21: Nonopioid Analgesics, Nonsteroidal Anti-inflammatory Drugs, and Antirheumatic and Antigout Drugs

CHAPTER 21 Nonopioid Analgesics, Nonsteroidal Anti-inflammatory Drugs, and Antirheumatic and Antigout Drugs

Nonopioid analgesics, nonsteroidal anti-inflammatory drugs (NSAIDs), and agents used in the control of rheumatoid arthritis and gout represent a diverse group of chemical compounds whose mechanism of action typically involves the inhibition of one or more components of the inflammatory response. Acute pain, which typically accompanies inflammatory insults, results from various dental surgical procedures and can often be controlled by the use of the nonopioid analgesic acetaminophen or NSAIDs such as ibuprofen. In addition, NSAIDs play an important role in the symptomatic relief of the inflammation and pain that accompany arthritis. These agents do not eliminate or reduce the underlying causes of the arthritic disease, however, and joint damage can continue to progress despite the long-term use of these drugs.

Disease-modifying antirheumatic drugs (DMARDs) play a major role in the management of rheumatoid arthritis. They represent a group of chemically unrelated agents that have additional uses in medicine, ranging from the treatment of malaria and cancer to the prevention of transplanted organ rejection. In some instances, these agents can slow and arrest some of the pathologic changes seen in rheumatoid arthritis. They are fraught with serious adverse effects, however, and many patients cannot tolerate their long-term use.

CAUSE OF INFLAMMATION

Inflammation typically represents the response to tissue injury and includes products of activated mast calls, leukocytes, and platelets; prostaglandins (PGs); leukotrienes; and complement-derived products. The clinical features of inflammation include tumor (edema), rubor (redness), calor (heat), dolor (pain), and loss of function.

Although inflammation is often thought of as only a pathologic event, it serves a normal homeostatic function. In the case of tissue injury from minor trauma or a dental surgical procedure, the inflammatory process results in a series of well-regulated humoral and cellular events leading to localization of injury, removal of noxious agents, repair of physical damage, and restitution of function in the injured tissue. In patients unable to mount a competent inflammatory response, such as patients with agranulocytosis induced by some cancer chemotherapeutic drug regimens (see Chapter 42), the results are often fulminant infection and death.

The inflammatory response is not always beneficial to the host. If it becomes excessive or chronic, as is the case with rheumatoid arthritis, it may result in the progressive destruction of joint tissue and a host of untoward systemic effects. Drugs are now being developed with relatively favorable therapeutic indices that show promise in halting some of the destructive inflammatory events of chronic rheumatic diseases.

Inflammation can be divided into three phases: acute inflammation, subacute inflammation, and chronic inflammation. In acute inflammation, small preformed inflammatory mediators such as histamine are released, causing vasodilation and increased capillary permeability. In the subacute stage, inflammatory cells migrate and invade the site. PGs, leukotrienes, platelet-activating factor (PAF), and cytokines also play major roles. The third, or chronic, stage of inflammation involves the lymphocytic phase of injury cleansing and repair. Cytokines, especially interleukins and tumor necrosis factor-α (TNF-α), are prominent in this stage. In reality these phases are not distinct entities. Components of the subacute phase participate in the acute inflammatory process, and acute inflammatory mediators are present in chronic inflammatory disorders such as arthritis. Even so, this classification still offers a useful way to categorize this highly complex process. The following section briefly reviews some of the key mediators of the inflammatory process. Table 21-1 provides a more complete list of inflammatory mediators.

TABLE 21-1 Classification of Some Endogenous Mediators of Inflammation

MAJOR GROUPS MAJOR MEDIATORS
Tissue  
Lymphocyte products MCP-1
  GM-CSF
  Other chemoactive factors
  Interferon-γ
  Interleukins
  Skin reactive factor
Macrophage products Interleukin-1
  Interferon-γ
  TNF-α
  PAF
Mast cell products Histamine
  Cytokines
  TNF-α
  Leukotrienes
  Prostaglandin D2
  PAF
Eosinophil products Lysosomal enzymes
  Major basic protein
  Other cationic proteins
  Leukotrienes
  PAF
Others Reactive metabolites of oxygen
  Endogenous pyrogens from leukocytes
  Leukocytosis factors
Plasma  
Kinin system Bradykinin
Complement system C3 fragments
  C5 fragments
  image complex
  Membrane attack complex
Clotting system Fibrinopeptides
  Fibrin degradation products

GM-CSF, Granulocyte-macrophage colony-stimulating factor; MCP-1, monocyte chemoattractive protein-1; PAF, platelet-activating factor.

Tissue Mediators

Histamine

Histamine is the first mediator for which a role in the inflammatory process was clearly established. This vasoactive amine is formed by decarboxylation of histidine and is widely distributed in the body. Although some free histamine exists in tissues, most is stored in mast cell and basophil granules in a physiologically inactive form. (For a more complete discussion, see Chapter 22.) Various physical and chemical stimuli, such as antigens, complement fragments, or simple mechanical trauma, can cause extrusion of the granules and release of active histamine into the extracellular fluid.

One of the most characteristic actions of histamine is dilation of vessels of the microcirculation and a marked, but transient, increase in the permeability of capillaries and postcapillary venules, reflecting an activation of H1 receptors in these tissues. These vascular changes are similar to the changes that occur in tissue after injuries of all sorts. The evidence that histamine released from the ubiquitous mast cell is responsible for the initial permeability changes seen in an inflammatory response is extensive. The histamine content of tissue fluid at the site of injury increases within minutes after the insult and then decreases. Concurrent with these changes, mast cells in the area of damage are found to be degranulated. It has been shown that prior depletion of tissue histamine stores by various means or pretreatment with classic antihistamines (H1 receptor blockers) reduces the initial vascular response to injury.101 Inhibition of initial histamine-dependent events does not block the further development of the inflammatory response, however.

In patients with chronic inflammation caused by rheumatoid arthritis, increased concentrations and penetration depth of mast cells in synovial tissue are found, possibly related to the expression of stem cell factor by synovial fibroblasts. Astemizole, a potent antihistamine, does not affect the clinical course of this disease.139 The role played by histamine in inflammation is early, transient, and nonessential for subsequent events that may lead to lasting tissue alterations.

Antihistamines have little use as general anti-inflammatory agents. In certain situations, such as immediate allergic reactions, large amounts of histamine are released locally or systemically from sensitized mast cells and basophils as a consequence of antigen-antibody reactions. In these instances, antihistamines that block the H1 receptor are useful in reducing symptoms attributable to histamine. As discussed in Chapter 22, antihistamines that block the action of histamine at the H2 receptor have a supporting role in the management of anaphylaxis and a major role in the treatment of gastric hyperacidity conditions.

Prostaglandins

The PGs are a unique family of closely related acidic lipids found in all tissues. The basic structure of all PGs is a prostanoic acid skeleton composed of a 20-carbon polyunsaturated fatty acid with a five-member ring at C8 through C12 (Figure 21-1). Similar to the leukotrienes described subsequently, PGs are derived from arachidonic acid and similar 20-carbon polyunsaturated fatty acids that are liberated from the cell membranes of local tissues by the action of acylhydrolases, principally phospholipase A2, and, in platelets, diacylglycerol lipase. Inflammatory cells, including human monocytes and mast cells, also have the ability to generate PGs. Although multiple oxygenation products are derived from arachidonic acid, the PG molecules all contain a five-membered carbon ring. The alphabetical PG nomenclature (A-F) is based on the structure of this cyclopentane ring. PGE and PGFα differ only in the presence of a ketone or hydroxyl group at C9. Also in the nomenclature, a subscript 1 indicates the presence of a double bond at C13 to C14 (PGE1), a subscript 2 indicates the presence of an additional double bond at C5 to C6 (PGE2), and a subscript 3 indicates the presence of a third double bond at C17 to C18 (PGE3).

A key event in the acute inflammatory process is the liberation of arachidonic acid from damaged cell membranes on exposure to phospholipase A2 (Figure 21-2).55 This step can be inhibited indirectly by a powerful group of anti-inflammatory agents known as glucocorticoids, which are described in detail in Chapter 35. From this point, the oxidative metabolism of arachidonic acid can proceed along two divergent pathways. One pathway uses the enzyme cyclooxygenase (COX), also known as PG endoperoxide synthase, and the second pathway uses the enzyme lipoxygenase. Virtually all cells in the body, with the exception of red blood cells, contain the COX enzyme, whereas lipoxygenase seems to be limited to inflammatory cells (neutrophils, mast cells, eosinophils, and macrophages).

COX catalyzes the transformation of arachidonic acid to the short-lived cyclic endoperoxide PGG2. PGG2 is converted to PGH2 by peroxidation, which is an additional function of COX. Unstable and potentially tissue-toxic oxygen radicals can be liberated by this process. From this point, PGH2 is converted to the stable PGs E2 and F, thromboxanes, or prostacyclin (PGI2) by appropriate enzymes.

It is now well established that COX exists in two isoforms. Both are 72-kDa proteins but differ in terms of their sequence homology (approximately 60%) and their genomic regulation.47,149,150 COX-1 is regarded as the constitutive or housekeeping isoform and is the major isoform found in healthy tissues. It is always present in a number of tissues, including the central nervous system (CNS), gastric mucosa, platelets, and kidneys.36 In the gastric mucosa, COX-1 plays a major role in the synthesis of PGs involved in the formation of the mucous protective barrier (so-called cytoprotection) against stomach acid. In platelets, COX-1 is the key enzyme involved in thromboxane production and its subsequent platelet aggregatory properties necessary for proper hemostasis.

COX-2 is, for the most part, an inducible isoform upregulated by such products as cytokines, growth factors, and mitogens in human monocytes, macrophages, endothelial cells, chondrocytes, synoviocytes, and osteoblasts.36 It is associated with elevated concentrations of PGs during inflammation, pain, and fever. Figure 21-3 illustrates some of the physiologic roles of the COX isoforms. Although initially it was hoped the COX-2 products participated only in inflammatory and other pathologic processes, it is now known that oxidation products of the COX-2 isoform help regulate some normal physiologic processes, including the maintenance of adequate water and Na+ excretion by the kidneys, the inhibition of excessive platelet aggregation, and dilation of certain vascular beds.77

image

FIGURE 21-3 Some physiologic roles of the cyclooxygenase (COX) isoforms. Renal, vascular, and platelet functions are influenced by both COX isoforms. GI, Gastrointestinal.

(From Hersh EV, Lally ET, Moore PA: Update on cyclooxygenase inhibitors: has a third COX isoform entered the fray? Curr Med Res Opin 21:1217-1226, 2005.)

PGs and the other active metabolites of the intermediate endoperoxides (e.g., PGI2 and thromboxane A2 [TXA2]) exert a multitude of effects in almost every biologic process examined so far. These processes include smooth muscle contraction and relaxation, vascular permeability, renal electrolyte and water transport, gastrointestinal (GI) and pancreatic secretion, various CNS and autonomic nervous system functions, release of hormones (e.g., growth hormone, steroids, and gonadotropins), luteolysis and parturition, lipolysis, bone resorption, and platelet aggregation. Not only are the affected processes diverse and the effects complex, but also the different PGs and related molecules sometimes seem to have antagonistic actions. PGE2 and PGI2 generally cause vasodilation and inhibit platelet aggregation, whereas TXA2 causes vasoconstriction and induces platelet aggregation. The effects of PGF on vascular tone depend on the vascular bed.

Qualitative and quantitative differences in response to the PGs exist among mammalian species, further complicating elucidation of the biologic roles of these substances. It is axiomatic that generalizations about the actions of PGs and related compounds are misleading; the response to a given agent must be considered in the context of the particular tissue involved, the assay system used, and the species of experimental animal.

There is abundant evidence that PGs and the intermediate endoperoxides are mediators of inflammation.42,107 Arachidonic acid and other fatty acid precursors of PGs present in the membrane phospholipid of cells can be released by hydrolase enzymes activated by direct cellular damage or by any nondestructive perturbation of the membrane, whether physical, chemical, hormonal, or neurohumoral. PG synthesis can ensue as shown in Figure 21-2. In acute inflammatory reactions, PGs appear in fluids and exudates later (2 to 12 hours after injury) than some other mediators, such as histamine and bradykinin. PGs are being formed at a time when tissue damage and disintegration are more prominent. It is possible that some of the PG content found in sites of inflammation is derived from infiltrating neutrophils and macrophages because these cells are capable of PG synthesis.1

When released in tissue, PGs may contribute to the inflammatory response in multiple ways. The evidence that they do so can be summarized as follows42: (1) PGs are found in experimentally or naturally produced inflammatory fluids; (2) neutrophils and macrophages produce PGs during phagocytosis; (3) PGI2 and PGE2 injected intradermally are potent inducers of vasodilation and of increased vascular permeability, an effect that is greatly augmented by the presence of histamine or 5-hydroxytryptamine and may last for several hours; (4) minute amounts of PGI2 and PGE2 injected intradermally markedly increase the pain sensitivity to other mediators, such as bradykinin and histamine; (5) PGE2 is pyrogenic when injected into the cerebral ventricles or anterior hypothalamus, suggesting a mediator function; (6) a severe disabling arthritis is produced in animals by injecting PGs into the knee joint, and rheumatoid synovial cells produce PGs in culture; and (7) certain anti-inflammatory drugs that are potent inhibitors of PG synthesis reduce experimentally produced inflammation.

Although PGs stimulate certain inflammatory events, they inhibit or modulate others. The fact that PGs inhibit the proliferation and release of certain inflammatory mediators from neutrophils and activated lymphocytes and the fact that some effects of PGE2 are opposed by PGF provide evidence of a modulating function.

The precise roles of PGs in the inflammatory process are far from established, but these unique compounds clearly have the potential to act as mediators, modulators, or both. If both functions are involved, PGs could occupy a central regulatory position. A balance between enhancement and suppression of inflammatory events could be achieved by local regulation of PG metabolism because in some systems PGs have been shown to be either stimulatory or inhibitory depending on their concentration. Altering the relative concentrations of PGE and PGF could provide an additional means of balance because different PGs have diverse and occasionally antagonistic actions in the same system (e.g., PGE2 causes bronchodilation, whereas PGF causes bronchoconstriction; PGI2 inhibits platelet aggregations, whereas TXA2 stimulates platelet aggregation).

Leukotrienes

The term slow-reacting substance (SRS) was first applied to a lipid-soluble material produced by treatment of lung tissue with cobra venom. This material was characterized by its production of a slow, prolonged contraction of a smooth muscle preparation in contrast to the rapid and transient action of histamine. A chemically and biologically similar material was subsequently found in the lungs of sensitized guinea pigs challenged with specific antigen in vitro.153 This material was designated as the SRS of anaphylaxis (SRS-A) to distinguish it from SRS produced by nonimmunologic mechanisms. Studies of the biologic properties of SRS-A indicated that it might be an important mediator of anaphylactic and other immediate allergic reactions. SRS-A can be found in most tissues, especially in the lung, after appropriate antigenic challenge. It is released along with histamine and other active products from mast cells.

Although SRS-A was known for some time to be an acidic, sulfur-containing lipid of low molecular weight, elucidation of its exact structure and biosynthesis was delayed until intensive study of the metabolism of arachidonic acid showed that SRS-A belonged to a class of compounds known as leukotrienes.103,132 Leukotrienes are formed by the conversion of arachidonic acid to noncyclized, 20-carbon carboxylic acids with one or two oxygen substitutes and three conjugated double bonds (see Figure 21-2). The critical step in the biosynthetic pathway is generation of a 5,6-epoxide of arachidonic acid (leukotriene A4) by the combined actions of 5-lipoxygenase and leukotriene A synthase. Leukotriene A4 may be converted to leukotriene B4 by a hydrolase enzyme or, alternatively, to leukotriene C4 by the addition of glutathione. Removal of glutamate from leukotriene C4 generates leukotriene D4.

These lipid-peptide derivatives apparently account for all the biologic activity of SRSs found in immediate allergic reactions. Leukotrienes C4 and D4 constitute SRS-A. Asthmatic reactions may also involve other leukotrienes, however. The ability of cells to produce leukotrienes seems to be limited to the lung, leukocytes, blood vessels, and epicardium. In contrast, all cells except erythrocytes can convert arachidonic acid to PGs and related compounds by the action of COX.

Leukotrienes C4 and D4 are potent in vivo and in vitro constrictors of bronchial smooth muscle in the guinea pig. Both compounds have similar effects in human bronchial muscle preparations, in which they are approximately 1000 times more potent than histamine. Because these leukotrienes also increase vascular permeability, it seems likely that either one or both play a role in the bronchial constriction and mucosal edema of asthma. Leukotriene B4 can enhance chemotactic and chemokinetic responses in human neutrophils, monocytes, and eosinophils.60 These findings suggest that leukotrienes may be involved in localized inflammatory processes and in asthma. Drugs that block leukotriene receptors or inhibit leukotriene synthesis by blocking the enzyme lipoxygenase are used in the treatment of asthma (see Chapter 32).

Lysosomal products

The lysosomes of neutrophils contain various enzymatic and nonenzymatic factors that play important roles in the manifestations and sequelae of inflammatory reactions (Box 21-1). During phagocytosis of bacteria or foreign material by neutrophils, the contents of lysosomes are released into the extracellular environment. They are also released on lysis of the cell. Cationic proteins from lysosomes contribute to the inflammatory process by triggering mast cell degranulation, which leads to increased vascular permeability. Other lysosomal enzymes may contribute to the inflammatory response in several ways. Several of these enzymes have the potential to damage host tissues. Collagen, elastin, mucopolysaccharides, basement membrane, and other structural elements may be degraded. Lysosomal proteases cause the production of kinin-like substances from plasma kininogen and can generate chemotactic factors for neutrophils from complement, as described in a later section. Leukotrienes and PAF are also released by neutrophils. Neutrophils may play a central role in perpetuating the inflammatory response by their dual ability to cause tissue damage and to elaborate specific mediators of inflammation. Another source of lysosomal factors, especially in chronic inflammatory lesions, may be the mononuclear phagocyte, or macrophage, the lysosomes of which contain substances similar to those of the neutrophil.1 These substances are released into the extracellular environment on activation of macrophages by various soluble factors, such as leukotriene B4, C5a complement factor, and PAF, and during the process of phagocytosis of bacteria or other particulate matter.

BOX 21-1 Factors in the Neutrophil with Inflammatory Potential

PAF, Platelet-activating factor.

Tissue-damaging enzymes Elastase
  Cathepsins B and G
  Collagenase
  Other proteases
Microbicidal enzymes Myeloperoxidase
  Lysozyme
Permeability factors Leukotrienes
  PAF
  Leukokinin-forming enzyme
  Basic peptides
Leukotactic factors Leukotrienes
  PAF
  C5-cleaving enzyme
  Basic peptides (chemotactic for monocytes)

Macrophage products

Similar to lymphocytes, macrophages apparently have little involvement in acute inflammatory responses, but they play a very prominent role in chronic inflammation and are crucial in the immune response. In addition to their phagocytic activity, macrophages have a major secretory function in established inflammatory lesions. Secretory products include the constituents of lysosomes (see earlier), reactive metabolites of oxygen, interferon-α, interleukin-1 (IL-1), and TNF-α. The latter two substances are crucial mediators of the complex interplay between macrophages and lymphocytes, which largely determines the course and eventual outcome of an inflammatory process. IL-1 is produced by macrophages exposed to bacterial, viral, and fungal products; antigens; or macrophage activation factor. It may have several roles, but chief among these seems to be the stimulation of differentiation of a pre–T-lymphocyte population to T cells capable of responding to an antigen processed and presented by macrophages.

Another mediator of inflammation produced by macrophages and other cells is PAF. PAF is a closely related family of substances derived from phosphatidylcholine generated in the metabolism of arachidonic acid. It is also synthesized in other cells, including mast cells and eosinophils. Platelets also contain PAF. PAF initiates various actions, including platelet activation, vasodilation, vascular permeability, neutrophil chemotaxis, and discharge of lysosomal enzymes. It also contributes to allergic and inflammatory responses.

Plasma Mediators

Kinins

The term kinins refers primarily to two small peptides that are similar in structure and actions: bradykinin and lysyl-bradykinin (or kallidin). Bradykinin can be considered the prototype. It is a linear nonapeptide with a molecular weight of 1060 Da. As with the release of histamine, almost any process causing tissue injury can trigger the series of events leading to the production of bradykinin. Bradykinin exists in plasma as an inactive precursor (kininogen) and is released in a cascade of reactions beginning with activation of Hageman factor (clotting factor XII). Hageman factor can be activated by exposure to numerous substances, including cartilage, collagen, basement membrane, sodium urate crystals, proteolytic enzymes, and bacterial lipopolysaccharides. Hageman factor activates an enzyme called prekallikrein to yield kallikrein. Kallikrein cleaves bradykinin from kininogen, an α2-globulin precursor. (In addition, activated Hageman factor triggers the clotting cascade by activating factor XI and the fibrinolytic system by activating plasminogen proactivator, ultimately yielding plasmin.) Kinins may also be produced extravascularly from tissue kininogen. After release, bradykinin is rapidly metabolized by enzymes present in plasma and tissues.

Bradykinin has striking pharmacologic effects in humans and animals. It is a potent but transient vasodilator of arteries and veins by a direct action on smooth muscle. Intradermal injection of bradykinin causes marked increases in vascular permeability; in this regard, it is more potent than histamine on a molar basis. Bradykinin applied to a blister base or injected intradermally or intra-arterially in humans evokes sharp pain. Experimental pain can also be produced by a bradykinin-like substance isolated from human blister fluid and from synovial fluid obtained from acutely inflamed joints. In extraction sockets, local concentrations of immunoreactive bradykinin and PGs increase in patients after the removal of impacted third molar teeth.129,159 All these phenomena implicate bradykinin in various aspects of acute inflammatory reactions, including acute pain.

Complement system

The complement system plays an important role in the inflammatory process. In humans, this system consists of at least 20 component proteins that react in a fixed sequence (Figure 21-4). An immune complex on a cell surface activates the first component, C1, and a cascade of events results in the formation of a complex that leads to membrane damage and cell lysis.

This so-called classic pathway of complement activation can be initiated by most antigen-antibody complexes and by nonimmune factors such as trypsin and plasmin. Other substances, such as complex polysaccharides, aggregated IgA, and bacterial endotoxin, may trigger an alternative pathway in which the first component to be activated is C3, followed by the usual components in the activation scheme.

In addition to the above-mentioned direct cellular damage, certain fragments produced during the cascade of complement activation have important biologic properties. Two of them (C3a and C5a) cause increased vascular permeability by inducing the release of histamine from mast cells. These substances are referred to as anaphylatoxins and have been implicated in anaphylaxis and other allergic reactions. The C5a anaphylatoxin is also a potent chemotactic factor. Neutrophils, monocytes, and eosinophils exhibit directed locomotion in response to it. Enhancement of phagocytosis and release of lysosomal enzymes have been attributed to other components of the activation scheme.

Complement fragments can be produced by mechanisms extrinsic to the complement system (e.g., by plasmin, trypsin, and bacterial proteases). This action suggests that complement fragments may participate in tissue injury and in the subsequent inflammatory response without classic or alternative complement activation.

Nitric oxide

The small gaseous molecule nitric oxide (NO) apparently plays a regulatory and a proinflammatory role in various inflammatory conditions, including arthritis, asthma, and inflammatory bowel disease.38,95,127 In mammalian cells (similar to COX), two isoforms of the NO-producing enzyme nitric oxide synthetase are constitutively expressed, and a third inducible isoform, inducible nitric oxide synthetase (iNOS), is upregulated in response to bacterial products and proinflammatory cytokines.92,94 Compounds that inhibit iNOS expression or activity possess anti-inflammatory properties.94,133 Currently approved drugs that target the nitric oxide system, such as nitroglycerin to treat angina (see Chapter 26) and the male erectile dysfunction drug sildenafil (Viagra) (see Chapter 28), increase NO levels; specific iNOS inhibitors are being developed to treat various inflammatory disorders.

NONSTEROIDAL ANTI-INFLAMMATORY DRUGS

NSAIDs include some of the most frequently taken medications. Because these agents share a common mechanism of action, they exert qualitatively similar therapeutic and toxic effects. For the treatment of pain and inflammation that accompany various dental surgical procedures, the short-term use (typically ≤1 week) of NSAIDs has generally proved to be highly efficacious and safe. Compared with opioid-combination drugs (described later in this chapter), NSAIDs lack various undesirable CNS depressant effects that contribute to the high incidence of drowsiness, dizziness, and nausea commonly seen with opioid-containing agents. This favorable efficacy and safety profile has led the U.S. Food and Drug Administration (FDA) to approve three NSAIDs (ibuprofen, naproxen sodium, and ketoprofen) in addition to aspirin for over-the-counter (OTC) use. Use of these drugs under OTC package insert guidelines mandates no more than 10 days of consecutive dosing for pain and only 3 days for fever, plus absolute maxima on single and daily doses that are lower than the prescription use of these drugs.81

When treating chronic inflammatory conditions such as rheumatoid arthritis, the duration of NSAID therapy is typically measured in months or years, and the daily doses required to control the arthritic symptoms are often twofold to threefold higher than doses required to control acute pain. This type of therapy leads to a greatly increased incidence of minor and major side effects, requiring more vigilant monitoring of these patients.

The development of NSAIDs that are highly selective COX-2 inhibitors seemed to offer a safety advantage regarding some of the more serious adverse effects seen with long-term NSAID therapy, specifically GI ulcers, perforations, and bleeds.16,143 More recent studies showing increased cardiovascular risk with long-term use of these agents compared with placebo in colon polyp prevention trials19,151 and increased cardiovascular risk with 10 days of dosing in the treatment of patients with pain after coronary artery bypass graft (CABG) surgery119 have led to the removal of several of these drugs from the worldwide marketplace.

Salicylates

The salicylates are among the oldest known drugs. Hippocrates recommended the consumption of the juices of the poplar and willow bark some 2400 years ago, which later were discovered to contain salicin (a glycoside of salicylic alcohol), for the treatment of the pain of childbirth. In 60 ad, Discorides reported that a boiled extract of willow bark could be used to treat various maladies, including corns, gout, and earache. In a report to the Royal Society in London in 1763, the Reverend Edward Stone made one of the earliest references to the antipyretic effect of willow bark extracts. The active principle of willow and poplar preparations, salicylic acid, was first extracted in 1835 from natural sources and later prepared by chemical synthesis. Kolbe was credited with the first full-scale commercial synthesis of salicylic acid and its derivative sodium salicylate. In 1853, Charles Frederich von Gerhardt was the first to synthesize aspirin (acetylsalicylic acid) by treating sodium salicylate with acetyl chloride. Despite the untoward GI effects of large doses of salicylic acid and sodium salicylate, the development of salicylates culminated in the introduction of aspirin into medicine in 1899 by Heinrich Dresser of the Bayer Company of Germany. The popularity of aspirin was immediate, and today it remains one of the most consumed drugs in the world.

Several additional salicylates have also been marketed. Choline salicylate, magnesium salicylate, and their combination product are ion complexes of salicylate. Salsalate is an ester composed of two salicylate molecules, which are freed as the molecule is hydrolyzed. These salicylate formulations are said to have fewer GI side effects than aspirin. Because released salicylate is the active moiety of all these drugs, however, the rest of their pharmacology is quite similar to aspirin. The structure of aspirin and some of the related salicylates is shown in Figure 21-5. Aspirin may be considered a prototype of the NSAIDs and is the standard of reference against which these agents are compared and evaluated.

Mechanism of action

The efficacy of salicylates and all related NSAIDs as analgesic, anti-inflammatory, and antipyretic agents results from their ability to inhibit COX activity, preventing the synthesis and release of COX products, most prominently the PGs. All salicylates and almost all the currently available NSAIDs, with the exception of the highly selective COX-2 inhibitors, inhibit COX-1 and COX-2. Most of these nonselective COX-inhibiting NSAIDs, including aspirin, are more potent or at least equipotent inhibitors of COX-1,128,169 which accounts for some of the more important adverse effects of these drugs. Figure 21-6 shows the relative COX-2 versus COX-1 selectivity of some representative NSAIDs. As shown in this figure, aspirin is an approximately 100-fold more selective inhibitor of COX-1 than COX-2. The published COX selectivities of individual drugs vary with the assay system being used.

image

FIGURE 21-6 The ratio of the log of inhibitory concentrations (IC) of various nonsteroidal anti-inflammatory drugs needed to block 50% of COX-2 activity versus 50% of COX-1 activity in the whole blood assay (WBA). The zero line indicates equipotency. Bars on the right represent drugs with greater selectivity for COX-1, whereas bars on the left represent drugs with greater selectivity for COX-2.

(Adapted from Riendau D, Percival MD, Brideau C, et al: Etoricoxib [MK-0663]: preclinical profile and comparison with other agents that selectively inhibit cyclooxygenase-2, J Pharmacol Exp Ther 296:558-566, 2001; Warner TD, Guiliano F, Vojnovic I, et al: Nonsteroid drug selectivities for cyclo-oxygenase-1 rather than cyclo-oxygenase-2 are associated with human gastrointestinal toxicity: a full in vitro analysis, Proc Natl Acad Sci U S A 96:7563-7568, 1999.)

Aspirin uniquely inactivates COX by irreversibly acetylating the enzyme. Acetylation occurs on serine 530 of COX-1.105 A comparable serine on COX-2, serine 516, is also acetylated by aspirin. The later modification not only inhibits PG production during inflammation, but also enables COX-2 to produce 15-hydroxyeicosatetraenoic acid.98,123 This metabolite may be associated with certain adverse effects. Other salicylates and NSAIDs do not acetylate COX but are reversible competitive inhibitors of the enzyme. Because PGs are not stored, but rather are synthesized immediately before release, the reduction of PG concentrations by NSAIDs can be observed quickly.

The potency of the salicylates as inhibitors of PG synthesis in vitro correlates well with their ability to alleviate carrageenin-induced inflammation in animals (Table 21-2). In humans, anti-inflammatory doses of aspirin (3 g daily), sodium salicylate (3 g daily), or indomethacin (100 mg daily) reduce the output of PG metabolites in the urine by more than 75%, indicating a close correlation of the inhibition of COX with anti-inflammatory effects.71 Although inhibition by COX is the major mechanism of action of the NSAIDs, participation in other anti-inflammatory mechanisms may occur and account for some of the variation in clinical response seen with these drugs. Salicylates may inhibit cell migration and some functions of neutrophils. A reduced production of rheumatoid factor may also occur by stimulation of suppressor T-cell activity. Other mechanisms contributing to anti-inflammatory effects include reduced capillary permeability, reduced antibody production, and alterations in connective tissue synthesis. The relative potencies against COX-1 and COX-2 also account for important differences among various NSAIDs.

Inhibition of PG synthesis at the site of injury or inflammation can explain at least some of the analgesic effect of aspirin. Although PGs themselves do not seem to cause pain when injected locally, PGE2 and PGF do sensitize pain receptors to other mediators such as histamine and bradykinin. In this connection, aspirin and related drugs can prevent the writhing response elicited by bradykinin but not that produced by PGs. This finding is explained by the fact that the salicylates and all other NSAIDs inhibit the synthesis of PGs induced by bradykinin but not the binding of PGs to their receptors. Animal experiments have revealed that NSAIDs also have central analgesic actions, which may involve the inhibition of COX or other unknown mechanisms at the level of the spinal dorsal horn or at higher levels of the CNS.106,110 The antipyretic effect of aspirin and similar drugs is also mediated by the reduction of PGE2 synthesis as a result of inhibition of COX.

General therapeutic effects

Aspirin has clinically useful analgesic, antipyretic, anti-inflammatory, and antiplatelet effects. The analgesic effect sought and attained with aspirin is probably caused in many cases by its anti-inflammatory actions, a fact not usually appreciated by its users. In addition to their widespread use for the symptomatic relief of acute pain and fever, salicylates (most commonly aspirin) are important drugs in the treatment of numerous chronic inflammatory diseases. Some of the major therapeutic uses of aspirin are considered next.

Acute pain

It is difficult to separate the analgesic and anti-inflammatory effects of NSAIDs because most painful conditions have an inflammatory component. There is little doubt that the cascade of reactions leading to the formation of PGs is integrally involved with the inflammatory response and that aspirin’s efficacy in treating inflammation and pain is closely related to its inhibition of PG synthesis. By using microdialysis techniques, it has been shown that after dental surgery the analgesic effects of NSAIDs correlate with a local reduction in PG synthesis.121,129 Nevertheless, several observations suggest that the analgesic and anti-inflammatory effects of NSAIDs may occur by different mechanisms. First, there is a different time course for the onset of analgesic and anti-inflammatory effects. Clinically significant analgesia usually occurs within 1 hour of drug administration, whereas anti-inflammatory effects sometimes take several days or weeks to reach maximum levels because chronic inflammatory processes may be occurring that cannot be quickly reversed by inhibiting PG production. Also, the maximal human analgesic effect usually occurs at lower doses than the antirheumatic and other anti-inflammatory effects.

Aspirin is an effective analgesic for almost any type of acute dental pain. Double-blind, controlled studies of the relief of pain after the surgical extraction of third molars have shown that 650 mg of aspirin is substantially more effective than 60 mg of codeine in relieving postoperative pain (Figure 21-7).31 Most controlled clinical studies have established that, regardless of the cause of the pain, aspirin (650 mg) provides equal or greater pain relief than codeine in standard doses (60 mg).12 Aspirin and other NSAIDs and acetaminophen have what is known as a ceiling or plateau effect in the treatment of acute pain. In other words, there is a dose-response for pain relief up to 650 to 1000 mg of aspirin, but increasing the dose beyond these amounts does not enhance the analgesic effect further and does increase the likelihood for toxic effects.

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FIGURE 21-7 Time-effect curves for placebo, aspirin, codeine, and an aspirin-codeine combination. The mean pain relief scores are plotted against time in hours.

(Adapted from Cooper SA, Engel L, Ladov M, et al: Analgesic efficacy of an ibuprofen-codeine combination, Pharmacotherapy 2:162-167, 1982.)

Rheumatoid arthritis

Rheumatoid arthritis is a chronic systemic disease of unknown origin. Several tissues and organs may be involved, but in most patients the chief clinical and pathologic features result from chronic inflammation of synovial membranes. Irreversible joint injury (subluxation, loss of motion, or ankylosis) results from formation of chronic granulation tissue that causes erosions of articular cartilage, subchondral bone, ligaments, and tendons. Extra-articular manifestations, such as subcutaneous or subperiosteal nodules of granulation tissue, peripheral neuropathy, and chronic skin ulcers, occur to a variable extent and seem to result from generalized focal vasculitis. Patients with rheumatoid arthritis are at increased risk of developing cardiovascular disease, including myocardial infarction (MI).168

The cause of the inflammatory response in rheumatoid arthritis is obscure, but the inflammatory events result largely from an autoimmune reaction. Rheumatoid arthritis is considered an autoimmune disease with many contributing factors. Lymphocytes that have become activated produce TNF-α and IL-1. These cytokines lead to the release of other inflammatory mediators, such as the PGs. Anti-immunoglobulins, referred to as the rheumatoid factor and found in rheumatoid synovial fluid, can form complexes with IgG. These complexes may activate complement, which triggers a number of inflammatory phenomena in the joint tissues, including histamine release, production of factors chemotactic for neutrophils and mononuclear cells, cell membrane damage, and PG synthesis. The antigen-antibody complexes also activate antigen-presenting cells, which stimulate T cells, leading to the further release of cytokines. Neutrophils and macrophages accumulate in the synovial fluid and are found to contain aggregated IgG, rheumatoid factor, complement fragments, and fibrin; these substances are apparently acquired by phagocytosis. Lysosomal materials are released that amplify the inflammatory reaction and may directly damage tissues. Cytokines produced by the lymphocytic cell infiltrate may also help propagate the reaction and participate in tissue destruction.

Salicylates (usually as aspirin) are still widely used in the clinical management of rheumatoid arthritis. The pain and inflammation of rheumatoid arthritis can often be controlled with salicylates alone (or with another NSAID).152 Salicylates produce a measurable reduction of inflammation in the joints and associated tissues, a lessening of symptoms, and improved mobility. Salicylates may also reduce neutrophil activity in addition to inhibiting PG synthesis. Clinical observation suggests that salicylate therapy can diminish or delay the development of crippling associated with the disease. This benefit is not a direct effect of the drug on the progression of the disease, but relates more to reduction of pain and subsequent facilitation of mobility. In addition to salicylates, the basic therapeutic regimen in rheumatoid arthritis includes rest, physical measures (primarily heat), and exercise.

When salicylate therapy is ineffective or is not well tolerated, other drugs, such as the NSAIDs ibuprofen and naproxen, or corticosteroids, can be used. Salicylates and related NSAIDs do not slow or arrest the joint destruction and extra-articular manifestations characteristic of the disease. For disease progression to be affected, DMARDs, which include gold compounds, sulfasalazine, penicillamine, antimalarials, methotrexate, azathioprine, cyclosporine, leflunomide, and TNF-α inhibitors, must be used.

In rheumatoid arthritis, salicylates are given in doses sufficient to control the symptoms, often 3 to 6 g/day. The degree of suppression of inflammation increases with the plasma salicylate concentration even beyond the point of toxicity. Patients with severe arthritis tolerate tinnitus and other mild toxic manifestations to obtain the anti-inflammatory effects gained by high plasma titers of salicylate. A regular dose interval to maintain constant effective blood concentrations is important. Evaluation of drug therapy in rheumatoid patients may be complicated by the spontaneous remissions and exacerbations characteristic of this disease.

Fever

Fever is typically a symptom of a disease process, usually a viral or bacterial infection brought about by exogenous (microbial products) and endogenous pyrogens.40,156 It is believed that exogenous pyrogens stimulate host cells to produce endogenous pyrogens, of which IL-1 has been the best characterized.51,156 IL-1 is thought to act on the anterior hypothalamus, generating the local release of PGs.51,155 Injection of PGs into the brain of various animal species is known to increase body temperature.53 The PGs and possibly other non-PG endogenous pyrogens elevate the thermal set-point of the body so that it retains the ability to regulate closely its temperature, but at a higher temperature than normal.40,156

By inhibiting the synthesis of PGs in the hypothalamus, aspirin, other NSAIDs, and acetaminophen are thought to reduce the thermal set-point toward normal. The decrease in body temperature also involves the ability of aspirin and other antipyretics to induce a vasodilation of superficial blood vessels. Because of its association with Reye’s syndrome, aspirin is no longer recommended to treat most febrile episodes in children.

Prophylaxis against platelet aggregation

The correlation between the ability of aspirin-like compounds to inhibit simultaneously platelet aggregation and the production of PGs has been known for almost 40 years.148 Aspirin inhibits the synthesis of TXA2 by irreversible acetylation of the COX enzyme in platelets.73,130 Lacking a nucleus, platelets cannot generate new enzyme, and the ability of affected platelets to produce TXA2 is permanently blunted during their 10-day lifetimes. Most platelet COX acetylation may occur presystemically as platelets pass through gut capillaries before the hydrolysis of aspirin to salicylate (a weak and reversible inhibitor of COX) in the gut and the liver.125 This possibility may partially explain the relative lack of effect of low-dose aspirin on the antiaggregatory PGI2 molecule produced by the systemic vascular endothelium.

The fact that endothelial cells, by possessing a nucleus, can generate new COX enzyme after aspirin administration may also contribute to the relatively selective and complete block of TXA2 synthesis over PGI2. This selective block of TXA2 synthesis in platelets provides the rationale for using long-term low-dose aspirin therapy to prevent MI and occlusive stroke in at-risk patients. Other salicylates and NSAIDs are either much weaker or only reversibly inhibit COX in platelets and have limited therapeutically beneficial antiplatelet effects.

In 1998, the FDA published a set of indications for aspirin prophylaxis that include definitive dosing guidelines for each condition (Table 21-3).44 Vascular indications include the reduction of death or nonfatal stroke in patients who have had ischemic strokes or transient ischemic attacks, reduction of vascular mortality in patients with acute MI, reduction of combined risk of death and nonfatal MI in patients with previous MI or unstable angina, and reduction of the combined risk of MI and sudden death in patients with chronic stable angina. The recommended daily dose for all these indications is low (≤325 mg/day) compared with the analgesic and anti-inflammatory uses of the drug. Aspirin also is indicated for patients who have undergone revascularization procedures, including CABG surgery, percutaneous transluminal coronary angioplasty, and carotid endarterectomy, when there are preexisting conditions for which aspirin is already indicated.

TABLE 21-3 Antiplatelet Indications and Dosing Guidelines for Aspirin

INDICATIONS RECOMMENDED DAILY DOSE DURATION OF THERAPY
Vascular Indications    
Ischemic stroke and TIA 50-325 mg Indefinitely
Suspected acute MI 160-162.5 mg taken as soon as MI is suspected, then once daily For 30 days after MI (after 30 days, consider further treatment if previous MI)
Prevention of recurrent MI 75-325 mg Indefinitely
Unstable angina pectoris 75-325 mg Indefinitely
Chronic stable angina pectoris 75-325 mg Indefinitely
Revascularization Procedures in Selected Patients    
CABG surgery 325 mg starting 6 hr after procedure 1 yr
PTCA 325 mg 2 hr before surgery; maintenance therapy 160-325 mg Indefinitely
Carotid endarterectomy 80-650 mg twice daily started before surgery Indefinitely

CABG, Coronary artery bypass graft; MI, myocardial infarction; PTCA, percutaneous transluminal coronary angioplasty; TIA, transient ischemic attack.

Absorption, fate, and excretion

When aspirin is taken orally, it is rapidly absorbed from the stomach and small intestine. Aspirin is a weak acid, with a pKa of approximately 3.5, which favors its absorption in the stomach. Most absorption occurs in the small intestine, however, because of its much larger surface area. The rate-limiting steps in the absorption of aspirin are the disintegration and dissolution of the tablet. These two steps can be greatly influenced by the manufacturing process, which determines factors such as particle size and compression of the tablet. Buffering the tablet increases the rate of dissolution, but the fastest absorption is obtained when aspirin is dissolved in hot water before ingestion. Other factors, such as gastric emptying time, gastric contents, and level of autonomic activity of the patient, may also influence the rate of absorption.100,102

Aspirin has a 15-minute half-life.124 Because its acetylation of COX in the platelet is irreversible, however, the full extent of its antiplatelet action depends on the life span of the platelet (8 days) and not on the short half-life of aspirin.4,124 It is quickly metabolized by gastric and plasma esterases to salicylate ion (Figure 21-8). Although some aspirin becomes bound to plasma proteins, 80% to 90% of the salicylate ion is bound for a short time, principally to albumin. Salicylate is distributed throughout most body fluids and tissues. It can be isolated from spinal, peritoneal, and synovial fluids; saliva; breast milk; and sweat. Salicylate freely crosses the placenta from mother to fetus.

The elimination half-life of sodium salicylate is 2 to 3 hours after a single analgesic dose. The liver is the main site of biotransformation, and conjugation is the primary route. Because the metabolism of salicylate is capacity limited, large repeated doses or single toxic ingestions result in plasma half-lives of 5 to 30 hours. When describing the duration of analgesic and anti-inflammatory action of aspirin, its ultimate dosing interval reflects the summed half-lives of the parent molecule and the active metabolite, salicylate. Salicylate, in contrast to the parent aspirin molecule, is only a reversible inhibitor of COX (most notably in the platelet), however. The three primary products of salicylate conjugation are salicyluric acid (the glycine conjugate), the ether or phenolic glucuronide, and the acyl or ester glucuronide. A small portion (<1%) is oxidized to gentisic acid (see Figure 21-8). Free salicylate and the salicylate metabolites are excreted by glomerular filtration and by active proximal tubular secretion in the kidney. In normal humans, approximately 10% of ingested salicylate appears unchanged in the urine; however, this fraction may decrease to 2% or increase to 30% with urinary acidosis or alkalosis. A higher percentage of free salicylate is excreted at higher doses because the liver is unable to maintain the same percentage of metabolism at higher doses of salicylates.

Adverse effects

The severity of side effects that can accompany aspirin ingestion depends on the overall health of the patient, the length of dosing, and the total daily intake of drug. When used under OTC package insert guidelines (for ≤10 days and ≤4 g/day), most reported side effects are more annoying than serious, with dyspepsia and nausea occurring in 10% of patients. In addition, occult bleeding (hidden amounts of blood in the stool), which is usually less than 10 mL/day, develops in more than 70% of patients ingesting the drug. The bleeding is thought to originate from direct capillary and mucosal damage as aspirin disintegrates in contact with gastric tissues and from the ability of aspirin to inhibit COX-1, which interferes with cytoprotective mechanisms and platelet aggregation. Although this occult bleeding is usually of little clinical significance, aspirin and all related NSAIDs are contraindicated in patients with active GI ulcers because their ingestion may lead to sudden, potentially fatal GI hemorrhage.

With more long-term, high-dose regimens of aspirin and other nonselective NSAIDs used in the treatment of various inflammatory disorders, the inhibition of COX-1 leads to several common and predictable effects, the occurrence of which varies with each drug. The inhibition of PGI2 and PGE2 synthesis and the resulting loss of their protective effects on the gastric mucosa lead to a significant increase in GI problems, the most serious of which include significant gastric bleeding, symptomatic peptic ulcers, and GI perforations and obstructions. The incidence of these more serious events ranges from 1% to 5% of patients per year. Even long-term low-dose (81 mg/day) aspirin therapy is associated with an increased risk of serious GI events, at a rate of 0.1% to 0.2% of patients per year.124 This increase in GI complications has led experts to question the widespread use of low-dose aspirin therapy in patients without significant cardiovascular or cerebrovascular risks. Nonaspirin salicylates generally elicit fewer adverse effects in the GI tract but cannot be used for platelet antiaggregatory therapy. Most of the other NSAIDs have some antiplatelet effect based on inhibition of the production of TXA2, but the effects are not as pronounced as with aspirin because aspirin is an irreversible inhibitor of COX.

The antiplatelet effects of aspirin can lead to pronounced increases in bleeding time. As previously discussed, this effect is long lasting compared with other NSAIDs because aspirin irreversibly acetylates COX-1 in the non-nucleated platelet. Even a single dose of aspirin can increase the bleeding time for several days. A theoretic concern is the fact that this prolongation of bleeding time can promote intraoperative and postoperative hemorrhage in dental surgical patients. Limited data suggest extractions and periodontal surgery may be performed without special risk in patients kept on aspirin therapy. Although the risk/benefit ratio of discontinuing long-term cardioprotective low-dose aspirin therapy before dental surgery remains controversial, from a medicolegal standpoint it should not be done without the approval of the patient’s physician. The remote but real chance of a patient having MI or occlusive stroke shortly after a dental practitioner interrupts low-dose aspirin therapy dictates medical consultation. In addition, aspirin therapy may be reinstituted when a clot is established.

The adverse effects of aspirin and other NSAIDs on the kidney are well known. Normal renal function is partly dependent on PG synthesis. It is believed that COX-1 and COX-2 are important in producing PGs involved in reducing water and Na+ reabsorption at the ascending loop of Henle and maintaining proper dilation of the renal vasculature (see Figure 21-3).17 With NSAID therapy, dose-dependent water and Na+ retention manifested by peripheral edema, elevation in blood pressure, and rarely congestive heart failure is thought to follow the inhibition of PGE2 synthesis. Renal artery vasoconstriction, possibly causing acute renal ischemia and kidney failure, is ascribed to an inhibition of PGI2 synthesis. Acute renal failure is more likely to develop in patients with preexisting renal insufficiency, congestive heart failure, or dehydration because the renal arterioles are more dependent on PGs to maintain normal perfusion of the glomeruli.117 Acute renal failure is also more likely when NSAIDs are given concurrently with an angiotensin-converting enzyme (ACE) inhibitor because the lack of angiotensin II weakens reactive constriction of the efferent arteriole, a normal protective response for maintaining glomerular filtration in patients with reduced renal blood flow.

NSAIDs are likewise responsible for chronic renal toxicity, commonly known as analgesic-associated nephropathy. This disorder sometimes occurs with long-term use of high doses of NSAIDs and is characterized by papillary necrosis and chronic interstitial nephritis. The mechanism may be related to the acute ischemic response described earlier, but the cause has not been definitely established. It is estimated that serious renal problems requiring hospitalization occur in 0.5% to 1% of long-term NSAID users.

The use of aspirin in children with viral infections has been associated with Reye’s syndrome.84 First described in 1963, Reye’s syndrome is an acute childhood illness that produces metabolic encephalopathy and liver disease.126 Typically, a child is recovering from influenza or varicella when the acute encephalopathic symptoms of lethargy, agitation, delirium, and seizures appear. Without aggressive supportive treatment, the disease progresses to deep coma, brainstem dysfunction, and death in 80% to 90% of cases.84 Even with heroic treatment, the mortality rate can exceed 30%, and survivors can be left with permanent brain damage. Clinical reviews and case-controlled studies performed in the 1970s and 1980s reported a strong association between the development of Reye’s syndrome and the ingestion of aspirin in children and teenagers with viral infections.85,104,171 Aspirin and related salicylates are contraindicated for the treatment of flulike symptoms, chickenpox, gastroenteritis, and, in the opinion of most pediatricians, any febrile respiratory condition in children or teenagers. Acetaminophen and ibuprofen have not been associated with the development of Reye’s syndrome.81

Toxicity caused by aspirin overdose is common. The symptoms and severity depend on the dose. Chronic toxicity caused by salicylates results in a syndrome termed salicylism, which is characterized by tinnitus, nausea, vomiting, headache, hyperventilation, and mental confusion. Aspirin is one of the more frequently used drugs for attempted suicide. The drug is commonly involved in accidental poisoning, especially in children, because it is found in almost every household and proper precautions for its storage are often neglected. Serious clinical manifestations of acute aspirin overdose typically occur at doses greater than 6 to 10 g in adults or when intake exceeds 150 to 200 mg/kg of body weight.

The cardinal signs and symptoms of acute aspirin overdose include nausea, vomiting, tinnitus, hyperthermia, and hyperventilation. Hyperventilation arises in part from a direct stimulation of respiratory centers in the brain and from a compensatory increase in respiration in response to excessive carbon dioxide produced by large doses of aspirin partially uncoupling oxidative phosphorylation. This uncoupling also accounts for the paradoxic (because therapeutic doses of aspirin are used for antipyresis) increase in body temperature.18 The hyperventilation eventually can lead to respiratory alkalosis, which may be followed by a combined respiratory and metabolic acidosis accompanied by dehydration. Acidosis is more prominent as the level of overdose increases. Acidosis is also more likely to occur in children and infants. Impaired vision, hallucinations, delirium, and other CNS effects may be evident, and the situation is considered life-threatening.

The treatment of aspirin overdose is primarily palliative and supportive. Chronic toxicity usually is treated simply by withholding the drug temporarily and then reinstituting therapy at lower doses. Acute toxicity often requires respiratory support, gastric lavage, maintenance of electrolyte balance (e.g., K+ replacement if necessary), maintenance of plasma pH, and alkalinization of the urine with intravenous bicarbonate. Alkalinization of the urine increases the percentage of ionized salicylate in the glomerular filtrate. Salicylate reabsorption is reduced, and renal clearance is increased up to fourfold. The carbonic anhydrase inhibitor acetazolamide may also be used to promote urinary alkalinization.

Allergic reactions to aspirin can also occur. Many patients confuse side effects such as nausea or tinnitus with true allergic responses manifested by skin rashes, hives, angioedema, or anaphylaxis. Patients with a history of skin eruptions caused by aspirin ingestion should be cautioned to avoid all proprietary compounds containing aspirin or any salicylate to avoid more serious anaphylactic reactions.

Intolerance to salicylates can occur, with symptoms ranging from rhinitis to severe asthma. This reaction does not seem to be immune mediated even though it resembles drug allergy in clinical presentation. Aspirin intolerance is more common in patients with preexisting asthma or nasal polyps. The incidence of this reaction in asthmatic patients has been reported as high as 20%. Patients with a history of asthma, allergic disorders, or nasal polyps should be questioned to ensure that they can tolerate aspirin and other NSAIDs. The bronchoconstriction may be caused by a shift in the arachidonic acid cascade when the COX enzyme is blocked. This inhibition prevents arachidonate metabolism from producing bronchodilating PGs, primarily PGE2.160 The lipoxygenase pathway predominates and produces leukotrienes that constrict bronchioles in sensitive individuals, mimicking the asthmatic attack.22,39 Other manifestations of aspirin intolerance include urticaria (hives) and angioedema. Switching from aspirin to another salicylate or even another NSAID does not prevent the reaction; acetaminophen is the only antipyretic analgesic that may be used safely in patients with aspirin intolerance. The clinician should be aware that, although relatively rare, there are reports of aspirin-intolerant asthmatic patients also displaying severe respiratory symptoms when ingesting therapeutic doses of acetaminophen.7

Contraindications and precautions

Aspirin is contraindicated or at least must be used with caution in numerous medical conditions (Table 21-4). Serious internal bleeding can result from the ingestion of aspirin by a patient with an ulcer. Patients with compromised liver function should use aspirin cautiously because, when used on a long-term basis, aspirin increases the prothrombin time, which could aggravate bleeding problems. Low doses of aspirin can increase plasma urate concentrations and exacerbate gouty arthritis as a result of competition between salicylate and uric acid at the active secretion sites in the proximal tubule of the kidney or by an increase in uric acid reabsorption. High doses of aspirin may increase or decrease plasma glucose concentrations by stimulating epinephrine and glucocorticoid release or by depleting liver glycogen. Salicylates may also increase insulin secretion because PGE2 inhibits insulin secretion.66

TABLE 21-4 Contraindications to the Use of Aspirin and Other Salicylates

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Jan 5, 2015 | Posted by in General Dentistry | Comments Off on 21: Nonopioid Analgesics, Nonsteroidal Anti-inflammatory Drugs, and Antirheumatic and Antigout Drugs
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