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PGH

P rostaglandins , cyclo-oxygenase and the GIT. HPETE. PGH. Linoleic acid (diet). Eicosanoids. Membrane Phospholipids. Phospho- lipase A 2. Arachidonic acid. PG LTs LX. Cell membrane phospholipids. Phospholipase A 2. Corticosteroids. lipoxins. isoprostanes. epoxygenase.

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PGH

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  1. Prostaglandins, cyclo-oxygenase and the GIT HPETE PGH

  2. Linoleic acid (diet) Eicosanoids Membrane Phospholipids Phospho- lipase A2 Arachidonic acid PG LTs LX

  3. Cell membrane phospholipids Phospholipase A2 Corticosteroids lipoxins isoprostanes epoxygenase Arachidonic acid Cyclooxygenase Lipoxygenase NSAID’s HPETE PGH PGI TX PGE/F/D HETE LT

  4. Arachidonic acid Leukotriene synthesis Mast cells, macro-phages, leukocytes Lipo-oxygenase LTC4 HPETE LTB4 Broncho-constrictor chemotaxis LTD4 LTA4

  5. Arachidonic acid Prostaglandin synthesis Cyclo-oxygenase PGE2 PGG2 Renal GIT PGH2 VSM platelets VSM GIT PGI2 PGF2 TXA2

  6. Cyclo-oxygenase isoforms COX-I COX-II constitutive inducible GIT Platelets renal vascular inflammation

  7. Pain & inflammation PG’s sensitize nociceptors to bradykinin, substance P, histamine PG’s = inflammation = pain NSAID’s decrease PG’s

  8. protects against stomach acid GIT mucosal protection PGE2 decrease HCl increase mucous increase sub mucosal blood flow increase bicarbonate

  9. long/circular muscle GIT peristalsis PGE2 PGF2 diarrhoea cramping

  10. Renal PGE2 Only under compromised conditions • renal failure • severe dehydration • antihypertensive • furosemide maintain GFR blood flow naturesis

  11. prostacyclin Thrombosis VSM -ve COX-I Ca2+ +ve Platelets TXA2 aggregation clots

  12. Inhibit PG synthesis Mainly peripheral Cortical site? Inhibition of COX-I Inhibition of COX-II Pain relief and NSAID’s

  13. PG synthesis Central -hypothalamus Interleukin 1 mediated Anti-pyretic

  14. Not related to corticosteroids Inhibit cyclo-oxygenase I & II Different kinetics Effective as aspirin Anti-inflammatory, analgesic, antipyretic Less toxic? Non steroidal anti-inflammatory drugs (NSAID’s)

  15. Non steroid anti -inflammatory drugs indomethacin naproxen diclofenac ibuprofen MOA • COX-II = COX-I • provide symptomatic relief • Adverse effects • Not antiplatelet?

  16. Common but mild Mild dyspepsia, heart burn, GORD Rare but lethal Perforation, ulcer, bleeds Obstructions PG via COX-I (mucosa) Side effects of NSAID's & aspirin GIT

  17. Bleeding Hypersensitivity 1: 200 people Renal Effect Renal blood flow  Antihypertensive Adverse effects cont.............................

  18. Prevent ulcers PGE1 misoprostil PPI ) No acid, no ulcer replace mucosal PG diarrhoea cramp prevent NSAID’s ulcers

  19. Misoprostil Cramps, diarrhoea, women • other • sucralfate? • H2RA antagonists? • Proton pump inhibitors COX-II specific Adverse effects NSAID’s…

  20. Selective COX– II inhibitors Non steroid anti -inflammatory drugs COX-II COX-I Inflammation Synthesized de novo House keeping GIT, renal, platelets

  21. NSAID’s COX II selective /specific meloxicam celecoxib MOA • COX - II>COX - I • provide symptomatic relief • not antiplatelet!! • CVS effects??

  22. Central site Analgesic Antipyretic Not anti-inflammatory No action on peripheral cyclo-oxygenase Less GIT Irritation Alternative to aspirin Paracetamol

  23. Toxicity 10g is toxic!! N-acetyl cysteine antidote Less if alcohol is added How strong analgesic? Very little dose response 500mg = 750 =1000mg No response over 1000mg Paracetamol

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