泌尿系统教学课件：Diuretics and Dehydrant Agents.ppt

单击此处编辑母版标题样式,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,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,*,Diuretics and Dehydrant Agents,Section1,Diuretics,Definition,Diuretics are a family of drugs that act on,kidney,and promote the,excretion of urine,(including water and electrolyte).,(mainly used in edema),The physiological basis of,diuretics,Excretion function of kidney,Urinary physiology of kidney and the,sites of diuretics,Excretion of inorganic ion,Excretion of organic ion,Excretion of water,Excretion function of kidney,Excretion function of kidney,1.Excretion of inorganic ion,Convection,Via ion channels,Simple diffusion,Facilitated diffusion,Active transport(primary),Active transport(secondary,),Symporter,Antiporter,space,lumen,tubular cell,K,+,2Cl,-,Na,+,Na,+,Cl,-,K,+,K,+,Ca,2+,Mg,2+,ATP,Na,+,-K,+,-2Cl,-,Symporter,Na,+,-K,+,ATPase,Na,+,K,+,space,lumen,Cl,-,Na,+,Na,+,Cl-,K,+,ATP,Ca,2+,Na,+,Ca,2+,K,+,K,+,tubular cell,Na,+,-Cl,-,Symporter,Na,+,-K,+,ATPase,HCO,3,-,+,H,+,Na,+,K,+,Na,+,ATP,H,2,O+,CO,2,CO,2,+,H,2,O,H,+,+HCO,3,-,H,2,CO,3,CA,CA,tubular cell,lumen,space,Na+-H+,Antiporter,Na,+,-K,+,ATPase,Excretion of inorganic ions,Excretion function of kidney,2.Excretion of organic ion,Secondary active transport,Anionic transport system,Cationic transport system,Pay attention:,competition,Excretion of organic ions,Excretion function of kidney,3.Excretion of water,Water channel aquaporins(AQPs),Noble prize in chemistry 2003,Peter Agre,(1949-),1988 protein,1991 -cDNA,2003 Nobel prize,AQP,Characteristics of AQPs,Water permeation:unique,Water follows passively,Driven by Na+-K+ATPase,Filtration,Reabsorption,Secretion,Excretion,Urinary physiology of kidney and the sites of diuretics,原尿量,终尿量,Filtration of glomerular,blood,Tubule fluid,glomerular,tubulus,urine,Reabsorption of renal tubule and collecting tube,Proximal tubules,Henles loop,Distal convoluted tubules,Collecting tubules,1.Proximal tubule,2.thick ascending limb of Henles loop,3.Distal tubule and collecting ducts,Proximal Tubule,Na,+,/K,+,ATPase:maintains gradient,Na,+,flows down via channel,Na,+_,H,+,exchange:carbonic anhydrase(CA),AQP1/7:Water follows passively,65%70%of Na,+,and water reabsorption,Cl,-,、,Ca,2+,、,K,+,、,Mg,2+,reabsorption,HCO,3,-,+,H,+,Na,+,K,+,Na,+,ATP,H,2,O+,CO,2,CO,2,+,H,2,O,H,+,+HCO,3,-,H,2,CO,3,CA,CA,tubular cell,lumen,space,Proximal tubule,acetazolamide,Na,+,Na,+,TAL:thick ascending limb,1.No AQPs:impermeable to water,2.Transports Na,+,by,Na,+,-,K,+,-,2Cl,-,symporter,25-35%of Na,+,reabsorbed,Reabsorption of Ca,2+,Mg,2+,and Cl,-,space,lumen,tubular cell,K+,2Cl,-,Na,+,Na,+,Cl,-,K,+,K,+,Ca,2,+,Mg,2,+,ATP,Symporter,Thick ascending limb of Henles loop,Furosemide,K+,Cl,-,Na,+,NaHCO3,NaCl,NaCl,K,+,K,+,Mg,2+,H,2,O,2Cl,-,Ca,2+,Ca,2+,(+PTH),Na,+,NaCl,醛固酮,K,+,H,2,O,(+ADH),H,+,K,+,2Cl,-,Na,+,皮质部,髓质部,近曲小管,髓袢,远曲小管,集,合,管,稀释,浓缩,高,渗,高,渗,Distal Convoluted Tubule,5,10%of Na,+,reabsorbed,(1)Na,+,-Cl,-,symporter,(2)Ca,2+,-channel(3)Na,+,-Ca,2+,exchange:,parathyroid hormone(PTH),(4)No AQPs:impermeable to water,space,lumen,Cl,-,Na,+,Na,+,Cl-,K,+,Thiazides,ATP,Ca,2+,Na,+,Ca,2+,K,+,K,+,Distal convoluted tubule,tubular cell,PTH,Collecting Duct,Water permeability:main site,Controlled by ADH,Via AQPs(2,3,4),Driven by medulla osmotic gradient,2-5%of Na,+,reabsorbed:,Via Na+channels,Regulated by ADS,K,+,secretion,:major site,lumen,space,ATP,R,ADH,R,Na,+,K,+,H,2,O,Cl,-,ADS,ADS-R,K,+,-Na,+,exchange,principal,cell,Na,+,K,+,Na,+,K,+,spironolactone,Triamterene,Amiloride,NaHCO3,NaCl,Na,+,K,+,K,+,Mg,2+,H,2,O,2Cl,-,Ca,2+,Ca,2+,(+PTH),Na,+,NaCl,醛固酮,K,+,H,2,O,(+ADH),H,+,K,+,2Cl,-,Na,+,皮质部,髓质部,近曲小管,髓袢,远曲小管,集,合,管,稀释,浓缩,高,渗,高,渗,Cl,-,Diuretics,Classification,Common used Diuretics,Classification of Diuretics,.Loop(high efficacy diuretics)diuretics,.Thiazide(moderate efficacy)diuretics,.Potassium-sparing(low efficacy,),diuretics,.Carbonic anhydrase inhibitors,.Osmotic diuretics(dehydrants),Common used Diuretics,.loop diuretics,(High,efficacy,diuretics),Furosemide(,呋塞米,呋喃苯氨酸,速尿,),Etacrynic acid(,依他尼酸,利尿酸,),Bumetanide (,布美他尼,),Torsemide,(,托拉塞米,),Pharmacokinetics,1.Absorption,2.Distribution:PPBR95%,3.Elimination:,Anionic transport system,Pharmacological actions,1.Diuresis:,fast and strong,Site of action:,Thick ascending limb of henles loop,Mechanism:,Na,+,-K,+,-2Cl,-,cotransporter,Result,：,Na,+,K,+,2Cl,-,Mg,2+,Ca,2+,excretion,space,lumen,tubular cell,K+,2Cl,-,Na,+,Na,+,Cl,-,K,+,K,+,Ca,2,+,Mg,2,+,ATP,Symporter,Thick ascending limb of Henles loop,Furosemide,K+,Cl,-,Na,+,NaHCO3,NaCl,NaCl,K,+,K,+,Mg,2+,H,2,O,2Cl,-,Ca,2+,Ca,2+,(+PTH),Na,+,NaCl,ADS,K,+,H,2,O,(ADH),H,+,K,+,2Cl,-,Na,+,皮质部,髓质部,近曲小管,髓袢,远曲小管,集,合,管,稀释,浓缩,高,渗,高,渗,Loop diuretics,肾的稀释功能,肾的浓缩功能,高,渗,2.Vasodilation,Renal vessel dilationrenal blood flow,Vessel dilation heart load,Possible mechanism:,PGE,2,synthesis,Pharmacological actions,1.Acute pulmonary and cerebral edema,2.Severe edema,Cautions,3.Renal failure,4.Hypercalcemia,5.Overdose of some toxicants,Clinical uses,Adverse reactions,1.Electrolyte disorders,hyponatremia,hypomagnesemia,hypochloremia alkalosis,hypokalemia,CHF:digitalis intoxication,Hepatic cirrhosis:hepatic,coma,2.Ototoxicity:,dose-related,Ethacrynic acid,Furosemide,Bumetanide,Pay attention!,Adverse reactions,3.Hyperuricemia,(1),reabsorption of uric acid,(2),secretion of uric acid,4.GI reactions,5.Allergic reactions,Adverse reactions,.Thiazides(,噻嗪类,):,(Moderate efficacy diuretics),Hydrochlorothiazide,(,氢氯噻嗪,双氢克尿噻,双克,),Chlorothiazide(,氯噻嗪,),Chlortalidon(,氯酞酮,),Indapamide(,吲哒帕胺，寿比山,),中效利尿药,噻嗪类,短效类,12h,氢氯噻嗪（,hydrochlorothiazide),氯噻嗪（,chlorothiazide),中效类,1224h,苄噻嗪（,benzthiazide),氢氟噻嗪（,hydroflumethiazide),环噻嗪（,cyclothiazide),三氯噻嗪（,trichlorothiazide),长效类,24h,苄氟噻嗪（,bendrofluazide),甲氯噻嗪（,methychlorothiazide),环戊噻嗪（,cyclopenthiazide),泊利噻嗪（,polythiazide),非噻嗪类,氯噻酮（,Chlortralidone,）,吲达帕胺（,Indapamide,）,美托拉宗（,Metolazone,）,喹乙宗（,Quinethazone,）,Classifications,1.,Diuresis:,moderate,Site of action:,early distal tubules,Mechanism:,Na,+,-Cl,-,symporter inhibition,CAI(in large dose),Results:,Na,+,K,+,Cl,-,Mg,2+,HCO,-,3,excretion,Ca,2+,in urine,(Ca,2+,reabsorption in distal tubules),Pharmacological actions,space,lumen,Cl,-,Na,+,Na,+,Cl-,K,+,Thiazides,ATP,Ca,2+,Na,+,Ca,2+,K,+,K,+,Distal convoluted tubule,tubular cell,-,+,NaHCO3,NaCl,NaCl,K,+,K,+,Mg,2+,H,2,O,2Cl,-,Ca,2+,Ca,2+,(PTH),Na,+,NaCl,ADS,K,+,H,2,O,(ADH),H,+,K,+,2Cl,-,Na,+,皮质部,髓质部,近曲小管,髓袢,远曲小管,集,合,管,稀释,浓缩,高,渗,高,渗,高,渗,Thiazides,-,+,2.,Anti-insipidus effect,Possible mechanisms,1)PDE(,磷酸二酯酶）,intracellular cAMP water permeability water reabsorption,2)excretion of NaCl plasma Osm thirst drinking urine,Pharmacological actions,Insipidus(,尿崩症,),尿崩症多是由于抗利尿激素缺乏、肾小管重吸收水的功能障碍，从而引起以多尿、烦渴、多饮与低比重尿为主要表现的一种疾病。本病是由于下丘脑,神经垂体部位的病变所致，但部分病例无明显病因，尿崩症可发生于任何年龄，但以青年为多见。,主要临床表现为多尿、烦渴与多饮，起病常较急。,24h,尿量可多达,5-10L,，但最多不超过,18L,。尿比重常在,1.005,以下，尿渗透压常为,50-200mOsm/kg,H O,，尿色淡如清水。,3.,Anti-hypertension effect,Mechanisms,Early stage:diuretic effectblood volume,Late stage:excretion of Na,+,Na,+,-Ca,2+,exchangeCa,2+,in smooth cell artery tension,Pharmacological actions,1.Edema:major indication,Mild and moderate cardiac edema:,first choice,Renal edema,related to renal function,Ascites due to cirrhosis:,combined with spironolactone,Clinical Uses,2.Insipidus,3.Hypertension,:,first-line drugs,Hydrochlorothiazide,Indapamide,4.Idiopathic,hypercalciuria,Clinical Uses,1.Electrolyte disorders,Hypokalemia,Hypomagnesemia,Hyponatremia,2.Metabolic disorders,Hyperglycemia,Hyperlipidemia,Hyperuricemia,3.Allergic reaction,Adverse reactions,.,Potassium-sparing diuretics,Spironolactone,(,螺内酯,安体舒通,),Triamterene(,氨苯蝶啶,),Amiloride(,阿米洛利,),distal tubules and collecting ducts,Na,+,excretion,K,+,excretion,Site of action,lumen,space,ATP,R,ADH,R,Na,+,K,+,H,2,O,Cl,-,ADS,ADS-R,K,+,-Na,+,交换,Tubular cell,Na,+,K,+,Na,+,K,+,ADH-R,spironolactone,Triamterene,Amiloride,Antisterone,:,Spironolactone,Spironolactone,aldosterone,Aldosterone antagonist,Mechanism,:,competing with ADS,Na,+,-K,+,exchange,Characteristics:,1.Effects dependent on ADS,2.Potassium-sparing diuretics,3.weak,slow and long,Pharmacological effects,1.Edema with high activity of aldosternone:eg.,liver cirrhosis and nephritis syndrome,2.In combination with other diuretics:,to,diuretic effect,；,prevent K loss,3.,congestive heart failure,diuretic effect,；（,-,）,myocardial fibrosis,Clinical uses,1.Hyperkalemia,2.Endocrine abnormality,(impotence,gynecomastia,hirsutism),3.GI reactions,4.CNS syndrome,Adverse reactions,Triamterene(,氨苯喋啶,)Amiloride(,阿米洛利,),Non-steroid in structure,not aldosterone antagonists,Mechanism:,Block Na,+,channel Na,+,reabsorb,K,+,secretion,Clinical uses,:,intractable,edema,Adverse reactions:,Hyperkalemia,GI,，,megaloblastic anemia:,Triamterene,Triamterene(,氨苯喋啶,)Amiloride(,阿米洛利,),Carbonic anhydrase inhibitor(CAI),Acetazolamide(,乙酰唑胺,),Effects:,CAI H+and H,+,-Na,+,exchange Na,+,water and HCO,3,-,excretiondiuresis,CAI in ciliary epithelial cells/neurons aqueous humor/CSF formation,intraocular/Intracranial pressure,HCO,3,-,+,H,+,Na,+,K,+,Na,+,ATP,H,2,O+,CO,2,CO,2,+,H,2,O,H,+,+HCO,3,-,H,2,CO,3,CA,CA,tubular cell,lumen,space,Proximal tubule,acetazolamide,Clinical uses,1.Glaucoma,2.Acute mountain sickness3.Alkalization urine,4.Treatment of metabolic alkalosis,Section2 Dehydrants,Common characteristics,Poor penetration to capillaries membrane(i.v.),Filtrated by glomerulus easily,Not be reabsorped by renal tubules,Not be metabolized,No,toxicity,and antigenicity,Mannitol(,甘露醇,),Sorbitol,（山梨醇）,Isosorbide,（异山梨醇）,Hypertonic glucose(,高渗葡萄糖）,Glycerin,（甘油）,Common used dehydrants,Pharmacological actions,1.Dehydrant effect,i.v.plasma osmotic pressure,pressure in extra fluid compartments,2.Diuretic effect,1)glomerular infiltration,2)tubular osmotic pressure,Mannitol(,甘露醇,20%),1.Brain edema,2.Glaucoma,3.Prevent acute renal failure,Clinical Uses,Adverse reactions,Extracellular volume expansion,Cautions!,表 常用利尿药药代动力学比较,药 物,利尿作用,开始时间（,h,）,峰值时间（,h,）,维持时间（,h,）,袢利尿药,呋塞米,口服,60,分,静注,5,10,分,1,2,15,20,分,6,8,1,3,依他尼酸,口服,30,分,静注,5,10,分,1,2,15,20,分,6,8,1,3,布美他尼,口服,30,分,静注,5,10,分,1,2,15,20,分,6,8,1,3,噻嗪类利尿药,氯噻嗪,2,4,6,12,氢氯噻嗪,2,4,6,12,氢氟噻嗪,1,2,3,4,18,24,苄氟噻嗪,1,2,6,12,18,24,环戊噻嗪,6,7,12,18,24,氯酞酮,2,6,48,72,留钾利尿药,螺内酯,24,48,72,72,96,氨苯蝶啶,2,4,6,7,9,阿米洛利,2,6,12,24,常用利尿药对电解质排泄及排钠力比较,尿电解质的排泄,药物,Na,+,K,+,Cl,-,HCO,3,排钠力,(%),主 要 作用 部 位,机制,袢利尿剂,+,+,+,0,23,髓袢升支粗段髓质和皮质部,抑制,Na,+,、,K,+,、,2Cl,-,共同转运系统,噻嗪类,+,+,+,+,8,髓袢升支粗段皮质部,(,远曲小管开始部,),抑制,NaCl,再吸收,保钾利尿药,+,-,-,0,2,远曲小管、集合管,竞争,ADS-R,(,螺内酯,),阻滞,Na,+,通道,(,氨苯蝶啶,/,阿米洛利,),乙酰唑胺,+,+,-,+,4,近曲小管,抑制碳酸酐酶,水肿时利尿药的选用及注意事项,在应用利尿药前要注意下列几点：,对基本疾病作病因治疗；,动员组织间水肿液或体腔中积液进入血液循环，便于利尿消肿。这就要求患者卧床休息并进行支持疗法等；,用低盐饮食以减少体内,Na,+,量；,注意治疗失败的可能，如观察肾小球滤过率是否下降，醛固酮分泌是否继发性增多等,。,水肿时利尿药的选用及注意事项,（,1,）心源性水肿：,一般选用噻嗪类利尿药，宜加用钾盐；对中度水肿可用氢氯噻嗪加留钾利尿药；对一般利尿药无效的严重水肿，可合用高效利尿药和留钾利尿药，要定期检查血钾含量。,（,2,）肾性水肿：,急性肾炎时，一般不用利尿药，必要时用氢氯噻嗪；肾病综合征时，对高度水肿者可用噻嗪类药物加留钾利尿药。效果不明显时可用高效利尿药加留钾利尿药。,（,3,）肝性水肿：,肝性水肿多伴有继发性醛固酮增多症，一般宜先用留钾利尿药，或留钾利尿药加噻嗪类利尿药，如疗效不显著，可合用留钾及高效利尿药。,（,4,）急性肺水肿及脑水肿：,静脉注射高效利尿药,Thank you,