Flashcards in Wk18D2 Glucocorticoids and Immunosuppressants Deck (15):
Four main pharmacological strategies of immunosuppression
1. Inhibit lymphocyte metabolism and proliferation
2. Disrupt transcription programs
3. Disrupt intracellular signal integration
4. Block/modulate cell surface receptors
Drug Categories that Inhibit lymphocyte metabolism and proliferation
Cytotoxic Drugs (Azathioprine, mycophenolate mofetil, methotrexate, cyclophosphamide)
Drug Categories that Disrupt transcription programs
Adrenocortical Steroids - target nuclear receptors
Cacineurin inhibitors - target NFAT pathway
Drug Categories that Disrupt intracellular signal integration
mTOR inhibitors (rapamycin analogs)
Drug Categories that Block/modulate cell surface receptors
FTY-720 - inhibitors of sphingosine 1-P receptor signaling
Monoclonal Antibodies - target cell surface receptors
MOA: Azathioprine and Mycophenolate Mofetil
inhibit the biosynthesis of purines and prevent DNA replication
NOTE: Azathioprine is metabolized to 6-MP
inhibits dihyrdrofolate reductase (DHFR), which causes immunosuppression b/c DNA synthesis is inhibited in B and T cells
alkylates (cross-links) DNA and inhibits DNA replication
Why is it important to remember the HPA axis when thinking about withdrawing glucocorticoid therapy??
High levels of circulating glucocorticoids suppress ACTH release from the pituitary and CRH release from the hypothalamus, which in turn suppress synthesis and release of cortisol from the adrenal.
The problem occurs when there is a sudden withdrawal. When a large amount of glucocorticoid was given (middle panel), the HPA axis was suppressed because the body has enough glucocorticoids. When there is a sudden withdrawal (right panel), the HPA axis is still suppressed, so we will see HYPOTENSION and HYPOGLYCEMIA.
endocrines produced by the adrenal gland and are used either alone or in combination with other immunosuppressive agents (e.g. cyclosporine or tacrolimus) for preventing transplant rejection and treating autoimmune disorders.
an adrenocortical steroid that acts by metabolic (act on glucose), anti-inflammatory, and immunosuppressive actions (e.g. Cortisol)
an adrenocortical steroid. Controls electrolyte and fluid balance
MOA: Calcineurin Inhibitors
Cyclosporin and FK506 act on different targets of the NFAT pathway. Both drugs inhibit calcineurin which prevents T Cells from producing cytokines
MOA: mTOR Inhibitors
Rapamycin targets mTOR, which is a TF that regulates cell growth by regulating transcription of certain mRNA. Blocks cytokine signal transduction that signals for activation and proliferation of T cells