M e chanism of NSAIDs

1. Chapter 20 Analgesic-Antipyretic and Antiinflammatory Drugs(Non-steroidal Anti-inflammatory Drugs,NSAIDs)

2. Mechanism of NSAIDs • The basis of these action of NSAIDs is due primarily to the inhibition of prostaglandin(PGs) synthesis.

3. Cell membrane phospholipids - PLA2 NSAIDs steroidals — PAF Arachidonic acid(AA) COX-1 COX-2 5-Lipoxygenase PGG2 PGH2 Leukotriene 血管舒张剂 血管通透性增加 支气管收缩 趋化性增强 PGE2 PGD2 PGF2 体温、炎症疼痛传递、胃粘膜保护 PGI2 血管舒张 血小板解聚 参与过敏反应诱发炎症 支气管收缩 白细胞趋化 TXA2 血栓形成血管收缩

4. Pharmacological effects of NSAIDs • Analgestic actionmild or moderate pain following injury,disease,or minor surgery,as well as chronic pain states including arthritis and cancer. • Antipyretic actionNSAIDs reset the set-point to the normal level and lower the elevated body temperature in patients with fever by inhibiting the endogenous synthesis of PGs in hypothalamus. • Anti-inflammatory actionNSAIDsmayprovide symptomatic relief from fever,pain,and other signs of rheumatic or rheumatoid arthritis,but do not arrest the progression of pathological injury to tissue. • Some nonselective NSAIDS also haveanti-thrombotic actions.

5. Classification of NSAIDs aspirin （sodium salicylate）阿司匹林 Acetaminophen 醋氨酚（扑热息痛） Indomethacin 吲哚美辛（消炎痛） Ibuprofen 布洛芬（芬必得） Phenylbutazone 保泰松 Nonselective COX inhibitors Selective COX-2 inhibitors Rofecoxib罗非昔布 Celecoxib塞来昔布 Etodolac依托度酸 Nimesulide尼美舒利

6. Salicylates---Aspirin [Pharmacological Effects and clinical Uses] • 1. Analgesic Effects: ☆ Aspirin is most effective in reducing pain of mild to moderate intensity (headache, toothache,dysmenorrhea<痛经>，arthralgia,etc). ☆ It is not effective for severe visceral pain, e.g. myocardial infarction or renal or biliary colic. ☆ It acts peripherally through its effects on inflammation but probably also inhibits pain stimuli at a subcortical site.

7. Aspirin • 2. Antipyretic Effects: ☆ Aspirin reduces elevated temperature, whereas normal body temperature is not affected. ☆Aspirin’s antipyretic effect is mediated by cyclooxygenase-2 (COX-2) inhibition in the central nervous system. ☆ The fall in temperature is related to increased dissipation of heat caused by vasodilation of superficial blood vessels and may be accompanied by profuse sweating.

8. Aspirin • 3. Anti-inflammatory Effects: ☆ The anti-inflammatory property of aspirin in high dosage (3-6 g/d) is responsible for treatment various kinds of inflammation including acute rheumatic fever, rheumatoid and other types of arthritis. ☆ It has been advocated as a diagnostic test when acute rheumatic fever(风湿热) is suspected.

9. Aspirin • 4. Effect on platelets ☆Low doses of aspirin can inhibit platelet aggregation and produce a slightly prolonged bleeding time by irreversible inhibition of platelet COX. ☆Low doses of aspirin can irreversibly inhibit the production of TXA2 in platelets without markedly interfering with PGI2 production in endothelial cells. ☆ In general, Aspirin should be stopped 1 week prior to surgery to avoid bleeding complication. ☆ Aspirin has been shown to decrease the incidence of transient isochemic attacks (短暂局部缺血性休克）, unstable angina,coronary artery thrombosis（血栓形成）with myocardial infarction,and thrombosis after coronary artery bypass grafting.

10. Aspirin Adverse Effects • 1. Gastrointestinal tract • This effect can be decreased with suitable buffering(taking Aspirin with meals ). The gastritis that occurs with Aspirin may be due to irritation of gastric mucosa by the undissolved tablet, or to inhibition of production of protective prostaglandins. ☆ Therefore, aspirin should be avoided by individuals with peptic ulcer disease.

11. Aspirin Adverse Effects • 2.Blood Aspirin increases bleeding time,decreases platelet adhesiveness,,and ,at large doses,may cause hypoprothrombinaemia. • 3.hepatotoxicity • 4.Hypersensitivity aspirin asthma • 5.Salicylate intoxication • 6. Reye’s syndrome

12. Antipyretic-analgesic and antiinflammatory drugs--苯胺类 Acetaminophen and Phenacetin ▽Acetaminophen is the active metabolite of phenacetin responsible for its analgesics effect. ▽It is a weak prostaglandin inhibitor in peripheral tissues and possesses no significant anti-inflammatory effects. ▽Acetaminophen is one of the most important drugs used for the treatment of mild to moderate pain when an anti-inflammatory effect is not necessary. ▽ Phenacetin is more toxic and has no rational indications

13. Antipyretic-analgesic and antiinflammatory drugs Indomethacin （吲哚美辛） ▽ Indomethacin is an indole derivative. ▽ It enjoys the usual indications for use in rheumatic conditions and is particularly popular for gout and ankylosing spondylitis （强直性脊柱炎）.In addition,it has been used to treat patient ductus arteriosus（动脉导管闭锁不全）. ▽It is one of the most potent COX inhibitors, and has more adverse effects.

14. Antipyretic-analgesic and antiinflammatory drugs--其他有机酸类 Ibuprofen (布洛芬）其缓释胶囊称“芬必得”. ☆ Ibuprofen is a simple derivative of Arylpropionic acid（芳基丙酸）. ☆ In doses of about 2400 mg daily,ibuprofen is equivalent to 4 g of aspirin in anti-inflammatory effect.Oral ibuprofen is often prescribed in lower doses(<2400mg/d),at which it has analagesic but not anti-inflammatory efficacy. ☆ It is used for treatment ofrheumatoid(类风湿的) arthritis and other inflammatory joint conditions ☆ It is available over the counter in lower dosage under several trade names.

15. Antipyretic-analgesic and antiinflammatory drugs--吡唑酮类 Phenylbutazone (保泰松） • Phenylbutazone,a pyrazolone derivative rapidly gained favor after its introduction in 1949 for the treatment of rheumatic syndromes, but its toxicities,particularly the hematologic effects (including aplastic anemia),have resulted in its withdrawal from many markets.It is rarely used today.

16. Antipyretic-analgesic and antiinflammatory drugs—selective COX-2 inhibitors Celecoxib(塞来昔布) • Celecoxib is a selective COX-2 inhibitor, having slight action on COX-1 in therapeutic dosage. • The incidence of gastric toxicity is much lower with it than with non-selective COX inhibitors. • It is used for treatment of osteoarthritis and rheumatoid(类风湿的) arthritis.