Uric Acid Synthesis Inhibitor

URIC ACID SYNTHESIS INHIBITOR

Allopurinol

This hypoxanthine analogue was synthesized as a purine antimetabolite for cancer chemotherapy. However, it had no antineoplastic activity but was a substrate as well as inhibitor of xanthine oxidase, the enzyme responsible for uric acid synthesis (Fig. 15.1).

Allopurinol itself is a short acting (t½ 2 hrs) competitive inhibitor of xanthine oxidase, but its major metabolite alloxanthine (oxypurine) is a long acting (t½ 24 hrs) and noncompetitive inhibitor— primarily responsible for uric acid synthesis inhibition in vivo. During allopurinol administration, plasma concentration of uric acid is reduced and that of hypoxanthine and xanthine is somewhat increased. In place of uric acid alone, all 3 oxipurines are excreted in urine. Since xanthine and hypoxanthine are more soluble, have a higher renal clearance than that of uric acid and each has its individual solubility, precipitation and crystallization in tissues and urine does not occur.

Because of raised levels of xanthine and hypoxanthine, some feedback inhibition of de novo purine synthesis and reutilization of metabolically derived purine also occurs.

Pharmacokinetics

About 80% of orally administered allopurinol is absorbed. It is not bound to plasma proteins; metabolized largely to alloxanthine. During chronic medication, it inhibits its own metabolism and about 1/3rd is excreted unchanged, the rest as alloxanthine.

Interactions

a)    Allopurinol inhibits the degradation of 6mercaptopurine and azathioprine: their doses should be reduced to 1/3rd, but not that of thioguanine, because it follows a different metabolic path (Smethylation).

b)  Probenecid given with allopurinol has complex interaction; while probenecid shortens t½ of alloxanthine, allopurinol prolongs t½ of probenecid.

c)   Allopurinol can potentiate warfarin and theophylline by inhibiting their metabolism.

d)  A higher incidence of skin rashes has been reported when ampicillin is given to patients on allopurinol.

e)   Iron therapy is not recommended during allopurinol treatment. The exact nature of interaction is not known, but interference with mobilization of hepatic iron stores is suggested.

Adverse Effects

These are uncommon. Hypersensitivity reaction consisting of rashes, fever, malaise and muscle pain is the most frequent. It subsides on stopping the drug. Renal impairment increases the incidence of rashes and other reactions to allopurinol.

Stevens-Johnson syndrome is a rare but serious risk.

Gastric irritation, headache, nausea and dizziness are infrequent; do not need withdrawal. Liver damage is rare.

Precautions And Contraindications

Liberal fluid intake is advocated during allopurinol therapy.

It is contraindicated in hypersensitive patients, during pregnancy and lactation.

It should be cautiously used in the elderly, children and in kidney or liver disease.

Uses

Allopurinol is the first choice drug in chronic gout. It can be used in both over producers and under excretors of uric acid, particularly more severe cases, with tophi or nephropathy. Uricosurics are infrequently used in India; they are less effective when g.f.r. is low and are inappropriate in stone formers. The two classes of drugs can also be used together when the body load of urate is large.

With long term allopurinol therapy, tophi gradually disappear and nephropathy is halted, even reversed.

Secondary hyperuricaemia due to cancer chemotherapy/radiation/thiazides or other drugs: can be controlled by allopurinol. It can even be used prophylactically in these situations.

To potentiate 6-mercaptopurine or azathioprine in cancer chemotherapy and immunosuppressant therapy.

Dose: Start with 100 mg OD, gradually increase to maintenance dose of 300 mg/day; maximum 600 mg/day.

ZYLORIC 100, 300 mg tabs., ZYLOPRIM, CIPLORIC 100 mg cap.

Caution

Allopurinol as well as uricosurics should not be started during acute attack of gout. During the initial 1–2 months of treatment with these drugs, attacks of acute gout are more common—probably due to fluctuating plasma urate levels favouring intermittent solubilization and recrystallization in joints; cover with NSAIDs/colchicine may be provided.

Kalaazar

Allopurinol inhibits Leishmania by altering its purine metabolism. It is used as adjuvant to sodium stibogluconate in resistant kalaazar cases (see Ch. No. 60).