What is the Major Side Effect of Methotrexate?

Methotrexate is a medication used by doctors to treat a variety of diseases. The medical community has confirmed the efficacy of methotrexate, but healthcare professionals and patients need to understand the potential side effects of using this potent drug in order to achieve the best treatment results. Among the many possible side effects, the main side effect of methotrexate is hepatotoxicity, which is a toxic effect on the liver. If not properly monitored, the severity can range from mild elevation of liver enzymes to severe liver damage.

Understanding Methotrexate and Its Mechanism

Methotrexate belongs to a class of drugs called antimetabolites. The drug functions through its ability to stop dihydrofolate reductase (DHFR) from working which prevents cells from creating DNA and multiplying. Methotrexate functions by stopping the growth of fast-replicating cells through its mechanism which prevents cell division from occurring. Methotrexate's therapeutic effect stems from this mechanism of action, but the same mechanism can also lead to organ toxicity during drug metabolism, especially in the liver.

Figure 1. MTX cellular pharmacology and mechanism of action. (Source: Vermeer E, et al.; 2023)

The three factors which determine side effect occurrence and intensity include drug dosage and administration schedule and delivery method. Low-dose methotrexate is commonly prescribed for autoimmune conditions and is generally well-tolerated. The cancer treatment drug high-dose methotrexate requires patients to receive close medical surveillance because it produces severe side effects which can be managed through folinic acid rescue treatment.

Other Notable Side Effects

While hepatotoxicity is the major side effect, methotrexate can also cause a range of other adverse effects that patients should be aware of:

• Bone Marrow Suppression: The drug Methotrexate causes white blood cells and red blood cells and platelets to decrease in number which results in higher infection risk and anemia and bleeding problems.
• The main gastrointestinal symptoms which occur at higher doses include nausea and vomiting and diarrhea and mouth ulcers. The side effects of this medication depend on the dosage amount and doctors can help patients control these effects through folic acid supplements.
• The use of methotrexate leads to pulmonary toxicity which results in pneumonitis that causes lung damage and produces symptoms including cough and shortness of breath and fever in patients. Doctors can prevent dangerous respiratory problems from developing when they identify symptoms at their beginning stage.
• The treatment causes skin-related side effects which include rash development and skin sensitivity to sunlight and hair loss. Stevens-Johnson syndrome exists as a rare medical condition which produces dangerous skin reactions.
• The high doses of methotrexate treatment lead to kidney damage which becomes more severe when patients have existing kidney problems or when they experience dehydration. The medical team needs to monitor patient kidney function at the same time as they manage their fluid requirements.

Preventing and Managing Side Effects

Healthcare providers use different methods to reduce dangerous side effects which methotrexate causes in patients.

• The standard medical practice includes routine blood tests which monitor liver function and kidney function and complete blood counts.
• The medical team provides folic acid or folinic acid supplements to patients who need them because these medications help prevent mouth sores and gastrointestinal problems and bone marrow suppression.
• The treatment plan needs dose adjustments which depend on patient age and kidney function and treatment response to reach the best results while minimizing potential side effects.
• The treatment plan includes advice for patients to reduce their alcohol consumption while keeping their weight normal and staying away from substances which harm the liver.
• The patient needs to learn about the first indicators which include jaundice and persistent cough and unusual bruising and shortness of breath to receive proper treatment at the right time.

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