Pharm: Immunosuppressants

Question 1

Immunosuppressive drugs acts To suppress T cells in two ways, or at two different stages/phases. What are they?

Answer 1

1. to inhibit T cell activation

2. to inhibit clonal expansion of T cells

Question 2

Regarding immunosuppressive regimens, induction refers to ___.

Answer 2

employing a high dose of immunosuppressant at the time of organ transplantation; toxic with prolonged dosing

Question 3

Regarding immunosuppressive regimens, maintenance refers to ___.

Answer 3

employing a low dose of immunosuppressant for chronic use; not as toxic as induction/rescue doses but also not without side effects. Typically uses a triple-drug therapy with agents that act at different levels of the inflammatory cascade

Question 4

Regarding immunosuppressive regimens, rescue refers to ___.

Answer 4

dose of immunosuppressant taken in response to a rejection episode; chronically intolerable

Question 5

What is CD3 and what is the effect of blocking it?

Answer 5

CD3 is a component of the T cell receptor; blocking it prevents T cell activation

Question 6

What is CD28-CD80-86 and what is the effect of blocking it?

Answer 6

CD28 is on the T cell, CD80-86 is on the APC; these proteins’ interaction is critical for co-stimulation so blocking it leads to a failure to fully active the T cell and it eventually apoptoses

Question 7

What is calcineurin, and what is the effect of blocking it?

Answer 7

a phosphatase located within a T cell; it is responsible for activating a nuclear factor of activated transcription (NFAT). Without activity of NFAT, the T cell will not transcribe IL-2

Question 8

Within the nucleus of a T cell, glucocorticoid drugs inhibit ____ of ____ genes, which diminished the T cell’s ability to release ____.

Answer 8

transcription; pro-inflammatory; IL-2

Question 9

What is CD25, and what is the effect of blocking it?

Answer 9

CD25 is the receptor on the T cell surface that bind IL-2; blocking the CD25 receptor would remove the T cell’s ability to bind and respond to IL-2, thus diminishing clonal expansion

Question 10

When a T cell is activated by IL-2, ____ is activated within the cell, initiating the cell cycling that is critical to ____ ____.

Answer 10

mTOR; clonal expansion

Question 11

When polyclonal IgG is used on lymphocytes, the result is ____ of the lymphocytes via ___ and ___ (what mechanisms?).

Answer 11

depletion via complement-dependent opsonization and lysis

Question 12

In general, the CDR/antigen-binding region of mAbs (monoclonal antibodies) binds to specific targets and causes ____ or ____.

Answer 12

antagonism or signaling

Question 13

The Fc region of a mAb is composed of the hinge and constant domains of the heavy chains, and binds ____ receptors, and is also involved in ____ ____.

Answer 13

Fc receptors; complement fixation

Question 14

mAbs can bind either to ____ or ____, ultimately preventing stimulation of the T cell.

Answer 14

receptors; ligands

Question 15

What are the options when a mAb binds a receptor?

Answer 15

it can either prevent stimulation at the receptor, or induce signal transduction (superagonist)

Question 16

What are the functions of mAbs controlled by the Fc region?

Answer 16

• complement-dependent cytotoxicity (CDC)
• antibody-dependent cell-mediated cytotoxicity (ADCC)
• antibody-dependent cellular phagocytosis

Question 17

Just for fun: what are the nomenclature meanings of mAb drugs?

Answer 17

'o' = murine
'xi' = chimeric
'zu' = humanized
'u' = human
-mab = monoclonal anitbody

Question 18

True or false (and why?): Muronamab is a mAb drug that targets IL-2 and is lymphocyte depleting.

Answer 18

False - muronamab (OKT3) targets CD3.

Question 19

True or false (and why?): Basilizimab is a mAb drug that targets Multiple targets and is lymphocyte depleting.

Answer 19

False - basiliximab (Simulect) targets IL-2 receptor (CD25) and IS NOT lymphocyte depleting. Alternatively rabbit ATG (Thymoglobulin) - which is a pAb - has multiple targets and is lymphocyte depleting.

Question 20

What drug targets CD80/86 (B7)?

Answer 20

Belatacept, aka Nulojix, a mAB

Question 21

What are the greatest risks to patients taking immunosuppressants? (Not side effects, but rather consequences of immunosuppression)

Answer 21

1. opportunistic infections
2. secondary malignancies - lymphomas, skin cancer, lymphoproliferative disorder (proliferation of B cells due to therapeutic immunosuppression after organ transplantation; some could mutate and cause lymphoma)

Question 22

What is calcineurin, and what is its role in T cell signaling?

Answer 22

calcineurin is an intracellular phosphatase; when APCs interact with T cell receptors, Ca enters the cell and activates calcineurin; when activated it dephosphorylates NFAT; NFAT enters the nucleus and becomes a TF for gene products that active T cells (IL-2 and IFg) and B cells (IL-4)

Question 23

What drugs inhibit calcineurin? What proteins does each associate with in order to carry out its inhibitory function?

Answer 23

cyclosporine - binds cyclophilin

tacrolimus - binds FK binding protein 12

Question 24

Patients taking calcineurin inhibitors are at risk for dose/duration-dependent ____, but this is sometimes hard to differentiate from ____ ____.

Answer 24

nephrotoxicity; graft rejection

Question 25

Mild-moderate HTN caused by increased sympathetic tone and renal vascoconstriction can be cause by what drug?

Answer 25

cyclosporine

Question 26

What are the major side effects seen in patients taking cyclosporine?

Answer 26

nephrotoxicity, HTN, hirsutism, hypertrichosis, and gingival hyperplasia; then of course infections and secondary malignancies

Question 27

Corticosteroids are a drug targeted at ____. Explain their MOA.

Answer 27

the nucleus: corticosteroid brought into cell, binds a cytosolic GR, complex moves into the nucleus, binds coactivators, and all together they inhibit HAT (histone acetyltransferase) AND recruit HDAC2 (histone deacetylase-2) to suppress activated inflammatory genes

Question 28

Corticosteroids, in addition to inhibiting T cell activity, also produce ____, which is ____ production.

Answer 28

neutrophilia; increased

Question 29

____ are one of the most potent classes of anti-inflammatory and immunosuppressive drugs that are available clinically.

Answer 29

corticosteroids

Question 30

Adverse effects of corticosteroids include ____ as a result of their interaction with transcriptional regulation. They also cause neurologic issues because of their interactions with ____.

Answer 30

adverse metabolic effects; cell surface receptors

Question 31

Sirolimus is an inhibitor of ____. It binds to ____ and causes ____ arrest.

Answer 31

mTOR; FK-binding protein 12; G1 phase

Question 32

True or false: sirolimus has no effect on ____ activity, but is synergistic with ____.

Answer 32

calcineurin; cyclosporine

Question 33

Sirolimus has what effect on B cells?

Answer 33

prevents their differentiation into antibody-producing cells, thereby decreasing the levels of IgM, G, and A

Question 34

mTOR is not exclusively a component of immune cells. What implications does this have for patients taking sirolimus?

Answer 34

this means that sirolimus can inhibit mTOR elsewhere in the body, leading to ADEs with effects on non-lymphoid tumor cells, smooth muscle cells, hepatocytes, and fibroblasts

Question 35

What are the major adverse effects of sirolimus?

Answer 35

dose-related HLD; azotemia (high N-containing components of blood); PE, DVT; anemia, leukopenia, thrombocytopenia, hypoK, diarrhea; HTN; hepatotoxicity including fatal hepatic necrosis; infections/tumors; renal toxicity

Question 36

Mycophenolate mofetil is an inhibitor of ____ and thereby interrupts ____.

Answer 36

monophosphate dehydrogenase, DNA synthesis | *MDH converts inosine MP to guanosine MP in purine synthesis

Question 37

Why does mycophenolate mofetil work primarily on T and B lymphocytes?

Answer 37

these cells can't synthesize GMP sufficiently through the salvage pathway, so when mycophenolate mofetil interrupts GMP synthesis, it's all over

Question 38

What are the most common side effects of mycophenolate mofetil?

Answer 38

GI tract issues - constipation, diarrhea, dyspepsia, N/V; infections/tumors; myelosuppression occurs infrequently

Question 39

Azathioprine is a cell cycle disruptor drug that undergoes extensive metabolic conversion to several products. Two of its products are 6-thioguanine TP and 6-thio-IMP. What is the MOA of these products?

Answer 39

6-thioguanine TP = blocks co-stimulation of T cells and promotes apoptosis in IL-2 stimulated memory T cells 6-thio-IMP = inhibts purine synthesis because this is a fraudulent purine which gets incorporated into DNA, resulting in cell cycle arrest

Question 40

What drugs, when taken together with AZA, can increase AZA toxicity?

Answer 40

allopurinol; 5-aminosalicylates (because they inhibit TPMT, an enzyme needed for AZA metabolism)

Question 41

____, a cell cycle disruptor, is a ___ requiring metabolic activation.

Answer 41

Cyclophosphamide; pro-drug

Question 42

Describe the MOA of cyclophosphamide.

Answer 42

it's an alkylating agent, producing DNA cross-links

Question 43

Why does cyclophosphamide have its greatest effect on humoral immunity?

Answer 43

because it's a lymphopenic drug, affecting more B cells than T cells

Question 44

Methotrexate (MTX) is a ____ inhibitor.

Answer 44

DHF reductase

Question 45

MTX is converted to ____ within the cell by ____. This product has three effects: 1)____; 2)____; 3)____.

Answer 45

MTXPG, GGH. 1. impede generation of bioactive forms of folate 2. inhibit de novo pyrimidine synthesis 3. cause AICAR accumulation which inhibits ADA and AMP deaminase, causing adenosine accumulation

Question 46

What is the effect of accumulated adenosine, as is the result of MTX activity?

Answer 46

adenosine, when bound to adenosine receptors on macrophages, decreases pro-inflammatory IL-12/TNF-a/MIP-1a/NO and increases anti-inflammatory IL-10/VEGF; it also suppresses IL-12 production by mature DCs which means diminished Th1 and increased Th2 development

Question 47

Major side effects of MTX include:

Answer 47

diarrhea, N/V, pulmonary fibrosis, hematologic toxicity, hepatotoxicity, infections, neurologic syndrome, tertogen (these are relatively infrequent but serious)

Question 48

True or false: most immunosuppressant drugs have relatively significant interethnic differences in pharmacokinetics.

Answer 48

True - because of the different levels of CYP3A4 and P-gp (metabolizers) in the intestine and liver

Question 49

Which organ has the best response to immunopharmacologic agents, and which has the least best response?

Answer 49

``` renal = best liver = least best ```

Question 50

Induction of immunosuppression is commonly effected with which agents?

Answer 50

basiliximab or thymoglobulin

Question 51

Maintenance of suppression often involves which drugs?

Answer 51

AZA, prednisone, cyclosporine