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Adverse Consequences of Diuretics:

Adverse Consequences of Diuretics

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Klabunde , R. http ://cvpharmacology.com/diuretic/diuretics Proximal Tubule Reabsorbs: 67% Na+, K+, and water All glucose, amino acids Most bicarbonate Loop of Henle Creates a hyperosmotic medullary interstitium ; Important for concentrating urine Early Distal Tubule Further reabsorption of Na+ causes additional dilution of forming urine EDT PT Late Distal Tubule/Collecting Duct Hormones fine tune ions & water reabsorption Nephron Function by Segment Late DT/CD

How do diuretics get to their site of action?:

How do diuretics get to their site of action?

Proximal Tubule and Distal Tubule/Collecting Duct: CARBONIC ANHYDRASE INHIBITORS (acetazolamide):

Proximal Tubule and Distal Tubule/Collecting Duct: CARBONIC ANHYDRASE INHIBITORS (acetazolamide) Seldin & Giebisch’s The Kidney. 2013

Proximal Tubule and Distal Tubule/Collecting Duct: CARBONIC ANHYDRASE INHIBITORS (acetazolamide):

Proximal Tubule and Distal Tubule/Collecting Duct: CARBONIC ANHYDRASE INHIBITORS (acetazolamide) METABOLIC ACIDOSIS HCO3 HCO3- Seldin & Giebisch’s The Kidney. 2013

Ascending Limb of Loop of Henle: LOOP DIURETICS (furosemide, torsemide, bumetanide, ethacrynic acid):

Na + /K + /2Cl - transporter is blocked Tubular lumen Peritubular Capillary Na + ATP K + H 2 O 2 Cl - Na + K + K + Cl - K + Interstitium Ascending Limb of Loop of Henle: LOOP DIURETICS (furosemide, torsemide , bumetanide, ethacrynic acid ) Ca 2+

Adverse Consequences of Loop Diuretics: Hypokalemia:

Adverse Consequences of Loop Diuretics: Hypokalemia ↓K+ ↑Na+ ↑ K+ AND, Decreased Effective Arterial Blood Volume Activates Renin-Angiotensin-Aldosterone Na, K, Cl in tubular fluid Thick Ascending Limb Loop of Henle Late Distal Tubule/Cortical Collecting Duct

Loop Diuretics: Decreased extracellular fluid volume/RAAS activation:

Loop Diuretics: Decreased extracellular fluid volume/RAAS activation Thick Ascending Limb Loop of Henle Late Distal Tubule/Cortical Collecting Duct RAAS Activation Aldosterone Decreased extracellular fluid volume

Adverse Consequences of Loop Diuretics: Metabolic Alkalosis:

Adverse Consequences of Loop Diuretics: Metabolic Alkalosis ATP H + Thick Ascending Limb Loop of Henle Late Distal Tubule/Cortical Collecting Duct Decreased extracellular fluid volume Aldosterone ↓H+ Relative ↑ HCO3- Urine H+ - - - - -

Adverse Consequences of Loop Diuretics: Hypocalcemia/Hypercalciuria:

Na + /K + /2Cl - transporter is blocked Na + /K + ATPase activity decreased Decrease intracellular K, leads to decreased K + secretion into the tubular fluid Decreased positive electrochemical gradient decreases passive Ca 2+ reabsorption = Calcium excretion in the urine Tubular lumen/urine Peritubular Capillary Na + ATP K + H 2 O 2 Cl - Na + K + K + Cl - K + Interstitium Adverse Consequences of Loop Diuretics: Hypocalcemia/ Hypercalciuria Ca 2+ More Ca 2+ In urine ↓Ca 2+

Early Distal Tubule: THIAZIDE DIURETICS (chlorthalidone, hydrochlorothiazide) :

Early Distal Tubule: THIAZIDE DIURETICS ( chlorthalidone , hydrochlorothiazide) Direct inhibition of NaCl cotransporter Tubular lumen Interstitium Peritubular Capillary Na + ATP K + Na + Cl - H 2 O

Adverse Consequences of Thiazide Diuretics: Hypokalemia:

Adverse Consequences of Thiazide Diuretics: Hypokalemia ↓K+ plasma ↑Na+ Distal nephron More ↑K+ urine AND, Decreased Effective Arterial Blood Volume Activates Renin-Angiotensin-Aldosterone Na, Cl in tubular fluid ↑ NaKATPase

Adverse Consequences of Thiazide Diuretics: Hyperglycemia:

Adverse Consequences of Thiazide Diuretics: Hyperglycemia Brenner & Rectors The Kidney 2016. Figure 51.21

Adverse Consequences of Loop and Thiazide Diuretics: Hyperuricemia and GOUT:

Adverse Consequences of Loop and Thiazide Diuretics: Hyperuricemia and GOUT Urate ↔ Diuretic Diuretic Urate

Principal Cells of the Late Distal Tubule/Cortical Collecting Duct K+ SPARING DIURETICS (amiloride, triamterene) :

Principal Cells of the Late Distal Tubule/Cortical Collecting Duct K+ SPARING DIURETICS ( amiloride , triamterene) Direct inhibition of Epithelial Na+ channel ( ENaC ) Tubular lumen Na + ATP K + K + K + Interstitium Na + ENaC Peritubular Capillary Principal cell

Principal Cells of the Late Distal Tubule/Cortical Collecting Duct K+ SPARING DIURETICS (amiloride, triamterene) :

Principal Cells of the Late Distal Tubule/Cortical Collecting Duct K+ SPARING DIURETICS ( amiloride , triamterene) Direct inhibition of Epithelial Na+ channel ( ENaC )Na + Lumen positive Decreased Na + K + exchange Unfavorable gradient (lumen positive) for K + secretion Tubular lumen Na + ATP K + K + K + Interstitium Na + ENaC Peritubular Capillary Principal cell HYPERKALEMIA + + + + + + + + + + ↑K+

α Intercalated cells of the Late Distal Tubule/Cortical Collecting Duct K+ SPARING DIURETIC:

α Intercalated cells of the Late Distal Tubule/Cortical Collecting Duct K+ SPARING DIURETIC Tubular lumen HCO3 - Cl - Interstitium Peritubular Capillary Alpha Intercalated cell ATP ATP H + H + K + ↑H+ METABOLIC ACIDOSIS NaCl NaCl NaCl NaCl NaCl

Principal Cells of the Late Distal Tubule/Cortical Collecting Duct ALDOSTERONE ANTAGONISTS (spironolactone, eplerenone) :

Principal Cells of the Late Distal Tubule/Cortical Collecting Duct ALDOSTERONE ANTAGONISTS (spironolactone, eplerenone ) Intracellular aldosterone receptors inhibited Tubular lumen Na + ATP K + K + K + Interstitium Na + ENaC Peritubular Capillary Principal cell ALDOSTERONE

Principal Cells of the Late Distal Tubule/Cortical Collecting Duct ALDOSTERONE ANTAGONISTS (spironolactone, eplerenone) :

Principal Cells of the Late Distal Tubule/Cortical Collecting Duct ALDOSTERONE ANTAGONISTS (spironolactone, eplerenone ) Aldosterone receptors inhibited Decreased ENaC production Decreased intracellular Na Decreased Na-K+ exchange Decreased K+ secretion by ROMK Tubular lumen Na + ATP K + K + K + Interstitium Na + ENaC Peritubular Capillary Principal cell ALDOSTERONE HYPERKALEMIA

α Intercalated cells of the Late Distal Tubule/Cortical Collecting Duct ALDOSTERONE ANTAGONISTS (spironolactone, eplerenone):

α Intercalated cells of the Late Distal Tubule/Cortical Collecting Duct ALDOSTERONE ANTAGONISTS (spironolactone, eplerenone ) Tubular lumen HCO3 - Cl - Interstitium Peritubular Capillary Alpha Intercalated cell ATP ATP H + H + K + ↑H+ METABOLIC ACIDOSIS

Hormonal Adverse Effects: ALDOSTERONE ANTAGONISTS:

Hormonal Adverse Effects: ALDOSTERONE ANTAGONISTS Increases conversion of testosterone to estradiol Decreases testosterone production Displaces testosterone from sex hormone-binding globulin (SHBG), increasing its metabolic clearance Competes with testosterone and dihydrotestosterone at site of action = GYNECOMASTIA

All Water Reabsorbing Portions Nephron OSMOTIC DIURETICS (mannitol):

All Water Reabsorbing Portions Nephron OSMOTIC DIURETICS (mannitol) ↓ [Na+] extracellular ↓ driving force [Na+]reabsorption = ↓ H20 reabsorption and increased tubular flow rate https ://www.studyblue.com/notes/note/n/diuretics/deck/9786968

Osmotic Diuretic Induced Increased Tubular Fluid Flow = Decreased Tubular Solute Concentration :

Osmotic Diuretic Induced Increased Tubular Fluid Flow = Decreased Tubular Solute Concentration Tubular lumen Na + ATP K + K + K + Interstitium Na + ENaC Peritubular Capillary Principal cell HYPOKALEMIA ↑ Tubular fluid ↓ [H+] and ↑ driving force for H+ secretion ATP H+ ATP ↑ Tubular fluid ↑ Tubular fluid ↓ [Solute] ↓ [K+] and ↑ driving force for K+ secretion METABOLIC ALKALOSIS

Summary: Adverse Consequences of Diuretics :

Diuretic Class Drugs Side effect Carbonic anhydrase inhibitors Acetazolamide Hypokalemia Metabolic acidosis Loop diuretics Furosemide Bumetanide Torsemide Ethacrynic acid Hypokalemia Hypercalcuria Hyperuricemia Metabolic alkalosis Thiazide diuretics Hydrochlorothiazide (HCTZ) Chlorthalidone Metolazone Indapamide Hypokalemia Hypocalcuria and hypercalcemia Hyperuricemia Metabolic alkalosis Hyponatremia Hyperglycemia Inhibitors of ENaC Triamterene Amiloride Hyperkalemia Metabolic acidosis Aldosterone antagonists Spironolactone Eplerenone Hyperkalemia Metabolic acidosis Gynecomastia and other sex hormone effects Osmotic diuretics Mannitol Hypokalemia Metabolic alkalosis All Classes Possible Acute kidney injury Summary: Adverse Consequences of Diuretics

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