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Eicosanoids

Eicosanoids. Overview. Eicosanoids are a large group of autocoids with potent effects on virtually every tissue in the body these agents are derived from metabolism of 20-carbon, unsaturated fatty acids ( eicosanoic acids). The eicosanoids include: the prostaglandins thromboxanes

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Eicosanoids

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  1. Eicosanoids

  2. Overview • Eicosanoidsare a large group of autocoids with potent effects on virtually every tissue in the body • these agents are derived from metabolism of 20-carbon, unsaturated fatty acids (eicosanoic acids).

  3. The eicosanoids include: • the prostaglandins • thromboxanes • leukotrienes • hydroperoxyeicosatetraenoic acids (HPETEs) • hydroxyeicosatetraenoic acids (HETEs).

  4. Biosynthesis • Arachidonic acid, the most common precursor of the eicosanoids, is formed by two pathways: • Phospholipase A2-mediated production from membrane phospholipids; this pathway is inhibited by glucocorticoids. • Phospholipase C.

  5. Eicosanoids are synthesized by two pathways: • The prostaglandin H synthase (COX, cyclooxygenase) pathwayproduces: • thromboxane • the primary prostaglandins • prostaglandin E, or PGE • prostaglandin F, or PGF • prostaglandin D, or PGD) • prostacyclin (PGI2)

  6. The lipoxygenase pathway produces: • HPETEs • HETEs • leukotrienes

  7. The eicosanoids all have short plasma half-lives (typically 0.5—5 min). • Most catabolism occurs in the lung. • Metabolites are excreted in the urine. • Thromboxane A2 (TXA2) is rapidly hydrated to the less active TXB2. • PGI2 is hydrolyzed to 6-keto-PGF1α.

  8. Various eicosanoids are synthesized throughout the body • synthesis can be very tissue specific: • PGI2 is synthesized in endothelial and vascular smooth muscle cells. • Thromboxane synthesis occurs primarily in platelets. • HPETEs, HETEs, and the leukotrienes are synthesized predominantly in mast cells, white blood cells, airway epithelium, and platelets.

  9. Actions: • Vascular smooth muscle • PGE2 and PGI2 are potent vasodilators in most vascular beds. • Thromboxaneis a potent vasoconstrictor.

  10. Inflammation • PGE2 and PGI2 cause an increase in blood flow and promote, but do not cause, edema. • HETEs (5-HETE, 12-HETE, 15-HETE) and leukotrienes cause chemotaxis of neutrophils and eosinophils.

  11. Bronchial smooth muscle • PGFs cause smooth muscle contraction. • PGEscause smooth muscle relaxation. • Leukotrienes and thromboxane are potent bronchoconstrictors and are the most likely candidates for mediating allergic bronchospasm.

  12. Uterine smooth muscle. • PGE2 and PGF2a • cause contraction of uterine smooth muscle in pregnant women. • The nonpregnant uterus has a more variable response to prostaglandins • PGF2a causes contraction • PGE2 causes relaxation.

  13. Gastrointestinal tract • PGE2 and PGF2a • increase the rate of longitudinal contraction in the gut and decrease transit time. • The leukotrienes • are potent stimulators of gastrointestinal smooth muscle. • PGE2 and PGI2 • inhibit acid and pepsinogen secretion in the stomach. • Prostaglandins • increase mucus, water, and electrolyte secretion in the stomach and the intestine.

  14. Blood • TXA2 • is a potent inducer of platelet aggregation. • PGI2 and PGE2 • inhibit platelet aggregation. • PGEs • induce erythropoiesis by stimulating the renal release of erythropoietin. • 5-HPETE • stimulates release of histamine • PGI2 and PGD • inhibit histamine release.

  15. Therapeutic uses Induction of labor at term. • Induction of labor is produced by: • infusion of PGF2a (carboprost tromethamine) [Hemabate] or • PGE2 (dinoprostone) [Prostin E].

  16. Therapeutic abortion: • Inducing abortion in the second trimester: • Infusion of carboprost tromethamine or • Administration of vaginal suppositories containing dinoprostone • inducing first-trimester abortion: • these prostaglandins are combined with mifepristone (RU486)

  17. Maintenance of ductus arteriosus • is produced by PGE1 [Prostin VR] infusion • PGE1 will maintain patency of the ductus arteriosus, which may be desirable before surgery.

  18. Treatment of peptic ulcer. • Misoprostol [Cytotec] • a methylated derivative of PGE1 • is approved for use in patients taking high doses of nonsteroidal antiinflammatory drugs (NSAIDs) to reduce gastric ulceration.

  19. Erectile dysfunction: • Alprostadil (PGE1) can be injected directly into the corpus cavernosum or administered as a transurethral suppository to cause vasodilation and enhance tumescence. injected directly into the corpus cavernosum transurethral suppository

  20. Adverse effectsof eicosanoids • local pain and irritation • bronchospasm • gastrointestinal disturbances: nausea, vomiting, cramping, and diarrhea.

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