Chpt 08中 Anticholinesterase drugs and cholinesterase reactivators抗胆碱酯酶药和胆碱酯酶复活药

1、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 acetylcholinesterase (ache) ach choline+acetic acid u process takes place in a

2、bout 150 ms when it binds to its receptor, it is split acetate ac-serine hydrolysed acetyl-group transferred to serine-oh acetylcholine binds esteratic siteanionic site reversible inhibition of ache indirect cholinergic stimulants allow ach to accumulate at receptor site exhibit m and n-cholinergic

3、effects fig.8-1 the interactions of ache with acetylcholine(a) , reversible anticholinesterase drugs (b) and irreversible anticholinesterase agents(c) . 裂解裂解 neostigmine 新斯的明 a.pharmacologic effects 1. inhibition of cholinesterase 2. very strong effect on skeletal muscle - ach accumulation at the mo

4、tor nerve endings -direct activating n2 receptors 3. strong stimulating effect on gi tract and gallbladder smooth muscle b. clinical uses 1. symptomatic treatment of myasthenia gravis 2.postoperative paralytic ileus , abdominal distension and uroschesis (retention of urine) -stimulates gi tract smoo

5、th muscle and bladder detrusor (contraction) 3. paroxysmal supraventricular tachycardia -decrease heart rate 4. overdose of nondepolarizing muscle relaxants -tubocurarine intoxication over dose of neostigmine accumulation of excess of ach sustained depolarization disturbance of neuromuscular transmi

6、ssion 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.

7、contraindications 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

8、豆碱 uses 1. glaucoma quicker effect than pilocarpine. stronger irritating action. 2. atropine intoxication edrophonium chloride 依酚氯铵 1. short half-life, short duration of action, 5-15min 2. commonly used for the diagnosis of myasthenia gravis 先快速静注先快速静注2mg，如在，如在3045秒后未见秒后未见 任何药物效应，可再静注任何药物效应，可再静注8mg药

9、物，给药药物，给药 后如受试者出现短暂肌肉收缩改善，同时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，则提示诊断阳未见有舌肌纤维收缩症状，则提示诊断阳 性性. ambenonium chloride 安贝氯铵 inhibits cholinesterase and direct stimulates nmreceptor stronger and longer than neostigmine n use orally myasthenia gravis demecarium bromide 地美溴铵 longer duration of action glaucoma wit

10、hout lens abnormality drug list prototype: neostigmine major variants: pyridostigmine, physostigmine, edrophonium chloride, ambenonium chloride , demecarium bromide part 2. organophosphate poisoning and ache reactivators 乙硫磷乙硫磷 对硫磷对硫磷 马拉硫磷马拉硫磷 fig.8-1 the interactions of ache with acetylcholine(a) ,

11、 reversible anticholinesterase drugs (b) and irreversible anticholinesterase agents(c) . background: organophosphates and carbamates(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 clinic

12、al syndrome that can be treated effectively if recognized early. organophosphates were first discovered more than 150 years ago; however, 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 p

13、athophysiology: organophosphates form an initially reversible bond with the enzyme cholinesterase. the organophosphate cholinesterase bond 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. p

14、athophysiology organophosphates are generally highly lipid soluble and well absorbed from the skin, mucous membranes, conjunctiva, gi system, and respiratory system. pathophysiology physical findings阳性体征阳性体征 : vary according to the route of exposure, the age of patient, and the specific chemical. mu

15、scarinic 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 salivation (dumbels). wheezing喘息and/or bronchoconstriction, pulmonary edema, increased pulmonary and oropharyngeal secretions, sweating, bradycar

16、dia, abdominal cramping绞痛 and intestinal hypermotility. nicotinic findings n样症状 may include : muscle fasciculations (twitching), fatigue, paralysis, respiratory muscle weakness, diminished respiratory effort呼吸使力, tachycardia, hypertension. cns findings 中枢症状 may include : anxiety, restlessness躁动不安, c

17、onfusion 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 care ensure airway support and ventilation and perform endotracheal intubation, if necessary, to support the p

18、atient before arrival. perform endotracheal intubation in patients with respiratory failure. prehospital care circulatory support with intravenous (iv) access, fluids, and cardiac and pulse oximetry脉搏血氧饱和度monitoring can facilitate safe transport. decontamination清除毒污is of the utmost importance in min

19、imizing continued exposure. decontamination involves removing all of the patients clothing and washing him or her with water and soap. hospital and emergency department care assess the patients airway, breathing, and circulation (abcs). secure the airway and perform cardiovascular resuscitation if n

20、eeded. 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 require expeditious迅 速的anticholinergic therapy. atropine antagonizes the central and muscarinic e

21、ffects 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 and emergency department care anticholinergic agents should be used in doses large enou

22、gh 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 for at least 24 hours to reverse the cholinergic signs while the organophosph

23、ate 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 affects the nicotinic receptors and does not reverse the cns effects. hospita

24、l 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 a loading dose until signs of weakness improve. hospital and emergency department care pralidoxim