Immunosuppressants

introduction

The immune system is the barrier that protects the body from the penetration of pathogens. It consists of a cellular and a so-called humoral part. Cellular components are, for example, the macrophages ("scavenger cells"), the natural killer cells and the lymphocytes.
The humoral part, i.e. the part that does not consist of cells, contains, among other things, antibodies and various carrier substances called interleukins.

Under normal circumstances, i.e. in a healthy organism, the immune system is able to differentiate between the body's own and foreign structures. Structures that have been recognized as foreign are then eliminated by the immune system. However, sometimes our immune system is faulty. In such a situation, it falsely recognizes the body's own tissue as foreign, an immune reaction is triggered and the body begins to attack itself. One speaks of so-called Autoimmune diseases. Examples of such diseases are rheumatism, multiple sclerosis or Crohn's disease.

In such cases, drugs are used to keep the immune system in check and downregulate it Immunosuppressants. They dampen immune reactions and thus prevent the immune system from developing its effectiveness. In addition, immunosuppressants are also used to prevent and treat rejection of the new organ after organ transplantation.

When are immunosuppressants used?

Immunosuppressants As mentioned above, they are mainly used in two major areas of medicine. On the one hand, these drugs are used for this Organ transplant rejection reactions to prevent, to let yourself be Autoimmune diseases Treat well with immunosuppressants.

Organ transplantation would never have been possible without the development of immunosuppressive drugs. Organs can only be transplanted if the tissue characteristics of the donor and recipient match as closely as possible. Despite the tissue characteristics that are as similar as possible, the body will always classify the transplanted organ as foreign and begin to attack it with inflammatory reactions. Immunosuppressants keep the immune system in check and here prevent thus that the Graft rejected becomes.

In autoimmune diseases, the immune system does not direct its defense mechanisms against foreign tissue, but against its own components. Here, too, it is important to dampen the immune system so that there is no major tissue destruction. Autoimmune diseases include the Ulcerative colitis, Crohn's disease, Myasthenia gravis and the Narcolepsy (Sleep sickness).

Which drugs are immunosuppressive drugs?

Many different substances can be summarized under the term immunosuppressants. They work through different mechanisms on the various components of the immune system and are therefore divided into different groups.
Probably the most commonly used group are the Glucocorticoids.

Also be Calcineurin inhibitors and mTOR inhibitors used as immunosuppressants. These substances develop their effect by inhibiting cellular signaling pathways.
There are also cytostatics Methotrexate as the main representative. In addition, they count monoclonal antibody or also called biologicals, which are manufactured in the laboratory, belong to the large group of immunosuppressants.

The immunosuppressants already mentioned are listed below with the associated active ingredients:

• Calcineurin inhibitors: The calcineurin inhibitors include ciclosporin A and tacrolimus. Calcineurin is an enzyme in T lymphocytes that controls the immune response of T helper cells. Ciclosporin is obtained from a hose fungus, tacrolimus from a bacterium called Streptomyces. Tacrolimus is more potent than ciclosporin.
  Read more about here Tacrolimus and Ciclospoprin A.
• Cytostatics: These drugs are actually used in cancer therapy because they inhibit cell division. If they are used as immunosuppressants, the doses are much lower than in cancer therapy. Possible substances are cyclophosphamide, azathioprine and methotrexate.
• Glucocorticoids: These actually endogenous hormones are used for the therapy of many diseases, such as rheumatic diseases. In addition to the natural glucocorticoids, there are also many synthetically produced preparations that have the same effects. They have an anti-inflammatory and immunosuppressive effect.
• Mycophenolat-Mofetil: This drug inhibits the multiplication of special immune cells called lymphocytes.
• Sirolimus: This immunosuppressant also inhibits the proliferation of lymphocytes, but works in a different place than mycophenolate mofetil.
• Biologicals: There are specific antibodies for many points of attack in the immune system that can be specifically switched off by using them. Due to their biotechnological production, they are usually very expensive, but their specific effects can significantly improve the success of the treatment if other immunosuppressants are ineffective.

Methotrexate

Methotrexate (MTX) is one of the antimetabolites, more precisely one of the folic acid analogues. The substance accumulates in the cells and thus disturbs them Dihydrofolate reductase. This enzyme produces when it is working Tetrahydrofolic acid, an extremely important building block for the production of purine molecules, which in turn are essential for the production of DNA.
While methotrexate is used in low doses to treat autoimmune diseases, it is used in high doses in tumor therapy and is usually quite effective. The disadvantage of using this ingredient is the side effects. Since methotrexate is eliminated via the kidneys, in the worst case scenario, kidney failure can result.

The substance also has an extremely toxic (poisonous) effect on the bone marrow. Interstitial pneumonia is a common side effect caused by methotrexate. Interstitial pneumonia means inflammation of the connective tissue of the lungs.

Read more about this under lung infection

Lung fibrosis, i.e. the increasing conversion of functioning lung tissue into non-functioning connective tissue due to chronic inflammatory processes, is the worst possible consequence of such interstitial pneumonia.

More information can be found here: The pulmonary fibrosis

How do immunosuppressants work?

Every drug group among the immunosuppressants develops its own effectiveness in another way.
The Glucocorticoids develop their effect by binding via a receptor (NF-kB) located in the cell, which prevents the DNA from being read. As a result, pro-inflammatory proteins and Messenger substances of the inflammatory reaction or the immune response Not more educated can be. Glucocorticoids have an anti-inflammatory and immunosuppressive effect, so that they can be used in a variety of ways in therapy. Frequently used active ingredients are for example Prednisone, Prednisolone or Dexamethasone.

The Calcineurin- and mTOR inhibitors influence various signaling pathways within the cell. Calcineurin inhibitors (inhibitor = inhibitor) inhibit, As the name indicates, Calcineurin. This is an enzyme that would normally cleave another protein so that it can get into the cell nucleus and drive transcription (transcribing DNA into RNA) there. The result of the transcription would ultimately be certain messenger substances that trigger inflammatory reactions.
Calcineurin inhibitors prevent the production of pro-inflammatory substances. The best-known substance among the calcineurin inhibitors is that Ciclosporinwhich is primarily used in transplants.

Sirolimus and Everolimus as representatives of the mTOR inhibitors are also mainly used to prevent rejection reactions. Their mechanism of action targets the enzyme mTOR, which is responsible for regulating the normal cell cycle. If this enzyme is inhibited, the regular cell cycle and thus the division of the cell can no longer proceed, fewer inflammatory cells are formed and the activity of the immune system is inhibited.

Another important class of immunosuppressive drugs are those Cytostatics. Such substances act on the cell cycle, interrupt this and to stop so that Multiplication of rapidly dividing cells by interfering with the genetic information of the cell. In high doses, cytostatics are therefore used in the Therapy of tumors used.
In lower doses, they act on the division of B and T immune cells and thus immunosuppression can be achieved.
Substances that count among the immunosuppressive cytostatics can be grouped into two subclasses. On the one hand there are so-called alkylating substances, on the other hand they play Antimetabolites a role.
The alkylating substances include e.g. Substances such as cyclophosphamide but also platinum compounds such as cisplatin. Methotrexate, on the other hand, is an antagonist of folic acid and inhibits a certain enzyme, dihydrofolate reductase. This enzyme activates folic acid, which is needed to produce DNA building blocks. The administration of methrotrexate therefore generally inhibits the formation of DNA.

While that Mycophenolate mofetil A certain enzyme (inosine monophosphate dehydrogenase) inhibits, whereby the production of DNA and DNA components is inhibited, especially in lymphocytes, and their reproduction is suppressed Biologicals composed of many active ingredients, each with different points of attack. They attack certain surface features of cells or of messenger substances of the immune reaction and thus lead to an inhibition. They can be used for many different autoimmune and tumor diseases because their spectrum of activity is so large.

Overall, it can be said that the immunosuppressant may attack in many places, but ultimately it always comes to either one Inhibition of cell division or one decreased production of pro-inflammatory messenger substances.

Side effects

Immunosuppressants intervene in extensive processes of the body and are therefore unfortunately associated with many side effects. Without a functioning immune system, the body is defenseless at the mercy of diseases, which is why all immunosuppressants basically increase the susceptibility to infections, some even increase the risk of certain tumor diseases (e.g. non-melanoma skin cancer with azathioprine). When taking immunosuppressants, it is important to observe whether side effects occur and to carry out regular blood tests so that side effects can be recognized and treated at an early stage.

Probably the most important side effect of immunosuppressive therapy is enormous increased susceptibility to infection. For example, viral infections are particularly dangerous under immunosuppression. A herpes virus infection that is harmless in healthy people can severely weaken a patient under immunosuppressive treatment, and in the worst case even kill them.

Depending on the used Differentiate immunosuppressant the additional occurring side effects partially:

• The glucocorticoids cause numerous, sometimes very strong, undesirable effects. This includes a redistribution of the fatty tissue, it comes to "bull neck", "full moon face" and "trunk obesity". In addition, the breakdown of muscle and bone tissue is accelerated, patients usually notice this from a weakness in the legs (osteoporosis, Muscular atrophy). The digestive tract is also heavily stressed during glucocorticoid therapy, so that ulcers in the gastrointestinal tract can occur or existing ulcers can be aggravated. In addition, wound healing is severely disturbed, and intraocular pressure increases (Glaucoma attack) as well as all kinds of skin symptoms. In addition, increased water retention, thrombosis and diabetes mellitus can occur. Glucocorticoids can also have an effect on mood, so that they can promote a depressive mood.
  
  • Read more on the topic Prednisolone side effect
    
• Ciclosporin A, as a representative of the calcineurin inhibitors, inhibits an enzyme that is responsible for the breakdown of drugs, which is why certain antibiotics and antifungal agents can slow down the breakdown of ciclosporin via this enzyme and thus increase the undesirable side effects. Ciclosporin can damage the liver, heart and kidneys, promote the development of diabetes and lead to increased blood pressure and water retention. A male hair pattern in women is also typical (Hirsutism), increased growth of the gums (Gingival hyperplasia) and a tremor (tremor). Tacrolimus has very similar side effects, but gingival hyperplasia and hirsutism are less common. But hair loss is one of the side effects of tacrolimus.
• mTOR inhibitors such as sirolimus and everolimus cause less liver and kidney damage than the calcineurin inhibitors, but they increase blood lipid levels dramatically.
• Cytostatic drugs have an extremely unpleasant side effect of severe nausea, which is often accompanied by severe vomiting. They suppress the normal blood formation in the bone marrow, which leads to anemia (consequence: feeling weak), a lack of white blood cells (consequence: susceptibility to infection) and a lack of blood platelets (consequence: tendency to bleed).
  
  • Platinum compounds, another group of cytostatics, often cause sensory disorders or symptoms of paralysis, while antimetabolites can damage the liver and pancreas.
  • A classic side effect of cyclophosphamide is hemorrhagic cystitis (bloody cystitis). It is caused by a toxic metabolic product of cyclophosphamide, which is excreted in the urine and can be treated preventively with the drug Mesna.

    • Immunosuppressants and alcohol - are they compatible?

      

      The consumption of alcohol and the simultaneous use of medication are compatible rarely good. During therapy with Immunosuppressants is the pleasure of alcohol also not recommendable.
      Alcohol affects the breakdown of drugs through its effects on the liver. Drug effects are often increased or weakened under the influence of alcohol. For example, the effects of cortisone or other glucocorticoids are weakened. The drugs then unfold Not more yours full effectiveness.

      Immunosuppressants that are used after organ transplants should not be taken at the same time as alcohol, because the drugs can increase the effects of alcohol. Alcoholic side effects such as dizziness, drowsiness or nausea and vomiting often occur after even small amounts of alcoholic beverages, and the strength of the effects is also difficult to assess.

      What should be considered when stopping immunosuppressants?

      Immunosuppressants are often taken for very long periods of time.
      Organ transplant recipients Patients need their immunosuppressive drugs lifelong take so that it doesn't become one after years Rejection reaction comes.
      Because of the strong side effects of immunosuppressants, many patients are less willing to take the medication.
      By independent withdrawal However, in the worst case, immunosuppressive drugs threaten Loss of the graft. Patients who are contemplating discontinuing their medication should definitely Consult your doctor, as he or she can adapt the therapy so that fewer side effects occur.

      Therapy with Glucocorticoids is also a challenge for many patients due to the massive side effects.
      When the Glucocorticoids allowed to no way the entire dose at once be dropped off; be discontinued; be deducted; be dismissed. The drug must "Sneaked out" become. In this case, “tapering off” means a slow one Reduction in dose until you stop taking it.
      Sudden cessation of glucocorticoid therapy can either cause the disease being treated to come back (Relapse) or adrenal insufficiency may occur. The adrenal cortex produces glucocorticoids in a healthy body. If you also take glucocorticoids as medication, the body perceives the increased level, and the adrenal cortex reduces the production of the glucocorticoids. After sudden discontinuation, the adrenal cortex can no longer "ramp up" production, it can kick it Symptoms how low blood pressure, low heart rate and Muscle weakness on.

      Immunosuppressants used to treat ulcerative colitis

      The Ulcerative colitis is one beginning at the rectum, chronic inflammation of the intestinal lining. The causes of this disease are not yet fully known; genetic, autoimmune and environmental and nutritional influences are suspected. Patients suffer greatly from the symptoms, such as bloody diarrhea and cramping abdominal pain.
      Acute ulcerative colitis is treated depending on the stage. In the first, usually somewhat more harmless stages, attempts at therapy are included Glucocorticoids made. Attention is paid to the lowest possible dose to reduce side effects.
      In later stages, the dose of glucocorticoids is first increased, others may come Immunosuppressants like the ciclosporine added. If particularly severe courses or complications, such as perforation (“bursting”) of the intestine or bleeding occur, are treated surgically. The focus of drug therapy is on the longest possible freedom from symptoms without recurring attacks of the disease.

      Immunosuppressants used to treat Crohn's disease

      Crohn's disease is a chronic inflammatory disease that can affect the entire gastrointestinal tract. The following immunosuppressants are used to treat an acute attack: Budesonide, Mesalazine and possibly Prednisolone.
      Budesonide is a glucocorticoid that is largely metabolized in the liver. It therefore mainly has a regional effect in the gastrointestinal tract and few systemic side effects.
      Mesalazine belongs to the group of aminosalicylates and can be used as an alternative. It has an anti-inflammatory and immunosuppressive effect in the intestine.

      Prednisolone, a strong glucocorticoid that, unlike budesonide, is systemically effective and therefore causes more side effects, is used for severe relapses.

      If the thrust doesn't respond to that either, biologicals are here Infliximab (TNF-alpha antibodies) are used to curb inflammation. In order to control the disease activity between attacks, immunosuppressants are used as long-term therapy Azathioprine as a first choice or Methotrexate used as a second choice. Therapy with infliximab is also possible.

      Immunosuppressants used to treat rheumatism

      Rheumatism, more precisely that Rheumatoid arthritis, can also be treated with immunosuppressive drugs.
      Rheumatoid arthritis is caused by an immune reaction in which the body attacks the joints through the formation of antibodies and activation of macrophages (phagocytes of the immune system), causing inflammation, usually in several joints. In the case of rheumatic diseases, a distinction is also made between continuous and relapse therapy. Painkillers are used for relapse therapy and glucocorticoids are used as immunosuppressants. Glucocorticoids delay the destruction of the affected joints.

      Long-term therapy should be started as early as possible. This is an important component and means of first choice here Methotrexatewhich must be taken once a week. It is often prescribed in combination with the anti-inflammatory glucocorticoids prednisone or prednisolone. In the course of therapy, attempts are often made to reduce the dose of the glucocorticoids somewhat so that the side effects of these drugs are less severe. Recently, antibodies produced in the laboratory have also been used in rheumatism therapy.
      Methotrexate must not be used at the same time with painkillers from NSAID type (Ibuprofen, Diclofenac, Paracetamol etc.), because otherwise the side effects will increase. Folic acid is taken 24-48h after taking MTX to reduce the side effects.

      Second choice agent Leflunomideif MTX does not work (sufficiently). Sulfasalazine can be used in combination with folic acid during pregnancy. In severe cases, various biologicals (anti-TNF-alpha antibodies or interleukin-1 receptor antagonists) can be used.

      Immunosuppressants used to treat multiple sclerosis

      multiple sclerosis is an inflammatory, autoimmune nerve disease, in the course of which the protective layer around the nerve fibers (Myelin layer) are destroyed. MS progresses intermittently, which means that intervals of almost complete freedom from pain alternate with strong attacks of the disease.
      High doses are used, especially during the flare-ups Methylprednisolone and Prednisolone used or, if necessary, plasmapheresis (washing out of the auto-antibodies) is carried out. Very high doses (up to 1000 milligrams) are often given intravenously at the beginning of an acute attack, after which the medication can be switched to tablets with lower doses.

      Count to basic therapy Glatiramer acetate and Interferon beta, also in relapsing-remitting MS Dimethyl fumarate, in relapsing-progressive MS Mitoxantrone. Mitoxantrone is a very powerful immunosuppressant that leads to the destruction of B immune cells. Relapsing-remitting MS can also escalate Alemtuzumab (Antibodies against CD52, a surface protein on immune cells), Fingolimod (reduces the migration of immune cells into the central nervous system) or Natalizumab (Antibodies, reduces the migration of immune cells into the central nervous system).
      Many of the immunosuppressive drugs used in MS are very powerful and can cause serious side effects. It is feared Progressive multifocal leukoencephalopathywhich can occur during therapy with dimethyl fumarate or natalizumab. Side effects are, for example, tiredness, headaches, depression and hypersensitivity reactions to the active ingredients.