Immunopharmacology PDF

IMMUNOPHARMACOLOGY Dr Aja Daniel  Immunopharmacology is a branch of pharmacology that deals with immune...

IMMUNOPHARMACOLOGY Dr Aja Daniel  Immunopharmacology is a branch of pharmacology that deals with immune system and of multiple The use combinational therapy. antitumour drugs that have different Mechanisms of action - combinational , often therapy drugs that target different phases of the cell cyple combines with overlapping toxicities with the of synergistic short of cytotoxic drings non use - These cytotoxic countants provide maxioal cell botting efficacy and may slow prevent or from developing resistant cancer cells. Despite intense eport over the last few decades , cancer continues to be the leading death unoted states , hung neoplason In accounts cause of. for largest percentage of the males and and cancer deaths amono, females although prostate breast cancer are highest in incidence Regular smoking modifiable risk factors - , are most common cause worldwide. of cancer At present , a curative or palliative approach to the treatment of cancer patients comprises five 5 modalities ; Surgery - Radiotherapy - chemotherapy - Gene Therapy - Immunotherapy - f Often 2 or more modalities may be combined in the hope of better divical outcome. Adjustment therapy is the of antineoplastic chemotherapy after surgery OT irradiation to diminish the risk of relapse from focu of Microscopic lesions left behind by The therapy y The cells normal goal is to will cancerous or inhibit their growth with minimal effect on cella Normal cells undergo apoptosis programmed cell death after a number of immortal and cell divisions but cancer cells do not undergo apoptosis and are rate of cell divisions are unregulated. Antinoplastic drugs exploit the unregulated↑ rapid rate of cell growth - Major side effects of these include ; - Hair loss Neutropenia - Thrombocytopenia-linked to rapid growth rate of hair follide and bone marrow- - Others include ; strition, - - Nausea. Immunomodulators are drugs that support the immune function by modifying in a beneficial way the immune system response to threat - They are used to treat conditions lime ; - multiple sclerosis -hereditary angioedema - Themator& arthritis cryopin associated periodic syndromes - - They work via; - decreasing inflammation and preventing nerve damage - preventing the immune system from attaching nerves in Spinal cord brain & - blocking Kallirein , brady minin responsible for hereditary angooedema slowing down stopping growth of or cancer cells - blocking activities of interlemming responsible for inflammation - - blocking natural proteins in the body" interlenin-1".  IMMUNO SUPPRESSION The following general principles underline the achievement of clinically effective immuno- suppression; 1 Primary initial immune responses be more easily and effectively suppressed can than secondary immune responses The initial steps in primary immune response. in antogen processing cell proliferation Lymphokine synthesis and differentiation , , are immunosuppressive therapy in general will have only most sensitive to - effect. 2 Immunosuppressive agents do not produce the same effect on a cell immune response - The dose wired to inhibit may differ from to rea an immune response antigen one that required to produce thesame effect with different antogen - Intribution · 3 of immune response is more likely to occur of the immunosuppressive therapy is begnn before rather than after exposure to the immunogen - Ironically all human autoimmune diseases are treated after the fact ie after , autoimmunity is established and chemically apparent or after graft placed are. CHEMICAL INDICATION FOR USE OF IMMUNOSUPPRESSIVE THERAPY There several chemical where are goal of therapy is to suppress an unwanted immune response. These include; 1 Organ transplantation. : 2 Prevention of Rh hemolyEc disease of the newborn. 3 Treatment autoimmune disorders· of  ORGAN TRANSPLANTATION To individual to another , it is transplant issue from one necessary to suppress the normal immune response recipient prevent wa in the to of foreign rection donor tissue - Due to availability of effective immunosuppressive agents , allograft transplantation has been - successful and corticosteroid The non-specific cytotoxic includes azothiopine x cyclophosphamide with cydosporine tacrolimus and mycophenolate They achieve their immunosuppressive effect through inhibition of Lymphocyte proliferation - However they produce side effects on other protigerating call such as bone marrow and 9) cells which suppression and infection can result in bone marrow - When steroids are added , the risk of serious infection and other complications increases further. With Cyclosporine cyclosporine andtacrolimus , many of the can be avoided. responsible for recent Organ transplant is success in - SELECTIVE IMMUNOSUPPRESSION PREVENTION OF RL HEMOLYTE DISEASE OF THE NEWBORN This of the most effective and specific immunosuppressive therapies is one available toda This is a y. design to control selectively immune response that develops in an Rh negative mother who becomes sensitized to the D antgen on fetal erythrocytes of her Rh positive infant at time of birth/miscarriage or ectopic pregnancy - When red cell from the fetus may cross the placenta into the mother circulation - With each subsequent pregnancy antibodies against Rh positive cells many continue to , with greater probability of transfer of antibody to the getus during the 3rd trimester This - result in the can development of erythroblastosis getalis or HDN - for immunosuppression in this setting is based the fact that the The rational on primary antibody response to the foren antigen D-antigen can be blocked of specific antiD antibody is administered passively at thetime of exposure to the antigen. Rh D immunoglobulin is a human IgG globulin solution containing an enriched antibodies fraction of against the Dantoen - As long as the Rh D antibody is administered to the Rh negative mother within 72hrs of birth of a Rh D positive baby any other exposure to antgen maternal or in after abortion miscarriage ectopic the maternal antibody response to circulation , , , Rh-positive cells from the fetus be suppressed- can This been able to HAN even with multiple pregnancies therapeutic approach has prevent - TREATMENT OF AUTOMMUNE AISORDERS Autoimmune diseases arise when the immune system is sensitized by entogenous that are recognized as 'foreign. This results in the formation of antibodies or cells that can react with these immune T antigens present in the tissue to produce destructive changes. Immunosuppressive therapies have been shown to be effective in suppressing autoimmune reaction- *IDX such idiopathic thrombocytopenia purpura autoimmune hemolytic anaemia as , and acute glomerulonephritis respont well to immunosuppressive regimen typically using corticosteroids alone enhancing with cytotoxic sings or - LIMITATIONS OF IMMUNSUPPRESSION Increases all 1 risk of infection of types : : 2 Increases related that have risk of Lymphoma or malignancies recognized in the transplant selling at least some related to impaired immune response to Epstein Barr wit.  CASSIFICATION OF SPECIFIC IMMUNOSUPPRESSIVE AGENTS 1 Cyclosporine and tacrolimus 2 Adrenocortical steroids Costimulation blockers - Relatacept 3 Cytotoxic drugs Abatacept - · 4) Antibody reagents MTOR inhibitors - Sinlimus. 3 Others - Methoxsalen - Everolimus - Thalidomide CYCLOSPORINE AND TACROLIMUS They do not share similar chemical structure and with different biochemical agents They produce similar effect signal transduction Lymphocytes resultin,. on in T desirable immunosuppressive in a - effect CYCLOSPORINE and AIDX Single most important immunosuppressive agent in transplantation : Mechanism of Action ↑ has selective inhibitory effect T Lymphocyte suppressing the early cellular on , to antigenic and regulatory stimuli - response The immunosuppression occurs due formation of theterodimeric complex consisting to a of cydosporine bound to a cytoplasmic receptor protein cyclophilin : The complex then binds to calcineurin inhibiting cast stimulated threonine phosphatase - activity critical for dephosphorylation of cytosolic rewater proteins which after , , are translocated submits removal of phosphate of transcription to the nucleus to serve as factor complex. activation leads to enhanced ↑ cell transcription of 7 cell gene coding for specific cytokines particularly, interlenkin 2 IL2 certain protooncogens and selected cytochine receptors - The to its consequence of cyclosporine binding receptor cyclophilia is the inhibition of , the calcineurin and calcineurin stimulated event - activity suppression of Cyclosporine also attenuate 12-2 production through increased expression of transforming can growth factor is which is potent inhibitor of 12-2 stimulated T cell proliferation a and generation of antigen-specific cytotoxic T Lymphocytes - Increased expression of growth factor may contribute the overall B TGF- B to immunosuppressive effect produced by cyclosporine - Pharmacokinetics Route IV -30mg/nl - Orally 25m 100 my soft get delayed by - as or Absorption story and delayed by falty meal with gelatin but not emulsion - - dioavailability 20-30% - - - Peak level 3 -this-oral 1 : Distributio distributed widely - - - Metabolism - metabolized exclusively in the liver to > 30 metabolites some the metabolites contribute to of of may immunosuppression or toxicity - - Excretion-through the bile mainly into fases - 6% excreted in urine - Doug Interaction It interacts with variety of commonly used drungs - responsible for clearance is accelerated with coadministration of phenobarbital phenytoin Septrin , , and to ampicin due to of hepatic at P450 - clearancedecreases with coadministration of amphotericin b , errythromycin , Ketoconazole - Therapeutic Uses To Immunosuppression for prevention and treatment of transplant rejection : Used for organ transplants 2a · 3 Usefu on disorders where dysfunction of immunoregulation throught to be is an etological factor.. 4 Management of acute Ocular Bencet's syndrome endogenous , atopic theumatoid arthirus active Crohn's disease & nephrotic syndrome - , , Toxicity Renal toxicity nephrotoxicity in 75 % of patients - , Hepatotoxicity - Neurotoxicity - Hypertension - - Hirsutism Gingival hyperplasia - diarrhoea and abdominal G1-nausea routing pain - , , amorexia - , TACROLIMUS Chemistry Machetanticthatis extracted from broth soil fermentation of microorganiso Mechanism of Action Ainhibits T cell activation by binding to the cytosolic protein FR-binding protein. The dong-RP complex stably associates with calcineurin and inhibits the serine/threonine phosphatase activity of the cast dependent ename this inhibiting the calcineurin dependent , activation of Lymphokines expression apoptosis & deregulation. , ↓ inhibits calcineurin and blocks dephosphonation went critical for early Lymphomine like cyclosporine gene expression - Pharmacokinetics - Routes - - proavailability 6-36% oral - - - Metabolism - Extensively in the liver with < 1 % unchanged. Clinical Uses 1 Organ transplant-hepatic 100 % more 2 potent than cyclosporine · - side Efact/Toxicity 1 Nephrotoxicity headache · 2 Neurotoxicity insomnia tremor - , , · 3 Aspertension 4 GI nausea , vomiting diathea anorexia , , Metabolic. 3 - hyperkalemia, hypomagnesenia hypoglycemia , ADRENOCORTICAL STEROID Glucocorticoids used alone combination with other or in immunosuppressive agents for preventing transplant rejection and for treating AX : =. Prednisone Prednisone and , Methylprednisolone. Mechanism of Action It is known that steroids can produce rapid transient reduction in peripheral a blood the circulating Lymphocytes especially in large dose Effect is. due to redistribution of , Lymphocyte- Recent study suggests that steroids inhibit 7- cell proliferation , T-cell dependent immunity and expression of genes encodingcytomines 12-1 , 12-2 , 12-6 , interferon and TNEX : These cytominestogether appear to be able to reverse corticosteroid-induced inhibition of morogen-stimulated T-cell proliferation - Therapeutic Uses To 1 prevent transplant rejection -. To minimize 2 allergic reaction... 3 Used to treat various AIDX. Toxictrs 1 Increased infection. 2 Uler. 3 Hyperglycemic Osteoporosis Cytotoxic Drugs Azathioprine motetal] - Mycopherolate see note in - cancer - Cyclophosphamide therape, Methotrexate Sotherethotrexate - - Chlorambical Vincristine has been - Vinblastin used for immunosuppression. - When corticosteroids bird to glucocorticoid receptors , they form complexa that can ruceus enter the. Inside the nucleus , this complex regulates the involved immune expression of genes in responses.  ANTIODY REAGENTS This is an attractive therapy strategy that enables rapid lowering of the number of Lymphoid cells Lymphocyte or thymocytes as well as suppression of the specific Lymphocyte population. Evolving, technologies hopefully will minimize of with recombinant human antibodies not eliminate the development of antibody response and allergic reaction to antibody reagents. i. Antithymocyte Globalin Prutigie↓ immunoglobulin prepared commercially from hyprimmune serum of horse , ~ abbit ,boat following immunization with human sheep or Lymphocytes - The antithymocyte globulin binds to the surface of the 7-lymphocytes found in circulation T cell immune resulting in Lymphopenia and unpaired responses. Pharmacokinetics kind no be Rontes IV 10-30 mg/kg in Saline Anti-thymocyte globulins to a variety T/2 3-9 days of proteins the leading to T cells on surface of cell death via complement-mediated cytotoxicity Clinical Uses or apoptosis- Treatment of acute allograft rejection 1: o Prophylactically 30 Toxicity ↓ Serum sickness : 2 Leukopenia 3.. Fever 4 - 3 Thrombocytopenia. ii. CD3 monoclonal antibody Murmomas - Mouse monoctional antibody Mechanism of Action The CD3 T Lymphocyte is in close proximity to the antigen recognition glycoprotein on complex - and cannot bind When monoclonal CD3 binds to the CDa glycoprotein antoen is blocked , to the antigen recognition complex. Muromonab CD3 also kinds T-lymphocyte leading to cytokine release through to As result these actions T-cell activating T cells · a of participation in immune response , is inhibited- ↑ cells are depleted from circulation within minutes of administration When I cells. reappear , the CA3 and antigen recognition complex absent These effects prevent are. organ graft rejection - Clinical Uses 1. Used primarily to prevent acute rejection of Kidney lover and heart transplant ,. Used to. 2 deplete T cell from donor bone narrow transplantation- TOXICITY ↑ Cytokine release syndrome r 2 Anaphylactor reaction. CNS 3 toxicity - seizure ence Cerebral Ordema Muromomab specifically targets& birds to CD3 T cells Protein on : called &asiliximal targets different protein a the interleukin-1 activated receptor 12-2R on T cells - iii Rho D Immune Globulin AA Rhogam. High solution of human 1oG with high totre of antibodies against RhD antogen on the RBC - The rationale for use of based on the Rho D immune globulin is fact that the primary anybody formed in response to foreign antoen can be blocked if specific antibody passiadministeredatthelme finalexposuretothearboneintoeno is her Rh born birth positive new or fetus at the time of , miscarriage or ectopic red blood cells pregnancy when feral may lear into the mother's circulation. Pharmacomination Route - IM T/2 21-29 days Clinical 1/ses Used in Rh-negative mothers to prevent sensitization to RhD antoen Toxicity Local ↓ discomfort at site of injection 2 Fevro.. 3 Anaphylactic shock & THER IMMUNO SUPPRESSANTS - Methoxsalin - Thalidomide.  IMMUNOSTIMULANTS General Principle The rationale development of immunostimulant should be for the is that such agents beneficial for individual with immune deficiency- Immunostimulating agents can produce an effect either through cellular or humoral immunity or both. Limitations to use immunostimulants of Effects are generalized throughout the immune system non-specific - - The magnitude of the effect achieved typically has been relatively small limiting its , USC - Indications 1 Immunodeficiency disorder eg. AIDS Chromic infections diseases 2. · Cancer 3 particularly , disorders involving the Lymphatic system - classification - Natural Synthetic - Cytokine - 1. Natural Adjuvants 9 BCG - Bacillus Calmette Guerin Viable attenuated strain of my bacterium boris 3 preparations of BCG - Live untyophilized - live lophilized killed lyophilized - Pharmacokinetics Routes - Intradermal - IV - Intralesional - Intravesicular - Oral Therapeutic Uses - Bladder cancer Many neoplasia -. do Immunoglobulin. 2- Synthetic agents - Levamisole looprnosine - Levamisole anthelminthes noted to increase delay hypersensitivity and or T cell mediated immunity - Clinical Uses Holgain disease - - Rheumatoid arthritis Adjuvant in colorectal - cancer. Isoprinosine Used to natural killer call well increase cytotoxicity as as increase the activity 7 cells o and monocytes - 3. Cytolines - Interferon < - Intertwin 2 Cytolines are a group of diverse produced by leukocytes and related cells They proteins. have discrete roles a number of in regulation of the immune system well as as haematopoiesis - used Interferon alpha and intervenin 2 are commonly as therapeutic agents a. Interferon alpha shown to activate macrophages T Lymphocyte and natural killer cells. Clinical Use - Hair cell lanemia Chronic myeloid lenenia - Raposi's - sarcoma several viral infection -. ↓ Interlenkin - D Recombinant protein Mechanism of Action IL-2 binds to 12-2 surface of responsive cells inducing the receptor on proliferation and diferentiation of 1 helper cells and cells 7 cytotoxic - ↓ also induces B cell proliferation stimulating macrophage activity and increase toxicity of natural miller cells -  Pharmacokinetics Route IV infusion - Sa - IM - Clinical Uses - Metastatic Melanoma - Renal cell carcinoma Toxicity - severe hypotension with life threatening cardiovascular toxicity Dedema Pulmonary - - Renal Toxicity , - Hematologic toxicity bone marrow suppression CNS-somnolence delirium Skin toxicity -