A-Textbook-of-Clinical-Pharmacology-and-Therapeutics-5th-edition

HYPERURICAEMIA AND GOUT 173
Pharmacokinetics
Allopurinol is well absorbed. Hepatic metabolism yields oxypurinol,
itself a weak xanthine oxidase inhibitor.
Drug interactions
• Allopurinol decreases the breakdown of 6-mercaptopurine
(the active metabolite of azathioprine) with a potential for
severe toxicity (haematopoietic and mucosal).
• Metabolism of warfarin is inhibited.
URICOSURIC DRUGS
Use
These drugs (e.g. sulfinpyrazone, probenecid) have been
largely superseded by allopurinol, but are useful for patients
who require prophylactic therapy and who have severe
adverse reactions to allopurinol. Uricosuric drugs inhibit
active transport of organic acids by renal tubules (Chapter 6).
Their main effect on the handling of uric acid by the kidney is
to prevent the reabsorption of filtered uric acid by the proximal
tubule, thus greatly increasing excretion. Probenecid can
precipitate an acute attack of gout. Sulfinpyrazone is a weak
NSAID in its own right, and a flare of gout is less likely to occur
when using it. Unlike other NSAIDs, there is also evidence that
it has a clinically useful antiplatelet action. The patient should
drink enough water to have a urine output of 2 L/day during
the first month of treatment and a sodium bicarbonate or
potassium citrate mixture should be given to keep the urinary
pH above 7.0 to avoid precipitation of uric acid stones. Other
adverse effects include rashes and gastro-intestinal upsets.
Case history
A 45-year-old publican presents to a locum GP with symptoms
of a painful, swollen and red big toe. There is a history
of essential hypertension, and he has had a similar but less
severe attack three months previously which settled spontaneously.
Following this, serum urate concentrations were
determined and found to be within the normal range. His
toe is now inflamed and exquisitely tender. His blood pressure
is 180/106 mmHg, but the examination is otherwise
unremarkable. The locum is concerned that treatment with
an NSAID might increase the patient’s blood pressure, and
that, since his uric acid was recently found to be normal, he
might not have gout. He therefore prescribes cocodamol for
the pain and repeated the serum urate measurement. The
patient returns the following day unimproved, having spent
a sleepless night, and you see him yourself for the first time.
The examination is as described by your locum, and serum
urate remains normal. What would you do
Comment
Normal serum urate does not exclude gout. The patient
requires treatment with an NSAID, such as ibuprofen. Review
his medication (is he on a diuretic for his hypertension) and
enquire about his alcohol consumption. Blood pressure is
commonly increased by acute pain. Despite his occupation,
the patient does not drink alcohol and he was receiving bendroflumethiazide
for hypertension. This was discontinued,
amlodipine was substituted and his blood pressure fell to
162/100 mmHg during treatment with ibuprofen. A short
period of poor antihypertensive control in this setting is not
of great importance. After the pain has settled and ibuprofen
stopped, the patient’s blood pressure decreases further to
140/84 mmHg on amlodipine. He did not have any recurrence
of gout. (Only if recurrent gout was a problem would prophylactic
treatment with allopurinol be worth considering.)
RASBURICASE
Rasburicase, a recently introduced preparation of recombinant
xanthine oxidase, is used to prevent complications of acute
hyperuricaemia in leukaemia therapy, especially in children.
Key points
Gout
• Gout is caused by an inflammatory reaction to
precipitated crystals of uric acid.
• Always consider possible contributing factors, including
drugs (especially diuretics) and ethanol.
• Treatment of the acute attack:
– NSAIDs (e.g. ibuprofen);
– colchicine (useful in cases where NSAIDs are
contraindicated).
• prophylaxis (for recurrent disease or tophaceous gout):
– allopurinol (xanthine oxidase inhibitor) is only
started well after the acute attack has resolved and
with NSAID cover to prevent a flare;
– uricosuric drugs (e.g. sulfinpyrazone, which has
additional NSAID and antiplatelet actions) are less
effective than allopurinol. They are a useful
alternative when allopurinol causes severe adverse
effects (e.g. rashes). A high output of alkaline urine
should be maintained to prevent stone formation.
FURTHER READING
Boers M. NSAIDs and selective COX-2 inhibitors: competition between
gastroprotection and cardioprotection. Lancet 2001; 357: 1222–3.
De Broe ME, Elseviers MM. Analgesic nephropathy. New England
Journal of Medicine 1998; 338: 446–42.
Emmerson BT. The management of gout. New England Journal of
Medicine 1996; 334: 445–51.
Feldmann M. Development of anti-TNF therapy for rheumatoid
arthritis. Nature Reviews. Immunology 2002; 2: 364–71.
FitzGerald GA, Patrono C. The coxibs, selective inhibitors of cyclooxygenase-2.
New England Journal of Medicine 2001; 345: 433–42.
Graham DJ, Campen D, Hui R et al. Risk of acute myocardial infarction
and sudden cardiac death in patients treated with cyclo-oxygenase
2 selective and non-selective non-steroidal anti-inflammatory
drugs: nested case control study. Lancet 2005; 365: 475–81.
Klippel JHK. Biologic therapy for rheumatoid arthritis. New England
Journal of Medicine 2000; 343: 1640–1.
Maini RN, Taylor PC. Anti-cytokine therapy for rheumatoid arthritis.
Annual Review of Medicine 2000; 51: 207–29.
O’Dell JR, Haire CE, Erikson N et al. Treatment of rheumatoid arthritis
with methotrexate alone, sulfasalazine and hydroxychloroquine
or a combination of all three medications. New England
Journal of Medicine 1996; 334: 1287–91.
Rongean JC, Kelly JP, Naldi L. Medication use and the risk of Stevens-
Johnson syndrome or toxic epidermal necrolysis. New England
Journal of Medicine 1995; 333: 1600–7.
Vane JR, Bakhle YS, Botting RM. Cyclo-oxygenases 1 and 2. Annual
Review of Pharmacology and Toxicology 1998; 38: 97–120.