Methotrexate

Class

• • DHF reductase inhibitor antimetabolite and antifolate

Indications

• cancer

• autoimmune diseases

  • psoriasis

  • psoriatic arthritis

  • Crohn's disease

  • rheumatoid arthritis

  • multiple sclerosis

• ectopic pregnancy

• induction of medical abortions

Administration/Absorption

• • Oral

  • IM/IV/IT/Subcut

• Mean oral bioavailability is 33% (13-76% range)

• Mean intramuscular bioavailability is 76%

Dosage

Distribution

Mechanism

• Competitively inhibits dihydrofolate reductase

  • The affinity of methotrexate for DHFR is about one thousand-fold that of folate

  • DHFR catalyses the conversion of dihydrofolate to the active tetrahydrofolate

  • Folic acid is needed for the de novo synthesis of the nucleoside thymidine, required for DNA synthesis

  • Scarcity of dTMP => thymineless death.

  • Also, folate is needed for purine base synthesis, so all purine synthesis will be inhibited

  • Methotrexate, therefore, inhibits the synthesis of DNA, RNA, thymidylates, and proteins.

• Different mechanism in RA treatment:

  • Inhibition of DHFR is not thought to be the main mechanism

  • Inhibition of enzymes involved in purine metabolism => accumulation of adenosine

  • Or the inhibition of T cell activation and suppression of intercellular adhesion molecule expression by T cells.^[5]

    • Similar mechanism in SCID (defect in adenosine / guanine deaminase)

  • Should supplement MTX therapy with folate

Excretion

Side effects

• ulcerative stomatitis

• low white blood cell count and thus predisposition to infection

• nausea, abdominal pain

• fatigue

• fever

• dizzines

Interactions

• Penicillins may decrease the elimination of methotrexate

Contraindications