Immunosuppressive drugs. Immunosuppressive agent

For the treatment of rheumatic diseases, cytostatic drugs are sometimes used, in particular azathioprine, methotrexate, cyclophosphamide. These drugs have a relatively fast and nonspecific cytostatic effect, especially pronounced against rapidly proliferating cells, including lymphoid cells.

The following basic rules for immunosuppressive therapy:

• the reliability of the diagnosis;
• availability of indications;
• no contraindications;
• appropriate doctor's qualifications;
• patient consent;
• systematic observation of the patient during treatment.

Immunosuppressants are considered “reserve drugs” and are traditionally the least used among pathogenetic therapies. The reasons for their appointment are generally the same as for glucocorticosteroids in patients. rheumatoid arthritis, diffuse diseases connective tissue and systemic vasculitis.

Specific indications for the immunosuppressive therapy of these diseases are their severe, life-threatening or disabling course, especially with kidney and central nervous system, as well as with resistance to prolonged steroid therapy, steroid dependence with the need to constantly take too high maintenance doses of glucocorticosteroids, contraindications to their appointment or poor drug tolerance.

Immunosuppressive therapy allows reduce the daily dose of glucocorticosteroids to 10-15 mg of prednisolone, or even abandon their use. Doses of immunosuppressants should be small to moderate and treatment should be continuous and prolonged. When the disease is in remission, the patient continues to take the drug in the minimum maintenance dose for a long time (up to 2 years).

Contraindications to the appointment of immunosuppressants are concomitant infection, including latent and chronic focal, pregnancy, lactation, hematopoiesis disorders (hemocytopenia).

Among the unfavorable side effects common to all immunosuppressants, relate depression of bone marrow function, development of infections, teratogenicity, carcinogenicity. Based on the severity of side effects, the following sequence of use of immunosuppressants is recommended: azathioprine, methotrexate, cyclophosphamide.

Azathioprine is a purine analogue and belongs to antimetabolites. The drug is administered orally at 2 mg per 1 kg of body weight per day. The therapeutic effect appears 3-4 weeks after the start of therapy. Upon achieving a clear improvement, the dose of the drug is reduced to a maintenance dose of 25-75 mg / day. Among the specific for azathioprine adverse reactions the most common hepatitis, stomatitis, dyspepsia, dermatitis.

Methotrexate - antagonist folic acid, included, like azathioprine, in the group of antimetabolites. The drug is administered orally or parenterally at a dose of 5-15 mg per week (divided into three doses). Positive effect observed 3-6 weeks after the start of treatment. To avoid kidney damage, it is undesirable to combine methotrexate with non-steroidal anti-inflammatory drugs. Clinical improvement can be achieved by using low doses of methotrexate, which almost do not cause serious complications, which is considered the basis for its appointment to patients with not only rheumatoid, but also psoriatic arthritis in severe, progressive forms of the disease that are resistant to therapy with non-steroidal anti-inflammatory and basic drugs. Of the side effects characteristic of methotrexate, it should be noted ulcerative stomatitis, skin depigmentation, alopecia, liver fibrosis, alveolitis.

Cyclophosphamide refers to alkylating agents and is a highly effective, but the most dangerous among immunosuppressants drug. This drug is indicated mainly for the treatment of severe forms of systemic vasculitis, especially Wegener's granulomatosis and polyarteritis nodosa in case of ineffectiveness of glucocorticosteroids and other drugs. Cyclophosphamide is usually administered orally at 2 mg per 1 kg of body weight per day, but during the first few days it can be administered intravenously at 3-4 mg per 1 kg of body weight. Signs therapeutic effect observed in 3-4 weeks. After stabilization clinical picture the daily dose is gradually reduced to a maintenance dose of 25-50 mg / day. Side effects common to cyclophosphamide include reversible baldness, disorders menstrual cycle, azoospermia, hemorrhagic cystitis, cancer bladder... To prevent damage to the bladder, it is recommended, in the absence of indications, to prophylactically take up to 3-4 liters of fluid daily. When renal failure the daily dose of cyclophosphamide is reduced.

Immunosuppressants are drugs that suppress the immune response. These include corticosteroids, azathioprine, cyclosporine, and aminosalicylic acid derivatives.

Corticosteroids

Prednisolone... Prednisolone (and methylprednisolone) is the immunosuppressive agent of choice for immunosuppressive therapy in adults and children. Dexamethasone has a similar immunosuppressive effect in equivalent doses; however, due to the adverse effect on the activity of the enzymes of the brush border, its use is not recommended.

Initial doses of prednisolone are 2-4 mg / kg / day for oral or parenteral administration, and then the dose is gradually reduced. The goal of therapy is always to determine the minimum effective dose, which, under favorable circumstances, will be zero or the lowest possible (0.5 mg / kg); in addition, it is advisable to give the drug every other day. The side effect of prednisone, Cushing's syndrome, is well known. In this regard, in the presence of pronounced adverse events when prescribing the minimum effective dose, additional immunosuppressive drugs should be used, which will allow achieving a therapeutic effect with low doses of steroids.

Budesonide... This new enteric-coated drug is available from pharmacies. Budesonide is extensively metabolized during the first pass through the liver, and therefore its systemic side effects of an immunosuppressive agent are minimal. However, in some patients, steroidal hepatopathy and some suppression of adrenal function were noted. There are isolated reports of the effectiveness of budesonide; however, some studies have used a non-enteric coated formulation available for inhalation treatment bronchial asthmaand other studies do not specify the appropriate dose. Further studies of immunosuppressive agents in small patients are needed to make informed recommendations regarding the use of budesonide.

Azathioprine

In humans, this immunosuppressive drug is ineffective unless the patient is already on steroids. It takes 24 weeks to achieve the desired result, and premature discontinuation of treatment may lead to relapse. In most cases, azathioprine is not used as a first-line immunosuppressive drug, but as a means to reduce the dose of steroids.

The toxic effect of an immunosuppressive agent on the bone marrow (neutropenia) is rare, but in some patients it can develop within a few weeks. These patients are likely to be deficient in thiopurine methyl transferase (TPMT), an enzyme necessary for the degradation of 6-mercaptopurine, the active metabolite of azathioprine. In children, TPMT activity is low, which explains the extremely low recommended doses for children compared to adults (0.3 mg / kg / day versus 2.0 mg / kg / day). The smallest commercially available immunosuppressive dose is 25 mg, and due to the inability to separate this cytotoxic drug, azathioprine is rarely prescribed for children. In other countries, this drug is commercially available in various dosages, but it is excreted in the urine, which may be of concern from an environmental point of view.

Other cytotoxic drugs

Children with inflammatory disease other immunosuppressants, such as chlorambucil or cyclophosphamide, are shown to a greater extent, in the absence of the effect of monotherapy with prednisolone.

Derivatives of 5-aminosalicylic acid (5-ASA)

Colitis is a fairly common disease in some countries. In addition, inflammatory changes in the large intestine may occur secondary to small intestine or be part of generalized IBD. In all cases of isolated acute or chronic colitis, the use of immunosuppressants - derivatives of 5-ASA as anti-inflammatory drugs is justified.

Sulfasalazine... Is a pro medicine; the diazo bond connecting sulfapyridine with 5-ASA is broken by the action of intestinal bacteria with the release of 5-ASA, which in high concentration has a local anti-inflammatory effect in the large intestine. Hepatotoxicity may occur, but keratoconjunctivitis dry (CKV) is the main side effect of an immunosuppressive drug, so the Schirmer test should be done regularly to assess the amount of tear produced. SSC is considered a complication associated with the action of a component such as sulfur, although it has also been observed with olsalazine, which does not contain sulfonamide.

Olsalazin... It consists of two 5-ASA molecules linked by a diazo bond and re-released under the influence of intestinal bacteria. An immunosuppressive drug was developed with the aim of reducing the incidence of SCC, which was considered as side effect sulfapyridine in sulfasalazine. Olsalazine has been used with success, although the development of CCM has sometimes been reported. The dose of the immunosuppressive agent olsalazine is half the dose of sulfasalazine because it contains twice the amount active substance.

Balsalazide... It is a new pro-drug (4-aminobenzoyl-p-alanine-mesalamine). Balsalazide is activated by the same mechanism as sulfasalazine, but its safety and efficacy in young patients has not been studied.

Mesalazine... It is 5-ASA without other molecules that make up its analogs (can also be called mesalamine). For the treatment of colitis in humans, there is dosage form an immunosuppressant with a slow release of the active substance due to the presence of a membrane that dissolves in the intestine. Premature release in the small intestine is likely to be absorbed and nephrotoxic, but at pH in the human intestine most of 5-ASK becomes active precisely in its thick section. The safety of oral immunosuppressive drugs is unknown. Mesalazine enemas and suppositories are safe, but these forms of immunosuppressive administration have not been widely used.

Immunosuppressant cyclosporine

Cyclosporin A (CsA) is an effective immunosuppressive agent, one of nine cyclosporins isolated from fungi, is a powerful immunosuppressive drug used in organ transplantation and certain (auto) immune diseases in humans. May be nephrotoxic, so close monitoring of the serum concentration of the immunosuppressive agent is ideally recommended.

In gastroenterology, CsA was used as monotherapy in the treatment of anal furunculosis. The activity of the immunosuppressant can be enhanced by the simultaneous administration of ketoconazole, which suppresses its metabolism in the liver. In preliminary studies, the efficacy of cyclosporine for IBD has been inconsistent and cannot yet be recommended.

Mycophenolate mofetil

Mycophenolate mofetil is an immunomodulator that is used to prevent transplant rejection. The drug is an antimetabolite that suppresses the synthesis of purines in lymphocytes. There is a report (Dewey et. Al. 2000) about successful treatment myasthenia gravis with the help of this tool, including focal myasthenia gravis of the esophagus in severe form. There is no evidence of widespread use of this immunosuppressant, and cases of spontaneous recovery may give a false impression of its effectiveness.

Immunosuppressant tacrolimus

Tacrolimus is a macrolide class derived from Streptomyces that suppresses T cell activation and is used as an immunosuppressive agent to prevent transplant rejection. In children, it is more toxic than cyclosporine, but can be used topically to treat furunculosis.

New types of immunosuppressants

Pentoxifylline (oxpentifylline), thromboxane synthesis inhibitors, leukotriene antagonists, thalidomide and cytokine modulators have been shown to have some effect in humans in inflammatory bowel disease (IBD). Their effectiveness as immunosuppressants is still poorly understood. Infliximab is a monoclonal antibody directed against tumor necrosis factor A and is used to treat IBD in humans.

The following basic rules for immunosuppressive therapy have been adopted:

· Reliability of the diagnosis;

· Availability of indications;

· Lack of contraindications;

· Appropriate qualifications of a doctor;

· Consent of the patient;

· Systematic observation of the patient during treatment.

Specific indications for immunosuppressive therapy of these diseases are their severe, life-threatening or disabling course, especially with damage to the kidneys and the central nervous system, as well as with resistance to prolonged steroid therapy, steroid dependence with the need to constantly take too high maintenance doses of glucocorticosteroids, contraindications to their appointment or poor drug tolerance.

Immunosuppressive therapy allows you to reduce the daily dose of glucocorticosteroids to 10-15 mg of prednisolone, or even abandon their use. Doses of immunosuppressants should be small to moderate, and treatment should be continuous and prolonged. When remission of the disease is achieved, the patient continues taking the drug in the minimum maintenance dose for a long time (up to 2 years).

Contraindications to the appointment of immunosuppressants are concomitant infections, including latent and chronic focal, pregnancy, lactation, hematopoiesis disorders (hemocytopenia).

Adverse side effects common to all immunosuppressants include bone marrow suppression, development of infections, teratogenicity, and carcinogenicity. Based on the severity of side effects, the following sequence of use of immunosuppressants is recommended: azathioprine, methotrexate, cyclophosphamide.

Allergic reactions Type I - anaphylactic - are associated with overproduction of IgE in response to a specific antigen-allergen, which is due to insufficient function of the corresponding T-suppressors. Pathological consequences are determined by the ability of IgE to firmly bind to the corresponding Fc-receptors of mast cells and basophils, on the membrane of which an antigen-antibody reaction occurs, which results in the release of biologically active substances from cells - histamine, serotonin, heparin, etc. These substances act on cells - targets of smooth muscles, blood vessels and other organs, in which receptors for each biologically active substance are located.

Therefore, pharmacological correction of immunopathogenesis in type I allergic reactions is achieved by using any means that suppress the immune response, proliferation and differentiation of antibody-forming cells, means that inhibit the synthesis of antibodies, and especially IgE. In the later stages of the development of anaphylactic reactions, the use of antihistamines becomes decisive.

Allergic reactions of type II - cytotoxic - are associated with the production of antibodies against antigens that make up the membrane of the body's cells. Pathological consequences are due to the fact that the antigen-antibody reaction occurring on the cell membrane activates the complement system, which leads to cell lysis.

Possibilities of interfering with immunopathogenesis in type II allergic reactions also include antiproliferative drugs and other means of suppressing the humoral immune response. In addition, drugs that inhibit the activation of the complement system, inhibitors of enzymes of this system are effective.

Allergic reactions of type III - immunocomplex - are associated with the accumulation of antigen-antibody complexes in the bloodstream and tissues, which are not excreted from the body due to their physicochemical characteristics or due to the lack of phagocytic cells. Long-term persistent immune complexes can cause a number of pathological consequences, including those associated with the activation of the complement system.

The prevention of the accumulation of immune complexes in this kind of pathologies is achieved by the use of immunosuppressive drugs that inhibit the synthesis of antibodies. In addition, it is advisable to prescribe anti-inflammatory drugs and enzyme inhibitors to stop inflammatory reactions induced by immune complexes.

Allergic reactions of type IV - cellular reactions of delayed-type hypersensitivity (HRT) - differ from allergic reactions of the first three types by the main mechanisms of immunopathogenesis. At the same time, sensitization is associated with the predominant proliferation of a clone of T-lymphocytes carrying recognition receptors specific for a given antigen. The activation of these T-lymphocytes-effectors upon repeated contact with the antigen has immunopathological consequences. Activation is accompanied by the synthesis and secretion of cellular mediators, lymphokines, which mobilize to the focus of immune inflammation and activate macrophages. In the focus of immune inflammation, damage to the cells and tissues of the body occurs due to the activity of T-effectors, T-killers and macrophages secreting lysosomal enzymes.

Allergic reactions of type IV are reduced by antiproliferative drugs that can predominantly suppress the proliferation of T-lymphocytes, as well as drugs that inhibit the functions of T-lymphocytes and macrophages.

Autoimmune processes are conditions in which the production of autoantibodies or the accumulation of a clone of sensitized lymphocytes to the antigens of the body's own tissues occurs. When autoimmune mechanisms cause disturbances in the structure and functions of organs and tissues, they talk about autoimmune aggression and autoimmune diseases. The emergence of autoimmune processes is associated, as a rule, with the loss of natural immunological tolerance. Lack of natural immunological tolerance can be a consequence of dysfunction or the ratio of Tc deficiency or excessive Tx activity. In immunopathogenesis autoimmune diseases the main mechanisms are the mechanisms of allergies of types II, III and IV and their various combinations. Therefore, pharmacological regulation of immunopathogenesis in autoimmune diseases is determined by the predominance of types of immunopathological mechanisms of humoral or cellular and the main direction of action of immunosuppressive drugs.

In any case, it is advisable to use drugs with immunosuppressive action, which is due to inhibition of proliferation and differentiation of an autoaggressive clone of lymphocytes or arises from inhibition of the functions of mature immunocompetent cells. When detecting dysfunctions or ratios of immunoregulatory T-lymphocytes, it becomes necessary to selectively suppress T-helpers or selectively activate T-suppressors. In addition, it is necessary to use the entire arsenal of drugs with anti-inflammatory action, enzyme inhibitors and other agents aimed at reducing the intensity of the effector reactions of immune inflammation.

The choice of means of immunosuppressive therapy and their combinations is based on the data of clinical and immunological examination of patients, with the obligatory consideration of the period, stage of the process, severity and prevailing immunopathological mechanisms.

When choosing a cytostatic agent for immunosuppression, one should take into account the toxicity of the drug, since almost all drugs in a dose exceeding individual tolerance severely damage the bone marrow. At first, it is advisable to prescribe an agent acting on a certain phase of the cell cycle to suppress cell division (synchronization), and then an active lymphotropic drug is applied at the optimal time period, regardless of the division phase. In this case, you can use smaller doses of the selected funds and achieve better effect... The choice of a cytostatic drug is based on the fact that different agents have different mechanisms of action.

Compared with treatment with glucocorticosteroids, immunosuppressive therapy with cytostatics has some features: with a selected dose, more dangerous side effects and complications can occur more often and more suddenly. Moreover, this treatment takes longer to achieve clinical effect. This form of treatment is relatively new.

The duration of immunosuppressive therapy depends on many factors: the nature of the disease, the tolerance of the drugs used and their side effects, the success of treatment, etc. The maintenance dose should be minimal, although this tactic often leads to relapse of the disease, increased symptoms or worsening of the general condition.

Given the nature of the action of immunosuppressive drugs, extra care must be observed in the following situations:

the presence of infection, since during immunosuppressive therapy, the course of infections is aggravated;

forthcoming surgical intervention (including kidney transplant), the risk of which increases with immunosuppressive therapy;

insufficient bone marrow function (the cytostatic effect of immunosuppressants is dangerous);

immunodeficiencies.

The age of the patients should also be taken into account. In children and adolescents, the indications are approached more strictly because of the possible mutagenic, teratogenic and carcinogenic effects.

It must be remembered that with immunosuppressive therapy, the risk of developing infectious complications increases. The danger is viral and fungal infectionsas well as septic processes. They develop in the presence of defects in the systems of the cellular and humoral response in violation of leukopoiesis.

Immunosuppressive drugs (immunosuppressants) are drugs of various pharmacological and chemical groups that suppress the body's immunological reactions. It is prescribed for the treatment of severe autoimmune diseases and suppression of the graft rejection reaction, as well as for weakening inflammatory processes unclear etiology. Some immunosuppressants are part of the arsenal of anticancer drugs.

Classification of immunosuppressive drugs:

1. Antimetabolites: mercaptopurine, azathioprine, methotrexate, brequinar, mycophenolate mofetil, allopurinol, etc .;

2. Alkylating compounds: cyclophosphamide, chlorobutin, etc.

3. Antibiotics cyclosporin A, tacrolimus (FK 506), chloramphenicol, antineoplastic (actinomycin: dactinomycin), etc .;

4. Alkaloids: vincristine, vinblastine;

5. GCS: hydrocortisone, prednisolone, dexamethasone, etc .;

6. Antibodies: anti-lymphocyte globulin (ALG), antithymocyte globulin (ATG), monoclonal antibodies (OKT-3, Simulect, Zenapax), etc .;

7. Derivatives of various groups of NSAIDs ( acetylsalicylic acid, paracetamol, diclofenac sodium, naproxen, mefenamic acid, etc.), Enzyme preparations (asparaginase), 4-aminoquinoline derivatives (delagil), heparin, aminocaproic acid, gold preparations, penicillamine, etc.

Among modern methods suppression of immunity (appointment specific antigens and antibodies, anti-lymphocyte and antimonocytic sera, X-ray irradiation, removal of lymphoid tissue), preference is given to the appointment of immunosuppressants both in the form of mototherapy and in combination with other drugs.

Pharmacodynamics. The action of immunosuppressants on cells of the immune competent system is non-specific. Their influence is directed to the fundamental mechanisms of cell division and key stages of protein biosynthesis in various cells, including immunocompetent ones. Despite the universal cytostatic properties, immunosuppressants differ in their direction of action at certain stages of immunogenesis, which is important to consider when choosing a drug that is adequate for each specific situation (Fig. 15.1). The pharmacology of individual groups is given in section. "Antineoplastic agents".

All currently known immunosuppressants exhibit different activity. NSAIDs, heparin, gold preparations, penicillamine, chloroquine and some others have a mild immunosuppressive effect, and therefore they are often called "small" immunosuppressants. Moderate immunosuppressive effect is shown by medium doses of GCS. There are powerful cytostatics (drugs used as antineoplastic), in particular antimetabolites and alkylating compounds, antibodies, antibiotics, etc., which are considered real immunosuppressants, or "large" immunosuppressants.

Figure: 15.1. Imunosuppressive application points

Indications. For the choice of immunosuppressants, a general guideline can be a classification, in which 3 main groups are distinguished:

I group combines compounds that exhibit the most pronounced immunosuppressive effect when administered before antigenic stimulation or simultaneously with it. Possible points of their influence are the mechanisms of recognition, processing of AG and information transfer. This group includes some alkylating compounds, GCS, etc.

II group drugs have an immunosuppressive effect when administered 1-2 days after antigenic stimulation, because at this time the proliferative phase of the immune response is inhibited. When they are introduced into the body in hypertension or more than a week after it, the immunosuppressive effect does not develop. This group includes antimetabolites, alkaloids, actinomycin, and most alkylating compounds.

III group contains compounds that are effective both before and after antigenic exposure. They are usually multiple points of application in the immune response chain. This group includes, for example, ALG, ATG, cyclophosphamide, asparaginase.

Following this classification, Group I drugs should be prescribed for organ transplantation when it is necessary to achieve immunotolerance in order to prevent the development of a graft-versus-host reaction. In case of autoimmune diseases, when it is necessary to slow down proliferative processes, in the case of prolonged sensitization with an antigen of the "chain reaction" type, it is advisable to use drugs of groups II or IN.

The range of drugs to be used and dosage regimens depend on the specific disorder. Table 15.3 summarizes some aspects clinical use immunosuppressive agents.

Table 15.3

Indications for the appointment of immunosuppressants

Practical experience shows that immunosuppressants easily suppress the primary immune response, more difficult - the secondary. In this regard, immunosuppressants are recommended to be prescribed at the very beginning of the disease. Since most of the true immune suppressors have a limited effect on the effector mechanisms of the immune response, glucocorticosteroids or NSAIDs are used concurrently with them, which reduce the intensity of the effector reactions.

It should be noted that although some drugs used in cancer chemotherapy are also used for immunosuppression, the treatment of these categories of patients is based on different principles. The difference in the nature and kinetics of proliferation of tumor and immune cells allows for greater selectivity of the toxic effect of the drug in relation to an unwanted immune clone in autoimmune diseases than in the treatment of a tumor. For immunosuppression, cytostatics are used daily in low doses. The same drugs for cancer chemotherapy are prescribed intermittently in large doses, causing the restoration of immunity between "shock" courses.

When prescribing immunosuppressants, it should be remembered that a number of drugs (for example, azathioprine, mercaptopurine, dactinomycin, cyclophosphamide, etc.) with a dose less than the therapeutic one can stimulate certain parts of the immune system and, thus, instead of an immunosuppressive action, produce an immunostimulating effect (effect " Therefore, immunosuppressants should be prescribed in such a dose that provides a pronounced inhibition of immunity (proliferation). Treatment, as a rule, lasts from several weeks to a year or more. Due to the withdrawal of the drug, relapses or worsening of the course of the disease are possible. When a therapeutic effect is achieved. you should switch to a maintenance dose, which is 2-3 times lower.

It is not yet possible to influence isolated cell groups and conduct selective immunotherapy, therefore, most often the greatest therapeutic effect causes combined use immunosuppressive agents. Combined treatment allows to reduce the doses of the selected drugs by 2-4 times against the usual ones and not only achieve a better effect, but also a better tolerance of drugs.

Side effect. Immunosuppressants are highly toxic. So, if the use of immunosuppressive agents in organ transplantation is vital, then the question of the advisability of prescribing them for the treatment of autoimmune diseases should be decided individually each time. Immunosuppressive drugs should be prescribed only when the possibilities of other therapy have been exhausted and the chances of success outweigh the risk of immunosuppression.

Complications caused by immunosuppressive drugs are extremely dangerous and must be taken into account when deciding whether to conduct immunosuppressive therapy. Side effects can occur early and late after the appointment of immunosuppressive therapy.

On early dates more often such complications are observed.

1. Dysfunction of the bone marrow. This complication is due to the low selectivity of immunosuppressants, which affect all cells with high mitotic activity. The bone marrow is affected in almost all patients with long-term therapy with the appointment of high doses. Hematopoietic disorders are especially common during treatment with methotrexate and alkylating compounds. They are rare with medium doses of azathioprine and actinomycin.

2. Dysfunction of the gastrointestinal tract. When using immunosuppressive drugs, nausea, vomiting, and diarrhea are often observed. Sometimes these disorders disappear on their own even with prolonged treatment. In some cases, gastrointestinal bleeding occurs, especially with methotrexate. To remove or reduce these side effects, it is recommended to administer the drugs parenterally.

3. Propensity to infections. The greatest danger for the occurrence of infections is observed when combining an immunosuppressant with corticosteroids. It should be noted that sometimes even against this background, severe fungal and bacterial diseases can occur. When conducting preventive vaccinations immunosuppressive therapy is canceled.

4. Allergic reactions. Most often, they occur with the introduction of immunosuppressants from the group of antibodies and manifest themselves in the form of skin lesions, drug fever, eosinophilia.

Disorders that manifest themselves at a later date have not yet been sufficiently studied. they should be distinguished both from the manifestations of the disease itself and from the disorders arising from the intake of immunosuppressants:

1. Carcinogenic effect. Cytostatic drugs can have an oncogenic effect, since they lead to changes in DNA and, at the same time, in the genetic code. At the same time, immunological control over the induction and growth of tumor cells can be blocked. Malignant tumors (lymphosarcomas) in patients who are subject to immunosuppression in order to suppress the transplant rejection reaction, appear 100 times more often than in the rest of the population.

2. Influence on reproductive function and teratogenic effect. Immunosuppressive therapy can cause infertility in women and men. This complication is noted from 10 to 70% of cases. Data on the teratogenic effect of drugs are not unambiguous. At the very least, it is recommended that you avoid pregnancy for at least 6 months after the end of your treatment.

3. Immunosuppressants cause growth retardation in children.

4. Other complications (pulmonary fibrosis, hyperpigmentation syndrome, hemorrhagic cystitis, alopecia). When using antimetabolites, liver dysfunctions are observed. Vinca alkaloids are neurotoxic.

Rational immunosuppressive therapy is possible only under the condition of immunological control and constant medical supervision.

Contraindications. Since immune diseases very often have poor prognosis, contraindications for immunosuppressive therapy are relative. You should be especially careful in such situations: the presence of infection, insufficient bone marrow function, decreased renal function (danger of cumulation), pregnancy, impaired liver function, kidney function, organic disorders in the immune system, oncological diseases. Should be approached carefully to the appointment of immunosuppressants for children and adolescents.

• Previously, the terms "immunosuppression" and "immunosuppressants" were used. However, today it is generally accepted to correctly define "suppression of immunity" as "immunosuppression" ("immunosuppressants").
• Medicines, designated in this section, do not have independent clinical significance, they are prescribed in complex immunosuppressive therapy in combination with other immunosuppressants that belong to the 1st to 5th groups.

Immunosuppressants - drugs that suppress the immune response. These include corticosteroids, azathioprine, cyclosporine, and aminosalicylic acid derivatives.

Are applied in medical practice with autoimmune and allergic diseases, to create transplant immunity, etc.

Classification immunosuppressants

• Glucorticosteroids: prednisone, dexamethasone
• Kalydineurin inhibitors: cyclosporin, tacrolimus
• Cytostatics: sirolimus (rapamycin), azathioprine, methotrexate, thalidomide, cyclophosphamide
• Monoclonal antibodies: muromonab-SIS, daclizumab, basiliximab, infliximab, etanercept
• Antihistamines

Prednisolone (and methylprednisolone) is the immunosuppressive agent of choice for immunosuppressive therapy in adults and children. Dexamethasone has a similar immunosuppressive effect in equivalent doses; however, due to the adverse effect on the activity of the enzymes of the brush border, its use is not recommended.

Azathioprine /In humans, this immunosuppressive drug is ineffective unless the patient is already on steroids. It takes 24 weeks to achieve the desired result, and premature discontinuation of treatment may lead to relapse. In most cases, azathioprine is not used as a first-line immunosuppressive drug, but as a means to reduce the dose of steroids.

The toxic effect of an immunosuppressant on the bone marrow (neutropenia, anemia) is rare, but in some patients it can develop within a few weeks.

Children with inflammatory disease are more likely to be shown other immunosuppressants, such as chlorambucil or cyclophosphamide, if they do not have the effect of prednisone monotherapy.

Olsalazin. It consists of two 5-ASA molecules linked by a diazo bond and re-released under the influence of intestinal bacteria. An immunosuppressive drug was developed to reduce the incidence of SBS, which was considered a side effect of sulfapyridine in sulfasalazine. Olsalazine has been used with success, although the development of CCM has sometimes been reported.

Balsalazide... It is a new prodrug (4-aminobenzoyl-p-alanine-mesalamine). Balsalazide is activated by the same mechanism as sulfasalazine, but its safety and efficacy in young patients has not been studied.

Mesalazine... It is 5-ASA without other molecules that make up its analogs (can also be called mesalamine). For the treatment of colitis in humans, there is a dosage form of an immunosuppressive agent with a slow release of the active substance due to the presence of a membrane that dissolves in the intestine. Premature release in the small intestine is likely to be absorbed and have a nephrotoxic effect, but at pH in the human intestine, most of the 5-ASA becomes active in the large intestine. The safety of oral immunosuppressive drugs is unknown. Mesalazine enemas and suppositories are safe, but these forms of immunosuppressive administration have not been widely used.

Immunosuppressant cyclosporine

Cyclosporin A(CsA) is an effective immunosuppressive agent, one of nine cyclosporins isolated from fungi, is a powerful immunosuppressive drug used in organ transplantation and certain (auto) immune diseases in humans. May be nephrotoxic, so close monitoring of the serum concentration of the immunosuppressive agent is ideally recommended.

In gastroenterology, CsA was used as monotherapy in the treatment of anal furunculosis. The activity of the immunosuppressant can be enhanced by the simultaneous administration of ketoconazole, which suppresses its metabolism in the liver. In preliminary studies, the efficacy of cyclosporine for IBD has been inconsistent and cannot yet be recommended.

Mycophenolate mofetil is an immunomodulator that is used to prevent transplant rejection. The drug is an antimetabolite that suppresses the synthesis of purines in lymphocytes.

Tacrolimus is an antibiotic of the macrolide class, obtained from Streptomyces, the drug suppresses the activation of T cells and is used as an immunosuppressive agent to prevent transplant rejection. In children, it is more toxic than cyclosporine, but can be used topically to treat furunculosis.