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1、Chapter 8 Anticholinesterase Drugs and Cholinesterase Reactivators,Pharmacology,Instructor:Lei Linsheng 雷林生,Part 1.Cholinesterase inhibitors comprise a large group of drugs that mimic acetylcholine.They can act indirectly by inhibiting the hydrolysis of endogenous acetylcholine.,Hydrolysis of Ach ac
2、etylcholinesterase(AChE)Ach choline+acetic acid process takes place in about 150 ms when it binds to its receptor,it is split,Acetyl-group transferred to serine-OH,Acetylcholine binds,Esteratic site,Anionic site,Reversible inhibition of AChE indirect cholinergic stimulants allow Ach to accumulate at
3、 receptor site exhibit M and N-cholinergic effects,Fig.8-1 The interactions of AChE with acetylcholine(A),reversible anticholinesterase drugs(B)and irreversible anticholinesterase agents(C).,裂解,Neostigmine 新斯的明Pharmacologic effects inhibition of cholinesterase2.very strong effect on skeletal muscle-
4、Ach accumulation at the motor nerve endings-direct activating N2 receptors 3.strong stimulating effect on GI tract and gallbladder smooth muscle,B.Clinical Uses symptomatic treatment of myasthenia gravis,Postoperative paralytic ileus,abdominal distension and uroschesis(retention of urine)-stimulates
5、 GI tract smooth muscle and bladder detrusor(contraction),3.Paroxysmal supraventricular tachycardia-Decrease heart rate4.Overdose of nondepolarizing muscle relaxants-tubocurarine intoxication,Over dose of neostigmine accumulation of excess of Ach sustained depolarizationdisturbance of neuromuscular
6、transmission the symptoms of myasthenia-“cholinergic crisis”,C.Adverse reaction large dosage-nausea,vomiting,abdominal pain,bradycardia,fibrillation of muscle fibers,“cholinergic crisis”,Treatment of“cholinergic crisis”-stop use-use atropine and cholinesterase activator,such as PAM(解磷定),D.Contraindi
7、cations Mechanical intestinal obstruction(ileus)urinary obstruction bronchial asthma,Pyridostigmine 吡斯的明 Similar to and weaker than neostigmine longer duration of action Uses myasthenia gravis Postoperative ileus,abdominal distension and uroschesis(retention of urine),Physostigmine 毒扁豆碱uses glaucoma
8、 quicker effect than pilocarpine.stronger irritating action.atropine intoxication,Edrophonium chloride 依酚氯铵1.Short half-life,short duration of action,5-15min commonly used for the diagnosis of myasthenia gravis,先快速静注2mg，如在3045秒后未见任何药物效应，可再静注8mg药物，给药后如受试者出现短暂肌肉收缩改善，同时未见有舌肌纤维收缩症状，则提示诊断阳性.,Ambenonium c
9、hloride 安贝氯铵 Inhibits cholinesterase and direct stimulates Nmreceptor stronger and longer than neostigmine use orally myasthenia gravis,Demecarium bromide 地美溴铵 longer duration of action glaucoma without lens abnormality,Drug listPrototype:neostigmine Major variants:Pyridostigmine,Physostigmine,Edrop
10、honium chloride,Ambenonium chloride,Demecarium bromide,Part 2.Organophosphate poisoning and AChE reactivators,乙硫磷,对硫磷,马拉硫磷,Fig.8-1 The interactions of AChE with acetylcholine(A),reversible anticholinesterase drugs(B)and irreversible anticholinesterase agents(C).,Background:Organophosphates and carba
11、mates(氨基甲酸脂)are the most frequently used insecticides worldwide.These compounds cause 80%of the reported toxic exposures to insecticides.Organophosphates produce a clinical syndrome that can be treated effectively if recognized early.,Organophosphates were first discovered more than 150 years ago;ho
12、wever,their widespread use began in Germany in the 1920s,when these compounds were first synthesized as insecticides and chemical warfare agents.,Background,奥斯威辛 比克瑙,Pathophysiology:Organophosphates form an initially reversible bond with the enzyme cholinesterase.The organophosphate cholinesterase b
13、ond can degrade spontaneously re-activating the enzyme or can undergo a process called aging(老化).The process of aging results in irreversible enzyme inactivation.,Pathophysiology,Organophosphates are generally highly lipid soluble and well absorbed from the skin,mucous membranes,conjunctiva,GI syste
14、m,and respiratory system.,Pathophysiology,Physical findings阳性体征:vary according to the route of exposure,the age of patient,and the specific chemical.,Muscarinic findings M样症状 may include:Diaphoresis发汗and diarrhea,urination,miosis,bradycardia,bronchorrhea支气管粘液溢,bronchospasm,emesis,lacrimation and sal
15、ivation(DUMBELS).Wheezing喘息and/or bronchoconstriction,Pulmonary edema,Increased pulmonary and oropharyngeal secretions,Sweating,Bradycardia,Abdominal cramping绞痛 and intestinal hypermotility.,Nicotinic findings N样症状 may include:Muscle fasciculations(twitching),Fatigue,Paralysis,Respiratory muscle wea
16、kness,Diminished respiratory effort呼吸使力,Tachycardia,Hypertension.,CNS findings 中枢症状 may include:Anxiety,Restlessness躁动不安,Confusion意识模糊,Headache,Slurred speech言语不清,Ataxia共济失调,Seizures,Coma,Central respiratory paralysis,Altered level of consciousness and/or hypotonia张力减退.,Medical Care 医疗护理:Prehospital
17、 careEnsure airway support and ventilation and perform endotracheal intubation,if necessary,to support the patient before arrival.Perform endotracheal intubation in patients with respiratory failure.,Prehospital careCirculatory support with intravenous(IV)access,fluids,and cardiac and pulse oximetry
18、脉搏血氧饱和度monitoring can facilitate safe transport.Decontamination清除毒污is of the utmost importance in minimizing continued exposure.Decontamination involves removing all of the patients clothing and washing him or her with water and soap.,Hospital and emergency department careAssess the patients airway,
19、breathing,and circulation(ABCs).Secure the airway and perform cardiovascular resuscitation if needed.Endotracheal intubation may be necessary for airway protection and ventilatory support.Gastric decontamination with activated charcoal should be performed in cases of ingestion.,Severe exposures requ
20、ire expeditious迅速的anticholinergic therapy.Atropine antagonizes the central and muscarinic effects by blocking these receptors.Atropine does not bind to nicotinic receptors;hence,muscular weakness,including respiratory muscle weakness,is not affected.,Hospital and emergency department care,Hospital a
21、nd emergency department careAnticholinergic agents should be used in doses large enough to reverse the cholinergic signs.It is recommend to give atropine until signs of atropinization appears.These signs include warm,dry,flushed skin;dilated pupils;and an increased heart rate.Atropine should be used
22、 for at least 24 hours to reverse the cholinergic signs while the organophosphate is metabolized.Atropine is indicated when evidence of bronchorrhea and other secretions is present.,Pralidoxime(PAM)is a cholinesterase reactivator and the antidote for organophosphate poisoning.This drug primarily aff
23、ects the nicotinic receptors and does not reverse the CNS effects.,Hospital and emergency department care,Administer PAM as soon as possible because its effectiveness decreases with prolonged exposure due to the aging of the organophosphate-cholinesterase bond.Administer PAM as an IV infusion after
24、a loading dose until signs of weakness improve.,Hospital and emergency department care,Pralidoxime(PAM)解磷定-Nucleophilic agent that reactivates phosphorylated AChE by binding to organophosphate molecule.-Used to treat muscle weakness and respiratory muscle weakness in known or suspected exposure.-Mus
25、t be administered within 24 h,before organophosphate-cholinesterase bond ages.-Earlier administered,better result.Effects should occur within 20-30 min.,Pralidoxime iodide 碘解磷定Pralidoxime chloride 氯解磷定The later is more stable,water-soluble,and can be administered both intramuscularly and intravenously.So it is extensively used in clinical practice.,Fig.8-1 The interactions of AChE with acetylcholine(A),reversible anticholinesterase drugs(B)and irreversible anticholinesterase agents(C).,思考题,试比较新斯的明、吡斯的明、毒扁豆碱、依酚氯铵、安贝氯铵、地美溴铵的药理学与临床应用特点？有机磷酸酯中毒的症状及解救药物有哪些?分别可解除哪些症状?,
