indication

For use in rheumatoid arthritis, preventing renal transplant rejection, Crohn's disease, and colitis.

pharmacology

Azathioprine is a chemotherapy drug, now rarely used for chemotherapy but more for immunosuppression in organ transplantation and autoimmune disease such as rheumatoid arthritis or inflammatory bowel disease or Crohn's disease. It is a pro-drug, converted in the body to the active metabolite 6-mercaptopurine. Azathioprine acts to inhibit purine synthesis necessary for the proliferation of cells, especially leukocytes and lymphocytes. It is a safe and effective drug used alone in certain autoimmune diseases, or in combination with other immunosuppressants in organ transplantation. Its most severe side effect is bone marrow suppression, and it should not be given in conjunction with purine analogues such as allopurinol. The enzyme thiopurine S-methyltransferase (TPMT) deactivates 6-mercaptopurine. Genetic polymorphisms of TPMT can lead to excessive drug toxicity, thus assay of serum TPMT may be useful to prevent this complication.

mechanism of action

Azathioprine antagonizes purine metabolism and may inhibit synthesis of DNA, RNA, and proteins. It may also interfere with cellular metabolism and inhibit mitosis. Its mechanism of action is likely due to incorporation of thiopurine analogues into the DNA structure, causing chain termination and cytotoxicity.

toxicity

The oral LD₅₀ for single doses of azathioprine in mice and rats are 2500 mg/kg and 400 mg/kg, respectively. Very large doses of this antimetabolite may lead to marrow hypoplasia, bleeding, infection, and death.

biotransformation

Primarily converted to the active metabolites 6-mercaptopurine and 6-thioinosinic acid via a non-enzymatica process. 6-mercaptopurine is subsequently metabolized primarily by xanthine oxidase.

absorption

Well absorbed following oral administration.

half life

Approximately 5 hours for the unchanged drug and its metabolites.

drug interactions

Acenocoumarol: Azathioprine may decrease the anticoagulant effect of acenocoumarol.

Allopurinol: Allopurinol may increase the effect of thiopurine, azathioprine.

Aminosalicylic Acid: Aminosalicylic acid may increase the toxicity of thiopurine, azathioprine.

Anisindione: Azathioprine may decrease the anticoagulant effect of anisindione.

Atracurium: The agent decreases the effect of the muscle relaxant

Dicumarol: Azathioprine may decrease the anticoagulant effect of dicumarol.

Doxacurium chloride: The agent decreases the effect of the muscle relaxant

Mesalazine: Mesalazine may increase the toxicity of thiopurine, azathioprine.

Metocurine: The agent decreases the effect of the muscle relaxant

Mivacurium: The agent decreases the effect of the muscle relaxant

Olsalazine: Olsalazine may increase the toxicity of thiopurine, azathioprine.

Pancuronium: The agent decreases the effect of the muscle relaxant

Sulfasalazine: Sulfasalazine may increase the toxicity of thiopurine, azathioprine.

Trandolapril: Trandolapril may increase the risk of neutropenia. Monitor for increased toxic effects of Azathioprine if Trandolapril is initiated or dose increased.

Trastuzumab: Trastuzumab may increase the risk of neutropenia and anemia. Monitor closely for signs and symptoms of adverse events.

Tubocurarine: The agent decreases the effect of the muscle relaxant

Vecuronium: The agent decreases the effect of the muscle relaxant

Warfarin: Azathioprine may decrease the anticoagulant effect of warfarin.