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Chapter: Modern Pharmacology with Clinical Applications: Immunomodulating Drugs

Individual Drugs Used to Suppress the Immune System

Cyclosporine (Sandimmune) is a potent inhibitor of an-tibody- and cell-mediated immune responses and is the immunosuppressant of choice for the prevention of transplant rejection. It also has application in the treat-ment of autoimmune diseases.





Cyclosporine (Sandimmune) is a potent inhibitor of an-tibody- and cell-mediated immune responses and is the immunosuppressant of choice for the prevention of transplant rejection. It also has application in the treat-ment of autoimmune diseases.


Cyclosporine is a highly stable 11–amino acid cyclic polypeptide. The molecule is very lipophilic and essen-tially is not soluble in water. It can be administered in-travenously, orally, or by injection.


Mechanism of Action


Cyclosporine can bind to the cytosolic protein cy-tophilin C. This drug–protein complex inhibits cal-cineurin phosphatase activity, which leads to a de-creased synthesis and release of several cytokines, including interleukins IL-2, IL-3, IL-4, interferon- , and tumor necrosis factor.


Cyclosporine exhibits a high degree of specificity in its actions on T cells without significantly impairing B-cell activity. It can inhibit the T cell–dependent limb of antibody production by lymphocytes by preventing the differentiation of B cells into antibody-secreting plasma cells. Because T cells appear to require IL-2 stimulation for their continuous growth, cyclosporine impairs the proliferative response of T cells to antigens. However, once T cells have been stimulated by antigens to syn-thesize IL-2, cyclosporine cannot suppress the prolifer-ation of T cells induced by this cytokine.


Absorption, Metabolism, and Excretion


After oral administration, cyclosporine is absorbed slowly and incompletely, with great variation among individuals. Peak plasma concentrations are reached in 3 to 4 hours, and the plasma half-life is 10 to 27 hours. The drug is extensively metabolized by hepatic mixed-function oxidase enzymes and is excreted principally via the bile into the feces. Metabolism results in inactiva-tion of the immunosuppressive activity. Agents that en-hance or inhibit the mixed-function oxidase enzymes will alter the therapeutic response to cyclosporine.


Clinical Uses


Cyclosporine has been approved for use in allogeneic kidney, liver, and heart transplant patients and is under study for use in pancreas, bone marrow, single lung, and heart–lung transplant procedures. It is recommended that corticosteroids, such as prednisone, be used con-comitantly, although at half or less of their usual dose. Such combined therapy leads to fewer side effects, a de-creased incidence of infectious complications, efficacy of lower doses of cyclosporine, and a better history of patient survival.


Cyclosporine appears to have promise in the treat-ment of autoimmune diseases. It has a beneficial effect on the course of rheumatoid arthritis, uveitis, insulin-dependent diabetes, systemic lupus erythematosus, and psoriatic arthropathies in some patients. Toxicity is more of a problem in these conditions than during use in transplantation, since higher doses of cyclosporine are often required to suppress autoimmune disorders.


Adverse Effects


Compared with previously available therapy, the adverse effects associated with cyclosporine are much less severe but still worthy of concern. Nephrotoxicity, which can oc-cur in up to 75% of patients, ranges from severe tubular necrosis to chronic interstitial nephropathy. This effect is generally reversible with dosage reduction. Vasocon-striction appears to be an important aspect of cyclo-sporine-induced nephrotoxicity. Hypertension occurs in 25% of the patients and more frequently in patients with some degree of renal dysfunction; the concomitant use of antihypertensive drugs may prove useful. Hypergly-cemia, hyperlipidemia, transient liver dysfunction, and unwanted hair growth are also observed.




Corticosteroids, such as prednisone (Deltasone, Meti-corten) and prednisolone (Prelone, Delta-Cortef), have been used alone or in combination with other agents in the treatment of autoimmune disorders and for the pre-vention of allograft rejection. However, the toxicity as-sociated with their use necessitates prudent administra-tion.

Although corticosteroids possess immunosuppressive properties, their real value is in controlling the inflamma-tion that can accompany transplantation and autoim-mune disorders. Virtually all phases of the inflammatory process are affected by these drugs. Corticosteroid ther-apy alone is successful in only a limited number of au-toimmune diseases, such as idiopathic thrombocytope-nia, hemolytic anemia, and polymyalgia rheumatica.




Tacrolimus (Prograf) is a second-generation immuno-suppressive agent that has been approved for use in liver transplantation. Its efficacy for other transplanta-tions is being evaluated. It has properties similar to those of cyclosporine except that weight for weight it is 10 to 100 times more potent. It is a macrolide antibiotic that selectively inhibits transcription of a specific set of lymphokine genes in T lymphocytes (e.g., IL-2, IL-4, and interferon- ) and binds to cytoplasmic proteins in lym-phocytes. Although the binding proteins (cytophilins) for cyclosporine and tacrolimus are different, they share similar functions in that the cytophilins are important for the intracellular folding of proteins. It is speculated that these proteins are important in regulating gene ex-pression in T lymphocytes and that both drugs some-how interfere in this process.


Absorption of tacrolimus from the gastrointestinal (GI) tract is variable. It is extensively metabolized in the liver and excreted in the urine. As with cyclosporine, nephrotoxicity is its principal side effect.




Sirolimus (Rapamune) is structurally related to tacrolimus. It is approved for use as an adjunctive agent in combination with cyclosporine for prevention of acute renal allograft rejection. It blocks IL-2-dependent T-cell proliferation by inhibiting a cytoplasmic serine– threonine kinase. This mechanism of action is different from those of tacrolimus and cyclosporine. This allows sirolimus to augment the immunosuppressive effects of these drugs.





Azathioprine (Imuran) is a cytotoxic agent that prefer-entially destroys any rapidly dividing cell. Since im-munologically competent cells are generally rapidly di-viding cells, azathioprine is very effective as an immunosuppressive drug. Unfortunately, any cell that is replicating is a target for this action. This lack of speci-ficity leads to serious side effects.


Azathioprine, in combination with corticosteroids, has historically been used more widely than any other drug in immunosuppressive therapy. It is classified as a purine antimetabolite and is a derivative of 6-mercap-topurine .


Mechanism of Action


Azathioprine is a phase-specific drug that is toxic to cells during nucleic acid synthesis. Phase-specific drugs are toxic during a specific phase of the mitotic cycle, usually the S-phase, when DNA synthesis is occurring, as opposed to cycle-specific drugs that kill both cycling and intermitotic cells.


Azathioprine is converted in vivo to thioinosinic acid, which competitively inhibits the synthesis of in-osinic acid, the precursor to adenylic acid and guanylic acid. In this way, azathioprine inhibits DNA synthesis and therefore suppresses lymphocyte proliferation. This effectively inhibits both humoral and cell-mediated im-mune responses.


Absorption, Metabolism, and Excretion


Azathioprine is well absorbed following oral adminis-tration, with peak blood levels occurring within 1 to 2 hours. It is rapidly and extensively metabolized to 6-mercaptopurine, which is further converted in the liver and erythrocytes to a variety of metabolites, including 6-thiouric acid. Metabolites are excreted in the urine. The half-life of azathioprine and its metabolites in the blood is about 5 hours.


Clinical Uses


Azathioprine is a relatively powerful antiinflammatory agent. Although its beneficial effect in various condi-tions is principally attributable to its direct immunosup-pressive action, the antiinflammatory properties of the drug play an important role in its overall therapeutic ef-fectiveness.


Azathioprine has been used widely in combination with corticosteroids to inhibit rejection of organ trans-plants, particularly kidney and liver allografts. However, it is usually reserved for patients who do not respond to cyclosporine plus corticosteroids alone.


Azathioprine also has applications in certain disor-ders with autoimmune components, most commonly rheumatoid arthritis. It is as effective as cyclophos-phamide in the treatment of Wegener’s granulomatosis. It has largely been replaced by cyclosporine in im-munosuppressive therapy. Relative to other cytotoxic agents, the better oral absorption of azathioprine is the reason for its more widespread clinical use.


Adverse Effects


The therapeutic use of azathioprine has been limited by the number and severity of adverse effects associated with its administration. Bone marrow suppression re-sulting in leukopenia, thrombocytopenia, or both mayoccur. GI toxicity may be a problem. It is also mildly he-patotoxic. Because of its immunosuppressive activity, azathioprine therapy can lead to serious infections. It has been shown to be mutagenic in animals and humans and carcinogenic in animals.


Mycophenolate Mofetil


Mycophenolate mofetil (CellCept), in conjunction with cyclosporine and corticosteroids, has clinical applica-tions in the prevention of organ rejection in patients re-ceiving allogeneic renal and cardiac transplants. By ef-fectively inhibiting de novo purine synthesis, it can impair the proliferation of both T and B lymphocytes. Following oral administration, mycophenolate mofetil is almost completely absorbed from the GI tract, me-tabolized in the liver first to the active compound my-cophenolic acid, and then further metabolized to an in-active glucuronide.


Early clinical trials indicate that mycophenolate mofetil in conjunction with cyclosporine and cortico-steroids is a more effective regimen than azathioprine in preventing the acute rejection of transplanted organs. GI side effects are most common.


Other Cytotoxic Drugs


Although azathioprine is the most popular cytotoxic drug used for immunosuppression, others have been employed. Among these is cyclophosphamide, a cycle-specific agent that acts by cross-linking and alkylating DNA, thereby preventing correct duplication during cell divisions. Methotrexate is a phase-specific agent that acts by inhibiting folate metabolism. It is highly toxic and appears to offer no advantages over azathio-prine. Chlorambucil, an alkylating agent, has actions similar to those of cyclophosphamide. In contrast, its ad-verse effects are fewer in that alopecia and GI intoler-ance are almost never encountered.




Antiserum can be raised against lymphocytes or thymo-cytes by the repeated injection of human cells into an appropriate recipient, usually a horse. The use of such antiserum or the immune globulin fraction derived from it has been used to produce immunosuppression. Although antilymphocytic serum can suppress cellular and often humoral immunity against a variety of tissue graft systems, the responses are variable, particularly from one batch of serum to another.


Antithymocyte Globulin


Antithymocyte globulin (Atgam) is purified immune globulin obtained from hyperimmune serum of horses immunized with human thymus lymphocytes. It has been used successfully alone and in combination with azathioprine and corticosteroids to prevent renal allo-graft rejection. Although it has benefits when adminis-tered prophylactically, its use during rejection episodes may be its greatest value.


Antithymocyte globulin binds to circulating T lym-phocytes in the blood, which are subsequently removed from the circulation by the reticuloendothelial system. This globulin also reduces the number of T lymphocytes in the thymus-dependent areas of the spleen and lymph nodes.


Since the preparations are raised in heterologous species, reactions against the foreign proteins may lead to serum sickness and nephritis. The concomitant use of corticosteroids may alleviate this response.




Muromonab-(CD3) (Orthoclone OKT3) is a mouse monoclonal antibody that is a purified IgG. It is used for the prevention of acute allograft rejection in kid-ney and hepatic transplants and as prophylaxis in car-diac transplantation. It is also used to deplete T cells in marrow from donors before bone marrow transplanta-tion.


Muromonab-(CD3) alters the cell-mediated im-mune response by binding to the CD3 (cluster of differ-entiation antigen, T3) glycoprotein on T lymphocytes. This binding inhibits lymphocyte activation so that af-fected T cells cannot recognize foreign antigen and can-not participate in rejecting an organ graft. Within min-utes of the first muromonab-(CD3) injection, total circulating T cells are rapidly depleted from the blood. They later reappear devoid of CD3 and antigen recog-nition complexes.


Adverse side effects include fever, pulmonary edema, vomiting, headache, and anaphylaxis. Neutral-izing antibodies may develop over time and necessitate adjusting the dosage upward to compensate for the loss of therapeutic activity.


Rho(D) Immune Globulin


An Rh-negative mother can become sensitized to Rh antigen during delivery of an Rh-positive infant. This sensitization may lead to Rh hemolytic disease in future newborns. Rho(D) immune globulin (RhoGAM) is a preparation of human IgG that contains a high titer of antibodies against the Rh(D) red cell antigen. Rho(D) immune globulin functions to prevent the mother from becoming sensitized to the Rh antigen by binding to and destroying fetal red blood cells that have entered her blood. It is generally given at 28 weeks of pregnancy and within 72 hours after delivery. Rh incompatibility can be identified with routine blood tests.



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