Chapter 7 Analgesics and Anesthetics

1. Chapter 7 Analgesics and Anesthetics

2. Part 1 Analgesics 1) Types of Pain (acute, chronic) Somatic(躯体） Superficial（ Skin ） Deep （Conn. tissues Bones Joints Muscles） Neuropathic（神经） Visceral（内脏） Kidney stones Gastric torsion Angina etc. 剧烈疼痛使病人感觉痛苦引起血压降低，呼吸衰竭，甚至导致休克而危及生命。

3. 2) Normal and pathophysiological transmission of pain 中枢 下行 上行 外周 脊髓

4. 3) Classificationof Analgesics: ①Morphine and Derivatives (Morphine, Codeine) R1=R2=H Morphine(吗啡） R1=CH3, R2=H Codeine(可待因） R1=R2=COCH3 Heroin(海洛因）

5. 4-phenylpiperidines (meperidine ) 4-phenylaminopiperidines (fentanyl) ②Synthetic Analgesics Aminoketones(methadone) Morphinane and Benzomorphane （吗啡烃及苯吗喃类）（pentazocine) Meperidine(哌替啶） Fentanyl(芬太尼） Methadone (美沙酮） Pentazocine（喷他佐辛）

6. 4）Morphine and Derivatives ① Opium 阿片 • Poppy Plant (Papaver somniferum罂粟) • Cultivated in: • Middle East (Afghanistan and Pakistan) • Thailand • South America and Mexico

7. 鸦片战争

9. ② Structure of morphine Structure features: Partial hydrogenated phenanthrene. Natural morphine have five chiral carbon (5R，6S，9R，13S，14R). B/C：cis，C/D：cis，C/E：trans.

10. ③ Actions of Morphine Actions analgesia 镇痛作用 chronic continuous dull pain(隐痛） superior to acute discontinuous sharp pain（刺痛） relief of pain without the loss of consciousness accompanied with sedation and euphoria 欣快 easy to fall asleep respiration depression 抑制呼吸 reducing the sensitivity of respiratory center to CO2 the most common cause of death in acute overdose

11. ④ Mechanism of action L-enkephalin （L-脑啡肽） M-enkephalin （M-脑啡肽）

12. ⑤ Opioid Receptors μ(μ1, μ2):镇痛、成瘾作用强 δ (δ1, δ2):镇痛、成瘾作用弱 κ (κ1 ,κ1):介于前两者之间 σ产生致幻作用 μ1调节痛觉 μ2 介导控制呼吸抑制 研究方向：μ1受体选择性激动剂，κ 受体选择性激动剂

13. ⑥ Structure modification

14. ⑦ A drawing for the interaction of morphine and opioid receptor (1) A basic center able to associate with an anionic site on the receptor surface. (2) A flat aromatic structure, coplanar with the basic center, allowing for van der Waals bonding to a flat surface on the receptor site to reinforce the ionic bond. (3) A suitably positioned projecting hydrocarbon moiety forming a three-dimensional geometric pattern with the basic center and the flat aromatic structure.

16. Naloxone(纳洛酮 ) 阿片受体拮抗剂 ⑧ SAR Hydromorphone (氢吗啡酮） Codeine (中枢镇咳药） Heroin (毒品）

17. 5) Synthetic Analgesics Action The major use of meperidine is for analgesia. It exerts analgesic effect that lies between the dose of morphine and codeine, but it shows little tendency toward hypnosis. It is indicated for the relief of pain in most patients for whom morphine and other alkaloids of opium generally are employed, but it is especially of value where the pain is due to spastic conditions of intestine, uterus, bladder, bronchi, and so on. Its most important use seem to be in lessening the severing of labor pains. ① Piperidines 【meperidine 盐酸哌替啶】 Chemical nane Ethyl-1-methyl-4-phenyl-piperidine carboxylate hydrochloride 1-甲基-4-苯基-4哌啶甲酸乙酯盐酸盐

18. Synthesis

19. ② 4-phenylaminopiperidines 【Fentanyl Citrate 芬太尼】 Chemical nane N-phenyl-N-[1-(2-phenylethyl)-4-piperidinyl]propanamide citrate N-苯基-N-[1-(2-苯乙基)-4-哌啶基]丙酰胺枸橼酸盐 Action The analgesic effects of fentanyl are similar to those of morphine and other m opioids. Fentanyl is approximately 100 times more potent than morphine.

20. Synthetic route

21. ③Aminoketones 【Methadone Hydrochloride 盐酸美沙酮】 Chemical nane 6-(Dimethylamino)-4, 4-diphenyl-3-heptanone hydrochloride 6-(二甲氨基)-4，4二苯基-3-庚酮盐酸盐 Action The primary uses of methadone hydrochloride are relief of chronic pain, treatment of opioid abstinence syndromes, and treatment of heroin users .

22. Synthetic route

23. 本节重点： 1．分类和代表性药物：中枢镇痛药可被分为阿片生物碱类和合成镇痛药两大类，阿片生物碱类代表性药物有吗啡、可待因等。合成镇痛药又可分为哌啶类如哌替啶、芬太尼等。氨基酮类如美沙酮等。 2．吗啡的结构修饰及构效关系：6位羟基被烷基化、酰化、氧化成酮或去掉，活性和成瘾性均增加；3位酚羟基被酰化或醚化，活性和成瘾性降低；7，8位双键被还原，活性和成瘾性增加；17位氮上有较大的烃基取代时，可能从激动剂转化为拮抗剂。 3．中枢镇痛药与阿片受体的相互作用：（1）一般含有一个碱性中心可以与受体表面的阴离子部位结合；（2）一个平面的芳香环结构与碱性中心共平面，以范德华力与受体表面平坦区域结合；（3）一个适当的烃基凸出部分与碱性中心及平面芳香结构形成一个三维几何图形，可以与受体表面凹槽部分互补。 4.代表性药物：哌替啶、芬太尼、美沙酮的结构、命名、合成和用途