What is the site of action of spironolactone?

Spironolactone's Site of Action

Spironolactone primarily acts as a competitive antagonist at the aldosterone receptor in the distal convoluted renal tubule, where it blocks the exchange of sodium and potassium, resulting in increased sodium and water excretion while retaining potassium. 1

Mechanism of Action

• Spironolactone and its active metabolites function as specific pharmacologic antagonists of aldosterone, primarily through competitive binding of receptors at the aldosterone-dependent sodium-potassium exchange site in the distal convoluted renal tubule. 1

• The drug slows the exchange of sodium and potassium in the distal tubule by competing with aldosterone for binding sites, leading to increased natriuresis while conserving potassium. 2

• Spironolactone causes increased amounts of sodium and water to be excreted, while potassium is retained, acting both as a diuretic and as an antihypertensive drug through this mechanism. 1

Pharmacokinetics and Metabolism

• After oral administration, spironolactone is rapidly and extensively metabolized with a mean half-life of approximately 1.4 hours. 1

• Its active metabolites, including canrenone, have longer half-lives (16.5 hours for canrenone), contributing to the prolonged pharmacological effect despite the short half-life of the parent compound. 1

• There is a lag of 3-5 days between the beginning of spironolactone treatment and the onset of the full natriuretic effect, which is important to consider when initiating therapy. 2

Clinical Applications

• Spironolactone is approved for treating conditions associated with secondary hyperaldosteronism, including:

  • Congestive heart failure 1
  • Hepatic cirrhosis with ascites 2
  • Primary hyperaldosteronism 1

• In liver cirrhosis, spironolactone is considered the drug of choice for initial treatment of ascites, typically starting at 100 mg/day and potentially increasing up to 400 mg/day to achieve adequate natriuresis. 2

• For hypertension management, spironolactone appears effective at doses of 25-100 mg/day, with no additional blood pressure reduction observed at higher doses. 3

Side Effects and Monitoring

• Common side effects (occurring in >10% of patients) include headache, diarrhea, fatigue, gynecomastia, decreased libido, and menstrual disruption. 2

• Hyperkalemia is a significant potential complication that requires monitoring, especially in patients with diabetes mellitus, liver disorders, kidney disorders, and elderly patients. 2

• Contraindications include concomitant use of:

  • Potassium supplements
  • Other potassium-sparing diuretics
  • Potent CYP3A4 inhibitors
  • Combined use of an angiotensin-converting enzyme inhibitor with an angiotensin receptor blocker 2

Comparison to Other Mineralocorticoid Receptor Antagonists

• Unlike eplerenone (a newer mineralocorticoid receptor antagonist), spironolactone is non-selective and has moderate affinity for both progesterone and androgen receptors, which explains its endocrine-related side effects. 4

• Spironolactone is currently considered the most potent mineralocorticoid receptor antagonist used in clinical practice, making it particularly effective despite its side effect profile. 2

Recent Research Applications

• Beyond its traditional uses, spironolactone has shown protective effects against hypertension-induced renal fibrosis by restoring autophagy and suppressing NLRP3 inflammasome activation. 5

• It has also demonstrated beneficial effects in central serous chorioretinopathy (CSC), including improved best-corrected visual acuity, reduced choroidal thickness, and reduced subretinal fluid. 2