人体结构与功能 10-Parasympathomimetics学习资料

Chapter6Parasympathomimetics

CholinoceptorAgonists

AnticholinesterasesSection1.M-RAgonistscholineesters:

均含有季铵基团acetylcholine(Ach)：unstable,lowselectivitymethacholine(醋甲胆碱)

carbachol(卡巴胆碱)bethanecholchloride(氯贝胆碱)

alkaloids:

pilocarpinemuscarinearecoline(槟榔碱)[Pharmacologicalactions]DirectlyactivateM,N-Rmuscarinicactions:insmalldosenicotinicactions:inlargedoseAcetylcholine(Ach,乙酰胆碱)EffectiveinlargedoseivLocaleffectbyim,scCholineesters1.muscarinicactions

(1)cardiovascularsystemvesseldilation,BP↓

(reflectiveHR↑)HR

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

b.NArelease↓Heartdepression:atrium>ventricles

negative(chronotropic,dromotropic,inotropic)effectDirecteffectNegativefeedbackNArelease↓

RobertFurchgottmechanismof

negativechronotropiceffect↓Ca2+→↓automaticdepolarizationmechanismof

negativedromotropiceffect

↑

ERPofAtrioventricularnode&Purkinjefibers→↓conductionmechanismof

negativeinotropiceffectatrium:↑K+efflux→↑repolarization→actionpotentialduration↓,ERP↓

ventricles:

presynapticmembraneM-R→NArelease↓(2)splanchnicsmoothmuscle①gastrointestinaltract:excitationmotilityincrease;secretionstimulation

②urinarybladder:

detrusor(逼尿肌)contractiontrigone(三角区)andsphincterrelaxation

③bronchus:contraction(3)others①glandssecretion:increasingly②eyes:

miosis

(irissphinctercontraction)nearvision(ciliarymusclecontraction)2.nicotinicactions(ganglion,skeletalmuscle,adrenalmedulla)NN-R:co-innervationanddominanttheoryadrenalinereleaseNM

-R:skeletalmusclecontraction

Carbachol

(卡巴胆碱):

onlyusedinglaucoma

Methacholine(醋甲胆碱):

xerosisoforalmucosa(口腔粘膜干燥症)Bethanechol(氯贝胆碱):

abdominaldistension,urinaryretentionOthercholineestersAlkaloids

Pilocarpine（毛果芸香碱，匹鲁卡品）Muscarine（毒蕈碱）

Arecoline

（槟榔碱）

Oxotremorine（震颤素）naturalsyntheticPilocarpine[Pharmacologicalactions]:selectively

activateM-R

1.Eye

miosis(pupiliarysphincter)

decreaseintraocularpressurespasmofaccommodation(ciliarymuscle)

2.Glandssecretion:

increase3.OthersEyesandglandsareparticularlysensitivetothisdrug.ItisprimarilyusedinophthalmologyCircularmuscleM-RRadialmuscleα-RClinicaluses

1.Glaucoma(青光眼）

angle-closureglaucomaopen-angleglaucoma

1~2%,4~8h2.iritis(虹膜炎),iridocyclitis(虹膜睫状体炎)3.others:drymouth

atropinepoisionAdversereactionsDiarrheaDiaphoresis(出汗)MiosisNauseaUrinaryurgencyMuscarine丝盖伞菌属杯伞菌属捕蝇蕈流涎、流泪、恶心、呕吐、头痛、视觉障碍、腹部绞痛、腹泻、支气管痉挛、心动过缓和血压下降、休克Section2N-Ragonists(nicotine,lobeline)Lobeline(洛贝林,山梗菜碱):respiratorycenterstimulantsNicotine：fromtobaccoAction:

NM,NN,CNSanddependence

(doublephase:agonistandantagonist)

Tobaccopoison:

Hypertension,Coronaryheartdisease,cancer,Cerebrovasculardisease,Atherosclerosis,PepticUlcersSection3

AnticholinesteraseAgentsCholinesterase(ChE)CommonpropertiesofanticholinesteraseagentsReversibleAnticholinesteraseagentsIrreversibleAnticholinesteraseagents

Cholinesterase（ChE）TrueCholinesterase(acetylcholinesterase,AChE)

(105

Ach/min

)

Pseudocholinesterase(butyrylcholinesterase,BChE)Commonpropertiesof

anticholinesteraseagents[Classifications]

chemicalstructurenon-covalentbondingagents:依酚氯铵、他克林、多奈哌齐carboxamide(氨甲酰类):毒扁豆碱、比斯的明、地美溴铵、利凡斯的明OrganophosphatespropertiesReversibleAnticholinesteraseagentsIrreversibleAnticholinesteraseagents药物与AChE形成的复合物水解速度慢[Pharmacologicalactions]1.eye:likePilocarpine2.gastrointestinaltract

(esophagus,stomach,intestine)

e.g.Neostigminecanincreasethemotility(amplitude,frequencyandtension)3.neuromuscularjunctionofskeletalmuscle(anti-AChE,neostigmine--excitereceptor)4.glandssecreteincreasingly5.others(urinarytract,bronchia,cardiovascularsystem)Dominanttheory,mainlynegativeeffect[ClinicalUses]1.

Myastheniagravis

(重症肌无力)2.Postoperativeabdominaldistension;Urinaryretention(!nomechanicalobstruction)3.Glaucoma（毒扁豆碱、地美溴铵）4.Intoxicationof

d-tubocurarine

and

cholinoceptor-blockers5.Alzheimer’sdisease

6.SupraventriculartachyarrhythmiasMyastheniagravisAdiseaseaffectingskeletalmuscleneuromuscularjunctions.Frequentsymptomsareptosis(上睑下垂),diplopia(复视),difficultyinspeakingandswallowing,andextremityweakness.Severediseasemayaffectallthemuscles,includingthosenecessaryforrespiration.

NeostigminePyridostigmine(吡斯的明)Ambenoniumchloride(安贝氯胺)Galanthamin(加兰他敏)

ReversibleAnticholinesteraseagentsNeostigmine(新斯的明）

Skelatalmuscle>GI、bladdersmoothmuscle

>CV、Glands、eyes、brachialsmoothmuscle[ClinicalUses]po,sc,im(NotintoCNS)1.Myastheniagravis:directandindirecteffects2.Postoperativeabdominaldistension;Urinaryretention3.Intoxicationofd-tubocurarineandatropine4.Supraventriculartachyarrhythmias5.glaucoma

Cautions:CholinergicCrisis

(atropine,d-tubocurarine)Physostigmine(毒扁豆碱)Eyes:similartopilocarpine(butmorerapid,strongerandlonger)Peripheraleffects:similartoneostigminebutstrongerCentraleffects:excitation→inhibitionClinicaluse:1.Glaucoma2.Intoxicationofcentralanticholinergics(tricyclicantidepressant,antihistaminics,anti-emetic,antiparkinsonagents,phenothiazinesantipsychoticagents)毒性大，除解毒外一般不全身应用OtherReversibleAnticholinesteraseagents1.Myastheniagravis:neostigminePyridostigmine（吡斯的明）Ambenoniumchloride（安贝氯铵）Galanthamine（加兰他敏）2.Glaucoma:Physostigmine(1~2d)

Demecariumbromide(地美溴铵,9d)3.Alzheimer’sdisease:Donepezil(多奈哌齐),Rivastigmine,Tacrine4.Diagnostictestformyastheniagravis:Edrophoniumchloride（依酚氯铵，腾喜龙）Edrophoniumchloride用于诊断重症肌无力和鉴别肌无力危象及胆碱能危象。也用作筒箭毒碱等非去极化肌松剂的拮抗剂。【用法及用量】①腾喜龙试验:iv10mg，注射后重症肌无力症状明显缓解，10分钟后恢复原状，可确定诊断。②肌无力危象和胆碱能危象的鉴别:先注射2mg，若症状好转，再将其余8mg注射完，诊断为肌无力危象；若注射2mg后症状加重，应立即停注，诊断为胆碱能危象。③筒箭毒碱等非去极化肌松弛剂的拮抗剂:静脉注射5～10mg/次，总剂量可达40mg。

IrreversibleAnticholinesteraseAgents—Organophosphates（有机磷酸酯类）1）弱：敌百虫、乐果、马拉硫磷2）强：敌敌畏3）剧：内吸磷、甲拌磷、对硫磷4）强剧：沙林、塔朋、梭曼（战争化学毒气）PathwayofintoxicationagingMechanismsofintoxicationSignsofintoxication

1.Acute

intoxication:

acutecholinergiccrisis

(1)Mmanifestation(muscariniceffects)(2)Nmanifestation(nicotiniceffects)(3)CNSeffects2.Chronicintoxication心率减慢、血压下降、缩瞳可不明显[signsofacuteintoxication]1.Mildintoxication:Msigns2.Moderateintoxication:M+Nsigns3.Severeintoxication:M+N+CNSsignPreventionandtreatmentofintoxicationDiagnosis:exposure,symptoms,AChEactivityPrevention:importantTreatmentofacute