Methotrexate

Summary

Methotrexate is an antimetabolite drug that interferes with DNA synthesis, targeting the S phase of the cell cycle. Methotrexate is also an immunosuppressant.

Clinically, methotrexate is used to treat rheumatoid arthritis, where it acts as a DMARD, or disease-modifying antirheumatic drug. It’s also used to treat psoriasis, ectopic pregnancy, and various cancers.

Side effects of methotrexate include kidney damage, mouth sores, diarrhea, and liver damage.

Methotrexate also has several important drug interactions. Specifically, NSAIDs and alcohol should be avoided, as they may increase the risk of toxicity and organ damage.

Leucovorin can be used as an antidote to reverse methotrexate toxicity.

Key Points

• Methotrexate
  • Mechanism
    • Antimetabolite
      • Interferes with cell division and rapidly dividing cells
      • S-phase specific
        • Acts during the S-phase of the cell cycle when DNA synthesis occurs
    • Immunosuppressant (systemic)
      • Inhibits the conversion of folic acid, thus stopping cell division and growth
  • Clinical Use
    • Rheumatoid arthritis (RA)
      • Disease-modifying antirheumatic drug (DMARD)
      • Reduces inflammation and slows progression of joint damage
      • Can also be used treat juvenile idiopathic arthritis (JIA)
      • Effects can take 3-6 weeks
    • Psoriasis
      • Reduces proliferation of epidermal cells
    • Cancer (Chemotherapy)
      • Used in the treatment of various cancers, including:
        • Acute lymphoblastic leukemia
        • Non-Hodgkin's lymphoma
        • Breast cancer
        • Lung cancer
        • Other cancers like colon, stomach, pancreatic
      • Part of chemotherapy protocols
      • Often used in combination with other chemotherapy agents
    • Ectopic pregnancy
      • Used to stop growth of embryo and save fallopian tube
  • Side Effects
    • Liver toxicity
      • Monitor liver function throughout treatment (AST, ALT)
      • Give folic acid to reduce GI and hepatic toxicity
    • Stomatitis
      • Sores and inflammation inside the mouth
      • Encourage frequent oral hygiene
    • Kidney damage
      • Kidney damage often caused by hyperuricemia
      • Monitor kidney function (BUN, creatinine)
      • Promote excretion by drinking 2-3 L of water/day
      • May need dose reduction in renal impairment
    • Diarrhea
    • Common Chemotherapy Side Effects
      • Bone marrow suppression
        • Leading to leukopenia (low WBC), anemia (low RBC), and thrombocytopenia (low platelets)
        • Patient becomes at risk for infection
          • Avoid crowds, sick people, live vaccines
          • Report signs of infection immediately (sore throat, fever, etc.)
        • Patient becomes at risk for bleeding
          • Report blood in stools, severe bruising, petechiae, and purpura
        • Monitor CBC regularly
      • Alopecia
        • Hair loss, common with chemotherapy agents
      • Teratogenic
        • Can cause birth defects and fetal death
        • Pregnancy Category X - Contraindicated in pregnancy
        • Women should use contraception while on methotrexate
      • Nausea/vomiting
        • Common with chemotherapy agents
  • Interactions
    • Avoid NSAIDS
      • NSAIDs can increase the risk of methotrexate toxicity by reducing its excretion from the body
      • NSAIDS increase risk of bleeding and increase risk of liver damage
    • Avoid alcohol
      • Increases risk of liver damage
  • Administration
    • Leucovorin to reduce toxicity
      • The administration of leucovorin with methotrexate helps prevent GI and liver-related side effects