1. Introduction to Anti-inflammatory Drugs Weiping Zhang Department of Pharmacology Zhejiang University School of Medicine 2012.10

2. Peripheral mechanisms of pain

3. Classification of anti-inflammatory drugs (1) non-steroid anti-inflammatory drugs (NSAIDs) (Antipyretic-Analgesic and Anti-inflammatory Drugs) (Antipyretic-Analgesic and Anti-inflammatory Drugs) 解热 - 镇痛 - 抗炎药 解热 - 镇痛 - 抗炎药 eg. aspirin, acetaminophen, indomethacin, COX inhibitor, ibuprofen eg. aspirin, acetaminophen, indomethacin, COX inhibitor, ibuprofen (2) Steroid anti-inflammatory drugs glucocorticoids: eg. dexamethasone glucocorticoids: eg. dexamethasone (3) 5-LOX inhibitors and leukotriene receptor antagonists antagonists Zafirlukast, zileuton Zafirlukast, zileuton

4. NSAIDs are just that - drugs that act to relieve inflammation, but are not structurally related to the corticosteroids 1. The classification of NSAIDs

5. 2. The mechanisms of NSAIDs

8. Cyclooxygenases: COX 1, COX 2 - PGs, mostly by COX-1, are constitutively expressed in almost all tissues; COX-2 appears to only be constitutively expressed in the brain, kidney, bones, reproductive organs, and some neoplasms - Under normal physiologic conditions, PGs play an essential homeostatic role in cytoprotection of gastric mucosa, hemostasis, renal physiology, gestation, and parturition - In platelets there is only COX-1exist (converts arachidonic acid to TxA 2 ) - COX-1 predominant in gastric mucosa (source of cytoprotective PGs) - The production of PGs, (inducible COX-2 activity >> COX-1) at sites of inflammation propagate pain, fever 2. The mechanisms of NSAIDs

9.  NSAID inhibition of PG production alleviates most of the pathologic effects associated with inflammation, but it also interferes with the physiologic role of these molecules  Consequently, long-term therapy with nonspecific NSAIDs is frequently limited by their adverse effects, particularly those caused by erosion of gastric mucosal protection —— GI bleeding 2. The mechanisms of NSAIDs

10. 3. Pharmacodynamic Effects of NSAIDs Positive Analgesic (0.3-0.6 g/day) - refers to the relief of pain by a mechanism other than the reduction of inflammation (for example, headache); - produce a mild degree of analgesia which is much less than the analgesia produced by opioid analgesics such as morphine anti-inflammatory (3-5 g/day) - these drugs are used to treat inflammatory diseases and injuries, and with larger doses - rheumatoid disorders antipyretic (0.3-0.6 g/day) - reduce fever; lower elevated body temperature by their action on the hypothalamus; normal body temperature is not reduced antiplatelet (30-100 mg/day)- inhibit platelet aggregation, prolong bleeding time; have anticoagulant effects

11. antipyretic : compared with chlorpromazine NSAIDs Chlorpromazine Effects Clinical usage Side effects GI reactions ， no addiction Lower the abnormal high temperature to normal. Used for various fever. artificial hibernation, Hypothermic anesthesia, Extrapyramidal effects Inhibit PGs synthesis and enhance thermolysis Inhibit thermotaxic center in hypothalamus. The body temperature change according to the environment. 3. Pharmacodynamic Effects of NSAIDs

12. Analgesic : compared with Opioids NSAIDs Opioids Effects Clinical usage Side effects GI reactions ， no addiction Headache, toothache ， neuralgia, arthronalgia, courbature, menalgia Various pain including severe pain Addiction Inhibit PGs and TxA 2 synthesis by inhibiting COX Stimulate opioid receptors 3. Pharmacodynamic Effects of NSAIDs

13. Anti-inflammatory: compared with glucocorticoid NSAIDs Glucocorticoid Effects Clinical usage Side effectsGI reactions Rheumatic, rheumatoid, trauma Various inflammation Various side effects, such as metabolism disturbance, damage of defense etc. Inhibit PGs and TxA 2 synthesis by inhibiting COX Various effects including inhibition of PLA 2 3. Pharmacodynamic Effects of NSAIDs

14. NSAIDs and Platelets/Endothelial Cells 3. Pharmacodynamic Effects of NSAIDs

15. - Reduces platelet aggregation - Most of these drugs will potentiate the action of oral anticoagulants such as coumadin, by their effects on platelet aggregation - An 80 mg dose will increase bleeding time for 2 folds NSAIDs and Platelets/Endothelial Cells SO ? Note: Selective inhibition of COX-2 will inhibit the production of PGI 2 but not of thromboxaneA2, which is produced by COX-1. SO ? 3. Pharmacodynamic Effects of NSAIDs

16. Negative or adverse effects Gastric irritant Decreased renal perfusion Bleeding 4. Adverse Effects associated with NSAIDs Non-selective

17. For patients presenting to hospital with upper gastrointestinal (UGI) bleeding - a significant percent were using NSAIDs Note: OTC use of NSAIDs was more prevalent than was prescribed NSAID usage 4. Adverse Effects associated with NSAIDs Gastrointestinal reactions

18. NSAIDs - Gastric Irritant Effects: Molecular Mechanisms PGs reduce H + secretion and increase mucous production Consequently, NSAIDs cause some degree of gastric upset due to inhibition of PG synthesis - Misoprostol. a synthetic prostaglandin analogue, can also decrease the risk of NSAID- induced ulceration and complications - PPIs can reduce the risk of peptic ulcer formation 4. Adverse Effects associated with NSAIDs

19. Afferent arteriole Efferent arteriole ACEI/ ARB  NSAIDS,  Low volume  Poor renal perfusion normal 4. Adverse Effects associated with NSAIDs NSAIDs – Effects on Renal Function PGs not participated PGs vasodilator when angiotensin II or catercholamines elevated

20. 5. Drug interactions 丙磺舒 苯磺唑酮 胆红素 苯妥英 萘普生 戊硫代巴比妥 甲状腺素

21. Salicylates - aspirin

22. History - Salicylates Salicylates were first discovered when the observation was made that chewing willow bark could relieve pain Hippocrates: Willow bark as a pain killer during childbirth Stone (1700) Extract of willow bark to reduce fever Piria (1838) Isolation of salicin from willow bark Kolbe (1853) Synthesis of salicylate ( 水杨酸盐 ) from salicin ( 水杨苷 ) Von Gerhardt at Beyer Pharmaceutical Co. synthesized acetyl SA (ASA) in 1850 Hoffman, at Beyer gave ASA to his rheumatoid father Beyer started sales of Aspirin in1899 Acetylsalicylic acid (aspirin) was introduced as a pain reliever in 1899, at that time it was used in doses of 650 mg every 4 hours

23. History - Salicylates

24. Aspirin-Mechanism of Action: Covalent Binding to COX ASA covalently and irreversibly modifies both COX-1 and COX-2 by acetylating serine-530 in the active site Acetylation results in a steric block, preventing arachidonic acid from binding Note: Acetylation of COX-2 retains the COX activity although the reaction produces a different product, 15-R-HETE

25. Aspirin Metabolism Pathways acetylsalicylic acid (ASA) ASA: t 1/2 ~20 min salicylate t 1/2 ~3-5 hrs irreversible acetylation of COX - Salicylate elimination is 1 st order at low and moderate doses; - When total body salicylate > 600mg (>3.5g/d), elimination is zero order 酯类和葡醛酸葡糖乙酯 龙胆酸 水杨酸甘氨酸

26. Aspirin Dose-Dependent Effects: Low: < 300mg blocks platelet aggregation Intermediate: 300-2400mg/day antipyretic and analgesic effects High: 2400-4000mg/day anti-inflammatory effects Salicylism

27. Side effects of aspirin Gastrointestinal symptoms CNS toxicity Allergic reaction (urticaria( 荨麻疹 ), angioneurotic edema, aspirin asthma, occasionally anaphylactic shock) Salicylate reaction (CNS reaction) Renal damage Hematologic effects Metabolic acidosis  stimulates medullary respiratory center  respiratory alkalosis

28. Salicylism ( 水杨酸反应 )Salicylism ( 水杨酸反应 ) dose > 5g/d: CNS symptoms, including mental dose > 5g/d: CNS symptoms, including mental confusion; hyperventilation. confusion; hyperventilation. Rescure: i.v. NaHCO 3 promote the excretion Rescure: i.v. NaHCO 3 promote the excretion Hepatic damageHepatic damage Overdose: Overdose: hepatic damage hepatic damage Reye’s syndrome( 瑞夷综合征 ) (kids) Reye’s syndrome( 瑞夷综合征 ) (kids) severe hepatic damage ( 严重的肝损害 ) and severe hepatic damage ( 严重的肝损害 ) and encephalopathy ( 脑病 ) encephalopathy ( 脑病 ) 4. Adverse Effects associated with NSAIDs

29. NSAIDs: Classification by half-life Plasma Elimination Half Lives Short Half Life (< 6 hours): more rapid effect and clearance Aspirin (0.25-0.33 hrs), Diclofenac ( 双氯酚酸 ) (1.1 ± 0.2 hrs) Ketoprofen ( 酮洛芬 ) (1.8 ± 0.4 hrs), Ibuprofen ( 布洛芬 ) (2.1 ± 0.3 hrs) Indomethacin ( 吲哚美辛 ) (4.6 ± 0.7 hrs) Long Half Life (> 10 hours): slower onset of effect and slower clearance Naproxen ( 萘普生 ) (14 ± 2 hrs) Sulindac ( 舒林酸 ) (14 ± 8 hrs), Piroxicam ( 吡罗昔康 ) (57 ± 22 hrs)

30. Sleisenger & Fordtran's Gastrointestinal and Liver Disease, 8th ed., Copyright © 2006 Saunders, An Imprint of Elsevier NSAIDs: Classification by COX selection Non-specific inhibition of COX-1 results in gastrointestinal and platelet side effects In vitro assessment of COX-1 – COX-2 activity

31. Summary of COX-1 vs COX-2 Inhibition

32. COX-1 compared to COX-2 COX-1 COX-2 Expression Tissue localization Role“Housekeeping” and maintenance UbiquitousInflammatory and neoplastic sites (small amounts in kidney, uterus, ovary, CNS [neocortex, hippocampus]) Pro-inflammatory and mitogenic functions (? neuronal plasticity) Constitutive (activated by physiologic stimuli Inducible by pro- inflammatory stimuli (LPS, TNF , IL-2, IFN  etc)

33. COX-2 selective inhibitors are generally larger molecules than NSAIDs and therefore preferentially inhibit COX-2 compared to COX-1 because the hydrophobic channel of COX-2 is larger. That is, COX-2 selective inhibitors are too bulky to access the binding pocket of the COX-1 enzyme COX-2 Selective Drugs COX-2 can be up-regulated in the CNS and plays an essential role in the mediation of pain and the febrile response

34. P atients with rheumatoid arthritis were treated with celecoxib (100, 200, or 400 mg twice daily), naproxen 500 mg twice daily, or a placebo for 12 weeks. Rates of gastroduodenal ulceration with naproxen were statistically higher (*P < 0.01) than rates with celecoxib or a placebo. (Data from Simon LS, Weaver AL, Graham DY, et al: Anti-inflammatory and upper gastrointestinal effects of celecoxib in rheumatoid arthritis. JAMA 282:1921–1928, 1999.) Incidence of endoscopic gastroduodenal ulcers with a COX-2 specific inhibitor Celecoxib （赛来考昔）

35. Celecoxib is now the only selective COX-2 inhibitor available in the US - withdrawal of rofecoxib (Vioxx, Merck & Co) Sept 2004 - suspension of valdecoxib (Bextra, Pfizer) Apr 2005 Note: The fact that it now carries exactly the same warning for gastrointestinal risk as the older nonselective NSAIDs is quite remarkable, new drugs—were supposedly less risky to the gastrointestinal tract than the older nonselective agents Celecoxib includes a boxed warning, highlighting the potential for increased risk of cardiovascular events and the well described, serious, potential life-threatening gastrointestinal bleeding associated with their use. Celecoxib: Current Status

36. Celecoxib: cardiovascular events Celecoxib compared with placebo is not associated with an increased risk for cardiovascular events for duration of use from 12 to 52 weeks. Celecoxib compared with nonselective NSAIDs is not associated with increased cardiovascular endpoints.

37. Acetaminophen （对乙酰氨基酚） -analgesia -antipyretic -no significant anti-inflammatory effects -no gastric irritation -no platelet function interference -half life 2 –3 h -weak inhibitor of COX-1, -2; -not contraindicated for asthma -not associated with Reye’s Syndrome - The major concern regarding the use of acetaminophen is the potential for high doses to cause liver toxicity

38. Differences between NSAIDs and Acetaminophen

39. indomethacin 吲哚美辛indomethacin 吲哚美辛 stronger efficacy, controlling special types of fever; severe adverse effects stronger efficacy, controlling special types of fever; severe adverse effects Sulindac 舒林酸Sulindac 舒林酸 Its metabolite possess 500 fold PG inhibition than itself. Its metabolite possess 500 fold PG inhibition than itself. Strong anti-inflammation and lower adverse effects than indomethacin. Strong anti-inflammation and lower adverse effects than indomethacin. Etodolac 依托度酸Etodolac 依托度酸 Used as a pain killer after operation Used as a pain killer after operation Lower GI upset Lower GI upset

40. Tolmetin 托美丁Tolmetin 托美丁 Moderate anti-inflammation and mild analgesic and antipyretic effect Moderate anti-inflammation and mild analgesic and antipyretic effect ibuprofen 布洛芬（芬必得）ibuprofen 布洛芬（芬必得） stronger antipyretic, analgesic and anti- inflammatory effects; weaker GI reactions; vision damage stronger antipyretic, analgesic and anti- inflammatory effects; weaker GI reactions; vision damage piloxicam 吡罗昔康 :piloxicam 吡罗昔康 : long-acting anti-inflammatory and analgesic agent; long-term use induces hemorrhage and ulcers in GI tract 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 (t 1/2 20 h) weaker GI reactions

42. TNF-  inhibitor Etanercept ( 伊那西普 ) Infliximab ( 英夫西单抗 ) Adalimumab ( 阿达木单抗 ) They are recombinant proteins that can not orally taken; The long-term safety is not determined.

43. References Basic & Clinical Pharmacology (11th edition), 2010. Goodman & Gilman’s the pharmacological basis of therapeutics (12th), 2010. 人民卫生出版社，药理学（第 2 版）， 2010