Spironolactone and Eplerenone

Mechanism

Pharmacologic Class and Drug Group

Potassium-sparing diuretics of the class of Selective and Non-Selective Mineralocorticoid Receptor Antagonists (MRA)..

Mechanism of Action

Aldosterone is an endogenous mineralocorticoid synthesized in response to angiotensin II and extracellular potassium that promotes sodium and water retention alongside potassium and hydrogen ion excretion. Furthermore, at tissue level, aldosterone is a potent activator of inflammation and collagen synthesis, driving pathological hypertrophy and progressive fibrosis in both myocardium and arterial resistance vessels.

Mecanismo Molecular de Bloqueo Mineralocorticoide

1. Competitive intracellular Mineralocorticoid Receptor (MR) blockade: Both drugs diffuse into distal and cortical collecting-duct cells and competitively bind the cytosolic mineralocorticoid receptor. This prevents nuclear translocation and transcription of aldosterone-regulated proteins (AIPs), reducing apical expression of sodium channels ENaC and the activity of the pump Na+/K+ ATPase basolateral:

MRA Aldosterone Receptor ↓ Reabsorption of Na⁺ and ↓ Excretion of K⁺ and H⁺

2. Reduction of Myocardial and Vascular Fibrosis: Mineralocorticoid receptor blockade in cardiac fibroblasts reduces type I and III procollagen production, contributing to reduced progressive ventricular stiffness, pathological remodelling and susceptibility to re-entrant arrhythmias.

3. Receptor Selectivity (Key Clinical Distinction):

• Spironolactone: Non-selective antagonist with residual affinity for progesterone and androgen receptors, explaining endocrine adverse effects such as painful gynecomastia, erectile dysfunction and menstrual irregularities.
• Eplerenone: Highly selective antagonist. An epoxide group substantially reduces its affinity for progesterone and androgen receptors (up to 300-fold), limiting endocrine adverse effects.

Pharmacokinetics

High-Resolution Pharmacokinetics

• Spironolactone: Rapid oral absorption enhanced by food. Undergoes extensive hepatic first-pass metabolism to active metabolites, principally canrenone and the 7-α-thiomethylspironolactone. Spironolactone's plasma half-life is 1.4 hours, while active metabolites have half-lives of 13 to 24 hours. About 60% is eliminated renally and the remainder through bile.
• Eplerenone: Bioavailability of 69%, unaffected by food. No known active metabolites. Metabolized hepatically by the isoenzyme CYP3A4. Short terminal elimination half-life of 4 to 6 hours; 67% is excreted in urine and 32% in faeces.

Indicators and dose

Clinical Indications and Uses

• Heart Failure with Reduced Ejection Fraction (HFrEF): Indicated to reduce general morbidity and mortality in patients with NYHA functional class II-IV who already receive optimal doses of ACEI/ARBs and Beta-blockers.
• Post-AMI Heart Failure: The use of eplerenone is especially indicated in patients with left ventricular systolic dysfunction (LVEF ≤ 40%) after an acute clinical myocardial infarction with concomitant clinical signs of pulmonary congestion.
• Primary Hyperaldosteronism (Conn Syndrome / Bilateral Adrenal Hyperplasia): Spironolactone is the priority drug of choice for medical management.
• Refractory Arterial Hypertension (Fourth Drug of Choice): Adjuvant treatment to block excessive sodium retention hidden by aldosterone escape.
• Liver Cirrhosis with Refractory Ascites: First-line due to its ability to reverse secondary hyperaldosteronism derived from extreme splanchnic vasodilation.

Dosage and Clinical Adjustment

Spironolactone:

• Heart Failure: Initial dose of 12.5 mg to 25 mg once daily orally. Maximum recommended dose of 50 mg per day.
• Hyperaldosteronism / Ascites: Usual therapeutic dose of 100 mg to 400 mg once daily.
• Renal adjustment: If eGFR is between 30 and 49 mL/min/1.73 m², start with 12.5 mg per day or every other day. Contraindicated if it is less than 30 mL/min.

Eplerenone:

• Heart Failure (Post-AMI or Chronic): Initial dose of 25 mg once a day. Increase to target dose of 50 mg once daily within the first 4 weeks of tolerance.
• Renal adjustment: Start with 25 mg every other day if eGFR is 30 to 49 mL/min/1.73 m². Contraindicated if it is less than 30 mL/min.

Security

Absolute and Relative Contraindications

Absolute Contraindications

• Basal severe hyperkalemia (K⁺ > 5.0 mEq/L at the beginning of therapy).
• Advanced or terminal renal failure: Contraindicated in patients with eGFR less than 30 mL/min/1.73 m² (or serum creatinine greater than 2.5 mg/dL in men and 2.0 mg/dL in women).
• Addison's disease diagnosed.
• Concomitant use of eplerenone with strong CYP3A4 inhibitors (Ketoconazole, Itraconazole, Ritonavir).

Relative Contraindications

• eGFR between 30 and 45 mL/min/1.73 m² (requires strict monitoring and a 50% reduction in the initial dose).
• Concurrent use of ACE inhibitors or ARBs (increases the risk of hyperkalemia).

Adverse Effects and Toxicity

• Hyperkalemia: It is the most prevalent undesirable effect and the highest clinical risk. Requires regular electrolyte monitoring.
• Gynecomastia and Mastodynia (Spironolactone 10%): Painful, bilateral, directly linked to peripheral androgen inhibition. It usually forces the patient to rotate to eplerenone.
• Dehydration and Mild Hyponatremia: Secondary to forced natriuresis.
• Hyperchloremic Metabolic Acidosis: Due to a concomitant decrease in the active excretion of hydrogen ions in the distal nephron.

Safety Alert: Strict Criteria to Prevent Fatal Hyperkalemia

According to heart failure clinical practice guidelines, safe initiation and maintenance of an ARM requires strict compliance with the following serum biological constants:

Starting Requirements: K⁺ < 5.0 mEq/L and eGFR > 30 mL/min/1.73 m²

Electrolytes and kidney function should be monitored on day 3 and day 7 of initiation, weekly for the first month, monthly for the first three months, and semi-annually thereafter for life. If serum potassium persistently exceeds 5.5 mEq/L, the dose should be reduced by 50% or the drug should be discontinued immediately.

Relevant Drug Interactions

• Potent and Moderate CYP3A4 Inhibitors (Clarithromycin, Diltiazem, Verapamil): They substantially increase the area under the eplerenone curve, which can increase the risk of arrhythmias secondary to hyperkalemia.
• NSAIDs: They attenuate the diuretic and nephroprotective effects of MRAs and predispose to the development of acute renal failure.
• Dual aldosterone receptor blockers (ACEI + concurrent ARB): This combination is formally discouraged due to unacceptably high rates of hyperkalemia and severe renal dysfunction.