Eicosanoids PDF

L1 Dr. Alaa AL- Sheek Mashhad Eicosanoids Eicosanoids are lipid derived autacoids. Autacoids are endogenous compounds formed by the tissues on which they act; thus, they act as local hormones. They differ from circulating hormones in that they are produced by...

L1 Dr. Alaa AL- Sheek Mashhad Eicosanoids Eicosanoids are lipid derived autacoids. Autacoids are endogenous compounds formed by the tissues on which they act; thus, they act as local hormones. They differ from circulating hormones in that they are produced by many tissues rather than in specific endocrine glands. Eicosanoids include Prostaglandins, Thromboxanes, and Leukotrienes. Two COX isozymes convert arachidonic acid into prostaglandin; (COX-1) that generates prostanoids for "housekeeping" as gastric epithelial cyto-protection. COX-2 is the major source of prostanoids in inflammation and cancer. Products of COX enzymes are termed the prostanoids while the products of Lipoxygenase include leukotriene B4 (LTB4), leukotriene C4 (LTC4), LTD4 and LTE4. LTC4 and LTD4 are potent bronchoconstrictors. 1 Effects of Prostaglandins& Thromboxanes: A Smooth muscle: 1- Vascular: TXA2 and PGF2α are potent VC, by increasing intracellular calcium and activation of protein kinase C. PGI2 and PGE2 promote VD by increasing cAMP, decreasing intracellular calcium and increasing potassium. Pulmonary hypertension: Prostacyclin lowers peripheral, pulmonary, and coronary resistance. Treprostinil is approved for pulmonary hypertension. 2  Peripheral vascular disease: PGE and PGI2 compounds uses in Raynaud's phenomenon and peripheral atherosclerosis. Patent ductus arteriosus: Alprostadil. 2- GIT: Longitudinal muscle is contracted by PGE2 by inhibiting adenylyl cyclase so decreasing cAMP and increasing intracellular calcium. PGF2α cause contraction by smooth muscle cells fusion and growth and increase intracellular calcium. Circular muscle is contracted strongly by PGF2α and weakly by PGI2, and relaxed by PGE2 Misoprostol, a PGE1 derivative, is a cytoprotective used to prevent peptic ulcer. 3- Airways: Smooth muscle is relaxed by PGE2 and PGI2 and contracted by PGD2 via increasing chemotaxis and degranulation of inflammatory cells. TXA2, and PGF2α cause contraction by increasing intracellular calcium. B-Platelets: Low concentrations of PGE2 enhance platelet aggregation because inhibit cAMP and enhance ADP-induced platelet aggregation, whereas higher concentrations inhibit, platelet aggregation by the opposite mechanism. Prostaglandin F2α antagonizes thromboxane A2-induced platelet aggregation. 3 Both PGD2 and PGI2 inhibit aggregation by decrease thromboxane A2 and decrease platelet adherence to the vessels wall. TXA2 is a platelet aggregator. This is achieved by platelet-shape change. Low-dose aspirin selectively inhibits platelet COX-1. Prostacyclin (PGI2, epoprostenol) is a powerful vasodilator and inhibitor of platelet aggregation. It is used for pulmonary hypertension and Porto-pulmonary hypertension. C-Kidney: Both PGE2 and PGI2 increase renin release, glomerular filtration and inhibit sodium reabsorption within kidney tubules. D-Reproductive organs Female: Uterine muscle is contracted by PGF2α by increasing oxytocin level. Also contracted by TXA2, and low concentrations of PGE2; PGI2 while high concentrations of PGE2 cause relaxation. Abortion: PGE2 and PGF2α are used to induce labor. Dinoprostone, a synthetic preparation of PGE2, is administered vaginally for oxytocic use. 4 Carboprost is PGF2α used to induce second-trimester abortions and to control postpartum hemorrhage. Vomiting and diarrhea occur commonly and transient elevations in temperature are seen. Antiprogestin e.g. mifepristone, have been combined with an oral oxytocic prostaglandin (e.g. misoprostol 'PGE1') to produce early abortion. The major toxicities are cramping pain and diarrhea. 5  Facilitation of labor: PGE2, PGF2α, and their analogs effectively initiate and stimulate labor. Male Reproductive System: Men with a low seminal fluid concentration of PG are relatively infertile. PGE 1 enhances penile erection. Alprostadil (PGE1) may be used for the treatment of impotence. E-Central and peripheral nervous systems: Fever: PGE2 Sleep: PGD2 induces natural sleep by stimulating DP1 receptors in the basal forebrain and the hypothalamus. Also stimulates releasing of adenosine which act on adenosine A2 receptor. 6 Neuro-transmission: PGE compounds inhibit the release of norepinephrine F-Neuroendocrine organs: PGE2 promotes the release of growth hormone, prolactin, TSH, ACTH, FSH, and LH. LTC4 and LTD4 stimulate LH secretion G-Bone metabolism: PGE2 increases bone turnover H-Eye: PGE and PGF derivatives lower intraocular pressure by increase out flow of aqueous humor via uveoscleral pathway. Latanoprost Bimatoprost Travaprost 7  Unoprostone They are topically active PGF2α derivatives used to treat open angle glaucoma. They increases eyelash prominence, length, and darkness I-Cancer: Angiogenesis, which is required for multistage carcinogenesis, is promoted by COX-2-derived TXA2, as well as PGE2 and PGI2. Effects of Lipoxygenase products: Blood cells and inflammation: they act as immunomodulator and chemotacting agents for many inflammatory cells Heart: LTC4 and LTD4 reduce myocardial contractility and coronary blood flow. Smooth muscle 8 1- Gastrointestinal: patients with inflammatory bowel disease express substantially increased amounts of LTB4. 2- Airways: LTC4 and LTD4 are potent bronchoconstrictors. PGE2 is a powerful bronchodilator when given in aerosol form. But it promotes coughing. Leukotriene-receptor inhibitors (e.g. zafirlukast, montelukast) are effective in asthma. A lipoxygenase inhibitor (zileuton) has also been used in asthma. 9 Cromolyn appears to inhibit the release of eicosanoids and other mediators such as histamine and platelet-activating factor from mast cells. Inhibition of eicosanoid synthesis: Corticosteroids block all the known pathways of eicosanoid synthesis. Corticosteroids, the first-line drugs used for treatment of acute rejection because inhibit both phospholipase and COX-2 activity. The NSAIDs (e.g. indomethacin, ibuprofen) block both prostaglandin and thromboxane formation by reversibly inhibiting COX activity. NSAIDs have been used to treat inflammatory disorders e.g., arthritis, rheumatoid arthritis..etc 10