Brody's Human Pharmacology: With STUDENT CONSULT

Chapter 15 Prostaglandins and Other Eicosanoids

MAJOR DRUG CLASSES

Corticosteroids

Prostaglandins

Leukotriene antagonists

Leukotriene synthesis inhibitors

Nonsteroidal antiinflammatory drugs

Therapeutic Overview

The term eicosanoid is used to represent a large family of endogenous compounds containing oxygenated unsaturated 20-carbon fatty acids and includes the prostaglandins (PGs), thromboxanes (TXs), and leukotrienes (LTs). The name PG was derived from the gland from which these compounds were first isolated, and the LTs derive their name from white blood cells and the inclusion of “trienes” or three conjugated double bonds. The PGs, TXs, and LTs are synthesized as shown schematically in Figure 15-1. Most pathways originate with the parent compound arachidonic acid, a major component of membrane phospholipids. Catalysis by cytochrome P450 monooxygenases produces epoxides, whereas the action of the cyclooxygenases (COXs) produces PGs and TXs, and that of the 5-lipoxygenases(5-LOX) produces LTs.

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FIGURE 15–1 General pathways mediating the synthesis of the major eicosanoids.

The PGs, TXs, and LTs exert profound effects on practically all cells and tissues, providing many potential targets for intervention in the treatment of disease. The PGs themselves are used as drugs to mimic effects they would produce if formed endogenously. In addition, many compounds such as the nonsteroidal antiinflammatory drugs (NSAIDs, see Chapter 36) and corticosteroids (see Chapter 39) produce their effects by inhibiting the formation of the PGs, whereas other compounds block the synthesis of the LTs. New drugs are also being introduced to block PG or LT receptors (see Chapter 16).

Because of the large number of physiological actions attributed to the eicosanoids, drugs affecting their action have diverse therapeutic applications as shown in the Therapeutic Overview Box.

Abbreviations

COX

Cyclooxygenase

DP

D prostanoid

EP

E prostanoid

GI

Gastrointestinal

HPETE

Hydroxyperoxyeicosatetraenoic acid

LOX

Lipoxygenase

LTs

Leukotrienes

NSAID

Nonsteroidal antiinflammatory drug

PGs

Prostaglandins

TXs

Thromboxanes

Therapeutic Overview

Drug

Effect

Use

Corticosteroids

Block eicosanoid production

Inflammation

Prostaglandins

Increased blood flow and oxygenation by vessel relaxation

Neonatal defects

 

Penile erection

 

Increased uterine contraction

Induction of labor, abortifacient

 

Reduced platelet aggregation

Peripheral vascular disease

 

Reduce intraocular pressure

Glaucoma

 

Suppress gastric acid secretion

Gastric ulcers

Leukotriene antagonists

Block leukotriene receptor-mediated bronchoconstriction

Asthma

Leukotriene synthesis inhibitors

Inhibit lipoxygenase

Asthma

Nonsteroidal antiinflammatory drugs

Block prostaglandin synthesis

Pain, inflammation

Mechanisms of Action

Synthesis

The structures and biosynthesis of PGs and TXs are shown in Figure 15-2. PGs are derived from essential fatty acids, usually arachidonic acid (C20:4). The numbering designation of arachidonic acid, 20:4, indicates 20 carbon atoms and 4 double bonds. The compounds that retain two double bonds in their alkyl side-chains are denoted by the subscript 2, and those that retain three double bonds are denoted by the subscript 3. Arachidonic acid and other fatty acids are cleaved from membrane phospholipids by the action of phospholipase A2 and are metabolized by three different types of enzymes: COXs, lipoxygenases, and cytochrome P450 monooxygenases.

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FIGURE 15–2 Chemical structures and biosynthesis of the principal prostaglandins by the cyclooxygenase pathway. PG, Prostaglandin; TX, thromboxane; PGI2, prostacyclin (PGE2, PGD2, and PGF differ from endoperoxide PGH2, as indicated).

COXs convert arachidonic acid into the PG endoperoxides PGG2 and PGH2. COXs are inhibited by NSAIDS such as aspirin and ibuprofen (see Chapter 36), leading to inhibition of PG and TX formation. Two distinct COXs have been described and have been designated as COX-1 and COX-2. COX-1 is constitutively expressed, whereas COX-2 is inducible and expressed in response to inflammatory mediators such as cytokines and lipopolysaccharides. Corticosteroids suppress the induction of COX-2 (see Chapter 39), suggesting that control of PG synthesis is involved in the antiinflammatory actions of these compounds. In addition, selective COX-2 inhibitors such as celecoxib (see Chapter 39) are useful in treating chronic inflammation, because they may cause less gastric disturbance than NSAIDS by allowing formation of cytoprotective PGE2 through COX-1.

Like the PGs, the LTs are acidic lipids synthesized from essential fatty acids through the action of 5-LOX (Fig. 15-3), a pathway not inhibited by NSAIDs. Three major LOXs have been discovered, which catalyze incorporation of a molecule of O2 into the 5-, 12-, or 15-position of arachidonic acid, forming the corresponding 5-, 12-, or 15-hydroxyperoxyeicosatetraenoic (HPETE) acids. The 5-LOX pathway gives rise to the LTs. LTB4 has potent chemotactic properties for polymorphonuclear leukocytes, promoting adhesion and aggregation, whereas LTC4 and LTD4 are potent constrictors of peripheral lung airways and other vessels, including coronary arteries. The biologic activity of LTC4, LTD4, and LTE4 was previously termed “slow-reacting substance.”

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FIGURE 15–3 Chemical structures and biosynthesis of the principal leukotrienes by the lipoxygenase pathway. LTC4, LTD4, LTE4, and LTF4 differ from LTA4 in the R groups. 5-HPETE, Unstable hydroxyperoxyeicosatetraenoic acid.

Metabolism and Concentration

PGs are synthesized and secreted in response to diverse stimuli; they are not stored. PGs and TXA2 act primarily as local hormones (autacoids), with their biological activities usually restricted to the cell, tissue, or structure where they are synthesized. Concentrations of PGE2 and PGF in arterial blood are very low because of pulmonary degradation, which normally removes more than 90% of these PGs from the venous blood as it passes through the lungs. Not all cells synthesize PGs; for example, there are segments of the nephron that lack COXs or show negligible capacity to transform added arachidonic acid to PGs. In contrast, COX is abundant within the vasculature, although the principal products vary longitudinally along the vasculature and cross-sectionally within the blood vessel wall (e.g., endothelium versus vascular smooth muscle). Within the coronary circulation, the larger blood vessels synthesize principally PGI2, whereas PGE2 predominates in microvessels.

Prostaglandin Receptors

PGs exert their effects by binding to specific cell surface receptors, which have been subdivided pharmacologically with respect to agonist potency and the signal transduction system to which they are coupled. All PG receptors are G-protein coupled receptors (see Chapter 1), which stimulate G-proteins to initiate transmembrane signaling. PGD2 activates D prostanoid (DP) receptors, PGE2 activates E prostanoid (EP) receptors, PGF activates F prostanoid (FP) receptors, and PGI2 activates I prostanoid (IP) receptors. PG receptors may stimulate (DP, EP2, EP4, IP) or inhibit (EP2) adenylyl cyclase, or stimulate phospholipase C (EP1, TP), leading to formation of diacylglycerol and inositol trisphosphate and Ca++ mobilization. Many cell types possess several PG receptor subtypes and respond in a variety of ways to PGs. For example, renal tubules possess multiple PG receptors, because low doses of PGE1 inhibit arginine-vasopressin induced H2O reabsorption through Gi-mediated inhibition of adenylyl cyclase, whereas high doses of PGE1 cause H2O reabsorption. The tissue-specific functional changes induced by PGE2 acting through four receptor subtypes include vasodilation, bronchodilation, promotion of salt and H2O excretion, and inhibition of lipolysis, glycogenolysis, and fatty acid oxidation. PGI2 produces effects through IP receptors with wide distribution. IP receptors are highly expressed in the vasculature, reflected in the high vasodilator activity of PGI2.

After being released, PGs are usually denied entrance into cells, presumably because they cannot permeate the lipid bilayer. In the lung, renal proximal tubules, thyroid plexus, and ciliary body of the eye, an active transport system is responsible for the rapid uptake of PGs from extracellular fluids. PGs differ in their affinity for this transport system. PGE2 and PGF have a high affinity, thus accounting for removal and subsequent metabolism within the lung. In contrast, PGI2 passes intact through the pulmonary circulation. It is possible to inhibit this transport system, which resembles the organic acid secretory system of the renal proximal tubules, with probenecid. The diuretic drug, furosemide, and other organic acids also inhibit this uptake in the lung, kidney, and possibly in the brain and eye. One effect of this drug class is to increase PG concentrations in blood, urine, and perhaps cerebrospinal fluid.

A practical application of suppressing the effects of PGE2 can be demonstrated in Bartter’s syndrome, a disease in which there is excessive renal PG production, leading to diuresis, kaliuresis, natriuresis, and hyperreninemia. Inhibition of COX activity with NSAIDs results in improvement in patients by allowing expression of salt- and H2O-retaining hormonal influences, chiefly angiotensin II and arginine-vasopressin.

Thromboxane Receptors

TXA2 activates thromboxane-prostanoid (TP) receptors, which have been identified on the plasma membranes of platelets, blood vessels, bronchial smooth muscle, and mesangial cells of glomeruli. The platelet TXA2 receptor activates Gq and phospholipase C. The PG endoperoxides, PGG2 and PGH2, also bind to TXA2 receptors.

There are no potent, selective antagonists of the PG or TP receptors in clinical use, although some compounds are effective in vitro.

Leukotriene Receptors

The LTs also act through specific G-protein coupled receptors. LTB4 binds to and activates both subtypes of BLT receptors, BLT1 and BLT2. The cysteinyl LTs bind to and activate two CysLT receptors, designated CysLT1, which binds LTD4 and LTE4, and CysLT2, which binds LTC4. Clinically useful CysLT receptor antagonists include montelukast and zafirlukast. In addition, LT formation can be inhibited by the 5-LOX inhibitor zileuton.* All these agents are useful in the treatment of asthma (see Chapter 16).

Pharmacokinetics

The pharmacokinetics of PGs, LT antagonists, NSAIDs, corticosteroids, and related drugs are discussed in Chapters 16182636 and Chapter 39.

Relationship of Mechanisms of Action to Clinical Response

Blood Flow Regulation

PGE1, PGE2, and PGI2 are potent vasodilators, and endogenously produced PGE2 and PGI2 may be local regulators in many vascular beds. Patients with peripheral vascular disease benefit from PGI2infusions into the femoral artery, although there are several side effects. TXA2 is a potent constrictor of cerebral and coronary arteries, and PGF constricts superficial veins in the hands. Prinzmetal’s (vasospastic or variant) angina is associated with coronary artery vasoconstriction, which may be caused, in part, by TXA2 released from activated platelets. LTC4 and LTD4 also constrict coronary arteries.

Platelet Aggregation

The dynamic interplay at the platelet-endothelium interface between proaggregatory vasoconstrictor and antiaggregatory vasodilator mediators influences the outcome of arterial insufficiency, thrombosis, and ischemia (see Chapter 26). Key components are the proaggregatory TXA2 and the antiaggregatory PGI2, with interventions that favor PGI2 production and lowering TXA2 formation having the most benefit. Aspirin irreversibly inhibits COXs by covalent acetylation. Therapeutic strategies strive to maximize the effect of aspirin on platelet COXs, while sparing as much as possible the effect on endothelial cell COXs. Unlike the endothelium, platelets lack nuclei and cannot synthesize new COX molecules to replace those inactivated by aspirin. Thus a deficient production of TXA2 by platelets cannot be corrected until new platelets form. The effects of aspirin therefore continue for the life of the platelet or more than 10 days. In contrast, after being inhibited, vascular COX can be replaced within a few hours by resynthesis in endothelial cells. Therefore the low-dose aspirin strategy limits the ability of aspirin to enter the systemic circulation to inhibit vascular COX but allows aspirin to act on platelet COX in the portal circulation (from the site of absorption of aspirin to its metabolism by the liver).

Ductus Arteriosus

The ductus arteriosus generally closes spontaneously at birth, but in some cases, especially in infants born prematurely, it remains patent (open) so that 90% of the cardiac output is shunted away from the lungs. The patency is probably maintained as a result of high production of PGs after delivery. Indomethacin inhibits PG production and closes the ductus arteriosus. On the other hand, neonates with certain congenital heart defects depend on an open ductus arteriosus for survival until corrective surgery can be performed. These defects include interruption of the aortic arch, transposition of the great vessels, and pulmonary atresia or stenosis. PGE1 (alprostadil) is administered by continuous intravenous infusion or by catheter through the umbilical vein to dilate the ductus.

Gastrointestinal Tract

PGE1 and PGE2 inhibit basal and stimulated gastric acid secretion and are used for treatment of ulcers, as discussed in Chapter 18. The propensity of NSAIDs to cause gastrointestinal (GI) ulcers is a consequence of eliminating the contribution of PGs to maintain mucosal integrity. Because PGs and their analogs have protective actions on the GI mucosa distinct from their ability to inhibit secretory activity, they are considered cytoprotective (see Chapter 18). COX-2 inhibitors are suggested to have the advantage over NSAIDs in long-term therapy because they do not suppress the cytoprotective effects of PGs and may therefore be less likely to cause ulcers. However, COX-2 inhibitors have serious adverse cardiovascular effects (see Chapter 18).

Inflammatory and Immune Responses

PGs and LTs released in response to infection, and to mechanical, thermal, chemical, and other injuries, participate in inflammatory responses. LTs affect vascular permeability, and LTB4 is a chemoattractant for polymorphonuclear leukocytes. PGE2 and PGI2 enhance edema by increasing blood flow and enhance the action of bradykinin in producing pain. Consequently, COX inhibitors are effective as analgesics and antiinflammatory agents (see Chapter 36).

Reproductive System

Elevated concentrations of PGs have been measured in the circulating blood of women during labor or spontaneous abortion, suggesting that initiation and maintenance of uterine contractions may be caused by increased PG synthesis. In fact, labor can be induced by PGE2 given orally; if labor does not occur within 12 hours, oxytocin is substituted. Use of PGE2 to induce labor is accompanied by uterine hypertonus and fetal bradycardia. In contrast to oxytocin, PGs will induce uterine contractions at all stages of pregnancy. Therefore the main use of PGE2 (dinoprostone) and PGF (dinoprost) in gynecological practice has been as abortifacients (see Chapter 17).

PGs are also useful in treating impotence, although they have largely been replaced for this purpose by specific phosphodiesterase inhibitors such as sildenafil. Smooth-muscle– relaxing PGs, such as PGE1 (alprostadil), enhance penile erections. Self-injection creates an erection by relaxing the smooth muscle and dilating the major artery in the penis, enhancing blood flow.

Bronchoconstriction

The lungs produce many PGs and LTs. Mast cells lining the respiratory passages are the likely source of LTs. Overproduction of these substances leads to bronchoconstriction, and they are potential mediators of asthma. PGF and TXA2 are also potent bronchoconstrictors, whereas PGE1, PGE2, and PGI2 are potent vasodilators. However, inhaled PGs irritate the airways and are not suitable as antiasthmatic drugs. LT receptor antagonists, including montelukast and zafirlukast, are useful in treating asthma (see Chapter 16).

Eye

PGs of the E and F series reduce intraocular pressure by enhancing uveoscleral outflow. Topical application of latanoprost, a stable PGF derivative, is useful in treating open-angle glaucoma in certain cases.

Cancer

PGs can induce mutations in tumor suppressor genes and alter other critical pathways that can lead to the development and progression of cancer. Based on evidence supporting an association between loss of function of a tumor suppressor for colon cancer and overexpression of COX-2, COX-2 inhibitors may have usefulness in cancer therapy. Epidemiological data suggest that nonselective and selective COX-2 inhibitors might prevent the development of several cancers, an idea supported by preclinical investigations of COX-2 inhibitors. Preliminary results of clinical trials combining COX-2 inhibitors with other forms of cancer therapy are encouraging.

Pharmacovigilance: Side Effects, Clinical Problems, and Toxicity

Attempts to use authentic PGI2 or its stable analogs to forestall or ameliorate myocardial infarction, cerebral ischemia, and other manifestations of arterial insufficiency are

CLINICAL PROBLEMS

PGE2

GI hypermotility, vomiting, diarrhea; uterine hypertonus and fetal bradycardia in labor

PGI2

Hypotension, headache, flushing

restricted by the hypotension, headache, and flushing that attend the intravenous infusion of these agents.

An unwanted side effect of PGE (and PGF) analogs is GI hypermotility and associated diarrhea, consequences of the contractile effects of E series PGs on GI smooth muscle. However, in appropriate dosage, misoprostol is usually devoid of major side effects.

Under unusual circumstances PGs may achieve relatively high concentrations in the circulation. For example, PGD2 is elevated in human mastocytosis, PGE2 is increased in some solid tumors with metastases to bone, and PGI2 achieves high levels in pregnancy. In a small group of patients with solid tumors that metastasize to bone, the associated hypercalcemia, related to elevated PGE2concentrations, responds to treatment with aspirin-like drugs. In late pregnancy the gravid uterus may serve as a reservoir of PGI2, which is released into the systemic circulation. In addition, diseases of the lung associated with the shunting of blood to the systemic circulation, thereby bypassing the lungs, can result in elevated PG concentrations in arterial blood.

New Horizons

Improved understanding of PG synthesis and function indicate that the EP3 receptor in the preoptic hypothalamus is involved in fever and the EP4 receptor is involved in closure of the ductus arteriosus. Thus these receptors represent new targets for drug development.

TRADE NAMES

(In addition to generic and fixed-combination preparations, the following trade-named materials are some of the important compounds available in the United States.)

Alprostadil (PGE1, Caverject, Edex, Muse, Topiglan)

Corticosteroids

Dinoprostone (PGE2, Cervidil, Prepidil, ProstinE2)

Epoprostenol (PGI2, Flolan)

Latanoprost (Xalatan)

Misoprostol (Cytotec)

Montelukast (Singulair)

Nonsteroidal antiinflammatory drugs

Zafirlukast (Accolate)

Recent studies have suggested that pharmacogenomic issues may be important therapeutically for the action of the eicosanoids. Genetic variations in at least four genes involved in encoding key proteins in the leukotriene pathway have been reported, which can influence responses to LT modifiers and could also influence pharmacokinetics, contributing to response heterogeneity. Indeed, several single nucleotide polymorphisms have been found to be associated with aspirin-intolerant asthma.

FURTHER READING

James MJ, Cleland LG. Cyclooxygenase-2 inhibitors: What went wrong? Curr Opin Clin Nutr Metab Care. 2006;9:89-94.

Liao Z, Mason KA, Milas L. Cyclooxygenase-2 and its inhibition in cancer: Is there a role? Drugs. 2007;67:821-845.

Lima JJ. Treatment heterogeneity in asthma: Genetics of response to leukotriene modifiers. Mol Diagn Ther. 2007;11:97-104.

Perwez HS, Harris CC. Inflammation and cancer: an ancient link with novel potentials. Int J Cancer. 2007;121(11):2373-2380.

Peters-Golden M, Henderson WRJr. Leukotrienes. N Engl J Med. 2007;57:1841-1854.

SELF-ASSESSMENT QUESTIONS

1. Which one of the following statements about eicosanoids is true?

A. Eicosanoids are unsaturated fatty acids.

B. Eicosanoids all contain a pentane ring.

C. Eicosanoids are synthesized from arachidonic acid only through the action of cytochrome P450.

D. Eicosanoids act through a single second messenger.

E. Eicosanoid synthesis results from activation of phospholipase C3.

2. Which one of the following statements about prostaglandins is true?

A. Prostaglandin synthesis is enhanced by aspirin.

B. Prostaglandins play an important role in blocking inflammation.

C. Prostaglandins are products of cyclooxygenase activity.

D. Prostaglandins act exclusively to stimulate adenylyl cyclase.

E. Either PGE2 or oxytocin can be used to delay labor.

3. Which of the following possess vasodilator activity?

A. TXA2

B. PGI2

C. PGF

D. LTD4

E. LTC4

4. Which one of the following statements is true?

A. Leukotrienes are products of lipoxygenases.

B. Prostaglandins act by blocking G-protein coupled receptors.

C. TXA2 is a stable metabolite of arachidonic acid.

D. Prostaglandin synthesis can be enhanced by corticosteroids.

E. Prostaglandins act primarily as systemic hormones.

5. A patient presents with wheezing and difficulty breathing. Examination reveals bronchoconstriction and inflammatory cell infiltration of the bronchi. Select the most appropriate drug to treat the condition.

A. COX-1 inhibitor

B. COX-2 inhibitor

C. Leukotriene receptor antagonist

D. PGI2

E. LTD4

* This drug is no longer available in the united states