Mechanism of Action of Potassium-Sparing Diuretics

Introduction

Potassium-sparing diuretics are a unique subclass of diuretics that help conserve potassium levels while promoting mild diuresis. Unlike other diuretics, they do not cause hypokalemia, making them ideal as adjunct therapy with thiazide or loop diuretics.

These drugs are grouped into two types:

1. Aldosterone antagonists:
   • Spironolactone
   • Eplerenone
2. Epithelial sodium channel (ENaC) blockers:
   • Amiloride
   • Triamterene

These drugs are tested frequently in USMLE, NCLEX, GPAT, NAPLEX, and used in treating heart failure, hypertension, hyperaldosteronism, and hypokalemia.

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Stepwise Mechanism of Action of Potassium-Sparing Diuretics

Aldosterone Antagonists (e.g., Spironolactone)

1. Site of action – Collecting duct (principal cells)
   Spironolactone and eplerenone act on intracellular mineralocorticoid receptors in the distal nephron.
2. Blockade of aldosterone effects
   They prevent aldosterone-mediated expression of ENaC and Na⁺/K⁺ ATPase, reducing sodium reabsorption and potassium excretion.
3. Net result
   • Mild natriuresis
   • Potassium retention
   • Reduction in blood pressure
   • Decreased fibrosis and remodeling in heart failure

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ENaC Blockers (e.g., Amiloride, Triamterene)

1. Direct blockade of epithelial sodium channels
   These drugs inhibit ENaC channels in the luminal membrane of principal cells, reducing sodium reabsorption directly.
2. Conservation of potassium
   Sodium-potassium exchange is reduced → less potassium is secreted → prevention of hypokalemia.

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Pharmacokinetic Parameters of Potassium-Sparing Diuretics

Drug	Absorption (Oral)	Half-life	Metabolism	Excretion
Spironolactone	60–90%	1.4 hours (active metabolite: 18–23 hrs)	Hepatic	Renal/Bile
Eplerenone	~70%	4–6 hours	CYP3A4	Renal/Fecal
Amiloride	~15–25%	6–9 hours	Minimal	Renal
Triamterene	~30–70%	4–6 hours	Hepatic	Renal

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Clinical Uses of Potassium-Sparing Diuretics

• Heart failure (esp. Spironolactone in HFrEF)
• Resistant hypertension
• Primary hyperaldosteronism
• Edema associated with liver cirrhosis
• Hypokalemia induced by thiazides/loops
• Polycystic ovarian syndrome (PCOS) – off-label use of spironolactone
• Liddle syndrome – amiloride is the drug of choice

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Adverse Effects of Potassium-Sparing Diuretics

• Hyperkalemia – major and potentially life-threatening
• Gynecomastia, impotence, menstrual irregularities (esp. spironolactone due to antiandrogen effects)
• GI upset, nausea
• Metabolic acidosis (rare)
• Kidney stones (with triamterene)

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Comparative Analysis: Spironolactone vs Amiloride

Feature	Spironolactone	Amiloride
Mechanism	Aldosterone receptor antagonist	ENaC blocker
Onset of action	Delayed	Rapid
Androgen effects	Yes (antiandrogenic)	No
Hyperkalemia risk	High	Moderate
Use in PCOS	Yes	No
Use in Liddle syndrome	No	Yes

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Practice MCQs

Q1. Potassium-sparing diuretics act on which part of the nephron?
a. Proximal tubule
b. Loop of Henle
c. Distal convoluted tubule
d. Collecting duct ✅

Q2. Which of the following is a direct ENaC blocker?
a. Spironolactone
b. Eplerenone
c. Amiloride ✅
d. Furosemide

Q3. What is the major risk associated with potassium-sparing diuretics?
a. Hypokalemia
b. Hyperkalemia ✅
c. Hypocalcemia
d. Dehydration

Q4. Which potassium-sparing diuretic has antiandrogenic effects?
a. Amiloride
b. Spironolactone ✅
c. Triamterene
d. Eplerenone

Q5. Which condition is best treated with amiloride?
a. PCOS
b. Diabetes insipidus
c. Liddle syndrome ✅
d. Cushing’s disease

Q6. What is the mechanism of action of spironolactone?
a. ENaC inhibition
b. Na⁺/Cl⁻ cotransporter inhibition
c. Mineralocorticoid receptor antagonism ✅
d. Na⁺/K⁺/2Cl⁻ symporter inhibition

Q7. Eplerenone differs from spironolactone in that it:
a. Has shorter half-life
b. Does not cause hyperkalemia
c. Has fewer endocrine side effects ✅
d. Is more potent diuretic

Q8. Hyperkalemia with potassium-sparing diuretics is more likely when combined with:
a. NSAIDs ✅
b. Beta-blockers
c. Calcium channel blockers
d. Thiazides

Q9. Triamterene causes which rare side effect?
a. Kidney stones ✅
b. Gynecomastia
c. Hypokalemia
d. Hypercalcemia

Q10. Which is a potassium-sparing diuretic and aldosterone antagonist?
a. Amiloride
b. Spironolactone ✅
c. Hydrochlorothiazide
d. Furosemide

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FAQs

Q1: Can potassium-sparing diuretics be used alone?
Yes, but due to weak diuretic effect, they’re mainly used with thiazides or loops to prevent potassium loss.

Q2: Which one is preferred in heart failure?
Spironolactone, as it improves survival in HFrEF patients (RALES trial).

Q3: What labs should be monitored during therapy?
Serum potassium and creatinine, to avoid hyperkalemia and nephrotoxicity.

Q4: Are they safe in pregnancy?
Not routinely recommended; spironolactone has antiandrogenic effects and should be avoided.

References

• KD Tripathi – Essentials of Medical Pharmacology
• Goodman & Gilman – The Pharmacological Basis of Therapeutics
• Review of Pharmacology – Sparsh Gupta
• AHA Guidelines for Hypertension
• NCBI: https://www.ncbi.nlm.nih.gov/books/NBK470437/