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Tuesday, August 19, 2025

Antihyperuricemic agents


Introduction

Antihyperuricemic agents are a therapeutic class of drugs designed to reduce elevated serum uric acid levels in patients with hyperuricemia. Hyperuricemia is the pathological basis of gout and is also implicated in conditions such as uric acid nephrolithiasis, tumor lysis syndrome, and chronic kidney disease. These agents either decrease the synthesis of uric acid, enhance its renal excretion, or degrade existing uric acid into more soluble metabolites.

The class includes several categories:

  1. Xanthine oxidase inhibitors (XOIs) – reduce uric acid synthesis.

  2. Uricosuric agents – increase renal excretion of uric acid.

  3. Recombinant uricase agents – degrade uric acid enzymatically.

  4. Other novel urate-lowering drugs – include selective URAT1 inhibitors.

Mechanism of Action

  • Xanthine oxidase inhibitors (e.g., allopurinol, febuxostat, topiroxostat):
    These drugs inhibit xanthine oxidase, the enzyme responsible for converting hypoxanthine to xanthine and xanthine to uric acid. This reduces uric acid production and increases levels of more soluble precursors.

  • Uricosurics (e.g., probenecid, lesinurad, benzbromarone):
    They block reabsorption of uric acid in the renal proximal tubules via URAT1 and OAT transporters, leading to increased uric acid excretion in urine.

  • Recombinant uricases (e.g., pegloticase, rasburicase):
    These convert uric acid into allantoin, which is more water-soluble and easily excreted. Humans lack endogenous uricase, so these agents serve as enzymatic substitutes.

  • Combination agents:
    Sometimes, uricosuric drugs are combined with XOIs for synergistic effect, especially in refractory gout.

Therapeutic Uses

Antihyperuricemic agents are primarily used in:

  • Gout (chronic and recurrent):
    Long-term management of chronic gout by reducing uric acid levels, thereby preventing acute flares and tophi formation.

  • Tumor lysis syndrome (TLS):
    Prophylaxis and treatment of TLS in patients undergoing chemotherapy for hematological malignancies.

  • Hyperuricemia due to enzyme defects:
    Management of inherited disorders like Lesch-Nyhan syndrome.

  • Uric acid nephrolithiasis:
    Prevention of uric acid kidney stones in recurrent cases.

Commonly Used Generic Agents

1. Xanthine Oxidase Inhibitors

  • Allopurinol

  • Febuxostat

  • Topiroxostat (Japan)

2. Uricosuric Agents

  • Probenecid

  • Sulfinpyrazone

  • Benzbromarone (limited use due to hepatotoxicity)

  • Lesinurad (selective URAT1 inhibitor, often used with XOIs)

3. Recombinant Uricases

  • Rasburicase (used in TLS, IV only)

  • Pegloticase (used in refractory chronic gout, IV only)

Dosage and Administration

Allopurinol

  • Oral: Initial 100 mg once daily, titrated up by 100 mg every 2–4 weeks.

  • Maintenance: 200–600 mg/day in divided doses.

  • Maximum: 800 mg/day.

  • Adjusted in renal impairment.

Febuxostat

  • Oral: 40–80 mg once daily.

  • No significant renal adjustment required (except severe impairment).

Probenecid

  • Oral: Start at 250 mg twice daily, after 1 week increase to 500 mg twice daily.

  • Maintenance: 1–2 g/day in divided doses.

Lesinurad

  • Oral: 200 mg once daily, used only in combination with an XOI.

Pegloticase

  • IV infusion: 8 mg every 2 weeks.

  • Pre-medication with antihistamines and corticosteroids required.

Rasburicase

  • IV: 0.2 mg/kg once daily for up to 5 days for TLS.

Contraindications

  • Allopurinol/Febuxostat: Severe hypersensitivity reactions, concurrent azathioprine or mercaptopurine use (without dose reduction).

  • Probenecid: Uric acid kidney stones, creatinine clearance <30 mL/min, peptic ulcer disease.

  • Lesinurad: Severe renal impairment, dialysis patients, monotherapy (increases renal toxicity).

  • Pegloticase/Rasburicase: G6PD deficiency (risk of hemolysis, methemoglobinemia).

Side Effects

Xanthine Oxidase Inhibitors

  • Rash, Stevens-Johnson syndrome (allopurinol hypersensitivity syndrome).

  • Liver function abnormalities.

  • GI upset, nausea, diarrhea.

  • Rare: agranulocytosis, aplastic anemia.

Uricosuric Agents

  • GI irritation, nausea.

  • Risk of uric acid kidney stones.

  • Rash, hypersensitivity.

  • Headache, dizziness.

Recombinant Uricases

  • Severe infusion-related reactions.

  • Anaphylaxis.

  • Hemolysis and methemoglobinemia in G6PD deficiency.

Precautions

  • Initiation of therapy can trigger acute gout attacks; therefore, prophylactic colchicine or NSAIDs are recommended for 3–6 months.

  • Adequate hydration and urine alkalinization may be required to reduce risk of uric acid stones.

  • Monitor serum uric acid levels regularly to ensure therapeutic targets (<6 mg/dL in gout patients).

  • In elderly and renally impaired patients, dose adjustments are critical to avoid toxicity.

Drug Interactions

  • Allopurinol/Febuxostat:

    • Increase toxicity of azathioprine and mercaptopurine (require 75% dose reduction).

    • Interaction with cyclophosphamide, enhancing myelosuppression.

    • Potentiates effects of oral anticoagulants (warfarin).

  • Probenecid:

    • Reduces renal clearance of penicillins and cephalosporins (sometimes used therapeutically to prolong antibiotic action).

    • Interacts with methotrexate, increasing toxicity.

    • Salicylates antagonize uricosuric effect.

  • Pegloticase/Rasburicase:

    • Should not be combined with other uric acid–lowering agents.

    • Contraindicated with agents that induce oxidative stress in G6PD deficiency.

Clinical Considerations

  • Choice of agent depends on patient profile:

    • XOIs are first-line therapy for chronic gout.

    • Uricosurics are useful in patients with under-excretion of uric acid and normal renal function.

    • Recombinant uricases are reserved for severe, refractory cases.

  • Treatment goals:

    • Reduce serum urate to <6 mg/dL.

    • Prevent formation of tophi and recurrence of gout attacks.

    • Reduce risk of uric acid nephrolithiasis and renal damage.

  • Special populations:

    • Renal impairment: XOIs require adjustment, uricosurics generally avoided.

    • Pediatrics: Rarely indicated except in enzyme disorders or TLS.

    • Elderly: Careful monitoring for drug interactions and organ impairment.

Emerging Therapies

Recent developments include:

  • Selective URAT1 inhibitors (e.g., verinurad, in trials) for enhanced safety.

  • Dual-action drugs combining xanthine oxidase inhibition and uricosuric activity.

  • Biologic therapies targeting urate metabolism more precisely.




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