Allopurinol
Aloprima, Zyloprim®
Classification:
Musculoskeletal Agents
Description: Allopurinol (Zyloprim) is a structural analog of the natural purine base, hypoxanthine. Allopurinol (Zyloprim) is used in the prevention of gout, renal calculi due to either uric acid or calcium oxalate, and in the prophylaxis and treatment of uric acid nephropathy. In addition, allopurinol is indicated for the prophylaxis of hyperuricemia and its complications associated with radiation and chemotherapy treatment of leukemia, lymphoma, other myeloproliferative disorders, and some solid tumors. Because uricosuric antigout agents can increase the formation of kidney stones in patients with high rates of uric acid excretion, gouty nephropathy, azotemia, or preexisting stones in the urinary tract, allopurinol is the preferred antigout agent in these patients. Allopurinol (Zyloprim) can be quite toxic if doses are not adjusted for renal dysfunction. Allopurinol (Zyloprim) was approved by the FDA in 1966. In 1992, Allopurinol (Zyloprim) sodium injection was given orphan drug status for the management of cancer patients who, due to their chemotherapy, are experiencing elevated serum and urinary uric acid levels and are unable to tolerate oral therapy. Allopurinol (Zyloprim) sodium injection was subseqently approved for this indication in May 1996 and become available in July 1999.
Mechanism of Action: Allopurinol inhibits the enzyme xanthine oxidase, which blocks the metabolism of hypoxanthine and xanthine (oxypurines) to uric acid. Xanthine oxidase inhibition is dose dependent. Unlike uricosuric agents, which increase the urinary excretion of uric acid, allopurinol interferes with the catabolism of purines. Concentrations of uric acid in the blood and urine are thereby lowered. In addition, secondary to elevated concentrations of oxypurine, allopurinol indirectly inhibits purine biosynthesis by stimulating negative feedback. Oxypurinol, an allopurinol metabolite, also inhibits xanthine oxidase and is the agent responsible for the pharmacologic effects of allopurinol. Allopurinol (Zyloprim) also facilitates the incorporation of hypoxanthine and xanthine into DNA and RNA, resulting in further reductions of serum uric acid concentrations. Although hypoxanthine and xanthine serum concentrations increase, their renal clearance is at least 10 times that of uric acid. A secondary result of decreased renal tubular transport of uric acid is increased nephron reabsorption of calcium ions.
Pharmacokinetics: Allopurinol (Zyloprim) may be administered orally or intravenously. The bioavailability of allopurinol following oral administration is approximately 80-90%. Peak plasma concentrations occur within 2-6 hours following oral administration. Following IV administration, the peak plasma concentration occurs in 30 minutes. Serum urate concentrations usually begin to decrease within 24-48 hours, although significant reductions may not be immediately evident due to the constant dissolution of uric acid deposits. Normal serum urate levels are usually achieved within 1-3 weeks. Allopurinol (Zyloprim) distributes throughout the body tissues and into breast milk.
Allopurinol (Zyloprim) is rapidly metabolized by hepatic oxidation to the active compound oxipurinol (alloxanthine). The plasma half-life of allopurinol is 1-3 hours. Oxypurinol half-life is 18-30 hours. Within 48-72 hours, approximately 12% of the drug is excreted as allopurinol, 70% is excreted as oxypurinol, and the remaining dose is excreted as riboside conjugates in the urine. Allopurinol (Zyloprim) requires dosage adjustment in patients with decreased creatinine clearance. Once the creatinine clearance is < 100 ml/min the interval must be extended and the dose decreased. Data for dosage adjustment in patients with hepatic impairment are not available.
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