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Chapter: Basic & Clinical Pharmacology : Immunopharmacology

Cytotoxic Agents - Immunosuppressive Agents

Azathioprine is a prodrug of mercaptopurine and, like mercap-topurine, functions as an antimetabolite.



Azathioprine is a prodrug of mercaptopurine and, like mercap-topurine, functions as an antimetabolite. Although its action is presumably mediated by conversion to mer-captopurine and further metabolites, it has been more widely used than mercaptopurine for immunosuppression in humans. These agents represent prototypes of the antimetabolite group of cyto-toxic immunosuppressive drugs, and many other agents that kill proliferative cells appear to work at a similar level in the immune response.

Azathioprine is well absorbed from the gastrointestinal tract and is metabolized primarily to mercaptopurine. Xanthine oxidase splits much of the active material to 6-thiouric acid prior to excre-tion in the urine. After administration of azathioprine, small amounts of unchanged drug and mercaptopurine are also excreted by the kidney, and as much as a twofold increase in toxicity may occur in anephric or anuric patients. Since much of the drug’s inactivation depends on xanthine oxidase, patients who are also receiving allopurinol for control of hyperuricemia should have the dose of azathioprine reduced to one-fourth to one-third the usual amount to prevent excessive toxicity. Azathioprine and mercaptopurine appear to produce immuno-suppression by interfering with purine nucleic acid metabolism at steps that are required for the wave of lymphoid cell proliferation that follows antigenic stimulation. The purine analogs are thus cytotoxic agents that destroy stimulated lymphoid cells. Although continued messenger RNA synthesis is necessary for sustained antibody synthesis by plasma cells, these analogs appear to have less effect on this process than on nucleic acid synthesis in proliferating cells. Cellular immunity as well as primary and secondary serum antibody responses can be blocked by these cytotoxic agents.

Azathioprine and mercaptopurine appear to be of definite benefit in maintaining renal allografts and may be of value in transplantation of other tissues. These antimetabolites have been used with some success in the management of acute glomerulone-phritis and in the renal component of systemic lupus erythemato-sus. They have also proved useful in some cases of rheumatoid arthritis, Crohn’s disease, and multiple sclerosis. The drugs have been of occasional use in prednisone-resistant antibody-mediated idiopathic thrombocytopenic purpura and autoimmune hemo-lytic anemias.

The chief toxic effect of azathioprine and mercaptopurine is bone marrow suppression, usually manifested as leukopenia, although anemia and thrombocytopenia may occur. Skin rashes, fever, nausea and vomiting, and sometimes diarrhea occur, with the gastrointestinal symptoms seen mainly at higher dosages. Hepatic dysfunction, manifested by very high serum alkaline phosphatase levels and mild jaundice, occurs occasionally, particu-larly in patients with preexisting hepatic dysfunction.


The alkylating agent cyclophosphamide is one of the most effica-cious immunosuppressive drugs available. Cyclophosphamide destroys proliferating lymphoid cells  but also appears to alkylate DNA and other molecules in some resting cells. It has been observed that very large doses (eg, > 120 mg/kg intravenously over several days) may induce an apparent specific tolerance to a new antigen if the drug is administered simultane-ously with, or shortly after, the antigen. In smaller doses, it has been effective against autoimmune disorders (including systemic lupus erythematosus) and in patients with acquired factor XIII antibodies and bleeding syndromes, autoimmune hemolytic ane-mia, antibody-induced pure red cell aplasia, and Wegener’s granu-lomatosis.

Treatment with large doses of cyclophosphamide carries con-siderable risk of pancytopenia and hemorrhagic cystitis and therefore is generally combined with stem cell rescue (trans-plant) procedures. Although cyclophosphamide appears to induce tolerance for marrow or immune cell grafting, its use does not prevent the subsequent graft-versus-host disease syn-drome, which may be serious or lethal if the donor is a poor histocompatibility match (despite the severe immunosuppres-sion induced by high doses of cyclophosphamide). Other adverse effects of cyclophosphamide include nausea, vomiting, cardiac toxicity, and electrolyte disturbances.


Leflunomide is a prodrug of an inhibitor of pyrimidine synthesis (rather than purine synthesis). It is orally active, and the active metabolite has a long half-life of several weeks. Thus, the drug should be started with a loading dose, but it can be taken once daily after reaching steady state. It is approved only for rheuma-toid arthritis at present, although studies are underway combining leflunomide with mycophenolate mofetil for a variety of autoim-mune and inflammatory skin disorders, as well as preservation of allografts in solid organ transplantation. Leflunomide also appears (from murine data) to have antiviral activity.

Toxicities include elevation of liver enzymes with some risk of liver damage, renal impairment, and teratogenic effects. A low frequency of cardiovascular effects (angina, tachycardia) was reported in clinical trials of leflunomide.


Hydroxychloroquine is an antimalarial agent with immunosup-pressant properties. It is thought to suppress intracellular antigen processing and loading of peptides onto MHC class II molecules by increasing the pH of lysosomal and endosomal compartments, thereby decreasing T-cell activation.

Because of these immunosuppressant activities, hydroxychloro-quine is used to treat some autoimmune disorders, eg, rheumatoid arthritis and systemic lupus erythematosus. It has also been used to both treat and prevent graft-versus-host disease after allogeneic stem cell transplantation.

Other Cytotoxic Agents

Other cytotoxic agents, including vincristine, methotrexate, and cytarabine , also have immunosuppressive properties. Methotrexate has been used extensively in rheuma-toid arthritis  and in the treatment of graft-versus-host disease. Although the other agents can be used for immunosuppression, their use has not been as widespread as the purine antagonists, and their indications for immunosuppres-sion are less certain. The use of methotrexate (which can be given orally) appears reasonable in patients with idiosyncratic reactions to purine antagonists. The antibiotic dactinomycin has also been used with some success at the time of impending renal transplant rejection. Vincristine appears to be quite useful in idiopathic thrombocytopenic purpura refractory to prednisone. The related vinca alkaloid vinblastine has been shown to pre-vent mast cell degranulation in vitro by binding to microtubule units within the cell and to prevent release of histamine and other vasoactive compounds.

Pentostatin is an adenosine deaminase inhibitor primarilyused as an antineoplastic agent for lymphoid malignancies, and produces a profound lymphopenia. It is now frequently used for steroid-resistant graft-versus-host disease after allogeneic stem cell transplantation, as well as in preparative regimens prior to those transplants to provide severe immunosuppression to prevent allograft rejection.


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