Immunosuppressant Drugs

Definition

Immunosuppressant drugs, also called anti-rejection drugs, are used to prevent the body from rejecting a transplanted organ.

Purpose

When an organ, such as a liver, a heart or a kidney, is transplanted from one person (the donor) into another (the recipient), the immune system of the recipient triggers the same response against the new organ it would have to any foreign material, setting off a chain of events that can damage the transplanted organ. This process is called rejection and it can occur rapidly (acute rejection), or over a long period of time (chronic rejection). Rejection can occur despite close matching of the donated organ and the transplant patient. Immunosuppressant drugs greatly decrease the risks of rejection, protecting the new organ and preserving its function. These drugs act by blocking the immune system so that it is less likely to react against the transplanted organ. A wide variety of drugs are available to achieve this aim but work in different ways to reduce the risk of rejection.

In addition to being used to prevent organ rejection, immunosuppressant drugs are also used to treat such severe skin disorders as psoriasis and such other diseases as rheumatoid arthritis, Crohn's disease (chronic inflammation of the digestive tract) and patchy hair loss (alopecia areata). Some of these conditions are termed "autoimmune" diseases, indicating that the immune system is acting against the body itself.

Description

Immunosuppressant drugs can be classified according to their specific molecular mode of action. The three main immunosuppressant drugs currently used in organ transplantations are the following:

• Cyclosporins (Neoral, Sandimmune, SangCya). These drugs act by inhibiting T-cell activation, thus preventing T-cells from attacking the transplanted organ.
• Azathioprines (Imuran). These drugs disrupt the synthesis of DNA and RNA and cell division.
• Corticosteroids such as prednisolone (Deltasone, Orasone). These drugs suppress the inflammation associated with transplant rejection.

Most patients are prescribed a combination of drugs after their transplant, one from each of the above main groups; for example cyclosporin, azathioprine and prednisolone. Over a period of time, the doses of each drug and the number of drugs taken may be reduced as the risks of rejection decrease. However, most patients need to take at least one immunosuppressive for the rest of their lives.

Immunosuppressants can also be classified depending on the specific transplant:

• basiliximab (Simulect) is also used in combination with such other drugs as cyclosporin and corticosteroids, in kidney transplants
• daclizumab (Zenapax) is also used in combination with such other drugs as cyclosporin and corticosteroids, in kidney transplants
• muromonab CD3 (Orthoclone OKT3) is used, along with cyclosporin, in kidney, liver and heart transplants
• tacrolimus (Prograf) is used in liver transplants and is under study for kidney, bone marrow, heart, pancreas, pancreatic island cell, and small bowel transplantation

Some immunosuppressants are also used to treat a variety of autoimmune diseases:

• Azathioprine (Imuran) is used not only to prevent organ rejection in kidney transplants, but also in treatment of rheumatoid arthritis. It has been used to treat chronic ulcerative colitis, but it has been of limited value for this use.
• Cyclosporin (Sandimmune, Neoral) is used in heart, liver, kidney, pancreas, bone marrow and heart/lung transplantation. The Neoral form has been used to treat psoriasis and rheumatoid arthritis. The drug has also been used for many other conditions including multiple sclerosis, diabetes and myesthenia gravis.
• Glatiramer acetate (Copaxone) is used in treatment of relapsing-remitting multiple sclerosis. In one study, glatiramer reduced the frequency of multiple sclerosis attacks by 75% over a two-year period.
• Mycopehnolate (CellCept) is used along with cyclosporin in kidney, liver and heart transplants. It has also been used to prevent the kidney problems associated with lupus erythematosus.
• Sirolimus (Rapamune) is used in combination with other drugs including cyclosporin and corticosteroids, in kidney transplants. The drug is also used for the treatment of psoriasis.

Recommended dosage

Immunosuppressant drugs are available only with a physician's prescription. They come in tablet, capsule, liquid and injectable forms.

The recommended dosage depends on the type and form of immunosuppressant drug and the purpose for which it is being used. Doses may be different for different patients. The prescribing physician or the pharmacist who filled the prescription will advise on correct dosage.

Taking immunosuppressant drugs exactly as directed is very important. Smaller, larger or more frequent doses should never be taken, and the drugs should never be taken for longer than directed. The physician will decide exactly how much of the medicine each patient needs. Blood tests often are necessary to monitor the action of the drug.

The prescribing physician should be consulted before stopping an immunosuppressant drug.

Precautions

Seeing a physician regularly while taking immunosuppressant drugs is important. These regular checkups will allow the physician to make sure the drug is working as it should and to watch for unwanted side effects. These drugs are very powerful and can cause serious side effects, such as high blood pressure, kidney problems and liver problems. Some side effects may not show up until years after the medicine is used. Anyone who has been advised to take immunosuppressant drugs should thoroughly discuss the risks and benefits with the prescribing physician

Immunosuppressant drugs lower a person's resistance to infection and can make infections harder to treat. The drugs can also increase the chance of uncontrolled bleeding. Anyone who has a serious infection or injury while taking immunosuppressant drugs should get prompt medical attention and should make sure that the treating physician knows about the immunosuppressant prescription. The prescribing physician should be immediately informed if signs of infection, such as fever or chills, cough or hoarseness, pain in the lower back or side, or painful or difficult urination, bruising or bleeding, blood in the urine, bloody or black, tarry stools occur. Other ways of preventing infection and injury include washing the hands frequently, avoiding sports in which injuries may occur, and being careful when using knives, razors, fingernail clippers or other sharp objects. Avoiding contact with people who have infections is also important. In addition, people who are taking or have been taking immunosuppressant drugs should not have immunizations, such as smallpox vaccinations, without checking with their physicians. Because of their low resistance to infection, people taking these drugs might get the disease that the vaccine is designed to prevent. People taking immunosuppressant drugs also should avoid contact with anyone who has taken the oral polio vaccine, as there is a chance the virus could be passed on to them. Other people living in their home should not take the oral polio vaccine.

Immunosuppressant drugs may cause the gums to become tender and swollen or to bleed. If this happens, a physician or dentist should be notified. Regular brushing, flossing, cleaning and gum massage may help prevent this problem. A dentist can provide advice on how to clean the teeth and mouth without causing injury.

Special conditions

People who have certain medical conditions or who are taking certain other medicines may have problems if they take immunosuppressant drugs. Before taking these drugs, the prescribing physician should be informed about any of these conditions:

ALLERGIES. Anyone who has had unusual reactions to immunosuppressant drugs in the past should let his or her physician know before taking the drugs again. The physician should also be told about any allergies to foods, dyes, preservatives, or other substances.

PREGNANCY. Azathioprine may cause birth defects if used during pregnancy, or if either the male or female is using it at time of conception. Anyone taking this medicine should use a barrier method of birth control, such as a diaphragm or condoms. Birth control pills should not be used without a physician's approval. Women who become pregnant while taking this medicine should check with their physicians immediately.

The medicine's effects have not been studied in humans during pregnancy. Women who are pregnant or who may become pregnant and who need to take this medicine should check with their physicians.

BREASTFEEDING. Immunosuppressant drugs pass into breast milk and may cause problems in nursing babies whose mothers take it. Breastfeeding is not recommended for women taking this medicine.

OTHER MEDICAL CONDITIONS. People who have certain medical conditions may have problems if they take immunosuppressant drugs. For example:

• People who have shingles (herpes zoster) or chickenpox, or who have recently been exposed to chickenpox, may develop severe disease in other parts of their bodies when they take these medicines.
• The medicine's effects may be greater in people with kidney disease or liver disease, because their bodies are slow to get rid of the medicine.
• The effects of oral forms of this medicine may be weakened in people with intestinal problems, because the medicine cannot be absorbed into the body.

Before using immunosuppressant drugs, people with these or other medical problems should make sure their physicians are aware of their conditions.

USE OF CERTAIN MEDICINES. Taking immunosuppressant drugs with certain other drugs may affect the way the drugs work or may increase the chance of side effects.

Side effects

Increased risk of infection is a common side effect of all the immunosuppressant drugs. The immune system protects the body from infections and when the immune system is suppressed, infections are more likely. Taking such antibiotics as co-trimoxazole prevents some of these infections. Immunosuppressant drugs are also associated with a slightly increased risk of cancer because the immune system also plays a role in protecting the body against some forms of cancer. For example, long-term use of immunosuppressant drugs carries an increased risk of developing skin cancer as a result of the combination of the drugs and exposure to sunlight.

Other side effects of immunosuppressant drugs are minor and usually go away as the body adjusts to the medicine. These include loss of appetite, nausea or vomiting, increased hair growth, and trembling or shaking of the hands. Medical attention is not necessary unless these side effects continue or cause problems.

The treating physician should be notified immediately if any of the following side effects occur:

• unusual tiredness or weakness
• fever or chills
• frequent need to urinate

KEY TERMS

Antibody— Protein produced by the immune system in response to the presence in the body of an antigen.

Antigen— Any substance or organism that is foreign to the body. Examples of antigens are: bacteria, bacterial toxins, viruses, or other cells or proteins.

Autoimmune disease— A disease in which the immune system is overactive and has lost the ability to distinguish between self and non-self.

Chronic— A word used to describe a long-lasting condition. Chronic conditions often develop gradually and involve slow changes.

Corticosteroids— A class of drugs that are synthetic versions of the cortisone produced by the body. They rank among the most powerful anti-inflammatory agents.

Cortisone— Glucocorticoid produced by the adrenal cortex in response to stress. Cortisone is a steroid with anti-inflammatory and immunosuppressive properties.

Inflammation— A process occurring in body tissues, characterized by increased circulation and the accumulation of white blood cells. Inflammation also occurs in such disorders as arthritis and causes harmful effects.

Inflammatory— Pertaining to inflammation.

Immune response— Physiological response of the body controlled by the immune system that involves the production of antibodies to fight off specific foreign substances or agents (antigens).

Immune system— The network of organs, cells, and molecules that work together to defend the body from foreign substances and organisms causing infection and disease such as: bacteria, viruses, fungi and parasites.

Immunosuppressant— Any chemical substance that suppresses the immune response.

Immunosuppressive— Any agent that suppresses the immune response of an individual.

Immunosuppresive cytotoxic drugs— A class of drugs that function by destroying cells and suppressing the immune response.

Lymphocyte— Lymphocytes are white blood cells that participate in the immune response. The two main groups are the B cells that have antibody molecules on their surface and T cells that destroy antigens.

Psoriasis— A skin disease characterized by itchy, scaly, red patches on the skin.

Rejection— Rejection occurs when the body recognizes a new transplanted organ as "foreign" and turns on the immune system of the body.

T cells— Any of several lymphocytes that have specific antigen receptors, and that are involved in cell-mediated immunity and destruction of antigen-bearing cells.

Transplantation— The removal of tissue from one part of the body for implantation to another part of the body; or the removal of tissue or an organ from one individual and its implantation in another individual by surgery.

Interactions

Immunosuppressant drugs may interact with other medicines. When this happens, the effects of one or both drugs may change or the risk of side effects may be greater. Other drugs may also have an adverse effect on immunosuppressant therapy. This is particularly important for patients taking cyclosporin or tacrolimus. For example, some drugs can cause the blood levels to rise, while others can cause the blood levels to fall and it is important to avoid such contraindicated combinations. Other examples are:

• The effects of azathioprine may be greater in people who take allopurinol, a medicine used to treat gout.
• A number of drugs, including female hormones (estrogens), male hormones (androgens), the antifungal drug ketoconazole (Nizoral), the ulcer drug cimetidine (Tagamet) and the erythromycins (used to treat infections), may increase the effects of cyclosporine.
• When sirolimus is taken at the same time as cyclosporin, the blood levels of sirolimus may be increased to a level where there are severe side effects. Although these two drugs are usually used together, the sirolimus should be taken four hours after the dose of cyclosporin.
• Tacrolimus is eliminated through the kidneys. When the drug is used with other drugs that may harm the kidneys, such as cyclosporin, the antibiotics gentamicin and amikacin, or the antifungal drug amphotericin B, blood levels of tacrolimus may be increased. Careful kidney monitoring is essential when tacrolimus is given with any drug that might cause kidney damage.
• The risk of cancer or infection may be greater when immunosuppressant drugs are combined with certain other drugs which also lower the body's ability to fight disease and infection. These drugs include corticosteroids such as prednisone; the anticancer drugs chlorambucil (Leukeran), cyclophosphamide (Cytoxan) and mercaptopurine (Purinethol); and the monoclonal antibody muromonab-CD3 (Orthoclone), which also is used to prevent transplanted organ rejection.

Not every drug that may interact with immunosuppressant drugs is listed here. Anyone who takes immunosuppressant drugs should let the physician know all other medicines he or she is taking and should ask whether the possible interactions can interfere with treatment.

Resources

BOOKS

Abbas, A. K., and A. H. Lichtman. Basic Immunology: Functions and Disorders of the Immune System. Philadelphia: W. B. Saunders Co., 2001.

Sompayrac, L. M. How the Immune System Works. Boston: Blackwell Science, 1999.

Travers, P. Immunobiology: The Immune System in Health and Disease. 5th edition. New York: Garland Publishers, 2001.

Immunosuppressant Drugs

Definition
Purpose
Description
Recommended dosage
Precautions
Side effects
Interactions

Definition

Immunosuppressant drugs, also called anti-rejection drugs, are used to inhibit or prevent the activity of the body’s immune system. They have three major uses as of the early 2000s: to prevent the body from rejecting a transplanted organ; to treat such autoimmune diseases as rheumatoid arthritis (RA), Crohn’s disease, ulcerative colitis, and systemic lupus erythematosus (SLE); and to treat a few inflammatory diseases that are not autoimmune disorders, such as long-term allergic asthma.

Purpose

When an organ, such as a liver, heart, or kidney, is transplanted from one person (the donor) into another (the recipient), the immune system of the recipient triggers the same response against the new organ that it would have against any foreign material, setting off a chain of events that can damage the transplanted organ. This process is called rejection. It can occur rapidly (acute rejection), or over a long period of time (chronic rejection). Rejection can occur despite close matching of the donated organ and the transplant patient. Immunosuppressant drugs greatly decrease the risks of rejection, protecting the new organ and preserving its function. These drugs act by blocking the recipient’s immune system so that it is less likely to react against the transplanted organ. A wide variety of drugs are available to achieve this aim but work in different ways to reduce the risk of rejection.

In addition to being used to prevent organ rejection, immunosuppressant drugs are also used to treat such severe skin disorders as psoriasis and such other diseases as rheumatoid arthritis, Crohn’s disease (chronic inflammation of the digestive tract), and patchy hair loss (alopecia areata). These conditions are termed autoimmune diseases, indicating that the immune system is reacting against the body itself.

Description

Immunosuppressant drugs can be classified according to their specific molecular mode of action. There are four main categories of immunosuppressant drugs currently used in treating patients with transplanted organs:

• Cyclosporins (Neoral, Sandimmune, SangCya). These drugs act by inhibiting T-cell activation, thus preventing T-cells from attacking the transplanted organ.
• Azathioprines (Imuran). These drugs disrupt the synthesis of DNA and RNA as well as the process of cell division. They are sometimes called cytostatic drugs because they inhibit cell division.
• Monoclonal antibodies, including basiliximab (Simulect), daclizumab (Zenpax), and muromonab (Ortho-clone OKT3). These drugs act by inhibiting the binding of interleukin-2, which in turn slows down the production of T-cells in the patient’s immune system.
• Such corticosteroids as prednisolone (Deltasone, Orasone). These drugs suppress the inflammation associated with transplant rejection.

Most patients are prescribed a combination of drugs—sometimes called a multiple-drug cocktail—after their transplant, one from each of the above main groups; for example, they may be given a combination of

KEY TERMS

Antibody— A protein produced by the immune system in response to the presence in the body of an antigen.

Antigen— Any substance or organism that is foreign to the body. Examples of antigens include bacteria, bacterial toxins, viruses, or other cells or proteins.

Autoimmune disease— A disease in which the immune system is overactive and produces antibodies that attack the body’s own tissues.

Corticosteroids— A class of drugs that are synthetic versions of the cortisone produced by the body. They rank among the most powerful anti-inflammatory agents.

Cortisone— A glucocorticoid compound produced by the adrenal cortex in response to stress. Cortisone is a steroid with anti-inflammatory and immunosuppressive properties.

Cytostatic— A type of drug that inhibits the process of cell division. Azathioprine is an example of a cytostatic drug.

Immune system— The network of organs, cells, and molecules that work together to defend the body from such foreign substances and organisms causing infection and disease as bacteria, viruses, fungi, and parasites.

Immunosuppresive cytotoxic drugs— A class of drugs that function by destroying cells and suppressing the immune response.

Inflammation— A process occurring in body tissues, characterized by increased circulation and the accumulation of white blood cells. Inflammation also occurs in such disorders as arthritis and causes harmful effects.

Lymphocyte— A type of white blood cell involved in the immune response. The two main groups of lymphocytes are the B cells, which carry antibody molecules on their surface; and T cells, which destroy antigens.

Psoriasis— A skin disease characterized by itchy, scaly, red patches on the skin.

T cells— Any of several lymphocytes that have specific antigen receptors, and are involved in cell-mediated immunity and the destruction of antigen-bearing cells.

cyclosporin, azathioprine, and prednisolone. Over a period of time, the doses of each drug and the number of drugs taken may be reduced as the risks of rejection decrease. Most transplant patients, however, will need to take at least one immunosuppressive medication for the rest of their lives.

The major limitation of the immunosuppressant drugs in use as of early 2008 is that they cannot target only those cells involved in graft or transplant rejection; they impair the immune responses of other cells as well. In 2007 a major action plan for further research in transplantation noted the importance of developing immunosuppressive drugs with more specific targets.

Immunosuppressants can also be classified according to the specific organ that is transplanted:

• Basiliximab (Simulect) is also used in combination with such other drugs as cyclosporin and corticosteroids in kidney transplants.
• Daclizumab (Zenapax)is also used in combination with such other drugs as cyclosporin and corticosteroids in kidney transplants.
• Muromonab CD3 (Orthoclone OKT3) is used along with cyclosporin in kidney, liver and heart transplants.
• Tacrolimus (Prograf) is used in liver and kidney transplants. It is under study for bone marrow, heart, pancreas, pancreatic island cell, and small bowel transplantation
• Sirolimus (Rapamune, Rapamycin) is used in kidney transplants.

Some immunosuppressants are also used to treat a variety of autoimmune diseases:

• Azathioprine (Imuran) is used not only to prevent organ rejection in kidney transplants, but also in treatment of rheumatoid arthritis. It has been used to treat chronic ulcerative colitis, although it has proved to be of limited value for this use.
• Cyclosporin (Sandimmune, Neoral) is used in heart, liver, kidney, pancreas, bone marrow, and heart/lung transplantation. The Neoral form of cyclosporin has been used to treat psoriasis and rheumatoid arthritis. The drug has also been used to treat many other conditions, including multiple sclerosis, diabetes, and myasthenia gravis.
• Glatiramer acetate (Copaxone) is used in the treatment of relapsing-remitting multiple sclerosis. In one study, glatiramer reduced the frequency of multiple sclerosis attacks by 75% over a two-year period.
• Mycopehnolate (CellCept) is used along with cyclosporin in kidney, liver, and heart transplants. It has also been used to prevent the kidney problems associated with lupus erythematosus.
• Sirolimus (Rapamune, Rapamycin) is used in combination with other drugs, including cyclosporin and corticosteroids, in kidney transplants. The drug is also used to treat patients with psoriasis.

Recommended dosage

Immunosuppressant drugs are available only with a physician’s prescription. They come in tablet, capsule, liquid, and injectable forms. The recommended dosage depends on the type and form of immunosuppressant drug and the purpose for which it is being used. Doses may be different for different patients. The prescribing physician or the pharmacist who filled the prescription will advise the patient on the correct dosages.

Patients who are taking immunosuppressant drugs should take them exactly as directed. They should never take smaller, larger, or more frequent doses of these medications. In addition, immunosuppressant drugs should never be taken for a longer period of time than directed. The physician will decide exactly how much of the medicine each patient needs. Blood tests are usually necessary to monitor the action of these drugs.

Patients should always consult the prescribing physician before they stop taking an immunosuppressant drug.

Precautions

Patients who are taking immunosuppressant drugs should see their doctor on a regular basis. Periodic checkups will allow the physician to make sure the drug is working as it should and to monitor the patient for unwanted side effects. These drugs are very powerful and can cause such serious side effects as high blood pressure, kidney problems and liver disorders. Some side effects may not show up until years after the medicine was used. Anyone who has been advised to take immunosuppressant drugs should thoroughly discuss the risks and benefits of these medications with the prescribing physician.

Immunosuppressant drugs lower a person’s resistance to infection and can make infections harder to treat. The drugs can also increase the chance of uncontrolled bleeding. Anyone who has a serious infection or injury while taking immunosuppressant drugs should get prompt medical attention and should make sure that the treating physician knows that he or she is taking an immunosuppressant medication. The prescribing physician should be immediately informed if such signs of infection as fever or chills; cough or hoarseness; pain in the lower back or side; painful or difficult urination; bruising or bleeding; blood in the urine; bloody or black, tarry stools occur. Other ways of preventing infection and injury include washing the hands frequently, avoiding sports in which injuries may occur, and being careful when using knives, razors, fingernail clippers, or other sharp objects. Avoiding contact with people who have infections is also important.

In addition, people who are taking or have been taking immunosuppressant drugs should not have such immunizations as smallpox vaccinations without consulting their physician. Because their resistance to infection has been lowered, people taking these drugs might get the disease that the vaccine is designed to prevent. People taking immunosuppressant drugs should avoid contact with anyone who has had a recent dose of oral polio vaccine, as there is a chance that the virus used to make the vaccine could be passed on to them.

Immunosuppressant drugs may cause the gums to become tender and swollen or to bleed. If this happens, a physician or dentist should be notified. Regular brushing, flossing, cleaning, and gum massage may help prevent this problem. A dentist can provide advice on how to clean the teeth and mouth without causing injury.

Special conditions

People who have certain diseases or disorders, or who are taking certain other medicines may have problems if they take immunosuppressant drugs. Before taking these drugs, patients should inform the prescribing physician about any of the following conditions:

ALLERGIES. Anyone who has had unusual reactions to immunosuppressant drugs in the past should let his or her physician know before taking the drugs again. The physician should also be told about any allergies to foods, dyes, preservatives, or other substances.

PREGNANCY. Azathioprine has been considered a cause of birth defects. The British National Formulary, however, states: “Transplant patients immunosuppressed with azathioprine should not discontinue it on becoming pregnant; there is no evidence that azathioprine is teratogenic. There is less experience of ciclosporin in pregnancy but it does not appear to be any more harmful than azathioprine. The use of these drugs during pregnancy needs to be supervised in specialist units. Any risk to the offspring of azathioprine-treated men is small.” Nonetheless, patients who are taking any immunosuppressive drug should consult with their physician before conceiving a child, and they should notify the doctor at once when there is any indication of pregnancy.

Basiliximab should not be used during pregnancy. The manufacturer recommends using adequate contraception during use of this drug, and for eight weeks following the final dose.

The manufacturers warn against the use of tacrolimus and mycophenolate during pregnancy, on the basis of findings from animal studies. They recommend using adequate contraception while taking these drugs, and for six weeks after the last dose.

The safety of corticosteroids during pregnancy has not been absolutely determined. There is some evidence that use of these drugs during pregnancy may affect the baby’s growth; however, this result is not certain, and may vary with the medication used. Patients taking any steroid drug should consult with their physician before starting a family, and should notify the doctor at once if they think they are pregnant.

Most of these medicines have not been studied in humans during pregnancy. Women who are pregnant or who may become pregnant and who need to take immunosuppressants should consult their physicians.

LACTATION. Immunosuppressant drugs pass into breast milk and may cause problems in nursing babies whose mothers take it. Breastfeeding is not recommended for women taking immunosuppressants.

OTHER MEDICAL CONDITIONS. People with any of the following conditions may have problems if they take immunosuppressant drugs:

• People who have shingles (herpes zoster) or chickenpox, or who have recently been exposed to chickenpox, may develop severe disease in other parts of their bodies when they take these medicines.
• Immunosuppressants may produce more intense side effects in people with kidney disease or liver disease, because their bodies are slow to get rid of the medicine.
• Oral forms of immunosuppressants may be less effective in people with intestinal problems, because the medicine cannot be absorbed into the body.

Before using immunosuppressants, people with these or other medical problems should make sure their physicians are aware of their conditions.

Side effects

Increased risk of infection is a common side effect of all immunosuppressant drugs. The immune system protects the body from infections; when the immune system is suppressed, infections are more likely. Taking such antibiotics as co-trimoxazole (SXT, TMP-SMX, or TMP-sulfa) prevents some of these infections. Immunosuppressant drugs are also associated with a slightly increased risk of cancer because the immune system plays a role in protecting the body against some forms of cancer. For example, the long-term use of immunosuppressant drugs carries an increased risk of developing skin cancer as a result of the combination of the drugs and exposure to sunlight.

Other side effects of immunosuppressant drugs are minor and usually go away as the body adjusts to the medicine. These include loss of appetite, nausea or vomiting, increased hair growth, and trembling or shaking of the hands. Medical attention is not necessary unless these side effects continue or cause problems.

The treating physician should be notified immediately if any of the following side effects occur:

• unusual tiredness or weakness
• fever or chills
• frequent need to urinate

Interactions

Immunosuppressant drugs may interact with other medicines. When interactions occur, the effects of one or both drugs may change or the risk of side effects may be greater. Other drugs may also have adverse effects on immunosuppressant therapy. It is particularly important for patients taking cyclosporin or tacrolimus to be careful about the possibility of drug interactions. Other examples of problematic interactions are:

• The effects of azathioprine may be greater in people who take allopurinol, a medicine used to treat gout.
• A number of drugs, including female hormones (estrogens), male hormones (androgens), the antifungal drug ketoconazole (Nizoral), the ulcer drug cimetidine (Tagamet), and the erythromycins (used to treat infections), may intensify the effects of cyclosporine. Certain herbs are also reported to interact with cyclosporine.
• When sirolimus is taken at the same time as cyclosporin, the blood levels of sirolimus may be increased to a level that produces severe side effects. Although these two drugs are usually used together, the dose of sirolimus should be taken four hours after the dose of cyclosporin.
• Tacrolimus is eliminated through the kidneys. When this drug is used with other medications that may harm the kidneys, such as cyclosporin, the antibiotics gentamicin and amikacin, or the antifungal drug amphotericin B, the blood levels of tacrolimus may rise. Careful kidney monitoring is essential when tacrolimus is given with any drug that might cause kidney damage. Tacrolimus is another immunosuppressive drug reported to interact with some over-the-counter herbal preparations.
• The risk of cancer or infection may be greater when immunosuppressant drugs are combined with certain other drugs that also lower the body’s ability to fight disease and infection. These drugs include corticosteroids, especially prednisone; the anticancer drugs chlorambucil (Leukeran), cyclophosphamide (Cytoxan) and mercaptopurine (Purinethol); and the monoclonal antibody muromonab-CD3 (Orthoclone), which is also used to prevent transplanted organ rejection.

Not every drug that may interact with immunosuppressant drugs is listed here. Anyone who takes immunosuppressant drugs should give their doctor a list of all other medicines—including herbal formulations—that he or she is taking and should ask whether there are any potential interactions that might interfere with treatment.

Resources

BOOKS

Abbas, A. K., and A. H. Lichtman. Basic Immunology: Functions and Disorders of the Immune System, 3rd ed. Philadelphia: Saunders/Elsevier, 2009.

Janeway, Charles A. Immunobiology: The Immune System in Health and Disease, 6th ed. New York: Garland Publishers, 2005.

Sompayrac, L. M. How the Immune System Works, 3rd ed. Malden, MA: Blackwell, 2008.

PERIODICALS

Allen, D., and J. Bell. “Herbal Medicine and the Transplant Patient.” Nephrology Nursing Journal 29 (June 2002): 269–274.

Augustine, J. J., and D. F. Hricik. “Minimization of Immunosuppression in Kidney Transplantation.” Current Opinion in Nephrology and Hypertension 16 (November 2007): 535–541.

Leichtman, A. B. “Balancing Efficacy and Toxicity in Kidney-Transplant Immunosuppression.” New England Journal of Medicine 357 (December 20, 2007): 2625–2627.

Yang, X.X., et al. “Drug-Herb Interactions: Eliminating Toxicity with Hard Drug Design.” Current Pharmaceutical Design 12 (2006): 4649–4664.

ORGANIZATIONS

American Association of Immunologists (AAI). 9650 Rockville Pike, Bethesda, MD 20814. (301) 634-7178. www.12.17.12.70/aai/default/asp.

American Society of Health-System Pharmacists (ASHP). 7272 Wisconsin Avenue, Bethesda, MD 20814. (866)279-0681. www.ashp.org.

National Cancer Institute (NCI). NCI Public Inquiries Office, Room 3036A, 6116 Executive Boulevard, Bethesda, MD 20892-8322. (800) 4-CANCER or (800) 332-8615 (TTY). www.nci.nih.gov.

United States Food and Drug Administration (FDA). 5600 Fishers Lane, Rockville, MD 20857-0001. (888) INFO-FDA. www.fda.gov.

OTHER

British National Formulary www.bnf.vhn.net/bnf/documents/bnf.2.html#BNFID_35091.

National Cancer Institute (NCI) and the National Institute of Allergy and Infectious Diseases (NIAID). Understanding the Immune System: How It Works. Bethesda, MD: NCI/NIAID, 2003. NIH Publication No. 03-5423.

Prescilla, Randy P., and Tej K. Mattoo. “Immunology of Transplant Rejection.” eMedicine, June 14, 2006. http://www.emedicine.com/ped/topic2841.htm [cited January 8, 2008].

U.S. Department of Health and Human Services, National Institutes of Health (NIH). Action Plan for Transplantation Research. Bethesda, MD: NIH, 2007. NIH Publication No. 07-5851. Available online in PDF format at http://www3.niaid.nih.gov/about/overview/planningPriorities/trap2007.pdf. [cited January 8, 2008].

Nancy Ross-Flanigan

Samuel Uretsky, PharmD

Rebecca Frey, Ph.D.

Immunosuppressant drugs

Definition

Immunosuppressant drugs, which are also called anti-rejection drugs, are used to prevent the body from rejecting a transplanted organ.

Purpose

When an organ, such as a liver, heart or kidney, is transplanted from one person (the donor) into another (the recipient), the immune system of the recipient triggers the same response against the new organ that it would have against any foreign material, setting off a chain of events that can damage the transplanted organ. This process is called rejection. It can occur rapidly (acute rejection), or over a long period of time (chronic rejection). Rejection can occur despite close matching of the donated organ and the transplant patient. Immunosuppressant drugs greatly decrease the risks of rejection, protecting the new organ and preserving its function. These drugs act by blocking the recipient's immune system so that it is less likely to react against the transplanted organ. A wide variety of drugs are available to achieve this aim but work in different ways to reduce the risk of rejection.

In addition to being used to prevent organ rejection, immunosuppressant drugs are also used to treat such severe skin disorders as psoriasis and such other diseases as rheumatoid arthritis, Crohn's disease (chronic inflammation of the digestive tract), and patchy hair loss (alopecia areata). Some of these conditions are termed "autoimmune" diseases, indicating that the immune system is reacting against the body itself.

Description

Immunosuppressant drugs can be classified according to their specific molecular mode of action. The four main categories of immunosuppressant drugs currently used in treating patients with transplanted organs are the following:

• Cyclosporins (Neoral, Sandimmune, SangCya). These drugs act by inhibiting T-cell activation, thus preventing T-cells from attacking the transplanted organ.
• Azathioprines (Imuran). These drugs disrupt the synthesis of DNA and RNA as well as the process of cell division.
• Monoclonal antibodies, including basiliximab (Simulect), daclizumab (Zenpax), and muromonab (Orthoclone OKT3). These drugs act by inhibiting the binding of interleukin-2, which in turn slows down the production of T-cells in the patient's immune system.
• Such corticosteroids as prednisolone (Deltasone, Orasone). These drugs suppress the inflammation associated with transplant rejection.

Most patients are prescribed a combination of drugs after their transplant, one from each of the above main groups; for example, they may be given a combination of cyclosporin, azathioprine, and prednisolone. Over a period of time, the doses of each drug and the number of drugs taken may be reduced as the risks of rejection decrease. Most transplant patients, however, will need to take at least one immunosuppressive medication for the rest of their lives.

Immunosuppressants can also be classified according to the specific organ that is transplanted:

• Basiliximab (Simulect) is also used in combination with such other drugs as cyclosporin and corticosteroids in kidney transplants.
• Daclizumab (Zenapax)is also used in combination with such other drugs as cyclosporin and corticosteroids in kidney transplants.
• Muromonab CD3 (Orthoclone OKT3) is used along with cyclosporin in kidney, liver and heart transplants.
• Tacrolimus (Prograf) is used in liver and kidney transplants. It is under study for bone marrow, heart, pancreas, pancreatic island cell, and small bowel transplantation

Some immunosuppressants are also used to treat a variety of autoimmune diseases:

• Azathioprine (Imuran) is used not only to prevent organ rejection in kidney transplants, but also in treatment of rheumatoid arthritis. It has been used to treat chronic ulcerative colitis, although it has proved to be of limited value for this use.
• Cyclosporin (Sandimmune, Neoral) is used in heart, liver, kidney, pancreas, bone marrow, and heart/lung transplantation. The Neoral form of cyclosporin has been used to treat psoriasis and rheumatoid arthritis. The drug has also been used to treat many other conditions, including multiple sclerosis, diabetes, and myasthenia gravis.
• Glatiramer acetate (Copaxone) is used in the treatment of relapsing-remitting multiple sclerosis. In one study, glatiramer reduced the frequency of multiple sclerosis attacks by 75% over a two-year period.
• Mycopehnolate (CellCept) is used along with cyclosporin in kidney, liver, and heart transplants. It has also been used to prevent the kidney problems associated with lupus erythematosus.
• Sirolimus (Rapamune) is used in combination with other drugs, including cyclosporin and corticosteroids, in kidney transplants. The drug is also used to treat patients with psoriasis.

Recommended dosage

Immunosuppressant drugs are available only with a physician's prescription. They come in tablet, capsule, liquid, and injectable forms. The recommended dosage depends on the type and form of immunosuppressant drug and the purpose for which it is being used. Doses may be different for different patients. The prescribing physician or the pharmacist who filled the prescription will advise the patient on the correct dosage.

Patients who are taking immunosuppressant drugs should take them exactly as directed. They should never take smaller, larger, or more frequent doses of these medications. In addition, immunosuppressant drugs should never be taken for a longer period of time than directed. The physician will decide exactly how much of the medicine each patient needs. Blood tests are usually necessary to monitor the action of these drugs.

Patients should always consult the prescribing physician before they stop taking an immunosuppressant drug.

Precautions

Patients who are taking immunosuppressant drugs should see their doctor on a regular basis. Periodic checkups will allow the physician to make sure the drug is working as it should and to monitor the patient for unwanted side effects. These drugs are very powerful and can cause such serious side effects as high blood pressure, kidney problems and liver disorders. Some side effects may not show up until years after the medicine was used. Anyone who has been advised to take immunosuppressant drugs should thoroughly discuss the risks and benefits of these medications with the prescribing physician.

Immunosuppressant drugs lower a person's resistance to infection and can make infections harder to treat. The drugs can also increase the chance of uncontrolled bleeding. Anyone who has a serious infection or injury while taking immunosuppressant drugs should get prompt medical attention and should make sure that the treating physician knows that he or she is taking an immunosuppressant medication. The prescribing physician should be immediately informed if such signs of infection as fever or chills; cough or hoarseness; pain in the lower back or side; painful or difficult urination; bruising or bleeding; blood in the urine; bloody or black, tarry stools occur. Other ways of preventing infection and injury include washing the hands frequently, avoiding sports in which injuries may occur, and being careful when using knives, razors, fingernail clippers, or other sharp objects. Avoiding contact with people who have infections is also important.

In addition, people who are taking or have been taking immunosuppressant drugs should not have such immunizations as smallpox vaccinations without consulting their physician. Because their resistance to infection has been lowered, people taking these drugs might get the disease that the vaccine is designed to prevent. People taking immunosuppressant drugs should avoid contact with anyone who has had a recent dose of oral polio vaccine, as there is a chance that the virus used to make the vaccine could be passed on to them.

Immunosuppressant drugs may cause the gums to become tender and swollen or to bleed. If this happens, a physician or dentist should be notified. Regular brushing, flossing, cleaning, and gum massage may help prevent this problem. A dentist can provide advice on how to clean the teeth and mouth without causing injury.

Special conditions

People who have certain diseases or disorders, or who are taking certain other medicines may have problems if they take immunosuppressant drugs. Before taking these drugs, patients should inform the prescribing physician about any of the following conditions:

allergies. Anyone who has had unusual reactions to immunosuppressant drugs in the past should let his or her physician know before taking the drugs again. The physician should also be told about any allergies to foods, dyes, preservatives, or other substances.

pregnancy. Azathioprine has been considered a cause of birth defects. The British National Formulary, however, states: "Transplant patients immunosuppressed with azathioprine should not discontinue it on becoming pregnant; there is no evidence that azathioprine is teratogenic. There is less experience of ciclosporin in pregnancy but it does not appear to be any more harmful than azathioprine. The use of these drugs during pregnancy needs to be supervised in specialist units. Any risk to the offspring of azathioprine-treated men is small." Nonetheless, patients who are taking any immunosuppressive drug should consult with their physician before conceiving a child, and they should notify the doctor at once when there is any indication of pregnancy.

Basiliximab should not be used during pregnancy. The manufacturer recommends using adequate contraception during use of this drug, and for eight weeks following the final dose.

The manufacturers warn against the use of tacrolimus and mycophenolate during pregnancy, on the basis of findings from animal studies. They recommend using adequate contraception while taking these drugs, and for six weeks after the last dose.

The safety of corticosteroids during pregnancy has not been absolutely determined. There is some evidence that use of these drugs during pregnancy may affect the baby's growth; however, this result is not certain, and may vary with the medication used. Patients taking any steroid drug should consult with their physician before starting a family, and should notify the doctor at once if they think they are pregnant.

Most of these medicines have not been studied in humans during pregnancy. Women who are pregnant or who may become pregnant and who need to take immunosuppressants should consult their physicians.

lactation. Immunosuppressant drugs pass into breast milk and may cause problems in nursing babies whose mothers take it. Breastfeeding is not recommended for women taking immunosuppressants.

other medical conditions. People with any of the following conditions may have problems if they take immunosuppressant drugs:

• People who have shingles (herpes zoster) or chickenpox, or who have recently been exposed to chickenpox, may develop severe disease in other parts of their bodies when they take these medicines.
• Immunosuppressants may produce more intense side effects in people with kidney disease or liver disease, because their bodies are slow to get rid of the medicine.
• Oral forms of immunosuppressants may be less effective in people with intestinal problems, because the medicine cannot be absorbed into the body.

Before using immunosuppressants, people with these or other medical problems should make sure their physicians are aware of their conditions.

Side effects

Increased risk of infection is a common side effect of all immunosuppressant drugs. The immune system protects the body from infections; when the immune system is suppressed, infections are more likely. Taking such antibiotics as co-trimoxazole prevents some of these infections. Immunosuppressant drugs are also associated with a slightly increased risk of cancer because the immune system plays a role in protecting the body against some forms of cancer. For example, the long-term use of immunosuppressant drugs carries an increased risk of developing skin cancer as a result of the combination of the drugs and exposure to sunlight.

Other side effects of immunosuppressant drugs are minor and usually go away as the body adjusts to the medicine. These include loss of appetite, nausea or vomiting, increased hair growth, and trembling or shaking of the hands. Medical attention is not necessary unless these side effects continue or cause problems.

The treating physician should be notified immediately if any of the following side effects occur:

• unusual tiredness or weakness
• fever or chills
• frequent need to urinate

Interactions

Immunosuppressant drugs may interact with other medicines. When interactions occur, the effects of one or both drugs may change or the risk of side effects may be greater. Other drugs may also have adverse effects on immunosuppressant therapy. It is particularly important for patients taking cyclosporin or tacrolimus to be careful about the possibility of drug interactions. Other examples of problematic interactions are:

• The effects of azathioprine may be greater in people who take allopurinol, a medicine used to treat gout.
• A number of drugs, including female hormones (estrogens), male hormones (androgens), the antifungal drug ketoconazole (Nizoral), the ulcer drug cimetidine (Tagamet), and the erythromycins (used to treat infections), may intensify the effects of cyclosporine.
• When sirolimus is taken at the same time as cyclosporin, the blood levels of sirolimus may be increased to a level that produces severe side effects. Although these two drugs are usually used together, the dose of sirolimus should be taken four hours after the dose of cyclosporin.
• Tacrolimus is eliminated through the kidneys. When this drug is used with other medications that may harm the kidneys, such as cyclosporin, the antibiotics gentamicin and amikacin, or the antifungal drug amphotericin B, the blood levels of tacrolimus may rise. Careful kidney monitoring is essential when tacrolimus is given with any drug that might cause kidney damage.
• The risk of cancer or infection may be greater when immunosuppressant drugs are combined with certain other drugs that also lower the body's ability to fight disease and infection. These drugs include corticosteroids, especially prednisone; the anticancer drugs chlorambucil (Leukeran), cyclophosphamide (Cytoxan), and mercaptopurine (Purinethol); and the monoclonal antibody muromonab-CD3 (Orthoclone), which is also used to prevent transplanted organ rejection.

Not every drug that may interact with immunosuppressant drugs is listed here. Anyone who takes immunosuppressant drugs should give their doctor a list of all other medicines that he or she is taking and should ask whether there are any potential interactions that might interfere with treatment.

Resources

books

Abbas, A. K., and A. H. Lichtman. Basic Immunology: Functions and Disorders of the Immune System. Philadelphia: W. B. Saunders Co., 2001.

Sompayrac, L. M. How the Immune System Works. Boston: Blackwell Science, 1999.

Travers, P. Immunobiology: The Immune System in Health and Disease, 5th ed. New York: Garland Publishers, 2001.

organizations

American Association of Immunologists (AAI). 9650 Rockville Pike, Bethesda, MD 20814. (301) 634-7178. <www.12.17.12.70/aai/default/asp>.

American Society of Health-System Pharmacists (ASHP). 7272 Wisconsin Avenue, Bethesda, MD 20814. (301) 657-3000. <www.ashp.org>.

British National Formulary. <www.bnf.vhn.net/bnf/documents/bnf.2.html#BNFID_35091>.

National Cancer Institute (NCI). NCI Public Inquiries Office, Suite 3036A, 6116 Executive Boulevard, MSC8332, Bethesda, MD 20892-8322. (800) 4-CANCER or (800) 332-8615 (TTY). <www.nci.nih.gov>.

United States Food and Drug Administration (FDA). 5600 Fishers Lane, Rockville, MD 20857-0001. (888) INFO-FDA. <www.fda.gov>.

Nancy Ross-Flanigan
Samuel Uretsky, PharmD

Immunosuppressant drugs

Immunosuppressant drugs are medications that reduce the ability of the immune system to recognize and respond to the presence of foreign material. Such drugs were developed and still have an important use as a means of ensuring that transplanted organs and tissues are not rejected by the recipient.

Rejection of transplanted organs or tissue is a natural reaction of a person's immune system. In a very real sense, the transplanted material is foreign and is treated, as would be an infectious microorganism. The immune system attacks and tries to destroy the foreign matter. Suppressing the immune system allows the transplanted material to be retained.

Drugs to suppress the immune system are available only with a physician's authorization. Some commonly prescribed drugs are azathioprine, cyclosporine, prednisolone, and tacrolimus. These can be taken orally, both in solid and liquid forms, or can be injected.

The main target of such immunosuppressant drugs are the white blood cells (which are also called lymphocytes). The main function of lymphocytes is to patrol the body and root out foreign material. Then these cells, in combination with other immune system components, destroy the foreign material.

Transplantation of animal kidneys into humans was tried in the early 1900s, and human-to-human transplant attempts were first made in 1933. These attempts were unsuccessful. It was not until the years of World War II that the immunological basis for these failures was deciphered. Then, Peter Medawar observed that a skin graft survived about a week before being rejected, but a subsequent graft was rejected much more quickly. This led him to propose that an immunological response was at play in the rejection of transplanted material. This led to the first successful transplant in 1954, when the kidney of one identical twin was transplanted to the other twin. In the twins, the absence of genetic differences in their tissues would eliminate an immunological response.

As the role of the immune system in transplantation failure became more clear, the use of compounds to suppress the immune system began in the 1960s. In the 1960s and 1970s, the antigenic basis of immune recognition of foreign and non-foreign tissue became evident. With these discoveries came the recognition that the suppression of the immune system could aid in maintaining transplanted tissue. Successful transplantation of the liver was achieved in 1963, of the heart and small bowel in 1967.

In the 1980s, cyclosporin was discovered and shown to be effective in maintaining transplanted material. The clinical use of cyclosporin became standard. By the end of that decade, the use of immunosuppressant drugs just prior to and forever after a transplant had boosted the one-year transplant success rate to more than 80 per cent for all transplants except for the small intestine. In the present day, the survival rate of a kidney transplant is 86 percent even after five years.

Immunosuppressant drugs have other uses as well. Suppressing the immune system can lessen the disfigurement caused by severe forms of skin disorders such as psoriasis. Other examples include rheumatoid arthritis, Crohn's disease (which is an ongoing inflammation of the intestinal tract) and alopecia areata (nonuniform hair loss). In such cases the use of immunosuppressant therapy needs to be evaluated carefully, especially when the condition is not life threatening. This is because the deliberate suppression of the immune system can leave the individual vulnerable to other infections. Also, the clotting of blood can be inhibited, which could produce uncontrolled bleeding.

Another potential risk in the use of immunosuppressant drugs involves the administration of vaccines. The use of vaccines is not advisable when immunosuppressant drugs are being used, especially vaccines that utilize living but weakened bacteria or a virus as the agent designed to elicit protection. The deliberately immunocompromised individual could develop the disease for which the vaccine is intended to prevent.

The same risk analysis applies to the possible side effects of immunosuppressant drugs, which can include a higher than normal risk of developing some kinds of cancer later in life. The link between immunosuppressant drugs and cancer is not yet clear. The link was assumed to be a consequence of the interference with the ability of the body to detect and respond to cancerous cells. Conversely, cancer development has been viewed as being due partially to a failure of the immune system. Yet people with acquired immunodeficiency system, whose immune systems are also compromised, do not show increased rates of cancer. Instead, immunosuppressant drugs such as cyclosporine may themselves encourage the development of cancer by activating a cellular factor that makes cells more invasive.

It is now well known that the deliberate suppression of the immune system carries risks. However, the risks of a side effect or developing another illness, is usually less than the immediate health risk associated with not suppressing the immune system.

See also Autoimmunity and autoimmune diseases; Immunodeficiency

im·mu·no·sup·pres·sion / ˌimyənōsəˈpreshən; iˌmyoō-/ • n. Med. the partial or complete suppression of the immune response of an individual. It is induced to help the survival of an organ after a transplant operation.DERIVATIVES: im·mu·no·sup·pres·sant / -səˈpresənt/ n.im·mu·no·sup·pressed / -səˈprest/ adj.