Potassium-sparing diuretics

Definition and Clinical Scope

Potassium-sparing diuretics are a pharmacological class of agents that promote the excretion of sodium and water while conserving potassium and hydrogen ions in the distal nephron of the kidney. Unlike thiazide and loop diuretics, which significantly increase potassium loss, potassium-sparing diuretics minimize the risk of hypokalemia, making them particularly useful when used in combination with other diuretic classes.

These agents are classified based on their mechanism into aldosterone antagonists (mineralocorticoid receptor antagonists) and epithelial sodium channel blockers (ENaC blockers). They are used for managing hypertension, heart failure, edema, and hyperaldosteronism, among other indications.

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1. Classification of Potassium-Sparing Diuretics

Potassium-sparing diuretics are grouped into two primary categories based on their site and mechanism of action in the nephron:

A. Aldosterone Antagonists (Mineralocorticoid Receptor Antagonists)

• Competitively inhibit aldosterone at the cytoplasmic mineralocorticoid receptor in the distal convoluted tubule and collecting duct

• Decrease sodium reabsorption and potassium secretion

Agents:

• Spironolactone

• Eplerenone

B. Epithelial Sodium Channel (ENaC) Blockers

• Inhibit sodium entry through apical epithelial sodium channels in the late distal tubule and collecting duct

• Reduce intracellular sodium, diminishing sodium-potassium exchange and potassium excretion

Agents:

• Amiloride

• Triamterene

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2. Mechanism of Action

Aldosterone Antagonists:

• Aldosterone increases the expression of ENaC and Na⁺/K⁺-ATPase pumps, promoting sodium reabsorption and potassium excretion.

• Spironolactone and eplerenone block aldosterone's action, resulting in:

  • Sodium and water excretion

  • Potassium retention

  • Weak diuretic effect due to the distal site of action

ENaC Blockers (Amiloride and Triamterene):

• Directly block the sodium channels in the luminal membrane of epithelial cells

• Reduced sodium uptake decreases the driving force for potassium excretion

• Do not rely on aldosterone activity

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3. Therapeutic Indications

A. Hypertension

• Used adjunctively with thiazides or loop diuretics to maintain normokalemia

• ENaC blockers like amiloride are useful in resistant hypertension

B. Heart Failure

• Spironolactone and eplerenone reduce morbidity and mortality in patients with:

  • Reduced ejection fraction

  • NYHA Class II–IV heart failure

  • Post-myocardial infarction (eplerenone)

C. Hyperaldosteronism

• Spironolactone is the drug of choice for:

  • Primary hyperaldosteronism (Conn’s syndrome)

  • Secondary hyperaldosteronism due to cirrhosis, nephrotic syndrome, or heart failure

D. Cirrhotic Ascites and Edema

• Spironolactone effectively treats sodium retention in liver cirrhosis

• Commonly used in combination with furosemide

E. Hypokalemia Prevention

• ENaC blockers added to thiazide or loop diuretics prevent potassium depletion

F. Polycystic Ovary Syndrome (PCOS)

• Spironolactone is used off-label due to its antiandrogenic effects

G. Lithium-Induced Nephrogenic Diabetes Insipidus

• Amiloride reduces lithium-induced ENaC activity, mitigating polyuria

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4. Pharmacokinetics

Drug	Bioavailability	Half-Life	Metabolism	Excretion
Spironolactone	~70% (oral)	1.5 h (active metabolite: ~18 h)	Hepatic to active metabolites (e.g., canrenone)	Renal and fecal
Eplerenone	~70%	4–6 h	CYP3A4 hepatic metabolism	Renal (67%), fecal
Amiloride	~15–25%	6–9 h	Not metabolized	Unchanged in urine
Triamterene	~50%	~4 h	Hepatic (active metabolites)	Renal and fecal

5. Generic Drug Names and Common Brands

Generic Name	Brand Name(s)	Class
Spironolactone	Aldactone, CaroSpir	Aldosterone antagonist
Eplerenone	Inspra	Aldosterone antagonist
Amiloride	Midamor	ENaC blocker
Triamterene	Dyrenium	ENaC blocker
Triamterene + HCTZ	Dyazide, Maxzide	Combination with thiazide
Amiloride + HCTZ	Moduretic	Combination with thiazide

6. Adverse Effects

Common Side Effects:

• Hyperkalemia (especially in renal insufficiency)

• Hyponatremia

• Dizziness

• GI upset (nausea, vomiting)

Specific to Spironolactone:

• Gynecomastia

• Menstrual irregularities

• Impotence

• Breast tenderness (due to antiandrogenic and anti-progestogenic activity)

Eplerenone:

• Lower risk of endocrine side effects due to receptor selectivity

Triamterene:

• May cause nephrolithiasis (kidney stones)

• Folic acid antagonism (rare)

Amiloride:

• Well tolerated; primary concern is hyperkalemia

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7. Contraindications

• Hyperkalemia (serum K⁺ > 5.5 mmol/L)

• Anuria

• Severe renal impairment or failure (eGFR < 30 mL/min/1.73 m²)

• Addison’s disease (risk of worsening hyperkalemia)

• Concomitant use of potassium supplements, high-potassium diets, or other potassium-sparing agents

• Known hypersensitivity to the drug or formulation

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8. Precautions and Monitoring

• Monitor serum potassium and renal function before initiation and periodically during treatment

• Use with caution in elderly, diabetics, and those with renal compromise

• Spironolactone should be used cautiously in patients with a history of breast cancer or gynecomastia

• Triamterene and amiloride should not be used with potassium supplements or salt substitutes unless closely monitored

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9. Drug Interactions

A. ACE Inhibitors / ARBs

• Increased risk of hyperkalemia when combined with potassium-sparing diuretics

B. NSAIDs

• Reduce diuretic efficacy and may impair renal function, increasing risk of hyperkalemia

C. Potassium Supplements

• Potentiates risk of hyperkalemia

D. Digoxin

• Hypokalemia potentiates digoxin toxicity; spironolactone may increase digoxin levels

E. CYP3A4 Inhibitors (e.g., ketoconazole, verapamil)

• May increase eplerenone levels

F. Lithium

• Increased risk of lithium toxicity due to reduced renal clearance

G. Trimethoprim-sulfamethoxazole

• Potentiates hyperkalemia risk when combined with amiloride or spironolactone

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10. Clinical Considerations

Heart Failure:

• Spironolactone is first-line for NYHA Class III–IV

• Eplerenone used post-MI in patients with LV dysfunction

Cirrhosis:

• Spironolactone preferred due to its effectiveness in hyperaldosteronism secondary to portal hypertension

Hypertension:

• Generally used as add-on therapy when blood pressure is uncontrolled with first-line agents

Resistant Hypertension:

• Spironolactone or amiloride can be added as a fourth-line agent

Gynecomastia Concern:

• Eplerenone preferred over spironolactone

Renal Impairment:

• Use extreme caution or avoid entirely if eGFR < 30 mL/min

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11. Summary of Key Agents

Drug	Primary Use	Mechanism
Spironolactone	HF, cirrhosis, hyperaldosteronism, HTN	Aldosterone antagonist
Eplerenone	Post-MI HF, hypertension	Selective aldosterone antagonist
Amiloride	HTN, hypokalemia prevention	ENaC blocker
Triamterene	HTN, edema, combined with thiazides	ENaC blocker