Spironolactone and Eplerenone

Pharmacokinetics

High Resolution Pharmacokinetics

• Spironolactone: Rapid oral absorption that is favored by food intake. It undergoes massive hepatic first-pass clearance and metabolism to active metabolites, mainly canrenone and 7-α-thiomethylspironolactone. The half-life of plasma spironolactone is 1.4 hours, but its active metabolites have long biological half-lives of 13 to 24 hours. It is eliminated 60% through the kidneys and the rest through bile.
• Eplerenone: Bioavailability of 69% not influenced by food intake. It does not generate known active metabolites. It is metabolized exclusively in the liver by the isoenzyme CYP3A4. It has a short terminal elimination half-life of 4 to 6 hours, and is excreted 67% in urine and 32% in feces.

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.