Chapter 34: Anti-inflammatory, Antipyretic, and Analgesic Agents; Pharmacotherapy of Gout

History. The history of aspirin provides an interesting example of the translation of a compound from the realm of herbal folklore to contemporary therapeutics. The use of willow bark and leaves to relieve fever has been attributed to Hippocrates but was most clearly documented by Edmund Stone in a 1763 letter to the president of The Royal Society. Similar properties were attributed to potions from meadowsweet (Spiraea ulmaria), from which the name aspirin is derived. Salicin was crystallized in 1829 by Leroux, and Pina isolated salicylic acid in 1836. In 1859, Kolbe synthesized salicylic acid, and by 1874, it was being produced industrially. It soon was being used for rheumatic fever, gout, and as a general antipyretic. However, its unpleasant taste and adverse GI effects made it difficult to tolerate for more than short periods. In 1899, Hoffmann, a chemist at Bayer Laboratories, sought to improve the adverse-effect profile of salicylic acid (which his father was taking with difficulty for arthritis). Hoffmann came across the earlier work of the French chemist, Gerhardt, who had acetylated salicylic acid in 1853, apparently ameliorating its adverse-effect profile, but without improving its efficacy, and therefore abandoned the project. Hoffmann resumed the quest, and Bayer began testing acetylsalicylic acid (ASA) in animals by 1899—the first time that a drug was tested on animals in an industrial setting—and proceeded soon thereafter to human studies and the marketing of aspirin.

Acetaminophen was first used in medicine by von Mering in 1893. However, it gained popularity only after 1949, when it was recognized as the major active metabolite of both acetanilide and phenacetin. Acetanilide is the parent member of this group of drugs. It was introduced into medicine in 1886 under the name antifebrin by Cahn and Hepp, who had discovered its antipyretic action accidentally. However, acetanilide proved to be excessively toxic. A number of chemical derivatives were developed and tested. One of the more satisfactory of these was phenacetin. It was introduced into therapy in 1887 and was extensively employed in analgesic mixtures until it was implicated in analgesic-abuse nephropathy, hemolytic anemia, and bladder cancer; it was withdrawn in the 1980s. Discussion of its pharmacology can be found in earlier editions of this textbook.

Many molecules are involved in the promotion and resolution of the inflammatory process (Nathan, 2002). Histamine was one of the first identified mediators of the inflammatory process. Although several H₁ histamine receptor antagonists are available, they are useful only for the treatment of vascular events in the early transient phase of inflammation (see Chapter 32). Bradykinin and 5-hydroxytryptamine (serotonin, 5-HT) also may play a role, but their antagonists ameliorate only certain types of inflammatory response (see Chapter 32). Leukotrienes (LTs) exert pro-inflammatory actions and LT-receptor antagonists (montelukast and zafirlukast) and have been approved for the treatment of asthma (see Chapters 33 and 36). Another lipid autacoid, platelet-activating factor (PAF), has been implicated as an important mediator of inflammation; however, inhibitors of PAF synthesis and PAF-receptor antagonists have proven disappointing in the treatment of inflammation (see Chapter 33).

TNF is composed of two closely related proteins: mature TNF (TNF-α) and lymphotoxin (TNF-β), both of which are recognized by the TNF receptors, a 75-kd type 1 receptor and a 55-kd type 2 receptor (Dempsey et al., 2003). TNF-α blockers (see Chapter 35) are used to treat inflammatory conditions, including rheumatoid arthritis, juvenile idiopathic arthritis, psoriasis and psoriatic arthritis, ankylosing spondylitis, and Crohn's disease. TNF-α blockers fall into the category of disease-modifying anti-rheumatic drugs (DMARDs) because they reduce the disease activity of rheumatoid arthritis and retard the progression of arthritic tissue destruction. NSAIDs generally are not considered DMARDs.

IL-1 comprises two distinct polypeptides (IL-1α and IL-1β) that bind to an 80-kd IL-1 receptor type 1 and a 68-kd IL-1 receptor type 2, which are present on different cell types (O'Neill, 2008). Plasma IL-1 levels are increased in patients with active inflammation. A naturally occurring IL-1 receptor antagonist (IL-1ra) competes with IL-1 for receptor binding and blocks IL-1 activity in vitro and in vivo. IL-1ra often is found in high levels in patients with various infections or inflammatory conditions and may act to limit the extent of an inflammatory response. Clinical studies suggest that the administration of a recombinant form of human IL-1ra (anakinra; see Chapter 35) antagonizes IL-1 action at its receptor and thereby inhibits the progression of structural damage associated with active rheumatoid arthritis and other inflammatory conditions. Canakinumab (ILARIS) is an IL-1β monoclonal antibody recently approved for two forms of the cryopyrin-associated periodic syndrome: familial cold auto-inflammatory syndrome and Muckle-Wells syndrome (see Chapter 35).

Many cytokines, including IL-1 and TNF-α, have been found in the rheumatoid synovium. Rheumatoid arthritis appears to be an autoimmune disease driven largely by activated T cells, giving rise to T cell–derived cytokines, such as IL-1 and TNF-α. Activation of B cells and the humoral response also are evident, although most of the antibodies generated are immunoglobulins G of unknown specificity, apparently elicited by polyclonal activation of B cells rather than from a response to a specific antigen (Brennan and McInnes, 2008).

Basal COX-2, expressed in both neurons and glia cells, contributes to central sensitization in the early phase of peripheral inflammation. COX-2 is upregulated widely in the spinal chord within a few hours to contribute to prolonged central sensitization (Samad et al., 2001). A role for COX-1 in nociception has been implicated by COX-1–deleted mice, which show increased tolerance to pain stimuli (Ballou et al., 2000). This isoform is predominant in neurons of dorsal root ganglia. Central sensitization reflects the plasticity of the nociceptive system that is invoked by injury. This usually is reversible within hours to days following adequate responses of the nociceptive system (e.g., in postoperative pain). However, chronic inflammatory diseases may cause persistent modification of the architecture of the nociceptive system, which may lead to long-lasting changes in its responsiveness. These mechanisms contribute to chronic pain.

Chemistry. NSAIDs are a chemically heterogeneous group of compounds, which nevertheless share certain therapeutic actions and adverse effects. The class includes derivatives of salicylic acid (e.g., aspirin, diflusinal), propionic acid (e.g., naproxen, ibuprofen, flurbiprofen, ketoprofen), acetic acid (e.g., indomethacin, etodolac, diclofenac, ketorolac), enolic acid (e.g., piroxicam, phenylbutazone), fenamic acid (e.g., mefenamic acid, meclofenamic acid), alkanones (nabumetone), and diaryl heterocyclic compounds (e.g., celecoxib, valdecoxib, rofecoxib, etoricoxib) (Figure 34–1).

The vast majority of tNSAID compounds are organic acids with relatively low pK_a values (Figure 34–1). Even the non-acidic parent drug nabumetone is converted to an active acetic acid derivative in vivo. As organic acids, the compounds generally are well absorbed orally, highly bound to plasma proteins, and excreted either by glomerular filtration or by tubular secretion. They also accumulate in sites of inflammation, where the pH is lower, potentially confounding the relationship between plasma concentrations and duration of drug effect. Most COX-2–selective NSAIDs are diaryl heterocyclic compounds with a relatively bulky side group, which aligns with a large side pocket in the AA binding channel of COX-2 but hinders its optimal orientation in the smaller binding channel of COX-1 (Figure 34–2) (Smith et al., 2000). Both tNSAIDs and the COX-2–selective NSAIDs generally are hydrophobic drugs, a feature that allows them to access the hydrophobic arachidonate binding channel and results in shared pharmacokinetic characteristics. Again, aspirin and acetaminophen are exceptions to this rule.

At higher concentrations, NSAIDs also are known to reduce production of superoxide radicals, induce apoptosis, inhibit the expression of adhesion molecules, decrease NO synthase, decrease pro-inflammatory cytokines (e.g., TNF-α, IL-1), modify lymphocyte activity, and alter cellular membrane functions in vitro. However, there are differing opinions as to whether any of these actions might contribute to the anti-inflammatory activity of NSAIDs (Vane and Botting, 1998) at the concentrations attained during clinical dosing. The hypothesis that their anti-inflammatory actions in humans derive solely from COX inhibition alone has not been rejected based on current evidence.

Observational studies suggest that acetaminophen, which is a very weak anti-inflammatory agent at the typical dose of 1000 mg, is associated with a reduced incidence of GI adverse effects compared to tNSAIDs. At this dose, acetaminophen inhibits both COXs by ∼50%. The ability of acetaminophen to inhibit the enzyme is conditioned by the peroxide tone of the immediate environment (Boutaud et al., 2002). This may partly explain the poor anti-inflammatory activity of acetaminophen, because sites of inflammation usually contain increased concentrations of leukocyte-generated peroxides.

COXs are configured such that the active site is accessed by the AA substrate via a hydrophobic channel. Aspirin acetylates serine 529 of COX-1, located high up in the hydrophobic channel. Interposition of the bulky acetyl residue prevents the binding of AA to the active site of the enzyme and thus impedes the ability of the enzyme to make PGs. Aspirin acetylates a homologous serine at position 516 in COX-2. Although covalent modification of COX-2 by aspirin also blocks the COX activity of this isoform, an interesting property not shared by COX-1 is that acetylated COX-2 synthesizes 15(R)-hydroxyeicosatetraenoic acid [15(R)-HETE]. This may be metabolized, at least in vitro, by 5-LOX to yield 15-epi-lipoxin A4, which has potent anti-inflammatory properties (see Chapter 33). Repeated doses of aspirin that acutely do not completely inhibit platelet COX-1–derived TxA₂ can exert a cumulative effect with complete blockade. This has been shown in randomized trials for doses as low as 30 mg/day. However, most of the clinical trials demonstrating cardioprotection from low-dose aspirin have used doses in the range of 75-81 mg/day.

The unique sensitivity of platelets to inhibition by such low doses of aspirin is related to their presystemic inhibition in the portal circulation before aspirin is deacetylated to salicylate on first pass through the liver (Pedersen and FitzGerald, 1984). In contrast to aspirin, salicylic acid has no acetylating capacity. It is a weak, reversible, competitive inhibitor of COX. Salicylic acid derivates, rather than the acid, are available for clinical use. The lack of acetylation often is used as justification to prefer trisalicylate or salsalate over aspirin in presurgical patients. High doses of salicylate inhibit the activation of NFκB in vitro, but the relevance of this property to the concentrations attained in vivo is not clear (Yin et al., 1998). Salicylic acid also may inhibit the expression of COX-2 by interfering with the binding of CCAAT/enhancer binding protein (C/EBP) β transcription factor to the COX-2 promoter (Cieslik et al., 2002). This was observed in vitro at concentrations of salicylic acid that are attained in humans.

The relative degree of selectivity for COX-2 inhibition is lumiracoxib = etoricoxib > valdecoxib = rofecoxib ≫ celecoxib (Figure 34–1). Although there were differences in relative hierarchies, depending on whether screens were performed using recombinantly expressed enzymes, cells, or whole-blood assays, most tNSAIDs expressed similar selectivity for inhibition of the two enzymes. Some compounds, conventionally thought of as tNSAIDs—diclofenac, meloxicam, and nimesulide (not available in the U.S.)—exhibit selectivity for COX-2 that is close to that of celecoxib in vitro (Figure 34–1) (Warner et al., 1999; FitzGerald and Patrono, 2001). Indeed, meloxicam achieved approval in some countries as a selective inhibitor of COX-2. Thus, selectivity for COX-2 should not be viewed as an absolute category; the isoform selectivity for COX-2 (just like selectivity for β₁ adrenergic receptors) is a continuous rather than a discreet variable, as illustrated in Figure 34–1.

Absorption. Most NSAIDs are rapidly absorbed following oral ingestion, and peak plasma concentrations usually are reached within 2-3 hours. All COX-2–selective NSAIDs are well absorbed, but peak concentrations are achieved with lumiracoxib and etoricoxib in ∼1 hour compared to 2-4 hours with the other agents. The poor aqueous solubility of most NSAIDs often is reflected by a less than proportional increase in area under the curve (AUC) of plasma concentration–time curves, due to incomplete dissolution, when the dose is increased. Food intake may delay absorption and sometimes decreases systemic availability (i.e., fenoprofen, sulindac). Antacids, commonly prescribed to patients on NSAID therapy, variably delay, but rarely reduce, absorption. Most interaction studies performed with proton pump inhibitors suggest that relevant changes in NSAID kinetics are unlikely. Little information exists regarding the absolute oral bioavailability of many NSAIDs, as solutions suitable for intravenous administration often are not available. Some compounds (e.g., diclofenac, nabumetone) undergo first-pass or presystemic elimination. Acetaminophen is metabolized to a small extent during absorption. Aspirin begins to acetylate platelets within minutes of reaching the presystemic circulation.

Distribution. Most NSAIDs are extensively bound to plasma proteins (95-99%), usually albumin. Plasma protein binding often is concentration dependent (i.e., naproxen, ibuprofen) and saturable at high concentrations. Conditions that alter plasma protein concentration may result in an increased free drug fraction with potential toxic effects. Highly protein bound NSAIDs have the potential to displace other drugs, if they compete for the same binding sites. Most NSAIDs are distributed widely throughout the body and readily penetrate arthritic joints, yielding synovial fluid concentrations in the range of half the plasma concentration (i.e., ibuprofen, naproxen, piroxicam). Some substances yield synovial drug concentrations similar to (i.e., indomethacin), or even exceeding (i.e., tolmetin), plasma concentrations. Most NSAIDs achieve sufficient concentrations in the CNS to have a central analgesic effect. Celecoxib is particularly lipophilic, so it accumulates in fat and is readily transported into the CNS. Lumiracoxib is more acidic than other COX-2–selective NSAIDs, which may favor its accumulation at sites of inflammation. Multiple NSAIDs are marketed in formulations for topical application on inflamed or injured joints. However, direct transport of topically applied NSAIDs into inflamed tissues and joints appears to be minimal, and detectable concentrations in synovial fluid of some agents (i.e., diclofenac) following topical use are primarily attained via dermal absorption and systemic circulation.

Elimination. Plasma t_1/2 varies considerably among NSAIDs. For example, ibuprofen, diclofenac, and acetaminophen have relatively rapid elimination (t_1/2 of 1-4 hours), while piroxicam has a t_1/2 of ∼50 hours at steady state that can increase to up to 75 hours in the elderly. Published estimates of the t_1/2 of COX-2–selective NSAIDs vary (2-6 hours for lumiracoxib, 6-12 hours for celecoxib, and 20-26 hours for etoricoxib). However, peak plasma concentrations of lumiracoxib at marketed doses considerably exceed those necessary to inhibit COX-2, suggesting an extended pharmacodynamic t_1/2. Hepatic biotransformation and renal excretion is the principal route of elimination of the majority of NSAIDs. Some have active metabolites (e.g., fenbufen, nabumetone, meclofenamic acid, sulindac). Elimination pathways frequently involve oxidation or hydroxylation (Table 34–1). Acetaminophen, at therapeutic doses, is oxidized only to a small fraction to form traces of the highly reactive metabolite, N-acetyl-p-benzoquinone imine (NAPQI). When overdosed (usually >10 g of acetaminophen), however, the principal metabolic pathways are saturated, and hepatotoxic NAPQI concentrations can be formed (see Chapters 4 and 6). Rarely, other NSAIDs also may be complicated by hepatotoxicity (e.g., diclofenac, lumiracoxib). Several NSAIDs or their metabolites are glucuronidated or otherwise conjugated. In some cases, such as the propionic acid derivatives naproxen and ketoprofen, the glucuronide metabolites can hydrolyze back to form the active parent drug when the metabolite is not removed efficiently due to renal insufficiency or competition for renal excretion with other drugs. This may prolong elimination of the NSAID significantly. NSAIDs usually are not removed by hemodialysis due to their extensive plasma protein binding; salicylic acid is an exemption to this rule. In general, NSAIDs are not recommended in the setting of advanced hepatic or renal disease due to their adverse pharmacodynamic effects.

In mice, PGE₂ maintains a low ductal smooth muscle cell tone via the G_s-coupled receptor EP₄ that increases intracellular cyclic AMP. In the late gestational period, pulmonary expression of an enzyme that eliminates PGE₂ from the bloodstream, PG 15-OH dehydrogenase (PGDH), is rapidly upregulated (Coggins et al., 2002). At birth, PGE₂ blood concentrations are dramatically reduced by pulmonary PGDH and by additional exposure of circulating PGE₂ to this enzyme with the increase of pulmonary blood flow. Due to reduced EP₄ signaling, intracellular cyclic AMP concentrations in the ductus arteriosus drop, and vasodilating effects are outweighed by vasoconstrictor signals, which initiate remodeling. However, surprisingly little information about the human ductal physiology exists, and a role for PGDH remains to be established in humans.

Given their relatively short t_1/2 and reversible COX inhibition, most other tNSAIDs are not thought to afford cardioprotection, a view supported by most epidemiological analyses (García Rodríguez et al., 2004). Data suggest that cardioprotection is lost when combining low-dose aspirin with ibuprofen. An exception in some individuals may be naproxen. Although there is considerable between-person variation, a small study suggests that platelet inhibition might be anticipated throughout the dosing interval in some, but not all, individuals on naproxen (Capone et al., 2005). Epidemiological evidence of cardioprotection is less impressive; it suggests an ∼10% reduction in myocardial infarction, compared to 20-25% with low-dose aspirin (Antithrombotic Trialists' Collaboration, 2002). This would fit with heterogeneity of response to naproxen. Reliance on prescription databases may have constrained the ability of this approach to address the question with precision. In the Alzheimer's Disease Anti-inflammatory Prevention Trial (ADAPT Research Group, 2008), naproxen was associated with a higher rate of cardiac events than celecoxib. Hence, naproxen should not be used as a substitute for aspirin for cardioprotection. COX-2–selective NSAIDs are devoid of antiplatelet activity, as mature platelets do not express COX-2.

Other Clinical Uses

Systemic Mastocytosis. Systemic mastocytosis is a condition in which there are excessive mast cells in the bone marrow, reticuloendothelial system, GI system, bones, and skin. In patients with systemic mastocytosis, PGD₂, released from mast cells in large amounts, has been found to be the major mediator of severe episodes of flushing, vasodilation, and hypotension; this PGD₂ effect is resistant to antihistamines. The addition of aspirin or ketoprofen has provided relief (Worobec, 2000). However, aspirin and tNSAIDs can cause degranulation of mast cells, so blockade with H₁ and H₂ histamine receptor antagonists should be established before NSAIDs are initiated.

Niacin Tolerability. Large doses of niacin (nicotinic acid) effectively lower serum cholesterol levels, reduce low-density lipoprotein, and raise high-density lipoprotein (see Chapter 31). However, niacin is tolerated poorly because it induces intense facial flushing. This flushing is mediated largely by release of PGD₂ from the skin, which can be inhibited by treatment with aspirin (Jungnickel et al., 1997), and would be susceptible to inhibition of PGD synthesis, or antagonism of its DP₁ receptor.

Bartter Syndrome. Bartter syndrome includes a series of rare disorders (frequency ≤1/100,000 persons) characterized by hypokalemic, hypochloremic metabolic alkalosis with normal blood pressure and hyperplasia of the juxtaglomerular apparatus. Fatigue, muscle weakness, diarrhea, and dehydration are the main symptoms. Distinct variants are caused by mutations in a Na⁺-K⁺-2Cl⁻ co-transporter, an apical ATP-regulated K⁺ channel, a basolateral Cl⁻ channel, a protein (barttin) involved in co-transporter trafficking, and the extracellular Ca²⁺-sensing receptor. Renal COX-2 is induced, and biosynthesis of PGE₂ is increased. Treatment with indomethacin, combined with potassium repletion and spironolactone, is associated with improvement in the biochemical derangements and symptoms. Selective COX-2 inhibitors also have been used (Guay-Woodford, 1998).

Cancer Chemoprevention. Chemoprevention of cancer is an area in which the potential use of aspirin and/or NSAIDs is under active investigation. Epidemiological studies suggested that frequent use of aspirin is associated with as much as a 50% decrease in the risk of colon cancer (Kune et al., 2007). Similar observations have been made with NSAID use in this and other cancers (Harris et al., 2005). NSAIDs have been used in patients with familial adenomatous polyposis (FAP), an inherited disorder characterized by multiple adenomatous colon polyps developing during adolescence and the inevitable occurrence of colon cancer by the sixth decade.

Studies in small numbers of patients over short periods of follow-up have shown a decrease in the polyp burden with the use of sulindac, celecoxib, or rofecoxib (Steinbach et al., 2000; Cruz-Correa et al., 2002; Hallak et al., 2003). Celecoxib is approved as an adjunct to endoscopic surveillance and surgery in FAP based on superiority in a short-term, placebo-controlled trial for polyp prevention/regression. However, more recently, the Adenoma Prevention with Celecoxib (APC) Trial showed a significant reduction in the incidence of adenomatous polyps in patients with a history of colorectal adenomas at high doses of celecoxib (200 mg twice a day and 400 mg twice a day versus placebo) (Bertagnolli et al., 2009). The trial was prematurely terminated because of a 2.5 times increase in cardiovascular risk for patients taking 200 mg twice a day of celecoxib and a 3.4 times increase in risk for patients taking 400 mg twice a day (Solomon et al., 2005). Similarly, the Prevention of colorectal Sporadic Adenomatous Polyps (PreSAP) trial found a reduction of polyps at a single daily dose of 400 mg of celecoxib (Arber et al., 2006), which was offset by an increase in cardiovascular risk (Solomon et al., 2006). Finally, the APPROVe trial of 25 mg of rofecoxib showed a reduction in the incidence of adenomatous polyps (Baron et al., 2006) and an increase in cardiovascular adverse events (Bresalier et al., 2005; Baron et al., 2008) that led to the termination of the trial and to rofecoxib's withdrawal from the market. Controlled evidence is not available to determine if selective COX-2 inhibitors differ from non-COX-2–selective tNSAIDs or aspirin in the extent of adenomatous colorectal polyp reduction in patients with FAP. Likewise, it is unknown whether there is even a clinical benefit from the reduction. Increased expression of COX-2 has been reported in multiple epithelial tumors, and in some cases, the degree of expression has been related to prognosis. Deletion or inhibition of COX-2 dramatically inhibits polyp formation in mouse genetic models of polyposis coli. Although the phenotypes in these models do not completely recapitulate the human disease, deletion of COX-1 had a similar effect. Speculation as to how the two COXs might interact in tumorigenesis includes the possibility that products of COX-1 might induce expression of COX-2. However, the nature of this interaction is poorly understood, as are its therapeutic consequences.

Alzheimer's Disease. Observational studies have suggested that NSAID use, in particular ibuprofen, is associated with lower risk of developing Alzheimer's disease. However, more recent prospective studies, including a randomized, controlled clinical trial comparing celecoxib, naproxen, and placebo (ADAPT Research Group, 2008), did not find a significant reduction in Alzheimer's dementia with the use of NSAIDs.

Large-scale comparative studies of tNSAIDs have not been performed, and there is no reliable information on which to assess the comparative likelihood of GI ulceration on anti-inflammatory doses of aspirin versus tNSAIDs. Thus, most information is derived from the use of surrogate markers or from epidemiological data sets and suggests that the relative risk for serious adverse GI events is elevated about 3-fold in tNSAID users compared to non-users. Epidemiological studies suggest that combining low-dose aspirin (for cardioprotection) with other NSAIDs synergistically increases the likelihood of GI adverse events (see "Drug Interactions"). Similarly, the combination of multiple tNSAIDs and high dosage of a single tNSAIDs (including inappropriately high dosage in the elderly) has been found to raise the risk for ulcer complications by 7- and 9-fold, respectively. Age >70 years alone increases the likelihood of complications almost 6-fold. The risk of ulcer complications is increased in patients with past uncomplicated (6-fold) or complicated ulcers (13-fold), or concurrent drug therapy including warfarin (12-fold), glucocorticoids (4-fold), or selective serotonin reuptake inhibitors (SSRIs; 3-fold) (Gabriel et al., 1991; Dalton et al., 2003; García Rodríguez and Barreales Tolosa, 2007).

COX-2–selective NSAIDs were originally designed for a niche indication, to improve treatment safety for patients at high risk for GI complications requiring chronic tNSAIDs—a population of <5% of tNSAID users (Dai et al., 2005). Prescription behavior changed over time, however, and more than one-third of patients at the lowest risk for GI events received a COX-2 inhibitor in 2002. Paradoxically, the incidence of GI adverse events had been falling sharply in the population prior to the introduction of the coxibs—which were developed to reduce the risk of serious GI complication, perhaps reflecting a move away from use of high-dose aspirin as an anti-inflammatory drug strategy. All selective COX-2 inhibitors are less prone to induce endoscopically visualized gastric ulcers than equally efficacious doses of tNSAIDs (Deeks et al., 2002). A more detailed discussion on this topic can be found in the prior edition of this textbook.

Gastric damage by NSAIDs can be brought about by at least two distinct mechanisms (see Chapter 33). Inhibition of COX-1 in gastric epithelial cells depresses mucosal cytoprotective PGs, especially PGI₂ and PGE₂. These eicosanoids inhibit acid secretion by the stomach, enhance mucosal blood flow, and promote the secretion of cytoprotective mucus in the intestine. Inhibition of PGI₂ and PGE₂ synthesis may render the stomach more susceptible to damage and can occur with oral, parenteral, or transdermal administration of aspirin or NSAIDs. There is some evidence that COX-2 also contributes to constitutive formation of these PGs by human gastric epithelium; products of COX-2 certainly contribute to ulcer healing in rodents (Mizuno et al., 1997). This may partly reflect an impairment of angiogenesis by the inhibitors (Jones et al., 1999). Indeed, coincidental deletion or inhibition of both COX-1 and COX-2 seems necessary to replicate NSAID-induced gastropathy in mice, and there is some evidence for gastric pathology in the face of prolonged inhibition or deletion of COX-2 alone (Sigthorsson et al., 2002). Another mechanism by which NSAIDs or aspirin may cause ulceration is by local irritation from contact of orally administered drug with the gastric mucosa. Local irritation allows backdiffusion of acid into the gastric mucosa and induces tissue damage. However, the incidence of GI adverse events is not significantly reduced by formulations that reduce drug contact with the gastric mucosa, such as enteric coating or efferent solutions, suggesting that the contribution of direct irritation to the overall risk is minor. It also is possible that enhanced generation of LOX products (e.g., LTs) contributes to ulcerogenicity in patients treated with NSAIDs.

Co-administration of the PGE₁ analog, misoprostol, or proton pump inhibitors (PPIs) in conjunction with NSAIDs can be beneficial in the prevention of duodenal and gastric ulceration (Rostom et al., 2002).

Several groups have attached NO–donating moieties to NSAIDs and to aspirin in the hope of reducing the incidence of adverse events. Benefit might be attained by abrogation of the inhibition of angiogenesis by tNSAIDs during ulcer healing, as observed in rodents (Ma et al., 2002); however, the clinical benefit of this strategy remains to be established. Similarly, LTs may accumulate in the presence of COX inhibition, and there is some evidence in rodents that combined LOX-COX inhibition may be a useful strategy.

The cardiovascular hazard is plausibly explained by the depression of COX-2-dependent prostanoids formed in vasculature and kidney (Grosser et al., 2006). Vascular PGI₂ constrains the effect of prothrombotic and atherogenic stimuli, and renal PGI₂ and PGE₂ formed by COX-2 contribute to arterial pressure homeostasis (see Chapter 33). Genetic deletion of the PGI₂ receptor, IP, in mice augments the thrombotic response to endothelial injury, accelerates experimental atherogenesis, increases vascular proliferation, and adds to the effect of hypertensive stimuli (Cheng et al., 2002; Egan et al., 2004; Kobayashi et al., 2004; Cheng et al., 2006). Genetic deletion or inhibition of COX-2 accelerates the response to thrombotic stimuli and raises blood pressure. Together, these mechanisms would be expected to alter the cardiovascular risk of humans, as COX-2 inhibition in humans depresses PGI₂ synthesis (Catella-Lawson et al., 1999; McAdam et al., 1999). Indeed, a human mutation of the IP, which disrupts its signaling, is associated with increased cardiovascular risk (Arehart et al., 2008).

Patients at increased risk of cardiovascular disease or thrombosis are likely to be particularly prone to cardiovascular adverse events while on NSAIDs. This includes patients with rheumatoid arthritis, as the relative risk of myocardial infarction is increased in these patients compared to patients with osteoarthritis or no arthritis. The risk appears to be conditioned by factors influencing drug exposure, such as dose, t_1/2, degree of COX-2 selectivity, potency, and treatment duration. Thus, the lowest possible dose should be prescribed for the shortest possible period. NSAIDs with selectivity for COX-2 should be reserved for patients at high risk for GI complications.

Experiments in mice that attribute the generation of vasodilator PGs (PGE₂ and PGI₂) to COX-2 raise the likelihood that the incidence of hypertensive complications (either new onset or worsened control) induced by NSAIDs in patients may correlate with the degree of inhibition of COX-2 in the kidney and the selectivity with which it is attained (Qi et al., 2002). Deletion of receptors for both PGI₂ and PGE₂ elevate blood pressure in mice, mechanistically integrating hypertension with a predisposition to thrombosis. Although this hypothesis has never been addressed directly, epidemiological studies suggest hypertensive complications occur more commonly in patients treated with coxibs than with tNSAIDs.

NSAIDs promote reabsorption of K⁺ as a result of decreased availability of Na⁺ at distal tubular sites and suppression of the PG-induced secretion of renin. The latter effect may account in part for the usefulness of NSAIDs in the treatment of Bartter syndrome (see "Bartter Syndrome").

Although less common in children, this cross-sensitivity may occur in 10-25% of patients with asthma, nasal polyps, or chronic urticaria and in 1% of apparently healthy individuals. It is provoked by even low doses (<80 mg) of aspirin and apparently involves COX inhibition. Cross-sensitivity extends to other salicylates, structurally dissimilar NSAIDs, and rarely acetaminophen (see "Adverse Effects" in the "Acetaminophen" section). Treatment of aspirin hypersensitivity is similar to that of other severe hypersensitivity reactions, with support of vital organ function and administration of epinephrine. Aspirin hypersensitivity is associated with an increase in biosynthesis of LTs, perhaps reflecting diversion of AA to LOX metabolism. Indeed, results in a small number of patients suggest that blockade of 5-LOX with the drug zileuton or off-label use of the LT-receptor antagonists may ameliorate the symptoms and signs of aspirin intolerance, albeit incompletely.

Prior occupancy of the active site of platelet COX-1 by the commonly consumed tNSAID ibuprofen impedes access of aspirin to its target Ser 529 and prevents irreversible inhibition of platelet function (Catella-Lawson et al., 2001). Epidemiological studies have provided conflicting data as to whether this adversely impacts clinical outcomes, but they generally are constrained by the use of prescription databases to examine an interaction between two drug groups commonly obtained without prescription. Evidence in support of this interaction has been observed in comparing ibuprofen-treated patients with and without aspirin in two coxib outcome studies (CLASS and TARGET), but the trials were not powered to address this question definitively. In theory, this interaction should not occur with selective COX-2 inhibitors, because mature human platelets lack COX-2. However, the GI safety advantage of NSAIDs selective for COX-2 is lost when they are combined with low-dose aspirin.

Pharmacokinetics in Children. Despite the recognition that age-dependent differences in gastric emptying time, plasma protein binding capacity and oxidative liver metabolism affect NSAID pharmacokinetics in children, dosing recommendations frequently are based on extrapolation of pharmacokinetic data from adults. The majority of pharmacokinetic studies that were performed in children involved patients >2 years of age, which often provide insufficient data for dose selection in younger infants. For example, the pharmacokinetics of the most commonly used NSAID in children, acetaminophen, differ substantially between the neonatal period and older children or adults. The systemic bioavailability of rectal acetaminophen formulations in neonates and preterm babies is higher than in older patients. Acetaminophen clearance is reduced in preterm neonates probably due to their immature glucuronide conjugation system (sulphatation is the principal route of biotransformation at this age). Therefore, acetaminophen dosing intervals need to be extended (8-12 hours) or daily doses reduced to avoid accumulation and liver toxicity. Aspirin elimination also is delayed in neonates and young infants compared to adults bearing the risk of accumulation.

Disease also may affect NSAID disposition in children. For example, ibuprofen plasma concentrations are reduced and clearance increased (∼80%) in children with cystic fibrosis. This probably is related to the GI and hepatic pathologies associated with this disease. Aspirin's kinetics are markedly altered during the febrile phase of rheumatic fever or Kawasaki vasculitis. The reduction in serum albumin associated with these conditions causes an elevation of the free salicylate concentration, which may saturate renal excretion and result in salicylate accumulation to toxic levels. In addition to dose reduction, monitoring of the free drug may be warranted in these situations.

Pharmacokinetics in the Elderly. Physiological changes in absorption, distribution, and elimination in aging patients can be expected to affect the pharmacokinetics of most drugs, including NSAIDs. Coincident diseases may further complicate the prediction of the response to the drug. The clearance of many NSAIDs is reduced in the elderly due to changes in hepatic metabolism. Particularly NSAIDs with a long t_1/2 and primarily oxidative metabolism (i.e., piroxicam, tenoxicam, celecoxib) have elevated plasma concentrations in elderly patients. For example, plasma concentrations after the same dose of celecoxib may rise up to 2-fold higher in patients >65 years of age than in patients <50 years of age (U.S. Food and Drug Administration, 2001), warranting careful dose adjustment. The capacity of plasma albumin to bind drugs is diminished in older patients and may result in higher concentrations of unbound NSAIDs. Free naproxen concentrations, e.g., are markedly increased in older patients, although total plasma concentrations essentially are unchanged. The higher susceptibility of older patients to GI complications may be due to both a reduction in gastric mucosal defense and to elevated total and/or free NSAID concentrations. Generally, it is advisable to start most NSAIDs at a low dosage in the elderly and increase the dosage only if the therapeutic efficacy is insufficient.

Chemistry. Salicylic acid (orthohydroxybenzoic acid) is so irritating that it can only be used externally; therefore various derivatives of this acid have been synthesized for systemic use. These comprise two large classes, namely esters of salicylic acid obtained from substitutions within the carboxyl group and salicylate esters of organic acids, in which the carboxyl group is retained and substitution is made in the hydroxyl group. For example, aspirin is an ester of acetic acid. In addition, there are sodium, magnesium, and choline salts of salicylic acid. The chemical relationships can be seen from the structural formulas shown in Figure 34–3. Substitutions on the carboxyl or hydroxyl groups change the potency or toxicity of salicylates. The ortho position of the hydroxyl group is an important feature for the action of the salicylates. The effects of simple substitutions on the benzene ring have been studied extensively. A difluorophenyl derivative, diflunisal, also is available for clinical use.

Salicylates generally act by virtue of their content of salicylic acid. The effects of aspirin are largely caused by its capacity to acetylate proteins, as described in "Irreversible Cyclooxygenase Inhibition by Aspirin," although high concentrations of aspirin result in therapeutic plasma concentrations of salicylic acid. In addition to their effect on PG biosynthesis (see the NSAIDs section and Chapter 33), the mechanism of action of the salicylates in rheumatic disease also may involve effects on other cellular and immunological processes in mesenchymal and connective tissues. Attention has been directed to the capacity of salicylates to suppress a variety of antigen–antibody reactions. These include the inhibition of antibody production, of antigen–antibody aggregation, and of antigen-induced release of histamine. Salicylates also induce a nonspecific stabilization of capillary permeability during immunological insults. The concentrations of salicylates needed to produce these effects are high, and the relationship of these effects to the anti-rheumatic efficacy of salicylates is not clear. Salicylates also can influence the metabolism of connective tissue, and these effects may be involved in their anti-inflammatory action. For example, salicylates can affect the composition, biosynthesis, or metabolism of connective tissue mucopolysaccharides in the ground substance that provides barriers to the spread of infection and inflammation.

Absorption. Orally ingested salicylates are absorbed rapidly, partly from the stomach but mostly from the upper small intestine. Appreciable concentrations are found in plasma in <30 minutes; after a single dose, a peak value is reached in ∼1 hour and then declines gradually. The rate of absorption is determined by many factors, particularly the disintegration and dissolution rates of the tablets administered, the pH at the mucosal surface, and gastric emptying time.

Salicylate absorption occurs by passive diffusion primarily of undissociated salicylic acid or ASA across GI membranes and hence is influenced by gastric pH. Even though salicylate is more ionized as the pH is increased, a rise in pH also increases the solubility of salicylate and thus dissolution of the tablets. The overall effect is to enhance absorption. As a result, there is little meaningful difference between the rates of absorption of sodium salicylate, aspirin, and the numerous buffered preparations of salicylates. The presence of food delays absorption of salicylates. Rectal absorption of salicylate usually is slower than oral absorption and is incomplete and inconsistent.

Salicylic acid is absorbed rapidly from the intact skin, especially when applied in oily liniments or ointments, and systemic poisoning has occurred from its application to large areas of skin. Methyl salicylate likewise is speedily absorbed when applied cutaneously; however, its GI absorption may be delayed many hours, making gastric lavage effective for removal even in poisonings that present late after oral ingestion.

Distribution. After absorption, salicylates are distributed throughout most body tissues and transcellular fluids, primarily by pH-dependent passive processes. Salicylates are transported actively by a low-capacity, saturable system out of the cerebrospinal fluid (CSF) across the choroid plexus. The drugs readily cross the placental barrier.

The volume of distribution of usual doses of aspirin and sodium salicylate in normal subjects averages ∼170 mL/kg of body weight; at high therapeutic doses, this volume increases to ∼500 mL/kg because of saturation of binding sites on plasma proteins. Ingested aspirin mainly is absorbed as such, but some enters the systemic circulation as salicylic acid after hydrolysis by esterases in the GI mucosa and liver. Aspirin can be detected in the plasma only for a short time as a result of hydrolysis in plasma, liver, and erythrocytes; for example, 30 minutes after a dose of 0.65 g, only 27% of the total plasma salicylate is in the acetylated form. Methyl salicylate also is hydrolyzed rapidly to salicylic acid, mainly in the liver.

Roughly 80-90% of the salicylate in plasma is bound to proteins, especially albumin, at concentrations encountered clinically; the proportion of the total that is bound declines as plasma concentrations increase. Hypoalbuminemia, as may occur in rheumatoid arthritis, is associated with a proportionately higher level of free salicylate in the plasma. Salicylate competes with a variety of compounds for plasma protein binding sites; these include thyroxine, triiodothyronine, penicillin, phenytoin, sulfinpyrazone, bilirubin, uric acid, and other NSAIDs such as naproxen. Aspirin is bound to a more limited extent; however, it acetylates human plasma albumin in vivo by reaction with the ∊-amino group of lysine and may change the binding of other drugs to albumin. Aspirin also acetylates hormones, DNA, and hemoglobin and other proteins.

Elimination. The biotransformation of salicylates takes place in many tissues, but particularly in the hepatic endoplasmic reticulum and mitochondria. The three chief metabolic products are salicyluric acid (the glycine conjugate), the ether or phenolic glucuronide, and the ester or acyl glucuronide. In addition, a small fraction is oxidized to gentisic acid (2,5-dihydroxybenzoic acid) and to 2,3-dihydroxybenzoic and 2,3,5-trihydroxybenzoic acids; gentisuric acid, the glycine conjugate of gentisic acid, also is formed.

Salicylates are excreted in the urine as free salicylic acid (10%), salicyluric acid (75%), salicylic phenolic (10%) and acyl glucuronides (5%), and gentisic acid (<1%). However, excretion of free salicylates is extremely variable and depends on the dose and the urinary pH. In alkaline urine, >30% of the ingested drug may be eliminated as free salicylate, whereas in acidic urine, this may be as low as 2%.

The plasma t_1/2 for aspirin is ∼20 minutes, and for salicylate is 2-3 hours at antiplatelet doses, rising to 12 hours at usual anti-inflammatory doses. The t_1/2 of salicylate may be as long as 15-30 hours at high therapeutic doses or when there is intoxication. This dose-dependent elimination is the result of the limited capacity of the liver to form salicyluric acid and the phenolic glucuronide, resulting in a larger proportion of unchanged drug being excreted in the urine at higher doses.

Salicylate metabolism shows high intersubject variability due to the variable contribution of different metabolic pathways. Women frequently exhibit higher plasma concentrations, perhaps due to lower intrinsic esterase activity and gender differences in hepatic metabolism. Salicylate clearance is reduced and salicylate exposure is significantly increased in the elderly (see "Pharmacokinetics in the Elderly"). The plasma concentration of salicylate is increased by conditions that decrease glomerular filtration rate or reduce proximal tubule secretion, such as renal disease or the presence of inhibitors that compete for the transport system (e.g., probenecid). Changes in urinary pH also have significant effects on salicylate excretion. For example, the clearance of salicylate is about four times as great at pH 8 as at pH 6, and it is well above the glomerular filtration rate at pH 8. High rates of urine flow decrease tubular reabsorption, whereas the opposite is true in oliguria. In case of an overdose, hemodialysis and hemofiltration techniques remove salicylic acid effectively from the circulation.

The analgesic–antipyretic dose of aspirin for adults is 324-1000 mg orally every 4-6 hours. The anti-inflammatory doses of aspirin recommended for arthritis, spondyloarthropathies, and systemic lupus erythematosus (SLE) range from 3-4 g/day in divided doses. Salicylates are contraindicated for fever associated with viral infection in children (see "Reye's Syndrome"); for nonviral etiologies, 40-60 mg/kg/day given in six divided doses every 4 hours is recommended. The maximum recommended daily dose of aspirin for adults and children >12 years or older is 4 g. The rectal administration of aspirin suppositories may be preferred in infants or when the oral route is unavailable. Although aspirin is regarded as the standard against which other drugs should be compared for the treatment of rheumatoid arthritis, many clinicians favor the use of other NSAIDs perceived to have better GI tolerability, even though this perception remains untested by randomized clinical trials. Salicylates suppress clinical signs and improve tissue inflammation in acute rheumatic fever. Much of the possible subsequent tissue damage, such as cardiac lesions and other visceral involvement, however, is unaffected by salicylate therapy.

Other salicylates available for systemic use include salsalate (salicylsalicylic acid), which is hydrolyzed to salicylic acid during and after absorption, and magnesium salicylate (tablets; DOAN'S, MOMEMTUM, others). A combination of choline salicylate and magnesium salicylate (choline magnesium–trisalicylate) also is available.

Diflunisal is a difluorophenyl derivative of salicylic acid that is not converted to salicylic acid in vivo. Diflunisal is more potent than aspirin in anti-inflammatory tests in animals and appears to be a competitive inhibitor of COX. However, it is largely devoid of antipyretic effects, perhaps because of poor penetration into the CNS. The drug has been used primarily as an analgesic in the treatment of osteoarthritis and musculoskeletal strains or sprains; in these circumstances, it is about three to four times more potent than aspirin. The usual initial dose is 1000 mg, followed by 500 mg every 8-12 hours. For rheumatoid arthritis or osteoarthritis, 250-1000 mg/day is administered in two divided doses; maintenance dosage should not exceed 1.5 g/day. Diflunisal produces fewer auditory side effects (see "Ototoxic Effects") and appears to cause fewer and less intense GI and antiplatelet effects than does aspirin.

Local Uses. Mesalamine (5-aminosalicylic acid) is a salicylate that is used for its local effects in the treatment of inflammatory bowel disease (see Chapter 47, especially Figure 47–4). The drug as an immediate-release formulation would not be effective orally because it is poorly absorbed and is inactivated before reaching the lower intestine. However, oral formulations that deliver drug to the lower intestine—mesalamine formulated in a pH-sensitive, polymer-coated, delayed-release tablet (ASACOL, LIALDA); an extended-release mesalamine capsule (APRISO); and olsalazine (sodium azodisalicylate, a dimer of 5-aminosalicylate linked by an azo bond; DIPENTUM)—are efficacious in the treatment of inflammatory bowel disease (in particular, ulcerative colitis). Mesalamine is available as a rectal enema (ROWASA, others) for treatment of mild to moderate ulcerative colitis, proctitis, and proctosigmoiditis and as a rectal suppository (CANASA) for the treatment of active ulcerative proctitis. Sulfasalazine (salicylazosulfapyridine; AZULFIDINE, others) contains mesalamine linked covalently to sulfapyridine, and balsalazide (COLAZAL, others) contains mesalamine linked to the inert carrier molecule 4-aminobenzoyl-β-alanine. Both drugs are absorbed poorly after oral administration and cleaved to the active moiety by bacteria in the colon. Sulfasalazine and olsalazine have been used in the treatment of rheumatoid arthritis and ankylosing spondylitis. Some over-the-counter medications to relieve indigestion and diarrhea agents contain bismuth subsalicylate (PEPTO-BISMOL, others) and have the potential to cause salicylate intoxication, particularly in children.

The keratolytic action of free salicylic acid is employed for the local treatment of warts, corns, fungal infections, and certain types of eczematous dermatitis. After treatment with salicylic acid, tissue cells swell, soften, and desquamate. Methyl salicylate (oil of wintergreen) is a common ingredient of ointments and deep-heating liniments used in the management of musculoskeletal pain; it also is available in herbal medicines and as a flavoring agent. The cutaneous application of methyl salicylate can result in pharmacologically active, and even toxic, systemic salicylate concentrations and has been reported to increase prothrombin time in patients receiving warfarin.

Respiration. Salicylates increase O₂ consumption and CO₂ production (especially in skeletal muscle) at anti-inflammatory doses; these effects are a result of uncoupling oxidative phosphorylation. The increased production of CO₂ stimulates respiration (mainly by an increase in depth of respiration with only a slight increase in rate). The increased alveolar ventilation balances the increased CO₂ production, and thus plasma CO₂ tension (PCO₂) does not change or may decrease slightly. Salicylates also stimulate the respiratory center directly in the medulla. Respiratory rate and depth increases, the Pco₂ falls, and primary respiratory alkalosis ensues. Both mechanisms can occur in parallel, although the stimulation of ventilation after initiation of therapy is predominantly driven by the increase in the metabolic rate, and direct effects of salicylates on the central nervous respiratory center contribute later at higher steady-state concentrations.

Acid–Base and Electrolyte Balance and Renal Effects. Therapeutic doses of salicylate produce definite changes in the acid–base balance and electrolyte pattern. Compensation for the initial event, respiratory alkalosis (see "Respiration" in the aspirin section), is achieved by increased renal excretion of bicarbonate, which is accompanied by increased Na⁺ and K⁺ excretion; plasma bicarbonate is thus lowered, and blood pH returns toward normal. This is the stage of compensatory renal acidosis. This stage is most often seen in adults given intensive salicylate therapy and seldom proceeds further unless toxicity ensues (see "Salicylate Intoxication"). Salicylates can cause retention of salt and water, as well as acute reduction of renal function in patients with congestive heart failure, renal disease, or hypovolemia. Although long-term use of salicylates alone rarely is associated with nephrotoxicity, the prolonged and excessive ingestion of analgesic mixtures containing salicylates in combination with other NSAIDs can produce papillary necrosis and interstitial nephritis (see "Analgesic Nephropathy").

Cardiovascular Effects. Low doses of aspirin (≤100 mg daily) are used widely for their cardioprotective effects. At high therapeutic doses (≥3 g daily), as might be given for acute rheumatic fever, salt and water retention can lead to an increase (≤20%) in circulating plasma volume and decreased hematocrit (via a dilutional effect). There is a tendency for the peripheral vessels to dilate because of a direct effect on vascular smooth muscle. Cardiac output and work are increased. Those with carditis or compromised cardiac function may not have sufficient cardiac reserve to meet the increased demands, and congestive cardiac failure and pulmonary edema can occur. High doses of salicylates can produce noncardiogenic pulmonary edema, particularly in older patients who ingest salicylates regularly over a prolonged period.

GI Effects. The ingestion of salicylates may result in epigastric distress, nausea, and vomiting. Salicylates also may cause gastric ulceration, exacerbation of peptic ulcer symptoms (heartburn, dyspepsia), GI hemorrhage, and erosive gastritis. These effects occur primarily with acetylated salicylates (i.e., aspirin). Because nonacetylated salicylates lack the ability to acetylate COX and thereby irreversibly inhibit its activity, they are weaker inhibitors than aspirin.

Aspirin-induced gastric bleeding sometimes is painless and, if unrecognized, may lead to iron-deficiency anemia. The daily ingestion of anti-inflammatory doses of aspirin (3-4 g) results in an average fecal blood loss of between 3 and 8 mL/day, as compared with ∼0.6 mL/day in untreated subjects. Gastroscopic examination of aspirin-treated subjects often reveals discrete ulcerative and hemorrhagic lesions of the gastric mucosa; in many cases, multiple hemorrhagic lesions with sharply demarcated areas of focal necrosis are observed.

Hepatic Effects. Salicylates can cause hepatic injury, usually in patients treated with high doses of salicylates that result in plasma concentrations of >150 ¨g/mL. The injury is not an acute effect; rather, the onset characteristically occurs after several months of treatment. The majority of cases occur in patients with connective tissue disorders. There usually are no symptoms, simply an increase in serum levels of hepatic transaminases, but some patients note right upper quadrant abdominal discomfort and tenderness. Overt jaundice is uncommon. The injury usually is reversible upon discontinuation of salicylates. However, the use of salicylates is contraindicated in patients with chronic liver disease. Considerable evidence, as discussed earlier in "Reye's Syndrome," implicates the use of salicylates as an important factor in the severe hepatic injury and encephalopathy observed in Reye's syndrome. Large doses of salicylates may cause hyperglycemia and glycosuria and deplete liver and muscle glycogen.

Uricosuric Effects. The effects of salicylates on uric acid excretion are markedly dependent on dose. Low doses (1 or 2 g/day) may decrease urate excretion and elevate plasma urate concentrations; intermediate doses (2 or 3 g/day) usually do not alter urate excretion. Large doses (>5 g/day) induce uricosuria and lower plasma urate levels; however, such large doses are tolerated poorly. Even small doses of salicylate can block the effects of probenecid and other uricosuric agents that decrease tubular reabsorption of uric acid.

Effects on the Blood. Irreversible inhibition of platelet function is the mechanism underlying the cardioprotective effect of aspirin (see "Concomitant NSAIDs and Low-Dose Aspirin"). If possible, aspirin therapy should be stopped at least 1 week before surgery; however, preoperative aspirin often is recommended prior to carotid artery stenting, carotid endarterectomy, infrainguinal arterial bypass, and PCI procedures. Patients with severe hepatic damage, hypoprothrombinemia, vitamin K deficiency, or hemophilia should avoid aspirin because the inhibition of platelet hemostasis can result in hemorrhage. Care also should be exercised in the use of aspirin during long-term treatment with oral anticoagulant agents because of the combined danger of prolongation of bleeding time coupled with blood loss from the gastric mucosa. On the other hand, aspirin is used widely for the prophylaxis of thromboembolic disease, especially in the coronary and cerebral circulation, and is coupled frequently with oral anticoagulants in patients with bioprosthetic or mechanical heart valves (see Chapter 30).

Salicylates ordinarily do not alter the leukocyte or platelet count, the hematocrit, or the hemoglobin content. However, doses of 3-4 g/day markedly decrease plasma iron concentration and shorten erythrocyte survival time. Aspirin can cause a mild degree of hemolysis in individuals with a deficiency of glucose-6-phosphate dehydrogenase. As noted earlier (see "Cardiovascular Effects"), high doses (>3 g/day) can expand plasma volume and decrease hematocrit by dilution.

Endocrine Effects. Long-term administration of salicylates decreases thyroidal uptake and clearance of iodine, but increases O₂ consumption and the rate of disappearance of thyroxine and triiodothyronine from the circulation. These effects probably are caused by the competitive displacement by salicylate of thyroxine and triiodothyronine from transthyretin and the thyroxine-binding globulin in plasma (see Chapter 39).

Ototoxic Effects. Hearing impairment, alterations of perceived sounds, and tinnitus commonly occur during high-dose salicylate therapy. Tinnitus, historically used as an index of exceeding the acceptable plasma concentration in patients, is not a reliable guide; thus, surveillance for this symptom is no substitute for periodic monitoring of serum salicylate levels. Ototoxic symptoms sometimes are observed at low doses, and no threshold plasma concentration exists. Symptoms usually resolve within 2 or 3 days after withdrawal of the drug. Ototoxic symptoms are caused by increased labyrinthine pressure or an effect on the hair cells of the cochlea, perhaps secondary to vasoconstriction in the auditory microvasculature. As most competitive COX inhibitors are not associated with hearing loss or tinnitus, a direct effect of salicylic acid rather than suppression of PG synthesis is likely.

Salicylates and Pregnancy. Infants born to women who ingest salicylates for long periods may have significantly reduced birth weights. When administered during the third trimester, there also is an increase in perinatal mortality, anemia, antepartum and postpartum hemorrhage, prolonged gestation, and complicated deliveries; thus, its use during this period should be avoided. As mentioned earlier in "Pregnancy and Lactation," administration of NSAIDs during the third trimester of pregnancy also can cause premature closure of the ductus arteriosus. The use of aspirin has been advocated for the treatment of women at high risk of preeclampsia, but it is estimated that treatment of 90 women is required to prevent one case of preeclampsia (Villar et al., 2004).

Local Irritant Effects. Salicylic acid is irritating to skin and mucosa and destroys epithelial cells.

Drug Interactions. The plasma concentration of salicylates generally is little affected by other drugs, but concurrent administration of aspirin lowers the concentrations of indomethacin, naproxen, ketoprofen, and fenoprofen, at least in part by displacement from plasma proteins. Important adverse interactions of aspirin with warfarin, sulfonylureas, and methotrexate are mentioned earlier in "Drug Interactions." Other interactions of aspirin include the antagonism of spironolactone-induced natriuresis and the blockade of the active transport of penicillin from CSF to blood. Magnesium-aluminum hydroxide antacids can alkalize the urine enough to increase salicylic acid clearance significantly and reduce steady-state concentrations. Conversely, discontinuation of antacid therapy can increase plasma concentrations to toxic levels.

Salicylate poisoning or serious intoxication often occurs in children and sometimes is fatal. CNS effects, intense hyperpnea, and hyperpyrexia are prominent symptoms. Salicylate intoxication should be seriously considered in any young child with coma, convulsions, or cardiovascular collapse. The fatal dose varies with the preparation of salicylate. Death has followed use of 10-30 g of sodium salicylate or aspirin in adults, but much larger amounts (130 g of aspirin in one case) have been ingested without a fatal outcome. The lethal dose of methyl salicylate (also known as oil of wintergreen, sweet birch oil, gaultheria oil, betula oil) is considerably less than that of sodium salicylate. As little as a taste of methyl salicylate by children <6 years of age and >4 mL (4.7 g) of methyl salicylate by children ≥6 years of age may cause severe systemic toxicity and warrants referral to an emergency department. Symptoms of poisoning by methyl salicylate differ little from those described earlier for aspirin in "Adverse Effects." The drug's odor can be detected easily on the breath and in the urine and vomitus. Poisoning by salicylic acid differs only in the increased prominence of GI symptoms due to the marked local irritation. Mild chronic salicylate intoxication is called salicylism. When fully developed, the syndrome includes headache, dizziness, tinnitus, difficulty hearing, dimness of vision, mental confusion, lassitude, drowsiness, sweating, thirst, hyperventilation, nausea, vomiting, and occasionally diarrhea.

Neurological Effects. In high doses, salicylates have toxic effects on the CNS, consisting of stimulation (including convulsions) followed by depression. Confusion, dizziness, tinnitus, high-tone deafness, delirium, psychosis, stupor, and coma may occur. Salicylates induce nausea and vomiting, which result from stimulation of sites that are accessible from the CSF, probably in the medullary chemoreceptor trigger zone. In humans, centrally induced nausea and vomiting often appear at plasma salicylate concentrations of ∼270 ¨g/mL, but these same effects may occur at much lower plasma levels as a result of local gastric irritation.

Respiration. The respiratory effects of salicylates contribute to the serious acid–base balance disturbances that characterize poisoning by this class of compounds. Salicylates stimulate respiration indirectly by uncoupling of oxidative phosphorylation and directly by stimulation of the respiratory center in the medulla (see "Respiration" in the aspirin section). Uncoupling of oxidative phosphorylation also leads to excessive heat production, and salicylate toxicity is associated with hyperthermia, particularly in children. Marked hyperventilation occurs when the level approaches 500 ¨g/mL. However, should salicylate toxicity be associated with the co-administration of a barbiturate or opioid, then central respiratory depression will prevent hyperventilation, and the salicylate-induced uncoupling of oxidative phosphorylation will be associated with a marked increase in plasma Pco₂ and respiratory acidosis. Prolonged exposure to high doses of salicylates leads to depression of the medulla, with central respiratory depression and circulatory collapse, secondary to vasomotor depression. Because enhanced CO₂ production continues, respiratory acidosis ensues. Respiratory failure is the usual cause of death in fatal cases of salicylate poisoning. Elderly patients with chronic salicylate intoxication often develop noncardiogenic pulmonary edema, which is considered an indication for hemodialysis.

Acid–Base Balance and Electrolytes. As described earlier in "Acid–Base and Electrolyte Balance and Renal Effects" in the aspirin section, high therapeutic doses of salicylate are associated with a primary respiratory alkalosis and compensatory renal acidosis. Subsequent changes in acid–base status generally occur only when toxic doses of salicylates are ingested by infants and children or occasionally after large doses in adults. The phase of primary respiratory alkalosis rarely is recognized in children with salicylate toxicity. They usually present in a state of mixed respiratory and renal acidosis, characterized by a decrease in blood pH, a low plasma bicarbonate concentration, and normal or nearly normal plasma Pco₂. Direct salicylate-induced depression of respiration prevents adequate respiratory hyperventilation to match the increased peripheral production of CO₂. Consequently, plasma Pco₂ increases and blood pH decreases. Because the concentration of bicarbonate in plasma already is low due to increased renal bicarbonate excretion, the acid–base status at this stage essentially is an uncompensated respiratory acidosis. Superimposed, however, is a true metabolic acidosis caused by accumulation of acids as a result of three processes. First, toxic concentrations of salicylates displace ∼2-3 mEq/L of plasma bicarbonate. Second, vasomotor depression caused by toxic doses of salicylates impairs renal function, with consequent accumulation of sulfuric and phosphoric acids; renal failure can ensue. Third, salicylates in toxic doses may decrease aerobic metabolism as a result of inhibition of various enzymes. This derangement of carbohydrate metabolism leads to the accumulation of organic acids, especially pyruvic, lactic, and acetoacetic acids.

The same series of events also causes alterations of water and electrolyte balance. The low plasma Pco₂ leads to decreased renal tubular reabsorption of bicarbonate and increased renal excretion of Na⁺, K⁺, and water. Water also is lost by salicylate-induced sweating (especially in the presence of hyperthermia) and hyperventilation; dehydration, which can be profound, particularly in children, rapidly occurs. Because more water than electrolyte is lost through the lungs and by sweating, the dehydration is associated with hypernatremia. Prolonged exposure to high doses of salicylate also causes depletion of K⁺ due to both renal and extrarenal factors.

Cardiovascular Effects. Toxic doses of salicylates lead to an exaggeration of the unfavorable cardiovascular responses seen at high therapeutic doses (see "Adverse Effects"), and central vasomotor paralysis occurs. Petechiae may be seen due to defective platelet function.

Metabolic Effects. Large doses of salicylates may cause hyperglycemia and glycosuria and deplete liver and muscle glycogen; these effects are partly explained by the release of epinephrine. Such doses also reduce aerobic metabolism of glucose, increase glucose-6-phosphatase activity, and promote the secretion of glucocorticoids. There is a greater risk of hypoglycemia and subsequent permanent brain injury in children. Salicylates in toxic doses cause a significant negative nitrogen balance, characterized by an aminoaciduria. Adrenocortical activation may contribute to the negative nitrogen balance by enhancing protein catabolism. Salicylates reduce lipogenesis by partially blocking incorporation of acetate into fatty acids; they also inhibit epinephrine-stimulated lipolysis in fat cells and displace long-chain fatty acids from binding sites on human plasma proteins. The combination of these effects leads to increased entry and enhanced oxidation of fatty acids in muscle, liver, and other tissues and to decreased plasma concentrations of free fatty acids, phospholipid, and cholesterol; the oxidation of ketone bodies also is increased.

Endocrine Effects. Very large doses of salicylates stimulate steroid secretion by the adrenal cortex through an effect on the hypothalamus and transiently increase plasma concentrations of free corticosteroids by their displacement from plasma proteins. The therapeutic anti-inflammatory effects of salicylate are independent of these effects.

Management of Salicylate Overdose. Salicylate poisoning represents an acute medical emergency, and death may result despite heroic efforts. Monitoring of salicylate levels is a useful guide to therapy but must be used in conjunction with an assessment of the patient's overall clinical condition, acid–base balance, formulation of salicylate ingested, timing, and dose (O'Malley, 2007).

There is no specific antidote for salicylate poisoning. Management begins with a rapid assessment followed by the ABCD approach to medical emergencies: "A (airway), B (breathing), C (circulation), D (decontamination)".

It has been suggested that COX inhibition might be disproportionately pronounced in the brain, explaining its antipyretic efficacy (Ouellet and Percival, 2001; Boutaud et al., 2002). A COX-1 splice variant identified in the canine brain shows some susceptibility for inhibition by acetaminophen in vitro (Chandrasekharan et al., 2002). However, this splice variant does not exist in humans.

Oral acetaminophen has excellent bioavailability. Peak plasma concentrations occur within 30-60 minutes, and the t_1/2 in plasma is ∼2 hours after therapeutic doses. Acetaminophen is relatively uniformly distributed throughout most body fluids. Binding of the drug to plasma proteins is variable but less than with other NSAIDs; only 20-50% is bound at the concentrations encountered during acute intoxication. Some 90-100% of the drug may be recovered in the urine within the first day at therapeutic dosing, primarily after hepatic conjugation with glucuronic acid (∼60%), sulfuric acid (∼35%), or cysteine (∼3%); small amounts of hydroxylated and deacetylated metabolites also have been detected (Table 34–1). Children have less capacity for glucuronidation of the drug than do adults. A small proportion of acetaminophen undergoes CYP-mediated N-hydroxylation to form NAPQI, a highly reactive intermediate. This metabolite normally reacts with sulfhydryl groups in glutathione (GSH) and thereby is rendered harmless. However, after ingestion of large doses of acetaminophen, the metabolite is formed in amounts sufficient to deplete hepatic GSH and contributes significantly to the toxic effects of overdose (see "Acetaminophen Intoxication").

In 2009, an FDA advisory panel recommended a lower maximum daily dose of acetaminophen of 2600 mg and a decrease in the maximum single dose from 1000 mg to 650 mg. Single doses for children 2-11 years of age range from 160-480 mg, depending on age and weight; no more than five doses should be administered in 24 hours. A dose of 10 mg/kg also may be used. Particular attention is warranted due to the availability of a wide variety of prescription and non-prescription multi-ingredient medications that represent potentially toxic overlapping sources of acetaminophen.

Adverse Effects. Acetaminophen usually is well tolerated at recommended therapeutic doses. Single or repeated therapeutic doses of acetaminophen have no effect on the cardiovascular and respiratory systems, platelets, or coagulation. Acid–base changes and uricosuric effects do not occur. Epidemiological studies suggest that GI adverse effects are less common than with therapeutic doses of tNSAIDs (García Rodríguez et al., 2004). Rash and other allergic reactions occur occasionally. The rash usually is erythematous or urticarial, but sometimes it is more serious and may be accompanied by drug fever and mucosal lesions. Patients who show hypersensitivity reactions to the salicylates only rarely exhibit sensitivity to acetaminophen. The use of acetaminophen has been associated anecdotally with neutropenia, thrombocytopenia, pancytopenia, hemolytic anemia, and methemoglobinemia. Kidney damage has been reported, and liver damage is a prominent feature of overdose.

Symptoms that occur during the first 2 days of acute poisoning by acetaminophen reflect gastric distress (e.g., nausea, abdominal pain, anorexia) and belie the potential seriousness of the intoxication. Plasma transaminases become elevated, sometimes markedly so, beginning ∼12-36 hours after ingestion. Clinical indications of hepatic damage manifest within 2-4 days of ingestion of toxic doses, with right subcostal pain, tender hepatomegaly, jaundice, and coagulopathy. Renal impairment or frank renal failure may occur. Liver enzyme abnormalities typically peak 72-96 hours after ingestion. The onset of hepatic encephalopathy or worsening coagulopathy beyond this time indicates a poor prognosis. Biopsy of the liver reveals centrilobular necrosis with sparing of the periportal area. In nonfatal cases, the hepatic lesions are reversible over a period of weeks or months.

Management of Acetaminophen Overdose. Acetaminophen overdose constitutes a medical emergency (Heard, 2008). Severe liver damage occurs in 90% of patients with plasma concentrations of acetaminophen >300 ¨g/mL at 4 hours or 45 ¨g/mL at 15 hours after the ingestion of the drug. Minimal hepatic damage can be anticipated when the drug concentration is <120 μg/mL at 4 hours or 30 ¨g/mL at 12 hours after ingestion. The Rumack-Matthew nomogram relates the plasma levels of acetaminophen and time after ingestion to the predicted risk of liver injury (Rumack et al., 1981).

Early diagnosis and treatment of acetaminophen overdose is essential to optimize outcome. Perhaps 10% of poisoned patients who do not receive specific treatment develop severe liver damage; 10-20% of these eventually die of hepatic failure despite intensive supportive care. Activated charcoal, if given within 4 hours of ingestion, decreases acetaminophen absorption by 50-90% and is the preferred method of gastric decontamination. Gastric lavage generally is not recommended.

N-acetylcysteine (NAC) (mucomyst, acetadote) is indicated for those at risk of hepatic injury. NAC therapy should be instituted in suspected cases of acetaminophen poisoning before blood levels become available, with treatment terminated if assay results subsequently indicate that the risk of hepatotoxicity is low. NAC functions by detoxifying NAPQI. It both repletes GSH stores and may conjugate directly with NAPQI by serving as a GSH substitute. There is some evidence that in cases of established acetaminophen toxicity, NAC may protect against extrahepatic injury by its anti-oxidant and anti-inflammatory properties. Even in the presence of activated charcoal, there is ample absorption of NAC, and neither should activated charcoal be avoided nor NAC administration be delayed because of concerns of a charcoal-NAC interaction. Adverse reactions to NAC include rash (including urticaria, which does not require drug discontinuation), nausea, vomiting, diarrhea, and rare anaphylactoid reactions. An oral loading dose of 140 mg/kg is given, followed by the administration of 70 mg/kg every 4 hours for 17 doses. Where available, the intravenous loading dose is 150 mg/kg by intravenous infusion in 200 mL of 5% dextrose over 60 minutes, followed by 50 mg/kg by intravenous infusion in 500 mL of 5% dextrose over 4 hours, then 100 mg/kg by intravenous infusion in 1000 mL of 5% dextrose over 16 hours.

In addition to NAC therapy, aggressive supportive care is warranted. This includes management of hepatic and renal failure if they occur and intubation if the patient becomes obtunded. Hypoglycemia can result from liver failure, and plasma glucose should be monitored closely. Fulminant hepatic failure is an indication for liver transplantation, and a liver transplant center should be contacted early in the course of treatment of patients who develop severe liver injury despite NAC therapy.

Absorption, Distribution, and Elimination. Oral indomethacin has excellent bioavailability. Peak concentrations occur 1-2 hours after dosing (Table 34–1). The concentration of the drug in the CSF is low, but its concentration in synovial fluid is equal to that in plasma within 5 hours of administration. There is enterohepatic cycling of the indomethacin metabolites and probably of indomethacin itself. The t_1/2 in plasma is variable, perhaps because of enterohepatic cycling, but averages ∼2.5 hours.

Indomethacin is FDA approved for closure of persistent patent ductus arteriosus in premature infants who weigh between 500 and 1750 g, who have a hemodynamically significant patent ductus arteriosus, and in whom other supportive maneuvers have been attempted. The regimen involves intravenous administration of 0.1-0.25 mg/kg every 12 hours for three doses, with the course repeated one time if necessary. Successful closure can be expected in >70% of neonates treated. The principal limitation of treating neonates is renal toxicity, and therapy is interrupted if the output of urine falls to <0.6 mL/kg/hr. Renal failure, enterocolitis, thrombocytopenia, or hyperbilirubinemia are contraindications to the use of indomethacin. Treatment with indomethacin also may decrease the incidence and severity of intraventricular hemorrhage in low-birth-weight neonates (Ment et al., 1994).

Adverse Effects and Drug Interactions. A very high percentage (35-50%) of patients receiving usual therapeutic doses of indomethacin experience untoward symptoms, and ∼20% must discontinue its use because of the side effects. GI adverse events are common and can be fatal; elderly patients are at significantly greater risk. Diarrhea may occur and sometimes is associated with ulcerative lesions of the bowel. Acute pancreatitis has been reported, as have rare, but potentially fatal, cases of hepatitis. The most frequent CNS effect (indeed, the most common side effect) is severe frontal headache, occurring in 25-50% of patients who take the drug for long periods. Dizziness, vertigo, light-headedness, and mental confusion may occur. Seizures have been reported, as have severe depression, psychosis, hallucinations, and suicide. Caution is advised when administering indomethacin to elderly patients or to those with underlying epilepsy, psychiatric disorders, or Parkinson's disease, because they are at greater risk for the development of serious CNS adverse effects. Hematopoietic reactions include neutropenia, thrombocytopenia, and rarely aplastic anemia.

The total plasma concentration of indomethacin plus its inactive metabolites is increased by concurrent administration of probenecid, but indomethacin does not interfere with the uricosuric effect of probenecid. Indomethacin antagonizes the natriuretic and antihypertensive effects of furosemide and thiazide diuretics and blunts the antihypertensive effect of β-receptor antagonists, AT₁-receptor antagonists, and ACE inhibitors.

Absorption, Distribution, and Elimination. The metabolism and pharmacokinetics of sulindac are complex. About 90% of the drug is absorbed in humans after oral administration (Table 34–1). Peak concentrations of sulindac in plasma are attained within 1-2 hours, while those of the sulfide metabolite occur ∼8 hours after oral administration. Sulindac undergoes two major biotransformations. It is oxidized to the sulfone and then reversibly reduced to the sulfide, the active metabolite. The sulfide is formed largely by the action of bowel microflora on sulindac excreted in the bile. All three compounds are found in comparable concentrations in human plasma. The t_1/2 of sulindac itself is ∼7 hours, but the active sulfide has a t_1/2 as long as 18 hours. Sulindac and its metabolites undergo extensive enterohepatic circulation, and all are bound highly to plasma protein. Little of the sulfide (or of its conjugates) is found in urine. The principal components excreted in the urine are the sulfone and its conjugates, which account for nearly 30% of an administered dose; sulindac and its conjugates account for ∼20%. Up to 25% of an oral dose may appear as metabolites in the feces.

Adverse Effects. Although the incidence of toxicity is lower than with indomethacin, untoward reactions to sulindac are common. The typical NSAID GI side effects are seen in nearly 20% of patients. CNS side effects as described earlier for indomethacin in "Adverse Effects and Drug Interactions" are seen in ≤10% of patients. Rash and pruritus occur in 5% of patients. Transient elevations of hepatic transaminases in plasma are less common.

Therapeutic Uses. Etodolac is an acetic acid derivative with some degree of COX-2 selectivity (Figure 34–1). Thus, at anti-inflammatory doses, the frequency of gastric irritation may be less than with other tNSAIDs (Warner et al., 1999). A single oral dose (200-400 mg) of etodolac provides postoperative analgesia that typically lasts for 6-8 hours. Etodolac also is effective in the treatment of osteoarthritis, rheumatoid arthritis, and mild to moderate pain, and the drug appears to be uricosuric. Sustained-release preparations are available, allowing once-a-day administration.

Adverse Effects. Etodolac appears to be relatively well tolerated. About 5% of patients who have taken the drug for ≤1 year discontinue treatment because of side effects, which include GI intolerance, rashes, and CNS effects.

Therapeutic Uses. Tolmetin (TOLECTIN, others), a heteroaryl acetic acid derivative, is approved in the U.S. for the treatment of osteoarthritis, rheumatoid arthritis, and juvenile rheumatoid arthritis; it also has been used in the treatment of ankylosing spondylitis. Accumulation of the drug in synovial fluid begins within 2 hours and persists for ≤8 hours after a single oral dose. It appears to be approximately equivalent in efficacy to moderate doses of aspirin, in recommended doses (200-600 mg three times/day). The maximum recommended dose is 1.8 g/day, typically given in divided doses with meals, milk, or antacids to lessen abdominal discomfort. However, peak plasma concentrations and bioavailability are reduced when the drug is taken with food. Tolmetin possesses typical tNSAID properties and side effects.

Adverse Effects. Side effects occur in 25-40% of patients who take tolmetin, and 5-10% discontinue use of the drug. GI side effects are the most common (15%), and gastric ulceration has been observed. CNS side effects similar to those seen with indomethacin and aspirin occur, but they are less common and less severe.

Therapeutic Uses. The use of ketorolac is limited to ≤5 days for acute pain requiring opioid-level analgesia and can be administered intramuscularly, intravenously, or orally. Like other NSAIDs, aspirin sensitivity is a contraindication to the use of ketorolac. Typical doses are 30-60 mg (intramuscular), 15-30 mg (intravenous), and 10-20 mg (oral). Ketorolac has a rapid onset of action and a short duration of action. It is widely used in postoperative patients, but it should not be used for routine obstetric analgesia. Topical (ophthalmic) ketorolac (ACULAR, others) is FDA approved for the treatment of seasonal allergic conjunctivitis and postoperative ocular inflammation after cataract extraction and after corneal refractive surgery. The pharmacology of ketorolac has been reviewed (Buckley and Brogden, 1990).

Adverse Effects. Side effects at usual oral doses include somnolence, dizziness, headache, GI pain, dyspepsia, nausea, and pain at the site of injection. The black box warning for ketorolac stresses the possibility of serious adverse GI, renal, bleeding, and hypersensitivity reactions from the use of this potent NSAID analgesic. Patients receiving greater than recommended doses or concomitant NSAID therapy and those at the extremes of age appear to be particularly at risk.

Therapeutic Uses. Nabumetone is an anti-inflammatory agent approved in 1991 for use in the U.S. It has been reviewed (Davies, 1997). Clinical trials with nabumetone have indicated substantial efficacy in the treatment of rheumatoid arthritis and osteoarthritis, with a relatively low incidence of side effects. The dose typically is 1000 mg given once daily. The drug also has off-label use in the short-term treatment of soft-tissue injuries.

Absorption, Distribution, and Elimination. Nabumetone is absorbed rapidly and is converted in the liver to one or more active metabolites, principally 6-methoxy-2-naphthylacetic acid, a potent nonselective inhibitor of COX. This metabolite, inactivated by O-demethylation in the liver, is then conjugated before excretion and is eliminated with a t_1/2 of ∼24 hours.

Common Adverse Effects. Nabumetone is associated with crampy lower abdominal pain and diarrhea, but the incidence of GI ulceration appears to be lower than with other tNSAIDs, although randomized, controlled studies directly comparing tolerability and clinical outcomes have not been performed. Other side effects include rash, headache, dizziness, heartburn, tinnitus, and pruritus.

Mechanism of Action. Diclofenac has analgesic, antipyretic, and anti-inflammatory activities. Its potency is substantially greater than that of indomethacin, naproxen, or several other tNSAIDs. The selectivity of diclofenac for COX-2 resembles that of celecoxib. In addition, diclofenac appears to reduce intracellular concentrations of free AA in leukocytes, perhaps by altering its release or uptake.

Absorption, Distribution, and Elimination. Diclofenac has rapid absorption, extensive protein binding, and a t_1/2 of 1-2 hours (Table 34–1). The short t_1/2 makes it necessary to dose diclofenac considerably higher than would be required to inhibit COX-2 fully at peak plasma concentrations to afford inhibition throughout the dosing interval. There is a substantial first-pass effect, such that only ∼50% of diclofenac is available systemically. The drug accumulates in synovial fluid after oral administration, which may explain why its duration of therapeutic effect is considerably longer than its plasma t_1/2. Diclofenac is metabolized in the liver by a member of the CYP2C subfamily to 4-hydroxydiclofenac, the principal metabolite, and other hydroxylated forms; after glucuronidation and sulfation, the metabolites are excreted in the urine (65%) and bile (35%).

Therapeutic Uses. Diclofenac is approved in the U.S. for the long-term symptomatic treatment of rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, pain, primary dysmenorrhea, and acute migraine. Four oral formulations are available: immediate-release tablets (cataflam, others) and capsules (zipsor), delayed-release tablets [voltaren, voltarol (U.K.), others], extended-release tablets (voltaren-xr, others), and a powder for oral solution (cambia). The usual daily oral dosage is 100-200 mg, given in several divided doses. For migraine, one packet of powder (50 mg) dissolved in 1-2 oz of water is administered. Diclofenac for topical use is available as a gel (voltaren) and as a transdermal patch (flector); systemically active concentrations released from these preparations are thought to contribute more to symptom relief than direct transport through the skin into the inflamed tissue. Diclofenac also is available in combination with misoprostol, a PGE₁ analog (arthrotec). This combination retains the efficacy of diclofenac while reducing the frequency of GI ulcers and erosions. In addition, an ophthalmic solution of diclofenac (VOLTAREN, others) is available for treatment of postoperative inflammation following cataract extraction and postoperative pain and photophobia following corneal refractive surgery.

Adverse Effects. Diclofenac produces side effects (particularly GI) in ∼20% of patients, and ∼2% of patients discontinue therapy as a result. The incidence of serious GI adverse effects did not differ between diclofenac and the COX-2–selective inhibitors, celecoxib (Juni et al., 2002) and etoricoxib (Cannon et al., 2006), likely because diclofenac exhibits a degree of COX-2 selectivity that is similar to that of celecoxib. The drug carries the same black box warning as all other tNSAIDs regarding cardiovascular events. Hypersensitivity reactions have occurred following topical application.

Modest elevation of hepatic transaminases in plasma occurs in 5-15% of patients. Although usually moderate, transaminase values may increase more than 3-fold in a small percentage of patients. The elevations usually are reversible. Another member of this phenylacetic acid family of NSAIDs, bromfenac, was withdrawn from the market because of its association with severe, irreversible liver injury in some patients. Bromfenac was re-licensed in the U.S. in 2005 as an ophthalmic solution (XIBROM) for postoperative ocular inflammation and pain following cataract extraction. The structurally similar nepafenac (NEVANAC) was licensed as an ophthalmic in the same year for the same indication. Lumiracoxib, another diclofenac analog (see the following section), was withdrawn from the market in several countries due to liver toxicity. Transaminases should be measured during the first 8 weeks of therapy with diclofenac, and the drug should be discontinued if abnormal values persist or if other signs or symptoms develop. Other untoward responses to diclofenac include CNS effects, rashes, allergic reactions, fluid retention, edema, and renal function impairment. The drug is not recommended for children, nursing mothers, or pregnant women. Consistent with its preference for COX-2, and unlike ibuprofen, diclofenac does not interfere with the antiplatelet effect of aspirin (Catella-Lawson et al., 2001).

Lumiracoxib

Lumiracoxib is an analog of diclofenac; it differs only by an additional methyl group and one fluorine substitution for chlorine. Lumiracoxib has greater COX-2 selectivity in vitro than any of the currently available coxibs. Its structural similarity to diclofenac is thought to account for their common hepatic adverse event profiles that may occur via a mechanism independent from COX inhibition. Lumiracoxib's potency is similar to that of naproxen. It is used at daily doses of 100 or 200 mg for osteoarthritis and 400 mg for acute pain. Lumiracoxib is not approved in the U.S., and marketing authorization was revoked in 2007 in many countries following reports of serious liver toxicity. Refer to earlier editions of this text for further details.

Mechanism of Action. Propionic acid derivatives are nonselective COX inhibitors with the effects and side effects common to other tNSAIDs. Although there is considerable variation in their potency as COX inhibitors, this is not of obvious clinical consequence. Some of the propionic acid derivatives, particularly naproxen, have prominent inhibitory effects on leukocyte function, and some data suggest that naproxen may have slightly better efficacy with regard to analgesia and relief of morning stiffness. This suggestion of benefit accords with the clinical pharmacology of naproxen that suggests that some but not all individuals dosed with 500 mg twice daily sustain platelet inhibition throughout the dosing interval.

Therapeutic Uses. Ibuprofen, naproxen, flurbiprofen, fenoprofen, ketoprofen, and oxaprozin, are available in the U.S. Several additional agents in this class, including fenbufen, carprofen, pirprofen, indobufen, and tiaprofenic acid, are in use or under study in other countries.

Propionic acid derivatives are approved for use in the symptomatic treatment of rheumatoid arthritis and osteoarthritis. Some also are approved for pain, ankylosing spondylitis, acute gouty arthritis, tendinitis, bursitis, and migraine and for primary dysmenorrhea. Small clinical studies suggest that the propionic acid derivatives are comparable in efficacy to aspirin for the control of the signs and symptoms of rheumatoid arthritis and osteoarthritis, perhaps with improved tolerability.

Drug Interactions. Ibuprofen also has been shown to interfere with the antiplatelet effects of aspirin (see "Concomitant NSAIDs and Low-Dose Aspirin"). There also is evidence for a similar interaction between aspirin and naproxen. Propionic acid derivatives have not been shown to alter the pharmacokinetics of the oral hypoglycemic drugs or warfarin.

Absorption, Distribution, and Elimination. Ibuprofen is absorbed rapidly, bound avidly to protein, and undergoes hepatic metabolism (90% is metabolized to hydroxylate or carboxylate derivatives) and renal excretion of metabolites. The t_1/2 is ∼2 hours. Slow equilibration with the synovial space means that its anti-arthritic effects may persist after plasma levels decline. In experimental animals, ibuprofen and its metabolites readily cross the placenta.

Therapeutic Uses. Ibuprofen [ADVIL, MOTRIN IB, BRUFEN (U.K.), ANADIN ULTRA (U.K.), others] is supplied as tablets, capsules, caplets, and gelcaps containing 50-800 mg; as oral drops; and as an oral suspension. Dosage forms containing ≤200 mg are available without a prescription. Ibuprofen is licensed for marketing in fixed-dose combinations with antihistamines, decongestants, oxycodone (COMBUNOX, others), and hydrocodone (REPREXAIN, IBUDONE, VICOPROFEN, others). An injectable formulation for closure of patent ductus (ibuprofen lysine; NEOPROFEN) has been licensed since 2006, and an injectable formulation for pain that was initially approved in 1974, CALDOLOR, was licensed by the FDA in 2009 for in-hospital use.

Doses of ≤800 mg four times daily can be used in the treatment of rheumatoid arthritis and osteoarthritis, but lower doses often are adequate. The usual dose for mild to moderate pain, such as that of primary dysmenorrhea, is 400 mg every 4-6 hours as needed. For pain or fever, intravenous ibuprofen is administered at a dose of 100-800 mg over 30 minutes every 4-6 hours. Ibuprofen has been reviewed (Davies, 1998a; Rainsford, 2003).

Adverse Effects. Ibuprofen is thought to be better tolerated than aspirin and indomethacin and has been used in patients with a history of GI intolerance to other NSAIDs. Nevertheless, 5-15% of patients experience GI side effects.

Epidemiological studies suggest that the relative risk of myocardial infarction is unaltered by ibuprofen or perhaps slightly increased but is considerably less than the risk from COX-2–selective inhibitors. Other adverse effects of ibuprofen have been reported less frequently. They include thrombocytopenia, rashes, headache, dizziness, blurred vision, and in a few cases, toxic amblyopia, fluid retention, and edema. Patients who develop ocular disturbances should discontinue the use of ibuprofen. Ibuprofen can be used occasionally by pregnant women; however, the concerns apply regarding third-trimester effects, including delay of parturition. Excretion into breast milk is thought to be minimal, so ibuprofen also can be used with caution by women who are breastfeeding.

Naproxen (aleve, naprosyn, others) is supplied as tablets, delayed-release tablets, controlled-release tablets, gelcaps, and caplets containing 200-750 mg of naproxen or naproxen sodium and as an oral suspension. Dosage forms containing ≤200 mg are available without a prescription. Naproxen is licensed for marketing in fixed-dose combinations with pseudoephedrine (ALEVE-D SINUS & COLD, others) and sumatriptan (TREXIMET) and is co-packaged with lansoprazole (PREVACID NAPRAPAC). Naproxen holds more FDA-approved indications than other tNSAIDs. It is indicated for juvenile and rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, pain, primary dysmenorrhea, tendonitis, bursitis, and acute gout. The pharmacological properties and therapeutic uses of naproxen have been reviewed (Davies and Anderson, 1997b).

Absorption, Distribution, and Elimination. Naproxen is absorbed fully when administered orally. Food delays the rate but not the extent of absorption. Peak concentrations in plasma occur within 2-4 hours and are somewhat more rapid after the administration of naproxen sodium. Absorption is accelerated by the concurrent administration of sodium bicarbonate but delayed by magnesium oxide or aluminum hydroxide. Naproxen also is absorbed rectally but more slowly than after oral administration. The t_1/2 of naproxen in plasma is variable. About 14 hours in the young, it may increase about 2-fold in the elderly because of age-related decline in renal function (Table 34–1).

Metabolites of naproxen are excreted almost entirely in the urine. About 30% of the drug undergoes 6-demethylation, and most of this metabolite, as well as naproxen itself, is excreted as the glucuronide or other conjugates.

Naproxen is almost completely (99%) bound to plasma proteins after normal therapeutic doses. Naproxen crosses the placenta and appears in the milk of lactating women at ∼1% of the maternal plasma concentration.

Common Adverse Effects. Epidemiological studies suggest that the relative risk of myocardial infarction may be reduced by ∼10% by naproxen, compared to a reduction of 20-25% by aspirin. This is consistent with its long t_1/2, which may result in complete and persistent platelet inhibition in some patients. However, increased rates of cardiovascular events also have been reported (see the "Cardioprotection" and "Cardiovascular" sections). Typical GI adverse effects with naproxen occur at approximately the same frequency as with indomethacin and other tNSAIDs but perhaps with less severity. CNS side effects range from drowsiness, headache, dizziness, and sweating to fatigue, depression, and ototoxicity. Less common reactions include pruritus and a variety of dermatological problems. A few instances of jaundice, impairment of renal function, angioedema, thrombocytopenia, and agranulocytosis have been reported.

Fenoprofen. The pharmacological properties and therapeutic uses of fenoprofen (NALFON 200, others) have been reviewed (Brogden et al., 1981). Oral doses of fenoprofen are readily but incompletely (85%) absorbed (Table 34–1). The concomitant administration of antacids does not seem to alter the concentrations that are achieved. The GI side effects of fenoprofen are similar to those of ibuprofen or naproxen and occur in ∼15% of patients.

Ketoprofen. A more potent S-enantiomer is available in Europe (Barbanoj et al., 2001). In addition to COX inhibition, ketoprofen may stabilize lysosomal membranes and antagonize the actions of bradykinin. It is unknown if these actions are relevant to its efficacy in humans. Ketoprofen is conjugated with glucuronic acid in the liver, and the conjugate is excreted in the urine (Table 34–1). Patients with impaired renal function eliminate the drug more slowly. Approximately 30% of patients experience mild GI side effects with ketoprofen, which are decreased if the drug is taken with food or antacids.

Flurbiprofen. Flurbiprofen is available as tablets (ANSAID, others) and as an ophthalmic solution (OCUFEN, others) indicated for intra-operative miosis. The pharmacological properties, therapeutic indications, and adverse effects of orally administered flurbiprofen are similar to those of other anti-inflammatory derivatives of propionic acid (Table 34–1) and have been reviewed (Davies, 1995).

Oxaprozin. Oxaprozin (DAYPRO, others) has similar pharmacological properties, adverse effects, and therapeutic uses to those of other propionic acid derivatives (Davies, 1998b). However, its pharmacokinetic properties differ considerably. Peak plasma levels are not achieved until 3-6 hours after an oral dose, while its t_1/2 of 40-60 hours allows for once-daily administration.

Mefenamic acid and meclofenamate are N-substituted phenylanthranilic acids. The pharmacological properties of the fenamates are those of typical tNSAIDs, and therapeutically, they have no clear advantages over others in the class.

Available Preparations and Therapeutic Uses. The fenamates include mefenamic, meclofenamic, and flufenamic acids. Mefenamic acid [PONSTEL, PONSTAN (U.K.), DYSMAN (U.K.)] and meclofenamate sodium have mostly been used in the short-term treatment of pain in soft-tissue injuries, dysmenorrhea, and rheumatoid and osteoarthritis; flufenamic acid is not licensed for use in the U.S. These drugs are not recommended for use in children or pregnant women.

Common Adverse Effects. Approximately 25% of users develop GI side effects at therapeutic doses. Roughly 5% of patients develop a reversible elevation of hepatic transaminases. Diarrhea, which may be severe and associated with steatorrhea and inflammation of the bowel, also is relatively common. Autoimmune hemolytic anemia is a potentially serious but rare side effect.

The pharmacological properties and therapeutic uses of piroxicam (feldene, others) have been reviewed (Guttadauria, 1986).

Mechanism of Action. Piroxicam can inhibit activation of neutrophils, apparently independently of its ability to inhibit COX; hence, additional modes of anti-inflammatory action have been proposed, including inhibition of proteoglycanase and collagenase in cartilage.

Absorption, Distribution, and Elimination. Piroxicam is absorbed completely after oral administration and undergoes enterohepatic recirculation; peak concentrations in plasma occur within 2-4 hours (Table 34–1). Food may delay absorption. Estimates of the t_1/2 in plasma have been variable; the average is ∼50 hours.

After absorption, piroxicam is extensively (99%) bound to plasma proteins. Concentrations in plasma and synovial fluid are similar at steady state (e.g., after 7-12 days). Less than 5% of the drug is excreted into the urine unchanged. The major metabolic transformation in humans is hydroxylation of the pyridyl ring (predominantly by an isozyme of the CYP2C subfamily), and this inactive metabolite and its glucuronide conjugate account for ∼60% of the drug excreted in the urine and feces.

Therapeutic Uses. Piroxicam is approved in the U.S. for the treatment of rheumatoid arthritis and osteoarthritis. Due to its slow onset of action and delayed attainment of steady state, it is less suited for acute analgesia but has been used to treat acute gout. The usual daily dose is 20 mg, and because of the long t_1/2, steady-state blood levels are not reached for 7-12 days.

Adverse Events. Approximately 20% of patients experience side effects with piroxicam, and ∼5% of patients discontinue use because of these effects. In 2007, the European Medicines Agency reviewed the safety of orally administered piroxicam and concluded that its benefits outweigh its risks, but advised it should no longer be used first-line, nor should it be used for the treatment of acute (short-term) pain and inflammation. Piroxicam was singled out for special review because of signals that it is associated with more GI and serious skin reactions than other nonselective NSAIDs.

Therapeutic Uses. Meloxicam (MOBIC, others) is FDA-approved for use in osteoarthritis. It has been reviewed (Davies and Skjodt, 1999; Fleischmann et al., 2002). The recommended dose for meloxicam is 7.5-15 mg once daily.

Adverse Events. On average, meloxicam demonstrates ∼10-fold COX-2 selectivity in ex vivo assays. However, this is quite variable, and a clinical advantage or hazard has yet to be established for the drug. Indeed, even with surrogate markers, the relationship to dose is nonlinear. There is significantly less gastric injury compared to piroxicam (20 mg/day) in subjects treated with 7.5 mg/day of meloxicam, but the advantage is lost with a dosage of 15 mg/day.

A number of other oxicam derivatives are under study or in use outside the U.S. These include several prodrugs of piroxicam (ampiroxicam, droxicam, and pivoxicam), which have been designed to reduce GI irritation. However, as with sulindac, any theoretical diminution in gastric toxicity associated with administration of a prodrug is offset by gastric COX-1 inhibition from active drug circulating systemically. Other oxicams under study or in use outside the U.S. include lornoxicam, cinnoxicam, sudoxicam, and tenoxicam. The efficacy and toxicity of these drugs are similar to those of piroxicam. Lornoxicam is unique among the enolic acid derivatives in that it has a rapid onset of action and a relatively short t_1/2 (3-5 hours).

This group of drugs includes phenylbutazone, oxyphenbutazone, antipyrine, aminopyrine, and dipyrone; currently, only antipyrine eardrops are available for human use in the U.S. These drugs were used clinically for many years but have essentially been abandoned because of their propensity to cause irreversible agranulocytosis. Dipyrone was reintroduced in the E.U. a decade ago because epidemiological studies suggested that the risk of adverse effects was similar to that of acetaminophen and lower than that of aspirin. However, the use of dipyrone remains limited. The pyrazolone derivatives are discussed in previous editions of this book and may be accessed on the G&G website.

Chemistry. Most members of the diaryl heterocyclic family of selective COX-2 inhibitors consist of a central 1,2-diaryl heterocyclic moiety. Celecoxib is a diaryl substituted pyrazole compound; valdecoxib is a diaryl substituted isoxazol derivative. Valdecoxib was made water soluble for parenteral use (parecoxib) by coupling propionic acid via an amide group to its sulfonamide moiety. Etoricoxib is slightly different; it is a monoaryl substituted bipyridine, which results in a three-ring configuration that is superimposable onto the diaryl heterocyclic pharmacophore. Celecoxib, valdecoxib, and its prodrug parecoxib contain a sulfonamide moiety that bares the risk for cross-reactivity in patients with sulfonamide hypersensitivity and, thus, must be avoided in such patients. Etoricoxib has a methylsulfonyl group that is thought to be free of such risk.

Mechanism of Action. Compounds with higher affinity for COX-2 than COX-1 were identified in screens of combinatorial libraries. Subsequent crystallography revealed a hydrophobic pocket in the substrate binding channel of COX-2, which is absent in COX-1 (Figure 34–2). Thus, selective inhibitors of COX-2 are molecules with side chains—the third ring—that fit within this hydrophobic pocket but are too large to block COX-1 with equally high affinity. There is considerable difference in response to the coxibs among individuals (Fries et al., 2006), and it is not known how the degree of selectivity may relate to either efficacy or adverse effect profile, although it seems likely to be related to both. No controlled clinical trials comparing outcomes among the coxibs have been performed. Several tNSAIDs (e.g., nimesulide, diclofenac, meloxicam) exhibit relative selectivity for COX-2 inhibition in whole blood assays that resembles that of celecoxib (FitzGerald and Patrono, 2001; Brune and Hinz, 2004).

Therapeutic Uses. All COX-2–selective NSAIDs have been shown to afford relief from postextraction dental pain and to afford dose-dependent relief from inflammation in osteoarthritis and rheumatoid arthritis. The European Medicines Agency advises that these medicines should not be used in patients with ischemic heart disease or stroke and that prescribers should exercise caution when using selective COX-2 inhibitors in patients with risk factors for heart disease such as hypertension, hyperlipidemia, diabetes, smoking, or peripheral arterial disease. As for all NSAIDs, the agency advises the lowest effective dose for the shortest possible duration of treatment.

Absorption, Distribution, and Elimination. The bioavailability of oral celecoxib is not known, but peak plasma levels occur at 2-4 hours after the dose is taken. The elderly (≥65 years of age) may have up to 2-fold higher peak concentrations and AUC values than younger patients (≤55 years of age). Celecoxib is bound extensively to plasma proteins. Little drug is excreted unchanged; most is excreted as carboxylic acid and glucuronide metabolites in the urine and feces. The elimination t_1/2 is ∼11 hours. The drug commonly is given once or twice per day during chronic treatment. Renal insufficiency is associated with a modest, clinically insignificant decrease in plasma concentration. Celecoxib has not been studied in patients with severe renal insufficiency. Plasma concentrations are increased by ∼40% and 180% in patients with mild and moderate hepatic impairment, respectively, and dosages should be reduced by at least 50% in patients with moderate hepatic impairment. Celecoxib is metabolized predominantly by CYP2C9. Although not a substrate, celecoxib is an inhibitor of CYP2D6. Clinical vigilance is necessary during co-administration of drugs that are known to inhibit CYP2C9 and drugs that are metabolized by CYP2D6. For example, celecoxib inhibits the metabolism of metoprolol and can result in its accumulation.

Therapeutic Uses. Celecoxib is approved in the U.S. for the management of acute pain in adults, for the treatment of osteoarthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, ankylosing spondylitis, and primary dysmenorrhea. The recommended dose for treating osteoarthritis is 200 mg/day as a single dose or divided as two 100-mg doses. In the treatment of rheumatoid arthritis, the recommended dose is 100-200 mg twice per day. In the light of its cardiovascular hazard, physicians are advised to use the lowest possible dose for the shortest possible time. Current evidence does not support use of celecoxib as a first choice among the tNSAIDs. Celecoxib also is approved for the chemoprevention of polyposis coli; however, placebo-controlled trials revealed a dose-dependent increase in myocardial infarction and stroke (Solomon et al., 2006).

Adverse Effects. Placebo-controlled trials have established that celecoxib confers a risk of myocardial infarction and stroke and this appears to relate to dose and the underlying risk of cardiovascular disease that anteceded drug administration. Effects attributed to inhibition of PG production in the kidney—hypertension and edema—occur with nonselective COX inhibitors and also with celecoxib. Studies in mice and some epidemiological evidence suggest that the likelihood of patients' developing hypertension while on NSAIDs reflects the degree of inhibition of COX-2 and the selectivity with which it is attained. Indeed, the prevalence of hypertension is higher in patients taking etoricoxib than diclofenac, consistent with the greater selectivity for inhibition of COX-2 of the former drug (Cannon et al., 2006; Laime et al., 2007). Thus, the risk of thrombosis, hypertension, and accelerated atherogenesis are mechanistically integrated. The coxibs should be avoided in patients prone to cardiovascular or cerebrovascular disease. None of the coxibs has established superior efficacy over tNSAIDs. Celecoxib carries the same cardiovascular and GI black box warning as tNSAIDs. Although selective COX-2 inhibitors do not interact to prevent the antiplatelet effect of aspirin, it now is thought that they lose their GI advantage over a tNSAID alone when used in conjunction with aspirin. Experience with selective COX-2 inhibitors in patients who exhibit aspirin hypersensitivity is limited, and caution should be observed.

Absorption, Distribution, and Elimination. Parecoxib is absorbed rapidly (∼15 minutes after intramuscular injection) and converted (15-50 minutes) by deoxymethylation to valdecoxib, the active drug (Table 34–1). Valdecoxib undergoes extensive hepatic metabolism by CYPs 3A4 and 2C9 and non–CYP-dependent glucuronidation. It is a weak inhibitor of CYP2C9 and a weak to moderate inhibitor of CYP2C19. The metabolites of valdecoxib are excreted in the urine. The t_1/2 is ∼7-8 hours but can be significantly prolonged in the elderly or those with hepatic impairment, with subsequent drug accumulation.

Therapeutic Uses. Parecoxib (DYNASTAT) is available in Germany and Australia, but not in the U.K. or U.S., for management of acute pain, including moderate to severe postsurgical pain. It is supplied as a lyophilized powder equivalent to 20 or 40 mg parecoxib to be reconstituted with sterile saline for injection.

Adverse Effects. The cardiovascular risk of parecoxib and valdecoxib was detected in two postoperative pain management trials of high-risk patients (Grosser et al., 2006). Patients undergoing coronary bypass graft (CABG) surgery were initially treated intravenously with parecoxib or placebo and then switched to oral valdecoxib or placebo. The majority of cardiovascular events occurred within days of treatment initiation in these populations, who were subject to acute hemostatic activation after bypass surgery. Clinical studies suggest that cardiovascular complications attributable to COX-2–selective NSAIDs is proportional to baseline cardiovascular risk and to the duration of drug exposure (Grosser et al., 2006). All NSAIDs and celecoxib carry a black box warning contraindicating their use for pain following CABG surgery.

Life-threatening skin reactions (including toxic epidermal necrolysis, Stevens-Johnson syndrome, and erythema multiforme) have been reported in association with valdecoxib, which contains a sulfonamide group. The risk of hypersensitivity or skin reactions applies also to parecoxib. The drug must be discontinued at the first sign of rash, mucosal lesion, or any other sign of hypersensitivity. This additional hazard renders valdecoxib an unlikely therapeutic choice.

Absorption, Distribution, and Elimination. Etoricoxib is incompletely (∼80%) absorbed and has a long t_1/2 of ∼20-26 hours (Table 34–1). It is extensively metabolized before excretion. Small studies suggest that those with moderate hepatic impairment are prone to drug accumulation, and the dosing interval should be adjusted. Renal insufficiency does not affect drug clearance.

Therapeutic Uses. Etoricoxib (ARCOXIA) is approved in some countries (not in U.S.) as a once-daily medicine for symptomatic relief in the treatment of osteoarthritis, rheumatoid arthritis, and acute gouty arthritis, as well as for the short-term treatment of musculoskeletal pain, postoperative pain, and primary dysmenorrhea (Patrignani et al., 2003).

Common Adverse Effects. In keeping with other coxibs, etoricoxib shows decreased GI injury as assessed endoscopically. The European regulatory agency concluded that etoricoxib, along with other coxibs, increased the risk of heart attack and stroke; the agency specifically restricted its use in patients with uncontrolled hypertension.

Rofecoxib (VIOXX) was introduced in 1999. Details of its pharmacodynamics, pharmacokinetics, therapeutic efficacy, and toxicity have been reviewed (Davies et al., 2003). Based on interim analysis of data from the Adenomatous Polyp Prevention on Vioxx (APPROVe) study, which showed a significant (2-fold) increase in the incidence of serious thromboembolic events in subjects receiving 25 mg of rofecoxib relative to placebo (Bresalier et al., 2005), rofecoxib was withdrawn from the market worldwide in 2004.

Apazone is a tNSAID that has anti-inflammatory, analgesic, and antipyretic activity and is a potent uricosuric agent. It is available in E.U. but not in U.S. Some of its efficacy may arise from its capacity to inhibit neutrophil migration, degranulation, and superoxide production.

Apazone has been used for the treatment of rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, and gout but usually is restricted to cases where other tNSAIDs have failed. Typical doses are 600 mg three times per day for acute gout. Once symptoms have abated, or for non-gout indications, typical dosage is 300 mg three to four times per day. Clinical experience to date suggests that apazone is well tolerated. Mild GI side effects (nausea, epigastric pain, dyspepsia) and rashes occur in ∼3% of patients, while CNS effects (headache, vertigo) are reported less frequently. Precautions appropriate to other nonselective COX inhibitors also apply to apazone.

Nimesulide is a sulfonanilide compound available in Europe that demonstrates COX-2 selectivity similar to celecoxib in whole-blood assays. Additional effects include inhibition of neutrophil activation, decrease in cytokine production, decrease in degradative enzyme production, and possibly activation of glucocorticoid receptors (Bennett, 1999).

Nimesulide is administered orally in doses ≤100 mg twice daily as an anti-inflammatory, analgesic, and antipyretic. Its use in the E.U. is limited to ≤15 days due to the risk of hepatotoxicity.

Treatment with single non-biological DMARDs can achieve remission or at least a state of very low disease activity in a large number of rheumatoid arthritis patients (Saag et al., 2008). Combinations of non-biological DMARDs (e.g., methotrexate + sulfasalazine, methotrexate + hydroxychloroquine, methotrexate + leflunomide, methotrexate + sulfasalazine + hydroxychloroquine) are indicated for patients with moderate or high disease activity or prolonged disease duration or for those who fail to respond to a single compound. Biological DMARDs remain reserved for patients with persistent moderate or high disease activity and indicators of poor prognosis such as functional impairment, radiographic bony erosions, extra-articular disease, and rheumatoid factor positivity. Therapy is tailored to the individual patient, and the use of these agents must be weighed against their potentially serious adverse effects. The combination of NSAIDs with these agents is common.

Short-term glucocorticoids often are used to bring the level of inflammation quickly under control. Glucocorticoids are not suitable for long-term use because of adrenal suppression. The older agents (gold, penicillamine) have unclear mechanisms of action and tend to have slight efficacy and significant side effects. Their pharmacology is described in more detail in previous editions of this book.

Mechanism of Action. Colchicine exerts a variety of pharmacological effects, but how these occur or how they relate to its activity in gout is not well understood. Its structure-activity relationship has been discussed (Levy et al., 1991). It has antimitotic effects, arresting cell division in G₁ by interfering with microtubule and spindle formation (an effect shared with vinca alkaloids). This effect is greatest on cells with rapid turnover (e.g., neutrophils, GI epithelium). Colchicine may alter neutrophil motility in ex vivo assays (Levy et al., 1991). Experimental data suggest that colchicine decreases the crystal-induced secretion of chemotactic factors and superoxide anions by activated neutrophils. It also limits neutrophil adhesion to endothelium by modulating the expression of endothelial adhesion molecules. Higher concentrations inhibit IL-1β processing and release from neutrophils in vitro.

Colchicine inhibits the release of histamine-containing granules from mast cells, the secretion of insulin from pancreatic β cells, and the movement of melanin granules in melanophores. These processes also may involve interference with the microtubular system, but whether this occurs at clinically relevant concentrations is questionable.

Colchicine also exhibits a variety of other pharmacological effects. It lowers body temperature, increases the sensitivity to central depressants, depresses the respiratory center, enhances the response to sympathomimetic agents, constricts blood vessels, and induces hypertension by central vasomotor stimulation. It enhances GI activity by neurogenic stimulation but depresses it by a direct effect, and alters neuromuscular function.

Absorption, Distribution, and Elimination. The absorption of oral colchicine is rapid but variable. Peak plasma concentrations occur 0.5-2 hours after dosing. In plasma, 50% of colchicine is protein bound. The formation of colchicine-tubulin complexes in many tissues contributes to its large volume of distribution. There is significant enterohepatic circulation. The exact metabolism of colchicine in humans is unknown, but in vitro studies indicate that it may undergo oxidative demethylation by CYP3A4. Indeed, other CYP3A4 substrates, such as cimetidine, have been associated with an increase in colchicine plasma t_1/2 and the emergence of colchicine toxicity. The drug is contraindicated in patients with hepatic or renal impairment requiring concomitant therapy with CYP3A4 or P-glycoprotein inhibitors. Only 10-20% is excreted in the urine, although this increases in patients with liver disease. The kidney, liver, and spleen also contain high concentrations of colchicine, but it apparently is largely excluded from heart, skeletal muscle, and brain. The plasma t_1/2 of colchicine is ∼9 hours, but the drug can be detected in leukocytes and in the urine for at least 9 days after a single intravenous dose.

Therapeutic Uses. A minimum of 3 days, but preferably 7 or 14 days, should elapse between courses of gout treatment with colchicine to avoid cumulative toxicity. Patients with hepatic or renal disease and dialysis patients should receive reduced doses and/or less frequent therapy. Great care should be exercised in prescribing colchicine for elderly patients, for whom the dose should be based on renal function. For those with cardiac, renal, hepatic, or GI disease, NSAIDs or glucocorticoids may be preferred.

Acute Gout. Colchicine dramatically relieves acute attacks of gout. It is effective in roughly two-thirds of patients if given within 24 hours of attack onset. Pain, swelling, and redness abate within 12 hours and are completely gone within 48-72 hours. In the past, the typical dosing regimen was 0.6 mg each hour until pain was relieved or diarrhea developed; the typical course of therapy ranged from 4-8 mg. The new regimen approved by the FDA in 2009 for adults recommends a total of only two doses taken 1 hour apart: 1.2 mg (two tablets) at the first sign of a gout flare followed by 0.6 mg (one tablet) 1 hour later. The dose must be adjusted in patients exposed to inhibitors of P-glycoprotein or CYP3A4 within the previous 14 days.

Prevention of Acute Gout. The main off-label indication for colchicine is in the prevention of recurrent gout, particularly in the early stages of antihyperuricemic therapy. The typical dose for prophylaxis is 0.6 mg taken orally 3 or 4 days/wk for patients who have <1 attack per year, 0.6 mg daily for patients who have >1 attack per year, and 0.6 mg two or three times daily for patients who have severe attacks. The dose must be decreased for patients with impaired renal function.

Familial Mediterranean Fever. The administration of daily colchicine is useful for the prevention of attacks of familial Mediterranean fever and prevention of amyloidosis, which may complicate this disease. The dose for adults and children >12 years of age is 1.2-2.4 mg daily. The dose for patients as young as 4 years is reduced on the basis of age.

Adverse Effects. Exposure of the GI tract to large amounts of colchicine and its metabolites via enterohepatic circulation and the rapid rate of turnover of the GI mucosa may explain why the GI tract is particularly susceptible to colchicine toxicity. Nausea, vomiting, diarrhea, and abdominal pain are the most common untoward effects and the earliest signs of impending colchicine toxicity. Drug administration should be discontinued as soon as these symptoms occur. There is a latent period, which is not altered by dose or route of administration, of several hours or more between the administration of the drug and the onset of symptoms. A dosing study required as part of FDA approval demonstrated that one dose initially and a single additional dose after 1 hour was much less toxic than traditional hourly dosing for acute gout flares. Acute intoxication causes hemorrhagic gastropathy. Intravenous colchicine was previously used to treat acute gouty arthritis; however, this route obviates early GI side effects that can be a harbinger of serious systemic toxicity. The FDA suspended the U.S. marketing of all injectable dosage forms of colchicine in 2008. Other serious side effects of colchicine therapy include myelosuppression, leukopenia, granulocytopenia, thrombopenia, aplastic anemia, and rhabdomyolysis. Life-threatening toxicities are associated with administration of concomitant therapy with P-glycoprotein or CYP3A4 inhibitors.

History. Allopurinol initially was synthesized as a candidate antineoplastic agent but was found to lack antineoplastic activity. Subsequent testing showed it to be an inhibitor of xanthine oxidase that was useful clinically for the treatment of gout.

Chemistry. Allopurinol is an analog of hypoxanthine. Its active metabolite, oxypurinol, is an analog of xanthine.

Mechanism of Action. Both allopurinol and its primary metabolite, oxypurinol (alloxanthine), inhibit xanthine oxidase and reduce urate production. Allopurinol competitively inhibits xanthine oxidase at low concentrations and is a noncompetitive inhibitor at high concentrations. Allopurinol also is a substrate for xanthine oxidase; the product of this reaction, oxypurinol, also is a noncompetitive inhibitor of the enzyme. The formation of oxypurinol, together with its long persistence in tissues, is responsible for much of the pharmacological activity of allopurinol.

In the absence of allopurinol, the dominant urinary purine is uric acid. During allopurinol treatment, the urinary purines include hypoxanthine, xanthine, and uric acid. Because each has its independent solubility, the concentration of uric acid in plasma is reduced and purine excretion increased, without exposing the urinary tract to an excessive load of uric acid. Despite their increased concentrations during allopurinol therapy, hypoxanthine and xanthine are efficiently excreted, and tissue deposition does not occur. There is a small risk of xanthine stones in patients with a very high urate load before allopurinol therapy, which can be minimized by liberal fluid intake and alkalization of the urine with sodium bicarbonate, potassium citrate, or citrate combinations such as modified Shohl's solution.

Allopurinol facilitates the dissolution of tophi and prevents the development or progression of chronic gouty arthritis by lowering the uric acid concentration in plasma below the limit of its solubility. The formation of uric acid stones virtually disappears with therapy, which prevents the development of nephropathy. Once significant renal injury has occurred, allopurinol cannot restore renal function but may delay disease progression.

The incidence of acute attacks of gouty arthritis may increase during the early months of allopurinol therapy as a consequence of mobilization of tissue stores of uric acid. Co-administration of colchicine helps suppress such acute attacks. After reduction of excess tissue stores of uric acid, the incidence of acute attacks decreases and colchicine can be discontinued.

In some patients, the allopurinol-induced increase in excretion of oxypurines is less than the reduction in uric acid excretion; this disparity primarily is a result of re-utilization of oxypurines and feedback inhibition of de novo purine biosynthesis.

Absorption, Distribution, and Elimination. Allopurinol is absorbed relatively rapidly after oral ingestion, and peak plasma concentrations are reached within 60-90 minutes. About 20% is excreted in the feces in 48-72 hours, presumably as unabsorbed drug, and 10-30% is excreted unchanged in the urine. The remainder undergoes metabolism, mostly to oxypurinol apparently by the catalytic activity of aldehyde oxidoreductase. Oxypurinol is excreted slowly in the urine by glomerular filtration, counterbalanced by some tubular reabsorption. The plasma t_1/2 of allopurinol and oxypurinol is ∼1-2 hours and ∼18-30 hours (longer in those with renal impairment), respectively. This allows for once-daily dosing and makes allopurinol the most commonly used antihyperuricemic agent.

Allopurinol and its active metabolite oxypurinol are distributed in total tissue water, with the exception of brain, where their concentrations are about one-third of those in other tissues. Neither compound is bound to plasma proteins. The plasma concentrations of the two compounds do not correlate well with therapeutic or toxic effects. The clinical pharmacology of allopurinol and its metabolite have been reviewed (Day et al., 2007).

Drug Interactions. Allopurinol increases the t_1/2 of probenecid and enhances its uricosuric effect, while probenecid increases the clearance of oxypurinol, thereby increasing dose requirements of allopurinol.

Allopurinol inhibits the enzymatic inactivation of mercaptopurine and its derivative azathioprine by xanthine oxidase. Thus, when allopurinol is used concomitantly with oral mercaptopurine or azathioprine, dosage of the antineoplastic agent must be reduced to one-fourth to one-third of the usual dose (see Chapters 35 and 61). This is of importance when treating gout in the transplant recipient. The risk of bone marrow suppression also is increased when allopurinol is administered with cytotoxic agents that are not metabolized by xanthine oxidase, particularly cyclophosphamide.

Allopurinol also may interfere with the hepatic inactivation of other drugs, including warfarin. Although the effect is variable, increased monitoring of prothrombin activity is recommended in patients receiving both medications.

It remains to be established whether the increased incidence of rash in patients receiving concurrent allopurinol and ampicillin should be ascribed to allopurinol or to hyperuricemia. Hypersensitivity reactions have been reported in patients with compromised renal function, especially those who are receiving a combination of allopurinol and a thiazide diuretic. The concomitant administration of allopurinol and theophylline leads to increased accumulation of an active metabolite of theophylline, 1-methylxanthine; the concentration of theophylline in plasma also may be increased (see Chapter 36).

Therapeutic Uses. Allopurinol (ZYLOPRIM, ALOPRIM, others) is available for oral and intravenous use. Oral therapy provides effective therapy for primary and secondary gout, hyperuricemia secondary to malignancies, and calcium oxalate calculi. Intravenous therapy is indicated for hyperuricemia secondary to cancer chemotherapy for patients unable to tolerate oral therapy.

Allopurinol is contraindicated in patients who have exhibited serious adverse effects or hypersensitivity reactions to the medication and in nursing mothers and children, except those with malignancy or certain inborn errors of purine metabolism (e.g., Lesch-Nyhan syndrome). Allopurinol generally is used in complicated hyperuricemia post-transplantation, to prevent acute tumor lysis syndrome, or in patients with hyperuricemia post-transplantation. If necessary, it can be used in conjunction with a uricosuric agent such as probenecid.

The goal of therapy is to reduce the plasma uric acid concentration to <6 mg/dL (<360 ¨mol/L). In the management of gout, it is customary to antecede allopurinol therapy with colchicine and to avoid starting allopurinol during an acute attack. Fluid intake should be sufficient to maintain daily urinary volume of >2 L; slightly alkaline urine is preferred. An initial daily dose of 100 mg in patients with estimated glomerular filtration rates >40 mg/min is increased by 100-mg increments at weekly intervals according to the antihyperuricemic effect achieved. Plasma uric acid concentration <6 mg/dL (<360 ¨mol/L) are attained in less than half of the patients on 300 mg/day, the most commonly prescribed dose. Achieving sufficient reduction of uric acid serum levels may require 400-600 mg/day. Those with hematological malignancies may need up to 800 mg/day beginning 2-3 days before the start of chemotherapy. Interindividual variability in drug response is high. Daily doses >300 mg should be divided. Dosage must be reduced in patients in proportion to the reduction in glomerular filtration (e.g., 300 mg/day if creatinine clearance is >90 mL/min, 200 mg/day if creatinine clearance is between 60 and 90 mL/min, 100 mg/day if creatinine clearance is 30-60 mL/min, and 50-100 mg/day if creatinine clearance is <30 mL/min) (Terkeltaub, 2003).

The usual daily dose in children with secondary hyperuricemia associated with malignancies is 150-300 mg, depending on age.

Allopurinol also is useful in lowering the high plasma concentrations of uric acid in patients with Lesch-Nyhan syndrome and thereby prevents the complications resulting from hyperuricemia; there is no evidence that it alters the progressive neurological and behavioral abnormalities that are characteristic of the disease.

Adverse Effects. Allopurinol generally is well tolerated, but the drug occasionally induces drowsiness. The most common adverse effects are hypersensitivity reactions that may manifest after months or years of therapy. Serious hypersensitivity reactions preclude further use of the drug.

The cutaneous reaction caused by allopurinol is predominantly a pruritic, erythematous, or maculopapular eruption, but occasionally the lesion is urticarial or purpuric. Rarely, toxic epidermal necrolysis or Stevens-Johnson syndrome occurs, which can be fatal. The risk for Stevens-Johnson syndrome is limited primarily to the first 2 months of treatment. Because the rash may precede severe hypersensitivity reactions, patients who develop a rash should discontinue allopurinol. If indicated, desensitization to allopurinol can be carried out starting at 10-25 ¨g/day, with the drug diluted in oral suspension and doubled every 3-14 days until the desired dose is reached. This is successful in approximately half of patients (Terkeltaub, 2003). Oxypurinol has orphan drug status and is available for compassionate use in the U.S. for patients intolerant of allopurinol.

Fever, malaise, and myalgias also may occur. Such effects are noted in ∼3% of patients with normal renal function and more frequently in those with renal impairment. Transient leukopenia or leukocytosis and eosinophilia are rare reactions that may require cessation of therapy. Hepatomegaly and elevated levels of transaminases in plasma and progressive renal insufficiency also may occur.

Chemistry. Febuxostat is a two-ring molecule with substituted phenyl and thiazole rings.

Mechanism of Action. Febuxostat is a non-purine inhibitor of xanthine oxidase. While oxypurinol, the active metabolite of allopurinol, inhibits the reduced form of the enzyme, febuxostat forms a stable complex with both the reduced and oxidized enzyme and inhibits catalytic function in both states.

Absorption, Distribution, and Elimination. Febuxostat is rapidly absorbed with maximum plasma concentrations between 1-1.5 hours post-dose. The absorption of radiolabeled compound was estimated to be at least 49%, however, the absolute bioavailability is unknown. Magnesium hydroxide and aluminum hydroxide delay absorption ∼1 hour. Food reduces absorption slightly, but has no clinically significant effect on the reduction of serum uric acid concentration. Febuxostat is highly plasma protein bound and has a volume of distribution of 50 L. It is extensively metabolized by oxidation by CYPs 1A2, 2C8, and 2C9 and non-CYP enzymes conjugation via UGTs 1A1, 1A3, 1A9 and 2B7. The relative contribution of each metabolic route is not known. The oxidation of the isobutyl side chain leads to the formation of four pharmacologically active hydroxy metabolites, all of which occur in plasma at markedly lower concentrations than febuxostat. Febuxostat has a t_1/2 of 5-8 hours and is eliminated by both hepatic and renal pathways. Mild to moderate renal or hepatic impairment does not affect its elimination kinetics relevantly.

Therapeutic Use. Febuxostat (uloric; adneuric [europe]) is approved for hyperuric patients with gout attacks, but not recommended for treatment of asymptomatic hyperuricemia. It is available in 40 and 80-mg oral tablets. Three randomized controlled clinical trials that compared febuxostat with allopurinol showed that 40 mg/day febuxostat lowered serum uric acid to similar levels as 300 mg/day allopurinol. More patients reached the target concentration of 6.0 mg/dL (360 ¨mol/L) on 80 mg/day febuxostat than on 300 mg/day allopurinol (Becker et al., 2005a; Becker et al., 2005b; Schumacher et al., 2008). Thus, therapy should be initiated with 40 mg/day and the dose increased if the target serum uric acid concentration is not reached within 2 weeks.

Common Adverse Events. The most common adverse reactions in clinical studies were liver function abnormalities, nausea, joint pain, and rash. Liver function should be monitored periodically. An increase in gout flares was frequently observed after initiation of therapy, due to reduction in serum uric acid levels resulting in mobilization of urate from tissue deposits. Concurrent prophylactic treatment with an NSAID or colchicine is usually required. There was also a numerically higher rate of myocardial infarction and stroke in patients on febuxostat than on allopurinol. It is currently unknown whether there is a causal relationship between the cardiovascular events and febuxostat therapy or whether these were due to chance. The FDA has imposed as a condition for approval that a prospective study designed to assess the drug's cardiovascular safety be performed. Meanwhile patients should be monitored for cardiovascular complications.

Drug Interactions. Plasma levels of drugs that are metabolized by xanthine oxidase (e.g., theophylline, mercaptopurine, azathioprine) can be expected to increase—possibly to toxic levels—when administered concurrently with febuxostat, although drug interaction studies with these drugs have not been conducted. Thus, febuxostat is contraindicated in patients on azathioprine, mercaptopurine, or theophylline. Based on in vitro studies, interactions between febuxostat and CYP inhibitors are likely, but interactions studies have not been performed in humans.

Produced by a genetically modified Saccharomyces cerevisiae strain, the therapeutic efficacy may be hampered by the production of antibodies against the drug. Hemolysis in glucose-6-phosphate dehydrogenase (G6PD)-deficient patients, methemoglobinemia, acute renal failure, and anaphylaxis have been associated with the use of rasburicase. Other frequently observed adverse reactions include vomiting, fever, nausea, headache, abdominal pain, constipation, diarrhea, and mucositis. Rasburicase causes enzymatic degradation of the uric acid in blood samples, and special handling is required to prevent spuriously low values for plasma uric acid in patients receiving the drug. The recommended dose of rasburicase is 0.15 mg/kg or 0.2 mg/kg as a single daily dose for 5 days, with chemotherapy initiated 4-24 hours after infusion of the first rasburicase dose.

URAT-1 exchanges urate for either an organic anion such as lactate or nicotinate or less potently for an inorganic anion such as chloride. The monocarboxylate metabolite of the anti-tuberculous drug pyrazinamide, an organic anion, is a potent stimulator of urate reuptake. Uricosuric drugs such as probenecid, sulfinpyrazone, benzbromarone, and losartan compete with urate for the transporter, thereby inhibiting its reabsorption via the urate–anion exchanger system. However, transport is bidirectional, and depending on dosage, some drugs, including salicylates, may either decrease or increase the excretion of uric acid. Decreased excretion usually occurs at a low dosage, while increased excretion is observed at a higher dosage. Not all agents show this phenomenon, and one uricosuric drug may either add to or inhibit the action of another.

Two mechanisms for a drug-induced decrease in urinary excretion of urate have been advanced; they are not mutually exclusive. The first presumes that the small secretory movement of urate is inhibited by very low concentrations of the drug. Higher concentrations may inhibit urate reabsorption in the usual manner. The second proposal suggests that the urate-retaining anionic drug gains access to the intracellular fluid by an independent mechanism and promotes reabsorption of urate across the brush border by anion exchange.

There also are two mechanisms by which one drug may nullify the uricosuric action of another. First, the drug may inhibit the secretion of the uricosuric agent, thereby denying it access to its site of action, the luminal aspect of the brush border. Second, the inhibition of urate secretion by one drug may counterbalance the inhibition of urate reabsorption by the other.

Many compounds have incidental uricosuric activity by acting as exchangeable anions, but only probenecid is prescribed routinely for this purpose. Sulfinpyrazone has been withdrawn from the U.S. market (see the previous edition of this book for the pharmacology of sulfinpyrazone). Benzbromarone is an alternative uricosuric agent that is available in the E.U. Conversely, a number of drugs and toxins cause retention of urate; these have been reviewed elsewhere (Maalouf et al., 2004). The angiotensin II–receptor antagonist, losartan, has a modest uricosuric effect and may be an option for those who are intolerant to probenecid and are hypertensive.

Mechanism of Action

Inhibition of Organic Acid Transport. The actions of probenecid are confined largely to inhibition of the transport of organic acids across epithelial barriers. When tubular secretion of a substance is inhibited, its final concentration in the urine is determined by the degree of filtration, which in turn is a function of binding to plasma protein, and by the degree of reabsorption. The significance of each of these factors varies widely with different compounds. Usually, the end result is decreased tubular secretion of the compound, leading to decreased urinary and increased plasma concentration. Probenecid inhibits the reabsorption of uric acid by organic anion transporters, principally URAT-1. Uric acid is the only important endogenous compound whose excretion is known to be increased by probenecid. The uricosuric action of probenecid is blunted by the co-administration of salicylates.

Inhibition of Transport of Miscellaneous Substances. Probenecid inhibits the tubular secretion of a number of drugs, such as methotrexate and the active metabolite of clofibrate. It inhibits renal secretion of the inactive glucuronide metabolites of NSAIDs such as naproxen, ketoprofen, and indomethacin, and thereby can increase their plasma concentrations.

Inhibition of Monoamine Transport to CSF. Probenecid inhibits the transport of 5-hydroxyindoleacetic acid (5-HIAA) and other acidic metabolites of cerebral monoamines from the CSF to the plasma. The transport of drugs such as penicillin G also may be affected.

Inhibition of Biliary Excretion. Probenecid depresses the biliary secretion of certain compounds, including the diagnostic agents indocyanine green and bromosulfophthalein (BSP). It also decreases the biliary secretion of rifampin, leading to higher plasma concentrations.

Absorption, Distribution, and Elimination. Probenecid is absorbed completely after oral administration. Peak concentrations in plasma are reached in 2-4 hours. The t_1/2 of the drug in plasma is dose dependent and varies from <5 hours to >8 hours over the therapeutic range. Between 85% and 95% of the drug is bound to plasma albumin. The 5-15% of unbound drug is cleared by glomerular filtration. The majority of the drug is secreted actively by the proximal tubule. The high lipid solubility of the undissociated form results in virtually complete absorption by backdiffusion unless the urine is markedly alkaline. A small amount of probenecid glucuronide appears in the urine. It also is hydroxylated to metabolites that retain their carboxyl function and have uricosuric activity.

Therapeutic Uses (Gout). Probenecid [probalan, benuryl (u.k.)] is marketed for oral administration. The starting dose is 250 mg twice daily, increasing over 1-2 weeks to 500-1000 mg twice daily. Probenecid increases urinary urate levels. Liberal fluid intake therefore should be maintained throughout therapy to minimize the risk of renal stones. Probenecid should not be used in gouty patients with nephrolithiasis or with overproduction of uric acid. Concomitant colchicine or NSAIDs are indicated early in the course of therapy to avoid precipitating an attack of gout, which may occur in ≤20% of gouty patients treated with probenecid alone.

Combination with Penicillin. Probenecid was developed for the purpose of delaying the excretion of penicillin. Higher doses of probenecid are used as an adjuvant to prolong penicillin concentrations. This dosing method usually is confined to those being treated for gonorrhea or neurosyphilis infections or to cases in which penicillin resistance may be an issue (see Chapter 53).

Common Adverse Effects. Probenecid is well tolerated. Approximately 2% of patients develop mild GI irritation. The risk is increased at higher doses, and caution should be used in those with a history of peptic ulcer. It is ineffective in patients with renal insufficiency and should be avoided in those with creatinine clearance of <50 mL/min. Hypersensitivity reactions usually are mild and occur in 2-4% of patients. Serious hypersensitivity is extremely rare. The appearance of a rash during the concurrent administration of probenecid and penicillin G presents the physician with an awkward diagnostic dilemma. Substantial overdosage with probenecid results in CNS stimulation, convulsions, and death from respiratory failure.

Benzbromarone

Benzbromarone is a potent uricosuric agent that is used in Europe. It was withdrawn from the market in Europe in 2003, but was registered again with restrictions in some countries in 2004. Hepatotoxicity has been reported in conjunction with its use. The drug is absorbed readily after oral ingestion, and peak concentrations in blood are achieved in ∼4 hours. It is metabolized to monobromine and dehalogenated derivatives, both of which have uricosuric activity, and is excreted primarily in the bile. The uricosuric action is blunted by aspirin or sulfinpyrazone. No paradoxical retention of urate has been observed. It is a potent and reversible inhibitor of the urate–anion exchanger in the proximal tubule. As the micronized powder, it is effective in a single daily dose of 40-80 mg. It is effective in patients with renal insufficiency and may be prescribed to patients who are either allergic or refractory to other drugs used for the treatment of gout. Preparations that combine allopurinol and benzbromarone are more effective than either drug alone in lowering serum uric acid levels, in spite of the fact that benzbromarone lowers plasma levels of oxypurinol, the active metabolite of allopurinol.