Aldactone (Spironolactone) and Eplerenone Share the Same Core Mechanism but Differ in Receptor Selectivity
Both aldactone (spironolactone) and eplerenone are mineralocorticoid receptor antagonists that block aldosterone binding at the mineralocorticoid receptor, but eplerenone is significantly more selective for the aldosterone receptor, resulting in fewer hormonal side effects. 1, 2, 3
Shared Mechanism of Action
Both medications work through competitive antagonism of aldosterone at the mineralocorticoid receptor:
Spironolactone binds to mineralocorticoid receptors primarily in the distal convoluted renal tubule, blocking aldosterone-dependent sodium-potassium exchange, causing increased sodium and water excretion while retaining potassium 3
Eplerenone similarly binds to mineralocorticoid receptors and blocks aldosterone binding, preventing sodium reabsorption in both epithelial (kidney) and non-epithelial tissues (heart, blood vessels, brain) 2
Both agents produce sustained increases in plasma renin and serum aldosterone levels due to inhibition of the negative regulatory feedback of aldosterone on renin secretion 2
Critical Difference: Receptor Selectivity
The fundamental distinction lies in receptor specificity:
Spironolactone is non-selective, binding not only to mineralocorticoid receptors but also to progesterone and androgen receptors with moderate affinity 4, 5
Eplerenone was specifically engineered with a 9,11-epoxide group (replacing the 17-alpha-thioacetyl group of spironolactone) to achieve selective binding to mineralocorticoid receptors with minimal affinity for progesterone and androgen receptors 6, 1, 5
Clinical Implications of Selectivity Differences
Side Effect Profile
The receptor selectivity difference translates directly to tolerability:
Gynecomastia and sexual dysfunction occur significantly more frequently with spironolactone (21.2% gynecomastia in men, 21.1% mastodynia in women) compared to eplerenone (4.5% and 0%, respectively) 7
Male patients particularly benefit from eplerenone due to minimal risk of gynecomastia and impotence 1, 4
In the RALES trial, 10% of patients on spironolactone developed painful gynecomastia 6
Efficacy Comparison
Spironolactone appears more potent than eplerenone in certain contexts:
In primary aldosteronism, spironolactone reduced diastolic blood pressure by 12.5 mmHg versus 5.6 mmHg with eplerenone (difference of 6.9 mmHg, P<0.001), demonstrating superior antihypertensive effect 7
However, in idiopathic hyperaldosteronism, both agents achieved similar blood pressure control (76.5% vs 82.4% normalization, P=1.00) 8
For heart failure mortality reduction, spironolactone showed 30% relative risk reduction (RALES) while eplerenone showed 15% reduction (EPHESUS) 9
Both are considered equally effective preferred agents for resistant hypertension and primary aldosteronism by ACC/AHA guidelines 1
Hyperkalemia Risk
The risk of hyperkalemia is similar between both agents, despite different receptor selectivity:
Clinical trials show no significant difference in hyperkalemia-induced drug withdrawals between spironolactone and eplerenone 4
Mild hyperkalemia occurred in 2 patients on spironolactone 400mg and 3 patients on eplerenone 150mg in one comparative trial 8
Spironolactone may theoretically pose slightly higher risk due to very long half-lives of active metabolites (canrenone 16.5 hours, TMS 13.8 hours, HTMS 15 hours) compared to eplerenone's 3-6 hour half-life 2, 3, 5
Pharmacokinetic Distinctions
Beyond receptor selectivity, important pharmacokinetic differences exist:
Spironolactone has multiple active metabolites with prolonged half-lives (16.5 hours for canrenone), is >90% protein bound, and has a parent half-life of only 1.4 hours 3, 5
Eplerenone has no active metabolites, a half-life of 3-6 hours, reaches steady state in 2 days, and is 50% protein bound 2, 5
Eplerenone is metabolized exclusively by CYP3A4, making drug interactions more predictable 2
Practical Clinical Algorithm
For male patients or women concerned about menstrual irregularities: Start with eplerenone 25mg daily to avoid hormonal side effects 1, 9
For patients requiring maximum aldosterone blockade (severe heart failure, resistant hypertension): Consider spironolactone 12.5-25mg daily given potentially greater potency 6, 7
For patients on CYP3A4 inhibitors: Avoid eplerenone entirely; use spironolactone with caution 2
If gynecomastia develops on spironolactone: Switch to eplerenone at equivalent or slightly higher dose (spironolactone 25mg = eplerenone 25-50mg) 9, 8
Monitoring Requirements (Identical for Both)
Both agents require the same rigorous monitoring protocol:
Check potassium and creatinine at baseline, then at 2-3 days, 7 days, monthly for 3 months, then every 3 months 6
Hold therapy if potassium >5.5 mEq/L; discontinue if >6.0 mEq/L 9
Contraindicated if baseline potassium >5.0 mEq/L or creatinine >2.5 mg/dL in men (>2.0 mg/dL in women) or eGFR <30 mL/min/1.73m² 6, 1
Discontinue potassium supplements when initiating either agent 6
Common Pitfalls
Assuming interchangeability: Guidelines explicitly state there are limited data to support that spironolactone and eplerenone are interchangeable, with the key difference being selectivity rather than effectiveness of mineralocorticoid blockade 6
Inadequate dose titration of eplerenone: Eplerenone may require twice-daily dosing or higher total daily doses (up to 300mg) for adequate effect compared to spironolactone 1, 7
Combining with other RAAS inhibitors: Routine triple combination of ACE inhibitor, ARB, and either aldosterone antagonist should be avoided due to hyperkalemia risk 6