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Methotrexate: what it is and how it acts

Methotrexate is a medicine that belongs to a group of drugs called antimetabolites. This means that its structure is similar to that of molecules of our organism (metabolites), which is why they bind to the same receptors.

If the drug is bound to the receptor, the original metabolite can not do so, thus decreasing its effect. Methotrexate is analogous to folic acid, also known as vitamin B9. It is used in the treatment of autoimmune diseases and as part of antineoplastic therapy.

What is folic acid?

Folic acid is a vitamin of plant origin, present in foods such as legumes or nuts. Involved in the synthesis, repair and replication of DNA . Once ingested, folic acid is absorbed in the intestine and passes into the blood in the form of methyl-tetrahydrofolate, to later become tetrahydrofolate (THF).

DNA is made up of a double chain of molecules called nucleotides. The chains are joined together thanks to the bonds that are established between the nitrogenous bases, structures that are part of the nucleotides.

There are four types of nitrogenous bases in DNA: adenine, thymine, guanine and cytosine. Adenine and thymine are known as purines, and guanine and cytosine as pyrimidines. Tetrahydrofolate intervenes in the synthesis of purine nucleotides. This means that a lack of folic acid will alter DNA synthesis, slowing cell replication.

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Mechanism of action of methotrexate

Methotrexate: what it is and how it acts

Methotrexate is an antimetabolite of folic acid. The active form of folic acid is achieved after a reaction catalyzed by an enzyme called dihydrofolate reductase. Methotrexate binds to this enzyme, preventing THF from activating, blocking cell proliferation. Consequently, the effects of methotrexate are:

  • Immunosuppressive effects , decreasing the activity of the immune system. Reduces lymphocyte action, especially that of B lymphocytes, responsible for the synthesis of antibodies. Therefore, methotrexate is used in the treatment of autoimmune diseases.
  • Anti-inflammatory effects. Methotrexate decreases the levels of some cytokines, substances released during inflammatory reactions.
  • Antifolate activity by inhibiting dihydrofolate reductase.
  • Inhibition of other substances involved in the metabolism of folates.

It is administered orally or intravenously. Once in the blood, it binds to plasma proteins that transport it, distributing it through the tissues. Methotrexate can be abortive, so it should be avoided during pregnancy and lactation. In addition, the liver and kidneys are involved in its metabolism and elimination. Consequently, its use should be monitored in patients with liver disease, especially alcoholic; and with renal failure.

Indications of methotrexate

Methotrexate: what it is and how it acts

Methotrexate is used in low doses in the treatment of autoimmune diseases and in high doses associated with other anticancer drugs in antineoplastic therapy.

  • Autoimmune diseases: in autoimmune diseases our immune system reacts against our body. They are synthesized molecules called antibodies that bind to cells or normal substances in our body and cause their destruction. We have said that methotrexate has anti-inflammatory effects and decreases antibody levels. From this fact can be deduced the utility of the drug in this type of diseases. For example, currently methotrexate is used for the treatment of rheumatoid arthritis .
  • Antineoplastic therapy: the tumor cells are cells that have undergone different modifications that allow them to have an abnormal growth. Tumor growth is nothing more than an uncontrolled cell division, for which large amounts of DNA are required. If we administer methotrexate, the synthesis of DNA decreases, so we control cell growth.

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Toxicity of methotrexate

Methotrexate: what it is and how it acts

One of the main drawbacks of the use of this drug is that its toxicity is high. In fact, treatment with methotrexate requires analytical checks every 2-3 months. The toxicity manifests in different ways:

  • Gastrointestinal toxicity . It is the most frequent form of toxicity, manifested by nausea, vomiting, loss of appetite and weight. Other symptoms such as ulcers or skin disorders may be associated.
  • Hepatic toxicity. It does not usually produce serious liver damage, but it may force a decrease in the dose of the drug. There is more risk if the patient had previous liver pathology.
  • Pulmonary toxicity. It is a serious type of toxicity, it can force to interrupt the treatment and apply measures of respiratory support. It manifests with cough, dyspnea or shortness of breath, headache and malaise.
  • Spinal toxicity. The decrease in folic acid affects the synthesis of blood cells, causing a decrease in all of them. This term is called pancytopenia .  

To decrease the toxic effects of the drug, folic acid or folinic acid (a derivative that does not need to be activated by dihydrofolate reductase) can be administered the day after treatment.

Methotrexate: what it is and how it acts

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