Several drugs used for their immunosuppressant effects in pa-tients undergoing allograft transplantation (transplantation be-tween two people who aren’t identical twins) are also used experi-mentally to treat autoimmune diseases (diseases resulting from an inappropriate immune response directed against the self). They in-clude:
· lymphocyte immune globulin (ATG [equine])
· mycophenolate mofetil
· thymoglobulin (antithymocyte globulin [rabbit]).
Cyclophosphamide, classified as an alkylating drug, is also used as an immunosuppressant; however, it’s primarily used to treat can-cer.
Anakinra is an immunosuppressant used to treat adults with moderate to severe active rheumatoid arthritis who haven’t re-sponded to at least one disease-modifying antirheumatic drug.
Immunosuppressants take different paths through the body.
When administered orally, azathioprine and mycophenolate are readily absorbed from the GI tract, whereas absorption of cy-closporine, tacrolimus, and sirolimus is varied and incomplete.
Anakinra, ATG, basiliximab, daclizumab, muromonab-CD3, and thymoglobulin are administered only by I.V. injection.
The distribution of azathioprine, basiliximab, and daclizumab isn’t fully understood. Cyclosporine and muromonab-CD3 are distrib-uted widely throughout the body. Azathioprine and cyclosporine cross the placental barrier. The distribution of ATG isn’t clear, butit may appear in breast milk. Distribution of tacrolimus depends on several factors; 75% to 99% is protein-bound. Sirolimus is 97% protein-bound.
§ Azathioprine and cyclosporine are metabolized in the liver.
§ Muromonab-CD3 is consumed by T cells circulating in the blood.
§ The metabolism of ATG is unknown.
· Mycophenolate is metabolized in the liver to mycophenolate acid, an active metabolite, and then further metabolized to an in-active metabolite, which is excreted in urine and bile. Concentra-tions of mycophenolate and acyclovir may increase in the pres-ence of nephrotoxicity.
· Azathioprine, anakinra, and ATG are excreted in urine; cy-closporine is excreted principally in bile. It’s unknown how muromonab-CD3 is excreted.
· Tacrolimus is extensively metabolized and excreted primarily in bile; less than 1% is excreted unchanged in urine. Sirolimus is metabolized by the mixed function oxidase system, primarily cy-tochrome P-450 (CYP3A4); 91% is excreted in stool and 2.2% in urine. Metabolism and excretion of basiliximab and daclizumab aren’t understood.
How certain immunosuppressants achieve their desired effects has yet to be determined.
§ The exact mechanism of action of azathioprine, cyclosporine, and
§ ATG is unknown, but may be explained by these theories:
§ Azathioprine antagonizes metabolism of the amino acid purine and, therefore, may inhibit ribonucleic acid and deoxyribonucleic acid structure and synthesis. It also may inhibit coenzyme forma-tion and function.
§ Cyclosporine is thought to inhibit helper T cells and suppressor T cells.
§ ATG may eliminate antigen-reactive T cells in the blood, alter T-cell function, or both.
In patients receiving kidney allografts, azathioprine suppresses cell-mediated hypersensitivity reactions and produces various al-terations in antibody production. Muromonab-CD3, a monoclonal antibody, is understood to block the function of T cells.Anakinra, basiliximab, and daclizumab block the activity of in-terleukin. Mycophenolate inhibits responses of T and B lymphocytes, suppresses antibody formation by B lymphocytes, and may inhibit recruitment of leukocytes into sites of inflammation and graft rejection.
Sirolimus is an immunosuppressant that inhibits T-lymphocyte activation and proliferation that occur in response to antigenic and cytokine stimulation; it also inhibits antibody formation.
Immunosuppressants are used mainly to prevent rejection in pa-tients who undergo organ transplantation. (See Cyclosporine:Miracle drug or death sentence?)
Most drug interactions with this class of drugs involve other im-munosuppressant and anti-inflammatory drugs and various antibi-otic and antimicrobial drugs. (See Adverse reactions to noncorti-costeroid immunosuppressants.)
§ Allopurinol increases the blood levels of azathioprine.
§ Verapamil increases blood levels of sirolimus.
§ Voriconazole shouldn’t be given with sirolimus because the combination inhibits CYP3A4 enzymes, resulting in increased sirolimus levels.
§ When mycophenolate is taken with antacids or cholestyramine, mycophenolate levels decrease.
§ Coadministration of mycophenolate with acyclovir, especially in patients with renal impairment, may increase concentrations of both drugs.
§ Cyclosporine levels may increase if cyclosporine is taken with ketoconazole, calcium channel blockers, cimetidine, anabolic steroids, hormonal contraceptives, erythromycin, or metoclo-pramide.
§ The risk of toxicity to the kidneys increases when cyclosporine or sirolimus is taken with acyclovir, aminoglycosides, or ampho-tericin B.
§ Taking anakinra, ATG, basiliximab, cyclosporine, daclizumab, muromonab-CD3, sirolimus, or thymoglobulin with other immuno-suppressants (except corticosteroids) increases the risk of infec-tion and lymphoma (neoplasm of the lymph tissue; typically malig-nant).
§ Barbiturates, rifampin, phenytoin, sulfonamides, and trimetho-prim decrease plasma cyclosporine and sirolimus levels.
§ Serum digoxin levels may increase when cyclosporine is taken with digoxin.
§ Anakinra shouldn’t be given to patients with active infections or neutropenia.