Immunosuppressive Agents

Question 1

Cyclosporine; Tacrolimus - Class

Answer 1

Immunosuppressive agent; calcineurin inhibitor

Question 2

Cyclosporine; Tacrolimus - MOA

Answer 2

Inhibits calcineurin phosphatase activity, which is needed to dephosphorylate and activate the transcription factor NFAT –> decreases IL-2 transcription –> suppression is somewhat selective for T cells

Question 3

Cyclosporine; Tacrolimus - Toxicity

Answer 3

Renal (less w/ tacrolimus)

Hyperglycemia w/ tacrolimus

Question 4

Sirolimus; Everolimus - Class

Answer 4

Immunosuppressive agent; protein kinase inhibitor

same family as cyclosporine and tacrolimus

Question 5

Sirolimus; Everolimus - MOA

Answer 5

Blocks T cell response to cytokines by inhibiting a kinase involved in cell-cycle progression

Specifically = IL-2 by binding FKBP –> complex binds and inhibits mTOR kinase (aka rapamycin)
–> prevents Cdk2 activation of cell proliferation; T cell/tumor cell specific; cell cycle arrest at G1-S transition

Question 6

Sirolimus; Everolimus - SE

Answer 6

Hyperlipidemia, myelosuppression, GI distress, mucocutaneous effects

Question 7

How does Everolimus differ from Sirolimus?

Answer 7

Shorter 1/2-life and quicker time to steady-state concentration

Question 8

Sirolimus; Everolimus - D/I

Answer 8

Some CytP450 inhibition, competes for efflux at efflux pump

Question 9

Azathioprine/6-mercaptopurine - Class

Answer 9

Immunosuppressive agent; purine antimetabolite

Question 10

Azathioprine/6-mercaptopurine - MOA

Answer 10

Converted to 6-mercaptopurine –> acts as purine analog (i.e. fraudulent nucleotide) to inhibit purine synthesis, esp in B/T cells

Question 11

Azathioprine/6-mercaptopurine - Toxicity

Answer 11

Inhibits proliferation of any rapidly dividing cell populations –> bone marrow suppressive

Question 12

Azathioprine/6-mercaptopurine - D/I

Answer 12

Allopurinol inhibits azathioprine metabolism

Question 13

Mycophenolate mofetil - Class

Answer 13

Immunosuppressive agent; prodrug of mycophenolic acid (MPA), an inhibitor of inosine monophosphate dehydrogenase (IMPDH)

Question 14

Mycophenolate mofetil - MOA (2)

Answer 14

1. Inhibition of inosine monophosphate dehydrogenase –> decreased de novo purine biosynthesis , esp in B/T cells (due to lack salvage pathway)
2. Anti-inflammatory via decreased leukocyte adhesion to endothelial cells by decreased E and P selectin synthesis

Question 15

Mycophenolate mofetil - SE

Answer 15

Bone marrow suppression

Question 16

What is a related drug to mycophenolate mofetil?

Answer 16

Mizoribine

Question 17

Cyclophosphamide - Class

Answer 17

Immunosuppressive agent; DNA alkylator

Question 18

Cyclophosphamide - MOA

Answer 18

Alkylating agent-> inhibits B/T-cell proliferation –> effects on rapidly proliferating cells

Question 19

Cyclophosphamide - SE (4)

Answer 19

Acrolein made as a breakdown product, toxic to bladder-> neutralize w/ MESNA
Immunosuppression; infertility; increased risk of infection and neoplasia

Question 20

Antithymocyte globulin - Class

Answer 20

Antibody reagent/immunosuppressive antibody

Question 21

Antithymocyte globulin - Tx

Answer 21

Acute renal transplant rejection

Question 22

Antithymocyte globulin - MOA

Answer 22

Mixture of cytotoxic Abs to various CD and HLA molecules on T cells –> block cell fxn and cytotoxic

Question 23

Antithymocyte globulin - SE (3) and how to make less severe

Answer 23

Fever, chills, hypotension –> less if pretreated w/ corticosteroids, acetaminophen, or antihistamines

Question 24

Muromonab-CD3 – Class

Answer 24

Antibody reagent/Immunosuppressive antibody

Question 25

Muromonab-CD3 – Tx

Answer 25

Acute renal transplant rejection

Question 26

Muromonab-CD3 – MOA

Answer 26

Ab against CD3 prevents binding of APC to T-cell –> prevents antigen recognition and thus blocks T-cell function and decreases T-cell number

Question 27

Muromonab-CD3 – SE and how to reduce risk

Answer 27

Initially induces cytokine release syndrome –> Ab binding causes initial T-cell activation –> increased serum levels of cytokines released by activated T cells and/or monocytes (fever, chills, nausea, vomiting, arthralgia > skin rxns, aseptic meningitis, pulmonary edema, cardiovascular collapse) –> decrease risk if pretreated w/ glucocorticoids

Question 28

Daclizumab; Basiliximab – Class

Answer 28

Antibody reagent/immunosuppressive antibody

Question 29

Daclizumab; Basiliximab – Tx

Answer 29

Acute renal transplant rejection

Question 30

Daclizumab; Basiliximab – MOA

Answer 30

Monoclonal Ab against IL-2 receptor –> blocks IL-2 mediated T-cell activation

Question 31

Which one has a longer half-life: Daclizumab or Basiliximab?

Answer 31

Daclizumab has a somewhat lower affinity but longer 1/2-life than basiliximab

Question 32

Daclizumab; Basiliximab – SE

Answer 32

Potential anaphylactic reactions