Transcript (2015汤慧芳V1)
Diuretics Huifang Tang (汤慧芳) [email protected] Dept. Pharmacology, Schoolof Medicine , Zhejiang University The Kidney: Excretion of water, ions, and toxic metabolites; Balance in electrolytes, water, and acid-base in the body. Overview Excretion in the kidney 1. Solutes (溶质) 1) Ions (electrolytes) 2) Organic anions (weak acids) and organic cations (weak bases) 3) Other solutes 2. Water Glomerular filtration Tubule secretion and reabsorption 65-70％ Na+ 10％ Na+ 25％ Na+ 2~5％Na+ urine concentration 1. Excretion of inorganic ion 1：对流扩散，溶于水中的离子借助于水流排出细胞外；2：简单扩散，为脂溶性物 质进入细胞的方式；3：通道介导的扩散，离子通过蛋白构成的孔道（通道）顺电化 学梯度进入细胞，通道开闭受电压、化学物质和机械力等的门控；4：载体介导的扩 散，离子在载体蛋白的帮助下，顺膜内外电化学梯度进行转运；5：ATP介导的转运， 以ATP水解提供能量，离子逆膜内外电化学梯度进行转运；6：同向转运，在主动转 运一种离子的同时，带动另一种离子作同方向转运；7：反向转运，在主动转运一种 离子的同时，带动另一种离子作反方向转运 2. Excretion of organic ion 近曲小管有机酸和有机碱分泌 1：原发性主动转运；2：继发性主动转运；3：三次主动转运；A-：有机 酸；C+：有机碱；KG2-：-酮戊二酸或其他二羧酸。 Proximal convoluted tubule (近曲小管) ATP-结合盒转运体（ ATP-binding cassette transporter , ABC转运体） 12次跨膜结构 图 、 17次跨膜结构 12次跨膜结构 6 次跨膜结构 溶质载体类转运体（solute carrier, SLC） • 有机阴离子转运体家族（organic anion transporter, OAT） • 有机阳离子转运体家族（organic cation transporter, OCT） •寡肽转运体(oligopeptide transporter, PEPT) •核苷转运体（nucleoside transporter, NT ） 3. Excretion of H2O AQPs有通透水分子的特殊构型 。例如，AQP1的N-和C-末端 均在细胞内，由6个跨膜区和5 个袢（A～E）组成， B和E袢 有天冬酰胺-脯氨酸-丙氨酸（ NPA）结构，该两个袢在细胞 膜形成水孔道，形状类似于“砂 漏（hourglass）”；四个AQP1 分子组成四聚体结构，其中一 个AQP1分子的细胞外部分有一 个长的多糖链。 Water excretion Water channels or aquaporins (AQPs) AQP0～AQP12 Luminal space or AQP4 ADH： antidiuretic hormone， 抗利尿激素 ADH or AQP4 Function and modulation of AQP2 and AQP3 Collecting tubule cells 65-70％ Na+ 10％ Na+ 25％ Na+ 2~5％Na+ urine concentration Proximal convoluted tubule(近曲小管) 65-70% Na+ reabsorption 60 % H2O reabsorption HCO3- resorption: carbonic anhydrase (CA，碳酸酐酶) Organic acid secretory systems 有机酸分泌系统 : Metabolites (uric acid), drugs (most of cephalosporins, loop diurects, NSAIDs, most of the blactams, thiazide diuretics, most of the sulfonamides, Acetazolamide(乙酰唑胺) Organic base secretory systems 有机碱分泌系统: Metabolites (choline), drugs (H2 receptor blocker, Amiloride(阿 米洛利), ephedrine(麻黄碱), morphine, quinine ) ㈠ CA inhibitor Acetazolamide 乙酰唑胺 Thick ascending limb of henle’s loop （髓袢升支粗段） 25% Na+ reabsorption 25% Ca+ reabsorption 50-60% Mg2+ reabsorption Water is impermeable due to lack of AQP水通道蛋白 ㈠ Loop diuretics （袢利尿药） Cation resorption 阳离子重吸收 13 Distal convoluted tubule(远曲小管) 10% Na+ reabsorption Water impermeable parathyroid hormone （PTH,甲状旁 腺激素） ㈠ Thiazide diuretics （噻嗪类利尿药） ⊕ 14 Collecting tubule and duct（集合管） 2-5% Na+ reabsorption Principal cells(主细胞) : the major sites of Na+, K+, and H2O transportation（Na+、 Cl-重吸收，K+分泌） Intercalated cells( 闰细胞) : the primary sites of proton secretion（H+分泌，少量K+重 吸收） Potassium-retaining diuretics （保钾利尿药） ㈠ A diuretic is any substance influencing the rates of transport of Na+, K+, Cl-, HCO3and urate, increases urine and solute excretion. Thiazides 65-70％ Na+ 10％ Na+ K+ sparing diuretics 25％ Na+ Loop diuretics Classification of diuretics 1、Loop diuretics: high efficacy (high-ceiling) diuretics. Affected sites: thick ascending tubule of Henle’s loop; Effect: inhibiting Na+-K+-2Cl- co-transporter; Classical drug: furosemide(呋塞米), etc. 2、Thiazide diuretics: moderate efficacy diuretics. Affected sites: distal convoluted tubule; Effect: inhibiting Na+-Cl- co-transporter; Classical drug: hydrochlorothiazide(氢氯噻嗪), etc. 3、K+-sparing diuretics: low efficacy diuretics. Affected sites: late distal tubule and collecting duct Effect: inhibiting renal epithelial Na+ channels; Classical drug: spironolactone(螺内酯), etc. 4、Carbonic anhydrase inhibitors( 碳酸酐酶抑制剂) : acetazolamide (乙酰唑胺) 5、Osmotic diuretics(渗透性利尿药): mannitol (甘露醇) 1、Loop diuretics (Na+-K+-2Cl- cotransporter inhibitors): Furosemide (呋塞米) : most potent diuretic effects; K+ only used for severe patients 1、Loop diuretics（袢利尿药） Sulfonamide derivatives 磺酰胺类衍生物 呋塞米 布美他尼 phenoxyacetic acid derivatives 苯氧乙酸衍生物 依他尼酸 sulfonylurea derivatives 磺酰脲类衍生物 Torsemide 托拉塞米 The diuretic activity correlates with their secretion by the proximal tubule • Furosemide（呋塞米） 1. Pharmacological effects (1) Diuretic effects Inhibiting the Na+-K+-2Cl- cotransporter (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. Blocking kidney’s ability to concentrate urine by decreasing the hypertonic medullary interstitium. Impairing kidney’s ability to dilute urine. Also, increasing excretion of Ca2+, Mg2+, HCO3- by abolition of transepithelial potential difference. (2) Vasodilatation Renal vasodilatation: renal blood flow Dilating veins: cardiac preload 65-70％ Na+ 10％ Na+ 25％ Na+ Loop diuretics 2. Clinical uses (1) Severe edema: ineffective with thiazides (2) Acute pulmonary edema: heart failure (3) Acute renal failure: combined with dopamine (多 巴胺) (4) Hypercalcemia (5) Detoxication of toxins or drug overdose 3. Adverse effects (1) Imbalance of water and electrolytes: acute hypovolumia; hypokalemia; etc. (2) Ototoxicity: hearing damage（听力损害）, contraindicated to combine with aminoglycoside antibiotics (氨基苷类抗生素) (3) Other effects: GI reactions, hyperuricemia (尿酸增高), arrhythmias, RAAS activity , etc. Other loop diuretic drugs Bumetanide（布美他尼）： 40-60 times more potent than furosemide, more reliable absorption (80% -95%), less ototoxicity. Torasemide（托拉塞米）：stronger and longer actions， more reliable absorption (80%), less K+/Ca2+ waste. Etacrynic acid（依他尼酸）：weaker actions and more severe adverse effects 2、Thiazide diuretics (Na+-Cl- cotransporter inhibitors): Hydroxychlorothiazide (氢氯噻嗪) : moderate potent diuretic effects; K+ most widely used for CHF and hypertensive patients Thiazide and thiazide-like diuretics Thiazides噻嗪类 非噻嗪类 Indapamide 吲达帕胺 苄氟噻嗪 氯噻嗪 氢氯噻嗪 Chlortalidone氯噻酮 氢氟噻嗪 甲氯噻嗪 泊利噻嗪 Metolazone美托拉宗 三氯噻嗪 28 thiazides 65-70％ Na+ 10％ Na+ K+ sparing diuretics 25％ Na+ Loop diuretics Thiazide diuretic drugs 1. Pharmacological effects and clinical uses (1) Diuretic effects Acting on distal convoluted tubule, inhibiting Na+Cl- cotransporter (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 Used in treatment of mild and moderate edema in cardiac and renal diseases, and hepatic diseases with cautions; Used in treatment of hypercalciuria (高尿钙症) and calcium oxalate stones in urinary tract. (2) Antihypertensive effects blood volume spasm responsiveness of arterial smooth muscles (3) 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. 2. Adverse effects (1) Imbalance of eletrolytes hypokalemia hypomagnesemia hyponatremia hypochloremia cautions: dose individualization, K+ supplement (2) Dysfunctio of metabolism hyperglycemia hyperlipidemia hyperuricemia contraindicated in diabetes and gout (痛风) patients (3) Hypersensitivity bone marrow suppression, dermatitis, necrotizing vasculitis, interstitial nephritis, etc. 3、Potassium-sparing diuretics Antagonists of mineralocorticoid Receptors (aldosterone Antagonists ） Spironolactone 螺内酯 Inhibitors of renal epithelial Na+ channels Triamterene 氨苯蝶啶 Amiloride 阿米洛利 Spironolactone Triamterene Amiloride K+ sparing diuretics: weaker diuretic effects; K+ used for the patients with increased aldosterone Spironolactone Spironolactone 螺内酯 螺内酯 Aldosterone 醛固酮 Spironolactone 螺内酯 1. Pharmacological effects Blocking aldosterone receptor Decreasing Na+ reabsorption and K+ excretion Weaker, slow acting（1d）, and lasting duration(2-4d) 2. Clinical uses Edema with increased aldosterone levels Combined with other diuretic drugs 3. Adverse effects (1) (2) (3) (4) Hyperkalemia Sex hormone-like effects GI reactions CNS reactions Triamterene 氨苯蝶啶 Amiloride 阿米洛利 triamterene 氨苯蝶啶 amiloride 阿米洛利 Triamterene 氨苯蝶啶 Amiloride 阿米洛利 1. Pharmacological effects Blocking renal epithelial Na+ channels: decreasing Na+-K+ exchange Fast acting（2h）, and lasting duration 16h-24h 2. Clinical uses Similar to spironolactone 3. Adverse effects Hyperkalemia, GI reactions, etc. Relative changes in the composition of urine induced by thiazide diuretics. Relative changes in the composition of urine induced by loop diuretics. Relative changes in the composition of urine induced by potassiumsparing diuretics. 4、Carbonic anhydrase inhibitor (碳酸酐酶抑制剂，sulfanilamides ) Acetazolamide 乙酰唑胺 dorzolamide brinzolamide Pharmacokinetics: Acetazolamide is given orally once to four times daily. It is secreted by the proximal tubule. Mechanism of action: Acetazolamide inhibits carbonic anhydrase located intracellularly (cytoplasm) and on the apical membrane of the proximal tubular epithelium. Therapeutic uses: a.Treatment of glaucoma: It is useful in the chronic treatment of glaucoma but should not be used for an acute attack. b.Mountain sickness: Adverse effects: Metabolic acidosis (mild), potassium depletion, renal stone formation, drowsiness, and paresthesia may occur. The drug should be avoided in patients with hepatic cirrhosis, because it could lead to a decreased excretion of NH4+. Relative changes in the composition of urine induced by acetazolamide. 5、Osmotic diuretics Dehydrant agents 甘油 异山梨醇 甘露醇 尿素 Mannitol OH OH 甘露醇 OH OH OH OH Dehydrant agents 1. Pharmacological effects (1) Dehydrant effects (2) Diuretic effects (osmotic diuretic effects) 2. Clinical uses (1) Brain edema (2) Glaucoma (3) Acute renal failure: prevention and early treatment Dehydrant agents 3. Adverse effects (1) Elevated extracellular osmolality: pulmonary edema, etc. (2) Hyponatremia and dehydration: headache, nausea, vomiting, etc. Contraindicated in anuric (无尿) duo to severe renal diseases, active cranial bleeding (颅内 出血), heart failure Dehydrant agents Other dehydrant drugs Sorbitol 山梨醇 Hypertonic glucose (50%) 高渗葡萄糖 类 别 (主要作用部位) 其他分类名 碳酸酐酶抑制药 （近曲小管） / 渗 透 性 利 尿 药 脱水药 （髓袢及其他部 位） 作用机制 利尿应用 非利尿应用 抑制碳酸酐酶 利尿药耐受的病 青光眼，高山病， 人,与袢利尿药合 代谢性碱中毒 用 增高尿液渗透压 急性肾功能衰竭 脑水肿，青光眼 袢 利 尿 药 （ 髓 袢 1. 高效能利尿药 抑制Na+ -K+ -2C1- 各 种 严 重 水 肿 ， 高 钙 血 症 ， 加 速 升支粗段） 2. Na+-K+-2C1-同 同向转运 急性肾功能衰竭 毒物排出 向转运体抑制药 噻 嗪 类 利 尿 药 1. 中效能利尿药 抑制Na + -C1 - 同向 各种水肿 （远曲小管） 2. Na+-C1-同向转 转运 运体抑制药 保 钾 利 尿 药 （ 集 低效能利尿药 合管、末段远曲 小管） 高血压，高尿钙 症，尿崩症 1. 拮抗醛固酮作 水 肿 （ 尤 其 对 伴 失钾和/或失镁 用（螺内酯） 有醛固酮增高者， 2. 抑制上皮细胞 如肝硬化病人） Na+通道（氨苯蝶 啶，阿米洛利） Thank you for attention!