Spironolactone

Mechanism

Pharmacological Group

Competitive steroid antagonist of the mineralocorticoid (aldosterone) receptor.

Mechanism of Action

Spironolactone competitively binds to the cytoplasmic Mineralocorticoid Receptor (MR) in the principal cells of the Cortical Collecting Tubulus (CCT). This prevents aldosterone from translocating to the cell nucleus and stimulating the transcription of aldosterone-induced proteins (AIPs). As a result, it occurs:

1. The internalization and degradation of ENaC apical sodium channels (inhibiting sodium entry down the gradient).
2. The decrease in the synthesis and activity of the basolateral Na+/K+-ATPase pump.
3. The attenuation in the expression of apical potassium channels (ROMK) and the proton transporter in intercalated cells.

This promotes a discrete natriuresis (less sodium is reabsorbed) while blocks the urinary secretion of potassium and protons (H⁺), acting as a potassium-sparing diuretic.

Pharmacokinetics

Key Pharmacokinetics

• Bioavailability: Greater than 90%, it increases substantially if administered with foods rich in fat.
• Metabolism: Rapid and extensive first-pass hepatic metabolism to long half-life active metabolites, mainly canrenone and 7-α-thiomethylspironolactone.
• Excretion: Mostly renal as conjugated metabolites.
• Half-life: 1.4 hours for the parent spironolactone, but 13 to 24 hours for its active metabolites. Its pharmacodynamic effect takes 2 to 3 days to be fully established.

Indicators and dose

Clinical Indications

• Heart failure (Reduced Ejection Fraction, Classes II-IV): Significantly reduces mortality and myocardial fibrosis (RALES clinical study).
• Primary Hyperaldosteronism (Conn Syndrome): Medical treatment of choice in bilateral adrenal hyperplasia.
• Ascites associated with liver cirrhosis: First-line diuretic of choice due to the marked secondary hyperaldosteronism that these patients present.
• Refractory hypertension: Considered the drug of choice as a fourth agent (PATHWAY-2 study).
• Hirsutism and Acne in women: Off-label use thanks to its antiandrogenic properties.

Dosage and Settings

• Heart Failure: 12.5 mg to 25 mg orally once a day. Maximum dose of 50 mg/day (RALES study).
• Cirrhotic Ascites: Start with 100 mg daily, titrating progressively (usual ratio 100:40 spironolactone:furosemide to maintain normokalemia) up to a maximum of 400 mg/day.
• Kidney adjustment:
  - CrCl 30-50 mL/min: Start with 12.5 mg per day or every other day. Monitor closely.
  - CrCl < 30 mL/min: Contraindicated in heart failure due to unacceptable risk of lethal hyperkalemia.

Security

Contraindications

• Absolute: Preexisting hyperkalemia (K+ > 5.0 mEq/L); Addison's disease; severe renal failure (CrCl < 30 mL/min in hypertension, or CrCl < 30 mL/min and hyperkalemia in heart failure); concomitant use with eplerenone or finerenone.

Adverse Effects (ADR)

• Very common: Hyperkalemia (especially if associated with ACEI, ARB or in diabetic patients).
• Endocrine / Non-selective: Due to its binding affinity for progesterone and androgen receptors, it produces painful gynecomastia in men (up to 10% at high doses), erectile dysfunction, menstrual irregularities in women and mastodynia.
• Common: Renal tubular acidosis type IV (hyperchloremic hyperkalemic acidosis), moderate cellular dehydration.

Interactions

• ACEI / ARA-II / Potassium Supplements: Critical increase in the risk of severe hyperkalemia with risk of cardiac asystole. Requires strict monitoring of electrolytes.
• NSAIDs: They can attenuate the natriuretic effect of spironolactone and increase the risk of acute nephrotoxicity.

Pregnancy and Breastfeeding

Category C. It has known antiandrogenic effects; potential risk of feminization of male fetuses. Avoid during pregnancy. It is compatible with breastfeeding since its metabolites are excreted in minimal proportions.