Allopurinol

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Allopurinol (Brand names: Zyloric, Zyloprim, among others) is a xanthine oxidase inhibitor. Allopurinol decreases serum uric acid and is primarily to treat hyperuricemia and its complications, including gout, kidney stones and certain types of kidney disease.

Gout is a disease where the body produces too much of uric acid. The uric acid builds up in the joints and tendons and forms crystals. These cause an inflammatory reaction. The inflammation causes the skin around certain joints to become swollen, tender and sore when only slightly touched. Severe pain may also be felt on slight movement of the joint.

Contents

[edit] BRAND NAMES

[edit] STRUCTURE

Allopurinol.jpg

[edit] MECHANISM OF ACTION

Uric acid is the end product of purine metabolism in humans and is generated in the cascade of hypoxanthine → xanthine → uric acid. Both steps in the above transformations are catalyzed by xanthine oxidase (XO). Hyperuricaemia (greater than 7 mg/dL) can lead to urate crystals forming and building up in the joints and the kidneys. When this happens in the joints and causes pain, it is known as gout.

Allopurinol is a purine analog; it is a structural isomer of hypoxanthine. Allopurinol inhibits xanthine oxidase and achieves its therapeutic effect by decreasing serum uric acid and stopping crystals from building up. This can reduce the symptoms of gout. Keeping uric-acid levels low for long enough can also shrink tophi (‘stones’, larger deposits of urate crystals that can cause joint and bone damage).

In contrast, inhibition of xanthine oxidase causes an increase in hypoxanthine and xanthine. Although the levels of hypoxanthine and xanthine are increased, the risk of their deposition is less than that of uric acid as they are more soluble and are rapidly cleared by the kidney. However to avoid xanthine stones being deposited, it is advisable to maintain a high fluid intake and a neutral or alkaline urinary pH, especially if initial uric acid concentrations are high and the patient is symptomatic.

In addition to blocking uric acid production, allopurinol increases reutilization of hypoxanthine and xanthine for nucleotide and nucleic acid synthesis via an action involving the enzyme hypoxanthine-guanine phosphorbosyltransferase (HGPRTase). The resultant increase in nucleotide concentration leads to feedback inhibition of de novo purine synthesis.

In a study another xanthine oxidase, Febuxostat was more effective than Allopurinol in reducing blood uric-acid levels. 48% of the patients taking 80 mg Febuxostat once a day and 65% of the patients taking 120 mg once a day had levels of uric acid below 6 mg/dl in the final three measurements. This was compared with 22% of the patients taking allopurinol.

[edit] INDICATIONS

Human

  • Chronic gout. Allopurinol is not, used to treat an acute attack of gout as it has no analgesic, antiinflammatory or uricosuric activity and may prolong the attack.
  • Hyperuricemia: Allopurinol is not recommended for the treatment of mild asymptomatic hyperuricaemia. It should generally only be considered if serum urate concentrations exceed 8 to 9 mg/dL with an aim of reducing levels to 6 mg/dL.
  • Renal calculi (uric acid lithiasis) due to either uric acid or calcium oxalate when daily uric acid excretion exceeds 800 mg/day in male patients and 750 mg/day in female patients.
  • Uric acid nephropathy
  • In patients with neoplastic disease and myeloproliferative disease with high cell turnover rates who are receiving cancer therapy which causes elevations of serum and urinary uric acid levels.
  • Certain enzyme disorders or blood disorders which lead to overproduction of urate (e.g.Lesch-Nyhan syndrome; hemolytic anaemia)


Veterinary

  • Treatment of canine visceral leishmaniasis

[edit] DOSAGE

Allopurinol may be taken once daily after a meal. Should the total daily dose exceed 300 mg and/or gastrointestinal intolerance be manifested, a divided doses regimen may be appropriate. The dosage should be adjusted by monitoring serum urate concentrations and urinary urate/uric acid levels at appropriate intervals.

  • Adults: The average daily dose is 100 mg to 200 mg for mild conditions, 300 mg to 600 mg daily for moderately severe conditions and 700 mg to 900 mg for severe conditions.
    After initiation of Allopurinol, an increase in gout flares is frequently observed. This increase is due to reduction in serum uric acid levels, resulting in mobilization of urate from tissue deposits. In order to prevent gout flares, it is recommended that low doses be given initially and slowly increased, and that an NSAID or colchicine should be given concomitantly during this period as prophylactic cover.
    In patients with good renal function, doses of 100mg should be given and increased by 50mg to 100mg at weekly intervals until serum urate levels of 0.6 mg per ml are achieved.
  • Hyperuricaemia of malignancy or cancer therapy: Therapy should be initiated 2 to 3 days prior to cytotoxic therapy after which maintenance doses are given according to response. Adequate hydration is essential throughout.
  • Children: The average daily dose is 10-20 mg/kg bodyweight up to a maximum of 400mg per day. Use in children is rarely indicated except in cancer and certain enzyme disorders.

[edit] CONTRAINDICATIONS

  • Hypersensitivity to allopurinol

[edit] WARNINGS AND PRECAUTIONS

  • Skin reactions: Allopurinol should be discontinued immediately at the first sign of a rash or other sign of immediate allergic reactions.

    The risk of skin reactions appears to be highest in the first 2 months of treatment and in patients taking higher doses. However reactions may also be delayed. Skin reactions can include erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis or a diffuse maculopapular or exfoliative dermatitis, fatal cases have been reported.

    Skin reactions may also occur as part of a generalised hypersensitivity reaction. A DRESS syndrome (drug rash with eosinophilia and systemic symptoms) characterised by exfoliative dermatitits with eosinophilia complicated by symptoms such as hepatitis and interstitial nephritis has been described in association with allopurinol treatment. Risk factos include renal impairment and use with thiazide diuretics. Patients have been successfully treated by immediate withdrawal of allopurinol and use of corticosteroids.
  • It is advisable to maintain a high fluid intake.

[edit] INTERACTIONS

[edit] PREGNANCY AND LACTATION

  • Allopurinol should not be used during pregnancy
  • Allopurinol and its metabolite, oxypurinol are distributed into breast milk. Allopurinol should thus be used with caution in view of the potential for adverse effects, especially hypersensitivity reactions.

[edit] SIDE EFFECTS

The most common side effects are nausea or vomiting.

Rare but potentially serious side effects:

  • Skin problems: Allopurinol can cause Rash, angioedema, Stevens-Johnson syndrome, toxic epidermal necrolysis.
  • Tiredness, vertigo, drowsiness and confusion. Avoid driving or operating machinery.
  • Liver: Allopurinol can inflame the liver. Alterations in liver function tests hepatatomegaly, hepatitis and jaundice Hepatic dysfunction has occasionally been reported. Blood tests can pick this up if it occurs and the dose of allopurinol may need to be reduced or it may need to be stopped.

Other: Headache, dizziness, taste disturbances, high blood pressure, feeling generally unwell, and hair loss can occur.

[edit] RELATED LINKS

Gout: Diet, Symptoms and Medication

[edit] BIBLIOGRAPHY

[edit] REFERENCES