Drugs Used in Gout & Hyperuricaemia

Gout is an inflammatory arthritis driven by deposition of monosodium urate (MSU) crystals in joints and soft tissue when serum urate exceeds its solubility limit (~6.8 mg/dL). Pharmacotherapy splits into two non-overlapping goals: abort the acute attack (anti-inflammatory) and lower the urate pool long-term (urate-lowering therapy, ULT). Mixing these up — or starting both wrong — is the single most tested concept in this chapter.

The two-compartment logic of gout therapy

The cardinal rule that drives almost every question:

High-yield: Drugs that abort an acute attack (colchicine, NSAIDs, steroids) do NOT lower serum urate. Drugs that lower urate (allopurinol, febuxostat, probenecid) do NOT treat the acute attack — and may even precipitate one if started during a flare.

Goal	Class	Examples	When started
Acute attack	NSAID	Indomethacin, naproxen	Within 24 h of onset
Acute attack	Anti-mitotic	Colchicine	Best within first 24 h
Acute attack	Corticosteroid	Prednisolone, intra-articular triamcinolone	Renal failure / polyarticular
Acute attack (refractory)	IL-1 blocker	Anakinra, canakinumab	NSAID/colchicine contraindicated
Chronic (ULT)	Xanthine oxidase inhibitor	Allopurinol, febuxostat	After attack settles
Chronic (ULT)	Uricosuric	Probenecid, lesinurad	Under-excretors, normal renal function
Chronic	Uricase	Rasburicase, pegloticase	Tumour lysis, refractory tophaceous gout

Flow of an acute gout attack: Onset of monoarticular pain (often first MTP = podagra) → confirm with joint aspiration showing negatively birefringent needle-shaped MSU crystals → start NSAID or colchicine or steroid → continue any existing ULT unchanged → once attack settles, initiate/optimise ULT under colchicine cover.

Acute attack drugs

Colchicine

Colchicine is the classic exam favourite because of its unique mechanism.

• Mechanism: Binds tubulin and prevents its polymerisation into microtubules. This blocks neutrophil chemotaxis, migration, phagocytosis and degranulation at the crystal site, and inhibits the NLRP3 inflammasome (reducing IL-1β release). It is anti-inflammatory but not analgesic and not anti-hyperuricaemic.
• Spindle poison action: Because it arrests mitosis in metaphase (a true mitotic spindle poison), it accounts for both its anti-inflammatory effect on neutrophils and its toxicity on rapidly dividing tissue (gut, marrow).
• Dosing: Modern low-dose regimen — 1.2 mg, then 0.6 mg one hour later (total 1.8 mg). High-dose "to-toxicity" dosing is obsolete.

High-yield: The dose-limiting toxicity of colchicine is GI — nausea, vomiting, abdominal cramps and profuse watery diarrhoea. Diarrhoea is the earliest sign of toxicity and the signal to stop the drug.

Other colchicine toxicities (chronic/overdose): bone marrow suppression (agranulocytosis, aplastic anaemia), myopathy and neuropathy (especially with renal impairment + statins/fibrates), alopecia, and azoospermia. Overdose is potentially fatal with multi-organ failure; there is no specific antidote.

High-yield: Colchicine is also used in familial Mediterranean fever (FMF) prophylaxis and in pericarditis (acute and recurrent) — non-gout uses commonly examined.

NSAIDs

Any potent NSAID works; the historic favourite is indomethacin, but naproxen and diclofenac are equally effective. They inhibit COX and prostaglandin-mediated inflammation. Aspirin is avoided — low-dose aspirin reduces urate excretion and high doses are not used for gout.

High-yield: Avoid NSAIDs in renal impairment, peptic ulcer, heart failure and the elderly — situations where colchicine (low dose) or corticosteroids are preferred.

Corticosteroids

Oral prednisolone, or intra-articular triamcinolone for a single accessible joint, or intramuscular/IV steroids. Preferred when NSAIDs and colchicine are contraindicated — particularly in chronic kidney disease and polyarticular flares. Equally effective as NSAIDs for acute gout.

IL-1 antagonists

Because MSU crystals activate the NLRP3 inflammasome → IL-1β, blocking IL-1 is rational. Anakinra (IL-1 receptor antagonist) and canakinumab (anti-IL-1β monoclonal) are reserved for patients in whom NSAIDs, colchicine and steroids are all contraindicated or ineffective.

Urate-lowering therapy (chronic)

ULT is indicated for recurrent attacks (≥2/year), tophi, gouty erosions on imaging, urate nephrolithiasis, or gout with CKD. Target serum urate < 6 mg/dL (and < 5 mg/dL in tophaceous/severe gout, to dissolve tophi).

High-yield: Two universal ULT initiation rules — (1) Never start ULT during an acute attack (wait until it settles, classically 2 weeks). (2) Always co-prescribe prophylaxis (low-dose colchicine 0.5–0.6 mg OD/BD, or low-dose NSAID) for the first 3–6 months, because a falling urate mobilises crystals and paradoxically triggers flares ("mobilisation flare").

Xanthine oxidase inhibitors (decrease urate production)

These block the conversion hypoxanthine → xanthine → uric acid catalysed by xanthine oxidase (XO).

Feature	Allopurinol	Febuxostat
Structure	Purine analogue	Non-purine selective inhibitor
XO inhibition	Competitive (and via active metabolite)	Non-competitive, more potent/selective
Active metabolite	Alloxanthine (oxypurinol) — long t½, sustains effect	None relevant
Renal dosing	Needs dose reduction in renal failure	No dose adjustment in mild–moderate renal impairment — major advantage
Hypersensitivity	Allopurinol hypersensitivity syndrome; SJS/TEN (HLA-B*5801)	Lower rash risk; useful in allopurinol-intolerant patients
Cardiovascular	Neutral	CARES trial: ↑ CV and all-cause mortality signal — caution in established CVD
Cost	Cheap, first-line	Expensive, second-line

High-yield: Allopurinol is metabolised by XO to oxypurinol (alloxanthine), the long-acting active metabolite — this is why once-daily dosing works despite allopurinol's short half-life.

High-yield (most-tested interaction): Allopurinol inhibits xanthine oxidase, which normally inactivates 6-mercaptopurine (6-MP) and azathioprine (a 6-MP prodrug). Co-administration causes dangerous accumulation → severe myelosuppression. Reduce the thiopurine dose to ~25% (one-quarter) or avoid the combination. Febuxostat carries the same interaction and is likewise contraindicated with azathioprine/6-MP.

Other allopurinol interactions: increases levels of theophylline and ciclophosphamide; with ampicillin/amoxicillin there is a higher incidence of skin rash. Allopurinol can rarely precipitate XO-deficiency-like xanthine stones.

High-yield: Febuxostat's advantages = no renal dose adjustment (safe in mild–moderate CKD) and useful in allopurinol hypersensitivity/HLA-B*5801 carriers; its disadvantage = cardiovascular mortality signal (CARES trial) and cost.

Uricosurics (increase urate excretion)

Probenecid (and sulfinpyrazone, benzbromarone, lesinurad) block the proximal tubular URAT1 transporter that reabsorbs urate, thereby increasing renal uric acid excretion.

• Indication: Urate under-excretors with good renal function (creatinine clearance > 50–60 mL/min) and no history of urate stones.
• Contraindications: Nephrolithiasis (increased urinary urate promotes stones — give plenty of fluids + urine alkalinisation), and renal impairment (ineffective at low GFR), and overproducers / tumour lysis.

High-yield: Probenecid also blocks tubular secretion of organic acids, raising plasma levels of penicillin, cephalosporins, methotrexate and PAS — historically used deliberately to prolong penicillin action. Conversely, low-dose aspirin antagonises uricosurics (do not combine).

High-yield: A drug paradox — aspirin is bidirectional on urate: low doses cause urate retention (anti-uricosuric), only very high doses are uricosuric. So aspirin is avoided in gout patients.

Uricase agents (convert urate to allantoin)

Humans lack uricase. Recombinant uricase converts uric acid to highly soluble allantoin.

• Rasburicase: Prevents/treats tumour lysis syndrome hyperuricaemia (haematological malignancy chemotherapy).
• Pegloticase: Pegylated uricase IV for refractory chronic tophaceous gout.

High-yield: Rasburicase/pegloticase cause haemolysis and methaemoglobinaemia in G6PD deficiency — screen first; G6PD deficiency is a contraindication.

A mechanistic map (where each drug acts)

Purine metabolism → hypoxanthine → [XO] xanthine → [XO] uric acid → (humans stop here; no uricase) → renal tubule reabsorption via URAT1.

• Allopurinol / Febuxostat block XO (↓ production).
• Probenecid / Lesinurad block URAT1 (↑ excretion).
• Rasburicase / Pegloticase add the missing uricase step (↑ degradation to allantoin).
• Colchicine / NSAID / steroid act downstream on the crystal-induced inflammation, not on urate at all.

Mnemonic — "PEEL the urate": Production down (allo/febu), Excretion up (probenecid), Enzyme replacement (uricase), Leucocyte block (colchicine).

Diagnosis & investigation of choice

• Investigation of choice / gold standard: Synovial fluid analysis under polarised light microscopy showing needle-shaped, negatively birefringent MSU crystals (appear yellow when parallel to the slow axis of the red compensator).
• Contrast with pseudogout (CPPD): rhomboid-shaped, positively birefringent crystals (blue when parallel).
• Serum urate may be normal during an acute attack (it can fall acutely) — a normal level does not exclude gout; recheck after the flare.
• Dual-energy CT (DECT) and ultrasound (double-contour sign) are useful non-invasive adjuncts.

	Gout (MSU)	Pseudogout (CPPD)
Crystal shape	Needle	Rhomboid
Birefringence	Negative	Positive
Colour ∥ to red filter	Yellow	Blue
Typical joint	1st MTP (podagra)	Knee, wrist
Radiology	Erosions with overhanging edge	Chondrocalcinosis

Complications

• Drug-related: colchicine GI/marrow toxicity and myoneuropathy; allopurinol hypersensitivity syndrome and SJS/TEN (HLA-B*5801, higher in renal failure and certain Asian populations); febuxostat cardiovascular mortality; probenecid uric acid stones; thiopurine myelosuppression with XO inhibitors; rasburicase haemolysis in G6PD deficiency.
• Disease-related: chronic tophaceous gout, gouty (urate) nephropathy, urolithiasis, joint destruction.
• Mobilisation flares on starting ULT (preventable with prophylaxis).

Key differentials

• Septic arthritis — must be excluded by aspiration in any acute hot joint (can coexist with gout).
• Pseudogout (CPPD) — crystal morphology distinguishes.
• Reactive / psoriatic arthritis, cellulitis, trauma.

Recently asked / exam angle

• Mechanism of colchicine = inhibits tubulin polymerisation / microtubule formation → blocks neutrophil migration (NOT urate lowering). Repeatedly asked single-best-answer.
• Colchicine dose-limiting toxicity = diarrhoea.
• Allopurinol + azathioprine/6-MP interaction → reduce thiopurine to one-fourth; mechanism = XO inhibition. Classic "which drug interaction" question.
• Allopurinol active metabolite = alloxanthine (oxypurinol).
• Febuxostat: non-purine XO inhibitor, safe in renal impairment, CARES trial CV mortality signal.
• Probenecid mechanism = inhibits URAT1 (decreases tubular reabsorption of urate); also blocks penicillin tubular secretion.
• Drug that should NOT be given during acute attack / that worsens an acute flare on initiation = allopurinol (start ULT only after attack settles, with colchicine cover).
• HLA-B*5801 associated with allopurinol SJS/TEN.
• Rasburicase for tumour lysis syndrome; contraindicated in G6PD deficiency.
• Aspirin is anti-uricosuric at low dose — avoid in gout.

Rapid revision

1. Acute gout: NSAID (indomethacin), colchicine, or steroid — none lowers urate.
2. Chronic gout: allopurinol/febuxostat (↓ production) or probenecid (↑ excretion).
3. Colchicine = tubulin polymerisation inhibitor → blocks neutrophil chemotaxis; also inhibits NLRP3 inflammasome.
4. Colchicine dose-limiting toxicity = diarrhoea; overdose can be fatal, no antidote.
5. Never start ULT during an acute attack; always give colchicine/NSAID prophylaxis for 3–6 months.
6. Target serum urate < 6 mg/dL (< 5 if tophi).
7. Allopurinol → active metabolite oxypurinol (alloxanthine), long-acting.
8. Allopurinol/febuxostat + azathioprine/6-MP → severe myelosuppression; cut thiopurine to ~25%.
9. Febuxostat: non-purine, no renal dose change, but CARES trial cardiovascular mortality signal.
10. Probenecid blocks URAT1; contraindicated in stones and renal failure; prolongs penicillin.
11. Diagnosis: synovial fluid — needle-shaped, negatively birefringent MSU crystals.
12. Rasburicase/pegloticase = uricase (urate → allantoin); avoid in G6PD deficiency.