How do immunosuppressants work?

Each group of immunosuppressive drugs unfolds its efficacy in a different way. The glucocorticoids unfold their effect by binding via a receptor (NF-kB) located in the cell, which prevents the reading of DNA. As a result, pro-inflammatory proteins and messenger substances of the inflammatory reaction or the immune response can no longer be produced.

Glucocorticoids thus have an anti-inflammatory and immunosuppressive effect so that they can be used in a variety of therapeutic applications. 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 suggests, calcineurin. This is an enzyme that would normally cleave another protein so that it can enter the cell nucleus and promote transcription (transcription of DNA into RNA). The result of the transcription would ultimately be certain messenger substances that trigger inflammatory reactions.

Calcineurin inhibitors thus prevent the production of pro-inflammatory substances. The best-known substance among the calcineurin inhibitors is ciclosporin, which 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 the regulation of the normal cell cycle. If this enzyme is inhibited, the regular cell cycle and thus the division of the cell can no longer take place, fewer inflammatory cells are produced and the activity of the immune system is inhibited. Another important class of immunosuppressants are cytostatic drugs.

Such substances act on the cell cycle, interrupt it and thus stop the proliferation of rapidly dividing cells by interfering with the genetic information of the cell. In high doses, cytostatic drugs are therefore used in the therapy of tumors. In lower doses, they act on the division of B and T immune cells and thus immunosuppression can be achieved.

Substances which belong to the immunosuppressive cytostatic drugs can be grouped in two subclasses. On the one hand, there are so-called alkylating substances, on the other hand the antimetabolites play a role. The alkylating substances include substances such as cyclophosphamide and platinum compounds such as cisplatin.

Methotrexate on the other hand is an antagonist of folic acid and inhibits a certain enzyme, the dihydrofolate reductase. This enzyme activates folic acid, which is needed for the production of DNA building blocks. The administration of methrotrexate thus generally inhibits the formation of DNA.

While the mycophenolate mofetil inhibits a specific enzyme (inosine monophosphate dehydrogenase), which inhibits the production of DNA and DNA components, especially in lymphocytes, and suppresses their proliferation, biologicals are composed of many active ingredients, each with different points of attack.They attack certain surface features of cells or messenger substances of the immune reaction and thus lead to inhibition. They can be used in many different autoimmune and tumor diseases because their spectrum of action is so broad. All in all, it can be said that although immunosuppressive drugs attack at many sites, in the end there is always either an inhibition of cell division or a reduced production of pro-inflammatory messenger substances.

Immunosuppressants intervene in extensive processes of the body and are therefore unfortunately afflicted with many side effects. Without a functioning immune system, the body is defenselessly exposed to diseases, which is why basically all immunosuppressants increase the susceptibility to infections, some even increase the risk of certain tumor diseases (e.g. non-melanoma skin cancer with azathioprine). When taking immunosuppressive drugs, it is important to observe whether side effects occur and to carry out regular blood tests in order to detect and treat side effects at an early stage.

Probably the most important side effect of immunosuppressive therapy is the enormous increase in susceptibility to infections. Viral infections, for example, are particularly dangerous under immunosuppressive therapy. A herpes virus infection, which is harmless in healthy people, can weaken a patient under immunosuppressive treatment, and in the worst case, even kill him.

Depending on the immunosuppressive agent used, the additional side effects that occur can differ in some cases:

Glucocorticoids cause numerous undesirable effects, some of them very strong. These include a redistribution of fatty tissue, “bull neck“, “full moon face” and “trunk obesity“. In addition, the breakdown of muscle and bone tissue is accelerated; patients usually notice this by a weakness in their legs (osteoporosis, muscle atrophy).
The digestive tract is also put under heavy strain under glucocorticoid therapy, so that ulcers can appear in the gastrointestinal tract or already existing ulcers can be aggravated. Furthermore, wound healing is massively disturbed, there is an increase in intraocular pressure (glaucoma attack) and skin symptoms of various kinds. In addition, increased water retention, thromboses and diabetes mellitus can occur.

Glucocorticoids can also have an effect on mood, so that they can promote depressive moods.
Ciclosporin A, as a representative of the calcineurin inhibitors, inhibits an enzyme responsible for the degradation of drugs, which is why certain antibiotics and antifungal agents can slow down the degradation 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. Also typical are a male pattern of hair in women (hirsutism), increased growth of the gums (gingival hyperplasia) and tremor (tremor).
Tacrolimus has very similar side effects, but gingival hyperplasia and hirsutism occur less frequently. On the other hand hair loss is one of the side effects of Tacrolimus.
MTOR inhibitors such as sirolimus and everolimus cause less liver and kidney damage than calcineurin inhibitors, but they dramatically increase blood lipid levels.
As an extremely unpleasant side effect, cytostatic drugs cause severe nausea, often accompanied by strong vomiting. They suppress the regular blood formation in the bone marrow, which results in anaemia (weakness), a lack of white blood cells (susceptibility to infection) and a lack of platelets (bleeding tendency).
Platinum compounds, another group of cytostatic drugs, often cause sensory disturbances or paralysis; 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 urine and can be treated preventively with the drug Mesna.
Platinum compounds, another group of cytostatic drugs, often cause sensory disturbances or paralysis, 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.
Platinum compounds, another group of cytostatic drugs, often cause sensory disturbances or paralysis, 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.

The consumption of alcohol and the simultaneous intake of medication are rarely well tolerated. During a therapy with immunosuppressive drugs, the consumption of alcohol is also not recommended.

Alcohol influences the breakdown of drugs through its effect on the liver. Under the influence of alcohol, the effects of medication are often intensified or weakened. For example, the effects of cortisone or other glucocorticoids are weakened.

The drugs then no longer develop their full effectiveness. Immunosuppressive drugs used after organ transplants should not be taken at the same time as alcohol either, because the drugs can intensify the effects of alcohol. Alcoholic side effects such as dizziness, drowsiness or nausea and vomiting often occur after only small amounts of alcoholic beverages.