Amiloride

Amiloride acts on the late distal tubule and collecting duct by directly inhibiting the luminal ENaC channel on principal cells, independent of aldosterone (unlike spironolactone/eplerenone, which block the mineralocorticoid receptor). By blocking sodium entry into the cell, it reduces the lumen-negative electrochemical gradient that normally drives potassium and hydrogen ion secretion into the tubular fluid. This results in mild natriuresis with potassium retention and can cause a mild hyperchloremic metabolic acidosis (Type 4 RTA-like picture) due to decreased H+ secretion.

Clinical uses: adjunct to thiazide or loop diuretics to prevent/treat hypokalemia, treatment of Liddle syndrome (a gain-of-function ENaC mutation causing hypertension with hypokalemic metabolic alkalosis—amiloride is first-line here since it directly blocks the overactive channel), and sometimes in heart failure or ascites management combined with other diuretics.

Key adverse effects: hyperkalemia (especially with renal insufficiency, ACE inhibitors/ARBs, or potassium supplements), metabolic acidosis, and rarely leg cramps or GI upset. Contraindicated in severe renal failure and with concurrent potassium-sparing agents or high-dose potassium supplementation.

Mechanistic distinction for boards: Amiloride and triamterene work directly on ENaC (aldosterone-independent), whereas spironolactone and eplerenone are aldosterone receptor antagonists (aldosterone-dependent). This distinction is tested when differentiating drug efficacy in conditions like primary hyperaldosteronism (spironolactone effective) vs Liddle syndrome (amiloride effective, spironolactone ineffective since the channel is aldosterone-independent).