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第十三章 非甾体抗炎药

第十三章 非甾体抗炎药. Nonsteroidal Anti-inflammatory Drugs. 非甾体抗炎药（ NSAIDs ） Nonsteroidal Anti-inflammatory Drugs. NSAIDs 抑制前列腺素 (PGs) 、白三烯 (LTs) 等炎性介质，具有优良的抗炎、镇痛和解热作用，其临床应用极为广泛，是仅次于抗感染药的第二大类药。 目前已有百余种 NSAIDs 上市， NSAIDs 已成为处方药和非处方药中用量最大的药物之一。 据估计，全球每天有 3000 － 4000 万患者应用 NSAIDs ，其中 60 岁以上老人超过 40% 。

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第十三章 非甾体抗炎药

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  1. 第十三章 非甾体抗炎药 Nonsteroidal Anti-inflammatory Drugs

  2. 非甾体抗炎药（NSAIDs ）Nonsteroidal Anti-inflammatory Drugs • NSAIDs抑制前列腺素(PGs)、白三烯(LTs)等炎性介质，具有优良的抗炎、镇痛和解热作用，其临床应用极为广泛，是仅次于抗感染药的第二大类药。 • 目前已有百余种NSAIDs上市，NSAIDs已成为处方药和非处方药中用量最大的药物之一。 • 据估计，全球每天有3000－4000万患者应用NSAIDs，其中60岁以上老人超过40%。 • NSAIDs每年的销售额已超过20亿美元，且每年还在递增。

  3. The development of NSAIDs 1940s 可的松、强的松 steroidal anti- inflammatory drugs, SAIDs 1950s nonsteroidal antiinflammatory drugs, NSAIDs 1950s Phenylbutazone 保泰松 1970s COX NSAIDs 1960s Indometacin 吲哚美辛 1970s ibuprofen 布洛芬 1980s 舒林酸、阿西美辛 奈丁美酮、吡罗昔康 1990s COX-2 选择性 COX-2抑制剂

  4. NSAIDs的不良反应 • 据美国FDA的资料，在药物引发的不良反应中，NSAIDs引起的不良反应占1/3。NSAIDs常见的不良反应有胃肠道反应、肝肾损害、血液系统不良反应和变态反应等，其中0.2%～0.4%致死。 • 流行病学调查结果显示，使用NSAIDs的人群，25%出现胃肠道(GI)副作用，15%~20%长期服用者可出现严重GI并发症(包括溃疡、出血和穿孔)。美国每年因NSAIDs诱发GI损伤而死亡的人数高达16500，每年用于治疗NSAIDs的GI副作用的费用就高达40亿美元。我国虽无这方面的统计数字报道，但情况大体上类似。

  5. NSAIDs • Antipyretic Analgesics(解热镇痛药) • Nonsteroidal Anti-inflammatory Drugs， (NSAIDs,非甾体抗炎药) • Disease Modifying Anti-rheumatic Drugs, (DMARDs, 改善病情抗风湿药) • Drugs Used to Treat Gout （用于治疗痛风的药）

  6. Section 1 The Mechanism of Action of NSAIDs • Inflammation is a normal, essential, protective response to any noxious stimulus that may threaten the host . • The symptoms of inflammation is pain, and fever.

  7. 1. Pathology of inflammation（炎症的病理） • 抗原进入机体 补体的活化 抗原－补体－抗体免疫复合物的形成 化学炎症介质的形成并释放 关节细胞的活化

  8. 炎症的顺序 • 初期损伤引起释放炎症介质（如组胺、5-羟色胺、溶酶体酶、缓激肽、白三烯和前列腺素等）； • 扩张血管； • 增加血管通透性和渗出液； • 白细胞渗出、白细胞趋化性和吞噬作用； • 结缔组织细胞的增生。

  9. The mediators of inflammation（炎症介质） • A large number of substances - the so-called mediators of inflammation - are formed or release either concurrently or in successive time sequences at the site of injury from various cell sources in the response to an etiologic factors.

  10. Prostaglandins (前列腺素,PGs) • One of the mediators of inflammation is prostaglandins（PGs）. • PGs are also a sort of important biological substances. • Considerable evidence has supported a role for PGs as primary contributors to conditions of inflammation, pain, and fever and NSAIDs act by inhabiting the biosynthesis of PGs through COX.

  11. 2. The biosynthesis and action of PGs and related compounds PGs (前列腺素) Arachidonic acid (AA, 花生四烯酸) metabolism Thromboxane (TXs, 血栓素) Leukotriene (LTs,白三烯) biological activity

  12. 1) The structure of PGs • PGs是一族含五元环和两条侧链的20个碳不饱和羟基脂肪酸，基本结构是前列腺烷酸（Prostanoic acid)。

  13. 按环戊烷上的取代基不同PGs分为

  14. The nomenclature of PGs • 侧链上双键数目用下标的阿拉伯数字附在后面； • 根据9位取代基的立体化学，在阿拉伯数字后面加上а或β。

  15. PGG2

  16. PGH2

  17. PGE2

  18. 6－keto－PGF1

  19. PGF2α • The αrefers to the stereochemistry of the OH at C9, below and therefore on the same side (cis) of cyclopentane ring as the OH on C11.

  20. PGD2

  21. PGI2

  22. The biosynthesis and action of PGs SAIDs NSAIDs

  23. PGs的致炎作用 • PGE2和PGI2：扩张血管，提高血管通透性，促进血浆渗出而导致水肿，并且能增强其它炎症介质的致炎作用，促进炎症发展；刺激白细胞的趋化性，抑制血小板聚集。 • 外周PGE2虽有一定的致痛作用，但它主要是能显著地提高痛觉神经末梢对缓激肽等致痛物质的敏感性，产生持续性的钝痛。 • 致热原引起体温的升高与下丘脑PGE2的合成与释放。中枢PGE2是最强的致热物质之一，引起体温升高。

  24. 2)The biosynthesis and action of TXs （血栓素的生物合成和作用) • The basic structure of thrombanes (TXS) is thrombanoic acid (血栓素烷酸)

  25. Biosynthesis of prostacyclin and TXs 血小板聚集

  26. 3) The biosynthesis and action of LTs • AA除COX途径合成PGs、TXs外，还可通过脂氧酶合成白三烯（leukotrienes, LTs)。

  27. Biosynthesis of LTs

  28. LTs的致炎作用 • LTs及其降解产物在类风湿关节炎、痛风渗出液内具有较高的浓度。它促进白细胞溶酶体酶的释放，导致炎症反应的扩大与加剧。 • LTB4是目前所知的最强的白细胞趋化剂。引起炎症部位白细胞的聚集，加重炎症症状。 • LTC4和LTD4是过敏性慢反应物质的主要成分，能增加血管通透性，促进血浆渗出，对许多过敏性炎症的发生起重要作用。

  29. 3) Mechanism of Action of NSAIDs • NSAIDs抑制AA代谢，使PGs的生物合成受阻，起到抗炎、解热、镇痛的作用。 • 抑制COX途径，也能抑制TXA的生物合成。特别是阿司匹林可选择性抑制血小板合成TXA2。因而可用于防治脑动脉和冠状动脉的栓塞。 • 胃肠道分泌的PGs，对胃黏膜有保护作用，大多数NSAIDs在抑制炎症部位的PGs合成的同时，也抑制了胃壁细胞的PGs的分泌。NSAIDs大都有胃肠道副作用。 • COX代谢途径受阻，使更多的AA进入5-LOX的代谢途径，使LTs的生成增加，导致炎症进一步发展。

  30. Section 2 Antipyretic Analgesics解热镇痛药 • Anilines (苯胺类) • Salicylic acid derivatives (水杨酸类) • Pyrazolone derivatives (吡唑酮类)

  31. 1. Anilines toxicity anemia(贫血) carcinogenesis toxicity

  32. Metabolism of phenacetin Hepatotoxic 肝毒的

  33. Paracetamol(扑热息痛) • N-(4-Hydroxyphenyl)-acetamide • N-（4-羟基苯基）-乙酰胺，又称醋氨酚(acetaminophen)。

  34. Metabolism of paracetamol toxicity N-acetylcystein

  35. Pharmcologic activity • Paracetamol, which inhabits COX, has analgesic and antipyretic activities, but it doesn’t have inflammatory activity. Paracetamol clinically used as fever, headache, neuralgia(神经痛) and dysmenorrhea (痛经).

  36. 2. Salicylic acid Derivatives • In 1838, Piria made Salicylic acid from salicin. • Buss first described the antipyretic and antirheumatic effects of sodium salicylate in 1875. • It was not until 1898 that Hoffman prepared acetylsalicylic acid (Aspirin).

  37. Salicylic acid Derivatives • The major chemical classes of salicylates used in medicine are the esters, salts, and amides of salicyclic acid obtained by substitution at the carboxyl group, and the salicylate esters of organic acids that are obtained by substitution at the phenolic OH group and that have an intact carboxyl group.

  38. The development of salicylic acid derivatives

  39. Aspirin (阿司匹林) • 2-(Acetyloxy)benzoic acid, Acetylsalicylic Acid • 2-（乙酰氧基）苯甲酸

  40. Synthesis of asprin

  41. Side product allergic response (过敏反应) >0.003%

  42. Chemical property • Aspirin is hydrolyzed to salicylic acid and acetate when met with wet or dissolved in based solution.

  43. Stability of asprin 碱、光线、高温、微量金属离子催化

  44. Absorption in the body • Asprin is an acidic drug (pKa=3.5), therefore, absorbed from the stomach, but mainly from the upper part of the small intestine.

  45. Metabolism of asprin majority

  46. Pharmacologic activity of aspirin • Aspirin is an irreversible inhibitor of COX, having analgesic, antipyretic and anti-inflammatory activities. • It is clinically used to treat fever, headache, toothache, neuralgia (神经痛) and dysmenorrhea (痛经). It is the first choice in the treatment of acute rheumatic fever (急性风湿热) and rheumatoid arthritis (类风湿性关节炎).

  47. 阿司匹林预防血栓形成作用 • 低浓度阿司匹林能抑制COX-1活性，减少血小板中TXA2的生成而影响血小板聚集。 • 小剂量（40～80mg）阿司匹林即可抑制血小板聚集，延长出血时间，防止血栓形成，作用持续2～3d，用于预防心肌梗塞、脑血栓及手术后血栓形成等。

  48. 阿司匹林的其它作用 • 最近研究表明，脑内COX－1过度表达与老年性痴呆有关，每日服用阿司匹林100mg对老年性痴呆有阻遏作用。 • 也有报道孕妇血中，TXA2/PGI2比值增高与妊娠高血压综合症和先兆性子痫的发生有关，每天服用40～80mg阿司匹林可明显降低妊娠高血压综合症的发生率和减少先兆子痫的危险。

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