Sunday, April 6, 2014

Azathioprine: A close-up of the immuneosuppressant drug widely used to treat myasthenia gravis

Azathioprine (abbreviated and often refereed to as AZA) is an immunosuppressive drug that is used in organ transplantation (especially kidney) and to reduce symptoms of autoimmune diseases. It belongs to the chemical class of purine analogues. Originally synthesized  as a cancer drug and as a prodrug for mercaptopurine in 1957, it has been widely used as an immunosuppressant for more than 50 years.

Azathioprine acts as a prodrug for mercaptopurine, inhibiting an enzyme that is required for the synthesis of DNA. Thus it most strongly affects proliferating cells, such as the T cells and B cells of the immune system.

The primary adverse effect of azathioprine is that it can
suppress the production of bone marrow. Such suppression can be life threatening . That is especially true in people with a genetic deficiency of the enzyme thiopurine S-methyltransferase. Azathiorprine is also listed by the International Agency for Research on Cancer as a Group 1 carcinogen (it is carcinogenic to humans).

Azathioprine is manufactured by a number of manufacturers under different brand names (Azasan by Salix in the U.S., Imuran by GlaxoSmithKline in Canada, the U.S., Australia, Ireland and the United Kingdom, Azamun in Finland and Imurel in Scandinavia and France, among others).

Azathioprine Use With Myasthenia Gravis -
Source: US National Library of Medicine / National Institute of Health / NCBI

Azathioprine is hepatically converted to 6-mercaptopurine, an active anti-metabolite that blocks nucleotide synthesis and T-lymphocyte proliferation. Azathioprine is an effective agent for long-term immune modulation in MG as a steroid sparing drug or as initial immunotherapy. Compared to corticosteroids, azathioprine has a favorable side effect profile for long-term use. However, the typically long delay of four to eight months from beginning treatment with azathioprine to improved strength in MG is a significant liability to its usefulness, particularly in MG patients with progressive disease or functionally limiting symptoms.

In a prospective, randomized, double-blind study comparing prednisolone with prednisolone plus azathioprine, the prednisolone plus azathioprine treatment group exhibited longer remissions, fewer treatment failures, fewer side effects, and reduced maintenance doses of prednisolone [46]. The initial dose is 50 mg/day is increased by 50 mg/day every week to a target therapeutic dose of 2–3 mg/kg/day.

Side effects include dose dependent myelosuppression with macrocytic anemia, leukopenia, and thrombocytopenia, toxic hepatitis, and alopecia. Hypersensitivity pancreatitis represents a rare, but serious idiosyncratic reaction, and patients with sustained abdominal pain taking azathioprine should be screened with serum amylase and lipase assays. With long-term use, there is a small increased risk for lymphoma [47].

Azathioprine is potentially teratogenic, and women of child bearing potential using azathioprine should practice effective contraception. An idiosyncratic allergic reaction with rash, fever, nausea, vomiting, and abdominal pain occurs in 10–15% patients within the first three weeks of treatment [48,49]. The reaction resolves within one day of stopping azathioprine, and will recur if the patient is rechallenged with the drug.

Monitoring for myelosuppression is recommended with weekly blood count and liver transaminase measurements weekly for the first month of treatment, then monthly for the first year, then every three months thereafter unless the dosage is increased. Erythrocyte macrocytosis is expected and acceptable within the therapeutic dosage range. If white blood cell count (WBC) falls below 3500/mm3, the dosage should be reduced, and if WBC falls below 3000/mm3, azathioprine should be discontinued.

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