Diuretic Agents

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

3. 10％Na+ 65-70％Na+ 酮 25％Na+

5. Proximal Tubule HCO3- 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. Ө acetazolamide

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 Ө Loop diuretics

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

9. Collecting Tubule • 2–5% of NaCl reabsorbed • Principal cells are the major sites of Na+, K+, and H2O 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

13. Basic Pharmacology of Diuretic Agents Carbonic Anhydrase Inhibitors acetazolamide (乙酰唑胺） • Inhibit bicarbonate reabsorption; • HCO3- 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

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

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

16. Foresemide Pharmacodynamics (1) Diuretic effects • Inhibiting the Na+-K+-2Cl- symportof 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.

18. Foresemide • Impairing kidney’s ability to excrete a dilute urine. • Blocking kidney’s ability to concentrateurine during hydropenia,by decreasing the hypertonic medullary interstitium. • Increasing excretion of Ca2+, Mg2+by abolition of transepithelial potential difference. • Inhibit Carbonic Anhydrase at large dose, increase excretion of HCO3-

19. urine dilute loop diuretics urine concentration

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

21. Foresemide 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

22. Foresemide 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

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

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

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 effortto synthesize more potent carbonic anhydrase inhibitors. • Some of the thiazides retain significant carbonic anhydrase inhibitory activity.

27. Thiazides 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 长效 短效 短效 中效 长效 长效 中效

28. Thiazides 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.

29. Thiazides 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+, Mg2+, HCO3-, but increasing the reabsorption of Ca2+ in distal convoluted tubule (2) The action of thiazides depends in part on renal prostaglandin production like loop diuretics.

31. thiazides urine dilute

32. Thiazides 3. Clinical Indications: (1) Antihypertensive effects • Blood volume , spasm responsiveness of arterial smooth muscles  (2) Edema: • Used in treatment of mild and moderate edemain cardiac and renal diseases, and hepatic diseases with cautions; (3) Nephrolithiasis due to idiopathic hypercalciuria (先天性高尿钙症) • Increase Ca2+ reabsorption.

33. Thiazides (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.

34. Thiazides 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

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

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

37. Potassium-sparing diuretics (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

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

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

40. Potassium-sparing diuretics 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

41. spironolactone

43. Potassium-sparing diuretics 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

44. Potassium-sparing diuretics 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

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

47. Mannitol 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

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

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

50. Diuretic Combinations • 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.