04 Immunopharmacology Flashcards
Review of cell mediated cytotoxicity
- Macrophage processing of antigen
- Presentation of antigen to T-lymphocyte
- Expression of IL-1 and IL-2 receptors on T-lymphocytes
- Secretion of IL-1 by macrophages
- IL-1 promotes IL-2 release from helper T-lymphocytes
- IL-2 acts on lymphocytes to promote replication of cytotoxic cells
How can you prevent allograft rejection or treat autoimmune diseases?
Immunosuppressant Drugs
Mech: block proliferation or interaction of immune cells or block action or release of cytokines
AEs at sites of rapidly proliferating cells (bone marrow, liver or GI) and increased incidence of infection
Function of Cytotoxic Agents on Immune Cells
Immune Cell Proliferation: burst of cell growth, synchronized, stimulated by Ag/cytokines
Therapy:
- used at initial exposure in response to Ag, kill rapidly proliferating cells (precursors)
- Relevant clone stimulated by antigen will be killed. Other immune cells and clones not stimulated also will be spared.
- Usually administered in a low daily dosage to block immunoproliferation continually.
Function of Cytotoxic Agents on Cancer Cells
Cancer Cell Proliferation: Random, unsynchronized, unstimulated
Therapy:
- kills rapidly growing cancer cells
- intermittent therapy to allow immune system to recover
- high doses
Start and End Products of Purine Synthesis
Start: Ribose 5-phosphate
End: ATP and GTP
2 pathways: de Novo and Salvage
Azathioprine
Cytotoxic Agents
- Metabolized to 6-mercaptopurine, which inhibits purine biosynthesis and thereby inhibits DNA synthesis. Inhibits De Novo and Salvage pathways.
- Used to inhibit rejection of transplanted organs and in some autoimmune diseases as rheumatoid arthritis.
AEs:
- Bone marrow depression is major side effect
- Gastrointestinal and hepatic toxicity may occur
What drug is metabolized to 6-mercaptopurine to inhibit purine biosynthesis?
Azathioprine
What drug is used to inhibit rejection of transplanted organs?
Azathioprine
What are the adverse effects of azathioprine?
AEs:
- Bone marrow depression is major side effect
- Gastrointestinal and hepatic toxicity may occur
What drug inhibits both de Novo and Salvage pathways of purine biosynthesis?
Azathioprine
Cyclophosphamide
Cytotoxic Agent
- An alkylating agent that results in cross-linking of DNA to kill replicating and non-replicating cells.
- Toxic effect more pronounced on B-cells so more effective in suppressing humoral immunity.
- Used in the treatment of autoimmune diseases in combination with other drugs. Not effective in preventing graft rejection.
AEs:
- Bone marrow depression is major side effect.
What drug is an alkylating agent that results in cross-linking of DNA to kill replicating and non-replicating cells?
Cyclophosphamide
What drug is used to suppress humoral immunity (B cells)?
Cyclophosphamide
What drug is used to treat autoimmune diseases in combination therapy but NOT for graft rejection?
Cyclophosphamide
What is the side effect of cyclophosphamide?
Bone marrow depression
Methotrexate
Cytotoxic Agent
Inhibits DNA synthesis:
- Inhibitor of dihydrofolate reductase –inhibits folate dependent steps in purine synthesis
- Inhibitor of thymidilate synthase
- Used to treat autoimmune diseases.
AEs:
- Hepatic toxicity
What drug is used to inhibit DNA synthesis by inhibiting dihydrofolate reductase?
Methotrexate
Prevents conversion of dihydrofolate into active tetrahydrofolate
What is methotrexate used to treat?
Autoimmune diseases
What is an adverse effect of methotrexate?
Hepatic toxicity
Mycophenolate Mofetil
Cytotoxic Agent
Metabolized to active mycophenolic acid
Mech:
1) Inhibits IMP Dehydrogenase IMP → GMP
- - Necessary for de novo purine synthesis
- - No effect on salvage pathway
2) Lymphocytes, cannot make GMP via salvage pathway – selectively toxic for lymphocytes.
3) Inhibits lymphocyte proliferation and expression of cell surface adhesion molecules.
4) More selective than azathioprine or methotrexate but equally effective.
- Used with cyclosporine and corticosteroids to prevent renal allograft rejection. Allows lower dose of cyclosporine to be used so less toxicity.
- Used to treat autoimmune diseases – rheumatoid arthritis and refractory psoriasis.
- caution in patients with active GI disease, reduced renal function and infections
AEs:
- infection, leukopenia, anemia
- associated with pregnancy loss and congenital malformations
What drug is metabolized to mycophenolic acid?
Mycophenolate Mofetil
What drug is a lymphocyte selective immunosuppressant?
Mycophenolate Mofetil
What drug inhibits IMP dehydrogenase?
Mycophenolate Mofetil
Selectively toxic for Lymphocytes
What drug is used with cyclosporine and corticosteroids to prevent renal allograft rejection?
Mycophenolate Mofetil
What drug is used to treat refractory psoriasis and rheumatoid arthritis?
Mycophenolate Mofetil
What are the side effects of using Mycophenolate Mofetil?
Infection, Luekopenia, Anemia
Why should pregnant women avoid Mycophenolate Mofetil?
Associated with pregnancy loss and congenital malformations
Cyclosporine
A lipophilic peptide antibiotic
Mechanism of action:
a. Binds to a cellular receptor (Cyclophilin) and inhibits calcium-dependent phosphatase (Calcineurin). Blocks activation of transcriptions factor (NFAT) necessary for IL-2 production.
b. Inhibits mRNA synthesis that codes for lymphokines as IL-2
c. By blocking IL-2 synthesis, it blocks T-cell helper function so inhibits T-cell proliferation and cytotoxicity.
- Used to prevent rejection of transplanted organs.
- Used in some autoimmune diseases.
AEs:
- Nephrotoxicity is a major side effect. Reversible with reduction in dosage or discontinuation.
- Hepatotoxicity may occur.
What drug is a lipophilic peptide antibiotic?
Cyclosporine
What drug binds to cellular receptor cyclophilin which inhibits Ca2+ dependent phosphatase calcineurin?
Cyclosporine
Once calcineurin is inhibited by cyclosporine, what happens downstream?
Transcription factor NFAT activation is blocked, which inhibits mRNA synthesis that codes for IL-2
No IL-2 blocks T-cell helper function of proliferation and cytotoxicity
Is cyclosporine lymphotoxic?
Since it is not lymphotoxic, it is more selective in its action
What drug is used to block IL-2 synthesis?
Cyclosporine, Tacrolimus, Sirolimus
What drug and lead to nephrotoxicity?
Cyclosporine
Reversible with reduction in dosage
Tacrolimus
Cyclosporine-like
Binds FK binding protein (FK BP-12), a cyclophilin-related protein. –inhibits Ca2+ dependent calcineurin
50-100 times more potent than cyclosporine
Less nephro- and hepatotoxicity.
What drug binds FK binding protein and inhibits calcineurin?
Tacrolimus
Which is more potent and less toxic: Cyclosporine or Tacrolimus?
Tacrolimus
50-100 times more potent than cyclosporine
Less nephro- and hepatotoxicity
Sirolimus
Cyclosporine-like
Inhibits T-Cell activation and proliferation downstream of IL-2
Binds FKBP-12. Sirolimus-FKBP-12 binds and inhibits mTOR, a kinase involved in cell cycle progression. Blocks G1→ S transition.
- Uses same as cyclosporine
- Coating of cardiac stents
What drug binds FKBP-12 and inhibits mTOR?
Sirolimus
What drug blocks G1→ S transition?
Sirolimus
What drug is used to coat cardiac stents?
Sirolimus
