Chapter 7 Analgesics

1. Chapter 7 Analgesics

2. Analgesics • Agents that decrease pain are referred to as analgesics or as analgetics（止痛药）.

3. Drugs used to relieve pain include: • the nonsteroidal anti-inflammatory agents • anesthetics (general or local) • central nervous system (CNS) depressants • opioid agents

4. Opioid agents • Opioid analgesics historically have been called narcotic (麻醉性) analgesics. • Narcotic analgesic literally means that the agents cause sleep or loss of consciousness in the conjunction with their analgesic effect. The term narcotic has become associated with the addictiveproperties of opioids and other CNS depressants. • Because the great therapeutic value of the opioids is their ability to cause analgesic without causing sleep (narcosis昏迷状态)，the term narcotic analgesic is not used further in this chapter.

5. Opium alkaloids • The use of the juice (opium in Greek) or gum from the unripe seed pods of the poppy (罂粟) is among the oldest recorded medications. • The pharmacist Surturner first isolated an alkaloid from opium in 1803. He named the alkaloid morphine, after the Greek god of dreams. • Codeine, thebaine(蒂巴因), and papaverine (罂粟碱) are other medically important alkaloids that were later isolated from opium gum.

6. Morphine and its analogous(类似物) • Morphine was among the first compounds to undergo structure modification. • Ethylmorphine (the 3-ethyl ether of morphine ) was introduced as a medicine in 1898. • Diacetylmorphine, which may be considered to be the first synthetic prodrug, was synthesized in 1874 and introduced as a nonaddicting analgesics, antidiarrheal(止泻剂), and antitussive agent (止咳药) in 1898.

7. Opiate • The term opiate was used extensively until the 1980s to describe any natural or synthetic agent that was derived from morphine. • An opiate was any compound that was structurally related to morphine.

8. Opioid The discovery, in the mid-1970s, of peptides in the brain that had pharmacologic actions similar to those of morphine prompted a change in nomenclature (命名). The peptides were not easily related to morphine structurally; yet, their actions were similar to the actions of morphine. The term opioid, meaning opium-like or morphine-like in terms of pharmacologic action, was introduced.

9. Opioids include: • alkaloid opioids，such as morphine; • synthetic analgesics, such as pethidine; • endogenous opioids, such as enkephalins • opioid antagonists, such as naloxone.

10. Principal pharmacologic effects of opioids • (-)-Morphine and its congeners modify the effects of pain impulses on the CNS. Awareness of the pain may persist or diminish but the ability to interpret, integrate, and react to pain is decreased with attendant sedation, euphoria(欣快), and reduced anxiety and suffering. • The only other useful effect of opioids on the CNS is cough suppression.

11. Side effect of Opioids • Constipation（便秘） • Respiratory depression, which is the cause of death from opioid overdose • Dependence • Tolerance, which refers to the need to increase the dose of opioid over a period of time in order to achieve the same level of analgesia or euphoria.

12. 吗啡连续反复使用，易产生耐受性和成瘾性，须严格按照国家颁布的《麻醉药品管理办法》管理。吗啡连续反复使用，易产生耐受性和成瘾性，须严格按照国家颁布的《麻醉药品管理办法》管理。

13. Opioid receptors • Narcotic analgesics(agonists and antagonists) are stereospecific binding, chemically specific binding, and competitive binding with opioid receptors. • Opioid receptors are classified: μ：μ1、μ2 κ：κ1、κ2、κ3 δ：δ1、δ2

14. Section 1 Morphine and related opioid agonists • (1)Opioid alkaloid • (2)Morphine’s derivatives • (3)Synthetic analgesics

15. (1) opioid alkaloid • (-)- Morphine Hydrochloride • (-)-Codeine Phosphate

16. (-)-Morphine Hydrochloride • (5α,6α)-7,8-didehydro-4,5-epoxy-17-methyl-morphinan-3,6-diol hydrochloride trihydrate

17. The Structure of (-)-Morphine • Morphine is composed of five fused rings, and the molecule has five chiral centers with absolute stereo- chemistry (5R, 6S, 9R, 13S and 14R). • The naturally occurring isomer of morphine is levo [(l) or (-)] rotatory. (+)-morphine has been synthesized, and it is devoid of analgesic and other opioid activities.

18. The configuration of (-)-morphine • B/C and C/E are cis, and C/D is trans. • Morphine is shaped like a three-dimensional "T" with rings A, B, and E forming a near perfect vertical plane and rings C and D forming a more distorted horizontal plane. The D ring is in the chair conformation and the C ring is a boat with atoms 6 and 14 fore and aft. The "T" is skewed.

19. 吗啡的理化性质 • 吗啡是从阿片中提取得到的。 • 吗啡显弱酸性, 可与强碱成盐。 • 吗啡显碱性，可与酸成盐，临床上常用其盐酸盐或硫酸盐。 • 吗啡具有左旋性。 • 吗啡及其盐易被氧化。

20. Oxidation of (-)-morphine • Its stability is related with pH of solution. it is the most stable in the solution (pH=4). • 在中性或碱性条件下极易氧化，在日光、重金属离子存在下可催化此反应，所以盐酸吗啡注射液放置过久颜色变深，在制备制剂及贮存时应加以注意。

21. Identification of apomorphine in morphine 催吐剂 醚层显宝石红 水层显绿色

22. Identification of little morphine in codeine (1)

23. Identification of morphine in codeine (2) • A. 水溶液与三氯化铁试液反应显蓝色(酚羟基)。 • B.水溶液加入稀铁氰化钾试液后再与三氯化铁试液反应，生成蓝色(酚羟基) 。 C17H19O3N+K3Fe(CN)6 → C34H36O6N2 C34H36O6N2+ K4Fe(CN)6 + FeCl3 → blue

24. Metabolism of morphine first pass effect morphine activity Nomorphine

25. The use and action in the body of morphine • It is available in intramuscular, subcutaneous(皮下的), oral, rectal, epidural(硬膜外的) and intrathecal(鞘内的) dosage forms. • Morphine is three to six times more potent when given intramuscularly than it is given orally. The difference in activity is due to extensive first-pass 3-O-glucuronidation of morphine -- an inactive metabolite. its bioavailability is about 25%.

26. Pharmacologic activity of (-)-morphine • (-)-Morphine, which is a μopioid agonist, is the natural product prototype for this class of analgesics. • Morphine hydrochloride or sulfate is the most often used analgesic for severe, acute, and chronic pain. • Overdoses of morphine as well as all μ agonists in this section can be effectively reversed with naloxone (盐酸纳洛酮) .

27. Side effects of (-)-morphine • Sedation(镇静), dizzy(眩晕), vomit(呕吐), drowsiness(嗜睡), constipation（便秘） • Tolerance, dependence • Respiratory depression, which is the cause of death from opioid overdose.

28. (-)-Codeine Phosphate • (5α,6α)-7,8-didehydro-4,5-epoxy-3-methoxy-17-methylmorphinan-6-ol phosphate sesquihydrate

29. Synthesis of Codeine

30. 可待因的理化性质 • 可待因具有左旋性。 • 较吗啡稳定，但遇光仍易变质。 • 水溶液加氨试液后无沉淀。 • 与三氯化铁试液反应不显色。

31. Stability of Codeine protection from light It is more stable than morphine.

32. Identification of little morphine in codeine

33. Metabolism of codeine 10% morphine Codeine nomorphine

34. Pharmacologic activity • Codeine is a weak μ agonist, which has about 1/10 analgesic potency of morphine. • Codeine phosphate is used extensively to treat moderate-to-mild pain and it is a more effective antitussive (止咳剂) agent than morphine. • Codeine causes less sedation, nausea(恶心), vomiting, constipation, tolerance, dependence and has less effect on the gastrointestinal and urinary tracts than morphine.

35. (2) Structural modification of morphine

36. SARs for morphine derivatives

37. Importance to structural modification of morphine • In the structure of morphine (or any other opioid) are likely to cause a change in the affinity and intrinsic activity of the new compound for each of the opioid receptor types, i.e., a selective μ agonist may shift to become a selective К agonist. • In addition, the new compound has different physical properties than its parent. The different physical properties (e.g. solubility, partition coefficient, pKa) result in different pharmacokinetic characteristics for the new drug and can affect its in vivo activity profile.

38. Heroin • The 3,6-diacetyl derivative of morphine is known commonly as heroin. • Heroin was synthesize from morphine in 1874 and was introduced to the market in 1898 by the friedrich Bayer Co. in Germany.

39. The reason that heroin has higher activities • Heroin itself has relatively low affinity for μ opioid receptors; however, its high lipophilicity compared with morphine results in enhanced penetration of the blood-brain barrier. • Once in the body, esterases hydrolyze the 3-acetyl group to produce 6-acetyl-morphine. This latter compound has μ agonist activity in excess of morphine.

40. The reason that heroin is limited • Heroin provides an “euphoric rush” that makes this compound a popular drug of abuse. • Repeated use of heroin results in the development of tolerance, physical dependence that is often destructive to the user and to society. • In addition, the use of unclean or shared hypodermic (皮下) needles for self-administering heroin often results in the transmission of AIDs, hepatitis, and other infections.

41. (3) Synthetic Analgesics • A. Morphinans （吗啡喃类） • B. Benzomorphans（苯吗喃类） • C. Piperidines（哌啶类） • D. Phenylpropylamines（苯丙胺类） • E. Aminotetralins（氨基四氢萘类） • F. Cyclohexane derivatives(环己烷衍生物 )

42. A. Morphinans（吗啡喃类） • Removal of 3,4-epoxide bridge in the morphine structure results in compounds that are referred to as morphinans. • The synthetic produce yields compounds as racemic mixtures, but only the levo (-) isomers possess opioid activity. The dextro isomers have useful antitussive activity.

43. Levophanol(左啡诺) • 17-methylmorphinan-3-ol tartrate dihydrate • Levophanol is about 8 times more potent as an analgesic in humans than morphine. • Levophanol’s increased activity is due to an increase in affinity for μ opioid receptors and its greater lipophilicity, which allows higher peak concentrations to reach the brain.

44. The configuration of levophanol

45. Butophanol（布托啡诺） • Butorphanol is a μ antagonistand К agonist. The mixed agonist / antagonist is an antagonist analgesic and has less dependence liability.

46. B. Benzomorphans （苯吗喃类） • Synthetic compounds that lack both the epoxide ring and the C ring of morphine retain opioid activity. • Compounds having only the A,B, and D rings are named chemically as derivatives of 6,7-benzomorphan or benzomorphans.

47. Pentazocine (喷他佐辛) • Pentazocine has an agonist action on κ opioid receptors--an effect that produces analgesia, and pentazocine is weak antagonist at μ receptors. • Pentazocine is a mixed agonist/antagonist and has less dependence.

48. C. Piperidine （哌啶类） • 4-phenylperidines （4-苯基哌啶类） • 4-anilidopiperidines （4-苯胺基哌啶类）

49. Pethide（哌替啶） • The analgesic activity of pethide was discovered during biologic screening of compounds that were designed as anticholinergics(抗胆碱能类) patterned on the structure of atropine. • Pethide is a typical μ agonist with 1/6~1/8 the potency of morphine.

50. The conformation of pethidine • Analgesic compounds in the 4-Phenylpiperidine class may be viewed as A, D ring analogs of morphine. • It created great interest because the structural simplicity of the drug and the synthesis of fragments of the morphine molecule to provide a nonaddictiveand potent analgesic was futile.