神经系统药理—魏尔清(传出药理概论-.拟胆碱药.ppt

单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,A,Muscarinic receptor agonists,A,Muscarinic receptor agonists,1.,Choline Esters,(,胆碱酯类,),Acetylcholine,乙酰胆碱,Carbachol,卡巴胆碱,Methacholine,醋甲胆碱,Bethanechol chloride,氯贝胆碱,2.,Natural Alkaloids,(,生物碱类,),Pilocarpine,毛果芸香碱（匹罗卡品）,Muscarine,毒蕈碱,Pilocarpine,毛果芸香碱（匹罗卡品）,Pilocarpine,毛果芸香碱,A,Muscarinic receptor agonists,Aqueous humor drainage,Pilocarpine,Atropine,（2）Promoting secretion of exocrine glands（,外分泌腺体,）,especially in sweat,salivary and tear glands,A,Muscarinic receptor agonists,2.,Clinical uses,（1）Ophthamological uses,Glaucoma:,narrow-,or,wide-angles,Iritis:,miotics/mydriatics,BOX,Glaucoma,Acute congestive glaucoma（narrow-angle）,Chronic simple glaucoma（wide-angle）,A,Muscarinic receptor agonists,（2）Systemic use,Dry mouth:,radiotherapy,Antidote for atropine poisoning,A,Muscarinic receptor agonists,3.,Adverse effects,（1）Local(eye):,pain,tears,（2）Systemic:,secretion of exocrine glands,treated with atropine,A,Muscarinic receptor agonists,B,Anticholinesterases,1.Reversible anticholinesterases,2.Irreversible anticholinesterases,anionic site esteratic site,Acetylcholinesterase is the mechanism of terminating ACh effects,B-1,Reversible anticholinesterases,Action of acetylcholinesterase,Acetylcholinese:,structure for interaction with substrate,B-1,Reversible anticholinesterases,Neostigmine,新斯的明,Neostigmine,新斯的明,1.,Pharmacological effects,binding to AChE,but slowly hydrolysis,inhibiting AChE activity,Properties of Effects,stronger effect on skeletal muscles,AChE(-),ACh release,stimulating N,M,receptor,effective on GI tract and urinary bladder,more polar and can not enter CNS,relatively ineffective on CVS,glands,eye,B-1,Reversible anticholinesterases,Effect of neostigmine on AChE,Action of neostigmine on acetylcholinesterase,2.,Clinical uses,1)Myasthenia gravis（,重症肌无力,）,:,symptomatic treatment,overdose:cholinergic crisis,(2)Paralytic ileus and bladder（,手术后肠道及膀胱麻痹,）,:,post operative abdominal distension and urinary retention,(,3)Antidote for nondepolarizing skeletal muscle relaxants poisoning（,解除非除极化型肌松药中毒,）,(4)Paroxysmal superventricular tachycardia（,阵发性室上性心动过速,）,B-1,Reversible anticholinesterases,3.,Adverse effects,（1）Cholinergic effects:,muscarinic and nicotinic effects,treated with atropine(muscarinic),（2）Contraindications：,mechanical ileus（,机械性肠梗阻,）,urinary obstruction（,尿路阻塞,）,bronchial asthma（,支气管哮喘,）,poisoning of depolarizing skeletal muscle relaxants,（,除极化型肌松药中毒,）,B-1,Reversible anticholinesterases,Other reversible anticholinesterases,Pyridostigmine(,吡斯的明,):,myasthenia gravis,paralytic ileus and bladder,Physostigmine(,毒扁豆碱,):,glaucoma,Edrophonium chloride(,依酚氯铵,)：,myasthenia gravis,Galantarmine(,加兰他敏,)：,myasthenia gravis,B-1,Reversible anticholinesterases,Anticholinesterases improving memory,Tacrine(,他克林,)：,improving memory/,hepatic toxicity,Donepezil(,多奈哌齐,),and,rivastigmine(,利凡斯的明,):,improving menory;,used in mild/moderate Alzheimer patients,Huperzine(,哈伯因，石杉碱甲,)：,myasthenia gravis,improving memory,B-1,Reversible anticholinesterases,B-2,Irreversible Anticholinesterases,and Cholinesterase reactivators,1.,Organophosphates,（,有机磷酸酯类,）,(1)Toxicology,Irreversible binding to esteric site of AChE by covalent attachment,phosphorylated,AChE,aging,ACh accumulated in the synaptic sites,and caused toxic effects,Irreversibly binding to esteric site of AChE by covalent attachment,phosphorylated AChE,(2)Toxic symptoms,Acute intoxication,Muscarinic symptoms,eye,exocrine glands,respiration,GI tract,urinary tract,CVS,Nicotinic symptoms,N,N,:,elevation of BP,increase of HR;,N,M,:,tremor of skeletal muscles,Central symptoms,excitation,convulsion;depression(advanced phase),B-2,Irreversible Anticholinesterases,and Cholinesterase reactivators,Chronic intoxication,usually occupational poisoning,plasma ChE activity,weakness,restlessness,anxiety,tremor,miosis,B-2,Irreversible Anticholinesterases,and Cholinesterase reactivators,(3)Detoxication,Elimination of poison;Supportive therapy,Antidotes,Atropine,antagonizing muscarinic effects;,early,larger dose,and repeated use,Cholinesterase reactivators,reactivation of phosphorylated AChE;,moderate-severe patients,early use,combined with atropine,B-2,Irreversible Anticholinesterases,and Cholinesterase reactivators,2.,Cholinesterase reactivators,Pyraloxime methoiodide,碘解磷定,PAM,Recognizing and binding to AChE,oxime group,Conjugated with organo-phosphates,B-2,Irreversible Anticholinesterases,and Cholinesterase reactivators,(1)Pharmacological effects,a.,Recognizing and binding to AChE,conjugating with organophosphate by oxime group(,肟基,),b.,Conjugation with free organophasphates,c.,Rapid reactivation of AChE of neuromuscular junctions,B-2,Irreversible Anticholinesterases,and Cholinesterase reactivators,1,2,(2)Clinical uses,a.,Moderate-severe patients,b.,Early use,ineffective for aging phosphorylated AChE,c.,More effective on tremor,d.,Combination with larger dose of atropine,B-2,Irreversible Anticholinesterases,and Cholinesterase reactivators,(3)Adverse effects,a.,Central reactions:,i.v.,500 mg/min,b.,Iodine toxic effects,c.,overdose:inhibiting AChE,B-2,Irreversible Anticholinesterases,and Cholinesterase reactivators,Other Cholinesterase Reactivators,Pralidoxime chloride(,氯解磷定,):,saver than PAM,Obidoxime chloride(,双复磷,):,two active oxime groups;,central active;,overdose:inhibiting AChE,B-2,Irreversible Anticholinesterases,and Cholinesterase reactivators,