ZYLORIC TABLETS

Indications

• Prophylaxis of hyperuricaemia associated with cancer chemotherapy
• Prophylaxis of hyperuricaemic nephropathy
• Management of gout
• Treatment of conditions associated with increased uric acid production (e.g., Lesch-Nyhan syndrome)

Dosage

Children: Child 1 month–14 years: 10–20 mg/kg daily, maximum 400 mg per day; Child 15–17 years: Initially 100 mg daily, increased according to response up to 900 mg daily.

Adults: Initially 100 mg daily, increased gradually according to uric acid levels; maximum 900 mg daily in divided doses.

Mechanism of action

Allopurinol inhibits xanthine oxidase, an enzyme involved in the conversion of hypoxanthine to xanthine and xanthine to uric acid, thereby reducing uric acid production.

Pharmacodynamics

By lowering uric acid levels, allopurinol helps to prevent gout attacks and the formation of uric acid crystals in the kidneys, which can lead to nephropathy. It may also reduce hyperuricaemia associated with chemotherapy.

Pharmacokinetics

Allopurinol is well absorbed from the gastrointestinal tract. It has a half-life of about 1 to 2 hours, but its active metabolite, oxypurinol, has a longer half-life and contributes to its pharmacological effects. Excretion is primarily renal.

Contra-indications

• G6PD deficiency
• Hypersensitivity to allopurinol or any of its components

Adverse effects

• Rash (discontinue therapy; if rash mild, re-introduce cautiously but discontinue with cytotoxic drugs immediately if recurrence)
• Hypersensitivity
• Nausea
• Vomiting
• Agranulocytosis
• Alopecia
• Angina pectoris
• Angioedema
• Aplastic anemia
• Asthenia
• Ataxia
• Boils
• Gastrointestinal disorders
• Headache
• Hepatic disorders
• Hyperlipidemia
• Hypertension
• Infertility (male)
• Malaise
• Oedema
• Paraesthesia
• Paralysis
• Severe cutaneous adverse reactions (SCARs)
• Skin reactions
• Stomatitis
• Taste altered
• Thrombocytopenia
• Vertigo
• Visual impairment

Interactions

• Allopurinol + azathioprine: Increased risk of haematological toxicity
• Allopurinol + capecitabine: Decreases effects
• Allopurinol + mercaptopurine: Increased risk of haematological toxicity
• Allopurinol + penicillins: Increased risk of skin rash
• Allopurinol + amoxicillin: Increased risk of skin rash
• Allopurinol + ampicillin: Increased risk of skin rash
• Allopurinol + pyrazinamide: Increased risk of hyperuricaemia
• Thiazide diuretics + allopurinol: Increased risk of hypersensitivity reactions

Precautions

• Monitor closely for hypersensitivity
• Ensure adequate fluid intake
• Allopurinol treatment should be started before cancer therapy

Pregnancy

Not known to be harmful; benefit outweighs risk.

Breast-feeding

Presence in milk unknown but benefit outweighs risk.

Storage

Store in a cool, dry place away from direct sunlight.

Mechanism of action

Allopurinol is a structural analog of the natural purine base, hypoxanthine. After ingestion, allopurinol is metabolized to its active metabolite, oxypurinol (_alloxanthine_) in the liver, which acts as an inhibitor of xanthine oxidase enzyme. Allopurinol and its active metabolite inhibit xanthine oxidase, the enzyme that converts hypoxanthine to xanthine and xanthine to uric acid. Inhibition of this enzyme is responsible for the effects of allopurinol. This drug increases the reutilization of hypoxanthine and xanthine for nucleotide and nucleic acid synthesis by a process that involves the enzyme hypoxanthine-guanine phosphoribosyltransferase (HGPRTase). This process results in an increased nucleotide concentration, which causes feedback inhibition of de novo purine synthesis. The end result is decreased urine and serum uric acid concentrations, which decreases the incidence of gout symptoms. Accompanying the reduction of serum uric acid by allopurinol is an increase in the serum and urine concentrations of hypoxanthine and xanthine (due to inhibition of xanthine oxidase). In the absence of allopurinol, regular urinary excretion of oxypurines almost entirely occurs in the form of uric acid. After the ingestion of allopurinol, the contents of excreted urine are hypoxanthine, xanthine, and uric acid. Because each substance has its own individual solubility, the concentration of uric acid in plasma is decreased without exposing the renal tissues to a high load of uric acid, thereby decreasing the risk of crystalluria. By lowering the uric acid concentration in the plasma below its limits of solubility, allopurinol encourages the dissolution of gout tophi. Although the levels of hypoxanthine and xanthine are found to be increased after allopurinol ingestion, the risk of deposition in renal tissues is less than that of uric acid, as they become more soluble and are rapidly excreted by the kidney. Allopurinol inhibits xanthine oxidase, the enzyme that catalyzes the conversion of hypoxanthine to xanthine and of xanthine to uric acid. Oxypurinol, a metabolite of allopurinol, also inhibits xanthine oxidase. By inhibiting xanthine oxidase, allopurinol and its metabolite block conversion of the oxypurines (hypoxanthine and xanthine) to uric acid, thus decreasing serum and urine concentrations of uric acid. The drug differs, therefore, from uricosuric agents which lower serum urate concentrations by promoting urinary excretion of uric acid. Xanthine oxidase concentrations are not altered by long-term administration of the drug. Allopurinol does not directly interfere with purine nucleotide or nucleic acid synthesis. The drug, however, indirectly increases oxypurine and allopurinol ribonucleotide concentrations and decreases phosphoribosylpyrophosphate concentrations, thus decreasing de novo purine biosynthesis by pseudofeedback inhibition. In addition, allopurinol increases the incorporation of hypoxanthine and xanthine into DNA and RNA, thereby further decreasing serum urate concentrations. Allopurinol may produce a deficit of total purines (uric acid and oxypurines) amounting to several hundred mg daily. Accompanying the decrease in uric acid produced by allopurinol is an increase in serum and urine concentrations of hypoxanthine and xanthine. Plasma concentrations of these oxypurines do not, however, rise commensurately with the fall in serum urate concentrations and are often 20-30% less than would be expected in view of urate concentrations prior to allopurinol therapy. This discrepancy occurs because renal clearance of the oxypurines is at least 10 times greater than that of uric acid. In addition, normal urinary purine output is almost exclusively uric acid, but after treatment with allopurinol, it is composed of uric acid, xanthine, and hypoxanthine, each having independent solubility. Thus, the risk of crystalluria is reduced. Alkalinization of the urine increases the solubility of the purines, further minimizing the risk

Pharmacodynamics

Allopurinol decreases the production of uric acid by stopping the biochemical reactions that precede its formation. This process decreases urate and relieves the symptoms of gout, which may include painful tophi, joint pain, inflammation, redness, decreased range of motion, and swelling.