Methotrexate Nursing Considerations

• Methotrexate was the first anticancer drug developed 50 years ago. It is an antimetabolite drug that interferes with the growth of cells, therefore used as a chemotherapeutic agent for cancers. It is also used in many other chronic inflammatory diseases, such as psoriatic arthritis and the maintenance phase of systemic vasculitis. 
• With methotrexate therapy, you must monitor the patient’s prescription for possible drug-drug interactions leading to life-threatening consequences. To avoid them, you must monitor the drugs closely that are given together. 
• Pharmacist, Mariya Rizwan, shares nursing considerations about methotrexate when it comes to indications, side effects, interactions and more! 

Here we study the pharmacology of Methotrexate- a drug previously known as amethopterin, an immunosuppressant, and a chemotherapeutic drug.  

You will get to know about its indications, side effects, mechanism of action, drug interaction, and dosing information.  

Methotrexate was the first anticancer drug developed 50 years ago. It is an antimetabolite drug that interferes with the growth of cells, therefore used as a chemotherapeutic agent for cancers.  

In the 1980s, studies demonstrated its efficacy in rheumatoid arthritis, and now it is the principal disease-modifying antirheumatic drugs (DMARDs) used in this disease.  

It is also used in many other chronic inflammatory diseases, such as psoriatic arthritis and the maintenance phase of systemic vasculitis.  

Methotrexate Indications

• Methotrexate is used in health conditions such as; 
• In malignant diseases such as leukemia and lymphomas; ALL, non-Hodgkin’s lymphoma, Burkitt’s lymphoma, and trophoblastic choriocarcinoma 
• For solid tumors as an adjuvant of the breast, head/neck, choriocarcinomas, osteosarcomas 
• In palliation of metastatic breast, head, neck, cervical, and lung carcinomas 
• In non-malignant conditions such as mycosis fungoides, severe psoriasis, moderate to severe rheumatoid arthritis  
• It is used unlabeled for the treatment of multiple sclerosis and inflammatory bowel disease-maintenance and remission of Crohn’s disease 
• Methotrexate is one of the few anticancer drugs that are safe to be given intrathecally for the treatment of meningeal metastases 
• Prophylaxis use in intrathecal chemotherapy in acute lymphoblastic leukemia has helped reduce the incidence of recurrences in the CNS, hence increasing the cure rate in this disease. 

Side Effects of Methotrexate

The immediate side effects of methotrexate are nausea and vomiting when given in high doses.  

During therapy cycles, it can cause anemia, thrombocytopenia, diarrhea, stomatitis, leukopenia, renal damage, and diarrhea.  

Methotrexate has toxic effects on rapidly dividing tissues, especially of the bone marrow. It can cause bone marrow toxicity, hepatotoxicity, and pneumonitis. To monitor its toxicity, frequent blood counts and liver function testing should be done. Before the first prescription, a chest X-ray should also be done. 

The toxicity of methotrexate is increased in the presence of reduced renal excretion. Therefore, it should be avoided if there is renal impairment.  

High-dose methotrexate causes mucositis and myelosuppression. To reduce that, folinic acid- leucovorin is given.  

Non-steroidal inflammatory drugs such as acetaminophen or aspirin can reduce the renal excretion of methotrexate, leading to its toxicity and increased side effects.  

Methotrexate dose should be altered in patients with renal function impairment, ascites, and pleural effusion because its elimination is reduced in these conditions. 

Methotrexate can cause soft tissue necrosis or osteonecrosis with concomitant radiotherapy. 

Tumor lysis syndrome can occur with methotrexate that should be managed symptomatically. Otherwise, it would be fatal. 

Methotrexate has a black box warning of diarrhea and ulcerative stomatitis. 

The patient should be advised to report immediately if they notice the onset of any symptoms of: 

• Blood disorders such as mouth ulcers, sore throat, and bruising. 
• Liver toxicity such as nausea, vomiting, abdominal discomfort, and dark urine. 
• Respiratory effects such as shortness of breath.
  

Methotrexate Mechanism of Action

Methotrexate has more than one mechanism of action. To get rid of cancerous cells, it acts as a folate antagonist that works by targeting an enzyme dihydrofolate reductase (DHFR)-an enzyme necessary for folic acid production.  Folic acid is a necessary compound for nucleotide synthesis. Therefore, its inhibition stops nucleotide formation.  

Under normal conditions in nucleotide synthesis, DHFR is converted to dihydrofolate which is reduced to tetrahydrofolate (TDHF) and acts as a carbon carrier and donates methyl groups to the end target molecules. This process takes place via the enzymatic action of thymidine synthetase.

Since folate antagonist uses DHFR, the nucleotide synthesis is stopped. Methotrexate targets actively dividing cells. Therefore, it is effective against cancerous cells.  

Drug resistance with methotrexate can occur due to: 

• Decreased drug transport into the cells 
• Genetic mutation- alters the enzyme binding constants or causes an increase in the enzyme DHFR within the cell. 

In inflammatory conditions, such as psoriasis and rheumatoid arthritis, methotrexate acts with a different mechanism of action, given intermittently once a week. It works by inhibiting enzymes involved in purine metabolism, leading to the accumulation of adenosine and its release from cells.  

Adenosine works by acting on cell surface receptors, suppressing the expression of adhesion molecules on T cells and neutrophils, eventually inhibiting their accumulation in inflamed tissues. Moreover, it lowers the release of cytokines from inflammatory cells. In this way, methotrexate acts as an anti-inflammatory drug.  

Methotrexate Drug Interactions

With methotrexate therapy, you must monitor the patient’s prescription for possible drug-drug interactions leading to life-threatening consequences. To avoid them, you must monitor the drugs closely that are given together.  

Trimethoprim, or cotrimoxazole when given with methotrexate can create a risk of pancytopenia and megaloblastic due to additive antifolate effect. To rescue it, folinic acid should be given.  

Sulfonamides, when given with methotrexate, can create a risk of megaloblastic anemia and pancytopenia due to additive antifolate effects. It also inhibits the renal tubular secretion of methotrexate and may displace it from plasma proteins, eventually leading to toxic effects.  

Salicylates and probenecid, when given with methotrexate, can inhibit its renal tubular secretion and may displace it from plasma proteins.  

Methotrexate can affect the action of fluorouracil, causing an enhancement or inhibition, depending upon the sequence of administration.  

NSAIDs can lower the renal excretion of methotrexate, causing its accumulation and enhanced toxic effects. The use of NSAIDs should be avoided along with methotrexate because their combination can increase the risk of aplastic anemia, myelosuppression, and severe gastrointestinal toxicities. 

Dosing Information for Methotrexate

Methotrexate is used in various conditions in different doses, such as: 

Crohn’s Disease

For severe Crohn’s disease- by intramuscular injection, initially, 25mg once weekly until remission occurs. The maintenance dose is 15 mg once weekly. 

For maintenance and remission of Crohn’s disease- by mouth, 10 to 25mg once weekly. 

Rheumatoid Arthritis

For moderate to severely active rheumatoid arthritis- by mouth, 7.5mg once weekly. The dose can be adjusted according to the response. However, the maximum dose is 20 mg per week.  

For severe active rheumatoid arthritis, by intramuscular or subcutaneous injection- initially, 7.5mg once weekly. The dose can be increased as per response in the steps of 2.5mg per week. However, the maximum dose can be 25mg per week.  

Psoriasis

For severe psoriasis unresponsive to conventional therapy- by mouth, intramuscular injection, subcutaneous injection, or intravenous injection, initially 2.5 to 10 mg once in a week. The dose can be adjusted according to the response. It should be done in the steps of 2.5 to 5mg at intervals of at least one week. The usual dose is 7.5 to 15mg per week. The therapy should be stopped if it shows an inadequate response in the period of three months on the optimal dosage. However, the maximum dose is 30 mg per week.  

Crohn’s Disease For Acute Lymphoblastic Leukemia

By mouth or parenterally, for induction, 3.3 mg/m2/day daily for 4 to 6 weeks.  

Maintaining dose during remission- by mouth or intramuscular injection, 30mg/m2 given two times a week. 

The alternate maintenance dose during remission can be intravenous, 2.5mg/kg, given every 14 days. 

The Bottom Line

That finalizes the quick review of methotrexate. While prescribing, you must monitor the patient for any symptoms of toxicity and adverse drug reactions.

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