Pharmacology of Azathioprine

Azathioprine is an immunosuppressant medicine. As such, it is used to treat a wide variety of disease states. Here, we review those indications as well as how azathioprine works, and what side effects and drug interactions it is associated with.

Azathioprine is marketed under Azasan and Imuran, among other trademarks.

It is a medicine that works to lower the body’s immune response. This makes it an effective medicine in the treatment of organ transplant rejection and in other situations in which the body attacks itself – such as autoimmune disease.

Indications of azathioprine include:

  • Prevention of kidney transplant rejection
  • Rheumatoid arthritis
  • Crohn’s disease
  • Ulcerative colitis
  • Multiple sclerosis

Azathioprine may also be used for indications not listed in this guide.

Azathioprine may be administered in either oral or intravenous form (mostly oral); it is often used in combination with other immunosuppressive medicines.

Mechanism of action

Azathioprine works by diminishing activity of the immune response.

Transplant rejections and autoimmune disease states are premised on the immune system targeting the body / transplanted organs. By reducing the activity of the immune response, it means transplanted organs are more likely to be accepted and that the autoimmune response is dampened, reducing symptoms.

More specifically, azathioprine inhibits purine synthesis.

DNA and RNA synthesis need purines. Without available purines, less DNA and RNA are produced for white blood cells (or leucocytes).

Ultimately, this is what leads to immunosuppression.

Azathioprine is taken up into tissues, where it is converted into 6-mercaptopurine. Some of that 6-mercaptopurine is converted to 6-thioguanine.

Both 6-mercaptopurine and 6-thioguanine act as the starting point for purine biosynthesis. With less DNA and RNA produced for the necessary white blood cells, the immune response is lessened, becomes dampened.

This is what leads to the immunosuppressive therapeutic effects of azathioprine.

Side effects

Side effects with azathioprine include:

  • Low white blood cell counts – due to bone marrow suppression
  • Increased risk of infections
  • GI effects – nausea, vomiting, abdominal discomfort, diarrhea
  • Hair loss – more common in transplant patients
  • Acute pancreatitis – more common in patients with Crohn’s disease
  • Hepatic dysfunction
  • Excessive weight loss
  • Fatigue

Azathioprine may also cause other side effects not listed in this guide.

Clinical considerations

When we talk about the clinical pharmacology of azathioprine, we need to think about the following factors:

  • That azathioprine should be taken after meals, where possible, to reduce the risk of nausea and vomiting. The latter symptoms are more common at the beginning of treatment.
  • That azathioprine is classified as pregnancy category D, meaning there is ample “evidence of risk” to the developing fetus.
  • That patients are unable to participate in blood donation, which is the case with many other immunosuppressants.
  • That azathioprine increases the risk, particularly over the long term, of developing cancers. Azathioprine is a carcinogenic medicine. Skin cancer is considerably more likely in post-transplant patients after receiving azathioprine therapy.
  • That bone marrow suppression is more serious in patients deficient in the enzyme thiopurine S-methyltransferase.
  • That azathioprine is degraded and destroyed by the enzyme xanthine oxidase; the enzyme inhibited by the anti-gout drugs, allopurinol and febuxostat. As a result, taking both drugs together can considerably increase azathioprine toxicity.
  • That azathioprine decreases the effects of warfarin.
  • That the risk of infection increases when azathioprine is taken with other medicines that reduce the immune response. This include cyclosporine, monoclonal antibodies and other TNF-inhibitors. Risk of infection also increases when azathioprine is taken with Co-Trimoxazole.
  • Live vaccines should be avoided.

Azathioprine is an important immunosuppressant medicine used for kidney transplant cases, as well as a wide variety of other autoimmune states.

However, its use does not come without risks. The clinical professional should understand these risks, and act accordingly, in the interests of the patient.

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