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Pharmacology Block 2 > 04 Immunopharmacology > Flashcards

04 Immunopharmacology Flashcards

1
Q

Review of cell mediated cytotoxicity

A
  1. Macrophage processing of antigen
  2. Presentation of antigen to T-lymphocyte
  3. Expression of IL-1 and IL-2 receptors on T-lymphocytes
  4. Secretion of IL-1 by macrophages
  5. IL-1 promotes IL-2 release from helper T-lymphocytes
  6. IL-2 acts on lymphocytes to promote replication of cytotoxic cells
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2
Q

How can you prevent allograft rejection or treat autoimmune diseases?

A

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

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3
Q

Function of Cytotoxic Agents on Immune Cells

A

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.
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4
Q

Function of Cytotoxic Agents on Cancer Cells

A

Cancer Cell Proliferation: Random, unsynchronized, unstimulated

Therapy:

  • kills rapidly growing cancer cells
  • intermittent therapy to allow immune system to recover
  • high doses
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5
Q

Start and End Products of Purine Synthesis

A

Start: Ribose 5-phosphate
End: ATP and GTP

2 pathways: de Novo and Salvage

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6
Q

Azathioprine

A

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
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7
Q

What drug is metabolized to 6-mercaptopurine to inhibit purine biosynthesis?

A

Azathioprine

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8
Q

What drug is used to inhibit rejection of transplanted organs?

A

Azathioprine

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9
Q

What are the adverse effects of azathioprine?

A

AEs:

  • Bone marrow depression is major side effect
  • Gastrointestinal and hepatic toxicity may occur
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10
Q

What drug inhibits both de Novo and Salvage pathways of purine biosynthesis?

A

Azathioprine

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11
Q

Cyclophosphamide

A

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.

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12
Q

What drug is an alkylating agent that results in cross-linking of DNA to kill replicating and non-replicating cells?

A

Cyclophosphamide

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13
Q

What drug is used to suppress humoral immunity (B cells)?

A

Cyclophosphamide

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14
Q

What drug is used to treat autoimmune diseases in combination therapy but NOT for graft rejection?

A

Cyclophosphamide

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15
Q

What is the side effect of cyclophosphamide?

A

Bone marrow depression

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16
Q

Methotrexate

A

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

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17
Q

What drug is used to inhibit DNA synthesis by inhibiting dihydrofolate reductase?

A

Methotrexate

Prevents conversion of dihydrofolate into active tetrahydrofolate

18
Q

What is methotrexate used to treat?

A

Autoimmune diseases

19
Q

What is an adverse effect of methotrexate?

A

Hepatic toxicity

20
Q

Mycophenolate Mofetil

A

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
21
Q

What drug is metabolized to mycophenolic acid?

A

Mycophenolate Mofetil

22
Q

What drug is a lymphocyte selective immunosuppressant?

A

Mycophenolate Mofetil

23
Q

What drug inhibits IMP dehydrogenase?

A

Mycophenolate Mofetil

Selectively toxic for Lymphocytes

24
Q

What drug is used with cyclosporine and corticosteroids to prevent renal allograft rejection?

A

Mycophenolate Mofetil

25
Q

What drug is used to treat refractory psoriasis and rheumatoid arthritis?

A

Mycophenolate Mofetil

26
Q

What are the side effects of using Mycophenolate Mofetil?

A

Infection, Luekopenia, Anemia

27
Q

Why should pregnant women avoid Mycophenolate Mofetil?

A

Associated with pregnancy loss and congenital malformations

28
Q

Cyclosporine

A

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.
29
Q

What drug is a lipophilic peptide antibiotic?

A

Cyclosporine

30
Q

What drug binds to cellular receptor cyclophilin which inhibits Ca2+ dependent phosphatase calcineurin?

A

Cyclosporine

31
Q

Once calcineurin is inhibited by cyclosporine, what happens downstream?

A

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

32
Q

Is cyclosporine lymphotoxic?

A

Since it is not lymphotoxic, it is more selective in its action

33
Q

What drug is used to block IL-2 synthesis?

A

Cyclosporine, Tacrolimus, Sirolimus

34
Q

What drug and lead to nephrotoxicity?

A

Cyclosporine

Reversible with reduction in dosage

35
Q

Tacrolimus

A

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.

36
Q

What drug binds FK binding protein and inhibits calcineurin?

A

Tacrolimus

37
Q

Which is more potent and less toxic: Cyclosporine or Tacrolimus?

A

Tacrolimus

50-100 times more potent than cyclosporine

Less nephro- and hepatotoxicity

38
Q

Sirolimus

A

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
39
Q

What drug binds FKBP-12 and inhibits mTOR?

A

Sirolimus

40
Q

What drug blocks G1→ S transition?

A

Sirolimus

41
Q

What drug is used to coat cardiac stents?

A

Sirolimus

Pharmacology Block 2 (12 decks)

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