Ximei Wu Dept. of Pharmacology, School of Medicine Zhejiang University

1. Introduction to Anti-inflammatory Drugs Ximei Wu Dept. of Pharmacology, School of Medicine Zhejiang University

2. Calssification of anti-inflammatory drugs • non-steroid anti-inflammatory drugs (NSAIDs) • (Antipyretic-Analgesic and Anti-inflammatory Drugs) • eg. aspirin, acetaminophen, indomethacin, COX inhibitor, ibuprofen • (2) Steroid anti-inflammatory drugs • glucocorticoids: eg. dexamethasone

3. General Pharmacological properties of NSAIDs

4. 1. Inhibition of prostaglandin production • inhibitingcyclooxygenase (COX，环氧酶) • decreasing the synthesis of PGs and TXA2 • resulting in antipyretic, analgesic, and anti-inflammatory effects • non-steroidal anti-inflammatory drugs (NSAIDs, 非甾体抗炎药）。

7. 2. Antipyretic effects • Inhibition of PGE2 production in the hypothalamus induced by endogenous pyregens after pathological stimuli  temperature  • notes: symptomatic control only, not be indicated in all patients with fever • The effect on body temperature is different from that of chlorpromazine.

8. Comparison of properties of two types of drugs

9. 3. Analgesic effects • Analgesic effect is resulted from inhibition of PGE2 production. • Effective on the pain of low to moderate intensity related to inflammatory responses • PGE2: a pain stimulant and hyperalgesic agent • The analgesic effect is different from opioid analgesics

10. Comparison of properties of two types of drugs

11. 4. Anti-inflammatory effects • PGs induce inflammatory responses • Inhibition of PG production can relieve inflammatory responses, such as congestion, exudation, pain • The effect is different from that of glucocorticosteroids

12. Comparison of properties of two types of drugs

13. 5. COX-1 / COX-2 and selectivity • COX-1:constructive;involved in physiologic regulatory functions in GI tract, kidney, etc. • inhibition of COX-1 is related to the adverse effects. • COX-2:inducible; involved in pathological responses such as inflammation, and pregnancy • inhibition of COX-2 is related to the therapeutic effects.

14. （－） （＋） （＋） （－）

18. Salicylates Representative: Aspirin 阿司匹林

19. Aspirin 阿司匹林 Acetylsalicylic acid 乙酰水杨酸 Salicylic acid 水杨酸 Aspirin 阿司匹林 Salicylic sodium 水杨酸钠

20. 1. ADME • transformed to salicylic acid form in the body • hepatic metabolism is primarily conjugation • excretion from urine, the excretion of unchanged forms of aspirin is increased in the alkalinized urine • larger doses ( > 1g/d):non-linear elimination, zero order kinetic process, easier to accumulation and intoxication.

22. 2. Pharmacological effects and clinical uses • (1) Antipyretic, analgesic and anti-inflammatory effects • moderate doses (0.3～0.6 g): antipyretic and analgesic effects • larger doses (3～5 g/d): anti-inflammatory and anti-rheumatic effects; only relieves symptoms • to treat acute rheumatic fever(急性风湿热) • to abate pain and symptoms of rheumatic & rheumatoid arthritis (风湿性和类风湿性关节炎)

23. (2) Inhibition of platelet aggregation • small doses (30～100 mg/d): inhibiting TXA2 synthesis, preventing thrombosis • used to treat ischemic heart disease, reduce the mortality of myocardiac infarction, and prevent cerebral thrombosis • larger doses: inhibiting PGI2 synthesis, promoting thrombosis • PGI2: vasodilation and platelet depolymerization (血小板解聚).

24. The mechanism of aspirin: Target enzymes acetylated

25. 3. Adverse effects • (1) GI reactions • stimulating gastric mucosa and CTZ (larger doses) • inhibiting PG synthesis in GI tract • irritant symptoms; gastric bleeding; ulcerous disorders • Contraindications: ulcerous disorders

26. (2) Prolongation of bleeding time • small doses: • inhibiting platelet aggregation • larger doses: • inhibiting synthesis of thrombogen • Contraindications: • one week prior to surgery • severe hepatic damage; • vitamin K deficiency,; • prothrombinopenia (凝血酶原减少症).

27. (3) Allergic reactions • urticaria(荨麻疹), • angioneurotic edema, • aspirin-induced asthma, • occasionally anaphylactic shock. • Contraindications:bronchial asthma

28. Aspirin-induced asthma: Phospholipids of cell menbrane AspirinPhospholipase A2 (PLA2) (-) Arachidonic acid Cyclooxygenase Lipoxygenenase (环氧酶) PGH2 5-HPETE (脂氧酶) ↓Prostaglandins (PGs)↑Leukotrienes (LTs) (前列腺素)(白三烯)

29. (4) Salicylism • dose > 5g/d: CNS symptoms, including mental confusion; hyperventilation. • Rescure: i.v. NaHCO3 promote the excretion • (5) Hepatic damage • Overdose: • hepatic damage • Reye’s syndrome(瑞夷综合征) (kids) • severe hepatic damage (严重的肝损害) and • encephalopathy (脑病)

30. Dose-response relationship of aspirin: therapeutic effects; adverse effects

31. 4. Drug interactions

32. Para-aminophenol derivatives

33. Acetaminophen 对乙酰氨基酚 Paracetamol扑热息痛

34. antipyretic and analgesic effects are mild and lasting, but almost no anti-inflammatory effects, - not aNSAID • higher selectivity to COX in CNS. • mainly used in cold, fever, and headache, etc. • overdose can damage liver and kidney.

35. Differences between NSAIDs and Acetaminophen

36. Toxic metabolites of acetaminophen

37. Other anti-inflammatory drugs

38. Salicylates: aspirin Para-aminophenol derivatives: acetaminophen Indole and indene acetic acid derivatives: indomethacin, sulindac Propionic acid derivatives: ibuprofen, naproxen, fenoprofen, ketoprofen COX-2 selective inhibitors: meloxicam, celecoxide, rofenxid Others: phenylbutazone, diclofenac

39. indomethacin 吲哚美辛 ibuprofen 布 洛 芬 piloxicam 吡罗昔康

40. indomethacin 吲哚美辛 • stronger efficacy, controlling special types of fever; severe adverse effects • ibuprofen 布洛芬（芬必得） • stronger antipyretic, analgesic and anti-inflammatory effects; weaker GI reactions; vision damage • piloxicam 吡罗昔康: • long-acting anti-inflammatory and analgesic agent; long-term use induces hemorrhage and ulcers in GI tract

41. COX-2 selective anti-inflammatory drugs Meloxicam 美洛昔康 stronger effect on COX-2 than COX-1 long-acting (t1/2 20 h) weaker GI reactions

43. The End