Immunosuppressive Drugs

Question 1

Which are more effectively suppressed: primary or secondary immune responses?

Answer 1

primary

Question 2

Is imune suppression more likely to occur if you start therapy before exposure or after exposure?

Answer 2

before exposure

Question 3

Immunosupression increases the risk of what?

Answer 3

infection, lymphomas

Question 4

What are the four major calsses of immunosuppressive drugs?

Answer 4

glucocorticoids
calcineurin inhibitors
antiproliferative/antimetabolic drugs
antibodies

Question 5

What are the three primary uses of immunosuppression?

Answer 5

Autoimmune disease, transplanation, hemolytic anemia of the newborn

Question 6

What are the two classes of steroids synthesized by the adrenal cortex?

Answer 6

glucocorticoids and mineralocorticoids

Question 7

What’s the main endogenous glucocorticoid? mineralocorticoid?

Answer 7

gluco = hydroxortisone (cortixol)
mineral = aldosterone

Question 8

Which one is anti-inflammatory?

Answer 8

glucocorticoids

Question 9

What are the four synthetic steroids we need to know that are used as anti-inflammatory drugs?

Answer 9

betamethasone
dexamethasone
methylprednisolone
prednisone

Question 10

Where are the receptors for steroids?

Answer 10

NOT on the plasma membrane - in the cytosol and then they dimerize and go to the nucleus

Question 11

Why are the effects of steroid usually delayed?

Answer 11

because they alter gene transcription, which taikes a while

Question 12

What are steroid effects on neutrophils/

Answer 12

release from marrow is accelerated and half time in circulation is increased, so you get more circulatin, HOWEVER< there’s a blockage of the neutrophil migration into inflammatory sites, so there are more but they can’t do their job

Question 13

What are steroid effects on lymphocyts?

Answer 13

profound transient lymphopenia

the cells aren’t lysed, but move to extracellular compartments like the spleen, LNs, htoracic duct and bone marrow

Question 14

What are the steroid effects on monocytes and eosinophils?

Answer 14

decreased in peripheral blood

Question 15

Which COX is more inhibited by steroids?

Answer 15

COX 2 (reduced expression)

Question 16

How do steroids inhibit prostaglandin and leuketriene formation (beyond just inhibiting COX)?

Answer 16

They inhibit the release of AA form phospholipids

Question 17

What effect do steroids hae on mast cells and basophils?

Answer 17

inhibit degranulation

Question 18

True of false: the negative side effects of steroids start to occur with the first dose?

Answer 18

false - one dose is totally harmeless

a few days is likely not harmful except at high doses

Question 19

Abrust cessation of prolonged high dose steroids will increase risk of organ failure?

Answer 19

renal insufficiency

Question 20

What are the adverse effects of continued use?

Answer 20

immunosuppression
peptic ulceration
behavioral disturbances
cataracts
osteoporosis and compression factors
inhibition of growth

Question 21

The withdrawal is associated with adrenal insufficiency - what adverse effects relfect this?

Answer 21

fever, myalgia, arthralgia, malaise, death with hypotension and shock!

Question 22

What does cyclosporine bind to? To inhibit what?

Answer 22

binds to cyclophilin to inhibit calcineurin activity and blocks the dephosphorylation event critical for cytokine gene expression and T cell activation

Question 23

What’s the most common use for cycloposinr?

Answer 23

long term therapy after transplantation

Question 24

WHat’s the major adverse effect of cyclosporine?

Answer 24

renal toxicity - in as many as 75% of patients!

Question 25

What does Tacrolimus bind to to inhibit clacineurin?

Answer 25

FK binding protein (FK506)

Question 26

Which is more potent: cyclosporine or tacrolimus?

Answer 26

tacrolimus - 100 time more!

Question 27

What are the two antiproliferative/antimetabolic drugs we need to know?

Answer 27

sirolimus and mycophenolate mofentil

Question 28

What is the mechanism of action for sirolimus?

Answer 28

it binds to the FKBP to inhibit mTOR, which blocks cell ccycle progression from G1 to S phase

Question 29

What’s the toxicity for sirolimus?

Answer 29

dose dependent increase in cholesterol and triglycerides
nephrotoxicity if given with cyclosporin
increased risk of lymphomas and infections
substrate for CYP3A4 - drug interactions

Question 30

What is the mechanism of action for mycophenolat emofentil?

Answer 30

A metabolite of the drug is an inhibitor of inosine monophosphate dehydrogenase which is required for de novoguanine nucleotide synthesis

Question 31

What are the toxicities for mycophenolate?

Answer 31

leukopenia, diarrhea, vomiting

Question 32

What are the four antibodies we need to know for immunosuppression?

Answer 32

Anti-thymocyte globulin
muromonab - CD3
daclizumab
basiliximab

Question 33

What do the anti-thymocyte globulins do?

Answer 33

like the name suggests…

they bind to thymocytes in the circulation, resultin gin lymphpenia and imparied T CELL RESPONSE

Question 34

What does muromonab-CD3 do?

Answer 34

like the name suggests…
binds to the epsilon chain of CD3 glycoprotein of the TCR complex on T cells, which makes the TCR be internalized, preventing further antigen recognition

Question 35

When is muromonab CD3 usually used?

Answer 35

to prevent kidney, liver or heart transplant rejections

Question 36

The initial interaction of muromonab CD3 with the TCR causes what?

Answer 36

cytokine release and cytokine release syndrome
(because you get a combo of Fc receptor mediated crosslinking, resulting in the initial activation of the cell and release of cytokines)

Question 37

Why is repeated use contraindicated with muromonab?

Answer 37

it’s a mouse monoclonal antibody, so you get immune respnse to is over time

Question 38

What do daclizumab and basiliximab do?

Answer 38

They are anti-IL2 antibodies that bind to the receptor presented on ACTIVATED T cells, thus inhibiting IL-2 mediated activation events

Question 39

Are daclizumab and basiliximab better or worse in terms of side effect profile?

Answer 39

better - no cytokine release syndrome, lower incidence of lymphoproliferative disorders/infections