Azathioprine

Azathioprine

Mechanism of action

Azathioprine is converted in the body to mercaptopurine, an immunosuppressant with potent anti-inflammatory properties. Azathioprine primarily acts against rapidly dividing cells, resulting in inhibition of purine synthesis, gene replication, and T-cell activation. It is used alone or in combination with other drugs, usually corticosteroids, in inflammatory autoimmune diseases such as rheumatoid arthritis and inflammatory bowel disease. It is also used to prevent organ transplant rejection.

Adverse effects

During the first few weeks of therapy, azathioprine may cause hypersensitivity reactions including malaise, headache, nausea, vomiting, diarrhoea, fever, rigors, rash, myalgia, joint pain, hypotension, disturbed liver function, pancreatitis, and renal impairment. These disturbances can be mistaken for a flare in the underlying illness. The nausea associated with azathioprine can be dose-limiting. Other reactions include bone marrow toxicity, liver toxicity, increased susceptibility to infections, hair loss, skin cancers, and other malignancy. Macrocytosis and lymphopenia are common effects of these drugs and are not an indication for cessation of therapy.

Allopurinol significantly increases the effect and toxicity of azathioprine and 6-mercaptopurine, by inhibiting their metabolism. The combination should generally be avoided; however, if their combined use is unavoidable, the dose of azathioprine or 6-mercaptopurine should be reduced by 75%, and the patient should be closely monitored.

Monitoring

Baseline full blood examination, serum creatinine, and liver function tests should be performed. Full blood count should be monitored every 1 to 2 weeks during dosage titration, then every 1 to 3 months. Regular liver function testing should also be performed.

Both azathioprine and mercaptopurine are metabolised to a number of inactive products and to 6-thioguanine nucleotides (6-TGNs). Remission rates are proportional to red blood cell (RBC) levels of 6-TGNs (therapeutic range 235–450 pmol/108 RBCs). The major enzyme catalysing the conversion of mercaptopurine to inactive metabolites is thiopurine methyltransferase (TPMT). There is trimodal distribution of this enzyme in the population controlled by a genetic polymorphism. One in 300 individuals have low or undetectable TPMT activity, 8% to 11% have intermediate, and the remainder normal to high activity. Those with low levels of enzyme produce fewer inactive metabolites but higher concentrations of 6-TGNs resulting in a greater risk of myelotoxicity. Those with very high enzyme content may produce inadequate red blood cell concentrations of 6-TGNs and hence therapeutic inefficacy. Red blood cell 6-TGN concentration or metabolism profiling may be available in specialist centres and could provide a means of predicting patients likely to respond to azathioprine and mercaptopurine. Individuals deficient in this enzyme are particularly susceptible to myelosuppression with azathioprine, especially if they are also taking other drugs that inhibit TPMT, such as sulfasalazine, olsalazine, or mesalazine. TPMT testing does not identify all patients at risk of severe toxicity, and close monitoring of blood counts is still recommended.

Use in gastroenterology

Azathioprine and mercaptopurine are used to treat inflammatory bowel disease in patients whose disease is refractory to other therapies or who have frequent relapses. The onset of action of these drugs is slow, with the maximum effect often taking 3 to 6 months. Therapy with these drugs is often initiated with the re-introduction of corticosteroids after the first relapse.