Distal Convoluted Tube Slide Thiazide Diuretics

2.3 – “Distal C Convoluted onvoluted Tube Slide”: Thiazi Thiazide de diuretics Distal convol convoluted uted tubule ((DCT) DCT) physiology • Sodium chloride are the most important ions in the DCT, but only about 10% of filtered Na resorbed here. • Na-K-ATPase pumps on the basolateral membrane (i.e. the intracellular compartment of the tubular epithelial cells [pool deck]) maintain a low intracellular sodium concentration to enable absorption from the lumen (salty peanuts at the banana vending machine; lumen = yellow slide). • Selectively impermeable to H2O. • NaCl resorption dilutes tubular fluid via electrically neutral NaCl transporter at the apical membrane transporting NaCl back into cell. • In LOH, back leak of potassium causes positive potential in lumen, driving out cations. Not so here. At DCT, calcium is actively resorbed by apical calcium channel regulated by PTH. Thiazide ddiuretics iuretics • Include hydrochlorothiazide (HCTZ), indapamide, metolazone, & chlorthalidone (kid on diving board in chloro suit with pasty thighs) • Bind to the Cl- site of the NaCl cotransporter, inhibiting NaCl resorption and dumping salt into the urine & causing natriuresis (security bumping salt barrel into pool) • Also enhance calcium reabsorption (ice cream falling off of slide). In PCT thiazide induced volume depletion → enhanced sodium & passive Ca resorption. In the DCT, block Na uptake into cell → ↑Na/Ca exchange at the basolateral membrane • Indications: o First line treatment of mild or moderate HTN with normal cardiac function (hypertensive pipes). Decrease cardiac output & vascular volume. Chlorthalidone is preferred to HCTZ d/t longer half-life. o Can be useful adjunctive treatment in HF, although not first line monotherapy (HF balloon). Often combined with loop diuretics, which are more effective in HTN secondary to HF or liver failure. o Paradoxically treat nephrogenic diabetes insipidus (DI) (urinating statue). Can reduce polyuria & polydipsia in this case. Thought to be by inducing a mild hypovolemia →↑ water & Na resorption in the PCT. ▪ Nephrogenic DI often caused by lithium o First line treatment for calcium nephrolithiasis (2/3 of kidney stones). Hypercalciuria can be leveraged to prevent calcium stone formation, e.g. secondary to sarcoidosis, hyperparathyroidism, hypervitaminosis D (removal of stones in slide). 2 mechanisms: ▪ Inhibition of Na/Cl cotransporter →↓intracellular Na concentration →activation of basolateral Na/Ca antiporter, which pumps Na into the cell in exchange for Ca, Resulting ↓intracellular Ca →↑ luminal Ca absorption. ▪ Hypovolemia →↑Na & H2O resorption in the PCT → passive increase in paracellular Ca2 resorption. o Attenuates osteoporosis therapy & may ↓fracture risk (broken chalk on “no accidents” chalkboard) • Side effects/toxicities o Hyperglycemia, hyperlipidemia, hyperuricemia, and hypercalcemia. Remember hyperGLUC (Glycemia, Lipidemia, Uric acid, Calcium) ▪ Hyperglycemia d/t impaired pancreatic release of insulin & ↓tissue glucose utilization. May return to baseline with prolonged use. (HCTZ on the high dive) ▪ Hyperlipidemia, although may return to baseline with prolonged use. (HCTZ on the high dive). Can imagine a fat kid up on diving board. ▪ Hyperuricemia (girl with yellow knitting) ▪ May cause hypercalcemia d/t enhanced calcium resorption (elevated high dive ice cream). Not especially common as a primary effect, but may unmask ↑calcium d/t other causes. o Sulfa drugs, although reactions are extremely rare (eggs). o Decrease renal clearance of lithium; lithium levels must be carefully monitored if coadministered. (lithium ion balloons) o Potassium wasting d/t blockage of Na-Cl cotransporter →↑K secretion in exchange for Na resorption. May see hypokalemia (banana peel) o Hyponatremia d/t decreased Na resorption with continued water absorption, unlike loop diuretics (spilled peanuts) o Contraction alkalosis secondary to hypovolemia induced activation of RAAS (contracted bleach bottle)