Eicosanoids, Prostaglandins PDF

# Introduction to Eicosanoids, Prostaglandins ## Introduction * Eicosanoids are an important group of endogenous fatty acid derivatives. * The eicosanoids include: * The straight-chain derivatives (Leukotrienes) * The cyclic derivatives (prostacyclin, prostaglandins, and thromboxane) * "Ei...

# Introduction to Eicosanoids, Prostaglandins ## Introduction * Eicosanoids are an important group of endogenous fatty acid derivatives. * The eicosanoids include: * The straight-chain derivatives (Leukotrienes) * The cyclic derivatives (prostacyclin, prostaglandins, and thromboxane) * "Eicosanoids" is derived from the Greek word "eikosi" ("twenty"). ## Precursors * Precursor essential fatty acids contain 20 carbons & 3, 4, or 5 double bonds as follows: * Eicosatrienoic acid (dihomo-y-linolenic acid). * Eicosatetraenoic acid (arachidonic acid (AA)). * Eicosapentaenoic acid (EPA). * Arachidonic acid (AA) is the most abundant of the eicosanoid precursors in humans. * AA must first be released from the membrane phospholipids by one or more lipases of the phospholipase A2 (PLA2) type for eicosanoid synthesis to occur. * AA can also be released by a combination of phospholipase C & diglyceride lipase. * Following mobilization, AA is oxygenated by 4 separate routes: * Cyclooxygenase (COX) * Lipoxygenase * P450 epoxygenase * Isoeicosanoid pathways (ref Fig 18-1 Katz B&CP 15th/16th Ed) ## Synthesis of Products of Prostaglandin Endoperoxide Synthases (Cyclooxygenases) * Two unique COX isozymes convert AA into prostaglandin endoperoxides. * COX-1, which is expressed constitutively in most cells. * COX-2, which is inducible & whose expression varies markedly depending on the stimulus. * COX-2 is markedly up-regulated by shear stress, growth factors, tumor promoters, & cytokines. * COX-1 generates prostanoids for physiological processes s.a gastric epithelial cytoprotection * However, COX-2 is the major source of prostanoids in inflammation & Cancer. * Both COX-1 & COX-2 promote the uptake of 2 molecules of oxygen by cyclization of AA to yield PGG2. * PGG2 is then rapidly modified by the peroxidase moiety of the COX enzyme to add a 15-hydroxyl grp that is essential for biologic activity to form PGH2. * Analogous families, PGH₁ & PGH3 and all their subsequent products are derived from homo-y-linolenic acid & eicosapentaenoic acid, respectively. * The prostaglandins, thromboxane, & prostacyclin, are collectively termed the prostanoids. * They are generated from PGH2 thru the action of downstream isomerases & synthases. * The prostaglandins differ from each other in 2 ways: * In the substituents of the pentane ring (indicated by the last letter, e.g., E & F in PGE & PGF) & * In the no. of double bonds in the side chains (Indicated by the subscript, e.g., PGE1, PGE2). ## Pharmacological Effects of Eicosanoids ### Receptor Mechanisms * Eicosanoids act in both an autocrine & paracrine fashion, i.e., within (autocrine) or close to (paracrine) the site of their synthesis & not as circulating hormones. * Eicosanoids bind to receptors on the cell surface. * All Eicosanoid receptors are G protein-coupled. ### Effects of Prostaglandins * PGE2 & prostacyclin (PGI2) may play important roles as endogenous vasodilators. * PGE₁ and its derivatives have significant protective effects on the gastric mucosa. The mechanism may involve increased secretion of bicarbonate & mucus, decreased acid secretion, or both. * PGE₁ and PGE2 relax vascular and other smooth muscle. * PGE2 appears to be the natural vasodilator that maintains patency of the ductus arteriosus during fetal development. * PGs are important modulators of glomerular filtration and act on the afferent and efferent arterioles and mesangial cells. Suppression of prostaglandin production with NSAIDs can markedly reduce the efficacy of diuretic agents. * PGE2 and PGF2α are released in large amounts from the endometrium during menstruation and may play a physiologic role in labor. PGE2 appears to be involved in the physiologic ripening of the cervix at term * Dysmenorrhea (painful menstrual periods) is assoc with uterine contractions induced by PGs, especially PGF2α. Platelet aggregation is strongly activated by thromboxane. PGF2a reduces intraocular pressure ## Biotransformation * The eicosanoids have short half-lives. * They undergo rapid metabolism to inactive products either by: * Hydration (for PGI2 & TXA2) or * Oxidation of the key 15-hydroxyl group to the corresponding ketone by PG 15-OH dehydrogenase. * Further metabolism is by reduction & oxidation. * The inactive metabolites can be determined in blood & urine by immunoassay or mass spectrometry as a measure of the in vivo synthesis of their parent cpds. ## Clinical Uses of Prostaglandins ### Alprostadil * Alprostadil (PGE₁) may be used for its smooth muscle relaxing effects: * To maintain the ductus arteriosus patent in neonates with congenital heart diseases (e.g., transposition of the great vessels, pulmonary atresia or pulmonary artery stenosis) until corrective cardiac surgery can be carried out. * Alprostadil is also used in the Rx of erectile dysfunction (impotence) by injection into the corpora cavernosa. It induces vascular smooth muscle relaxation & erection. ### Misoprostol * Misoprostol, a PGE₁ derivative is used: * As a cytoprotective PG to prevent peptic ulcers in patients who must take high doses of NSAIDs for arthritis & who have a history of peptic ulcer associated with this use. * For labor induction * Misoprostol in combination with mifepristone (a progesterone antagonist) or methotrexate (cytotoxic antifolate drug) are used for terminating early pregnancies. ### PGs Causing Uterine Contraction * PGE2 & PGF2α cause contraction of the uterus. Both have been used to induce abortion (abortifacients) in the 2nd trimester of pregnancy. #### Carboprost Tromethamine * Carboprost tromethamine, a PGF2α analog used to: * Induce 2nd trimester abortion * Control postpartum hemorrhage that is not responding to conventional methods of management #### Dinoprostone * PGE2 (as dinoprostone) is used in obstetrics to dilate the cervix during induction of labor: * At term * For missed abortion * For benign hydatidiform mole. * A missed abortion is an in-utero death of the embryo or fetus before the 20th week of gestation with retained conception products. A missed abortion may also be referred to as a blighted ovum or an anembryonic pregnancy. * A hydatidiform mole contains many cysts (sacs of fluid). It is the most common type of gestational trophoblastic tumor. #### Enprostil * Enprostil, a synthetic analogue of PGE2, is effective in the Rx of patients with duodenal or gastric ulcers. * It is cytoprotective at low doses & * Is a highly potent inhibitor of gastric HCI secretion at higher doses. * Both PGE2 & PGF2α are effective in inducing labor at term. However, they produce more adverse effects (e.g., nausea, vomiting, diarrhea) than do other oxytoxics (e.g., oxytocin) that are used for this indication. ### Latanoprost Bimatoprost Travoprost Unoprostone * Latanoprost Bimatoprost, travoprost, & unoprostone are topically active PGF2a derivatives. * They are used in ophthalmology to Rx open angle glaucoma or ocular hypertension. These agents apparently increase the outflow of aqueous humor, to reduce intraocular pressure. ### Bimatoprost * Bimatoprost is also FDA approved for Rx of eyelash hypotrichosis. It has shown efficacy in enhancing eyelash growth after chemotherapy ### Prostacyclin * Prostacyclin (PGI2) is produced mainly by the vascular endothelium. It is a powerful vasodilator & inhibitor of platelet aggregation. * Synthetic PGI2 (epoprostenol) & PGI2 analogs (iloprost, selexipag, treprostinil) are used clinically: * To RX pulmonary HTN * Porto-pulmonary HTN which arises secondary to liver disease & * To prevent platelet aggregation in dialysis machines ## Thromboxane * Thromboxane (TXA2) has undesirable properties (e.g., aggregation of platelets, vasoconstriction). * Therefore, TXA2-receptor antagonists (TXRA) & synthesis inhibitors (TXSI) have been developed for cardiovascular indications. However, these (except aspirin) have yet to establish a place in clinical usage, because large clinical trials have failed to show superiority over low-dose aspirin for secondary stroke protection. * Terutroban is an orally active TXRA in clinical development for use in secondary prevention of thrombotic events in cardiovascular disease. * A thromboxane synthase inhibitor (ozagrel) and a receptor antagonist (seratrodast) are used in the treatment of asthma in Japan. However, their effects in asthma are small.