Cyclooxygenase pathway Cyclooxygenase pathway (COX PGH synthase) prostaglandins PGE, PGI, PGF, thromboxane A2

Basic and Clinical Pharmacology, 2005

enzyme cyclooxygenase (COX) 2 isoforms COX-1 COX-2 - COX-1 isoform constitutive COX physiological COX COX-2 isoform inducible COX 10-20 growth factor, tumor promoter, cytokines, endotoxin COX-2 expression macrophage, synoviocyte, chondrocyte, fibroblast endothelial cells

Arachidonic Acid
COX COX-1

PGS

COX-2

Physiology
Stomach (cytoprotection) Kidney (renal function) Platelet (homeostasis) Endothelium (vascular tone)

Pathology
Macrophage (inflammation) Synovium (Arthritis) Mitogenesis (tumor) Endothelium (shock)

 cyclooxygenase enzyme (nonsteroidal anti-inflammatory drugs, NSAIDS) 2 1) nonselective COX inhibitor COX-1 COX-2 aspirin ibuprofen , indomethacin COX-1 2) selective COX-2 inhibitor COX-2 isoform coxibs (celecoxib, etoricoxib) COX-1 physiological COX nonselective COX inhibitor

Cell Membrane Phospholipid Glucocorticosteroids Lipocortin Phospholipid

Arachidonic Cyclooxygenase PGG2 Uterine contraction Peroxidase PGF2 PGI2 TXA2 Vasodilation Gastric cytoprotection Platelet Platelet Inhibition of platelet aggregation aggreation aggregation PGH2 Oxidant PGD2 PGE2 Bronchoconstriction
Vasodilation Vasodilation Uterine contraction Gastric cytoprotection Gastric cytoprotection

NSAIDs 2O2

O2

5- HPETE

LTB4

LTA4

Chemotaxis Phagocyte activation

LTC4

LTD4

LTE4

Role of PG and LT in inflammation and immunity LTB4 potent chemotactic agent for pmn leukocyte,eosinophil,monocyte,stimulate proinflammatory cytokine PGE 2 depress the humoral antibody response PGD2 potent chemoattractant for eosinophil and induce chemotaxis

PG RECEPTORS PGs act locally near their site of action 5 subtypes ( all are G protein -coupled receptor) IP receptor for PGI2 FP receptor for PGF2 TP receptor for thromboxane A2 EP1-4 receptor for PGE2 DP1 ,DP2 receptor for PGD2

 prostaglandins thromboxane Autacoids Physiological Function Therapeutic use (PG Therapeutic use (PG analogue)* antagonist)** PGE2 : dinoprostone PGE2 - protection of GI tract - renal hemostasis - induce labour - body temperature - uterine function PGI2 : epoprostenol PGI2 - protection of GI tract - renal hemostasis - innibit platelet - vascular hemostasis aggregation (vasodilatation) - primary pulmonary - antiplatelet action hypertension Thromboxane - platelet aggregation A2(TXA2) PGF2 : dinaprost PGF2 - uterine function - embryo implantation and - termination of labour pregnancy PGE1 - body temperature 1. PGE1 : misoprostol - protection of GI tract - prophylaxis of peptic ulcer associated with NSAIDS 2. PGE1 : alprostadil - treatment of impotent (intracavernosum injection) * eicosanoids eicosanoids derivative systemics half life ** potent selective antagonists of prostanoid receptor clinical use