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The principal eicosanoid subgroups are the leukotrienes and a group of cyclic molecules, including prostaglandins, prostacyclin, and thromboxane. The leukotrienes retain the straight-chain configuration of the parent arachidonic acid. Prostacyclin, thromboxane, and other members of the prostaglandin group are cyclized derivatives of arachidonic acid. There are several series for most of the principal subgroups, based on different substituents (indicated by letters A, B, etc) and different numbers of double bonds (indicated by a subscript number) in the molecule.
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Active eicosanoids are synthesized in response to a wide variety of stimuli (eg, physical injury, immune reactions). These stimuli activate phospholipases in the cell membrane or cytoplasm, and arachidonic acid (a tetraenoic [4 double bonds] fatty acid) is released from membrane phospholipids (Figure 18–1). Arachidonic acid is then metabolized by several different enzymes. The 2 most important are lipoxygenase (LOX), which results in straight-chain leukotrienes, and cyclooxygenase (COX), which results in cyclization to prostacyclin, prostaglandins, or thromboxane. COX exists in at least 2 forms. COX-1 is found in many tissues; the prostaglandins produced by COX-1 appear to be important for a variety of normal physiologic processes (see later discussion). In contrast, COX-2 is found primarily in inflammatory cells; the products of its actions play a major role in tissue injury (eg, inflammation). In addition to these inflammatory functions, COX-2 is also responsible for synthesis of prostacyclin and of prostaglandins important in normal renal function. Thromboxane is preferentially synthesized in platelets, whereas prostacyclin is synthesized in the endothelial cells of vessels. Naturally occurring eicosanoids have very short half-lives (seconds to minutes) and are inactive when given orally.
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Replacement of tetraenoic fatty acids in the diet with trienoic (3 double bonds) or pentaenoic (5 double bonds) precursors results in the synthesis of much less active prostaglandin and leukotriene products. Thus, dietary therapy with fatty oils from plant or cold-water fish sources can be useful in conditions involving pathogenic levels of eicosanoids.
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C. Mechanism of Action
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Most eicosanoid effects are brought about by activation of cell surface receptors (Table 18–1) that are coupled by the Gs protein to adenylyl cyclase (producing cyclic adenosine monophosphate [cAMP]) or by the Gq protein coupled to the phosphatidylinositol cascade (producing inositol 1,4,5-trisphosphate [IP3] and diacylglycerol [DAG] second messengers).
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A vast array of effects are produced in smooth muscle, platelets, the central nervous system, and other tissues. Some of the most important effects are summarized in Table 18–1. Eicosanoids most directly involved in pathologic processes include prostaglandin F2α, thromboxane A2 (TXA2), and the leukotrienes LTC4 and LTD4. LTC4 and LTD4 are components of the important mediator of bronchoconstriction and shock, slow-reacting substance of anaphylaxis (SRS-A). Leukotriene LTB4 is a chemotactic factor important in inflammation. PGE2 and prostacyclin may act as endogenous vasodilators. PGE1 and its derivatives have significant protective effects on the gastric mucosa. The mechanism may involve increased secretion of bicarbonate and 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. In the kidney, prostaglandins are important modulators of glomerular filtration and act on the afferent and efferent arterioles and mesangial cells. Suppression of prostaglandin production with nonsteroidal anti-inflammatory drugs (NSAIDs, see following text) can markedly reduce the efficacy of diuretic agents (see Chapter 15). PGE2 and PGF2α are released in large amounts from the endometrium during menstruation and can cause dysmenorrhea. PGE2 appears to be involved in the physiologic softening of the cervix at term; PGE2 and PGF2α may play a physiologic role in labor. Platelet aggregation is strongly activated by thromboxane. Topical PGF2α reduces intraocular pressure (see later discussion), but it is not known whether this is a physiologic effect of endogenous PGF2α.
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PGE2 and PGF2α cause contraction of the uterus. PGE2 (as dinoprostone) is approved for use to soften the cervix at term before induction of labor with oxytocin. Both PGE2 and PGF2α have been used as abortifacients in the second trimester of pregnancy. Although effective in inducing labor at term, they produce more adverse effects (nausea, vomiting, diarrhea) than do other oxytocics (eg, oxytocin) used for this application. The PGE1 analog misoprostol has been used with the progesterone antagonist mifepristone (RU 486) as an extremely effective and safe abortifacient combination. Misoprostol has been used for this purpose in combination with either methotrexate or mifepristone in the United States. Misoprostol may cause diarrhea.
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PGE1 is given as an infusion to maintain patency of the ductus arteriosus in infants with transposition of the great vessels until surgical correction can be undertaken.
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3. Pulmonary hypertension and dialysis
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Prostacyclin (PGI2) is approved for use (as epoprostenol) in severe pulmonary hypertension and to prevent platelet aggregation in dialysis machines.
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4. Peptic ulcer associated with NSAID use
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Misoprostol is approved in the United States for the prevention of peptic ulcers in patients who must take high doses of NSAIDs for arthritis and who have a history of ulcer associated with this use.
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PGE1 (as alprostadil) is used in the treatment of impotence by injection into the cavernosa or as a urethral suppository.
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Latanoprost, a PGF2α derivative, is used extensively for the topical treatment of glaucoma. Bimatoprost, travoprost, and unoprostone are related drugs. These agents reduce intraocular pressure, apparently by increasing the outflow of aqueous humor.