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Objectives e What’s inflammation ? e How does NSAIDs work ? e Effect of NSAIDs on different organs ° Groups of NSAIDs e Acetaminophen e The specific chemical mediators vary with the type of inflammation and include : Amines : histamine and 5Hydroxytryptamine (serotonin ) Lpids : prostaglandines ( PGs ) , thromboxanes ( TXs ) and leukotrienes ( LTs ) . Small peptides : Bradykinin . Larger peptides : interleukin 1 and tumor necrosis factor o N.B Anti inflammatory drugs act by interfere with the action of specific mediator important in inflammation . e Non Steroidal anti inflammatory drugs ( NSAIDs ) have analgesic ( pain killer ) , anti pyretic ( fever reducing ) and anti inflammatory effect . e Steroidal anti inflammatory : Corticosteroids Acetaminophen ( paracetamol ) isnot considered an NSAID because it has a very weak anti inflammatory activity . e Two main pathways are involved in the biosynthesis of eicosanoids . 1- PGs and TXs are synthesized by cyclic pathway . 2- LTs are synthesized by linear pathway . Arachidonic acid esterified in membrane phospholipids Free radicals Diverse physical, chemical, inflammatory, and mitogenic stimuli ———B> | Phospholipase Az ‘ ; , ; Isoprostanes Epoxyeicosatrienoic acids (EETs) bee 5 1 COOH Cytochrome K P450 AA an eo 4 cis D5,8,11,14) Pe ee Lipoxygenases Cyclooxygenases (LOX) (COX) \ en Prostaglandins Leukotrienes Prostacyclin Prostanoids Lipoxins Thromboxane Source: Bertram G. Katzung: Basic & Clinical Pharmacology, Fourteenth Edition Copyright © McGraw-Hill Education. All rights reserved. e Major rules of Eicosanoids : PGs Modulate pain , inflammation and fever . Control acid secertion and mucus production in the GIT Control renal blood flow. Control uterine contraction . Prostacyclin ( PGIs ) Inhibit platelet aggregation . Induce vasodilation . TXs Induce platelet aggregation . Induce vasconstriction . LTs Powerful bronchoconstriction . Increase vascular permeability . e Pharmacokinetics Most are excreted renally . e Pharmacodynamics Inhibit of COX activity Aspirin is an irreversibly inhibitor of COX enzyme while other NSAIDs are reversible inhibitors . e Effect of NSAIDs on different organs bleeding and ulceration Normally NSAIDs inhibit COX1 patients with high risk for GI events : NSAIDs with PPI or Misoprostol ( PG analogue ) Patient counseling © TXAs enhance platelet aggregation © PGls decrease platelet aggregation Dose of aspirin ? Afferent Arteriole PGs; Increase GFR (VD) NSAIDs; Decrease GFR (VC) = , Efferent Arteriole Angiotensin tl; Increase GFR (VC) ACEts; Decrease GFR (VD) Bowman's capsule proximal convoluted tubule GCloretolar Filiathon | Bowman's Capsle L etteren’ atteriale G\omerviar keg (visceral \o Firtoinon Rote padocytes ( yet) (GFR) 2 aout ; simple sqpamnov§ epithelium oe Riltrane ereiucs) (parieval \oyer\ : loy Kidteys eon mnore \2Sem\ [tn (\cotn'e\dreys) NEW BRITAIN EMERGENCY MEDICAL SERVICES 7A AC ATYEMAY Normally : there is a balance between PGIs and TXA2 In heart cells PGIs is mediated by COX2 TXAz2 is mediated by COX1 SO NSAIDs with a very high degree of COX1 selectivity such as ASPIRIN have a cardiovascular protective effect . NSAIDs with a very degree of COX2 selectivity have a high risk for cardiovascular events ( MI and strock ) e Aspirin in high dose = 325 mg inhibit PGl2 production and may carry a risk for CVS events . N.B ALL NSAIDs aren't without CVS risk Naproxen appears to be the least CVS risk . 
