Antimetabolites (FETT)

Cytotoxic agents.

Methotrexate

Antifolates

Antineoplastic agent and immunosuppressant; folic acid antagonist.

• Competitive inhibition of dihydrofolate reductase via displacement of dihydrofolate → ↓ formation of pyrimidine nucleotides (↓ dTMP) and purine nucleotides → ↓ DNA synthesis

• Inhibition of AICAR transformylase → inhibition of adenosine deaminase → ↑ intracellular concentration of adenosine and adenine nucleotides

• Neoplastic conditions

  • Leukemias (especially ALL)

  • Lymphomas (e.g., cutaneous T-cell lymphoma, non-Hodgkin lymphomas)

  • Sarcomas

  • Choriocarcinoma

  • Breast cancer

  • Head and neck cancers (e.g., squamous cell carcinoma)

  • Lung cancer

• Nonneoplastic conditions

  • Hydatidiform moles

  • Ectopic pregnancy

  • Medical abortion (in combination with misoprostol)

  • Immunosuppression for autoimmune diseases (e.g., rheumatoid arthritis, inflammatory bowel disease, psoriasis, vasculitides)

• Myelosuppression, anemia

• Hepatotoxicity, hepatic fibrosis

• Pulmonary fibrosis, pneumonitis

• Nephrotoxicity

• Mucositis (e.g., oral ulcerations)

• Megaloblastic anemia

• Birth defects (due to folate deficiency), e.g., neural tube defects

• Neurotoxicity (e.g., seizures)

• Breast cancer

• Head and Neck Cancer

• Leukemias

• Lung cancer

• Lymphomas

• Osteosarcoma

• Psoriasis

• Rheumatoid arthritis

• Trophoblastic Neoplasms

• Bladder cancer

• Crohns disease

• Ectopic pregnancy

• Multiple sclerosis

• Psoriatic arthritis

• Pregnant women with psoriasis or rheumatoid arthritis; use in treatment of neoplastic diseases only when potential benefit outweighs risk to fetus. 

• Nursing women.

• Excessive alcohol consumption, alcoholic liver disease, or other chronic liver disease in patients with psoriasis or rheumatoid arthritis.

• Overt or laboratory evidence of immunodeficiency syndromes in patients with psoriasis or rheumatoid arthritis. 

• Preexisting blood dyscrasias (e.g., bone marrow hypoplasia, leukopenia, thrombocytopenia, clinically important anemia) in patients with psoriasis or rheumatoid arthritis. 

• Known hypersensitivity to methotrexate. 

Ulcerative stomatitis, leukopenia, nausea, abdominal distress, malaise, undue fatigue, chills, fever, dizziness, decreased resistance to infection

• Protein-bound drugs (increase toxicity because of displacement from protein-binding sites)

• weak organic acids (potential to delay renal exretion —> accumulation MTX)

• Hepatotoxic agents

• Nephrotoxic drugs

• Methotrexate and its polyglutamate metabolites reversibly inhibit dihydrofolate reductase (enzyme that reduces folic acid to tetrahydrofolic acid); inhibition of tetrahydrofolate formation limits availability of one-carbon fragments necessary for synthesis of purines and conversion of deoxyuridylate to thymidylate in DNA synthesis and cell reproduction. 

• Also causes an increase in intracellular deoxyadenosine triphosphate, which is thought to inhibit ribonucleotide reduction, and polynucleotide ligase, an enzyme concerned in DNA synthesis and repair. 

• Tissues with high rates of cellular proliferation (e.g., neoplasms, psoriatic epidermis, bone marrow, lining of GI tract, hair matrix, fetal cells, urinary bladder) are most sensitive. 

• Also has immunosuppressive activity, possibly because of lymphocyte multiplication inhibition. 

• Mechanism(s) of action in rheumatoid arthritis not known; suggested mechanisms have included immunosuppressive and/or anti-inflammatory effects.