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IMMUNOSUPPRESSANT DRUGS 31st March, 2017 Revision: • READ ON: • Cellular mechanisms:host defence (Pharmacology by Rang & Dale-7th Edition, chapter 6) • Mediators of inflammation and immune reactions (Pharmacology by Rang & Dale-7th Edition, chapter 17) • Understanding the cellular responses and their functions provides an essential basis for understanding the actions of anti-inflammatory and immunosuppressant drugsa major class of therapeutic agents. 2 Immunosuppressants • Most immunosuppressants act in the induction phase of immunological response, • Reducing lymphocyte proliferation; some also inhibit aspects of the effector phase. • The drugs used for immunosuppression can roughly be divided into agents that-: Inhibit interleukin-2 (IL-2) production or action, e.g. Ciclosporin, Tacrolimus; Rapamycin ( also known as Sirolimus ). 3 Immunosuppressants… Inhibit cytokine gene expression e.g. the Corticosteroids. • Act by cytotoxic mechanism; e.g. Cyclophosphamide; Chlorambucil Inhibit purine or pyrimidine synthesis, e.g. Azathioprine; Myclophenolate mofetil Block the T cell surface molecules involved in signaling, e.g. Polyclonal and monoclonal antibodies. 4 Immunosuppressants… • Immunosuppressants are used in the therapy of auto-immune disease and to prevent and/or treat transplant rejection. • Because they impair immune responses, they carry the hazard of a decrease response to infections and may facilitate the emergence of malignant cells. • However; the relationship between these adverse effects and potency in preventing graft rejection varies with different drugs. 5 Summary: Clinical Use of Immunosuppressants • Are used for three main purposes: To suppress rejection of transplanted organs and tissues ( kidneys, bone marrow, heart, liver, etc) To suppress graft-versus-host disease (i.e. the response of lymphocytes in the graft to host antigens) in bone marrow transplants 6 Summary: Clinical Use of Immunosuppressants… To treat a variety of conditions that, while not completely understood, are believed to have an important autoimmune component in their pathogenesis: -idiopathic thrombocytopenic purpura, -some forms of haemolytic anaemia, -some forms of glomerulonephritis, -myasthenia gravis, -systemic lupus erythematosus, -rheumatoid arthritis, -psoriasis and ulcerative colitis 7 Summary: Clinical Use of Immunosuppressants… • The therapy for this third category often involves a combination of glucocorticoid and cytotoxic agents • For transplantation of organs or bone marrow, ciclosporin is usually combined with glucocorticoid, a cytotoxic drug or an antilymphocyte immunoglobin 8 1. CYCLOSPORIN • Is a fungal peptide with potent immunosuppressive activity but no effect on the acute inflammatory reaction per se. • It was discovered by Borel and his coworkers in 1976 in the course of screening fungal products for anti-fungal activity and soon revolutionized the field of organ transplantation; significantly reducing the morbidity and the incidence of rejection. 9 Mechanism of Action • Cyclosporin has numerous actions on various cell types; including-: Decreased clonal proliferation of T cells, primarily by inhibiting interleukin-2 release and possibly also by decreasing expression of interleukin-2 receptors. Reduced induction of and clonal proliferation of cytotoxic T cells from CD8+ precursor T cells. 10 Mechanism of Action… Reduced function of the effector T cells that mediate cell-mediated responses ( e.g. decreased delayed-type hypersensitivity ). Some reduction of T-cell-dependent B cell responses 11 Pharmacokinetic Aspects • Cyclosporin can be given orally or by intravenous infusion. • After oral administration, absorption from G.I.T. is rather poor and varies in different individuals but peak plasma concentrations are usually attained in about 3 to 4 hours. 12 Pharmacokinetic Aspects… • Alternative formulations with improved oral absorption are now available. • Plasma half-life is approx. 24 hours. • Metabolism occurs in the liver and most of metabolite ( of which 14 have been identified ) are excreted in the bile. 13 Pharmacokinetic Aspects… • It accumulates in most tissues at concentrations 3 to 4 times that seen in the plasma. • Some of the drug remains in lymphomyeloid tissue and later in fat depots for some time after administration has been stopped. • Other drugs (e.g. Ketoconazole ) may increase the plasma concentration of cyclosporin. 14 Unwanted Effects • The commonest and most serious is nephrotoxicity. Hepatotoxicity and hypertension can also occur. • Less important unwanted effects are anorexia; lethargy; hirsutism; tremor paraesthesia ( tingling sensation ) gum hypertrophy and G.I.T. disturbances. • Cyclosporin has no depressant effects on the bone marrow. 15 2. TACROLIMUS • Originally termed FK506; is a macrolide antibiotic with a very similar mechanism of action to cyclosporin, the main difference being that the internal receptor for this drug is not cyclophilin but FK-binding protein ( FKBP ). • The tacrolimus-FKBP complex inhibits calcineurin with the effects described above. • Tacrolimus is active at lower 16 concentrations than Cyclosporin. Pharmacokinetic aspects • Tacrolimus can be given orally or by intravenous injection. • It is 99 % metabolized by the liver and has a half-life of approximately 7 hours. 17 Unwanted Effects • The unwanted effects of Tacrolimus are similar to those of Cyclosporin but are more severe. • Nephrotoxicity and hypertension have so far not been a serious problem. • Neurotoxicity; G.I.T. upsets and metabolic disturbances (hyperglycaemia) can occur. • Thrombocytopenia and hyperlipidaemia have been reported but are reversible by 18 reducing the dosage. 3. GLUCOCORTICOIDS • Immunosuppression by glucocorticoids involves both their effects on the immune response and their inflammatory actions. • Glucocorticoids are immunosuppressant mainly because, like Cyclosporin, they restrain the clonal proliferation of the Th cells, through decreasing transcription of the gene for IL-2; 19 GLUCOCORTICOIDS… • However, they also decrease the transcription of many other cytokine genes ( including those for tumour necrosis factor-TNF-, interferon-, IL-1 and many other interleukins ) in both the induction and effector phases of the immune response. • These effects on transcription are mediated through inhibition of the action of transcription factors, such as AP-1 and NF-KappaB 20 4. AZATHIOPRINE • It interferes with purine synthesis and is cytotoxic. • It is widely used for immunosuppression particularly for control of tissue rejection in transplant surgery. • This drug is metabolized to give Mercaptopurine, a purine analogue that inhibits DNA synthesis. 21 AZATHIOPRINE… • Both cell-mediated and antibody-mediated immune reactions are depressed by this drug since it inhibits clonal proliferation in the induction phase of the immune response by a cytotoxic action on dividing cells. • The unwanted effect in this drug is depression of bone-marrow. • Other toxic effects are nausea and vomiting, skin eruptions and a mild 22 hepatotoxicity. 5. CYCLOPHOSPHAMIDE • Is a cytotoxic agent with powerful immunosuppressive effects. • It is an alkylating agent with particular action on lymphocytes. • As an immunosuppressant it affects the clonal proliferative phase of immune response and reduces both antibodymediated and cell-mediated immune reactions. 23 6. CHLORAMBUCIL • Another alkylating cytotoxic agent; is also used for immunosuppression and has effects similar to those of Cyclophosphamide. 24 7. MYCOPHENOLATE MOFETIL • Is a semi-synthetic derivative of fungal antibiotic. • In the body it is converted to Mycophenolic acid which restrains proliferation of both T and B lymphocytes and reduces production of cytotoxic T cells by inhibiting inosine monophosphate dehydrogenase; an enzyme crucial for de novo purine biosynthesis. • T and B cells are particularly dependent on this pathway so the drug has a fairly selective action on these cells. 25 Pharmacokinetic Aspects & Unwanted Effects • It is given orally and well absorbed. • Magnesium and Aluminium hydroxides impair absorption and Cholestyramine reduces plasma concentrations. • The metabolite Mycophenolic acid, undergoes enterohepatic cycling and is eliminated by the kidney as the inactive glucuronide. 26 • Unwanted G.I.T. effects are common. • Used with Cyclosporin and Steroids; it has proved to have effective immunosuppressant action in several clinical trials of kidney transplant rejection. 27 8. IMMUNOGLOBULINS • Antibodies against human lymphocytes have significant immunosuppressant action. • These antibodies are raised by immunizing horses or rabbits, or from mice using hybridoma technology. 28 8. IMMUNOGLOBULINS… • Their disadvantage is that the foreign antibodies themselves elicit an immune response. • To avoid this, animal immunoglobulin can now be ‘ humanized ‘ by genetic engineering to combine the antigenbinding ( Fab ) site of a mouse monoclonal antibody with human immunoglobulin. 29 9. POLYCLONAL ANTIBODIES • Anti-lymphocyte immunoglobulin (ALG ) and anti-thymocyte immunoglobulin ( ATG ) are obtained by immunizing horses with human lymphocytes or with fetal thymic tissue respectively. • These antibodies interact with multiple surface proteins implicated in T cell signal transduction and have indiscriminate action against both useful T cells and 30 those that produce unwanted effects. POLYCLONAL ANTIBODIES… • The immunoglobulin ‘ recognizes ‘ and binds to protein on the lymphocyte surface causing exposure of the complementbinding site on the Fc portion of the immunoglobulin; this activates the complement system leading to the lysis of the lymphocyte. 31 POLYCLONAL ANTIBODIES… • The unwanted effects are mainly those to be expected with injection of foreign protein. • Antibodies against the foreign immunoglobulin can be produced; anaphylactic reaction can occur. 32 10. MONOCLONAL ANTIBODIES • Monoclonal antibodies directed against surface component of T cells include immunoglobulin targeting the complex CD3 protein with antigen receptor ( muromonab-CD3; OKT3 ), the CD4 co-receptor and IL-2 receptor. • Some are currently being used, some are being assessed. • Initial doses of OKT3 can cause fever, hypotension, pulmonary oedema, nephropathy and encephalopathy, which is thought to be due to cytokine release; pretreatment with steroids 33 diminishes these effects. 11. RAPAMYCIN ( SIROLIMUS ) • This is a macrolide antibiotic that, like Tacrolimus, binds to the intracellular immunophilin FKBP. • However, the complex does not bind calcineurin nor does it affect IL-2 gene transcription; it interferes with the IL-2 signal transduction pathway, blocking the cell cycle of activated T cell in G1 phase . • Rapamycin competes with Tacrolimus for FKBP in vitro but their effects are additive in vivo. 34 RAPAMYCIN ( SIROLIMUS ) • This drug also reduces smooth muscle proliferation. • Phase I and II clinical trials of Rapamycin supplementation of Cyclosporin regimes are under way. • Nephrotoxicity and hypertension have not been serious problems and hyperlipidaemia and thrombocytopenia, have responded to reduction in drug dosage. 35 36