potassium-sparing diuretic

MECHANISM / CLASSES 1) Aldosterone receptor antagonists (competitive): spironolactone, eplerenone. Block the mineralocorticoid receptor in principal cells of the cortical collecting duct, decreasing transcription of ENaC, Na+/K+-ATPase, and ROMK. Result: less Na+ reabsorption, less K+ and H+ secretion. Spironolactone is also an androgen receptor antagonist and inhibits steroid synthesis; eplerenone is more selective for the mineralocorticoid receptor. Onset is slow (requires gene transcription changes, days). 2) ENaC (epithelial sodium channel) blockers: amiloride, triamterene. Directly block luminal Na+ channels in principal cells. This reduces the lumen-negative potential that drives K+ and H+ secretion. Aldosterone-independent and act faster than spironolactone.

PHYSIOLOGY Principal cells of the late distal tubule and collecting duct reabsorb Na+ via ENaC (aldosterone-regulated) and secrete K+ via ROMK. Only about 2-3% of filtered Na+ is reabsorbed here, so these drugs are weak natriuretics when used alone. Alpha-intercalated cells secrete H+, which is also reduced, which can cause a hyperkalemic (type 4) metabolic acidosis.

CLINICAL USES - Spironolactone/eplerenone: primary hyperaldosteronism (Conn syndrome); resistant hypertension; heart failure with reduced EF (RALES: spironolactone; EPHESUS: eplerenone post-MI, mortality benefit); hepatic cirrhosis with ascites (drug of choice, along with salt restriction); PCOS and hirsutism (antiandrogen effect); acne in women. - Amiloride: lithium-induced nephrogenic diabetes insipidus (blocks lithium entry via ENaC); Liddle syndrome (gain-of-function ENaC mutation; treated with amiloride or triamterene, not spironolactone, because aldosterone is low). - Triamterene/amiloride: combined with thiazides or loop diuretics to prevent hypokalemia. - Hypokalemia prevention in patients on loop or thiazide diuretics.

ADVERSE EFFECTS - Hyperkalemia (most important; can cause peaked T waves, widened QRS, arrhythmias). Risk increases with ACE inhibitors, ARBs, NSAIDs, beta-blockers, renal impairment, and K+ supplements/salt substitutes, and with trimethoprim (which has an amiloride-like ENaC effect). - Metabolic acidosis (hyperkalemic, non-anion gap). - Spironolactone: gynecomastia, impotence, decreased libido, menstrual irregularities (antiandrogen/progestogenic effects). Eplerenone avoids these. - Triamterene: nephrolithiasis (triamterene stones), folate antagonism (megaloblastic anemia). - Contraindicated in hyperkalemia, advanced CKD/anuria, and Addison disease. Use cautiously with other K+-raising drugs.

HIGH-YIELD COMPARISON Diuretic effects on urine and blood: - Urine: increased NaCl; K+ unchanged or decreased (excretion falls with K+-sparing agents, vs increased with loop/thiazides). - Blood: increased K+ (vs decreased with loop/thiazides), decreased pH (acidosis, vs alkalosis with loop/thiazides).

Board pearls - Heart failure + mortality benefit: spironolactone and eplerenone. - Gynecomastia on a BP/HF/ascites drug: spironolactone. Switch to eplerenone. - Hypertension with low renin, low aldosterone, and hypokalemia (Liddle): amiloride/triamterene. - Hyperkalemia in a patient on an ACE inhibitor plus spironolactone: stop or reduce the offending agents and treat per hyperkalemia protocol (calcium gluconate for ECG changes, insulin plus glucose, albuterol, etc.). - Mnemonic: "The K+ STAyS": Spironolactone, Triamterene, Amiloride, Eplerenone (the "STAyS" mnemonic from First Aid is for K+-sparing diuretics).