Methotrexate

Methotrexate is an anticancer drug belonging to the class of antimetabolites. It's a folic acid antagonist, a substance that plays a fundamental role in many cellular processes. Methotrexate also has anti-inflammatory and immunosuppressive properties, which make it also suitable for the treatment of diseases 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 treating childhood acute 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

The administration of methotrexate must be carried out under close medical supervision.
More precisely, the administration of methotrexate in high doses for the treatment of tumors must be performed at the hospital level by physicians specialized in the administration of anticancer chemotherapeutic agents.

Interactions

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

The concomitant use of aminoglycoside antibiotics and methotrexate can decrease intestinal absorption.

Care must be taken when administering sulfonamides, salicylates, tetracyclines or chloramphenicol concomitantly with methotrexate. These molecules, in fact, have the ability to displace the drug from the bond it forms with 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, the intake of folic acid or folate could mask the symptoms of a possible vitamin B12 deficiency.

Side effects

As with all drugs, the side effects that can occur following the intake of methotrexate vary from individual to individual. They also depend on the route of administration (oral or intravenous), the dose administered and the type of pathology to be treated.
Below is a list of the main side effects that can occur following methotrexate therapy.

Myelosuppression

Methotrexate can induce myelosuppression. Suppression of the bone marrow causes a reduction in the production of blood cells, which can lead to:

• Anemia, that is, a decrease in blood levels of hemoglobin. The main symptom of the onset of anemia is the sensation of physical exhaustion;
• Leukopenia, i.e. decreased levels of white blood cells; leukopenia can manifest itself with the onset of fever accompanied by chills. Leukopenia makes the patient more susceptible to getting infections;
• Thrombocytopenia, i.e. decrease in the number of platelets in the blood; this decrease causes the risk of bleeding and favors the appearance of bruising (bruises).

Myelosuppression is a side effect dose-dependent, that is, it depends on the amount of drug administered. When methotrexate is used in combination with other anticancer chemotherapy, the risk of myelosuppression increases.
Therefore, periodic blood tests are necessary to evaluate and monitor the functionality of the bone marrow.

Hepatotoxicity

Methotrexate therapy can induce hepatotoxicity, i.e. toxicity to the liver. A increase blood levels of transaminases (enzymes used as indicators to identify the presence of possible liver damage).
Prolonged use of methotrexate can also favor the onset of fibrosis And cirrhosis of the liver. During therapy it is therefore necessary to keep liver function under control at all times.

Kidney dysfunction

The use of methotrexate can cause a temporary renal dysfunction, which manifests itself as a increase levels of creatinine (a breakdown product of creatine metabolism) in the blood. Generally, the increase in blood creatinine is transient and kidney function is not impaired. However, if creatinine blood levels are persistently elevated, therapy may need to be changed or discontinued.

Respiratory system disorders

Methotrexate therapy can cause lung toxicity by inducing fibrosis. Fibrosis can be reversible and gradually disappears when the therapy is suspended.
Furthermore, methotrexate can induce interstitial pneumonia acute or chronic, which is not always reversible upon discontinuation of treatment.
The symptom that usually indicates lung damage is dry cough, for this - in case of appearance - it is good to inform the doctor and carry out all the necessary analyzes.

Asthenia

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

Pain or ulcers of the mouth

Methotrexate therapy can lead to small mouth ulcers, dry mouth and pain. Furthermore, it may happen to incur a temporary loss of the sense of taste, which usually regains itself at the end of the therapy.

Gastrointestinal disorders

Methotrexate can cause ulcerative stomatitis or hemorrhagic enteritis, which could lead to perforation of the intestinal mucosa.
Methotrexate therapy can also provoke diarrhea, in both mild and severe form.For the mild form, usually, the use of antidiarrheals is sufficient; for the severe form it may be necessary to suspend the drug or reduce the dose administered.
It is up to the doctor to evaluate what to do in case 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 skin rashes which are itchy. It is advisable to use neutral and delicate personal hygiene products.
The intravenous administration of methotrexate can also cause problems at the injection site, such as pain, redness or leakage of fluid. It is essential to inform the healthcare professional if any of these events occur.

Nausea and vomit

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

Alopecia

Methotrexate therapy can lead to hair loss and hair loss in general. This side effect usually 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 skin rashes, fever, chills, localized redness of the face, headache, anxiety, shortness of breath. These symptoms occur in both mild and severe forms; if they appear, it is essential to inform the doctor.

Mechanism of action

DNA is made up of two strands joined around each other 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 unique AT (adenine-thymine) and CG (cytosine-guanine) pairs 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 antimetabolite agents. 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 constituent molecules of 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, inhibits protein synthesis leading to cell death.
Thanks to its anti-inflammatory and immunomodulatory action, methotrexate can be used - in low doses - in the treatment of inflammatory and / or autoimmune diseases.

Method of Use - Dosage

Methotrexate can be administered both orally and parenterally.
Methotrexate for oral administration comes in the form of yellow tablets. For parenteral administration, on the other hand, 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 disease that is intended to be treated (tumors, psoriasis, rheumatoid arthritis, etc.). The quantity of drug administered also depends on the patient's condition.
It is the physician's task to identify the therapeutic strategy that best suits each individual.

Oncological indications

The doses of methotrexate vary according to the type of tumor and the stage in which it is, as well as the condition of the patient. Generally, methotrexate is preferred orally - because it is absorbed very quickly - but it can also be given intravenously, intraarterial, intramuscular, intrathecal or intratumoral.
The dosage is usually the following:

• Babies: 1.25 mg to 2.5 mg, given 3 to 6 times per week.
• Children: 2.5 mg to 5 mg, administered 3 to 6 times per week.
• Adults: 5 mg to 10 mg, given 3 to 6 times per week.

Indications for rheumatoid arthritis and psoriatic arthritis

For this type of condition, the recommended dose is 7.5 mg of methotrexate orally, once a week.
Alternatively, 2.5 mg of the drug can be administered every twelve hours, for a total of three doses, administered 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 intramuscular methotrexate once a week is considered standard.

Indications for polyarticular juvenile arthritis

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

Indication for psoriasis

Again, methotrexate is administered once a week. Usually, methotrexate is given as 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 achieved. Once the desired response is achieved, it would be wise to reduce the drug dose to the lowest possible maintenance dose.
However, 30 mg of methotrexate per week should not be exceeded.

Pregnancy and breastfeeding

Methotrexate can cause embryotoxicity (toxicity to the embryo), congenital anomalies, fetal death And abortion. For this reason, the administration of methotrexate to women of childbearing age can only be carried out after excluding the state of pregnancy. In addition, precautions should be taken by both sexes to avoid pregnancy, both during and after treatment with methotrexate, for a period ranging from three months to a year.
Since methotrexate is excreted in breast milk, this drug should not be used during breastfeeding, as it may have serious toxic effects on the infant.
Due to these effects, the Food and Drug Administration (FDA) has included methotrexate in the so-called class X. This class includes all those drugs for which the development of fetal abnormalities has been scientifically evidenced (both in animals and in humans) and which, therefore, must not be used during 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.
Due to its side effects, the use of methotrexate is contraindicated in patients suffering from renal or hepatic dysfunction, anemia, leukopenia or thrombocytopenia, or suffering from gastrointestinal diseases such as ulcerative stomatitis, ulcerative colitis and peptic ulcer.
Furthermore, for the reasons mentioned above, methotrexate is contraindicated in pregnancy and breastfeeding.