1. Diuretic Agents 利尿药与脱水药 Weiping Zhang （张纬萍） weiping601@zju.edu.cn weiping601@zju.edu.cn Tel: 88208223 Dept. Pharmacology, Medical School, Zhejiang University

2. The Kidney: Excretion water, ions, and toxic metabolites

3. BA Renal structures for urine generation (A) and osmotic gradient (B) Thin descending limb Thin ascending limb Thick ascending limb convoluted

4. Functional proteins in cell membrane

5. A. Excrete functin of kidney 1. Excretion of inorganic ion

6. A. Excrete functin of kidney 1. Excretion of inorganic ion (1) ATP mediated active transport: Na + -K + pump, Ca 2+ -ATP, H + -ATP (2) Symporter (Cotransporter): Na + -K + -2Cl - symporter, Na + -K + symporter (3) Antiporter (countertransporter): Na + -H + exchanger, Ca 2+ -Na + exchanger, HCO 3 - -H + exchanger (4) Ion channel: Na +, K +, Cl -

7. A. Excrete functin of kidney 2. Excretion of organic ion (1)Anionic transporter （阴离子转运体） Metabolites (uric acid), drugs (most of cephalosporins, loop diurects, NSAIDs, most of the  -lactams, thiazide diuretics, most of the sulfonamides) (2) Cationic transporter （阳离子转运体） Metabolites (choline), drugs (amiloride, efedrina, H 2 receptor antagonists, morphine, quinine)

8. ABC 转运体 溶质载体类转运体（ SLC ）

9. A. Excrete functin of kidney 2. Excretion of organic ion

10. A. Excrete functin of kidney 3. Excretion of H 2 O

11. A. Excrete functin of kidney 3. Excretion of H 2 O Proximal Tubule: AQP1, 7; Collecting Tubule: AQP2, 3, 4; No AQPs in ascending limb of Loop of Henle and distal tubule The regulation of AQPs: H2OH2O H2OH2O AQP2 减少：遗传性肾源性 尿崩症、锂盐、低蛋白饮 食、慢性肾衰竭、肾病综 合征、肾缺血、顺铂、钙 通道阻滞药等； AQP2 增加：血管加压素、 充血性心力衰竭、肝硬化 等。

12. 25 ％ Na + 65-70 ％ Na + 10 ％ Na +

13. Proximal Tubule luminal membrane Basolateral membrane carbonic anhydrase acetazolamide Organic acid secretion systems are located in the middle third of the proximal tubule: uric acid, nonsteroidal anti-inflammatory drugs NSAIDs, diuretics, antibiotics. Organic base secretion Systems: creatinine, choline, etc 85 % HCO 3 - 60 % H 2 O 60 % Na +

14. Loop of Henle 25% of the filtered sodium Water impermeable Blocked by "loop" diuretics Ca 2+ -ATP H + -ATP

15. BA Renal structures for urine generation (A) and osmotic gradient (B) Thin descending limb Thin ascending limb Thick ascending limb convoluted

16. Distal Convoluted Tubule 10% of the filtered NaCl Water impermeable Blocked by diuretics of the thiazide class. Affected by parathyroid hormone K+K+

17. Collecting Tubule 2–5% of NaCl reabsorption principal cells are the major sites of Na +, K +, and H 2 O transport intercalated cells （暗细胞） are the primary sites of proton secretion.

18. Introduction  What do diuretics do? They all increase renal sodium excretion thereby reducing blood volume.  What are the different types of diuretics? Different classes of diuretics interfere with different sodium transport processes that are featured along the nephron.  What determines their potency? Diuretic dose, bioavailability, serum protein binding, the quantity of sodium delivered at the site of action, the ability more distal nephron segments to reabsorb the excess sodium (compensation).

19.  What are the major side-effects of diuretics? Low blood volume and the disturbance of electrolytes (K +, Na +, Cl -, Ca 2+ and HCO 3 - ).  Are there special uses of specific diuretics? All diuretics cause reduction in extracellular sodium and fluid and are useful in treating hypertension, CHF and other edema-forming states. Because specific diuretics may have other actions, they may be useful for treating other conditions. Introduction

20. Factors that Counteract Diuretic Action After Volume Depletion  RAS: Angiotensin II stimulates proximal sodium reabsorption. Aldosterone increases collecting duct sodium reabsorption;  Sympathetic nervous system: Nnorepinephrine stimulates proximal sodium reabsorption.  These counter-regulatory responses limit the amount of sodium-wasting that can be induced by a fixed diuretic dose.  All of the net sodium losses occur within the first week on a fixed dose of diuretic and dietary salt intake.

21. Factors that Counteract Diuretic Action After Volume Depletion  RAS: Angiotensin II stimulates proximal sodium reabsorption. Aldosterone increases collecting duct sodium reabsorption;  Sympathetic nervous system: Nnorepinephrine stimulates proximal sodium reabsorption.  These counter-regulatory responses limit the amount of sodium-wasting that can be induced by a fixed diuretic dose.  All of the net sodium losses occur within the first week on a fixed dose of diuretic and dietary salt intake.

22. Classification of diuretic drugs §Loop diuretics: high efficacy § thick ascending limb of Henle loop § inhibiting Na + -K + -2Cl - symport § furosemide 呋塞米 §Thiazide diuretics: moderate efficacy § distal convoluted tubule § inhibiting Na + -Cl - symport § hydrochlorothiazide 氢氯噻嗪 §K + -sparing diuretics: low efficacy § late distal tubule and collecting duct § inhibiting renal epithelial Na + channels § spironolactone 螺内酯 §Carbonic Anhydrase Inhibitors: acetazolamide Basic Pharmacology of Diuretic Agents

24. Patient 1 A 65 y.o. man with a long history of chronic obstructive pulmonary disease (COPD) is in the ICU with congestive heart failure. He was previously treated with diuretics that initially resulted in improvement in his heart failure but he developed further carbon dioxide retention that was felt to be due to the development of metabolic alkalosis ( Metabolic alkalosis is primary increase in HCO 3 − with or without compensatory increase in Pco 2 ; pH may be high or nearly normal ) from the diuretic he was receiving. You still want to induce a diuresis without worsening of his metabolic alkalosis. What do you do?

25. Carbonic Anhydrase Inhibitors The prototypical carbonic anhydrase inhibitor is acetazolamide ( 乙酰唑胺）, dorzolamide （多佐胺）, brinzolamide （布林唑胺） Clinical use: Clinical use: carbonic anhydrase–dependent bicarbonate transport at sites other than the kidney. Such as eye, formation of cerebrospinal fluid by the choroid plexus Basic Pharmacology of Diuretic Agents

26. Carbonic Anhydrase Inhibitors Clinical use: Clinical use: carbonic anhydrase–dependent bicarbonate transport at sites other than the kidney. Eye: glaucoma （青光眼） ; Brain: decrease CSF; Alkalise urine and increase the acidic drug excretion; Correct the metabolic alkalosis Basic Pharmacology of Diuretic Agents

27. Carbonic Anhydrase Inhibitors Allergy Hyperchloremic Metabolic Acidosis Renal Stones Renal Potassium Wasting Drowsiness and paresthesias ( 感觉异常 ) Basic Pharmacology of Diuretic Agents Toxicity

28. Back to Patient 1 A 65 y.o. man with a long history of chronic obstructive pulmonary disease is in the ICU with congestive heart failure. He was previously treated with diuretics that initially resulted in improvement in his heart failure but he developed further carbon dioxide retention that was felt to be due to the development of metabolic alkalosis (high bicarbonate) from the diuretics he was on. You still want to induce a diuresis without worsening of his metabolic alkalosis. What do you do?

29. Patient 1 The patient had congestive heart failure but also had metabolic alkalosis (elevated bicarbonate level with high pH) that was due to the use of diuretics. Acetazolamide blocks bicarbonate absorption in the proximal tubule which can lead to bicarbonate wasting in the urine, resulting in a reduction in serum bicarbonate level.

30. Patient 2 The blood pressure of a man with chronic kidney disease (GFR 20 ml/min) has been increasing in recent weeks as his creatinine has slowly increased (Kidney failure). He has ankle and leg edema. To control his BP, he has been using an angiotensin converting enzyme inhibitor, beta-blocker and a calcium channel blocker and a thiazide diuretic. What other measures would you take to improve his blood pressure?

31. Basic Pharmacology of Diuretic Agents sulfonamide derivative phenoxyacetic 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

32. ForesemidePharmacodynamics (1) Diuretic effects §Inhibiting the Na + -K + -2Cl - cotransporter （ symport) §Most efficacious among the diuretic drugs, Basic Pharmacology of Diuretic Agents

33. §Blocking kidney’s ability to concentrate urine during hydropenia, by decreasing the hypertonic medullary interstitium. §Impairing kidney’s ability to excrete a dilute urine. §Also, increasing excretion of Ca 2+, Mg 2+ by abolition of transepithelial potential difference. Basic Pharmacology of Diuretic Agents Foresemide

34. loop diuretics urine concentration urine dilute

35. (2) Vasodilatation ， maybe related to increase of PGs §Renal vasodilatation: renal blood flow  §Dilating veins: cardiac preload  (3) Induce renal prostaglandin synthesis Basic Pharmacology of Diuretic Agents Foresemide

36. Clinical Indications & Dosage (1) Severe edema: ineffective by thiazides (2) Acute pulmonary edema: heart failure (3) Acute renal failure (4) Hypercalcemia (5) Detoxication of toxins or drug overdose (6) Hyponatremia Basic Pharmacology of Diuretic Agents Foresemide

37. Loop Diuretics to Treat Hyponatremia  In patients with good intravascular volume to start with, loop diuretics will induce the excretion of relatively hypotonic urine (about half isotonic)  Replacement of the volume of urine losses with isotonic sodium chloride (NS) will result in a rise in serum sodium

38. Toxicity (1)Imbalance of electrolytes §Hypokalemic Metabolic Alkalosis: §Hypokalemic Metabolic Alkalosis: can be reversed by K + replacement and correction of hypovolemia. §Hypomagnesemia: §Hypomagnesemia: can be reversed by administration of oral magnesium preparations. §Hyponatremia §Hypochloremic Metabolic alkalemia (2) Hyperuricemia: (2) Hyperuricemia: caused by hypovolemia-associated enhancement of uric acid reabsorption in the proximal tubule. Basic Pharmacology of Diuretic Agents Foresemide

39. Toxicity (3) Ototoxicity: hearing damage, contraindicated to combine with aminoglycoside antibiotics or the (3) Ototoxicity: hearing damage, contraindicated to combine with aminoglycoside antibiotics or the patients who have diminished renal function. (4) Allergic Reactions: (4) Allergic Reactions: Skin rash, eosinophilia and, less often, interstitial nephritis. less common with ethacrynic acid. (5) Other effects: dehydrationarrhythmias, RAAS activity , etc. (5) Other effects: dehydration, arrhythmias, RAAS activity , etc. Basic Pharmacology of Diuretic Agents Foresemide

40. §Other loop diuretic drugs §Bumetanide 布美他尼： similar to furosemide, but less adverse effects and stronger effects §Torasemide 托拉塞米： stronger and longer actions §Etacrynic acid 依他尼酸： weaker actions and more severe adverse effects Basic Pharmacology of Diuretic Agents

41. Back to Patient 2 The blood pressure of a man with chronic kidney disease (GFR 20 ml/min) has been increasing in recent weeks as his creatinine has slowly increased. He has ankle and leg edema. To control his b.p., he has been using an angiotensin converting enzyme inhibitor, beta- blocker and a calcium channel blocker and a thiazide diuretic. What other measures would you take to improve his blood pressure?

42. Patient 2 Most of our patients with late-stage chronic kidney disease have hypertension. The vast majority of the time, the hypertension of progressive CKD has some volume dependence. Therefore, use of a diuretic that works in patients with marked renal impairment such as a loop diuretic is appropriate. Loop diuretics need to be used with some care to avoid marked volume depletion that can worsen renal function esp. in the presence of an ACEI or ARB.

43. Patient 3 You have decided to start a woman on a diuretic for the treatment of hypertension. What factors would make you re-consider the use of certain diuretics? What if the patient has hypercalcemia? What if the patient has a history of gout? What if the patient has a condition that causes hyponatremia?

44. Thiazides Basic Pharmacology of Diuretic Agents This kind of drugs are came from the effort to synthesize more potent carbonic anhydrase inhibitors. The prototypical thiazide is hydrochlorothiazide. All of the thiazides can be administered orally,

45. Thiazides Basic Pharmacology of Diuretic Agents 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

46. Thiazides Short acting thiazides (< 12hrs): hydrochlorothiazide, chlorothiazide Media acting thiazides （ 12-24 hrs): benzthiazide, hydroflumethiazide, cyclothiazide, trichlormethiazide Long acting thiazides (>24 hrs): bendrofluazide, methyclothiazide, cyclopenthiazide, polythiazide Non-Thiazides Chlortalidone( 氯噻酮 ), indapamide （吲哒帕胺）, metolazone （美托拉宗）, quinethazone （奎乙宗）, xipamide （希帕胺）

47. 1. 1. Pharmacodynamics and clinical indications (1) Diuretic effects inhibiting Na + -Cl - cotransporter (symport) §Acting on distal convoluted tubule, inhibiting Na + -Cl - cotransporter (symport) §Decreasing kidney’s ability to dilute urine §Increasing the excretion of Na +, Cl -, K +, Mg 2+, HCO 3 -, but increasing the re-absorption of Ca 2+ in distal convoluted tubule §The action of thiazides depends in part on renal prostaglandin production like loop diuretics. Thiazides Basic Pharmacology of Diuretic Agents

48. thiazides urine dilute

49. (2) Antihypertensive effects §blood volume  §spasm responsiveness of arterial smooth muscles  (3) edema: §Used in treatment of mild and moderate edema in cardiac and renal diseases, and hepatic diseases with cautions; (4) nephrolithiasis due to idiopathic hypercalciuria §Increase Ca 2+ reabsorption. Thiazides Basic Pharmacology of Diuretic Agents

50. (5) Diabetes insipidus ( 尿崩症） §Thiazides have the unique ability to produce a hyperosmolar urine, and can substitute for the antidiuretic hormone 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 Basic Pharmacology of Diuretic Agents

51. 2. Adverse effects (1) Imbalance of eletrolytes § hypokalemia hypomagnesemia § hyponatremia hypochloremia § cautions: dose individualization, K + supplement (2) Dysfunction of metabolism § hyperglycemia hyperlipidemia § hyperuricemia § contraindicated in diabetes and gout patients Thiazides Basic Pharmacology of Diuretic Agents

52. 2. Adverse effects (3) Hypersensitivity §Bone marrow suppression, dermatitis, necrotizing vasculitis, interstitial nephritis, etc. (4) Allergic Reactions §Photosensitivity or generalized dermatitis (5) Others §Weakness, fatigability, and paresthesias Thiazides Basic Pharmacology of Diuretic Agents

53. Back to Patient 3 You have decided to start a woman on a diuretic for the treatment of hypertension. What are some of the factors that would make you reconsider the use of certain diuretics? What if the patient has hypercalcemia? What if the patient has a history of gout? What if the patient has a condition that causes hyponatremia?

54. Back to Patient 3 Thiazide diuretics are frequently considered as first-line drugs in the treatment of hypertension. Use caution in patients with: Gout (they reduce renal uric acid excretion) Hypercalcemia (they reduce calcium excretion) Hyponatremia (they reduce water excretion) Hypokalemia

55. Patient 4 A 30 year-old woman presented with high blood pressure and hypokalemia. Subsequent evaluation showed that she had high aldosterone levels and low renin levels consistent with primary aldosteronism. She had no adrenal masses on imaging studies. What should your treatment be?

56. Potassium-sparing diuretics (1) Antagonize the effects of aldosterone at the late distal tubule and cortical collecting tubule Spironolactone 螺内酯 Spironolactone 螺内酯 eplerenone 依普利酮 eplerenone 依普利酮 (2) Inhibition of Na + influx through ion channels in the luminal membrane Triamterene 氨苯喋啶 Triamterene 氨苯喋啶 Amiloride 阿米洛利 Amiloride 阿米洛利 Basic Pharmacology of Diuretic Agents

57. Spironolactone 螺 内酯 Aldosterone Potassium-sparing diuretics

58. Spironolactone §A synthetic steroid §Blocking aldosterone receptor §Decreasing Na + re-absorption and K + excretion §Weaker, slow acting, and lasting duration Eplerenone Eplerenone ( 依普利酮 ), a new spironolactone analog with greater selectivity for the aldosterone receptor. Basic Pharmacology of Diuretic Agents Potassium-sparing diuretics

59. 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. Triamterene is extensively metabolized, it has a shorter half-life and must be given more frequently than amiloride. §Blocking renal epithelial Na + channels: decreasing Na + -K + exchange Basic Pharmacology of Diuretic Agents Potassium-sparing diuretics

61. spironolactone

62. Clinical Indications & Dosage §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 Basic Pharmacology of Diuretic Agents Potassium-sparing diuretics

63. Toxicity §(1) Hyperkalemia §(2) Hyperchloremic Metabolic Acidosis: By inhibiting H + secretion in parallel with K + secretion, §(3) Sex hormone-like effects: Gynecomastia §(4) Acute Renal Failure: Only found in the combination of triamterene with indomethacin §(5) Kidney Stones: triamterene §(6) GI reactions §(7) CNS reactions Basic Pharmacology of Diuretic Agents Potassium-sparing diuretics

64. Patient 4 A 30 year-old woman presented with high blood pressure and hypokalemia. Subsequent evaluation showed that she had high aldosterone levels and low renin levels consistent with primary aldosteronism. She had no adrenal masses on imaging studies. What should your treatment be?

65. Back to Patient 4 Patients with primary aldosteronism and no adrenal adenoma may be treated medically with an aldosterone receptor blocker (e.g., spironolactone). Although K-sparing Na-channel blockers are sometimes used because they block the renal effects of aldosterone, they do not block the potential non-renal untoward effects of high aldosterone levels.

66. Mannitol 甘露醇 OH OH OH OH OH OH OH OH OH OH OH OH Agents That Alter Water Excretion Osmotic Diuretics

67. Agents That Alter Water Excretion Osmotic Diuretics An osmotic agent that is excreted usually by glomerular filtration and not reabsorbed. An osmotic agent that is excreted usually by glomerular filtration and not reabsorbed. The prototypic osmotic diuretic is mannitol. The prototypic osmotic diuretic is mannitol. To reduce increased intracranial pressure and to promote prompt removal of renal toxins. To reduce increased intracranial pressure and to promote prompt removal of renal toxins. natriuresis natriuresis Pharmacodynamics §(1) Dehydrant effects §(2) Diuretic effects (osmotic diuretic effects)

68. Clinical Indications & Dosage (1) to increase urine volume (2) Reduction of intracranial and intraocular pressure: used in brain edema and glaucoma (3) Acute renal failure: prevention and early treatment Agents That Alter Water Excretion Osmotic Diuretics

69. Toxicity (1) Elevated extracellular osmolality: pulmonary edema, etc. (2) Hyponatremia and dehydration: headache, nausea, vomiting, etc. §Contraindicated in anuric due to severe renal diseases, active cranial bleeding, heart failure Agents That Alter Water Excretion Osmotic Diuretics

70. §Other dehydrant drugs §Sorbitol 山梨醇 §Hypertonic glucose (50%) 高渗葡萄糖 §Urea 尿素 §Glycerin 甘油 §Isosorbide 异山梨醇 Agents That Alter Water Excretion

71. 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.

72. Diuretic Combinations 2. Potassium-Sparing Diuretics & Loop Agents or Thiazides it should be avoided in patients with renal insufficiency

73. Clinical Pharmacology of Diuretic Agents

74. 1.Edematous States To reduce peripheral or pulmonary edema that has accumulated as a result of cardiac, renal, or vascular diseases, or abnormalities in the blood oncotic pressure. To mobilize interstitial edema fluid without significant reductions in plasma volume. But this therapy will also reduce perfusion of vital organs. E.g. low blood pressure after cardiac ischemia

75. Clinical Pharmacology of Diuretic Agents 2. Heart Failure Cardiac output in these patients is being maintained in part by high filling pressures and that excessive use of diuretics may diminish venous return and thereby impair cardiac output. Metabolic alkalosis Hypokalemia Diuretics can never correct the underlying cardiac disease.

76. Clinical Pharmacology of Diuretic Agents 3. Kidney Disease Patients with milder degrees of renal insufficiency can be treated with diuretics when they retain sodium. Patients with severe renal function deficiency, diuretic agents are of little benefit, 4. Hepatic Cirrhosis Liver disease is often associated with edema and ascites in conjunction with elevated portal hydrostatic pressures. 5. Idiopathic Edema （特发性水肿）

77. Clinical Pharmacology of Diuretic Agents 1. Hypertension 2. Nephrolithiasis （肾结石） 3. Hypercalcemia 4. Diabetes Insipidus （尿崩症） Nonedematous States