Chapter7

cholinesteraseinhibitingdrugs&cholinesterasereactivators

第七章

抗膽堿酯酶藥和膽堿酯酶復活藥TAISHANmedicaluniversityzhangfengCholinesterase（膽堿酯酶，AChE）acetylcholinesterase（乙酰膽堿酯酶）也稱真性膽堿酯酶：主要存在于膽堿能神經(jīng)末梢突觸間隙。Pseudocholinesterase（假性膽堿酯酶）：主要存在于血液及肝臟中。Neostigmine（新斯的明）1.Pharmacologicaleffects

①cholinesteraseinhibitor

②verystrongeffectonskeletalmuscle--directactivatingN2receptors--releaseAChatthemotornerveendings（運動神經(jīng)）

③strongstimulatingeffectongastrointestinaltract（胃腸道平滑?。゛ndgallbladdersmoothmuscle（膽囊平滑?。㊣.易逆性抗膽堿酯酶藥

2.ClinicalUses

①myastheniagravis（重癥肌無力）

②Postoperativeileus（術后腸梗阻）andurinaryretention（尿潴留）

③Paroxysmalsupraventriculartachycardia（陣發(fā)性室上性心動過速）

④Overdosageofmusclerelaxants

⑤Atropineintoxication3.SideEffectslargedosage----nausea（惡心）,vomiting（嘔吐）,abdominalpain（腹痛）,HR,fibrillationofmusclefibers（肌束顫動）,“cholinergiccrisis”（膽堿能危機）4.Contraindications

①Mechanicalintestinalobstruction(ileus)（機械性腸梗阻）②urinaryobstruction（尿路阻塞）③bronchialasthma（支氣管哮喘）Physostigmine(毒扁豆堿，又稱Eserine）ClinicalUses

①glaucoma（青光眼）

②awakeningoftraditionalChineseherbanesthesia（中藥麻醉的催醒）

③atropineintoxication病例討論Ⅱ.難逆性抗膽堿酯酶藥

Organophosphates(有機磷酸酯類，OPs）1.Classification①Organophosphorus--dipterex（敵百蟲）,rogor（樂果）,DDVP,Parathion（對硫磷）,Malathion（馬拉硫磷）--usedasaninsecticide.--rapidlyabsorbed–skin,respiratory,GIetc.②Nervegases--tabun（塔崩）,sarin（沙林）,soman（梭曼）有機磷酸酯類抑制膽堿酯酶過程示意圖2.Mechanismof

OrganophosphateIntoxication

①WithexposuretoOpsanticholinesteraseagents,theenzyme(AChE)isphosphorylated（使磷酸化）andbecomesunabletofunction.②Acetylcholinebuild-up,whichcausesinterfer-encewithnerveimpulsetransmissionatnerveendings.4.ChronicIntoxication

ReductionofAChE,headache,dizziness,fatigue（疲勞）,sometimesmusclefasciculation,miosis（瞳孔縮小）.5.TreatmentofAcuteIntoxication

①Terminateexposure②Maintainairway

③Atropine

④cholinesterasereactivator

⑤othertreatmentAtropine(阿托品）“及早、足量、反復”--阿托品化（大、紅、快、干、凈）①Atropineblocksacetylcholinereceptors(M-R)andhaltsthecholinergicstimulation；②Verylargedosesofatropineareusuallyrequired；③Thepatientshouldbekeptatropinelized（阿托品化）bygivingatropineeveryhour.Ⅲ.CholinesteraseReactivator（膽堿酯酶復活藥）

①Compoundscalledoximes（肟）cancausedephosphorylation（脫磷酸）.

②OximeshavethegeneralstructureR-CH=N-OH（肟基）.

③Reactivateacetylcholinesteraseandiseffectiveinrestoringskeletalmusclefunction.④Butseemslesseffectiveatreversingmuscarinicorcentralsigns.Pralidoximeiodide(碘解磷定，派姆，PAM）1.Pharmacologicaleffects①Dephosphorylation

Phosphorylatedcholinesterase+PAM--→phosphorylatedPAM+reactivatedAChE

②Directandminoreffect

PAM+organophosphate--→phosphorylatedPAM2.Improvethesymptoms①stopmusclefasciculation（肌束顫動）②improveCNSsymptoms--awakethepatients--stopconvulsion（躁動不安）3.SideEffects

Generalmalaise（不適）,blurredvision（視力模糊）,dizziness,nausea（惡心）,Vomiting,tachycardia（心動過速）Pralidoximechloride,PAM-Cl(氯解磷定）SimilartoP