Immunosuppressant

• In the case of organ transplantation, the immune system can elicit a damaging immune response, causing rejection of the transplanted tissue.
• The drug is generally well tolerated.
• GI toxicity is the main adverse effect.
• Transplantation of organs and tissues, such as kidney, heart, or bone marrow, has become routine due to improved surgical techniques and better tissue typing.
• Drugs are now available that more selectively inhibit rejection of transplanted tissues while preventing the patient from becoming immunologically compromised.
• Earlier drugs were nonselective, causing patients to frequently succumb to infections due to suppression of both the antibody-mediated (humoral) and cell-mediated arms of the immune system.
• The principal approach to immunosuppressive therapy is to alter lymphocyte function using drugs or antibodies against immune proteins.
• Immunosuppressive drug regimens usually consist of two to four agents with different mechanisms of action that disrupt various levels of T-cell activation.
• Immunosuppressive agents may be generally used for prevention of organ transplantation rejection, psoriasis, rheumatoid arthritis, multiple sclerosis, Crohn's disease and ulcerative colitis.
• Cytokines are soluble, antigen-nonspecific signaling proteins that bind to cell surface receptors on a variety of cells.
• The term cytokine includes interleukins (ILs), interferons (IFNs), tumor necrosis factors (TNFs), transforming growth factors (TGF), colony-stimulating factors.
• IL-2 is a growth factor that stimulates the proliferation of “antigen-primed (helper) T cells”, which subsequently produce more IL-2, IFN-γ, and TNF-α.
• These cytokines collectively activate natural killer cells, macrophages, and cytotoxic T lymphocytes.
• Drugs that interfere with the production or activity of IL-2 significantly dampen the immune response and, thereby, decrease graft rejection.
• These drugs can be further divided into three main classes: calcineurin inhibitors (cyclosporine and tacrolimus), co-stimulation blockers (belatacept), and mTOR inhibitors (sirolimus and everolimus).
• Cyclosporine, a calcineurin inhibitor, suppresses cell-mediated immune reactions and is used to prevent rejection of kidney, liver, and cardiac allogeneic transplants.
• Nephrotoxicity is the most common and important adverse effect of Cyclosporine, requiring careful monitoring of kidney function.
• Reduction of the cyclosporine dosage can result in reversal of nephrotoxicity in most cases.
• Co-administration of drugs that also can cause kidney dysfunction, such as aminoglycosides and NSAIDs, can potentiate the nephrotoxicity of cyclosporine.
• Hepatotoxicity is another adverse effect of Cyclosporine, for which liver function should be periodically assessed.
• Viral infections due to the herpes group and cytomegalovirus (CMV) are life-threatening infections associated with Cyclosporine use.
• Other toxicities of Cyclosporine include lymphoma, hypertension, hyperlipidemia, hyperkalemia, hirsutism, glucose intolerance, gum hyperplasia, and gum hyperplasia.
• Tacrolimus is preferred over cyclosporine because of its increased potency, decreased episodes of rejection, and steroid-sparing effects.
• Tacrolimus is used for prevention of liver, kidney, heart and pancreas rejections, rescue therapy in patients after failure of standard rejection therapy, and for the treatment of atopic dermatitis.
• Adverse effects of Tacrolimus include neurotoxicity, nephrotoxicity, development of post-transplant insulin-dependent diabetes, and other toxicities.
• Tacrolimus does not cause hirsutism or gingival hyperplasia, but it can cause alopecia.
• Compared with cyclosporine, tacrolimus has a lower incidence of cardiovascular toxicities, such as hypertension and hyperlipidemia.
• Sirolimus does not lower IL-2 production but, rather, inhibits the cellular response to IL-2.
• Sirolimus is approved for use in renal transplantation, in combination with cyclosporine and corticosteroids, allowing lower doses of those medications to be used thus lowering their toxic potential.
• Adverse effects of Sirolimus include hyperlipidemia, leukopenia, and thrombocytopenia.
• Azathioprine is a prodrug that is converted first to 6-mercaptopurine (6-MP), with lymphocytes being predominantly affected by the cytotoxic effects of azathioprine.
• Basiliximab is an anti-CD25 antibody that binds to the α chain of the IL-2 receptor on activated T cells and, thus, interferes with the proliferation of these cells, used for prophylaxis of acute rejection in renal transplantation.