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Chapter 36 Treatment of gout and hyperuricemia
Chapter 36
Treatment of Gout and Hyperuricemia
ALAN N. BAER
Introduction Treatment of Acute Gouty Arthritis Management of Intercritical Gout Therapy of Symptomatic Hyperuricemia
The Uricosuric Agents Xanthine Oxidase Inhibitors Therapy of Asymptomatic Hyperuricemia Summary
INTRODUCTION Gout is a disorder of purine metabolism in which hyperuricemia,sustained for many years, results in the gradual deposition of monosodium urate crystals in the articular cartilage, synovium, and periarticular connective tissue. Recurrent episodes of acute arthritis (acute gout) occur when monosodium urate crystals are either released from tissue deposits in the joint or are formed de novo in synovial fluid supersaturated with urate and incite an inflammatoryresponse. If the hyperuricemia is left untreated, a destructive, chronic arthritis (tophaceous gout) may supervene, resulting from persistent inflammation and enlarging tophaceous deposits in the joint and adjacent bone. Patients with gout are prone to the development of renal
Principles of Medical Biology, Volume 8C Molecular and Cellular Pharmacology, Pages 723-735. Copyright 63 1997 by JAI Press Inc. All rights of reproduction in any form reserved. ISBN: 1-55938-813-7
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calculi, the majority of which contain uric acid as their principal component. Renal parenchymal disease (urate nephropathy) is also common in patients with gout, but its genesis is usually related to diseases which are strongly associated with gout, such as hypertension, atherosclerosis, diabetes mellitus and pre-existing primary disease. Hyperuricemia is found in approximately 5% of the adult male and less than 1% of the adult female population of the United States (Mikkelsen et al., 1965; Hall et al., 1967). The development of hyperuricemia may be related to impairment of the renal excretion of uric acid, overproduction of uric acid, or both. Approximately 10% of patients with hyperuricemia are classified as overproducers of uric acid on the basis of the urinary excretion of more than 600 mg of uric acid per day on a purine-free diet. In a small minority of gout patients, this overproduction of uric acid can be related directly to a specific inborn error in purine metabolism. Hyperuricemiacan also be secondary to a variety of diseases or to the administration of certain drugs which directly impair renal excretion or result in the excessive production of uric acid. When such secondary factors cannot be defined, gout is considered "primary". A discrete etiology cannot be defined in the vast majority of individuals with "primary" gout even though inherited abnormalities in purine metabolism or in the renal handling of urate are assumed to be present. Only a minority of patients with hyperuricemia develop articular gout or uric acid nephrolithiasis. The height of the serum urate level is the principal risk factor for the development of articular gout. In the Boston Normative Aging Study of healthy adult males with asymptomatic hyperuricemia, the cumulative incidence of gout after five years was 22% in individuals with serum urate levels of 9 mgldl or higher and only 3% in individuals with serum urate values of less than 9 mgldl (Campion et al., 1987). Similarly, the risk of developing a uric acid calculus is proportional to the urinary excretion of uric acid and, to a lesser extent, to the serum urate level. This risk approaches 50% in individuals with daily urinary uric acid excretion of 1100 mg and a serum urate level of 13 mgldl (Yii and Gutman, 1967a). Additional risk factors for the development of gout include renal insufficiency,lead exposure, alcohol intake, hypertension,obesity, and excessive weight gain in young adulthood (Roubenoff et al., 1991). Modification of several of these risk factors is possible and might serve to prevent the development of gout. There are two aspects to the management of gout: treatment of the acute arthritis and correction of the metabolic defect, hyperuricemia. With sustained correction of hyperuricemia, episodes of acute gouty arthritis decline in frequency and eventually cease to occur. In some individuals, correction of hyperuricemia is critical in preventing the development of tophaceous gout.
TREATMENT OF ACUTE GOUTY ARTHRITIS Gout was described in the writings of Hippocrates as "the most violent, tenacious, and painful of joint affections." The disease occurs most commonly in males. At
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the onset of the disease, acute gouty arthritis is usually monoarticular and tends to involve the peripheral joints of the lower extremities. The most commonly affected joints, in order of frequency,are the first metatarsophalangealjoint, the instep, the ankle, the heel, and the knee. Acute gout is noteworthy for its sudden and often nocturnal onset and the severity of the joint pain. The overlying skin of the affected joint is often hot, dusky red, and exquisitely tender and may be mistaken for a cellulitis. Gouty arthritis is diagnosed definitively by aspirating synovial fluid from the affected joint and demonstrating the presence of monosodium urate crystals within synovial fluid leukocytes using a polarizing microscope. Arthrocentesis and examination of the synovial fluid with the aid of a polarizing microscope is not always practical. Many physicians thus rely on a presumptive diagnosis of gout based on a classic clinical history of an acute monoarticular arthritis followed by symptom-free intercritical periods, a prompt response to anti-inflammatory therapy, and hyperuricemia (Wallace et al., 1977). The possibility that an acute arthritis is infectious in origin must always be considered, particularly when there is isolated involvement of a single large joint (such as the knee, shoulder, elbow), when the host is irnrnunocompromised or has other risk factors for septic arthritis (such as diabetes mellitus, intravenous drug abuse, treatment by hemodialysis, or intravenous catheterization), or when there are prominent systemic signs, including fever, chills, or leukocytosis. Nonsteroidal anti-inflammatory drugs (NSAIDs) are the agents of choice for the treatment of acute gout. These agents inhibit cyclooxgenase and interfere with the synthesis of prostaglandins. Some NSAIDs have also been shown in vitro to interfere with neutrophil function. The drug most commonly used for the treatment of gout is indomethacin (initial dose, 50 mg four times a day). However, virtually all of the non-salicylate NSAIDs have been shown to be effective in the treatment of acute gout when each is used initially at its maximum recommended dose. The NSAID should be continued in full dose until there is significant improvement at which point it can be gradually tapered and discontinued. Those agents with a shorter half-life may produce a more rapid clinical response. In elderly patients with acute gout, lower doses of NSAIDs may be effective and advisable, particularly in the presence of renal impairment. The choice of a NSAID may be guided by recognition of pharmacologic properties commonly associated with specific agents. Indomethacin may cause significant central nervous system side effects, such as headaches, somnolence, and dizziness, and should be used with caution in the elderly. Sulindac is less likely than other NSAIDs to suppress renal function at its maximum recommended anti-inflammatory dose (200 mg bid) and is often preferred for patients with mild to moderate renal impairment. Phenylbutazone is no longer recommended for the routine treatment of gout because of the rare occurrence of drug-induced marrow aplasia. NSAIDs should not be used in the presence of an active peptic ulcer or gastrointestinal bleeding and should be used with extreme caution in patients with inflammatory bowel disease, congestive heart failure, hepatic cirrhosis, or severe renal insufficiency. NSAIDs
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may aggravate hypertension. The common occurrence of dyspepsia with NSAID therapy can be reduced by taking the drug with meals. Colchicine is a lipid-soluble alkaloid of the lilly, Colchicum autumnale (autumn crocus), and has been used to treat gout since the 6th century A.D. Colchicine rapidly enters cells where it binds to tubulin, the microtubular subunit protein, and thus interferes with the assembly of microtubules. The effect of colchicine on microtubular assembly is thought to interfere with a variety of neutrophil functions, such as chemotaxis, phagocytosis, and release of lysosomal enzymes, which are essential for the propagation of crystal-induced inflammation. Colchicine also affects leucocyte margination and diapedesis by inhibiting the expression of both L-selection on leucocytes and intercellular adhesion molecule on endothelial cells. (Cronstein and Weissman, 1993). Colchicine is absorbed rapidly from the gastrointestinaltract; large amounts of the drug and its metabolites are excreted into the intestines via bile and intestinal secretions. After intravenous administration, the drug is rapidly distributed in a space larger than that of body water and can be detected in leucocytes as long as 9 days later, implying very slow excretion. lbenty percent of colchicine and its metabolites are excreted in the urine. The common occurrence of gastrointestinal symptoms, including abdominal cramps, nausea, vomiting, and diarrhea, during oral colchicine therapy has resulted in its declining use as a treatment for acute gout. The usual dose of oral colchicine in acute gout is 0.6 mg every 1-3 hours until the joint pain resolves or gastrointestinal symptoms occur. No more than 8-10 mg of colchicine should be administered during the treatment of a single episode of gouty arthritis. In most patients, adverse gastrointestinal effects precede or coincide with the improvement of the arthritis. Colchicine is most effective when it is taken within 24-48 hours after the onset of acute gout. Colchicine can be administered intravenously in patients who can not take the drug orally or in whom a rapid response is desired. Gastrointestinal side effects are avoided with intravenous colchicine. Intravenous colchicine is intensely sclerotic and the drug must be diluted with 10-20 ml of saline and administered through a secure intravenous line in order to avoid the possibility of infiltration. The usual initial intravenous dose is 2 mg; a dose of 0.5 mg may be repeated every 6 hours until a satisfactory response is achieved. The patient should receive no more than 4 mg for the treatment of a single episode of acute gout. There are considerable hazards to the use of colchicine in the treatment of gout, particularly in patients who have impairment of hepatic or renal function. The therapeutic dose of colchicine is close to its toxic dose. Elderly patients, in whom a "normal" serum creatinine level may not accurately reflect the presence of renal impairment due to a reduced muscle mass, should not be given more than 2 mg of intravenous colchicine for the treatment of an episode of acute gout. The total dose should also be restricted to 2 mg if the patient has been taking prophylactic colchicine (vide' infra). Serious toxicity from intravenous colchicine occurs most
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often in patients who have been given over 3-4 mg per day, who have been given a combination of oral and intravenousdoses, or who have been given recommended doses but have hepatic or renal dysfunction (Roberts et al., 1987). Toxic reactions from colchicine include marrow suppression, disseminated intravascular coagulation, seizures, and ascending paralysis. There are several alternative approaches to the treatment of acute gout which may be used in special circumstances.When acute gout involves a single largejoint, it can be treated effectively and promptly by thorough aspiration of the joint and intraarticular injection of microcrystalline adrenocorticosteroid esters. When the use of colchicine or NSAIDs is contraindicated or poses significant risks, such as in patients with renal insufficiency, congestive heart failure, or hepatic cirrhosis, acute gout can be treated with ACTH and glucocorticoids. An intramuscular dose of ACTH (40-80 international units) is particularly effective when used within 24 hours of the onset of pain. If needed, the dose may be repeated every 12 hours for 1-3 days. Oral prednisone may also be used in doses of 20-30 mg per day; the duration of therapy must last from 1-3 weeks depending on the severity of the attack (Groff et al., 1990). An intramuscular injection of triamcinolone acetonide, 60 mg, is an effective alternative (Alloway et al., 1993). Corticosteroids and ACTH should not be used in high risk patients such as those with diabetes mellitus or those in whom there is concurrent infection. In a patient with acute gout and multiple medical problems that preclude the safe use of NSAIDs, colchicine, or systemic corticosteroids, it may be most prudent to treat the patient with analgesics alone. Acute gout is self limited and will resolve without the use of specific medications.
MANAGEMENT OF INTERCRITlCAt GOUT The symptom-free interval between episodes of acute gout is termed "intercritical gout". After the onset of gout, approximately three-fourths of patients will have a second episode of acute gout within two years. However, some patients may not have a subsequent episode of gouty arthritis for over ten years (Yu and Gutman, 1967b).The frequency of acute gout may be reduced by losing excess body weight, avoiding excessive alcohol intake, stopping the use of diuretic agents, and adhering to a diet restricted in purines. In patients with only mild hyperuricemia, this approach may provide adequate control of the gout. If a patient has repeated attacks of gout, particularly clustered in a short period of time, most physicians choose to initiate therapy to correct the patient's hyperuricemia. Once begun, therapy to correct hyperuricemia is continued indefinitely and requires daily medication. Some patients will not choose to take daily doses of urate-lowering drugs. Alternative approaches include expectant observation with treatment of each episode of acute gout with coIchicine or a NSAID or the use of a daily dose of colchicine ("prophylactic colchicine"). Colchicine, 0.6 mg bid or tid, can significantly reduce the frequency of acute gout (Yu, 1982). The daily use of a NSAID may also be
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effective for this purpose. In elderly patients, particularly those with renal impairment, the dose of prophylactic colchicine should be reduced to 0.6 mg once daily or every other day in order to avoid chronic toxicity (Kuncl et al., 1987;Wallace et al., 1991). If hyperuricemia is left untreated, patients with gout are at risk of developing tophi and chronic gouty arthritis, characterizedby persistentjoint pain and stiffness and eventual joint destruction and deformity. Correction of hyperuricemia is the only definitive means to reduce the incidence of subsequent episodes of acute gout and to prevent the development of tophaceous gout.
THERAPY O F SYMPTOMATIC HYPERURICEMIA The indications for treating symptomatic hyperuricemia include the presence of: (1) frequent, recurrent episodes of acute gouty arthritis; (2) tophaceous deposits, or (3) nephrolithiasis. Asymptomatic hyperuricemia is generally not treated (vide' infra). Since treatment of hyperuricemia is continued indefinitely, the diagnosis of gout should have been made definitively at some time during the patient's disease course through the identification of monosodium urate crystals in synovial fluid or in a tophus. There are several important principles that apply to the pharmacological management of hyperuricemia. A sudden reduction in serum urate level tends to precipitate acute gout; thus, urate-lowering drugs should be introduced at a low dose and their dose subsequently titrated upward to achieve a serum urate value of less than 6 mgldl. When treatment of hyperuricemia is initiated, the patient should receive daily prophylactic colchicine to reduce the incidence of acute gout; this is continued until a stable serum urate level is achieved or until all visible tophi are gone. Therapy of hyperuricemia should not be started until after an episode of acute gout has subsided. Hyperuricemia can be treated either with allopurinol, a xanthine oxidase inhibitor which blocks the formation of uric acid, or with a uricosuric drug, which increases the urinary excretion of uric acid. Both types of drugs are suitable and effective in the majority of patients with gout. Allopurinol is the preferred drug in patients with tophaceous gout, nephrolithiasis, significant renal impairment, and overproduction of uric acid (as defined by the urinary uric acid excretion of > 600 mglday on a purine-free diet, > 800 mg on an unrestricted diet). In surveys of prescribing practices, it has been found that the majority of physicians use allopurinol to treat hyperuricemia, irrespective of the degree of uricosuria (Bellamy et al, 1988). This preference for allopurinol may be related to the fact that it is effective in a single daily dose and in patients with impaired renal function and does not pose a significant risk for precipitating renal calculi. However, allopurinol is more likely than the uricosuric agents to cause severe and potentially life-threatening hypersensitivity reactions, and its use should thus be supervised with care.
Treatment of Gout
The Uricosuric Agents Uricosuric agents are organic acids which inhibit reabsorption of urate secreted in the renal tubule and thereby increase the urinary excretion of uric acid. Their efficacy is reduced or nullified in patients with significant renal impairment (creatinine clearance < 20-30 mllmin) and in patients who are using concomitant salicylates. In view of the fact that these agents increase urinary uric acid excretion and predispose to stone formation, they should be used with caution or not at all in patients with a history of nephrolithiasis or in patients with gross overexcretion of uric acid (e.g., > 1000 mgld on a purine-free diet). The two uricosuric agents which are available and commonly used in the United States for the treatment of hyperuricemia are probenicid and sulfinpyrazone (Figure 1). Benzbromarone is a potent uricosuric agent that is available and widely used in Europe. Both probenicid and sulfinpyrazone are readily absorbed from the gastrointestinal tract. The half-life of each is less than 12 hours and thus each must be dosed at least twice daily. Both drugs are extensively bound to serum proteins and remain primarily within the extracellular fluid space. Probenicid is rapidly metabolized in vivo to an acyl glucuronide which is excreted in the urine. Approximately 20-45% of sulfinpyrazone is excreted unchanged in the urine; the remaining drug is excreted in the urine as the parahydroxyl metabolite which is also uricosuric. Since sulfinpyrazone prolongs platelet survival and may be effective in preventing myocardial infarction and venous thrombosis, it has potential advantages in a gout patient with cardiovascular risk factors, such as hypertension. Both probenicid and sulfinpyrazone can inhibit the transport of other organic anions across epithelial barriers. Probenicid has been shown to block the biliary secretion of rifampin and the renal elimination of penicillin, ampicillin, cephradine, indomethacin, acetazolamide, and dapsone. The doses of indomethacin and dapsone should be reduced in a patient taking probenicid in order to avoid toxicity. The starting dose of probenecid is 250 mg twice daily. The daily dose is then increased by 500 mg every 2-3 weeks until the serum urate level is below 6 mgldl. The usual maintenance dose is 500 mg twice a day; 40% of patients may require a daily dose of 1.5 grams or more. The starting dose of sulfinpyrazoneis 50 mg twice a day. The dose can then be increased every week or two by 100 mg until the serum urate is less than 6 mgldl. The usual maintenance dose is 300-400 mg per day in divided doses. When uricosuric therapy is initiated, the patient should increase his daily fluid intake in order to maintain a generous urinary output (e.g., 2-3 liters per day). This should be continued until the hyperuricemia is corrected or until all visible tophi are gone. If a uricosuric agent must be used in an individual with a history of nephrolithiasis or excessive urinary excretion of uric acid (i.e., in an individual allergic to allopurinol), the risk of precipitating a renal calculus can be substantially
ALAN N. BAER
CH' 3' CH ,CH
c ~\2 Nso2<=>
COOH
\ /
,CH',
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reduced by alkalinizing the urine (pH > 6) with acetazolamide (500 mg qhs), oral sodium bicarbonate (2-6 grams per day) or sodium citrate (Shohl's) solution (20-60 ml per day).
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The side effects of probenecid and sulfinpyrazone are similar and include gastrointestinal symptoms, skin rash and other hypersensitivity phenomena. The gastrointestinal symptoms can be reduced in frequency by taking the drug after meals. Serious toxicity related to either drug is rare. Benzbromarone is a halogenated uricosuric agent which is available outside the United States. This potent uricosuric agent is well-absorbed from the gastrointestinal tract and reaches peak serum concentrations within 4 hours of oral administration. It is debrominated in the liver and excreted in the bile in its free or conjugated form. The usual maintenance dose is 100 mg once daily; the dose range is 25 to 120 mg per day. In contrast to prohenicid and sulfinpyrazone,benzbromarone can promote uricosuria in patients with moderate renal insufficiency (e.g., serum creatinine 2-3 mgldl). Xanthine Oxidase lnhibitors
Allopurinol is a potent competitive inhibitor of xanthine oxidase. Since xanthine oxidase converts hypoxanthineto xanthine and xanthine to uric acid, administration of this drug is associated with a significant decrease in the plasma concentration of urate and the urinary excretion of uric acid, as well as a rise in the plasma levels and urinary excretion of xanthine and hypoxanthine (Figure 2). These oxypurines have a rapid renal clearance and thus do not accumulate to any extent; the increased urinary excretion of these more soluble oxypurine precursors of uric acid is rarely associated with the development of xanthine stones. Allopurinol is completely absorbed from the gastrointestinaltract and has a serum half-life of 3 hours or less. The major pathway of metabolism of allopurinol is oxidation to oxipurinol; this metabolite retains the capacity to inhibit xanthine oxidase and has a half-life of 12-17 hours. Thus, the biologic half-life of allopurinol is significantly prolonged by conversion to an active metabolite with a long half-life. Allopurinol has unique utility in patients with a history of nephrolithiasis and in those with renal impairment since its urate-lowering efficacy is associated with a decrease in the concentration of uric acid in the urine and is not dependent on renal function. The dose of allopurinol required to control the serum urate level ranges from 100 mg to 800 mg per day. In most patients, a single daily dose of 300 mg suffices. It is unusual for a patient to require doses of 400 mg or more to coiltrol hyperuricemia; poor compliance is the usual cause for this failure. The initial dose of allopurinol should be low (50-100 mg) and then increased gradually to find the lowest effective dose. Such a dosing regimen inay serve to minimize the risk of precipitating acute gout. A lower dose of allopurinol (e.g., 50-200 mg) should be effective and employed in patients with renal insufficiency in view of the dependence of oxipurinol on renal excretion (Hande et al., 1984). Allopurinol is generally well tolerated. Undesirable side effects are observed in 5 to 20% of patients treated with this drug, but most patients do not need to discontinue the medication. The most frequent side effects include skin rash,
ALAN N. BAER
allopurinol
hypoxanthine
ox~pur~nol
xanthlne
U ~ I Cacld
Figure 2. Inhibitory effects of allopurinol and its metabolite, oxipurinol, on the final
steps of purine metabolism.
abdominal pain, diarrhea and headache. The skin rash is generally a pruritic maculopapular erythema; if mild, the drug can be stopped until the rash resolves and then reinstituted at a lower initial dose. In a small number of patients, a severe hypersensitivity syndrome occurs with allopurinol therapy, marked by exfoliative dermatitis or toxic epidermal necrolysis, fever, worsening renal function, eosinophilia, hepatitis, and leucocytosis (Hande et al., 1984). This allopurinol hypersensitivity syndrome has a high mortality and tends to occur within 3 weeks of initiating allopurinol therapy. It has been described more commonly in patients with renal insufficiency receiving doses of allopurinol that were not adjusted in relation to the renal function. Other serious side effects reported with allopurinol include bone marrow suppression, hepatic toxicity, and interstitial nephritis. Several drug interactions with allopurinol are noteworthy. Allopurinol impairs the metabolism of the 6-mercaptopurine metabolite of azathioprine; thus, the concomitant use of azathioprine and allopurinol is associated with a heightened cytotoxic effect of azathioprine. The dose of azathioprine must be reduced by about 75% when used in combination with therapeutic doses of allopurinol. The hepatic microsomal oxidation of theophylline and coumadin is impaired by allopurinol; the dose of these two drugs may thus need to be reduced if a patient begins therapy with allopurinol. Allopurinol increases the frequency of an ampicillin-related drug rash.
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THERAPY O F ASYMPTOMATIC HYPERURICEMIA Only a minority of individuals with asymptomatic hypenuicemia develop gouty arthritis or uric acid nephrolithiasis.Treatment of hyperuricemia is costly, long-term, and potentially toxic and can only be justified in asymptomatic individuals if it prevents sigdcant organ damage in the minority at risk. However, there is no compelling evidence to indicate that such benefit exists (Liang and Fries, 1978). The two principal organs that may be damaged directly by sustained hyperuricemia are the joints (tophaceous gout) and the kidneys (uratenephropathy and uric acid nephrolithiasis). Tophaceous gout virtually never occurs without the patient h t developing acute gout. The decision to treat hyperuricemia is thus reasonably deferred until the clinical onset of gout. The absolute risk of nephrolithiasis among patients with asymptomatic hyperuricemia was found to be one stone per 295 individuals per year in the study of Fessel (1979) and only 2.8 times higher than in normouricemic control subjects. This risk is sufficiently small to justify withholding therapy of asymptomatic hyperuricemia until the first stone occurs. Patients with gout have a high frequency of renal parenchymal disease marked by vascular nephrosclerosis, tubular atrophy, and interstitial fibrosis. The only histologic finding specific to patients with gout is monosodium urate crystal deposition in the renal medulla and pyramids with a surrounding giant cell reaction ("urate nephropathy"). The development of renal insufliciency and failure has been shown to be related to co-morbid conditions common to the gouty population, including atherosclerosis, hypertension, diabetes mellitus, and pre-existing primary renal disease, rather than to hyperuricemia and the deposition of urate in renal tissue (Yii and Berger, 1982). In the absence of these co-morbid conditions there is no evidence that chronic hyperuricemia adversely affects renal function. An exception may be men and women who maintain serum urate levels above 13 mg/dl and 10 mg/dl, respectively (Fessel, 1979). Thus, the vast majority of patients with asymptomatic hyperuricemia do not require treatment with urate-lowering drugs. The cytolytic treatment of patients with rapidly proliferating mahgnancies, such as leukemias and lymphomas, results in an acute, dramatic increase in urate production and urinary uric acid excretion. Precipitation of uric acid crystals in the distal tubules and collecting ductsmay ensue,with the production of an obstructiveuropathy.This syndrome, "uric acid nephropathy," is characterized by acute oliguria and the presence of uric acid crystals and sludge in the urine. It is prevented by the administration of allopurinol and maintenance of high urinary output during cytolytic therapy. Individuals with hypoxanthine-guanine phosphoribosyl transferase deficiency have marked mate overproduction and very high rates of urinary uric acid excretion and may also develop uric acid nephropathy, particularly during illnesses complicated by volume depletion.
SUMMARY There are two aspects to the management of gout: treatment of episodes of acute gouty arthritis and sustained correction of hyperuricemia. Acute gout is most
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commonly treated with non-steroidal anti-inflammatory drugs or oral colchicine. Other modalities, including intravenous colchicine, intra-articular corticosteroid injection, ACTH, and systemic corticosteroids may be used in special circumstances. Correction of hyperuricemia is the only definitive means to reduce the incidence of acute gout and to prevent the development of tophaceous gout, a chronic, potentially debilitating form of gouty arthritis. Urate-lowering drugs are indicated when the patient has recurrent episodes of acute gouty arthritis, tophaceous deposits, or nephrolithiasis. Two types of urate-lowering drugs are available, uricosuric agents which increase the renal excretion of uric acid and a xanthine oxidase inhibitor, allopurinol, which blocks the formation of uric acid. Allopurinol is the preferred drug in patients with tophaceous gout, nephrolithiasis, significant renal impairment, and overproduction of uric acid.
REFERENCES Alloway, J.A., Moriarty, M.J., Hoogland, Y.T., & Nashel, D.J. (1993). Comparison of triamcinolone acetonide with indomethacin in the treatment of acute gouty ~ 0 . 2 0 , 1 1 1 - 1 1 3 . Bellarny, N, Gilbert, J.R., Brooks, P.M., Emmerson, B.T., & Campbell, J. (1988). A survey of current prescribing practices of antiinflammatory and urate lowering drugs in gouty arthritis in the province of Ontario. J. Rheum. 15, 1841-1847. Campion, E.W., Glynn, R.J., & DeLabry, L.O. (1987). Asymptomatic hypenuicemia. Risks and consequences in the Normative Aging Study. Amer. J. Med. 82,421-426. Cronstein, B.N., & Weissman, G. (1993). The adhesion molecules of inflammation. Arthritis Rheum. 36, 147-157. Fessel, J. (1979). Renal outcomes of gout and hyperuricemia. Amer. J. Med. 67, 174-182. Groff, G.D., Franck, W.A., & Raddatz, D.A. (1990). Systemic steroid therapy for acute gout: A clinical trial and review of the literature. Sem. Arthr. Rheum. 19,329-336. Hall, A.P., Bany, P.E., Dawber, T.R., & McNamara, P.M. (1967). Epidemiology of gout and hyperuricemia. A long-term population study. Amer. J. Med. 42,27-37. Hande, K.R., Noone, R.M., &Stone W.J. (1984). Severe allopurinol toxicity. Description and guidelines for prevention in patients with renal insufficiency. Amer. J. Med. 76.47-56. Kuncl, R.W., Duncan, G., Watson, D., Alderson, K., Rogawski, M.A., & Peper, M. (1987). Colchicine rnyopathy and neuropathy. New Engl. J. Med. 316,1562-1568. Liang, M.H., & Fries, J.F. (1978). Asymptomatic hyperuricemia: The case for conservative management. Ann. Int. Med. 88,666-670. Mikkelsen, W .M., Dodge, H.J., & Valkenburg, H. (1965).The distribution of serum uric acid values in a population unseleded as to gout or hyperuricemia. Amer. J. Med. 39, 242-251. Roberts, W.N., Liang, M.H., & Stem, S.H. (1987). Colchicine in acute gout. Reassessment of risks and benefits. JAMA. 257,1920-1922. Roubenoff, R, Klag, M.J., Mead, L.A., Liang, K.-Y., Seidier, A.J., & Hochberg, M.C. (1991).Incidence and risk factors for gout in white men. JAMA. 266,3004-3007. Wallace, S.L., Robinson, H., Masi, A.T., Decker, J.L., McCarty, D.J., & Yii, T-F. (1977). Preliminary criteria for the classification of the acute arthritis of primary gout. Arthr. Rheum. 20,895-900. Wallace, S.L., Singer, J.Z., Duncan, G.J., Wigley, F.M., & Kuncl, R.W. (1991). Renal function predicts colchicine toxicity: Guidelines for the prophylactic use of colchicine in gout. J. Rheum. 18, 264-269. Yii, T.-F., & Gutman, A.B. (1967a). Uric acid nephrolithiasis in gout. Predisposing factors. Ann. Int. Med. 67, 1133-1148.
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Yii, T.-F., & Gutman, A.B. (1967b). Principles of current management of primary gout. Amer. J. Med. Sci. 253,893-907. Yii, T.-F. (1982). The efficacy of colchicine prophylaxis in articular gout. A reappraisal after 20 years. Sem. Arthr. Rheum. 12,256-264. Yii, T.-F., & Berger, L. (1982). Impaired renal function in gout. Its association with hypertensive vascular disease and intrinsic renal disease. Amer. J. Med. 72.95-100.
Treatment of Gout and Hyperuricemia
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Introduction Treatment of Acute Gouty Arthritis Management of Intercritical Gout Therapy of Symptomatic Hyperuricemia
The Uricosuric Agents Xanthine Oxidase Inhibitors Therapy of Asymptomatic Hyperuricemia Summary
INTRODUCTION Gout is a disorder of purine metabolism in which hyperuricemia,sustained for many years, results in the gradual deposition of monosodium urate crystals in the articular cartilage, synovium, and periarticular connective tissue. Recurrent episodes of acute arthritis (acute gout) occur when monosodium urate crystals are either released from tissue deposits in the joint or are formed de novo in synovial fluid supersaturated with urate and incite an inflammatoryresponse. If the hyperuricemia is left untreated, a destructive, chronic arthritis (tophaceous gout) may supervene, resulting from persistent inflammation and enlarging tophaceous deposits in the joint and adjacent bone. Patients with gout are prone to the development of renal
Principles of Medical Biology, Volume 8C Molecular and Cellular Pharmacology, Pages 723-735. Copyright 63 1997 by JAI Press Inc. All rights of reproduction in any form reserved. ISBN: 1-55938-813-7
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calculi, the majority of which contain uric acid as their principal component. Renal parenchymal disease (urate nephropathy) is also common in patients with gout, but its genesis is usually related to diseases which are strongly associated with gout, such as hypertension, atherosclerosis, diabetes mellitus and pre-existing primary disease. Hyperuricemia is found in approximately 5% of the adult male and less than 1% of the adult female population of the United States (Mikkelsen et al., 1965; Hall et al., 1967). The development of hyperuricemia may be related to impairment of the renal excretion of uric acid, overproduction of uric acid, or both. Approximately 10% of patients with hyperuricemia are classified as overproducers of uric acid on the basis of the urinary excretion of more than 600 mg of uric acid per day on a purine-free diet. In a small minority of gout patients, this overproduction of uric acid can be related directly to a specific inborn error in purine metabolism. Hyperuricemiacan also be secondary to a variety of diseases or to the administration of certain drugs which directly impair renal excretion or result in the excessive production of uric acid. When such secondary factors cannot be defined, gout is considered "primary". A discrete etiology cannot be defined in the vast majority of individuals with "primary" gout even though inherited abnormalities in purine metabolism or in the renal handling of urate are assumed to be present. Only a minority of patients with hyperuricemia develop articular gout or uric acid nephrolithiasis. The height of the serum urate level is the principal risk factor for the development of articular gout. In the Boston Normative Aging Study of healthy adult males with asymptomatic hyperuricemia, the cumulative incidence of gout after five years was 22% in individuals with serum urate levels of 9 mgldl or higher and only 3% in individuals with serum urate values of less than 9 mgldl (Campion et al., 1987). Similarly, the risk of developing a uric acid calculus is proportional to the urinary excretion of uric acid and, to a lesser extent, to the serum urate level. This risk approaches 50% in individuals with daily urinary uric acid excretion of 1100 mg and a serum urate level of 13 mgldl (Yii and Gutman, 1967a). Additional risk factors for the development of gout include renal insufficiency,lead exposure, alcohol intake, hypertension,obesity, and excessive weight gain in young adulthood (Roubenoff et al., 1991). Modification of several of these risk factors is possible and might serve to prevent the development of gout. There are two aspects to the management of gout: treatment of the acute arthritis and correction of the metabolic defect, hyperuricemia. With sustained correction of hyperuricemia, episodes of acute gouty arthritis decline in frequency and eventually cease to occur. In some individuals, correction of hyperuricemia is critical in preventing the development of tophaceous gout.
TREATMENT OF ACUTE GOUTY ARTHRITIS Gout was described in the writings of Hippocrates as "the most violent, tenacious, and painful of joint affections." The disease occurs most commonly in males. At
Treatment of Gout
725
the onset of the disease, acute gouty arthritis is usually monoarticular and tends to involve the peripheral joints of the lower extremities. The most commonly affected joints, in order of frequency,are the first metatarsophalangealjoint, the instep, the ankle, the heel, and the knee. Acute gout is noteworthy for its sudden and often nocturnal onset and the severity of the joint pain. The overlying skin of the affected joint is often hot, dusky red, and exquisitely tender and may be mistaken for a cellulitis. Gouty arthritis is diagnosed definitively by aspirating synovial fluid from the affected joint and demonstrating the presence of monosodium urate crystals within synovial fluid leukocytes using a polarizing microscope. Arthrocentesis and examination of the synovial fluid with the aid of a polarizing microscope is not always practical. Many physicians thus rely on a presumptive diagnosis of gout based on a classic clinical history of an acute monoarticular arthritis followed by symptom-free intercritical periods, a prompt response to anti-inflammatory therapy, and hyperuricemia (Wallace et al., 1977). The possibility that an acute arthritis is infectious in origin must always be considered, particularly when there is isolated involvement of a single large joint (such as the knee, shoulder, elbow), when the host is irnrnunocompromised or has other risk factors for septic arthritis (such as diabetes mellitus, intravenous drug abuse, treatment by hemodialysis, or intravenous catheterization), or when there are prominent systemic signs, including fever, chills, or leukocytosis. Nonsteroidal anti-inflammatory drugs (NSAIDs) are the agents of choice for the treatment of acute gout. These agents inhibit cyclooxgenase and interfere with the synthesis of prostaglandins. Some NSAIDs have also been shown in vitro to interfere with neutrophil function. The drug most commonly used for the treatment of gout is indomethacin (initial dose, 50 mg four times a day). However, virtually all of the non-salicylate NSAIDs have been shown to be effective in the treatment of acute gout when each is used initially at its maximum recommended dose. The NSAID should be continued in full dose until there is significant improvement at which point it can be gradually tapered and discontinued. Those agents with a shorter half-life may produce a more rapid clinical response. In elderly patients with acute gout, lower doses of NSAIDs may be effective and advisable, particularly in the presence of renal impairment. The choice of a NSAID may be guided by recognition of pharmacologic properties commonly associated with specific agents. Indomethacin may cause significant central nervous system side effects, such as headaches, somnolence, and dizziness, and should be used with caution in the elderly. Sulindac is less likely than other NSAIDs to suppress renal function at its maximum recommended anti-inflammatory dose (200 mg bid) and is often preferred for patients with mild to moderate renal impairment. Phenylbutazone is no longer recommended for the routine treatment of gout because of the rare occurrence of drug-induced marrow aplasia. NSAIDs should not be used in the presence of an active peptic ulcer or gastrointestinal bleeding and should be used with extreme caution in patients with inflammatory bowel disease, congestive heart failure, hepatic cirrhosis, or severe renal insufficiency. NSAIDs
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ALAN N. BAER
may aggravate hypertension. The common occurrence of dyspepsia with NSAID therapy can be reduced by taking the drug with meals. Colchicine is a lipid-soluble alkaloid of the lilly, Colchicum autumnale (autumn crocus), and has been used to treat gout since the 6th century A.D. Colchicine rapidly enters cells where it binds to tubulin, the microtubular subunit protein, and thus interferes with the assembly of microtubules. The effect of colchicine on microtubular assembly is thought to interfere with a variety of neutrophil functions, such as chemotaxis, phagocytosis, and release of lysosomal enzymes, which are essential for the propagation of crystal-induced inflammation. Colchicine also affects leucocyte margination and diapedesis by inhibiting the expression of both L-selection on leucocytes and intercellular adhesion molecule on endothelial cells. (Cronstein and Weissman, 1993). Colchicine is absorbed rapidly from the gastrointestinaltract; large amounts of the drug and its metabolites are excreted into the intestines via bile and intestinal secretions. After intravenous administration, the drug is rapidly distributed in a space larger than that of body water and can be detected in leucocytes as long as 9 days later, implying very slow excretion. lbenty percent of colchicine and its metabolites are excreted in the urine. The common occurrence of gastrointestinal symptoms, including abdominal cramps, nausea, vomiting, and diarrhea, during oral colchicine therapy has resulted in its declining use as a treatment for acute gout. The usual dose of oral colchicine in acute gout is 0.6 mg every 1-3 hours until the joint pain resolves or gastrointestinal symptoms occur. No more than 8-10 mg of colchicine should be administered during the treatment of a single episode of gouty arthritis. In most patients, adverse gastrointestinal effects precede or coincide with the improvement of the arthritis. Colchicine is most effective when it is taken within 24-48 hours after the onset of acute gout. Colchicine can be administered intravenously in patients who can not take the drug orally or in whom a rapid response is desired. Gastrointestinal side effects are avoided with intravenous colchicine. Intravenous colchicine is intensely sclerotic and the drug must be diluted with 10-20 ml of saline and administered through a secure intravenous line in order to avoid the possibility of infiltration. The usual initial intravenous dose is 2 mg; a dose of 0.5 mg may be repeated every 6 hours until a satisfactory response is achieved. The patient should receive no more than 4 mg for the treatment of a single episode of acute gout. There are considerable hazards to the use of colchicine in the treatment of gout, particularly in patients who have impairment of hepatic or renal function. The therapeutic dose of colchicine is close to its toxic dose. Elderly patients, in whom a "normal" serum creatinine level may not accurately reflect the presence of renal impairment due to a reduced muscle mass, should not be given more than 2 mg of intravenous colchicine for the treatment of an episode of acute gout. The total dose should also be restricted to 2 mg if the patient has been taking prophylactic colchicine (vide' infra). Serious toxicity from intravenous colchicine occurs most
Treatment of Gout
727
often in patients who have been given over 3-4 mg per day, who have been given a combination of oral and intravenousdoses, or who have been given recommended doses but have hepatic or renal dysfunction (Roberts et al., 1987). Toxic reactions from colchicine include marrow suppression, disseminated intravascular coagulation, seizures, and ascending paralysis. There are several alternative approaches to the treatment of acute gout which may be used in special circumstances.When acute gout involves a single largejoint, it can be treated effectively and promptly by thorough aspiration of the joint and intraarticular injection of microcrystalline adrenocorticosteroid esters. When the use of colchicine or NSAIDs is contraindicated or poses significant risks, such as in patients with renal insufficiency, congestive heart failure, or hepatic cirrhosis, acute gout can be treated with ACTH and glucocorticoids. An intramuscular dose of ACTH (40-80 international units) is particularly effective when used within 24 hours of the onset of pain. If needed, the dose may be repeated every 12 hours for 1-3 days. Oral prednisone may also be used in doses of 20-30 mg per day; the duration of therapy must last from 1-3 weeks depending on the severity of the attack (Groff et al., 1990). An intramuscular injection of triamcinolone acetonide, 60 mg, is an effective alternative (Alloway et al., 1993). Corticosteroids and ACTH should not be used in high risk patients such as those with diabetes mellitus or those in whom there is concurrent infection. In a patient with acute gout and multiple medical problems that preclude the safe use of NSAIDs, colchicine, or systemic corticosteroids, it may be most prudent to treat the patient with analgesics alone. Acute gout is self limited and will resolve without the use of specific medications.
MANAGEMENT OF INTERCRITlCAt GOUT The symptom-free interval between episodes of acute gout is termed "intercritical gout". After the onset of gout, approximately three-fourths of patients will have a second episode of acute gout within two years. However, some patients may not have a subsequent episode of gouty arthritis for over ten years (Yu and Gutman, 1967b).The frequency of acute gout may be reduced by losing excess body weight, avoiding excessive alcohol intake, stopping the use of diuretic agents, and adhering to a diet restricted in purines. In patients with only mild hyperuricemia, this approach may provide adequate control of the gout. If a patient has repeated attacks of gout, particularly clustered in a short period of time, most physicians choose to initiate therapy to correct the patient's hyperuricemia. Once begun, therapy to correct hyperuricemia is continued indefinitely and requires daily medication. Some patients will not choose to take daily doses of urate-lowering drugs. Alternative approaches include expectant observation with treatment of each episode of acute gout with coIchicine or a NSAID or the use of a daily dose of colchicine ("prophylactic colchicine"). Colchicine, 0.6 mg bid or tid, can significantly reduce the frequency of acute gout (Yu, 1982). The daily use of a NSAID may also be
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effective for this purpose. In elderly patients, particularly those with renal impairment, the dose of prophylactic colchicine should be reduced to 0.6 mg once daily or every other day in order to avoid chronic toxicity (Kuncl et al., 1987;Wallace et al., 1991). If hyperuricemia is left untreated, patients with gout are at risk of developing tophi and chronic gouty arthritis, characterizedby persistentjoint pain and stiffness and eventual joint destruction and deformity. Correction of hyperuricemia is the only definitive means to reduce the incidence of subsequent episodes of acute gout and to prevent the development of tophaceous gout.
THERAPY O F SYMPTOMATIC HYPERURICEMIA The indications for treating symptomatic hyperuricemia include the presence of: (1) frequent, recurrent episodes of acute gouty arthritis; (2) tophaceous deposits, or (3) nephrolithiasis. Asymptomatic hyperuricemia is generally not treated (vide' infra). Since treatment of hyperuricemia is continued indefinitely, the diagnosis of gout should have been made definitively at some time during the patient's disease course through the identification of monosodium urate crystals in synovial fluid or in a tophus. There are several important principles that apply to the pharmacological management of hyperuricemia. A sudden reduction in serum urate level tends to precipitate acute gout; thus, urate-lowering drugs should be introduced at a low dose and their dose subsequently titrated upward to achieve a serum urate value of less than 6 mgldl. When treatment of hyperuricemia is initiated, the patient should receive daily prophylactic colchicine to reduce the incidence of acute gout; this is continued until a stable serum urate level is achieved or until all visible tophi are gone. Therapy of hyperuricemia should not be started until after an episode of acute gout has subsided. Hyperuricemia can be treated either with allopurinol, a xanthine oxidase inhibitor which blocks the formation of uric acid, or with a uricosuric drug, which increases the urinary excretion of uric acid. Both types of drugs are suitable and effective in the majority of patients with gout. Allopurinol is the preferred drug in patients with tophaceous gout, nephrolithiasis, significant renal impairment, and overproduction of uric acid (as defined by the urinary uric acid excretion of > 600 mglday on a purine-free diet, > 800 mg on an unrestricted diet). In surveys of prescribing practices, it has been found that the majority of physicians use allopurinol to treat hyperuricemia, irrespective of the degree of uricosuria (Bellamy et al, 1988). This preference for allopurinol may be related to the fact that it is effective in a single daily dose and in patients with impaired renal function and does not pose a significant risk for precipitating renal calculi. However, allopurinol is more likely than the uricosuric agents to cause severe and potentially life-threatening hypersensitivity reactions, and its use should thus be supervised with care.
Treatment of Gout
The Uricosuric Agents Uricosuric agents are organic acids which inhibit reabsorption of urate secreted in the renal tubule and thereby increase the urinary excretion of uric acid. Their efficacy is reduced or nullified in patients with significant renal impairment (creatinine clearance < 20-30 mllmin) and in patients who are using concomitant salicylates. In view of the fact that these agents increase urinary uric acid excretion and predispose to stone formation, they should be used with caution or not at all in patients with a history of nephrolithiasis or in patients with gross overexcretion of uric acid (e.g., > 1000 mgld on a purine-free diet). The two uricosuric agents which are available and commonly used in the United States for the treatment of hyperuricemia are probenicid and sulfinpyrazone (Figure 1). Benzbromarone is a potent uricosuric agent that is available and widely used in Europe. Both probenicid and sulfinpyrazone are readily absorbed from the gastrointestinal tract. The half-life of each is less than 12 hours and thus each must be dosed at least twice daily. Both drugs are extensively bound to serum proteins and remain primarily within the extracellular fluid space. Probenicid is rapidly metabolized in vivo to an acyl glucuronide which is excreted in the urine. Approximately 20-45% of sulfinpyrazone is excreted unchanged in the urine; the remaining drug is excreted in the urine as the parahydroxyl metabolite which is also uricosuric. Since sulfinpyrazone prolongs platelet survival and may be effective in preventing myocardial infarction and venous thrombosis, it has potential advantages in a gout patient with cardiovascular risk factors, such as hypertension. Both probenicid and sulfinpyrazone can inhibit the transport of other organic anions across epithelial barriers. Probenicid has been shown to block the biliary secretion of rifampin and the renal elimination of penicillin, ampicillin, cephradine, indomethacin, acetazolamide, and dapsone. The doses of indomethacin and dapsone should be reduced in a patient taking probenicid in order to avoid toxicity. The starting dose of probenecid is 250 mg twice daily. The daily dose is then increased by 500 mg every 2-3 weeks until the serum urate level is below 6 mgldl. The usual maintenance dose is 500 mg twice a day; 40% of patients may require a daily dose of 1.5 grams or more. The starting dose of sulfinpyrazoneis 50 mg twice a day. The dose can then be increased every week or two by 100 mg until the serum urate is less than 6 mgldl. The usual maintenance dose is 300-400 mg per day in divided doses. When uricosuric therapy is initiated, the patient should increase his daily fluid intake in order to maintain a generous urinary output (e.g., 2-3 liters per day). This should be continued until the hyperuricemia is corrected or until all visible tophi are gone. If a uricosuric agent must be used in an individual with a history of nephrolithiasis or excessive urinary excretion of uric acid (i.e., in an individual allergic to allopurinol), the risk of precipitating a renal calculus can be substantially
ALAN N. BAER
CH' 3' CH ,CH
c ~\2 Nso2<=>
COOH
\ /
,CH',
Probenicid
N-C,
I
N-C/
,
II
CHCH CH, S
Sulfinpyrazone
Br Benzbromarone Figure 1 . Chemical structures of the uricosuric agents.
reduced by alkalinizing the urine (pH > 6) with acetazolamide (500 mg qhs), oral sodium bicarbonate (2-6 grams per day) or sodium citrate (Shohl's) solution (20-60 ml per day).
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731
The side effects of probenecid and sulfinpyrazone are similar and include gastrointestinal symptoms, skin rash and other hypersensitivity phenomena. The gastrointestinal symptoms can be reduced in frequency by taking the drug after meals. Serious toxicity related to either drug is rare. Benzbromarone is a halogenated uricosuric agent which is available outside the United States. This potent uricosuric agent is well-absorbed from the gastrointestinal tract and reaches peak serum concentrations within 4 hours of oral administration. It is debrominated in the liver and excreted in the bile in its free or conjugated form. The usual maintenance dose is 100 mg once daily; the dose range is 25 to 120 mg per day. In contrast to prohenicid and sulfinpyrazone,benzbromarone can promote uricosuria in patients with moderate renal insufficiency (e.g., serum creatinine 2-3 mgldl). Xanthine Oxidase lnhibitors
Allopurinol is a potent competitive inhibitor of xanthine oxidase. Since xanthine oxidase converts hypoxanthineto xanthine and xanthine to uric acid, administration of this drug is associated with a significant decrease in the plasma concentration of urate and the urinary excretion of uric acid, as well as a rise in the plasma levels and urinary excretion of xanthine and hypoxanthine (Figure 2). These oxypurines have a rapid renal clearance and thus do not accumulate to any extent; the increased urinary excretion of these more soluble oxypurine precursors of uric acid is rarely associated with the development of xanthine stones. Allopurinol is completely absorbed from the gastrointestinaltract and has a serum half-life of 3 hours or less. The major pathway of metabolism of allopurinol is oxidation to oxipurinol; this metabolite retains the capacity to inhibit xanthine oxidase and has a half-life of 12-17 hours. Thus, the biologic half-life of allopurinol is significantly prolonged by conversion to an active metabolite with a long half-life. Allopurinol has unique utility in patients with a history of nephrolithiasis and in those with renal impairment since its urate-lowering efficacy is associated with a decrease in the concentration of uric acid in the urine and is not dependent on renal function. The dose of allopurinol required to control the serum urate level ranges from 100 mg to 800 mg per day. In most patients, a single daily dose of 300 mg suffices. It is unusual for a patient to require doses of 400 mg or more to coiltrol hyperuricemia; poor compliance is the usual cause for this failure. The initial dose of allopurinol should be low (50-100 mg) and then increased gradually to find the lowest effective dose. Such a dosing regimen inay serve to minimize the risk of precipitating acute gout. A lower dose of allopurinol (e.g., 50-200 mg) should be effective and employed in patients with renal insufficiency in view of the dependence of oxipurinol on renal excretion (Hande et al., 1984). Allopurinol is generally well tolerated. Undesirable side effects are observed in 5 to 20% of patients treated with this drug, but most patients do not need to discontinue the medication. The most frequent side effects include skin rash,
ALAN N. BAER
allopurinol
hypoxanthine
ox~pur~nol
xanthlne
U ~ I Cacld
Figure 2. Inhibitory effects of allopurinol and its metabolite, oxipurinol, on the final
steps of purine metabolism.
abdominal pain, diarrhea and headache. The skin rash is generally a pruritic maculopapular erythema; if mild, the drug can be stopped until the rash resolves and then reinstituted at a lower initial dose. In a small number of patients, a severe hypersensitivity syndrome occurs with allopurinol therapy, marked by exfoliative dermatitis or toxic epidermal necrolysis, fever, worsening renal function, eosinophilia, hepatitis, and leucocytosis (Hande et al., 1984). This allopurinol hypersensitivity syndrome has a high mortality and tends to occur within 3 weeks of initiating allopurinol therapy. It has been described more commonly in patients with renal insufficiency receiving doses of allopurinol that were not adjusted in relation to the renal function. Other serious side effects reported with allopurinol include bone marrow suppression, hepatic toxicity, and interstitial nephritis. Several drug interactions with allopurinol are noteworthy. Allopurinol impairs the metabolism of the 6-mercaptopurine metabolite of azathioprine; thus, the concomitant use of azathioprine and allopurinol is associated with a heightened cytotoxic effect of azathioprine. The dose of azathioprine must be reduced by about 75% when used in combination with therapeutic doses of allopurinol. The hepatic microsomal oxidation of theophylline and coumadin is impaired by allopurinol; the dose of these two drugs may thus need to be reduced if a patient begins therapy with allopurinol. Allopurinol increases the frequency of an ampicillin-related drug rash.
Treatment of Gout
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THERAPY O F ASYMPTOMATIC HYPERURICEMIA Only a minority of individuals with asymptomatic hypenuicemia develop gouty arthritis or uric acid nephrolithiasis.Treatment of hyperuricemia is costly, long-term, and potentially toxic and can only be justified in asymptomatic individuals if it prevents sigdcant organ damage in the minority at risk. However, there is no compelling evidence to indicate that such benefit exists (Liang and Fries, 1978). The two principal organs that may be damaged directly by sustained hyperuricemia are the joints (tophaceous gout) and the kidneys (uratenephropathy and uric acid nephrolithiasis). Tophaceous gout virtually never occurs without the patient h t developing acute gout. The decision to treat hyperuricemia is thus reasonably deferred until the clinical onset of gout. The absolute risk of nephrolithiasis among patients with asymptomatic hyperuricemia was found to be one stone per 295 individuals per year in the study of Fessel (1979) and only 2.8 times higher than in normouricemic control subjects. This risk is sufficiently small to justify withholding therapy of asymptomatic hyperuricemia until the first stone occurs. Patients with gout have a high frequency of renal parenchymal disease marked by vascular nephrosclerosis, tubular atrophy, and interstitial fibrosis. The only histologic finding specific to patients with gout is monosodium urate crystal deposition in the renal medulla and pyramids with a surrounding giant cell reaction ("urate nephropathy"). The development of renal insufliciency and failure has been shown to be related to co-morbid conditions common to the gouty population, including atherosclerosis, hypertension, diabetes mellitus, and pre-existing primary renal disease, rather than to hyperuricemia and the deposition of urate in renal tissue (Yii and Berger, 1982). In the absence of these co-morbid conditions there is no evidence that chronic hyperuricemia adversely affects renal function. An exception may be men and women who maintain serum urate levels above 13 mg/dl and 10 mg/dl, respectively (Fessel, 1979). Thus, the vast majority of patients with asymptomatic hyperuricemia do not require treatment with urate-lowering drugs. The cytolytic treatment of patients with rapidly proliferating mahgnancies, such as leukemias and lymphomas, results in an acute, dramatic increase in urate production and urinary uric acid excretion. Precipitation of uric acid crystals in the distal tubules and collecting ductsmay ensue,with the production of an obstructiveuropathy.This syndrome, "uric acid nephropathy," is characterized by acute oliguria and the presence of uric acid crystals and sludge in the urine. It is prevented by the administration of allopurinol and maintenance of high urinary output during cytolytic therapy. Individuals with hypoxanthine-guanine phosphoribosyl transferase deficiency have marked mate overproduction and very high rates of urinary uric acid excretion and may also develop uric acid nephropathy, particularly during illnesses complicated by volume depletion.
SUMMARY There are two aspects to the management of gout: treatment of episodes of acute gouty arthritis and sustained correction of hyperuricemia. Acute gout is most
ALAN N. BAER
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commonly treated with non-steroidal anti-inflammatory drugs or oral colchicine. Other modalities, including intravenous colchicine, intra-articular corticosteroid injection, ACTH, and systemic corticosteroids may be used in special circumstances. Correction of hyperuricemia is the only definitive means to reduce the incidence of acute gout and to prevent the development of tophaceous gout, a chronic, potentially debilitating form of gouty arthritis. Urate-lowering drugs are indicated when the patient has recurrent episodes of acute gouty arthritis, tophaceous deposits, or nephrolithiasis. Two types of urate-lowering drugs are available, uricosuric agents which increase the renal excretion of uric acid and a xanthine oxidase inhibitor, allopurinol, which blocks the formation of uric acid. Allopurinol is the preferred drug in patients with tophaceous gout, nephrolithiasis, significant renal impairment, and overproduction of uric acid.
REFERENCES Alloway, J.A., Moriarty, M.J., Hoogland, Y.T., & Nashel, D.J. (1993). Comparison of triamcinolone acetonide with indomethacin in the treatment of acute gouty ~ 0 . 2 0 , 1 1 1 - 1 1 3 . Bellarny, N, Gilbert, J.R., Brooks, P.M., Emmerson, B.T., & Campbell, J. (1988). A survey of current prescribing practices of antiinflammatory and urate lowering drugs in gouty arthritis in the province of Ontario. J. Rheum. 15, 1841-1847. Campion, E.W., Glynn, R.J., & DeLabry, L.O. (1987). Asymptomatic hypenuicemia. Risks and consequences in the Normative Aging Study. Amer. J. Med. 82,421-426. Cronstein, B.N., & Weissman, G. (1993). The adhesion molecules of inflammation. Arthritis Rheum. 36, 147-157. Fessel, J. (1979). Renal outcomes of gout and hyperuricemia. Amer. J. Med. 67, 174-182. Groff, G.D., Franck, W.A., & Raddatz, D.A. (1990). Systemic steroid therapy for acute gout: A clinical trial and review of the literature. Sem. Arthr. Rheum. 19,329-336. Hall, A.P., Bany, P.E., Dawber, T.R., & McNamara, P.M. (1967). Epidemiology of gout and hyperuricemia. A long-term population study. Amer. J. Med. 42,27-37. Hande, K.R., Noone, R.M., &Stone W.J. (1984). Severe allopurinol toxicity. Description and guidelines for prevention in patients with renal insufficiency. Amer. J. Med. 76.47-56. Kuncl, R.W., Duncan, G., Watson, D., Alderson, K., Rogawski, M.A., & Peper, M. (1987). Colchicine rnyopathy and neuropathy. New Engl. J. Med. 316,1562-1568. Liang, M.H., & Fries, J.F. (1978). Asymptomatic hyperuricemia: The case for conservative management. Ann. Int. Med. 88,666-670. Mikkelsen, W .M., Dodge, H.J., & Valkenburg, H. (1965).The distribution of serum uric acid values in a population unseleded as to gout or hyperuricemia. Amer. J. Med. 39, 242-251. Roberts, W.N., Liang, M.H., & Stem, S.H. (1987). Colchicine in acute gout. Reassessment of risks and benefits. JAMA. 257,1920-1922. Roubenoff, R, Klag, M.J., Mead, L.A., Liang, K.-Y., Seidier, A.J., & Hochberg, M.C. (1991).Incidence and risk factors for gout in white men. JAMA. 266,3004-3007. Wallace, S.L., Robinson, H., Masi, A.T., Decker, J.L., McCarty, D.J., & Yii, T-F. (1977). Preliminary criteria for the classification of the acute arthritis of primary gout. Arthr. Rheum. 20,895-900. Wallace, S.L., Singer, J.Z., Duncan, G.J., Wigley, F.M., & Kuncl, R.W. (1991). Renal function predicts colchicine toxicity: Guidelines for the prophylactic use of colchicine in gout. J. Rheum. 18, 264-269. Yii, T.-F., & Gutman, A.B. (1967a). Uric acid nephrolithiasis in gout. Predisposing factors. Ann. Int. Med. 67, 1133-1148.
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Yii, T.-F., & Gutman, A.B. (1967b). Principles of current management of primary gout. Amer. J. Med. Sci. 253,893-907. Yii, T.-F. (1982). The efficacy of colchicine prophylaxis in articular gout. A reappraisal after 20 years. Sem. Arthr. Rheum. 12,256-264. Yii, T.-F., & Berger, L. (1982). Impaired renal function in gout. Its association with hypertensive vascular disease and intrinsic renal disease. Amer. J. Med. 72.95-100.