Potassium-sparing Diuretics

Potassium-sparing diuretics are medications that act in the principal cells in the collecting ducts to induce diuresis that does not result in excretion of potassium. These diuretics include 2 subclasses: sodium channel blockers and aldosterone antagonists. Because these agents act so distally in the nephron, there is no significant potassium wasting associated with their use. These agents are typically used in the treatment of mineralocorticoid excess, which may be either primary (e.g., Conn syndrome) or secondary (e.g., states of depleted intravascular volume, especially in heart failure patients). Additionally, spironolactone can be used for its antiandrogenic properties in women with androgen excess (e.g., hirsutism) and for androgen suppression in transgender women (male-to-female). These drugs are contraindicated in cases of hyperkalemia.

Last update:

Table of Contents

Share this concept:

Share on facebook
Share on twitter
Share on linkedin
Share on reddit
Share on email
Share on whatsapp



Potassium-sparing diuretics are medications that act in the principal cells in the collecting ducts (CDs) to induce diuresis that does not result in excretion of potassium.

Potassium-sparing diuretics

Potassium-sparing diuretics work in the collecting ducts in the nephron.

Image by Lecturio. License: CC BY-NC-SA 4.0

Overview of antihypertensive agents

Table: Drugs used to treat hypertension
Location of actionClassSubclasses
Renal drugsDrugs affecting the RAAS
  • ACEis
  • ARBs
  • Direct renin inhibitors
  • Thiazide diuretics
  • Loop diuretics
  • Potassium-sparing diuretics
Extrarenal drugsDirect vasodilators
  • Calcium channel blockers
  • Potassium channel openers
  • Nitrodilators
  • Endothelin antagonists
Agents acting via the sympathetic nervous system
  • Drugs affecting CNS sympathetic outflow (e.g., clonidine)
  • Drugs affecting the ganglia (e.g., hexamethonium)
  • Drugs affecting the nerve terminals (e.g., guanethidine, reserpine)
  • Drugs affecting the α and β receptors

Drugs in the potassium-sparing diuretic class

Drugs in this class include: 

  • Aldosterone antagonists:
    • Spironolactone
    • Eplerenone
  • Sodium channel blockers:
    • Triamterene
    • Amiloride

Chemistry and Pharmacodynamics

Chemical structure

  • Spironolactone and eplerenone: synthetic steroids 
  • Triamterene: pteridine derivative
  • Amiloride: pyrazine derivative
Structure of triamterene

Structure of triamterene

Image: “Structure of Triamterene” by NEUROtiker. License: Public Domain

Mechanism of action (MOA) and physiologic effects

Aldosterone antagonists (spironolactone, eplerenone):

  • Also called mineralocorticoid receptor antagonists (MRAs)
  • MOA: binds to the basolateral mineralocorticoid receptor in the collecting duct as a competitive aldosterone receptor antagonist, blocking the effects of aldosterone 
  • Effects of aldosterone: 
    • Aldosterone stimulates production of the following proteins within the principle cells in the CD:
      • Na+/K+-ATPase on the basolateral side
      • ENaC (epithelial sodium channel) on the lumen side: allows Na+ reabsorption from the lumen into the principal cells
      • Renal outer medullary potassium channel (ROMK) on the lumen side: allows excretion of K+ into the urine
    • Aldosterone stimulates Na+ reabsorption from the renal tubules:
      • Water follows the Na+
      • Creates a negative electrical gradient across the lumen, promoting the secretion of K+ and H+ into the urine
  • Results of aldosterone antagonists: 
    • ↓ Na+ reabsorption → water stays in the tubular lumen with the Na+ → diuresis
    • ↓ K+ excretion → potassium-sparing
    • ↓ H+ excretion → trend toward metabolic acidosis
  • Antiandrogenic effects:
    • Spironolactone: significant antiandrogenic effects
      • Nonselective MRA, which also can bind estrogen and progesterone receptors → can ↑ aromatization of testosterone to estradiol
      • ↓ Testosterone production
      • Binds to androgen receptors and competitively inhibits testosterone and dihydrotestosterone
      • Can help improve acne, but also causes gynecomastia, impotence, decreased libido, and menstrual irregularities
    • Eplerenone: 
      • More selective for the mineralocorticoid receptor, with much fewer antiandrogenic effects
      • Better tolerated
  • Antiinflammatory effects (low-dose eplerenone): 
    • ↓ Myocardial perfusion defects after an MI → ↓ cardiac mortality
    • May slow the progression of albuminuria in diabetic patients

Sodium channel blockers (triamterene, amiloride):

  • Cations that bind to and directly block the ENaCs on the apical side of cells lining the distal convoluted tubules (DCTs) and CDs.
  • Results: 
    • ↓ Na+ reabsorption 
    • ↓ K+ excretion 
    • Water always follows Na+ → water stays with Na+ in the tubules (rather than being reabsorbed).
  • Physiologic effects:
    • Diuresis results from the osmotic effect of Na+ in the tubules.
    • No significant loss of potassium
Mechanism of action of aldosterone antagonists and sodium channel blockers

Mechanism of action of aldosterone antagonists and sodium channel blockers

Image by Lecturio. License: CC BY-NC-SA 4.0


  • Absorption: 
    • All are absorbed well orally.
    • Peak activity occurs at about 2–4 hours.
  • Metabolism:
    • Spironolactone and triamterene are metabolized to active metabolites.
    • Eplerenone is metabolized to inactive metabolites.
    • Amiloride is not metabolized hepatically.
  • Excretion: primarily via the kidneys; secondarily via the bile/feces
Table: Pharmacokinetics of the potassium-sparing diuretics
  • Bioavailability: approximately 90% when taken with food
  • Peak activity: approximately 2.5–4 hours
Protein binding: > 90%Rapid and extensive hepatic metabolism to active metabolites
  • Urine (primarily as metabolites)
  • Bile (secondary)
  • Bioavailability: approximately 70%
  • Peak activity: 2 hours
  • VD: 42–90 L
  • Protein binding: 50%
Hepatic metabolism by CYP3A4 to inactive metabolites
  • Urine (67%)
  • Feces (32%)
  • Half-life: 3–6 hours
  • Rapidly absorbed
  • Bioavailability: 50%
  • Peak activity: 3 hrs
VD: 1.5 L/kgHepatic metabolism by CYP1A2 to active metabolitesExcreted renally
  • Readily absorbed
  • Peak activity: 3–4 hours
  • VD 350–380 L
  • Protein binding: minimal
Not metabolized
  • Urine (50%)
  • Feces (40%)
  • Half-life: 6–9 hours
VD: volume of distribution


General indications

The potassium-sparing diuretics are most useful for treating edema related to states of mineralocorticoid excess, which may be either primary or secondary. Indications include:

  • Edema due to primary causes of mineralocorticoid excess:
    • Conn syndrome
    • Ectopic adrenocorticotropic hormone (ACTH) production
  • Edema due to states of depleted intravascular volume resulting in secondary mineralocorticoid excess: 
    • Heart failure/post-MI (especially eplerenone)
    • Cirrhosis
    • Nephrotic syndrome
    • Resistant hypertension (typically in addition to 1st-line antihypertensive agents)

Unique indications of spironolactone

Spironolactone has additional indications owing to its antiandrogenic properties:

  • States of hyperandrogenism in females, including:
    • Acne vulgaris 
    • Hirsutism
    • Polycystic ovary syndrome
    • Congenital adrenal hyperplasia
  • Hormone therapy for transgender women (male-to-female)

Adverse Effects and Contraindications

Adverse effects of potassium-sparing diuretics

  • Fluid and electrolyte abnormalities:
    • Hyperkalemia (↑ K+)
    • Hyperchloremic metabolic acidosis
    • Hyponatremia (↓ Na+
    • Hypomagnesemia (↓ Mg2+)
    • Hypocalcemia (↓ Ca2+)
    • Hypovolemia
  • Symptoms:
    • Dizziness
    • Headache
    • Muscle cramps
    • GI distress: abdominal cramping, nausea, vomiting, diarrhea
    • Photosensitivity (triamterene)
  • Additional effects specific to spironolactone (related to its antiandrogenic properties):
    • Gynecomastia
    • Impotence and ↓ libido
    • Menstrual abnormalities


  • Hyperkalemia
  • Addison disease/adrenal insufficiency
  • Anuria or severe/progressive CKD
  • Severe hepatic disease
  • Pregnancy (especially the aldosterone antagonists, which may cause feminization of a male fetus)


  • Diabetes (especially triamterene and amiloride)
  • Gout
  • Lactation

Comparison of Medications

Some of the other most common diuretics include thiazide diuretics (e.g., hydrochlorothiazide), loop diuretics (e.g., furosemide), carbonic anhydrase inhibitors (e.g., acetazolamide), and osmotic diuretics (e.g., mannitol).

Table: Comparison of diuretics
MedicationMechanismPhysiologic effectIndication
Thiazide diuretic: Hydrochlorothiazide↓ Reabsorption of NaCl in the DCT through the inhibition of Na+/Cl cotransporter
  • ↓ Blood pressure
  • ↓ Edema
  • Hypertension
  • Edema
Loop diuretic: FurosemideInhibits the luminal Na+/K+/Cl cotransporter in the thick ascending limb of the loop of Henle
  • ↓ Edema
  • ↓ Blood pressure
  • Edema/ascites
  • CHF
  • Hypertension
Potassium-sparing diuretic: Spironolactone
  • ↓ Reabsorption of Na through the ENaC channels in the CD
  • Inhibition of aldosterone receptors in the CD
  • ↓ Blood pressure
  • ↓ Edema
  • Does not cause ↑ excretion of K+
  • Anti-androgenic effects
  • CHF
  • Edema/ascites
  • Hypertension
  • Hirsutism in females
  • Primary hyperaldosteronism
Carbonic anhydrase inhibitor: AcetazolamideInhibits both the hydration of CO2 in the PCT epithelial cells and the dehydration of H2CO3 in the PCT lumen; results in ↑ HCO3 and Na+ excretion
  • ↑ Urinary excretion of HCO3 → metabolic acidosis
  • ↓ Intraocular pressure
  • Edema in patients with metabolic alkalosis
  • Altitude sickness
  • ↑ Intraocular pressure
  • Off label: normal pressure hydrocephalus
Osmotic diuretics: Mannitol↑ Osmotic pressure in the glomerular filtrate → ↑ tubular fluid and prevents water reabsorption
  • ↓ Free water
  • ↓ Cerebral blood volume
  • Increased intracranial pressure
  • Increased intraocular pressure
PCT: proximal convoluted tubule
DCT: distal convoluted tubule
CHF: congestive heart failure

The sites of action within the nephron for the diuretic drug classes

Image by Lecturio. License: CC BY-NC-SA 4.0


  1. Ives, H.E. (2012). Diuretic agents. In Katzung, B.G., Masters, S.B., Trevor, A.J. (Eds.), Basic and Clinical Pharmacology, 12th ed. pp. 261–263.
  2. National Center for Biotechnology Information (2021). PubChem compound summary for CID 5546, triamterene. Retrieved June 15, 2021, from https://pubchem.ncbi.nlm.nih.gov/compound/Triamterene.
  3. National Center for Biotechnology Information. (2021). PubChem compound summary for CID 5833, sSpironolactone. Retrieved June 15, 2021, from https://pubchem.ncbi.nlm.nih.gov/compound/Spironolactone.
  4. Pitt, B., et al. (1999). The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators. New England Journal of Medicine 341:709–717. https://pubmed.ncbi.nlm.nih.gov/10471456/ 
  5. Yancy, C.W., et al. (2017). ACC/AHA/HFSA focused update of the 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America. Journal of Cardiac Failure 23:628–651. https://pubmed.ncbi.nlm.nih.gov/28461259/
  6. McDiarmid, A.K., et al. (2020). Myocardial Effects of Aldosterone Antagonism in Heart Failure With Preserved Ejection Fraction. Journal of the American Heart Association. 9(1), e011521 https://pubmed.ncbi.nlm.nih.gov/31852424/
  7. Agrawal, S., et al. (2015). Heart failure and chronic kidney disease: should we use spironolactone? American Journal of the Medical Sciences 350:147–151. https://pubmed.ncbi.nlm.nih.gov/26086152/
  8. Yang, C.T., et al. (2018). Long-Term Effects of spironolactone on kidney function and hyperkalemia-associated hospitalization in patients with chronic kidney disease. Journal of Clinical Medicine 7:459. https://pubmed.ncbi.nlm.nih.gov/30469400/
  9. Nishizaka, M.K., Zaman, M.A., Calhoun, D.A. (2003). Efficacy of low-dose spironolactone in subjects with resistant hypertension. American Journal of Hypertension 16(11 Pt 1):925–930. https://pubmed.ncbi.nlm.nih.gov/14573330/
  10. Tu, W., et al. (2016). Triamterene enhances the blood pressure lowering effect of hydrochlorothiazide in patients with hypertension. Journal of General Internal Medicine 31:30–36. https://pubmed.ncbi.nlm.nih.gov/26194642/
  11. Hoorn, E.J., Ellison, D.H. (2017). Diuretic resistance. American Journal of Kidney Diseases 69:136–142. https://pubmed.ncbi.nlm.nih.gov/27814935/
  12. Knauf, H., Wais, U., Albiez, G., Lübcke, R. (1976). Inhibition of the exchange of Na for K and and H by triamterene (in epithelia)(author’s transl.). Arzneimittel-Forschung 26:484–486. https://pubmed.ncbi.nlm.nih.gov/133688/
  13. Horisberger, J.D., Giebisch, G. (1987). Potassium-sparing diuretics. Renal Physiology 10:198–220. https://pubmed.ncbi.nlm.nih.gov/2455308/
  14. Ettinger, B., Oldroyd, N.O., Sörgel, F. (1980). Triamterene nephrolithiasis. JAMA 244:2443–2445. https://pubmed.ncbi.nlm.nih.gov/7431573/
  15. Thürmann, P.A. (2016). Influence of drugs on urological diseases. Der Urologe 55:401–409. https://pubmed.ncbi.nlm.nih.gov/26908119/
  16. Nolan, P.J, D’Arcy, G. (1987). Triamterene drug fever and hepatitis. Medical Journal of Australia 147:262. https://pubmed.ncbi.nlm.nih.gov/3670184/
  17. Nasr, S.H., et al. (2014). Triamterene crystalline nephropathy. American Journal of Kidney Diseases 63:148–152. https://pubmed.ncbi.nlm.nih.gov/23958399/
  18. Tetti, M., et al. (2018). Liddle syndrome: review of the literature and description of a new case. Int J Mol Sci 19:812. https://pubmed.ncbi.nlm.nih.gov/29534496/
  19. Viswanathan, V., et al. (2013). Effect of spironolactone and amiloride on thiazolidinedione-induced fluid retention in South Indian patients with type 2 diabetes. Clin J Am Soc Nephrol 8:225–232. https://pubmed.ncbi.nlm.nih.gov/23184569/
  20. Pattanayak, R.D., et al. (2017). Lithium-induced polyuria and amiloride: key issues and considerations. Indian J Psychiatry 59:391–392. https://pubmed.ncbi.nlm.nih.gov/29085107/
  21. Tomkiewicz, R.P., et al. (1993). Amiloride inhalation therapy in cystic fibrosis: influence on ion content, hydration, and rheology of sputum. Am Rev Respir Dis 148(4 Pt 1):1002–1007. https://pubmed.ncbi.nlm.nih.gov/8214916/

Study on the Go

Lecturio Medical complements your studies with evidence-based learning strategies, video lectures, quiz questions, and more – all combined in one easy-to-use resource.

Learn even more with Lecturio:

Complement your med school studies with Lecturio’s all-in-one study companion, delivered with evidence-based learning strategies.

🍪 Lecturio is using cookies to improve your user experience. By continuing use of our service you agree upon our Data Privacy Statement.