## Receptor Selectivity: The Key Discriminator **Key Point:** The critical distinction between spironolactone and eplerenone is receptor selectivity, which directly impacts tolerability and side-effect profile. ### Pharmacological Comparison | Feature | Spironolactone | Eplerenone | |---------|---|---| | **Receptor selectivity** | Non-selective aldosterone antagonist | Selective mineralocorticoid receptor (MR) antagonist | | **Androgen receptor antagonism** | Yes (significant) | Minimal/None | | **Progesterone receptor antagonism** | Yes | Minimal/None | | **Gynecomastia/sexual dysfunction** | 10–20% incidence | <1% incidence | | **Onset of action** | 2–3 days (slower) | 1–2 hours (faster) | | **HF mortality benefit** | Proven (RALES trial) | Proven (EMPHASIS-HF trial) | | **Cost** | Lower | Higher | **High-Yield:** Eplerenone's selectivity for mineralocorticoid receptors makes it the preferred aldosterone antagonist in patients who cannot tolerate spironolactone's endocrine side effects. **Clinical Pearl:** Spironolactone's non-selective antagonism of androgen and progesterone receptors causes dose-dependent gynecomastia, erectile dysfunction, and menstrual irregularities. Eplerenone avoids these side effects because it does not significantly bind to these off-target receptors. **Mnemonic:** **SELECTIVE = SIDE-EFFECT-FREE** — Eplerenone's selectivity for MR means fewer hormonal side effects; Spironolactone's non-selectivity means more off-target effects. ## Clinical Application Both agents reduce mortality in systolic HF and are indicated in the same populations. However, eplerenone is preferred when spironolactone is not tolerated due to sexual dysfunction or gynecomastia. [cite:Harrison 21e Ch 297; KD Tripathi 8e Ch 12]
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