Summary

Azathioprine and mercaptopurine have a significant drug interaction due to azathioprine being metabolized to mercaptopurine in the body. Concurrent use can lead to enhanced toxicity, particularly severe bone marrow suppression and increased risk of infections.

Introduction

Azathioprine is an immunosuppressive medication belonging to the thiopurine class, commonly used to treat autoimmune conditions such as rheumatoid arthritis, inflammatory bowel disease, and to prevent organ transplant rejection. Mercaptopurine (6-MP) is also a thiopurine immunosuppressant primarily used in the treatment of acute lymphoblastic leukemia and inflammatory bowel disease. Both medications work by interfering with DNA synthesis and cell division, particularly affecting rapidly dividing immune cells.

Mechanism of Interaction

The interaction between azathioprine and mercaptopurine occurs because azathioprine is a prodrug that is converted to mercaptopurine in the liver through non-enzymatic processes. When both drugs are administered together, the total mercaptopurine exposure is significantly increased beyond what would be expected from mercaptopurine alone. Both drugs are metabolized by the same enzymatic pathways, including thiopurine methyltransferase (TPMT) and xanthine oxidase, leading to competitive inhibition and prolonged drug exposure.

Risks and Symptoms

The primary risk of combining azathioprine and mercaptopurine is severe bone marrow suppression, manifesting as leukopenia, thrombocytopenia, and anemia. This can lead to life-threatening complications including severe infections, bleeding disorders, and increased susceptibility to opportunistic pathogens. Additional risks include hepatotoxicity, gastrointestinal toxicity with severe nausea and vomiting, increased risk of malignancies (particularly lymphomas), and potential teratogenic effects. Patients with TPMT deficiency are at particularly high risk for severe toxicity.

Management and Precautions

Concurrent use of azathioprine and mercaptopurine is generally contraindicated and should be avoided. If combination therapy is absolutely necessary under exceptional circumstances, it requires extreme caution with significant dose reductions (typically 75% reduction in mercaptopurine dose), frequent monitoring of complete blood counts (weekly initially, then bi-weekly), liver function tests, and close clinical observation for signs of toxicity. TPMT genotyping or phenotyping should be performed before initiating therapy. Patients should be educated about infection precautions and instructed to report any signs of infection, unusual bleeding, or severe gastrointestinal symptoms immediately.

Azathioprine interactions with food and lifestyle

Azathioprine should be taken with food to reduce gastrointestinal side effects such as nausea and stomach upset. Alcohol consumption should be limited or avoided while taking azathioprine, as both the medication and alcohol can affect liver function, potentially increasing the risk of liver toxicity. Patients should also avoid live vaccines while on azathioprine due to its immunosuppressive effects, which can reduce the body's ability to respond to vaccines and increase infection risk. Sun exposure should be minimized and protective measures (sunscreen, protective clothing) should be used, as azathioprine increases the risk of skin cancer and photosensitivity reactions.

Mercaptopurine interactions with food and lifestyle

Mercaptopurine should be taken on an empty stomach, preferably 1 hour before or 2 hours after meals, as food can significantly reduce absorption and effectiveness. Alcohol consumption should be avoided or limited while taking mercaptopurine, as both the medication and alcohol are processed by the liver, potentially increasing the risk of liver toxicity. Patients should also avoid excessive sun exposure and use appropriate sun protection, as mercaptopurine can increase photosensitivity and skin cancer risk. Additionally, live vaccines should be avoided during treatment due to the immunosuppressive effects of mercaptopurine.