COX-1 vs COX-2 Inhibition Prostaglandin Synthesis Membrane Phospholipids Phospholipase 4A2 Arachidonic Acid Lipoxygenase Leukotrienes Phvsiological Inflammatory Non-Selective cox Regulation response by newly by cOX-1 Inhibitors expressed CoX-2 selective MSAID's PGE PGI TXA PGE PGI Other Chemical GI Mediators Protection Protection Platelet Function Platelet function Inflammation Regulation of Regulation of Pain blood flow blood flow Fever Kidney function
COX-1 vs COX-2 Inhibition
CoX-1 Channel COX-2 Channel COX-1 channel with aspirin COX-1 channel with a non-selective active site NSAID (Ibuprofen)and aspirin Isoleucine 523 Side Acetyl serine Serine iSoleucine PGH active site Isoleucine 523 +Valine 523 Irreversible inactivation on-selective nsa Side Asprin Arginine 120 Arginine 120 Selective COX-2 inhibitors bind in COX-2 sidepocket to block ent The CoX active site of of arachidonic acid into CoX-2 but not COX-1 channel CoX-1 and CoX2 is characterised by a hydrophobic, long and Isoleucine 523 Valine 523 narrow channel Arginine 120 Arginine 1 Patrignani P, Capone ML, Tacconelli S Clinical pharmacology of etoricoxib: a novel selective COX2 celecoxib, rofecoxib, etoricoxib nhibitor. Expert Opin Pharmacother 2003 Feb: 4(2) DOI: 10. 1517/14656566.4.2.265
Patrignani P, Capone ML, Tacconelli S. Clinical pharmacology of etoricoxib: a novel selective COX2 inhibitor.Expert Opin Pharmacother 2003 Feb;4(2) DOI：10.1517/14656566.4.2.265 celecoxib, rofecoxib, etoricoxib non-selective NSAIDS The COX active site of COX-1 and COX2 is characterised by a hydrophobic, long and narrow channel Irreversible inactivtion Asprin
NSAIDS: Classification by COX selection 罗非昔布 rofecoxib etoricoxib valdecoxib >50-fold COX-2 selective etodolac 塞来昔布 celecoxib Diclofenac 5 to 50-fold cOX-2 selective fenoprofen 5-fold COX-2 selective ibuprof In vitro assessment naproxen aspirin of coX-1-COX-2 activity indomethacin ketoprofen flurbiprofen ketorolac Increasingly COX-2 selective Increasingly COX-1 selective Range of Cox selectivity for COX-1 and COX-2 (log1o ICso COX-2/COX-1) Sleisenger Fordtran's Gastrointestinal and Liver Disease, 8th ed, Copyright 8 2006 满大昔学流
Sleisenger & Fordtran's Gastrointestinal and Liver Disease, 8th ed., Copyright © 2006 Saunders, An Imprint of Elsevier NSAIDs: Classification by COX selection In vitro assessment of COX-1 – COX-2 activity 罗非昔布 塞来昔布
表20-10OX1和COX2的特性比较 C0X-1 COX-2 生成 固有的 需经诱导 功能 生理学 生理学:妊娠时PG生成增加 保护胃肠 病理学:生成蛋白酶PG及其他致炎介 调节血小板聚集(TXA2) 质引起炎症 调节外周血管阻力(PGI2) 调节肾血流量分布(PGⅠ、PGE) 抑制剂 选择性吲哚美辛阿司匹林吡罗昔康美洛昔康尼美舒利、萘丁美酮 非选择性 萘普生、布洛芬、双氯芬酸钠 满大告学流
表203非甾体抗炎药的分类 化学分类 代表药物 苯胺类 对乙酰氨基酚 吡唑酮类 保泰松 甲酸类 水杨酸类 阿司匹林 乙酸类 吲哚乙酸类 吲哚美辛 茚乙酸类 舒林酸 有机酸类 羧酸类 萘乙酸类 萘丁美酮 邻氨苯乙酸类 双氯芬酸 苯乙酸类 芬布芬 丙酸类 苯丙酸类 布洛芬 萘丙酸类 荼普生 吡罗昔康 烯酸类 苯并噻嗪类 美洛昔康 其他 尼美舒利