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PHRM 865 > Final - Transplant > Flashcards

Final - Transplant Flashcards

1
Q

Immunology behind immunosuppression:

_____ mediated rejection = infiltration of the allograft by lymphocytes and other inflammatory cells

A

T cell mediated (cellular response)

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2
Q

Immunology behind immunosuppression:
_____ mediated rejection = circulating donor-specific antibodies/immunological evidence of an antibody mediated destruction

A

B cell (antibody) rejection (humoral response)

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3
Q

T cell activation requires __#__ signals

A

3 signals

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4
Q 
T cell activation steps:
#1. The T cell receptor (\_\_\_\_) interacts with \_\_\_\_\_\_\_
A

CD3 interacts with APC (antigen presenting cells)

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5
Q 
T cell activation steps:
#2. The co-stimulatory signal of \_\_\_\_\_\_ on the surface of APCs interacting with \_\_\_\_\_\_ on T cells
A

CD80/86 on APCs interacts with CD28 on T cells

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6
Q 
T cell activation steps:
#3. \_\_\_\_ binds to CD25 (which activates the mammalian target of \_\_\_\_\_\_) and subsequent proliferation and activation of the T-Cell
A

IL-2 binds to CD35;

target of rapamycin pathway

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7
Q

Rejection Timeline:
Hyperacute rejection – happens minutes to hours after transplant
& is mediated by ___________

A

preformed circulating antibodies

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8
Q

Rejection Timeline:
Acute rejection – occurs within days - months after transplant
& is mediated by _______

A

by host T-lymphocytes

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9
Q

Rejection Timeline:
Chronic rejection – happes over months to years after transplant
& is mediated by _________
& will see progressive decline in organ function….

A

mediated by BOTH cell mediated and humoral processes

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10
Q

Pre-Transplant Immunologic Evaluation:

what 4 things should be looked at?

A

ABO blood group determination
MHC
Determination of PRA (panel reactive antibodies)
Determination of Cross-Match

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11
Q

3 different types of immunosuppressive strategies

A
  • induction therapy
  • maintenance therapy
  • rescue therapy
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12
Q

Patients who are at higher risk of rejection?

A
  • Depends on the organ (intestines are the highest risk)
  • Race: African Americans are at highest risk
  • If poor PRA result
  • Age: if younger = higher rejection risk
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13
Q

Induction Regimens consist of what?

A

Steroids + (Depleting agent or Non-Depleting Agent)

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14
Q

examples of Depleting agents?

A

Thymoglobulin
Atgam
Alemtuzumab

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15
Q

example of non-depleting agent?

A

basilximab

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16
Q

Thymoglobulin comes from what animal?

Atgam comes from what animal?

A

thymp: rabbit
Atgam: horse

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17
Q

The Antithymocyte globulins (Thymo and Atgam) are animal derived _____ antibodies directed against multiple _________

A

IgG antibodies;

multiple T cell specific antigens (aka polyclonal)

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18
Q

Antithymocyte globulins:
when the antibody and antigen bind:
it results in what things?

A
  • opsonization (marking something for phagocyte to come get)
  • T cell lysis
  • rapid/profound lymphopenia

aka depleting allll lymphocytes in the body

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19
Q

What Immunosuppression strategy is it?

intense prophylactic therapy at the time of transplantation

A

induction

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20
Q

What Immunosuppression strategy is it?

chronic immunosuppression

A

Maintenace

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21
Q

What Immunosuppression strategy is it?

intense therapy utilized in response to a rejection episode

A

rescue

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22
Q

Antithymocyte globulins

which one is often capped at 150 mg/dose

A

Thymoglobulin

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23
Q

Antithymocyte globulins

which one is dosed as 10 - 15 mg/kg/day

A

atgam

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24
Q

Antithymocyte globulins

which one is dosed as 1-1.5 mg/kg/day for 4 - 7 days

A

Thymoglobulin

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25
Q

Antithymocyte globulins

ADEs?

A
  • Myelosuppression (leukopenia/thrombocytopenia)
  • cytokine release syndrome
  • serum sickness
  • infections
  • lymphoproliferative disease
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26
Q

Antithymocyte globulins: ADEs

Has dose limiting myelosuppression — monitor what two things?

A

WBC and Platelets

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27
Q

Antithymocyte globulins: ADEs

Reduce dose by 50% when?

A

if WBC are 2000 - 3000 cells/mm3
OR
Platelet count is 50,000 - 75,000 cells/mm3

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28
Q

Antithymocyte globulins: ADEs

consider discontinuation when?

A

if WBC < 2000 cells/mm3
OR
Platelet count < 50,000 cells/mm3

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29
Q

Antithymocyte globulins: ADEs

sxs of cytokine release syndrome?

A

fever/chills
tachycardia
hypotension

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30
Q

Antithymocyte globulins: ADEs

how to prevent cytokine release syndrome?

A

pre-medicate: Steroids, diphenhydramine, APAP

also hella frequent vital sign monitoring :Q15 min for 1st hour then hourly

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31
Q

Antithymocyte globulins: ADEs

sxs of serum sickness?

A

arthralgias
myalgias
headaches

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32
Q

Antithymocyte globulins: ADEs

treat serum sickness how?

A

tx with corticosteroids

happens as a hypersensitivity reaction — thus do not retry any of the globulins

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33
Q

Antithymocyte globulins: ADEs

serum sickness happens when in relation to the dose?

A

it is a delayed rxn = can be up to 2 weeks post dose

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34
Q

Antithymocyte globulins: Administration
infused over _____ hours
______ line preferred

A

over 6 - 8 hours
central line
(can do peripheral — just add heparin/hydrocortisone to prevent phlebitis)

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35
Q

Antithymocyte globulins: How to manage infusion related rxns?

A

slow down the infusion by 50%

antihistamines/methylpred/epinephrine should be available

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36
Q

Alemtuzumab:

Is a _________ monoclonal antibody

A

humanized; ANTI-CD52

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37
Q

Alemtuzumab MOA:
is anti-CD52 antibody;
CD52 is a cell surface glycoprotein located on ______ and ______
but CD52 is not found on _____ or ____ that much = how it is selective

A

T and B lymphocytes
and natural killer cells

found on monocytes; macrophages

38
Q

Dosing of Alemtuzumab?

A

30 mg IV or SQ as one dose (done during surgery)

IV is over 2 - 4 hours!! NEVER IV Push

39
Q

ADEs of Alemtuzumab?

A
  • Neutropenia/Thrombocytopenia, Pancytopenia
  • hypotension/supracentricular tachycardia
  • infusion related: chills, rigor, fever (pre-medicate: APAP/steroids/diphenhydramine)
40
Q

Monitoring Parameters for Alemtuzumab?

A

WBC
Platelets
ALC (absolute lymphocyte count)
vital signs for at least 2 hours post infusion

41
Q

Basiliximab:

MOA?

A

chimeric antibody that binds to alpha subunit of IL-2 receptor

42
Q

Dosing considerations of Basiliximab?

A
  • 20 mg IVPB AND post-op day 4

- yields 4 - 6 weeks of IL-2 receptor saturation

43
Q

ADEs of Basiliximab?

A

Anaphylaxis/hypersensitivity rxns (rare tho)

well tolerated!! no pre-medications needed

44
Q

Comparing Induction Agents:
(Thymoglobulin, Atgam, Alemtuzumab, Basiliximab)
which does NOT have an approved indication for induction?

A

atgam and alemtuzumab do NOT

45
Q

Comparing Induction Agents:
(Thymoglobulin, Atgam, Alemtuzumab, Basiliximab)

which one is NOT depleting

A

basiliximab

46
Q

Comparing Induction Agents:
(Thymoglobulin, Atgam, Alemtuzumab, Basiliximab)
which one is chimeric (70% human/30% murine)

A

basiliximab (xi-=chimeric)

47
Q

Comparing Induction Agents:
(Thymoglobulin, Atgam, Alemtuzumab, Basiliximab)
which one is DNA-derived/humanixed

A

Alemtuzumab

48
Q

Comparing Induction Agents:
(Thymoglobulin, Atgam, Alemtuzumab, Basiliximab)
which one is CD52 targeted

A

alemtuzumab

49
Q

Comparing Induction Agents:
(Thymoglobulin, Atgam, Alemtuzumab, Basiliximab)
which one is CD25 targeted

A

basiliximab

50
Q

Comparing Induction Agents:
(Thymoglobulin, Atgam, Alemtuzumab, Basiliximab)
which one has many targets?

A

thymoglobulin and atgam have many targets (polyclonal)

51
Q

How to choose an induction agent:

Depleting or non-depleting is more commonly used?

A

depleting (especially when high immunologic risk)

52
Q

How to choose an induction agent:

Basiliximab is reserved for what kind of patients?

A

pts with hx of malignancy
high infection risk/immunocompromised
Advanced age (> 65 yo)

53
Q

Main classes of drugs used in maintenace therapy?

A 
Calcineurin inhibitor
m-TOR inhibitor
Antimetabolite
corticosteroids
selective T-cell co-stimulation blocker
54
Q

examples of calcineurin inhibitors?

A

Cyclosporine

Tacrolimus

55
Q

examples of m-TOR inhibitors?

A

sirolimus

everolimus

56
Q

examples of antimetabolites

A

azathioprine

mycophenolate (mofetil or sodium)

57
Q

example of selective T cell costimulation blocker

A

Belatcept

58
Q

Calcineurin Inhibitors MOA?

A
  • inhibits first phase of T-Cell activation

- blocks synthesis of pro-inflammatory cytokines (IL-2)

59
Q

Cyclosporine:
______ formulation has poor/erratic bioavailability
______ formulation has improved bioavailabiltiy

A

non-modified is wack

modified/microemulsion = better bioavailability

60
Q

Cyclosporine:

what general drug interactions?

A

CYP3A4 and PGP

it is a substrate AND an inhibitor of CYP

61
Q

Cyclosporine PO to IV conversion?

A

3:1 (90 mg of oral = 30 mg IV)

62
Q

ADEs of Cyclosporine?

A 
nephrotoxicity!!!
hypertension!!!
hypercholesterolemia/hypertriglyceridemia
gingival hyperplasia
hirustism
neurotoxic
hyperglycemia/diabetes
hematologic adverse reactions
63
Q

Tacrolimus is more or less potent than cyclosporine?

A

100 x more potent

64
Q

Tacrolimus General Drug interaction?

A

is a CYP3A substrate (NOT an inhibitor like cyclosporine tho)

65
Q

Tacrolimus: IV to PO conversion?

A

5:1 (2 mg IV = 10 mg PO)

66
Q

which XR formulation of tacrolimus is 1:1 conversion b/w IR and which one needs to be administered at 80% of IR dose?

A

1:1 with IR is Astagraf XL

80% dose reduction: Envarsus

67
Q

ADEs of Tacrolimus?

A 
Neurotoxicity!! (headache, insomnia, tremor, dizziness)
Hyperglycemia and Diabetes!!
Nephrotoxic
HTN
GI
Hematologic ADE
Alopecia
68
Q

What CYP related drugs will decrease Calcineurin inhibitors (aka are CYP enzyme inducers)

A

phenytoin
CBZ
phenobarbitol
rifampin

69
Q

What CYP related drugs will increase Calcineurin inhibitors (aka are CYP enzyme inhibitors)

A 
Erythryomycin/Clarithromycin
Azole antifungals
Diltiazem/Verapamil
Ritonavir
Grapefruit Juice
70
Q

mTOR inhibitors:

which one is approved ONLY for kidney transplants

A

sirolimus

71
Q

mTOR inhibitors:

which one is approved for kidney and liver transplants

A

everolimus (“every-one”)

72
Q

MOA of mTOR inhibitors?

A

binds to FKBP-12 = inhibits mTOR aka inhibits serine/threonine kinase

the kinase normally regulates synthesis of proteins needed for cell cycle progression and T cell proliferation

73
Q

drug interactions with mTOR inhibitors?

A

CYP3A4/PGP – same as Calcineurin inhibitors

74
Q

mTOR ADEs??

A 
Edema
Elevated Lipids
mouth ulcers
DELAYED WOUND HEALING
anemia
hepatic artery thrombosis
interstitial pneumonitis
proteinuria
75
Q

mTOR inhibitors: roles of therapy:

  • replace ________ in patients with _____ toxicity (ex: nephrotoxicity)
  • in combo with _____ to lower dose of both drugs
  • to replace ______ in patients with intolerable side effects
A
  • replace CNIs when CNI toxicity
  • combo with CNIs
  • replace mycophenolate
76
Q

MOA of Azathioprine (AZA)?

A
  • purine analog/converted to 6-mercaptopurine

- incorporated into nucleic acids = inhibits DNA and RNA synthesis = inhibits immune cell proliferation

77
Q

main drug interaction with Azathioprine?

A

allopurinol

78
Q

ADEs of Azathioprine?

A
  • leukopenia/thrombocytopenia, macrocytic anemia,
  • N/V, abdominal pain
  • pancreatitis/hepatotoxicity
  • malignancy
  • infection
79
Q

MOA of mycophenolic acid (MPA)?

A

inhibits de novo pathway of purine synthesis = selective for lymphocytes = limits progression of T and B cells

80
Q

Mycophenolate mofetil or sodium?

which one is enteric coated/delayed release

A

sodium formulation

81
Q

Mycofenolate mofetil PO to IV conversion?

A

1:1

82
Q

drug interactions of mycophenolic acid?

A

Aluminum/Magnesium containing antacids
Cholestyramine
(both decrease AUC of mycophenolic acid)

83
Q

ADEs of mycophenolic acid?

A

GI events!!!
Hematologic/Lymphatic adverse events
FDA pregnancy category D!!

84
Q

MOA of corticosteroids:

A
  • non specific immunosuppressive effects

- down regulation of IL-2 (aka cytokine gene expression)

85
Q

MOA of Belatacept?

A

selective T cell costimulation blocker

binds to CD80/86 on APCs to block the CD28 mediated costimulation of T lymphocytes

86
Q

Belatacept: it is contraindicated for use in _______ transplant

A

liver!!!

87
Q

ADEs of Belatacept?

A

well tolerated…
but also PTLD (post transplant lymphoproliferaetive disorder)
Anemia
GI complications

88
Q

what is PTLD (post transplant lymphoproliferaetive disorder)

A

mainly involves the central nervous system…

if EBV seronegative had a MUCH higher risk….. therefore contraindicated in EBV seronegative patients!!

89
Q

common immunosuppresive regimen?

A
  1. Calcineurin inhibitor (tacrolimus or cyclosporine)
  2. antiproliferative agent (mycophenolate or azathioprine)
  3. corticosteroids
90
Q

Options that are good if pt needs to avoid/minimize calcineurin inhibitors

A
  • Belatacept + mycophenolic acid + corticosteroids
  • Sirolimus + mycophenolic acid or azathioprine + corticosteroids
  • Everolimus + low dose tacro/cyclo + corticosteroids

PHRM 865 (59 decks)

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