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Prostaglandin, Leukotriene, and Thromboxane Synthesis

Prostaglandin, Leukotriene, and Thromboxane Synthesis. Eric Niederhoffer SIU-SOM. Pathway overview Prostaglandin receptors Pathway details Differential actions of cyclooxygenases COX-1 and COX-2 comparison COX-1 specificity of common NSAIDs Tissue comparison. Anti-inflammatory steroids

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Prostaglandin, Leukotriene, and Thromboxane Synthesis

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  1. Prostaglandin, Leukotriene, and Thromboxane Synthesis Eric Niederhoffer SIU-SOM • Pathway overview • Prostaglandin receptors • Pathway details • Differential actions of cyclooxygenases • COX-1 and COX-2 comparison • COX-1 specificity of common NSAIDs • Tissue comparison

  2. Anti-inflammatory steroids Glucocorticoids Zileuton NSAIDs aspirin Arachidonic acid Prostaglandins (PG) Leukotrienes (LT) Thromboxanes (TXA) Pathway Overview Linoleic acid Lipoxygenase Prostaglandin H2 synthase Thromboxane A2 synthase

  3. Prostaglandin Receptors http://www.caymanchem.com/app/template/scientificIllustrations%2CIllustration.vm/illustration/2018/a/z

  4. IL-1 (inflammation) IL-1R Anti-inflammatory steroids Glucocorticoids (mediated by lipocortin-Ca2+) Arachidonic acid LTA4 NSAIDS (aspirin) Glutathione S-transferase PGG2 LTB4 LTC4 2GSH PGH2 synthase LTD4 GSSG PGH2 LTE4 PGJ2 TXA2 synthase PGD2 TXA2 PGI2 (PC) PGE2 PGF2a Pathway Details Membrane phospholipids Phospholipase A2 (or PLC) O2 Cyclooxygenase PG hydroperoxidase PGD2 synthase PGI2 synthase PGE2 synthase PGF2 synthase

  5. Unwanted side-effects PGI2 COX1 Constitutive PGE2 TXA2 PGE2 PGF2a Inducible Inflammatory COX2 Proteases Therapeutic anti-inflammatory effects Differential Actions of Cyclooxygenases Housekeeping Endothelial integrity Vascular patency Gastric mucosal integrity Bronchodilation Renal function Platelet function NSAIDs Inflammation

  6. COX-1 and COX-2 Comparison http://elfstrom.com/arthritis/nsaids/actions.html

  7. COX-1 Specificity of Common NSAIDs Generally, the more selective for COX-1, the more serious side-effects appear http://elfstrom.com/arthritis/nsaids/actions.html

  8. Brain/nerve Synovial cells Vascular beds Ar Ar Ar PGH2 PGH2 PGH2 PGD2 PGE2 PGI2 (PC) PGE2 PGI2 (PC) PGE2 PGF2a TXA2 Tissue Comparison So what would happen if we gave a patient a large dose of aspirin or Coxib to reduce inflammation/pain in these tissues?

  9. Review Questions • How are prostaglandins, leukotrienes, and thromboxanes synthesized (substrates, enzymes, cofactors)? • What is the nomenclature for prostaglandin receptors? • How do NSAIDs work? • How do steroids work? • What are the important characteristics of COX-1 and COX-2?

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