Q5 LONG ANSWER 10M ★ High-yield

Describe the drugs used in acute and chronic gout with their mechanisms and adverse effects.

Pharmacology · 2nd Professional — Para-Clinical

Pathophysiology and Aims of Treatment

Gout is inflammatory arthritis caused by deposition of monosodium urate crystals in joints and tissues, resulting from hyperuricaemia.

Uric acid is the end product of purine metabolism, formed by xanthine oxidase from hypoxanthine and xanthine
Hyperuricaemia results from overproduction (about 10% — enzyme defects, myeloproliferative disease, tumour lysis, high purine diet, alcohol) or under-excretion (about 90% — renal impairment, thiazides and loop diuretics, low-dose aspirin, alcohol, lead)
Treatment has two entirely separate aims — (1) suppress the acute inflammation, and (2) lower urate in the long term. The drugs for each are different, and confusing them is the commonest error in management

Drugs for the Acute Attack

Drug	Mechanism	Notes
NSAIDs — first-line	Cyclo-oxygenase inhibition	Indomethacin, naproxen, diclofenac in full dose. Aspirin must be avoided — at low dose it retains urate and worsens the attack
Colchicine	Binds tubulin and prevents microtubule assembly, so neutrophils cannot migrate to or phagocytose the crystals	Not an analgesic and not uricosuric; diarrhoea, nausea and vomiting are dose-limiting; marrow suppression and neuromyopathy in overdose. Low-dose regimens are as effective and far better tolerated
Corticosteroids	Broad anti-inflammatory action	Oral, intramuscular or intra-articular; the choice where NSAIDs and colchicine are contraindicated, as in renal impairment
Interleukin-1 blockers	Anakinra, canakinumab	Refractory cases; expensive

CLINICAL PEARL

Colchicine relieves gout without touching uric acid at all. It works entirely on the neutrophil — blocking the migration and phagocytosis that generate the inflammation. That is why it is almost specific for gout, why it does nothing for other joint pain, and why it neither prevents crystal deposition nor treats the underlying hyperuricaemia.

Drugs for Long-term Urate Lowering

Drug	Mechanism	Notes
Allopurinol	Inhibits xanthine oxidase; its metabolite oxypurinol is the main long-acting inhibitor	First-line; effective in both overproducers and under-excretors, and safe in renal impairment at reduced dose. Rash, and rarely a severe hypersensitivity syndrome (associated with HLA-B*58:01)
Febuxostat	Non-purine xanthine oxidase inhibitor	For allopurinol intolerance; a cardiovascular safety signal has been reported
Probenecid, sulphinpyrazone	Uricosuric — block tubular reabsorption of urate	Only for under-excretors with good renal function; require high fluid intake and urinary alkalinisation to prevent stones; ineffective if GFR is low
Rasburicase	Recombinant urate oxidase, converting urate to soluble allantoin	Tumour lysis syndrome; contraindicated in G6PD deficiency
Losartan, fenofibrate	Mildly uricosuric	A useful incidental benefit when treating coexisting hypertension or dyslipidaemia

Principles of Starting Urate-lowering Therapy

Never start or stop allopurinol during an acute attack — any sudden change in urate level mobilises crystals and worsens or precipitates an attack
Start 2 to 4 weeks after the attack settles, at a low dose, and titrate upward against the serum urate
Cover the first 3 to 6 months with low-dose colchicine or an NSAID, since attacks are common while urate is falling
Target a serum urate below 6 mg/dL (below 5 where there are tophi), which is below the saturation point and allows deposits to dissolve
Treatment is usually lifelong; stopping allows urate to rise and attacks to return
Asymptomatic hyperuricaemia is generally not treated — most people with a raised urate never develop gout

Other Manifestations of Urate Deposition

Manifestation	Features
Acute gouty arthritis	Sudden, exquisitely painful monoarthritis, classically the first metatarsophalangeal joint (podagra); red, hot and swollen — often mistaken for septic arthritis or cellulitis
Tophi	Chalky deposits in the helix of the ear, olecranon bursa, tendons and joints, appearing after years of untreated hyperuricaemia; they dissolve if urate is kept below about 5 mg/dL
Chronic tophaceous gout	Destructive arthropathy with punched-out erosions on radiographs
Urate nephrolithiasis	Radiolucent stones; favoured by acid and concentrated urine; prevented by high fluid intake and urinary alkalinisation
Urate nephropathy	Chronic interstitial deposition; and acute urate nephropathy in tumour lysis syndrome
Pseudogout — the differential	Calcium pyrophosphate crystals; rhomboid and positively birefringent, the opposite of urate; affects the knee and wrist; chondrocalcinosis on radiographs

Interactions and Applied Aspects

Allopurinol with azathioprine or 6-mercaptopurine is dangerous — xanthine oxidase normally inactivates them, so blocking it causes severe marrow suppression. The thiopurine dose must be reduced to about a quarter, or the combination avoided
Allopurinol also potentiates warfarin and cyclophosphamide
Colchicine toxicity is increased by clarithromycin, ciclosporin and statins, and in renal impairment; deaths have occurred from this combination
Review diuretics and low-dose aspirin in a gouty patient — both raise urate, and an alternative antihypertensive such as losartan may serve better
Lifestyle — reduce alcohol (especially beer), fructose-sweetened drinks, red meat and shellfish; lose weight; maintain good hydration. Dairy products and coffee appear protective
Rising affluence has increased gout markedly in urban India, and it is frequently misdiagnosed as septic arthritis or cellulitis; joint aspiration showing needle-shaped, negatively birefringent crystals settles the question
Serum urate may be normal during an acute attack, because urate shifts into the joint; a normal level therefore does not exclude gout, and the level should be rechecked after the attack settles
Always exclude septic arthritis in an acutely inflamed joint — the two can coexist, and missing infection is far more dangerous than delaying gout treatment
Explain that allopurinol does not treat the attack; patients who take it only when the joint hurts, and stop when it settles, guarantee recurrent attacks and often conclude the drug does not work
Screen for the metabolic syndrome in every gouty patient — hypertension, diabetes, dyslipidaemia and obesity cluster with it, and treating them matters more for survival than the joint disease does
Test for HLA-B*58:01 before allopurinol where feasible in populations with a high carrier rate, since the severe hypersensitivity syndrome carries a substantial mortality
Start allopurinol at a low dose and titrate — 100 mg daily, or 50 mg in renal impairment, increasing every few weeks; this reduces both attacks and the risk of hypersensitivity
Colchicine has a very narrow margin in renal or hepatic impairment, and the older high-dose regimens caused more diarrhoea than benefit; low-dose regimens are now standard
Measure urate 4 weeks after each dose change and continue titrating until the target is reached; stopping at an arbitrary dose is a common reason for treatment failure
Do not stop allopurinol during an attack if the patient is already established on it — only avoid starting it; stopping causes a further shift in urate and prolongs the attack
Intra-articular steroid is ideal for a single affected joint in a patient with renal impairment or heart failure, in whom NSAIDs and colchicine are both hazardous
Educate the patient that gout is a lifelong metabolic disease, not a series of unrelated attacks; that single change in understanding does more for adherence than any drug choice
Tumour lysis syndrome is prevented, not treated — hydration and allopurinol before chemotherapy, or rasburicase where the risk is high
Alcohol raises urate by two mechanisms — increased purine load from beer, and lactate competing with urate for tubular secretion; both are worth explaining rather than simply advising abstinence
Diuretic-induced gout is common and often correctable by substituting another antihypertensive, and this should be considered before committing a patient to lifelong urate-lowering therapy
Colchicine is also used in pericarditis and familial Mediterranean fever, where its anti-inflammatory action on neutrophils is equally useful

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