Antipyretic, analgesic and anti-inflammatory drugs

1. Antipyretic, analgesic and anti-inflammatorydrugs Liming Zhou (周黎明）Department of pharmacology Huxi medical center Sichuan university

2. Contents • Overview • History • Common pharmacological effects • Aspirin 阿斯匹林 • Selective COS-2 inhibitor • Other Drugs

3. Overview • This kind of drug is a group of chemically dissimilar agents that have antipyretic, analgesic and anti-inflammatory effects. • The structure of this kind of drug differs from that of steroidal anti-inflammatory drugs. • Nonsteroidal anti-inflammatory drugs NSAIDs

4. History • In ancient Egypt & Greece, dried leaves of myrtle, the bark of willow & poplar tree • In England, active component from willow bark was identified as salicin (水杨苷）,which is metabolized to salicylate（水杨酸盐）in 1763. • In Germany, salicylic acid（水杨酸）was synthesized in 1860. • In 1875, acetylsalicylic acid （乙酰水杨酸）was synthesized.

5. History • In 1899， “Aspirin“ （acetylsalicylic acid）was named; the "a" --- acetyl grouping and the "spirin" --- botanical genus spiraea, from which salicylates could be extracted. • Now, more than 30 million people consume NSAIDs daily and of these 40% of the patients are more than 60 years of age. • The consumption of NSAIDs is No. 1 among all drugs.

6. History • In 1969 the first association between prostaglandin production and the actions of aspirin- like drugs • In 1992 new enzyme was cloned & was called cyclooxygenase 2 (COX- 2) or PGH 2 synthase 2

7. Common pharmacological effects These drugs show the same pharmacological effects • -- antipyretic effect （解热） • -- analgesic effect （镇痛） • -- anti-inflammatory effect （抗炎）

8. 1. Antipyretic Effects • "normal" temperature: slightly affected • "elevated" temperature: reduced • The higher temperature, the more potent • Mechanisms of Antipyretic Action Blocks pyrogen-induced prostaglandin production in thermoregulatory center (CNS)

9. Prostaglandins pGE2 Pyrogen • NSAIDs thermoregulatory center • Antipyretic Mechanism • Block prostaglandins production • Sites of action:Central Nervous System set point↑ heat production↑ Heat dissipation ↓ Fever

10. 2. Analgesic Effects • Effective to mild to moderate pain 0.5g of aspirin is a weak or mild analgesic that is effective in short, intermittent types of pain as encountered in neuralgia, myalgia (肌肉痛), toothache.

11. Analgesic Effects • Pain may arise from: Musculature, dental work , vascular , postpartum conditions, arthritis , bursitis • Sites of action: peripherally -- sites of inflammation subcortical sites

12. NSAIDs Prostaglandins pGE2 pGF2 factors + Bradrkinin histamine Nerve ending of pain • block prostaglandins production • Sites of action: peripheral tissue Pain

13. 3. Anti-inflammatory Effects • NSAIDs only inhibit the symptoms of inflammation • But they neither arrest the progress of the disease nor do they induce remission

14. Anti-inflammatory Effects • Reduced synthesis: --eicosanoid mediators • Interference: --kallikrein system mediators --inhibits granulocyte adherence --stabilizes lysosomes --inhibits leukocyte migration

15. How can NSAIDs inhibit the prostaglandin production? The Mechanism of NSAIDs

16. Mechanism of action The principal pharmacological effect of NSAIDs is due to their ability to inhibit prostaglandin synthesis by blocking the cyclooxygenase （COX） activity of both COX-1 and COX-2. NSAIDs----- acetylation of COX (reversible or irreversible)

17. NSAIDs Prostaglandins pGE2 pGF2 Inflammatory factors + Bradrkinin Histamine 5-HT Symptoms of inflammation • block prostaglandins production • Sites of action: peripheral tissue Red, swelling, Heating, Pain

20. PGE2 vasodilatation, pain sensitization, gastric cytoprotection [mucous/HCO3 secretion], fever • PGF2 bronchoconstriction, uterine contraction • PGI2 inhibition of platelet aggregation, gastric cytoprotection • TXA2 platelet aggregation

21. Salicylates 水杨酸类 • Acetylsalicyclic acid乙酰水杨酸 Aspirin 阿斯匹林 • Sadium Salicylate 水杨酸钠

22. Pharmacokinetics • Rapidly absorbed: stomach and upper small intestine • Distribution：through the body rapidly hydrolyzed --------- acetic acid + salicylate, catalyzed by tissue/blood esterases

23. Elimination----- Pharmacokinetics • metabolite in liver dose ＜1g/day：one-order elimination T1/2: 3--5 hrs dose ＞1g/day：zero-order elimination ＞4g/day T1/2: • Excretion: kidney, influenced by pH of urine

24. Pharmacodynamics • Analgesic Effects (300-600mg) • Antipyretic Effects (300-600mg) • Anti-inflammatory Effects (3-6g) do not influence the progress of disease • Effects on Platelets (40-100mg) Reduced platelet aggregation reduces thromboxane A2 (TXA2) formation

25. Effects on Platelets (40-100mg) 磷脂 血小板 磷脂 花生四烯酸 PGH2 PGH2 PGI2 血管壁 花生四烯酸 （－） 阿斯匹林 环氧化酶 cAMP 抑 制血小 板集聚 松弛血 管平滑肌 cAMP 血小板释 放ADP 促进血小板集聚 收缩 血管平滑肌 TXA2

26. Platelets No nuclei No new COX1 produce TXA2 production ↓ Lifetime: 8-11 days Endothelial cell Has nuclei New COX1produce Low doses 40-100mg/day

27. Pharmacodynamics 5. Other effects • Immune inhibition • Effect on metabolism of connective tissue • Effects on metabolism of glucose, fat, protein ---- catabolism ↑ • ACTH release ↑

28. Clinical Uses • Commonly used for management of mild to moderate pain(300-600mg) • Combination agents (cold) • Used for reducing fever (300-600mg) • Useful in treatment of: (high doses 3-6g) T1/2 > 12 hours 0 rheumatic fever 0 rheumatoid arthritis 0 other inflammatory joint diseases

29. Clinical Uses • Antiplatelet: (low doses) 40-100mg • reduce incidence of transient ischemic attacks (prophylaxis) • reduce incidence of unstable angina (prophylaxis) • may reduce incidents of coronary artery thrombosis

30. Clinical Uses • Hypertension in pregnancy : (low doses) 60-100mg TXA2↓ • Local indication GI inflammation : 5-amido-salicylic acid

31. SIDE EFFECTS • CNS: excitation----inhibition salicylic acid reaction: Headaches; confusion; hallucinations; tremors; vertigo; behavior disturbance • GI effects: direct stimulation PGE2 & PGI2↓ Esophagitis; gastric ulcerations; GI hemorrhage

32. SIDE EFFECTS 3. Liver & renal toxicity • Dose dependence toxicity • Reye's syndrome a potentially fatal disease that causes numerous detrimental effects to many organs, especially the brain and liver. The disease causes hepatitis with jaundice and encephalopathy

33. SIDE EFFECTS • Other reaction Hematologic: decreased platelet aggregation; prolonged bleeding time. Exacerbations of asthma Hypersensitivity: rashes Acid-base Imbalance

34. Acetaminophen 乙酰氨基酚（醋氨酚，扑热息痛） Phenacetin 非拉西丁 • Rapidly absorbed from GI • Phenacetin is largely converted to Acetaminophen • Similar antipyretic, analgesia to aspirin • Weak anti-inflammatory properties • used to reduce fever and pains (a major ingredient in numerous cold and flu medications) (choice for child) • used appropriately, side effects are rare

35. Indomethacin 吲哚美辛（消炎痛） More potent than aspirin As an anti-inflammatory agent More adverse reaction Ibuprofen 布洛芬 More analgesia Fewer adverse reaction Brufen；Benzeneacetic acid； Fenbid； Emodin；Motrin 异丁苯丙酸；异丁洛芬；拔怒风；芬必得；炎痛停；

36. Phenylbutazone 保泰松 羟基保泰松 • Powerful anti-inflammatory effects • Weak analgesic & antipyretic activities • Promote excretion of uric acid • Used for acute gout, rheumatic & rheumatoid arthritis • More adverse reaction • Can induce activities of drug metabolize-E • Can displace other drugs from plasma proteins

37. Selective COX-2 inhibitors • Less adverse reactions • Do not impact platelet aggregation • Meloxicam 美洛昔康 • Celecoxib 塞来昔布 • Nimesulide 尼美舒力 • Rofecoxib • Valdecoxib

39. 常用感冒药组成 • 解热镇痛药：对乙酰氨基酚、布洛芬 • H1受体阻断药：氯苯那敏、苯海拉明 • 止咳药：右美沙芬等 • 缩血管药：伪麻黄碱 • 抗病毒药：金刚烷胺 • 中枢兴奋药：咖啡因 • 其他：中草药、人工牛黄