药理学英文版教学课件：Chapter 10 Cholinoceptor Antagonist

CholinoceptorAntagonist(p50)Case1Male,30yrsold,farmerbeganprogressivelyabdominalpain5hoursago,accompaniedbytachypnea（呼吸急促）andtremor,thenfillintocoma.PEfound:profusesweating（大汗）,salivation,teethclenched,sursumversion(两眼上翻)，vomitting,tromer,urinaryandfecalincontinence（失禁）,dysphoric(烦躁不安).HRincreasedandmiosis(瞳孔缩小)ineye.History:clothesdrenched（浸透）withorganophosphatesolutionwhenworkedinthefarmlandthismorning.Treatment:skinwashingwithclearwater;i.vatropine;i.vPAM(解磷定)Cholinoceptorantagonists

haveaffinitybutnointrinsicactivitywithcholinoceptors

aredividedintoMandNsubgroupsbasedontheirspecificreceptoraffinities.

颠茄曼陀罗莨菪§1M-ReceptorblockingDrugs(p50)

Atropine（阿托品）andsimilaralkaloidsNaturallyoccurringcompoundswithanti-Mreceptoreffectshavebeenusedformillennia(千年)asmedicines,poisons,andcosmetics.Atropineistheirprototype.Manysimilarplantalkaloidsareknown,suchasanisodamine(654-2，山莨菪碱)andscopolamine（东莨菪碱）.Hundredofsyntheticanti-Mreceptorcompoundshavebeenprepared.Deadlynightshade(Atropenabelladonna，颠茄)isthenaturalsourceofthealkaloidatropine.Thetermatropenaisderivedfrom

Atroposbecauseof

itshightoxicity.AtroposistheGreek

goddessofFateandisresponsibleforthefinalpartofamortal

life,theunturninginevitabilityofdeath.Atropinewasapopularchoiceofpoisonamongstprofessionalpoisonersduringthe

MiddleAgesbecauseoftheslownessoftheireffectswhichallowedtheperpetratortoescapebeforesuspicionswere

aroused.AccordingtotheScottishlegend,thesoldiersof

MacbethslippedatropineintothedrinksoftheinvadingDanesthenslaughterthemintheirslumber.

InRomantime,ladies

intheCourtusedthejuicefromtheberrytodilatetheirpupils

tomakethemlookmoresensualandattractiveandhencethe

namebelladonna(beautifullady).Atropenabelladonnacan

betranslatedasfemmefatale（美女）.

Inophthalmology,itisusedincycloplegicrefraction,post-operativedilatationasfollowingtrabeculectomyandinthetreatmentofanterioruveitistopreventposteriorsynechiae.Atropinealsodumbsnerveendingsandlessenpainwhen

appliedlocally.atropine

MostofantimuscarinicarewellabsorbedfromtheGItractandwidelydistributedinthebody,reachestheCNS.ScopolamineisrapidlyandfullydistributedintotheCNS

Thequaternaryderivativesarepoorlytakenupbythebrain.TheyarerelativelylesseffectiveonCNSPharmacokineticsAtropine

fromatropabelladonna.F=50%byP.O,disappearsrapidlyfromtheblood,t½of2h.Theeffectdeclinesrapidlyinallorgansexcepttheeye.Effectsontheeyepersistfor≥3days.About60%ofthedoseisexcretedunchangedintheurine.Therestappearsashydrolysisandconjugationproducts.A.MechanismofAction:

(p51)

blocksMreceptorreversiblely,competitiveantagonistTheeffectivenessvarieswithtissues.

Themostsensitive

tissuestoatropinearethesalivary,sweatglands,digestivetract,bladder,bronchial,anduterus.

Theleastsensitive

isthegastricparietalcellssecretingacid.AntimuscarinicagentsblockexogenousMreceptoragonistsmoreeffectivelythanendogenousACh.PharmacodynamicsB.

OrganSystemEffects1.Glands—Decreasesalivaryglands,lacrimalglands（泪腺）,bronchialglandssecretionsweatglands.Atropinesuppressesthermoregulatory（体温调节性）sweating.Inadults,bodytemperatureiselevatedbylargedose.Ininfantsandchildrenevenordinarydosemaycause“atropinefever.”2.Eye:BlockMreceptor(p51)

Mydriasis扩瞳

Thepupillaryconstrictormuscle,irisdependsonMreceptor.

Atropineandotheranti-MdrugsblockMreceptorandresultsindilatationofirisandmydriasis（扩瞳）.Mydriasis扩瞳

intraocularpressure↑升眼压

cycloplegia调节麻痹AtropineblockMreceptor,contracttheiris,andreducetheanglespaceofanteriorchambersoastopreventoutflowofaqueoushumor,increasingthetheintraocularpressure.AtropineblocksMreceptor,inhibitsthecontractionoftheiris,andnarrowtheanglespaceofanteriorchamber,soastopreventoutflowofaqueoushumor,increasingtheintraocularpressure.Anti-MdrugsblockMreceptor,inhibitthecontractionoftheciliarymuscle,resultincycloplegia（睫状肌麻痹，调节麻痹）.3.RespiratorySystemBothsmoothmuscleandsecretoryglandsoftheairwayreceivevagal(迷走N)innervationandcontainmuscarinicreceptors.

Atropinedilatesbronchiandinhibitssecretionofgland.Theeffectismoresignificantinpatientswithairwaydisease.4.GastrointestinalTractPancreaticandintestinalsecretionarelittleaffectedbyatropine，theyareprimarilyunderhormoneeffect.1)Atropinehasmarkedeffectonsalivarysecretion——Drymouth.inhibitsgastricsecretionlesseffectively,reducesthevolumeandamountofacid,pepsin,andbasalsecretioninlargedoses.2)AtropineinhibitsgastrointestinalmovementbyblockingMreceptor.Spasmolysis（解痉）5.Genitourinary（泌尿生殖）TractAtropinerelaxsmoothmuscleoftheureters（输尿管）andbladderwallandslowsemptying.Thisactionisusefulinthetreatmentofspasminducedbyinflammation,surgery,andcertainneurologicconditions,butitcancauseurinaryretention（尿潴留）inelderlymenwithprostatichyperplasia（前列腺肥大）.

Theantimucarinicdrugshavenosignificanteffectontheuterus（子宫）.6.Heart(p52)Cardiacmuscle

iscontrolledbylesserdegreeofMreceptor.

Atropinehasnoclinicalsignificanteffectonit.

SinoatrialnodeAtropineblocksMreceptorandcausestachycardia.LowerdosesresultsininitialbradycardiaduetoblockpresynapticMreceptorwhichlimitAChrelease.

blocksMreceptoron

atrioventricularnode,increasetheconduction,andthePRintervalofECG.Intoxicdoses,atropineblocks

intraventricularconductionTheskeletalmusclevascularbedcontainsMreceptor.AlmostallvesselscontainendothelialMreceptorsthatmediatevasodilation.

Thereceptorsarereadilyblockedbyantimuscarinicdrugs.Attoxicdoses,andinsomeindividualsatnormaldoses,atropinecauseskinvasodilation.Butthereislittleeffectonbloodpressure.

7.BloodVesselsIntoxicdosescancauseexcitement,agitation,hallucinations,andcoma.Scopolamine(东莨菪碱)hasmarkedcentralinhibiteffects,producingdrowsinessandamnesia.

8.CentralNerveSystem

AtropinehasminimaleffectsontheCNSatcommondose.

MotionSickness（舟车晕浪）

Scopolamineisoneoftheoldestremediesforseasickness.

ClinicalUses1.spasmolysis（解痉作用）:GIhypermotility（diarrhea）,inflammatorybladderdisorder（urinaryurgency，尿急

）2.inhibitglandsecretion:AtropineorscopolaminePre-anestheticadministration;Hyperhidrosis（多汗）3.ophthalmologicdisordersOphthalmoscopicexamofretinaCiliaryparalysis.Forchildren,thegreaterefficacyofatropineisnecessary,

Preventsynechia(虹膜粘连)formationiniritis4.Bradyarrhythmia（过缓性心律失常）5.infectiousshock6.organophosphatetoxication,poisonmashroomintoxicationAdverseEffects(p52)

atropineanditscongeners(同类物)almostalwaysinduceundesirableeffectsfortheirlowselectivityAtropinepoisoninginclude

drymouth,mydriasis,cycloplegia,tachycardia,hotandflushedskin,agitation,delirium,hightemperature,urinaryretention.Thepoisoningcanbetreatedwithcholinesteraseinhibitorsuchasneostigmine.

Atropinization（阿托品化）Atropineisappliedinthetreatmentoforganophosphatepoisoning,whenSkinturneddryandred,pupildilating,nomorebellyacheandsalivationHRincreased,normalbreathingAtropinizationmeansslighttoxicationofatropineContraindicationsThecontraindicationsarerelative.Glaucoma,especiallyangle-closureglaucomaInelderlymenwith

prostatichyperplasia（前列腺肥大）,Antimuscarinicagentsatropine654-2(山莨菪碱)Scopolamine（东莨菪碱）AT3(樟柳碱)SmoothmusclerelaxweaksimilarweakglandssecreteweakpotentweakeyemydriasisweakpotentweakCardiovasculartachycardiasimilarweakweakCNSexcitesimilarSedationhypnosisSedationhypnosisLD50mg/kg98115155506Antimuscarinicagentsatropine654-2anisodaminescopolamineAT3applicationgastrointestinalspasmOphthalmologicdisordersarrhythmiainfectionshockorganophosphatespoisoningpreanesthetictreatmentgastrointestinalspasminfectionshockorganophosphatespoisoningpreanesthetictreatmentMotionsicknessparkinsonismHeadacheacuteparalysisinducedbybrainbloodvesselsSubstituteforatropine（p54）1.formydriasisHomatropine（后马托品）,tropicamide（托吡卡胺）2.forspasmolysis:Propanthelinebromide（普鲁本辛）3.selectiveM-RantagonistM1-pirenzepine（哌仑西平）,gastricacidM2-tripitamine（尚无中译名）,heart§2N-ReceptorAntagonistTheNreceptorantagonistsconsistofganglion-blockers(N1,NN)andneuromuscularjunctionblockers(N2,NM).Ganglion-BlockingDrugsTheseagentsblocktheactionofAChandsimilaragonistsattheN1receptorsofautonomicganglia.Theylackselectivityandhavebroadsideeffectssothattheyhavebeenabandonedforclinicaluse.Theganglionblockingdrugsarestillimportantandusefulinpharmacologicresearchbecauseoftheirabilitytoblockallautonomicoutflow.

Mecamylamine（美加明）andTrimethaphan（米噻吩）blockstheN1receptor.Theblockadecanbeovercomebyagonist,ACh.

OrganfunctionandchieflyinnervatedtypesEyeBecausetheciliarymusclereceiveprimarilytheparasympatheticnervousinnervation,theganglion-blockingdrugcauseapredictablecycloplegiawith

lossofaccommodation.Theirisreceivesbothsympatheticandparasympa-theticinnervation.Becauseparasympathetictoneisusuallydominantinthistissue,ganglionicblockadecausesmoderate

dilationofthepupil.CardiovascularSystemThebloodvesselsreceivechieflyvasoconstrictorfibersfromthesympatheticnervoussystem;Ganglionicblockadecauseanobvious

decreaseofarteriolarandvenomotortone,anddecreaseofthe

bloodpressure,Hypotension（低血压）

isespeciallymarkedintheuprightposition,becauseposturalreflexesareblocked.

Cardiac

effectsinclude

diminishedcontractility

and,becausethesinoatrialnodeisusuallydominatedbytheparasympatheticnervoussystem,amoderate

tachycardia.GastrointestinalTractGIsystemisusuallydominatedbytheparasympatheticnervoussystem.

N1blockcause:secretionisreduced,althoughnotenoughtotreatpepticdisease.motilityisprofoundlyinhibited,and

constipation（便秘）

maybemarked.

ClinicalApplicationsBecauseoftheavailabilityofmoreselectiveautonomicblockingagents,the

applicationsoftheganglionblockershavealmostdisappeared.SkeletalMuscleRelaxantsneuromuscularblockingagentsDepolarizing（去极化）muscularrelaxantsNon-depolarizingmuscularrelaxants1.DepolarizingskeletalmusclerelaxantsMechanisms:activateN2-Rmaintainendplatemembranedepolarizationandthuspreventtransmissionofanotheractionpotential.succinylcholine(scoline