24 作用于肾素-血管紧张素-醛固酮系统的药物-2009双语缩减版

第24章肾素-血管紧张素－醛固酮系统抑制药华中科技大学同济医学院药理学系主讲教师金满文2009年10月Inhibitorsoftherenin-angiotensin-aldosteronesystem1/70本次课要求掌握的内容2.ACE抑制药的药理作用、作用机理、主要的临床应用和不良反应。2/703.全面比较AT1受体拮抗药与ACE抑制药在药理作用、作用机理、临床应用和不良反应方面的异同。4.通过本章学习，你对靶点发现、确认及与药物研发的关系有何心得？1.RAAS抑制药分类及各类的主要代表药。hypertension,congestiveheartfailure,myocardialinfarction,anddiabeticnephropathyPathophysiologyRenin-Angiotensin-AldosteroneSystemRAAS×××3/70renin-angiotensin-aldosteronesystem•History•ComponentsofRAAS•FunctionsandEffectsofRAAS(RAAS)4/70In1898,TiegerstedtandBergmanfoundthatcrudesalineextractsofthekidneycontainedapressorsubstancethattheynamedrenin.History1898,Tiegerstedt和Bergman发现肾脏的盐水粗提物含有加压物质，他们将其命名为“肾素”。5/70TigerstedtR,BergmanPG:NiereundKreislauf肾脏和循环.SkandArchPhysiol1898;8:223-271.1934,Goldblatt证明收缩肾血管可产生持续的高血压(renalhypertension)In1940,Braun-Menendez(Argentina),PageandHelmer(USA)分别报道肾素是酶，产生缩血管物质，前者称其为hypertensin，后者称其为angiotonin.大约20年后，将此过程中的升压物质命名为血管紧张素angiotensin，血浆中的底物称为血管紧张素原angiotensinogen.7/70Inthemid-1950s,adecapeptideandanoctape-ptidewererecognized.Theoctapeptidewasshowntobethemoreactiveform.decapeptideoctapeptideangiotensin-convertingenzymeenzyme(AngiotensinI)(AngiotensinII)in1957,synthesizedbySchwyzerandBumpus8/70Intheearly1970s,importantphysiologicalandpathophysiologicalrolesfortheRAASwererevealed.上个世纪七十年代早期，开始认识RAAS的重要的生理和病理生作用。PhysiologicalrolesPathohysiologicalrolesPharmacologicalintervention9/70ThirstConvertingenzymePressoreffectSympatheticstimulationADHsecretionConvertingenzymeantagonistCaptoprilenalaprilenalkirenRemikirenAliskirenRenininhibitorAngIIreceptorAntagonistlosartanAldosteronesecretionReninComponentsofRAASAldosteronesecretionAngIIIAngIVAng1-710/70。Angiotensin(3-8)AT4AngIVAng(1-7)receptorAT1AT2?Phe-His89GG11th,200611/70×AngiotensinReceptors(AT)AT1AT2359aminoacids363aminoacidshighaffinityforlosartanlowaffinityforlosartanlowaffinityforPD123177highaffinityforPD123177mostoftheknownbiologicaleffectsofangiotensinII？Antiproliferative抗增生Proapoptotic促凋亡Vasodilatory扩血管Antihypertensive抗高血压12/70ExtrinsicLocalRAASLocal(Tissue)RAAS(局部或组织RAAS)IntrinsicLocalRAASThetraditionalviewoftheRAASisthatofaclassicalendocrinesystem.Renin(kidney)angiotensinogen(liver)ACEThistraditionalviewisanoversimplificationthatmustbeexpandedtoincludelocalRAAS(tissue).AngIAngIIAldosterone(kidney)Biologicaleffects13/70ExtrinsicLocalRAAS(takeup)Circulatingreninofrenalorigincanbetakenupbythearterialwallandbyothertissues.动脉壁和其他组织从循环中摄取肾源性肾素，激活局部的RAAS。14/70许多组织（脑、血管、心脏、肾脏、肾上腺）表达肾素、血管紧张素原、转换酶的mRNA，源于这些组织的细胞培养可产生肾素、血管紧张素原、转换酶、AngI,II,andIII.IntrinsicLocalRAAS(denovosynthesis)Manytissues－includingthebrain,bloodvessels,heart,kidney,andadrenalgland－express①mRNAsforrenin,angiotensino-gen,and/orACE,andvariouscellsculturedfromthesetissuesproduce②renin,angioten-sinogen,ACE,andAngI,II,andIII.15/70FunctionsandEffectsoftheRAAS17/70.AlteredPeripheralResistanceI.Directvasoconstriction直接收缩血管II.↑peripheralnoradrenergicneurotransmissionA.↑NErelease增加NE释放B.↓NEreuptake减少NE再摄取C.↑vascularresponsiveness增加血管反应性III.↑sympatheticdischarges(CNS)增强交感中枢输出IV.↑releaseofcatecholaminesfromadrenalMedullaRapidPressorResponse快加压反应MechanismResult.AlteredRenalFunctionI.Direct↑Na+reabsorptioninproximaltubuleII.Releaseofaldosteronefromadrenalcortex（↑Na+reabsorptionand↑K+excretion)III.Alteredrenalhemodynemics:A.DirectrenalvasoconstrictionB.↑noradrenergicneurotransmissioninkidneyC.↑renalsympathetictone(CNS)SlowPressorResponse慢加压反应MechanismResult19/70.AlteredCardiovascularstructureI.Non-hemodynamicallymediatedeffects:↑expressionofproto-oncogenes↑productionofgrowthfactors↑synthesisofextracellularmatrixproteinsII.Hemodynamicallymediatedeffects:↑afterload(cardiac)↑walltension(vascular)Vascularandcardiachypertrophy&remodelling血管和心脏肥厚、重构MechanismResultThirstConvertingenzymePressoreffectSympatheticstimulationADHsecretionConvertingenzymeAntagonist1981captoprilenalaprilAngIIreceptorAntagonist1995losartantelmisartanAldosteronesecretionMRantagonistspirolactoneeplerenone2002ReninRenininhibitorremikirenremikirenAliskiren2007INHIBITORSOFTHERAAS20/7021/70RAAS抑制药上市时间1981,captopril(ACEI)1995,losartan(ARB)2002,eplerenone(MRA)2007,alisliren(RI)onthemarket上市ThirstConvertingenzymePressoreffectSympatheticstimulationADHsecretionConvertingenzymeantagonistCaptoprilenalaprilremikirenRenininhibitorAngIIreceptorAntagonistlosartantelmisartanAldosteronesecretionMRantagonistSpirolactoneeplerenoneReninremikirenaliskiren补进展INHIBITORSOFTHERAAS22/7023/70ACEInhibitors(AngiotensinConvertingEnzymeInhibitors)Inthe1960s,Ferreiraandcolleaguesfoundthatthevenomsofpitvipers(颊窝毒蛇)containfactorsthatintensifyresponsestobradykinin.Erdosandcoworkersestablished:ACE＝kininaseIIsynthesisofAngIIdestructionofbradykinin24/701971年，Ondetti等*合成了tiprotide，是第一个用于临床的肽类ACEI。*:Bristol-MyersSquibbPharmaceuticalResearchInstitute,Princeton,N.J)1981年，卡托普利用于临床。ACEI是目前主要的心血管药物类别之一。一、ACE的分类和构效关系25/70(二)ACEI与酶的结合27/70PharmacologicalEffects↓thesynthesisofangiotensinII,AngII↓↓thedestructionofbradykinin,BK↑principalpharmacologicalandclinicaleffectsAllACEinhibitorshavesimilartherapeuticindications