Immunosuppressive drug.pdf

1 IMMUNOPHARMACOLOGY SBT VI-MPHA 4306 By Dr. Soudabeh  2 Introduction The importance of the immune system in protecting the body against harmful foreign molecules is well recognized. However, in some in...

1 IMMUNOPHARMACOLOGY SBT VI-MPHA 4306 By Dr. Soudabeh  2 Introduction The importance of the immune system in protecting the body against harmful foreign molecules is well recognized. However, in some instances, this protection can result in serious problems. For example, the introduction of an allograft (that is, the graft of an organ or tissue from one individual to another who is not genetically identical) can elicit a damaging immune response, causing rejection of the transplanted tissue. Transplantation of organs and tissues (for example, kidney, heart, or bone marrow) has become routine due to improved surgical techniques and better tissue typing. Drugs are now available that more selectively inhibit rejection of transplanted tissues while preventing the patient from becoming immunologically compromised.  3 The immune activation cascade The immune activation cascade can be described as a three- signal model. Signal 1 constitutes T-cell triggering at the CD3 receptor complex by an antigen on the surface of an antigen-presenting cell (APC). Signal 2, occurs when CD80 and CD86 on the surface of APCs engage CD28 on T cells. Both Signals 1 and 2 activate several intracellular signal transduction pathways, one of which is the calcium calcineurin pathway, which is targeted by cyclosporine and tacrolimus. These pathways trigger the production of cytokines such as interleukin (IL)-2, IL-15, CD154, and CD25. Signal 3, L-2 then binds to CD25 (also known as the IL-2 receptor) on the surface of other T cells to activate mammalian target of sirolimus (mTOR), the stimulus for T-cell proliferation. 4  5 Classification  Immunosuppressive drugs can be categorized according to their mechanisms of action: 1. Some agents interfere with cytokine production or action 2. Some disrupt cell metabolism, preventing lymphocyte proliferation 3. Mono- and polyclonal antibodies block T-cell surface molecules  6 Immunosuppressive drugs SELECTIVE INHIBITORS OF ANTIBODIES CYTOKINE PRODUCTION AND 1. Antithymocyte globulins FUNCTION 2. Basiliximab 1. Cyclosporine 3. Daclizumab 2. Everolimus 4. Muromonab 3. Sirolimus ADRENOCORTICOIDS 4. Tacrolimus 1. Methylprednisolone MMUNOSUPPRESSIVE 2. Prednisolone ANTIMETABOLITES 3. Prednisone 1. Azathioprine 2. Mycophenolate mofetil 3. Mycophenolate sodium  7 SELECTIVE INHIBITORS OF CYTOKINE PRODUCTION AND FUNCTION The term cytokine includes the molecules known as interleukins (ILs), interferons (IFNs), tumor necrosis factors (TNFs), transforming growth factors, and colony-stimulating factors that bind to cell surface receptors on a variety of cells. Of particular interest when discussing immunosuppressive drugs is IL-2, a growth factor that stimulates the proliferation of antigen-primed (helper) T cells, which subsequently produce more IL-2, IFN-γ, and TNF-a. These cytokines collectively activate natural killer cells, macrophages, and cytotoxic T lymphocytes. Drugs that interfere with the production or activity of IL-2, such as cyclosporine, will significantly dampen the immune response and, thereby, decrease graft rejection.  8 Cyclosporine Cyclosporine is used to prevent rejection of kidney, liver, and cardiac allogeneic transplants. Cyclosporine is most effective in preventing acute rejection of transplanted organs when combined in a double-drug or triple- drug regimen with corticosteroids and an antimetabolite such as mycophenolate mofetil. Cyclosporine is an alternative to methotrexate for the treatment of severe, active rheumatoid arthritis. It can also be used for patients with recalcitrant psoriasis that does not respond to other therapies, and it is also used for xerophthalmia. recalcitrant : non responsive to therapy  9 Mechanism of action Cyclosporine preferentially suppresses cell mediated immune reactions, whereas humoral immunity is affected to a far lesser extent. After diffusing into the T cell, cyclosporin binds to a cyclophilin (more generally called an immunophilin) to form a complex that binds to calcineurin. The latter is responsible for dephosphorylating NFATc (cytosolic Nuclear Factor of Activated T cells). Because the cyclosporine-calcineurin complex cannot perform this reaction, NFATc cannot enter the nucleus to promote the reactions that are required for the synthesis of a number of cytokines, including IL-2. The end result is a decrease in IL-2, which is the primary chemical stimulus for increasing the number of T lymphocytes.  10 Pharmacokinetics Cyclosporine may be given either orally or by (IV) infusion. Oral absorption is variable. Cyclosporine is a substrate for P-glycoprotein (P-gp), a drug efflux pump, which limits cyclosporine absorption by transporting the drug back into the gut lumen. Cyclosporine is extensively metabolized, primarily by hepatic CYP3A4. When other drug substrates for this enzyme are given concomitantly, many drug interactions have been reported. Excretion of the metabolites is through the biliary route, with only a small fraction of the parent drug appearing in the urine.  11 Adverse effects Many of the adverse effects caused by cyclosporine are dose dependent. Nephrotoxicity is the most common and important adverse effect of cyclosporine, and it is critical to monitor kidney function, although nephrotoxicity may be irreversible in 15 percent of patients. Coadministration of drugs that also can cause kidney dysfunction (for example, the aminoglycoside antibiotics) and anti-inflammatories, can potentiate the nephrotoxicity of cyclosporine. Because hepatotoxicity can also occur, liver function should be periodically assessed. Infections in patients taking cyclosporine are common and may be life-threatening. Viral infections due to the herpes group and cytomegalovirus (CMV) are prevalent. Anaphylactic reactions can occur on parenteral administration. Other toxicities include hypertension, hyperlipidemia, hyperkalemia , tremor, hirsutism, glucose intolerance, and gum hyperplasia.  12 Tacrolimus (FK506 ) Tacrolimus is approved for the prevention of rejection of liver and kidney transplants and is given with a corticosteroid and/or an antimetabolite. This drug has found favour over cyclosporine, not only because of its potency and decreased episodes of rejection but also because lower doses of corticosteroids can be used, thus reducing the likelihood of steroid-associated adverse effects. An ointment preparation has been approved for moderate to severe atopic dermatitis that does not respond to conventional therapies.  13 Mechanism of action Tacrolimus exerts its immunosuppressive effect in the same manner as cyclosporine, except that it binds to a different immunophilin, FKBP-12 (FK-binding protein).  14 Pharmacokinetics Tacrolimus may be administered orally or IV. The oral route is preferable, but, as with cyclosporine, oral absorption of tacrolimus is incomplete and variable, requiring tailoring of doses. Tacrolimus is subject to gut metabolism by CYP3A4/5 isoenzymes and is a substrate for P-glycoprotein (P-gp). Absorption is decreased if the drug is taken with high-fat or high-carbohydrate meals. Like cyclosporine, tacrolimus undergoes hepatic metabolism by the CYP3A4/5 isozyme, and the same drug interactions occur. Renal excretion is very low, and most of the drug and its metabolites are found in the feces.  15 Adverse effects Nephrotoxicity and neurotoxicity (tremor, seizures, and hallucinations) tend to be more severe in patients who are treated with tacrolimus than in patients treated with cyclosporine. Development of post transplant, insulin-dependent diabetes mellitus is a problem. Other toxicities are the same as those for cyclosporine, except that tacrolimus does not cause hirsutism or gingival hyperplasia. Compared with cyclosporine, tacrolimus has also been found to have a lower incidence of cardiovascular toxicities, such as hypertension and hyperlipidemia, both of which are common disease states found in kidney transplant recipients. The drug interactions are the same as those described for cyclosporine.  16 Sirolimus Sirolimus is approved for use in renal transplantation, to be used together with cyclosporine and corticosteroids, allowing lower doses of those medications to be used, thereby lowering their toxic potential. The combination of sirolimus and cyclosporine is apparently synergistic because sirolimus works later in the immune activation cascade. The antiproliferative action of sirolimus has found use in cardiology. Sirolimus-coated stents (a tube of plastic used to prevent blood vessel from closing, esp after angioplasty) inserted into the cardiac vasculature inhibit restenosis of the blood vessels by reducing proliferation of the endothelial cells.  17 Mechanism of Sirolimus and tacrolimus bind to the same action cytoplasmic FK-binding protein, but instead of forming a complex with calcineurin, sirolimus binds to mTOR, interfering with Signal 3 ,the latter is a serine-threonine kinase. TOR proteins are essential for many cellular functions, such as cell-cycle progression, DNA repair, and as regulators involved in protein translation. Binding of sirolimus to mTOR blocks the progression of activated T cells from the G1 to the S phase of the cell cycle and, consequently, the proliferation of these cells Unlike cyclosporine and tacrolimus, sirolimus does not owe its effect to lowering IL-2 production but, rather, to inhibiting the cellular responses to IL-2.  18 Pharmacokinetics The drug is available only as oral preparations. Although it is readily absorbed, high-fat meals can decrease the drug’s absorption. Like both cyclosporine and tacrolimus, sirolimus is metabolized by the CYP3A4 isozyme and interacts with the same drugs as do cyclosporine and tacrolimus. Sirolimus also increases the drug concentrations of cyclosporine, and careful blood level monitoring of both agents must be done to avoid harmful drug toxicities. The parent drug and its metabolites are predominantly eliminated in feces.  19 Adverse effects A common side effect of sirolimus is hyperlipidemia. The combination of cyclosporine and sirolimus is more nephrotoxic than cyclosporine alone due to the drug interaction between the two, necessitating lower doses. Although the administration of sirolimus and tacrolimus appears to be less nephrotoxic, sirolimus can still potentiate the nephrotoxicity of tacrolimus, and drug levels of both must be monitored closely. Other adverse effects are headache, nausea and diarrhea, leukopenia, and thrombocytopenia, impaired or delayed wound healing following transplantation.  20 Everolimus Everolimus (another mTOR inhibitor) was recently approved for use in renal transplantation in combination with low-dose cyclosporine and corticosteroids. It was originally approved for second-line treatment in patients with advanced renal cell carcinoma. Mechanism of action Everolimus has the same mechanism of action as sirolimus. It inhibits activation of T cells by forming a complex with FKBP-12 and subsequently blocking mTOR.  21 Pharmacokinetic Everolimus is a substrate of CYP3A4 and P-glycoprotein (P-gp) and, thus, is subject to the same drug interactions as previously mentioned immunosuppressants. It has a much shorter half-life than does sirolimus at 30 ― 11 hours and requires twice-daily dosing.  22 Adverse effects Everolimus has similar side effects to sirolimus, including hyperlipidemia, impaired or delayed wound healing following transplantation, and enhanced nephrotoxicity in combination with higher doses of cyclosporine. There is also an increased risk of kidney arterial and venous thrombosis, resulting in graft loss, usually in the first 30 days post transplantation.  23 IMMUNOSUPPRESSIVE ANTIMETABOLITES Immunosuppressive antimetabolite agents are generally used in combination with corticosteroids and the calcineurin inhibitors, cyclosporine and tacrolimus.  24 Azathioprine It is a prodrug that is converted first to 6-mercaptopurine (6MP) and then to the corresponding nucleotide, thioinosinic acid. The immunosuppressive effects of azathioprine are due to this nucleotide analog. Because of their rapid proliferation in the immune response and their dependence on the de novo synthesis of purines required for cell division, lymphocytes are predominantly affected by the cytotoxic effects of azathioprine. Its major nonimmune toxicity is bone marrow suppression. Allopurinol, an agent used to treat gout, significantly inhibits the metabolism of azathioprine. Therefore, the dose of azathioprine must be reduced by 60 to 75 percent. Nausea and vomiting are also encountered.  25 Mycophenolate mofetil Mycophenolate mofetil has, for the most part, replaced azathioprine because of its safety and efficacy in prolonging graft survival. It has been successfully used in heart, kidney, and liver transplants. This is a potent, reversible, uncompetitive inhibitor of inosine monophosphate dehydrogenase, which blocks the de novo formation of guanosine phosphate. Thus, like 6-MP, it deprives the rapidly proliferating T and B cells of a key component of nucleic acids. Lymphocytes lack the pathway for purine synthesis and, therefore, are dependent on de novo purine production.  26 Mechanism of action of mycophenolate GMP = guanosine monophosphate  27 Mycophenolate mofetil Mycophenolic acid is quickly and almost completely absorbed after oral administration. The glucuronide metabolite is excreted predominantly in urine. The most common adverse effects include diarrhea, nausea, vomiting, abdominal pain, leukopenia, and anemia. Higher doses of mycophenolate mofetil were associated with a higher risk of CMV infection. Concomitant administration with antacids containing magnesium or aluminum, can decrease absorption of the drug.  28 ANTIBODIES The use of antibodies plays a central role in prolonging allograft survival. They are prepared either by immunization of rabbits or horses with human lymphoid cells (producing a mixture of polyclonal antibodies directed against a number of lymphocyte antigens), or by hybridoma technology (producing antigen- specific, monoclonal antibodies). Recombinant DNA technology can also be used to replace part of the mouse gene sequence with human genetic material, thus “humanizing” the anti bodies produced, making them less antigenic.  29 Antithymocyte globulins Thymocytes are cells that develop in the thymus and serve as T-cell precursors. The antibodies developed against them are prepared by immunization of rabbits or horses with human lymphoid cells and, thus, are polyclonal. They are primarily used, together with other immunosuppressive agents, at the time of transplantation to prevent early allograft rejection, or they may be used to treat severe rejection episodes or corticosteroid-resistant acute rejection. Rabbit formulations of polyclonal antithymocyte globulin are more commonly used over the horse preparation due to greater potency.  30 Antithymocyte globulins The antibodies bind to the surface of circulating T lymphocytes, which then undergo various reactions, such as complement- mediated destruction, antibody-dependent cytotoxicity, apoptosis. The antibody-bound cells are phagocytosed in the liver and spleen, resulting in lymphopenia and impaired T-cell responses. The antibodies are slowly infused intravenously, and their half- life extends from 3 to 9 days. Adverse effects include chills and fever, leukopenia and thrombocytopenia, infections due to CMV or other viruses, and skin rashes.  31 Muromonab-CD3 This MAb binds to the CD3 antigen on the surface of human thymocytes and mature T cells. It blocks the killing action of cytotoxic T cells and probably interferes with other T-cell functions. Muromonab-CD3 is used to manage renal, cardiac, and liver transplant rejection crises. Serious anaphylactic reactions can occur, especially with the first few doses. Neuropsychiatric may also occur. The suffix mab (monoclonal antibody) identify the category of drug.  32 Daclizumab Daclizumab is a highly specific MAb that binds to the alpha subunit of the IL-2 receptor displayed on the surface of T cells and prevents activation by IL-2. It is used in combination with other immunosuppressants to prevent renal transplant rejection. In contrast to cyclosporine, tacrolimus, or cytotoxic immunosuppressants, the adverse effects of daclizumab are equivalent to those of placebo. Basiliximab is a chimeric human-mouse IgG with an action that is equivalent to that of daclizumab.  33 Corticosteroids Mechanism of Action Glucocorticoids act at multiple cellular sites to cause broad effects on inflammatory and immune processes. At the biochemical level, their actions on gene expression decrease the synthesis of prostaglandins, leukotrienes, cytokines, and other signaling molecules that participate in immune responses (eg, platelet activating factor). At the cellular level, the glucocorticoids inhibit the proliferation of T lymphocytes and are cytotoxic to certain subsets of T cells. Although glucocorticoids impair cell-mediated immunity to the greatest extent, and continuous therapy lowers IgG levels by increasing the catabolic rate of this class of immunoglobulins.  34 Corticosteroids Clinical Use Glucocorticoids are used alone or in combination with other agents in a wide variety of medical conditions that have an underlying undesirable immunologic reaction. They are also used to suppress immunologic reactions in patients who undergo organ transplantation and to treat hematologic cancers. Toxicity Predictable adverse effects include adrenal suppression, growth inhibition, osteoporosis, salt retention, glucose intolerance, and behavioral changes.  35 Immunomodulating Agents Agents that stimulate immune responses represent a newer area in immunopharmacology with the potential for important therapeutic uses, including the treatment of immune deficiency diseases, chronic infectious diseases, and cancer.  36 Aldesleukin Aldesleukin is recombinant interleukin-2 (IL-2), that promotes the production of cytotoxic T lymphocytes and activates NK cells. Aldesleukin is indicated for the adjunctive treatment of renal cell carcinoma and malignant melanoma. It is investigational for possible efficacy in restoring immune function in AIDS and other immune deficiency disorders.  37 Mechanisms of Drug Allergy Immunologic reactions to drugs can fall into any of the 4 categories of hypersensitivity reactions. Type I (Immediate) Drug Allergy Type II Drug Allergy Type III Drug Allergy Type IV Drug Allergy  38 Type I (Immediate) Drug Allergy This form of drug allergy involves IgE-mediated reactions to animal and plant stings and pollens as well as to drugs. Such reactions include anaphylaxis, urticaria, and angioedema. Type I (immediate) sensitivity allergy to certain drugs occurs when the drug, not capable of inducing an immune response by itself, covalently links to a host carrier protein (hapten). When this happens, the immune system detects the drug-hapten conjugate and initiate B- cell proliferation and formation of IgE antibodies. Fixation of the IgE antibody to high-affinity Fc receptors (FcRs) on blood basophils or mast cells sets the stage for an acute allergic reaction. When the offending drug is reintroduced into the body, it binds and cross-links basophil and mast cell-surface IgE to signal release of the mediators (eg, histamine, leukotrienes). Drugs that commonly cause type I reactions include penicillins and sulfonamides.  39 Autoimmune (Type II) Reactions to Drugs Certain autoimmune syndromes can be induced by drugs. Type II reactions include autoimmune syndromes such as a. hemolytic anemia from methyldopa b. systemic lupus erythematosus from hydralazine c. thrombocytopenic purpura from quinidine d. agranulocytosis from exposure to many drugs such as clozapine In these drug-induced autoimmune states, IgG antibodies bind to drug-modified tissue and are destroyed by the complement system or by phagocytic cells with Fc receptors. Fortunately, autoimmune reactions to drugs usually subside within several months after the offending drug is withdrawn.  40 Type III Drug Allergy Immunologic reactions to drugs resulting in serum sickness are more common than immediate anaphylactic responses. The clinical features of serum sickness include urticarial and erythematous skin eruptions, arthralgia or arthritis, lymphadenopathy, glomerulonephritis, peripheral edema, and fever. The reactions generally last 6–12 days and usually subside once the offending drug is eliminated. Antibodies of the IgM or IgG class are usually involved. The mechanism of tissue injury is immune complex formation and deposition on basement membranes (eg, lung, kidney), followed by complement activation and infiltration of leukocytes, causing tissue destruction. Drug-induced serum sickness and vasculitisan (inflammation of the blood vessels) are examples of type III reactions. Stevens-Johnson syndrome (associated with sulfonamide therapy) may also result from type III mechanisms.  41 Type IV Drug Allergy Type IV hypersensitivity is often called delayed type hypersensitivity as the reaction takes two to three days to develop. Unlike the other types, it is not antibody mediated but rather is a type of cell-mediated response and occur from topical application of drugs. It results in contact dermatitis.  42 T H A N K Y O U ;))