膽堿受體阻斷劑

CholinoceptorblockingdrugsDepartmentofpharmacologyZhuling(朱玲)2023.3第1頁CholinoceptorblockingdrugsCholinoceptorblockingdrugs

:Bindtocholinoceptor(affinity),butcannotorhaslittleresultincholinomimeticaction(intrinsicactivity),preventingthebindingthereceptorsitetothecholinergictransmitterorcholinoceptoragonist，thereforeresultinanticholiniceffects.Onthebasisofspecificreceptoraffinities(receptorselectivityoftheseantagonists),theantagonistfallintotwomajorfamilies.第2頁Cholinoceptorblockingdrugs

classify

drugsAntimuscarinicagents

M1、M2Rantagonistsatropinescopolamineanisodamine

M1Rantagonistspirenzepine

M2RantagonistsgallamineAntinicotinicagents

N1Rantagonistsmecamylamine

N2Rantagonistssuccinylcholinetubocurarine第3頁第4頁Antimuscarinicagents

plant

alkaloidsAtropabelladonnaHyoscyamine(atropine)DaturastramoniumHyoscyamineDaturasp.FengqieerscopolamineHyoscyamusnigertianxianziHyoscyamineScopoliatanguticaAT3anisodamine第5頁第6頁第7頁AntimuscarinicagentsAtropabelladonna

顛茄Atropine阿托品

dl-hyoscyamineScopolamine東莨菪堿Anisodamine山莨菪堿654654-2AT3樟柳堿第8頁第9頁Antimuscarinicagents

atropine阿托品

1.pharmocokineticstertiaryaminealkaloidestersAbsorption:wellabsobedfromthegutandacrosstheconjunctivalmembrane.Oraladministrationtmax1h；injectiontmax15-20min.Distribution:widely，passingacrossblood-brainbarrier第10頁Antimuscarinicagents

atropine阿托品Metabolismandexcretion:disappearrapidlyfromtheblood,half-life

of2-2.5hours,1/3ofthedoseisexcretedunchangedintheurine,mostoftherest(2/3)appearsintheurineashydrolysisandconjugationproducts.Theeffectofthedrugonparasympatheticfunctiondeclinerapidlyinallorgansexcepttheeye.Effectsontheirisandciliarymusclepersistfor72hoursorlonger.第11頁Antimuscarinicagents

atropine阿托品2.pharmacodynamicsandclinicalusesMechanismofaction

competitivelyblockmuscarinicreceptors(atropineandAchorcholinomimeticscompetitionforacommonbindingsiteonthereceptorprotein)

highlyselectiveformuscarinicreceptor,itspotencyatnicotinicreceptorsismuchlowerthanatMR,largedoseithasganglion-blockingaction.第12頁Antimuscarinicagents

atropine阿托品Theeffectivenessvarieswiththetissueandatropineeffectsaredosedependent,theactionappearsinorderasfollowduotoincreaseofdose：

glandssecretionsdecrease,

mydriasis,

bradycardia,smoothmusclerelax,tachycardia,gastricsecretiondepress,CNSsigns.第13頁第14頁Antimuscarinicagents

atropine阿托品

1reductionofglandsecretion

salivarygland,sweatglands:greatlyreduced(smalldose0.5mg)drymouth,dryskin(orredskin)

lacrimalglands,bronchialglands:decreased(largedose)dryorsandyeyes,reductiontheaccumulationofsecretionsinthetrachea.gastricsecretion↓，gastricacid↓(morelargedose)

thermoregulatorysweatingsuppressedandbodytemperatureiselevated(largedosesorinfantsandchildren):maycauseatropinefever第15頁Antimuscarinicagents

atropine阿托品Clinicalpharmacology(therapeuticapplications)

salivate,nightsweat,(hyperhidrosis)preanesthetictreatment

(usedpriortoadministrationofinhalantanestheticstodepressbronchialsecretionandtoreducethepossibilityoflaryngospasm,topreventpronouncedbradycardiaduringabdominalsurgicalprocedures)第16頁Antimuscarinicagents

atropine阿托品

2ophthalmologicdisorders

mydriasis

cycloplegiablockedoftheciliarymuscle,lossoftheabilitytoaccommodate,cannotfocusfornearvision

increase

intraocularpressurenarrowanteriorchamberangle第17頁Antimuscarinicagents

atropine阿托品application：

1)preventsynechia(adhesion)formationinuveitisandiritis

2)ophthalmoscopicexamination:becauseitisalong-actingdrug(durationofeffectsare7-10days),soshorter-actingdrugsarepreferred(homatromine)

3)optometry

alwaysmeasurementinyoungchildren第18頁第19頁Antimuscarinicagents

atropine阿托品第20頁第21頁Antimuscarinicagents

atropine阿托品

3cadiovascularsysterm

1)heart

0.5mgbradycardiabrevity,andnotmarked,(initial)(central)1--2mgtachycardia(blockadeofvagal)

toxicconcentrationintraventricularconductionblock第22頁第23頁Antimuscarinicagents

atropine阿托品

2)theeffectsonbloodvesselsandbloodpressure

treatmentdosage(nodirectinnervationfromtheparasympatheticnervoussysterm)noeffectsonBP

largerdosevasodilation(cutaneous,especiallyintheupperportionofthebody)Application:infectiousshockbradycardiaandA-Vblock第24頁Antimuscarinicagents

atropine阿托品

4smoothmuscles:relaxation

characteristic1)selectivity

gastrointestinalsmoothmuscle>bladderdetrusor>bileductandureter>uterus,bronchialmuscle;noeffectonsphincter

2)atropineabolishesanyexcessivetoneandmobilityoftheintestinaltract,butithasrelativelylittleeffectonnormalmotility.第25頁atropine阿托品4smoothmuscle:relaxationapplication：gastrointestinaldisorder(spasm,bellyacheetc),reduceinvoluntaryvoidinginpatients(urinaryincontinence)egchildrenwithmeninggomyeloceleurinaryurgency(inflammatorybladderdisorder),

gallbladderangina（addingpethidine)第26頁Antimuscarinicagents

atropine阿托品5CNS:

Therapeuticdose:nosignificanteffectThenhighdose:minimalstimulanteffectsonthecentralnervoussystem,especiallytheparasympatheticmedullarycenters(respirationcenter,excitement,agitation,hallucinations)

severityinhibition(coma)第27頁Antimuscarinicagents

atropine阿托品

6Therapeuticapplications：

cholinergicpoisoning

Treatmentofpoisoningoforganophosphatesorsomemushroom

rapidlycombatthemuscariniceffects

reversesomecentralnervoussystemeffects

largedoseblockadeN1receptorprincipleofapplication：forepart,largedoses(enoughdose),repeat(continuance)

administration第28頁Antimuscarinicagents

atropine阿托品

atropinechange阿托品化Reversalofmiosis(mydriasis),drymouth,faceflushed,dryskin,mildrestlessness,rapidpulse(100--120/min）,pulmonaryraleobviouslyreduceordisappear第29頁atropine阿托品

adversereaction*broadrangeofantimuscariniceffects,treatmentwithatropinedirectedatoneorgansystemalmostalwaysinducesundesirableeffectsintheotherorgansystemsigns:drymouth,mydriasis,blurredvision,photophobia,faceflushed,hotandflushedskin,slightrestlessness,tachycardia,agitation,delirium,hightemperature,

dysuriaetc*Theantidoteofatropinepoisoning:pilocarpine,neostigiminecontraindications

glaucomaprostatehyperplasia(hypertrophy)第30頁Antimuscarinicagentsatropine654-2scopolamineAT3Smoothmuscle

relaxweaksimilarweakglandssecreteweakpotentweakeyemydriasis

weakpotentweakCardiovascularStachycardiasimilarweakweakCNSexcitesimilarSedationhypnosisSedationhypnosisLD50mg/kg98115155506第31頁Antimuscarinicagentsatropine654-2anisodaminescopolamineAT3applicationgastrointestinalspasmOphthalmologicdisordersarrhythmiainfectionshockorganophosphatespoisoningpreanesthetictreatmentgastrointestinalspasminfectionshockorganophosphatespoisoningpreanesthetictreatmentMotionsicknessparkinsonismHeadacheacuteparalysisinducedbybrainbloodvessels第32頁Antimuscarinicagents

SubstituteofatropineOphthalmicrefractionhomatropine

tropicamideSpasmolyticagentspropanthelineglycopyrrolateoxybutyninGastriculcer,duodenumpepticulcer

pirenzepine,telenzepine第33頁AntinicotinicagentsN1Rantagonists

ganglion-blockingdrugsN2Rantagonistsskeletalmusclerelaxants

Themuscle-relaxantdrugsmostcommonlyusedactbyinterruptingtransmissionatthejunctionbetweensomaticmotornervesandskeletalmusclefibers(interferewithtransmissionattheneuromuscularendplate),preventaccessofthetransmittertoitsreceptorandpreventmusclecontraction.第34頁AntinicotinicagentsThetwoclassesofneuromuscularblockingdrugsblockthisprocessbydifferentmechanisms：

nondepolarizingdrugs(competitiveantagonists)competewithAchinbindingtothereceptorsite.depolarizingdrugsmaintainendplatemembranedepolarizationandthusprevent