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USMLE Step 1 Web Prep — Diuretics Pt. II 145510 >>> 0:00:01 SLIDE 1 of 6 Fig III-15. Actions of Thiazides on the Distal Convoluted Tubule (DCT) Inhibit Na+/Cl- cotransporter on luminal membrane of DCT. Normally, Na+ is exchanged for K+ via a “pump” on basolateral membrane, K+ returns to blood by back-diffusion. Ca2+ diffuses across luminal membrane via channels (PTH regulated) & returns to blood by a Ca2+/Na+ antiporter Inhibition of the Na+/Cl- cotransporter luminal levels hypokalemia & alkalosis occur consequent to the Na+ load “downstream”. activity of Ca2+/Na+ antiporter Thus, thiazide diuretics of Ca2+. reabsorption of Ca2+ hypercalcemia. urinary levels of Na+, K+ & Cl-, but urinary levels 145520 >>> 0:04:29 SLIDE 2 of 6 Thiazides Hydrochlorothiazide, indapamide, metolazone are organic acids, both filtered & secreted in the proximal tubule. Rx uses: HTN & CHF (proven longterm efficacy), edematous states (+/- loops) including pulmonary edema, nephrolithiasis & diabetes insipidus (ADH resistance or lithium-induced). Adverse effects:allergies, alkalosis, hypokalemia, hypercalcemia, hyperuricemia, hypovolemia, hyperglycemia, hyperlipidemia ( not indapamide) & sexual dysfunction. 145525 >>> 0:08:07 LDL-C & TGs, SLIDE 3 of 6 Fig III-16. Actions of Potassium Sparing Agents on Collecting Tubules CT determines final urinary Na+ concentration and secretes K+ & H+. Normally, aldosterone (principal cell) and formation of Na+ channels on luminal membrane activity of Na+/K+ & H+ exchangers. Na+ entry Na+ entry energy-dependent extrusion of H+ across luminal membranes (intercalated cell). The aldosterone receptor antagonist & Na+ channel blockers prevent above effects minor effects on Na+ reabsorption, but major effects on retention of K+ ions & protons. intracellular +ve charge Thus, K-sparing agents cause small & H+ (hyperkalemia & acidosis). extrusion of K+ into the lumen. urinary Na+, but marked in urinary K+ 145535 >>> 0:14:22 SLIDE 4 of 6 + K Sparing Agents Spironolactone, amiloride & triamterene are weak diuretics, since most of filtered Na+ is reabsorbed before reaching the CT. Rx uses of spironolactone: hyperaldosteronism, adjunctive with other diuretics in HTN & CHF, antiandrogenic uses (eg, female hirsutism). Rx uses of Na+ channel blockers: adjunctive with other diuretics in HTN & CHF to decrease K+ loss, lithium-induced diabetes insipidus (amiloride) Adverse effects: acidosis, hyperkalemia, azotemia, gynecomastia & libido changes (spironolactone), nephrolithiasis (triamterene). 145540 >>> 0:16:39 SLIDE 5 of 6 Table III-6. Modes of Action and Effects of Diuretics (A) Drug Mechanisms of Action acetazolamide Inhibit carbonic anhydrase in PCT Urinary Blood Chemistry & Electrolytes pH Na+ hypokalemia, K+ acidosis ( pH) Ca2+ HCO3 PO4 ethacrynic acid, Inhibit furosemide Na+/K+/2Clcotransporter in TAL Na+ K+ Ca2+ hypokalemia, alkalosis ( pH), hypomagnesemia Mg2+ ClHCO3 145545 >>> 0:17:33 SLIDE 6 of 6 Table III-6. Modes of Action and Effects of Diuretics (B) Drug Thiazides Mechanisms of Action inhibition of Na+/Clcotransporter in PCT Urinary Electrolytes Blood Chemistry & pH Na+ hypokalemia, K+ alkalosis ( pH), hypercalcemia ClCa2+ Amiloride & block Na+ channels triamterene, block spironolactone aldosteronereceptors in CT Na+ (small) hyperkalemia, acidosis ( pH) K+ H+