Immunopharmacology

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  • 1. IMMUNOPHARMACOLOGY Ma. Janetth B. Serrano, M.D., DPBA
  • 2. IMMUNOPHARMACOLOGY
    • 2 major components of the immune system:
      • INNATE
        • Physical – skin, mucus membrane
        • Biochemical – complement, lyzosyme
        • Cellular – macrophages, neutrophils
      • ADAPTIVE
        • Antibodies – HUMORAL immunity
        • T-lymphocyte – CELL MEDIATED immunity
  • 3.
    • COMPLEMENTS in Innate Immunity:
    • 1. C3a, C5a  chemotaxis
    • 2. C3b  opsonization
    • 3. C5b, C6, C7, C8, C9  MAC
    IMMUNOPHARMACOLOGY
  • 4. IMMUNOPHARMACOLOGY 0psonized bacteria Macrophage APC T lymphocyte IL-2 IL-2 IFN-  Activated Macrophage Activated NK cells Activated Cytotoxic T cell CELL-MEDIATED IMMUNITY B lymphocyte IL-4,IL-5 TH 1 TH 2 Memory B Cells
    • Plasma Cells:
    • IgG - IgM
    • IgA - IgD
    HUMORAL IMMUNITY IFN-  TNF-  IFN- 
  • 5.
    • T-helper cells:
    • 1. T H 1 subset
    • - IFN-  , IL-2, TNF- 
    • 2. T H 2 subset
    • - IL-4, IL-5, IL-6, IL-10
    IMMUNOPHARMACOLOGY
  • 6.
    • ABNORMAL IMMUNE RESPONSES:
        • HYPERSENSITIVITY
        • AUTOIMMUNITY
        • IMMUNODEFICIENCY
    IMMUNOPHARMACOLOGY
  • 7.
      • 1. Corticosteroids
      • 2. Cyclosporine
      • 3. Sirolimus
      • 4. Tacrolimus
      • 5. Interferons
      • 6. TNF-alpha binding drugs
      • 7. Mycophenolate mofetil
      • 8. 15-Deoxyspergualin
      • 9. Thalidomide
      • 10. Glatiramer
    Immunosuppressants IMMUNOPHARMACOLOGY
  • 8. Corticosteroids IMMUNOPHARMACOLOGY
  • 9.
    • MOA:
      • inhibit T-cell proliferation & T-cell dependent immunity
      • Inhibit expression of genes encoding cytokines
      • Inhibit production of inflammatory mediators
    • Affects cell-mediated immunity more than humoral immunity
    IMMUNOPHARMACOLOGY
  • 10.
    • Continuous administration:
      • ↑ fractional catabolic rate of IgG
    • Indications:
      • Autoimmune disorders
        • - autoimmune hemolytic anemia, LE
        • - ITP, Inflammatory Bowel Dse,, Hashimoto’s
      • Modulate allergic reactions - asthma
      • Organ transplantation – rejection crisis
    IMMUNOPHARMACOLOGY
  • 11.
    • Immunosuppressive dose:
      • 10-100 mg/day
    • Adverse effects:
      • GI bleeding
      • adrenal suppression
      • fluid retention
      • diabetes
      • proximal muscle wasting
      • superinfections
    IMMUNOPHARMACOLOGY
  • 12. Corticosteroids IMMUNOPHARMACOLOGY
  • 13. Cyclosporin IMMUNOPHARMACOLOGY
  • 14.
    • Blocks T-cell activation
    • binds to cyclophillin  inhibits calcineurin activity  inhibits gene transcription of IL-2, IL-3, IFN  & other factors
    • Most commonly used immunosuppresant for renal transplantation
    • Indications:
      • transplant rejection (kidney, liver, pancreas, cardiac)
      • Autoimmune disorders (uveitis, RA, DM type1)
    • Toxicities:
      • nephrotoxicity, hyperglycemia, hyperlipidemia, osteoporosis, ↑ hair growth, transient liver dysfunction
    IMMUNOPHARMACOLOGY
  • 15. Cyclosporin IMMUNOPHARMACOLOGY
  • 16. Tacrolimus IMMUNOPHARMACOLOGY
  • 17.
    • Binds to FK-binding protein  inhibits T-cell activation
    • 10-100 times more potent than cyclosporine
    • Liver & kidney transplant
    • Oral or IV : t½ = 9-12 hrs
    • Toxicity:
      • nephrotoxicity, neurotoxicity, hyperglycemia, GI dysfunction
    IMMUNOPHARMACOLOGY
  • 18. Tacrolimus IMMUNOPHARMACOLOGY
  • 19. Sirolimus (rapamycin) IMMUNOPHARMACOLOGY
  • 20.
    • Binds also to immunophyllin  blocks the response of T-cell to cytokines
    • Potent inhibitor of B-cell proliferation & Ig production
    • Indications:
      • Kidney & heart allografts
      • C syclosporin  psoriasis & uveoretinitis
    IMMUNOPHARMACOLOGY
  • 21. Sirolimus (rapamycin) IMMUNOPHARMACOLOGY
  • 22. Interferons IMMUNOPHARMACOLOGY
  • 23.
    • Type 1: induced by viral inf.
      • IFN-alpha  prod. by leukocytes
      • IFN-beta  fibroblasts & epithelial cells
    • Type 2: IFN-gamma  produced by activated T-lymphocytes
    • Indications: cancer
    • IFN-   multiple sclerosis
    • IFN-   chronic granulomatous disease
    IMMUNOPHARMACOLOGY
  • 24. Interferons IMMUNOPHARMACOLOGY
  • 25. TNF- α binding drugs IMMUNOPHARMACOLOGY
  • 26.
    • INFLIXIMAB
      • Chimeric IgG1 monoclonal antibody with human region & murine regions
      • Suppress generation of cytokines
      • Crohn’s disease; RA
    • ETANERCEPT
      • Chimeric protein with human regiom
      • Similar MOA with infliximab but shorter half-life
      • RA
    IMMUNOPHARMACOLOGY
  • 27. TNF- α binding drugs IMMUNOPHARMACOLOGY
  • 28. Mycophenolate Mofetil IMMUNOPHARMACOLOGY
  • 29.
    • Inhibits a series of T & B lymphocyte responses
    • Inhibit de novo pathway of purine synthesis
    • Renal & heart transplantation
    • Mizoribine – inh. nucleotide synthesis PW; kidney transplants
    • Brequinar Sodium – inh. de novo pathway of pyrimidine synthesi; cancer & organ transplantation
    IMMUNOPHARMACOLOGY
  • 30. Mycophenolate Mofetil IMMUNOPHARMACOLOGY
  • 31. 15-Deoxyspergualin IMMUNOPHARMACOLOGY
  • 32.
    • Potent antimonocytic & antilymphocytic effect
    • Inhibits T & B lymphocyte response
    • Renal transplants; pancreas & heart transplants
    IMMUNOPHARMACOLOGY
  • 33. 15-Deoxyspergualin IMMUNOPHARMACOLOGY
  • 34. Thalidomide IMMUNOPHARMACOLOGY
  • 35.
    • Sedative drug
    • Favors TH2 over TH1
    • Suppress TNF- α production
    • Antiangiogenesis action: teratogenicity & anticancer
    • Indications
      • Erythema nodosum leprosum (skin manifestations of SLE)
      • Lung transplantation
    IMMUNOPHARMACOLOGY
  • 36. Thalidomide IMMUNOPHARMACOLOGY
  • 37. Glatiramer IMMUNOPHARMACOLOGY
  • 38.
    • Relapsing-remitting form of multiple sclerosis
    • Subcutaneous injection
    • Toxicities:
      • Transient post-injection reaction
    IMMUNOPHARMACOLOGY
  • 39. Glatiramer IMMUNOPHARMACOLOGY
  • 40.
    • 1. Azathioprine
    • 2. Leflunomide
    • 3. Cyclophosphamide
    IMMUNOPHARMACOLOGY CYTOTOXIC Agents:
  • 41. Azathioprine IMMUNOPHARMACOLOGY
  • 42.
    • Metabolized to 6-mercaptopurines
    • Inhibit purine synthesis  interferes with nucleic acid metabolism  inhibits cellular & humoral responses
    • Highly teratogenic
    • Well absorbed from GI tract
    IMMUNOPHARMACOLOGY
  • 43.
    • Renal allograft, AGN, SLE(renal), RA, Crohn’s disease
    • Prednisone-resistant antibody-mediated ITP
    • Autoimmune hemolytic anemia
    • Toxicities:
      • Bone marrow suppression
      • GI disturbances: N&V, diarrhea
      • Skin rashes, drug fever, hepatic dysfunction
    IMMUNOPHARMACOLOGY
  • 44. Azathioprine IMMUNOPHARMACOLOGY
  • 45. Leflunomide IMMUNOPHARMACOLOGY
  • 46.
    • Prodrug of an inhibitor of pyrimidine synthesis
    • Inhibits lymphoid cells
    • Orally active
    • RA
    • Toxicities:
      • Headache, nausea & diarrhea
      • Hepatic dysfunction, renal impairment
    • Teratogenic
    IMMUNOPHARMACOLOGY
  • 47. Leflunomide IMMUNOPHARMACOLOGY
  • 48. Cyclophosphamide IMMUNOPHARMACOLOGY
  • 49.
    • Most potent immunosuppressive drug
    • Destroys proliferating lymphoid cells
    • Autoimmune disorders: SLE
    • Acquired factor XIII antibodies
    • Bleeding syndromes
    • Toxicities:
      • Pancytopenia, hemorrhagic cystitis
    IMMUNOPHARMACOLOGY
  • 50. Cyclophosphamide IMMUNOPHARMACOLOGY
  • 51. Antibodies as Immunosuppressive Agents
    • Antilymphocytic antibody
    • Immune Globulin IV
    • Hyperimmune Immunoglobulins
    • Monoclonal Antibodies
    • Rh o (D) Immune Globulin Micro-Dose
      • Prevention of hemolytic disease of the newborn
      • Given to mother within 72 hrs after delivery of an Rh-negative baby
    IMMUNOPHARMACOLOGY
  • 52.
    • 1.Muromonab- CD3
    • 2. Palivizumab
    • 3. Rituxumab
    • 4.Trastuzumab
    IMMUNOPHARMACOLOGY MONOCLONAL ANTIBODIES :
  • 53. Muromonab-CD3 IMMUNOPHARMACOLOGY
  • 54.
    • A T-cell specific antibody
    • Renal transplantation, heart / renal
    IMMUNOPHARMACOLOGY Muromonab-CD3
  • 55. Muromonab-CD3 IMMUNOPHARMACOLOGY
  • 56.
    • 2. Palivizumab
    • 3. Rituxumab
    • 4.Trastuzumab
    IMMUNOPHARMACOLOGY MONOCLONAL ANTIBODIES :
  • 57.
    • P – RSV
    • R – follicular B-cell non-hodgekins lymphma
    • T – metastatic breast CA
    IMMUNOPHARMACOLOGY
  • 58. Interferon-alpha
  • 59. IMMUNOMODULATORS
    • CYTOKINES
    - hairy cell leukemia - chronic myelogenous leukemia - malignant melanoma - Kaposi’s sarcoma - anticancer  renal cell CA, carcinoid syndrome, T cell leukemia
  • 60. Interferon-alpha
  • 61. IMMUNOMODULATORS
    • CYTOKINES
    GM-CSF Interferons & IL-2 TNF-alpha Interleukin-2 Interferon-gamma Interferon-beta
  • 62. IMMUNOMODULATORS
    • CYTOKINES
    Melanoma and Prostate cancer (+) effects in response to Hep B vaccine Malignant melanoma Soft tissue sarcoma of extremities Metastatic renal cell CA Malignant melanoma Chronic granulomatous disease Relapsing type multiple sclerosis
  • 63. IMMUNOMODULATORS
    • CYTOKINES
    GM-CSF Interferons & IL-2 TNF-alpha Interleukin-2 Interferon-gamma Interferon-beta
  • 64. LEVAMISOLE IMMUNOPHARMACOLOGY IMMUNOMODULATORS IMMUNOPHARMACOLOGY
  • 65. IMMUNOPHARMACOLOGY IMMUNOMODULATORS IMMUNOPHARMACOLOGY - antiparasitic agent - potentiate action of fluorouracil in adjuvant therapy of Dukes class C colorectal CA - other uses: > hodgkin’s lymphoma > RA
  • 66. LEVAMISOLE IMMUNOPHARMACOLOGY IMMUNOMODULATORS IMMUNOPHARMACOLOGY
  • 67. BCG (Bacille-Camille-Guarin) IMMUNOPHARMACOLOGY IMMUNOMODULATORS IMMUNOPHARMACOLOGY
  • 68. IMMUNOPHARMACOLOGY IMMUNOMODULATORS IMMUNOPHARMACOLOGY - immunization against tuberculosis - Adjuvant in intravesical therapy for SF bladder CA
  • 69. BCG (Bacille-Camille-Guarin) IMMUNOPHARMACOLOGY IMMUNOMODULATORS IMMUNOPHARMACOLOGY
  • 70. IMMUNOPHARMACOLOGY IMMUNOMODULATORS IMMUNOPHARMACOLOGY
    • HIV:
    • - Inosiplex
    • - Diethylcarbamate (DTC)
    • DiGeorge Syndrome of T cell deficiency
    • - give THYMOSIN