Methotrexate: instructions and use

Methotrexate, an incoming and antimetabolite group, resembles folic (pteroylglutamic) acid, consisting of pteridine groups linked to para-aminobenzoic acid combined with glutamic acid residues.

Methotrexate differs from folic acid by substitution of the amino group for the carboxyl group in the fourth position of the pteridinic molecule and the addition of the methyl group B10 to the positions of 4-aminobenzoic acid.

[1], [2], [3], [4]

When is methotrexate shown?

Based on the results of the analysis of controlled trials and their meta-analysis, as well as the materials of a long, open, controlled trial, the following conclusions were drawn.

1. Methotrexate is the drug of choice (the "gold standard") for seropositive active rheumatoid arthritis.
2. Compared with others, the BPRI has the best efficiency / toxicity ratio.
3. Interruption of treatment is most often associated with the toxicity of the drug, and not with the lack of its effect.
4. In the early stages (less than 3 years) of severe rheumatoid arthritis monotherapy is not inferior to the effectiveness of monotherapy with TNF-a inhibitors.
5. Methotrexate is the main drug in combination therapy with BPVP.
6. Methotrexate, in comparison with other standard approaches, is associated with a reduction in the risk of mortality in patients.

There are also data confirming the effectiveness 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 fluctuations in the bioavailability of methotrexate for oral administration in different patients are one of the reasons limiting the use of the drug.

The maximum concentration of the drug in the blood is noted after 2-4 hours. If methotrexate is taken with food, it slows the peak concentration by about 30 minutes, but the level of absorption and bioavailability does not change, so patients can take methotrexate while eating. 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%) by 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; when the creatinine clearance is less than 50 ml / min, the dose of methotrexate should be reduced by at least 50%.

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

How does methotrexate work?

The 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 cleaved by the enzyme dihydrofolate reductase, with the formation of dihydrofolate and tetrahydrofolic acids metabolically active in the product, taking part in the conversion of homocysteine to methionine, the formation of purines and thymidylate, necessary for DNA synthesis. One of the main pharmacological effects of methotrexate is the inactivation of dihydrofolic reductase. In addition, in the cell, methotrexate undergoes polyglutamylation with the formation of metabolites. Strongly affecting the biological activity of the drug. These metabolites, in contrast to native methotrexate, have an inhibitory effect not only on dihydrofolate reductase, but also on other folate-dependent enzymes, including thymidylate synthetase, 5-aminoimidazole-4-carboxamidoribonucleotide, transamylase, and others.

It is suggested that complete inhibition of dihydrogenadetradase, leading to a decrease in the synthesis of DNA, occurs mainly in the administration of ultra-high doses of methotrexate (100-1000 mg / m2) and forms the basis of the antiproliferative effect 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 glutamine metabolites, inhibiting the activity of 5-aminoimidazole-4-carboxamidoboronucleotide, which leads to an excessive accumulation of adenosine. Purine nucleoside adenosine, formed after intracellular cleavage of adenosine triphosphate, has the ability to suppress platelet aggregation and modulate immune and inflammatory responses.

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

Methotrexate has an anti-inflammatory and immunomodulatory effect, these effects are based on 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;
• inhibition of matrix metalloproteinase activity.

Methotrexate: What does the patient need to know?

• convince them to avoid drinking alcohol (strong drinks, wine and beer): the risk of liver damage increases; excess intake of caffeine: the effectiveness of treatment, uncontrolled intake of NSAIDs decreases;
• informing men and women of reproductive age about the need for contraception;
• to discuss potential drug interactions, especially the use of salicylates and non-prescription NSAIDs.
• persuade immediately to stop taking methotrexate if there are signs of infection, coughing, shortness of breath, bleeding;
• pay special attention to the fact that methotrexate is taken once a week, and the daily intake of the drug can lead to fatal complications;
• pay attention to the need for careful dynamic observation;
• tell about the most frequent side effects of treatment and give recommendations on reducing their risk and severity.

Dosing

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

The drug is taken fractional, with a 12-hour interval, in the morning and evening hours. The initial dose is 7.5 mg / week, and for the elderly and with renal dysfunction, 5 mg / week. Efficacy and toxicity is assessed after about 4 weeks; with normal tolerability, the dose of methotrexate is increased by 2.5-5 mg per week.

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

If there is no effect with oral administration or with the development of toxic reactions from the digestive tract, it is necessary to switch to parenteral administration (intramuscularly or subcutaneously). The absence of the effect of oral methotrexate may be associated with a low absorption in the gastrointestinal tract.

By modern standards, methotrexate in rheumatoid arthritis should necessarily be combined with folic acid intake (5-10 mg / week after taking methotrexate), which reduces the risk of esophageal, gastrointestinal and hepatic side effects; cytopenia and homocysteine levels.

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

[5], [6], [7], [8],

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;
• moderate renal insufficiency;
• cytopenia;
• malignant neoplasms;
• stomach 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, a 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. For some, methotrexate does not increase the risk of developing early postoperative infections or other complications during the observation year. In patients receiving methotrexate, a decrease in the frequency of exacerbation of rheumatoid arthritis in the postoperative period is noted.

Indications for cancellation of methotrexate before surgical operations: 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, hematopoietic suppression), amenable to correction in the appointment of folic acid or folinic acid.
2. "Idiosyncratic" or allergic reactions (pneumonitis), sometimes docked upon interruption of treatment.
3. Reactions associated with the accumulation of polyglutaminate metabolites (liver damage).

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

The risk factors for the development of adverse reactions include:

• hyperglycemia;
• an increase in the body mass index;
• absence of folic acid in therapy (leads to an increase in the level of hepatic transaminases);
• decrease in albumin level (leads to thrombocytopenia);
• alcohol consumption;
• high cumulative dose and long-term use of methotrexate (leads to liver damage);
• impaired renal function;
• the presence of extraarticular symptoms (hematological disorders).

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

• use in combination therapy with it, NSAIDs of short duration;
• avoid the appointment of acetylsalicylic acid (and, if possible, diclofenac);
• on the day of taking methotrexate, replace NSAIDs with glucocorticosteroids in low doses;
• 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;
• Exclude the use of alcohol (increases the toxicity of methotrexate) and substances or foods containing caffeine (reduces the effectiveness of methotrexate).

Methotrexate should not be given to patients with renal insufficiency, as well as to patients with suspected severe lung damage.

Recommendations for physicians on the training of patients taking methotrexate.