Autonomic drugs （ II ）

1. Autonomic drugs （II）

2. 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

3. cholinoceptor agonists • nonselective M, N receptor agonists • M receptor agonists • N receptor agonists • cholinesterase inhibitors • reversible cholinesterase inhibitors • irreversible cholinesterase inhibitors • cholinesterase reactivators

4. Subtypes and characteristics of cholinoceptors Type location structure mechanism M1(M1a) nerves STS, G protein IP3, DAG M2(M2b) heart nerve STS, G protein cAMP, K+ channel smooth muscle M3(M2b) glands STS, G proteinIP3, DAG smooth muscle endothelium NN(N1) postganglionic pentamer Na+ channel cell body NM(N2) skeletal muscle pentamer Na+ channel neuromuscular junction

5. STS: seven transmembrane segments

6. STS: seven trans-membrane segments M1 receptor

7. 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.

8. 1, nonselective M, N AchR agonists acetylcholine 乙酰胆碱 M, NN and NM like effects need to be understood action complex, wide, many untoward reactions, short-lived only as research tool

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

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

11. 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。

12. Pilocarpine （毛果芸香碱）

13. pilocarpine: actions: through M3 receptor (1) eye: （作用群） miosis 缩瞳 reduction of intraocular pressure cyclospasm 调节痉挛

18. 房水的产生及回流

21. 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

22. 2, Iritis（虹膜炎）： prevention of adherence of iris and lens when alternatively used with atropine

23. 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

24. 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）…

26. 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

27. 3, paroxysmal supraventricular tarchycardia 阵发性室上性心动过速

30. 4，muscle relaxant intoxication 肌松药中毒 5, Alzheimer’s disease (mild-modest)

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

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

33.  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”

34. 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

35. 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

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