2. 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).

3.  The eicosanoids include: 1.the prostaglandins 2.thromboxanes 3.leukotrienes 4.hydroperoxyeicosatetraenoic acids (HPETEs) 5.hydroxyeicosatetraenoic acids (HETEs).

4. Biosynthesis  Arachidonic acid, the most common precursor of the eicosanoids, is formed by two pathways: 1.Phospholipase A 2 -mediated production from membrane phospholipids; this pathway is inhibited by glucocorticoids. 2.Phospholipase C.

7. Eicosanoids are synthesized by two pathways: 1. The prostaglandin H synthase (COX, cyclooxygenase) pathway produces: A. thromboxane B. the primary prostaglandins  prostaglandin E, or PGE  prostaglandin F, or PGF  prostaglandin D, or PGD) C. prostacyclin (PGI 2 )

8. 2. The lipoxygenase pathway produces:  HPETEs  HETEs  leukotrienes

9.  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 A 2 (TXA 2 ) is rapidly hydrated to the less active TXB 2.  PGI 2 is hydrolyzed to 6-keto-PGF 1α.

10.  Various eicosanoids are synthesized throughout the body  synthesis can be very tissue specific:  PGI 2 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.

11. Actions:  Vascular smooth muscle  PGE 2 and PGI 2 are potent vasodilators in most vascular beds.  Thromboxane is a potent vasoconstrictor.

12.  Inflammation  PGE 2 and PGI 2 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.

13.  Bronchial smooth muscle  PGFs cause smooth muscle contraction.  PGEs cause smooth muscle relaxation.  Leukotrienes and thromboxane are potent bronchoconstrictors and are the most likely candidates for mediating allergic bronchospasm.

14.  Uterine smooth muscle.  PGE 2 and PGF 2a  cause contraction of uterine smooth muscle in pregnant women. nonpregnant uterus  The nonpregnant uterus has a more variable response to prostaglandins  PGF 2a causes contraction  PGE 2 causes relaxation.

15.  Gastrointestinal tract  PGE 2 and PGF 2a  increase the rate of longitudinal contraction in the gut and decrease transit time.  The leukotrienes  are potent stimulators of gastrointestinal smooth muscle.  PGE 2 and PGI 2  inhibit acid and pepsinogen secretion in the stomach.  Prostaglandins  increase mucus, water, and electrolyte secretion in the stomach and the intestine.

16.  Blood  TXA 2  is a potent inducer of platelet aggregation.  PGI 2 and PGE 2  inhibit platelet aggregation.  PGEs  induce erythropoiesis by stimulating the renal release of erythropoietin.  5-HPETE  stimulates release of histamine  PGI 2 and PGD  inhibit histamine release.

17. Therapeutic uses Induction of labor at term.  Induction of labor is produced by:  infusion of PGF 2  (carboprost tromethamine) [Hemabate] or  PGE 2 (dinoprostone) [Prostin E].

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

19. Maintenance of ductus arteriosus  is produced by PGE 1 [Prostin VR] infusion  PGE 1 will maintain patency of the ductus arteriosus, which may be desirable before surgery.

20. Treatment of peptic ulcer.  Misoprostol [Cytotec]  a methylated derivative of PGE 1  is approved for use in patients taking high doses of nonsteroidal antiinflammatory drugs (NSAIDs) to reduce gastric ulceration.

21. Erectile dysfunction:  Alprostadil (PGE 1 ) 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

22. Adverse effects of eicosanoids  local pain and irritation  bronchospasm  gastrointestinal disturbances: nausea, vomiting, cramping, and diarrhea.