Summary

The combination of methotrexate and cotrimoxazole (trimethoprim-sulfamethoxazole) represents a clinically significant drug interaction that can lead to enhanced methotrexate toxicity. Both medications interfere with folate metabolism through different pathways, creating an additive antifolate effect that increases the risk of serious adverse reactions including bone marrow suppression and severe skin reactions.

Introduction

Methotrexate is a folate antagonist medication primarily used as an immunosuppressant for autoimmune conditions like rheumatoid arthritis and psoriasis, and as a chemotherapy agent for various cancers. It belongs to the class of antimetabolites and works by inhibiting dihydrofolate reductase. Cotrimoxazole, also known as trimethoprim-sulfamethoxazole or TMP-SMX, is a combination antibiotic consisting of trimethoprim and sulfamethoxazole. It's commonly prescribed for urinary tract infections, pneumocystis pneumonia prophylaxis, and other bacterial infections. Both medications affect folate metabolism, making their concurrent use potentially problematic.

Mechanism of Interaction

The interaction between methotrexate and cotrimoxazole occurs through complementary interference with the folate metabolic pathway. Methotrexate inhibits dihydrofolate reductase, preventing the conversion of dihydrofolate to tetrahydrofolate, which is essential for DNA synthesis and cellular division. Trimethoprim, a component of cotrimoxazole, also inhibits dihydrofolate reductase, though with greater selectivity for bacterial enzymes. However, at therapeutic doses, trimethoprim can still affect human dihydrofolate reductase. Additionally, sulfamethoxazole inhibits bacterial dihydropteroate synthase, further disrupting folate synthesis. When used together, these medications create an enhanced antifolate effect that can lead to severe folate deficiency and increased methotrexate toxicity.

Risks and Symptoms

The primary risks of combining methotrexate with cotrimoxazole include severe bone marrow suppression manifesting as pancytopenia, thrombocytopenia, or neutropenia. Patients may experience increased susceptibility to infections due to immunosuppression. Gastrointestinal toxicity can be enhanced, leading to severe mucositis, nausea, vomiting, and diarrhea. Hepatotoxicity risk is elevated, potentially resulting in elevated liver enzymes or hepatic dysfunction. Severe cutaneous reactions, including Stevens-Johnson syndrome, have been reported. Renal toxicity may also be increased. The interaction is considered major and can be life-threatening, particularly in elderly patients or those with compromised renal function.

Management and Precautions

Methotrexate interactions with food and lifestyle

Alcohol consumption should be avoided or strictly limited while taking methotrexate due to increased risk of liver toxicity and hepatotoxicity. Both methotrexate and alcohol can cause liver damage, and their combination significantly increases this risk. Patients should also maintain adequate hydration and avoid excessive sun exposure, as methotrexate can increase photosensitivity. Folic acid supplementation is commonly recommended to reduce certain side effects, though this should be discussed with a healthcare provider as timing and dosing are important.

Cotrimoxazole interactions with food and lifestyle

Cotrimoxazole should be taken with adequate fluid intake to prevent kidney stone formation. Alcohol consumption should be avoided or limited as it may increase the risk of side effects and reduce the effectiveness of the medication. Patients should maintain adequate folate intake through diet, as cotrimoxazole can interfere with folate metabolism. Sun exposure should be minimized and sunscreen used, as cotrimoxazole increases photosensitivity and risk of sunburn.