1. Diuretic Agents Weiwei HU huww@zju.edu.cn Dept. Pharmacology, Medical School, Zhejiang University

3. 25 ％ Na + 65-70 ％ Na + 10 ％ Na + 酮

5. Proximal Tubule HCO 3 - reabsorption: carbonic anhydrase (CA) Organic acid secretory systems are located in the middle third of the proximal tubule: uric acid, NSAIDs, diuretics, antibiotics. Organic base secretory systems: H2R antagonists, choline, morphine, etc. acetazolamide Ө

6. Proximal Tubule Organic acid secretory systems are located in the middle third of the proximal tubule: uric acid, NSAIDs, diuretics, antibiotics. Organic base secretory systems: H2R antagonists, choline, morphine, etc.

7. Loop of Henle 25% of the filtered sodium Water impermeable Loop diuretics Ө

8. Distal Convoluted Tubule 10% of the filtered NaCl Water impermeable thiazide diuretics parathyroid hormone K+K+ Ө ⊕

9. Collecting Tubule  2–5% of NaCl reabsorbed  Principal cells are the major sites of Na +, K +, and H 2 O transportation  Intercalated cells are the primary sites of proton secretion. ^

10. Classification of diuretics Loop diuretics: high-ceiling diuretics (high efficacy), acting at thick ascending limb of Henle loop, inhibiting Na + -K + -2Cl - symport ： furosemide ( 呋塞米 ) Thiazide diuretics: moderate efficacy, acting at distal convoluted tubule, inhibiting Na + -Cl - symport: hydrochlorothiazide ( 氢氯噻嗪 ) K + -sparing diuretics: low efficacy, late distal tubule and collecting duct, inhibiting ADH and renal epithelial Na + channels: spironolactone ( 螺内酯 ) Carbonic anhydrase inhibitors: acetazolamide ( 乙酰唑胺 ) Osmotic diuretics: mannitol ( 甘露醇 )

11. 常用利尿药对电解质排泄及排钠力的比较 药物 尿电解质排泄 滤过 Na + 量 % 主要作用部位机制 Na + K+K+ Cl - HCO 3 - 高效 利尿药 ++++++++023 髓袢升支粗段 髓质和皮质部 抑制 Na + -K + -2Cl - 共同转运系统 中效 利尿药 +++ +8 远曲小管近段 抑制 Na + -Cl - 共同 转运系统 低效 利尿药 +-+02 远曲小管远段 和集合管 对抗醛固酮，阻 滞 Na + 通道 乙酰 唑胺 +++0+++4 近曲小管 抑制胞内 H + 形成， 抑制 H + -Na + 交换

13. Carbonic Anhydrase Inhibitors acetazolamide ( 乙酰唑胺） Inhibit bicarbonate reabsorption; HCO 3 - depletion leads to enhanced NaCl reabsorption by the remainder of the nephron; Causes significant bicarbonate losses and hyperchloremic metabolic acidosis; Clinical use: glaucoma, metabolic alkalosis, acute mountain sickness (cerebral edema), urinary alkalinization Basic Pharmacology of Diuretic Agents

14. Carbonic Anhydrase Inhibitors Toxicity: Hyperchloremic metabolic acidosis Renal stones Renal potassium wasting Drowsiness and paresthesias Allergy Basic Pharmacology of Diuretic Agents

15. sulfonamide derivativephenoxyacetic acid derivative the diuretic activity correlates with their secretion by the proximal tubule Loop diuretics 呋塞米 布美他尼 依他尼酸

16. Pharmacodynamics (1) Diuretic effects §Inhibiting the Na + -K + -2Cl - symport of the luminal membrane in the thick portion of the ascending limb of the loop of Henle, and reducing the reabsorption of Na +, K + and Cl -. §Most efficacious among the diuretic drugs, because the ascending limb accounts for the reabsorption of 25-30% of filtered NaCl and downstream sites are not able to compensate for this increased Na + load. Foresemide

18. §Impairing kidney’s ability to excrete a dilute urine. §Blocking kidney’s ability to concentrate urine during hydropenia, by decreasing the hypertonic medullary interstitium. §Increasing excretion of Ca 2+, Mg 2+ by abolition of transepithelial potential difference. §Inhibit Carbonic Anhydrase at large dose, increase excretion of HCO 3 - Foresemide

19. loop diuretics urine concentration urine dilute

20. (2) Vasodilatation (induced renal prostaglandin synthesis) §Renal vasodilatation: renal blood flow  §Dilating veins: cardiac preload , pulmonary edema  Foresemide

21. Clinical Indications: (1) Severe edema: not first choice for chronic edema, used for those are ineffective by thiazides (2) Acute pulmonary edema: heart failure (3) Hypercalcemia (4) Detoxication of toxins or drug overdose Foresemide

22. Clinical Indications: (5) Others: In mild hyperkalemia; Acute renal failure: increase the rate of urine flow and renal blood flow, ameliorate cell edema and jam in the kidney tubules. Normally combined with dopamine. Anion overdose: bromide, fluoride, and iodide Foresemide

23. Toxicity (1) Hypokalemia, hypomagnesemia, hyponatremia, hypochloremic metabolic alkalosis (2) Ototoxicity: hearing damage, contraindicated to combine with aminoglycoside antibiotics or the patients who have diminished renal function. (3) Hyperuricemia: decreased excretion and enhancement of uric acid reabsorption in the proximal tubule,. Foresemide

24. Toxicity (4) Allergic reactions: Skin rash, interstitial nephritis. (5) Other effects: nausea, vomit, GI bleeding. Foresemide

25. Other loop diuretic drugs Bumetanide 布美他尼： stronger than furosemide, but less adverse effects Torasemide 托拉塞米： stronger and longer actions Etacrynic acid 依他尼酸： weaker actions and more severe adverse effects

26. Thiazides This kind of drugs are come from the effort to synthesize more potent carbonic anhydrase inhibitors. Some of the thiazides retain significant carbonic anhydrase inhibitory activity.

27. 苄氟噻嗪氯噻嗪氢氯噻嗪氢氟噻嗪甲氯噻嗪泊利噻嗪三氯噻嗪 Thiazides 短效 中效 长效

28. 1. Pharmacokinetics §All of the thiazides can be administered orally, chlorothiazide is the only thiazide available for parenteral administration. §All of the thiazides are secreted by the organic acid secretory system in the proximal tubule, and compete with the secretion of uric acid. Thiazides

29. 2. Pharmacodynamics (1) Diuretic effects §Acting on distal convoluted tubule, inhibiting Na + -Cl - symport, decreasing kidney’s ability to dilute urine §Increasing the excretion of Na +, Cl -, K +, Mg 2+, HCO 3 -, but increasing the reabsorption of Ca 2+ in distal convoluted tubule (2) The action of thiazides depends in part on renal prostaglandin production like loop diuretics. Thiazides

31. thiazides urine dilute

32. 3. Clinical Indications: (1) Antihypertensive effects §Blood volume , spasm responsiveness of arterial smooth muscles  (2) Edema: §Used in treatment of mild and moderate edema in cardiac and renal diseases, and hepatic diseases with cautions; (3) Nephrolithiasis due to idiopathic hypercalciuria ( 先天性高 尿钙症 ) §Increase Ca 2+ reabsorption. Thiazides

33. (4) Diabetes insipidus ( 尿崩症） §Thiazides have the unique ability to produce a hyperosmolar urine, and can substitute for the antidiuretic hormone (ADH) in the treatment of nephrogenic diabetes insipidus. §The urine volume of such individuals may drop from 11 L/day to 3 L/day when treated with the drug. Thiazides

34. 4. Adverse effects (1) Imbalance of electrolytes hypokalemia hypomagnesemia hyponatremia cautions: dose individualization, K + supplement (2) Dysfunction of metabolism hyperglycemia hyperlipidemia hyperuricemia contraindicated in diabetes and gout ( 痛风 ) patients Thiazides

35. 4. Adverse effects (3) Hypersensitivity §Bone marrow suppression, dermatitis, necrotizing vasculitis, interstitial nephritis, etc. (4) Others §Weakness, fatigability, and paresthesias Thiazides

36.  Chlortalidone ( 氯噻酮 )  Indapamide ( 吲达帕胺 )  Metolazone ( 美托拉宗 )  Quinethazone ( 喹乙宗 )  Xipamide ( 希帕胺 )

37. (1) Antagonize aldosterone at the late distal tubule and cortical collecting tubule Spironolactone 螺内酯 Eplerenone 依普利酮 (2) Inhibit Na + influx in the luminal membrane Triamterene 氨苯喋啶 Amiloride 阿米洛利 Potassium-sparing diuretics

38. Spironolactone (antisterone) §A synthetic steroid §Blocking aldosterone receptor §Decreasing Na + reabsorption and K + excretion §Weaker, slow acting, and lasting duration Eplerenone Eplerenone, a new spironolactone analog with greater selectivity for the aldosterone receptor. Potassium-sparing diuretics

39. Action of spironolactone: Blocking the effects of aldosterone AIP: aldosterone induced protein 1.Activation of Na + membrane-bound channels 2.Redistribute (3) 3.De novo synthesis of (3) 4.Activation of membrane- bound Na + /K + ATPase 5.Redistribution of (4) 6.De novo synthesis of (4) 7.Changes in permeability of tight junctions 8.Increased mitochondrial production of ATP

40. Triamterene 氨苯喋啶 Amiloride 阿米洛利 §Amiloride is excreted unchanged in the urine. §Triamterene is metabolized in the liver and renal excretion, has a shorter half-life and must be given more frequently than amiloride. §Blocking renal epithelial Na + channels: decreasing Na + -K + exchange Potassium-sparing diuretics

41. spironolactone

43. Clinical Indications: §In states of mineralocorticoid excess: Primary hypersecretion (Conn's syndrome, ectopic ACTH production) Secondary aldosteronism (from heart failure, hepatic cirrhosis, nephrotic syndrome, and other conditions associated with diminished effective intravascular volume) §Combined with other diuretic drugs Potassium-sparing diuretics

44. Toxicity (1) Hyperkalemia (2) Hyperchloremic Metabolic Acidosis: By inhibiting H + secretion in parallel with K + secretion, (3) Sex hormone-like effects: Gynecomastia( 男性乳腺发育 ) (4) Acute renal failure: only found in the combination of triamterene with indomethacin (5) Kidney Stones: triamterene (poorly soluble) (6) GI reactions (7) CNS reactions: headache, fatigue Potassium-sparing diuretics

45. Dehydrant Agents ( Osmotic Diuretics ) Increase plasma osmotic pressure, induce tissue dehydration. Excreted usually by glomerular filtration and not reabsorbed, to induce osmotic diuretic effects. To reduce increased intracranial pressure and to promote prompt removal of renal toxins.

46. Pharmacodynamics (1) Dehydrant effects (2) Diuretic effects (osmotic diuretic effects) Mannitol 甘露醇 OH OH OH OH OH OH OH OH OH OH OH OH

47. Clinical Indications (1) Increase in urine volume (2) Reduction of intracranial and intraocular pressure: used in brain edema and glaucoma (3) Acute renal failure: prevention and early treatment Mannitol

48. Toxicity (1) Extracellular volume expansion: pulmonary edema, etc. (2) Hypernatremia and dehydration: headache, nausea, vomiting, etc. §Contraindicated in anuric due to severe renal diseases, active cranial bleeding, heart failure Mannitol

49. Other dehydrant drugs Sorbitol 山梨醇 Hypertonic glucose (50%) 高渗葡萄糖

50. Diuretic Combinations 1.Loop Agents & Thiazides Salt and water reabsorption in either the thick ascending limb or the distal convoluted tubule can increase when the other is blocked. Thiazide diuretics may produce a mild natriuresis in the proximal tubule that is usually masked by increased reabsorption in the thick ascending limb. Mobilize large amounts of fluid and K + -wasting is extremely common.

51. 2. Potassium-Sparing Diuretics & Loop Agents or Thiazides When hypokalemia cannot be managed with dietary NaCl restriction or KCl supplements in patients using loop diuretics or thiazides, the addition of a potassium- sparing diuretic can significantly lower potassium excretion. it should be avoided in patients with renal insufficiency Diuretic Combinations

53. A 65-year-old man comes to the emergency department with severe shortness of breath. His wife reports that he has long known that he is hypertensive but never had symptoms, so he refused to take antihypertensive medications. During the last month, he has noted increasing ankle edema, reduced exercise tolerance, and difficulty sleeping lying down, but he reports no episodes of chest pain or discomfort. He now has pitting edema to the knees and is acutely uncomfortable lying down. Vital signs include blood pressure of 190/140 mm Hg, pulse 120/ min, and respirations 20/min. Chest auscultation reveals loud rhonchi, but an electrocardiogram is negative except for evidence of left ventricular hypertrophy. He is given a diuretic intravenously and admitted to intensive care. What diuretic would be most appropriate for this man’s case of acute pulmonary edema associated with heart failure? What are the possible toxicities of this therapy? CASE