ALLOPURINOL

By | 2010-06-13

Chemistry

A xanthine oxidase inhibitor, allopurinol occurs as a tasteless, fluffy white to off-white powder with a slight odor. It melts above 300° with decomposition and has an apparent pKa of 9.4. Oxypurinol (aka oxipurinol, alloxanthine), its active metabolite, has a pKa of 7.7. Allopurinol is only very slightly soluble in both water or alcohol.

Storage – Stability – Compatibility

Allopurinol tablets should be stored at room temperature in well-closed containers. The drug is stated to be stable in both light and air.

An extemporaneously prepared suspension containing 20 mg/ml allopurinol for oral use can be prepared from the commercially available tablets. Tablets are crushed and mixed with an amount of Cologel® suspending agent equal to 1/3 the final volume. A mixture of simple syrup and wild cherry syrup at a ratio of 2:1 is added to produce the final volume. This preparation has been reported to be stable for at least 14 days when stored in an amber bottle at either room temperature or refrigerated.

Pharmacology

Allopurinol and its metabolite, oxypurinol, inhibit the enzyme xanthine oxidase. Xanthine oxidase is responsible for the conversion of oxypurines (e.g., hypoxanthine, xanthine) to uric acid. Hepatic microsomal enzymes may also be inhibited by allopurinol. It does not increase the renal excretion of uric acid nor does it possess any anti-inflammatory or analgesic activity.

Allopurinol, by inhibiting xanthine oxidase, can also inhibit the formation of superoxide anion radicals, thereby providing protection against hemorrhagic shock and myocardial ischemia in laboratory conditions. The clinical use of the drug for these indications requires further study.

Uses – Indications

The principle veterinary uses for allopurinol are for the prophylactic treatment of recurrent uric acid uroliths and hyperuricosuric calcium oxalate uroliths in small animals. It has also been used in an attempt to treat gout in pet birds.

Pharmacokinetics

No information was located on the pharmacokinetics of this agent in veterinary species. In humans, allopurinol is approximately 90% absorbed from the GI after oral dosing. Peak levels after oral allopurinol administration occur 1.5 and 4.5 hours later, for allopurinol and oxypurinol, respectively.

Allopurinol is distributed in total body tissue water, but levels in the CNS are only about 50% of those found elsewhere. Neither allopurinol or oxypurinol are bound to plasma proteins, but both drugs are excreted into milk.

Xanthine oxidase metabolizes allopurinol to oxypurinol. The serum half-life for allopurinol is 1 to 3 hours and for oxypurinol, 18-30 hours. Half-lives are increased in patients with diminished renal function. Both allopurinol and oxypurinol are dialyzable.

Contraindications/Precautions

Allopurinol is contraindicated in patients who are hypersensitive or have previously developed a severe reaction to it. It should be used cautiously and with intensified monitoring in patients with impaired hepatic or renal function. When used in patients with renal insufficiency, dosage reductions and increased monitoring are usually warranted.

While the safe use of allopurinol during pregnancy has not been established, dosages of up to 20 times normal in rodents have not demonstrated decreases in fertility. Infertility in males (humans) has been reported with the drug, but a causal effect has not been firmly established.

Adverse Effects – Warnings

Although adverse effects in dogs are apparently uncommon with allopurinol, several adverse effects have been reported in humans including GI distress, bone marrow suppression, skin rashes, hepatitis, and vasculitis. Human patients with renal dysfunction are at risk for further decreases in renal function and other severe adverse effects, unless dosages are reduced. Until further studies are performed in dogs with decreased renal function, the drug should be used with caution and at reduced dosages.

Prolonged use of allopurinol in dogs at dosages of 30 mg/kg/day may result in xanthine urolith formation. If the drug is required for chronic therapy, dosage reduction should be considered.

Overdosage

No reports of massive overdoses in either humans or veterinary species were located.

Drug Interactions

Increased bone marrow depression may occur in patients receiving both allopurinol and cyclophosphamide.

Urocosuric agents (e.g probenecid, sulfinpyrazone) may increase the renal excretion of oxypurinol and thereby reduce xanthine oxidase inhibition. In treating hyperuricemia however, the additive effects on blood uric acid may in fact be beneficial to the patient.

Urinary acidifiers (e.g., methionine, ammonium chloride) may reduce the solubility of uric acid in the urine and induce urolithiasis.

In humans, concomitant use of allopurinol and amoxicillin, hetacillin or ampicillin has been implicated in increased occurrences of skin rashes. The veterinary significance of this interaction is unknown.

Allopurinol may inhibit the metabolism of azathioprine or mercaptopurine and increase their toxicity. If concurrent use is necessary, dosages of the antineoplastic/immunosuppressive agent should be reduced initially to 25-33% of their usual dose and then adjusted, dependent upon patient’s response.

Most diuretics (furosemide, thiazides), diazoxide, and alcohol can increase uric acid levels.

In a few human patients, allopurinol used with trimethoprim/sulfamethoxazole has been associated with thrombocytopenia.

Allopurinol may reduce the metabolism of oral anticoagulants (e.g., warfarin), thereby increasing their effect.

Large doses of allopurinol may decrease the metabolism of aminophylline or theophylline, thereby increasing their serum levels.

Doses

Doses for dogs

For urate uroliths:

a) 7-10 mg/kg PO tid for both dissolution or prevention. Goal is to reduce urine uratexreatinine ratio by 50%.

b) For dissolution: 30 mg/kg/day PO divided into 2-3 doses per day. For prevention: 10 -20 mg/kg/day.

c) Alkalinize urine to a pH of 6.5 – 7 (see sodium bicarbonate monograph), give low purine diet and eliminate any UTI. Allopurinol at 10 mg/kg tid for the first month, then 10 mg/kg once daily thereafter. Reduce dose in patients with renal failure.

Prior to surgery:

a) 5 mg/kg PO 2 hours before surgery

Doses for cats:

For urate uroliths:

a) 9 mg/kg PO per day

Doses for birds

For gout:

a) In budgies and cockatiels: Crush one 100 mg tablet into 10 ml of water. Add 20 drops of this solution to one ounce of drinking water.

b) For parakeets: Crush one 100 mg tablet into 10 ml of water. Add 20 drops of this solution to one ounce of drinking water or give 1 drop 4 times daily.

Monitoring Parameters

1) Urine uric acid (for urolithiasis)

2) Adverse effects

3) Periodic CBC, liver & renal function tests (e.g., BUN, Creatinine, liver enzymes); especially early in therapy.

Client Information

Unless otherwise directed, administer after meals. Notify veterinarian if animal develops a rash, becomes lethargic or ill.

Dosage Forms – Preparations – FDA Approval Status – Withholding Times

Veterinary-Approved Products:

None

Human-Approved Products:

Allopurinol Tablets 100 mg, 300 mg; Zyloprim® (Glaxo Wellcome); Purinol® (Horner); Generic. (Rx)