Immunosuppressive agents toxic effects

This chapter addresses immunosuppressive drugs, or immunosuppressants, that are currently available to prevent the rejection of transplants or to treat specific diseases caused by an autoimmune response. Clearly, these drugs must be used very cautiously because too much suppression of the immune system will increase a patient s susceptibility to infection from foreign pathogens. Likewise, these drugs are rather toxic and often cause a number of adverse effects to the kidneys, lungs, musculoskeletal system, and other tissues. Nonetheless, immunosuppressive agents are often life-... 

Cyclophosphamide (Cytoxan and Endoxan) is used in the treatment of Hodgkin s disease, lymphosarcoma, and other lymphomas. It is employed as a secondary drug in patients with acute leukemia and in combination with doxorubicin in women with breast cancer. A drug combination effective in the treatment of breast cancer is cyclophosphamide, methotrexate, fluorouracil, and prednisone (CMFP). Cyclophosphamide is also an immunosuppressive agent. The toxicity of cyclophosphamide causes alopecia, bone marrow depression, nausea and vomiting, and hemorrhagic cystitis. 

Cyclosporine is a macrolide antibiotic and has been used as an immunosuppressive agent. Cyclosporine can cause both renal and nonrenal toxicity. Clinically renal toxicity consists of four discrete syndromes which include acute reversible renal functional impairment, delayed renal allograft function, acute vasculopathy, and chronic nephropathy with interstitial fibrosis. Proximal tubular epithelium is uniquely sensitive to the toxic effect. The toxic effect is characterized by isometric cytoplasmic vacuolations (several small equally sized vacuoles in cytoplasm), necrosis with or without subsequent mineralization, inclusion bodies (giant mitochondria), and giant lysosomes. Acute vasculopathy consists of vacuolization of the arteriolar smooth muscles and endothelial cells leading to necrosis. In some cases, thrombotic microangiopathy develops, characterized by thrombosis of the renal micro vasculature. Long-term treatment with cyclosporine results in chronic nephropathy with interstitial fibrosis (Chamey et al., 2004). 

A feature of the pharmacologic action of azathioprine is its delayed onset, which may take 8-12 weeks to become apparent, possibly due to the slow accumulation of 6-TGN within the cells. The same is not necessarily true for the toxic effects of azathioprine, some of which may occur at any time during treatment (e.g., bone marrow suppression). Azathioprine appears to be a more potent immunosuppressive agent than does 6-MP itself, which may reflect differences in the pharmacodynamics and pharmacokinetics of the two compounds, as well as the relative abundance of different metabolites which are formed after their administration. Studies with hepatocytes have found that azathioprine toxicity involves depletion of reduced glutathione leading to mitochondrial injury with profound depletion of ATP and cell death by necrosis. Cell death was... 

Commonly reported adverse effects of mycophenolate mofetil include gastrointestinal toxicity (diarrhea, nausea, and vomiting), hematologic effects (anemia, neutropenia, and thrombocytopenia), and an increased incidence of viral and bacterial infections. Lym-phoproliferative disease or lymphoma has developed in up to 1 % of patients who received mycophenolic acid with other immunosuppressive agents. 

Immunosuppressive/Anti-inflammatory Agents - Reports on the apparent clinical effectiveness of immunosuppressive agents in rheumatoid arthritis have greatly stimulated research in this area. ICI hTJl is in toxicity tr i s with the aim to investigate clinical efficacy in auto-immune diseases ... 

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