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The eicosanoids: prostaglandins, thromboxanes, leukotriens

The eicosanoids: prostaglandins, thromboxanes, leukotriens. By S.Bohlooli, PhD. Pathways of arachidonic acid (AA) release and metabolism. Cylcooxygenase pathway. Lipoxygenase pathway. Prostanoids Metabolism. Basic pharmacology of eicosanoids. Receptor mechanisms Organ effects.

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The eicosanoids: prostaglandins, thromboxanes, leukotriens

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  1. The eicosanoids: prostaglandins, thromboxanes, leukotriens By S.Bohlooli, PhD Ardabil University of Medical Sciences

  2. Pathways of arachidonic acid (AA) release and metabolism Ardabil University of Medical Sciences

  3. Cylcooxygenase pathway Ardabil University of Medical Sciences

  4. Ardabil University of Medical Sciences

  5. Lipoxygenase pathway Ardabil University of Medical Sciences

  6. Ardabil University of Medical Sciences

  7. Prostanoids Metabolism Ardabil University of Medical Sciences

  8. Ardabil University of Medical Sciences

  9. Basic pharmacology of eicosanoids Receptor mechanisms Organ effects Ardabil University of Medical Sciences

  10. Ardabil University of Medical Sciences

  11. Ardabil University of Medical Sciences

  12. Prostanoid receptors and their signaling pathways Ardabil University of Medical Sciences

  13. Effect of prostaglandins and thromboxanes Ardabil University of Medical Sciences

  14. Smooth muscle • Vascular: • vasocontrictors • TXA2  mitogen • PGF2 • Vasodilators • PGI2 • PGE2 • Gastrointestinal tract • Longitudinal muscle: PGE2, PGF2 • Circular muscle: PGF2, PGI2, relaxed by PGE2 • Airways: • Relaxed: PGD2, PGE1, PGE2, PGI2 • Contracted:PGF2, TXA2 Ardabil University of Medical Sciences

  15. Platelets and Blood Cells • Aggregation: • Inhibtion:PGE1, PGI2 • Aggregator: TXA2 Ardabil University of Medical Sciences

  16. Kidney • Major one: PGE2, PGI2 • GFR  (vasodilator effect) • Some effects of loop diuretics • TXA2: renal vasoconstrictor may play a role in renal function? ( inflammatory renal disease) Ardabil University of Medical Sciences

  17. Reproductive Organs • Female reproductive organ • Male reproductive organ • Fertility? PGE, PGF • Penile erection: PGE: alprostadil Ardabil University of Medical Sciences

  18. Central and Peripheral nervous system • Fever • Sleep • Neurotransmission • Inhibition of Norepinephrine release postganglionic sympathetic nerves Ardabil University of Medical Sciences

  19. Neuroendocrine organs • PGE: • GH, prolactin, TSH,ACTH, FSH, LH  • LTC4, LTD4: • LHRH, LH Ardabil University of Medical Sciences

  20. Bone metabolism • Increasing bone turnover • PGE2 ? Ardabil University of Medical Sciences

  21. EYE • PGE, PGF • Increasing outflow of aqueous humor Ardabil University of Medical Sciences

  22. Effect of Lipoxygenase & Cytochrome P450 derived Metabolites • Blood Cell and Inflammation • Chemoattractant: • Neutrophils: LTB4, lipoxin A • Eosinophils: LTC4, LTD4 • Heart and Smooth Muscle • Cardiovascular • Smooth Muscle Chemoattractant: 12(S)-HETE • Gastrointestinal: LTB4 • Airways:LTC4, LTD4 • Increased vascular permeability, mucus secretion • Renal system • Speculative? • Product of free radical attack: 8-epi-PGF2 Ardabil University of Medical Sciences

  23. Inhibition of Eicosanoid synthesis • Corticosteroids • By producing annexins, lipocortins • Inhibiting phospholipase A2 • NSAIDs • Inhibition of COX activity • May increase the lipoxygenase activity? Ardabil University of Medical Sciences

  24. Clinical pharmacology of Eicosanoids Stable oral or long acting parenteral analogs Enzyme inhibitors and receptor antagonists Dual Cox and Lipoxygenase inhibitors Decreasing preexisting side effects Dietary manipulation Change the polyunsaturated fatty acid Ardabil University of Medical Sciences

  25. Chemistry-1 Ardabil University of Medical Sciences

  26. Chemistry-2 Ardabil University of Medical Sciences

  27. Female reproductive system • Abortion • PGF2, PGE2: oxytocic and ripening and priming of the cervix • Dinoprostone ( PGE2) • Plasma t1/2: 2-2.5 min • Carboprost tromethamine (PGF2) • Drawback: pulmonary hypertension • Facilitation of labor • Potency:PGE2 >> PGF2 • Side effect: PGF2 >> PGE2 • Dysmenorrhea Ardabil University of Medical Sciences

  28. Male Reproductive system • Erectile dysfunction: • Alprostadil (PGE1) • Intracavernosal injection • Urethral suppository Ardabil University of Medical Sciences

  29. Cardiovascular system • Pulmonary hypertension • Prostacylin (epoprostenol) • As intravenous infusion • Peripheral vascular diseases • PGE , PGI • Patent Ductus Arteriosis • PGE, PGI Ardabil University of Medical Sciences

  30. Blood TXA2, PGI2 involved in thrombosis Respiratory System Peptidoleukotriens; LTC4, LTD4 synthesis and receptor inhibitors Gastrointestinal System Cytoprotection: misoprostol (PGE1 analog) Glaucoma Latanoprost (PGF2), bimatoprost, unoprostone Ardabil University of Medical Sciences

  31. Immune system • Cell mediated organ transplant rejection • Inflammation • Rheumatoid arthritis • infection Ardabil University of Medical Sciences

  32. Ardabil University of Medical Sciences

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