Immunomodulators

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Immunomodulators are very important drugs to regulate the dysregulated immune system

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IMMUNOMODULATORS:

IMMUNOMODULATORS Prof. R. K. Dixit Pharmacology and Therapeutics King George’s Medical University Lucknow

Line of Defense in the Body:

Line of Defense in the Body Innate Adaptive

Immunity System:

Immunity System

Cells of the Immune System :

Cells of the Immune System Antibodies

Immune System:

Immune System A biochemical complex that protects the body against Pathogenic organisms, Foreign bodies and Its own cells that become cancerous. Immunity: Innate, Natural -Complement, Granulocytes, Monocytes /macrophages, NK cells, Mast cells, Basophils Adaptive, Learned - B and T lymphocytes, B: antibodies, T : helper, cytolytic , suppressor

Immune System:

Immune System The system incorporates the Humoral immune response- B Cells- antibodies Cell mediated response, - uses T-cells Dysregulation of this system can result into serious problem. Autoimmune diseases Allergic reactions including anaphylaxis Tissue/organ rejection

Immunostimulants:

Immunostimulants Increase the immune responsiveness of patients who have either selective or generalized immunodeficiency. Use for immunodeficiency disorders, chronic infectious diseases, and cancer.

Addiction:

Addiction Immunostimulants

Cytokines :

Cytokines Developed by rDNA (recombinant) technology TNF Colony Stimulating factors (G-CSF, M-CSF, GM-CSF, etc) Interferon (INF): INF- α,β,γ Antiviral, anticancer, Adverse Effects: flu-like symptoms, fatigue malaise Interleukin-2 (IL-2) T cell proliferation, T H , NK, LAK cell activation Treatment of malignant melanoma, renal cell carcinoma, Hodgkin disease Adverse Effects: fever, anorexia Applications in the treatment of viral infections, autoimmune and neoplastic diseases

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Interferons : - Group of proteins produced by white blood cells, fibroblasts, or T-cells as part of an immune response to a viral infection or other immune trigger. Application in treatment of viral infection, autoimmune and neoplastic diseases. Therapeutic uses- Hairy cell leukemia, Malignant melanoma, Hepatitis B Adverse Rections :- Flu like symptoms – Fever, chills, headache, CVS – Hypotension, Arrhythmia, CNS- Depression, Confusion

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INTERLEUKIN:- It is a protein that regulates the activities of white blood cells (leukocytes, often lymphocytes) that are responsible for immunity. IL-2 is part of the body's natural response to microbial infection, and in discriminating between foreign ("non-self") and "self". IL-2 mediates its effects by binding to IL-2 receptors, which are expressed by lymphocytes. Therapeutic uses: Metastatic renal cell carcinoma

Other Immunomodulators:

Other Immunomodulators Levamisol - antihelmenthic drugs BCG as adjuvants and probably act by activation of macrophages Etanercept :- acting as a TNF inhibitor THALIDOMIDE:- Enhanced T cell production of cytokines IL-2, IFN- 𝝲 . Increases TNF𝝰 in patients who are HIV seropositive . Therapeutic uses: Multiple Myeloma, Adverse effects:- Birth defect . Contraindicated in women having child bearing potential. ISOPRINOSINE ( Methisoprinol ):- Leads the production of cytokines such as IL-1, IL-2, and IFN- 𝝲, increase proliferation of lymphocytes in response to mitogenic or antigenic stimuli. Therapeutic uses: Herpes simplex infection, Measles viruses, Adverse reactions:- Rise in uric acid in serum and urine, Nausea Aldesleukin : - Aldesleukin is in a class of drugs known as cytokines, Aldesleukin increases the body ability to fight cancer.

Immunization:

Immunization Active – Stimulation with an Antigen. antigen as a whole, killed organism, or a specific protein or peptide constituent of an organism Passive – Preformed antibody Nonspecific immunoglobulins Antibody-deficiency disorders Specific immune globulins High titers of desired antibody Hepatitis B, Rabies, Tetanus

Vaccines:

Vaccines Suspensions of live, attenuated (weakened) or killed (inactivated) micro-organisms The weakened form prevents the person from contracting the disease Also stimulate the production of antigens against a specific antibody Vaccinations with live bacteria or virus provide lifelong immunity Vaccinations with killed bacteria or virus provide partial immunity, and booster shots are needed periodically

Revise:

Revise

IMMUNOSUPPRESSIVE DRUGS:

IMMUNOSUPPRESSIVE DRUGS Alkylating Agents Chlorambucil Melphalan Cyclophosphamide Busulfan Antimetabolites Methotrixate Azathioprine 6-mercaptopurine Cortcosteroids Selective immunosuppressors Calcineurin Inhibitors Cyclosporine

Immunosuppressants:

Immunosuppressants Glucocorticoids - Prednisolone . Calcineurin inhibitors Cyclosporine Tacrolimus Antiproliferative / antimetabolic agents Sirolimus Everolimus Azathioprine Mycophenolate Mofetil Methotrexate , Cyclophosphamide , Chlorambucil Others:- Thalidomide , Interferon

Immunosuppressants:

Immunosuppressants Calcinurin Inhibitors Cyclosporine, Tacrolimus m-TOR inhibitors Sirolimus , Everolimus Antiproliferative drugs Azathioprine , Methotrexate , Cyclophosphamide , Chlorambucil , Mycophenolate mofetil Glucocorticoids Prednisolone Biological agents TNF alpha inbitors - Etanercept , Infliximab , Adalimumab IL-1 receptor antagonist- Anakinra IL-2 receptor antagonist- Daclizumab , Basiliximab Anti CD-3 antibody- Muromonab CD3 Polyclonal antibodies- Antithymocytes antibodies, RhO (D) immunoglobulin

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Mechanism of Action Drug Inhibitors of lymphocyte gene expression Glucocorticoids Inhibitors of lymphocyte signaling Calcineurin inhibitors Cyclosporin , Tacrolimus mTOR ( mammalian target of rapamycin ) inhibitors Sirolimus , Everolimus Cytotoxic agents (Anticancer Drugs) Antimetabolites Azathioprine , Methotrexate , Leflunomide , Alkylating agents Cyclophosphamide Cytokine Inhibitors ( Anticytokine antibodies) TNF-alpha inhibitors Etanercept , Infliximab , Adalimumab IL-1 Inhibitors Anakinra IL-2 Inhibitors Daclizumab , Basiliximab Antibodies against specific immune cell molecules Polyclonal Antibodies Antithymocyte Globulin (ATG) Monoclonal antibodies Alemutuzmab , Muromunab , Efalizumab Miscellaneous Rho(D) immune globulin

Glucocorticoids:

Glucocorticoids Induce redistribution of lymphocytes – decrease in peripheral blood lymphocyte counts Intracellular receptors – regulate gene transcription Down regulation of IL-1, IL-6 Inhibition of T cell proliferation Neutrophils , Monocytes display poor chemotaxis Broad anti-inflammatory effects on multiple components of cellular immunity

USES - Glucocorticoids:

USES - Glucocorticoids Transplant rejection GVH – BM transplantation Autoimmune diseases – RA, SLE, Hematological conditions Psoriasis Inflammatory Bowel Disease

Toxicity:

Toxicity Growth retardation Avascular Necrosis of Bone Risk of Infection Poor wound healing Cataract Hyperglycemia Hypertensio n Osteoporosis

CALCINEURIN INHIBITORS:

CALCINEURIN INHIBITORS • Calcineurin (CN) is a protein phosphatase activates the T cells of the immune system and can be blocked by drugs. Cyclosporine – Bind to the cytosolic protein cyclophilin (an immunophilin ) of immunocompetent lymphocytes, especially T-lymphocytes . This complex of cyclosporin and cyclophilin inhibits the phosphatase calcineurin, which under normal circumstances induces the transcription of interleukin-2 . The drug also inhibits lymphokine production and interleukin release, leading to a reduced function of effector T-cells.

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Uses Organ transplantation: Kidney, Liver, Heart Rheumatoid arthritis, IBD, uveitis Psoriasis Aplastic anemia Skin Conditions- Atopic dermatitis, Alopecia Areata, Pemphigus vulgaris, Lichen planus, Pyoderma gangrenosum

Toxicity : Cyclosporine:

Toxicity : Cyclosporine Renal dysfunction Tremor Hirsuitism Hypertension Hyperlipidemia Gum hyperplasia Hyperuricemia – worsens gout Calcineurin inhibitors + Glucocorticoids = Diabetogenic

Tacrolimus :

Tacrolimus – It binds to the immunophilin FKBP1A , followed by the binding of the complex to calcineurin and the inhibition of its phosphatase activity. In this way, it prevents the cell from transitioning from the G 0 into G 1 phase of the cell cycle . Tacrolimus is more potent than ciclosporin and has less pronounced side-effects. Use - Prophylaxis of solid-organ allograft rejection –Topical preparation available for use in atopic dermatitis and psoriasis.

Toxicity - Tacrolimus:

Toxicity - Tacrolimus Nephrotoxicity Neurotoxicity-Tremor, headache, motor disturbances, seizures GI Complaints Hypertension Hyperglycemia Risk of tumors, infections

Sirolimus (rapamycin) :

Sirolimus ( rapamycin ) Contrary to ciclosporin and tacrolimus , drugs that affect the first phase of T lymphocyte activation, sirolimus affects the second phase (namely signal transduction and lymphocyte clonal proliferation ). It binds to FKBP1A like tacrolimus , however the complex does not inhibit calcineurin but another protein, mTOR (mammalian target of rapamycin ).

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It indirectly inhibits several T lymphocyte-specific kinases and phosphatases , hence preventing their transition from G 1 to S phase of the cell cycle. Sirolimus prevents B cell differentiation into plasma cells, reducing production of IgM , IgG , and IgA antibodies.

Anti-IL-2 Receptor Antibodies :

Anti-IL-2 Receptor Antibodies ( Daclizumab and Basiliximab ) Bind to IL-2 receptor on surface of activated T cells  Block IL-2 mediated T-cell activation Uses Prophylaxis of Acute organ rejection Toxicity Anaphylaxis, Opportunistic Infections

Anti-TNF Agents:

Anti-TNF Agents TNF – Cytokine at site of inflammation Infliximab Etanercept Adalimumab

Infliximab:

Infliximab Uses Rheumatoid arthritis Chron’s disease – fistulae Psoriasis Psoriatic arthritis Ankylosing spondylosis Toxicity Infusion reaction – fever, urticaria , hypotension, dyspnoea Opportunistic infections – TB, RTI, UTI

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Thalidomide – inhibits angiogenesis, reduces phagocytosis , enhances cell mediated immunity – Increases levels of IL- 10 . – Used in multiple myeloma, graft versus host disease , myelodysplastic syndrome, colon and prostrate Cancer. • Mycophenolate Mofetil – mycophenolic acid – Inhibits inosine monophosphate dehydrogenase which is a key enzyme in guanine nucleotide synthesis . – Used in steroid refractory GVHD, RA, SLE.

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Leflunomide – it inhibits pyrimidine synthesis in actively dividing cells. Antibodies by B cells is depressed. Used in RA. • Cyclophosphamide – alkylating agent which destroys proliferating lymphoid cells. Used in SLE, autoimmune haemolytic anaemia , multiple sclerosis, Wegener’s granulomatosis . • Muromonab CD3 – T cell receptor complex ( blocks Ag recognition ). – Used in steroid resistant rejection. • Daclizumab , Basiliximab – IL-2 receptor (blocks IL-2 mediated T cell activation ). – Used in acute organ rejection in renal transplant patients.

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Azathioprine ( Mercaptopurine ) – interferes with purine nucleic acid metabolism and incorporates false nucleotide. –Used in Renal allograft, RA, SLE, ITP, Crohn’s disease, glomerulonephritis

General Principle of Immunosuppression:

General Principle of Immunosuppression Primary immune responses are more easily repressed than secondary (memory) Suppression is more likely to be achieved if therapy is begun before exposure to the immunogen Over immunosupression may produce opportunistic infections and cancers

Therapeutic Applications of Immunosuppressants:

Therapeutic Applications of Immunosuppressants Autoimmune Diseases Thyroiditis Myasthenia gravis Type I diabetes mellitus Glomerulonephritis Rheumatoid arthritis Organ/Tissue Transplant Kidney, Heart, Bone marrow Pancreatic islets

Nursing Implications:

Nursing Implications Perform a thorough assessment before administering these drugs Renal, liver, and cardiovascular function studies CNS baseline function Respiratory assessment Baseline vital signs Baseline laboratory studies, including hemoglobin, hematocrit , WBC, and platelet counts Assess for contraindications, drug allergies, and drug interactions Monitor WBC counts throughout therapy; if the count drops below 3000/mm 3 , discontinue the drug, but only after contacting the physician Observe the oral cavity often for white patches on the tongue, mucous membranes, and oral pharynx Patients taking immunosuppressant should be encouraged to take measures to reduce the risk of infection Avoiding crowds Avoiding people with colds or other infections Inform patients to immediately report fever, sore throat, chills, joint pain, fatigue, or other signs of a severe infection Monitor for therapeutic responses and adverse effects and signs of drug toxicity

THANKS:

THANKS

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