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支氣管擴(kuò)張劑作用的分子藥理機(jī)制上海市瑞金醫(yī)院黃紹光
1ControlofairwaydiameterEpidemiology/pathology
2自主神經(jīng)參與調(diào)節(jié)許多氣道功能，影響氣道平滑肌，粘液分泌，血管、微血管通透性，炎癥細(xì)胞的遷移和釋放。神經(jīng)機(jī)制在氣道炎癥疾病中可放大或調(diào)節(jié)炎癥反應(yīng)，其中膽堿能神經(jīng)是引起氣道收縮的主要因素。
3IncreasedmaximalairwaynarrowinginasthmaThickeningandincreasedstiffnessInnerairwaywallHypertrophyandincreasedcontractilityAirwaysmoothmuscleLossofelastioparenchymalrecoil
4NormalCOPDDisruptedalveolarattachments(emphysema)MucosalinflammationandfibrosisMucushypersecretionAirwayheldopenbyalveolaratteachmentsAirwayobstructedbylossofattachmentsMucosalinflammationandfibrosisMucusobstructionoflumenAirwaypathologyinCOPD
5抗膽堿能藥物?2-受體激動(dòng)劑茶堿平滑肌細(xì)胞收縮舒張cAMPAMPM1M2M3三大類支氣管擴(kuò)張劑作用機(jī)制cGMP
6β腎上腺素能受體激動(dòng)劑做為最主要的支氣管擴(kuò)張劑在支氣管哮喘及慢性阻塞性肺?。–OPD）等慢性氣道疾病的治療中得到了廣泛的應(yīng)用。
7b2-AgonistsEosinophilMastcellCholinergicnerveb2-AgonistsSmoothmuscleAcetylcholineHistamineLTD4----?
8所有β受體激動(dòng)劑都是苯乙胺的衍生物，其兒茶酚環(huán)上的羥基位置與作用持續(xù)時(shí)間相關(guān)，改變羥基位置，如間羥異丙腎上腺素、或加上其他基團(tuán)作為替代物，如沙丁胺醇（配基糖苷類），可防止兒茶酚－氧－甲基轉(zhuǎn)移酶（COMT）的代謝；而N端的結(jié)構(gòu)則關(guān)系到作用的選擇性，其取代基越大對(duì)β受體的選擇性就越強(qiáng)，而α受體的活性就下降（如異丙腎上腺素），還可促進(jìn)對(duì)單胺氧化酶（MAO）的抵抗，進(jìn)一步增加N端的結(jié)構(gòu)則對(duì)β2受體的選擇性更強(qiáng)。
9b受體激動(dòng)劑的母核abCHCHNH苯乙胺核
10b2-agonists化學(xué)結(jié)構(gòu)Formoterol:mediumsidechainSalbutamol:shortsidechainSalmeterol:longsidechainOHNHOCHCH2NHCHCH2HOCH3OHCH3CHCH2NHCH2OHCH3CH3CH3OHOHCHCH2NHCH2OHOHOOHCH2CH2CH2CH2CH2CH2CH2CH2CH2CH2
11人類b2腎上腺受體的分子結(jié)構(gòu)糖基化413氨基酸b2激動(dòng)劑結(jié)合點(diǎn)TMDI胞漿COOHIIIIIIVVVIVII432IL1EL123細(xì)胞外細(xì)胞膜NH2棕櫚酰化櫚
12β受體是通過(guò)細(xì)胞內(nèi)腺苷酸環(huán)化酶增加而介導(dǎo)其活化過(guò)程。β受體的信號(hào)轉(zhuǎn)導(dǎo)系統(tǒng)是核苷酸調(diào)節(jié)蛋白Gs，β受體和腺苷酸環(huán)化酶的偶聯(lián)是通過(guò)三維體Gs蛋白，包括α、β、γ亞單位，G蛋白可以興奮（Gs）或抑制（Gi）腺苷酸環(huán)化酶，因此可以增加或減少細(xì)胞cAMP的濃度。
13b2激動(dòng)劑激動(dòng)b2受體(b2AR)程序圖BlockedbyCHARYBDOTOXINCellmembraneasbgasbgb2-Agonistb2ARGSGSATPCyclic3’5’AMPCa2+-activatedK+channelactivation↓PIhydrolysis↑Na+/Ca2+exchange↑Na+/K+ATPase↓MLCKPKGPKAACK+GS：興奮型G鳥核苷酸結(jié)合蛋白（Gs）；AC：腺苷酸環(huán)化酸；PKA：蛋白激酶API：磷酸肌醇；MLCK：肌凝蛋白輕鏈激酶BarnesPJAJRCCM1995
14Anderson.,LifeSci1993AqueousbiophaseCellmembranewith?2-receptorSalbutamolHydrophilicShortdurationFastonsetFormoterolIntermediateLongdurationFastonsetSalmeterolLipophilicLongdurationSlowonset微動(dòng)力彌散理論
15福莫特羅中度親脂性長(zhǎng)作用起效快微動(dòng)力學(xué)
16微動(dòng)力學(xué)沙美特羅親脂性長(zhǎng)作用起效慢油/水＝23000/1膜吸收(<1分鐘)慢吸入(?25分鐘)如穿透上皮、支氣管腔、平滑肌靶
17ActivesiteExo-siteG-ProteinASP113SER205SER207bga
18Johnson,MedResRev,1995TheexositebindinghypothesisExo-site-CHHOHOH2C-HO--CH2NH-CH2---CH2CH2CH2CH2OCH2----CH2CH2CH2-?2-receptorActivesite
19Classesofb2-agonistsfastonset,shortdurationfastonset,longdurationslowonset,shortdurationslowonset,longdurationinhaledterbutalineinhaledsalbutamolinhaledformoteroloralterbutalineoralsalbutamoloralformoterolinhaledsalmeteroloralbambuterolMA I N T E N A N C ERESCUEMEDICATIONSpeedofonsetDurationofactionfastslowlongshort
20福莫特羅是b2受體完全激動(dòng)劑(fullagonist)沙美特羅是b2受體部分激動(dòng)劑(partialagonist)部分激動(dòng)劑是指藥物與受體結(jié)合后只可激發(fā)較弱的生理效應(yīng)，即內(nèi)在活性(intrinsicactivity)小，但它同時(shí)卻都妨礙其他激動(dòng)藥與此受體結(jié)合和激發(fā)效應(yīng)。
21Mechanismofactionofb2-agonists?Plasmaexudation?MucociliaryclearanceNeutrophilfunctionBronchodilatation?Cholinergicneurotransmission?Bacterialadherenceb2-agonists
22AMP>methachaline/histamineprotection=MastcellstabilisingeffectAllergenAdenosineHistamineLTD4IndirectMastcellHistamineMethacholineMASTCELLb2-DRENOCEPTIORSDirectAirwaySmoothmuscleb2-Agonists
23EFFECTOFINHALEDb2-AGONWISTSONPLASMAEXUDATIONINAIRWAYSGuineapigtracheaFormoterolSalbutamolb2-AgonistHistaminePlasmaexudation?control706050403020100
24PtopranololFormoterolContraction(%control)e-NANCVenceenGetal:JApplPhysiol1992100806040200EFFECTOFFORMOTEROLONAIRWAYSENSORYNERVESGuinespigbronchiinvitroEFS:40v,0.5ms,6HzSPSPSPSPSensorynerveb2-receptorSmooth5P
25減敏機(jī)制包括三個(gè)主要過(guò)程：1.受體從腺苷酸環(huán)化酶上解偶聯(lián)；2.解偶聯(lián)的受體從細(xì)胞膜上內(nèi)陷；3.內(nèi)陷后的受體磷酸化。
26PPPPPPCellmembraneBArrestinCOOHBARK(GRK)asNH2b2-AgonistcAMPPKAPKCPTKb受體磷酸化，導(dǎo)致受體功能缺失。磷酸化過(guò)程中，通過(guò)b2受體特異激酶活化，使受體與G蛋白介偶聯(lián)該過(guò)程涉及CAMP依賴蛋白激酶A(PKA),b腎上腺素受體激酶(bARK)和其他G蛋白受體激酶(GRK)
27B2ACDOWN-REGULATIONCellmembranemRNANucleusB2-ReceptorGeneCREBATPcAMPPKAb2-AgonistB2asgBPPcAMPPKACREBB2mRNASTABILITYTRANSCRIPTIONUNCOUPLING發(fā)生在接觸激動(dòng)劑后數(shù)小時(shí),可能是抑制了受體基因的轉(zhuǎn)錄或是增加了細(xì)胞內(nèi)mRNA轉(zhuǎn)錄后的分解代謝細(xì)胞表面受體數(shù)目減少(下調(diào)現(xiàn)象)受體從細(xì)胞膜的內(nèi)陷，引起細(xì)胞表面受體某種程度的缺失，該過(guò)程又稱為隔離。
28
29CNSNodose ganglionLaryngealEsophagealafferentsCfibreAfibreCfibrereceptorsIrritantreceptorsAirwayirritants,mediatorsAirway epitheliumVagusnerveParasympatheticnerveAChParasympatheticganglionAChAChSubmucosalglandInflammatory cellCholinergicPathwaysBarnesPJ(1999)
30PPUncouplingDown-regulationReducedadrenergicresponsivenessB2GsACPKCPLCRGqIP3DlacylglycerolCa2+InfammatorymediatorAcetylcholineb2-agonist炎癥介質(zhì)，乙酰膽堿及M受體的關(guān)系
31+++-節(jié)前神經(jīng)副交感神經(jīng)節(jié)NM1節(jié)后神經(jīng)M2ACHM3氣道平滑肌膽堿能受體
32ReceptorLocationinHumanLungM1AutonomicgangliaSubmucosalglands AlveolarwallsM2Post-ganglionicparasympatheticnervesM3AirwaysmoothmuscleSubmucosalglands EndothelialcellsM4NotdetectedM5NotdetectedMuscarinicReceptorsintheLungs
33ParasympatheticPost-ganglionicAirwayganglioncholinergicnervesmoothmuscleM1M2M3AgonistMcN-A-343Pilocarpine–AntagonistPirenzepineGallamine4-DAMPTelenzepineAF-DX116HHSiFMethoctramineMuscarinicReceptorSubtypesM1M2M3
34Pre-ganglionic nerveParasympathetic ganglionPost-ganglionic nerveAChAirwaysmooth muscleNicotinicreceptors(+)M1receptors(+)M2receptors(–)M3receptors(+)MuscarinicReceptorSubtypesinAirwaysBarnesPJ.EurRespirRev(1996)
35抗膽堿藥物神經(jīng)機(jī)制在氣道炎癥疾病中可放大或調(diào)節(jié)炎癥反應(yīng)，其中膽堿能神經(jīng)是引起氣道收縮的主要因素。它表現(xiàn)為迷走神經(jīng)張力增加，乙酰膽堿釋放增多，作用氣道平滑肌細(xì)胞膜上的M3受體，通過(guò)偶合G蛋白（GP/GQ）使磷脂酶C活化，后者促使二磷酸肌醇轉(zhuǎn)化為三磷酸肌醇，從而使細(xì)胞內(nèi)鈣離子釋放，導(dǎo)致平滑肌收縮，乙酰膽堿還作用于M2受體，通過(guò)耦合抑制性G蛋白（Gi），降低腺苷酸環(huán)化酶的活性，從而減少cAMP的生成，膽堿能拮抗劑的應(yīng)用，有其重要意義。
36抗膽堿藥物有效的支氣管擴(kuò)張劑1,2通過(guò)抑制膽堿能受體來(lái)防止支氣管收縮。作用時(shí)間長(zhǎng)于沙丁胺醇1異丙托溴銨:4-6小時(shí)噻托溴銨:24小時(shí)2適合用于維持治療和其它支氣管擴(kuò)張劑一起使用，可增加運(yùn)動(dòng)量和改善癥狀及生活質(zhì)量2,31.Pauwelsetal.20012.Casaburietal.20023.Vinckenetal.2002
37正常COPD迷走張力迷走神經(jīng)乙酰膽堿抗膽堿能藥物阻力∝1/半徑4COPD沒(méi)有支氣管痙攣時(shí)也可明顯降低氣流阻力，緩解呼吸困難。COPD穩(wěn)定期，膽堿能張力為氣流阻塞主要可逆因素。-PeterJ.Barnes,“Theoreticalaspectsofanticholinergictreatment”異丙托溴銨的作用不僅限于解除支氣管痙攣
38調(diào)節(jié)膽堿能張力，有效舒張氣道。愛(ài)全樂(lè)與氣道平滑肌上M受體(毒蕈堿受體)結(jié)合，阻斷由膽堿能神經(jīng)引起的支氣管痙攣支氣管痙攣膽堿能阻斷劑膽堿能阻斷劑解除支氣管痙攣的機(jī)制
39PPUncouplingDown-regulationReducedadrenergicresponsivenessB2GsACPKCPLCRGqIP3DlacylglycerolCa2+InfammatorymediatorAcetylcholineb2-agonistb2受體激動(dòng)劑和抗膽堿能藥物
40茶堿相對(duì)其它支氣管擴(kuò)張劑來(lái)說(shuō)，應(yīng)用的較少僅當(dāng)吸入支氣管擴(kuò)張劑無(wú)法使用時(shí)才考慮使用緩釋茶堿適度的支氣管擴(kuò)張劑在治療劑量范圍內(nèi)可常見(jiàn)有副作用治療指數(shù)窄，因此其它支氣管擴(kuò)張劑優(yōu)先考慮和許多藥物有相互作用吸煙能影響茶堿的代謝Pauwelsetal.2001
41茶堿的支氣管擴(kuò)張作用是通過(guò)抑制磷酸二酯酶（PDE）而產(chǎn)生的，該作用打斷了細(xì)胞內(nèi)核苷的循環(huán)途徑，從而使細(xì)胞內(nèi)環(huán)磷酸腺苷（cAMP）和環(huán)磷酸鳥苷（cGMP）的濃度升高。茶堿是一種非選擇性PDE抑制劑。
42TheophyllineasaninhibitorofphosphodiesterasesCyclicadenosinemonophosphateAgonistReceptorGuanylatecyclaseGuanosinetriphosphateCyclicguanosinemonophosphateGuanosinemonophosphateAgonistReceptorAdenylatecyclaseAdenosinetriphosphateAdenosinemonophosphateProteinkinaseAInflammatorycellinhibitionProteinkinaseGфBronchodilatationTheophyllinePhosphodiesterase3,4Phosphodiesterase5InhibitionInhibition
43腺苷酸受體抑制劑（包括A1和A2受體)，這提示了其支氣管擴(kuò)張作用的基礎(chǔ)，增強(qiáng)兒茶酚胺的釋放，茶堿可增加腎上腺髓質(zhì)分泌腎上腺素
44MultipleactionoftheophyllineinasthmaEosinophilTlymphoctyeMastcellMacrophageEndothelialcellAirwaysmoothmuscleBronchodilatationMechanism?Effects?BonemarrowDiaphragmSensorynerve?Phosphodiesterase?Mediators?Mediators?Mediators?Neuropeptides?Leak?MigrationofLymphocytes??Numbers?Trafficking??Cytokines??Strengththeophylline
45聯(lián)合治療聯(lián)合不同作用機(jī)理和持續(xù)時(shí)間藥物進(jìn)行治療可以增加支氣管擴(kuò)張的程度，而副作用相等或更少1已確定的聯(lián)合用藥:短效?2-受體激動(dòng)劑+短效的抗膽堿劑新的聯(lián)合用藥:長(zhǎng)效的?2-受體激動(dòng)劑+吸入激素1.Pauwelsetal.2001
46急性炎癥慢性炎癥結(jié)構(gòu)改變急性炎癥激素治療的應(yīng)答狀況時(shí)間哮喘炎癥過(guò)程BarnesPJ
47EffectofwallareaonairwayresistanceduringAirwaysmoothmuscleshorteningR=airwayresistanceASM=airwaysmoothmuscleWallarea=20%R=1R=1Wallarea=40%R=1.8R=80R=7.830%ASMshorteningASMshortening30%
48癥狀炎癥致敏重塑氣道高反應(yīng)性
49激發(fā)因子，氣道高反應(yīng)性及哮喘癥狀的關(guān)系序貫激發(fā)因子氣道炎癥BHR可變性氣道堵塞癥狀分離旁路激發(fā)因子氣道炎癥BHR癥狀可變性氣道堵塞平行激發(fā)因子激發(fā)因子氣道炎癥BHR氣道上皮可變性氣道損傷堵塞癥狀
50ASTHMACONTROLAirwaySmoothmusclsMastcellsPlasmaleakINFLAMMATIONSGenesAtopyEnvironmentalfactorsCPRTTCDSTERPODSLAb2-AgonistsSYMPTOMCONTROL
51CorticosteroidsVirus?AIRWAYHYPERRESPONSIVENESSMacrophageEosinophilT-lymphocyte－－－b2-AgonistsBRONCHOCONSTRICTIONTreatmentofasthma:cellulareffectsAntigenVirus?AdenosineExerciseFogMastcellAirwaysmoothmuscle－－
52CellulareffectsofglucocorticoidsCORTICOSTEROIDSEosinophilT-lymphocyteMastcellMacrophageDendriticcellNumbers(apoptosis)CytokinesNumbersCytokinesNumbersInflammatorycellsEpithelialcellEndothelialcellAirwaysmoothmuscleMucusglandCytokinesMediatorsLeak2-ReceptorsMucussecretionStructuralcellsCytokines
53MolecularMechanismofSteroidActionmRNAGRbhsp90CytokinesAdhesionmolsEnzymesLipocortion-1b2-AdrenoceptorsGRCorticosteroidNucleus+GRE-GRESteroid-responsiveTargetgenes
54EFFECTOFSTEROIDSONb2-ADRENOCEPTORSGREGREGREb2-ReceptorgeneGlucocortiaidreceptorNucleusb2ARmRNACorticosteroid
55激素與β激動(dòng)劑的協(xié)同作用示意圖
56b2-AGONISTSACTIVATEGLUCOCORTICOIDRECEPTORSb2-AgonistsNuclearlocalisationofglucocorticoidreceptorsGrebindingBlockedbypropranololMimickedbycgclicAMPexpressionofasteroidInduciblegene(P21(WAF1/CIP1))EickelbergOctal:JBiolchem1999AFR00.52.54600.52.54600.52.54600.52.546FRBGR/GREcomplexunspecificbandfreeprobeGR/GREcomplexunspecificbandfreeprobe+fluticasone+dexamothasone+salmeterol+salbutamol
57EFFECTPFb-AGONISTONGRNUCLEARTRANSLOCATION1007550250ControlHumanairwaysmoothmusclecellsP<0.01BudRatioofcytosolic:nuclearCarbitraryO.D.unitsControlBudesonide10-9McytosolnucleusGRGRRothMetal:ATS2001
58EFFECTOFb-AGONISTONGRNUCLEARTRANSLOCATION1007550250ControlHumanairwaysmoothmusclecellsBudRatioofcytosolic:nuclearCarbitraryO.D.unitsP<0.01FormForm+BudControlBudesonide10-9McytosolnucleusGRGRP<0.04P<0.01KomSetalEurRespirJ2001
59互補(bǔ)的作用機(jī)制????癥狀/惡化吸入激素????????AdaptedfromBousquetetal.AmJRespirCritCareMed.2000;161:1720-1745.平滑肌功能障礙氣道炎癥炎癥細(xì)胞的滲出/活化粘膜水腫細(xì)胞的增殖上皮損傷基底膜增厚支氣管狹窄氣道高反應(yīng)性過(guò)度增生/增大炎癥介質(zhì)釋放長(zhǎng)效?2受體 激動(dòng)劑
60b2-AgonistBronchodilatationINTERACTIONSBETWEENCORTICOSTEROIDSANDb2-AGONISTSb2-AdrenoceptorGlucocorticoidreceptorCorticosteroidAnti-inflammatoryeffectEffectofcorticosteroidsonb2-adrenoceptorsEffectofb2-agonistsonglucocorticoidrecptors
61ThankyouThankyou
