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

5. Lipoxygenase pathway Ardabil University of Medical Sciences

7. Prostanoids Metabolism Ardabil University of Medical Sciences

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

10. Table 25-1. Eicosanoid Receptors MAJOR PHENOTYPE IN KNOCKOUT MICE PRIMARY COUPLING SECONDARY LIGAND PRIMARY LIGAND RECEPTOR ↓ Allergic asthma↑ cAMP (G s ) PGD 2 DP 1 ?↑ Ca 2+ i (G i )15d-PGJ 2 ?PGD 2 DP 2 /CHRT 2 Decreased response of colon to carcinogens GqGq PGE 2 EP 1 Impaired ovulation and fertilization; salt sensitive hypertension ↑ cAMP PGE 2 EP 2 Resistance to pyrogens↓ cAMP (G i ) ↑ cAMP (G s ) ↑ PLC (G q ) PGE 2 EP 3A-D Patent ductus arteriosus↑ cAMP (G s ) PGE 2 EP 4 Failure of parturitionGqGq IsoP?PGF 2α FP A,B Ardabil University of Medical Sciences

11. ↑ Thrombotic response, ↓ response to vascular injury ↑ cAMP (G s )PGE 2 PGI 2 IP ↑bleeding time, ↑ response to vascular injury ↑ PLC (G q, G i, G 12/13, G 16 ) IsoPsTxA 2 TP α,β Some suppression of inflammatory response G 16, G i LTB 4 BLT 1 ?G q -like, G i - like, G z -like 12(S)-HETE 12(R)- HETE LTB 4 BLT 2 ↓ Innate and adaptive immune vascular permeability response, ↑ pulmonary inflammatory and fibrotic response ↑ PLC (G q )LTC 4 /LTE 4 LTD 4 CysLT 1 ↓ Pulmonary inflammatory and fibrotic response ↑ PLC (G q )LTE 4 LTC 4 /LTD 4 CysLT 2 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 TXA 2  mitogen PGF 2  Vasodilators PGI 2 PGE 2 Gastrointestinal tract Longitudinal muscle: PGE 2, PGF 2  Circular muscle: PGF 2 , PGI 2, relaxed by PGE 2 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