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IMMUNOSUPPRESSANTS

Dr. RAGHU PRASADA M SMBBS,MDASSISTANT PROFESSOR DEPT. OF PHARMACOLOGYSSIMS & RC.

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

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

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

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)

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)

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

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

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

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

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)

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)

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

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

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

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

Mycophenolate Mofetil

Adverse Effectsdiarrhea, leukopenia and CMV infectionsincreased incidence of lymphomas and other

malignancies

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

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

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

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

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

Antimetabolites

Immunosuppresion by inhibition of lymphocyte proliferation and cause bone marrow suppressionAzathioprine Cyclophosphamide

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

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

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