What is azathioprine?
Azathioprine is a chemotherapy drug, which is often used in the treatment of cancers. It is also commonly used as an immunosuppressant medication in the treatment of kidney transplantation, and also in autoimmune diseases, such as Crohn’s disease, ulcerative colitis, lupus, and rheumatoid arthritis. If we take Crohn’s disease, for example, the immune system over reacts to a pathogen, can not suppress itself, and so begins to attack the digestive system. Azathioprine can be used as a long term ‘maintenance’ drug to dampen the immune system, preventing it from attacking the body.
What are the side effects of azathioprine?
This is a very potent and toxic medication, and should not be used lightly. Common side effects of azathioprine include nausea, hair loss, rashes, and diarrhoea. Because it is an immunosuppressant medication, patients will have a dampened immune system. This means they will be more likely to develop infection which can be more difficult to treat than in a healthy person. Azathioprine can affect the blood and the liver, so regular blood tests are compulsory whilst this medication is being taken. Serious side effects include jaundice, unexplained bruising and bleeding, and skin cancer. (Arthritis Research 2017)
Hazards of azathioprine use
Azathioprine is known to increase the risk of certain cancers developing in patients. Its classification of carcinogenicity is sufficient (group 1). All patients are at an increased risk of skin cancer and are therefore advised to wear protective clothing, avoid exposure to the sun, and to always wear suncream. This is because azathioprine inhibits DNA, alters it, and then makes skin extremely sensitive to UV rays. Anyone who is prescribed azathioprine to lower the risk of organ rejection after kidney transplantation is more likely to develop reticulum cell tumours (lymphomas). Whereas those prescribed this drug for Crohn’s disease or ulcerative colitis are at an increased risk of a rare but aggressive type of T-cell lymphoma, which is mostly fatal. (McLeod HL, 2002)
Azathioprine should not be used when breastfeeding or during pregnancy, as it has been found to cause birth defects, and increase the risk of miscarriage. (Pounder RE, et al.1987)
Anybody that is taking any dose of azathioprine is not eligible to become a blood donor because of how this medication effects blood cells. (Eustice C, 2017)
The oral LD50 dose in humans has not yet been studied for azathioprine, it has however, in rats and mice. A standard dose of azathioprine in humans can be between 50mg to 175mg daily. Doses are generally kept as low as possible to prevent long term side effects. It was found that in a patient who took an overdose of 150 tablets (7.5g), there was no sign of any significant detrimental effect.
The LD50 dose in rats is 400mg per kg, and 2500mg per kg in mice. Symptoms of overdose and toxicity include under development of bone marrow, bleeding, infection, and death. (Seale JR, 2017)
Chemistry of azathioprine
The chemical formula of azathioprine is C9H7N7O2S. It is a powdery yellowish substance, and has a melting point of 238°C. Azathioprine is insoluble in water, and only slightly soluble in lipophilic solvents like ethanol. It will dissolve in alkaline solutions, where it then hydrolyses to become 6-mercaptopurine. This is the chemical reaction which takes place within the body. It is an organic compound, and belongs to a class known as diarylthioethers.
Azathioprine is made by 3 substances; 6-mercaptopurine in dimethyl sulfoxide and 5-chloro-1-methyl-4-nitro-1H-imidazole. The following diagram demonstrates the full chemical reaction of azathioprine synthesis. (Hitchings GH, 1962)
The biochemistry of azathioprine
Azathioprine is generally administered orally, although in some cases, it can be given intravenously. The role of azathioprine is to ‘attack’ white blood cells, specifically T-lymphocytes, which are responsible for fighting off foreign bodies, like a transplanted kidney or a pathogen. It does this by targeting the cells DNA, RNA, and proteins, thus stopping white blood cells from replicating. This is important when treating lymphocytic leukaemia. It is designed so that if azathioprine enters the T-lymphocytes to stop them from reproducing, then this will mean that the reproduction of cancer cells is halted. (Marshall H, 2016) Azathioprine incorporates thiopurine analogues into the structure of DNA which then causes cytotoxicity and amino acid chains to break down. (Drug Bank, 2015)