3. Explain the biochemical basis of the drugs used to treat this condition.

Allopurinol, a structural analog of hypoxanthine, inhibits uric acid synthesis and is used
in patients who are overproducers of uric acid. It acts through enzyme inhibition (Allopurinol
is converted in the body to oxypurinol). It inhibits xanthine oxidase (XO), the key enzyme of uric
acid synthesis, in a reversible manner. Because of its structural resemblance with xanthine and
hypoxanthine (the natural substrates of XO, compounds more soluble than uric acid and,
therefore, less likely to initiate an inflammatory response.), allopurinol can inhibit this enzyme
by substrate competition. The above resemblance permits the allopurinol to occupy the enzyme
active site, thereby blocking the latter form acting on its natural substrate. Further, the enzyme
activity causes conversion of allopurinol to alloxanthine. The latter inhibits the enzyme activity
more effectively: this method of enzyme inhibition is called suicide inhibition, since the enzyme
itself is generating a substance deleterious to its own activity.
In patients with normal levels of HGPRT (Hypoxanthine-guanine
phosphoribosyltransferase), the hypoxanthine can be salvaged, thus reducing the levels of PRPP
and, therefore, de novo purine synthesis. Febuxostat, a non-purine inhibitor of XO, is now
available.

Ibuprofen is a reversible inhibitor of prostaglandin synthase, the key enzyme of

protaglandin synthesis. Prostagladins are known to be important mediators of inflammatory
response. Inhibition of their synthesis, therefore, reduces the inflammation. This is helpful in this
patient to relieve inflammation of joints

Colchicine, steroidal drugs such as prednisone, Colchicine prevents formation of

microtubules, thus decreasing the movement of neutrophils into the affected area. Like the other
anti-inflammatory drugs, it has no effect on uric acid levels.

Uricosuric agents, such as probenecid or sulfinpyrazone, that increase renal excretion of

uric acid (they act directly on renal tubules) are used in patients who are underexcretors of uric
acid.

References:
Lippincotts Illustrated Reviews: Biochemistry Fifth Edition, Page 301
Textbook of Medical Biochemistry, Dinesh Puri
Clinical Rheumatology 2007, Biochemical effectiveness of allopurinol and allopurinol probenecid in
previously benzbromarone-treated gout patients, Mattheus K. Reinders & Eric N. van Roon