class immunosuppressants 2
DESCRIPTION
TRANSCRIPT
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1
IMMUNOSUPPRESSANTS
Dr. RAGHU PRASADA M SMBBS,MDASSISTANT PROFESSOR DEPT. OF PHARMACOLOGYSSIMS & RC.
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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
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CLASSIFICATION
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
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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
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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)
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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)
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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
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Calcineurin inhibitors
Cyclosporine –cyclic polypeptideInhibits T-cell proliferation, IL-2 and other cytokine
productionIt binds to cyclophilin inhibits response of helper T-
cells to antigenic stimulation failsIt enhances expression of TGF-β (Transformation
growth factor – β), an inhibitor of IL-2
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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
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Cyclosporine
Pharmacokineticsvariable, incomplete oral absorptionextensive hepatic metabolism, excreted in bileused alone or in combination with prednisone and
azathioprine (or other antineoplastic drugs)Adverse Effects
nephrotoxicity, hepatotoxicity, hirsutism, neurotoxicityDrug interactions due to induction and inhibition of
hepatic cytochrome P450
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Tacrolimus
Structuremacrolide (structure like erythromycin)
Mechanismsimiliar 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)
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Tacrolimus
given by IV infusion or orallyused concomitantly with corticosteroids
Adverse Effectsnephrotoxicity, increased risk of lymphomas,
hypersensitivity, hyperglycemia, GI complaints, hypertension, neurotoxicity (tremor, headache, motor disturbances, seizures)
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Sirolimus
Structuremacrolide 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
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Properties of M-TOR InhibitorsSirolimus
Selective blockade of cytokine signal transduction Inhibition of T cell division and proliferation Potent and effective immunosuppression Potential for synergy with other immunosuppressants
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Sirolimus
Bioavailabilitylow oral absorptionhepatic metabolism by CYP4 (drug interactions may
occur)long half-life (60 hours)
Adverse Effectsthrombocytopenia, hyperlipidemia, rashlacks direct end organ toxicity but increased incidence
impaired renal function when combined with cyclosporine
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Mycophenolate Mofetil Structure
derivative of mycophenolic acid Mechanism
inhibits inosine monophosphate dehydrogenase involved in denovo synthesis of purines
selectively suppresses T- and B-cell proliferationAlso suppresses some macrophage functions (may
explain anti-inflammatory actions) Pharmacokinetics
oral absorption and hepatic metabolism
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Mycophenolate Mofetil
Adverse Effectsdiarrhea, leukopenia and CMV infectionsincreased incidence of lymphomas and other
malignancies
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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
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Antibodies Used for Acute Rejection of Organ Transplants OKT3 (Muromonab-CD3)
monoclonal antibody to CD3 on T cellinhibits cytotoxic T killer cell functionopsonizes circulating T lymphocytes and enhances their
removalused to prevent or reverse acute graft rejection
Antilymphocyte Globulinpolyclonal antibody similiar to OKT3
Antithymocyte Globulin-Rabbit used to treat acute renal transplant rejection
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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
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IL-2 Receptor Antibodies
Basiliximab Chimeric murine monoclonal antibody against human
IL-2 receptor alpha subunit of activated T to block T cellBlocks activation and inhibits clonal expansion of T cellsUsed to induce immunosuppression and to prolong
organ transplants in combination with immunosuppressants
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Other IL-2 Receptor Antibodies
Daclizumaba humanized immunoglobulin similar to Basiliximab
which blocks IL-2 receptorFormed 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
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Antimetabolites
Immunosuppresion by inhibition of lymphocyte proliferation and cause bone marrow suppressionAzathioprine Cyclophosphamide
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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
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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
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Other Antibody Preparations
Rh(D) Immune Globulinfor Rh (neg.) mother after delivery of Rh(pos.) baby
Abciximabfor 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
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