Methotrexate is an antimetabolite of the antifolate type. It is thought to affect cancer and rheumatoid arthritis by two different pathways. For cancer, methotrexate competitively inhibits dihydrofolate reductase (DHFR), an enzyme that participates in the tetrahydrofolate synthesis. The affinity of methotrexate for DHFR is about 1000-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. Also, folate is essential for purine and pyrimidine base biosynthesis, so synthesis will be inhibited. Methotrexate, therefore, inhibits the synthesis of DNA, RNA, thymidylates, and proteins.
For the treatment of rheumatoid
arthritis, inhibition of DHFR is not thought to be the main mechanism, but
rather multiple mechanisms appear to be involved, including the inhibition of
enzymes involved in purine metabolism, leading to accumulation of adenosine;
inhibition of T cell activation and suppression of intercellular
adhesion molecule expression by T cells; selective down-regulation
of B cells; increasing CD95 sensitivity of activated T cells;
and inhibition of methyltransferase activity, leading to deactivation of enzyme
activity relevant to immune system function. Another mechanism of MTX is
the inhibition of the binding of interleukin 1-beta to its cell
Methotrexate was originally developed and continues to be used for chemotherapy, either alone or in combination with other agents. It is effective for the treatment of a number of cancers, including: breast, head and neck, leukemia, lymphoma, lung, osteosarcoma, bladder, and trophoblastic neoplasms.
It is used as a disease-modifying treatment for some autoimmune diseases, including rheumatoid arthritis, juvenile dermatomyositis, psoriasis, psoriatic arthritis, lupus, sarcoidosis, Crohn's disease, eczema and many forms of vasculitis. Although originally designed as a chemotherapy drug (using high doses), in low doses, methotrexate is a generally safe and well tolerated drug in the treatment of certain autoimmune diseases. Because of its effectiveness, low-dose methotrexate is now first-line therapy for the treatment of rheumatoid arthritis. Weekly doses are beneficial for 12 to 52 weeks duration therapy, although discontinuation rates are as high as 16% due to adverse effects. Although methotrexate for autoimmune diseases is taken in lower doses than it is for cancer, side effects such as hair loss, nausea, headaches, and skin pigmentation are still common. Use of low doses of methotrexate together with NSAIDS such as aspirin or analgesics such as paracetamol is relatively safe in people being treated for rheumatoid arthritis, if adequate monitoring is done.
Not everyone with rheumatoid arthritis responds favorably to treatment with methotrexate, but multiple studies and reviews showed that the majority of people receiving methotrexate for up to one year had less pain, functioned better, had fewer swollen and tender joints, and had less disease activity overall as reported by themselves and their doctors. X-rays also showed that the progress of the disease slowed or stopped in many people receiving methotrexate, with the progression being completely halted in about 30% of those receiving the drug. Those individuals with rheumatoid arthritis treated with methotrexate have been found to have a lower risk of cardiovascular events such as myocardial infarctions (heart attacks) and strokes.
Recently, use of methotrexate in combination with anti-TNF agents has been shown to be effective for the treatment of ulcerative colitis.
Methotrexate has also been used for multiple sclerosis.
It is not commonly used for lupus, and only tentative evidence exists to support the practice.
Methotrexate is an abortifacient and
is commonly used to terminate pregnancies during the early stages,
generally in combination with misoprostol. It is also used to treat ectopic
pregnancies, provided the fallopian tube has not ruptured. Methotrexate
with dilatation and curettage is used to treat molar pregnancy.
Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.
Check with your doctor immediately if any of the following side effects occur:
Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:
side effects not listed may also occur in some patients. If you notice any
other effects, check with your healthcare professional.
The dose of this medicine will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of this medicine. If your dose is different, do not change it unless your doctor tells you to do so.
The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.
medicine needs to be given on a fixed schedule. If you miss a dose or forget to
use your medicine, call your doctor or pharmacist for instructions.
Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are taking this medicine, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.
Using this medicine with any of the following medicines is not recommended. Your doctor may decide not to treat you with this medication or change some of the other medicines you take.
Using this medicine with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.
Using this medicine with any of the following medicines may cause an increased risk of certain side effects, but using both drugs may be the best treatment for you. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.
Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.
Using this medicine with any of the following is usually not recommended, but may be unavoidable in some cases. If used together, your doctor may change the dose or how often you use this medicine, or give you special instructions about the use of food, alcohol, or tobacco.
Take this medicine only as directed by your doctor. Do not use more of it, do not use it more often, and do not use it for a longer time than your doctor ordered.
In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For this medicine, the following should be considered:
Tell your doctor if you have ever had any unusual or allergic reaction to this medicine or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.
Appropriate studies performed to date have not demonstrated pediatric-specific problems that would limit the usefulness of methotrexate for the treatment of cancer and juvenile idiopathic arthritis in children. However, safety and efficacy have not been established in children with psoriasis.
Appropriate studies performed to date have not demonstrated geriatric-specific problems that would limit the usefulness of methotrexate in the elderly. However, elderly patients are more likely to have kidney problems, which may require caution and an adjustment in the dose.
Studies in animals or pregnant women have demonstrated positive evidence of fetal abnormalities. This drug should not be used in women who are or may become pregnant because the risk clearly outweighs any possible benefit.
Studies in women breastfeeding have demonstrated harmful
infant effects. An alternative to this medication should be prescribed or you
should stop breastfeeding while using this medicine.