Chapter6Parasympathomimetics

CholinoceptorAgonists

AnticholinesterasesSection1.M-RAgonistscholineesters:

均含有季銨基團acetylcholine(Ach)：unstable,lowselectivitymethacholine(醋甲膽堿)

carbachol(卡巴膽堿)bethanecholchloride(氯貝膽堿)

alkaloids:

pilocarpinemuscarinearecoline(檳榔堿)[Pharmacologicalactions]DirectlyactivateM,N-Rmuscarinicactions:insmalldosenicotinicactions:inlargedoseAcetylcholine(Ach,乙酰膽堿)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(三角區(qū))andsphincterrelaxation

③bronchus:contraction(3)others①glandssecretion:increasingly②eyes:

miosis

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

-R:skeletalmusclecontraction

Carbachol

(卡巴膽堿):

onlyusedinglaucoma

Methacholine(醋甲膽堿):

xerosisoforalmucosa(口腔粘膜干燥癥)Bethanechol(氯貝膽堿):

abdominaldistension,urinaryretentionOthercholineestersAlkaloids

Pilocarpine（毛果蕓香堿，匹魯卡品）Muscarine（毒蕈堿）

Arecoline

（檳榔堿）

Oxotremorine（震顫素）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(虹膜睫狀體炎)3.others:drymouth

atropinepoisionAdversereactionsDiarrheaDiaphoresis(出汗)MiosisNauseaUrinaryurgencyMuscarine絲蓋傘菌屬杯傘菌屬捕蠅蕈流涎、流淚、惡心、嘔吐、頭痛、視覺障礙、腹部絞痛、腹瀉、支氣管痙攣、心動過緩和血壓下降、休克Section2N-Ragonists(nicotine,lobeline)Lobeline(洛貝林,山梗菜堿):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:依酚氯銨、他克林、多奈哌齊carboxamide(氨甲酰類):毒扁豆堿、比斯的明、地美溴銨、利凡斯的明OrganophosphatespropertiesReversibleAnticholinesteraseagentsIrreversibleAnticholinesteraseagents藥物與AChE形成的復合物水解速度慢[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

(重癥肌無力)2.Postoperativeabdominaldistension;Urinaryretention(!nomechanicalobstruction)3.Glaucoma（毒扁豆堿、地美溴銨）4.Intoxicationof

d-tubocurarine

and

cholinoceptor-blockers5.Alzheimer’sdisease

6.SupraventriculartachyarrhythmiasMyastheniagravisAdiseaseaffectingskeletalmuscleneuromuscularjunctions.Frequentsymptomsareptosis(上瞼下垂),diplopia(復視),difficultyinspeakingandswallowing,andextremityweakness.Severediseasemayaffectallthemuscles,includingthosenecessaryforrespiration.

NeostigminePyridostigmine(吡斯的明)Ambenoniumchloride(安貝氯胺)Galanthamin(加蘭他敏)

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(毒扁豆堿)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應用OtherReversibleAnticholinesteraseagents1.Myastheniagravis:neostigminePyridostigmine（吡斯的明）Ambenoniumchloride（安貝氯銨）Galanthamine（加蘭他敏）2.Glaucoma:Physostigmine(1~2d)

Demecariumbromide(地美溴銨,9d)3.Alzheimer’sdisease:Donepezil(多奈哌齊),Rivastigmine,Tacrine4.Diagnostictestformyastheniagravis:Edrophoniumchloride（依酚氯銨，騰喜龍）Edrophoniumchloride用于診斷重癥肌無力和鑒別肌無力危象及膽堿能危象。也用作筒箭毒堿等非去極化肌松劑的拮抗劑。【用法及用量】①騰喜龍試驗:iv10mg，注射后重癥肌無力癥狀明顯緩解，10分鐘后恢復原狀，可確定診斷。②肌無力危象和膽堿能危象的鑒別:先注射2mg，若癥狀好轉，再將其余8mg注射完，診斷為肌無力危象；若注射2mg后癥狀加重，應立即停注，診斷為膽堿能危象。③筒箭毒堿等非去極化肌松弛劑的拮抗劑:靜脈注射5～10mg/次，總劑量可達40mg。

IrreversibleAnticholinesteraseAgents—Organophosphates（有機磷酸酯類）1）弱：敵百蟲、樂果、馬拉硫磷2）強：敵敵畏3）劇：內(nèi)吸磷、甲拌磷、對硫磷4）強劇：沙林、塔朋、梭曼（戰(zhàn)爭化學毒氣）PathwayofintoxicationagingMechanismsofintoxicationSignsofintoxication

1.Acute

intoxication:

acutecholinergiccrisis

(1)Mmanifestation(muscariniceffects)(2)Nmanifestation(nicotiniceffects)(3)CNSeffects2.Chronicintoxication心率減慢、血壓下降、縮瞳可不明顯[signsofacuteintoxication]1.Mildintoxication:Msigns2.Moderateintoxication:M+Nsigns3.Severeintoxication:M+N+CNSsignPreventionandtreatmentofintoxicationDiagnosis:exposure,symptoms,AChEactivityPrevention:importantTreatmentofacute