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IMMUNOPHARMACOLOGY Ma. Janetth B. Serrano, M.D., DPBA
IMMUNOPHARMACOLOGY <ul><li>2 major components of the immune system: </li></ul><ul><ul><li>INNATE </li></ul></ul><ul><ul><u...
<ul><li>COMPLEMENTS in Innate Immunity: </li></ul><ul><li>1. C3a, C5a     chemotaxis </li></ul><ul><li>2. C3b    opsoniz...
IMMUNOPHARMACOLOGY 0psonized bacteria Macrophage APC T lymphocyte IL-2 IL-2 IFN-  Activated Macrophage Activated NK  cell...
<ul><li>T-helper cells: </li></ul><ul><li>1. T H 1 subset </li></ul><ul><li>- IFN-   , IL-2, TNF-  </li></ul><ul><li>2. ...
<ul><li>ABNORMAL  IMMUNE  RESPONSES: </li></ul><ul><ul><ul><li>HYPERSENSITIVITY </li></ul></ul></ul><ul><ul><ul><li>AUTOIM...
<ul><ul><li>1. Corticosteroids </li></ul></ul><ul><ul><li>2. Cyclosporine </li></ul></ul><ul><ul><li>3. Sirolimus </li></u...
Corticosteroids <ul><li>MOA:  </li></ul><ul><ul><li>inhibit  T-cell  proliferation &  T-cell  dependent immunity </li></ul...
<ul><li>Continuous administration: </li></ul><ul><ul><li>↑  fractional catabolic rate of IgG </li></ul></ul><ul><li>Indica...
<ul><li>Immunosuppressive dose:  </li></ul><ul><ul><li>10-100 mg/day </li></ul></ul><ul><li>Adverse effects: </li></ul><ul...
<ul><li>Blocks  T-cell  activation </li></ul><ul><li>binds to cyclophillin    inhibits  calcineurin  activity    inhibit...
Tacrolimus <ul><li>Binds to FK-binding protein    inhibits  T-cell  activation </li></ul><ul><li>10-100 times more potent...
<ul><li>Binds also to immunophyllin    blocks the response of  T-cell  to cytokines </li></ul><ul><li>Potent inhibitor of...
<ul><li>Type 1: induced by viral inf. </li></ul><ul><ul><li>IFN-alpha    prod. by leukocytes </li></ul></ul><ul><ul><li>I...
<ul><li>INFLIXIMAB  </li></ul><ul><ul><li>Chimeric IgG1 monoclonal antibody with human region & murine regions </li></ul><...
<ul><li>Inhibits a series of  T & B lymphocyte  responses </li></ul><ul><li>Inhibit de novo pathway of purine synthesis </...
<ul><li>Potent antimonocytic & antilymphocytic effect </li></ul><ul><li>Inhibits  T & B lymphocyte  response </li></ul><ul...
<ul><li>Sedative drug </li></ul><ul><li>Favors  TH2  over  TH1 </li></ul><ul><li>Suppress TNF- α  production </li></ul><ul...
<ul><li>Relapsing-remitting form of multiple sclerosis </li></ul><ul><li>Subcutaneous injection </li></ul><ul><li>Toxiciti...
<ul><li>1. Azathioprine </li></ul><ul><li>2. Leflunomide </li></ul><ul><li>3. Cyclophosphamide </li></ul>IMMUNOPHARMACOLOG...
<ul><li>Metabolized to 6-mercaptopurines </li></ul><ul><li>Inhibit purine synthesis   interferes with nucleic acid metabo...
<ul><li>Renal allograft, AGN, SLE(renal), RA, Crohn’s disease </li></ul><ul><li>Prednisone-resistant antibody-mediated ITP...
<ul><li>Prodrug of an inhibitor of pyrimidine synthesis </li></ul><ul><li>Inhibits  lymphoid  cells </li></ul><ul><li>Oral...
<ul><li>Most potent immunosuppressive drug </li></ul><ul><li>Destroys proliferating  lymphoid  cells </li></ul><ul><li>Aut...
Antibodies as Immunosuppressive Agents <ul><li>Antilymphocytic antibody </li></ul><ul><li>Immune Globulin IV </li></ul><ul...
<ul><li>1.Muromonab- CD3 </li></ul><ul><li>2. Palivizumab </li></ul><ul><li>3. Rituxumab </li></ul><ul><li>4.Trastuzumab <...
<ul><li>T-cell  specific antibody </li></ul><ul><li>Renal transplantation, heart / renal  </li></ul>IMMUNOPHARMACOLOGY Mur...
<ul><li>Palivizumab  – RSV </li></ul><ul><li>Rituximab  – follicular B-cell non-hodgekins lymphma </li></ul><ul><li>Trastu...
IMMUNOMODULATORS <ul><li>CYTOKINES </li></ul><ul><li>Interferon-alpha: </li></ul><ul><li>-  hairy cell leukemia </li></ul>...
IMMUNOMODULATORS <ul><li>CYTOKINES </li></ul>Melanoma and Prostate cancer GM-CSF (+) effects in response to Hep B vaccine ...
IMMUNOPHARMACOLOGY IMMUNOMODULATORS IMMUNOPHARMACOLOGY <ul><li>LEVAMISOLE: </li></ul><ul><li>- antiparasitic agent </li></...
IMMUNOPHARMACOLOGY IMMUNOMODULATORS IMMUNOPHARMACOLOGY <ul><li>BCG (Bacille-Camille-Guarin): </li></ul><ul><li>- immunizat...
IMMUNOPHARMACOLOGY IMMUNOMODULATORS IMMUNOPHARMACOLOGY <ul><li>HIV: </li></ul><ul><li>- Inosiplex </li></ul><ul><li>- Diet...
<ul><li>The winds and waves are always on the side of the ablest navigator </li></ul>“ The winds and waves are always on t...
QUIZ <ul><li>Most common adverse effect of corticosteroids </li></ul><ul><li>The most potent immunosuppressive agent. </li...
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Immunopharmacology

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Immunopharmacology

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

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