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thiazide-diuretics-mechanism-of-action-and-adverse-side-effects

Thiazide Diuretics: Mechanism of Action and Adverse Side Effects Thiazide diuretics Authors: Huneza Nadeem Reviewers: Ran (Marissa) Zhang, Julian Midgley* * MD at time of publication Thiazides in circulation enter the proximal convoluted tubule (PCT) cells by basolateral Organic Acid Transporter 1 (OAT1) ↑ Intracellular thiazide availability for apical OAT4 exchangers OAT4 reabsorb urate in lumen in exchange for thiazide that is excreted ↑ Urate in serum Hyperuricemia Uric acid build up in joints Gout Block the Na-Cl cotransporter (NCC) in the distal convoluted tubule (DCT) of the nephron Impaired water excretion, vasopressin release, and ↑ water intake (mechanisms unclear) Hyponatremia Lack of intracellular Na+ needed to drive the Na+/K+ ATPase (moves 2 K+ into cell, 3 Na+ out into peritubular capillary) ↓ Intracellular Na+ drives Ca-ATPase and 3:Na:Ca exchanger activity (moves 3 Na+ into cell, 1 Ca+2 out into peritubular capillary) ↑ Ca+2 in serum Hypercalcemia See Hypercalcemia: Clinical Findings slide ↓ Na+ and Cl- reabsorption into proximal DCT cells ↑ Na+ in DCT filtrate by ∼3-5% Water follows Na+ to maintain balanced osmotic pressure ↑ Water available for excretion Mild Diuresis ↓ Blood volume Hypotension ↑ Na+ filtrate delivery to cortical collecting duct (CCD) Epithelial sodium channels (ENaC)s on principal cells of the CCD transport Na+ from filtrate into the principal cells ↑ Intracellular Na+ drives Na/K+ ATPase activity on principal cells (moves 2 K+ into cell, 3 Na+ out into peritubular capillary) ↑ Intracellular K+ drives H/K+ ATPase activity on intercalated cells (moves 1 H+ into cell, 1 K+ out into tubular filtrate) ↓ K+ in serum Hypokalemia See Hypokalemia: Clinical Findings slide Acute response to high dose thiazide diuretics (mechanism unclear) Hyperlipidemia Hypokalemia induces hyperpolarization of pancreatic beta cells ↓ Number of voltage gated Ca+2 channels open given intracellular charge ↓ Ca+2 influx prevents exocytosis mediated insulin release ↓ Glucose uptake in the body Hyperglycemia Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published October 18, 2022 on www.thecalgaryguide.com