Medicine & USMLE

ENaC Blockers (Amiloride, Triamterene)

Renal Pharm
  1. ACE Inhibitors
  2. Aldosterone Receptor Blockers (Spironolactone, Eplerenone)
  3. Ethacrynic Acid
  4. Loop Diuretics (Furosemide, Bumetanide, Torsemide)
  5. Mannitol
  6. Acetazolamide
  7. ENaC Blockers (Amiloride, Triamterene)
  8. Thiazide Diuretics
  9. Angiotensin II Receptor Blockers (ARBs)


ENaC blockers are a class of drugs that include Triamterene and Amiloride. As their name suggests, ENaC blockers inhibit the epithelial sodium channels located in the distal tubules and principal cells of collecting ducts in the kidneys. By inhibiting sodium reabsorption, ENaC blockers increase sodium excretion into the urine. They also reduce potassium and hydrogen ion secretion, which is why these drugs are sometimes called “potassium-sparing” drugs.

These drugs are often used for the treatment of nephrogenic diabetes insipidus, including that caused by lithium. These drugs can also be used to treat Liddle disease, a syndrome of overactive ENaC channels. The adverse effects of the ENac blocks are related to their mechanism. In particular, retention of potassium and hydrogen ions can lead to hyperkalemia and metabolic acidosis.

Key Points

  • Topic Anchor: Epithelial Sodium Channel Blockers
    • Drug names:
      • Triamterene
      • Amiloride
    • Mechanism:
      •  Inhibits epithelial sodium channel (ENaC)
        • In the apical membrane of principal cells in collecting ducts
          • ↑ excretion of Na+
            • ENaC channels in the principal cells of the collecting tubule are used to reabsorb sodium in tubular fluid. Blocking them prevents reabsorption and leads to the urinary loss of sodium.
          • Decreased K+ secretion (K+ sparing) and H+ secretion 
            • By inhibiting the reabsorption of Na+, ENaC blockers cause the tubular fluid to have a more positive luminal potential. This creates an unfavorable charge environment for the secretion of K+ and H+ (positive charges repel positive charges).
    • Indications:
      • Nephrogenic DI (amiloride)
        • Defective ADH receptors in the kidney and an inability to concentrate urine
        • Particularly in patients with lithium-induced DI [UTD]
      • Liddle syndrome
        • Lidle syndrome is an autosomal dominant renal disease caused by a gain of function mutation in the ENaC channel, leading to unregulated Na+ reabsorption. By blocking ENaC channels, Amiloride can reduce the rate of reabsorption and restore a normal Na+ balance.
    • Adverse effects:
      • Hyperkalemia
        • It is called K+ sparing for a reason
        • Seen especially when compounded with other drugs (e.g. ACEI)
      • Non-anion gap metabolic acidosis