Drug immunosuppression. Immunosuppressive drugs

Immunosuppression refers to the suppression of the immune response by the normal immune system to antigenic stimulation, either intentionally or as a negative effect of a therapeutic agent such as anticancer chemotherapy. In this article we will look at what immunosuppression is.

It can also happen when the immune system is compromised, such as systemic lupus erythematosus or diabetes.

What is immunosuppression

Many people who receive organ transplants take medications to suppress the immune system so the body does not reject the organ. These "immunosuppressants" make the immune system less able to detect and destroy cancer cells or fight infections that cause cancer. HIV infection also weakens the immune system and increases the risk of developing certain types of cancer.

Research has shown that transplant recipients are at increased risk for a wide variety of cancers. Some of these cancers can be caused by infectious agents, while others are not. The four most common cancers among transplant recipients, which occur more frequently in these individuals than in the general population, are non-Hodgkin's lymphoma and cancer of the lung, kidney, and liver. It can be caused by Epstein-Barr virus infection and liver cancer due to chronic infection with hepatitis B and hepatitis C viruses. Typically, lung and kidney cancer are associated with infection.

Causes of immunosuppression

Causes of immune suppression can be classified as:

Systemic diseases:

Diabetes.
Chronic alcoholism.
Kidney or liver failure.
Autoimmune disorders such as systemic lupus erythematosus or rheumatoid arthritis.
CNS infection.

Immunosuppressive treatment.

Corticosteroids.
Polyclonal immunoglobulins such as antilymphocyte globulin and monoclonal immunoglobulins such as daclizumab (both monoclonal and polyclonal immunoglobulins target only cellular immunity by depleting lymphocytes).
Antimetabolites:

Calcineurin inhibitors, which prevent T cell transcription, such as cyclosporine.
Rapamycins, which block mTOR kinase pathways in lymphocytes, such as everolimus.
Mitosis inhibitors that block purine metabolism, such as azathioprine.

Ionizing radiation.
Biological alkylating agents such as cyclophosphamide and chlorambucil.

Indications for immunosuppression

Immunosuppression is clinically indicated in three different situations:

The period after transplantation to prevent graft rejection and graft-versus-host disease.
Having an autoimmune or hypersensitivity disorder that causes self-antigens to be identified as foreign targets of immune attack, leading to tissue and organ damage and
The occurrence of lymphoproliferative disorders.

Immunosuppressants are drugs that are used to intentionally suppress the production and activity of immune cells. However, these drugs also suppress the normal immune response to infectious agents and even to the appearance of malignant or pre-cancerous changes in cells.

Chemotherapy drugs also reduce the normal immune response.

Normal immune response

The immune response has two phases, namely the inductive and productive phase. In the inductive phase, small lymphocytes interact with a foreign antigen. In the productive phase, stimulated cells multiply and also stimulate more cells and also produce antibodies from plasma cells depending on the nature of the stimulated cells.

Most immunosuppressants work by preventing the proliferation of immune cells. Thus, they block the primary immune response. A secondary or anamnestic response, which depends on already formed memory cells, is more difficult to block.

Symptoms and signs of immunosuppression

In general, immunocompromised patients have altered communication with foreign antigens, including pathogenic microbes. This leads to the following clinically significant changes:

Opportunistic infections with other harmless organisms. These include:
Viral infections such as herpes infections, shingles,
Bacterial infections such as Staphylococcus aureus,
Fungal infections such as aspergillosis,
Rapid progress of infections
Changes in usual signs and symptoms of infection, including laboratory parameters resulting in an atypical presentation of the infection, and
Malignancies, such as tumors in transplant recipients, or secondary malignancies in patients receiving chemotherapy for leukemia.

In addition to systemic infection, the general health of these patients is weakened by many factors, such as:

The main disease
Adverse drug reactions
Malnutrition and
Side effects of various medical procedures.

Diagnosis and treatment

Immunosuppression is diagnosed using immune function tests such as:

Cellular immunity tests, including:

Phagocytic functional tests such as nitrobulin tetrazolium reduction.
Skin testing to delay hypersensitivity reaction,
T - cell activation tests such as transformation after exposure to a mitogen, lymphokine assays such as migration inhibitory factor.

Tests for humoral immunity such as:

Serum immunoglobulin tests, such as radial immunodiffusion and serum electrophoresis,
Specific antibodies such as agglutination, radioimmunoassay or enzyme immunoassay and
Quantitative determination of B cells.

Treatment is aimed at preventing and treating infections as early and aggressively as possible.

Drugs used for allergic hypersensitivity not due to IgE

1. Immunosuppressants -suppress the immunological and pathophysiological stage of allergic reactions

2. Anti-inflammatory drugs -suppress the pathophysiological stage of allergic reactions - the actual clinical manifestations

Immunosuppressants (immunosuppressants) - drugs that suppress the body's immune response.

Immunosuppressants are used:

1) for autoimmune diseases,

2) to prevent graft rejection (RTR) during organ and tissue transplantation.

Autoimmune diseases - diseases caused by autoantibodies (ATs to self-antigens) and cytotoxic T-lymphocytes directed against self-antigens. For example, rheumatic diseases (RD), which include rheumatism; rheumatoid arthritis (RA); systemic lupus erythematosus (SLE), systemic vasculitis; Sjögren's disease; Bechterew's disease, etc. The pathogenetic basis of RB is the predominant damage to connective tissue. Autoimmune diseases also include ulcerative colitis, Crohn's disease, glomerulonephritis, etc.

Immunosuppressants for autoimmune diseases are means of basic (pathogenetic) therapy, that is drugs that slow down the progression of the disease.Mechanism d-i: suppress pathological activation of the immune system, which prevents tissue damage and the development of inflammation.

Based on the strength of suppressing immune reactions, immunosuppressants are divided into “large” and “small”.

Classification of immunosuppressants

I. “Big” immunosuppressants

1. Cytostatics:

a) alkylating agents: cyclophosphamide

b) antimetabolites: azathioprine

methotrexate

2. Glucocorticoids: prednisolone, etc.

3. Agents that inhibit the formation or action of IL-2:

a) antibiotics: cyclosporine

tacrolimus, rapamycin

b) MAbs to IL-2 receptors:

basiliximab, daclizumab.

4. Antibody preparations:

a) Polyclonal antibodies - antithymocyte immunoglobulin

b) MAT to TNF-alpha – infliximab and etc.

II. "Small" immunosuppressants

1. 4-Aminoquinoline derivatives

2. D-penicillamine ,

3. Gold preparations

"Big" immunosuppressants

Used to prevent transplant rejection, as well as for autoimmune diseases.

Cytostatics

Cytostatics have a particularly pronounced inhibitory effect on rapidly dividing cells: bone marrow cells, gastrointestinal epithelium, gonad cells, tumor cells. Cytostatics are used mainly for tumor diseases, some as immunosuppressants.

Cytostatics used as immunosuppressants are presented 1) alkylating agents and 2) antimetabolites.

Alkylating agents form a covalent alkyl bond (crosslink) between DNA strands and thus disrupt cell division.

Of the drugs in this group, they are used as an immunosuppressant. cyclophosphamide(cyclophosphamide). The drug is prescribed intravenously. The active metabolite of cyclophosphamide inhibits lymphoid and myeloid hematopoiesis. Suppresses the proliferation of B and T lymphocytes and their precursors.

Cyclophosphamide is used for autoimmune diseases (rheumatoid arthritis, systemic lupus erythematosus, etc.).

By inhibiting cellular immunity, cyclophosphamide effectively prevents graft rejection during organ and tissue transplantation. However, by suppressing myeloid hematopoiesis and humoral immunity, cyclophosphamide can cause leukopenia, anemia, and thrombocytopenia. Significantly reduces the body's resistance to infections.

Cyclophosphamide is used as an antitumor agent for lung cancer, breast cancer, lymphogranulomatosis, and lymphocytic leukemia.

Side effects of cyclophosphamide: bone marrow suppression (leukopenia, anemia, thrombocytopenia), interstitial pulmonary fibrosis, hemorrhagic cystitis, amenorrhea, azoospermia, nausea, vomiting, alopecia.

To antimetabolites include azathioprine and methotrexate.

Azathioprine in the body it turns into 6-mercaptopurine, which disrupts purine metabolism and thus interferes with DNA synthesis. Since this transformation occurs largely in the lymphoid system, the drug inhibits lymphoid hematopoiesis more and myeloid hematopoiesis less. Under the influence of azathioprine, cellular immunity is inhibited to a greater extent than humoral immunity. In addition to its immunosuppressive properties, azathioprine has anti-inflammatory properties.

To prevent transplant rejection, the drug is administered intravenously and then continued orally. Azathioprine is also used for autoimmune diseases (rheumatoid arthritis, systemic lupus erythematosus, dermatomyositis, myasthenia gravis). In rheumatoid arthritis, the therapeutic effect of azathioprine appears after 2-3 months of systematic administration.

Side effects of azathioprine: leukopenia, thrombocytopenia, decreased resistance to infections, dyspepsia, liver dysfunction, skin rashes.

Methotrexate interferes with the metabolism of folic acid (inhibits dihydrofolate reductase) and disrupts the formation of purine and pyrimidine bases and, accordingly, DNA synthesis. It has immunosuppressive, anti-inflammatory and anti-blastoma properties. Used for rheumatoid arthritis and tumor diseases.

Reduces the proliferation and activity of T-lymphocytes, the activity of macrophages, the release of IL-1 and TNF-α (tumor necrosis factor - alpha).

In small doses, methotrexate has an anti-inflammatory effect, which is explained by the release of adenosine at the site of inflammation, which reduces the levels of IL-1 and TNF-α, and reduces the production of collagenase, stromelysin and oxygen toxic radicals.

The effect of methotrexate develops several weeks after the start of treatment and reaches a maximum after 4 months.

Glucocorticoids

Glucocorticoids - hydrocortisone, prednisolone, dexamethasone and others (see section “Glucocorticosteroid preparations”) inhibit the expression of cytokine genes. The main “target” of the immunosuppressive action of glucocorticoids is macrophages. Glucocorticoids reduce the phagocytic activity of macrophages, their ability to process and present antigen, the production of IL-1 and IL-2, TNF-α (tumor necrosis factor), interferon-γ, reduce Th activity, and disrupt the proliferation of T and B lymphocytes (Fig. 3.5 and section “The concept of the immune response...”).

As immunosuppressants, glucocorticoids are used for autoimmune diseases (rheumatoid arthritis, systemic lupus erythematosus, dermatomyositis, ankylosing spondylitis, eczema), and also as adjuncts for organ and tissue transplantation.

Basic side effects of glucocorticoids: ulcerogenic effect, osteoporosis, secondary infections (bacterial, viral, fungal), cataracts, etc.

Fig.3.5. Elements of cellular and humoral immune response.

Note: APC - antigen-presenting cell, B - B-lymphocyte, T - T-lymphocyte, P - plasma cells, Th - T-helper cells, Tc - T-killer cells, IFN-γ - gamma interferon, MPH - macrophage, TNF-α - tumor necrosis factor, IL 1, 2, 4 – interleukins 1, 2, 4.

Agents that inhibit the formation or action of interleukin-2

Interleukin-2 (IL-2) is produced by Th1 and stimulates the proliferation and differentiation of T lymphocytes. Under the influence of IL-2, the formation of Tc-lymphocytes increases, which suppress the vital activity of cells infected with viruses, tumor cells and cells of transplanted foreign tissue. Inhibition of the formation or action of IL-2 reduces cellular immunity and, in particular, prevents the rejection of transplanted tissue. In this case, myeloid hematopoiesis remains virtually unchanged, humoral immunity is slightly suppressed, and problems with secondary infections do not arise.

Cyclosporine(sandimmune) interacts with the intracellular Th1 protein cyclophyllin. The cyclosporine-cyclophylline complex inhibits the enzyme calcineurin, which activates the production of IL-2. As a result, the proliferation of T-lymphocytes and the formation of T-lymphocytes are inhibited.

The drug is administered intravenously and then prescribed orally to prevent graft rejection during kidney, heart, and liver transplants. In addition, cyclosporine is used for autoimmune diseases (rheumatoid arthritis, psoriasis, myasthenia gravis, ulcerative colitis, etc.).

Side effects cyclosporine: severe renal dysfunction with a slight excess of the therapeutic concentration of cyclosporine in the blood plasma (continuous monitoring of drug concentration is required), liver dysfunction, increased blood pressure, hyperkalemia, hyperuricemia, dyspepsia, anorexia, etc.

Tacrolimus(FK-506), like cyclosporine, reduces the activity of calcineurin in Th1. As a result, the formation of IL-2 and, accordingly, the proliferation of T-lymphocytes decreases.

The drug is used for liver, heart, and kidney transplantation. Side effects similar to the side effects of cyclosporine.

Rapamycin(sirolimus) interferes with the action of IL-2. Relatively little effect on kidney function and blood pressure. Used for organ and tissue transplantation.

Basiliximab(simulect) and daclizumab- preparations of chimeric mouse-human MAbs (monoclonal antibodies) to IL-2 receptors. Suppress IL-2-dependent proliferation of T-lymphocytes, inhibits the synthesis of antibodies and the immune response to antigens.

Administered intravenously to prevent transplant rejection. Prescribed in combination with cyclosporine and glucocorticoids. The following may cause side effects: difficulty breathing, fever, hypertension or hypotension, tachycardia, swelling in the legs, pulmonary edema, tremor, nausea, infectious complications, hyperglycemia, arthralgia, myalgia, headache, insomnia, dyspepsia, diarrhea.

Antibody preparations

Antithymocyte immunoglobulin(IgG) is obtained by immunizing horses or rabbits with human T lymphocytes. The action of such drugs reduces the activity of T-lymphocytes and thus selectively inhibits cellular immunity. The drugs are administered intravenously or intramuscularly to prevent rejection during heart, kidney, and liver transplantation. Side effects: allergic reactions, neutropenia, thrombocytopenia.

Infliximab(Remicade) is a preparation of chimeric mouse-human monoclonal antibodies to TNF-α (TNF-alpha - tumor necrosis factor), which is involved in autoimmune processes. In addition to rheumatoid arthritis, the drug is used for systemic lupus erythematosus and ankylosing spondylitis; administered intravenously.

Etanercept- blocks receptors for TNF-α. and thus interferes with the action of TNF-α. The drug is injected under the skin 2 times a week. After 3 months, a significant improvement in the condition of patients with rheumatoid arthritis is noted.

When using drugs that interfere with the activity or action of TNF-α, resistance to infectious diseases is reduced (coccal, pneumocystis, and fungal infections are possible).

“Minor” immunosuppressants (anti-rheumatoid drugs) :

1. 4-Aminoquinoline derivatives (chloroquine, hydroxychloroquine),

2. D-penicillamine ,

3. Gold preparations (sodium aurothiomalate, auranofin, etc.).

4. Other drugs( leflunomide, anakinra)

Along with the “big” immunosuppressants, they are used as basic drugs mainly for rheumatoid arthritis, less often for other rheumatic diseases.

Rheumatoid arthritis (RA) is an autoimmune disease; develops over several years and leads to osteoarthritis, which affects not only the cartilage, but also the bone tissue of the joints. In RA, the content of interleukin-1 (IL-1) and tumor necrosis factor alpha (TNF-α) increases in the synovial tissue of the joints, which stimulate the synthesis of proteinases (collagenase, stromelysins) by fibroblasts and chondrocytes, causing degradation of the cartilage tissue of the joints, and also activate osteoclasts.

NSAIDs and glucocorticoids temporarily improve the quality of life of patients with rheumatoid arthritis (reduce pain, joint swelling), but do not slow down the development of the disease. When used systematically, NSAIDs even accelerate the development of rheumatoid arthritis (they inhibit the production of prostaglandins E and I 2, which reduce the formation of IL-1).

The first drugs that slowed the development of rheumatoid arthritis were gold drugs, D-penicillamine and antimalarials - chloroquine and hydroxychloroquine. These drugs came to be called disease-modifying antirheumatoid drugs.

Since the therapeutic effect of these drugs, when taken systematically, does not appear immediately (after several months), these drugs began to be called slow-acting. Domestic clinicians call them basic drugs

Hydroxychloroquine– has anti-inflammatory and immunosuppressive effects. The mechanism of antirheumatoid action is not clear enough. The drug is believed to reduce the ability of macrophages to release IL-1 and TNF-α.

When administered systematically orally, hydroxychloroquine begins to have an antirheumatoid effect after about 1-2 months. Compared to gold and D-penicillamine preparations, they are less toxic. Possible nausea, headache, visual impairment (retinopathy), proteinuria, dermatitis.

D-Penicillamine- dimethylcysteine (one of the hydrolysis products of penicillin). Forms chelate compounds with Cu, Hg, Pb, Zn. Due to its ability to bind Cu, it is used for Wilson-Konovalov disease (hepatocerebral dystrophy). It is also used as an antidote for poisoning with Hg and Pb compounds.

In rheumatoid arthritis, D-penicillamine, when systematically administered orally, has a pronounced therapeutic effect after 2-3 months of treatment. The mechanism of action is unclear. It is possible that due to chelation of Cu, Zn reduces the activity of metalloproteinases

Due to side effects D-penicillamine approximately 40% of patients stop treatment prematurely. The drug causes nausea, mouth ulcers, alopecia, dermatitis, renal dysfunction (proteinuria), bone marrow depression (leukopenia, anemia, thrombocytopenia); pneumonitis and pulmonary fibrosis are possible.

Sodium aurothiomalate and auranofin- water-soluble gold salts, which have a pronounced therapeutic effect in 30-60% of patients with rheumatoid arthritis. Not very effective for arthritis of other etiologies.

Sodium aurothiomalate is administered intramuscularly. Auranofin is prescribed orally. Significant improvement occurs after 4 - 6 months.

Gold preparations are deposited in synovial tissue and taken up by macrophages. The mechanism of action of gold preparations is associated with a decrease in the activity of macrophages (the ability to present antigen, the production of IL-1, TNF-α, the release of lysosomal enzymes and toxic oxygen radicals).

Side effects gold preparations:

Epithelial lesions - ulcerative stomatitis, tracheitis, bronchitis, gastritis, colitis, vaginitis;

Renal dysfunction (proteinuria);

Hepatotoxic effect;

Neuropathies;

Encephalopathy;

Hematopoietic disorders (possible agranulocytosis, aplastic anemia, thrombocytopenia).

Gold and D-penicillamine drugs cause serious side effects and are rarely used today.

Leflunomide– isoxazole derivative; synthesized as an antirheumatoid agent. Inhibits dihydroorotate dehydrogenase and thus disrupts the synthesis of pyrimidine nucleotides and DNA synthesis. Reduces the synthesis of TNF-α, the production of antibodies, reduces the activity of COX-2, the expression of adhesion molecules. In this regard, it has antiproliferative, immunosuppressive and anti-inflammatory effects.

The drug is prescribed orally. The antirheumatoid effect begins within a month and increases over 4-5 months.

Anakinra– a recombinant preparation of a natural IL-1 receptor blocker. For rheumatoid arthritis, daily subcutaneous injections of the drug after 4-6 weeks cause a significant improvement in the patient's condition. There was no increased risk of infectious diseases.

Anti-inflammatory drugs

Acute inflammation is a protective reaction of the body. However, if this reaction is excessive and interferes with any functions, or if the inflammation becomes chronic, anti-inflammatory drugs are used.

Inflammation is divided into vascular and cellular phases.

IN vascular phase arterioles dilate and hyperemia occurs; The permeability of postcapillary venules increases, exudation and edema develop.

IN cell phase neutrophils, and then monocytes, thanks to the interaction of adhesion molecules, connect with the endothelium and penetrate through the intercellular spaces into the lesion, where monocytes turn into macrophages.

Macrophages and neutrophils secrete lysosomal enzymes (proteinases) and toxic oxygen radicals (superoxide anion, etc.), which act on foreign particles and on the cells of the surrounding tissue. In this case, tissue cells, in particular mast cells, release inflammatory mediators.

Main mediators of inflammation- histamine, bradykinin, prostaglandins E and I leukotrienes, platelet activating factor (PAF).

Histamine and bradykinin dilate small arterioles and increase the permeability of postcapillary venules. Bradykinin also stimulates sensory nerve endings (pain mediator).

Prostaglandins E 2 and I 2 dilate arterioles and enhance the effect of histamine and bradykinin on the permeability of postcapillary venules, as well as the effect of bradykinin on sensory nerve endings.

Prostaglandin E 2, in addition, causes an increase in temperature (acts on the thermoregulation centers in the hypothalamus) and stimulates myometrial contractions.

Prostaglandin I 2 (prostacyclin) prevents platelet aggregation.

Prostaglandins E 2 and I 2 have a gastroprotective effect: they reduce the secretion of HCl, increase the secretion of mucus and bicarbonates, increase the resistance of the cells of the mucous membrane of the stomach and duodenum to damaging factors, and improve blood circulation of the mucous membrane.

Leukotrienes C 4 , D 4 and E 4 dilate blood vessels, increase their permeability, lower blood pressure and increase bronchial tone.

PAF dilates blood vessels, increases vascular permeability, lowers blood pressure, increases platelet aggregation and bronchial tone.

Highlight 3 groups of anti-inflammatory drugs, reducing the formation of inflammatory mediators:

1) non-steroidal anti-inflammatory drugs (NSAIDs): diclofenac, ibuprofen, etc. - reduce the formation of prostaglandins

2) steroidal anti-inflammatory drugs (SAIDs): prednisolone, etc. - reduce the formation of prostaglandins, leukotrienes and PAF,

3) 5-aminosalicylic acid preparations: mesalazine, sulfasalazine - reduce the formation of prostaglandins and leukotrienes.

Nonsteroidal anti-inflammatory drugs (NSAIDs) : acetylsalicylic acid, indomethacin, diclofenac sodium, ibuprofen, naproxen, piroxicam, meloxicam

NSAIDs have mainly three properties: anti-inflammatory, analgesic and antipyretic. Mechanism anti-inflammatory action of these substances is associated with inhibition of cyclooxygenase (Fig. 3.2.6.5.). In this case, the formation of pro-inflammatory prostaglandins E and I is disrupted (see section “Non-opioid analgesics of peripheral action”).

Rice. Arachidonic acid cascade.

Note: 5-HPETE - 5-hydroperoxyeicosatetraenoic acid; PGE 2, PP 2, PGF 2a - prostaglandins; TxA 2 - thromboxane A 2; LTA 4, LTV 4, LTS 4, LTO 4, LTE 4 – leukotrienes; PAF is a platelet activating factor.

Steroidal anti-inflammatory drugs (glucocorticoids)

Glucocorticosteroids are highly effective anti-inflammatory drugs. The mechanism of their anti-inflammatory action is associated with stimulation of the expression of the gene responsible for the formation of lipocortin-1, which reduces the activity of phospholipase A 2. In this case, the formation of prostaglandins E 2 and 1 2, leukotrienes and PAF is disrupted.

In addition, glucocorticoids reduce the formation of the gene responsible for the synthesis of COX-2.

Glucocorticoids inhibit the expression of adhesion molecules, hinder the penetration of monocytes and neutrophils into the site of inflammation, and also reduce the ability of macrophages and neutrophils to release lysosomal enzymes and toxic oxygen radicals.

Glucocorticoids prevent mast cell degranulation and the release of histamine and other inflammatory mediators.

Glucocorticoids also have immunosuppressive properties. Therefore, they are especially often used for autoimmune diseases that are accompanied by inflammation (rheumatoid arthritis, systemic lupus erythematosus, eczema, etc.).

Glucocorticoids have significant side effects. Main side effects: ulcerogenic effect, osteoporosis, decreased resistance to infections (for other side effects, see the section “Glucocorticosteroid preparations”).

5-aminosalicylic acid preparations

Mesalazine(salofalk) - 5-aminosalicylic acid. Inhibits the cyclooxygenase and 5-lipoxygenase pathways for the conversion of arachidonic acid and, accordingly, disrupts the synthesis of prostaglandins and leukotrienes. In addition, under the influence of mesalazine, the production of interleukin-1 and immunoglobulins decreases, the formation of free oxygen radicals decreases, and the migration of neutrophils decreases. In this regard, mesalazine has not only anti-inflammatory, but also immunosuppressive properties.

The drug is used for nonspecific ulcerative colitis. Prescribed in tablets that release 5-aminosalicylic acid only in the large intestine.

Sulfasalazine- a combined preparation of 5-aminosalicylic acid and sulfapyridine. It is broken down in the large intestine under the influence of intestinal microflora with the release of 5-aminosalicylic acid. The drug is used for nonspecific ulcerative colitis, as well as for rheumatoid arthritis.

Prescribed orally; about 20-30% is absorbed in the small intestine. The antirheumatoid effect appears after about 2 months.

Control questions:

1. Define immunosuppressants, anti-inflammatory drugs, autoimmune diseases?

2. Classification of immunosuppressants?

3. “Large” immunosuppressants, cytostatic drugs, their pharmacological properties, indications for use, side effects?

4. “Major” immunosuppressants, glucocorticoid drugs, their pharmacological properties, indications for use, side effects?

5. “Large” immunosuppressants, drugs that inhibit the formation or action of interleukin-2, their pharmacological properties, indications for use, side effects?

6. “Large” immunosuppressants, antibody preparations, their pharmacological properties, indications for use, side effects?

7. “Minor” immunosuppressants (anti-rheumatoid drugs), their pharmacological properties, indications for use, side effects?

8. Anti-inflammatory drugs?

9. Nonsteroidal anti-inflammatory drugs (NSAIDs), their pharmacological properties, indications for use, side effects?

10. Steroidal anti-inflammatory drugs (glucocorticoids) and 5-aminosalicylic acid preparations, their pharmacological properties, indications for use, side effects?

4.13.3 Immunostimulants .

Immunostimulants – This drugs that increase the activity of the immune system, that is, enhance the immune response.

The use of immunostimulants for therapeutic or prophylactic purposes is called “immunotherapy” and “immunoprophylaxis,” respectively.

Indications for immunotherapy: immunodeficiency states accompanied by infectious complications. The presence of immunodeficiency must be confirmed by an immunogram.

Immunodeficiencies(ID) are divided into:

1. Primary immunodeficiencies – congenital, genetically determined

2. Secondary immunodeficiencies – acquired.

Probably every person has heard about how important immunity is for the normal functioning of all human organs and systems. After all, it is thanks to the activity of the protective forces that our body can resist attacks from viruses, infections and other aggressive particles. Every year, many people turn to doctors with complaints of decreased immunity, and try with all their might to improve it. However, sometimes the normal functioning of this body system can be harmful. In this case, doctors have to prescribe immunosuppressants to the patient - let's look at such drugs on the www.site. Also, their action, application by example, and we will also answer the question of what benefits and harms of immunosuppressants for the body can be from their consumption.

Immunosuppressants or immunosuppressants are medications that can artificially suppress human immunity. Most often, such drugs are used during organ transplant surgery, as they can prevent the rejection of new tissue. In addition, immunosuppressants may become the drugs of choice for autoimmune diseases.

Effect of immunosuppressants

There are several groups of drugs that are characterized by immunosuppressive properties. They have different effects on the body.

Thus, cytostatics have pronounced immunosuppressive properties, which are explained by their inhibitory effect on the processes of lymphocyte division. However, such medications cannot act selectively and often cause side effects. Cytostatics inhibit hematopoietic processes and can provoke the development of leukopenia, thrombocytopenia, anemia, secondary infections, etc. Azathioprine is considered the most popular drug in this group.

Immunosuppressants also include glucocorticoids, which suppress the production of interleukins and the proliferation of T-lymphocytes. Such drugs have a selective effect, these include Prednisolone, Methioprednisolone, Triamcinolone, Betamethasone, etc.

Also among the immunosuppressants are some antibiotics: cyclosporine and tacrolimus, and the monoclonal antibody drug Daclizumab.

Use of immunosuppressants

Azathioprine

This medication is usually prescribed to the patient in the amount of four milligrams per kilogram of body weight, taken 1-7 days before surgery, after which the dosage is reduced to two to three milligrams per kilogram. For other ailments, the recommended amount of medication consumption is one to one and a half milligrams per kilogram per day.

Cyclosporine

This medicine is administered intravenously, the daily dosage is divided into two doses. The concentrate is diluted with a five percent glucose solution and administered over two to six hours. The initial daily dosage is considered to be three to five milligrams per kilogram. This intravenous administration is indicated for patients who will undergo a bone marrow transplant.

The solution for internal consumption is diluted with milk, fruit juice or a cold chocolate drink and drunk immediately. And the capsules are swallowed whole.

If the patient is undergoing an organ transplant, he is prescribed 10-15 mg/kg four to twelve hours before surgery. Next, the same dosage is used for one to two weeks, and after that it is reduced to maintenance, which is approximately 2-6 mg/kg. To correct autoimmune diseases, the patient is advised to take 2.5-5 mg/kg Cyclosporine per day.

Daclizumab

The medicine is intended for intravenous administration; it is injected slowly into a peripheral or central vein. Typically, 1 mg/kg of the drug is used per day, diluted with 0.9% sodium chloride solution. The first administration is carried out one day before transplantation, subsequent administrations are carried out at intervals of two weeks.

The benefits of immunosuppressants for the human body

Immunosuppressants during organ transplantation help prevent the rejection of foreign tissue. As practice shows, the use of such drugs (accompanied by suppression of lymphocyte activity) helps to prolong the life of the transplanted organ.

When treating diseases of the immune system, immunosuppressants help stop the pathological processes of such diseases (for example, rheumatoid arthritis, lupus erythematosus, etc.) or slow down their course by an order of magnitude.

Harm of immunosuppressants to the human body

Every drug that has immunosuppressive properties can harm the body due to a wide range of side effects. There are especially many of them in cytostatics. For example, Azathioprine can provoke nausea, vomiting, loss of appetite, etc. And in some cases, its consumption causes the development of toxic hepatitis.

In addition, it should be noted that the use of immunosuppressants causes natural suppression of the immune system. Accordingly, patients undergoing treatment with immunosuppressants are unstable to the effects of pathogens and other aggressive substances, including those that are resistant to antibiotic drugs. There is also evidence that immune suppression can increase the likelihood of developing cancer by an order of magnitude.

Immunosuppressants are quite serious medications that can only be used for certain indications for a limited period of time and only under the close supervision of a qualified specialist.

Artificial immunosuppression as a method treatment is used primarily when transplantation organs And fabrics, such as kidneys , heart , liver , lungs , Bone marrow.

In addition, artificial immunosuppression (but less profound) is used in the treatment autoimmune diseases and diseases presumably (but not yet proven) to be or may be of an autoimmune nature.

Types of drugs

The class of immunosuppressive drugs is heterogeneous and contains drugs with different mechanisms of action and varying side effect profiles. The profile of the immunosuppressive effect also differs: some drugs suppress all types more or less evenly. immunity, others have particular selectivity for transplantation immunity and autoimmunity, with a relatively lesser effect on antibacterial, antiviral and antitumor immunity. Examples of such relatively selective immunosuppressants are cyclosporine A And tacrolimus. Immunosuppressive drugs also differ in their primary effect on cellular or humoral immunity.

It is worth noting that the successful allotransplantation organs and tissues, a sharp reduction in the percentage of transplant rejection and long-term survival of patients with transplants became possible only after the discovery and introduction into widespread practice transplantology cyclosporine A. Before its advent, there were no satisfactory methods of immunosuppression that would provide the necessary degree of suppression of transplantation immunity without severe, life-threatening side effects and a deep decrease in anti-infective immunity.

The next stage in the development of the theory and practice of immunosuppressive therapy in transplantology was the introduction of protocols for combined - three- or four-component immunosuppression for organ transplantation. Standard triple immunosuppression today consists of a combination of cyclosporine A, glucocorticoid and cytostatics ( methotrexate or azathioprine, or mycophenolate mofetil). In patients with a high risk of transplant rejection (high degree of non-homologousness of the graft, previous unsuccessful transplantations, etc.), four-component immunosuppression is usually used, which also includes anti-lymphocyte or anti-thymocyte globulin. Patients who cannot tolerate one or more components of a standard immunosuppressive regimen or are at high risk infectious complications or malignant tumors, prescribe two-component immunosuppression or, less commonly, monotherapy.

A new breakthrough in transplantology is associated with the emergence of a new cytostatic fludarabine phosphate(Fludara), which has strong selective cytostatic activity against lymphocytes, and with the development of a method of short-term (several days) high-dose pulse therapy with glucocorticoids using methylprednisolone in doses 100 times higher than physiological. The combined use of fludarabine phosphate and ultra-high doses of methylprednisolone made it possible in a matter of days and even hours to stop acute transplant rejection reactions occurring during standard immunosuppressive therapy, which was a very difficult matter before the advent of Fludara and high-dose glucocorticoids.

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Azathioprine Chemical compound IUPAC 6 [(1 Methyl 4 nitro 1H imidazol 5 yl)thio] 1H purine (and as sodium salt) Gross formula ... Wikipedia

Chemical structure of the Tacrolimus molecule Tacrolimus is an immunosuppressive drug belonging to the group of natural macrolides. Produced... Wikipedia

Chemical structure of the Tacrolimus molecule Tacrolimus is an immunosuppressive drug belonging to the group of natural macrolides. Produced by the actinomycete Streptomyces tsukubaensis. Opened in 1987 in Japan by the group T. Goto, T. Kino... ... Wikipedia

- (Basiliximab) Monoclonal antibody Organism source Chimeric/Human Target CD25 Classification ... Wikipedia

Mycophenolate mofetil is a new powerful immunosuppressive drug with a cytostatic mechanism of action. Is a morpholinoethyl ether... Wikipedia