Mechanism of Action of Spironolactone
Spironolactone functions primarily as a specific pharmacologic antagonist of aldosterone, acting through competitive binding of receptors at the aldosterone-dependent sodium-potassium exchange site in the distal convoluted renal tubule. 1
Primary Mechanism
- Spironolactone competitively binds to mineralocorticoid receptors, blocking the action of aldosterone at these sites 1, 2
- This antagonism occurs primarily in the distal convoluted tubules of the kidney 1, 2
- By blocking aldosterone receptors, spironolactone prevents sodium reabsorption and potassium excretion that would normally be stimulated by aldosterone 1
Physiological Effects
- Increases natriuresis (sodium excretion in urine) while conserving potassium 2
- Counteracts secondary aldosteronism induced by volume depletion and sodium loss 1
- Has a lag period of 3-5 days between initiation of treatment and onset of full natriuretic effect 2
- Produces both diuretic and antihypertensive effects through this mechanism 1, 3
Clinical Applications
- First-line diuretic for treatment of ascites due to cirrhosis 2
- Effective in treating conditions with secondary hyperaldosteronism including:
- Can be used alone or with other diuretics that act more proximally in the renal tubule 1, 2
Pharmacokinetics
- Rapidly and extensively metabolized in the body 1
- Has active metabolites including canrenone, which contributes to its therapeutic effects 1, 5
- Mean half-life of spironolactone itself is approximately 1.4 hours 1
- Active metabolites have longer half-lives (13.8-16.5 hours), prolonging the drug's effect 1, 5
- Terminal half-life is increased in patients with cirrhotic ascites 1
Side Effects Related to Mechanism
- Hyperkalemia is a significant potential complication due to potassium retention 2, 6
- Antiandrogenic side effects (not directly related to primary mechanism) include:
Comparison to Other Agents
- More effective than loop diuretics like furosemide when used alone for ascites in cirrhosis 2
- More effective than amiloride (another potassium-sparing diuretic) 2
- Unlike eplerenone (a newer selective aldosterone antagonist), spironolactone has moderate affinity for progesterone and androgen receptors, explaining its endocrine side effects 5, 7
Clinical Considerations
- Typically dosed at 25-400 mg/day depending on the condition being treated 2, 4
- Food increases bioavailability by approximately 95.4%, so consistent timing with meals is important 1
- Should be used cautiously in patients at risk for hyperkalemia, especially those with renal impairment or taking other potassium-sparing medications 6, 5