Methotrexate

Methotrexate  abbreviated MTX and formerly known as amethopterin, is an antimetabolite and antifolate drug.

It is used in treatment of cancer, autoimmune diseases, ectopic pregnancy, and for the induction of medical abortions.^[5] It acts by inhibiting the metabolism of folic acid.^[3]

Methotrexate began to replace the more toxic antifolate aminopterin starting in the 1950s. The drug was originally synthesised by the Indian biochemist Yellapragada Subbarow and clinically developed by the American paediatricianSidney Farber.^[6][7] It is on the World Health Organization's List of Essential Medicines, a list of the most important medications needed in a basic health system

Medical uses

Chemotherapy

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.^[5]

Autoimmune disorders

It is used as a treatment for some autoimmune diseases, including rheumatoid arthritis, juvenile dermatomyositis, psoriasis,psoriatic arthritis, lupus, sarcoidosis, Crohn's disease (although a recent review has raised the point that it is fairly underused in Crohn's disease^[9]), eczema and many forms of vasculitis.^[3][4] 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 is beneficial for 12 to 52 weeks duration therapy although discontinuation rates are as high as 16% due to adverse effects.^[10] 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.^[3][11][12] Use of methotrexate together with NSAIDS is safe, if adequate monitoring is done.^[13] Not everyone is responsive 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.^[14] 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.^[15] It has also been used formultiple sclerosis.^[5]

Abortion[edit]

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.^[5][16]

Administration

Methotrexate can be taken orally or administered by injection (intramuscular, intravenous, subcutaneous, or intrathecal).^[5]Oral doses are taken weekly, not daily, to limit toxicity.^[5] Routine monitoring of the complete blood count, liver function tests, and creatinine are recommended.^[5] Measurements of creatinine are recommended at least every 2 months.^[5]

Adverse effects

The most common adverse effects include: hepatotoxicity(liver damage), ulcerative stomatitis, low white blood cell count and thus predisposition to infection, nausea, abdominal pain, fatigue, fever, dizziness, acute pneumonitis, rarely pulmonary fibrosis and kidney failure.^[3][5] Methotrexate is teratogenic (harmful to fetus) and hence not used in pregnancy (pregnancy category X).

Central nervous system reactions to methotrexate have been reported, especially when given via the intrathecal route, which include myelopathies and leucoencephalopathies. It has a variety of cutaneous side effects, particularly when administered in high doses.^[17]

Another little understood but serious possible adverse effect of methotrexate is neurological damage and memory loss. Neurotoxicity may result from the drug crossing the blood-brain barrier and damaging neurons in the cerebral cortex. Cancer patients who receive the drug often nickname these effects 'Chemo brain or 'Chemo fog' ^[18]

Drug interactions

Penicillins may decrease the elimination of methotrexate and thus increase the risk of toxicity.^[5] While they may be used together increased monitoring is recommended.^[5] The aminoglycosides, neomycin and paromomycin, have been found to reduce GI absorption of methotrexate.^[19] Probenecid inhibits methotrexate excretion, which increases the risk of methotrexate toxicity.^[19] Likewise retinoids and trimethoprim have been known to interact with methotrexate to produce additive hepatotoxicity and haematotoxicity, respectively.^[19] Other immunosuppressants like ciclosporin may potentiate methotrexate's haematologic effects, hence potentially leading to toxicity.^[19] NSAIDs have also been found to fatally interact with methotrexate in numerous case reports.^[19] Nitrous oxide potentiating the haematological toxicity of methotrexate has also been documented.^[19]Proton-pump inhibitors like omeprazole and the anticonvulsant valproate have been found to increase the plasma concentrations of methotrexate, as have nephrotoxic agents such as cisplatin, the GI drug, colestyramine and dantrolene.^[19] Caffeine may antagonise the effects methotrexate on rheumatoid arthritis by antagonising the receptors for adenosine.^[1]