Prostaglandins and the mechanism of action of anti-inflammatory drugs

Prostaglandins and the Mechanism of Action of Anti-Inflammatory Drugs

DWIGHT R. ROBINSON, M.D. Boston, Messechus.etts

Fromthe Departmentof Medicine,HarvardMedical School, and the Arthritis Unit of the Medical Service, Massachusetts General Hospital, Boston, Massachusetts. Requests for reprints should be addressed to Dr. Dwight Ft. Robinson, Department of Arthritis, Massachusetts General Hospital, Boston, Massachusetts 02114.

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Aspirin and a large number of nonsteroidai anti-inflammatory drugs act primarily through the inhibition of prostaglandin synthesis by inhibiting the enzyme cyciooxygenase. Other groups of biologically active polyunsaturated fatty acid derivatives including the ieukotrienes, ‘are generaiiy not inhibited by this class of drugs in the same concentration ranges. inhibition of the vasodiiator prost&iandins, prostagiandin E2 and prostacyciin, as well as the ieukotrienes, may reduce their inflammatory effects in several disease states. in addition, prostagiandin synthesis is also inhibited by giucocorticoids even though their mode of action may involve other effects as well. Prostagiandin E2 stimulates the osteociastic reabsorption of juxtaarticuiar bone; its inhibition by nonsterokiai anti-inflammatory agents may, therefore, retard the process of bone erosion in rheumatoid arthritis and in other inflammatory processes. inhibition of prostagiandin synthesis by these drugs accounts for many oi their major toxic effects, including gastritis, which is the most dbmmon side effect; precipitation or aggravation of renal failure; fluid retention; hyperkaiemia; antipiateiet effects with hemorrhagic phenomena; and aggravation of asthma and rhinosinusitis. inhibition of prostagiandin synthesis can, therefore, account for most of the therapeutic as well as toxic effects of the nonsteroidai anti-inflammatory agents. inhibition of pathways of synthesis of other important qdiators, such as ieukotrienes, are currently under investigation and may provide another approach for the development of new therapeutic agents. The generation of inflammatory reactions appears to require the action of a number of mediators, but the class of mediators most directly linked to the action of anti-inflammatory drugs is the prostaglandins. This biologically active group of molecules is now known to be a part of a broader class of lipids, the eicosanoids, which are derived from 20-carbon polyunsaturated fatty acids and include the recently discovered leukotrienes and other lipoxygenase products [l-3]. The biologic activity of the prostaglandins was recognized in the 1930s by von Euler and others, but it remained for Bergstrom over 30 years later to establish their basic structure [4]. The relationship of prostaglandins to inflammation was inferred from the discovery by Vane and co-workers in 1971 that aspirin and related compounds inhibited the synthesis of prostaglandins. Shortly thereafter, these investigators postulated that the major pharmacologic effects of the nonsteroidal anti-inflammatory drugs may be accounted for by the ability of these compounds to inhibit prostaglandin synthesis-a hypothesis that remains generally accepted today [4].

The American Journal of Medicine

ARTHRITIS SYMPOSIUM-ROBINSON

F&we 7. Structures and biosynthesis of prostaglandins and thromboxane A2. FGD2, PGE2, FGF2 and ffit4 = prostaglandins 4, E2, F2 and 4.

OH Thrbnboxane A,

Subsequently, the biosynthetic pathway of prostaglandins was clarified by Samuelson and colleagues through the identification of labile endoperoxide intermediates (for example prostaglandin H2) (Figure 1) and the labile platelet product thromboxane AZ. An additional labile compound, prostacyclin, or prostaglandin 12was characterized by Vane’s group in 1976. Then, in 1979, Samuelson’s group described an important new class of eicosanoids, the leukotrienes (Figure 2), beginning a new chapter in the investigation of lipid mediators with increasing potential importance for biology and medicine. The significance of work in this area was highlighted by the award of the 1962 Nobel Prize in Biology and Medicine to Bergstrom, Samuelson, and Vane. STRUCTURES AND BIOSYNTHESIS OF PROSTAGLANDINS AND LEUKOTRIENES The most important prostaglandins and leukotrienes are

derived from arachidonic acid (Figures 1 and 2) which is stored in tissue membranes, primarily in phospholipids. Prostaglandin synthesis is initiated by the cleavage of arachidonic acid from membrane phospholipids through the action of phospholipases. After hydrolysis, arachidonic acid undergoes a complex rearrangement, including addition of two molecules of oxygen, to form the characteristic five-membered prostaglandin ring. The initial product, the endoperoxide prostaglandin Hz, then reacts in one of several isomerase reactions to form the stable prostaglandins (ES, Fz~, and Dz), the labile prostaglandin 12(prostacyclin), or the related compound thromboxane A2 (which contains a six- rather than five-membered ring). The structural

Prostacyctin (PGI,)

differences of these end-products may be accompanied by profound differences in function, as will be discussed. The functional consequences of prostaglandin synthesis is, in part, determined by the specific isomerases present in tissues, since these determine which compounds will eventually be formed from the cyclooxygenase product, prostaglandin H2 [2,3]. The second important class of eicosanoids-the leukotrienes (Figure 2)-bear some resemblance to prostaglandins in that they are products of reactions of molecular oxygen and arachldonic acid. However, they lack the five- or six-membered ring structures seen in prostaglandins and thromboxanes, respectively. Some of the leukotrienes (C, D, and E) are derived from the addition of glutathione to leukotriene A4 with subsequent stepwise removal of amino acids from the glutathione moiety to fm leukotriene Dd and leukotriene E2 [5]. Both prostaglandins and leukotrienes are synthesized when they appear to be needed in tissues. They are not stored in appreciable quantities in either cells or tissues. They are secreted shortly after their biosynthesis and act on cells in the vicinity of their cell of origin. In this respect the prostaglandins and leukotrienes, sometimes termed autocoids, differ from circulating hormones. Both prostaglandins and leukotrienes are labile in tissues, being rapidly degraded by enzymatic and nonenzymatic pathways into inactive products. FUNCTIONS OF PROSTAGLANDINS AND LEUKOTRIENES RELATED TO INFLAMMATION

The prostaglandins and leukotrienes have a wide variety of effects involving several organ systems (Table I). Many, but not all, of these effects involve augmenting

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ARTHRITIS SYMPOSIUM--ROBINSON

ARACHIDONIC ACID

NH,

GJutathtone S-

5-bpmygenose

tronsferose

LEUKOTRIENE C, (LTC,)

/

Gtutmnyl Tronspephdose

I ! &COOH

~

5-HPTE

+cooH

LEUKOTRIENE A4 CLTA,J NH2

LEUKOTRIENE D4 (LTD4)

/ COOH

tiH2

LEUKOTRIENE B4 (LTQ) LEUKOTRIENE Figure 2.

Structures and biosynthesis of leukotrienes.

either constriction or relaxation of smooth muscle. Prostaglandin E2 and prostacyclin promote infbmmatory reactions by their activity as vasodilators [6]; in addition, they act synergistically with other mediators, histamine,

TABLE I

Functions of Arachldonlc Acid Products In lnflammatkbn

Prostsglandins PGEs, PGls Vasodiiation Synergistic with histamine, prostaglandins. C5a’, LTB., in producing vasopermeability Stimulation of bone resorption (PGf,. PGE?) Leukotrlems LTB, Chemotactic for neutrophils and eosinophils Promotes leukocyte adherence to endothelium Produces synergistic vasodilation with PGEp, PGI*, PGDl LTC,, LCD4. LTE4 Vasoconstriction Bronchoconstrlctlon Elicit wheal and flare (increases vascular permeability) ’ C5a = 11 ,ooO dafton glycopeptkle fragment of the fifth component of complement.

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E, (LTE,)

5-HPTE = 5 hydroperoxyeicosatetraenoic

acid.

C5a, and leukotriene B4 in promoting increased vascular permeability [7]. The sulfidopeptide group of leukotrienes-C4, D4, and E4-account for the activity of slow-reacting substance of anaphylaxis and are potent mediators of increased vascular permeability. These leukotrienes, in contrast with prostaglandin E2 and prostacyclin, are potent vasoconstrictors and bronchoconstrictors [5]. Finally, leukotriene 84 acts as an extremely potent chemotactic agent toward neutrophils and eosinophils, and it promotes the adherence of leukocytes to endothelium; this, in turn, leads to leukocyte migration into extravascular sites of inflammation [5]. MECHANISM OF ACTION OF NONSTEROIDAL ANTIINFLAMMATORY DRUGS The work of Vane and colleagues in the early 1970s led to the hypothesis that the major therapeutic as well as toxic effects of nonsteroidal anti-inflammatory drugs may be accounted for by their ability to inhibit prostaglandin synthesis [6]. The drugs of this class currently available for clinical use in the United States are listed in Table II.These drugs inhibit prostaglandin synthesis

ARTHRITIS

by acting on the enzyme, cyclooxygenase (Figure 3); therefore, the synthesis of all prostaglandins is inhibited, nonselectively. Presumably, the anti-inflammatory effects of these drugs are related to inhibition of prostaglandin E2 and prostacyclin synthesis [8]. Although limited experimental data are available, the nonsteroidal anti-inflammatory drugs have no known major effects on leukotriene pathways. Corticosteroids, the most potent anti-inflammatory drugs, are also potent inhibitors of prostaglandin synthesis [8]. The mechanisms of other anti-inflammatory drugs such as gold salts, penicillamine, and antimalarials are unknown at present, but they clearly differ from the nonsteroidal anti-inflammatory drugs and seem to have no important effects on prostaglandin synthesis. Evidence indicates that glucocotticoids, in contrast with nonsteroidal anti-inflammatory drugs, inhibit the release of arachidonic acid from phospholipids by inhibiting phospholipases [9]. It has been reported that glucocorticoids stimulate the synthesis of a protein phospholipase inhibitor termed macrocortin or lipomodulin [ 10,l l]. In one study it was suggested that the phospholipase inhibitor is in turn inactivated by an antilipomodulin present in serum from patients with systemic lupus erythematosus [ 121. Regardless of the detailed mechanism, it is clear that inhib’ition of prostaglandin synthesis by glucocorticoids,occurs in many cell types, and this effect may contribute to the anti-inflammatory effects of these agents. Inhibition of phospholipase activity implies that leukotriene synthesis would also be inhibited by glucocorticoids, although studies of this effect have not yet been reported in the literature. In any event, it is likely that inhibition of prostaglandin synthesis is only partially responsible for the anti-inflammatory

effects of glucocorticoids. Toxic or Side Effects of Nonsteroidal Anti-inflammatory Drugs. Although the nonsteroidal anti-inflammatory drugs are among the most widely used drugs in medicine and are generally well tolerated, toxic effects are common and may be serious. Some of these effects are related to inhibition of prostaglandin synthesis, the anti-inflammatory property of the nonsteroidal antiinflammatory drugs. Awareness of the toxic potentials of these drugs and a high degree of vigilance will contribute to the safety and effectiveness of nonsteroidal anti-inflammatory drugs in clinical practice. Gastrointestinal Effects. The most common troublesome side effects of nonsteroidal anti-inflammatory drugs are those of the upper gastrointestinal tract. Nonsteroidal anti-inflammatory drugs may cause erosive gastritis, peptic ulceration, and gastrointestinal bleeding. Since prostaglandin E2 suppresses gastric acid secretion and helps to maintain the gastric mucosal barrier, inhibition of prostaglandin synthesis may account for many of the upper gastrointestinal symptoms caused

TABLE II

SYMPOSIUM-ROBINSON

NonsteroidalAnti-inflammatory Drugs GenericName

TradeName

Aspirin Other salicylates Phenylbutazone Oxyphenbutazone lndomethacin Ibuprofen Mefenamic acid Naproxen Fenoprofen Tolmetin Sulindac Meclofenamate Piroxicam Diflunisal

Butazolidin Tanderil lndocin Motrin, Brufen Ponstel Naprosyn Nalfon Tolectin Clinoril Meclomen Feldene Dolobid

by these drugs [ 131. In addition, the tendency toward anti-inflammatory of prostaglandininduced gut mobility [ 131. Some of the gastrointestinal side effects of the nonsteroidal anti-inflammatory drugs are probably related to local effects on the gastric mucosa. These locally induced gastric effects should be less severe when agents that are ingested as a biologically inactive prodrug (for example, sulindac, fenbufen) are used. These drugs are converted to active forms by metabolism after absorption from the gastrointestinal tract. Although it is also possible that gastric cyclooxygenase may be inhibited by active forms of these drugs in the circulation, leading to gastrointestinal symptoms, nonsteroidal anti-inflammatory drugs designed to be converted to active forms after absorption from the gastrointestinal tract in principal should provide a mechanism for reducing gastrointestinal side effects. Antiplatelet Effects. Nonsteroidal anti-inflammatory drugs impair platelet aggregation through inhibition of constipation produced by nonsteroidal drugs may be related to inhibition

Nonsteroidal anti-inflammatory

I L

drugs

Cyclooxygenase A

Prostaglandins

Arachidonic acid

Leukotrienes HETES

Figure 3.

Nonsteroidal anti-inflammatory drugs inhibit the enzyme cyclooxygenase, but these drugs do not inhibit lipoxygenase. HETEs = hydroxyeicosatetraenoic acids.

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1

I

Phospholipases Phospholiplds 4 Llpomddulin or macrocortln

Arachidonic acid

PGs ,LTs HETEs

Glucockicoids

Figure 4. Glucocorticoids inhibit arachidonic acid release by increasing the levels of a protein inhibitor of phospholipase, called macrocortin or lipomodulin. PGs = prostaglandins, LTs = leukotrienes, HETEs = hydroxyeicosatetraenoic acids.

platelet cyclooxygenase-induced synthesis of thromboxane A2 (Figure 1). In particular, this metabolic process is exquisitely sensitive to aspirin; it has been estimated that less than 80 mg a day of aspirin is sufficient to completely inactivate platelet cyclooxygenase activity and thromboxane A2 synthesis [ 14,151. However, because thromboxane A2 is only one of several agents that induces platelet aggregation, the bleeding defect produced by aspirin generally is mild, although it may be more severe under some circumstances (described herein). Conceivably, large doses of aspirin, and presumably other nonsteroidal anti-inflammatory drugs, would inhibit prostacyclin production by endothelial and vascular smooth muscle cells, as well as platelet thromboxane A2 production. Since the effects of prostacyclin-inhibition of platelet aggregation and promotion of vasodilation-oppose those of thromboxane A*, at large doses the anti-thrombotic effects of these agents may cancel out. Thus, extremely small doses of aspirin may actually produce greater antihemostatic effects than large doses. The validity of these concepts rests with future clinical trials. It seems clear that aspirin, in particular, and other nonsteroidal anti-inflammatory drugs share antiplatelet effects. Although these effects produce only a mild bleeding diathesis in hematologically normal patients, in patients with defects in coagulation caused either by the administration of anticoagulants, such as coumarin drugs, or by hereditary clotting factor deficiencies, bleeding consequences may be severe. Therefore, nonsteroidal anti-inflammatory drugs should be used with great caution, if at all, in patients receiving anticoagulants or with clotting factor deficiencies. TABLE III

Toxicity of Cyclooxygenase lnhibltors Presumably Unrelated to Proataglandin Inhibition

Hepatotoxicity Toxic amblyopia Central nervous system effects Headaches, dizziness, tinnitus, deafness, drowsiness, confusion, nervousness, increased sweating, aseptic meningitis

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In hemodynamically normal persons, prostaglandins appear to be unimportant in renal physiology. Inhibition of prostaglandin synthesis has few consequences for renal function in hemodynamically normal persons. On the other hand, under conditions of circulatory stress such as congestive heart failure, cirrhosis of the liver, nephrotic syndrome, and others, the vasodilator prostaglandins, E2 and prostacyclin, are important in maintaining renal blood flow. In these states, inhibition of prostaglandin synthesis may lead to precipitation or exacerbation of renal failure, sometimes to a severe degree. This effect of nonsteroidal anti-inflammatory drugs is usually reversible if recognized [ 161. Prostaglandin E2 also is natriuretic, and the inhibition of renal prostaglandin E2 synthesis by nonsteroidal anti-inflammatory drugs probably accounts for the fluid retention seen with these agents. Hyperkalemia induced by nonsteroidal anti-inflammatory drugs has not been widely recognized but may develop, particularly under conditions of circulatory stress, or in certain patients receiving diuretics. This complication may be potentially life-threatening and deserves careful monitoring in susceptible patients [ 161. Respiratory Effects. Patients with rhinosinusitis, nasal polyps, and asthma may have severe exacerbations related to the ingestion of aspirin and other nonsteroidal anti-inflammatory drugs. Although the mechanism is unproved, it has been suggested that cyclooxygenase inhibition in these patients may reduce bronchodilator prostaglandins while leaving leukotriene synthesis unaffected. The anaphylactic activity of the leukotrienes may precipitate bronchospasm. Patients exhibiting this reaction to nonsteroidal anti-inflammatory drugs generally have similar adverse reactions to all cyclooxygenase inhibitors [ 17,181. Obstetric Effects. The use of cyclooxygenase inhibitors should be avoided in late pregnancy for several reasons. Inhibition of the uterine contractile effects of prostaglandins may delay parturition, and the antiplatelet effects of the nonsteroidal anti-inflammatory drugs, especially aspirin, increase postpartum and neonatal bleeding. There is also evidence that the nonsteroidal anti-inflammatory drugs may promote premature closure of the ductus arteriosus and impair fetal circulation. On the other hand, inhibition of vasodilator prostaglandins by nonsteroidal anti-inflammatory drugs had led to their use in newborns to promote closure of patent ductus arteriosus. Alternatively, prostaglandin administration has been recommended for maintaining a patent ductus in complex congenital cardiac malformations until corrective surgery may be carried out. Finally, nonsteroidal anti-inflammatory drugs are often the drugs of choice in the treatment of dysmenorrhea Renal Effects.

[191. Other Side Effects.

There are a variety of side effects

ARTHRITIS SYMPOSIUM-ROBINSON

The anti-inflammatory drugs are some of the most widely used drugs in clinical medicine. The major therapeutic and toxic effects of the nonsteroidal anti-

inflammatory drugs may be accounted for by their ability to inhibit prostaglandin synthesis through direct blocking of the cyclooxygenase enzyme. Other mediators derived from polyunsaturated fatty acids, including the leukotrienes, are not inhibited by the usual therapeutic doses of these drugs. Glucocorticoids also inhibit prostaglandin synthesis, and evidence indicates that these agents may also inhibit formation of other lipid mediators. Toxic effects of nonsteroidal anti-inflammatory drugs related to inhibition of prostaglandin synthesis include gastrointestinal symptoms, hemorrhagic complications, renal insufficiency and hyperkalemia, aggravation of rhinosinusitis and asthma in hypersensitive subjects, and obstetric complications. The development of new drugs with the capacity to inhibit mediators other than prostaglandins, especially leukotrienes, may be useful. Alternatively, new cyclooxygenase inhibitors differing in tissue specificity or metabolism from those drugs now in use, may improve therapeutic effects while lowering toxicity.

Flower RJ: Drugs which inhibit prostaglandin biosynthesis. Pharmacol Rev 1974; 20: 33-67. Metz SA: Anti-inflammatory agents as inhibitors of prostaglandin synthesis in man. Med Clin North Am 1981; 65: 713. Robinson DR: Prostaglandins and anti-inflammatory drugs. Disease-A-Month 1963; May 12: in press. Nelson NA, Kelly RC, Johnson RA: Prostaglandins and the arachidonic acid cascade. Chem Eng News 1982; (August 16): 30-34. Lewis RA, Austen KF: Mediation of local homeostasis and inflammation by leukotrienes and other mast cell-dependent compounds. Nature 1981; 293: 103-108. Ferreira SJ, Vane JR: New aspects of the mode of action of nonsteroid anti-inflammatory drugs. Ann Rev Pharmacol 1974; 14: 57. Wedmore CV, Williams TJ: Control of vascular permeability by polymorphonuclear leukocytes in inflammation. Nature 1981; 289: 646-650. Robinson DR. Smith H, McGuire MB: Prostaglandin synthesis by rheumatoid synovium and its stimulation by colchicine. Prostaglandins 1975; 10: 67-85. Hong SL, Levine L: Inhibition of arachklonic acid release from cells as the biochemical action of anti-inflammatory corticosteroids. Proc Natl Acad Sci USA 1976; 73: 17301734. Blackwell GJ, Carnuccio R, DiRosa M, et al: Macrocortin: a polypeptide causing the anti-phospholipase effect of glucocorticoids. Nature 1980; 287: 147-149. Hirata F: The regulation of lipomodulin, a phospholipase in-

hibitory protein, in rabbit neutrophils by phosphorylation. J Biol Chem 1981; 256: 7730-7733. Hirata F, Del Carmine R, Nelson CA, et al: Presence of autoantibody for phosholipase inhibitory protein, lipomodulin, in patients with rheumatic diseases. Proc Natl Acad Sci USA 1981; 76: 3190-3194. Wilson DE, Kaymakcalan H: Prostaglandins: gastrointestinal effects and peptic ulcer disease. Med Clin North Am 1981; 65: 773-787. Patrignani P, Filabozzi P, Patron0 C: Selective cumulative inhibition of platelet thromboxane production by lowdose aspirin in healthy subjects. J Clin Invest 1982; 69: 1366-1372. Weksler BB, Pett SB, Alonso D, et al: Differential inhibition by aspirin of vascular and platelet prostaglandin synthesis in atherosclerotic patients. N Engl J Med 1983; 308: 800-805. Horton R, Zipser R, Fichman M: Prostaglandins, renal function and vascular regulation. Med Clin North Am 1981; 65: 891-914. Szczeklik A, Gryglewski RJ, Czerniawska-Mysik G: Clinical patterns of hypersensitivity to nonsteroidal anti-inflammatory drugs and their pathogenesis. J Allergy Clin lmmunol 1977; 60: 276-284. Stevenson DD: Aspirin and rhinosinusitislasthma: desenitization. N Engl Sot Allergy Proceed 1981; 2: 88-93. Caldwell BV, Behrman HR: Prostaglandins in reproductive processes. Med Clin North Am 1981; 65: 927-936. Simon LS, Mills JA: Nonsteroidal anti-inflammmatory drugs. New Engl J Med 1980; 302: 1179-1185.

of nonsteroidal anti-inflammatory drugs that are not thought to be related to inhibition of prostaglandin synthesis, although this mechanism has not been definitely excluded. Many of these effects are related to the central nervous system (Table III). Hepatotoxicity has been seen most frequently with aspirin, especially in association with juvenile-onset rheumatoid arthritis and systemic lupus erythematosus. It is usually associated with mild histologic changes and is readily reversible following withdrawal of the drug [20]. Severe hepatic reactions have been reported, however, with many nonsteroidal anti-inflammatory drugs and a warning to this effect is now required by the U.S. Food and Drug Administration on package inserts for all nonsteroidal anti-inflammatory drugs. CONCLUSION

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