What are Mineralocorticoid Receptor Antagonists (MRAs)?

Mineralocorticoid Receptor Antagonists (MRAs)

Mineralocorticoid receptor antagonists (MRAs) are medications that block aldosterone binding at mineralocorticoid receptors, primarily used in heart failure with reduced ejection fraction, resistant hypertension, and certain kidney disorders to reduce mortality and morbidity.

Mechanism of Action

• MRAs competitively bind to mineralocorticoid receptors, blocking the effects of aldosterone 1
• This blockade occurs primarily in the distal convoluted renal tubule, causing:
  • Increased sodium and water excretion
  • Retention of potassium
• Beyond diuretic effects, MRAs have important antifibrotic and anti-remodeling effects on the heart and vasculature 2

Available MRAs

There are currently two main FDA-approved MRAs in clinical use:

1. Spironolactone

   • First-generation steroidal MRA
   • Less selective for mineralocorticoid receptors
   • May cause endocrine side effects (gynecomastia, impotence) due to binding to other steroid receptors
   • Half-life of active metabolites: 13-17 hours 1

2. Eplerenone

   • Second-generation steroidal MRA
   • More selective for mineralocorticoid receptors
   • Fewer endocrine side effects
   • Half-life: 3-6 hours 3

3. Finerenone (newer non-steroidal MRA)

   • Recently studied in heart failure and diabetic kidney disease 4
   • Not yet as widely used as spironolactone or eplerenone

Clinical Indications

1. Heart Failure with Reduced Ejection Fraction (HFrEF)

• Class I recommendation for patients with NYHA class II-IV symptoms and LVEF ≤35% 5, 6
• Added to standard therapy (ACE inhibitor/ARB and beta-blocker)
• Reduces mortality by 30% (spironolactone in RALES trial) 5
• Reduces cardiovascular death or HF hospitalization by 37% (eplerenone in EMPHASIS-HF) 5

2. Resistant Hypertension

• Indicated for patients not meeting BP targets on three antihypertensive medications including a diuretic 6, 7
• Particularly effective when mineralocorticoid receptor overactivation contributes to hypertension 8

3. Diabetic Kidney Disease

• Used in patients with type 2 diabetes, eGFR ≥25 ml/min/1.73 m², normal potassium, and albuminuria 5, 6

Dosing and Administration

• Starting dose:

  • Spironolactone: 25 mg once daily 6
  • Eplerenone: 25 mg once daily 3

• Target dose:

  • Both can be titrated to 50 mg once daily after 4 weeks if potassium <5.0 mEq/L 6
  • For patients with eGFR 31-49 mL/min/1.73 m², reduce dose by half 5, 6

Monitoring Requirements

• Initial monitoring:

  • Check serum potassium and renal function within 1-2 weeks after initiation
  • Recheck at 4 weeks after initiation or dose change 6

• Long-term monitoring:

  • Every 6 months once stable
  • More frequent testing during clinical instability 5

Contraindications and Precautions

• Absolute contraindications:

  • eGFR <30 mL/min/1.73 m² 5, 6
  • Serum potassium ≥5.0 mEq/L 5, 6

• Major precautions:

  • Hyperkalemia risk is the most significant concern
  • Combination with ACE inhibitors or ARBs increases this risk 5, 6
  • Discontinue MRA if serum potassium cannot be maintained <5.5 mEq/L despite mitigation measures 5

Clinical Benefits Beyond Diuresis

• Reduction in mortality in HFrEF 5, 4
• Prevention of cardiac remodeling and fibrosis 2
• Reduction in heart failure hospitalizations across the spectrum of heart failure 4
• Potential prevention of heart failure development in hypertensive patients 8

Common Pitfalls and Practical Considerations

• Hyperkalemia risk: The most common reason for inappropriate discontinuation

  • Risk can be mitigated with proper patient selection and monitoring
  • Serious hyperkalemia (K+ >6.0 mmol/L) occurs in only 2.9% of patients on MRAs vs. 1.4% on placebo 4

• Underprescribing: Despite strong evidence and guideline recommendations, MRAs remain underutilized in eligible patients

• Combination therapy: Avoid combining MRAs with both ACE inhibitors and ARBs due to excessive hyperkalemia risk 5

• Medication adherence: Consider barriers such as cost and side effects when prescribing MRAs 6

MRAs represent a high-value therapy for appropriate patients, with significant mortality and morbidity benefits when used according to guidelines with proper monitoring.