Pharmacology of Potassium-Sparing Diuretics

Potassium-sparing diuretics are a class of diuretic medications that increase diuresis (urine production) while conserving potassium, contrasting with thiazide and loop diuretics that promote potassium loss. They are used primarily to counteract hypokalemia and as adjuncts in conditions involving excessive fluid retention or aldosterone excess.

Classification and Key Agents

Class	Main Drugs	Site of Action	Mechanism
Aldosterone antagonists	Spironolactone, eplerenone	Collecting duct	Competitive inhibition at mineralocorticoid (aldosterone) receptor
ENaC blockers	Amiloride, triamterene	Collecting duct (principal cells)	Inhibit epithelial sodium channel (ENaC), decreasing Na⁺ influx

Mechanisms of Action

1. Aldosterone Antagonists

Spironolactone, Eplerenone:
- Compete with aldosterone for intracellular receptors in principal cells of the late distal tubule and collecting duct.
- Block transcription and synthesis of proteins that promote Na⁺ reabsorption and K⁺/H⁺ secretion.
- Result: Modest natriuresis, reduced K⁺/H⁺ loss, decreased remodeling in heart failure.

potassium-sparing-diuretics — #Potassium-sparing diuretics MOA

2. ENaC Blockers

Amiloride, Triamterene:
- Directly block the ENaC on the luminal membrane of the same nephron segments.
- Prevent Na⁺ entry, reducing potential for K⁺ secretion.
- Effect not dependent on aldosterone level.

Pharmacokinetics

Drug	Oral Bioavailability	Hepatic Metabolism	Excretion	Half-life (hrs)
Spironolactone	~100%	Yes (active metabolites)	Renal/fecal	1.4 (parent), up to 16 (active)
Eplerenone	~70%	Yes (CYP3A4)	Renal	4–6
Amiloride	~50%	Minimal	Renal	6–9
Triamterene	~50%	Yes (active metabolite)	Renal	4

Clinical Uses

Indication	Role of Potassium-sparing Diuretics
Hypertension (esp. with hypokalemia)	Combined with thiazides or loop diuretics
Heart failure (esp. reduced ejection fraction)	Spironolactone, eplerenone reduce mortality, hospitalizations
Primary hyperaldosteronism	First-line therapy
Edematous states (cirrhosis, nephrotic syndrome)	Adjuncts, esp. spironolactone
Polycystic ovary syndrome (PCOS), acne, hirsutism	Spironolactone for antiandrogenic properties
Lithium-induced nephrogenic diabetes insipidus	Amiloride

Adverse Effects

Drug/Class	Main Side Effects
All	Hyperkalemia: Risk rises with renal insufficiency, ACE inhibitors, ARBs, NSAIDs, K⁺ supplements; can be serious/life-threatening
Aldosterone antagonists	Gynecomastia, menstrual irregularity, impotence, reduced libido (esp. spironolactone—due to non-selective steroid effects); eplerenone more selective, fewer hormonal effects
ENaC blockers	Nausea, vomiting, headache, photosensitivity, kidney stones (rare, esp. triamterene)
All	Hyponatremia, metabolic acidosis (esp. in hepatic or renal compromise)

Drug Interactions & Precautions

ACE Inhibitors, ARBs, NSAIDs: ↑ Hyperkalemia risk.
CYP3A4 inhibitors (for eplerenone): May increase concentration/toxicity.
Contraindications: Hyperkalemia, severe renal insufficiency, Addison disease.

Comparative Summary Table

Feature	Spironolactone	Eplerenone	Amiloride	Triamterene
Receptor target	Aldosterone	Aldosterone	ENaC	ENaC
Relative potency	+++	++	+	+
CV effect	Proven mortality benefit (HF)	Proven (HF)	None	None
Endocrine effects	Gynecomastia, menstrual changes	Minimal	None	None
Use in hyperaldosteronism	Yes	Yes	No	No
Renal dosing	Reduce/avoid in dysfunction	Reduce in dysfunction	Avoid in dysfunction	Avoid in dysfunction

References

Goodman & Gilman’s The Pharmacological Basis of Therapeutics. 14th ed. New York: McGraw-Hill; 2022.
Potassium-sparing diuretic. Wikipedia. 2023.
Amiloride—StatPearls [Internet]. 2024 Feb 27.
Potassium sparing diuretics—Osmosis. Jan 2025.

Key Pearls:

Not potent diuretics alone; best used in combination to reduce K⁺ loss.
Regularly monitor renal function and serum potassium.
Spironolactone, eplerenone: mainstay in heart failure and hyperaldosteronism; be mindful of hormonal side effects with spironolactone, less with eplerenone.
Amiloride/triamterene: primarily adjuncts; do not affect hormonal pathways.

How to cite this page - Vancouver Style

Mentor, Pharmacology. Pharmacology of Potassium-Sparing Diuretics. Pharmacology Mentor. Available from: https://pharmacologymentor.com/potassium-sparing-diuretics-pharmacology-mechanism-of-action-and-clinical-use/. Accessed on February 2, 2026 at 14:15.

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