Basic & Clinical Pharmacology, 10th Edition

18. The Eicosanoids: Prostaglandins, Thromboxanes, Leukotrienes, & Related Compounds - Emer M Smyth, PhD, & Garret A FitzGerald, MD*

INTRODUCTION

Acronyms

COX Cyclooxygenase

DHET Dihydroxyeicosatrienoic acid

EET Epoxyeicosatrienoic acid

HETE Hydroxyeicosatetraenoic acid

HPETE Hydroxyperoxyeicosatetraenoic acid

LTB, LTC Leukotriene B, C, etc

LOX Lipoxygenase

LXA, LXB Lipoxin A, B

NSAID Nonsteroidal anti-inflammatory drug

PGE, PGF Prostaglandin E, F, etc

PLA, PLC Phospholipase A, C

TXA, TXB Thromboxane A, B, etc

The eicosanoids are oxygenation products of polyunsaturated long-chain fatty acids. They are ubiquitous in the animal kingdom and are also found¾together with their precursors¾in a variety of plants. They constitute a very large family of compounds that are highly potent and display an extraordinarily wide spectrum of biologic activity. Because of their biologic activity, the eicosanoids, their specific receptor antagonists and enzyme inhibitors, and their plant and fish oil precursors have great therapeutic potential. Their short half-lives, which are seconds to minutes, make special delivery systems or synthesis of stable analogs mandatory for their clinical use.

*The authors acknowledge the contributions of the previous authors of this chapter, Drs. Marie L. Foegh and Peter W. Ramwell.

ARACHIDONIC ACID & OTHER POLYUNSATURATED PRECURSORS

Arachidonic acid, the most abundant and important of the eicosanoid precursors, is a 20-carbon (C20) fatty acid that contains four double bonds beginning at the omega-6 position to yield a 5,8,11,14-eicosatetraenoic acid (designated C20:4-6). For eicosanoid synthesis to occur, arachidonate must first be released or mobilized from membrane phospholipids by one or more lipases of the phospholipase A₂ (PLA₂) type (Figure 18-1). At least three phospholipases mediate arachidonate release from membrane lipids: cytosolic (c) PLA₂, secretory (s) PLA₂, and calcium-independent (i) PLA₂. In addition, arachidonate is also released by a combination of phospholipase C and diglyceride lipase.

Following mobilization, arachidonic acid is oxygenated by four separate routes: the cyclooxygenase (COX), lipoxygenase, P450 epoxygenase, and isoprostane pathways (Figure 18-1). A number of factors determine the type of eicosanoid synthesized: (1) the species, (2) the type of cell, and (3) the cell's particular phenotype. The pattern of eicosanoids synthesized also frequently reflects (4) the manner in which the cell is stimulated. Finally, an important factor governing the pattern of eicosanoid release is (5) the nature of the precursor polyunsaturated fatty acid that has been esterified in specific membrane phospholipids. For example, homo-g-linoleic acid (C20:3-6), which is trienoic, yields products that differ from those derived from arachidonate (C20:4-6), which has four double bonds. Similarly, the products derived from eicosapentaenoic acid (C20:5-3), which has five double bonds, are also quantitatively different. This is the basis for using as nutritional supplements in humans the structurally different fatty acids obtained from cold water fish or from plants. An example of the significance of the polyunsaturated fatty acid precursors is evident when one considers thromboxane A (TXA) derived from the COX pathway. TXA₂ is synthesized from arachidonate, a tetraenoic acid, and is a powerful vasoconstrictor and aggregator of platelets. However 5,8,11,14,17-eicosapentaenoic acid yields TXA₃, which is relatively inactive. In theory, dietary eicosapentaenoate substitution for arachidonate should minimize thrombotic events due to the displacement of tetraenoic arachidonate in the membrane by a pentaenoic acid.

SYNTHESIS OF EICOSANOIDS

Products of Prostaglandin Endoperoxide Synthases (Cyclooxygenases)

Two unique COX isozymes convert arachidonic acid into prostaglandin endoperoxide. PGH synthase-1 (COX-1) is expressed constitutively in most cells. In contrast, PGH synthase-2 (COX-2) is inducible; its expression varies markedly depending on the stimulus. COX-2 is an immediate early-response gene product that is markedly up-regulated by shear stress, growth factors, tumor promoters, and cytokines. COX-1 generates prostanoids for "housekeeping" such as gastric epithelial cytoprotection, whereas COX-2 is the major source of prostanoids in inflammation and cancer. This distinction is overly simplistic, however; there are both physiologic and pathophysiologic processes in which each enzyme is uniquely involved and others in which they function coordinately. For example, endothelial COX-2 is the primary source of vascular prostacyclin, whereas renal COX-2-derived prostanoids are important for normal renal development and maintenance of function. An additional COX-1 variant termed "COX-3" has been described in dogs, but it does not appear functionally relevant in other species.

The synthases are important because it is at this step that the nonsteroidal anti-inflammatory drugs (NSAIDs) exert their therapeutic effects (see Chapter 36). Indomethacin and sulindac are slightly selective for COX-1. Meclofenamate and ibuprofen are approximately equipotent on COX-1 and COX-2, whereas celecoxib, diclofenac, rofecoxib, lumiracoxib, and etoricoxib inhibit COX-2 with increasing selectivity. Aspirin acetylates and inhibits both enzymes covalently. Low doses (< 100 mg/day) inhibit preferentially, but not exclusively, COX-1, whereas higher doses inhibit both COX-1 and COX-2.

Both COX-1 and COX-2 promote the uptake of two molecules of oxygen by cyclization of arachidonic acid to yield a C₉-C₁₁ endoperoxide C₁₅ hydroperoxide (Figure 18-2). This product is PGG₂, which is then rapidly modified by the peroxidase moiety of the COX enzyme to add a 15-hydroxyl group that is essential for biologic activity. This product is PGH₂. Both endoperoxides are highly unstable. Analogous families¾PGH₁ and PGH₃ and all their subsequent products¾are derived from homo-g-linolenic acid and eicosapentaenoic acid, respectively.

The prostaglandins, thromboxane, and prostacyclin, collectively termed the prostanoids, are generated from PGH₂ through the action of isomerases and synthases. These terminal enzymes are expressed in a relatively cell-specific fashion, such that most cells make one or two dominant prostanoids. The prostaglandins differ from each other in two ways: (1) in the substituents of the pentane ring (indicated by the last letter, eg, E and F in PGE and PGF) and (2) in the number of double bonds in the side chains (indicated by the subscript, eg, PGE₁, PGE₂). Several products of the arachidonate series are of current clinical importance. Alprostadil (PGE₁) may be used for its smooth muscle relaxing effects to maintain the ductus arterosus patent in some neonates awaiting cardiac surgery and in the treatment of impotence. Misoprostol, a PGE₁ derivative, is a cytoprotective prostaglandin used in preventing peptic ulcer and in combination with mifepristone (RU486) for terminating early pregnancies. PGE₂ and PGF_2a are used in obstetrics to induce labor. Latanoprost and several similar compounds are topically active PGF_2a derivatives used in ophthalmology to treat open angle glaucoma. Prostacyclin (PGI₂, epoprostenol) is synthesized mainly by the vascular endothelium and is a powerful vasodilator and inhibitor of platelet aggregation. It is used clinically to treat pulmonary hypertension and portopulmonary hypertension. In contrast, thromboxane (TXA₂) has undesirable properties (aggregation of platelets, vasoconstriction). Therefore TXA₂-receptor antagonists and synthesis inhibitors have been developed for cardiovascular indications, although these (except for aspirin) have yet to establish a place in clinical usage.

All the naturally occurring COX products undergo rapid metabolism either initially by hydration to inactive products, which are then metabolized (PGI₂, TXA₂), or by oxidation of the key 15-hydroxyl group to the corresponding ketone by prostaglandin 15-OH dehydrogenase. Further metabolism is by D¹³ reduction, b-oxidation, and w-oxidation. The inactive metabolites can be determined in blood and urine by immunoassay or mass spectrometry as a measure of the in vivo synthesis of their parent compounds.

Products of Lipoxygenase

The metabolism of arachidonic acid by the 5-, 12-, and 15-lipoxygenases (LOX) results in the production of hydroperoxyeicosatetraenoic acids (HPETEs), which rapidly convert to hydroxy derivatives (HETEs) and leukotrienes (Figure 18-3). The most actively investigated leukotrienes are those produced by the 5-lipoxygenase present in inflammatory cells (polymorphonuclear leukocytes [PMNs], basophils, mast cells, eosinophils, macrophages). This pathway is of great interest since it is associated with asthma, anaphylactic shock, and cardiovascular disease. Stimulation of these cells elevates intracellular Ca²⁺ and releases arachidonate; incorporation of moleular oxygen by 5-LOX, in association with 5-LOX-activating protein (FLAP), then yields the unstable epoxide leukotriene A₄ (LTA₄). This intermediate either converts to the dihydroxy leukotriene B₄ (LTB₄) or conjugates with glutathione to yield leukotriene C₄ (LTC₄), which undergoes sequential degradation of the glutathione moiety by peptidases to yield LTD₄ and LTE₄. These three products are called cysteinyl leukotrienes or peptidoleukotrienes.

LTC₄ and LTD₄ are potent bronchoconstrictors and are recognized as the primary components of the slow-reacting substance of anaphylaxis (SRS-A) that is secreted in asthma and anaphylaxis. There are four current approaches to anti-leukotriene drug development: 5-lipoxygenase enzyme inhibitors, leukotriene-receptor antagonists, inhibitors of FLAP, and phospholipase A₂ inhibitors. Selective leukotriene-receptor antagonists (zafirlukast, montelukast, and pranlukast) are currently used or in trials for treatment of asthma.

LTA₄, the primary product of 5-LOX, can be converted via 12-LOX in platelets to the lipoxins LXA₄ and LXB₄. These mediators can also arise through 5-LOX metabolism of 15-HETE, the product of 15-LOX-2 metabolism of arachidonic acid. 15-LOX-1 prefers linoleic acid as a substrate forming 15S-hydroxyoctadecadienoic acid. The stereochemical isomer, 15 R-HETE, may be derived from the action of aspirin-acetylated COX-2 and further transformed in leukocytes by 5-LOX to 15-epi-LXA₄ or 15-epi-LXB₄, the so-called aspirin-triggered lipoxins. 12-HETE can also undergo a catalyzed molecular rearrangement to epoxy-hydroxyeicosatrienoic acids called hepoxilins. The biologic roles of these mediators remain ill-defined.

The LOX located in epidermal cells are distinct from "conventional" enzymes¾arachidonic acid and linoleic acid are apparently not the natural substrates for epidermal LOX. Epidermal accumulation of 12R-HETE is a feature of psoriasis and ichthyosis and inhibitors of 12R-LOX are under investigation for the treatment of these proliferative skin disorders.

Epoxygenase Products

Specific isozymes of microsomal cytochrome P450 monooxygenases convert arachidonic acid to four epoxyeicosatrienoic acids (EETs) (Figure 18-1). These are the 5,6-, 6,9-, 11,12-, and 14,15-oxido products. Each EET has two stereoisomers (R and S). Their biosynthesis can be altered by pharmacologic, nutritional, and genetic factors that affect P450 expression. These epoxides are unstable and rapidly form the corresponding dihydroxyeicosatrienoic (DHET) acid, eg, 5,6-DHET. Unlike the prostaglandins, both the EETs and the DHETs can be incorporated into phospholipids, which then act as storage sites. Intracellular fatty acid-binding proteins may differentially bind EETs and DHETs, thus modulating their metabolism, activities, and targeting. The epoxygenase products are synthesized in endothelial cells, and cause vasodilation in a number of vascular beds by activating the smooth muscle large conductance Ca²⁺-activated K⁺ channels. This results in smooth muscle cell hyperpolarization and vasodilation, leading to reduced blood pressure. Substantial evidence indicates that EETs may function as endothelium-derived hyperpolarizing factors, particularly in the coronary circulation.

Isoprostanes

The generation of isoprostanes from arachidonic acid is another potentially important pathway. The isoprostanes are prostaglandin stereoisomers. Because prostaglandins have many asymmetric centers, they have a large number of potential stereoisomers. COX is not needed for the formation of the isoprostanes, and its inhibition with aspirin or other NSAIDs should not affect the isoprostane pathway. The primary epimerization mechanism is peroxidation of arachidonate by free radicals. Peroxidation occurs while arachidonic acid is still esterified to the membrane phospholipids. Thus, unlike prostaglandins, these stereoisomers are "stored" as part of the membrane. They are then cleaved, presumably by phospholipases, circulate, and are excreted in urine. Isoprostanes are present in relatively large amounts (ten-fold greater in blood and urine than the COX-derived prostaglandins). They have potent vasoconstrictor effects when infused into renal and other vascular beds and may activate prostanoid receptors. It has been speculated that they may contribute to the pathophysiology of inflammatory responses in a manner insensitive to COX inhibitors.

I. BASIC PHARMACOLOGY OF EICOSANOIDS

MECHANISMS & EFFECTS OF EICOSANOIDS

Receptor Mechanisms

As a result of their short half-lives, the eicosanoids act in an autocrine and paracrine fashion, ie, close to the site of their synthesis. These ligands bind to receptors on the cell surface, and pharmacologic specificity is determined by receptor density and type on different cells. A single gene product has been identified for the PGI₂ receptor (IP receptor), PGF_2a (FP), and TXA₂ (TP), while four distinct PGE₂ receptors (EPs 1-4) and two PGD₂ receptors (DP₁ and DP₂) have been cloned. Additional isoforms of the TP (a and b), FP (A and B), and EP₃ (A-D) receptors can arise through differential mRNA splicing. Two receptors exist for both LTB₄ (BLT₁ and BLT₂) and the cysteinyl-leukotrienes (cysLT₁ and cysLT₂). A single lipoxin receptor termed ALX was found to be the same as the formyl peptide (fMPL)-1 receptor. All of these receptors are G protein-coupled; properties of the best-studied receptors are listed in Table 18-1.

EP₂, EP₄, IP and DP₁ receptors activate adenylyl cyclase via G_s. This leads to increased intracellular cAMP levels, which in turn activates specific protein kinases (see Chapter 2). These kinases phosphorylate internal calcium pump proteins, an action that decreases free intracellular calcium concentration. In contrast, EP₁, FP, and TP receptors activate phosphatidylinositol metabolism, leading to the formation of InsP₃ (IP₃), with subsequent mobilization of Ca²⁺ stores and an increase of free intracellular calcium. Activation of the TP-receptor isoforms may activate or inhibit adenylyl cyclase via G_s (TP_a) or G_i(TP_b), respectively, and signal via G_q and related proteins to membrane associated protein (MAP) kinase signaling pathways. EP₃ receptors can couple to both elevation of intracellular calcium and a decrease in cAMP. The DP₂ receptor, which is unrelated to the other prostanoid receptors, is a member of the fMLP receptor superfamily. This receptor couples through to a G_i-type G protein and leads to inhibition of cAMP synthesis and increases in intracellular calcium in a variety of cell types.

LTB₄ also generates InsP₃ release via the BLT₁ receptor, causing activation, degranulation, and superoxide anion generation in PMNs. The BLT₂ receptor, the low-affinity receptor for LTB₄, is bound with reasonable affinity by 12S- and 12R-HETE, although the biologic relevance of this observation is not clear. CysLT₁ receptors couple to G_q, leading to increased intracellular Ca²⁺.

The contractile effects of eicosanoids on smooth muscle are mediated by the release of calcium, while their relaxing effects are mediated by the generation of cAMP. The effects of eicosanoids on many target systems, including the immune system, can be similarly explained (see below). Many of the eicosanoids' contractile effects on smooth muscle can be inhibited by lowering extracellular calcium or by using calcium channel blocking drugs.

Although prostanoids can activate peroxisome proliferator-activated receptors (PPARs) if added in sufficient concentration in vitro, it is questionable whether these compounds attain concentrations sufficient to function as endogenous nuclear-receptor ligands in vivo.

Effects of Prostaglandins & Thromboxanes

The prostaglandins and thromboxanes have major effects on four types of smooth muscle: vascular, gastrointestinal, airway, and reproductive. Other important targets include platelets and monocytes, kidneys, the central nervous system, autonomic presynaptic nerve terminals, sensory nerve endings, endocrine organs, adipose tissue, and the eye (the effects on the eye may involve smooth muscle).

A. SMOOTH MUSCLE

1. Vascular¾ TXA₂ is a potent vasoconstrictor. It is also a smooth muscle cell mitogen and is the only eicosanoid that has convincingly been shown to have this effect. The mitogenic effect is potentiated by exposure of smooth muscle cells to testosterone, which up-regulates smooth muscle cell TP receptors. PGF_2a is also a vasoconstrictor but is not a mitogen for smooth muscle cells. Another vasoconstrictor is the isoprostane 8-iso-PGF_2a, also known as iPF_2aIII, which may act via the TP receptor. In patients with cirrhosis, it is produced in large amounts in the liver and is thought to play a pathophysiologic role as an important vasoconstrictor substance in the hepatorenal syndrome.

Vasodilator prostaglandins, especially PGI₂ and PGE₂, promote vasodilation by increasing cAMP and decreasing smooth muscle intracellular calcium, primarily via IP and EP₄ receptors. Vascular prostacyclin is synthesized by both smooth muscle and endothelial cells, with the latter being the major contributor. In the microcirculation, PGE₂ is a vasodilator produced by endothelial cells.

2. Gastrointestinal tract¾ Most of the prostaglandins and thromboxanes activate gastrointestinal smooth muscle. Longitudinal muscle is contracted by PGE₂ (via EP₃) and PGF_2a (via FP receptors), whereas circular muscle is contracted strongly by PGF_2a and weakly by PGI₂, and relaxed by PGE₂ (via EP₄ receptors). Administration of either PGE₂ or PGF_2a results in colicky cramps (see Clinical Pharmacology of Eicosanoids, below). The leukotrienes also have powerful contractile effects.

3. Airways¾ Respiratory smooth muscle is relaxed by PGE₂ and PGI₂ and contracted by PGD₂, TXA₂, and PGF_2a. Studies of DP₁ knockout mice suggest an important role of this receptor in asthma. The cysteinyl leukotrienes are bronchoconstrictors. They act principally on smooth muscle in peripheral airways and are a thousand times more potent than histamine both in vitro and in vivo. They also stimulate bronchial mucus secretion and cause mucosal edema. Bronchospasm occurs in about 10% of people taking NSAIDs, probably because of a shift in arachidonate metabolism from COX-1 metabolism to leukotriene formation.

4. Reproductive¾ The actions of prostaglandins on reproductive smooth muscle are discussed below under D. Reproductive Organs.

B. PLATELETS
Platelet aggregation is markedly affected by eicosanoids. Low concentrations of PGE₂ enhance, whereas higher concentrations inhibit, platelet aggregation. Both PGD₂ and PGI₂ inhibit aggregation. TXA₂ is the major product of platelet COX-1, is a platelet aggregator, and amplifies the effects of other more potent platelet agonists such as thrombin. The platelet actions of TXA₂ are restrained in vivo by PGI₂, which inhibits platelet aggregation by all recognized agonists. Platelets release TXA₂ during activation and aggregation. Urinary metabolites of TXA₂ increase in patients experiencing a myocardial infarction; this increment is suppressed substantially by low-dosage aspirin, but a variable contribution, presumably from macrophage COX-2, may be insensitive to such a regimen. Comparative trials of the cardioprotective actions of low- and high-dose aspirin have not been performed. However, indirect comparisons across placebo controlled trials do not suggest an increasing benefit with dose; in fact, they suggest an inverse dose-response relationship, perhaps reflecting increasing inhibition of PGI₂ synthesis at higher doses of aspirin. Platelet COX-1-derived thromboxane synthesis is irreversibly inhibited by chronic dosing with aspirin in low doses. Macrophage COX-2 appears to contribute roughly 10% of the increment in TX biosynthesis observed in smokers, while the rest is derived from platelets.

C. KIDNEY
Both the medulla and the cortex of the kidney synthesize prostaglandins, the medulla substantially more than the cortex. The kidney also synthesizes several hydroxyeicosatetraenoic acids, leukotrienes, cytochrome P450 products, and epoxides. These compounds play important autoregulatory roles in renal function by modifying renal hemodynamics and glomerular and tubular function. This regulatory role is especially important in marginally functioning kidneys, as shown by the decline in kidney function caused by COX inhibitors in elderly patients and those with renal disease.

The major eicosanoid products of the renal cortex are PGE₂ and PGI₂. Both compounds increase renin release; normally, however, renin release is more directly under b₁-adrenoceptor control.

PGE₂ and PGI₂ increase glomerular filtration through their vasodilating effects. These prostaglandins also increase water and sodium excretion. The increase in water clearance probably results from an attenuation of the action of antidiuretic hormone (ADH) on adenylyl cyclase. It is uncertain whether the natriuretic effect is caused by the direct inhibition of sodium reabsorption in the distal tubule or by increased medullary blood flow. Loop diuretics, eg, furosemide, produce some of their effect by stimulating COX activity. In the normal kidney, this increases the synthesis of the vasodilator prostaglandins. Therefore, patient response to a loop diuretic is diminished if a COX inhibitor is administered concurrently (see Chapter 15).

TXA₂ causes intrarenal vasoconstriction (and perhaps an ADH-like effect), resulting in a decline in renal function. The normal kidney synthesizes only small amounts of TXA₂. However, in renal conditions involving inflammatory cell infiltration (such as glomerulonephritis and renal transplant rejection), the inflammatory cells (monocyte-macrophages) release substantial amounts of TXA₂. Theoretically, TXA₂ synthase inhibitors or receptor antagonists should improve renal function in these patients, but no such drug is clinically available.

Hypertension is associated with increased TXA₂ and decreased PGE₂ and PGI₂ synthesis in some animal models, eg, the Goldblatt kidney model. It is not known whether these changes are primary contributing factors or secondary responses. Similarly, increased TXA₂ formation has been reported in cyclosporine-induced nephrotoxicity, but no causal relationship has been established.

D. REPRODUCTIVE ORGANS

1. Female reproductive organs¾ Uterine muscle is contracted by PGF_2a, TXA₂, and low concentrations of PGE₂; PGI₂ and high concentrations of PGE₂ cause relaxation. PGF_2a, together with oxytocin, is essential for the onset of parturition. The effects of prostaglandins on uterine function are discussed below. (See Clinical Pharmacology of Eicosanoids.)

2. Male reproductive organs¾ The role of prostaglandins in semen is still conjectural. The major source of these prostaglandins is the seminal vesicle; the prostate¾despite the name "prostaglandin"¾and the testes synthesize only small amounts. The factors that regulate the concentration of prostaglandins in human seminal plasma are not known in detail, but testosterone does promote prostaglandin production. Thromboxane and leukotrienes have not been found in seminal plasma. Men with a low seminal fluid concentration of prostaglandins are relatively infertile.

Smooth muscle-relaxing prostaglandins such as PGE₁ enhance penile erection by relaxing the smooth muscle of the corpora cavernosa. (See Clinical Pharmacology of the Eicosanoids.)

E. CENTRAL AND PERIPHERAL NERVOUS SYSTEMS

1. Fever¾ PGE₂ increases body temperature, probably via EP₃ receptors, especially when administered directly into the cerebral ventricles. Exogenous PGF_2a and PGI₂ induce fever, whereas PGD₂ and TXA₂ do not, but none of these contributes to the natural pyretic response. Instead, pyrogens release interleukin-1, which in turn promotes the synthesis and release of PGE₂. This synthesis is blocked by aspirin and other antipyretic compounds.

2. Sleep¾ When infused into the cerebral ventricles, PGD₂ induces natural sleep (as determined by electroencephalographic analysis) via activation of DP₁ receptors and secondary release of adenosine.

3. Neurotransmission¾ PGE compounds inhibit the release of norepinephrine from postganglionic sympathetic nerve endings. Moreover, NSAIDs increase norepinephrine release in vivo, suggesting that the prostaglandins play a physiologic role in this process. Thus, vasoconstriction observed during treatment with COX inhibitors may be due, in part, to increased release of norepinephrine as well as to inhibition of the endothelial synthesis of the vasodilators PGE₂ and PGI₂. PGE₂ and PGI₂ sensitize the peripheral nerve endings to painful stimuli by lowering the threshold of nociceptors. Centrally, PGE₂ can increase excitability in neuronal pain transmission pathways in the spinal cord. Hyperalgesia is also produced by LTB₄. The release of these eicosanoids during the inflammatory process thus serves to amplify nociception.

F. NEUROENDOCRINE ORGANS
Both in vitro and in vivo tests have shown that some of the eicosanoids affect the secretion of anterior pituitary hormones. PGE₂ promotes the release of growth hormone, prolactin, TSH, ACTH, FSH, and LH. However, endocrine changes reflecting significant release of these hormones have not been reported in patients receiving PGE compounds. In parturition PGF_2ainduces an oxytocin-dependent decline in progesterone levels. LOX metabolites also have endocrine effects. LTC₄ and LTD₄ stimulate LHRH and LH secretion (see below). 12-HETE stimulates the release of aldosterone from the adrenal cortex and mediates a portion of the aldosterone release stimulated by angiotensin II but not that by ACTH.

G. BONE METABOLISM
Prostaglandins are abundant in skeletal tissue and are produced by osteoblasts and adjacent hematopoietic cells. The major effect of prostaglandins (especially PGE₂, acting on EP₄receptors) in vivo is to increase bone turnover, ie, stimulation of bone resorption and formation. Deletion of the EP₄ receptors in mice results in an imbalance between bone resorption and formation, leading to a negative balance of bone mass and density in older animals. Prostaglandins may mediate the effects of mechanical forces on bones and changes in bone during inflammation. EP₄-receptor deletion and inhibition of prostaglandin biosynthesis have both been associated with impaired fracture healing in animal models. COX inhibitors can also slow skeletal muscle healing by interfering with prostaglandin effects on myocyte proliferation, differentiation, and fibrosis in response to injury. Prostaglandins may contribute to the bone loss that occurs at menopause; it has been speculated that NSAIDs may be of therapeutic value in osteoporosis and bone loss prevention in older women. However, controlled evaluation of such therapeutic interventions remains to be carried out.

H. EYE
PGE and PGF derivatives lower intraocular pressure. The mechanism of this action is unclear but probably involves increased outflow of aqueous humor from the anterior chamber via the uveoscleral pathway (see Clinical Applications).

Effects of Lipoxygenase & Cytochrome P450-Derived Metabolites

The actions of lipoxygenases generate compounds that can regulate specific cellular responses important in inflammation and immunity. Cytochrome P450-derived metabolites affect nephron transport functions either directly or via metabolism to active compounds (see below). The biologic functions of the various forms of hydroxy- and hydroperoxyeicosaenoic acids are largely unknown, but their pharmacologic potency is impressive.

A. BLOOD CELLS AND INFLAMMATION
LTB₄ is a potent chemoattractant for PMNs, eosinophils, and monocytes; LTC₄ and LTD₄ are potent chemoattractants for eosinophils. At higher concentrations, these leukotrienes also promote eosinophil adherence, degranulation, and oxygen radical formation.

The leukotrienes have been strongly implicated in the pathogenesis of inflammation, especially in chronic diseases such as asthma and inflammatory bowel disease. Prostaglandins, on the other hand, generally inhibit lymphocyte function and proliferation, suppressing the immunological response. PGE₂ inhibits the differentiation of B lymphocytes into antibody-secreting plasma cells and depress the humoral antibody response. It also inhibits mitogen-stimulated proliferation of T lymphocytes and the release of lymphokines by sensitized T lymphocytes. PGE₂ and TXA₂ may also play a role in T-lymphocyte development by regulating apoptosis of immature thymocytes. PGD₂, a major product of mast cells, is a potent chemoattractant for eosinophils and induces chemotaxis and migration of TH2 lymphocytes. Its degradation product, 15d-PGJ₂, at concentrations actually formed in vivo, may also activate eosinophils via the DP₂ (CRTH2) receptor.

Lipoxins have diverse effects on leukocytes, including activation of monocytes and macrophages and inhibition of neutrophil, eosinophil, and lymphocyte activation. Both lipoxin A and lipoxin B inhibit natural killer cell cytotoxicity.

B. HEART AND SMOOTH MUSCLE

1. Cardiovascular¾ 12(S)-HETE is a potent chemoattractant for smooth muscle cells, causing migration at low concentrations; it may play a role in myointimal proliferation that occurs after vascular injury such as that caused by angioplasty. Its stereoisomer, 12(R)-HETE, is not a chemoattractant, but is a potent inhibitor of the Na⁺/K⁺ ATPase in the cornea. LTC₄ and LTD₄ reduce myocardial contractility and coronary blood flow, leading to cardiac depression. Lipoxin A and lipoxin B exert coronary vasoconstrictor effects in vitro.

2. Gastrointestinal¾ Human colonic epithelial cells synthesize LTB₄, a chemoattractant for neutrophils. The colonic mucosa of patients with inflammatory bowel disease contains substantially increased amounts of LTB₄.

3. Airways¾ The cysteinyl leukotrienes, particularly LTC₄ and LTD₄, are potent bronchoconstrictors and cause increased microvascular permeability, plasma exudation, and mucus secretion in the airways. Controversies exist over whether the pattern and specificity of the leukotriene receptors differ in animal models and humans. LTC₄-specific receptors have not been found in human lung tissue, whereas both high- and low-affinity LTD₄ receptors are present.

C. RENAL SYSTEM
The roles of leukotrienes and cytochrome P450 products in the human kidney are currently speculative, but the 5,6-epoxide has been shown to be a powerful vasodilator in animal experiments.

D. CANCER
There has been significant interest in the role of prostaglandins and COX-2 in the development of malignancies. Angiogenesis, which is required for multistage carcinogenesis, is promoted by COX-2-derived TXA₂, as well as PGE₂ and PGI₂. COX inhibitors reduce colon tumor formation in experimental animals. In large epidemiologic studies, the incidental use of NSAIDs is associated with a 40-50% reduction in relative risk for developing colon cancer. Furthermore, in patients with familial polyposis coli, COX inhibitors significantly decrease polyp formation. A polymorphism in COX-2 has been associated with increased risk of colon cancer. Several studies have suggested that COX-2 expression is associated with markers of tumor progression in breast cancer. In mouse mammary tissue, COX-2 is pro-oncogenic whereas aspirin use is associated with a reduced risk of breast cancer in women, especially for hormone receptor-positive tumors.

E. MISCELLANEOUS
The effects of these products on the reproductive organs remain to be elucidated. Similarly, actions on the nervous system have been suggested but not confirmed. 12-HETE stimulates the release of aldosterone from the adrenal cortex and mediates a portion of the aldosterone release stimulated by angiotensin II but not that by ACTH. Very low concentrations of LTC₄increase and higher concentrations of arachidonate-derived epoxides augment LH and LHRH release from isolated rat anterior pituitary cells.

INHIBITION OF EICOSANOID SYNTHESIS

Corticosteroids block all the known pathways of eicosanoid synthesis, perhaps by stimulating the synthesis of several inhibitory proteins collectively called annexins or lipocortins. They inhibit phospholipase A₂ activity, probably by interfering with phospholipid binding and thus preventing the release of arachidonic acid.

The NSAIDs (eg, indomethacin, ibuprofen) block both prostaglandin and thromboxane formation by reversibly inhibiting COX activity. The traditional NSAIDs are not selective for COX-1 or COX-2. Selective COX-2 inhibitors, which were developed more recently, vary in their degree of selectivity. Aspirin is an irreversible COX inhibitor. In platelets, which are anuclear, COX cannot be restored via protein biosynthesis resulting in extended inhibition of TXA₂ biosynthesis.

EP-receptor agonists and antagonists are under evaluation in the treatment of bone fracture and osteoporosis, whereas TP-receptor antagonists are being investigated for usefulness in treatment of cardiovascular syndromes.

Selective inhibitors of the lipoxygenase pathway are also mainly investigational. With a few exceptions, NSAIDs do not inhibit lipoxygenase activity at concentrations that markedly inhibit COX activity. In fact, by preventing arachidonic acid conversion via the COX pathway, NSAIDs may cause more substrate to be metabolized through the lipoxygenase pathways, leading to an increased formation of the inflammatory leukotrienes. Even among the COX-dependent pathways, inhibiting the synthesis of one derivative may increase the synthesis of an enzymatically related product. Therefore, drugs that inhibit both COX and lipoxygenase are being developed.

II. CLINICAL PHARMACOLOGY OF EICOSANOIDS

Introduction

Several approaches have been used in the clinical application of eicosanoids. First, stable oral or parenteral long-acting analogs of the naturally occurring prostaglandins have been developed. Several such compounds have been approved for clinical use overseas and are being introduced in the USA (Figure 18-4). Second, enzyme inhibitors and receptor antagonists have been developed to interfere with the synthesis or effects of the eicosanoids. The discovery of COX-2 as a major source of inflammatory prostanoids led to the development of selective COX-2 inhibitors in an effort to preserve the gastrointestinal and renal functions directed through COX-1, thereby reducing toxicity. Third, dietary manipulation¾to change the polyunsaturated fatty acid precursors in the cell membrane phospholipids and so change eicosanoid synthesis¾is used extensively in over-the-counter products and in diets emphasizing increased consumption of cold water fish.

Female Reproductive System

Studies with knockout mice have confirmed a role for prostaglandins in reproduction and parturition. COX-1-derived PGF_2a appears important for luteolysis, consistent with delayed parturition in COX-1-deficient mice. A complex interplay between PGF_2a and oxytocin is critical to the onset of labor. EP₂ receptor-deficient mice demonstrate a preimplantation defect, which underlies some of the breeding difficulties seen in COX-2 knockouts.

A. ABORTION
PGE₂ and PGF_2a have potent oxytocic actions. The ability of the E and F prostaglandins and their analogs to terminate pregnancy at any stage by promoting uterine contractions has been adapted to common clinical use. Many studies worldwide have established that prostaglandin administration efficiently terminates pregnancy. The drugs are used for first- and second-trimester abortion and for priming or ripening the cervix before abortion. These prostaglandins appear to soften the cervix by increasing proteoglycan content and changing the biophysical properties of collagen.

Dinoprostone, a synthetic preparation of PGE₂, is administered vaginally for oxytocic use. In the USA, it is approved for inducing abortion in the second trimester of pregnancy, for missed abortion, for benign hydatidiform mole, and for ripening of the cervix for induction of labor in patients at or near term.

Dinoprostone stimulates the contraction of the uterus throughout pregnancy. As the pregnancy progresses, the uterus increases its contractile response, and the contractile effect of oxytocin is potentiated as well. Dinoprostone also directly affects the collagenase of the cervix, resulting in softening. The vaginal dose enters the maternal circulation, and a small amount is absorbed directly by the uterus via the cervix and the lymphatic system. Dinoprostone is metabolized in local tissues and on the first pass through the lungs (about 95%). The metabolites are mainly excreted in the urine. The plasma half-life is 2.5-5 minutes.

For the induction of labor, dinoprostone is used either as a gel (0.5 mg PGE₂) or as a controlled-release formulation (10 mg PGE₂) that releases PGE₂ in vivo at a rate of about 0.3 mg/h over 12 hours. An advantage of the controlled-release formulation is a lower incidence of gastrointestinal side effects (< 1%).

For abortifacient purposes, the recommended dosage is a 20-mg dinoprostone vaginal suppository repeated at 3- to 5-hour intervals depending on the response of the uterus. The mean time to abortion is 17 hours, but in more than 25% of cases the abortion is incomplete and requires additional intervention.

For softening of the cervix at term, the preparations used are either a single vaginal insert containing 10 mg PGE₂ or a vaginal gel containing 0.5 mg PGE₂ administered every 6 hours. The softening of the cervix for induction of labor substantially shortens the time to onset of labor and the delivery time.

The use of PGE analogs for "menstrual regulation" or very early abortions¾within 1-2 weeks after the last menstrual period¾has been explored extensively. There are two problems: prolonged vaginal bleeding and severe menstrual cramps.

Antiprogestins (eg, mifepristone, RU486) have been combined with an oral oxytocic prostaglandin (eg, misoprostol) to produce early abortion. This regimen is available in the USA and Europe (see Chapter 39). The ease of use and the effectiveness of the combination have aroused considerable opposition in some quarters. The major toxicities are cramping pain and diarrhea. The oral and vaginal routes of administration of misoprostol are equally effective, but the vaginal route has been associated with an increased incidence of sepsis, so the oral route is now recommended by all authorities.

PGF_2a is available for clinical gynecologic use. This drug, carboprost tromethamine (15-methyl-PGF_2a; the 15-methyl group prolongs the duration of action) is used to induce second-trimester abortions and to control postpartum hemorrhage that is not responding to conventional methods of management. The success rate is approximately 80%. It is administered as a single 250-mcg intramuscular injection, repeated if necessary. Vomiting and diarrhea occur commonly, probably because of gastrointestinal smooth muscle stimulation. Transient elevations in temperature are seen in approximately one eighth of patients.

B. FACILITATION OF LABOR
Numerous studies have shown that PGE₂, PGF_2a, and their analogs effectively initiate and stimulate labor, but PGF_2a is one tenth as potent as PGE₂. There appears to be no difference in the efficacy of PGE₂ and PGF_2a when they are administered intravenously; however, they may be of more use locally to promote labor through ripening of the cervix. These agents and oxytocin have similar success rates and comparable induction-to-delivery intervals. The adverse effects of the prostaglandins are moderate, with a slightly higher incidence of nausea, vomiting, and diarrhea than that produced by oxytocin. PGF_2a has more gastrointestinal toxicity than PGE₂. Neither drug has significant maternal cardiovascular toxicity in the recommended doses. In fact, PGE₂ must be infused at a rate about 20 times faster than that used for induction of labor to decrease blood pressure and increase heart rate. PGF_2a is a bronchoconstrictor and should be used with caution in women with asthma; however, neither asthma attacks nor bronchoconstriction have been observed during the induction of labor. Although both PGE₂ and PGF_2a pass the fetoplacental barrier, fetal toxicity is uncommon.

The effects of oral PGE₂ administration (0.5-1.5 mg/h) have been compared with those of intravenous oxytocin and oral demoxytocin, an oxytocin derivative, in the induction of labor. Oral PGE₂ is superior to the oral oxytocin derivative and in most studies is as efficient as intravenous oxytocin. Oral PGF_2a causes too much gastrointestinal toxicity to be useful by this route.

Theoretically, PGE₂ and PGF_2a should be superior to oxytocin for inducing labor in women with preeclampsia-eclampsia or cardiac and renal diseases because, unlike oxytocin, they have no antidiuretic effect. In addition, PGE₂ has natriuretic effects. However, the clinical benefits of these effects have not been documented. In cases of intrauterine fetal death, the prostaglandins alone or with oxytocin seem to cause delivery effectively.

C. DYSMENORRHEA
Primary dysmenorrhea is attributable to increased endometrial synthesis of PGE₂ and PGF_2a during menstruation, with contractions of the uterus that lead to ischemic pain. NSAIDs successfully inhibit the formation of these prostaglandins (see Chapter 36) and so relieve dysmenorrhea in 75-85% of cases. Some of these drugs are available over the counter. Aspirin is also effective in dysmenorrhea, but because it has low potency and is quickly hydrolyzed, large doses and frequent administration are necessary. In addition, the acetylation of platelet COX, causing irreversible inhibition of platelet TXA₂ synthesis, may increase the amount of menstrual bleeding.

Male Reproductive System

Intracavernosal injection or urethral suppository therapy with alprostadil (PGE₁) is a second line treatment for erectile dysfunction. Doses of 2.5-25 mcg are used. Penile pain is a frequent side effect, which may be related to the algesic effects of PGE derivatives; however, only a few patients discontinue the use because of pain. Prolonged erection and priapism are less frequent side effects that occur in less than 4% of patients and are minimized by careful titration to the minimal effective dose. When given by injection, alprostadil may be used as monotherapy or in combination with either papaverine or phentolamine.

Renal System

Increased biosynthesis of prostaglandins has been associated with one form of Bartter's syndrome. This is a rare disease characterized by low-to-normal blood pressure, decreased sensitivity to angiotensin, hyperreninemia, hyperaldosteronism, and excessive loss of K⁺. There also is an increased excretion of prostaglandins, especially PGE, in the urine. After long-term administration of COX inhibitors, sensitivity to angiotensin, plasma renin values, and the concentration of aldosterone in plasma return to normal. Although plasma K⁺ rises, it remains low, and urinary wasting of K⁺ persists. Whether an increase in prostaglandin biosynthesis is the cause of Bartter's syndrome or a reflection of a more basic physiologic defect is not yet known.

Cardiovascular System

The vasodilator effects of PGE compounds have been studied extensively in hypertensive patients. These compounds also promote sodium diuresis. Practical application will require derivatives with oral activity, longer half-lives, and fewer adverse effects.

A. PULMONARY HYPERTENSION
Prostacyclin lowers peripheral, pulmonary, and coronary resistance. It has been used to treat both primary pulmonary hypertension and secondary pulmonary hypertension, which sometimes occurs after mitral valve surgery. In addition, prostacyclin has been used successfully to treat portopulmonary hypertension, which arises secondary to liver disease. A commercial preparation of prostacyclin (epoprostenol) is approved for treatment of primary pulmonary hypertension, in which it appears to improve symptoms, prolong survival, and delay or prevent the need for lung or lung-heart transplantation. However, because of its extremely short plasma half-life, the drug must be administered as a continuous intravenous infusion through a central line. Several prostacyclin analogs with longer half-lives have been developed, and treprostinil is approved for use in pulmonary hypertension. This drug is administered by continuous subcutaneous infusion.

B. PERIPHERAL VASCULAR DISEASE
A number of studies have investigated the use of PGE and PGI₂ compounds in Raynaud's phenomenon and peripheral atherosclerosis. In the latter case, prolonged infusions have been used to permit remodeling of the vessel wall and to enhance regression of ischemic ulcers.

C. PATENT DUCTUS ARTERIOSUS
Patency of the fetal ductus arteriosus depends on COX-2-derived PGE₂ acting on the EP₄ receptor. At birth, reduced PGE₂ levels, a consequence of increased PGE₂ metabolism, allow ductus arteriosus closure. In certain types of congenital heart disease (eg, transposition of the great arteries, pulmonary atresia, pulmonary artery stenosis), it is important to maintain the patency of the neonate's ductus arteriosus before corrective surgery. This is done with alprostadil, PGE₁. Like PGE₂, PGE₁ is a vasodilator and an inhibitor of platelet aggregation, and it contracts uterine and intestinal smooth muscle. Adverse effects include apnea, bradycardia, hypotension, and hyperpyrexia. Because of rapid pulmonary clearance, the drug must be continuously infused at an initial rate of 0.05-0.1 mcg/kg/min, which may be increased to 0.4 mcg/kg/min. Prolonged treatment has been associated with ductal fragility and rupture.

In delayed closure of the ductus arteriosus, COX inhibitors are often used to inhibit synthesis of PGE₂ and so close the ductus. Premature infants in whom respiratory distress develops due to failure of ductus closure can be treated with a high degree of success with indomethacin. This treatment often precludes the need for surgical closure of the ductus.

Blood

As noted above, eicosanoids are involved in thrombosis because TXA₂ promotes platelet aggregation and PGI₂ inhibits it. Low-dose aspirin selectively inhibits platelet COX-1. TXA₂, in addition to activating platelets amplifies the response to other platelet agonists; hence inhibition of its synthesis inhibits secondary aggregation of platelets induced by ADP, by low concentrations of thrombin and collagen, and by epinephrine.

Overview analyses have shown that low-dose aspirin reduces the secondary incidence of heart attack and stroke by about 25%. It elevates the low risk of serious GI bleeds about twofold over placebo. Low-dose aspirin also reduces the incidence of first myocardial infarction. However, in this case, the benefit versus risk of GI bleeding is less clear. The effects of aspirin on platelet function are discussed in greater detail in Chapter 34.

Respiratory System

PGE₂ is a powerful bronchodilator when given in aerosol form. Unfortunately, it also promotes coughing, and an analog that possesses only the bronchodilator properties has been difficult to obtain.

PGF_2a and TXA₂ are both strong bronchoconstrictors and were once thought to be primary mediators in asthma. Polymorphisms in the genes for PGD₂ synthase and the TP have been linked with asthma in humans, and deletion of DP₁ sharply reduces allergen-induced infiltration of lymphocytes and eosinophils and airway hyperreactivity. However, the cysteinyl leukotrienes¾LTC₄, LTD₄, and LTE₄¾probably dominate during asthmatic constriction of the airway. As described in Chapter 20, leukotriene-receptor inhibitors (eg, zafirlukast, montelukast) are effective in asthma. A lipoxygenase inhibitor (zileuton) has also been used in asthma but is not as popular as the receptor inhibitors. It remains unclear whether leukotrienes are partially responsible for the acute respiratory distress syndrome.

Corticosteroids and cromolyn are also useful in asthma. Corticosteroids inhibit eicosanoid synthesis and thus limit the amounts of eicosanoid mediator available for release. Cromolyn appears to inhibit the release of eicosanoids and other mediators such as histamine and platelet-activating factor from mast cells.

Gastrointestinal System

The word "cytoprotection" was coined to signify the remarkable protective effect of the E prostaglandins against peptic ulcers in animals at doses that do not reduce acid secretion. Since then, numerous experimental and clinical investigations have shown that the PGE compounds and their analogs protect against peptic ulcers produced by either steroids or NSAIDs. Misoprostol is an orally active synthetic analog of PGE₁. The FDA-approved indication is for prevention of NSAID-induced peptic ulcers. The drug is administered at a dosage of 200 mcg four times daily. This and other PGE analogs (eg, enprostil) are cytoprotective at low doses and inhibit gastric acid secretion at higher doses. The adverse effects are abdominal discomfort and occasional diarrhea; both effects are dose-related. More recently, dose-dependent bone pain and hyperostosis have been described in patients with liver disease who were given long-term PGE treatment.

Selective COX-2 inhibitors were developed in an effort to spare gastric COX-1 so that the natural cytoprotection by locally synthesized PGE₂ and PGI₂ is undisturbed (see Chapter 36). However, this benefit is seen only with highly selective inhibitors and may be offset by increased cardiovascular toxicity.

Immune System

Cells of the immune system contribute substantially to eicosanoid biosynthesis during an immune reaction. T and B lymphocytes are not primary synthetic sources; however, they may supply arachidonic acid to monocyte-macrophages for eicosanoid synthesis. In addition, there is evidence for eicosanoid-mediated cell-cell interaction by platelets, erythrocytes, PMNs, and endothelial cells.

The eicosanoids modulate the effects of the immune system, as illustrated by the cell-mediated immune response. PGE₂ and PGI₂ limit T-cell proliferation in vitro as corticosteroids do. T-cell clonal expansion is attenuated through inhibition of interleukin-1 and interleukin-2 and class II antigen expression by macrophages or other antigen-presenting cells. The leukotrienes, TXA₂, and platelet-activating factor stimulate T-cell clonal expansion. These compounds stimulate the formation of interleukin-1 and interleukin-2 as well as the expression of interleukin-2 receptors. The leukotrienes also promote interferon-g release and can replace interleukin-2 as a stimulator of interferon-g. These in vitro effects of the eicosanoids agree with in vivo findings in animals with acute organ transplant rejection, as described below.

A. CELL-MEDIATED ORGAN TRANSPLANT REJECTION
Acute organ transplant rejection is a cell-mediated immune response (Chapter 56). Administration of PGI₂ to renal transplant patients has reversed the rejection process in some cases. Experimental in vitro and in vivo data show that PGE₂ and PGI₂ can attenuate T-cell proliferation and rejection, which can also be seen with drugs that inhibit TXA₂ and leukotriene formation. In organ transplant patients, urinary excretion of metabolites of TXA₂ increases during acute rejection. Corticosteroids, the first-line drugs used for treatment of acute rejection because of their lymphotoxic effects, inhibit both phospholipase and COX-2 activity.

B. INFLAMMATION
Aspirin has been used to treat arthritis for approximately 100 years, but its mechanism of action¾inhibition of COX activity¾was not discovered until 1971. Aspirin and other anti-inflammatory agents that inhibit COX are discussed in Chapter 36. COX-2 appears to be the form of the enzyme most associated with cells involved in the inflammatory process. With the exception of PGD₂, the prostanoids are not chemoattractants, but the leukotrienes and some of the HETEs (eg, 12-HETE) are strong chemoattractants. PGE₂ inhibits both antigen-driven and mitogen-induced B-lymphocyte proliferation and differentiation to plasma cells, resulting in inhibition of IgM synthesis. The concomitant elevation of serum IgE and monocyte PGE₂ synthesis, seen in patients with severe trauma and patients with Hodgkin's disease, is explained by the ability of PGE₂ to enhance immunoglobulin class switching to IgE.

C. RHEUMATOID ARTHRITIS
In rheumatoid arthritis, immune complexes are deposited in the affected joints, causing an inflammatory response that is amplified by eicosanoids. Lymphocytes and macrophages accumulate in the synovium, whereas PMNs localize mainly in the synovial fluid. The major eicosanoids produced by PMNs are leukotrienes, which facilitate T-cell proliferation and act as chemoattractants. Human macrophages synthesize the COX products PGE₂ and TXA₂ and large amounts of leukotrienes.

D. INFECTION
The relationship of eicosanoids to infection is not well defined. The association between the use of the anti-inflammatory steroids and increased risk of infection is well established. However, NSAIDs do not seem to alter patient responses to infection.

Glaucoma

Latanoprost, a stable long-acting PGF_2a derivative, was the first prostanoid used for glaucoma. The success of latanoprost has stimulated development of similar prostanoids with ocular hypotensive effects, and bimatoprost, travaprost, and unoprostone are now available. These drugs act at the FP receptor and are administered as drops into the conjunctival sac once or twice daily. Adverse effects include irreversible brown pigmentation of the iris and eyelashes, drying of the eyes, and conjunctivitis.

DIETARY MANIPULATION OF ARACHIDONIC ACID METABOLISM

Because arachidonic acid is derived from dietary linoleic and a-linolenic acids, which are essential fatty acids, the effects of dietary manipulation on arachidonic acid metabolism have been extensively studied. Two approaches have been used. The first adds corn, safflower, and sunflower oils, which contain linoleic acid (C18:2), to the diet. The second approach adds oils containing eicosapentaenoic (C20:5) and docosahexaenoic acids (C22:6), so-called omega-3 fatty acids, from cold water fish. Both types of diet change the phospholipid composition of cell membranes by replacing arachidonic acid with the dietary fatty acids. It has been claimed that the synthesis of both TXA₂ and PGI₂ is reduced and that changes in platelet aggregation, vasomotor spasm, and cholesterol metabolism follow.

As indicated previously, there are many possible oxidation products of the different polyenoic acids. It is probably naive to ascribe the effects of dietary intervention reported thus far to such metabolites. However, subjects on diets containing highly saturated fatty acids clearly show increased platelet aggregation when compared with other study groups. Such diets (eg, in Finland and the USA) are associated with higher rates of myocardial infarction than are more polyunsaturated diets (eg, in Italy).



PREPARATIONS AVAILABLE

NONSTEROIDAL ANTI-INFLAMMATORY DRUGS ARE LISTED IN CHAPTER 36.

Alprostadil
Penile injection (Caverject, Edex): 5, 10, 20, 40 mcg sterile powder for reconstitution
Penile pellet (Muse): 125, 250, 500, 1000 mcg
Parenteral (Prostin VR Pediatric): 500 mcg/mL ampules
Bimatoprost (Lumigan)
Ophthalmic drops: 0.03% solution
Carboprost tromethamine (Hemabate)
Parenteral: 250 mcg carboprost and 83 mcg tromethamine per mL ampules
Dinoprostone [prostaglandin E₂] (Prostin E2, Prepidil, Cervidil)
Vaginal: 20 mg suppositories, 0.5 mg gel, 10 mg controlled-release system
Epoprostenol [prostacyclin] (Flolan)
Intravenous: 0.5, 1.5 mg powder to reconstitute
Latanoprost (Xalatan)
Topical: 0.005% ophthalmic solution
Misoprostol (generic, Cytotec)
Oral: 100 and 200 mcg tablets
Monteleukast (Singulair)
Oral: 4, 5 mg chewable tablets, 10 mg tablets, 4 mg granules
Travaprost (Travatan)
Ophthalmic solution: 0.004%
Treprostinil (Remodulin)
Parenteral: 1, 2.5, 5, 10 mg/mL for continuous subcutaneous infusion
Unoprostone (Rescula)
Ophthalmic solution 0.15%
Zafirleukast (Accolate)
Oral: 10, 20 mg tablets
Zileuton (Zyflo)
Oral: 600 mg tablets



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