第8章抗胆碱酯酶药Chapter8AnticholinesteraseDrugs中山医学院林明栋第一节第一节胆碱酯酶胆碱酯酶水解过程结合裂解水解EsteraticsiteAnionicsite脂解部位阴离子部位AcetateAc-serinehydrolysedAcetyl-grouptransferredtoserine-OHAcetylcholinebindsEsteraticsiteAnionicsite结合裂解水解第二节抗胆碱酯酶药第二节抗胆碱酯酶药(anticholinesteraseagents)(anticholinesteraseagents)非共价结合的抑制药氨甲酰类抑制药有机磷化合物易逆性抗AChE药难逆性抗AChE药OONOONneostigminecholinecarbamyl-serinehydrolysed(slow)acetyl-grouptransferredtoserine-OHAChac-serinehydrolysed(fast)acetateNHONNHOHisSerGluCOONNHOHisSerGluCOONNHisSerGluCOONNHisSerGluCOONNHisSerGluCOONNHisSerGluCOOphospatetransferredto-NOHreactivationAChEreactivateddyfloscarbamyltransferredtoserine-OHnospontaneoushydrolysisesteraticsitephosphorylatedenzymepralidoximeNNHOHisSerGluCOOOONNNHisSerGluCOOOOONNOOOONNOONFPHOOPrOPrOPrOPrHOPOHONNOPrOPrHOPOHONNONNOPHOOPrCABAChEanionicsiteOONNOONOONneostigminecholinecarbamyl-serinehydrolysed(slow)acetyl-grouptransferredtoserine-OHAChac-serinehydrolysed(fast)acetateNHONNHOHisSerGluCOONNHOHisSerGluCOONNHOHisSerGluCOONNHOHisSerGluCOONNHisSerGluCOONNHisSerGluCOONNHisSerGluCOONNHisSerGluCOONNHisSerGluCOONNHisSerGluCOONNHisSerGluCOONNHisSerGluCOOphospatetransferredto-NOHreactivationAChEreactivateddyfloscarbamyltransferredtoserine-OHnospontaneoushydrolysisesteraticsitephosphorylatedenzymepralidoximeNNHOHisSerGluCOONNHOHisSerGluCOOOONNNHisSerGluCOONNHisSerGluCOOOOONNOOOONNOONFPHOOPrOPrOPrOPrHOPOHONNOPrOPrHOPOOPrOPrHOPOHONNONNOPHOOPrCABAChEanionicsiteOONNFig.8-1TheinteractionsofAChEwithacetylcholine(A),reversibleanticholinesterasedrugs(B)andirreversibleanticholinesteraseagents(C).anticholinesteraseagentsanticholinesteraseagents非共价结合的抑制药依酚氯铵（edrophonium）他克林（tacrine）多奈哌齐（donepezil）anticholinesteraseagentsanticholinesteraseagents氨甲酰类抑制药新斯的明（neostigmine）吡斯的明（pyridostigmine）地美溴铵（demecarium）利凡斯的明（rivastigmine）易逆性抗易逆性抗AChEAChE药药一般特性药理作用o体内过程临床应用不良反应药理作用药理作用眼缩瞳调节痉挛降低眼内压药理作用药理作用胃肠道胃收缩，胃酸分泌食管蠕动，张力增加小肠、大肠(尤其结肠)活动，肠内容排出药理作药理作用用心血管系统作用兴奋神经节、效应器ACh受体*对心血管的影响较胆碱激动剂弱骨骼肌神经肌肉接头药理作药理作用用效应负性频率、负性传导、负性肌力作用*对心血管的影响较胆碱激动剂弱心排出量下降药理作药理作用用其他部位作用增加腺体分泌（高剂量，基础分泌率）收缩细支气管收缩输尿管平滑肌体内过体内过程程特点化学结构中含季铵基团p.o吸收生物利用度低不易透过BBB血浆酯酶水解失活临床应用临床应用重症肌无力（myastheniagravis）腹气胀及尿潴留青光眼（glaucoma）解毒治疗阿尔茨海默病（Alzheimer’sdisease）老年期痴呆的发病率逐年上升,阿尔茨海默病(AD)就是老年期痴呆中的主要类型之一新斯的明新斯的明NeostigmineNeostigmine体内过程特点季铵类p.o生物利用度低较少进入BBB新斯的明新斯的明NeostigmineNeostigmine作用抑制AChE完全拟胆碱兴奋M、N受体对腺体、眼、心血管及支气管平滑肌作用弱对骨骼肌及胃肠平滑肌兴奋作用较强其他机制？新斯的明新斯的明NeostigmineNeostigmine用途重症肌无力腹气胀及尿潴留阵发性室上性心动过速竞争性肌松药中毒禁忌证机械性肠梗阻泌尿道梗阻新斯的明新斯的明NeostigmineNeostigmine吡斯的明吡斯的明pyridostigmpyridostigmineine特点起效缓慢，作用时间较长...
