Immunosuppressive Drugs

Question 1

Which immunosuppressive drug works via the following mechanism?

Inhibits DNA topoisomeraise, therefore inhibits DMA polymerase and DNA repair

Answer 1

Cytarabine

S-phase specific

(Coates)

Question 2

MOA of glucorticoids for immunosuppression:

Answer 2

Genomic effects:

• Modulate transcription of genes necessary for leukocyte function, inflammation
  
  • Reduced migration of leukocytes to regions of inflammation, than leukocyte function –> THUS affects cell-mediated immunity > humoral immunity
• Inhibit IL1, IL2, IL6 (lymphocyte differentiation/proliferation)
• Decrease number of Fc receptors on macrophages, reduce lysosomal membrane function (thus inhibit phagocytic activity)
• Decrease complement activation
• Inhibit phospholipase A2 –> decrease the production of prostaglandins and leukotrienes
  
  • PG + LK are first steps in generation of proinflammatory state

Nongenomic effects (higher dose)

• Reduced ATP production
• Inhibit cellular metabolism
• Inhibit intracellular Ca rise (which is required for lymphocyte activation)

(VCNASAP Kent)

Question 3

________________ is a purine analog that inhibits DNA and RNA synthesis, used for immunosuppressive therapy

Side effects?

Answer 3

Azathioprine

• T lymphocytes >> B lymphocytes
• Decreased killer/NK cells
• Reduced cytokine production in monocytes and lymphocytes
• Side effects - Myelosuppression (WBC > others)
  
  • Vomiting, diarrhea, hepatotoxicity, acute pancreatitis
  • Neuromuscular blockade in cats
• 2-8 weeks to see clinical effect
• 4/5 dogs with MG treated with azathioprine had a good clinical outcome

(VCNASAP Kent)

Question 4

MOA of cyclophosphamide?

Answer 4

Nitrogen mustard alkylating agent –> cross linkage of DNA strands, breakage of DNA, formation of inappropriate bonds between strands –. reduction in protein synthesis and DNA synthesis
Cell cycle nonspecific
Humoral immunity >> cell-mediated immunity

Hepatic metabolism

Adverse effects:

• Leukopenia - monitor segmented neutrophil count
• GI upset
• Sterile hemorrhagic cystitis (after single admin or prolonged admin)
  
  • Coadministration with MESNA, furosemide

(VCNASAP Kent)

Question 5

What drug works via inhibition of intracellular calcineurin?

Answer 5

Cyclosporine - inhibits calcineurin (Ca-calmdulin dependent protein phosphatase) –> reduced production of IL2 –> decreased activation of T helper cells

(VCNASAP Kent)

Question 6

What drug is a selective inhibitor of nucleotide production?

Answer 6

Mycophenolate mofetil - selective inhibitor of B and T lymphocyte proliferation
* specifically inhibits inosine monophosphate dehydrogenase - enzyme needed for synthesis of guanosine - specifically the enzyme type in B and T lymphocytes

Also has proapoptotic effect on activated lymphoid and monocytic cell lines
Inhibits clonal expansion of B and T lymphocytes
Alters expression of lymphocyte cellular adhesion molecules –> decrease transendothelial migration of immune cells

Used successfully in treatment of MG in vet med

Adverse effects: Vomiting, diarrhea

(VCNASAP Kent)

Question 7

MOA of IVIg?

Answer 7

1. Bind Fab portion of autoantibodies - neutralize autoantibodies
2. Prevents recycling of autoantibodies
3. Suppression of cytokines, chemokines, metalloproteases
   
   • Reduction of IL1, IL1B, TNF a, MMP2 and 9, various chemokines
4. Inhibition of complement binding, prevents formation of membrane attack complex
5. Blockade of Fc receptors on phagocytic cells - saturating these receptors
6. Modulate function of T lymphocytes

Risks

• Thromboembolism secondary to hyperviscosity
• Anaphylaxis

(VCNASAP Kent)

Question 8

What immunosuppressive drug works via the following mechanism?

Pyrimidine synthesis inhibitor
Induces DNA x-linking
Inhibits B cell and T cell proliferation

Answer 8

Leflunomide

(Coates)

Question 9

What immunosuppressive drug works via the following mechanism?

Monoamine oxidase inhibitor
T cell specific
Causes DNA methylation and free radical production

Answer 9

Procarbazine

(Coates)