Methotrexate: instruction and use

Methotrexate, a member of the antimetabolite group, is structurally similar to folic (pteroylglutamic) acid, consisting of pteridine groups linked to para-aminobenzoic acid, which is linked to glutamic acid residues.

Methotrexate differs from folic acid by the replacement of the amino group with a carboxyl group at the fourth position of the pteridine molecule and the addition of a methyl group at the 10 position of 4-aminobenzoic acid.

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When is methotrexate indicated?

Based on the results of the analysis of controlled studies and their meta-analysis, as well as the materials of long-term open controlled trials of the drug, the following conclusions were made.

1. Methotrexate is the drug of choice (“gold standard”) for seropositive active rheumatoid arthritis.
2. Compared with other DMARDs, it has the best efficacy/toxicity ratio.
3. Treatment discontinuation is most often due to drug toxicity rather than lack of effect.
4. In the early stages (less than 3 years of duration) of severe rheumatoid arthritis, monotherapy is not inferior in effectiveness to monotherapy with TNF-a inhibitors.
5. Methotrexate is the main drug in combination therapy with DMARDs.
6. Methotrexate is associated with a reduced risk of mortality in patients compared with other standard approaches.

There is also evidence to support the efficacy of methotrexate in other inflammatory rheumatological diseases.

General characteristics

When taken orally, methotrexate is absorbed in the gastrointestinal tract due to active transport, then enters the liver through the portal vein. The drug in a dose of 10-25 mg is absorbed by 25-100%, on average - by 60-70%, and its bioavailability varies from 28 to 94%. Such variations in the bioavailability of methotrexate when taken orally in different patients are one of the reasons limiting the use of the drug.

The maximum concentration of the drug in the blood is observed after 2-4 hours. If methotrexate is taken with food, this delays the achievement of peak concentration by about 30 minutes, but the level of its absorption and bioavailability do not change, so patients can take methotrexate during meals. The drug binds to albumin (50%) and competes with other drugs for binding sites with this molecule.

Methotrexate is excreted from the body mainly by the kidneys (80%) through glomerular filtration and tubular secretion and to a lesser extent by the biliary system (10-30%). T1/2 of the drug in blood plasma is 2-6 hours. The development of renal failure leads to a slowdown in the excretion of the drug and increases its toxicity; with creatinine clearance less than 50 ml/min, the dose of methotrexate should be reduced by at least 50%.

Despite its fairly rapid elimination from the blood, methotrexate metabolites are found intracellularly for 7 or more days after a single dose of the drug. In patients with rheumatoid arthritis, methotrexate accumulates intensively in the synovial tissue of the joints. At the same time, methotrexate does not have a significant toxic effect on chondrocytes in vitro and in vivo.

How does methotrexate work?

Therapeutic efficacy and toxic reactions that occur during treatment are largely due to the antifolate properties of the drug. In the human body, folic acid is broken down by the enzyme dihydrofolate reductase to form metabolically active products of dihydrofolic and tetrahydrofolic acids, which participate in the conversion of homocysteine to methionine, the formation of purines and thymidylate, which are necessary for DNA synthesis. One of the main pharmacological effects of methotrexate is the inactivation of dihydrofolate reductase. In addition, methotrexate undergoes polyglutamylation in the cell to form metabolites that greatly affect the biological activity of the drug. These metabolites, unlike native methotrexate, have an inhibitory effect not only on dihydrofolate reductase, but also on other folate-dependent enzymes, including thymidylate synthetase, 5-aminoimidazole-4-carboxamido ribonucleotide, transamylase, etc.

It is assumed that complete inhibition of dihydrofodate reductase, leading to a decrease in DNA synthesis, occurs mainly with the administration of ultra-high doses of methotrexate (100-1000 mg/m2) and is the basis of the antiproliferative action of the drug, which is important in the treatment of cancer patients. If methotrexate is used in low doses, the pharmacological effects of the drug are associated with the action of its glutaminated metabolites, inhibiting the activity of 5-aminoimidazole-4-carboxamido ribonucleotide, which leads to excessive accumulation of adenosine. The purine nucleoside adenosine, formed after intracellular cleavage of adenosine triphosphate, has the ability to suppress platelet aggregation and modulate immune and inflammatory reactions.

Some of the pharmacological effects of methotrexate may be related to its effect on the synthesis of polyamines, which are necessary for cell proliferation and protein synthesis and are involved in cell-mediated immune responses.

Methotrexate has anti-inflammatory and immunomodulatory effects, the basis of these effects are the following mechanisms:

• induction of apoptosis of rapidly proliferating cells, and in particular activated T-lymphocytes, fibroblasts and synoviocytes;
• inhibition of the synthesis of proinflammatory cytokines IL-1 and TNF-a:
• increased synthesis of anti-inflammatory cytokines IL-4 and IL-10;
• suppression of matrix metalloproteinase activity.

Methotrexate: What does a patient need to know?

• convince them to avoid alcohol (spirits, wine and beer): the risk of liver damage increases; excessive caffeine intake: the effectiveness of treatment decreases; uncontrolled use of NSAIDs;
• inform men and women of reproductive age about the need for contraception;
• discuss potential drug interactions, especially with salicylates and over-the-counter NSAIDs.
• convince to immediately stop taking methotrexate if signs of infection, cough, shortness of breath, bleeding appear;
• pay special attention to the fact that methotrexate is taken once a week, and daily use of the drug can lead to fatal complications;
• draw attention to the need for careful dynamic monitoring;
• describe the most common side effects of treatment and provide recommendations for reducing their risk and severity.

Dosage

Methotrexate is prescribed once a week (orally or parenterally); more frequent use of the drug is associated with the development of acute and chronic toxic reactions.

The drug is taken fractionally, with a 12-hour interval, in the morning and evening hours. The initial dose is 7.5 mg/week, and for elderly people and those with impaired renal function - 5 mg/week. Efficacy and toxicity are assessed after about 4 weeks; with normal tolerance, the methotrexate dose is increased by 2.5-5 mg per week.

The clinical efficacy of methotrexate depends on the dose in the range from 7.5 to 25 mg/week. Taking the drug at a dose of more than 25-30 mg/week is not advisable (an increase in effect has not been proven).

If there is no effect with oral administration or if toxic reactions from the gastrointestinal tract develop, parenteral administration (intramuscular or subcutaneous) should be used. The lack of effect with oral administration of methotrexate may be due to low absorption in the gastrointestinal tract.

According to modern standards, methotrexate for rheumatoid arthritis must be combined with folic acid (5-10 mg/week after taking methotrexate), which reduces the risk of developing side effects from the esophagus, gastrointestinal tract and liver; cytopenia and homocysteine levels.

In case of methotrexate overdose or development of acute hematological side effects, it is recommended to take two to eight doses of folic acid (15 mg every 6 hours) depending on the methotrexate dose.

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When is methotrexate contraindicated?

Absolute contraindications:

• liver disease;
• severe infections;
• pregnancy;
• severe lung damage;
• severe renal failure (creatinine clearance <50 ml/min);
• pancytopenia;
• malignant neoplasms;
• excessive alcohol consumption;
• X-ray therapy.

Relative contraindications:

• obesity;
• diabetes mellitus;
• moderate renal failure;
• cytopenia;
• malignant neoplasms;
• gastric ulcer and duodenal ulcer;
• anticoagulant therapy;
• infection with the human immunodeficiency virus (HIV);
• moderate alcohol consumption;
• use of other hepatotoxic drugs.

Before methotrexate is prescribed and during the course of therapy, regular clinical examination of the patient is necessary to monitor his condition.

Data on the risk of postoperative complications in patients taking methotrexate are contradictory. According to some of them, methotrexate does not increase the risk of early postoperative infections or other complications during the year of observation. In patients receiving methotrexate, a decrease in the frequency of exacerbation of rheumatoid arthritis in the postoperative period is noted.

Indications for discontinuing methotrexate before surgery: old age, renal failure, uncontrolled diabetes mellitus, severe liver and lung damage, taking glucocorticosteroids >10 mg/day.

Side effects

Methotrexate can cause the development of various side effects. They are conventionally divided into three main categories:

1. Effects associated with folate deficiency (stomatitis, suppression of hematopoiesis) that can be corrected by prescribing folic or folinic acids.
2. "Idiosyncratic" or allergic reactions (pneumonitis), sometimes relieved by interrupting treatment.
3. Reactions associated with the accumulation of polyglutaminated metabolites (liver damage).

It should be emphasized that many side effects can be caused by incorrect use of the drug due to errors by patients, pharmacists or doctors.

Risk factors for the development of adverse reactions include:

• hyperglycemia;
• increase in body mass index;
• lack of folic acid in therapy (leads to an increase in the level of liver transaminases);
• decreased albumin levels (leads to thrombocytopenia);
• alcohol consumption;
• high cumulative dose and long-term use of methotrexate (leads to liver damage);
• renal dysfunction;
• presence of extra-articular symptoms (hematological disorders).

To reduce the severity of the side effects of methotrexate, it is recommended:

• use short-acting NSAIDs in combination therapy with it;
• avoid prescribing acetylsalicylic acid (and, if possible, diclofenac);
• on the day of taking methotrexate, replace NSAIDs with low-dose glucocorticosteroids;
• take methotrexate in the evening;
• reduce the dose of NSAIDs before and/or after taking methotrexate;
• switch to another NSAID;
• switch to parenteral administration of methotrexate;
• prescribe antiemetic drugs;
• Avoid drinking alcohol (increases the toxicity of methotrexate) and substances or foods containing caffeine (reduces the effectiveness of methotrexate).

Methotrexate should not be administered to patients with renal impairment or to patients suspected of having severe lung disease.

Recommendations for physicians on the education of patients taking methotrexate.