Final - Transplant Flashcards Preview

Therapeutics V Spring 2019 (P3 Spring) > Final - Transplant > Flashcards

Flashcards in Final - Transplant Deck (90):
1

Immunology behind immunosuppression:
_____ mediated rejection = infiltration of the allograft by lymphocytes and other inflammatory cells

T cell mediated (cellular response)

2

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

B cell (antibody) rejection (humoral response)

3

T cell activation requires __#__ signals

3 signals

4

T cell activation steps:
#1. The T cell receptor (____) interacts with _______

CD3 interacts with APC (antigen presenting cells)

5

T cell activation steps:
#2. The co-stimulatory signal of ______ on the surface of APCs interacting with ______ on T cells

CD80/86 on APCs interacts with CD28 on T cells

6

T cell activation steps:
#3. ____ binds to CD25 (which activates the mammalian target of ______) and subsequent proliferation and activation of the T-Cell

IL-2 binds to CD35;
target of rapamycin pathway

7

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

preformed circulating antibodies

8

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

by host T-lymphocytes

9

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

mediated by BOTH cell mediated and humoral processes

10

Pre-Transplant Immunologic Evaluation:
what 4 things should be looked at?

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

11

3 different types of immunosuppressive strategies

-induction therapy
-maintenance therapy
-rescue therapy

12

Patients who are at higher risk of rejection?

-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

13

Induction Regimens consist of what?

Steroids + (Depleting agent or Non-Depleting Agent)

14

examples of Depleting agents?

Thymoglobulin
Atgam
Alemtuzumab

15

example of non-depleting agent?

basilximab

16

Thymoglobulin comes from what animal?
Atgam comes from what animal?

thymp: rabbit
Atgam: horse

17

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

IgG antibodies;
multiple T cell specific antigens (aka polyclonal)

18

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

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

aka depleting allll lymphocytes in the body

19

What Immunosuppression strategy is it?
intense prophylactic therapy at the time of transplantation

induction

20

What Immunosuppression strategy is it?
chronic immunosuppression

Maintenace

21

What Immunosuppression strategy is it?
intense therapy utilized in response to a rejection episode

rescue

22

Antithymocyte globulins
which one is often capped at 150 mg/dose

Thymoglobulin

23

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

atgam

24

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

Thymoglobulin

25

Antithymocyte globulins
ADEs?

-Myelosuppression (leukopenia/thrombocytopenia)
-cytokine release syndrome
- serum sickness
- infections
- lymphoproliferative disease

26

Antithymocyte globulins: ADEs
Has dose limiting myelosuppression --- monitor what two things?

WBC and Platelets

27

Antithymocyte globulins: ADEs
Reduce dose by 50% when?

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

28

Antithymocyte globulins: ADEs
consider discontinuation when?

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

29

Antithymocyte globulins: ADEs
sxs of cytokine release syndrome?

fever/chills
tachycardia
hypotension

30

Antithymocyte globulins: ADEs
how to prevent cytokine release syndrome?

pre-medicate: Steroids, diphenhydramine, APAP
also hella frequent vital sign monitoring :Q15 min for 1st hour then hourly

31

Antithymocyte globulins: ADEs
sxs of serum sickness?

arthralgias
myalgias
headaches

32

Antithymocyte globulins: ADEs
treat serum sickness how?

tx with corticosteroids
happens as a hypersensitivity reaction --- thus do not retry any of the globulins

33

Antithymocyte globulins: ADEs
serum sickness happens when in relation to the dose?

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

34

Antithymocyte globulins: Administration
infused over _____ hours
______ line preferred

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

35

Antithymocyte globulins: How to manage infusion related rxns?

slow down the infusion by 50%
antihistamines/methylpred/epinephrine should be available

36

Alemtuzumab:
Is a _________ monoclonal antibody

humanized; ANTI-CD52

37

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

T and B lymphocytes
and natural killer cells

found on monocytes; macrophages

38

Dosing of Alemtuzumab?

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

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

39

ADEs of Alemtuzumab?

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

40

Monitoring Parameters for Alemtuzumab?

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

41

Basiliximab:
MOA?

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

42

Dosing considerations of Basiliximab?

-20 mg IVPB AND post-op day 4
-yields 4 - 6 weeks of IL-2 receptor saturation

43

ADEs of Basiliximab?

Anaphylaxis/hypersensitivity rxns (rare tho)
well tolerated!! no pre-medications needed

44

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

atgam and alemtuzumab do NOT

45

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

which one is NOT depleting

basiliximab

46

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

basiliximab (xi-=chimeric)

47

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

Alemtuzumab

48

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

alemtuzumab

49

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

basiliximab

50

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

thymoglobulin and atgam have many targets (polyclonal)

51

How to choose an induction agent:
Depleting or non-depleting is more commonly used?

depleting (especially when high immunologic risk)

52

How to choose an induction agent:
Basiliximab is reserved for what kind of patients?

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

53

Main classes of drugs used in maintenace therapy?

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

54

examples of calcineurin inhibitors?

Cyclosporine
Tacrolimus

55

examples of m-TOR inhibitors?

sirolimus
everolimus

56

examples of antimetabolites

azathioprine
mycophenolate (mofetil or sodium)

57

example of selective T cell costimulation blocker

Belatcept

58

Calcineurin Inhibitors MOA?

-inhibits first phase of T-Cell activation
-blocks synthesis of pro-inflammatory cytokines (IL-2)

59

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

non-modified is wack
modified/microemulsion = better bioavailability

60

Cyclosporine:
what general drug interactions?

CYP3A4 and PGP
(it is a substrate AND an inhibitor of CYP)

61

Cyclosporine PO to IV conversion?

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

62

ADEs of Cyclosporine?

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

63

Tacrolimus is more or less potent than cyclosporine?

100 x more potent

64

Tacrolimus General Drug interaction?

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

65

Tacrolimus: IV to PO conversion?

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

66

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

1:1 with IR is Astagraf XL
80% dose reduction: Envarsus

67

ADEs of Tacrolimus?

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

68

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

phenytoin
CBZ
phenobarbitol
rifampin

69

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

Erythryomycin/Clarithromycin
Azole antifungals
Diltiazem/Verapamil
Ritonavir
Grapefruit Juice

70

mTOR inhibitors:
which one is approved ONLY for kidney transplants

sirolimus

71

mTOR inhibitors:
which one is approved for kidney and liver transplants

everolimus ("every-one")

72

MOA of mTOR inhibitors?

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

drug interactions with mTOR inhibitors?

CYP3A4/PGP -- same as Calcineurin inhibitors

74

mTOR ADEs??

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

75

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

-replace CNIs when CNI toxicity
-combo with CNIs
- replace mycophenolate

76

MOA of Azathioprine (AZA)?

-purine analog/converted to 6-mercaptopurine
-incorporated into nucleic acids = inhibits DNA and RNA synthesis = inhibits immune cell proliferation

77

main drug interaction with Azathioprine?

allopurinol

78

ADEs of Azathioprine?

-leukopenia/thrombocytopenia, macrocytic anemia,
- N/V, abdominal pain
- pancreatitis/hepatotoxicity
- malignancy
- infection

79

MOA of mycophenolic acid (MPA)?

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

80

Mycophenolate mofetil or sodium?
which one is enteric coated/delayed release

sodium formulation

81

Mycofenolate mofetil PO to IV conversion?

1:1

82

drug interactions of mycophenolic acid?

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

83

ADEs of mycophenolic acid?

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

84

MOA of corticosteroids:

-non specific immunosuppressive effects
-down regulation of IL-2 (aka cytokine gene expression)

85

MOA of Belatacept?

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

86

Belatacept: it is contraindicated for use in _______ transplant

liver!!!

87

ADEs of Belatacept?

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

88

what is PTLD (post transplant lymphoproliferaetive disorder)

mainly involves the central nervous system...
if EBV seronegative had a MUCH higher risk..... therefore contraindicated in EBV seronegative patients!!

89

common immunosuppresive regimen?

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

90

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

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