Mechanism of Action of Spironolactone
Spironolactone acts as a competitive antagonist of aldosterone at the mineralocorticoid receptor in the distal convoluted renal tubule, blocking the aldosterone-dependent sodium-potassium exchange site, which results in increased sodium and water excretion while retaining potassium. 1
Primary Pharmacologic Mechanism
Spironolactone and its active metabolites competitively bind to aldosterone receptors at the distal tubule, preventing aldosterone from exerting its normal effect of sodium reabsorption and potassium excretion 1
This competitive inhibition at the mineralocorticoid receptor leads to natriuresis (increased sodium excretion) while conserving potassium, making it a potassium-sparing diuretic 2, 3
The drug produces both diuretic and antihypertensive effects through this aldosterone receptor blockade mechanism 3
Important Pharmacodynamic Considerations
There is a characteristic lag period of 3-5 days between initiating spironolactone and achieving full natriuretic effect, which is critical to understand when starting therapy 2, 3
This delayed onset occurs because the drug must compete with existing aldosterone and allow time for changes in sodium-potassium exchange to manifest clinically 2
Active Metabolites and Their Role
Spironolactone is rapidly and extensively metabolized, with the active metabolite canrenone being a major contributor to its therapeutic effects 1
The metabolites can be divided into two categories: those where sulfur is removed (like canrenone) and those where sulfur is retained (like TMS and HTMS), all contributing to mineralocorticoid receptor antagonism 1
Canrenone has a mean half-life of 16.5 hours, much longer than spironolactone's 1.4-hour half-life, explaining the sustained therapeutic effect 1
Additional Pharmacologic Properties
Spironolactone has significant anti-androgenic effects due to competitive inhibition of testosterone and dihydrotestosterone binding to androgen receptors, which explains its endocrine side effects 4
The anti-androgenic properties include decreased testosterone production and direct receptor blockade, leading to gynecomastia in men and menstrual irregularities in women 4, 5
Spironolactone is considered the most potent mineralocorticoid receptor antagonist currently used in clinical practice, more effective than other potassium-sparing diuretics like amiloride 2, 3
Clinical Pitfalls Related to Mechanism
The potassium-retaining mechanism creates significant risk for hyperkalemia, particularly in patients with renal impairment, diabetes, elderly patients, or those taking ACE inhibitors, ARBs, or potassium supplements 2, 3
The lack of selectivity for the mineralocorticoid receptor (compared to newer agents like eplerenone) results in more frequent endocrine side effects, occurring in more than 10% of patients 4, 6
Food increases spironolactone bioavailability by approximately 95%, so patients should establish a consistent pattern of taking it with or without meals 1