drugs

Methotrexate

Methotrexate is an anticancer drug belonging to the class of antimetabolites. It is an antagonist of folic acid, a substance that plays a fundamental role in many cellular processes. Methotrexate also has anti-inflammatory and immunosuppressive properties, which make it suitable also for the treatment of pathologies other than neoplastic ones.

Methotrexate - Chemical Structure

Therapeutic indications

Methotrexate can be used, alone or in combination, to treat various types of cancer, including:

  • Breast cancer;
  • Head and neck cancer;
  • Bladder cancer;
  • Lung cancer;
  • Non-Hodgkin's lymphoma;
  • Acute leukemia; methotrexate was found to be more effective in the treatment of acute childhood leukemia than that affecting adults.

Thanks to its anti-inflammatory and immunosuppressive properties, methotrexate is also used for the treatment of other diseases, such as:

  • Rheumatoid arthritis;
  • Psoriatic arthritis;
  • Polyarticular juvenile arthritis;
  • Psoriasis;
  • Crohn's disease;
  • Systemic Lupus Eritomatosus;
  • Myopathies.

Warnings

Methotrexate administration should be carried out under strict medical supervision.

More precisely, the administration of methotrexate at high doses for the treatment of tumors must be performed at the hospital level by doctors specialized in the administration of anticancer chemotherapy agents.

Interactions

Concomitant administration of high-dose methotrexate and NSAIDs (Non-Steroidal Anti-Inflammatory Drugs) may result in increased blood levels of the drug. In some cases - this increase in the concentration of methotrexate in the blood - can lead to myelosuppression (bone marrow suppression) or aplastic anemia .

Concomitant use of aminoglycoside antibiotics and methotrexate may decrease intestinal absorption.

It is essential to pay attention to the administration of sulfonamides, salicylates, tetracyclines or chloramphenicol together with methotrexate. These molecules, in fact, have the ability to displace the drug from the binding that forms with the plasma proteins, thus increasing its toxicity.

The administration of folic acid or folate concomitantly with methotrexate appears to be able to reduce some of its side effects, such as alopecia or gastrointestinal effects. However, these substances appear to reduce the response to methotrexate when administered systemically.

Furthermore, taking folic acid or folate could mask the symptoms of a possible vitamin B12 deficiency.

Side effects

As with all medicines, the side effects that can occur after taking methotrexate vary from individual to individual. They also depend on the route of administration (oral or intravenous), on the dose administered and on the type of pathology to be treated.

The following is a list of the main side effects that may occur following methotrexate therapy.

Myelosuppression

Methotrexate may induce myelosuppression. Bone marrow suppression causes a reduction in blood cell production, which can lead to:

  • Anemia, ie a decrease in hemoglobin blood levels. The main symptom of the onset of anemia is the feeling of physical exhaustion ;
  • Leukopenia, or decrease in white blood cell levels; leukopenia can occur with the onset of fever accompanied by chills. Leukopenia makes the patient more susceptible to infections ;
  • Plateletopenia, or decrease in the number of platelets in the blood; this decrease causes the risk of bleeding to increase and favors the appearance of ecchymoses (bruises).

Myelosuppression is a dose-dependent side effect, ie it depends on the amount of drug administered. When methotrexate is used in combination with other cancer chemotherapy drugs, the risk of myelosuppression increases.

Therefore, periodic blood tests are required to assess and monitor bone marrow function.

Hepatotoxicity

Methotrexate therapy may induce hepatotoxicity, ie liver toxicity. There may be an increase in blood levels of transaminases (enzymes used as indicators to detect the presence of possible liver damage).

In addition, prolonged use of methotrexate may favor the onset of fibrosis and cirrhosis of the liver . Therefore, liver therapy should always be monitored during therapy.

Kidney dysfunctions

The use of methotrexate can cause temporary renal dysfunction, which is manifested by increased levels of creatinine (a degradation product of creatine metabolism) in the blood. Generally, the increase in creatinine in the blood is transient and kidney function is not damaged. However, if the blood creatinine values ​​are persistently high, it may be necessary to modify or suspend the therapy.

Respiratory system disorders

Methotrexate therapy can cause lung toxicity, inducing fibrosis . Fibrosis can be reversible and gradually disappears by discontinuing therapy.

Methotrexate can also induce acute or chronic interstitial pneumonia, which is not always reversible with treatment suspension.

The symptom that usually indicates pulmonary damage is dry cough, for this reason - in case of appearance - it is good to inform the doctor and carry out all the necessary analyzes.

Pulmonary toxicity is increased in patients with pre-existing lung diseases.

Asthenia

Almost all anticancer drugs cause fatigue ( feeling of fatigue ), accompanied by decreased appetite. Asthenia may also be caused by anemia.

Pain or ulcers of the oral cavity

Methotrexate therapy can lead to the appearance of small ulcers of the oral cavity, the sensation of a dry mouth and pain. Moreover, it can happen to incur a temporary loss of the sense of taste, which is generally reacquired at the end of the therapy.

Gastrointestinal disorders

Methotrexate may cause ulcerative stomatitis or hemorrhagic enteritis, which could cause perforation of the intestinal mucosa.

Methotrexate therapy can also cause diarrhea, both mild and severe. For the mild form, usually the use of antidiarrheal is sufficient; for the severe form it may be necessary to stop the drug or reduce the dose administered.

It is the doctor's job to evaluate what to do if these side effects occur. In any case, it is good to introduce plenty of fluids to avoid dehydration.

Skin and subcutaneous tissue disorders

The use of methotrexate can cause rashes that itch. The use of neutral and delicate personal hygiene products is recommended.

Intravenous administration of methotrexate can also cause problems at the site where the injection is made, such as pain, redness or leakage of fluid. It is essential to inform health personnel if any of these events occur.

Nausea and vomit

These side effects are typical of anticancer agents. The intensity with which they manifest varies from individual to individual and can last from a few hours to a few days. Usually - in conjunction with anti-cancer therapy - anti- emetic drugs are given (antivomit) to try to avoid, or at least limit, the onset of these effects.

Alopecia

Methotrexate therapy can lead to hair and hair loss in general. This side effect generally disappears after the end of the treatment.

Allergic reactions

Methotrexate - like any other drug - can cause allergies in sensitive individuals. Allergic reactions that can occur include itchy rashes, fever, chills, localized redness in the face, headache, anxiety, shortness of breath . These symptoms occur both mild and severe; if they appear, it is essential to inform the doctor.

Action mechanism

DNA consists of two strands joined together to form a double helix.

DNA is made up of many monomers, called nucleotides. There are 4 types of nucleotides: adenine (A), guanine (G), cytosine (C) and thymine (T), which combine with exclusive pairs of AT (adenine-thymine) and CG (cytosine-guanine) held together by hydrogen bonds .

The sequence of bases present along the DNA molecule carries the genetic information.

Methotrexate is considered an anticancer drug belonging to the class of antimetabolites . It is an antagonist of folic acid, a substance that performs important functions in various cellular processes. In particular, folic acid plays a fundamental role in some steps of DNA synthesis.

Methotrexate is able to inhibit all the synthesis of purine bases which - together with pyrimidine bases - are the molecules that make up the double strand of DNA.

By inhibiting the synthesis of purine bases, methotrexate is therefore able to inhibit the synthesis of DNA and RNA and, consequently, inhibit protein synthesis leading to cell death.

Thanks to its anti-inflammatory and immunomodulatory action, methotrexate can be used - at low doses - in the treatment of inflammatory and / or autoimmune diseases.

Mode of Use - Posology

Methotrexate can be administered either orally or parenterally.

Methotrexate for oral administration comes in the form of yellow tablets. Instead, for parenteral administration, it appears as a yellow liquid.

The type of administration and the dose of the drug depend on the type, severity and stage of the pathology to be treated (tumors, psoriasis, rheumatoid arthritis, etc.). The amount of drug administered also depends on the patient's condition.

It is the duty of the physician to identify the therapeutic strategy that best suits each individual.

Oncological indications

Methotrexate doses vary according to the type of tumor and the stage in which it is found, as well as the patient's condition. Generally, methotrexate is preferred to be administered orally - because it is absorbed very quickly - but it can also be administered intravenously, intra-arterially, intramuscularly, intrathecally or intratumorally .

The dosage is usually the following:

  • Newborns : from 1.25 mg to 2.5 mg, administered 3 to 6 times a week.
  • Children : 2.5 mg to 5 mg, given 3 to 6 times a week.
  • Adults : 5 mg to 10 mg, administered 3 to 6 times a week.

Indications for rheumatoid arthritis and psoriatic arthritis

For this type of disease, the recommended dose is 7.5 mg of methotrexate taken orally once a week.

Alternatively, 2.5 mg of drug can be administered every twelve hours, for a total of three doses, given once a week. In any case, the weekly dose of 20 mg should never be exceeded.

For parenteral administration, the dosage of 5-15 mg of intramuscular methotrexate is considered standard once a week.

Indications for polyarticular juvenile arthritis

The recommended methotrexate dose is usually 10 mg / m2 of body surface area, given once a week. In most cases the administration is oral, but it can also be administered intramuscularly.

Indication for psoriasis

Also in this case, the administration of methotrexate occurs once a week. Usually, methotrexate is administered in 2.5 mg tablets. If the response is not optimal, the oral dose can be increased or treatment continued with parenteral administration. The administered dose is gradually increased until an optimal response to therapy is reached. Once the desired response is reached, it would be good to reduce the dose of the drug to the lowest possible maintenance dose.

However, you should not exceed 30 mg of methotrexate weekly.

Pregnancy and breastfeeding

Methotrexate can cause embryotoxicity (embryo toxicity), congenital anomalies, fetal death and abortion . For this reason, the administration of methotrexate to women of childbearing age can be performed only after excluding the state of pregnancy. In addition, precautions should be taken by both sexes to avoid pregnancy, both during treatment with methotrexate and after the end of it, for a period ranging from three months to one year.

Since methotrexate is excreted in breast milk, this drug should not be used during breastfeeding, as it could have serious toxic effects on the infant.

Because of these effects, the Food and Drug Administration (FDA) has included methotrexate in the so-called X class . This class includes all those drugs for which the development of fetal anomalies (both in animals and humans) has been scientifically demonstrated and which, therefore, should not be used during the period of pregnancy and lactation.

Contraindications

Methotrexate is contraindicated in patients allergic to the active substance itself or to any of the excipients contained in the pharmaceutical formulation.

Because of its side effects, the use of methotrexate is contraindicated in patients suffering from renal or hepatic dysfunction, from anemia, leukopenia or thrombocytopenia, or suffering from gastrointestinal disorders such as ulcerative stomatitis, ulcerative colitis and peptic ulcer.

Furthermore, for the reasons mentioned above, methotrexate is contraindicated in pregnancy and lactation.