Introduction
One of the first anticancer medications created was a folate inhibitor. The related medicine Methotrexate (MTX), first used to aid recovery in children with acute lymphoblastic leukemia (ALL), is now a crucial part of modern ALL therapy. MTX has been used to treat psoriasis and rheumatoid arthritis (RA). Today, it is also utilized to treat ectopic pregnancy and several malignant illnesses. The Food and Drug Administration (FDA) authorized MTX as a therapy for RA in 1988. MTX may be more effective with other biological disease-modifying antirheumatic medications (DMARDs). As its benefits outweigh its drawbacks, MTX is a first-line antirheumatic medication in many nations.
To produce purine nucleotides and thymidylate, both necessary for cell replication and deoxyribonucleic acid (DNA) synthesis, MTX may inhibit the development of dihydrofolate reductase and decrease the stockpiles of tetrahydrofolate. This is why cytotoxic MTX has such strong anti-inflammatory, immunosuppressive, and apoptotic properties - it primarily affects quickly growing cells like lymphocytes.
The term "high-dose MTX" (HD-MTX) refers to 500 mg or above doses. Higher doses can cause toxicity and side effects, including bone marrow suppression, lung toxicity, nephrotoxicity, hematological toxicity, and an elevated risk of infections, even if they are frequently more useful. According to earlier studies, 25 percent of people who take HD-MTX suffer hyperbilirubinemia, and 60 percent of patients get reversible hepatitis. In addition, 9.1 percent of lymphoma patients undergoing HD-MTX treatment will experience nephrotoxicity. Therefore, only life-threatening neoplastic illnesses, chronic, severe RA, or psoriasis that do not respond to existing medications should be treated with MTX.
It will take two to three days after a deadly dose of MTX, during which the patient will get multiple doses of Leucovorin, to end the negative effects of MTX. Leucovorin's optimal recovery from MTX clearance by the kidneys necessitates a thorough pretreatment regimen, follow-up therapy fluids, and urine alkalinization. In addition, high blood transaminase levels and renal impairment, which could delay medication clearance, are among HD-significant MTX's side effects. As a result, lessening HD-toxicity MTXs and comprehending its adverse effects can lead to better treatment, higher adherence, and lower mortality.
What Are Some Examples of Methotrexate Toxicity?
If misused, MTX could be hazardous. The most severe side effect, which accounts for most of MTX's relatively occasional fatalities, is severe myelosuppression. Furthermore, side effects include alopecia, liver fibrosis, pneumonitis, homeopathy, and bone marrow suppression. Being overweight, diabetes, hepatitis, and kidney disease are all MTX risk factors. The original method of administering MTX in small daily doses, which is no longer in use, increased this impact. MTX is a hepatotoxic medicine that may develop cirrhosis and hepatitis. A cumulative dosage seldom results in cirrhosis. Numerous people stop taking MTX due to unacceptable toxicity; consequently, factors like genetic variations, which may make it possible to forecast such a consequence, could lessen suffering and even save lives. Below are some examples of MTX toxicity:
Liver Toxicity:
Patients receiving MTX to treat psoriasis showed changed liver functioning in random research. It stated that during the initial two to four years of MTX treatment, hepatotoxicity in people with RA could increase to 70 percent. According to research, increased liver enzymes, particularly alanine aminotransferase and aspartate aminotransferase, were linked to MTX. Although the exact mechanism by which MTX causes hepatotoxicity is unknown, it is related to the drug's cellular pathways. Among the many hypotheses is that MTX causes the liver's Ito cells to become active. Long-term liver injury causes Ito cells to transform into myofibroblasts, which are makers of collagen and other matrix proteins like fibronectin, leading to cell growth. Another theory is that long-term intracellular MTX storage, particularly of MTX metabolites, causes a persistent depletion of folate, a nutrient necessary for the creation of DNA. While hepatotoxicity is rare, certain risk factors, such as a family history of hereditary liver failure, a history of alcohol consumption, diabetes, a lack of supplemental folate, and exposure to high concentrations of hepatotoxic chemical agents, can make it worse.
Kidney Toxicity:
A study discovered a connection between MTX and renal damage and the potential for mortality in people with kidney failure. Because RA patients already have impaired renal function, MTX-induced renal impairment is a serious issue. Since the renal tubules excrete more than 90 percent of MTX, any kidney issue could result in inefficient MTX removal. Consequences include prolonged, persistent, or elevated plasma levels of MTX, which may impair leucovorin rescue and significantly raise MTX-related toxicities. Although the discovery casts doubt on this theory and suggests that MTX may have a directly harmful effect on the kidney tubules, renal impairment was previously thought to be caused by the precipitation of MTX and its metabolites in the renal tubules. According to studies, renal failure is brought on by MTX because of renal tubular expansion, and MTX brings on kidney failure. Therefore, as soon as MTX treatment starts, it is crucial to regularly evaluate plasma and serum creatinine MTX levels to forecast the onset of renal failure. Recent studies have demonstrated that kidney damage can be identified using biomarkers like kidney injury molecule-1 (KIM-1) and cystatin C. The alkalinization of the urine is one symptomatic treatment to prevent MTX-related nephritis and the precipitation of MTX and its metabolites.
Hematological Toxicity of MTX:
Patients with RA who use MTX may experience hematological side effects such as leukopenia, neutropenia, and megaloblastic anemia. Additionally, up to 25 percent of patients stop their therapy because of the mortality risk brought on by hematological toxicities. One of the hazards associated with MTX is pancytopenia, which can develop during treatment without warning. While the precise mechanism is uncertain, MTX-induced hematological damage has been linked to the development of RA. Excess unbound extracellular MTX has been identified as one cause of MTX-induced hematopoietic damage. Another study discovered that patients' sociocultural status, cognitive ability, and distress might impact the neutropenia brought on by MTX.
What Is the Management of MTX Toxicity?
Reverse barrier nursing should be closely monitored, and patients who display probable MTX poisoning symptoms and signs should be admitted in an intensive care setting. The three main objectives in managing severe MTX toxicity are to clear MTX from the bloodstream, folinic acid therapy, and organ treatment.
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Folinic Acid Therapy: Folic acid is the preferred treatment for MTX toxicity. This course of treatment restores intracellular folate reserves while lowering the toxicity of MTX. Even though serum MTX concentrations should be evaluated in all acute cases of MTX poisoning, it is typically impossible to quantify blood MTX levels. Hence the majority of cases are managed based on the diagnosis. Serum MTX concentrations must be the basis for a Folinic acid recovery treatment strategy. While altering the dosage of Folinic acid, MTX levels should be considered. Serum MTX levels should be monitored every 24 hours until they fall below 0.2 mol/L. Additionally, medication monitoring is not required in cases of low-dose poisoning brought on by weekly dosages of 5 to 25 mg of MTX.
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Hydration: The kidneys eliminate more than 90 percent of the MTX. Therefore, an adequate diuresis of 600 milliliters of urine over six hours or 200 milliliters of urine over two hours must be maintained to maintain urine production and help remove MTX. In addition, to prevent nephrotoxicity and excess fluid, fluid equilibrium must be carefully controlled. The goal is to produce around 2 L/m2 of urine daily until MTX levels reach 0.2 mol/liter.
Conclusion
Although MTX effectively treats various conditions, including RA, psoriasis, and various types of malignant tumors, it can have serious side effects when misused, whether intentionally or accidentally, particularly in the elderly and young. These side effects include pulmonary toxicity, nephrotoxicity, hepatotoxicity, hematological toxicity, and an increased risk of infections. Therefore, the three main objectives in managing severe MTX toxicity are to clear MTX from the bloodstream, folinic acid therapy, and organ treatment.
