Methotrexate (or MTX) is one of the most widely used and versatile drugs in modern medicine. Because it inhibits the metabolism of rapidly dividing cells, methotrexate is used to treat a broad range of conditions, especially cancer, rheumatoid arthritis , and ectopic pregnancy. Brand names for Methotrexate include Rheumatrex, Trexall, Folex, and Mexate.


Chemistry

The chemical composition of methotrexate is N-(4-(((2,4-diamino-6-pteridinyl)methyl)methylamino)benzoyl)-L-glutamic acid. Methotrexate is classed as an antimetabolite drug because interferes with cell metabolism, by inhibiting the body's use of folic acid, a vitamin essential for cell growth. Specifically, methotrexate and its active metabolites compete for the folate binding site of the dihydrofolate reductase, the enzyme which reduces folic acid to the tetrahydrofolic acid needed to synthesize DNA, RNA, and other proteins. Methotrexate is cell cycle phase-specific (S phase).


Side Effects

Methotrexate is a nasty drug in large doses, with numerous side effects, mostly accruing from its inhibition of rapidly dividing cells, such as hair cells, skin cells, blood cells, and gastrointestinal lining cells.

Notable side effects include:

Even when it is administered in relatively low doses, methotrexate's side effects must be carefully monitored to prevent a host of more severe conditions from developing. Most or all of the side effects can be reduced with a daily intake of 1-5mg of folic acid, which doesn't reduce the effectiveness of the drug. Alcohol, aspirin, and ibuprofen increase some of the side effects, and should be avoided.


Indications

Methotrexate is used to treat numerous neoplastic diseases including leukemia, head and throat cancers, bladder cancer, breast cancer, lung cancer, non-Hodgkins lymphoma, sarcoma, choriocarcinoma, and Mycosis fungoides, immunological diseases such as sever adult-onset rheumatoid arthritis (RA), psoriasis, Reiter's syndrome, and acute organ rejection (Graft versus host disease), and ectopic pregnancy.

Cancer

Methotrexate is one of the oldest chemotherapy drugs, and is still commonly prescribed for that purpose. In chemotherapy, the drug is administered in high doses for short periods of time, typically 4-6 weeks followed by a "cooling-off" period. Exact treatment schedules and effectiveness varies widely with the type and severity of the cancer. The generally high dosages often result in particularly severe side effects.

Rheumatoid Arthritis

In recent years Methotrexate has replaced gold salts and antimalarials as the "gold standard" for treating the most severe cases of rheumatoid arthritis, because of its early onset (4-6 weeks), high efficacy, favorable toxicity profile, ease of administration (usually taken orally), and relatively low cost. The drug is usually administered once a week in doses of 7.5-15mg. Classified as a Disease Modifying Anti-rheumatic Drug (DMARD), methotrexate has proven highly effective at both reducing the symptoms of arthritis and slowing (although not preventing) joint degeneration.

Because of its side effects, methotrexate is only administered after nonsteroidal anti-inflammatory drugs (NSAIDs) and milder drugs such as plaquenil have failed to adequately contain the disease. Methotrexate does not replace these drugs, and is usually administered in combination with NSAIDS, steroids, and plaquenil. Methotrexate is administered to approximately 15 percent of RA sufferers, and 70% of patients show some response to the drug. Most patients remain on the drug for five years or longer. Generally, arthritic symptoms return in full force immediately upon cessation of methotrexate treatment.

Ectopic Pregnancy

Methotrexate has proven successful in a single dose in treating ectopic pregnancy, in which a fertilized egg mistakenly embeds in the fallopian tube instead of the uterus. When administered early in pregnancy, methotrexate induces a miscarriage, usually 2-6 weeks after administration, when the uterus expels the dead fetus. Methotrexate should not be administered late in pregnancy, as the fetus will usually not miscarry and instead will likely be born with severe deformities. Recently, methotrexate has been used for abortion purposes as well.


History

Methotrexate was initially developed as a drug for leukemia in 1941 and first used clinically to treat cancer in 1948. The drug has been used to abort ectopic pregnancies since 1982, and was approved for use in adults for the treatment of immunological diseases by the FDA in 1988.


Other Info

In the United States, methotrexate powder is classified as dangerous goods under the Transportation of Dangerous Goods Act and must be declared as such for the purposes of transportation.

Successful pregnancies have followed the use of methotrexate prior to conception, although the drug must be discontinued 6 months before, and for the duration of the pregnancy. Methotrexate is excreted in breast milk in small concentrations and may accumulate in neonatal tissues, and therefore, breast-feeding is not recommended for women on the drug. Men planning to have children should also go off the drug six months before conception, to avoid birth defects, and should also be warned that long-term use of the drug may lead to sterility.

Ironically, given that it is an anti-cancer drug, methotrexate itself may be carcinogenic, and has also been reported to cause chromosome damage. Nasty.




Sources:
http://www.bccancer.bc.ca/HPI/DrugDatabase/DrugIndexPro/Methotrexate.htm
http://www.christie.nhs.uk/patientinfo/booklets/chemocards/methotrexate.htm
http://www.arthritis.co.za/methotrexate.htm
http://www.fwhc.org/abortion/mtxinfo.htm
http://arthritis.about.com/cs/mtx/a/mtx.htm
http://www.medicinenet.com/methotrexate/article.htm
http://www.orthop.washington.edu/arthritis/medications/methotrexate/01
http://www.tirgan.com/methot.htm
a since assimilated writeup by OneDragons

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