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