Methotrexate

Methotrexate is a widely used medication with applications in both oncology and rheumatology. Its use varies based on the condition being treated, and it operates differently depending on the dosage.

1. Use in Oncology
   1. Mechanism: At high doses, methotrexate works as an antimetabolite and antifolate drug. It inhibits the enzyme dihydrofolate reductase, which is necessary for DNA synthesis. This inhibition is effective in treating certain types of cancer because it impedes the rapid growth of malignant cells.
   2. Conditions Treated: It’s used for a variety of cancers, including leukemia, lymphoma, breast cancer, lung cancer, and osteosarcoma.
   3. Administration: Given either intravenously or intramuscularly in oncology settings.
2. Use in Rheumatology
   1. Mechanism: At lower doses, methotrexate exhibits anti-inflammatory and immunomodulatory properties. The exact mechanism in this context is not fully understood but is believed to involve inhibition of enzymes related to immune cell function.
   2. Conditions Treated: Commonly used for rheumatoid arthritis (RA), psoriatic arthritis, and severe psoriasis. It can reduce symptoms and slow disease progression in these conditions which is why it is classified as a DMARD (Disease Modifying Anti-Rheumatic Drug)
   3. Administration: Typically administered orally or via subcutaneous injection for rheumatologic conditions.
3. Monitoring and Side Effects
   1. Side Effects: Can include
      1. alopecia
      2. mouth ulcers
      3. gastrointestinal upset
      4. liver toxicity
      5. bone marrow suppression
         1. anemia
         2. leukopenia
         3. thrombocytopenia
      6. macrocytosis
      7. pulmonary toxicity.
   2. Monitoring: Regular blood tests are crucial to monitor liver function, renal function, and blood cell counts. Patients on methotrexate should avoid alcohol due to the increased risk of liver damage.
   3. Folic Acid Supplementation: Often prescribed to reduce some of the side effects, particularly gastrointestinal and hepatic.
4. Pregnancy and Fertility
   1. Teratogenic Effects: Methotrexate is highly teratogenic and is contraindicated during pregnancy. Women of childbearing age and men wishing to father a child should use effective contraception and discuss family planning with their healthcare provider.
   2. Fertility Considerations: There may be temporary effects on fertility for both men and women.
5. Patient Education
   1. Importance of Compliance: Regular medication intake and adherence to monitoring schedules are essential.
   2. Recognition of Side Effects: Patients should be educated on recognizing signs of toxicity or adverse reactions and advised to seek medical attention as needed.
6. Interactions with Other Medications
   1. Drug Interactions: Methotrexate can interact with various medications, including NSAIDs, certain antibiotics SMX/TMP, and others, which can increase the risk of toxicity.
7. Administration Considerations
   1. Dosage and Frequency: Varies depending on the condition being treated. For RA, it’s typically once weekly, not daily, to minimize side effects.
8. Long-Term Use
   1. In rheumatological conditions, methotrexate may be used long-term. Regular monitoring is critical to manage and detect any long-term adverse effects.

Methotrexate is a cornerstone drug in the treatment of various inflammatory and neoplastic diseases, but its use requires careful patient selection, monitoring, and education to mitigate risks and maximize benefits.

Interactions

Methotrexate toxicity can be increased by interactions with various drugs. These drugs belong to different classes and can affect methotrexate metabolism, excretion, or its action in the body. Here’s a list categorized by drug class:

1. Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)
   1. Examples: Ibuprofen, Naproxen, Diclofenac, Indomethacin.
   2. Mechanism: They can inhibit renal excretion of methotrexate, leading to increased levels and potential toxicity.
2. Antibiotics
   1. Trimethoprim: also blocks dihyrofolate reductase and amplifies effect of methotrexate.
   2. Sulfonamides (e.g., Sulfamethoxazole): Part of co-trimoxazole; can displace methotrexate from plasma proteins, increasing its toxicity.
   3. Penicillins (e.g., Penicillin, Amoxicillin): May reduce renal clearance of methotrexate.
   4. Fluoroquinolones (e.g., Ciprofloxacin): Potential interaction with renal excretion.
   5. Tetracyclines (e.g., Doxycycline): Can interfere with methotrexate metabolism.
3. Proton Pump Inhibitors (PPIs)
   1. Examples: Omeprazole, Esomeprazole, Pantoprazole.
   2. Mechanism: May decrease renal elimination of methotrexate.
4. Ulcer Medications
   1. H2 Blockers (e.g., Nazitidine, Ranitidine, Cimetidine): Can reduce renal clearance of methotrexate.
5. Diuretics
   1. Loop Diuretics (e.g., Furosemide): May reduce renal clearance of methotrexate.
   2. Thiazides: Similar effect as loop diuretics.
6. Antiepileptics
   1. Examples: Phenytoin, Phenobarbital.
   2. Mechanism: May alter methotrexate metabolism.
7. Immunosuppressants
   1. Examples: Leflunomide, Azathioprine.
   2. Mechanism: Combined immunosuppressive effect can increase the risk of hematologic toxicity.
8. Disease Modifying Anti-Rheumatic Drugs (DMARDs)
   1. Examples: Hydroxychloroquine, Sulfasalazine.
   2. Mechanism: Used concomitantly with methotrexate in rheumatic diseases; requires monitoring for additive toxic effects.
9. Oral Hypoglycemics
   1. Sulfonylureas (e.g., Glipizide, Glyburide): Potential for increased methotrexate toxicity.
10. Retinoids
    1. Examples: Acitretin, Isotretinoin.
    2. Mechanism: Potential interaction, especially in psoriasis treatment.
11. Hepatotoxic Drugs
    1. Various Classes: Concurrent use with drugs having hepatotoxic potential can exacerbate liver toxicity.
    2. Alcohol
    3. Mechanism: Increase risk of hepatotoxicity when used with methotrexate.
12. General Considerations
    1. Individual Variability: Responses to drug interactions can vary widely among individuals.
    2. Monitoring: Regular monitoring of blood counts and liver function tests is essential when methotrexate is used with these drugs.
    3. Consultation with Healthcare Provider: It’s important patients discuss all medications, including over-the-counter drugs and supplements, with their healthcare provider when on methotrexate therapy.

This list highlights the importance of being vigilant about drug interactions in patients receiving methotrexate, as these can significantly increase the risk of adverse effects and toxicity.

Other DMARDS and their side effects

Disease-modifying antirheumatic drugs (DMARDs) are a cornerstone in the management of rheumatoid arthritis (RA). They help to slow down the progression of the disease and alleviate symptoms. DMARDs can be broadly categorized into conventional synthetic DMARDs, biologic DMARDs, and targeted synthetic DMARDs.

• Conventional Synthetic DMARDs:
  • Methotrexate: Nausea, fatigue, mouth ulcers, elevated liver enzymes, pulmonary toxicity, bone marrow suppression.
  • Hydroxychloroquine: Gastrointestinal discomfort, skin rash, retinal toxicity (rare but can lead to vision changes), muscle weakness.
  • Sulfasalazine: Gastrointestinal upset, headache, rash, liver enzyme elevation, hemolytic anemia, neutropenia.
  • Leflunomide: Diarrhea, liver toxicity, hair loss, hypertension, rash, bone marrow suppression.
• Biologic DMARDs:
  • TNF Inhibitors (e.g., Adalimumab, Infliximab, Etanercept) Injection site reactions, increased risk of infections (including tuberculosis reactivation), infusion reactions (infliximab), autoantibody formation, potential for heart failure exacerbation.
  • Rituximab: Infusion reactions, severe skin reactions, hepatitis B reactivation, increased risk of infections.
  • Tocilizumab: Elevated liver enzymes, neutropenia, increased cholesterol levels, increased risk of gastrointestinal perforation.
• Targeted Synthetic DMARDs:
  • Janus Kinase (JAK) Inhibitors (e.g., Tofacitinib, Baricitinib): Increased risk of infections (including herpes zoster), elevated cholesterol levels, liver enzyme elevation, venous thromboembolism risk.
• Monitoring and Precautions:
  • Regular monitoring for side effects is essential, especially liver function tests for drugs like methotrexate and leflunomide, and full blood count for most DMARDs.
  • Screening for tuberculosis and hepatitis B is recommended before starting biologic DMARDs.
  • Ophthalmologic examination is advised for patients on hydroxychloroquine.
  • Vaccination status should be reviewed, particularly for live vaccines which are contraindicated with most biologic DMARDs and JAK inhibitors.
  • Patient education on the recognition of infection signs is crucial due to the increased infection risk associated with many DMARDs.

The choice of DMARDs depends on several factors, including the disease severity, patient’s comorbidities, and the risk-benefit profile of the medications. Regular follow-up and collaboration with a rheumatologist are key to effective management.