03阿托品atropine-山東大學藥理學英文課件03Introduction-ACh-atropine

pharmacologyGeneralintroductionDrugsactingonefferentnervoussystemDrugsactingoncentralnervoussystemDrugsactingoncardiovascularsystemDrugsactingonvisceraChemotherapeuticagentsChapter5IntrductiontoPharmacology

ofEfferentNervousSystemZhangBinInstituteofPharmacologySchoolofMedicineShandongUniversityOrganizationofNervoussystemefferentnervoussystem(ENS)

autonomicnervoussystem(vegetativenervoussystem)somaticmotornervoussystem

Efferentneuronsoftheautonomic

nervoussystemClassificationofENSaccordingtothereleasedneurotransmitters

cholinergicnerve:acetylcholine(Ach)

noradrenergicnerve:noradrenaline(NA)

ClassificationofENSParasympatheticnerveCentralnervoussystem

Achskeletalmuscle

AchNA

AchAchsweatglands

Ach

AchAchadrenalmedullasomaticmotornerve

sympatheticnerveglands,smoothmuscle,heartheart,vessel,smoothmuscleSection1Neurotransmitterand

ReceptorofENS

NeurotransmitterofENSThereceptorsofENS一.NeurotransmitterofENS1.Developmentofneurotransmittertheory100yearsagoChemicaltransmissionelectronictransmission1946VonEulerNA(noradrenaline)1921loewidoublefrogheartexperiment1926DaleAch(acetylcholine)2.Biosynthesis,storage,releaseandterminationofneurotransmittersAch(acetylcholine)NA(noradrenaline)inhibitor2.Biosynthesis,storage,releaseandterminationofneurotransmitters

(1)Biosynthesischoline+acetylcoenzymeAAchtyrosinedopaDANAcholineacetylaseTHDDDH(2)Storage

+ATP+proteinstoreinvesicles

AchNA(3)releaseexocytosisquantalrealeasecotransmission(4)Termination

Ach:

acetylcholinesterase(AchE)insynapseNA:

uptake1(neuronaluptake)75%-90%storageinvesicles\MAOuptake2(non-neuronaluptake)COMT\MAO

二.ThereceptorsofENS

Classification,DistributionandEffectCholinereceptors(Cholinoceptors)M-R:

muscarineN-R:nicotine

CholinoceptorsM-R:M1-R:ganglion,CNSM2-R:heart,presynapticsites(negativefeedback),CNSM3-R:exocrineglands,smoothmuscle,endothelium,CNSM4–R:exocrineglands,smoothmuscle,CNSM5-R:CNSCholinoceptorsN-R:nicotineNM-R:skeletalmuscle

NN-R:ganglionandCNSadrenoceptor:NAAD

α-Rα1-R:

postsynapticeffectorcells

(especiallysmoothmuscle)α2-R:

presynapticnerveterminals(negativefeedback),platelet,smoothmuscle,lipocytesadrenoceptorβ-Rβ1-R:postsynapticeffectorcells,(especiallyheart,lipocytes,)

presynapticnerveterminalsβ2-R:postsynapticeffectorcells,(especiallysmoothmuscle)β3-R:postsynapticeffectorcells,

(especiallylipocytes)ClassificationofreceptoraccordingtotheirstructureG-protein-coupledreceptor:

-R,-R,M-R,DA-R,5-HT-RLigand-gatedreceptors

N-RStructureofG-protein-coupledReceptorMolecularMechanismofGq-protein-coupledReceptorMolecularMechanismofGi/s-protein-coupledReceptorStructureofligand-gatedionchannelReceptorMolecularMechanismofligand-gatedionchannelreceptor1.Cholinoceptors

M-R:G-protein-coupledreceptor

M1-R:Gq-protein-coupledreceptor

M2-R-Gi-protein-coupledreceptor

N-R:ligand-gatedionchannelreceptor2.

adrenoceptor:

G-protein-coupledreceptorα1–R:Gq-protein-coupledreceptorα2–R:Gi-protein-coupledreceptorβ-R:Gs-protein-coupled

receptorMolecularMechanismofReceptor

N-RNa+,K+,

Ca2+G-protein-coupledreceptor

ligand-gatedreceptor:(-)

PKA

cAMPM1-R

M2-R

GqGiK+,

Ca2+(-)AC

cAMPPLC

IP3DAGα1

-R

α2

-R

β-R(+)

AC

(-)

AC

GiGqPLC,PLA2,PLD

GscAMP(-)

PKA

(+)

PKA

Ca2+(+)

PKCterminologyadrenergicadrenergicreceptorcholinergiccholinergicreceptorpostsynapticreceptorpresynapticreceptorSection2

Thephysiological

actionsofENSCo-innervationandDominantTheorySympatheticactions:

fightandflightresponseParasympatheticactions:

restanddigestresponseSection3Thebasicmechanismsof

actionsofENSdrugs

1.Directactionofreceptors

agonistblocker(antagonist)2.lnfluenceofneurotransmitters

biosynthesisreleasestorageconversion

Section4Theclassificationofthe

ENSdrugs

（三）抗膽堿酯酶藥Chapter6parasympathomimeticsCholinoceptoragonists(cholinomimetics)Anticholinesteraseagents(cholinesterase-inhibitingdrugs)DrugsofenhancersofAChreleaseCholinoceptorAgonists

M-Ragonists:

Cholineesters:acetylcholine(ACh)

alkaloids:pilocarpine

N-Ragonists:

nicotine

Section1M-Ragonists

Acetylcholine(ACh)1.unstable2.lowselectivity3.administrationroute[Pharmacologicalactions]DirectlyactivateM-R,N-Rmuscarinicactions:smalldosenicotinicactions:largedose1.muscarinicactions:smalldose

1.cardiovascularsystemvesseldilate

a.NOrelease↑(M3R→EDRF(NO)↑→GC→cGMP↑→intracellularCa2+↓)b.NArelease↓

BP(HR)

Heartdepress:negative(chronotropic,dromotropic,inotropic)effect1.muscarinicactions:smalldose2.glands↑3.gastrointestinaltract:

motilityincrease,secretionstimulation4.urinarybladder:

detrusormuscle(逼尿?。ヽontraction,trigoneandsphincterrelaxation5.eye:

sphinctermuscleofiris(虹膜）contract:miosisciliarymusclecontract:nearvision2.nicotinicactions:largedoseNN-R:dominantnerveactionsNM

-R:skeletalmusclecontraction

alkaloidsPilocarpine（毛果蕓香堿，匹魯卡品）Muscarine（毒蕈堿）

Arecoline

（檳榔堿）Oxotremorine（氧化震顫素）Pilocarpine

Pharmacologicalactions:selectivelyactivateM-R

1.Eye

miosis:pupiliarysphincter

decreaseintraocularpressurespasmofaccommadation:ciliarymuscle

2.Glandssecreteincreasingly

(sweatgland,salivarygland)3.Smoothmuscle4.CardiovascularsystemClinicaluses

1.Glaucoma(青光眼）angle-closureglaucomaopen-angleglaucomaWhatisGlaucoma?increasedpressurewithintheeye.Cellsinsidetheeyeproduceaqueoushumorthatmaintainstheshapeoftheeyeandnourishesthetissuesinsidetheeye.Thebalanceoffluidproductionanddrainageisresponsibleformaintainingnormalpressurewithintheeye.Inglaucoma,thedrainbecomescloggedbuttheeyekeepsproducingfluid.Therefore,thepressureintheeyeincreases.TheincreasedpressureintheeyeactuallycancausetheeyetostretchandenlargeHowdoesGlaucomaaffecttheeye?VisionLoss.Pressuredamagetotheopticnerveanddecreasedbloodflowtotheretina,resultsinlossofvision.However,ifthepressureintheeyeremainsuncontrolled,theretinadegeneratesandvisionispermanentlylost.PermanentblindnesscanoccurwithinseveralhoursifthepressureisveryhighandtheglaucomadevelopsrapidlyPain.Humanshavenormalintraocularpressuresbetween10and20mmHg.Glaucomaoftenresultsinpressuresof20-28mmHginhumans.Thepainpersistsintheformofaconstantheadacheormigraine.Thisdiscomfortcanresultindecreasedactivity,lessdesiretoplay,irritability,ordecreasedappetite2.iritis（虹膜炎），iridocyclitis（虹膜睫狀體炎）3.others

:drymouthAdversereactions

Muscarine（毒蕈堿）Amanitamuscaria（捕蠅蕈）Inocybe（絲蓋傘菌屬）Clitocybe（杯傘菌屬）Section2N-Ragonists

——nicotineNicotine:fromtobaccoAction:NM,NN,CNSanddependence(doublephase)Tobaccopoison:

Hypertension,coronaryheartdisease,cerebrovasculardisease,cancer,AtherosclerosisChina:Largesttobaccoproductivecountry,LargesttobaccoconsumptioncountryNosmoking！Stopsmoking！Section3

AnticholinesteraseAgentsCholinesterase:trueCholinesterase(AChE)PseudocholinesteraseAnticholinesteraseAgents

-----indirectactingcholinomimetics

Classificationaccordingtostructurenon-covalentbondingagents:

Edrophoniumchloride(依酚氯銨):strongpolarity,short

tacrine(他克林):stronglipophilia,long

donepezil(多奈哌齊):stronglipophilia,longCarboxamide(氨甲酰類):

Physostigmine(毒扁豆堿)

Pyridostigmine(吡斯的明)Demecarium(地美溴銨)rivastigmine(利凡斯的明)orgnaophosphoruscompound(有機磷化合物)親和力親脂性BBB維持時間依酚氯銨一般弱—短他克林較高強＋長多奈哌齊較高強＋長ClassificationaccordingtopharmacologicalpropertyReversibleAnticholinesteraseagentsirreversibleAnticholinesteraseagents

Mechanismsofactions:Pharmacologicalactions:

1.eye2.gastrointestinaltract（esophagus,stomach,intestine)3.motorendplate4.glands5.cardiovascularsystemClinicalUses

1.Myastheniagravis(重癥肌無力):NeostigminePyridostigmine(吡斯的明)Ambenoniumchloride(安貝氯胺)

ClinicalUses2.Postoperativeabdominaldistension;Urinaryretention:Neostigmine3.glaucoma:Physostigmine(毒扁豆堿)Demecarium(地美溴銨)

4.intoxicationofd-tubocurarine:Neostigmine，Edrophoniumchloride(依酚氯銨):5.Alzheimer’sdisease:

tacrine,donepezil,

rivastigmine,galanthamin

6.Supraventriculartachyarrhythmias

CommonusedagentsReversibleAnticholinesteraseagents

Neostigmine(新斯的明）actions：1.InhibitAChE2.ActivateNM-Ronmotorendplate3.Strongeffectonskeletalmuscle4.NotintoCNSUses:1.Myastheniagravis:Skeletalmusclecontraction

po,sc,imiv2.Postoperativeabdominaldistension;Urinaryretention3.intoxicationofd-tubocurarineandatropine4.Supraventriculartachyarrhythmias5.GlaucomaAdversereactions:

Cholinergicoverexcitation(cholinergiccrisis)Treatment:atropine

d-tubocurarine

Pyridostigmine(吡斯的明)WeakerthanNeostigmineslowerthanNeostigmineLongerthanNeostigmineNotintoCNSUsedtotreatMyastheniagravisContraindication:mechanicalileus，urinaryobstructionPhysostigminecharacteristics1.Strongerthanneostigmine2.CanenterCNS3.HavenodirectactiononRactions：1.eye2.systemicactionUses:1.Glaucoma2.Intoxicationofanticholineagents:

Atropine

TricyclicantidepressantDibenzothiazineantipsychotics

Comparisontopilocarpine1.Morerapid2.Stronger3.longerDonepezilRivastigmineTacrine

——Alzheimer’sdiseaseReversibleanticholinesteraseagentsneostigmine\Pyridostigmine\Ambenonium\Galanthamine:MyastheniagravisPhysostigmine\Demecarium:Glaucoma

Edrophoniumchloride:diagnostictestformyastheniagravisDonepezil\rivastigmine\Tacrine\:Alzheimer’sdiseaseIrreversibleAnticholinesteraseAgents--Organophosphates

MechanismsofintoxicationPathwayofintoxication

signsofacuteintoxication1.Mmanifestation(muscarinicexcess)2.Nmanifestation(nicotiniceffects)3.CNSeffectsChronicintoxication

Preventionandtreatmentof

organophosphatesintoxication

PreventionTreatmentofacuteintoxication

1.maintenanceofvitalsigns2.Decontaminationtopreventfurtherabsorption3.Symptomatictreatment1)atropine2)cholinesterasereactivator

CholinesteraseReactivators

Pralidoximeiodide(PAM):碘解磷定Mechanismsofactiontherapeuticeffect

1.inhibitNmmanifestation——strong2.inhibitMmanifestation——weak3.CNS

碘解磷定磷?；疉ChE復合物磷?；饨饬锥ˋChEPralidoximechloride

(PAM-Cl):氯解磷定betterwater-solubilityimandivlittleadversereactionChapter7cholinoceptor-blockingdrugsM-RblockersN-Rblockers:NN-RblockersNM-RblockersMuscariniccholinoceptor

-blockingdrugs

Atropineandatropine-likealkaloidsSyntheticatropinesubstitutesatropine-likealkaloidsandtheirresources植物主要生物堿

顛茄(atropabelladonna)莨菪堿(hyoscyamine)曼陀羅(daturastramonium)莨菪堿洋金花(datruasp)東莨菪堿

(scopolamine)莨菪(hyoscyamusniger)莨菪堿

唐古特莨菪(scopoliatangutica)山莨菪堿

(anisodamine)

樟柳堿(anisodine顛茄莨菪曼陀羅洋金花Atropine

pharmacologicalactions:

blockM-RblockNN-Rinlargedosepharmacologicalactions1.glands:

secretion↓salivary,sweat>lacrimal,respiratory>gastricacid,pancreatic,intestinaljuice2.eyes

(1)mydriasis(2)increaseintraocularpressure(3)paralysisofaccommodation3.splanchnic

smoothmuscle:relaxation

(spasmodic)GItract,detrusormuscleofbladder:significant

Biletract,bronchial,uterine(子宮):weak4.heart:(1)HR

Therapeuticdose:decrease

(presynapticM1blockade)Largedose:increase(blockvagaleffectonM2–R)(2)A-Vconduction:5.vessels:dilation(inlargedose)

(1)Directeffect(2)Compensativereactionbytemperaturerise6.CNS:excitationOrgansensitivity:Gland＞eye＞splanchnicsmoothmuscle＞cardiovascularsystem＞CNS.ClinicalUses1.Anti-smoothmusclespasm2.

Pre-anaesthesiamedicationagent3.

Ophthalmologicaluse(1)iridocyclitis

(2)optometry

(3)examinationofretina4.Bradyarrhythmias5.

Shock(septicshock):Cautions6.Intoxicationoforganophosphateadversereactions1.CommonSideEffects2.AcutePoisoningminimallethaldose:adults–80~130mgchildren--10mgPrevention1.Decontamination:topreventfurtherabsorption2.Antidotes:

Parasympathomimetics3.Maintenanceofvitalsignscontraindictions

Glaucomaprostatichypertrophy

anisodamine(654-2)

山莨菪堿Characteristicofactions1.highselectivity(smoothmuscleandvessels)2.littlesideeffect(notpassthroughBBB)Uses1.septicshock2.visceralcolics.

Scopolamine(東莨菪堿)

[Characteristics]1.CNSactions:depression(strong)

2.peripheralactions:glands:strongothers:weakUses:1.preanaesthesiamedication2.preventionmotionsickness

3.Parkinsondisease

4.traditionalmedicineanaesthesia中藥麻醉華佗（公元141～203年）“麻沸散”

曼陀羅(洋金花)徐州醫(yī)學院附屬醫(yī)院:中藥麻醉湯(針劑)東莨菪堿Section2SyntheticatropinesubstitutesSyntheticMydriaticsSyntheticA