Allopurinol ®

Mechanism of action

Allopurinol is a structural isomer of hypoxanthine (a naturally occurring purine in the body) and is an enzyme inhibitor, inhibiting xanthine oxidase.^[1] Xanthine oxidase is responsible for the successive oxidation of hypoxanthine and xanthine resulting in the production of uric acid, the product of human purine metabolism.^[1] In addition to blocking uric acid production, inhibition of xanthine oxidase causes an increase in hypoxanthine and xanthine, which are converted to closely related purine ribotidesadenosine and guanosine monophosphates. Increased levels of these ribotides causes feedback inhibition of amidophosphoribosyl transferase, the first and rate-limiting enzyme of purine biosynthesis. Allopurinol therefore decreases both uric acid formation and purine synthesis.

Uses

The primary use of allopurinol is to treat hyperuricemia (excess uric acid in blood plasma) and its complications. Allopurinol does not alleviate acute attacks of gout, but is useful in chronic gout to prevent future attacks. Similarly, allopurinol commonly is used as prophylaxis with chemotherapeutic treatments, which can rapidly produce severe hyperuricemia. Other established indications for allopurinol therapy include ischemic reperfusion injury, kidney stones with a uric acid component (uric acid nephrolithiasis) and protozoal infections (Leishmaniasis). Also used to prevent tumor lysis with certain types of cancer.

Because allopurinol is not a uricosuric, it can be used in patients who have poor kidney function. However, allopurinol has two important disadvantages: its dosing is complex,^[2] and some patients will be hypersensitive to it. Therefore, use of this drug requires careful monitoring.

Metabolism

Allopurinol is rapidly metabolized by its target, xanthine oxidase, to its active metabolite oxypurinol, which is also an inhibitor of xanthine oxidase. Allopurinol is almost completely metabolized to oxypurinol within two hours of oral administration, whereas oxypurinol is slowly excreted by the kidneys over 18-30 hours. For this reason, oxypurinol is believed to be responsible for the majority of allopurinol’s effect.

Side effects

Side effects of allopurinol are rare, though significant when they occur. A small percentage of people develop a rash and must discontinue this drug. The most serious adverse effect is a hypersensitivity syndrome consisting of fever, skin rash, eosinophilia, hepatitis, worsened renal function and, in some cases, allopurinol hypersensitivity syndrome. Allopurinol is one of the drugs commonly known to cause Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TENS), two life-threatening dermatological conditions.

Allopurinol can cause severe pancytopenia if given with azathioprine or mercaptopurine, due to inhibition of xanthine oxidase which metabolizes these drugs. It can also cause breast enlargement in both males and females.

Allopurinol can lower blood pressure in mild hypertension.^[3]