Clinical Pharmacology of Eicosanoids

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.

Female Reproductive System

Studies with knockout mice have confirmed a role for prostaglan-dins in reproduction and parturition. COX-1-derived PGF_2α appears important for luteolysis, consistent with delayed parturi-tion in COX-1-deficient mice. A complex interplay between PGF_2α 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.

A. Abortion

PGE₂ and PGF_2α 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 PGF_2α is also used in obstetrics. This drug, car-boprost tromethamine (15-methyl-PGF_2α; 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.

B. Facilitation of Labor

Numerous studies have shown that PGE₂, PGF_2α, and their ana-logs effectively initiate and stimulate labor, but PGF_2α is one tenth as potent as PGE₂. There appears to be no difference in the efficacy of PGE₂ and PGF_2α 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.

PGF_2α 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. PGF_2α 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_2α 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_2α causes too much gastrointestinal toxicity to be useful by this route.

Theoretically, PGE₂ and PGF_2α 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.

C. Dysmenorrhea

Primary dysmenorrhea is attributable to increased endometrial syn-thesis of PGE₂ and PGF_2α 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.

Male Reproductive System

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.

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 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.

Cardiovascular System

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.

A. Pulmonary Hypertension

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.

B. Peripheral Vascular Disease

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.

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 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.

Blood

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.

Respiratory System

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.

PGF_2α 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.

Gastrointestinal System

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.

Immune System

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.

A. Cell-Mediated Organ Transplant Rejection

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.

B. Inflammation

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.

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 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.

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.

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