浙江大学医学院：《药理学》课程教学资源（PPT讲稿）消炎药 Introduction to Anti-inflammatory Drugs

Introduction to Anti-inflammatory Drugs Peiping Zhang Department of Pharmacology Zhejiang University School of Medicine 2012.10

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

Promotes Mast cell swelling Bradykinin o Substance P Prostaglandins Histamine Noxious signal Dorsal root Blood Noxious essel Substance P Spinal cord Peripheral mechanisms of pain

Peripheral mechanisms of pain

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

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

1. The classification of nsaids 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 林酸 萘乙酸类 萘丁美酮 有机酸类 羧酸类 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 萘普生 吡罗昔康 酸类 苯并噻嗪类 美洛昔康 其他 尼美舒利 NSAIDs are just that- drugs that act to relieve inflammation, but are not structurally related to the corticosteroids

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

2. The mechanisms of nsaids Arachidonic acid esterified in membrane phospholipids Free radicals Diverse physical, chemical inflammatory and mitogenic stimuli Phospholipase A2 eicosatrienoic acids Isoprostanes EETS 9865 COOH Cytochrome P450 AA(204csD5,8,1114) 20 11121415 19 Lipoxygenases Cyclooxygenases (LOX) HETEs Prostaglandins Leukotrienes Prostacyclin 7 Prostanoids Lipoxins Thromboxane

2. The mechanisms of NSAIDs

2. The mechanisms of nsaids Disturbance of cell membranes Phospholipase inhibitors Corticosteroids Phosphol Fatty acid substitution(diet)(Arachidonic acid Lipoxygenase inhibitors - Lipoxygenase Cyclo-oxygenase- NSAID Receptor level antagonists Leukotriene LTB LTC//D/Es (Prostaglandin Thromboxane Prostacyclin Alteration of vascular attraction permeability, bronchial activation constriction, increased Leukocyte modulation secretion Colchicine Inflammation Bronchospasm Inflammation mucous plugging Copyright @2006 by The McGraw-Hill Companies, Inc

2. The mechanisms of NSAIDs

2. The mechanisms of nsaids CyclooxygenaseCOX-1 COX-2 COOH PGG2 OOH PeroxidaseCOX-1 COX-2 ∠coOH COOH OH PGH (prostacyclin) ( thromboxane) COOH OH PGD OH PGE2 15 deoxy-△12 PGJ

2. The mechanisms of NSAIDs

2. The mechanisms of NsaiDs Cyclooxygenases: COX1, 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-lexist(converts arachidonic acid to TxA2 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

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 TxA2 ) - 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

2 The mechanisms of nsaids 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 - Gl bleeding

➢ 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

3. Pharmacodynamic effects of NSaIds Positive Analgesic(0.3-0.6g/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 anal gesics 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 effect

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