IMMUNOSUPPRESSANT THERAPY DR FATAI OLUYADI USMLEINCLINED.COM 1

IMMUNOSUPPRESSANT (OVERVIEW)  These drugs prevent the rejection of transplanted organ as well as for the treatment of autoimmune diseases.  Many of them interfere with the lymphocyte cell signalling pathways  Common side effects include immunosuppression and susceptibility to Opportunistic infections such as Cytomegalovirus infections. USMLEINCLINED.COM 2

GROUPS  SELECTIVE INHIBITORS OF CYTOKINE PRODUCTION AND FUNCTION  IMMUNOSUPPRESSIVE ANTIMETABOLITES  ANTIBODIES  CORTICOSTEROIDS USMLEINCLINED.COM 3

Calcium/Calcineurin Pathway USMLEINCLINED.COM 4 Tacrolimus Cyclosporine

SELECTIVE INHIBITORS OF CYTOKINE PRODUCTION AND FUNCTION  CYCLOSPORINE  TACROLIMUS  SIROLIMUS USMLEINCLINED.COM 5

CYCLOSPORINE Inhibits calcineurin by binding cyclophilins. This prevents the transcription of genes responsible for the production of Interleukin 2. Also causes a decrease in expression of Interferon-gamma. Cummulatively results in decreased activity and decreased growth of T-Lymphocytes. Clinical uses This was the first widely used drug to prevent transplant rejection. It is also used to treat autoimmune diseases such as psoriasis and Rheumatoid arthritis. Used as an ophthalmic solution in the treatment of dry eyes. Predominantly metabolized by cytochrome CYP3A4. Watch drug interactions wth CYP inhibitors and inducers. USMLEINCLINED.COM 6

CYCLOSPORINE Adverse effects:  Dose-limiting nephrotoxicity  Neuropathy  Gingival hyperplasia  Hypertension  Hyperlipidemia  Hirsuitism USMLEINCLINED.COM 7

TACROLIMUS Similar to Cyclosporine but binds to FK binding proteins to inhibit calcineurin. Prevents Interleukin 2 transcription and blocking activation and growth of T-cells. Used for transplant rejection prophylaxis and autoimmune diseases e.g ulcerative colitis and vitiligo. Adverse effects Similar to Cyclosporine with the Nephrotoxicity and Neurotoxicity. Can increase risk of diabetes. It does not cause any hirsuitism and ginigival hyperplasa USMLEINCLINED.COM 8

SIROLIMUS(RAPAMYCIN) Inhibits mTOR, a serine/threonine kinase involved in cell growth, proliferation and motility. Involved also in T-cell growth and activation. Clinical Uses Anti-rejection drug that is used most commonly in kidney transplant recipients. Preferred over cyclosporine and tacrolimus for kidney transplant patients due to the latter drugs nephrotoxicity. Sirolimus does not cause nephrotoxicity. It is also used as a coating on cardiac stents to prevent restenosis following ballon angioplasty. Adverse effects: Can cause Interstitial Pneumonitis, Anemia, Thrombocytopenia, Leukopenia, Insulin resistance and hyperlipidemia. USMLEINCLINED.COM 9

IMMUNOSUPPRESSIVE ANTIMETABOLITES  AZATHIOPRINE  MYCOPHENOLATE MOFETIL USMLEINCLINED.COM 10

AZATHIOPRINE This drug is a precursor of 6-Mercaptopurine. Both drugs will inhibit PRPP amidotransferase in the purine synthesis pathway Clinical uses To prevent transplant rejection. Also used in the treatment of autoimmune diseases such as rheumatoid arthritis, crohn’s disease, glomerulonephritis. Adverse effects: Leukopenia, anemia, thrombocytopenia. *Toxicity is increased by Allopurinol USMLEINCLINED.COM 11

MYCOPHENOLATE MOFETIL This drug inhibits 5’-monophosphate dehydrogenase, an enzyme in the purine synthesis pathway, specifically for Guanine. Prevents DNA synthesis and decrease in proliferation of immune cells. Clinical use Used fpr prevention of allograft rejection. Also used for the treatment of autoimmune diseases. Adverse effects: Opportunistic infections and cytopenias are the most common serious adverse effects. USMLEINCLINED.COM 12

ANTIBODIES  ANTITHYMOCYTE GLOBULINS  MUROMONAB-CD3 (OKT3)  DACLIZUMAB/BASILIXIMAB  ALEMTUZUMAB  ADALIMUMAB /INFLIXIMAB  ECULIZUMAB  NATALIZUMAB USMLEINCLINED.COM 13

ANTITHYMOCYTE GLOBULINS These are antibodies developed against thymocytes(T-cell precursors). The antibodies bound to these developing T-cells trigger immune cell activity against these cells via complement mediated destruction, antibody dependent cytotoxicity, apoptosis and opsonisation. Clinical uses: Combine with immune suppressive agents to prevent early allograft rejection, to treat severe rejection episodes or corticosteroid-resistant acute rejection. Adverse effects include chills, fever, leukopenia and thrombocytopenia USMLEINCLINED.COM 14

MUROMONAB Monoclonal antibody directed against CD3 glycoproteins on on human T-cells. Prevents Signal transduction and activation of the T-cells. Clinical uses Treatment of of acute rejection of renal allografts as well as for corticosteroid- resistant acute allograft rejection in cardiac and hepatic transplant patients. Adverse effects Anaphylactoid reactions may occur, CNS effects such as seizures, encephalopathy, cerebral edema, asceptic meningitis, and headache may occur. USMLEINCLINED.COM 15

DACLIZUMAB/BASILIXIMAB These are Monoclonal antibodies against Interleukin 2 receptor. Prevents T-cell proliferation and activation. Clinical uses Used for prophylaxis of acute rejection in renal transplant in combination with cyclosporine. Not used in the treatment of ongoing transplant rejection. Adverse effects: GI toxicity. Edema, Hypertension and tremors can also be seen. USMLEINCLINED.COM 16

ALEMTUZUMAB Monoclonal antibody directed against CD52. Exerts its effect by causing profound depletion of T cells from the peripheral circulation. Clinical uses It is mainly used for the treatment of Refractory Chronic lymphocytic Lymphoma, however it can be used in combination with Sirolimus to prevent organ transplant rejection. Adverse effects include Neutropenia, anemia and rarely Pancytopenia. USMLEINCLINED.COM 17

ADALIMUMAB/INFLIXIMAB Humanized monoclonal antibody directed against tumor necrosis factor alpha. Clinical uses Autoimmune diseases: Rheumatoid arthritis, Ankylossing spondylitis, Psoriasis, Crohn Disease, Ulcerative colitis. Adverse effects: Risk of bone marrow suppression, with increased rate of serious infections. Reactivation of hepatitis B, Fungal Infections and Tuberculosis. USMLEINCLINED.COM 18

MISCELLANEOUS ECULIZUMAB Antibody against complement protein C5. Used in the treatment of Paroxysmal Nocturnal Hemoglobinuria NATALIZUMAB Antibody against Alpha4-integrin. Used in the treatment of Multiple sclerosis and Crohn’s disease. Risk of Progressive Multifocal Leukoencephalopathy by JC virus. USMLEINCLINED.COM 19

CORTICOSTEROIDS  REFER TO LECTURE ON ADRENOCORTICAL PHARMACOLOGY USMLEINCLINED.COM 20