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

Mechanism of Action of Allopurinol

Allopurinol works by inhibiting xanthine oxidase, the enzyme responsible for converting hypoxanthine to xanthine and xanthine to uric acid, thereby reducing uric acid production in the body. 1

Primary Mechanism

Allopurinol acts on purine catabolism through the following mechanisms:

• Structural analog: Allopurinol is a structural analog of hypoxanthine, a natural purine base 1
• Enzyme inhibition: It inhibits xanthine oxidase (XO), preventing the conversion of:
  • Hypoxanthine to xanthine
  • Xanthine to uric acid (the end product of purine metabolism) 1
• Active metabolite: Allopurinol is metabolized to oxipurinol (alloxanthine), which also inhibits xanthine oxidase and has a longer half-life (15 hours vs. 1-2 hours for allopurinol) 1

Biochemical Effects

When xanthine oxidase is inhibited by allopurinol:

• Serum uric acid levels decrease
• Serum concentrations of hypoxanthine and xanthine increase (typically to 0.3-0.4 mg/dL compared to normal levels of approximately 0.15 mg/dL) 1
• Reutilization of hypoxanthine and xanthine for nucleotide and nucleic acid synthesis is enhanced 1
• This reutilization doesn't disrupt normal nucleic acid metabolism because feedback inhibition remains intact in purine biosynthesis 1

Pharmacokinetics

• Absorption: Approximately 90% absorbed from the gastrointestinal tract 1
• Peak plasma levels:
  • Allopurinol: 1.5 hours
  • Oxipurinol: 4.5 hours 1
• Half-life:
  • Allopurinol: 1-2 hours
  • Oxipurinol: 15 hours (allows for once-daily dosing) 1
• Elimination:
  • Allopurinol: primarily by glomerular filtration
  • Oxipurinol: reabsorbed in kidney tubules similar to uric acid 1
  • Approximately 20% of ingested allopurinol is excreted in feces 1

Clinical Applications

Allopurinol is primarily used for:

• Management of hyperuricemia in gout 2, 3
• Prevention of tumor lysis syndrome (TLS) in patients with malignancies 2
• Treatment of recurrent kidney stones related to hyperuricemia 3

Limitations and Considerations

• Allopurinol only prevents the formation of new uric acid; it doesn't reduce uric acid produced before treatment initiation 2
• It may take several days for reductions in uric acid levels to occur 2
• Increased levels of xanthine and hypoxanthine can potentially lead to xanthine crystal deposition in renal tubules, though this is rare 2, 1
• Allopurinol reduces clearance of purine-based chemotherapeutic agents (e.g., 6-mercaptopurine, azathioprine), requiring dose reductions of these medications 2, 3
• Dose adjustment is necessary in patients with renal insufficiency 3

Potential Side Effects

• Hypersensitivity reactions (skin rash, fever) 2
• Rare but serious adverse effects include bone marrow suppression and aplastic anemia 4
• Drug interactions with medications like dicumarol, thiazide diuretics, and cyclophosphamide 3

By inhibiting xanthine oxidase, allopurinol effectively reduces uric acid production, making it a cornerstone therapy for conditions characterized by hyperuricemia.