The chapter describes the nonsteroidal anti-inflammatory drugs (NSAIDs) used to treat inflammation, pain, and fever and the drugs used for hyperuricemia and gout. The NSAIDS are first considered by class, then by groups of chemically similar agents described in more detail. Many of the basic properties of these drugs are summarized in Tables 34–2, 34–3, and34–4. Most currently available traditional NSAIDs (tNSAIDs) act by inhibiting the prostaglandin (PG) G/H synthase enzymes, colloquially known as the cyclooxygenases (COXs; seeChapter 33). The inhibition of cyclooxygenase-2 (COX-2) is thought to mediate, in large part, the antipyretic, analgesic, and anti-inflammatory actions of tNSAIDs, while the simultaneous inhibition of cyclooxygenase-1 (COX-1) largely but not exclusively accounts for unwanted adverse effects in the GI tract. Selective inhibitors of COX-2 (celecoxib, etoricoxib, lumiracoxib) are a subclass of NSAIDs. Aspirin irreversibly acetylates COX; several structural subclasses of tNSAIDs, including propionic acid derivatives (ibuprofen, naproxen), acetic acid derivatives (indomethacin), and enolic acids (piroxicam) compete in a reversible manner with arachidonic acid (AA) at the active site of COX-1 and COX-2. Acetaminophen (paracetamol) is effective as an antipyretic and analgesic agent at typical doses that partly inhibit COXs, has only weak anti-inflammatory activity, and exhibits fewer GI side effects than the tNSAIDs.
INFLAMMATION, PAIN, AND FEVER
INFLAMMATION. The inflammatory process is the response to an injurious stimulus. It can be evoked by noxious agents, infections, antibodies, physical injuries. The ability to mount an inflammatory response is essential for survival in the face of environmental pathogens and injury; in some situations and diseases, the inflammatory response may be exaggerated and sustained without apparent benefit and even with severe adverse consequences. The inflammatory response is characterized mechanistically by:
• Transient local vasodilation and increased capillary permeability
• Infiltration of leukocytes and phagocytic cells
• Tissue degeneration and fibrosis
Many molecules are involved in the promotion and resolution of the inflammatory process. Histamine, bradykinin, 5-HT, prostanoids, leukotrienes (LTs), and platelet-activating factor are important mediators of inflammation (see Chapter 33).
Prostanoid biosynthesis is significantly increased in inflamed tissue. Inhibitors of the COXs, which depress prostanoid formation, are effective and widely used anti-inflammatory agents. Prostaglandin E2 (PGE2) and prostacyclin (PGI2) are the primary prostanoids that mediate inflammation. They increase local blood flow, vascular permeability, and leukocyte infiltration through activation of their respective receptors, EP2 and IP. PGD2, a major product of mast cells, contributes to inflammation in allergic responses, particularly in the lung.
Activation of endothelial cells plays a key role in “targeting” circulating cells to inflammatory sites. Endothelial activation results in leukocyte adhesion as the leukocytes recognize newly expressed L- and P-selectin and E-selectin with sialylated Lewis X and other glycoproteins on the leukocyte surface and endothelial intercellular adhesion molecule-1 (ICAM-1) with leukocyte integrins.
The recruitment of inflammatory cells to sites of injury also involves the concerted interactions of several types of soluble mediators. These include the complement factor C5a, PAF, and the eicosanoid LTB4 (see Chapter 33). All can act as chemotactic agonists. Several cytokines also play essential roles in orchestrating the inflammatory process, especially tumor necrosis factor (TNF) and interleukin-1 (IL-1). Other cytokines and growth factors (e.g., IL-2, IL-6, IL-8, GM-CSF) contribute to manifestations of the inflammatory response. The concentrations of many of these factors are increased in the synovia of patients with inflammatory arthritis. Glucocorticoids interfere with the synthesis and actions of cytokines, such as IL-1 or TNF-t (see Chapter 35). Although some of the actions of these cytokines are accompanied by the release of PGs and thromboxane A2 (TxA2), cyclooxygenase (COX) inhibitors appear to block only their pyrogenic effects.
PAIN. Inflammatory mediators released from nonneuronal cells during tissue injury increase the sensitivity of nociceptors and potentiate pain perception. Among these mediators are bradykinin, H+, 5-HT, ATP, neurotrophins (nerve growth factor), LTs, and PGs. PGE2 and PGI2 reduce the threshold to stimulation of nociceptors, causing peripheral sensitization. Centrally active PGE2 and perhaps also PGD2, PGI2, and PGF2α contribute to central sensitization, an increase in excitability of spinal dorsal horn neurons that causes hyperalgesia and allodynia in part by disinhibition of glycinergic pathways.
FEVER. The hypothalamus regulates the set point at which body temperature is maintained. This set point is elevated in fever, reflecting an infection, or resulting from tissue damage, inflammation, graft rejection, or malignancy. These conditions all enhance formation of cytokines such as IL-1 β, IL-6, TNF-α, and interferons, which act as endogenous pyrogens. The initial phase of the thermoregulatory response to such pyrogens may be mediated by ceramide release in neurons of the preoptic area in the anterior hypothalamus. A late response is mediated by coordinate induction of COX-2 and formation of PGE2. PGE2 can cross the blood-brain barrier and acts on EP3 and perhaps EP1 receptors on thermosensitive neurons. This triggers the hypothalamus to elevate body temperature by promoting an increase in heat generation and a decrease in heat loss. NSAIDs suppress this response by inhibiting PGE2 synthesis.
NONSTEROIDAL ANTI-INFLAMMATORY DRUGS
NSAIDs are classified as tNSAIDs, which inhibit both COX-1 and COX-2, and COX-2–selective NSAIDs. Most NSAIDs are competitive, reversible, active site inhibitors of the COX enzymes. However, aspirin (acetyl salicylic acid, ASA) acetylates the isozymes and inhibits them irreversibly; thus, aspirin often is distinguished from the tNSAIDs. Similarly, acetaminophen, which is antipyretic and analgesic but largely devoid of anti-inflammatory activity, also is conventionally segregated from the group.
The vast majority of tNSAID compounds are organic acids with relatively low pKa values (Figure 34–1). Even the nonacidic 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. 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.
Figure 34–1 Classification of NSAIDs by chemical similarity (panel A), cyclooxygenase (COX) isoform selectivity (panel B), and plasma t1/2 (panel C). The COX selectivity chart is plotted from data published in Warner et al., 1999, and FitzGerald and Patrono, 2001. tNSAIDs, traditional nonsteroidal anti-inflammatory drugs.
MECHANISM OF ACTION
CYCLOOXYGENASE INHIBITION. The principal therapeutic effects of NSAIDs derive from their ability to inhibit PG production. The first enzyme in the PG synthetic pathway is COX, also known as PG G/H synthase. This enzyme converts AA to the unstable intermediates PGG2 and PGH2 and leads to the production of the prostanoids, TxA2, and a variety of PGs (see Chapter 33). There are 2 forms of COX, COX-1 and COX-2. COX-1, expressed constitutively in most cells, is the dominant source of prostanoids for housekeeping functions. Conversely, COX-2, induced by cytokines, shear stress, and tumor promoters, is the more important source of prostanoid formation in inflammation and perhaps in cancer (see Chapter 33). COX-1 is the dominant isoform in gastric epithelial cells and is thought to be the major source of cytoprotective PG formation. Inhibition of COX-1 accounts for the gastric adverse events that complicate therapy with tNSAIDs.
Aspirin and NSAIDs inhibit the COX enzymes and PG production; they do not inhibit the lipoxygenase (LOX) pathways of AA metabolism and hence do not suppress LT formation (see Chapter 33).
IRREVERSIBLE CYCLOOXYGENASE INHIBITION BY ASPIRIN. Aspirin covalently modifies COX-1 and COX-2, irreversibly inhibiting COX activity. This is an important distinction from all the NSAIDs because the duration of aspirin’s effects is related to the turnover rate of COXs in different target tissues.
The importance of enzyme turnover in recovery from aspirin action is most notable in platelets, which, being anucleate, have a markedly limited capacity for protein synthesis. Thus, the consequences of inhibition of platelet COX-1 last for the lifetime of the platelet. Inhibition of platelet COX-1–dependent TxA2 formation therefore is cumulative with repeated doses of aspirin (at least as low as 30 mg/day) and takes ~8-12 days (the platelet turnover time) to recover fully once therapy has been stopped. 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. In contrast to aspirin, salicylic acid has no acetylating capacity. It is a weak, reversible, competitive inhibitor of COX.
SELECTIVE INHIBITION OF CYCLOOXYGENASE-2. The therapeutic use of the tNSAIDs is limited by their poor GI tolerability. Since COX-1 was the predominant source of cytoprotective PGs formed by the GI epithelium, selective inhibitors of COX-2 were developed to afford efficacy similar to tNSAIDs with better GI tolerability. Six COX-2 inhibitors, the coxibs, were initially approved for use: celecoxib, rofecoxib, valdecoxib and its prodrug parecoxib, etoricoxib, and lumiracoxib. Most coxibs have been either restricted in their use or withdrawn from the market in view of their adverse event profile. Celecoxib (CELEBREX) currently is the only COX-2 inhibitor licensed for use in the U.S.
NSAIDs are rapidly absorbed following oral ingestion, and peak plasma concentrations are reached within 2-3 h. Food intake may delay absorption and systemic availability (i.e., fenoprofen, sulindac). Antacids, commonly prescribed to patients on NSAID therapy, variably delay, absorption. Some compounds (e.g., diclofenac, nabumetone) undergo first-pass or presystemic elimination. Aspirin begins to acetylate platelets within minutes of reaching the presystemic circulation.
Most NSAIDs are extensively bound to plasma proteins (95-99%), usually albumin. 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). Most NSAIDs achieve sufficient concentrations in the CNS to have a central analgesic effect. Celecoxib is particularly lipophilic and moves readily into the CNS. Lumiracoxib is more acidic than other COX-2–selective NSAIDs, which may favor its accumulation at sites of inflammation.
Plasma t1/2 varies considerably among NSAIDs. Ibuprofen, diclofenac, and acetaminophen have t1/2 of 1-4 h, while piroxicam has a t1/2 of 50 h at steady state. The t1/2 of COX-2–selective NSAIDs vary (2-6 h for lumiracoxib, 6-12 h for celecoxib, and 20-26 h for etoricoxib). Hepatic biotransformation and renal excretion are the principal routes of metabolism and elimination of the majority of NSAIDs. Acetaminophen, at therapeutic doses, is oxidized only to a small degree to form traces of the highly reactive metabolite, N-acetyl-p-benzoquinone imine (NAPQI). Following overdose (usually >10 g of acetaminophen), however, the principal metabolic pathways are saturated, and hepatotoxic NAPQI concentrations can be formed (see Figure 4–5). Rarely, other NSAIDs also may be complicated by hepatotoxicity (e.g., diclofenac, lumiracoxib). NSAIDs usually are not removed by hemodialysis due to their extensive plasma protein binding; salicylic acid is an exemption to this rule. NSAIDs are not recommended in advanced hepatic or renal disease.
All NSAIDs are antipyretic, analgesic, and anti-inflammatory, with the exception of acetaminophen, which is antipyretic and analgesic but is largely devoid of anti-inflammatory activity.
INFLAMMATION. NSAIDs provide mostly symptomatic relief from pain and inflammation associated with musculoskeletal disorders, such as rheumatoid arthritis and osteoarthritis. Some NSAIDs are approved for the treatment of ankylosing spondylitis and gout.
PAIN. NSAIDs are effective only against pain of low to moderate intensity. Although their maximal efficacy is much less than the opioids, NSAIDs lack the unwanted adverse effects of opiates. Coadministration of NSAIDs can reduce the opioid dose needed for sufficient pain control and reduce the likelihood of adverse opioid effects. NSAIDs are particularly effective when inflammation has caused peripheral and/or central sensitization of pain perception. An exception to this is menstrual pain. The release of PGs by the endometrium during menstruation may cause severe cramps and other symptoms of primary dysmenorrhea; treatment of this condition with NSAIDs has met with considerable success. NSAIDs are commonly used to treat migraine attacks and can be combined with drugs such as the triptans (e.g., TREXIMET, a fixed-dose combination of naproxen and sumatriptan) or with antiemetics to aid relief of the associated nausea. NSAIDs lack efficacy in neuropathic pain.
FEVER. Antipyretic therapy is reserved for patients in whom fever in itself may be deleterious and for those who experience considerable relief when fever is lowered. NSAIDs reduce fever in most situations, but not the circadian variation in temperature or the rise in response to exercise or increased ambient temperature. COX-2 is the dominant source of PGs that mediate the rise in temperature evoked by bacterial lipopolysaccharide (LPS) administration.
FETAL CIRCULATORY SYSTEM. PGs are implicated in the maintenance of patency of the ductus arteriosus, and indomethacin, ibuprofen, and other tNSAIDs have been used in neonates to close the inappropriately patent ductus.
CARDIOPROTECTION. Ingestion of aspirin prolongs bleeding time. This effect is due to irreversible acetylation of platelet COX and the consequent inhibition of platelet function. It is the permanent suppression of platelet TxA2 formation that is thought to underlie the cardioprotective effect of aspirin.
Aspirin reduces the risk of serious vascular events in high-risk patients (e.g., those with previous myocardial infarction) by 20-25%. Low-dose (<100 mg/day) aspirin is relatively selective for COX-1 and is associated with a lower risk for GI adverse events. However, low-dose aspirin increases the incidence of serious GI bleeds. It also increases the incidence of intracranial bleeds. The benefit from aspirin outweighs these risks in the case of secondary prevention of cardiovascular disease. Given their relatively short t1/2 and reversible COX inhibition, most other tNSAIDs are not thought to afford cardioprotection. Data suggest that cardioprotection is lost when combining low-dose aspirin with ibuprofen. 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 is the major mediator of severe episodes of flushing, vasodilation, and hypotension. The addition of aspirin or ketoprofen has provided relief. 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 induces intense facial flushing mediated largely by release of PGD2 from the skin, which can be inhibited by treatment with aspirin.
Cancer Chemoprevention. Epidemiological studies suggested that frequent use of aspirin is associated with as much as a 50% decrease in the risk of colon cancer. Similar observations have been made with NSAID use in this and other cancers.
ADVERSE EFFECTS OF NSAID THERAPY
Common adverse events of aspirin and NSAIDs are outlined in Table 34–1.
Common and Shared Side Effects of NSAIDs
GASTROINTESTINAL. The most common symptoms associated with these drugs are GI, including anorexia, nausea, dyspepsia, abdominal pain, and diarrhea. These symptoms may be related to the induction of gastric or intestinal ulcers, which is estimated to occur in 15-30% of regular users. Ulceration may be complicated by bleeding, perforation, or obstruction. The risk is further increased in those with Helicobacter pylori infection, heavy alcohol consumption, or other risk factors for mucosal injury, including the concurrent use of glucocorticoids. All selective COX-2 inhibitors are less prone to induce gastric ulcers than equally efficacious doses of tNSAIDs.
CARDIOVASCULAR. COX-2–selective NSAIDs were developed to improve the GI safety. However, clinical trials—with celecoxib, valdecoxib (withdrawn), and rofecoxib (withdrawn)—revealed an increase in the incidence of myocardial infarction, stroke, and thrombosis. COX-2-inhibitors depress formation of PGI2 but do not inhibit COX-1 catalyzed formation of platelet thromboxane TxA2. PGI2inhibits platelet aggregation and constrains the effect of prothrombotic and atherogenic stimuli by TxA2.
BLOOD PRESSURE, RENAL, AND RENOVASCULAR ADVERSE EVENTS. NSAIDs and COX-2 inhibitors have been associated with renal and renovascular adverse events. In patients with congestive heart failure, hepatic cirrhosis, chronic kidney disease, hypovolemia, and other states of activation of the sympathoadrenal or renin–angiotensin systems, PG formation becomes crucial. NSAIDs are associated with loss of the PG-induced inhibition of both the reabsorption of Cl– and the action of antidiuretic hormone, leading to the retention of salt and water. Epidemiological studies suggest hypertensive complications occur more commonly in patients treated with coxibs than with tNSAIDs.
ANALGESIC NEPHROPATHY. Analgesic nephropathy is a condition of slowly progressive renal failure, decreased concentrating capacity of the renal tubule, and sterile pyuria. Risk factors are the chronic use of high doses of combinations of NSAIDs and frequent urinary tract infections.
PREGNANCY AND LACTATION. Myometrial COX-2 expression and levels of PGE2 and PGF2α increase markedly in the myometrium during labor. Prolongation of gestation by NSAIDs has been demonstrated in humans. Some NSAIDs, particularly indomethacin, have been used off-label to terminate preterm labor. However, this use is associated with closure of the ductus arteriosus and impaired fetal circulation in utero, particularly in fetuses older than 32 weeks’ gestation. COX-2–selective inhibitors have been used off-label as tocolytic agents; this use has been associated with stenosis of the ductus arteriosus and oligohydramnios. Finally, the use of NSAIDs and aspirin late in pregnancy may increase the risk of postpartum hemorrhage. Therefore, pregnancy, especially close to term, is a relative contraindication to the use of all NSAIDs. In addition, their use must be weighed against potential fetal risk, even in cases of premature labor, and especially in cases of pregnancy-induced hypertension.
HYPERSENSITIVITY. Hypersensitivity symptoms to aspirin and NSAIDs range from vasomotor rhinitis, generalized urticaria, and bronchial asthma to laryngeal edema, bronchoconstriction, flushing, hypotension, and shock. Aspirin intolerance is a contraindication to therapy with any other NSAID because cross-sensitivity. Treatment of aspirin hypersensitivity is similar to that of other severe hypersensitivity reactions, with support of vital organ function and administration of epinephrine.
ASPIRIN RESISTANCE. All forms of treatment failure with aspirin have been collectively called aspirin resistance. Genetic variants of COX-1 that cosegregate with resistance have been described, but the relation to clinical outcome is not clear.
REYE SYNDROME. Due to the possible association with Reye syndrome, aspirin and other salicylates are contraindicated in children and young adults < 20 years of age with viral illness–associated fever. Reye syndrome, a severe and often fatal disease, is characterized by the acute onset of encephalopathy, liver dysfunction, and fatty infiltration of the liver and other viscera. Although a mechanistic understanding is lacking, the epidemiologic association between aspirin use and Reye syndrome is sufficiently strong that aspirin and bismuth subsalicylate labels now must indicate the risk. As the use of aspirin in children has declined dramatically, so has the incidence of Reye syndrome. Acetaminophen has not been implicated in Reye syndrome and is the drug of choice for antipyresis in children and young adults.
CONCOMITANT NSAIDS AND LOW-DOSE ASPIRIN. Many patients combine either tNSAIDs or COX-2 inhibitors with low-dose aspirin for “cardioprotection.” Epidemiological studies suggest that this combination therapy increases significantly the likelihood of GI adverse events over either class of NSAID alone.
Angiotensin-converting enzyme (ACE) inhibitors act, at least partly, by preventing the breakdown of kinins that stimulate PG production (see Figure 32–2). Thus, it is logical that NSAIDs might attenuate the effectiveness of ACE inhibitors by blocking the production of vasodilator and natriuretic PGs. Due to hyperkalemia, the combination of NSAIDs and ACE inhibitors also can produce marked bradycardia leading to syncope, especially in the elderly and in patients with hypertension, diabetes mellitus, or ischemic heart disease. Corticosteroids and SSRIs may increase the frequency or severity of GI complications when combined with NSAIDs. NSAIDs may augment the risk of bleeding in patients receiving warfarin both because almost all tNSAIDs suppress normal platelet function temporarily during the dosing interval and because some NSAIDs also increase warfarin levels by interfering with its metabolism. Many NSAIDs are highly bound to plasma proteins and thus may displace other drugs from their binding sites. Such interactions can occur in patients given salicylates or other NSAIDs together with warfarin, sulfonylurea hypoglycemic agents, or methotrexate; the dosage of such agents may require adjustment to prevent toxicity. Patients taking lithium should be monitored because certain NSAIDs (e.g., piroxicam) can reduce the renal excretion of this drug and lead to toxicity, while others can decrease lithium levels (e.g., sulindac).
PEDIATRIC AND GERIATRIC USE
THERAPEUTIC USES IN CHILDREN. Therapeutic indications for NSAID use in children include fever, mild pain, postoperative pain, and inflammatory disorders, such as juvenile arthritis and Kawasaki disease. Only drugs that have been extensively tested in children should be used (acetaminophen, ibuprofen, and naproxen).
PHARMACOKINETICS IN CHILDREN. NSAID dosing recommendations frequently are based on extrapolation of pharmacokinetic data from adults or children >2 years, and there is often 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 (sulfation is the principal route of biotransformation at this age). Therefore, acetaminophen dosing intervals need to be extended (8-12 h) 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. The clearance of many NSAIDs is reduced in the elderly due to changes in hepatic metabolism. NSAIDs with a long t1/2 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 than in patients <50 years of age, warranting dose adjustment. The capacity of plasma albumin to bind drugs is diminished in older patients and may result in higher concentrations of unbound NSAIDs. The higher susceptibility of older patients to GI complications may be due to 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.
SPECIFIC PROPERTIES OF INDIVIDUAL NSAIDS
General properties shared by NSAIDs were considered in the preceding section, “Nonsteroidal Anti-Inflammatory Drugs.” In this section, important characteristics of individual substances are discussed. NSAIDs are grouped by their chemical similarity, as in Figure 34–1.
ASPIRIN AND OTHER SALICYLATES
The salicylates include, aspirin, salicylic acid, methyl salicylate, diflunisal, salsalate, olsalazine, and sulfasalazine. Aspirin is the most widely consumed analgesic, antipyretic, and anti-inflammatory agent. Because aspirin is so available, the possibility of misuse and serious toxicity is underappreciated.
Salicylic acid is so irritating that it can only be used externally; therefore various derivatives of this acid have been synthesized for systemic use. For example, aspirin is the acetate ester of salicylic acid. Table 34–2 summarizes the clinical pharmacokinetic properties of 2 salicylates, aspirin and diflunisal.
Comparison of NSAIDS: Salicylates, Acetaminophen, and Acetic Acid Derivatives
MECHANISM OF ACTION
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,” above.
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 min; after a single dose, the peak plasma level is reached in ~1 h and then declines gradually. The rate of absorption is determined by disintegration and dissolution rates of the tablets administered, the pH at the mucosal surface, and gastric emptying time. 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 out of the CSF across the choroid plexus. The drugs readily cross the placental barrier. 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. Roughly 80-90% of the salicylate in plasma is bound to proteins, especially albumin; 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 ε-amino group of lysine and may change the binding of other drugs to albumin. Aspirin also acetylates hormones, DNA, and hemoglobin and other proteins.
METABOLISM AND ELIMINATION. The 3 chief metabolic products are salicyluric acid (the glycine conjugate), the ether or phenolic glucuronide, and the ester or acyl glucuronide. Salicylates and their metabolites are excreted in the urine The excretion of free salicylates is variable and depends on the dose and the urinary pH. For example, the clearance of salicylate is about 4 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. The plasma t1/2 for aspirin is ~20 min, and for salicylate is 2-3 h at antiplatelet doses, rising to 12 h at usual anti-inflammatory doses. The t1/2 of salicylate may rise to 15-30 h 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 clearance is reduced and salicylate exposure is significantly increased 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).
SYSTEMIC USES. The analgesic–antipyretic dose of aspirin for adults is 324-1000 mg orally every 4-6 h. The anti-inflammatory doses of aspirin recommended for arthritis, spondyloarthropathies, and systemic lupus erythematosus (SLE) range from 3-4 g/day in divided doses. 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. Salicylates suppress clinical signs and improve tissue inflammation in acute rheumatic fever. Other salicylates available for systemic use include salsalate (salicylsalicylic acid), magnesium salicylate, and a combination of choline salicylate and magnesium salicylate (choline magnesium–trisalicylate).
Diflunisal is a difluorophenyl derivative of salicylic acid that is not converted to salicylic acid in vivo. Diflunisal is a competitive inhibitor of COX, it is a potent anti-inflammatory but is largely devoid of antipyretic effects, perhaps because of poor penetration into the CNS. The drug has been used as an analgesic in the treatment of osteoarthritis and musculoskeletal strains or sprains; in these circumstances, it is 3-4 times more potent than aspirin. The usual initial dose is 1000 mg, followed by 500 mg every 8-12 h. Diflunisal produces fewer auditory side effects (see “Ototoxic Effects”) and appears to cause fewer 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 Figure 47–4). Oral formulations that deliver drug to the lower intestine are efficacious in the treatment of inflammatory bowel disease (in particular, ulcerative colitis). These preparations rely on pH-sensitive coatings and other delayed release mechanisms, such as linkage to another moiety to create a poorly absorbed parent compound that must be cleaved by bacteria in the colon to form the active drug. 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. 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, a result of uncoupling oxidative phosphorylation. The increased production of CO2 stimulates respiration. Salicylates also stimulate the respiratory center directly in the medulla. Respiratory rate and depth increases, the Pco2 falls, and primary respiratory alkalosis ensues.
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, 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. 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 capacity to acetylate COX and irreversibly inhibit its activity, they are weaker inhibitors than aspirin.
HEPATIC EFFECTS. Salicylates can cause hepatic injury, usually after high doses of salicylates that result in plasma concentrations of >150 μg/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 implicates the use of salicylates as an important factor in the severe hepatic injury and encephalopathy observed in Reye 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.
HEMATOLOGIC EFFECTS. Irreversible inhibition of platelet function underlies the cardioprotective effect of 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 (percutaneous coronary intervention) 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. Aspirin is used widely for the prophylaxis of thromboembolic disease.
OTOTOXIC EFFECTS. Hearing impairment, alterations of perceived sounds, and tinnitus commonly occur during high-dose salicylate therapy. Ototoxic symptoms sometimes are observed at low doses. Symptoms usually resolve within 2 or 3 days after withdrawal of the drug. 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, and complicated deliveries; thus, its use during this period should be avoided. NSAIDs during the third trimester of pregnancy also can cause premature closure of the ductus arteriosus.
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 above (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. Death has followed use of 10-30 g of sodium salicylate or aspirin in adults, but much larger amounts (130 g of aspirin in 1 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 4 mL (4.7 g) of methyl salicylate may cause severe systemic toxicity in children. 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.
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 (described above). Uncoupling of oxidative phosphorylation also leads to excessive heat production, and salicylate toxicity is associated with hyperthermia, particularly in children. 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.
ACID–BASE BALANCE AND ELECTROLYTES. High therapeutic doses of salicylate are associated with a primary respiratory alkalosis and compensatory renal acidosis. 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 3 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 low plasma Pco2 leads to decreased renal tubular reabsorption of bicarbonate and increased renal excretion of Na+, K+, and water. 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.
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. 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).
Acetaminophen (paracetamol; TYLENOL, others) is the active metabolite of phenacetin.
Acetaminophen is available without a prescription and is used as a common household analgesic. It also is available in fixed-dose combinations containing narcotic and nonnarcotic analgesics (including aspirin and other salicylates), barbiturates, caffeine, vascular headache remedies, sleep aids, toothache remedies, antihistamines, antitussives, decongestants, expectorants, cold and flu preparations, and sore throat treatments. Acetaminophen is well tolerated and has a low incidence of GI side effects. However, acute overdosage can cause severe hepatic damage (see Figure 4–4), and the number of poisonings with acetaminophen continues to grow.
MECHANISM OF ACTION
Acetaminophen has analgesic and antipyretic effects similar to those of aspirin, but only weak anti-inflammatory effects. Acetaminophen is postulated to have a poor ability to inhibit COX isoforms in the presence of high concentrations of peroxides, as occur at sites of inflammation. COX inhibition might be disproportionately pronounced in the brain, explaining its antipyretic efficacy.
Oral acetaminophen has excellent bioavailability. Peak plasma concentrations occur within 30-60 min, and the t1/2 in plasma is ~2 h. 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 drug may be recovered in the urine within the first day at therapeutic dosing, primarily after hepatic conjugation with glucuronic acid (see Table 34–2). Children have less capacity for glucuronidation of the drug than do adults. A small proportion of acetaminophen undergoes CYP-mediatedN-hydroxylation to form NAPQI, a highly reactive intermediate.
Acetaminophen is suitable for analgesic or antipyretic uses; it is particularly valuable for patients in whom aspirin is contraindicated (e.g., those with peptic ulcer, aspirin hypersensitivity, children with a febrile illness). The conventional oral dose of acetaminophen is 325-650 mg every 4-6 h; total daily doses should not exceed 4000 mg (2000 mg/day for chronic alcoholics). Single doses for children 2-11 years old range from 160-480 mg, depending on age and weight; no more than 5 doses should be administered in 24 h. A dose of 10 mg/kg also may be used. An injectable preparation is now available (see recent review on the Goodman & Gilman website at AccessMedicine.com).
ADVERSE EFFECTS AND TOXICITY
Acetaminophen usually is well tolerated. Rash and other allergic reactions occur occasionally, 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 most serious acute adverse effect of overdosage of acetaminophen is a potentially fatal hepatic necrosis. Hepatic injury with acetaminophen involves its conversion to the toxic metabolite, NAPQI. The glucuronide and sulfate conjugation pathways become saturated, and increasing amounts undergo CYP-mediated N-hydroxylation to form NAPQI. This is eliminated rapidly by conjugation with GSH and then further metabolized to a mercapturic acid and excreted into the urine. In the setting of acetaminophen overdose, hepatocellular levels of GSH become depleted. The highly reactive NAPQI metabolite binds covalently to cell macromolecules, leading to dysfunction of enzymatic systems and structural and metabolic disarray. Furthermore, depletion of intracellular GSH renders the hepatocytes highly susceptible to oxidative stress and apoptosis (see Figure 4–4). Renal tubular necrosis and hypoglycemic coma also may occur.
MANAGEMENT OF ACETAMINOPHEN OVERDOSE. Severe liver damage occurs in 90% of patients with plasma concentrations of acetaminophen >300 μg/mL at 4 h or 45 μg/mL at 15 h after the ingestion of the drug. Activated charcoal, if given within 4 h 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 functions by detoxifying NAPQI. It both repletes GSH stores and may conjugate directly with NAPQI by serving as a GSH substitute. 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.
ACETIC ACID DERIVATIVES
Indomethacin (INDOCIN, others) is indicated for the treatment of moderate to severe rheumatoid arthritis, osteoarthritis, and acute gouty arthritis; ankylosing spondylitis; and acute painful shoulder. Indomethacin is a more potent nonselective inhibitor of the COXs than is aspirin; it also inhibits the motility of polymorphonuclear leukocytes, depresses the biosynthesis of mucopolysaccharides, and may have a direct, COX-independent vasoconstrictor effect. Indomethacin has prominent anti-inflammatory and analgesic–antipyretic properties similar to those of the salicylates. The ADME data for indomethacin are summarized in Table 34–2.
THERAPEUTIC USES. Indomethacin is estimated to be ~20 times more potent than aspirin. A high rate of intolerance limits the long-term analgesic use of indomethacin. Indomethacin is 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. 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/h.
ADVERSE EFFECTS AND DRUG INTERACTIONS. A very high percentage (35%-50%) of patients receiving indomethacin experience untoward symptoms. 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 is severe frontal headache. 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.
Sulindac (CLINORIL, others) is a congener of indomethacin. Sulindac, which is less than half as potent as indomethacin, is a prodrug whose anti-inflammatory activity resides in its sulfide metabolite (which is >500 times more potent than sulindac as an inhibitor of COX but less than half as potent as indomethacin). ADME data are summarized in Table 34–2.The same precautions that apply to other NSAIDs regarding patients at risk for GI toxicity, cardiovascular risk, and renal impairment also apply to sulindac.
THERAPEUTIC USES. Sulindac is used for the treatment of rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, tendonitis, bursitis, and the pain of acute gout. Its analgesic and anti-inflammatory effects are comparable to those achieved with aspirin. The most common dosage for adults is 150-200 mg twice a day.
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 above for indomethacin are seen in <10% of patients. Rash and pruritus occur in 5% of patients. Transient elevations of hepatic transaminases in plasma are less common.
Etodolac is an acetic acid derivative with some degree of COX-2 selectivity (see Table 34–2). At anti-inflammatory doses, the frequency of gastric irritation may be less than with other tNSAIDs. A single oral dose (200-400 mg) of etodolac provides postoperative analgesia that lasts for 6-8 h. 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. Etodolac is relatively well tolerated. About 5% of patients who have taken the drug for <1 year discontinue treatment because of GI side effects, rashes, and CNS effects.
Tolmetin (TOLECTIN, others) is approved for the treatment of osteoarthritis, rheumatoid arthritis, and juvenile rheumatoid arthritis; and has been used in the treatment of ankylosing spondylitis. ADME and comparison to aspirin are in Table 34–2. Tolmetin recommended doses (200-600 mg 3 times/day) typically given with meals, milk, or antacids to lessen abdominal discomfort. However, peak plasma concentrations and bioavailability are reduced when the drug is taken with food. Side effects occur in 25-40% of patients who take tolmetin. 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.
Ketorolac is a potent analgesic but only a moderately effective anti-inflammatory drug. The use of ketorolac is limited to <5 days for acute pain requiring opioid-level analgesia and can be administered intramuscularly, intravenously, or orally. 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 (seeTable 34–2). It is widely used in postoperative patients, but it should not be used for routine obstetric analgesia. Topical (ophthalmic) ketorolac (ACULAR, others) is approved for the treatment of seasonal allergic conjunctivitis and postoperative ocular inflammation. Side effects 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. Patients receiving greater than recommended doses or concomitant NSAID therapy and the elderly appear to be particularly at risk.
Nabumetone is the prodrug of 6-methoxy-2-naphthylacetic acid. Nabumetone is an anti-inflammatory agent with substantial efficacy in the treatment of rheumatoid arthritis and osteoarthritis. Its comparative pharmacokinetic properties are summarized in Table 34–2. Nabumetone is associated with crampy lower abdominal pain and diarrhea, but the incidence of GI ulceration appears to be lower than with other tNSAIDs. Other side effects include rash, headache, dizziness, heartburn, tinnitus, and pruritus.
Diclofenac, a phenylacetic acid derivative, is among the most commonly used NSAID in the E.U. 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. Diclofenac displays rapid absorption, extensive protein binding, and at1/2 of 1-2 h (see Table 34–2). The short t1/2 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 t1/2.
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. Myriad oral formulations are available to provide a range of release times; the usual daily oral dosage is 100-200 mg, given in several divided doses. For migraine, a powdered form is available for dissolution in water; a gel and a transdermal patch are also available. 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.
ADVERSE EFFECTS. Diclofenac produces side effects (particularly GI) in ~20% of patients. The incidence of GI adverse effects are similar to the COX-2–selective inhibitors celecoxib and etoricoxib. Hypersensitivity reactions have occurred following topical application. Modest reversible elevation of hepatic transaminases in plasma occurs in 5-15% of patients. Transaminases should be monitored during the first 8 weeks of therapy with diclofenac. 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. Unlike ibuprofen, diclofenac does not interfere with the antiplatelet effect of aspirin.
PROPIONIC ACID DERIVATIVES
The propionic acid derivatives ibuprofen, naproxen, flurbiprofen, fenoprofen, ketoprofen, and oxaprozin, are available in the U.S. (Table 34–3). Ibuprofen is the most commonly used tNSAID in the U.S. and is available without a prescription. Naproxen, also available without prescription, has a longer but variable t1/2. Oxaprozin also has a long t1/2 and may be given once daily.
Comparison of NSAIDS: Fenamates and Propionic Acid Derivatives
MECHANISM OF ACTION
Propionic acid derivatives are nonselective COX inhibitors with the effects and side effects common to other tNSAIDs. 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.
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. These agents may be comparable in efficacy to aspirin for the control of the signs and symptoms of rheumatoid arthritis and osteoarthritis.
Ibuprofen has been shown to interfere with the antiplatelet effects of 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.
Table 34–3 summarizes the comparative pharmacokinetics of ibuprofen.
THERAPEUTIC USES. Ibuprofen [ADVIL, MOTRIN IB, BRUFEN, 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). The usual dose for mild to moderate pain is 400 mg every 4-6 h as needed.
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. Less frequent adverse effects of ibuprofen include rashes, 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 copackaged with lansoprazole (PREVACID NAPRAPAC). Naproxen is indicated for juvenile and rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, pain, primary dysmenorrhea, tendonitis, bursitis, and acute gout.
Naproxen is absorbed fully after oral administration. The t1/2 of naproxen in plasma is variable; from 14 h in the young, it may increase ~2-fold in the elderly because of age-related decline in renal function (see Table 34–3). Naproxen crosses the placenta and appears in the milk of lactating women at ~1% of the maternal plasma concentration.
ADVERSE EFFECTS. The relative risk of myocardial infarction may be reduced by ~10% by naproxen, compared to a reduction of 20-25% by aspirin. However, increased rates of cardiovascular events also have been reported. 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.
The fenamates include mefenamic, meclofenamic, and flufenamic acids. The pharmacological properties of the fenamates are those of typical tNSAIDs, and therapeutically, they have no clear advantages over others in the class. See Table 34–3. Mefenamic acid [PONSTEL, PONSTAN (U.K.), DYSMAN (U.K.)] and meclofenamate sodium are used in the short-term treatment of pain in soft-tissue injuries, dysmenorrhea, and rheumatoid and osteoarthritis. These drugs are not recommended for use in children or pregnant women. 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.
ENOLIC ACIDS (OXICAMS)
The oxicam derivatives are enolic acids that inhibit COX-1 and COX-2 and have anti-inflammatory, analgesic, and antipyretic activity. These agents are similar in efficacy to aspirin, indomethacin, or naproxen for the long-term treatment of rheumatoid arthritis or osteoarthritis. The main advantage suggested for these compounds is their long t1/2, which permits once-a-day dosing (see comparative pharmacokinetic and dosing data in Table 34–4).
Comparison of NSAIDS: Enolic Acid Derivatives and Coxibs
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. Piroxicam is approved 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, steady-state blood levels are reached in 7-12 days. Approximately 20% of patients experience side effects with piroxicam, and ~5% of patients discontinue use because of these effects. Piroxicam may be with more GI and serious skin reactions than other nonselective NSAIDs. The European Medicines Agency no longer considers piroxicam a first-line agent.
Meloxicam (MOBIC, others) is approved for use in osteoarthritis. The recommended dose for meloxicam is 7.5-15 mg once daily. Meloxicam demonstrates some COX-2 selectivity, however, a clinical advantage or hazard has yet to be established. 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.
Celecoxib, a diaryl heterocyclic coxib, is the only such compound still approved in the U.S. (see its clinical pharmacokinetic properties and precautions in Table 34–4).
Etoricoxib is approved in several countries; rofecoxib (VIOXX) and valdecoxib were withdrawn worldwide. Lumiracoxib, a derivative diclofenac, has been discussed earlier. Selective inhibitors of COX-2 are used for relief of dental pain and relief from inflammation in osteoarthritis and rheumatoid arthritis.
ADME. The bioavailability of oral celecoxib (CELEBREX) is not known, peak plasma levels occur at 2-4 h after administration. 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. Most is excreted as carboxylic acid and glucuronide metabolites in the urine and feces. The elimination t1/2 is ~11 h. The drug commonly is given once or twice daily during chronic treatment. Celecoxib has not been studied in patients with severe renal insufficiency. Plasma concentrations are increased in patients with mild and moderate hepatic impairment, requiring reduction in dose. Celecoxib is metabolized predominantly by CYP2C9 and inhibits CYP2D6. Clinical vigilance is necessary during coadministration of drugs that are known to inhibit CYP2C9 and drugs that are metabolized by CYP2D6.
THERAPEUTIC USES. Celecoxib is used for the management of acute pain 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 2 doses. In the treatment of rheumatoid arthritis, the recommended dose is 100-200 mg twice daily. Due to cardiovascular hazard, physicians are advised to use the lowest possible dose for the shortest possible time. Celecoxib also is approved for the chemoprevention of polyposis coli.
ADVERSE EFFECTS. Celecoxib confers a risk of myocardial infarction and stroke and this appears to relate to dose and the underlying risk of cardiovascular disease. Effects attributed to inhibition of PG production in the kidney—hypertension and edema—occur with nonselective COX inhibitors and also with celecoxib. None of the coxibs has established superior efficacy over tNSAIDs. Selective COX-2 inhibitors lose their GI advantage over a tNSAID alone when used in conjunction with aspirin.
Parecoxib is the only COX-2–selective NSAID administered by injection and has been shown to be an effective analgesic for the perioperative period when patients are unable to take oral medication. It is not widely available, and clinical experience is limited.
Etoricoxib (ARCOXIA) is a COX-2–selective inhibitor with selectivity second only to that of lumiracoxib. Etoricoxib is incompletely (m80%) absorbed and has a long t1/2 of 20-26 h. It is extensively metabolized before excretion. Patients with hepatic impairment are prone to drug accumulation. Renal insufficiency does not affect drug clearance. Etoricoxib is approved 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. The drug is associated with increased the risk of heart attack and stroke.
APAZONE (AZAPROPAZONE). Apazone is a tNSAID that has anti-inflammatory, analgesic, and antipyretic activity and is a potent uricosuric agent. 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 3 times per day for acute gout. Once symptoms have abated, or for non-gout indications, typical dosage is 300 mg 3 to 4 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. 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. 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.
DISEASE-MODIFYING ANTIRHEUMATIC DRUGS
Rheumatoid arthritis is an autoimmune disease that affects ~1% of the population. The pharmacological management of rheumatoid arthritis includes symptomatic relief through the use of NSAIDs. However, although they have anti-inflammatory effects, NSAIDs have minimal, if any effect on progression of joint deformity. Disease-modifying antirheumatic drugs (DMARDs), on the other hand, reduce the disease activity of rheumatoid arthritis and retard the progression of arthritic tissue destruction. DMARDs include a diverse group of small molecule nonbiological and biological agents (mainly antibodies or binding proteins), as summarized in Table 34–5.
Disease-Modifying Anti-Rheumatic Drugs
Biological DMARDs remain reserved for patients with persistent moderate or high disease activity and indicators of poor prognosis. 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.
PHARMACOTHERAPY OF GOUT
Gout results from the precipitation of urate crystals in the tissues and the subsequent inflammatory response. Acute gout usually causes painful distal monoarthritis and also can cause joint destruction, subcutaneous deposits (tophi), and renal calculi and damage. Gout affects ~0.5-1% of the population of Western countries.
The pathophysiology of gout is incompletely understood. Hyperuricemia, while a prerequisite, does not inevitably lead to gout. Uric acid, the end product of purine metabolism, is relatively insoluble compared to its hypoxanthine and xanthine precursors, and normal serum urate levels (~5 mg/dL, or 0.3 mM) approach the limit of solubility. In most patients with gout, hyperuricemia arises from underexcretion rather than overproduction of urate. Mutations of one of the renal urate transporters, URAT-1, are associated with hypouricemia. Urate tends to crystallize as monosodium urate in colder or more acidic conditions. Monosodium urate crystals activate monocytes/macrophages via the toll-like receptor pathway mounting an innate immune response. This results in the secretion of cytokines, including IL-1 β and TNF-α; endothelial activation; and attraction of neutrophils to the site of inflammation. Neutrophils secrete inflammatory mediators that lower the local pH and lead to further urate precipitation.
The aims of treatment are to:
• Decrease the symptoms of an acute attack.
• Decrease the risk of recurrent attacks.
• Lower serum urate levels.
The substances available for these purposes are:
• Drugs that relieve inflammation and pain (NSAIDs, colchicine, glucocorticoids)
• Drugs that prevent inflammatory responses to crystals (colchicine and NSAIDs)
• Drugs that act by inhibition of urate formation (allopurinol, febuxostat) or to augment urate excretion (probenecid)
NSAIDs have been discussed earlier. Glucocorticoids are discussed in Chapter 42. This section focuses on colchicine, allopurinol, febuxostat, and the uricosuric agents probenecid and benzbromarone.
Colchicine is one of the oldest available therapies for acute gout. Colchicine is considered second-line therapy because it has a narrow therapeutic window and a high rate of side effects, particularly at higher doses.
MECHANISM OF ACTION. Colchicine exerts a variety of pharmacological effects, but how these relate to its activity in gout is not well understood. It has antimitotic effects, arresting cell division in G1by 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 and decreases the secretion of chemotactic factors and superoxide anions by activated neutrophils. 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. 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.
ADME. Absorption of oral colchicine is rapid but variable. Peak plasma concentrations occur 0.5-2 h after dosing. In plasma, 50% of colchicine is protein bound. 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. 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 t1/2 of colchicine is 9 h.
THERAPEUTIC USES. A minimum of 3 days, but preferably 7-14 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. For elderly patients, adjust the dose for renal function.
Acute Gout. Colchicine dramatically relieves acute attacks of gout. It is effective in roughly two-thirds of patients if given within 24 h of attack onset. Pain, swelling, and redness abate within 12 h and are completely gone within 48-72 h. The regimen approved for adults recommends a total of 2 doses taken 1 h apart: 1.2 mg (2 tablets) at the first sign of a gout flare followed by 0.6 mg (1 tablet) 1 h later.
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 2-3 times daily for patients who have severe attacks. The dose must be decreased for patients with impaired renal function.
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 demonstrated that 1 dose initially and a single additional dose after 1 h was much less toxic than traditional hourly dosing for acute gout flares. Acute intoxication causes hemorrhagic gastropathy. 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. The FDA suspended the U.S. marketing of all injectable dosage forms of colchicine in 2008.
Allopurinol inhibits xanthine oxidase (XO) and prevents the synthesis of urate from hypoxanthine and xanthine. Allopurinol is used to treat hyperuricemia in patients with gout and to prevent it in those with hematological malignancies about to undergo chemotherapy (acute tumor lysis syndrome). Even though underexcretion rather than overproduction is the underlying defect in most gout patients, allopurinol remains effective therapy.
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), reduce urate production by inhibiting XO, which converts xanthine to uric acid. Allopurinol competitively inhibits XO at low concentrations and is a noncompetitive inhibitor at high concentrations. Allopurinol also is a substrate for XO; 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.
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. Coadministration of colchicine helps suppress such acute attacks. 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 reutilization of oxypurines and feedback inhibition of de novo purine biosynthesis.
ADME. Allopurinol is absorbed relatively rapidly after oral ingestion, and peak plasma concentrations are reached within 60-90 min. About 20% is excreted in the feces in 48-72 h, presumably as unabsorbed drug, and 10-30% is excreted unchanged in the urine. The remainder undergoes metabolism, mostly to oxypurinol. Oxypurinol is excreted slowly in the urine by glomerular filtration, counterbalanced by some tubular reabsorption. The plasma t1/2 of allopurinol and oxypurinol is ~1-2 h and 118-30 h (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 2 compounds do not correlate well with therapeutic or toxic effects.
DRUG INTERACTIONS. Allopurinol increases the t1/2 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 XO. Thus, when allopurinol is used concomitantly with oral mercaptopurine or azathioprine, dosage of the antineoplastic agent must be reduced to 25-33% 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 XO, 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. The goal of therapy is to reduce the plasma uric acid concentration to <6 mg/dL (<360 μmol/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 >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. Most patients can be maintained on 300 mg/day. Those with hematological malignancies may need up to 800 mg/day beginning 2-3 days before the start of chemotherapy. Daily doses >300 mg should be divided. Dosage must be reduced in patients in proportion to the reduction in glomerular filtration.
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. 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 ug/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. 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 in ~3% of patients, 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.
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 patients with hyperuricemia post-transplantation. It can be used in conjunction with a uricosuric agent.
Febuxostat is an XO inhibitor approved for treatment of hyperuricemia in patients with gout.
MECHANISM OF ACTION. Febuxostat is a nonpurine inhibitor of XO. Unlike oxypurinol, the active metabolite of allopurinol, which inhibits the reduced form of XO, febuxostat forms a stable complex with both the reduced and oxidized enzymes and inhibits catalytic function in both states.
ADME. Febuxostat is rapidly absorbed with maximum plasma concentrations at 1-1.5 h postdose. The absolute bioavailability is unknown. Magnesium hydroxide and aluminum hydroxide delay absorption by ~1 h. Food reduces absorption slightly. Febuxostat, t1/2 of 5-8 h, is extensively metabolized by oxidation by CYPs 1A2, 2C8, and 2C9 and non-CYP enzymes 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; ADENURIC) 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. A dose of 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 μmol/L) on 80 mg/day febuxostat than on 300 mg/day allopurinol. 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.
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 a higher rate of myocardial infarction and stroke in patients on febuxostat than on allopurinol. Whether there is a causal relationship between the cardiovascular events and febuxostat therapy or whether these were due to chance is not clear. Meanwhile patients should be monitored for cardiovascular complications.
DRUG INTERACTIONS. Plasma levels of drugs metabolized by XO (e.g., theophylline, mercaptopurine, azathioprine) will increase when administered concurrently with febuxostat. Thus, febuxostat is contraindicated in patients on azathioprine, mercaptopurine, or theophylline.
Rasburicase (ELITEK) is a recombinant urate oxidase that catalyzes the enzymatic oxidation of uric acid into the soluble and inactive metabolite allantoin. It has been shown to lower urate levels more effectively than allopurinol. It is indicated for the initial management of elevated plasma uric acid levels in pediatric patients with leukemia, lymphoma, and solid tumor malignancies who are receiving anticancer therapy expected to result in tumor lysis and significant hyperuricemia.
Rasburicase is produced by a genetically modified Saccharomyces cerevisiae strain. The drug’s efficacy may be hampered by the production of antibodies against the drug. Hemolysis 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 h after infusion of the first rasburicase dose.
Uricosuric agents increase the rate of excretion of uric acid. In humans, urate is filtered, secreted, and reabsorbed by the kidneys. Reabsorption is robust, such that the net the amount excreted usually is ~10% of that filtered. Reabsorption is mediated by an organic anion transporter family member, URAT-1, which can be inhibited.
URAT-1 exchanges urate for either an organic anion such as lactate or nicotinate or less potently for an inorganic anion such as chloride. 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, a drug may either decrease or increase the excretion of uric acid. There are 2 mechanisms by which 1 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 1 drug may counterbalance the inhibition of urate reabsorption by the other.
PROBENECID. Probenecid is a highly lipid-soluble benzoic acid derivative (pKa 3.4).
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. 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 coadministration 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. 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. 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.
ADME. Probenecid is absorbed completely after oral administration. Peak plasma concentrations are reached in 2-4 h. The t1/2 of the drug in plasma is dose-dependent and varies from <5 h to >8 h. Between 85% and 95% of the drug is bound to plasma albumin; the 5% to 15% of unbound drug is cleared by glomerular filtration and active secretion by the proximal tubule. 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] 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. Higher doses of probenecid are used as an adjuvant to prolong the dwell-time of penicillin in the body. This dosing method usually is confined to those being treated for gonorrhea or neurosyphilis infections or penicillin resistance (see Chapter 53).
ADVERSE EFFECTS. Probenecid is well tolerated. Approximately 2% of patients develop mild GI irritation. The risk is increased at higher doses. 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. Substantial overdosage with probenecid results in CNS stimulation, convulsions, and death from respiratory failure.
Benzbromarone is a potent uricosuric agent that is used in Europe. It is a reversible inhibitor of the urate–anion exchanger in the proximal tubule. Hepatotoxicity has been reported in conjunction with its use. The drug is absorbed readily after oral ingestion; peak plasma levels are achieved in ~4 h. It is metabolized to monobrominated and dehalogenated derivatives, both of which have uricosuric activity, and is excreted primarily in the bile.
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. The uricosuric action is blunted by aspirin or sulfinpyrazone.