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CMOD- Block1 > Pharm: Immunosuppressants > Flashcards

Pharm: Immunosuppressants Flashcards

1
Q

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

A
  1. to inhibit T cell activation

2. to inhibit clonal expansion of T cells

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2
Q

Regarding immunosuppressive regimens, induction refers to ___.

A

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

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3
Q

Regarding immunosuppressive regimens, maintenance refers to ___.

A

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

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4
Q

Regarding immunosuppressive regimens, rescue refers to ___.

A

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

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5
Q

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

A

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

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6
Q

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

A

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

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7
Q

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

A

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

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8
Q

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

A

transcription; pro-inflammatory; IL-2

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9
Q

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

A

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

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10
Q

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

A

mTOR; clonal expansion

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11
Q

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

A

depletion via complement-dependent opsonization and lysis

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12
Q

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

A

antagonism or signaling

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13
Q

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 ____ ____.

A

Fc receptors; complement fixation

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14
Q

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

A

receptors; ligands

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15
Q

What are the options when a mAb binds a receptor?

A

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

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16
Q

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

A
  • complement-dependent cytotoxicity (CDC)
  • antibody-dependent cell-mediated cytotoxicity (ADCC)
  • antibody-dependent cellular phagocytosis
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17
Q

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

A 
'o' = murine
'xi' = chimeric
'zu' = humanized
'u' = human
-mab = monoclonal anitbody
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18
Q

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

A

False - muronamab (OKT3) targets CD3.

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19
Q

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

A

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.

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20
Q

What drug targets CD80/86 (B7)?

A

Belatacept, aka Nulojix, a mAB

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21
Q

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

A
  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)
22
Q

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

A

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)

23
Q

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

A

cyclosporine - binds cyclophilin

tacrolimus - binds FK binding protein 12

24
Q

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

A

nephrotoxicity; graft rejection

25
Q

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

A

cyclosporine

26
Q

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

A

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

27
Q

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

A

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

28
Q

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

A

neutrophilia; increased

29
Q

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

A

corticosteroids

30
Q

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

A

adverse metabolic effects; cell surface receptors

31
Q

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

A

mTOR; FK-binding protein 12; G1 phase

32
Q

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

A

calcineurin; cyclosporine

33
Q

Sirolimus has what effect on B cells?

A

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

34
Q

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

A

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

35
Q

What are the major adverse effects of sirolimus?

A

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

36
Q

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

A

monophosphate dehydrogenase, DNA synthesis

*MDH converts inosine MP to guanosine MP in purine synthesis

37
Q

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

A

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

38
Q

What are the most common side effects of mycophenolate mofetil?

A

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

39
Q

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?

A

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

40
Q

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

A

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

41
Q

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

A

Cyclophosphamide; pro-drug

42
Q

Describe the MOA of cyclophosphamide.

A

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

43
Q

Why does cyclophosphamide have its greatest effect on humoral immunity?

A

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

44
Q

Methotrexate (MTX) is a ____ inhibitor.

A

DHF reductase

45
Q

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

A

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
46
Q

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

A

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

47
Q

Major side effects of MTX include:

A

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

48
Q

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

A

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

49
Q

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

A 
renal = best
liver = least best
50
Q

Induction of immunosuppression is commonly effected with which agents?

A

basiliximab or thymoglobulin

51
Q

Maintenance of suppression often involves which drugs?

A

AZA, prednisone, cyclosporine

CMOD- Block1 (36 decks)

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