters more than the level. Risk is higher with renal impairment, diabetes, proteinuria, ACE inhibitors, ARBs, NSAIDs and, for eplerenone, moderate CYP3A inhibitors. After RALES, hyperkalemia hospitalizations and deaths rose as spironolactone was used without the trial’s close monitoring.
- Metabolic acidosis
- α-intercalated cells lose the lumen-negative drive for H⁺ secretion, and hyperkalemia impairs ammonia excretion, so bicarbonate is consumed: a hyperchloremic (normal anion gap) metabolic acidosis.
- Gynecomastia, breast tenderness, menstrual irregularity, reduced libido (spironolactone)
- Spironolactone also binds androgen and progesterone receptors. In RALES about 9% of men developed gynecomastia; the risk rises with dose, onset ranges from 1–2 months to over a year, and it is usually reversible. Eplerenone’s far lower affinity for these receptors means gynecomastia was no more common than with placebo, and it has been used to reverse spironolactone-induced gynecomastia.
- Dehydration, dizziness, hypotension, GI upset
- These come from the (weak) diuresis and natriuresis; dehydration and hyponatremia head the list of spironolactone adverse effects in one study, ahead of GI problems.
- Acute kidney injury / renal impairment
- Renal impairment amplifies hyperkalemia, and amiloride in particular accumulates when tubular secretion falls. Triamterene has also caused acute interstitial nephritis and acute renal failure.
- Triamterene kidney stones (and megaloblastosis)
- Triamterene itself has been found in renal stones, so patients with a stone history should avoid it. It is also a weak folic acid antagonist, which can unmask megaloblastosis when folate stores are depleted, as in cirrhosis.
Toxicity & antidote
The expected problems are hyperkalemia — especially with impaired renal function — plus dehydration, electrolyte imbalance and hypotension. There is no specific antidote; care is supportive, with active measures to lower potassium. For hyperkalemia with ECG changes, calcium comes first because it stabilizes cardiac membranes (it does not lower potassium), followed by shifting potassium into cells and removing it. The ECG progresses roughly from peaked T waves to loss of P waves, QRS widening and finally a sine-wave pattern and asystole. Eplerenone is not dialyzable but binds charcoal.
Interactions
Contraindications
- Hyperkalemia — These drugs raise potassium further; giving them to an already-hyperkalemic patient risks fatal arrhythmia — an absolute contraindication.
- Addison’s disease (adrenal insufficiency) — Aldosterone is already deficient, so blocking it worsens sodium loss and hyperkalemia.
- Concurrent potassium supplements, salt substitutes, or another potassium-sparing agent — Stacking potassium sources drives hyperkalemia — avoid the combination and counsel patients about salt substitutes (KCl).
- Anuria or significant renal impairment (amiloride, triamterene) — Labeled contraindication for amiloride and triamterene (anuria, renal insufficiency); impaired excretion makes hyperkalemia far more likely.
- Eplerenone: creatinine clearance ≤ 30 mL/min or strong CYP3A inhibitors (for hypertension also type 2 diabetes with microalbuminuria or CrCl < 50 mL/min) — Labeled contraindications — reduced clearance and CYP3A inhibition raise eplerenone levels and hyperkalemia risk; use caution with ACEi/ARB.
High-yield
- Spills over — spironolactone also binds androgen and progesterone receptors: gynecomastia, libido loss, menstrual change (and an off-label use in acne)
- Exact — eplerenone is selective for the mineralocorticoid receptor (100–1000-fold less off-target binding), cleared by CYP3A4
Both still block the same mineralocorticoid receptor, so both carry the hyperkalemia risk.
- A — amiloride: blocks ENaC directly, needs no aldosterone, unmetabolized and renally excreted (treats Liddle syndrome)
- T — triamterene: blocks ENaC directly, metabolized by the liver, found in kidney stones, weak antifolate
The A-T pair acts at the channel itself; spironolactone and eplerenone act one step upstream, at the receptor.
Practice questions
Q1A 63-year-old man with heart failure with reduced ejection fraction, maintained on lisinopril and carvedilol, is started on spironolactone. Six months later he reports tender enlargement of both breasts. His potassium is 4.8 mEq/L.
Which change best keeps the benefit of aldosterone blockade while addressing this problem?
- A.Switch spironolactone to amiloride
- B.Switch spironolactone to triamterene
- C.Increase the spironolactone dose
- D.Switch spironolactone to eplerenone
- E.Stop lisinopril
Show answer
D. Switch spironolactone to eplerenone — Spironolactone also binds androgen and progesterone receptors, causing dose-dependent, usually reversible gynecomastia — about 9% of men in RALES. Eplerenone blocks the same mineralocorticoid receptor but has 100–1000-fold lower affinity for these off-target receptors: gynecomastia was no more common than with placebo, and it has reversed spironolactone gynecomastia. Amiloride and triamterene block ENaC rather than the receptor, so they do not provide aldosterone blockade, and raising the spironolactone dose increases the gynecomastia risk. Stopping lisinopril would not help: aldosterone escapes ACE-inhibitor suppression, which is why the antagonist was added.
Q2A 16-year-old girl has resistant hypertension, hypokalemia and metabolic alkalosis. Plasma renin and aldosterone are both low, and her blood pressure did not respond to spironolactone. Her father had early-onset hypertension. Genetic testing shows a mutation in the β subunit of the epithelial sodium channel.
Which drug most directly targets the underlying defect?
- A.Spironolactone
- B.Amiloride
- C.Eplerenone
- D.Furosemide
- E.Lisinopril
Show answer
B. Amiloride — In Liddle syndrome, ENaC gain-of-function mutations (β or γ subunit) raise channel activity independently of aldosterone. The extra sodium reabsorption expands volume and suppresses renin and aldosterone, while potassium is secreted. Amiloride blocks ENaC directly and works even without aldosterone, so it treats Liddle syndrome. Liddle syndrome does not respond to aldosterone antagonism, so spironolactone and eplerenone, which act at the mineralocorticoid receptor, are not the answer. Furosemide acts on NKCC2 in the loop of Henle, and lisinopril on angiotensin II production — neither touches ENaC.
Q3A 70-year-old man with diabetic kidney disease takes losartan and has recently started amiloride for diuretic-induced hypokalemia. His potassium is now 6.6 mEq/L and his ECG shows tall, peaked T waves and flattened P waves.
Which treatment should be given first, and why?
- A.IV calcium, because it stabilizes the cardiac membrane
- B.Sodium bicarbonate, because it corrects his alkalosis
- C.IV calcium, because it rapidly lowers serum potassium
- D.Spironolactone, because it antagonizes aldosterone
- E.Triamterene, because it increases potassium excretion
Show answer
A. IV calcium, because it stabilizes the cardiac membrane — Calcium comes first in hyperkalemia with ECG changes because it stabilizes cardiac membranes. It does not lower serum potassium; potassium is then shifted into cells and removed. Peaked T waves followed by loss of P waves track rising potassium. Amiloride blocks ENaC and reduces K⁺ and H⁺ secretion, so the expected acid–base change is a hyperchloremic metabolic acidosis, not alkalosis. Spironolactone and triamterene are themselves potassium-sparing and would worsen the hyperkalemia; renal impairment, diabetes and an ARB all add to the risk.
Q4A 55-year-old man with HIV starts ritonavir-boosted therapy. He has been taking eplerenone for resistant hypertension.
What is the main concern with this combination?
- A.Ritonavir induces CYP3A4, so eplerenone becomes ineffective
- B.Eplerenone is removed by hemodialysis, so its levels fall
- C.Both drugs bind androgen receptors, causing gynecomastia
- D.Eplerenone’s active metabolites accumulate in renal failure
- E.Ritonavir, a strong CYP3A inhibitor, raises eplerenone levels and hyperkalemia risk; the combination is contraindicated
Show answer
E. Ritonavir, a strong CYP3A inhibitor, raises eplerenone levels and hyperkalemia risk; the combination is contraindicated — Eplerenone is cleared predominantly by CYP3A4, and the label contraindicates strong CYP3A inhibitors such as ritonavir, ketoconazole and clarithromycin. Higher levels raise hyperkalemia risk. Ritonavir inhibits CYP3A rather than inducing it. Eplerenone is not removed by hemodialysis, has no active metabolites, and its selectivity for the mineralocorticoid receptor is what spares the androgen receptor.
Q5A 48-year-old woman with alcohol-related cirrhosis and tense ascites has a serum sodium of 134 mEq/L and potassium of 3.6 mEq/L. Diuretic therapy is planned.
Which drug is the usual first choice, and on what mechanism?
- A.Furosemide alone, because loops are the most potent diuretics
- B.Hydrochlorothiazide, because it blocks NCC in the distal tubule
- C.Spironolactone, because it competes with the aldosterone driving secondary aldosteronism
- D.Amiloride, because it is an aldosterone receptor antagonist
- E.Eplerenone, because spironolactone is contraindicated in cirrhosis
Show answer
C. Spironolactone, because it competes with the aldosterone driving secondary aldosteronism — Ascites in cirrhosis involves secondary aldosteronism. By competing with aldosterone for its receptor, spironolactone treats the edema and ascites, and StatPearls calls it the drug of choice for initial therapy, with a loop added as an adjunct or from the outset — so a loop alone is not the usual first step. Amiloride is not an aldosterone antagonist; it blocks ENaC. Spironolactone, not eplerenone, is the named drug of choice to start in cirrhotic ascites. Thiazides act on NCC and do not address the aldosterone excess.
Sources
- Spironolactone (Aldactone) — HF (RALES) & ascites indications, hyperkalemia & endocrine effects (FDA label) — FDA / DailyMed
- INSPRA (eplerenone) — selective MR antagonist, potassium/renal thresholds & CYP3A4 contraindication (FDA label) — FDA / DailyMed
- Spironolactone — mechanism, HF mortality benefit, antiandrogen effects & hyperkalemia — StatPearls (NCBI)
- Amiloride — ENaC blockade & hyperkalemia boxed warning — StatPearls (NCBI)
- Amiloride HCl tablets — boxed warning (hyperkalemia) — DailyMed (NLM)
- DYRENIUM (triamterene) — boxed warning (hyperkalemia) — DailyMed (NLM)
- Drugs@FDA — MAXZIDE (NDA 019129) marketing status — U.S. FDA
- Drugs@FDA — MIDAMOR (NDA 018200) marketing status — U.S. FDA
- Therapeutic Uses of Diuretic Agents — ENaC, amiloride boxed warning — StatPearls (NCBI)
- Eplerenone — selectivity, gynecomastia — StatPearls (NCBI)
- Hyperkalemia — definition, ECG, symptoms — StatPearls (NCBI)
- Antihypertensive Medications — eplerenone vs spironolactone — StatPearls (NCBI)
- Sodium Polystyrene Sulfonate — hyperkalemia symptoms — StatPearls (NCBI)
- 24-Hour Urine Testing for Nephrolithiasis — potassium-chloride salt substitutes — StatPearls (NCBI)
- Electrolytes — hyperkalemia muscle cramps — StatPearls (NCBI)
- Diuretics — spironolactone (Ch. 6.9) — Open RN — Nursing Pharmacology
- StatPearls: Triamterene — StatPearls (NCBI)
- Physiology, Renin Angiotensin System — aldosterone on principal cells, primary hyperaldosteronism — StatPearls (NCBI)
- Liddle Syndrome — ENaC gain of function, Nedd4-2/SGK-1, low renin and aldosterone, no response to spironolactone — StatPearls (NCBI)
By LearnDrugs
Educational summary for medical students. Always verify against current prescribing information and guidelines. Not medical advice.