Usage
Allopurinol is prescribed for the management of conditions characterized by hyperuricemia, including:
- Gout: A form of arthritis caused by the accumulation of uric acid crystals in the joints.
- Uric acid nephropathy: Kidney disease caused by uric acid crystal formation in the kidneys.
- Kidney stones (uric acid and calcium oxalate): Prevention of formation or recurrence.
- Hyperuricemia secondary to malignancy or Lesch-Nyhan syndrome: Elevated uric acid levels due to cancer treatment or the rare genetic disorder.
- Tumor Lysis Syndrome: Elevated uric acid levels caused by the breakdown of cancer cells during chemotherapy.
Pharmacological Classification: Xanthine oxidase inhibitor.
Mechanism of Action: Allopurinol reduces uric acid production by inhibiting the enzyme xanthine oxidase, which is responsible for converting hypoxanthine to xanthine and xanthine to uric acid.
Alternate Names
- International Nonproprietary Name (INN): Allopurinol
- Brand Names: Zyloprim, Aloprim
How It Works
Pharmacodynamics: Allopurinol and its active metabolite, oxypurinol, decrease serum and urinary uric acid levels by inhibiting xanthine oxidase. This action prevents the formation of uric acid crystals, which are responsible for the symptoms of gout and other related conditions.
Pharmacokinetics:
- Absorption: Allopurinol is well-absorbed orally, reaching peak plasma concentrations in 1-2 hours.
- Metabolism: Allopurinol is metabolized in the liver primarily to oxypurinol, which also inhibits xanthine oxidase and has a longer half-life than allopurinol.
- Elimination: Oxypurinol is primarily excreted by the kidneys. Allopurinol is also excreted renally. Dose adjustment is necessary in renal impairment.
Mode of Action: Allopurinol acts as a competitive inhibitor of xanthine oxidase, binding to the enzyme’s active site and preventing the conversion of hypoxanthine and xanthine to uric acid.
Receptor Binding, Enzyme Inhibition, or Neurotransmitter Modulation: Allopurinol’s primary mechanism is enzyme inhibition of xanthine oxidase.
Elimination Pathways: Primarily renal excretion of both allopurinol and its active metabolite, oxypurinol.
Dosage
Standard Dosage
Adults:
- Gout: Initial dose: 100 mg orally once daily. Increase weekly by 100 mg until the target serum uric acid level (usually <6 mg/dL) is reached. Maximum dose: 800-900 mg/day. Dosages >300mg should be divided into two doses.
- Hyperuricemia secondary to malignancy: 600-800 mg/day orally divided into 2-3 doses, starting 1-2 days before chemotherapy.
- Prevention of recurrent kidney stones: 200-300 mg/day orally in single or divided doses.
Children:
- Lesch-Nyhan syndrome or hyperuricemia secondary to malignancy: Dosing must be individualized based on weight and clinical response. General recommendations are 10-20 mg/kg/day divided into 2-3 doses (max: 400 mg/day) or based on body surface area (BSA) calculation.
Special Cases:
- Elderly Patients: Start at a lower dose (e.g., 50 mg/day) and titrate cautiously to minimize the risk of adverse effects.
- Patients with Renal Impairment: Reduce the dose based on creatinine clearance (CrCl).
- Patients with Hepatic Dysfunction: No specific dose adjustments are typically required, but monitor closely for adverse effects.
- Patients with Comorbid Conditions: Close monitoring is recommended for patients with comorbidities, especially cardiovascular disease and diabetes.
Clinical Use Cases Allopurinol isn’t typically administered through intravenous routes or used in clinical settings like intubation, surgical procedures, mechanical ventilation, the intensive care unit (ICU), or emergency situations. Rasburicase or Febuxostat might be preferred in acute conditions or tumor lysis syndrome.
Dosage Adjustments
Adjustments are necessary based on renal function, patient response, and concomitant medications. Consider pharmacogenomic testing for HLA-B*58:01 allele in patients at high risk of hypersensitivity reactions, particularly those of Han Chinese, Thai, or Korean descent.
Side Effects
Common Side Effects
- Rash (maculopapular, often itchy)
- Nausea
- Diarrhea
- Drowsiness
- Headache
- Increased gout flares (especially at the beginning of treatment)
Rare but Serious Side Effects
- Severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN)
- Drug reaction with eosinophilia and systemic symptoms (DRESS)
- Hepatotoxicity
- Bone marrow suppression
- Renal failure
- Hypersensitivity reactions (e.g., vasculitis)
Long-Term Effects
Adverse Drug Reactions (ADR)
The most serious ADRs are SCARs (SJS/TEN), DRESS, and hypersensitivity reactions, which require immediate discontinuation of allopurinol and supportive care.
Contraindications
- Hypersensitivity to allopurinol
- Active hypersensitivity reaction to allopurinol
- During breastfeeding (unless benefits outweigh the risks for the infant).
Drug Interactions
- Azathioprine and 6-mercaptopurine: Increased risk of myelosuppression. Reduce azathioprine/6-MP dose significantly (e.g. to 25%).
- Didanosine: Increased risk of didanosine toxicity.
- Warfarin: Increased risk of bleeding.
- Theophylline: Increased theophylline levels.
- Angiotensin-converting enzyme (ACE) inhibitors (e.g., captopril, enalapril): Increased risk of hypersensitivity reactions.
- Thiazide diuretics: Increased risk of allopurinol-induced rash.
- Cytotoxic drugs (e.g., cyclophosphamide): Potential for increased bone marrow suppression.
Pregnancy and Breastfeeding
- Pregnancy Safety Category: C (data are limited, risks to fetus cannot be ruled out)
- Breastfeeding: Allopurinol is excreted in breast milk. The manufacturer recommends avoiding allopurinol during breastfeeding and for one week after the last dose.
Drug Profile Summary
- Mechanism of Action: Xanthine oxidase inhibitor, reducing uric acid production.
- Side Effects: Rash, nausea, diarrhea, drowsiness, headache, increased gout flares initially, rarely SJS/TEN, DRESS, and hypersensitivity reactions.
- Contraindications: Hypersensitivity, active hypersensitivity reaction.
- Drug Interactions: Azathioprine, 6-MP, didanosine, warfarin, theophylline, ACE inhibitors, thiazide diuretics.
- Pregnancy & Breastfeeding: Generally avoided.
- Dosage: Individualized based on indication and renal function.
- Monitoring Parameters: Serum uric acid, creatinine, liver function tests, complete blood count (CBC), signs of hypersensitivity.
Popular Combinations
- Colchicine or NSAIDs are often co-administered during the initial phase of allopurinol therapy to prevent or manage acute gout flares.
Precautions
- General Precautions: Start with a low dose and titrate gradually to minimize the risk of acute gout flares and hypersensitivity. Monitor renal and liver function, especially in patients with pre-existing disease.
- Specific Populations: Pregnancy and breastfeeding (avoided if possible), children (use limited to specific conditions), elderly (start low dose).
- Lifestyle Considerations: Encourage adequate hydration.
FAQs (Frequently Asked Questions)
Q1: What is the recommended starting dosage for Allopurinol in gout?
A: 100 mg orally once daily, increased weekly by 100 mg as needed until target serum uric acid is achieved (usually <6 mg/dL).
Q2: How is the Allopurinol dose adjusted for patients with renal impairment?
A: Reduce the dose based on creatinine clearance. Consider starting at 50 mg daily and titrating very cautiously.
Q3: What are the most serious side effects of Allopurinol?
A: Severe cutaneous adverse reactions (SJS/TEN), DRESS syndrome, hypersensitivity reactions, hepatotoxicity, and bone marrow suppression.
Q4: Can Allopurinol be used during pregnancy or breastfeeding?
A: Generally avoided due to limited safety data. If necessary, weigh the potential benefits against the unknown risks to the fetus or infant.
Q5: What should be done if a patient develops a rash while taking Allopurinol?
A: Discontinue Allopurinol immediately and evaluate the patient for hypersensitivity. Do not rechallenge the patient if a hypersensitivity reaction is suspected.
Q6: How does Allopurinol interact with Azathioprine or 6-Mercaptopurine?
A: Allopurinol inhibits the metabolism of these drugs, leading to increased risk of myelosuppression. Reduce azathioprine/6-MP dose significantly.
Q7: Why is Allopurinol sometimes given to patients receiving chemotherapy?
A: To prevent or treat hyperuricemia and tumor lysis syndrome, which can occur due to the rapid breakdown of cancer cells.
Q8: What is the role of HLA-B*58:01 testing before starting Allopurinol?
A: This genetic test can identify patients at increased risk of severe cutaneous adverse reactions to Allopurinol, especially in certain ethnic groups.
Q9: What are common drug combinations with Allopurinol?
A: Co-administration with colchicine or NSAIDs is common during initial therapy to manage acute gout flares.
Q10: How does Allopurinol work at the cellular level?
A: It competitively inhibits the enzyme xanthine oxidase, thereby preventing the formation of uric acid from its precursors, hypoxanthine and xanthine.
