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Flashcards in Immunomodulatros Deck (17)
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Azathioprine

General growth inhibitor
- Prevent clonal expansion and cell-mediated immunity

Metabolized to 6-mercaptopurine then to 6-thioguanine
- Inhibit purine synthesis, becomes incorporated into DNA as thio-guanine nucleotide

Inactivated by Xanthine Oxidase
- Decreased inactivation when combined with allopurinol= NEED DECREASE DOSAGE

Use:
- Renal/tissue transplantation
- Autoimmune disease (lupus, Rh Art)

Adverse Effects:
- Myelosuppression
- Nausea
- Vomiting

1

Cyclophosphamide

General Growth Inhibitor
- Prevent Clonal Expansion and Cell-mediated immunity
- Not specific to leukocytes/leukocytes

Effective immunosuppresant by cross-linking DNA and killing proliferating cells
- Prevent expansion of lymphocytes (antigen specific)

Uses:
- Autoimmune disease
- Bone marrow transplant

Adverse Effects:
- Myelosuppression
- Nausea
- Vomiting
- Infertility

2

Leflunomide

General Growth Inhibitor

Metabolized to A77-1726 (active)

Inhibits dihyrdoorate Dehydrogenase leading to decreased pyrimidine synthesis
- Subject to enterohepatic recirculation and has a half-life of 19 days

Uses:
- Rh Art
- Some autoimmune disease

Adverse Effects:
- Diarrhea
- Hepatotoxicity
- myelosuppression
- less pronounced than other anti-metabolites

3

Methotrexate

General Growth Inhibitor

Inhibits dihydrofolate reducatase
- Direct inhibition and accumulated intermediates prevents synthesis of thymidine as well as purine nucleotides

Uses:
- DRUG OF CHOICE: RH ART
- Some autoimmune diseases

Adverse Effects:
- Nausea
- Mucosal Ulcers
- Modest Hepatotoxicity
- Myleosuppression less pronounced than other anti-metabolites

4

Mycophenoate Mofetil

General Growth Inhibitor

Hydrolyzed to mycophenolic acid (active Form)

Inhibits inosine monophosphate dehydrogenase, preventing purine synthesis

USE:
- Solid Organ Transplant
- Alternative to Cyclosporine
- Some autoimmune diseases

Adverse Effects:
- Myelosuppression
- Nausea
- Vomiting

5

Prednisone

Glucocorticoid

Anti-inflammatory and immunosuppressive effects

Induces transcription of Annexins (lipocortins)
- Inhibit PLA2 and synthesis of lipid derived mediators

Repress transcription of
- IL-1, 2, 3, 5, TNF alpha, IFN gamma, GM-CSF
- Reduces Th mediated responses, B cell antibody production, cytotoxic response

Repress TF NFkB and AP-q
- Targets cyclooxygenase, nitric oxide synthase, phospholypase A to REDUCE mediator release
- Target IL-8 and other Chemotaxins: Reduce recruitment of leukocytes

FIRST Line immunosuppresant for Transplant

Combined anti-inflammatory/immunosuppressant activity useful in managing immune-based disorders

Adverse effects: ( greater than 2 week administration)
- CUSHINGS syndrome
- Glucose Intolerance
- Susceptibility to Infection
- Osteoporosis
- Hypertension

6

Sirolimus

mTOR Inhibitor

Prevent Cytokine Induced Growth due to mTOR inhibition
- Can be used alone or in combination with other therapies to preserve solid organ transplant

Useful in steroid resistant Graft-Vs-Host disease (hematopoietic stem cell transplants)

ANTAGONIZES tacrolimus effects

SYNERGIZES with cyclosporine (consistent with selective dependence on immunophilins)

Adverse Effects:
- Myelosuppression
- Hyperlipidemia, hypertension, edema
- Hepatotoxicity

Inhibits IL-2 receptor signal transduction

7

Cyclosporine

Calcineurin Inhibitor

Prevent TCR-induced cytokine expression by inhibiting Calcineurin Activity

- Binds with CYCLOPHILIN and endogenous protein

Can be effective without use of other immuno-suppressants in some patients

Commonly useful in kidney, liver, and cardiac transplants

Useful in a variety of autoimmune disorders and may have applications in some inflammatory diseases (asthma)

ADVERSE EFFECTS:
- Nephrotoxicity, hypertension, hyperglycemia, liver dysfunction
- Increased cancer incidence

8

Tacrolimus

Calcineurin Inhibitor

FK506 binds with FKBP12 to inhibit calcineurin activity when increased Ca in the cell

Uses:
- Kidney, liver, cardiac transplant
- Useful in variety of autoimmune disorders and may have some application in inflammatory diseases (asthma)

10-100 times more potent than cyclosporine

ANTAGONIZES sirolimus effects

9

Anti-T cell globulin

Antibody

Suppress immune activity by opsonizing and depleting critical immune cells

10

Alemtuzumab

Chimeric Antibody

Activate human complement leukocytes

Do NOT induce anti-antibody response

Few side effects

HUMANIZED anti-CD52 antibody
- Depletes a broad variety of cells involved in adaptive and innate immune
- ADVERSE EFFECTS:
- Myelosuppression, flu-like symptoms
- Effect: Produces prolonged depletion of T cell and other cells of
the immune system (ONE YEAR)

11

Basiliximab

Chimeric Antibody

Activates human complement leukocytes

Does NOT induce an anti-antibody response

Anti-IL-2 receptor (anti-CD25): humanized antibody
- Mechanism: Blocks and opsonizes the alpha-chain of IL-2 receptor (CD25) present on ACTIVE T cells

Well Tolerated

Effect: Depletes only antigen-activated T cells
- Moderate effect compared to ATG, more appropriate for patients with low - to moderate risk for rejections
- Reduced immune-depletion is associated with reduced incidence of infection (chronic CMV infection) and malignancy

12

Rh(D) immune Globulin

Human Antibody

Activate human complement leukocytes

DO NOT induce anti-antibody response

Treatment for RH HEMOLYTIC DISEASE
- Occurs when RH negative mothers sensitized to D antigen of RH positive fetus
- Subsequent pregnancies maternal antibodies against RH-positive cells can transfer to the fetus leading to Hemolytic Disease

Concentrated solution of human IgG with a high titer of Rh(D) antibodies. Maternal administration of Rh(D) immune globulin prevents initiation of a maternal immune response to the fetal Rh(D) antigen

Mechanisms immune suppression mediated through opsonization and clearance of D antigens

Dantigen/antibody complexes inhibit activation of maternal naive Rh(D) reactive B cells

T cell responses not specifically affected are not harmful to the fetus

13

Belatacept

New biologic immunosuppressant that is approved for kidney Transplant

Blocks Co-Stimulatory Receptors for Immunosuppression

Fusion Protein of a high-affinity B7 ligand (CTLA4) with IgG Fc domain
- Second generation abatacept, higher affinity for B7

Mechanism:
- Prevents interaction between B7 on APC and CD28 (T cell)
- T cells activated by antigen presentation and TCR activation become anergic in the absence of CD28 activation
- No proliferation
- NO cytokine production
- T cell dies

Adverse Effects:
- Anemia, neutropenia, peripheral edema
- Increase risk of infection and maliganancy

14

Interleukin-2

Cytokine

Activated T cells secrete this and express IL-2 receptor protein

Stimulate proliferation and clonal expansion of the antigen-specific T cell population

Increase Prolliferation of activated T cells, production of IFN gamma,
and cytotoxic killer cell activity

Use:
- Treatmenet of metastatic melanoma and renal cell carcinoma

Associated with serious capillary leak syndrome, hypotension, and reduced organ perfusion

CAN BE FATAL

15

IFN-gamma

Cytokine

Part of the TH1 response
- Increases cell-mediated cytotoxicity
- Effective against intracellular pathogens

Stimulated by IL-2

Stimulate cell mediated cytotoxic immune response
- Application in treating severe recurrent infections

16

BCG

Adjuvant

Live Attenuated Bacillus Calmette-guerin

Surface antigens interact directly with pattern recognition receptors on APCs to increase activity

Useful in some cancer therapies

Direct activation of leukocytes (macrophages) can produce SIRS and Septic shock