Antipyretic-Analgesic and Antiinflammatory Drugs

1. Antipyretic-Analgesic and Antiinflammatory Drugs

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

5. A. General Pharmacological properties • 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.

6. Comparison of properties of two types of drugs

7. A. General Pharmacological properties • 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.

8. Comparison of properties of two types of drugs

9. A. General Pharmacological properties • 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.

10. Comparison of properties of two types of drugs

11. A. General Pharmacological properties • 5. COX-1 / COX-2 and selectivity of the drugs • 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.

12. （－） （＋） （＋） （－）

16. B. Salicylates Aspirin 阿司匹林 Acetylsalicylic acid 乙酰水杨酸 Salicylic acid 水杨酸 Salicylic sodium 水杨酸钠 Aspirin 阿司匹林

17. B. Salicylates • Aspirin 阿司匹林 • 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.

19. B. Salicylates • 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).

20. B. Salicylates • (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).

21. The mechanism of aspirin: Target enzymes acetylated

22. B. Salicylates • 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

23. B. Salicylates • (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).

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

25. 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)

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

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

28. B. Salicylates 4. Drug interactions

29. C. Para-aminophenol derivatives Acetaminophen 对乙酰氨基酚 Paracetamol扑热息痛

30. C. Para-aminophenol derivatives • Acetaminophen （对乙酰氨基酚）： • 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.

31. Differences between NSAIDs and Acetaminophen

32. Toxic metabolites of acetaminophen

33. D. Other anti-inflammatory drugs Salicylates: aspirin Para-aminophenol derivatives: acetaminophen Indole and indene acetic acid derivatives: indomethacin, sulindac Propionic acid derivatives: ibuprofen, naproxen, fenopofen, ketoprofen COX-2 selective inhibitors: meloxicam, celecoxide, rofenxid Others: phenylbutazone, diclofenac

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

36. D. Other anti-inflammatory drugs • 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-inflammatoryeffects; 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

37. 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