Xanthine oxidase inhibitors: Uses, common brands, and safety info

Gout attacks can be an intensely painful experience, marked by a warm, swollen, and tender joint, such as the great toe, wrist, or knee. For anyone who has experienced one, the thought of another is frightening. Fortunately, there are a number of ways to prevent acute gout recurrences. One such option is the xanthine oxidase inhibitor (XO inhibitors) class of medications. These drugs present a powerful opportunity to reduce the chances of a gout attack. This article will review the members of the class, how they work, and what costs and concerns must be considered before using them.

Other xanthine oxidase inhibitors

• Topiroxostat

What are xanthine oxidase inhibitors?

Xanthine oxidase inhibitors are urate-lowering drugs used in the treatment of gout. Urate is the salt form of uric acid. At low levels, uric acid circulates harmlessly through our bloodstream and is excreted by our kidneys. If levels become too high, above the saturation level, uric acid precipitates into the crystal monosodium urate within our joints and soft tissues. These crystals provoke the smoldering inflammation and joint damage of chronic gout as well as the searing inflammation and severe pain of acute gout. By lowering the level of uric acid in the body below the saturation level, XO inhibitors can reduce the harms of chronic gout and the risk of recurrent acute gout attacks.

How do xanthine oxidase inhibitors work?

Uric acid is the end product of purine metabolism. Purines are chemical compounds found in the food we eat, and they are also produced endogenously by our bodies. Purines are broken down into uric acid by a number of enzymatic steps, with the last two steps being catalyzed by xanthine oxidase. Inhibition of xanthine oxidase results in a reduction in uric acid levels, and less uric acid translates to less chance of gout.

The reason why some individuals experience the consequences of high uric acid and gout is primarily genetic. Their kidneys do not eliminate uric acid optimally, which results in high concentrations of uric acid in the blood. Historically, there was a stigma around a gout diagnosis, as patients believed the condition was caused by their diet or alcohol use. In reality, these factors can be gout triggers but are not the principal causes. Lowering red meat, shellfish, high fructose corn syrup-sweetened beverages, and alcohol consumption can all help to reduce uric acid levels and are worth doing for multiple reasons. Weight loss in general can result in less gout problems. However, individuals who experience repeated gout attacks should strongly consider pharmacological methods for uric acid reduction. 

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XO inhibitors are a preferred treatment of hyperuricemia (high blood levels of uric acid). Uricosuric medications, like probenecid, are less commonly used alternative agents that promote uric acid elimination in the urine instead of reducing uric acid production. Pharmacological methods for uric acid reduction are generally begun if one has had repeated gout attacks, has chronic joint damage from gout, has developed joint tophi (harm lumps of uric acid crystals), or has gout along with kidney dysfunction.

Uric acid levels can also be perilously high during certain chemotherapy courses. The destruction of large numbers of cancer cells can release a massive amount of purines into circulation, which is subsequently broken down into uric acid. The elevated uric acid levels are coupled with high potassium and phosphorus concentrations, and collectively, the condition is termed tumor lysis syndrome. Leukemia and lymphoma patients can be at significant risk of tumor lysis syndrome. Xanthine oxidase inhibitors may be useful drugs to reduce the body’s uric acid load in this setting.

Interestingly, high levels of uric acid in the urine are associated with a heightened risk of calcium oxalate kidney stones, the most common kidney stone variety. For those individuals with recurrent calcium oxalate stones and identified high urinary uric acid levels, XO inhibitors are a therapeutic option.

RELATED: Kidney stone treatment and medications

What are xanthine oxidase inhibitors used for?

• Gout prophylaxis

• Chemotherapy-related hyperuricemia (tumor lysis syndrome)

• Recurrent calcium oxalate nephrolithiasis (kidney stones)

Types of xanthine oxidase inhibitors

Zyloprim

The most commonly used xanthine oxidase inhibitor is allopurinol or its brand name version, Zyloprim. Allopurinol and its primary breakdown product oxypurinol inactivate xanthine oxidoreductase, the enzyme complex made up of xanthine oxidase and the sister version of XO, xanthine dehydrogenase. Consequently, in the setting of allopurinol, xanthine oxidase cannot act on its two substrates to produce urate. Hypoxanthine cannot be converted to xanthine and xanthine cannot be converted to urate.

Initiating a XO inhibitor like allopurinol is typically done after an acute gout flare has subsided. During a flare, much of the circulating serum urate has precipitated in a joint, so blood levels of uric acid may not accurately reflect the true baseline concentration. For this reason, waiting to measure a uric acid level until after the attack has subsided may be best. Furthermore, XO inhibitor therapy would likely be recommended only if the individual has a uric acid level over 6 mg/dL since the dose of allopurinol is adjusted to keep uric acid levels below 6 mg/dL. Another reason to delay xanthine oxidase inhibitor start-up is that a rapid drop in uric acid can trigger a gout flare.

Although allopurinol and other XO inhibitors can reduce the serum uric acid level fairly quickly, the resolution of preformed monosodium urate crystals in joints and tophi can take months. The residual crystals can continue to cause gout problems temporarily while the urate-lowering medication is doing its job. Many healthcare providers recommend a concurrent anti-inflammatory, such as colchicine or an NSAID like naproxen, for the first weeks or months after starting a xanthine oxidase inhibitor to keep gout attacks at bay.

Gout is associated with higher rates of cardiovascular disease and hypertension (high blood pressure). The basis of the connection with cardiovascular disease could be the synthesis of free radical superoxide anions during uric acid production and resultant vascular endothelial dysfunction within blood vessels. In other words, xanthine oxidase activity leads to reactive oxygen species which damage blood vessels. Allopurinol’s inhibition of xanthine oxidase can therefore explain its ability to be an antioxidant by reducing the oxidative stress caused by these reactive oxygen species. The antioxidant effect and vascular beneficial effect could be a mechanism for clinical trials showing a reduction in cardiovascular event rate and improvement in heart failure measures with allopurinol.

Uloric

Unlike Zyloprim, which inhibits xanthine oxidase by being a purine analog (look alike), Uloric acts as a xanthine oxidase inhibitor by inserting itself into a channel in the enzyme so that purines cannot bind to it. Ultimately, Uloric is used less than allopurinol, partly due to cost and partly because it only has an FDA indication for gout prophylaxis. At times, it is used off-label for tumor lysis syndrome. Uloric can be a chosen XO inhibitor in the setting of chronic kidney disease. 

Who can take xanthine oxidase inhibitors?

Can men take xanthine oxidase inhibitors?

At most ages, men have a higher incidence rate of gout than women of similar age. Fortunately, they can take xanthine oxidase inhibitors to prevent gout flares. 

Can women take xanthine oxidase inhibitors?

In general, women tend to have lower uric acid levels than men, but these levels start to rise after menopause. Predisposing genetic and comorbid disease factors can prompt a rise in uric acid in women at any age. If hyperuricemic, women can use an XO inhibitor.

Can you take xanthine oxidase inhibitors while pregnant or breastfeeding?

Caution is advised before the use of xanthine oxidase inhibitors during pregnancy or while breastfeeding. The hesitation is based on a lack of safety data from clinical trials.

Can children take xanthine oxidase inhibitors?

Uric acid levels are typically lower in children, and therefore, gout is rare. Unfortunately, hyperuricemia from chemotherapy can occur in children. In this circumstance, Zyloprim can be used to lower uric acid levels in children as young as 2 years old. Uloric is not approved for use in children.

Can seniors take xanthine oxidase inhibitors?

Both gout and cardiovascular events, such as myocardial infarctions (heart attacks), are more prevalent in seniors. This makes xanthine oxidase inhibitors particularly important tools for their protective effects in the senior demographic. However, the elevated potential for toxicity and drug interactions in seniors necessitates cautious usage of the drug class. 

Are xanthine oxidase inhibitors safe?

Black box warnings

The FDA has placed its highest warning label, a black box warning, on Uloric based on a study that found that febuxostat had a higher cardiovascular death rate than allopurinol. In the warning label, the FDA recommends risk factors and benefits be considered before starting or continuing febuxostat and that febuxostat only be used when allopurinol treatment is inadequate, not tolerated, or not advised.

Recalls

There are no current recalls on xanthine oxidase inhibitors, but the FDA’s database can be searched for updated information. 

Restrictions

• Neither Zyloprim nor Uloric should be used in the setting of a previous hypersensitivity allergic reaction to the drug or other members of the drug class. 

• Caution is advised before using either drug in the setting of renal (kidney) or hepatic (liver) impairment.

• Uloric has a caution advisory for anyone with a cardiovascular disease history. 

• Zyloprim has a higher rate of severe adverse effects in individuals from an African American, Han Chinese, Korean, Thai, Native Hawaiian, or Pacific Islander ancestry due to the higher prevalence of the HLA B*58:01 genetic allele. Screening for this allele may be worthwhile in some circumstances.

Are xanthine oxidase inhibitors controlled substances?

None of the XO inhibitors are controlled substances.

Common xanthine oxidase inhibitors side effects

• Gout exacerbation (upon initiation usually)

• Rash (more commonly mild but can be associated with rare, life-threatening syndromes)

• Urticaria (hives) or eosinophilia (elevated allergy-mediating cell count)

• Nausea or diarrhea

• Somnolence (tiredness)

• Pruritus (itching)

• Elevated liver enzymes (alkaline phosphatase, ALT, or AST)

How much do xanthine oxidase inhibitors cost?

The brand-name xanthine oxidase inhibitors Zyloprim and Uloric can cost $460 for a one-month supply. Even a one-month supply of generic allopurinol may carry a $40 price tag. To reduce the expense of xanthine oxidase inhibitors, try using a SingleCare discount card at your pharmacy.