药理学英文版教学课件：Chapter 9 Cholinoceptor agonist

Cholinoceptor-activatingDrugs(p40)Case1Female,64yearsoldRighteyepainaccompaniedwithimpairedvisionandheadachefor3days.PE：Righteyesightwas0.4,pupildiameter7mm,intraocularpressure55mmHg.Treatedwith2%pilocarpineeyedrop2hoursago,nowtherighteyesightwas0.6,pupildia.2mm,pressure36mmHg,andfeelgeneralmalaise,withtearsandsalivation,abdominalpain.Diagnosis:acuteangleclosureglucoma(青光眼）Case2Female,46yrs.ProgressivelyDiplopia(复视)，ptosis（眼睑下垂），lassitude（疲乏无力）3months.PE:tiredafterrepeatopen&closetheeyes，ruminate(咀嚼)，andriseherarms.diagnosis:Myastheniagravis(重症肌无力）

．Cholinoceptor-activatingdrugs(拟胆碱药，cholinomimetics,)aretheonesthatmimictheeffectsofACh.Cholinomimeticscanbedividedintotwogroupsbasedonthemodeofaction:Modeofactionofcholinoceptor-activatingdrugsSomecholinomimeticdrugsbinddirectlytoandactivatecholinoceptors(cholinoceptoragonist)OthersactindirectlybyinhibitingthehydrolysisofendogenousACh(anticholinesterases,抗胆碱酯酶).

ManyofthesedrugshaveeffectsonbothMandNreceptors,afewofthedrugsarehighlyselectiveforMorNreceptors.§1M&NCholinoceptorAgonists(p40)

Acetylcholine(Ach，乙酰胆碱）.AChactivatesMandNreceptorsonpost-synapticmembraneofeffectorstoalterorganfunctiondirectly.AChactivatesMreceptorsonpre-synapticmembranetoinhibitthereleaseofAChBloodvessels(MR)arteriesdilation(viaEDRF)constriction(high-dosedirecteffect)Heart(M2R)sinoatrialnode（窦房结）decreaseinrateatriadecreaseincontractilestrength(收缩力)&inrefractoryperiod（不应期）atrioventricularnode（房室结）decreaseinconductionvelocity.increaseinrefractoryperiodventriclessmalldecreaseincontractilestrength

A：endotheniumintact

乙酰胆碱扩张去甲肾上腺素引起的血管收缩作用依赖于血管内皮的完整性（A），如内皮细胞受损，则ACh的扩张血管作用消失（B）

B：endotheniuminjured

gastrointestinaltract(MR)motilityincreaseSphincters（括约肌）relaxationglandssecretionurinarybladder(MR)detrusor(逼尿肌)contractionTrigone（三角区）andsphincterrelaxationAchincreasesalivarysecretionbyexcitingMreceptortotreatdrymouth.glands(MR)sweat,salivary,lacrimal（泪）,

nasopharyngeal（鼻咽）secretionEye(MR)sphincterofiris（虹膜）contraction(miosis缩瞳)ciliarymuscle（睫状肌）contractionfornearvisionlung(MR)bronchialmusclecontractionbronchialglandsstimulationAchalsoactivateNreceptorinlargerdose,seldombeusedinclinicalworkforitsshortt1/2andlowselectivity.OtherM&NCholinoceptorAgonistsCarbachol(卡巴胆碱)：forGI&GUMethacholine（醋甲胆碱）§2M-receptoragonist

pilocarpine(匹鲁卡品，毛果芸香碱)EffectonTheEye:M-Rontheiris（虹膜）andciliary（睫状体）sphinctermuscle（括约肌）Diagramofeyedepictingmajorpathwayforoutflowofaqueoushumor(heavyarrow)whichdrainsatSchlemm'scanal.Iftheanglebetweentheirisandthecorneaisnarrow,aphysicalimpedimentmayexisttodrainageandtheintraocularpressureisincreases.Thisisexacerbatedduringmydriasisbecausetheiriscontractstowardthatangle(narrowangleglaucoma)tofurtherimpedeoutflow.Theciliarymuscleisasphincter.Whencontracting,itrelaxesthesuspensoryligaments（悬韧带）onthelens（晶状体）.WhenM-Ractivated,themusclegoesintocyclospasm（睫状肌痉挛，调节痉挛）.Thelensroundsofitsownelasticitytoaccommodate（适应）tonearvision(视近物),andcannotreaccomodateforfarvision（视远物）.Thesmoothmusclesoftheiris

Thesphinctermuscleisinnervatedbycholinergicfibers.(Mreceptors)Itscontractionresultsinmiosis,Theintraocularpressure（眼内压）isformedbyaqueoushumor（房水）whichisproducedbythebloodvesselsintheciliarybody（睫状体）.Itflowsintoposteriorchamber,throughthepupil

intotheanteriorchamber,andthendrainsintotheepiscleralvein（巩膜静脉）

viathetrabecularmeshwork（小梁网）Mreceptoragonistscontracttheirisandincreasetheanglespaceofanteriorchambersoastofacilitateoutflowofaqueoushumor,decreasingtheintraocularpressure.Glaucoma（青光眼）

-Caseischaracterizedbyincreasedintraocularpressure,whichcanresultinvisionloss.

Acuteangle-closureglaucomaisamedicalemergencythatistreatedwithbothaMreceptoragonistandaAChEinhibitor.Open-angleglaucomaisnotamenableto（适用）thedrugs.Clinicalusesofpilocarpine1.glaucoma,pressawhile2.irisinflammation.Preventsynechia（粘连）formationiniritis(虹膜炎)3.drymouth,atropinetoxicationMuscarine(毒蕈碱)InpoisonmushroomsToxicology§3NcholinoceptoragonistNicotine(烟碱)：NN，NMLobeline(洛贝林)RespiratorycenterstimulatorAnticholinesteraseDrugs＆

CholinesteraseReactivators

（p44）

Acetylcholinesterase，AChE（乙酰胆碱酯酶）Acetylcholinesterase，AChE（乙酰胆碱酯酶）Pseudocholinesterase(假性胆碱酯酶)AchErelativelyspecificforacetylcholine，rapidhydrolysisatcholinergicsynapsesClassificationofAnticholinesteraseDrugs

TheChEinhibitorsfallintotwogroups:

(1)ReversibleAchEinhibitors;

(2)IrreversibleAchEinhibitors:

organophosphate

．Anti-ChEagentsproduceeffectsbyinhibitingAChE,decreasinghydrolysisofACh,andincreasing［AＣh］.AChevokeanincreasedresponses.ActionofAnticholinesterasedrugsDrugsactprimarilywhereAChisphysiologicallyreleasedandareamplifiersofendogenousACh.ReversibleAchEinhibitor Neostigmine新斯的明

Physostigmine毒扁豆碱

Tacrine他克林

Donepezil多奈哌齐Mechanismofanti-ChEagentClinicalusesmyastheniagravis（重症肌无力）Intestinalinflationanduroschesis（尿潴留）glaucoma:physostigmine,eyedropAtropinetoxicationAlzheimer’sdiseaseMyastheniagravis(MG)

isadiseaseaffectingskeletalmuscleneuromuscularjunction.AnautoimmuneprocessproducesantibodiesthatdecreasethenumberofN2receptors.Frequentptosis(眼睑下垂),difficultyinspeakingandswallowing,andextremityweakness.Evenrespiratorymuscles.ChEinhibitorscanincreaseAChconcentration,exciteN2receptors,whichstrengthenmusclecontraction.neostigmine(新斯的明)clinicallyusedasdifferentialdiagnosisforMGGastrointestinalandUrinaryTractsPostoperativeileusandcongenitalmegacolon（先天巨结肠）involvedepressionofsmoothmuscleactivitywithoutobstruction.Urinaryretentionmayoccurpostoperativeorpostpartumorsecondarytospinalcordinjury.neostigmineisthemostwidelyusedfortheseapplications.OntheEyeCholinesteraseinhibitorsreduceintraocularpressurebyincreasingAChconcentration,contractingtheirisandciliarybodyandfacilitatingoutflowofaqueoushumor.Physostigmine(毒扁豆碱)HeartSlowtheheartrateTheshort-actingcholinesteraseinhibitorhadbeenusedtotreatsupraventriculartachycardia.（室上速）AntimuscarinicDrugintoxicationAtropineintoxication（阿托品中毒）Thetricyclicantidepressants（三环类抗抑郁药）inoverdosage,alsocauseseveremuscarinicblockade.CNS:Alzheimer’sdiseaseTacrineisaanticholinesterasedrugthathasbeenusedforthetreatmentAlzheimer’sdisease.Donepezil,galantamine,andrivastigminearemoreselectiveAChEinhibitorsthatappeartohavethesamemodestclinicalbeneficastacrineintreatmentofcognitivedysfunctioninAlzheimer’spatient.Metrifonate（Dipterex，敌百虫）,HuperzineA(石杉碱甲)Irreversibleanti-AchEagents（p47）Organophosphate(pesticides)Othersimilartoxins：chemicalweaponsDipterex(敌百虫),rogor(乐果),DDVP(敌敌畏),wargases(sarin,soman,tabun)Malathion(马拉硫磷)arerapidlymetabolizedtoinactiveproductsinbirdsandmammalsbutnotininsects;theyareconsideredsafeenough.Parathion(对硫磷)isnotdetoxifiedeffectivelyinvertebrate;itisconsiderablydangeroustohumansandisnotavailableforgeneralpublicuse.AChEinhibitors

bindtoAChEactivesiteandarehydrolyzedChChChMechanismofActionofAChEInhibitors

ElectrostaticallyHydrogenbondCovalentbondIrreversiblebondOrgano-phosphatesalsoundergoinitialbindingandhydrolysisbytheenzyme,resultinginaphosphorylatedactivesite.Thecovalentphosphorus-enzymebondisextremelystableandhydrolyzedinaveryslowrate.Aftertheinitialbinding-hydrolysisstep,thephosphorylatedenzymecomplexmayundergoaprocesscalledaging.Thisprocessinvolvesthebreakingofoneoftheoxygen-phosphorusbondsoftheinhibitorandfurtherstrengthensthephosphorusenzymebond.ToxicityofCholinesteraseInhibitorsTheacutetoxicity:TheinitialsignsarethoseofMsymptoms:miosis,salivation,sweating,vomiting,diarrhea,andbronchialconstriction.Neffects,especiallydepolarizingN2blockade.CNSinvolvementusuallyfollowrapidly,ChronicexposuretoorganophosphateChEinhibitorcauseneuropathywithdemyelinationofaxonsOrganSystemEffectsCentralNervousSystem—Inlowconcentrations,thelipid-solublecholinesteraseinhibitorscausediffuseactivationontheelectroencephalogramandasubjectivealertingresponse.Inhigherconcentrations,theycausegeneralizedconvulsions,whichmaybefollowedbycomaandrespiratoryarrestEye,RespiratoryTract,GastrointestinalTract,UrinaryTract—

CardiovascularSystem：Negativechronotropic,dromotropic,andinotropiceffectsareproduced,andcardiacoutputfalls.NeuromuscularJunction—Athigherconcentration,theaccumulationofAChmayresultinfibrillationofmusclefibers.ChEReactivators（p48）Cholinesterasereactivation,capableofregeneratingactiveenzymefromtheorganophosphosphorus-cholinesterasecomplex,isavailabletotreatorganophosphoruspoisoning.Theseoximeagentsincludepralidoxime(PAM),Pralidoximechlorideandothers.ModeandUseofActionoftheCholinesteraseReactivatorsTheoximegroup(NOH)hasa