Mechanism of Action of Spironolactone

Introduction

Spironolactone is a potassium-sparing diuretic and aldosterone antagonist used primarily in the treatment of heart failure, hypertension, primary hyperaldosteronism, and conditions involving androgen excess such as polycystic ovary syndrome (PCOS) and hirsutism. It works by blocking the action of aldosterone in the distal nephron, thereby reducing sodium reabsorption and potassium excretion. Its antiandrogenic effects result from inhibition of androgen receptors and testosterone synthesis.

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Step-by-Step Mechanism of Action

1. Aldosterone receptor blockade in the distal nephron
   Spironolactone is a competitive antagonist of the mineralocorticoid receptor located in the distal convoluted tubule and collecting duct of the nephron.
2. Prevention of aldosterone-induced protein synthesis
   Normally, aldosterone binds to its intracellular receptor, leading to the synthesis of proteins such as epithelial sodium channels (ENaC) and Na⁺/K⁺-ATPase. Spironolactone inhibits this gene transcription.
3. Reduced sodium reabsorption
   Decreased ENaC and Na⁺/K⁺-ATPase activity reduces sodium reabsorption, leading to natriuresis and reduced extracellular fluid volume.
4. Decreased potassium and hydrogen ion excretion
   As sodium reabsorption falls, the electrochemical gradient driving potassium and H⁺ excretion is diminished, thereby retaining potassium (K⁺-sparing effect) and potentially causing hyperkalemia.
5. Antiandrogenic actions
   Spironolactone inhibits androgen receptors and blocks 17α-hydroxylase, thereby reducing testosterone synthesis and mitigating symptoms like hirsutism and acne.
6. Cardioprotective effects in heart failure
   By antagonizing aldosterone, spironolactone helps prevent aldosterone-mediated cardiac remodeling, fibrosis, and inflammation.

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Pharmacokinetic Parameters

Parameter	Value
Bioavailability	~60–90% (oral)
Peak Plasma Time	2–4 hours
Active Metabolites	Canrenone, 7α-thiomethylspironolactone
Protein Binding	>90%
Half-life	Parent: ~1.5 h; Metabolites: ~16–20 h
Metabolism	Hepatic
Excretion	Renal and fecal

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Clinical Uses

• Heart failure (especially NYHA class III–IV)
• Resistant hypertension (adjunct therapy)
• Primary hyperaldosteronism (Conn’s syndrome)
• Cirrhotic ascites and edema
• Polycystic ovary syndrome (PCOS)
• Hirsutism, acne in women
• Hypokalemia prevention

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Adverse Effects

• Hyperkalemia
• Gynecomastia, decreased libido, impotence (due to antiandrogenic effects)
• Menstrual irregularities, breast tenderness in females
• Gastrointestinal disturbances: nausea, vomiting
• CNS effects: drowsiness, confusion
• Rare: metabolic acidosis, agranulocytosis

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Comparative Analysis

Drug	K⁺-Sparing	Antiandrogenic	Clinical Use in HF	Risk of Gynecomastia
Spironolactone	Yes	Yes	Yes	High
Eplerenone	Yes	Minimal	Yes	Low
Amiloride	Yes	No	Limited	None

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MCQs

1. Spironolactone exerts its diuretic effect by antagonizing:
a) ADH receptors
b) Aldosterone receptors
c) Na⁺/K⁺/2Cl⁻ cotransporter
d) H⁺/K⁺ ATPase
Answer: b) Aldosterone receptors

2. In which part of the nephron does spironolactone act?
a) Proximal tubule
b) Loop of Henle
c) Distal convoluted tubule and collecting duct
d) Glomerulus
Answer: c) Distal convoluted tubule and collecting duct

3. Spironolactone is classified as a:
a) Loop diuretic
b) Thiazide diuretic
c) Potassium-sparing diuretic
d) Osmotic diuretic
Answer: c) Potassium-sparing diuretic

4. Which of the following is a known adverse effect of spironolactone?
a) Hypernatremia
b) Hypokalemia
c) Gynecomastia
d) Hypoglycemia
Answer: c) Gynecomastia

5. Spironolactone’s antiandrogenic effect is useful in:
a) Hypogonadism
b) PCOS
c) Cushing’s syndrome
d) Diabetes
Answer: b) PCOS

6. Which metabolite of spironolactone is pharmacologically active?
a) Spironolactonone
b) Canrenone
c) Aldosterone
d) Acetylspironolactone
Answer: b) Canrenone

7. Spironolactone prevents cardiac remodeling by:
a) Blocking beta receptors
b) Increasing aldosterone
c) Reducing aldosterone effects
d) Inhibiting ACE
Answer: c) Reducing aldosterone effects

8. Hyperkalemia with spironolactone is more likely in combination with:
a) Loop diuretics
b) Thiazides
c) ACE inhibitors
d) Beta blockers
Answer: c) ACE inhibitors

9. In a male patient, spironolactone may cause:
a) Virilization
b) Gynecomastia
c) Hirsutism
d) Prostatic hypertrophy
Answer: b) Gynecomastia

10. Which condition is a contraindication for spironolactone?
a) Heart failure
b) PCOS
c) Hyperkalemia
d) Liver cirrhosis
Answer: c) Hyperkalemia

11. Spironolactone differs from eplerenone by:
a) Site of action
b) Potency
c) Higher antiandrogenic activity
d) More renal elimination
Answer: c) Higher antiandrogenic activity

12. What effect does spironolactone have on acid-base balance?
a) Metabolic alkalosis
b) Metabolic acidosis
c) Respiratory alkalosis
d) No effect
Answer: b) Metabolic acidosis

13. Spironolactone therapy in cirrhosis targets:
a) Portal vein thrombosis
b) Ascites via RAAS blockade
c) Esophageal varices
d) Hepatic encephalopathy
Answer: b) Ascites via RAAS blockade

14. Which of the following is not a potassium-sparing diuretic?
a) Spironolactone
b) Eplerenone
c) Furosemide
d) Amiloride
Answer: c) Furosemide

15. What is the clinical significance of spironolactone’s long-acting metabolites?
a) Causes tolerance
b) Requires TDM
c) Sustains therapeutic effect
d) Enhances protein binding
Answer: c) Sustains therapeutic effect

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FAQs

1. Can spironolactone be used in heart failure with reduced ejection fraction?
Yes, it significantly reduces morbidity and mortality in such cases.

2. Is spironolactone safe in pregnancy?
It is not recommended due to potential antiandrogenic effects on the fetus.

3. How is hyperkalemia managed during spironolactone therapy?
Monitor potassium regularly and avoid concurrent use with ACE inhibitors or potassium supplements.

4. Can spironolactone be used in men?
Yes, especially in heart failure, but side effects like gynecomastia must be monitored.

5. What labs should be monitored with spironolactone?
Serum potassium, sodium, renal function (BUN, creatinine), and possibly hormonal markers in PCOS.

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References

• Goodman & Gilman’s The Pharmacological Basis of Therapeutics, 13th Edition
• KD Tripathi. Essentials of Medical Pharmacology, 8th Edition
• PubMed: Spironolactone in heart failure therapy
• PubMed: Antiandrogenic uses of spironolactone
• PubMed: Pharmacokinetics of spironolactone
• StatPearls: Spironolactone overview