i Mu No Modulator 2014

IMUNOMODULATORIta Armyanti/Farmakologi 2014

1. Int J Pharm Pharm Sci, Vol 4, Suppl 1, 20122. GG 12ed3. Farmakologi FK UI

28/04/23 imunomodulator/2013 1

IMMUNOPHARMACOLOGY

• Basic role of immune system distinguish self and non self

• 2 major components of the immune system:– INNATE (natural or non specific)

Physical – skin, mucus membrane Biochemical – complement, lyzosyme Cellular – macrophages, neutrophils

– ADAPTIVE (aquired or specific) Antibodies – HUMORAL immunity T-lymphocyte – CELL MEDIATED immunity


COMPLEMENTS in Innate Immunity:

1. C3a, C5a chemotaxis

2. C3b opsonization

3. C5b, C6, C7, C8, C9 MAC


0psonized bacteria


Macrophage

APC

T lymphocyte

IL-2 IL-2

IFN-

Activated

MacrophageActivated

NK cells

Activated

Cytotoxic T cell

CELL-MEDIATED IMMUNITY

B lymphocyte

IL-4,IL-5

TH1

TH2

Memory B Cells

Plasma Cells:

-IgG - IgM

- IgA - IgD

HUMORAL IMMUNITY

IFN-

TNF-IFN-

T-helper cells:1. TH1 subset

- IFN- , IL-2, TNF-

2. TH2 subset- IL-4, IL-5, IL-6, IL-10


IMMUNOPHARMACOLOGY

HYPERSENSITIVITY

AUTOIMMUNITY

IMMUNODEFICIENCY


ABNORMAL IMMUNE RESPONSES:

1. Inhibitor of lymphocyte gene expression : glucocorticoids

2. Inhibitors of lymphocyte signaling3. Cytotoxic agents4. Cytokine inhibitors5. Antibodies against specific immune cell

molecules6. Inhibitors of immune cell adhesion7. Tolerogens or inhibitors of immune cell

costimulation8. miscellaneous


IMMUNOsuppressants

Inhibitor of lymphocyte gene expression : glucocorticoids

• 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


• 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


• Immunosuppressive dose: 10-100 mg/day

• Adverse effects: GI bleeding adrenal suppression fluid retention diabetes proximal muscle wasting superinfections


Inhibitors of lymphocyte signaling

1. Calcineurin inhibitors : cyclosporine, tacrolimus

2. mTOR inhibitors : sirolimus, everolimus


• produced by the fungus species Beauveria nivea• 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


Cyclosporin

Tacrolimus• Macrolide antibiotic produced by Streptomyces

tsukubaensis• Binds to an intracelluler protein FK506-binding

protein inhibits T-cell activation

• 10-100 times more potent than cyclosporine

• Pediatric Liver transplantion & kidney transplant

• Oral or IV : t½ = 9-12 hrs, 99% metabolized by CYP3A

• Toxicity: nephrotoxicity, neurotoxicity, hyperglycemia, GI

dysfunction


• 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


Sirolimus (rapamycin)

CYTOTOXIC Agents:

1. Azathioprine2. Mycophenolate mofetil3. Leflunomide4. Cyclophosphamide


• Metabolized to 6-mercaptopurines

• Inhibit purine synthesis interferes with nucleic acid metabolism inhibits cellular & humoral responses

• Highly teratogenic

• Well absorbed from GI tract


Azathioprine

• 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


Azathioprine

• Inhibits a series of T & B lymphocyte responses

• Inhibit de novo pathway of purine synthesis

• Renal & heart transplantation

• Mizoribine – inhibitor nucleotide synthesis pathway; kidney transplants

• Brequinar Sodium – inhibitors de novo pathway of pyrimidine synthesi; cancer & organ transplantation


Mycophenolate Mofetil

• Prodrug of an inhibitor of pyrimidine synthesis

• Inhibits lymphoid cells

• Orally active

• RA

• Toxicities: – Headache, nausea & diarrhea– Hepatic dysfunction, renal impairment

• Teratogenic28/04/23 imunomodulator/2013 19

Leflunomide

• Most potent immunosuppressive drug

• Destroys proliferating lymphoid cells

• Autoimmune disorders: SLE

• Acquired factor XIII antibodies

• Bleeding syndromes

• Toxicities: – Pancytopenia, hemorrhagic cystitis


Cyclophosphamide

• 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


Cytokine inhibitors : TNF- α inhibitors

Antibodies as Immunosuppressive Agents

• Antilymphocytic antibody

• Immune Globulin IV

• Hyperimmune Immunoglobulins

• Monoclonal Antibodies

• Rho(D) Immune Globulin Micro-DosePrevention of hemolytic disease of the

newbornGiven to mother within 72 hrs after delivery of

an Rh-negative baby28/04/23 imunomodulator/2013 22

1.Muromonab- CD3

2. Palivizumab

3. Rituxumab

4.Trastuzumab28/04/23 imunomodulator/2013 23

MONOCLONAL ANTIBODIES:

• T-cell specific antibody IL2

• I : Renal transplantation, heart / renal


Muromonab-CD3

• Palivizumab – RSV

• Rituximab – follicular B-cell non-hodgekins lymphma

• Trastuzumab – metastatic breast CA


IMMUNOPARMACOLOGY

IMMUNOSTIMULANTS

LEVAMISOLE:

- antiparasitic agent - potentiate action of fluorouracil in adjuvant therapy of Dukes class C colorectal CA- other uses:

> hodgkin’s lymphoma> RA


BCG (Bacille-Camille-Guarin):

- immunization against tuberculosis

- Adjuvant in intravesical therapy for SF bladder CA


• Type 1: induced by viral inf.– IFN-alpha prod. by leukocytes– IFN-beta prod. by fibroblasts & epithelial cells

• Type 2: IFN-gamma produced by activated T-lymphocytes

• Indications: cancer• IFN- multiple sclerosis• IFN- chronic granulomatous disease


Interferons

• Potent antimonocytic & antilymphocytic effect

• Inhibits T & B lymphocyte response

• Renal transplants; pancreas & heart transplants


15-Deoxyspergualin

• Sedative drug

• Favors TH2 over TH1

• Suppress TNF-α production

• Antiangiogenesis action: teratogenicity & anticancer

• Indications– Erythema nodosum leprosum (skin

manifestations of SLE)– Lung transplantation


Thalidomide

• Relapsing-remitting form of multiple sclerosis

• Subcutaneous injection

• Toxicities:– Transient post-injection reaction


Glatiramer

IMMUNOMODULATORS• CYTOKINES


Interferon-alpha:

- hairy cell leukemia- chronic myelogenous leukemia- malignant melanoma- Kaposi’s sarcoma- anticancer renal cell CA, carcinoid syndrome, T cell leukemia

RECOMBINANT CYTOKINES

Interferon-beta Relapsing type multiple sclerosis

Interferon-gamma Chronic granulomatous disease

Interleukin-2 Metastatic renal cell CA Malignant melanoma

TNF-alpha Malignant melanomaSoft tissue sarcoma of extremities

Interferons & IL-2 (+) effects in response to Hep B vaccine

GM-CSF Melanoma and Prostate cancer28/04/23 imunomodulator/2013 33

IMMUNOMODULATORSHIV:

- Inosiplex- Diethylcarbamate (DTC)

DiGeorge Syndrome of T cell deficiency - give THYMOSIN


postest

Pada kasus transplantasi organ, kortikosteroidpilihan yang dapat diberikan adalah ?Indikasi interferons?Monoklonal antibodi?Efek samping talidomide ?MoA levamisole?BCG?


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i Mu No Modulator 2014