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Diuretics and Dehydrant Agents

Diuretics and Dehydrant Agents. Jin Wang Institute of Pharmacology School of Medicine Shandong University wangj@sdu.edu.cn. Section1 Diuretics. Definition

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Diuretics and Dehydrant Agents

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  1. Diuretics and Dehydrant Agents Jin Wang Institute of Pharmacology School of Medicine Shandong University wangj@sdu.edu.cn

  2. Section1 Diuretics Definition Diuretics are a family of drugs that act on kidney and promote the excretion of urine (including water and electrolyte). (mainly used in edema)

  3. The physiological basis of diuretics ⅠExcretion function of kidney ⅡUrinary physiology of kidney and the sites of diuretics

  4. ⅠExcretion function of kidney Excretion of inorganic ion Excretion of organic ion Excretion of water

  5. ⅠExcretion function of kidney 1. Excretion of inorganic ion • Convection • Via ion channels • Simple diffusion • Facilitated diffusion • Active transport (primary) • Active transport (secondary) • Symporter • Antiporter

  6. tubular cell lumen space Ca2+ Mg2+ K+ K+ K+ K+ ATP Na+ Na+ Na+ 2Cl- Cl- Na+-K+-2Cl- Symporter Na+-K+ ATPase

  7. tubular cell lumen space K+ Cl- Cl- K+ K+ ATP Na+ Na+ Na+ Ca2+ Ca2+ Na+-K+ ATPase Na+-Cl- Symporter

  8. Na+-K+ ATPase Na+-H+ Antiporter tubular cell lumen space Na+ Na+ ATP K+ HCO3-+H+ H++ HCO3- H2CO3 CA CA H2O+CO2 CO2+ H2O

  9. Excretion of inorganic ions

  10. ⅠExcretion function of kidney 2. Excretion of organic ion Secondary active transport • Anionic transport system • Cationic transport system Pay attention: competition

  11. Excretion of organic ions

  12. ⅠExcretion function of kidney 3. Excretion of water Water channel – aquaporins (AQPs) Noble prize in chemistry 2003 Peter Agre (1949-) 1988 protein 1991 -cDNA 2003 Nobel prize

  13. AQP

  14. Characteristics of AQPs Water permeation: unique Water follows passively Driven by Na+-K+ ATPase

  15. ⅡUrinary physiology of kidney and the sites of diuretics Secretion Reabsorption Excretion Filtration

  16. Filtration of glomerular blood 原尿量 glomerular Tubule fluid tubulus 终尿量 urine

  17. Reabsorption of renal tubule and collecting tube Proximal tubules Henle’s loop Distal convoluted tubules Collecting tubules

  18. 2. thick ascending limb of Henle’s loop 1. Proximal tubule 3. Distal tubule and collecting ducts

  19. Proximal Tubule • Na+/ K+ ATPase: maintains gradient • Na+ flows down via channel • Na+_ H+ exchange: carbonic anhydrase (CA) • AQP1/7: Water follows passively • 65%~70% of Na+ and water reabsorption • Cl- 、Ca2+ 、 K+ 、 Mg2+ reabsorption

  20. Proximal tubule lumen space tubular cell Na+ Na+ Na+ Na+ ATP K+ HCO3-+H+ H++ HCO3- H2CO3 CA CA H2O+CO2 CO2+ H2O acetazolamide

  21. TAL: thick ascending limb • 1. No AQPs: impermeable to water • 2. Transports Na+ by Na+ -K+ -2Cl-symporter • 25-35% of Na+ reabsorbed • Reabsorption of Ca2+ , Mg2+ and Cl-

  22. Thick ascending limb of Henle’s loop tubular cell Ca2+ lumen space Mg2+ K+ K+ K+ K+ ATP Na+ Na+ Na+ 2Cl- Cl- Cl- Furosemide Symporter

  23. NaCl Ca2+ (+PTH) NaHCO3 NaCl 稀释 近曲小管 K+ 远曲小管 集 合 管 Ca2+ Mg2+ 皮质部 Na+ K+ 2Cl- NaCl 醛固酮 髓质部 Na+ K+ 高 渗 高 渗 2Cl- H2O (+ADH) 浓缩 K+ H2O H+ 髓袢

  24. Distal Convoluted Tubule • 5~10% of Na+ reabsorbed (1) Na+-Cl- symporter (2) Ca2+-channel (3) Na+-Ca2+ exchange : parathyroid hormone (PTH) (4) No AQPs: impermeable to water

  25. Distal convoluted tubule tubular cell lumen space K+ Cl- Cl- K+ K+ ATP Na+ Na+ Na+ Ca2+ Ca2+ Thiazides PTH

  26. Collecting Duct • Water permeability: main site Controlled by ADH Via AQPs(2,3,4) Driven by medulla osmotic gradient • 2-5% of Na+ reabsorbed : Via Na+ channels Regulated by ADS • K+ secretion : major site

  27. R R spironolactone principal cell Cl- ADS-R ADS lumen space Na+ Na+ Na+ K+ -Na+exchange ATP K+ K+ K+ ADH H2O Triamterene Amiloride

  28. NaCl Ca2+ (+PTH) NaHCO3 Na+ Cl- 稀释 近曲小管 K+ 远曲小管 集 合 管 Ca2+ Mg2+ 皮质部 Na+ K+ NaCl 醛固酮 2Cl- 髓质部 Na+ K+ 高 渗 高 渗 2Cl- H2O (+ADH) 浓缩 K+ H2O H+ 髓袢

  29. Diuretics Classification Common used Diuretics

  30. Classification of Diuretics Ⅰ. Loop (high efficacy diuretics) diuretics Ⅱ. Thiazide (moderate efficacy ) diuretics Ⅲ. Potassium-sparing (low efficacy) diuretics Ⅳ. Carbonic anhydrase inhibitors Ⅴ. Osmotic diuretics (dehydrants)

  31. Common used Diuretics

  32. Ⅰ.loop diuretics (High efficacy diuretics) Furosemide (呋塞米, 呋喃苯氨酸,速尿) Etacrynic acid (依他尼酸,利尿酸) Bumetanide (布美他尼) Torsemide (托拉塞米)

  33. Pharmacokinetics • 1.Absorption • 2.Distribution:PPBR>95% • 3.Elimination:Anionic transport system

  34. Pharmacological actions • 1. Diuresis: fast and strong • Site of action: • Thick ascending limb of henle’s loop • Mechanism: ↓ Na+- K+-2Cl-cotransporter Result： Na+, K+, 2Cl-, Mg2+, Ca2+ excretion↑

  35. Thick ascending limb of Henle’s loop tubular cell Ca2+ lumen space Mg2+ K+ K+ K+ K+ ATP Na+ Na+ Na+ 2Cl- Cl- Cl- Furosemide Symporter

  36. NaCl Ca2+ (+PTH) NaHCO3 NaCl 稀释 近曲小管 K+ 远曲小管 集 合 管 Ca2+ Mg2+ 皮质部 Na+ K+ 2Cl- NaCl ADS 髓质部 Na+ 高 渗 K+ 高 渗 2Cl- 高 渗 H2O (ADH) 浓缩 K+ H2O H+ • Loop diuretics • 肾的稀释功能 • 肾的浓缩功能 髓袢

  37. Pharmacological actions • 2. Vasodilation Renal vessel dilation→renal blood flow↑ Vessel dilation → heart load ↓ Possible mechanism:↑ PGE2 synthesis

  38. Clinical uses 1. Acute pulmonary and cerebral edema 2. Severe edema Cautions 3. Renal failure 4. Hypercalcemia 5. Overdose of some toxicants

  39. Adverse reactions 1. Electrolyte disorders • hyponatremia, hypomagnesemia, hypochloremia alkalosis, hypokalemia※ • CHF: ↑ digitalis intoxication • Hepatic cirrhosis: hepaticcoma

  40. Adverse reactions • 2. Ototoxicity: dose-related Ethacrynic acid > Furosemide > Bumetanide Pay attention!

  41. Adverse reactions • 3. Hyperuricemia (1)reabsorption of uric acid ↑ (2)secretion of uric acid ↓ 4. GI reactions 5. Allergic reactions

  42. Ⅱ. Thiazides(噻嗪类): (Moderate efficacy diuretics) Hydrochlorothiazide (氢氯噻嗪,双氢克尿噻 ,双克) Chlorothiazide (氯噻嗪) Chlortalidon (氯酞酮) Indapamide (吲哒帕胺，寿比山)

  43. Classifications

  44. Pharmacological actions 1.Diuresis: moderate • Site of action: early distal tubules • Mechanism: Na+-Cl- symporter inhibition CAI ( in large dose) • Results: Na+, K+, Cl- ,Mg2+,HCO-3excretion ↑ Ca2+ in urine ↓ (↑ Ca2+reabsorption in distal tubules)

  45. Distal convoluted tubule tubular cell lumen space K+ Cl- Cl- K+ K+ ATP Na+ Na+ Na+ Ca2+ Ca2+ - + Thiazides

  46. Thiazides + NaCl Ca2+ (PTH) NaHCO3 NaCl - 稀释 近曲小管 K+ 远曲小管 集 合 管 Ca2+ Mg2+ 皮质部 Na+ K+ 2Cl- NaCl ADS 髓质部 Na+ 高 渗 K+ 高 渗 2Cl- 高 渗 H2O (ADH) 浓缩 K+ H2O H+ 髓袢

  47. Pharmacological actions 2.Anti-insipidus effect Possible mechanisms 1) ↓ PDE (磷酸二酯酶）→ intracellular cAMP↑→ water permeability ↑ → water reabsorption ↑ 2) excretion of NaCl↑ → plasma Osm ↓ → thirst ↓ → drinking↓ → urine↓

  48. Insipidus (尿崩症) • 尿崩症多是由于抗利尿激素缺乏、肾小管重吸收水的功能障碍，从而引起以多尿、烦渴、多饮与低比重尿为主要表现的一种疾病。本病是由于下丘脑—神经垂体部位的病变所致，但部分病例无明显病因，尿崩症可发生于任何年龄，但以青年为多见。 • 主要临床表现为多尿、烦渴与多饮，起病常较急。24h尿量可多达5-10L，但最多不超过18L。尿比重常在1.005以下，尿渗透压常为50-200mOsm/kgH O，尿色淡如清水。

  49. Pharmacological actions 3.Anti-hypertension effect Mechanisms Early stage: diuretic effect→↓blood volume Late stage: excretion of Na+↑→Na+-Ca2+ exchange→↓Ca2+ in smooth cell→ artery tension↓

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