Wk18D2 Glucocorticoids and Immunosuppressants

Question 1

Four main pharmacological strategies of immunosuppression

Answer 1

1. Inhibit lymphocyte metabolism and proliferation
2. Disrupt transcription programs
3. Disrupt intracellular signal integration
4. Block/modulate cell surface receptors

Question 2

Drug Categories that Inhibit lymphocyte metabolism and proliferation

Answer 2

Cytotoxic Drugs (Azathioprine, mycophenolate mofetil, methotrexate, cyclophosphamide)

Question 3

Drug Categories that Disrupt transcription programs

Answer 3

Adrenocortical Steroids - target nuclear receptors

Cacineurin inhibitors - target NFAT pathway

Question 4

Drug Categories that Disrupt intracellular signal integration

Answer 4

mTOR inhibitors (rapamycin analogs)

Question 5

Drug Categories that Block/modulate cell surface receptors

Answer 5

FTY-720 - inhibitors of sphingosine 1-P receptor signaling

Monoclonal Antibodies - target cell surface receptors

Question 6

MOA: Azathioprine and Mycophenolate Mofetil

Answer 6

inhibit the biosynthesis of purines and prevent DNA replication

NOTE: Azathioprine is metabolized to 6-MP

Question 7

MOA: Methotrexate

Answer 7

inhibits dihyrdrofolate reductase (DHFR), which causes immunosuppression b/c DNA synthesis is inhibited in B and T cells

Question 8

MOA: Cyclophosphamide

Answer 8

alkylates (cross-links) DNA and inhibits DNA replication

Question 9

Why is it important to remember the HPA axis when thinking about withdrawing glucocorticoid therapy??

Answer 9

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.

Question 10

Adrenocortical Steroids

Answer 10

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.

Question 11

Glucocorticoids

Answer 11

an adrenocortical steroid that acts by metabolic (act on glucose), anti-inflammatory, and immunosuppressive actions (e.g. Cortisol)

Question 12

Aldosterone

Answer 12

an adrenocortical steroid. Controls electrolyte and fluid balance

Question 13

MOA: Calcineurin Inhibitors

Answer 13

Cyclosporin and FK506 act on different targets of the NFAT pathway. Both drugs inhibit calcineurin which prevents T Cells from producing cytokines

Question 14

MOA: mTOR Inhibitors

Answer 14

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

Question 15

MOA: FTY720

Answer 15

a potent sphingosine-1-phosphate (S1P) receptor agonist (involved in lymphocyte trafficking at all sites). Its mechanism of action is believed to sequester lymphocytes in lymph nodes and thus prevent immune cells from moving to target organs or tissues for immune responses