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CLINICAL PHARMACOLOGY OF EICOSANOIDS
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 (Figure 18–5). Second, enzyme inhibitors and receptor antago-nists 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 toxic-ity. However, it is apparent that the marked decrease in biosynthe-sis of PGI2 that follows COX-2 inhibition occurring without a concurrent inhibition of platelet COX-1-derived TXA2 removes a protective constraint on endogenous mediators of cardiovascular dysfunction and leads to an increase in cardiovascular events in patients taking selective COX-2 inhibitors. Third, efforts at dietary manipulation—to change the polyunsaturated fatty acid precursors in the cell membrane phospholipids and so change eicosanoid synthesis—is used extensively in over-the-counter products and in diets emphasizing increased consumption of cold-water fish.
Studies with knockout mice have confirmed a role for prostaglan-dins in reproduction and parturition. COX-1-derived PGF2α appears important for luteolysis, consistent with delayed parturi-tion in COX-1-deficient mice. A complex interplay between PGF2α and oxytocin is critical to the onset of labor. EP2 receptor-deficient mice demonstrate a preimplantation defect, which under-lies some of the breeding difficulties seen in COX-2 knockouts.
PGE2 and PGF2α 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 estab-lished that prostaglandin administration efficiently terminatespregnancy. 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 adminis-tered 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 ripen-ing of the cervix for induction of labor in patients at or near term.
Dinoprostone stimulates the contraction of the uterus through-out 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 collage-nase 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 abor-tion 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 short-ens the time to onset of labor and the delivery time.
Antiprogestins (eg, mifepristone) have been combined with an oral oxytocic synthetic analog of PGE1 (misoprostol) to produce early abortion. This regimen is available in the USA and Europe . The ease of use and the effectiveness of the com-bination have aroused considerable opposition in some quarters. The major toxicities are cramping pain and diarrhea. The oral and vaginal routes of administration are equally effective, but the vaginal route has been associated with an increased incidence of sepsis, so the oral route is now recommended.
An analog of PGF2α is also used in obstetrics. This drug, car-boprost tromethamine (15-methyl-PGF2α; the 15-methyl groupprolongs 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 diar-rhea occur commonly, probably because of gastrointestinal smooth muscle stimulation. In some patients transient bronchoconstric-tion can occur. Transient elevations in temperature are seen in approximately one eighth of patients.
Numerous studies have shown that PGE2, PGF2α, and their ana-logs effectively initiate and stimulate labor, but PGF2α is one tenth as potent as PGE2. There appears to be no difference in the efficacy of PGE2 and PGF2α when they are administered intravenously; however, the most common usage is local application of PGE2 analogs (dinoprostone) 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.
PGF2α has more gastrointestinal toxicity than PGE2. Neither drug has significant maternal cardiovascular toxicity in the recom-mended 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. PGF2α 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 PGF2α 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 PGF2α causes too much gastrointestinal toxicity to be useful by this route.
Theoretically, PGE2 and PGF2α should be superior to oxytocin for inducing labor in women with preeclampsia-eclampsia or car-diac 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 docu-mented. In cases of intrauterine fetal death, the prostaglandins alone or with oxytocin seem to cause delivery effectively.
Primary dysmenorrhea is attributable to increased endometrial syn-thesis of PGE2 and PGF2α during menstruation, with contractions of the uterus that lead to ischemic pain. NSAIDs successfully inhibit the formation of these prostaglandins 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 acetyla-tion of platelet COX, causing irreversible inhibition of platelet TXA2 synthesis, may increase the amount of menstrual bleeding.
Intracavernosal injection or urethral suppository therapy with alpros-tadil (PGE1) is a second-line treatment for erectile dysfunction. Dosesof 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 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.
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 angio-tensin, hyperreninemia, hyperaldosteronism, and excessive loss of K+. There also is an increased excretion of prostaglandins, espe-cially PGE metabolites, in the urine. After long-term administra-tion 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 bio-synthesis is the cause of Bartter’s syndrome or a reflection of a more basic physiologic defect is not yet known.
The vasodilator effects of PGE compounds have been studied extensively in hypertensive patients. These compounds also pro-mote sodium diuresis. Practical application will require derivatives with oral activity, longer half-lives, and fewer adverse effects.
PGI2 lowers peripheral, pulmonary, and coronary vascular resistance. It has been used to treat primary pulmonary hypertension as well as sec-ondary 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. The first commercial preparation of PGI2 (epoprostenol) approved for treatment of primary pulmonary hypertension improves symptoms, prolongs survival, and delays or prevents the need for lung or lung-heart transplantation. Side effects include flushing, headache, hypotension, nausea, and diarrhea. The extremely short plasma half-life (3–5 minutes) of epoprostenol necessitates continuous intravenous infusion through a central line for long-term treatment, which is its greatest limitation. Several prostacyclin analogs with longer half-lives have been developed and used clinically. Iloprost (half-life about 30 minutes) is usually inhaled six to nine times per day, although it has been delivered by intravenous administration outside the USA. Treprostinil (half-life about 4 hours) may be delivered by subcutaneousor intravenous infusion.
A number of studies have investigated the use of PGE1 and PGI2 compounds in Raynaud’s phenomenon and peripheral arterial disease. However, these studies are mostly small and uncontrolled, and these therapies do not have an established place in the treat-ment of peripheral vascular disease.
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 until corrective surgery can be carried out. This can be achieved 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 half-life is about 5–10 minutes in healthy adults and neonates), 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 suc-cess with indomethacin. This treatment often precludes the need for surgical closure of the ductus.
As noted above, eicosanoids are involved in thrombosis because TXA2 promotes platelet aggregation while PGI 2, and perhaps also PGE2 and PGD 2, are platelet antagonists. Chronic administration of low-dose aspirin (81 mg/d) selectively and irreversibly inhibits platelet COX-1 without modifying the activity of systemic COX-1 or COX-2 . Because their effects are reversible within the typical dosing interval, nonselective NSAIDs (eg, ibu-profen) do not reproduce this effect, although naproxen, because of its variably prolonged half-life, may provide antiplatelet benefit in some individuals. 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 adenosine diphosphate, by low concentrations of thrombin and collagen, and by epinephrine. Not surprisingly, selective COX-2 inhibitors do not alter platelet TXA2 biosynthesis and are not platelet inhibitors. However, COX-2-derived PGI2 generation is substantially suppressed during selective COX-2 inhibition, removing a restraint on the cardiovascular action of TXA2, and other platelet agonists. It is highly likely that selective depression of PGI2 generation contributes to the increased thrombotic events in humans treated with selective COX-2 inhibitors.
Overview analyses have shown that low-dose aspirin reduces the secondary incidence of heart attack and stroke by about 25%. However, low-dose aspirin also elevates the low risk of serious gastrointestinal bleeding about twofold over placebo. Low-dose aspirin also reduces the incidence of first myocardial infarction. However, in this case, the benefit versus risk of gastrointestinal bleeding is less clear.
PGE2 is a powerful bronchodilator when given in aerosol form. Unfortunately, it also promotes coughing, and an analog that pos-sesses only the bronchodilator properties has been difficult to obtain.
PGF2α and TXA2 are both strong bronchoconstrictors and were once thought to be primary mediators in asthma. Polymorphisms in the genes for PGD2 synthase, both DP receptors, and the TP recep-tor have been linked with asthma in humans. DP antagonists, par-ticularly those directed against DP2, are being investigated as potential treatments for allergic diseases including asthma. However, the cysteinyl leukotrienes—LTC4, LTD4, and LTE4—probably dominate during asthmatic constriction of the airways. As described, 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 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.
The word “cytoprotection” was coined to signify the remarkable protective effect of the E prostaglandins against peptic ulcers inanimals 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 with food. This and other PGE analogs (eg, enprostil) are cytoprotective at low doses and inhibit gastric acid secretion at higher doses. Misoprostol use is low, probably because of its adverse effects including abdom-inal discomfort and occasional diarrhea. 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 syn-thesized PGE2 and PGI2 is undisturbed . However, this benefit is seen only with highly selective inhibitors and may be offset by increased cardiovascular toxicity.
Cells of the immune system contribute substantially to eico-sanoid biosynthesis during an immune reaction. T and B lym-phocytes 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, leukocytes, and endothelial cells.
The eicosanoids modulate the effects of the immune system. PGE2 and PGI2 limit T-lymphocyte proliferation in vitro, as do corticosteroids. PGE2 also inhibits B-lymphocyte differentiation and the antigen-presenting function of myeloid-derived cells, sup-pressing the immune response. T-cell clonal expansion is attenu-ated 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 stimu-late T-cell clonal expansion. These compounds stimulate the for-mation of interleukin-1 and interleukin-2 as well as the expression of interleukin-2 receptors. The leukotrienes also promote interferon-γ release and can replace interleukin-2 as a stimulator of interferon-γ. PGD2 induces chemotaxis and migration of TH2 lymphocytes. These in vitro effects of the eicosanoids agree with in vivo findings in animals with acute organ transplant rejection, as described below.
Acute organ transplant rejection is a cell-mediated immune response . Administration of PGI2 to renal trans-plant 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.
Aspirin has been used to treat arthritis of all types for approxi-mately 100 years, but its mechanism of action—inhibition of COX activity—was not discovered until 1971. COX-2 appears to be the form of the enzyme most associated with cells involved in the inflammatory process, although, as outlined above, COX-1 also contributes significantly to prostaglandin biosynthesis during inflammation.
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 leukocytes localize mainly in the synovial fluid. The major eicosanoids produced by leukocytes 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.
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.
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