Immunosuppressant Drugs

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. .

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

British National Formulary. .

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). .

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

Nancy Ross-Flanigan
Samuel Uretsky, PharmD