胆碱酯酶抑制药物.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,文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。,The indirect-acting agents produce their primary effects by inhibiting the action of acetylcholinesterase(AchE),which hydrolyzes acetylcholine to choline and acetic acid.,1,2,By inhibiting,acetylcholinesterase,the indirect-acting drugs increase the concentration of endogenous acetylcholine in the synaptic clefts and,neuroeffector,junctions,and the excess acetylcholine in turn stimulates,cholinoceptors,to evoke increased responses.,These drugs are,in effect,amplifiers of endogenous acetylcholine and act primarily where acetylcholine is physiologically released.,Cholinesterase-lnhibiting Drugs,3,Some cholinesterase inhibitors,even in low concentration,also inhibit,butyrylcholinesterase,(,pseudocholinesterase,),and most inhibit this enzyme when they are present in high concentrations.,However,inhibition of,butyrylcholinesterase,action plays little role in the action of indirect-acting,cholinomimetic,drugs because this enzyme is not important in the physiologic termination of synaptic acetylcholine action,.,4,Some cholinesterase inhibitors also have a modest direct action as well;this is especially true of some quaternary,carbamates,eg,neostigmine,which activate neuromuscular nicotinic,cholinoceptors,directly in addition to blocking cholinesterase.,5,Cholinesterase-lnhibiting Drugs,Anticholinesterases are drugs that inhibit or inactivate acectylcholinesterase,causing the accumulation of acetylcholine at the cholinergic receptors.This produces effects similar to prolonged stimulation of cholinergic fibers.,Classified by the stability of the enzyme-drug complex,(marked differences in duration of action),Reversible Cholinesterase-lnhibiting Drugs,neostigimine physostigimine,Irrevesible Cholinesterase-lnhibiting Drugs,organophosphates,6,Neostigmine 新斯的明,1,Pharmacokinetics,Quaternary ammonium agent,Oral absorption is predictable poor,much larger doses(at least 10 multiple)are required for oral administration than for parenteral injection,Distribution into the CNS is negligible,(difficult penetrate blood-brain barrier),7,Neostigmine,新斯的明,2,Mechanism of action,inhibit acectylcholinesterase,causing the accumulation of acetylcholine at the cholinergic receptors.,muscarinic and nicotinic action,8,-anionic site,(process 150ms),ser-o hydrolyzable covalent bond at the eseratic site,9,-anionic site,(process hours),ser-o hydrolyzable covalent bond at the eseratic site,10,Neostigmine,新斯的明,3.,Effects and clinical uses,1)skeletal muscle:contraction,inhibit AchE,，,accumulation of Ach at the cholinergic receptors;,activate neuromuscular nicotinic cholinoceptors directly in addition to blocking cholinesterase;,promote motor nerve to release Ach,*therapy of,myasthenia gravis,11,Neostigmine,新斯的明,Myasthenia gravis,A disease affecting skeletal muscle neuromuscular junction.An autoimmune process causes production of antibodies that decrease the number of functional nicotinic receptor on the postjunctional endplates.,Symptoms:weakness and fatigability(remit with rest and worsen with exercise);affect skeletal muscle(small muscle:ptosis all muscle:dyspnea),therapy,:,usually oral administration,，,severe or emergency subcutaneously or i.m.,12,Neostigmine,新斯的明,2),gastrointestinal and bladder smooth muscle exciting(muscrinic effect),*,therapy:,postoperative abdominal distention,(postoperative ileus,atony or paralysis of the stomach or bowel following surgical manipulation),and urinary retention,(atony of the urinary bladder),3),*,therapy:treatment of,overdose of the nondepolarizing neuromuscular relaxants;,reverses the peripheral signs of antimuscarinic drug intoxication(eg.atropine),(central signs use Physostigimine),4)modest bradycardia,*,treatment of paroxysmal supraventricular tachycardia(in the past),13,Neostigmine,新斯的明,4.,toxicity,Therapeutic dosage:few side effects,Excessive drug therapy:cholinergic crisis,（,worsen myasthenic signs,）,small dose of edrophonium used to distinguish,emergency and support systems avilable,contraindication,：,asthma,atrioventricular block,mechanical obstruction,14,Cholinesterase-lnhibiting Drugs,Physostigi-mine(eserine),Pyridostig-mine,Edrophon-ium(tensilon),ambenonium,clinic-al uses,glaucoma,refresh after anesthetics,(,analeptic),myasthenia gravis,myasthenia gravis,diagnose and,Distinguish,myasthenia gravis,action,tertiary nitrogens,Lipid-solubility,poor selectivity,Local medication,long duration,weak effect,rapid and short effect,weak effect,similar to neostigmine,long duration,15,Irreversible Cholinesterase-lnhibiting Drugs,organophosphates,Organophosphates inhibitor poisoning and treatment,1.Insecticides and chemical warfare,pesticides:isoflurophate(DFP),parathion,malathion,DDVP(dichlorvos),dipterex,rogor,“nerve(war)gas”soman,sarin,tabun et al.,2.Mechanism of organophosphates inhibitor poisoning,16,撰稿、制做：李红宇,17,-anionic site (process hundreds of hours),ser-o covalent bond at the eseratic site(stable and slow hydrolyze),18,3,signs of organophosphates inhibitor poisoning,Muscarinic signs,：,eye,gland,smooth muscle,Nicotinic signs,：,N,1,ganglia excite,(all of autonomic nerve excite),N,2,neuromuscular junction,(skeletal muscle contraction muscle tremble),CNS effects,：,stimulate(tremor,emesis,mania,stimulant respiratory center et al),inhibit(convulsion coma),19,1,),Muscarinic effect,cardiovascular system,miosis,glands secretion,smooth muscle,2)nicotinic effect,to excite,ganglia,adrenal medulla,secrete Adr,cardiovascular system:,smooth muscle,glands secretion,skeletal muscle,20,4.,Treatment of organophosphates inhibitor poisoning,Maintenance of vital signsrespiration in particular may be impaired,Decontamination to prevent further absorption removal of all clothing,washing of the skin and stomach,conducting of rushing down,et al,Therapy includes treatment with atropine and cholinesterase reactivators,Others sedation et al,21,cholinesterase reactivators,cholinesterase reactivators,a class of oxime compounds,capable of regenerating active enzyme(AchE)from the organophosphorus-cholinesterase complex,available for the treatment of organophosphates poisoning inhibit.,These oxime agents include,Pralidoxime PAM-Cl,（氯解磷定）,Pralidoxime iodide PAM,（碘解磷定）,iacetylmonoxime DAM and others,22,cholinesterase reactivators,23,cholinesterase reactivators,1,treatment,Obviously reverse nicotinic effects,，,rapidly inhibit skeletal muscle tremble,Poorly control muscarinic effects,relieve part of CNS effects,2 principle of application,Early,large dose(enough dose),repeat administration,24,cholinesterase reactivators 3.Mechanism,1),reactivating active enzyme(AChE)by splitting off the phosphorus from the organophosphorus-cholinesterase complex,2)binding of free organophosphates,25,cholinesterase reactivators 3.,Mechanism,1),organophosphates+AchE,Phosphorylated AchE,Phosphorylated PAM,regenerating active AchE,PAM,2)PAM+organophosphates,Phosphorylated PAM,26,cholinesterase reactivators,4.,adverse reaction,Local prickle(ache),Instead inhibit AchE when overdosage,27,