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CMOD > Immunosuppresive agents > Flashcards

Immunosuppresive agents Flashcards

1
Q

Calcineurin inhibitors (2)

A

Cyclosporin

Tacrolimus

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2
Q

Nuclear transcription inhibitors (1)

A

prednisone

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3
Q

mTOR inhibitors (1)

A

sirolimus (Rapamune)

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4
Q

Cell Cycle disruptors (4)

A

mycophenolate mofetil (CellCept)
azathioprine (imuran)
Methotrexate (trexall)
Cyclophosphamide (cytoxan)

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5
Q

Overall goal of immunosuppresive therapy

A

reduce T cell population

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6
Q

Critical cytokine released by an activated T cell, for proliferation/clonal expansion

A

IL-2

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7
Q

CD28 on T cell binds to?

A

B7 on APC

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8
Q

3 types of immunosuppressive therapies

A
  1. induction
  2. maintenance
  3. Rescue
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9
Q

Hallmarks of induction therapy

A
  1. at the time of the transplant
  2. relatively intense
  3. prolonged use prihibitively toxic
  4. may include donor specific transfusion or irradiation as drug alternatives
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10
Q

hallmarks of maintenance therapy

A

tolerable in chronic use, but not without side effects

*tends to employ drugs of milder potency that are more tolerable throughout the course of treatment

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11
Q

hallmarks of rescue therapy

A

intense and effective
chronically intolerable
*applied in response to rejection episode

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12
Q

classic maintenance therapy 3-drug combo

A
  1. calcineurin inhibitor (cylosporin)
  2. anti-proliferative (mycophenolate mofetil)
  3. steroids (prednisone)
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13
Q

list the order of graft immunogenicity

A

lungs > heart > kidney > liver > dick

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14
Q

Bind FKB12 protein

A

Tacrolimus

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15
Q

Polyclonal IgG drugs against human T-Lymphocytes

A

Thymoglobulin

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16
Q

Nuclear Transcription inhibitors

A

Prednisone

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17
Q

Binds to FKBP12 (2)

A

Tacrolimus

Sirolimus

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18
Q

Where do most of these immunosuppressive drugs work?

A

T cells: Targets include:

  • cell surface inhibitors
  • calcineurin inhibitors
  • transcription inhibitors
  • mTOR inhibitors
  • cell-cycle inhibitors
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19
Q

Most common drug used in renal transplantation currently

A

thymoglobulin (poly clonal IgG against T cells)

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20
Q

transplantation between two non-identical organisms

A

allograft

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21
Q

second signal required for activation of T cell

A

CD28 must bind to B7 of APC to release autocrine growth factor IL2
IL-2 activated adjacent t cells to udndergo proliferation and differentiation

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22
Q

drugs that target T cell surface would be attempting to inhibit what

A
  1. proliferation of T cells in response to IL2

2. targeting the t cell for death by other immuno components

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23
Q

normal treatment path for induction therapy

A

there is none–> tx is different in each specific case
more similarites between donor/recipient will probably require less potent drugs
more dissimilar–>more potent drugs at higher concentrations

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24
Q

Calcineurin inhibitors MOA

A

a phosphatase that controls NFAT–>This prevents T cell from upregulate IL-2–>inhibits t cell proliferation and differentiation signal

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25
Q

Monoclonal Ab’s MOA

A

block secreted IL from an activated T cell from binding to the CD25 receptor on adjacent T cells
*diminishes t cell proliferation

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26
Q

glucocorticoids MOA

A

act in the cell nucleus to INHIBIT REGULATION of transcription of many proinflammatory cytokines…one of which is IL-2 this downregulate t cell proliferation

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27
Q

Normally, activation by IL-2 leads to what

A

activation of mTOR and initiation of cell-cycling

*inhibition of mTOR causes the IL-signal to be irrelevant

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28
Q

Where is CD52 expressed

A

surface of mature lymphocytes

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29
Q

Binding of CD52 by mAb’s leads to what processes

A
  1. ADCC (NK cell and is FC dependent) FCgammaR3

2. compliment mediated cytotoxicity

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30
Q

Thymoglobulin MOA

A

polyclonal IgG against human T lymphocytes–> leads to t lymphocyte depletion via Compliemnt dependent opsonization and lysis

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31
Q

mAb’s that bind to a ligand (2)

A

infliximab

omalizumab

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32
Q

mAb’s that bind to a receptor (2)

A

natalizumab

daclizumab

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33
Q

TGN1412 is what

A

mAb that is a CD28 superagonist

*binding to CD28 receptor can activate the Tcell without TCR ligation to antigen

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34
Q

What does FcRn do

A

controls transpot or IgG across cell barriers

*fucking Miller keeps calling this the FcRb receptor

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35
Q

Does drugs acting on IL-2 receptor or release lead to cell depletion

A

NO

36
Q

target of muromonab

A

CD3 (transduction unit for a t cell)

37
Q

target of basiliximab

A

Cd-25 the IL2 receptor

38
Q

target of daclizumab

A

IL 2 receptor (cd25)

39
Q

drugs that target B7

A

belacept

40
Q

drug that targets CD52

A

alemtuzumab (leads to ADCC and CDC)

41
Q

problems associated with imunosuppressive

A

I. increased risk for opportunistc infections

2. secondary malignancies

42
Q

toxicity associated with CNI’s

A
  1. renal toxicity (calcification, vasoconstricton etc)
  2. mild-moderate HTN from renal vasoconstrcition and increased sympathetic tone
  3. secondary malignancies
43
Q

does CNI’s affect T cell, Bcells or both

A

Both
INHIBITS IFg and IL-2 production in t cells
Il-4 production in B cells

44
Q

Hirsutism or hypertrichosis is associated with

A

cyclosporine

45
Q

CNI with neurotoxicity

A

Tac (headache, insomnia, parasthesias and dizziness)

46
Q

Gingival hyperplasia is associated with

A

cyclosporine

47
Q

two ways in which corticosteroids+GR inhibit gene transcription of inflammatory proteins

A
  1. directly

2. indirectly by recruitment of HDAC–> leads to diminished transcription bc the DNA is too tightly wound up

48
Q

Blood content reactions (other than inhibition of T cell activity) due to prolonged corticosteroid therapy

A
  1. neutrophilia: increased production and decreased apoptosis
  2. eosinopenia: increased apoptosis
  3. monocytopenia: decreased production and differentiation
49
Q

Sirolimus MOA

A

binds to FKB12–>inhibits mTOR–>leading to cell-cycle arrest

50
Q

“first phase of T cell activation”

A

production of autocrine growth factors like IL-2 that lead to proliferation and differentiation

51
Q

“second phase of T cell activation”

A

signal transduction and clonal proliferation of T cells (G1 arrest)

52
Q

synergistic drug that you can give with cyclosporin

A

sirolimus (does not affect CN activity)

53
Q

Sirolimus affect on B cells

A

prevents differntition into antibody producing cells –>decreased host levels of IgM, IgG and IGa

54
Q

Pt’s taking sirolimus must be monitored for

A

hyperlipidemia. HTN, fever, diarrhea,

55
Q

Blood content reaction to sirolimus

A

anemia, leukopenia, thrompocytopenia, hypokalemia, azotemia (high nitrogen),increased serum creatinine, defreased GFR

56
Q

pt.s taking sirolimus are at increased risk for?

A

thromboembolism and DVT’s, secondary malignancies, infections

57
Q

organ affected by sirolimus

A

liver–>hepatotoxicity including fatal necrosis of the liver

kidney as well

58
Q

risk of secondary malignancies is associated with which drug classes

A

Sirolimus (mTOR inhibitor)
CNI’s (cyclosporin)
mAb’s
MMF
azothiprine (skin cancer with increased UV)
*all due to weakend self-monitoring respnses by immunosuppression

59
Q

MMF MOA

A

inhibits inosine monophosphate dehydrogenase–>interrupts DNA synthesis

60
Q

Cell cycle disruptors affect which cell lines the most?

A

B and T cells
*cannot synthesize GTP sufficiently through the salvage pathway–>therby if DNA becomes a rate limiting reagent T cell proliferation is inhibited

61
Q

drug wtih selective effect on lymphocyte proliferation

A

MMF

62
Q

drugs without selctive effect on lymphocyte proliferation

A

methotrexate

asathioprine

63
Q

Adverse effects of MMF

A

secondary malignancies
Gi upset
neutropenia (myelosuppression)

64
Q

Azathioprine is converted to

A

6 mercaptopurine (an anticancer drug in its own right)

65
Q

Metabolism for azothiprine

A

azo->6mc–> 6 thioguanine triphosphate–>

66
Q

6 thioguanine triphosphate does what

A

1.Inhibits RAC1
blocks CD28 co stimulation
promotes apoptosis
especially CD45RO (IL2 stimulated)memory T cells
2. leads to cell cycle arrest by incorporating a decoy DNA precursor (6 thio GTP) in to chain

67
Q

cannot give azothioprine in concert with which drugs

A
  1. allopurinol (increases azothioprine toxicity)

2. warfarin (decreased INR)

68
Q

cyclophosphamide

A

requires activation of its pro-drug form

69
Q

greatest effect of cyclophosphamide

A

suppression of humoral immunity

70
Q

ADE’s of cyclophosphamide

A 
cardiovascular risks: CHF, toxicity, PE
skin cancer
azoospermia
fibrosis of bladder
fibrosis of lungs
71
Q

uptake of MTX follows

A

folate pathway

72
Q

efflux of MTX is via

A

ABC transporter

73
Q

MTXPG leads to accumulation of

A

AICAR

74
Q

AICAR inhibits ADA and AMp deaminase and leads to

A

build up of adenosine (which is anti-inflammatory)

75
Q

where would you find adenosine receptors

A

APC’s

76
Q

Adenosine-AR binding does what in APC’s

A

via cAMP and increased cytosolic calcium

  • ->dimnished production of ILa anf TNF-a, MIP1a, and NO
  • ->increase production of IL10 and VEGF
77
Q

S phase specific cell-cycle disruptor

A

methotrexate
dirreah, NV
pulmonary fibrosis

78
Q

blood reactions cause by MTX

A

anemia

leuko, thrompo, neutro, pancytopenias

79
Q

MTX is a teratogen

A

yes

80
Q

drug with no pGp or cyp34 involvment

A

MMF

81
Q

substrate + inhibitor for pGp and CYP3a4

A

cyclosporine

82
Q

substrate for cyp3a4/ no involvement with pGp

A

tacrolimus

83
Q

substrate for CYP3a4 and substrate + inhibitor for PGP

A

sirolimus

84
Q

drug used for established rejection pulsed high dosage

A

muromonab CD3
and
Thymoglobulin
(anti-t lumphocyte ab’s)

85
Q

used for cardiac transplant via impregnanted stents

A

sirolimus

CMOD (19 decks)

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