8-利尿药PPT参考课件.ppt

单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,单击此处编辑母版标题样式,利 尿 药,高分飞,1,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。,2,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),3,肾脏排泄,4,溶质跨膜转运的七种基本机制,5,ATP,介导的转运：,原发主动转运,Na,+,-K,+,ATPase(sodium pump),Ca,2+,-ATPase(calcium pump),H,+,-ATPase(hydrogen pump),同向转运体,(symporter,cotransporter),Na,+,-K,+,-2Cl,-,Na,+,-Cl,-,反向转运体,(antiporter,countertransporter),Na,+,/H,+,exchanger,Na,+,/Ca,2+,exchanger,离子通道,Na,+,channel,继发主动转运,6,水转运,水通道，水通道蛋白,(Aquaporin,AQP),Peter Agre,1991,Nobel Prize in Chemistry in 2003,7,8,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.,9,有机离子排泄,肾小球滤过：,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。,10,尿液形成,肾小球滤过：,超滤,原尿,.,球管平衡，利尿作用弱。,近曲小管分泌：,将利尿药运送到活性部位的肾小管腔面。,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),11,近曲小管,85%NaHCO,3,、,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%H,2,O,被动重吸收。,12,13,HCO,3,-,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,HCO,3,-,大部分重吸收，,Na,+,/H,+,继续交换促使,Cl,-,/,碱交换，导致,NaCl,重吸收。,H,2,O,伴随,NaHCO,3,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。,14,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,15,16,远曲小管,10%NaCl,重吸收,相对对水不通透,Na,+,-Cl,-,同向转运体,Na,+,-Ca,2+,交换体,甲状旁腺激素调节,17,18,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,+,H,2,O,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,+,19,20,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+V,2,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!,21,22,23,24,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,+,/CA,2+,and Mg,2+,;85%of NaHCO,3,and nearly 100%of glucose and amino acids.Isosmotic reabsorption of water.,Very high,Na/H,1,(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 Ca,2+,and Mg,2+,Very low,Na/K/2Cl(NKCC2),Loop,diuretics,Distal,convoluted,tubule(DCT),Active reabsorption of 48%of filtered Na,+,and Cl,;Ca,2+,reabsorption under parathyroid hormone control,Very low,Na/Cl(NCC),Thiazides,Cortical,collecting tubule,(CCT),Na,+,reabsorption(25%)coupled to K,+,and H,+,secretion,Variable,2,Na channels(ENaC),K channels,1,H transporter,1,aquaporins,K,+,-sparing,diuretics,Medullary,collecting duct,Water reabsorption under vasopressin control,Variable,2,Aquaporins,Vasopressin,antagonist,1,Not a target of currently available drugs.,2,Controlled by vasopressin activity.,25,利尿药分类,碳酸酐酶抑制药,(carbonic anhydrase inhibitors),：,乙酰唑胺,(acetazolamide,diamox),渗透性利尿药,(osmotic diuretics;,称脱水药,dehydrant agents),：,甘露醇,(mannitol),袢利尿药,(loop diuretics;,高效能利尿药,high efficacy diuretics),：,呋塞米,(furosemide),噻嗪类利尿药,(thiazide diuretics;,中效能利尿药,moderate efficacy diuretics),：,氢氯噻嗪,(hydrochlorothiazide),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),26,Diuretics were first classified,according to their dose-response,relationship as ceiling quality.,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.,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,.,36,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,Mg,2+,和,Ca,2+,排泄,低镁血症,Ca,2+,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,37,临床应用,急性肺水肿和脑水肿,其他严重水肿,急慢性肾衰竭,高钙血症,袢利尿药,+,生理盐水,i.v.,高钾血症,袢利尿药,+NaCl+H,2,O,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,38,39,不良反应,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,-,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,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,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,40,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,.,41,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.,42,43,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,50100,本类药的原形药物,吲达帕胺,2.510,利尿强度相等，对碳酸酐酶抑制作用强,氯噻酮,50100,利尿作用相等，作用持久，对,K,+,影响小,美托拉宗,2.510,利尿作用强，作用持久,喹乙宗,50100,与,美托拉宗,相似,44,药代动力学,脂溶性较高，口服吸收迅速而完全；,1 h,内起效；,代谢,氯噻嗪脂溶性相对小，需用较大剂量,(,t,1/2,1.5 h).,氯噻酮,(Chlorthalidone),吸收较慢，作用时间长,(,t,1/2,44 h).,吲达帕胺,(Indapamide),主要通过胆汁排泄，但仍有足够的活性形式从肾脏清除以发挥利尿作用,.肾小管有机酸分泌途径分泌，可与尿酸竞争分泌,.,45,药效学,与远曲小管上皮细胞管腔面上,Na,+,-Cl,-,同向转运体结合而抑制,NaCl,重吸收,促进集合管的,Na,+,-K,+,交换,低血钾,促进,Ca,2+,重吸收,细胞内,Na,+,基底膜,Na,+,/Ca,2+,交换,罕见高钙血症,可治疗高钙引起的肾结石,作用也依赖于肾脏前列腺素的产生,被,NSAIDs,抑制,46,临床应用,水肿（轻度至中度）：,CHF,引起的效果好,高血压,充血性心衰,(Congestive,heart failure,CHF),特发性高尿钙引起的肾结石,(nephrolithiasis),肾性尿崩症,(nephrogenic diabetes insipidus),低血容量导致肾小球滤过率,(GFR),抑制磷酸二酯酶,cAMP,激活,PKA,AQP2,47,不良反应,电解质紊乱,低钾代谢性碱中毒,低镁血症,低钠血症,高尿酸血症,高血糖：糖耐量受损,抑制胰岛素分泌，减少组织利用葡萄糖,.,纠正低血钾可部分逆转,.,高血脂,过敏反应,其他：虚弱、疲乏、感觉异常,48,保钾利尿药,(Potassium-sparing Diuretics),螺内酯,(spironolactone,安体舒通,),醛固酮的竞争性拮抗药,氨苯蝶啶,(triamterene),，阿米洛利,(amiloride),抑制远曲小管末端和集合管的管腔膜的钠通道,49,50,药代动力学,螺内酯是一种合成的甾体化合物，竞争性拮抗醛固酮。它的起效和作用持续时间取决于醛固酮在靶组织中反应的动力学。,口服，胃肠道吸收,70%,；,首过消除效应，有肝肠循环；,代谢产物坎利酮,(canrenone),，具有活性；,氨苯蝶啶,口服,50%,吸收；,血浆蛋白结合率为,60%,；,肝脏代谢，肾脏排泄；,在近曲小管通过有机阳离子转运体分泌。,阿米洛利,口服,50%,吸收；,不与血浆蛋白结合；,原型从尿中排泄；,在近曲小管通过有机阳离子转运体分泌。,t,1/2,：氨苯蝶啶,阿米洛利,51,药效学,降低集合管,Na,+,吸收,.,降低主细胞,K,+分泌和闰细胞,H,+,分泌,醛固酮通过促进,Na,+,-K,+,-ATPase,活性和,Na,+,、,K,+,通道活性，提高,Na,+,的重吸收和,K,+,的分泌,.,氨苯蝶啶和螺内酯的作用依赖于肾脏前列腺素的产生。,52,临床应用,与排钾利尿药合用治疗顽固性水肿,螺内酯：,醛固酮增多症；,充血性心力衰竭：抑制心肌纤维化,53,不良反应,高钾血症,高氯代谢性酸中毒,性激素样作用,(spironolactone),：,拮抗雄激素受体和孕酮受体,男性乳房女性化，阳痿，良性前列腺增生,肾结石：氨苯蝶啶溶解度低,54,促进水排泄的药物,渗透性利尿药,(osmotic diuretics),，又称脱水药,(dehydrant agents),甘露醇,(mannitol),，山梨醇,(sorbitol),，高渗葡萄糖,(hypertonic glucose),ADH,拮抗剂,非选择性药物：,Li,+,，地美环素,(demeclocycline),55,渗透性利尿药,(Osmotic Diuretics),特点：,肾小球自由滤过,肾小管重吸收少,惰性或无活性,肾小管中不降解,不被重吸收的溶质形成渗透压，阻止水分重吸收，增加尿量；,近曲小管,髓袢降支,集合管,56,药代动力学,甘露醇,不代谢,给药,3060 min,从肾小球滤过，肾小管不吸收、不分泌；,口服，导致渗透性腹泻。合用活性炭从胃肠道排出毒物。,57,药效学,限制水重吸收,利尿,尿流速增加，减少尿液与肾小管上皮细胞接触的时间，使,Na,+,的重吸收减少,.,但：尿钠排泄,水排泄,高钠血症,(hypernatremia).,58,59,临床应用,脱水,静脉注射不易从毛细血管渗入组织，提高血浆渗透压,提高细胞外渗透压，从细胞中抽取水分,降低颅内压和眼内压,利尿,排水,排钠,预防肾衰,脱水，减轻肾间质水肿,渗透性利尿维持足够尿量，稀释肾小管内有害物质,改善急性肾衰早期的血流动力学变化,60,不良反应,细胞外液增加,加重心衰，引发肺水肿,头痛、恶心、呕吐,过敏反应,脱水、高钾血症和高钠血症,低钠血症,肾功能降低者，甘露醇保留在静脉产生渗透压，从细胞内从抽取水分，导致低钠血症,61,抗利尿激素拮抗剂,(ADH Antagonists),Nonselective agents:Li,+,salts and Tetracycline derivatives(demeclocycline),Reduce the formation of cAMP in response to ADH and also to interfere with the actions of cAMP in the collecting tubule cells.,Clinical Indications,Syndrome of inappropriate ADH secretion,Other causes of elevated ADH,Toxicity,Nephrogenic Diabetes Insipidus,Renal Failure,Other,62,63,Diuretic Combinations,Loop Agents&Thiazides,Acting at different nephron sites may exhibit synergy.,Mobilize large amounts of fluid,outpatient use cannot be recommended.,Potassium wasting is extremely common,require parenteral K,+,administration.,Potassium-sparing Diuretica&Loop agents or Thiazides,K,+,-sparing,and K,+,-losing,counteract,64,.Summary:Sites of Diuretic Action,65,66,各类利尿药（包括脱水药）的特点比较,类别,（主要作用部位）,其他分类名,作用机制,利尿应用,非利尿应用,碳酸酐酶抑制药（近曲小管）,抑制碳酸酐酶,利尿药抵抗的病人，与袢利尿药合用,青光眼、高山病、代谢性碱中毒,渗透性利尿药（髓袢及其他部位）,脱水药,增高尿液渗透压,急性肾衰竭,脑水肿、青光眼,袢利尿药（髓袢升支粗段）,1.,高效能利尿药,2.Na,+,-K,+,-2Cl,-,同向转运体抑制药,抑制,Na,+,-K,+,-2Cl,-,同向转运,各种严重水肿，急性肾衰竭,高钙血症、加速毒物排出,噻嗪类利尿药（远曲小管）,1.,中效能利尿药,2.Na,+,-Cl,-,同向转运体抑制药,抑制,Na,+,-Cl,-,同向转运,各种水肿,高血压、高尿钙症、尿崩症,保钾利尿药（集合管、末端远曲小管）,低效能利尿药,1.,拮抗醛固酮作用（螺内酯）,2.,抑制上皮细胞,Na,+,通道（氨苯蝶啶、阿米洛利）,水肿（尤其对伴有醛固酮增高者，如肝硬化病人）,失钾和,/,或失镁,67,Changes in urinary electrolyte patterns in response to diuretic drugs,Agent,Urinary Electrolyte Patterns,NaCl,NaHCO,3,K,+,Carbonic anhydrase inhibitors,+,+,+,Loop agents,+,+,Thiazides,+,+,Loop agents plus thiazides,+,+,+,K,+,-sparing agents,+,+,increase;,decrease,68,69,70,利尿的中药和食物,Herbal medications are not inherently diuretics.They are more correctly called aquaretics(促水排泄药).,Herbal aquaretics include,adonis,agrimony,bearberry,buchu,dandelion,heartsease,hydrangea,ladys mantle,larch,and,sassafras,.These increase blood flow to the,kidneys,without increasing,sodium,and,chloride,resorption,thus causing an increase in urine whilst retaining,electrolytes,.However,the increase in intravascular fluid volume that they cause translates into an increase vascular resistance,and higher,blood pressure,.,车前子、泽泻、茯苓、海金砂、茯苓、冬瓜皮、猪苓、石韦、泽泻、木通,西瓜、薏米、玉米须,玉蜀黍,本草纲目,、赤 豆,日华子本草,、冬 瓜,本草经集注,、莴苣,食疗本草,、鲤 鱼,神农本草经,、鲫 鱼,名医别录,71,Examples,Mechanism,Location,(numbered in distance along nephron),ethanol,water,inhibits vasopressin secretion,1.,Acidifying salts,CaCl,2,NH,4,Cl,1.,Aquaretics,Goldenrod,Juniper,Increases blood flow in kidneys,1.,Xanthines,caffeine,theophylline,inhibit reabsorption of Na,+,increase GFR,1.tubules,Carbonic anhydrase inhibitors,acetazolamide,dorzolamide,inhibit H,+,secretion,resultant promotion of Na,+,and K,+,excretion,2.proximal tubule,Na-H exchanger antagonists,dopamine,promote Na+excretion,2.proximal tubule,Osmotic diuretics,glucose(uncontrolled diabetes),mannitol,promote osmotic diuresis,2.proximal tubule,descending limb,Loop diuretics,furosemide,bumetanide,ethacrynic acid,torsemide,inhibit the Na,+,-K,+,-2Cl,-,symporter,3.medullary thick ascending limb,Thiazides,bendroflumethiazide,hydrochlorothiazide,inhibit reabsorption by Na,+,/Cl,-,symporter,4.distal convoluted tubules,Potassium-sparing diuretics,spironolactone,amiloride,triamterene,potassium canrenoate,inhibition of Na+/K+exchanger:Spironolactone inhibits aldosterone action,Amiloride inhibits epithelial sodium channels,5.cortical collecting ducts,Arginine vasopressin receptor 2 antagonists,amphotericin B,lithium citrate,inhibit vasopressins action,5.collecting duct,Classification of common diuretics and their mechanisms of action:,72,Adverse effect,Diuretics,Symptoms,hypovolemia,loop diuretics,thiazides,lassitude,thirst,muscle cramps,hypotention,hypokalemia,acetazolamide,loop diuretics,thiazides,muscle weakness,paralysis,arrhythmia,hyperkalemia,spironolactone,amiloride,triamterene,arrhythmia,muscle cramps,paralysis,hyponatremia,thiazides,furosemide,CNS symptoms,coma,metabolic alkalosis,loop diuretics,thiazides,arrhythmia,CNS symptoms,metabolic acidosis,acetazolamide,amiloridetriamterene,Kussmaul respirations,muscle weakness,neurological symptoms,lethargy,coma,seizures,stupor,hypercalcemia,thiazides,gout,tissue calcification,fatigue,depression,confusion,anorexia,nausea,vomiting,constipation,pancreatitis,increased urination,hyperuricemia,thiazides,loop diuretics,gout,73,Review and Key Points,The classification and representative agent of diuretics.,The mechanisms of each.,The pharmacological actions of diuretics,The clinical uses of diuretics.,The principal ADR of diuretics.,Some special PK.,74,Thank You!,ffgao,75,