Azathioprine

There are two main purine analogues - 6-mercaptopurine and azathioprine, however, only the latter is currently used in clinical practice.

6-mercaptopurine is an analogue of hypoxanthine, in which the 6-OH radical is replaced by a thiol group. In turn, azathioprine is a molecule that differs from 6-mercaptopurine by the inclusion of an imidazole ring in the S-position. Compared with 6-mercaptopurine, azathioprine is better absorbed when taken orally and has a longer duration of action. In the body, azathioprine is metabolized in erythrocytes and the liver to form biologically active molecules (6-thioguanine and 6-thioinosinic acids), and is excreted by the kidneys.

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Treatment tactics

To exclude acute hypersensitivity reaction to azathioprine, treatment should be initiated with a test dose of 25-50 mg per day during the first week.

Then the dose is increased by 0.5 mg/kg per day every 4 weeks. The optimal dose is 1-3 mg/kg per day. At the beginning of treatment, it is necessary to regularly (every 1 week) perform a general blood test (with determination of the number of platelets), and when a stable dose is achieved, laboratory monitoring should be carried out every 6-8 weeks. It should be remembered that the effect of azathioprine begins to manifest itself no earlier than 5-12 months after the start of therapy. The dose of azathioprine should be significantly reduced (by 50-75%) in patients receiving allopurinol or having renal failure.

General characteristics

According to its mechanism of action, azathioprine belongs to a class of substances called "antimetabolites". It has the ability to be included as a "false base" in the DNA molecule and thus disrupt its replication. Azathioprine is considered a phase-specific drug that affects cells in a certain growth phase, mainly in the G phase. In higher doses, azathioprine disrupts RNA and protein synthesis in the G1 and G2 phases. Unlike alkylating agents, azathioprine has cytostatic rather than cytotoxic activity.

Mechanism of action of azathioprine

Azathioprine causes peripheral T- and B-lymphopenia, in high doses it reduces the level of T-helpers, and with prolonged use it reduces the synthesis of antibodies. However, since T-suppressors are especially sensitive to the action of azathioprine, the synthesis of antibodies may increase slightly against the background of taking low doses of the drug. Azathioprine is characterized by the suppression of the activity of NK cells and K cells, which participate in the development of natural and antibody-dependent cellular cytotoxicity, respectively.

Clinical application

The efficacy of azathioprine at a dose of 1.25-3 mg/kg/day in RA has been confirmed by a series of controlled studies. In general, the clinical efficacy of azathioprine in rheumatoid arthritis is comparable to that of cyclophosphamide, parenterally administered gold preparations, D-penicillamine, and antimalarial drugs. It is assumed that in rheumatoid arthritis, azathioprine should be prescribed to elderly patients with an onset resembling polymyalgia rheumatica, when a steroid-sparing effect is required.

In systemic lupus erythematosus, according to short-term observations (1-2 years), no significant differences in clinical efficacy were observed between groups of patients receiving only glucocorticoids or glucocorticoids in combination with azathioprine. However, when evaluating the results of treatment after 5-15 years, it was found that combination therapy has certain advantages, including slowing the progression of kidney damage, reducing the number of exacerbations and the possibility of using a lower maintenance dose of glucocorticoids. However, in patients receiving azathioprine, the frequency of various side effects significantly increases, including infectious complications (especially herpes zoster), ovarian failure, leukopenia, liver damage, and an increased risk of tumors.

In idiopathic inflammatory myopathies, about a third of patients resistant to glucocorticoids respond to the commonly used dose of azathioprine (2-3 mg/kg/day), and the steroid-sparing effect is observed in half of the cases, which is somewhat worse than with methotrexate treatment. The maximum clinical and laboratory effect of azathioprine treatment appears only after 6-9 months. The maintenance dose of the drug is 50 mg/day.

Results of small controlled studies indicate the effectiveness of azathioprine in psoriatic arthritis, Reiter's syndrome, and Behcet's disease.

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