Gout| Treatment of gout|Pharmacology of Gout

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Gout

It is a disease characterized by elevated serum uric acid level. Uric acid has low water
solubility and gets precipitated in the joints, kidney and subcutaneous . Secondary
hyperuricemia may result due to excessive production (breakdown of proteins and nucleic
acids during cancer chemotherapy) or decreased excretion (due to the use of thiazides, loop
diuretics, ethambutol, clofibrate etc.) of uric acid.

Acute gout

It is manifested as severe inflammation of joints (due to precipitation of uric acid crystals)

• NSAIDs like indomethacin are drug of choice due to better tolerability. Aspirin is not
used as it may cause hyperuricemia. Tolmetin is not effective.

• Colchicine is more effective and faster acting than NSAIDs but is used rarely due to
its high toxicity. It acts by inhibiting granulocyte migration into the inflamed joint.
It causes metaphase arrest (other drugs causing metaphase arrest are vinca alkaloids,
ixabepilone and taxanes). Most common and dose limiting toxicity is diarrhea. It can also
cause kidney damage, myopathy and bone marrow depression.

• Two indications for daily colchicine are:
∆ To prevent further attacks
∆ Along with urate-lowering therapy to suppress attacks precipitated by abrupt
changes in serum uric acid

• Intra-articular corticosteroids can be used in the refractory cases.

• IL-1 inhibitors like anakinara, canakinumab and rilonacept have efficacy for
management of acute gout but are not FDA-approved for this indication

Chronic gout

Strategies to decrease uric acid in the serum are to decrease the synthesis or to increase the
excretion and metabolism.

Drugs Decreasing Synthesis

Allopurinol (hypoxanthine analog) and recently approved drug, febuxostat (a non-purine
drug) decrease the production of uric acid by inhibiting the enzyme xanthine oxidase. Allopurinol
is metabolized by the same enzyme to alloxanthine which is a long acting inhibitor of
xanthine oxidase. These are indicated as drug of choice for chronic gout in the inter-critical
period (between two acute attacks) and also with anticancer drugs (to decrease secondary
hyperuricemia). 6-Mercaptopurine and azathioprine are metabolized by xanthine oxidase;
therefore dose of these drugs should be decreased when given with allopurinol. Allopurinol is also
used as an adjuvant to sodium stibogluconate in the treatment of kala azar. It is contra-indicated in
acute gout because uric acid has inhibitory effect on release of cytokines and allopurinol may
aggravate the inflammation by reducing uric acid.

• Most frequent adverse effect with xanthine oxidase inhibitors is precipitation of
acute attack of gout.
• There is strong association between HLA–B*5801 and allopurinol hypersensitivity
• Combined use of allopurinol and ampicillin causes a drug rash in 20% of patients.
• Allopurinol requires dose adjustment in renal failure whereas febuxostat can be
administered without dose adjustment.
• Febuxostat can result in abnormal liver function tests
Drugs Increasing Excretion
Probenecid, sulfinpyrazone and benzbromarone acts as competitive inhibitors of
reabsorption of uric acid in proximal tubules. Plenty of fluids and urinary alkalinizers should
be given concurrently to prevent precipitation of uric acid crystals in the kidney tubules.
These drugs are ineffective in the presence of renal damage. Probenecid is also used along with
penicillins to decrease their renal excretion.

• Uricosuric drugs should not be used if
   ∆Creatinine clearance is <50ml/min.
   ∆ history of nephrolithiasis (uric acid or calcium  stone
v Evidence of overproduction of uric acid (> 800 mg of uric acid in a 24-hour urine
collection)


Drugs Increasing Metabolism

Urate oxidase (uricase) metabolizes insoluble uric acid to soluble allantoin in the birds.
This enzyme is absent in humans. Recombinant urate oxidase is now available as rasburicase.
Pegloticase is another similiar drug that is pegylated to increase duration of action. Pegloticase
and rasburicase are administered by i.v. route and are indicated only in patients with chronic
gout refractory to other treatments.