药理学教学课件：Chapter 6 Cholinoceptor Agonists

2023/9/191

Chapter6CholinoceptorAgonists2023/9/192

Whatisefferentnervoussystem（ENS）?

ceptOrANSeffectorENSCNS2023/9/193

TransmitterClassificationofENScholinergicnervenoradrenergicnerveImportantWordsandExpressions

：Neurotransmitter

Acetylcholine

Acetylcholinesterase

Muscarine

Nicotine

EyeGlandSmoothMuscles

CardiovascularsystemPilocarpine

CorneaPupilLensIrisOpticnerveConstrictpupil

SpasmofaccommodationDecreaseintraocularpressureThicker

ThinerRetinaMaculaMyopiaGlaucomaAqueouswater

Suspensoryligament2023/9/197

2023/9/198Section1M、N-cholinoceptorAgonistsCholineesters，includedrugsbelow:

Acetylcholine，ACh

EndogenousNeurotransmitterEasytobehydrolizedbyacetylcholinesteraseinvivo.

【Principle】（+）Muscarinereceptor(MR):M1——M5

（+）Nicotinereceptor(NR)：

N1andN22023/9/199

【PharmacologicalEffects】1．CardiovascularsystemA.DiastoliceffectofbloodvesselItcanresultinthereleasingofendothelium-derivedrelaxingfactor（EDRF,ie,nitricoxide，

NO）throughM3receptor.B.Negativechronotropiceffect：

delaythedepolarizationindiastolicperiodC.Negativedromotropiceffect：

delaytheconductionofatrioventricularnodeandPurkinjefibersD.Negativeinotropiceffect：

inhibitthereleasingofNAE.Sortentheeffectiverefractoryperiodofatrium2023/9/19102.EyePupilcontraction,Myopia，

decreaseintraocularpressureetc.3．SmoothMusclesGastrointestinaltractexcitement——

Increaseoftensionandperistalsisnausea,vomiting,belchingUrinarytract——Increaseofmaximalvoluntaryvoidingpressure。Bronchialconstriction4．GlandIncreasedsecretion2023/9/1911

5OthersStimulateautonomicganglion——Excitementofsympathetic,parasympatheticganglionStimulateneuromuscularjunction——Excitementofskeletalmuscle【ClinicalApplication】Researchtoolsinmedicine2023/9/1912

Carbachol（M、NR）

Moresideeffects

Mainlyusedforlocaleyedropsintreatmentofglaucoma2023/9/1913

Section2M-CholinoceptorAgonists

（pilocarpineetc）Includepilocarpine，muscarine,methacholinebethanecholetc.2023/9/1914

Pilocarpine

Derivedfromtheleavesoftheplant——pilocarpus.

2023/9/1915

【Principle】Pilocarpine

stimulatesM-receptor2023/9/1916【PharmacologicEffects】1.Eye2023/9/1917a.Miosis(constrictpupil)circularmuscleM

radialmuscle2023/9/1918b.DecreaseintraocularpressureReduceaqueousproduction（Timolol）Promotethecirculationofaqueouswater（Pilocarpine）2023/9/1919

cornea

iriscanalschlemnciliarymusclesuspensoryligaments2023/9/19202023/9/1921c.Cyclospasm(spasmofaccommodation)ThelensbecomesthickerToseenearobjectsmoreclearly2.Glandsincreasesecretionofsweatglandandsalivarygland（fromnormally40—50ml/hto350ml/h）3.Smoothmuscle

AsAchabove2023/9/1922【ClinicalUses】1.Glaucomaclose-angleglaucoma：ofchoiceopen-angleglaucoma：earlyperiod2.Iritis

usedalternatelywithmydriatictopreventadhesionbetweenirisandlens3．Savingatropinepoisoning【AdverseReaction】

salivation,nausea,vomitingandbronchialspasm2023/9/1923

MuscarineClassicM（muscarinic）receptoragonistPoisoningperformance：salivation,nausea,vomiting,headache,visualdisturbances,etcCanbesavedbyatropine2023/9/1924

Methacholine(MR)ThelowerrateofhydrolysisbycholinesteraseObviouseffectstoglandandismainlyusedinoralmucosaxerosisContraindication：bronchialasthma，

coronaryischemiaandpepticulcer2023/9/1925

Bethanechol(MR)ThelowerrateofhydrolysisbycholinesteraseObviouseffectstogastrointestinaltract、

urinarytractandismainlyusedinabdominalflatulence

，gastricretentionContraindication：justlikemethacholine2023/9/1926Section3N-CholinoceptorAgonists

NicotineNicotineisthemaincomponentsoftobacco;Extensivefunction

BiphasiceffectStimulateN1receptor:GanglionStimulateN2receptor:Neuromuscularjunction2023/9/1927HighlytoxicAdultlethaldose：50mg,acigarette：containnicotine20—30mg。Smokingisrelatedtocancer,hypertension,ulcerdisease,centralnervoussystemdiseaseandrespiratorysystemdisease2023/9/1928Chapter7AnticholinesteraseDrugsandCholinesteraseReactivators2023/9/1929Abstract1ProcesswhichAchishydrolizedbyacetylcholinesterase2Summaryofanticholinesteraseagents

AnticholinesteraseagentscanbecombinatedwithAChE.TheCombinationismoresolid，sothehydrolisisisslower.ThereforetheactivityofAChEisinhibitited.ThenaccumulationofAChintheterminalsofcholinergicnerveispresentandthecholinergiceffectsisobserved.

Itincludereversibleanticholinesteraseagentsandunreversibleanticholinesteraseagents.2023/9/19303ReversibleAnticholinesteraseAgents

MechanismPropertiesReversibleanticholinesteraseagentscommonlyused4UnreversibleAnticholinesteraseAgents

－OrganophosphatesPoisoningmechanismPoisoningperformanceDiagnosis,preventionandcureofpoisoning2023/9/1931Section1ProcesswhichAChishydrolizedbyacetylcholinesteraseCholinesterase，ChEAcetylcholinesterase，AChErelativelyspecificforacetylcholinerapidacetylcholinehydrolysisatcholinergicsynapses2023/9/1932

MolecularCompositionofAChEAChEAChCholine+Aceticacid2023/9/1933Section2AnticholinesteraseAgents

ReversibleAnticholinesteraseAgents

Neostigmine

PhysostigmineTacrine

DonepezilUnreversibleAnticholinesteraseAgentsOrganophosphates

2023/9/1934

ReversibleAnticholinesteraseAgents

PharmacologicaleffectMechanismofactionTheinvivoprocessClinicalapplication

Chemicalstructureof

ReversibleanticholinesteraseagentsPhysostigmineCarbarylTengXilongNeostigmine2023/9/1935【PharmacologicalEffects】EyeNarrowingofthepupilSpasmofaccommodationLoweredintraocularpressure2023/9/1936GastrointestinalTract（Neostigmine

）Gastriccontraction

，Gastricacidsecretion

Esophagealperistalsis

，Tension

Activitiesofsmallintestine,especiallycolon

Discharge

intestinalcontents

2023/9/1937

SkeletalNeuromuscularJunction

InhibitingAChEofneuromuscularjunction

DirectlyexcitatoryeffectofN2R

TopromotethereleaseofACh（Therapeuticdose）

2023/9/1938

CardiovascularSystemNegativechronotropiceffect、

Negativedromotropiceffect、

Negativeinotropiceffect

Decreasedcardiacoutput

Others

IncreasingthesecretionofglandsBronchiolarsmoothmusclecontractionContractionofsmoothmuscleoftheureterTheexcitementofcentral,Inducinganesthesiaathighdose

【ClinicalApplications】Myastheniagravis

AbdominalflatulenceandurinaryretentionGlaucoma

Detoxificationof

competitivemusclerelaxants

Alzheimer’sdisease

NeostigmineHasquaternaryammoniumgroupsinchemicalstructure

1.Lowerbioavailability（p.o.）

2.DifficulttopasstheBBB 3.DifficulttopasstheCorneaClinicalApplications：MyastheniagravisDetoxificationof

competitivemusclerelaxantsAbdominalflatulenceandUrinaryretention（Post-operation

）Paroxysmalsupraventriculartachycardia

Physostigmine（Eserine）

similartoneostigmine,but—

EasytobeabsorptedbyP.O.orinjection;

Easy

topasstheBBB(centraleffects）EasytopasstheCornea

Hassameeffectstopilocarpine,but—

Differentmechanism;

Faster、strongerandlastereffctswithstrongerirritant

EdrophoniumChlorideCharacteristicsWeakeffectsofanti-AChE，StrongerSkeletalmusclefunctionFastacting，Shortlastingtime

UsesDiagnosisofmyastheniagravis

Myastheniagravis

CholinergiccrisisEtiologyLessAch

MoreAchSymptomMyastheniaMyastheniaMuscularfibrillationNoObviousPupilNormalShrinkage

IntestinalperistalsisNormalExcitementSweatNormalHeavySweatingAnti-ChEagents

EffectiveWorse

AmbenoniumChlorideCharacteristicsCompoundofdoublequaternaryammoniumHassimilareffectswithNeostigmine，butlonger

Uses

Forthetreatmentofmyastheniagravis,especiallyforthepatientsnotsuitbleforneostigmine

DemecariumBromide

CharacteristicsNeedlongertimetoshoweffects;

UsesOpenangleglaucomaThecomparisonoftherateofhydrolysis1、Ach：（106）Acetyl-ChEHAc+Ch+ChE（Resurrection）2、Neostigmine：（1）Twomethylaminoformyl-ChE

Twomethylcarbamate＋ChE（Resurrection）3、Organophosphates：（10－6）Phosphoryl-ChEOrganophosphates＋ChE（Resurrection）【PoisoningofOrganophosphatesandtheSaving】Organophosphatesisunreversibleanticholinesteraseagents

1MechanismofPoisoning

Organophosphates

+AChE→Phosphoryl-ChE→Ach↑↑“Ageing”inseveralminitusorhours2PoisoningPerformance

SymptomsofM、Nlikesymptoms

、centralsymptomsMlikesymptoms

A.EyeNeedlelikepupil

B.GlandSecretion↑

C.RespiratorysystemDifficulty

D.GastrointestinalsystemFecalincontinenceE.UrinarysystemUrinaryincontinenceF.Cardiovascularsystem