Methotrexate is a drug used for the treatment of certain cancers, chronic relapsing diseases of the skin (such as psoriasis) and rheumatoid arthritis. The mode of action is by inhibition of enzymes involved in the metabolism of an essential nutrient (folate). Methotrexate targets inflammatory cells and cancerous cells but can damage normal tissues that have higher folate demands. This article focuses on the effects of methotrexate on folate metabolism, which can produce the side effects associated with methotrexate injections.
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The most-reported side effects of methotrexate are ulcers, nausea and abdominal discomfort. Low white blood cells can result in increased susceptibility to infections. Other side effects are indicated below by the toxicity on organ systems. These toxicities and side effects are produced by inhibition of essential biochemical pathways. Methotrexate is an antimetabolite of folate and inhibits an enzyme (dihydrofolate reductase) that metabolises folate compounds. By inhibition of this enzyme, it decreases the type and amount of folates available for biochemical reactions. These reactions include the synthesis of nucleic acids (e.g. DNA and RNA), and the cellular processing of proteins. Depressed nucleic acid synthesis inhibits cellular division, which disrupts the proliferation of various cancerous cells. This activity is not exclusively targeted to cancer cells, and the side effects of methotrexate cause disruption of other folate-related cellular activity. The general toxicity of methotrexate is a function of inhibition of normal cellular proliferation in cells and tissues with high turnover and disruption of cellular signals.
The bone marrow is constantly producing new cells. These cells are essential in oxygen transport, immune function and wound healing. Methotrexate can inhibit cell production in the bone marrow and cause depression in levels of red blood cell (RBC), white blood cell (WBC) and platelet production. This can ultimately lead to low RBC (anaemia), low WBC (leukopenia) and increased risk of bruising or bleeding due to low platelets, which are essential in scab formation.
Acute and chronic liver toxicity is reported most often due to large dosages or long-term exposure to methotrexate. Chronic toxicity can be fatal and must be carefully monitored. Toxicity risk is increased by alcohol use, diabetes, obesity and old age. Liver damage may result due to decreased cellular reactions (i.e., methylation) by the liver and suppressed proliferation.
Immune & Pulmonary
Methotrexate must be used with extreme caution when an active infection is present. It may cause immunisation to be ineffective. Potentially fatal opportunistic infections (e.g., pneumonias) may also occur due to suppressed white blood cell activation and production.
Nerve damage (neurotoxicity) has been reported in patients treated with intravenous methotrexate. Side effects are reported as leukoencephalopathy, which is white matter (leuko-) brain (-encephalo) damage (-pathy) and present as certain types of seizures. The brain and spinal fluid have high levels of folate, which functions in maintaining neurotransmitter production and repair of amino acids. Disruptions of these processes are indicated in seizure production and neurotoxicity.
Methotrexate can induce kidney damage and kidney failure. Kidney toxicity is due to the large concentration of methotrexate that naturally is filtered from the blood. These high concentrations can lead to crystal formation within the kidney, causing damage or failure.
Severe and occasionally fatal skin reactions are reported with methotrexate. Topical reactions include itching, changes in pigmentation, hives, rashes and ulcerations. Severe reactions include cellular death of tissues and Stevens-Johnson syndrome. These conditions can result due to disruption of the immune system, leading to infections, and disruption of tissue repair and replication at injection or wound sites.
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