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Prostaglandins & Related compounds

Prostaglandins & Related compounds. EICOSANOIDS . Compounds that originate from polyunstaurated fatty acids with 20 carbons P rosta g landins ( PG ) T hrombo x anes ( TX ) L euko t rienes ( LT ). Eicosanoids cont. Potent compounds

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Prostaglandins & Related compounds

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  1. Prostaglandins &Related compounds

  2. EICOSANOIDS Compounds that originate from polyunstaurated fatty acids with 20 carbons • Prostaglandins (PG) • Thromboxanes (TX) • Leukotrienes (LT)

  3. Eicosanoids cont. • Potentcompounds • Their action mediated by plasma & nuclear receptors • notstored in tissues • Have extremely short half-life(rapidly metabolized) Eicosanoids Differ from true hormones in that they: • Elicit bothphysiologic & pathologicresponses • Produced in very small amounts • In almost all tissues(not by a specialized glands) • Act locally(not transported in blood to distant sites)

  4. Synthesis of Prostaglandins (PG) & Thromboxanes (TX) Dietcell membrane PL (esp. PI) linoleic acid (18 carbons, 2 double bonds) elongation & desaturation Arachidonic acid (20 carbons, 4 double bonds) PG & TX Sources of arachidonic acid: 1-Dietary linoleic acid 2-Phospholipids of cell membrane : by phospholipase A2

  5. Synthesis of PGH2 • Arachidonic acid is subject to oxidative cyclization by prostaglandin endoperoxidase synthase to yield PGH2 • Prostaglandin endoperoxidase synthase has 2 catalytic activities: 1- COX (cycoloxygenase) 2- peroxidase • PGH2 is converted to a variety of PGs & TXs

  6. Linoleic acid In diet Synthesis of PG & TX Arachidonicacid COX-1 Peroxidase COX Peroxidase PGH2 PG & TX

  7. Isozymes of PG endoperoxidase synthase • COX-2 • inducible • in a limited number of cells • in response to inflammation • (substances from inflam.cells) • Resulting in increased • PG synthesis causing pain, • heat, redness & swelling of • inflammation& fever in • infection • (Pathological Role) COX-1 • constitutively synthesis • in most tissues • required to Maintain healthygastric tissue, renal homeostasis & platelet aggregation (Physiological Role)

  8. Inhibition of Prostaglandins Synthesis 1- Steroidal anti-inflammatory agent (as CORTISOL) 1- Cortisol Inhibits phospholipase A2 activity So, the precursor arachidonic acid is not available 2- Cortisol inhibits COX-2(but notCOX-1)

  9. Inhibition of Prostaglandins Synthesis 2- All non-steroidal anti-inflammatory agents (as aspirin, indomethacin & phenylbutazone) • Inhibits COX-2 So, prevent synthesis of PGH2 (anti inflammatory) • BUT: They also inhibit COX-1 with subsequent (aspirin's toxicity): Damage to stomach & kidneys Impaired clotting of blood 3- Inhibitors of COX-2 (as celecoxib) • Maintain the physiologic functions of COX-1(no inhibition of COX-1) • While having anti-inflammatory power (inhibition of COX-2) • BUT: Their use has been associated with increased risk of heart attacks

  10. Role of PG in Platelet Homeostasis • Thromboxane A2 (TXA2) produced by activated platelets promotes adherence & aggregation of platelets So, promotes formation of blood clots (thrombotic) • Prostacyclin (PGI2) produced by vascular endothelial cells inhibits platelet aggregation So, prevents formation blood clots (anti thrombotic)

  11. Aspirin has Antithrombogenic Effect In platelets As aspirin inhibits TXA2 production in platelets by irreversible inhibition of COX-1 as platelets can not synthesize more COX-1 (no nucleus) So, TXA2 synthesis is permanently inhibited in platelets In endothelium Although COX-1 is inhibited also in endothelium. However, this is not permanent as more COX-1 can be synthesized (endothelium is nucleated) So, prostacyclin synthesis is not inhibited in endothelium Basis of : Low-dose aspirin therapy To avoid risk of stroke & heart attacks (by decreasing formation of thrombi)

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