Aldosterone Receptor Blockers (Spironolactone, Eplerenone)

Summary

Aldosterone receptor antagonists are a class of diuretics that include Spironolactone and Eplerenone. As their name suggests, these drugs inhibit aldosterone receptors located in the principal cells of the distal tubules and collecting ducts of the kidneys. By blocking aldosterone signaling, these drugs increase the excretion of sodium and water, causing diuresis. These drugs also reduce the excretion of potassium and hydrogen ions, which is why they are sometimes called “potassium-sparing” drugs.

Because aldosterone receptor antagonists are not very specific for aldosterone receptors, they can also bind to and block androgen receptors, leading to anti-androgenic effects blocking the actions of testosterone. As such, aldosterone receptor antagonists are known as antiandrogen drugs.

Clinically, aldosterone receptor antagonists are used for the treatment of systolic heart failure. Being diuretics, they are also used to treat ascites and other fluid overload states. Finally, because of their antiandrogenic effects, they can be used to treat hirsutism, such as that caused by polycystic ovarian syndrome. 

Potential side effects to know for these drugs include gynecomastia, reduced libido and impotence, which are all related to antiandrogenic effects. Since these drugs increase the retention of potassium and hydrogen ions, they can potentially lead to hyperkalemia and metabolic acidosis.

Key Points

• Topic Anchor: Aldosterone receptor antagonists
  • Drug names:
    • Spironolactone
    • Eplerenone
      • a more specific receptor antagonist than spironolactone with fewer side effects
  • Mechanism:
    • Competitively inhibits aldosterone (mineralocorticoid) receptors
      • Distal tubule and collecting duct
        • Increased excretion of Na+ (and water) = diuresis
          • Causing downregulation of apical ENaCs and basolateral Na+/K+ pumps.
          • Generally a weaker diuretic effect
          • By blocking the effect of aldosterone, aldosterone receptor antagonists reduce the exchange of Na+ and K+ that occurs in principal cells, leading to loss of Na+ in the urine.
        • Decreased K+ secretion (K+ sparing) and H+ secretion
          • Aldosterone normally activates the H+ ATPase in principal and alpha-intercalated cells, leading to H+ secretion into the tubular lumen. Blocking this effect causes H+ to build up in the body and can lead to acidosis.
      • Note a compensatory increase in renin (PRA) may be observed
    • Antiandrogen
      • Antagonist at the androgen receptor (AR)
        • Androgen receptors are normally bound by testosterone and dihydrotestosterone (DHT)
      • Inhibitor of 17,20 desmolase/17-alpha hydroxylase
        • These enzymes are involved in the synthesis of sex hormones, including androgens.
  • Indications:
    • Systolic heart failure
      • Provides a mortality benefit!
      • Along with ACE inhibitors/ARBs and beta-blockers.  
      • Spironolactone and eplerenone are preferred in patients with heart failure as they can also prevent the deleterious effects of aldosterone-induced cardiac remodelling.
    • Ascites (liver disease)
      • Treatment of ascites secondary to cirrhosis involves restriction of sodium intake combined with diuretics. The most commonly prescribed initial therapy is a combination of furosemide and spironolactone.
    • Hirsutism (in polycystic ovarian syndrome)
      • Related to blocking of the androgen receptor
    • Hyperaldosteronism
      • Ex) Congenital adrenal hyperplasia, adrenal adenoma (Conn’s Syndrome)
    • Hypokalemia
  • Adverse effects:
    • Hyperkalemia
      • It’s called K+ sparing for a reason
    • Non-anion gap metabolic acidosis
    • Gynecomastia
      • Due to their antiandrogenic effects, which lead to an increase in the ratio of estrogens/androgens and the growth of breast tissue.
      • Eplerenone (~1%) poses less risk for gynecomastia than spironolactone (~10%).
    • Impotence/decreased libido
      • Think about this as secondary to androgen receptor blockade