Autonomic drugs （ II ）

Chapter 6 Cholinoceptor agonists and drugs affecting cholinesterase activity 胆碱受体激动药和作用于胆碱酯酶药 pay attention to action types and representative drugs, instead of all drugs

 cholinoceptor agonists nonselective M, N receptor agonists M receptor agonists N receptor agonists  cholinesterase inhibitors reversible cholinesterase inhibitors irreversible cholinesterase inhibitors  cholinesterase reactivators

Subtypes and characteristics of cholinoceptors Type location structure mechanism M 1 (M 1a ) nerves STS, G protein IP3, DAG M 2 (M 2b ) heart nerve STS, G protein cAMP, K + channel smooth muscle M 3 (M 2b ) glands STS, G protein IP3, DAG smooth muscle endothelium N N (N 1 ) postganglionic pentamer Na + channel cell body N M (N 2 ) skeletal muscle pentamer Na + channel neuromuscular junction

STS: seven transmembrane segments

STS: seven trans- membrane segments M 1 receptor

Intramolecular interactions proposed to stabilize the ground state of the M1 muscarinic acetylcholine receptor. Interacting groups of amino acids are shown in the same colour. (a) View from the extracellular surface; side-chains participating in the hydrophobic latch structure are shown in space-filling format. (b) Lateral view.

1, nonselective M, N AchR agonists acetylcholine 乙酰胆碱 M, N N and N M like effects need to be understood action complex, wide, many untoward reactions, short-lived only as research tool

Structures of Ach and carbamylcholine Carbamylcholine （氨甲酰胆碱）

carbamylcholine （氨甲酰胆碱，卡巴可） like Ach, but action lasts longer only used in glaucoma （青光眼）

2, M AchR agonists pilocarpine 毛果芸香碱 南美植物 Pilocarpusjaborandin 或 pilocarpusmicrophylus 的叶子提取的植物碱。

Pilocarpine （毛果芸香碱）

pilocarpine: actions: through M 3 receptor (1) eye: （作用群） miosis 缩瞳 reduction of intraocular pressure cyclospasm 调节痉挛

房水的产生及回流

2, glands: secretion of sweat, salivary, lacrimal gland, etc 3, smooth muscle: excitation in GI, respiratory, … Clinical uses: 1, Glaucoma normal pressure: 11~21 mmHg > 24 mmHg

2, Iritis （虹膜炎）： prevention of adherence of iris and lens when alternatively used with atropine

3,3, N AchR agonists nicotine not used clinically because of complex actions and toxicity lobeline 山梗菜碱 : seldom used as respiratory stimulant

Cholinesterase inhibitors acetylcholinesterase: 突触后膜、 RBC 、 肌肉 butyrocholinesterase: 血浆、肝脏、胶质 细胞 1, reversible AchE inhibitors 可逆性胆碱 酯酶抑制剂： neostigmine （新斯的明）, huperzine A （石杉碱甲）, galanthamine （加兰他敏）, donepezil （多奈哌齐）, reverstigmine （瑞伐斯的明） …

一、可逆性胆碱酯酶抑制剂 Neostigmine 新斯的明 Weak Ach like actions with more potent effects on gastrointestinal tract and bladder and even more on skeletal muscle Clinical uses: 1 ， myasthenia gravis 重症肌无力 2 ， postoperative ilius and urinary retention 术后肠梗阻和尿潴留

3, paroxysmal supraventricular tarchycardia 阵发性室上性心动过速

4 ， muscle relaxant intoxication 肌松药中 毒 5, Alzheimer’s disease (mild-modest)

二、 irriversible cholinesterase inhibitors 难逆性胆碱酯酶抑制剂

irreversible AchE inhibitors ： organophosphates nerve gas: VX, tabun, soman, sarin

 Organophosphates and nerve gas  Only of toxicological significance  Toxicological mechanism: covalent combination with the enzyme; “ 老化 ” 酶的抑制造成 Ach “ 堆积 ”

M 样作用：瞳孔缩小、流涎、出汗、腹痛 N 样作用：肌肉颤抖 中枢作用：头晕、谵妄、昏迷 解救原则： 清除毒物：洗皮肤、胃、吐 解除症状：阿托品 胆碱酯酶复活剂：碘解磷定

Cholinesterase reactivators 胆碱酯酶复活剂 pralidoxime iodide 碘解磷定 肟基结构将磷从磷酰化胆碱酯酶中游离 出来

与阿托品合用于中度和重度有机磷中 毒病人 attention: early use; large dose