Class immunosuppressants 2

1. IMMUNO SUPPRESSANTS Dr. RAGHU PRASADA M S MBBS,MD ASSISTANT PROFESSOR DEPT. OF PHARMACOLOGY SSIMS & RC. 1

2. CLASSIFICATION Inhibitors of lymphocyte gene expression- glucocorticoids - PREDNISOLONE Calcineurin Inhibitors-specific T-cell inhibitors-CYCLOSPORINE, TACROLIMUS M-TOR inhibitors- SIROLIMUS, EVEROLIMUS Antiproliferative drugs- AZATHIOPRINE, METHOTREXATE,, MYCOPHENOLATE MOFETIL CYCLOPHOSPHAMIDE, CHLORAMBUCIL

3. CLASSIFICATION Biological agents- TNF α inhibitors- ETANERCEPT, INFLIXIMAB, ADALIMUMAB IL-1 receptor antagonist : ANAKINRA, RILONACEPT IL-2 receptor antagonist: DACLIZUMAB, BACILIXIMAB Monoclonal antibodies- Anti CD3 antibody : MUROMONAB Anti CD52 antibody: ALEMTUZUMAB

4. CLASSIFICATION Inhibitors of immune cell adhesion- EFALIZUMAB Tolerogens or inhibitors of immune cell costimulation - ABETACEPT, BELATACEPT Polyclonal antibodies: Antithymocyte antibody(ATG), Rho(D) immune globulin

5. Corticosteroid Actions Inhibition of IL-1 and TNF gene expression and synthesis Decreased activation of T lymphocytes by decreasing IL-1 release Decreased neutrophil functions esp chemotaxis Decreased antibody production (high doses) Decreased release of kinins and proinflammatory eicosanoids (prostaglandins and leukotrienes )

6. Corticosteroid Actions Decreased cell-mediated immune reactions that mediate rejection of organ transplants Mechanisms: decreased activation of T lymphocytes by inhibition of IL-1 synthesis by macrophages decreased lymphocyte mobilization out of lymphoid organs ( lymphopenia )

7. Corticosteroid Adverse Reactions All commonly occur because high doses used for immunosuppression Suppression of hypothalamic-pituitary adrenal axis (HPA) function Osteoporosis Hypertension Weight gain Hyperglycemia Euphoric personality changes Cataracts

8. Calcineurin inhibitors Cyclosporine –cyclic polypeptide Inhibits T-cell proliferation, IL-2 and other cytokine production It binds to cyclophilin  inhibits response of helper T-cells to antigenic stimulation fails It enhances expression of TGF- β (Transformation growth factor – β ), an inhibitor of IL-2

9. Cyclosporine other cytokine expression (IL-3, gamma interferon) site of action is a binding protein that inhibits calcineurin (a phosphatase ) involved in signal transduction upon antigen stimulation of T cell receptor

10. Cyclosporine Pharmacokinetics variable, incomplete oral absorption extensive hepatic metabolism, excreted in bile used alone or in combination with prednisone and azathioprine (or other antineoplastic drugs) Adverse Effects nephrotoxicity, hepatotoxicity, hirsutism , neurotoxicity Drug interactions due to induction and inhibition of hepatic cytochrome P450

11. Tacrolimus Structure macrolide (structure like erythromycin) Mechanism similiar to cyclosporine except binds to different protein that inhibits calcineurin (a phosphatase enzyme involved in gene transcription of IL-2, gamma interferon and other cytokines)

12. Tacrolimus given by IV infusion or orally used concomitantly with corticosteroids Adverse Effects nephrotoxicity, increased risk of lymphomas, hypersensitivity, hyperglycemia, GI complaints, hypertension, neurotoxicity (tremor, headache, motor disturbances, seizures)

13. Sirolimus Structure macrolide similiar to tacrolimus Mechanism Binds to FKBP and later binds to calcineurin binds to immunophilin protein that binds to a key regulatory kinase required for T cell activation (new unique mechanism to inhibit T lymphocyte activation by IL-2) different site of action than cyclosporine and tacrolimus

14. Properties of M- TOR Inhibitors Sirolimus Selective blockade of cytokine signal transduction Inhibition of T cell division and proliferation Potent and effective immunosuppression Potential for synergy with other immunosuppressants

15. Sirolimus Bioavailability low oral absorption hepatic metabolism by CYP4 (drug interactions may occur) long half-life (60 hours) Adverse Effects thrombocytopenia, hyperlipidemia , rash lacks direct end organ toxicity but increased incidence impaired renal function when combined with cyclosporine

16. Mycophenolate Mofetil Structure derivative of mycophenolic acid Mechanism inhibits inosine monophosphate dehydrogenase involved in denovo synthesis of purines selectively suppresses T- and B-cell proliferation Also suppresses some macrophage functions (may explain anti-inflammatory actions) Pharmacokinetics oral absorption and hepatic metabolism

17. Mycophenolate Mofetil Adverse Effects diarrhea, leukopenia and CMV infections increased incidence of lymphomas and other malignancies

18. Alemtuzumab New Immunosuppressant Recombinant DNA-derived humanized monoclonal antibody Binds to CD52. a nonmodulating antigen present on surface of all T and B cells Some bone marrow cells express CD52 including some CD34+ cells Produces profound T cell depletion Used for for selected leukemias and lymphomas also for stem cell transplant procedures

19. Antibodies Used for Acute Rejection of Organ Transplants OKT3 (Muromonab-CD3) monoclonal antibody to CD3 on T cell inhibits cytotoxic T killer cell function opsonizes circulating T lymphocytes and enhances their removal used to prevent or reverse acute graft rejection Antilymphocyte Globulin polyclonal antibody similiar to OKT3 Antithymocyte Globulin-Rabbit used to treat acute renal transplant rejection

20. Adverse Effects of Antibody Preps Hypersensitivity reactions may occur with nonhuman antibodies resulting in chills, fever, thrombocytopenia, erythema, pruritis Problem with murine monoclonal antibody called OKT3 is formation of anti-OKT3 antibodies limit its action so only given by IV infusion for 7-14 days

21. IL-2 Receptor Antibodies Basiliximab Chimeric murine monoclonal antibody against human IL-2 receptor alpha subunit of activated T to block T cell Blocks activation and inhibits clonal expansion of T cells Used to induce immunosuppression and to prolong organ transplants in combination with immunosuppressants

22. Other IL-2 Receptor Antibodies Daclizumab a humanized immunoglobulin similar to Basiliximab which blocks IL-2 receptor Formed by splicing complementary portions of light and heavy chain variable regions of murine antibody into human-derived Fab framework and fusing the Fab to the Fc portion of human IgG

23. Antimetabolites Immunosuppresion by inhibition of lymphocyte proliferation and cause bone marrow suppression Azathioprine Cyclophosphamide

24. Interferon Uses Interferon Alpha (prod. by leukocytes) (antiviral, antiproliferative ) malignant melanoma, renal cell carcinoma, hairy cell leukemia, Kaposi’s sarcoma Interferon Beta (prod. by fibroblasts) (antiviral, antiproliferative ) relapsing type MS Interferon Gamma (prod. by lymphocytes) (stimulates NK cells and macrophages) chronic granulomatous disease

25. Cytokine Inhibitors TNF inhibitors (disease modifiers to treat rheumatoid arthritis) Etanercept Recombinant version of TNF receptor Infliximab Chimeric human/ murine anti-TNF monoclonal antibody Anakinra Human IL-1 receptor antagonist Disease modifier agent for Rheumatoid arthritis

26. Other Antibody Preparations Rh (D) Immune Globulin for Rh (neg.) mother after delivery of Rh (pos.) baby Abciximab for surface receptor on activated platelets to prevent restenosis after coronary angioplasty Rituximab for CD20 on pre-B and mature B cells to treat non- hodgkins lymphoma