Immunosupressant drugs

  1. Cyclosporine: mechanism of action
    • cyclosporine-cyclophilin inhibits calcineurin-mediated activation of NF-AT that leads to cytokine production
    • Early activation of T cells is blocked
  2. Cyclosporine: Adverse Effects
    • Nephrotoxicity
    • Hypertension
    • Neurotoxicity
    • Hyperkalemia
    • Hyperlipidemia
    • Hirsutism
    • Hyperuricemia
    • Gigival hyperplasia
  3. Cyclosporine: Absolute contraindications
    • Breastfeeding
    • caution in patients with conditions that CsA's side effects can worsen
  4. Cyclosporine: Drug Interactions
    • Substrate for CYP3A4
    • Inhibitor of CYP3A4
    • Substrate of pgp
    • Inhibitor of pgp
    • Avoid in combination with: Nephrotoxic drugs, drugs that cause hyperkalemia, ACE inhibitors and ARBs
  5. Tacrolimus: mechanism of action
    • Tacrolimus-FKBP inhibits calcineurin-mediated activation of NF-AT that leads to cytokine production
    • Early activation of T cells is blocked
  6. Tacrolimus: Adverse Effects
    • Nephrotoxicity
    • Hypertension
    • Neurotoxicity
    • Hyperkalemia

    • Hyperglycemia / diabetes
    • Elevated liver enzymes
    • GI upset
    • Hematological abnormalities
  7. Tacrolimus: Absolute contraindications
    • Breast feeding
    • caution in patients with conditions that Tacrolimus' side effects can worsen
  8. Tacrolimus: drug interactions
    • Substrate for CYP3A4
    • competes for binding of plasma proteins
    • interacts with nephrotoxic drugs
    • interacts with drugs that cause hyperkalemia, etc
  9. Sirolimus: mechanism of action
    • sirolimus-FKBP inhibits mTOR, which blocks cell cycle progression to G1.
    • so it inhibits T cell proliferation in response to cytokines
  10. sirolimus: adverse effects
    • Hypertension
    • Hyperlipidemia
    • Elevated risk of lymphocele
    • delayed graft function
    • impaired wound healing
    • clotting disorders
    • anemia
  11. sirolimus: drug interactions
    • substrate of CYP3A4
    • substrate of pgp
    • interacts with CsA causing increased sirolimus levels, and increased nephrotoxicity of CsA
  12. Mycophenolate: mechanism of action
    • MPA is a noncompetitive inhibitor of inosine monophosphate dehydrogenase (IMPDH)
    • this enzyme is used in de novo purine synthesis converting IMP to GMP
    • B and T cells depend on de novo synthesis
    • so ultimate function of MPA is to inhibit protein synthesis (cytokines, antibodies, adhesion molecules) and inhibition of cell proliferation in B and T cells
  13. Mycophenolate: adverse effects
    • GI upset
    • Renal tubular necrosis
    • myelosuppression
  14. Mycophenolate: absolute contraindications
  15. Mycophenolate: drug interactions
    • MPA is conjugated w/ glucuronide, so CsA decreases MPA levels
    • MPA is highly bound to plasma proteins
  16. Methotrexate: general information
    • rarely used as immunosuppressant
    • more common uses in cancer chemotherapy and inflammatory/autoimmune disease
  17. Azathioprine: mechanism of action
    • Azathioprine is metabolized to 6-mercaptopurine (6-MP), which is converted to 6-thioguanine nucleotides (6-TGNs)
    • 6-TGN is incorporated into WBC and causes mismatch repair, which then induces cell cycle arrest and apoptosis. This is a short term effect on activated T cells
    • 6-MP to MeTIMP. MeTIMP inhibits de novo purine synthesis. this inhibits proliferation and is a long term effect.
  18. Azathioprine: adverse effects
    • GI disturbances
    • myelosuppression
    • hepatotoxicity
  19. Azathioprine: absolute contraindications
    • pregnancy
    • breastfeeding
  20. Azathioprine: drug interactions
    • Allopurinol
    • allopurinol inhibits xanthine oxidase, which breaks down 6-MP,  so this increases 6-MP toxicity.
  21. Antithymocyte Globulin: mechanism of action
    • antithymocyte antibodies bind to circulating T cells and opsonize them. 
    • thus, it depletes T cells!!
  22. Antithymocyte Globulin: adverse effects
    • injection site reaction
    • serum sickness
    • antibodies made against the drug
    • thrombocytopenia, neurtopenia (due to cross-reactivity)
  23. Antithymocyte: contraindications
    hypersensitivity to rabbit / horse proteins
  24. Antithymocyte: drug interaction
    did not discuss
  25. Muromonoab: mechanism of action
    • Note: ONLY used for trating rejected transplated organs
    • Muromonab antibody targets CD3, which causes the TCR to be internalized. This causes the T cell to either die or not work well (impaired cytokine secretion).
  26. Muromonab: adverse effects
    • Cytokine release syndrome (CD3 binding causes T cell activation and rapid TNFalpha release --> high fever, flu-like symptoms)
    • Severe Pulmonary edema
  27. Muromonab: absolute contraindications
    • hypervolemia or uncompensated heart failure (since it predisposes patient to pulmonary edema)
    • mouse protein hypersensitivity
  28. Muromonab: drug interactions
    did not discuss
  29. Daclizumab & Basiliximab: mechanism of action
    • Daclizumab antibodies directed against IL-2 receptor. 
    • Blocks IL-2 activation of T cells
  30. Daclizumab & Basiliximab: adverse effects
    • minimal
    • both can produce effects caused by foreign protein injection
  31. Daclizumab & Basiliximab: absolute contraindications
  32. Daclizumab & Basiliximab: drug interactions
    did not discuss
  33. Belatacept: mechanism of action
    antibody against proteins that bind CD28
  34. Belatacept: adverse effects
    did not discuss
  35. Belatacept: absolute contraindications
    EBV-negative, causes lymphoproliferative disorder
  36. Belatacept: drug interactions
    did not discuss
  37. Glucocorticoids: general information
    • used for prevention and treatment of rejection
    • used for many other conditions of excess immune or inflammatory actions
Card Set
Immunosupressant drugs