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Drugs Used in Gout - MBBS Guide

Overview

1. Relieve acute attack symptoms
2. Prevent recurrent attacks
3. Lower serum urate levels long-term

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PART 1: Drugs for Acute Gout Attack

1. NSAIDs (First-Line)

• Examples: Indomethacin (drug of choice classically), naproxen, diclofenac, etoricoxib
• Mechanism: Inhibit COX enzymes -> reduce prostaglandin synthesis -> reduce inflammation
• Dose: Indomethacin 50 mg TID for 5-7 days (high dose, then taper)
• Avoid: In renal impairment, peptic ulcer disease, heart failure, the elderly
• Note: NSAIDs are preferred first-line unless contraindicated

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2. Colchicine (Second-Line)

• Binds tubulin -> depolymerizes microtubules -> impairs neutrophil migration and adhesion
• Arrests cell division in G1 phase (antimitotic)
• Inhibits NLRP3 inflammasome activation -> reduces IL-1β and IL-18 secretion
• Decreases release of chemotactic factors and superoxide anions from neutrophils
• Reduces mast cell histamine release

• 1.2 mg initially, then 0.6 mg 1 hour later (total 1.8 mg)
• As effective as high-dose with far fewer GI side effects

• Oral absorption rapid; peak at 0.5-2 h
• 39% protein bound (mainly albumin)
• Metabolized by CYP3A4; substrate of P-glycoprotein
• t½ ~31 hours
• 40-65% excreted unchanged in urine

• Dose-dependent GI toxicity: nausea, vomiting, diarrhea, abdominal pain (most common)
• Bone marrow suppression (high dose/chronic use)
• Neuromyopathy (especially with renal impairment)
• Alopecia (rare)

• Hepatic or renal impairment with concomitant CYP3A4 or P-glycoprotein inhibitors (e.g., clarithromycin, cyclosporine)
• NOT removed by hemodialysis

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3. Glucocorticoids (Third-Line / When Others Contraindicated)

• Examples: Prednisolone 30-35 mg/day x 5 days; or intra-articular triamcinolone
• Preferred in: renal failure, heart failure (avoid NSAIDs), patients on anticoagulants
• IL-1β inhibitors (e.g., canakinumab) are used in refractory cases (approved by EMA; not FDA-approved for gout in the US)

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PART 2: Urate-Lowering Therapy (ULT) - Chronic Gout

4. Allopurinol (Drug of Choice for ULT)

• Structural analogue of hypoxanthine
• Inhibits xanthine oxidase (XO) - the enzyme responsible for converting hypoxanthine -> xanthine -> uric acid
• Allopurinol is oxidized by XO to oxypurinol, which is the active metabolite
• Oxypurinol inhibits the reduced form of XO (competitive inhibition)
• Net result: decreased uric acid production; increased hypoxanthine and xanthine (more soluble) excreted

• Recurrent gout attacks (>2/year)
• Tophaceous gout
• Renal urate calculi
• Uric acid overproducers
• Starting dose: 100 mg/day, titrate up to 300-600 mg/day
• Target serum urate: <6 mg/dL (or <5 mg/dL in tophaceous gout)

• Rash (most common; can progress to severe Stevens-Johnson syndrome)
• GI upset
• Allopurinol hypersensitivity syndrome (fever, rash, hepatitis, renal failure) - more common with HLA-B*5801 (in Asians)
• Xanthine renal calculi (rare)

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5. Febuxostat

• Non-purine selective XO inhibitor
• Unlike oxypurinol (which only inhibits reduced XO), febuxostat inhibits both reduced AND oxidized forms of XO -> more complete inhibition

• Not a purine analogue -> less risk of the azathioprine interaction
• Metabolized by CYP1A2, 2C8, 2C9 and UGT enzymes (NOT XO)
• Mild-to-moderate renal/hepatic impairment does NOT affect its kinetics
• t½ = 5-8 hours

• 80 mg febuxostat > 300 mg allopurinol in achieving urate <6 mg/dL

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6. Uricosuric Agents

Probenecid

• Mechanism: Inhibits URAT-1 (urate transporter 1) in renal proximal tubule -> blocks reabsorption of urate -> increases renal excretion
• Also inhibits OAT1/OAT3 tubular secretion of many drugs (raises penicillin levels - historically used to prolong penicillin action)
• Indications: Underexcretors of urate (90% of gout patients); used when allopurinol is not tolerated
• Contraindicated in: Uric acid nephrolithiasis, overproducers, renal impairment (GFR <50)
• Ensure high fluid intake to prevent urate stone formation

Benzbromarone

• More potent uricosuric agent; inhibits multiple urate transporters
• Risk of hepatotoxicity

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7. Pegloticase & Rasburicase

• Mechanism: Recombinant uricase (enzyme that converts urate to allantoin, which is freely water-soluble)
• Humans lack uricase naturally
• Pegloticase (PEGylated uricase): For refractory/tophaceous gout - IV infusion
• Rasburicase: Used mainly for tumor lysis syndrome prophylaxis/treatment (not for chronic gout)
• Contraindicated in G6PD deficiency (allantoin production can cause hemolytic anemia)

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Summary Table

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High-Yield Exam Points

1. Do NOT start allopurinol during an acute attack - it can precipitate/worsen the attack by mobilizing urate crystals. Start 2-4 weeks after the acute attack resolves.
2. Always co-prescribe colchicine or NSAID prophylaxis when initiating ULT (first 3-6 months) to prevent flares.
3. Allopurinol + azathioprine = dangerous combination; reduce azathioprine to 25-33% of dose.
4. Colchicine mechanism: blocks NLRP3 inflammasome + disrupts microtubule polymerization.
5. Febuxostat: inhibits both oxidized and reduced forms of XO (vs allopurinol which only inhibits reduced form).
6. Rasburicase contraindicated in G6PD deficiency.
7. Gout in heart failure: use colchicine or steroids - avoid NSAIDs (worsen renal function and fluid retention); prefer allopurinol over febuxostat.
8. Probenecid raises penicillin levels (blocks tubular secretion).

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