A Textbook of Clinical Pharmacology and Therapeutics

(acute gout), cause chalky deposits (tophi) and cause renal
stones and/or renal tubular obstruction. The final enzymatic
reactions in the production of uric acid are shown in Figure 26.2.
Two of these stages are dependent on xanthine oxidase. In most
mammals, uricase converts uric acid to allantoin, which is rap-
idly eliminated by the kidneys, but humans lack uricase, so the
less soluble uric acid must be excreted. It is more soluble in
an alkaline urine (Chapter 6). Plasma uric acid concentration is
lowered either by increasing renal excretion or, more often, by
inhibiting synthesis.
Hyperuricaemia often occurs in the setting of obesity and
excessive ethanol consumption. Genetically determined
defects of metabolism causing overproduction of uric acid are
rare. Increased breakdown of nuclear material occurs in malig-
nancies, particularly when treated by cytotoxic drugs, and is
extremely important because it can lead to acute renal failure if
measures are not taken to reduce urate formation and enhance
its excretion in this setting (see below). Hyperuricaemia also
occurs when excretion is decreased, for example, in renal fail-
ure or when tubular excretion is diminished by diuretics, pyraz-
inamide(Chapter 44) or low doses of salicylate(Chapter 25).

ACUTE GOUT

The acute attack is treated with anti-inflammatory analgesic
agents (e.g. indometacin).Aspirinis contraindicated because
of its effect on reducing urate excetion. Colchicine(derived
from the autumn crocus) is relatively specific in relieving the
symptoms of acute gout and is an alternative to an NSAID. It
does not inhibit COX, so it lacks the side effects of NSAIDs, but
commonly causes diarrhoea.

COLCHICINE

Use

Colchicineis a useful alternative to NSAIDs in patients with
gout in whom NSAIDs are contraindicated. Its efficacy is simi-
lar to indometacin. It is also used in patients with familial
Mediterranean fever and Behçet’s disease. Unlike many
NSAIDs, it does not interact with warfarin. For acute attacks,
it is given up to four times a day. A low dose can be used pro-
phylactically. It is relatively contraindicated in the elderly and
in those with renal or gastro-intestinal disease.

Mechanism of action

Colchicinebinds to the tubulin protein of microtubules and

impairs their function This has important results:

• toxic concentrations cause arrest of cell division (exploited
  in making chromosome preparations ex vivo);


• inhibition of leukocyte migration and hence reduced
  inflammation.

Adverse effects

Adverse effects include the following:

• nausea, vomiting and diarrhoea;


• gastro-intestinal haemorrhage;


• rashes;


• renal failure;


• peripheral neuropathy;


• alopecia;


• blood dyscrasias.

Pharmacokinetics

Colchicineis well absorbed from the gastro-intestinal tract. It

is partly metabolized, and a major portion is excreted via the

bile and undergoes enterohepatic circulation, contributing to

its gastro-intestinal toxicity.

PROPHYLAXIS FOR RECURRENT GOUT

ALLOPURINOL

Use

Allopurinolis used as long-term prophylaxis for patients

with recurrent gout, especially tophaceous gout, urate renal

stones, gout with renal failure and acute urate nephropathy,

and to prevent this complication in patients about to undergo

treatment with cytotoxic drugs, especially patients with

haematological malignancies. The plasma uric acid concentra-

tion should be kept below 0.42 mmol/L. Allopurinolmay

provoke acute gout during the first few weeks of treatment. It

must not be commenced till several weeks after an acute

attack has completely resolved. Concurrent indometacinor

colchicineis given during the first month of treatment.

Mechanism of action

Allopurinolis a xanthine oxidase inhibitor and decreases

the production of uric acid (Figure 26.2). This reduces the

concentration of uric acid in extracellular fluid, thereby pre-

venting precipitation of crystals in joints or elsewhere. Uric

acid is mobilized from tophaceous deposits which slowly

disappear.

Adverse effects

Precipitating an acute attack (see above) is common if the

above precautions are not adhered to. Mild dose-related

rashes and life-threatening hypersensitivity reactions (includ-

ing Stevens Johnson syndrome) can occur. Malaise, nausea,

vertigo, alopecia and hepatotoxicity are uncommon toxicities.

172 ANTI-INFLAMMATORY DRUGS AND THE TREATMENT OF ARTHRITIS

Adenine Guanine

Hypoxanthine Xanthine

Xanthine oxidase

Uric

acid

Figure 26.2:The final stages of the production of uric acid.