Xanthine Oxidase Inhibitor Treatment of Hyperuricemia




Key Points





  • Xanthine oxidase is a critical enzyme in the metabolism of purines to uric acid. Both allopurinol and febuxostat reduce serum urate concentration through inhibition of xanthine oxidase.



  • The active metabolite of allopurinol, oxypurinol, is largely eliminated unchanged via the kidneys and its half-life is dependent on renal function.



  • Risk factors for allopurinol hypersensitivity syndrome (AHS) are impaired renal function, short treatment duration, diuretic use, and HLA-B 5801 . The role of allopurinol dosing as a risk factor for AHS remains controversial.



  • Febuxostat is metabolized by hepatic conjugation and oxidation, and dose adjustment is not required in patients with mild to moderate renal impairment.



  • Randomized controlled trials have consistently demonstrated that febuxostat has superior urate-lowering efficacy compared with fixed-dose allopurinol. Further studies are required to determine the comparative efficacy of allopurinol and febuxostat when a treat-to-target serum urate approach is used with allopurinol.



  • Effective urate lowering via xanthine oxidase inhibition therapy is associated with a high risk of gout flares at the start of therapy, and intensive gout prophylaxis is required to ensure that adherence to xanthine oxidase inhibitor treatment is maintained in the early phases of treatment.



  • In addition to treatment of gout, xanthine oxidase inhibitors have potentially beneficial effects in renal impairment, hypertension, angina, and cardiac failure.





Introduction


Urate-lowering therapy is an essential component in the long-term management of gout. A serum urate (SU) concentration below 6 mg/dL (0.36 mmol/L) is recommended as a treatment target for patients with gout. This is the concentration that corresponds to that required to ultimately, with extended therapy, achieve resolution of monosodium urate (MSU) crystals within synovial fluid, suppression of acute gout attacks, and resolution of gouty tophi. Xanthine oxidase (XO) is a critical enzyme in the metabolism of purines to uric acid. It catalyzes the conversion of hypoxanthine to xanthine and xanthine to uric acid. As such, inhibition of XO has been one of the mainstays of urate-lowering therapy (ULT) in gout since the introduction of allopurinol in 1963. Until the recent development and approval of febuxostat, allopurinol was the only XO inhibitor available for ULT. This chapter will review the XO inhibitors allopurinol and febuxostat and compare the clinical efficacy of these two urate-lowering drugs in controlling the hyperuricemia of gout.


Xanthine Oxidase and Uric Acid Production Pathways


Uric acid is the end product of purine degradation. Purines are obtained either though the diet or from endogenous sources such as cellular turnover. XO is a critical enzyme in the metabolism of purines to uric acid, catalyzing the conversion of hypoxanthine to xanthine and xanthine to uric acid (see Chapter 3 ).


XO belongs to the family of enzymes known as molybdenum hydroxylases. A common feature of this family of enzymes is the use of water rather than O 2 as the source of the oxygen atoms required for the reaction. Structurally XO consists of flavin molecules (bound as flavin adenine dinucleotide [FAD]), molybdenum, and iron-sulfur clusters. The molybdenum atoms are contained as molybdopterin cofactors and are the active sites of the enzyme. In the reaction with xanthine to form uric acid, an oxygen atom is transferred from molybdenum to xanthine. Active molybdenum is reformed by the addition of water.


In most other mammals, uric acid is broken down by urate oxidase to form allantoin, which is more water soluble and hence more easily excreted. Lack of urate oxidase in humans results in the final product of the purine degradation pathway being uric acid. The critical role of XO in this pathway led to it being a therapeutic target for the management of hyperuricemia.




Allopurinol


Structure and Mechanisms of Action


Allopurinol (4-hydroxypyrazolo[3,4- d ]pyrimidine) is a structural analog of hypoxanthine, while its active metabolite oxypurinol is a structural analog of xanthine ( Fig. 13-1 ). The mechanisms of action of allopurinol and oxypurinol are summarized in Table 13-1 . Both allopurinol and oxypurinol inhibit XO, thereby reducing the production of uric acid. XO exists in both oxidized and reduced forms. Allopurinol weakly inhibits the oxidized form, while oxypurinol binds and inhibits the reduced form of XO. The binding of oxypurinol to the reduced form of XO is strong and renders the binding site inaccessible to reoxidation; thus, dissociation of oxypurinol from XO is slow. Therefore, oxypurinol provides the majority of the inhibition of XO by virtue of its longer half-life and much stronger binding to the reduced form of XO. Oxypurinol has been described as a mechanism-based inhibitor of XO as it binds to the molybdenum atom of the molybopterin cofactor within XO at sites that are essential for its catalytic reaction.




Figure 13-1


Chemical structure of allopurinol and oxypurinol.


Table 13-1

Comparison of Febuxostat, Allopurinol, and Oxypurinol Structure and Pharmacokinetics (Febuxostat Data Following Multiple Dosing of Febuxostat 120 mg/day)









































































Allopurinol Oxypurinol Febuxostat
Structure Structurally similar to hypoxanthine Structurally similar to xanthine No structural resemblance to purines or pyrimidines
Mechanism of XO inhibition Mechanism-based inhibitor: binds at sites within XO that are critical for enzyme activity Structure-based inhibitor: binds in a long, narrow channel leading to the molybdenum-pterin active site
Inhibition of XO Weakly inhibits oxidized form of XO Inhibits reduced form of XO Inhibits oxidized and reduced forms of XO
Oral absorption About 80% N/A ≥84%
Time to maximum plasma drug concentration ( t max ) 1.5 hr 4 hr 1.1 hr
Maximum plasma drug concentration (C max ) 2 mg/L 7 mg/L 5.31 μg/ml
Area under the plasma concentration-time curve for the dose administration from 0 to 24 hr (AUC 24 ) 4.35 ± 0.67 μg • hr/ml 166 ± 23 μg • h/ml 11.96 μg • hr/ml
Metabolism Metabolized by aldehyde oxidase to oxypurinol N/A Hepatic; conjugation by uridine diphosphate-glucuronosyltransferase (UGT) enzymes and oxidation to active metabolites by CYP1A2, CYP2C8, and CYP2C9
Active metabolites Oxypurinol N/A 67M-1, 67M-2, and 67M-4
Enterohepatic recirculation No No Yes, above doses of 120 mg/day
Volume of distribution at steady state 1.3 L/kg 0.62 L/kg 0.7 L/kg
Plasma protein binding <1% No 99.2% (primarily albumin)
Elimination half-life ( t ½ ) about 1 hr Depends on renal function, about 23 hr 11.9 hr

N/A, Not applicable; XO, xanthine oxidase .


The importance of oxypurinol in XO inhibition was confirmed by a study comparing the effect of allopurinol and oxypurinol administered at equimolar doses, which reported only a small difference in urate-lowering effect (average reduction in SU from baseline 3.0 mg/dL with allopurinol and 2.6 mg/dL with oxypurinol, p = .027).


The structural similarity between allopurinol/oxypurinol and the purines xanthine/hypoxanthine means they may act as a substrate for other metabolic enzymes. Hypoxanthine-guanine phosphoribosyltransferase (HGPRT) and orotate phosphoribosyltransferase (OPRT) can convert allopurinol and oxypurinol to their respective ribonucleotides (allopurinol-1′-ribonucleoside, oxypurinol-1′-ribonucleoside, and oxypurinol-7′-ribonucleoside). Allopurinol, oxypurinol, and allopurinol-1′-ribonucleoside may inhibit other enzymes in the purine and pyrimidine metabolic pathways, including purine nucleoside phosphorylase (PNP) (possibly via accumulation of hypoxanthine and xanthine) and orotidine-5′-monophosphate decarboxylase (OMPDC), respectively.


In addition to its urate-lowering effects through XO inhibition, allopurinol reduces total purine production. Allopurinol utilizes phosphoribosyl pyrophosphate (PRPP), which is required for purine synthesis, in the reaction catalyzed by HGPRT. Increased concentrations of the ribonucleotides also cause feedback inhibition of amidophosphoribosyl transferase, a rate-limiting enzyme required for the biosynthesis of purines.


Recent data have shown that allopurinol can also rapidly produce mild inhibition of nociceptive responses induced by injection of capsaicin or glutamate in a dose-dependent manner in a murine model. Furthermore, the effects of allopurinol were reversed by administration of a specific adenosine A 1 receptor antagonist. The exact mechanism by which allopurinol produces such pain-relieving effects remains unclear. To date there are no studies that examine the analgesic effects of allopurinol in gout, other than through its ability to reduce SU, thereby preventing gout flares. Further studies will be required to determine whether allopurinol has a role in acute and/or chronic pain states.


Clinical Pharmacology


The clinical pharmacology of allopurinol and oxypurinol is summarized in Table 13-1 . Allopurinol is readily absorbed from the gastrointestinal tract. The major route of elimination of allopurinol is through metabolism to oxypurinol (about 80%), while about 10% is metabolized to allopurinol 1′-riboside. It has been widely assumed that XO is responsible for the conversion of allopurinol to oxypurinol. Given that allopurinol and oxypurinol both inhibit XO, metabolism of allopurinol to oxypurinol should be saturable if XO is also primarily responsible for the metabolism of allopurinol. However, steady-state plasma oxypurinol concentrations increase in a linear fashion as the dose of allopurinol increases, suggesting that the metabolism of allopurinol to oxypurinol is not saturable and that another enzyme must be involved. The closely related enzyme aldehyde oxidase (AO) appears to be more important in the metabolism of allopurinol to oxypurinol. This is supported by the ability of those rare patients who lack XO but who do have AO to metabolize allopurinol to oxypurinol, while those patients who lack both XO and AO cannot convert allopurinol to oxypurinol.


In comparison to allopurinol, which has short half-life (t ½ about 1 hour), oxypurinol has a much longer half-life. Oxypurinol is largely eliminated unchanged via the kidneys and thus its half-life is dependent on renal function.


Drug Interactions With Allopurinol


Azathioprine


Gout is common in patients with solid organ transplantation, and azathioprine is a commonly used immunosuppressive agent after transplantation. 6-Mercaptopurine, the active metabolite of azathioprine, is partly inactivated by XO. Inhibition of XO by allopurinol may therefore lead to increased concentrations of 6-mercaptopurine and myelosuppression. It is recommended that the dose of azathioprine be reduced by 50% to 75% before commencing allopurinol and that the starting dose of allopurinol be lower than normal. However, despite dose adjustment patients can become pancytopenic with this combination after months or even years of therapy. Thus, the azathioprine-allopurinol combination must be used with great caution and with careful blood monitoring for the duration of combination therapy. While there may be a reluctance to reduce immunosuppression for fear of transplant rejection, there are case reports of successful management of gout by this means.


Furosemide


Furosemide is a powerful loop diuretic that inhibits the absorption of chloride and sodium within the kidney, increasing the rate of urine formation and sodium excretion. Furosemide also decreases urinary excretion of uric acid, which along with the reduction in extracellular fluid results in an increase in SU concentrations. The increase in SU occurs within a few days of commencing diuretics and persists for the duration of therapy. In addition to increasing SU, furosemide has been shown to have effects on plasma oxypurinol concentrations. In a small study of six healthy subjects, a single intravenous dose of 20 mg furosemide reduced urinary oxypurinol excretion by about 40%, although there was no effect on serum oxypurinol concentrations during the study period. However, a significant interaction between furosemide and allopurinol may occur during long-term treatment, and the authors suggest that the hypouricemic effect of allopurinol may become more potent as a result of this interaction. Patients with gout on furosemide require higher doses of allopurinol relative to their renal function to attain SU less than 6 mg/dL (0.36 mml/L) compared to those not on frusemide. Furthermore, concomitant use of furosemide results in a significantly higher plasma oxypurinol concentration for any given allopurinol dose compared to no concomitant furosemide use ( p < .001) (Lisa Stamp, unpublished data). Combined, these data suggest that allopurinol/oxypurinol is less effective rather than more effective in patients on furosemide. Further studies of this interaction are required.


Thiazide Diuretics


Thiazide diuretics also decrease the renal clearance of uric acid leading to hyperuricemia. Small studies of patients with normal renal function have shown no effect of thiazide diuretics on the renal excretion of oxypurinol or increase in the half-life of oxypurinol. However, studies in patients with gout or renal impairment have not been undertaken.


Probenecid and Benzbromarone


Probenecid and benzbromarone are uricosuric agents that may be used in the management of gout. Combination therapy with allopurinol and probenecid may be used in patients who respond poorly to either agent alone, resulting in further reduction in SU. Despite this improvement in urate lowering, efficacy studies in healthy volunteers have shown that coadministration of allopurinol and probenecid reduces plasma oxypurinol concentrations with no effect on plasma probenecid concentrations. Thus, the uricosuric effect of probenecid interferes with the reduction in plasma oxypurinol concentrations, resulting in a reduction in SU.


Similar effects are observed when allopurinol and benzbromarone are combined with a reduction in SU concentrations. However, the effects of this combination on plasma oxypurinol concentrations are inconsistent with both a reduction in plasma oxypurinol and an increase in the renal elimination rate of oxypurinol, and no effect on renal oxypurinol elimination is reported.


Clinical Trials of Allopurinol for the Hyperuricemia of Gout


Key clinical outcomes for patients with gout include number of gout flares, tophus regression, dissolution of crystals, radiographic damage, patient function and quality of life, and cardiovascular outcomes. A recent review has highlighted the role of SU as a biomarker in chronic gout and summarizes the key evidence with respect to the clinical outcomes regardless of the therapy used. Allopurinol has specifically been shown to be effective in reducing SU, resorbing tophi, reducing the number of gout flares, and improving some cardiovascular outcomes ( Table 13-2 ). However, there are no clinical data to date that demonstrate the effect of allopurinol on radiographic joint damage or on patient function or quality of life.



Table 13-2

Summary of Clinical Trials of the Efficacy of Allopurinol








































































































Reference Trial Design Allopurinol Results
SU reduction Allopurinol discontinued in 33 patients with gout and effects observed


  • Mean serum urate (SU) prior to allopurinol 8.4 ± 1.1 mg/dL, after allopurinol therapy 5.5 ± 1.2 mg/dL, and after withdrawal of allopurinol 8.8 ± 1.2 mg/dL



  • Rise in SU occurred rapidLy with a return to pretreatment SU concentrations within 1 week

Prospective parallel open study of 86 males with gout. Allopurinol 300 mg/day compared to benzbromarone 100 mg/day.


  • Mean reduction in SU of 2.75 mg/dL in normal urate excretors and 3.34 mg/dL in urate underexcretors. 53% patients on allopurinol 300 mg/day achieved SU <6 mg/dL.



  • Dose of allopurinol increased to 450 mg/day in 21 patients and 600 mg/day in 2 patients to achieve SU <6 mg/dL.

Open randomized study in 36 patients with CrCl 20 to 80 ml/min/1.73 m 2 . Allopurinol 100-300 mg/day compared to benzbromarone 100-200 mg/day. Follow-up 9-24 mo 7/19 patients on allopurinol did not achieve SU <6 mg/dL. SU reduced from 8.96 ± 1.84mg/dL to 5.9 ± 0.92 mg/dL.
Prospective study of 57 patients attempting to attain SU <6 mg/dL. All patients received allopurinol. Follow-up 2-10 yr 67% never achieved SU <6 mg/dL—9 patients admitted noncompliance.
Retrospective review of 23 patients with crystal proven gout receiving allopurinol 50-400 mg/d SU concentrations reduced during a year of allopurinol therapy mean 9.4 mg/dL baseline vs. 7.4 mg/dL in first year of treatment ( p < .0001). Only 20.4% patients achieved SU <6.4 mg/dL.
Prospective observational study in 63 patients with tophaceous gout. Patients received allopurinol, benzbromarone, or combination. Allopurinol dose adjusted for renal function. Five-year follow-up Of the 24 patients who received allopurinol mean baseline SU was 8.78 ± 1.34 mg/dL and reduced to a mean SU during follow-up 5.37 ± 0.79 mg/dL ( p < .001 compared to baseline).
FACT study (n = 762). Patients with gout and SU ≥8.0 mg/dL randomized to febuxostat (80 or 120 mg/day) or allopurinol (300 mg/day) for 52 weeks. Primary endpoint (SU <6 mg/dL at last 3 monthly visits) achieved by 21% of those on allopurinol
Prospective randomized controlled trial of 54 hyperuricemic patients with chronic kidney disease. Randomized to allopurinol 100 or 300 mg/day or placebo for 12 mo Allopurinol reduced SU from baseline 9.75 ± 1.18 mg/dL to 5.88 ± 1.01 mg/dL ( p < .0001) at 12 mo.
Prospective open study in 51 gout patients. Commenced allopurinol 200-300 mg/day. Probenecid added if SU >5.0 mg/dL at 2 mo. After 2 mo 8/32 (25%) SU <5.0 mg/dL and 53% ≤6 mg/dL
SU reduced by 36 ± 11% from baseline
APEX study (n = 1072). Patients with gout and SU ≥8.0 mg/dL and serum creatinine ≤2.0 mg/dL randomized to febuxostat (80, 120, or 240 mg/day), allopurinol (100 or 300 mg/day depending on renal function) or placebo for 28 weeks. Last 3 monthly SU <6 mg/dL achieved in 22%
Prospective open-label study of 12 patients with-stage renal disease undergoing hemodialysis. All patients received allopurinol 300 mg/day for 3 mo Allopurinol resulted in a reduction in SU from baseline median of 10.13 mg/dL to a median of 6.6 mg/dL at 3 mo ( p < .01). The mean reduction in SU was –3.53 ± 2.4 mg/dL.
Randomized open labeled trial in gout patients (n = 65) with CrCl ≥50 ml/min. Patients randomized to allopurinol 300 mg/day, which was increased to 600 mg/day if SU not ≤5 mg/dL after 2 mo OR benzbromarone 100 mg/day increased to 200 mg/day at 2 mo


  • 8/31 (26%) patients achieved SU ≤5.0 mg/dL on allopurinol 300 mg/day.



  • 21/27 (78%) patients achieved SU ≤5.0 mg/dL on allopurinol 300 or 600 mg/day.



  • Mean SU reduction from baseline –33 ± 13% for allopurinol 300 mg/day and –49 ± 14% for allopurinol 600 mg/day

EXCEL study (n = 1086) 3-yr open-label extension study febuxostat 80 or 120 mg/day vs. allopurinol 300 mg/day. Primary endpoint SU <6 mg/dL.


  • 46% achieved SU <6 mg/dL after 1 mo. 56.6% allopurinol-treated patients reassigned to febuxostat to attain target SU.



  • Between 12 and 36 mo 75% to 100% maintained target SU

Open labeled 12-mo dose escalation study of 45 patients on allopurinol. Dose of allopurinol increased by 50-100 mg/mo to attain target SU <6 mg/dL


  • 88% patients achieved target SU at 12 mo. Mean % reduction in SU from baseline ranged from 10% to 37% depending on the dose of allopurinol in mg/day above the CrCl-based dose.



  • Increase in SU associated with noncompliance with therapy as assessed by plasma oxypurinol concentration

CONFIRMS study (n = 2269). Patients with gout and SU ≥8.0 mg/dL and CrCl ≥30 ml/min randomized to febuxostat (40 or 80 mg/day), allopurinol (200 or 300 mg/day depending on renal function) for 28 weeks. Primary endpoint SU <6 mg/dL at the final visit.


  • Primary endpoint achieved by 42% of all patients on allopurinol.



  • In those with renal impairment (CrCl 30-89 ml/min), primary endpoint achieved by 42% of patients on allopurinol.

Gout flare rates Open randomized study in 36 patients with CrCl 20-80 ml/min/1.73 m 2 . Allopurinol 100-300 mg/day compared to benzbromarone 100-200 mg/day. Follow-up 9-24 mo Number of flares reduced: 3.4 ± 1.62/yr before ULT to 0.93 ± 1.16 in first year of follow-up and 0.06 ± 0.25/yr during second year of follow-up. No difference between allopurinol and benzbromarone groups
Prospective study of 57 patients attempting to attain SU <6 mg/dL. All patients received allopurinol. Follow-up 2-10 yr Of the 33% patients who achieved SU ≤6 mg/dL for at least a year the mean number of attacks in the last year was 1 (range 0-3) compared to a mean of 6 (range 4-12) in those patients with SU >6 mg/dL.
Retrospective review of 23 patients with crystal proven gout receiving allopurinol 50-400 mg/day Mean dose of allopurinol was 211 mg/day. There was a significant reduction in the number of gout flares during a year of allopurinol therapy. Mean flares in year prior to allopurinol 2.69/yr compared to 0.3/yr during the first year of treatment ( p < .0001)
EXCEL study (n = 1086) 3-yr open-label extension study febuxostat 80 or 120 mg/day vs. allopurinol 300 mg/day. Primary endpoint SU <6 mg/dL. Maintenance of SU <6 mg/dL resulted in progressive reduction in flare rates such that flares occurred in <4% patients after 18 mo of ULT
Prospective observational study in 63 patients with tophaceous gout. Patients received allopurinol, benzbromarone or combination. Allopurinol dose adjusted for renal function. Five-year follow-up Of the 24 patients who received allopurinol mean diameter of target tophus at baseline was 16.2 ± 6.1mm. The time until tophus resolution was 29.1 ± 8.3 mo with a velocity of tophus reduction of 0.57 ± 0.18 mm/mo.
Tophus resorption Prospective study of 57 patients attempting to attain SU <6 mg/dL. All patients received allopurinol. Follow-up 2-10 yr Mean of 3 tophi in patients with SU ≤6 mg/dL compared to 14 tophi in patients with SU >6 mg/dL.
FACT study (n = 762). Patients with gout and SU ≥8.0 mg/dL randomized to febuxostat (80 or 120 mg/day) or allopurinol (300 mg/day) for 52 wk. Median reduction in tophus area was 50%
EXCEL study (n = 1086) open label extension study febuxostat 80 or 120 mg/day vs. allopurinol 300 mg/day. Tophus resolution achieved by 29%


Lowering of Serum Urate Concentration


A number of clinical trials have reported a reduction in SU with allopurinol therapy (see Table 13-2 ). Compliance with allopurinol therapy is often poor, and only one of these studies assessed patient compliance with allopurinol therapy using plasma oxypurinol concentrations. In this study, there was clear evidence of effective SU reduction with allopurinol therapy that was lost when patients became noncompliant.


Tophus Reduction


Allopurinol has been shown to result in a reduction in the size and number of tophi (see Table 13-2 ). However, the combination of benzbromarone and allopurinol results in a more rapid reduction in tophus size compared to either agent alone.


Flare Rates


A sustained reduction in SU is required for cessation of gout flares. Even after SU reaches the target (less than 6 mg/dL), it may take months for the gouty flares to subside. Furthermore, commencement of allopurinol can precipitate an acute attack of gout. Therefore, careful patient education and use of prophylactic therapy when allopurinol is commenced are required. Studies have confirmed that allopurinol can reduce the number of gout flares (see Table 13-2 ) and may have an effect even if SU does not reach the target. As expected, patients with gout flares are less likely to be compliant with allopurinol (odds ratio [OR] 0.5; 95% confidence interval [CI] 1.25 to 8.23), highlighting the need for patient education and compliance monitoring.




Other Potential Indications for Allopurinol: Renal Disease, Cardiovascular Disease, and Hypertension


Effects of Allopurinol on Renal Function


Hyperuricemia is an independent risk factor for renal impairment in healthy normotensive individuals, is a predictor of renal progression in IgA nephropathy, and is associated with early glomerular filtration rate (GFR) loss in patients with type 1 diabetes. Furthermore, in a large Japanese cohort study, hyperuricemia was associated with an increased incidence of end-stage renal disease (ESRD) and was an independent predictor of ESRD in women. Allopurinol has been shown to slow the progression of renal disease. In a study of 54 hyperuricemic patients with chronic kidney disease, only 16% of patients receiving allopurinol had a significant deterioration in renal function (serum creatinine increase greater than 40% of baseline) or dialysis dependence after 12 months compared to 46.1% of controls ( p = .015). In another study of 113 patients with GFR less than 60 ml/min, allopurinol 100 mg/day slowed the progression of renal disease independently of age, gender, C-reactive protein (CRP), diabetes, and use of angiotensin-converting enzyme (ACE) inhibitors.


Effects of Allopurinol on Cardiovascular Disease and Mortality


Hyperuricemia is increasingly recognized as an independent risk factor for a number of vascular disorders including hypertension, cardiovascular disease, and cerebrovascular disease (see review ). Hyperuricemia, in the absence of gout, is also associated with poor prognosis in patients with congestive heart failure (CHF). More recently, it has been recognized that gout per se is associated with an increase risk of cardiovascular disease and death.


Studies in patients with CHF have demonstrated an increase in both the amount and activity of XO, which leads to an increase in production of both SU and reactive oxygen species. These data led to the suggestion that XO inhibition may improve long-term cardiovascular outcomes through reduction of both superoxide and SU production.


Recent studies have reported a survival benefit in hyperuricemic patients treated with allopurinol. In a study of 9924 hyperuricemic veterans, therapy with allopurinol was associated with a lower risk of all-cause mortality, even after adjusting for other confounding variables including comorbidities and SU (hazard ratio [HR] 0.77; 95% CI 0.65 to 0.91). In patients with CHF, long-term high-dose allopurinol (300 mg/day or greater) was associated with significantly reduced mortality compared to patients receiving low-dose allopurinol (299 mg/day or less) (risk ratio [RR] 0.59; 95% CI 0.37 to 0.95). More recently, a large retrospective, nested case-control study of 25,090 patients with CHF demonstrated that a history of gout as well as a recent acute episode of gout (within 60 days) were associated with an increased risk of readmission for CHF or death (RR 2.06; 95% CI 1.39 to 3.06; p < .001). Allopurinol use was not associated with a reduction in CHF readmission or death in the total population (RR 1.02; 95% CI 0.95 to 1.1; p = .55). However, in those patients with gout, allopurinol use was associated with a significant reduction in CHF readmissions or death (RR 0.69; 95% CI 0.60 to 0.79) and reduced all-cause mortality (RR 0.74; 95% CI 0.61 to 0.90). These results are supported by the results of a placebo-controlled trial examining the effect of adding oxypurinol or placebo to standard CHF therapy in 405 patients. Although the addition of oxypurinol (600 mg/day) for 24 weeks did not improve outcomes in the cohort as a whole, there was a trend toward improved outcomes in the subgroup of patients with high baseline SU (9.5 mg/dL or higher) but not those with SU less than 9.5 mg/dL. Furthermore, there was an association between the extent of SU reduction and outcomes, with those patients who had a lesser reduction in SU having worse outcomes. Taken together, these data suggest that in the subgroup of patients with gout or hyperuricemia (9.5 mg/dL or higher), XO inhibition improves long-term outcomes.


Allopurinol, through its ability to reduce myocardial oxygen demand, may also be beneficial in patients with ischemic heart disease. In patients with chronic stable angina, allopurinol 600 mg/day for 6 weeks increased the median time to ST-segment depression on exercise testing, increased median total exercise time, and increased the time to chest pain compared to placebo. In another placebo-controlled study of 40 patients with ST-segment elevation myocardial infarction who underwent primary coronary intervention, the addition of allopurinol 400 mg stat followed by 100 mg/day for 1 month resulted in lower peak troponin I ( p = .04) and creatinine kinase (CK) ( p = .01) concentrations and more effective ST-elevation recovery ( p < .05). In addition, at 1 month, those patients who received allopurinol had a 13% lower incidence of major adverse cardiac events compared to placebo ( p < .002).


While further larger studies are required, these data give further weight to the need for ULT in patients with gout who are at high risk of cardiovascular disease. Whether the current target SU of less than 6 mg/dL is appropriate for preventing cardiovascular events remains to be determined. Finally, further studies will be required to determine the role of allopurinol in patients with asymptomatic hyperuricemia with cardiovascular disease. The effects of allopurinol on the cardiovascular system are summarized in Table 13-3 .



Table 13-3

Effects of Allopurinol on the Cardiovascular System



















Effect References
Improves myocardial contractility by restoring myocardial calcium sensitivity and β-adrenergic responsiveness in heart failure
Decreases oxidative stress leading to improved endothelial function
Decreases myocardial oxygen consumption for a particular stroke volume
May reduce plasma renin leading to reduced blood pressure


Serum Urate, Allopurinol, and Blood Pressure


Hypertension and hyperuricemia are commonly associated; 25% of patients with untreated hypertension, 50% of patients on diuretics, and more than 75% of patients with malignant hypertension have hyperuricemia. In patients with gout, up to about 40% have hypertension. While hyperuricemia may have a pathogenic role in hypertension (see review ), medications frequently used in the management of hypertension also contribute. Loop and thiazide diuretics both increase SU. In comparison, the angiotensin II receptor antagonist losartan and the calcium channel blocker amlodipine significantly increase uric acid clearance, thereby reducing SU. Thus, clinicians need to consider the underlying reasons for the use of loop or thiazide diuretics and whether alternative agents, which do not result in retention of uric acid, could be used in patients with gout.


Allopurinol may also contribute to a reduction in blood pressure. In a small study of 48 patients with hyperuricemia, allopurinol 300 mg/day for 3 months resulted in a significant reduction in both systolic and diastolic blood pressures. In another study of 30 adolescents (aged 11 to 17 years) with newly diagnosed essential hypertension, allopurinol 200 mg twice daily for 4 weeks resulted in a significant reduction in blood pressure. Similar studies have not been undertaken in patients with gout.


Allopurinol Hypersensitivity Syndrome


Allopurinol is generally well tolerated. Approximately 2% of patients develop a mild rash and up to 5% of patients stop allopurinol due to adverse events. The most devastating adverse effect is the potentially life-threatening allopurinol hypersensitivity syndrome (AHS). AHS is characterized by rash (e.g., Stevens-Johnson syndrome [SJS], toxic epidermal necrolysis [TEN], exfoliative dermatitis) ( Fig. 13-2 ), eosinophilia, leukocytosis, fever, hepatitis, and progressive renal failure. Criteria for the diagnosis of AHS that incorporate the clinical features after exposure to allopurinol have been published ( Table 13-4 ). Although SJS is not included in these criteria, it is common in AHS and should be included as one of the forms of rash in the major criteria.




Figure 13-2


Ocular, mucosal and cutaneous involvement in allopurinol hypersensitivity syndrome.

(From Fernando SL, Broadfoot AJ. Prevention of severe cutaneous adverse drug reactions: the emerging value of pharmacogenetic screening. CMAJ 2010;182(5):476-80.)


Table 13-4

Diagnostic Criteria for Allopurinol Hypersensitivity Syndrome
















Diagnostic Criteria for Allopurinol Hypersensitivity Syndrome
Clear history of exposure to allopurinol
Lack of exposure to another drug that may have caused the same clinical picture
Clinical picture including:


  • At least two of the following major criteria



  • Worsening renal function



  • Acute hepatocellular injury



  • Rash, including toxic epidermal necrolysis, erythema multiforme, or a diffuse maculopapular or exfoliative dermatitis

OR
One of the major criteria and at least one of the following minor criteria


  • Fever



  • Eosinophilia



  • Leukocytosis


From Gutierrez-Macias A, Lizarralde-Palacios E, Martinez-Odriozola P, et al. Fatal allopurinol hypersensitivity syndrome after treatment of asymptomatic hyperuricemia. Br Med J 2005;331:623-4.


The incidence of AHS is estimated to be about 0.1%. In the hospital-based Boston Collaborative Drug Surveillance Program, 7 of 1835 (0.38%) patients treated with allopurinol had a life-threatening reaction, although not all of these were AHS. A more recent European study of patients with SJS or TEN reported that allopurinol was the most common causative drug and that the incidence of allopurinol-associated SJS or TEN had increased in the past 15 years.


Risk Factors for AHS


Risk factors for the development of AHS include renal impairment, diuretic use, and recent commencement of allopurinol therapy ( Table 13-5 ). More recently, HLA-B 5801 has been identified as a significant risk factor for AHS and allopurinol-associated SJS and TEN. In Han Chinese, the HLA-B 5801 allele was found in 100% of AHS cases and 15% of allopurinol-tolerant controls (OR 580.3; 95% CI 34.4 to 9780.9). A similar association has been observed in several ethnic populations including Thai, Japanese, and a mixed population of Europeans. Whether HLA profiling can help prevent these life-threatening reactions remains to be determined and will likely require large international trials within different ethnic groups. Many cases of AHS have been reported in patients receiving allopurinol for asymptomatic hyperuricemia. It remains unclear whether asymptomatic hyperuricemia is a specific risk factor for AHS, although a recent case-control study of AHS did report lower rates of gout in AHS cases than in allopurinol-tolerant controls.



Table 13-5

Risk Factors for Allopurinol Hypersensitivity Reactions






















Risk Factor References
Recent onset of allopurinol treatment
Renal impairment
Diuretic therapy
Presence of HLA-B 5801 allele
? Allopurinol dose Positive association:
Negative association:


Outcome and Treatment of AHS


AHS is a life-threatening condition with mortality associated reported to be as high as 27%. There is no cure for AHS, and early recognition and drug withdrawal are critical. Supportive care is the mainstay of treatment. Corticosteroids have been used; however, their role is controversial. Whether increased excretion of oxypurinol through uricosuric drugs (such as probenecid ) or hemodialysis has a role in the management of AHS is unknown.


Mechanism of AHS


The exact mechanism of AHS is unclear. Some cases of AHS occur as a result of T-cell–mediated immune reactions to oxypurinol. Although it has been suggested that AHS may be due to an accumulation of oxypurinol, AHS can occur even with low oxypurinol concentrations.




Other Adverse Effects of Allopurinol


Allopurinol has been reported to be the most common cause of drug reaction with eosinophilia and systemic symptoms (DRESS). DRESS is characterized by fever, rash, eosinophilia, multiorgan involvement, and lymphocyte activation. There is some debate as to whether DRESS is a separate clinical entity from other drug-induced reactions such as AHS. While there may be some pathologic differences between AHS and DRESS, the clinical picture can be very similar. Whether HLA-B 5801 is also a risk factor for DRESS is unclear.


Allopurinol has also been associated with hypersensitivity vasculitis with a variety of clinical manifestations, including rash, cerebral vasculitis, eosinophilia, glomerulonephritis, and liver disease. Less commonly, allopurinol has been associated with drug-induced antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis.


Some allopurinol adverse effects may be related to effects on pyrimidine metabolism. Murine studies have shown that high-dose allopurinol results in abnormal pyrimidine metabolism and nephrotoxicity, an effect that was limited by provision of uridine.


Allopurinol, through its ability to increase purines, including adenosine, may have effects on the central nervous system (CNS). Adenosine has a number of inhibitory effects within the CNS including anticonvulsant, sedative, antipsychotic, and antiaggression effects. Such effects may be of benefit in the treatment of conditions such as schizophrenia. However, these effects, particularly the sedating effects, can be considered unwanted adverse effects in patients receiving allopurinol for the treatment of hyperuricemia.




Allopurinol Dosing


There is currently no clear evidence base or consensus regarding allopurinol dosing, especially in patients with renal impairment. The U.S. Food and Drug Administration (FDA) has approved allopurinol in doses up to 800 mg/day in patients with gout, while the British Society of Rheumatology (BSR) recommends a maximum dose of 900 mg/day. The FDA, BSR, and European League Against Rheumatism (EULAR) all recommend that allopurinol is commenced at a low dose (50 to 100 mg/day) and increased in 50- to 100-mg increments until the target SU is achieved, a measure that could reduce development of gout attacks when commencing urate-lowering therapy. However, all acknowledge that the maximum dose of allopurinol should be reduced in patients with renal impairment.


Dose reduction in renal impairment is based on reports of a relationship between full-dose allopurinol (300 mg/day or greater) in patients with renal impairment and development of AHS. This observation, along with the recognition that oxypurinol excretion was significantly reduced in patients with impaired renal function, led to the suggestion that allopurinol should be dosed according to creatinine clearance (CrCl) ( Table 13-6 ).



Table 13-6

Allopurinol Dose Based on Creatinine Clearance


































Creatinine Clearance (ml/min) Maintenance Dose Allopurinol
0 100 mg every 3 days
10 100 mg every 2 days
20 100 mg/day
40 150 mg/day
60 200 mg/day
80 250 mg/day
100 300 mg/day
120 350 mg/day
140 400 mg/day

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