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Methotrexate
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Methotrexate (rINN) , abbreviated MTX and formerly known as amethopterin, is an antimetabolite and antifolate drug used in treatment of cancer and autoimmune diseases. It acts by inhibiting the metabolism of folic acid. Methotrexate replaced the more powerful and toxic antifolate aminopterin, and the two should not be confused with each other.
otrexate originated in the 1940s when Dr. Sidney Farber at Children's Hospital Boston was testing the effects of folic acid on acute leukemic children (severe blood cancer).
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Encyclopedia
Methotrexate (rINN) , abbreviated MTX and formerly known as amethopterin, is an antimetabolite and antifolate drug used in treatment of cancer and autoimmune diseases. It acts by inhibiting the metabolism of folic acid. Methotrexate replaced the more powerful and toxic antifolate aminopterin, and the two should not be confused with each other.
History
Methotrexate originated in the 1940s when Dr. Sidney Farber at Children's Hospital Boston was testing the effects of folic acid on acute leukemic children (severe blood cancer). Inspired, he asked Dr. Y. Subbarao, then Director of the Research Division of Lederle Labs (part of American Cyanamid), to synthesize the anti-folate (methotrexate). Dr. Subbarao, who also happened to be the head of the team which had earlier synthesized folic acid (1946) readily synthesized this anti-folate and handed it over to Dr. Farber, who in turn administered it to a small group of very ill leukemic children. The remarkable clinical improvement that was observed in these patients heralded the era of cancer chemotherapy in modern medicine. This was reported by Dr. S. Farber in the June 3rd, 1948 issue of NEJM. In 1950 Dr. Farber founded in Boston the world's first Cancer Research Center. Methotrexate gained Food and Drug Administration (FDA) approval as an oncology drug in 1953.
Mode of action
Methotrexate competitively and reversibly inhibits dihydrofolate reductase (DHFR), an enzyme that participates in the tetrahydrofolate synthesis. 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. 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.
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 as causing the side effects listed above.
Lower doses of methotrexate have been shown to be very effective for the management of rheumatoid arthritis, Crohn's disease, and psoriasis. In these cases inhibition of dihydrofolate reductase (DHFR) is not thought to be the main mechanism, but 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.
Uses
In cancer chemotherapy
Methotrexate was originally used as part of combination chemotherapy regimens to treat many kinds of cancers. It is still the mainstay for the treatment of many neoplastic disorders including acute lymphoblastic leukemia.
Medical termination of pregnancy
Methotrexate is commonly used (generally in combination with misoprostol) to terminate early pregnancies. It is also used to treat ectopic pregnancies. In the case of early missed miscarriage (particularly a blighted ovum), in which fetal demise has occurred but the body has not expelled the fetus, methotrexate may be used to help the body begin the miscarriage process.
Other uses
It has come into use as a treatment for some autoimmune diseases, including ankylosing spondylitis, Crohn's disease, psoriasis, psoriatic arthritis, rheumatoid arthritis, and scleroderma (see disease-modifying antirheumatic drugs). A parallel use with TNFa blockers such as infliximab or etanercept has been shown to markedly improve symptoms.
It is also sometimes used to treat a rare condition called Behçet's disease where it is taken weekly, along with folic acid daily. In the case of immune disorders, such as Behçet's disease and rheumatoid disorders, the clinical goal of the low dose methotrexate regimen is to inhibit AICAR transformylase, which leads to increased AICA ribose (AICAR transformylase's substrate). The AICA ribose inhibits adenosine deaminase, resulting in a build-up of extracellular adenosine. Extracellular adenosine inhibits the expression of IL-2 receptors on circulating T-lymphocytes, causing a suppression of the immune system, and thus ameliorating the effects of the immune disorder.
Pharmacokinetics
Methotrexate is a weak dicarboxylic acid with pKa 4.8 and 5.5, and thus it is mostly ionized at physiologic pH. Oral absorption is saturatable and thus dose-dependent, with doses less than 40 mg/M2 having 42% bioavailability and doses greater than 40 mg/M2 only 18%. Mean oral bioavailability is 33% (13-76% range), and there is no clear benefit to subdividing an oral dose. Mean intramuscular bioavailability is 76%.
Methotrexate is metabolized by intestinal bacteria to the inactive metabolite 4-amino-4-deoxy-N-methylpteroic acid (DAMPA) and accounts for less than 5% loss of the oral dose.
Factors that decrease absorption include food, oral non-absorbable antibiotics (e.g. vancomycin, neomycin, and bacitracin), and more rapid transit through the gastrointestinal tract (GI) tract such as diarrhea, while slower transit time in the GI tract from constipation will increase absorption. Methotrexate is also administered in the placenta accreta, inhibiting the blood circulation to the target site.
Administration
It can be taken orally or administered by injection (subcutaneous, intramuscular, intravenous or intrathecal). Although daily preparations are occasionally used, most patients take weekly doses, which decreases the risk of certain side-effects.
Adverse 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 where dry cough can be an important sign.
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 Leucovorin "rescue"- as this is the folic acid based drug used)
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. There have also been some reports of central nervous system reactions to methotrexate especially when given via the intrathecal route which include myelopathies and leucoencephalopathies.
Generally, the more "non-specific" action a pharmacological substance has, the more possible side effects can be expected. Methotrexate has like all "cell toxic" substances a broad array of possible adverse effects. Care shall always be taken to read the manufacturer's original instructions for the preparation in question.
Here is a more thorough list of potential side effects for Methotrexate:
Most frequent
Ulcerative stomatitis, leukopenia, nausea, abdominal distress
Other frequent
Malaise, undue fatigue, chills and fever, dizziness and lowered resistance to infection.
Other rarer reactions
(related to or attributed to Methotrexate) nodulosis, vasculitis, arthralgia/myalgia, loss of libido/impotence, diabetes, osteoporosis, sudden death, reversible lymphomas, tumor lysis syndrome, soft tissue necrosis, steonecrosis, anaphylactoid reactions.
By organ system:
Alimentary System
Anorexia, nausea, vomiting, diarrhea; Gingivitis, pharyngitis, stomatitis, hematemesis, melena, gastrointestinal ulceration/bleeding, enteritis, pancreatitis.
Blood/Lymphatic System
Anemia, aplastic anemia, pancytopenia, leukopenia, neutropenia, thrombocytopenia, lymphadenopathy and lymphoproliferative disorders. Hypogammaglobulinemia.
Cardiovascular System
Pericarditis, pericardial effusion, hypotension, thromboembolic events (cerebral thrombosis, deep vein thrombosis, retinal vein thrombosis, thrombophlebitis, and pulmonary embolus).
Central Nervous System
Headaches, drowsiness, blurred vision, transient blindness, speech impairment including dysarthria and aphasia, hemiparesis, paresis and convulsions. Occasional reports of transient subtle cognitive dysfunction, mood alteration (depression), unusual cranial sensations, leukoencephalopathy, encephalopathy.
Hepatobiliary System
Hepatotoxicity, acute hepatitis, chronic fibrosis/cirrhosis, decrease in serum albumin, liver enzyme elevations.
Immune System (Infections)
Fatal opportunistic infections (Pneumocystis carinii pneumonia, pneumonia, sepsis, nocardiosis, histoplasmosis, cryptococcosis, Herpes zoster, Herpes simplex hepatitis and disseminated Herpes simplex.
Musculoskeletal System
Stress fracture.
Ophthalmic
Conjunctivitis, serious visual changes (without known cause).
Respiratory System
Respiratory fibrosis, respiratory failure, interstitial pneumonitis, and chronic interstitial obstructive pulmonary disease. Dry cough possibly being a symptom of these aforementioned conditions.
Dermatologic
Acne, rashes (Erythematous rashes), pruritus, urticaria, photosensitivity, pigmentary changes, alopecia, ecchymosis, telangiectasia, furunculosis, erythema multiforme, toxic epidermal necrolysis, Stevens-Johnson Syndrome, skin necrosis, skin ulceration and exfoliative dermatitis.
Urogenital System
Severe nephropathy or renal failure, azotemia, cystitis, hematuria; defective oogenesis or spermatogenesis, transient oligospermia, menstrual dysfunction, vaginal discharge, and gynecomastia; infertility, abortion, fetal defects.
External links
- entry on methotrexate
- general article from NIH
- MedlinePlus article from NIH
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- from American College of Rheumatology
- as seen on Flintbox
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