Antigout agents

Introduction

Gout is a chronic metabolic disorder characterized by hyperuricemia (serum uric acid >6.8 mg/dL), leading to monosodium urate crystal deposition in joints and soft tissues. Clinically, it manifests as acute arthritis, chronic tophaceous gout, uric acid nephrolithiasis, and urate nephropathy.

The therapeutic strategies for gout are divided into two major objectives:

1. Management of acute gout flares – controlling inflammation and pain.

2. Long-term urate-lowering therapy (ULT) – reducing serum urate levels to prevent recurrences and complications.

Antigout agents are therefore classified as anti-inflammatory agents (for acute attacks) and urate-lowering agents (for chronic management).

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Classification of Antigout Agents

1. Drugs for Acute Gout Attacks

• Nonsteroidal Anti-inflammatory Drugs (NSAIDs): indomethacin, naproxen, ibuprofen, diclofenac

• Colchicine: unique microtubule inhibitor used in acute attacks and prophylaxis

• Glucocorticoids: prednisone, prednisolone, methylprednisolone, triamcinolone (oral, intra-articular, or systemic)

2. Urate-Lowering Therapy (Chronic Management)

• Xanthine Oxidase Inhibitors (XOIs): allopurinol, febuxostat, topiroxostat (in some regions)

• Uricosuric Agents: probenecid, sulfinpyrazone, benzbromarone, lesinurad

• Recombinant Uricase Enzymes: rasburicase, pegloticase

3. Adjunctive/Preventive Agents

• Low-dose colchicine or NSAIDs – for prophylaxis during initiation of urate-lowering therapy.

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Mechanisms of Action

NSAIDs

• Inhibit cyclooxygenase (COX-1 and COX-2), reducing prostaglandin synthesis and thereby inflammation.

Colchicine

• Binds tubulin, inhibiting microtubule polymerization → prevents neutrophil chemotaxis and phagocytosis of urate crystals.

Glucocorticoids

• Broad anti-inflammatory effect by suppressing cytokines and leukocyte migration.

Xanthine Oxidase Inhibitors

• Allopurinol and febuxostat inhibit xanthine oxidase, decreasing conversion of hypoxanthine/xanthine into uric acid.

Uricosuric Agents

• Probenecid and benzbromarone inhibit renal tubular reabsorption of uric acid (via URAT1 and OAT transporters), increasing urinary urate excretion.

Recombinant Uricases

• Rasburicase and pegloticase convert uric acid into allantoin, which is more soluble and easily excreted.

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Representative Generic Agents

Acute Gout Therapy

• NSAIDs: indomethacin, naproxen, ibuprofen, diclofenac

• Colchicine: colchicine

• Glucocorticoids: prednisone, methylprednisolone, triamcinolone

Chronic ULT

• XOIs: allopurinol, febuxostat, topiroxostat

• Uricosurics: probenecid, benzbromarone, sulfinpyrazone, lesinurad

• Uricases: rasburicase, pegloticase

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Therapeutic Uses

1. Acute gout attacks: NSAIDs (first-line), colchicine (early initiation), glucocorticoids (if NSAIDs contraindicated).

2. Chronic hyperuricemia: XOIs (allopurinol, febuxostat) as first-line ULT.

3. Underexcretion of uric acid: uricosurics (probenecid, benzbromarone).

4. Refractory gout: pegloticase (IV, for severe tophaceous gout not responsive to other drugs).

5. Tumor lysis syndrome (TLS): rasburicase for prophylaxis and treatment.

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Dosage (Common Ranges)

• Allopurinol: Start 100 mg daily; titrate up to 300–600 mg/day depending on uric acid levels (max 800 mg/day). Adjust in renal impairment.

• Febuxostat: 40–80 mg once daily.

• Probenecid: Start 250 mg twice daily; increase to 500 mg twice daily; max 2 g/day.

• Colchicine (acute): 1.2 mg initially, then 0.6 mg after 1 hour (max 1.8 mg in 24h).

• Colchicine (prophylaxis): 0.6 mg once or twice daily.

• Pegloticase: 8 mg IV every 2 weeks.

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

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Contraindications

• NSAIDs: Peptic ulcer disease, renal impairment, uncontrolled hypertension, cardiovascular disease.

• Colchicine: Severe renal/hepatic impairment, blood dyscrasias, concomitant strong CYP3A4/P-gp inhibitors.

• Allopurinol: Prior hypersensitivity reactions, caution in HLA-B*58:01 positive patients (higher risk of severe cutaneous reactions).

• Febuxostat: Severe hepatic impairment; caution in patients with cardiovascular disease (increased risk of CV death in some studies).

• Probenecid: Nephrolithiasis, renal insufficiency (CrCl <30 mL/min), history of uric acid kidney stones.

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

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Precautions

• Initiation of ULT can precipitate acute gout attacks: prophylaxis with low-dose colchicine or NSAIDs for 3–6 months is recommended.

• Renal monitoring: especially with allopurinol, uricosurics, NSAIDs.

• Liver function monitoring: with febuxostat and benzbromarone.

• Hydration and urine alkalinization: may reduce kidney stone risk with uricosurics.

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Adverse Effects

NSAIDs

• GI bleeding, ulcers, renal toxicity, hypertension, fluid retention.

Colchicine

• GI upset (diarrhea, nausea, vomiting), myopathy, bone marrow suppression (rare at low dose, more with overdose).

Glucocorticoids

• Hyperglycemia, weight gain, osteoporosis, immunosuppression.

Allopurinol

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

• Elevated liver enzymes.

Febuxostat

• Elevated liver enzymes, increased risk of cardiovascular mortality (controversial, still under monitoring).

Probenecid

• GI upset, uric acid stones, rash.

Pegloticase/Rasburicase

• Infusion reactions, anaphylaxis, hemolysis in G6PD deficiency.

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Drug Interactions

• Allopurinol/Febuxostat: Increase toxicity of azathioprine and mercaptopurine (require dose reduction).

• Probenecid: Inhibits renal clearance of penicillin, methotrexate, and other drugs.

• Colchicine: Dangerous with CYP3A4 inhibitors (clarithromycin, ketoconazole) or P-gp inhibitors (cyclosporine).

• NSAIDs + Anticoagulants: Increased bleeding risk.

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Clinical Considerations

• Target uric acid level: <6 mg/dL for most patients; <5 mg/dL in severe tophaceous gout.

• First-line ULT: Allopurinol; febuxostat if intolerant or contraindicated.

• Probenecid and other uricosurics: Reserved for underexcretors and patients without kidney stones or renal dysfunction.

• Refractory cases: Pegloticase is used when conventional agents fail.

• Special populations:

• Elderly: careful dosing to reduce toxicity.

• Pregnancy: NSAIDs avoided in third trimester, colchicine may be considered but requires caution.