Azathioprine

Clinical Applications

• Azathioprine works as an adjunctive and steroid-sparing medication during initial stages of immunosuppression.

  • Clinical indications include immune-mediated hemolytic anemia or thrombocytopenia, immune-mediated polyarthropathy, inflammatory CNS disease, autoimmune dermatoses, acquired myasthenia gravis, and inflammatory bowel disease.

• Azathioprine, a prodrug, is metabolized in the liver to 6-MP (also known as mercaptopurine), an antimetabolite that inhibits the enzyme responsible for purine synthesis, preventing DNA synthesis and, therefore, cell proliferation.

  • 6-MP is subsequently metabolized by several enzymes, the most important being thiopurine methyltransferase (TPMT).  

    • Low TPMT activity correlates with increased myelosuppression in humans.  

    • TPMT activity in dogs is similar to that in humans and is significantly higher than that in cats and horses. 

    • Because low TPMT activity in cats correlates with a clinical finding of significant azathioprine-induced myelosuppression, use in cats is generally contraindicated.

• Effects associated with azathioprine include

  • Compromise of RNA synthesis through thioguanosine triphosphate incorporation

  • Blocking of T-cell activation

  • Increased apoptosis of activated T-cells by preventing upregulation of the pro-survival protein Bcl-xL

  • Proliferating T- and B-lymphocytes lack nucleoside salvage pathways and are particularly sensitive to azathioprine

Protocol & Monitoring

• Initial dosage is 1.0–2 mg/kg PO or 50 mg/m² q24h (may be ideal, particularly in large dogs) until remission is achieved and the overall dose of corticosteroids can be reduced (usually 2–4 weeks), followed by q48h administration.¹

  • For long-term maintenance, twice-weekly administration at half the initial dose, often on alternate days from corticosteroid administration, is recommended.

    • Tablets can be split, but owners should wear gloves or wash their hands after use, as azathioprine is mutagenic/teratogenic.¹

• Hemograms (with platelet counts) should be monitored q2wk during induction and periodically during maintenance.  

  • Based on author's clinical experience, dose should be reduced by 25% if WBCs drop below 7000 cells/mm³ and discontinued if below 5000 cells/mm³.

• Serum liver enzymes should be monitored periodically within 1–4 weeks of starting the drug.²

• Clinical response may occur after 1–6 weeks.³

  • During this time, concurrent glucocorticoid use may be beneficial.

• Owners should be instructed to monitor pets and immediately report to their veterinarian any signs of depression, fever, or inappetence, as these may signal an adverse effect.

Adverse Reactions

• Bone marrow suppression is a dose-dependent side effect, with up to 90% of patients demonstrating changes in blood counts, but is often not severe enough to warrant discontinuation of the drug.⁴

  • Most often seen as neutropenia and thrombocytopenia; nonregen-erative anemia also possible²

• Additional adverse reactions include GI upset (acute), increased ALT, demodicosis, dermatophytosis, and pyoderma with chronic use.  

  • Pancreatitis may occur but is more likely caused by concurrent use of glucocorticoids.

  • Clinically significant hepatopathies have been reported.^2,5

• Adverse effects may be worse with coadministration of such drugs as ACE inhibitors or trimethoprim–sulfamethoxazole.¹

6-MP = mercaptopurine, TPMT = thiopurine methyltransferase