What is Methotrexate? What are the approved uses of Methotrexate? Methotrexate was introduced as an anti-cancer drug. The on-label uses for Methotrexate are the following:
- severe psoriasis (a skin disease in which red, scaly patches form on some areas of the body) that cannot be controlled by other treatments.
- severe, active rheumatoid arthritis (a condition in which the body attacks its own joints, causing pain, swelling, and loss of function) that cannot be controlled by certain other medications.
- certain cancers that begin in the tissues that form around a fertilized egg in the uterus (womb)
- breast cancer
- certain cancers of the head and neck
- lung cancer
- certain types of lymphomas
- leukemia
- Crohn's Disease and Ankylosing Spondylitis
PRESCRIBED FOR: Methotrexate is used for cancer treatment generally in higher doses than for other uses, and is often administered intravenously or intramuscularly. Methotrexate is used to treat psoriasis, an inflammatory skin disease, as well as the arthritis that occurs in 10 percent of these patients (psoriatic arthritis). It is also used to treat active rheumatoid arthritis in adults and children. It is also used to treat other rheumatic diseases, including polymyositis and systemic lupus erythematosus. Methotrexate has been used to induce miscarriage in patients with ectopic pregnancy.
DOSING: May be taken with or without food. For rheumatoid arthritis and psoriasis, the dose of methotrexate is given WEEKLY, whether by injection or orally. For psoriasis, the weekly dose is often divided into three doses given at 12 hour intervals each week. This has been shown to be more effective, as it relates to the natural growth cycling of the skin.
DRUG INTERACTIONS: Because methotrexate can cause serious liver disease, patients with alcoholism or liver disease should not receive it. Patients should curtail alcohol consumption while taking methotrexate. Methotrexate can suppress the body's immunity. Therefore, any symptoms of infection should be reported to the doctor. Patients with underlying immune deficiency diseases should not receive methotrexate. A dry, non-productive cough can be a result of a rare lung toxicity. Methotrexate can impair fertility, decrease sperm count and cause menstrual dysfunction. Safety and effectiveness has not been established in children.
PREGNANCY: Methotrexate should not be used in pregnancy, as it can be toxic to the embryo and can cause fetal defects and spontaneous abortion (miscarriage). It should be discontinued prior to conception if used in either partner. Male patients should stop taking methotrexate at least 3 months prior to a planned conception and females should discontinue use for at least one ovulatory cycle before conception.
(see www.medicinenet.com/methotrexate/article.htm)
SIDE EFFECTS:
Possible side effects can include anemia, neutropenia, increased risk of bruising, nausea and vomiting, dermatitis and diarrhea. A small percentage of patients develop hepatitis, and there is an increased risk of pulmonary fibrosis.
The higher doses of methotrexate often used in cancer chemotherapy can cause toxic effects to the rapidly-dividing cells of bone marrow and gastrointestinal mucosa. The resulting myelosuppression and mucositis are often prevented (termed methotrexate "rescue") by using folinic acid supplements (not to be confused with folic acid).
Methotrexate is a highly teratogenic drug and categorized in Pregnancy Category X by the FDA. Women must not take the drug during pregnancy, if there is a risk of becoming pregnant, or if they are breastfeeding. Men who are trying to get their partner pregnant must also not take the drug. To engage in any of these activities (after discontinuing the drug), women must wait until the end of a full ovulation cycle and men must wait three months.
There is a risk of a severe adverse reaction if penicillin is prescribed alongside methotrexate.
Methotrexate competitively and reversibly inhibits dihydrofolate reductase (DHFR), an enzyme that is part of the folate synthesis metabolic pathway. The affinity of methotrexate for DHFR is about one thousand-fold that of folate for DHFR. Dihydrofolate reductase 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. Methotrexate, therefore, inhibits the synthesis of DNA, RNA, thymidylates, and proteins.
Methotrexate acts specifically during DNA and RNA synthesis, and thus it is cytotoxic during the S-phase of the cell cycle. Logically, it therefore has a greater toxic effect on rapidly dividing cells (such as malignant and myeloid cells, and GI & oral mucosa), which replicate their DNA more frequently, and thus inhibits the growth and proliferation of these non-cancerous cells as well causing side effects listed above.
Lower doses of methotrexate have been shown to be very effective for the management of rheumatoid arthritis and psoriasis. In these cases inhibition of dihydrofolate reductase (DHFR) is not thought to be the main mechanism, rather the inhibition of enzymes involved in purine metabolism, leading to accumulation of adenosine, or the inhibition of T cell activation and suppression of intercellular adhesion molecule expression by T cells.
(see en.wikipedia.org/wiki/Methotrexate)
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