Class immunosuppressants 2

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Class immunosuppressants 2

  1. 1. Dr. RAGHU PRASADA M S MBBS,MD ASSISTANT PROFESSOR DEPT. OF PHARMACOLOGY SSIMS & RC. 1
  2. 2.  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. 3.  Biological agents-  TNFα 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. 4.  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. 5. _ Inhibition of IL-1 and TNF gene expression and synthesis 1. Activation of T lymphocytes by decreasing IL-1 release 2. Neutrophil functions esp. chemotaxis 3. Antibody production (high doses) 4. Release of kinins and proinflammatory eicosanoids (prostaglandins and leukotrienes) 5. lymphocyte mobilization out of lymphoid organs (lymphopenia)
  6. 6.  All commonly occur because high doses used for immunosuppression  Suppression of hypothalamic-pituitary adrenal axis (HPA)  Osteoporosis  Hypertension  Weight gain  Hyperglycemia  Euphoric personality changes  Cataracts
  7. 7. 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
  8. 8. _ 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
  9. 9. _ 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
  10. 10. Structure-macrolide like (Multi-membered lactone ring ) Mechanism Similar 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)
  11. 11. _ 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)
  12. 12. Structure-macrolide like (Multi-membered lactone ring ) _ 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 _ Selective blockade of cytokine signal transduction _ Potential for synergy with other immunosuppressants
  13. 13. P/K-low oral absorption _ hepatic metabolism by CYP4 (drug interactions) _ 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
  14. 14.  MTX is an antifolate belonging to the antimetabolite class of antineoplastic agents.  MTX is a cell cycle specific chemotherapeutic agents that acts on S-phase & thus inhibit DNA synthesis Metabolism Methotrexate undergoes hepatic and intracellular metabolism to active polyglutamated forms and is partially metabolized by intestinal flora after oral administration. Folic acid Tetrahydrofolic acid Dihydrofolate reductase
  15. 15. Absorption Oral absorption is dose dependent. 1 to 2 h (oral) and 30 to 60 min (IM). The mean bioavailability is 60%. Food delays absorption and reduces peak concentration. Distribution Approximately 50% is protein bound. Methotrexate does not penetrate the blood-cerebrospinal fluid barrier in therapeutic amounts when given orally or parenterally, but it has been detected in breast milk. Elimination Renal excretion is the primary route of elimination and is dependent upon dosage and route of administration. With IV administration, 80% to 90% is excreted unchanged in urine within 24 h and less than 10% through biliary excretion. Anti proliferative-Methotrexate
  16. 16. 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 Adverse Effects-diarrhea, leukopenia and CMV infections _ increased incidence of lymphomas
  17. 17.  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 selected leukemias and lymphomas also for stem cell transplant procedures
  18. 18. _ 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 similar to OKT3 _ Antithymocyte Globulin-Rabbit _ used to treat acute renal transplant rejection
  19. 19.  Hypersensitivity reactions may occur with nonhuman antibodies resulting in chills, fever, thrombocytopenia, erythema, pruritus  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
  20. 20. _ 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
  21. 21. 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
  22. 22. _ Immunosuppression by inhibition of lymphocyte proliferation and cause bone marrow suppression _ Azathioprine _ Cyclophosphamide
  23. 23. _ 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
  24. 24.  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
  25. 25. _ 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- Hodgkin's lymphoma

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