Katzung & Trevor's Pharmacology Examination and Board Review, 9th Edition

Chapter 18. Prostaglandins & Other Eicosanoids

Chapter Prostaglandins & Other Eicosanoids: Introduction

The eicosanoids are an important group of endogenous fatty acid derivatives that are produced from arachidonic acid, a 20-carbon fatty acid lipid in cell membranes. Major families of eicosanoids include the straight-chain derivatives (leukotrienes) and cyclic derivatives (prostacyclin, prostaglandins, and thromboxane). Inhibitors of the eicosanoids are shown in Figure 18-1 and discussed in the text.

FIGURE 18-1

Synthesis of eicosanoid autacoids. Arachidonic acid is released from membrane lipids by phospholipase A2 and then converted into straight-chain derivatives by lipoxygenase or into cyclized derivatives by cyclooxygenase. Because many of the effects of these products are pathogenic, drugs that inhibit synthesis or prevent the actions of the products are clinically useful.

High-Yield Terms to Learn

Abortifacient A drug used to cause an abortion. Example: prostaglandin F2

Cyclooxygenase Enzyme that converts arachidonic acid to PGG and PGH, the precursors of the prostaglandins Dysmenorrhea Painful uterine cramping caused by prostaglandins released during menstruation EndoperoxideGeneral term for prostaglandin precursors, for example, PGG, PGH Great vessel transposition Congenital anomaly in which the pulmonary artery exits from the left ventricle and the aorta from the right ventricle. Incompatible with life after birth unless a large patent ductus or ventricular septal defect is present Lipoxygenase Enzyme that converts arachidonic acid to leukotriene precursors (HPETEs) NSAID Nonsteroidal anti-inflammatory drug, for example, aspirin, ibuprofen, celecoxib. Inhibitor of cyclooxygenase Oxytocic A substance that causes uterine contraction Patent ductus arteriosus Persistence after birth of the fetal shunt between the pulmonary artery and the aorta Phospholipase A2 Enzyme in the cell membrane that generates arachidonic acid from membrane lipid constituents Slow-reacting substance of anaphylaxis (SRS-A) Material originally identified by bioassay from tissues of animals in anaphylactic shock; now recognized as a mixture of leukotrienes, especially LTC4, and LTD4

Eicosanoid Agonists

Classification

The principal eicosanoid subgroups are the straight-chain leukotrienes and the cyclic molecules, including prostaglandins, prostacyclin, and thromboxane. The leukotrienes retain the straight-chain configuration of 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.

Synthesis

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 mechanisms, 2 of which are most important. First, metabolism to straight-chain products is performed by lipoxygenase, ultimately producing leukotrienes. Alternatively, cyclization by the enzyme cyclooxygenase (COX) may occur, ultimately resulting in the production of prostacyclin, prostaglandins, or thromboxane. COX exists in at least 2 forms. COX-1 is found in many tissues; the prostaglandins produced in these tissues by COX-1 appear to be important for a variety of normal physiologic processes (see later discussion). In contrast, COX-2is found primarily in inflammatory cells; the products of its actions play a major role in tissue injury (eg, inflammation). In contrast to these inflammatory functions, COX-2 is also responsible for synthesis of prostacyclin in the vascular endothelium and of prostaglandins important in renal function. Thromboxane is preferentially synthesized in platelets, whereas prostacyclin, as noted, 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.

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 eicosanoids.

Mechanism of Action

Most eicosanoid effects appear to be 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 to the phosphatidylinositol cascade (producing inositol 1,4,5-trisphosphate [IP 3] and diacylglycerol [DAG] second messengers).

TABLE 18-1 Effects of some important eicosanoids.

Effect PGE 2

PGF 2

PGI 2

TXA 2

LTB 4

LTC 4

LTD 4

Major receptors EP1-4

FPA,B

IP TP,

BLT1,2

CysLT2

CysLT1

Coupling protein Gs, Gq

Gq

Gs

Gq

Gq

Gq

Gq, Gi

Vascular tone   or    ?  or   or  Bronchial tone     ?   Uterine tone a

   ? ? ? Platelet aggregation  or    ? ? ? Leukocyte chemotaxis ? ? ? ?   

aLow concentrations cause contraction, higher concentrations cause relaxation.

? = unknown effect

Effects

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 (PG) F2, thromboxane A2 (TXA2), and the leukotrienes LTC4 and LTD4. LTC4 and LTD4 comprise the important mediator of bronchoconstriction, slow-reacting substance of anaphylaxis (SRS-A). Leukotriene LTB4 is a chemotactic factor important in inflammation. PGE2 and prostacyclin 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 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. 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 PGF2 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 is associated with uterine contractions induced by prostaglandins, especially PGF2. Platelet aggregation is strongly activated by thromboxane. PGF2 reduces intraocular pressure (see later discussion), but it is not known whether this is a physiologic effect of endogenous PGF2.

Clinical Uses

Obstetrics

PGE2 and PGF2 cause contraction of the uterus. PGE2 (as dinoprostone ) is approved for use to ripen the cervix at term before induction of labor with oxytocin. Both PGE2 and PGF2 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 extensively with the progesterone antagonist mifepristone (RU 486) as an extremely effective and safe abortifacient combination in Europe. Misoprostol has been used for this purpose in combination with either methotrexate or mifepristone in the United States.

Pediatrics

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.

Pulmonary Hypertension and Dialysis

Prostacyclin (PGI2 ) is approved for use (as epoprostenol ) in severe pulmonary hypertension and to prevent platelet aggregation in dialysis machines.

Peptic Ulcer Associated with NSAID Use

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.

Urology

PGE1 (as alprostadil ) is used in the treatment of impotence by injection into the cavernosa.

Ophthalmology

Latanoprost, a PGF2 derivative, is used extensively for the topical treatment of glaucoma. Bimatoprost, travoprost, and unoprostone are newer, related drugs. These agents apparently increase the outflow of aqueous humor, thus reducing intraocular pressure.

Eicosanoid Antagonists

Phospholipase A2 and cyclooxygenase can be inhibited by drugs and some of these inhibitors are mainstays in the treatment of inflammation (Figure 18-1 and Chapter 36). Zileuton is a selective inhibitor of lipoxygenase and some cyclooxygenase inhibitors exert a mild inhibitory effect on leukotriene synthesis. Inhibitors of the receptors for the prostaglandins and the leukotrienes are being actively sought. Zafirlukast and montelukast, inhibitors at the LTD4 receptor, are currently available for the treatment of asthma (Chapter 20).

Corticosteroids

As indicated in Figure 18-1, corticosteroids inhibit the production of arachidonic acid by phospholipases in the membrane. This effect is mediated by intracellular steroid receptors that, when activated by an appropriate steroid, increase expression of specific proteins capable of inhibiting phospholipase. Steroids also inhibit the synthesis of COX-2. These effects are thought to be the major mechanisms of the important anti-inflammatory action of corticosteroids.

NSAIDs

Aspirin and other nonsteroidal (ie, noncorticosteroid) anti-inflammatory drugs inhibit cyclooxygenase and the production of the thromboxane, prostaglandin, and prostacyclin branches of the synthetic path (see Fig. 18-1). Most of the currently available NSAIDs nonselectively inhibit both COX-1 and COX-2. In fact, many inhibit COX-1 somewhat more effectively than COX-2, the isoform thought to be responsible for synthesis of inflammatory eicosanoids. Celecoxib is the most selective COX-2 inhibitor available in the United States; meloxicam is also slightly COX-2-selective. The highly COX-2-selective rofecoxib and valdecoxib were withdrawn from the US market because of reports of cardiovascular toxicity (see Chapter 36).

Inhibition of cyclooxygenase by aspirin, unlike that by other NSAIDs, is irreversible. It is thought that aspirin allergy results from diversion of arachidonic acid to the leukotriene pathway when the cyclooxygenase-catalyzed prostaglandin pathway is blocked. The resulting increase in leukotriene synthesis causes the bronchoconstriction that is typical of aspirin allergy. For unknown reasons, this form of aspirin allergy is more common in persons with nasal polyps.

The antiplatelet action of aspirin results from the fact that the drug's inhibition of thromboxane synthesis is essentially permanent in platelets; they lack the machinery for new protein synthesis. In contrast, inhibition of prostacyclin synthesis in the vascular endothelium is temporary because these cells can synthesize new enzyme. Inhibition of prostaglandin synthesis also results in important anti-inflammatory effects. Inhibition of synthesis of fever-inducing prostaglandins in the brain produces the antipyretic action of NSAIDs. Closure of a patent ductus arteriosus in an otherwise normal infant can be accelerated with an NSAID such as indomethacin or ibuprofen.

Leukotriene Antagonists

As noted, an inhibitor of lipoxygenase (zileuton) and LTD4 and LTE4 receptor antagonists (zafirlukast, montelukast) are available for clinical use. Currently, these agents are approved only for use in asthma (see Chapter 20).

Checklist

When you complete this chapter, you should be able to:

 List the major effects of PGE2, PGF2, PGI2, LTB4, LTC4, and LTD4.

 List the cellular sites of synthesis and the effects of thromboxane and prostacyclin in the vascular system.

List the currently available therapeutic antagonists of leukotrienes and prostaglandins and their targets (receptors or enzymes).

 Explain the different effects of aspirin on prostaglandin synthesis and on leukotriene synthesis.

Drug Summary Table: Prostaglandins & Other Eicosanoids

Subclass Mechanism of Action Clinical Applications Pharmacokinetics Toxicities, Interactions Leukotrienes LTB4

Chemotactic factor in inflammation None Local release Duration: seconds Inflammatory mediator LTC4, LTD4

Bronchoconstrictors important in anaphylaxis; cause edema None Local release Duration: seconds Inflammatory mediator Leukotriene antagonists Lipoxygenase inhibitor: zileuton Blocks synthesis of leukotrienes Asthma prophylaxis Oral Duration: ~3 h Liver enzyme elevation Leukotriene receptor inhibitors: montelukast, zafirlukast Block CysLT1 receptor; reduce bronchoconstriction in asthma

Asthma prophylaxis Oral Duration: 3-10 h Liver enzyme elevation Thromboxane TXA2

Activates TP receptors, causes platelet aggregation, vasoconstriction

None Local release Duration: seconds See Mechanism of Action Prostacyclin PGI2: epoprostenol

Activates IP receptors, causes vasodilation, reduces platelet aggregation Vasodilator in pulmonary hypertension, antiplatelet agent in extracorporeal dialysis Infusion Duration: minutes Hypotension, flushing, headache PGI2 analog, treprostinil: parenteral for pulmonary hypertension Prostaglandins PGE1 derivative: misoprostol Activates EP receptors, causes increased HCO3- and mucus secretion in stomach; uterine contraction

Protective agent in peptic ulcer disease; abortifacient Oral Duration: minutes Diarrhea, uterine cramping PGE1 analog, alprostadil: injectable form for erectile dysfunction PGE1 Relaxes smooth muscle in ductus arteriosus Transposition of great vessels, to maintain patent ductus until surgery Infusion Duration: minutes Hypotension PGE2: dinoprostone

Low concentrations contract, higher concentrations relax uterine and cervical smooth muscle Abortifacient, cervical ripening Vaginal Duration: 3-5 h Cramping, fetal trauma PGF2 derivative: latanoprost

Increases outflow of aqueous humor, reduces intraocular pressure Glaucoma Topical Duration: 4-8 h Color change in iris Cyclooxygenase inhibitors (NSAIDs) Nonselective COX-1, COX-2 inhibitors: ibuprofen, indomethacin, naproxen, others Reversibly inhibit COX-1 and COX-2; reduce synthesis of prostaglandins See Chapter 36 Aspirin Irreversibly inhibits COX-1 and COX-2; reduce synthesis of prostaglandins See Chapter 36 Selective COX-2 inhibitor: celecoxib Selectively reversibly inhibits COX-2 See Chapter 36 Phospholipase A2 inhibitors

Corticosteroids Reversibly inhibits phospholipase A2 and reduces synthesis of COX enzymes

See Chapter 39



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