Allopurinol
Blockade of xanthine oxidase (XO)
Generic Name
Blockade of xanthine oxidase (XO)
Mechanism
- Blockade of xanthine oxidase (XO) → ↓ conversion of hypoxanthine → xanthine → uric acid.
- Results in ↓ serum urate and ↓ urinary urate excretion.
- Does not directly dissolve existing urate crystals; used for long‑term prevention, not acute flare relief.
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Pharmacokinetics
- Absorption: ~70 % oral bioavailability, peak serum conc. in 2 h.
- Distribution: Wide tissue distribution; 15–30 % plasma protein binding.
- Metabolism & Elimination:
- Metabolized to *allopurinol uric acid* (an inactive metabolite).
- Primarily renal excretion (≈80 % unchanged ± metabolites).
- Half‑life: 3–4 h (allopurinol), 20–30 h for metabolite.
- Renal impairment: Dose adjustment; severe renal disease requires ¼ dosing interval or lower maximal dose (≤200 mg d⁻¹).
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Indications
- Chronic gout prophylaxis (uric acid <6 mg/dL).
- Recurrent gout attacks—maintenance after acute flare.
- Prevention of uric acid kidney stones (hyperuricosuria).
- Tumor lysis syndrome—reduce uric acid load during chemo.
- Xanthinuria & urate nephropathy in select cases.
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Contraindications
| Category | Key Points |
| Contraindications | Hypersensitivity to allopurinol or sulfonamides; severe renal dysfunction (CrCl <10 mL/min) without dose adjustment. |
| Warnings |
• Allopurinol hypersensitivity syndrome (AHS): rash, fever, eosinophilia, organ failure (1–5 % after 2–3 weeks). • Drug interactions: • ↑ 6‑mercaptopurine, azathioprine -> hepatotoxicity. • ↓ methotrexate clearance (risk of hepatic toxicity). • ↑ NSAID nephrotoxicity risk. |
| Precautions |
• Not for acute gout flares. • Avoid in pregnancy (category X) unless benefits > risks; no human data for lactation. |
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Dosing
- Typical starting dose: 100 mg orally once daily.
- Titration: Increase 100 mg every 1–2 weeks based on serum urate and kidney function.
- Target serum urate: <6 mg/dL (or 800 mg).
- Kidney impairment: Reduce maintenance dose proportional to CrCl; e.g., 200 mg/d for CrCl 30–60 mL/min.
- Administration tips: Take with a meal or at bedtime to reduce GI upset; avoid concurrent NSAIDs unless necessary.
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Adverse Effects
| Common | Serious |
| GI upset (nausea, diarrhea) | Stevens–Johnson syndrome / toxic epidermal necrolysis |
| Rash (maculopapular) | Hypersensitivity syndrome (fever, eosinophilia) |
| Headache, dizziness | Hepatotoxicity (↑ ALT/AST) |
| Leukopenia | Renal failure (especially with NSAIDs) |
| ↑ serum uric acid (flare if dose not adequate) | Severe allergic reaction (anaphylaxis) |
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Monitoring
- Baseline: CBC, CMP (renal & hepatic), serum urate, uric acid crystals on urinalysis.
- Follow‑up:
- Serum urate 2–4 weeks after dose titration, thereafter every 3–6 months.
- Renal & hepatic function at 2 weeks, then every 3–6 months.
- Look out for rash or fever within first 3 weeks.
- Special: In tumor lysis syndrome, monitor uric acid, electrolytes, renal function daily.
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Clinical Pearls
- Begin prophylaxis early – start allopurinol before the first gout flare to avoid crystallization.
- Watch the “allopurinol–AZA/6‑MP” combo – if patients on azathioprine or 6‑mercaptopurine, reduce these to 1/3–1/2 the dose or switch to mercaptopurine‑independent immunosuppression.
- Use with caution in NSAID users – allopurinol increases NSAID renal toxicity; use acetaminophen if possible.
- Alternative for intolerance: Febuxostat is a non‑sulfonamide XO inhibitor; preferred in patients with allopurinol hypersensitivity or severe renal impairment.
- Re‑exposure risk: If past rash, avoid allopurinol and consider desensitization protocols under specialist care.
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• References – Key pharmacology texts (e.g., Katzung & Trevor, Goodman & Gilman's) and latest U.S. FDA labeling.