What is the mechanism of action (MOA) of Allopurinol (xanthine oxidase inhibitor)?

From the Guidelines

Allopurinol works by inhibiting xanthine oxidase, the enzyme responsible for converting hypoxanthine to xanthine and xanthine to uric acid in purine metabolism, thereby reducing uric acid production and preventing the formation of urate crystals in joints and tissues. This mechanism makes it effective for treating conditions associated with hyperuricemia, such as gout and kidney stones. According to the most recent evidence 1, allopurinol is recommended as first-line therapy for patients with normal kidney function, starting at a low dose (100mg daily) and increasing by 100mg increments every 2-4 weeks if required, to reach the uricaemic target. The goal is to maintain serum urate levels below 6 mg/dL, which is below the saturation point for monosodium urate (MSU) to dissolve all crystal deposits.

Key Points

• Allopurinol inhibits xanthine oxidase, reducing uric acid production and preventing urate crystal formation.
• It is typically started at a low dose (100mg daily) and gradually increased as needed to achieve target serum urate levels.
• The medication is taken orally, usually once daily or divided into multiple doses for higher amounts.
• Patients should be monitored for potential side effects including rash, liver function abnormalities, and hypersensitivity reactions.
• Adequate hydration should be maintained during treatment to prevent crystallization of uric acid in the urinary tract.

Dosage and Administration

The dosage of allopurinol should be adjusted based on renal function, with the maximum dosage adjusted to creatinine clearance in patients with renal impairment 1. If the serum urate target cannot be achieved at this dose, the patient should be switched to febuxostat or given benzbromarone with or without allopurinol, except in patients with eGFR <30 mL/min.

Monitoring and Maintenance

Serum urate levels should be monitored regularly to ensure that the target level is maintained, and the dose of allopurinol should be adjusted as needed 1. The goal is to maintain serum urate levels below 6 mg/dL, which is below the saturation point for MSU to dissolve all crystal deposits. In patients with severe gout, a lower serum urate target (<5 mg/dL) may be recommended to facilitate faster dissolution of crystals.

From the FDA Drug Label

Allopurinol acts on purine catabolism, without disrupting the biosynthesis of purines. It reduces the production of uric acid by inhibiting the biochemical reactions immediately preceding its formation. Allopurinol is a structural analogue of the natural purine base, hypoxanthine It is an inhibitor of xanthine oxidase, the enzyme responsible for the conversion of hypoxanthine to xanthine and of xanthine to uric acid, the end product of purine metabolism in man. The mechanism of action (MOA) of allopurinol is through the inhibition of xanthine oxidase, an enzyme responsible for the conversion of hypoxanthine to xanthine and xanthine to uric acid. This inhibition reduces the production of uric acid without disrupting the biosynthesis of purines. Key points about allopurinol's MOA include:

• Inhibition of xanthine oxidase: Allopurinol inhibits the enzyme xanthine oxidase, which is involved in the conversion of hypoxanthine to xanthine and xanthine to uric acid.
• Reduction of uric acid production: By inhibiting xanthine oxidase, allopurinol reduces the production of uric acid.
• No disruption of purine biosynthesis: Allopurinol does not disrupt the biosynthesis of purines, allowing for normal nucleic acid anabolism to occur 2, 2.

From the Research

Allopurinol Mechanism of Action

• Allopurinol is a xanthine oxidoreductase (XOR) inhibitor, which is the rate-limiting enzyme in purine catabolism 3.
• It converts hypoxanthine to xanthine and then xanthine into uric acid, and by inhibiting this enzyme, allopurinol reduces the formation of uric acid 3, 4.
• Allopurinol is metabolized to oxypurinol, which also inhibits XOR, but with a weaker effect than allopurinol 5.
• The inhibition of XOR by allopurinol and oxypurinol reduces the production of uric acid, thereby preventing the formation of monosodium urate crystals, which can cause gout 3, 5.

Xanthine Oxidoreductase Inhibition

• Xanthine oxidoreductase is a metalloenzyme that catalyzes the final steps in purine metabolism, converting hypoxanthine to xanthine and then uric acid 5, 6.
• Inhibitors of xanthine oxidoreductase, such as allopurinol and febuxostat, are used to treat gout by reducing uric acid production 3, 6.
• Natural products, such as flavonoids, tannins, and triterpenes, have also been shown to have xanthine oxidoreductase inhibitory activity and may be potential treatments for gout 6.

Clinical Use of Allopurinol

• Allopurinol is established as first-line therapy for gout, reducing the formation of uric acid and preventing the formation of monosodium urate crystals 3.
• It is also used experimentally for the treatment of conditions associated with ischemia and reperfusion injury, such as cardiac ischemia 4.
• However, the use of allopurinol has been associated with potential side effects, and research is ongoing to find new and safer xanthine oxidoreductase inhibitors for the treatment of gout 6, 7.