8-利尿药.ppt

利利 尿尿 药药 高分飞高分飞 学习目标 在本次课结束时，每位同学能 说出各类利尿药的作用位点和作用机制；列举各类利尿药的主要作用、临床应用和不良反应。Introduction 利尿药(Diuretics)：尿钠排泄药(natriuretic)排水利尿剂(aquaretics)渗透性利尿药(osmotic diuretics)抗利尿激素拮抗剂(ADH Antagonists)肾脏排泄 溶质跨膜转运的七种基本机制 1.ATP介导的转运：原发主动转运 Na+-K+-ATPase(sodium pump)Ca2+-ATPase(calcium pump)H+-ATPase(hydrogen pump)2.同向转运体(symporter,cotransporter)Na+-K+-2Cl-Na+-Cl-3.反向转运体(antiporter,countertransporter)Na+/H+exchanger Na+/Ca2+exchanger 4.离子通道 Na+channel 继发主动转运 水转运 水通道，水通道蛋白(Aquaporin,AQP)Peter Agre,1991 Nobel Prize in Chemistry in 2003 肾小管上皮细胞转运的通用机制 S,symporter;A,antiporter;CH,ion channel;WP,water pore;U,uniporter;ATPase,Na+,K+ATPase(sodium pump);X and Y,transported solutes;P,membranepermeable(reabsorbable)solutes;I,membrane-impermeable(nonreabsorbable)solutes;PD,potential difference across indicated membrane or cell.有机离子排泄 1.肾小球滤过：2.肾小管分泌：阴离子转运系统：利尿剂、抗生素等；阳离子转运系统：阿米洛利、吗啡等。尿液形成 1.肾小球滤过：超滤 原尿.球管平衡，利尿作用弱。2.近曲小管分泌：将利尿药运送到活性部位的肾小管腔面。3.肾小管和集合管重吸收：近曲小管(proximal convoluted tubule)髓袢(loop of henle)远曲小管(distal convoluted tubule)集合管(collecting tubule)近曲小管 85%NaHCO3、40%NaCl(totalling 66%Na+)、葡萄糖、氨基酸和有机溶质通过特殊转运载体重吸收。65%K+通过旁细胞途径重吸收。60%H2O 被动重吸收。HCO3-的重吸收依赖于碳酸酐酶。Cl的重吸收（两种观点）：近曲小管末端，由于HCO3-大部分重吸收，Na+/H+继续交换促使Cl-/碱交换，导致NaCl重吸收。H2O伴随NaHCO3重吸收后，使管腔中Cl浓度升高，通过旁细胞途径扩散进 组织间液。髓袢 髓袢降支细段 水因渗透压被动重吸收 髓袢升支细段 水相对不通透；髓袢升支粗段 25%Na+重吸收 与尿素共同形成髓质高渗区，逆流倍增机制(countercurrent-multiplier mechanism)对水不通透.稀释段”Na+-K+-2Cl-同向转运体 远曲小管 10%NaCl重吸收 相对对水不通透 Na+-Cl-同向转运体 Na+-Ca2+交换体 甲状旁腺激素调节 集合管 2%5%NaCl重吸收 主细胞管腔膜存在离子通道 主细胞(Principal cells):Na+,K+,H2O 转运 Na+进入 管腔负电位 驱动Cl-通过旁细胞途径重吸收，K+外流 闰细胞(Intercalated cells):质子泵，分泌H+集合管 醛固酮(Aldosterone)基因转录 管腔膜离子通道,基底膜Na+-K+-ATPase Na+重吸收,K+分泌 抗利尿激素(ADH;加压素)受血浆渗透压和血容量调节 ADH+V2 受体 cAMP AQP2 囊泡胞吐插入管腔膜 水通道 水重吸收 a potential target of drugs!Major Segments of the Nephron and Their Functions.Segment Functions Water Permeability Primary Transporters and Drug Targets at Apical Membrane Diuretic with Major Action Glomerulus Formation of glomerular filtrate Extremely high None None Proximal convoluted tubule(PCT)Reabsorption of 65%of filtered Na+/K+/CA2+,and Mg2+;85%of NaHCO3,and nearly 100%of glucose and amino acids.Isosmotic reabsorption of water.Very high Na/H1(NHE3),carbonic anhydrase Carbonic anhydrase inhibitors Proximal tubule,Straight segments Secretion and reabsorption of organic acids and bases,including uric acid and most diuretics Very high Acid(eg,uric acid)and base transporters None Thin descending limb of Henles loop Passive reabsorption of water High Aquaporins None Thick ascending limb of Henles loop(TAL)Active reabsorption of 1525%of filtered Na+/K+/Cl;secondary reabsorption of Ca2+and Mg2+Very low Na/K/2Cl(NKCC2)Loop diuretics Distal convoluted tubule(DCT)Active reabsorption of 48%of filtered Na+and Cl;Ca2+reabsorption under parathyroid hormone control Very low Na/Cl(NCC)Thiazides Cortical collecting tubule(CCT)Na+reabsorption(25%)coupled to K+and H+secretion Variable2 Na channels(ENaC),K channels1,H transporter1,aquaporins K+-sparing diuretics Medullary collecting duct Water reabsorption under vasopressin control Variable2 Aquaporins Vasopressin antagonist 1 Not a target of currently available drugs.2 Controlled by vasopressin activity.利尿药分类 1.碳酸酐酶抑制药(carbonic anhydrase inhibitors)：乙酰唑胺(acetazolamide,diamox)2.渗透性利尿药(osmotic diuretics;称脱水药,dehydrant agents)：甘露醇(mannitol)3.袢利尿药(loop diuretics;高效能利尿药,high efficacy diuretics)：呋塞米(furosemide)4.噻嗪类利尿药(thiazide diuretics;中效能利尿药,moderate efficacy diuretics)：氢氯噻嗪(hydrochlorothiazide)5.保钾利尿药(potassium-retaining diuretics;低效能利尿药,low efficacy diuretics)：螺内酯(spironolactone);氨苯蝶啶(triamterene)Diuretics were first classified according to their dose-response relationship as ceiling quality.1.High ceiling diuretics:the loop diuretics cause a substantial diuresis-up to 20%of the filtered load of NaCl and water.This is huge when compared to normal renal sodium reabsorption which leaves only 0.4%of filtered sodium in the urine.increase saluresis over a broad dose range,and therefore are the diuretics of choice in patients with advanced renal failure.2.Low ceiling diuretics:thiazides,antikaliuretics,etc.The dose-response curve is flat,which means that their saluretic effect is limited(呋塞米 起效迅速。通过肾小球滤过和肾小管分泌排泄.与吲哚美辛或丙磺舒等同用产生竞争性抑制分泌.药效学 抑制髓襻升支粗段管腔膜Na+-K+-2Cl-同向转运体 NaCl重吸收 大量等渗尿液 K+重吸收 K+再循环导致的管腔正电位 Mg2+和Ca2+排泄 低镁血症 Ca2+可在远曲小管主动重吸收，不引起低钙血症.促进肾前列腺素合成 肾血流，小静脉扩张 减轻肺水肿，降低充血性心衰的左室充盈压.NSAIDs能干扰利尿作用，尤其是对肾病综合征和肝硬化患者 临床应用 1.急性肺水肿和脑水肿 2.其他严重水肿 3.急慢性肾衰竭 4.高钙血症 袢利尿药+生理盐水i.v.5.高钾血症 袢利尿药+NaCl+H2O 6.毒物排泄 巴比妥类、水杨酸类 溴化物、氟化物、和碘化物都在TALH重新吸收 不良反应 1.水与电解质紊乱 低钾代谢性碱中毒 低镁血症 低血容量，Na+,Cl-2.耳毒性 剂量相关的听力受损，通常可逆.肾衰或同用其他耳毒性药物（如氨基糖苷类抗生素），更易发生；毒性大小：依他尼酸 布美他尼 3.高尿酸血症 低血容量，细胞外液容积减少，尿酸在近曲小管重吸收增加 竞争尿酸分泌 4.其他 过敏反应：有交叉过敏；非磺胺衍生物的依他尼酸少见。大剂量引起胃肠道出血 血糖 血脂，LDH，HDL 偶有WBC，Pt 噻嗪类(Thiazide)噻嗪类是苯并噻二嗪的简称.连有一个磺胺集团.有些仍保留碳酸酐酶抑制活性.原型是氢氯噻嗪.分类 短效：24 h bendrofluazide(苄氟噻嗪),methychlothiazide(甲氯噻嗪),cyclopenthiazide(环戊噻嗪),polythiazide(泊利噻嗪),etc.常用的中效能噻嗪类或非噻嗪类利尿药剂量和药理特性比较 Agents Daily Oral Dose(mg)Pharmacological property 氢氯噻嗪氢氯噻嗪 50100 本类药的原形药物 吲达帕胺吲达帕胺 2.510