Immunosuppressants (MC) - Block 4 Flashcards
Indications for immunosuppressants?
For solid organ and bone marrow transplantation and autoimmune disorders
ADR of immunosuppressants?
- Increase risk of infection and malignanciess
- Nephrotoxicity
- Diabetes
MOA of glucocorticoids?
Reduce size and lymphoid content of lymph nodes and spleen -> interferes with cell cycle of activated lymphoid cells
Corticosteroids Examples?
- Hydrocortisone
- Prednisone
- Prednisolone
- Methylprednisolone
- Dexamethasone
- Betamethasone
- Triamcinolone
MOA of cyclosporine?
Blocks activation of T cells by binding to cyclophilin
Metabolism of cyclosporine?
CYP3A family -> requiring individual patient dosage adjustments
ADR of cyclosporine (calcineurin inhibitors)?
Nephrotoxicity (additive with NSAIDs)
HTN
Hyperglycemia
Hyperkalemia
How does tacrolimus binding differ from cyclosporine?
Binds to FK-BP instead of cyclophilin
What is a natural mTOR inhibitor?
Rapamycin
MOA of rapamycin?
Bind to FKBP12 -> complex blocks mTOR
What is mTOR?
Mammalian target of rapamycin: serine/threonin kinase
* Phosphorylated kinases result in de novo synthesis of proteins -> inhibition of T cell proliferation
PK properties of rapamycin?
Lot of hydrophobic interactions (carbon rich)
* Only 3 atoms aren’t buried in the protein - one of which is O -> can modify
Metabolism of sirolimus?
Substrate for both CYP3A family and P-gp many DDIs are possible
ADR of sirolimus?
- Hyperglycemia
- DLD (elevated cholesterol and TG)
- HTN
- Myelosuppression
Not as nephrotoxic -> good for kindey transplants
Describe the structural modifications of Temsirolimus/Everolimus?
Increased solubility - O is not in protein and ester/ether are polor -> exposed to surrounding environment (aqueous)
How is temsirolimus metabolized?
To rapamycin (active) by CYP3A4
What mTOR Inhibitors must be pretreated with Benadryl to prevent hypersensitivity reactions?
Temsirolimus
What is the drug name of rapamycin?
Sirolimus
MOA of mycophenolate mofetil?
Prodrug for F -> inhibits T and B lymphocyte responses
* Selectively inhibits lymphocyte proliferation and function
* Inhibits de novo synthesis of purines
What is different about the metabolism of mycophenolate mofetil?
Not metabolized by CYP 3As
ADR of mycophenolate mofetil?
HTN, reversible myelosuppression
What is the prodrug of mercaptopurine?
Azathioprine
Additional MOA of azathioprine?
Antimetabolite: interferes with purine nucleic acid metabolism at steps required for lymphoid cell proliferation after antigenic stimulation
ADR of azathioprine?
Myelosuppression
