Azathioprine

Common indications

1. Maintenance of remission of Crohn’s disease and ulcerative colitis (UC).
2. As a disease-modifying agent in rheumatoid arthritis and autoimmune conditions not responding to corticosteroids or other standard treatments. 
3. To prevent organ rejection in transplant recipients.

Mechanisms of action

• Azathioprine is a pro-drug. This means that it is not itself pharmacologically active, but human metabolism converts it to active substances. 
• The main metabolite is 6-mercaptopurine, which is further metabolised to active substances. 
• These inhibit synthesis of purines (notably the nucleosides adenine and guanine) and therefore inhibit DNA and ribonucleic acid (RNA) replication. 
• Whereas most cells can ‘salvage’ or ‘recycle’ purines, lymphocytes are dependent on purine synthesis, and so are particularly affected by azathioprine metabolites. 
• Metabolism and elimination of azathioprine and its metabolites involves the enzymes xanthine oxidase and thiopurine methyltransferase (TPMT). The activity of the latter is reduced or absent in some individuals.

Important adverse effects

• The most serious dose-related adverse effect of azathioprine is bone marrow suppression, which results most significantly in leukopenia and an increased risk of infection. A reduction in dose or temporary break in therapy may resolve this. TPMT phenotyping may identify those at risk. 
• Nausea is common and may be reduced by dividing the daily dose. 
• Hypersensitivity reactions, which may manifest as diarrhoea and vomiting, rash, fever, myalgia, hypotension and pancreatitis, may occur. 
• Other rare but serious adverse effects include veno-occlusive disease, hepatotoxicity and an increased risk of some tumours, such as lymphoma.

Warnings

• TPMT phenotyping should be performed before starting therapy. Azathioprine should not be prescribed for patients with absent TPMT activity. Those with reduced TPMT activity should be treated only by a specialist. 
• Hypersensitivity reactions may be serious and should prompt cessation of therapy. 
• Dosage should be reduced in hepatic and renal impairment. 
• Azathioprine is teratogenic in animal studies, although the effects in humans are less clear. In general, treatment should not be initiated in pregnancy but may continue in those already established on treatment where the benefits outweigh the risks of stopping (e.g. transplant recipients).

Important interactions

• The risk of infection is increased if used with other immunosuppressants, such as corticosteroids, although co-prescription may be unavoidable in the conditions indicated. 
• Azathioprine should not be prescribed with xanthine oxidase inhibitors such as allopurinol, as they reduce azathioprine metabolism and increase the risk of toxicity. 
• The risk of leukopenia is increased when prescribed with other drugs that are myelosuppressive or have effects on purine synthesis (e.g. trimethoprim). 
• Azathioprine may reduce the effect of warfarin, necessitating dosage adjustment.