Azathioprine is one of the immunosuppressants and has multiple uses in organ transplantation, autoimmune diseases, and certain chronic inflammatory conditions. The drug’s mode of action is mediated by inhibition of nucleic acid synthesis. Because the drug acts with delays, it is always used in combination with other immunosuppressants in organ transplantation.
What is azathioprine?
Azathioprine is one of the immunosuppressants and has many uses in organ transplantation, autoimmune diseases, and certain chronic inflammatory conditions. Azathioprine represents a drug used to suppress the immune system. Thus, it is used in cases of excessive, misdirected or undesirable immune reactions of the organism. This applies to rejection reactions in organ transplantation, autoimmune reactions and other misdirected immune reactions of the organism. The active substance consists of a purine ring connected to the heterocyclic imidazole ring via a sulfur bridge. In metabolism, this compound undergoes several degradation reactions, in the course of which a variety of intermediate compounds (metabolites) are formed. Important metabolites are 6-mercaptopurine and 1-methyl-4-nitro-5-thioimidazole. In the process, 6-mercaptopurine passes through the cell membrane with conversion into other active and inactive metabolites. 6-Mercaptopurine is the actual metabolite, which interferes with nucleic acid metabolism. It represents an analogous purine base that can be incorporated into DNA or RNA instead of the physiological purine base. In addition, the formation of new purine bases is also inhibited in the course of these metabolic processes. This leads to an overall inhibition of nucleic acid synthesis. The role of the other metabolite (1-methyl-4-nitro-5-thioimidazole) is not yet clearly understood.
Pharmacologic action
As mentioned above, the drug provides inhibition of nucleic acid synthesis via its metabolites. This simultaneously suppresses the formation of new cells, since nucleic acids can no longer be provided in sufficient quantities. This particularly affects cells and organs that rely on a greater rate of cell division. To respond to foreign invaders, the immune system must react quickly and therefore rapidly produce new immune cells, which are then subject to further differentiation. Azathioprine therefore has an antiproliferative effect, i.e., inhibits cell division. The necessary T lymphocytes, natural killer cells and B lymphocytes can then not be produced in sufficient quantities. The secretion of the tumor necrosis factor TNF-alpha is also reduced. However, azathioprine reaches its full efficacy only after two to five months. Therefore, therapy must be started with other faster-acting immunosuppressants, such as glucocorticoids or ciclosporin, to achieve efficacy from the beginning. The delayed efficacy of azathioprine results from the slow reduction in nucleic acid concentration.
Medical Application and Use
Azathioprine has a broad spectrum of use. It is suitable for all indications requiring suppression of the immune system. This applies to organ transplantation, autoimmune reactions, or allergic reactions. In almost all areas, improvements and attenuation of inflammatory reactions can be achieved. A particularly important area of application is the use of the drug in organ transplants to attenuate rejection reactions. However, azathioprine is also used in diseases such as arthritis and rheumatic diseases, multiple sclerosis, sarcoidosis, myasthenia, lupus erythematosus, granulomatosis with polyangiitis, Behcet’s disease, autoimmune hepatitis or idiopathic interstitial pneumonia. Azathioprine is also often used in severe atopic dermatitis. The same applies to such diseases as Crohn’s disease or ulcerative colitis. All these are diseases, which are caused by the reaction of the immune system to the organs of the patient’s own body.
Risks and side effects
However, in addition to the wide range of uses, many contraindications, side effects, interactions, and precautions must also be considered. For example, in a relatively large proportion of the population (10 percent), the enzyme thiopurine methyltransferase (TPMT) has reduced activity. Thiopurine methyltransferase (TPMT) is responsible for the metabolism of 6-mercaptopurine.As mentioned above, 6-mercaptopurine can be incorporated into DNA or RNA as an analogous purine base instead of the physiological purine base, thereby interfering with normal nucleic acid synthesis. Without the enzyme TPMT, this metabolite cannot be effectively degraded and accumulates. This increases the toxicity of azathioprine. Decreased nucleic acid synthesis also attenuates the repair mechanism on DNA when mutations occur. Therefore, exposure to solar radiation should be minimized during the period of treatment to lower the risk of skin cancer. Other contraindications to the use of azathioprine include liver and kidney dysfunction, severe infections, or bone marrow damage. Since azathioprine has embryotoxic effects, it must also not be used during pregnancy. Sometimes unpleasant or even severe side effects occur. These include a general feeling of illness, nausea, vomiting, loss of appetite, changes in the blood count with the development of anemia, leukopenia or thrombocytopenia. In rare cases, megaloblastic anemia may also occur. Megaloblastic anemia is a form of anemia that results from impairment of DNA synthesis. In males, restriction of germ cell formation may also be observed at times. However, this phenomenon is reversible and occurs only during treatment.
