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Complications of immunosuppressive therapy ? * Suppression of immune system .... (lead to infections such as CMV)
Major classes of immunosuppressive agent classes ? * Glucocorticoids -- Calcineurin inhibitors -- Cytotoxic agents -- Biologics
Glucocorticoids = ? * Prednisone -- methylprednisolone -- dexamethasone
Gluco. Uses ? * Prevent rejection - best if given at time of transplant ..... * high doses treat Acute Rejection phases ..... * helps supress/lower GVHD
Gluco. MOA ? * Inhibits innate and acquired immunity by inhibiting T cell proliferation and inhibits IL-2 production (which increase T-cells)
Gluco. SEs ? * Steroid Man
Calcineurin inhibitors (antibiotics)= ? * Cyclosporine and Tacrolimus
Cyclosporine use ? * prophylaxis only - not effective in ongoing rejection
Cyclosporine MOA ? * Binds to cyclophilin --> Cyclosporin-cyclophilin complex binds calcineurin --> prevents IL-2 from being activated (no T-cells) .... * Prevents transcription factors from being made to activate IL-2
Cyclosporine pharmokinetics ? * Narrow TI ….. Need enough dose to prevent rejection, but have to monitor as to not get toxicity
Cyclosporine SEs ? * typical stuff and weird ones --> hirsutism and gingival bleeding ..... * Highly Nephrotoxic (give to prevent rejection, yet it is damaging to an organ you are trying to help) .... * Hyperkalemia - due to decreased K excretion
Tacrolimus MOA and SEs ? * Similar MoA and Use as cyclosporine except binds FKBP rather than cyclophilin.... * No side effects like cyclosporine
Antiproliferative Agent - Sirolimus use and MOA ? * USE: prophylaxis (usually in combo) - + calcineurin inhibitor + glucocorticoid ...... * Binds to FKBP like tacrolimus but Does NOT block IL-2 production, the Sirolimus-FKBP complex binds to mTOR which blocks kinases needed for genes binds mTOR
MOA basics ? * Interrupts T-cell activation downstream of IL-2 receptor --> Inhibits proliferation bc stops cell proliferation at G1-S phase
Sirolimus SEs ? * hyperlipidemia and myelosuppression --> (thrombocytopenia, anemia, leukopenia)
Antiproliferative - Azathioprine uses ? * Prodrug converted to mercaptopurine..... * Primary cytotoxic agent used for immunosuppression to prevent and maintain transplant.... * CAN use in ongoing Rejection
Azathioprine MOA ? * the active metabolite (6-MP) Interferes with purine nucleotide de novo synthesis --> inhibits DNA synthesis ..... acts just like the anti-cancer antimetab purine drugs by (-) TMP/IMP synthesis needed for G and A synthesis
Azathioprine pharmokinetics ? * Metabolized (cleared) by the enzyme xanthine oxidase..... * So Azathioprine dose reduction required when allopurinol is being used
Azathioprine SEs ? * bone marrow suppression -- leukopenia (most common)
Immunosupressant - Mycophenolate mofetil MOA and USE? * Selective, noncompetitive inhibitor of IMPDH --> Stops IMP from being made --> no pureines made ..... * Used w/ glucocorticoid + calcineurin inhibitor --- Has mostly replaced azathioprine for maintenance immunosuppression
Methotrexate use ? * Used extensively to treat GVHD and Rheumatoid arthritis
Immunosuppressive Antibodies purpose ? * lower/impair T-Cells, while keeping humoral immunity intact
Immunosuppressive Antibody ALG when to use ? * is a Polyclonal anti-lymphocyte .... * Major use in kidney transplants after transplant .... *
ATG ? * Polyclonal anti-thymocyte also.... *Used during acute rejection episodes...... * also be used in immunosuppression like ALG
ALG & ATG summary ? * Used to treat donor BM prior to transplantation to destroy T cells to avoid GVHD
ALG AND ATG SEs ? * allergic type reactions from body recognizing foreign particles and mounting a response to them
Muromonab-CD3 (OKT3) MOA? * Directed against CD3 on surface of human thymocytes & mature T-cells ......... * Shuts down activation of T-cell proliferation
Muromonab-CD3 (OKT3) uses and SEs ? * USES: - Treat acute rejection episodes in combination with other drugs --- Deplete donor BM of T-cells prior to BM transplant ...... * not really used anymore bc SEs...... * SEs: fever, chills,and Cytokine Storm ... * body can develop ABs to it also
Daclizumab & Basiliximab MOA ? * Monoclonal antibodies to part of IL-2 receptor (CD25) … IL-2 antagonist ...... * prevents IL-2 from binding to lymphocytes...... ---- * Daclizumab – humanized IgG1 ---- Basiliximab – chimeric mouse-human IgG1
Daclizumab & Basiliximab use ? * Can use long term ..... * Primarily used for prophylaxis against acute rejection of renal transplants in combination with cyclosporine and corticosteroids
For a renal graft rejection, what Treatment (frequency of use) is most commonly used ? * High dose corticosteroid pulse (76%) - 1st line therapy in most centers ...... * Anti T-cell antibody therapy -- Thymoglobulin (ALG AND ATG)(28%)
GVHD Prophylaxis ? * Methotrexate + cyclosporine and deplete T-Cells
Created by: thamrick800