膽堿受體激動藥cholinoceptor agonists

1、第六章 膽堿受體激動藥cholinoceptor agonists擬膽堿藥(cholinergic drugs)一類作用與膽堿能神經遞質ACh相似的藥物 直接作用于膽堿受體的擬膽堿藥 間接作用的抗膽堿酯酶藥M M、N N膽堿受體激動藥 ： 乙酰膽堿M M膽堿受體激動藥：毛果蕓香堿N N膽堿受體激動藥：煙堿膽堿受體激動藥cholinoceptor agonists第一節(jié) M、N膽堿受體激動藥A A：血管內皮完整：血管內皮完整B B：血管內皮受損：血管內皮受損圖圖6 61 1 乙酰膽堿擴張去甲腎上腺素引起的血管收縮作用依乙酰膽堿擴張去甲腎上腺素引起的血管收縮作用依賴于血管內皮的完整性（賴于血管內皮

2、的完整性（A A），如內皮細胞受損，則），如內皮細胞受損，則AChACh的擴的擴張血管作用消失（張血管作用消失（B B）n特點n不易被AChE水解，作用時間長n選擇性差，對M、N膽堿受體均有激動作用n對膀胱和腸道作用明顯n用途n主要用于局部滴眼治療青光眼n術后腹氣脹和尿潴留（皮下注射，禁用靜注） *副作用較多，且atropine對它的解毒效果差毛果蕓香堿毛果蕓香堿 (匹魯卡品，匹魯卡品，pilocarpine)第二節(jié) M膽堿受體激動藥Parasympathetic-constricts pupil Parasympathetic-constricts pupil -thus atropine

3、causes relaxation of circular muscleM circular muscleRadial muscle房水回流通路房水回流通路前房角間隙n 青光眼開角型 閉角型n虹膜炎(與擴瞳藥交替使用）n口腔干燥臨床用途A woman develops a painful red eye. The ophthalmologist diagnosis acute closed-angle glaucoma and plans surgery to correct this. To reduce the intraocular pressure pilocarpine eye dr

4、ops are prescribed.Clinical sketch眼科專家青光眼Comment: pilocarpine is a direct-acting cholinergic agonist. It causes pupillary constriction, thereby opening up the angle between iris and the cornea. This enhances drainage of the aqueous humour.Clinical sketch瞳孔的虹膜角膜毒蕈堿(muscarine) 經典M膽堿受體激動藥 絲蓋傘菌屬和杯傘菌屬含毒蕈

5、堿成分 毒蕈堿中毒癥狀表現(xiàn)：流涎、流淚、惡心、嘔吐、頭痛、視覺障礙、腹部絞痛、腹瀉、支氣管痙攣、心動過緩、血壓下降和休克等治療：每隔30 min，肌內注射1-2 mg阿托品第 七 章 抗 膽 堿 酯 酶 藥和膽堿酯酶復活藥 Anticholinesterase Drugs & 乙酰膽堿酯酶（AChE，真性膽堿酯酶）丁酰膽堿酯酶（Bu-ChE，假性膽堿酯酶）膽堿酯酶第一節(jié) 膽堿酯酶(cholinesterase,ChE)膽堿膽堿乙酸乙酸AchAchEAchE乙?；阴；疉chEagentAch與與AchE復合物復合物AchEAchAchAch第二節(jié) 抗膽堿酯酶藥n易逆性抗膽堿酯酶藥Rev

6、ersible Anticholinesterase Agentsn難逆性抗膽堿酯酶藥Irreversible Anticholinesterase Agents抗膽堿酯酶藥分類易逆性抗AchE藥的一般特性Reversible Anticholinesterase Agents藥理作用 M樣和N樣作用作用特點：1.脂溶性低,口服吸收少,難透過血腦屏障（無中樞作用）及角膜2.對骨骼肌興奮作用最強3.對胃腸、膀胱興奮作用次之對骨骼肌作用最強原因：抑制AchE直接激動骨骼肌運動終板上N2受體促進運動神經末梢釋放Ach1.重癥肌無力2.術后腸脹氣, 尿潴留3.陣發(fā)性室上性心動過速4.競爭性神經肌肉阻滯

7、藥過量時的解毒不良反應n過量可產生M及N樣作用n膽堿能危象(cholinergic crisis) 禁忌癥n機械性腸梗阻, 尿路阻塞, 支氣管哮喘重癥肌無力的病人，短時間內反復給藥，造成劑量過大所致。表現(xiàn)為惡心、嘔吐、腹痛、心動過緩、肌震顫和無力。n作用特點1.脂溶性高,口服易吸收,易透過血腦屏障（有中樞作用）及角膜2.對眼部作用比毛果蕓香堿強3.使用不慎可產生中樞及N樣作用n臨床應用:青光眼A farmer is brought as an emergency after an accident with crop-spraying equipment, during which he wa

8、s copiously sprayed with insecticide. He is salivating profusely and has difficulty breathing; his pulse rate is 40 beats/min.1. What is the mechanism of the poisoning?2. What should be done?過量分泌唾液Irreversible Anticholinesterase Agents有機磷酸酯類organphosphorus compounds中毒途徑：皮膚、呼吸道及消化道吸收 中毒機制： 有機磷酸酯類膽堿酯酶

9、 磷?；憠A酯酶 （難水解，持久抑制酶） 在數(shù)分鐘或數(shù)小時內，酶發(fā)生“老化(aging)”，須等待新生膽堿酯酶急性中毒表現(xiàn)n輕M樣癥狀n中 M樣+ N樣癥狀n重 M樣+ N樣+中樞癥狀輕度中毒虹膜括約肌及睫狀肌收縮腺體分泌增加 胃腸道、呼吸道平滑肌收縮膀胱括約肌松弛 小便失禁心臟抑制 心動過緩血管擴張 血壓降低M樣作用：同上 N樣作用: 激動骨骼肌N2受體: 肌肉震顫、抽搐、嚴重者肌無力甚至麻痹 激動神經節(jié)N1受體: 心動過速、血壓升高除M樣及N樣表現(xiàn)外，還表現(xiàn)中樞樣癥狀。先興奮,后抑制 。引起不安、頭痛、頭暈、昏迷、窒息、血壓降低。 致死主要原因：呼吸道阻塞、肺水腫和呼吸肌麻痹等Organo

10、phosphorus insecticides are potent and long-acting anticholinesterases: overactivity at parasympathetic receptor is responsible for the clinical features, and his breathlessness may be caused by bronchospasm. What should be done?1清除毒物，避免繼續(xù)吸收 應用溫水或肥皂水清洗染毒皮膚對經口中毒者，可用2碳酸氫鈉或1食鹽水反復洗胃，然后再用硫酸鎂導瀉敵百蟲口服中毒時，不能

11、用堿性溶液洗胃對硫磷中毒者忌用高錳酸鉀洗胃及早用M受體阻斷藥和膽堿酯酶復活藥輕癥單用阿托品,反復,阿托品化 中度以上及早加用解磷定,反復用藥 根據(jù)病情調整劑量Contaminated clothes should be removed , and he should be washed in copious water-the compound can cross the skin. Bronchospasm should be treated according to asthma guidelines, and he should be given frequent doses of i.

12、v. atropine for its antimuscarinic effects. Pralidoxime is a specific antidote capable of regenerating active cholinesterase by releasing it from covalent binding to the insecticide.解毒藥慢性中毒n多發(fā)生于長期接觸農藥的人員n血中AChE活性持續(xù)明顯下降n臨床表現(xiàn)：神經衰弱、腹脹、多汗；偶見肌束顫動及瞳孔縮小膽堿酯酶復活藥解毒機制n磷?；憠A酯酶解磷定 磷?；饬锥憠A酯酶n與有機磷形成無毒復合物n阻斷N2受體n但

13、是：過量可與ChE結合,使之失活解毒療效nN樣癥狀中樞癥狀M樣癥狀n劇毒農藥 敵敵畏,敵百蟲 樂果 不良反應1.暈眩, 乏力, 惡心, 心動過速2.過量引起有機磷中毒癥狀加重, 但肌顫消失常用藥物比較1.碘解磷定水溶性差,溶液不穩(wěn)定,需新鮮配制2.氯解磷定無此缺點,作用較強,可imChlinomimetic drugsDirect-acting Indirect-acting(Cholinesterase Inhibitors)MuscarinicNicotinicReversible IrreversiblePilocarpine is a muscarinic agonist applie

14、d topically to cause pupillay constriction (miosis) in the treatment of glaucomaDirect Cholinergic AgonistsThe side effects of these drugs are directly related to their interaction with muscarinic receptors Indirect-acting DrugsCholinesterase Inhibitors These drugs have all the same actions (and sid

15、e effects) as the direct-acting drugs (muscarinic). In addition, because they increase the concentration of acetylcholine, they have effects at the neuromuscular junction (nicotinic).NEOSTIGMINE is used in the treatment of myasthenia gravis.Other uses of the reversible cholinesterase inhibitors are

16、in the treatment of open-angle glaucoma and the reversal of nondepolarizing neuromuscular blockade after surgery.reversible cholinesterase inhibitorsirreversible cholinesterase inhibitorsThere are no therapeutic uses for the irreversible cholinesterase inhibitorsPRALIDOXIME and ATROPINE are uses to treat poisoning with organophosphatesThe organophosphates phosphorylate the cholinesterase enzyme, thus inactivating itAtropine (muscarinic antagonist) can be used in organophosphate poisoning because it will block the effects of the excess acetylcholin