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446- ID and transplant > Transplant > Flashcards

Transplant Flashcards

1
Q

what are the 2 categories of graft rejection

A

acute cellular
humoral/ chronic

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2
Q

describe acute cellular graft rejection

A

infiltration of T cells into allograft = inflam + cytotoxic effects

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3
Q

describe humoral/ chronic graft rejection

A

cellular cytokines, CD4+ and CD8+ T cells, B cells, antibodies

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4
Q

what are the 3 steps of the T cell activation process

A

T cell identifies antigen bound to MHC
Costimulatory signal needed for T cell activation (CD80/86- CD28 interaction)
Increased IL2 generation, feedback amplification

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5
Q

3 main targets of transplant pharmacotherapy

A

Optimize ABO blood type + HLA match (organ donation team, Canadian Blood Services)

Combinatorial pharmacotherapy:
- Induction: short duration, max immunosuppression, peritransplant
- Maintenance therapy

Maintaining fine balance between drug efficacy and toxicity in the setting of multiple comorbidities (CV, endocrine, bone mineral, infectious disease)

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6
Q

AZA and MPA are part of the ________ class and work by ____________

A

antimetabolites
inhibiting purine synthesis and T cell proliferation

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7
Q

cyclosporin and tacrolimus are part of the ________ class and work by _______

A

calcineurin inhibitors
reducing IL2 and T cell activation

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8
Q

sirolimus is part of the _____ class and works by ________

A

mTOR
decreasing IL2 production

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9
Q

MPA’s primary indication is

A

solid organ transplant (kidney, lung, heart, liver)

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10
Q

why did MPA replace AZA as anchor drug

A

increased efficacy, pt and graft survival

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11
Q

MPA MOA (3)

A

Noncompetitive binding to inosine monophosphate dehydrogenase (IMPDH - type 2 (lymphocyte specific) = ↓ off target toxicity)

Blocks guanosine nucleotide synthesis, ↓ DNA polymerase activities

↓ T and B cell proliferations

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12
Q

MPA IV is not preferred because

A

will have to switch to PO anyways
max 14 days IV use only if not tolerating IV

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13
Q

what is the dose limit of MPA in pts with severe kidney impairment

A

2g/d

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14
Q

people who develop _________ may require a decrease in MPA dose

A

neutropenia

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15
Q

what is the conventional starting dose of MPA

A

1g PO BID MMF

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16
Q

T or F: typically a LD of MPA is delivered

A

F

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17
Q

T or F: MMF and EC-MPS are not interchangeable due to differences in metabolism and distribution

A

F- not interchangeable due to differences in absorption

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18
Q

what is the effect of food on MMF and EC-MPS

A

decreases Cmax by 30-40% but AUC stays the same
consistency is key

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19
Q

MPA distribution characteristics (into what? bound? placenta? lactation?)

A

primarily into plasma
extensively bound to albumin
may distribute into fetus and milk = CI in pregnancy = switch to AZA

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20
Q

T or F: MMF is a prodrug

A

T

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21
Q

MPAG is excreted into bile by

A

MRP2

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22
Q

MPAG is deconjugated in intestines by bacteria and ___________

A

recycled back into systemic circulation by enterohepatic recirculation

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23
Q

MPAG is excreted ________ by ____ and ____

A

renally
PAT3 and MRP2

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24
Q

3 SEs of MPA

A

Gi upset
hematological- neutropenia, leukopenia, anemia
infections

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25
Q

what can you do about MPA GI upset

A

switch MMT to EC-MPS or split dose into QID with food or snack

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26
Q

what can you do about MPA neutropenia

A

empirically decrease dose by 25-50% + monitor pt for CBC, renal fxn, sx infxn, sx rejection

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27
Q

what drugs increase MPA AUC? how?

A

acyclovir- decreases renal excretion

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28
Q

what drugs decrease MPA AUC? how

A

↓ AUC: Al/Mg containing antacids (abs), cholestyramine (abs), PPIs (abs), cyclosporin (enterohepatic recirc), antibiotics

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29
Q

what types of drugs cause PD intx with MPA

A

Drugs that can cause immunosuppression/ leukopenia/ neutropenia

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30
Q

is TDM practiced with MPA?

A

no unless active rejection, evidence of AEs, abnormal kinetics

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31
Q

how is TDM of MPA done?

A

limited sampling strategy

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32
Q

what is the therapeutic target of MPA

A

AUC 30-60mgh/L

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33
Q

AZA indication

A

kidney transplant and RA

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34
Q

what is the 2nd line antimetabolite in transplant

A

AZA

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35
Q

AZA is a ______

A

prodrug

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36
Q

describe AZA metabolism

A

AZA to 6MP to 6 thioguanine nucleotide (halts lymphocyte DNA replication)

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37
Q

AZA is deactivated by (3)

A

xanthine oxidase, TPMT, NUDT 15

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38
Q

describe AZA absorption characteristics

A

F 40%
effects of food not well characterized = just be consistent

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39
Q

describe AZA distribution

A

6-MP distributes into today body water = ~ Vd
not extensively protein bound
distributes into placenta

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40
Q

what converts AZA to 6-MP

A

hepatic glutathione S-transferase

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41
Q

what converts 6-MP to 6-TGN

A

hypoxanthine guanine phosphoribosyltransferase

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42
Q

what deactivates 6-MP

A

xanthine oxidase and TPMT

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43
Q

what 2 drugs inhibit xanthine oxidase, causing an increase in 6MP?

A

allopurinol and feboxustat

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44
Q

TGN is deactivated by

A

NUDT15

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45
Q

AZA metabolites are ________ excreted

A

renally

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46
Q

AEs of AZA

A

GI
hematological (can occur within wks - typically manage with dose reduction) + (correlated with reduced TPMT and NUDT15 activities or concurrent xanthine oxidase inhibitors)

dose dependent liver toxicity (cholestatic and hepatocellular)

alopecia, pancreatitis (Rare)

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47
Q

hematological AEs from AZA are typically due to

A

reduced TPMT and NUDT15
xanthine oxidase inhibitors

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48
Q

2 drug gene intx with AZA

A

TPMT
NUDT15

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49
Q

what happens with AZA and xanthine oxidase inhibitors

A

XO increases 6-MP conc by up to 4x = shunts metabolism to increase 6-TGN production = bone marrow suppression

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50
Q

is TDM commonly done for AZA?

A

no

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51
Q

tacrolimus indication

A

SOT (kidney, liver, heart)

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52
Q

why is tacro preferred to cyclo

A

improved renal function, graft survival, reduced acute rejection

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53
Q

MOA tacrolimus

A

binds to cytoplasmic immunophilins FK binding protein 12
tacrolimus immunophilin complex inhibits calcineurin
blocks activation/ translocation of NFAT = decr transcription/ translation/ production of IL2
decr T cell activation and proliferation

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54
Q

describe tacrolimus absorption characteristics

A

bioavailability highly variable
affected by intestinal/ hepatic CYP3A4 and P-gp activities
food decreases amt and rate of absorption
grapefruit juice dec 3A4 and P-gp = incr bioavailability
diarrhea = incr abs = incr bioavailability

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55
Q

what is the effect of grapefruit juice and diarrhea on tacro absorption

A

grapefruit juice dec 3A4 and P-gp = incr bioavailability
diarrhea = incr abs = incr bioavailability

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56
Q

tacrolimus primarily distributes into

A

erythrocytes

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57
Q

for tacrolimus TDM, a _____ should be used

A

whole blood sample

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58
Q

76-99% of tacro is protein bound to ___ and _____

A

albumin
alpha-1-acid glycoprotein

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59
Q

tacrolimus is eliminated

A

fecally

60
Q

what is a major conc dependent AE of tacro

A

nephrotoxicity- reversible, incr SCr, BUN, K+

61
Q

how to mitigate tacro nephrotoxicity

A

delayed dosing of CI, dose adjust, avoid other nephrotoxic drugs (aminoglycosides, NSAIDs, vanco)

62
Q

what is the mech of tacrolimus induced nephrotoxicity

A

afferent arteriole renal vasoconstriction = 30% decrease in eGFR

63
Q

list 4 sx of acute kidney rejection

A

fever, <4wks post op, weight gain, graft tenderness/ swelling, decreased daily urine volume, rapid rise in SCr, normal CSA or TAC concs, interstitial lymphocytic infiltrates

64
Q

list 4 sx of CSA or TAC nephrotoxicity

A

> 6wks post up, no fever, nontender graft, good urine output, gradual rise in SCr, elevated CSA or TAC, interstitial fibrosis, tubular atrophy, glomerular thrombosis, arterial inflam

65
Q

list 3 other sx of TAC AEs conc dependent

A

Neurotoxicity: hand tremors, HA, peripheral neuropathy
More likely than cyclosporine

Dermatologic: alopecia (rev)
cyclo causes hirsutism

GI: diarrhea, Infections

Post transplant DM
More likely than cyclosporin
MOA: direct toxic effects on pancreatic islet cells
↑ in obese pts, African Americans, Hispanics, prior hx HM
Monitor DDI (steroids, HCTZ, etc = ↑ risk)

Hyperkalemia
Monitor DDI; ACEi, K sparing diuretics like amiloride, spironolactone, eplerenone, triamterene

Hypomagnesemia: v common with IV
Take Mg = diarrhea = ↑ tac conc = caution

66
Q

post transplant DM is more common in (cyclo or tacro)

A

tacrolimus

67
Q

hypomagnesia with tacrolimus is more common with

A

IV

68
Q

what is a caution in tx tacro induced hypomagnesia

A

Mg = diarrhea = increased tac conc = AEs

69
Q

what drugs increase tacro exposure

A

azole antifungals
macrolide antibiotics
fluoroquinolones
NDHP-CCBs
antidepressants

70
Q

what drugs decrease tacro exposure

A

antibiotics (rifampin)
antiseizure meds (carbamazepine, phenytoin, phenobarbital)

71
Q

what is the pref antiseizure med if pt is using tacro

A

levetiracetam

72
Q

what is the preferred antihypertensive if the pt is using tacro

A

amlodipine

73
Q

tacro has PD intx with drugs that cause

A

immunosuppression, nephrotoxicity, CNS toxicities

74
Q

is TDM commonly used with tacrolimus

A

sometimes to monitor SS at 2-3 days

75
Q

list the 4 ways of tacro TDM

A

trough conc in whole blood
limited sampling strategies
trough conc variability
dried blood spot testing

76
Q

the target in trough conc testing in whole blood for tacro is

A

5-20ng/mL- but based on indication and time post transplant
target typically higher immediately post transplant + gradually reduced over 3-4mths

77
Q

how often is limited sampling strategies of tacro used

A

rarely

78
Q

T or F: different analytical assays for tacro are interchangeable

A

F- not interchangeable
immune assays may report higher conc due to cross reactivity
target ranges are tailored to each specific assay

79
Q

how does PGX play a role in using tacro

A

only for initiating doses, not for maintenance

80
Q

how should tacro dose be adjusted for EM or IM

A

increase starting dose by 1.5-2x starting dose

81
Q

how should tacro dose be adjusted for PM

A

initiate tx with standard rec dose

82
Q

cyclosporin indication

A

solid organ transplant (kidney, liver, heart)
2nd line comp tacro

83
Q

cyclosporin MOA

A

binds to cycophilin
cyclosporin-cyclophilin complex inhibits calcineurin
blocks activation/ translocation of NFAT = decreased transcription/ translocation/ production of IL2
= decr T cell activation and proliferation

84
Q

what are the 2 cyclosporin formulations

A

original- variable + incomplete GI absorption, v large interindividual variability- not commonly used
modified- microemulsion with improved bioavailability

85
Q

are the original and modified formulations of cyclosporin interchangeable?

A

no

86
Q

describe cyclosporin bioavailability and absorption

A

bioavail highly variable
food decreases Cmax by 33$ and AUC by 13$

87
Q

cyclosporin is metabolized by ___________ and has _______ (active/ inactive) metabolites

A

CYP3A4 and P-gp
>25 inactive metabolites

88
Q

describe cyclosporin distribution

A

distributes outside of vascular compartment (much larger than tacro which stays in vasculature)
highly protein bound (90% to lipoproteins)
can distribute into placenta and breast milk

89
Q

cyclosporin is highly ____ bound

A

lipoprotein

90
Q

cyclosporin is mainly _____ eliminated

A

biliary/ fecal

91
Q

list 3 conc dep AEs of tacro

A

nephrotoxicity
neurotoxicity
HPTN and hyperlipidemia
dermatological
gingival hyperplasia
hyperkalemia
hypomagnesemia
hepatotoxicity

92
Q

which of the following AEs are more likely with tacrolimus? (select all that apply)
1. nephrotoxicity
2. neurotoxicity
3. HPTN
4. hyperlipidemia
5. gingival hyperplasma

A

2

93
Q

allergic reactions to cyclosporin are likely due to

A

cremophor derivative in IV formulation

94
Q

how does cyclosporin impact mycophenolate and MPA CL

A

inhibits enterohepatic recirculation- dose adjustment needed when MPA given with cyclo (not an issue with tacro)

95
Q

cyclosporin can inhibit ___, ____, ____

A

CYP3A4, P-gp, OAT

96
Q

what is the interaction between statins and cyclosporin

A

cyclosporin inhibits CYP3A4 = more [statin] if metabolized by 3A4 = rhabdo = use rosuvastatin to avoid intx

97
Q

there are clinically relevant PD interactions with tacro and drugs that cause (4)

A

immunosuppression, nephrotoxicity, HPTN, dyslipidemia

98
Q

how is cyclosporin TDM done

A

trough conc in whole blood
C2 level
limited sampling strategies

99
Q

what is the target for trough conc in whole blood of cyclosporin

A

75-450mcg/L or ng/mL
target typically higher immediately post transplant + gradually reduced over 3-4mths

100
Q

which of the following is more accurate for estimating exposure to cyclosporin
1. trough conc in whole blood
2. C2 level
3. limited sampling strategy

A

2

101
Q

describe the use of pharmacogenomics with cyclosporin

A

no evidence to use it yet

102
Q

the oral dose of cyclosporin should be ____ parenteral dose

A

3x

103
Q

there is a higher risk of rejection within ____ post transplant

A

1mth

104
Q

what is the primary indication for sirolimus

A

kidney transplant (but also for liver and heart)

105
Q

T or F: sirolimus is 1st line tx in transplant combo tx

A

F

106
Q

sirolimus is used in pts ___________________________

A

intolerant to CI (nephrotoxicity) or those with evident skin cancer

107
Q

sirolimus is used in combo with

A

lower dose CI (+ prednisone) or calcineurin inhibitor free regimens (+MOA and prednisone)

108
Q

sirolimus is only started after ___________ due to ___________

A

> 3 mths post transplant
delayed wound healing effects (typically not used in de novo pts)

109
Q

what is sirolimus MOA

A

binds to FKBP12, but complex doesn’t inhibit calcineurin activity
sirolimus-FKBP12 inhibits mTOR (a protein kinase responsible for G1 to S cell cycle progression) = stops cell division = decr T cell proliferation + anticancer effects

110
Q

is a LD required for sirolimus

A

maybe- some centers will just overlap immuosuppressants

111
Q

are tablet and solution sirolimus interchangeable

A

no- but the 2mg dose is roughly eq between the 2 doses

112
Q

describe sirolimus absorption

A

F ~15%
fatty foods decrease Cmax by 30% (consistency is key)
grapefruit juice decreases CYP 3A4 and P-gp = higher bioavailability

113
Q

describe sirolimus distribution

A

blood:plasma ration 37:1- use whole blood for TDM
~92% bound to albumin

114
Q

can sirolimus be used in pregnancy

A

no

115
Q

sirolimus is extensively metabolized by ___________ and transported by _____

A

intestinal/ hepatic CYP3A4/ 5 and transported by P=gp

116
Q

sirolimus undergoes primarily _____ elimination

A

fecal

117
Q

in pts with liver dysfxn, sirolimus dose should be decreased by ___

A

1/3

118
Q

is a LD required for sirolimus?

A

yes- due to time it takes to reach SS (half life is 62hrs)

119
Q

list 3 SEs of sirolimus

A

↑ neurotoxicity associated with CI
Myelosuppression = thrombocytopenia, leukopenia, anemia (may be transient), observed within 1st weeks of initiating drug)
hypercholesterolemia/ hypertriglyceridemia (may req pharmtx, obs within first few mths)
↑ lipoproteins + ↓ lipoprotein lipase
GI toxicities/ mouth ulcers (up to 60% pts)
Lymphocele: lymph fluid drains out + accum in cavities
Hypokalemia
Delayed wound healing/ hepatic artery thrombosis
Avoid immediately post surgery/ liver operations

nonconc dep: anaphylaxis, dermatitis, angioedema, vasculitis, interstitial lung disease, arthralgia

120
Q

_____ increases sirolimus Cmax and AUC (and vice versa)

A

cyclosporin

121
Q

if you must give cyclosporin and sirolimus, how should they be dosed

A

separate admin by 4 hrs

122
Q

what are 3 clinically relevant DDIs for sirolimus

A

myelosuppression, hypercholesterolemia, hypertriglyceridemia

123
Q

what is everolimus used for

A

similar indication as sirolius + also used in liver transplant pts

124
Q

which has more SEs on wound healing- sirolimus or everolimus?

A

sirolimus

125
Q

which has less SEs regarding neurotoxicity with tacro or cyclo- sirolimus or everolimus

A

everolimus

126
Q

prednisone indication

A

Solid organ transplant (kidney, liver, heart, lung) and many other inflammatory conditions
Prednisone primarily used in transplant (others include prednisolone, methylprednisone)

127
Q

prednisone MOA

A

multiple targets with decrease in translocation/ fxn of proinflammatory transcription factors = decreased cytokine production = decreased overall inflammation

128
Q

what is the steroid avoidance type of prednisone dosing

A

only methylprednisolone peritransplant (for low immunologic risk)

129
Q

what is rapid steroid withdrawal dosing of prednisone

A

prednisone withdrawal quickly post transplant over 7 days (for low immunological risk

130
Q

what is early steroid withdrawal type of steroid dosing

A

prednisone withdrawal over first few months post transplant (low imm risk)

131
Q

withdrawal of prednisone can increase risk of acute rejection but __________

A

may not affect LT outcomes in select pst

132
Q

what is the low dose steroid maintenance

A

prednisone never withdrawn, but tapered to lowest maintenance dose possible

133
Q

what is the most common type of prednisone dosing

A

low dose steroid maintenance- admin in am to mimic body’s diurnal release of cortisol

134
Q

how is prednisone’s bioavailability

A

90%, well absorbed
food effect no well characterized- may increase T max- can take with food to decrease GI upset

135
Q

prednisone requires bioactivation to

A

perdnisolone

136
Q

prednisone has _____ kinetics and ______ with large doses

A

nonlinear
increased Vd with large doses

137
Q

T or F: prednisone can’t distribute into placenta and breastmilk

A

F- can

138
Q

prednisone has saturable binding to ____ and _____

A

albumin and transcortin

139
Q

how is prednisone metabolized

A

phase 1 and 2

140
Q

how is prednisone excreted

A

renally

141
Q

is TDM commonly done on prednisone? why or why not

A

not commonly done due to wide therapeutic range

142
Q

is PGX relevant to prednisone dosing?

A

no- insuff evidence

143
Q

ist 3 prednisone AEs

A

CNS toxicity: nightmares, psychosis, depression
Ocular: IOP, glaucoma, cataract
Adrenal suppression: ↓ HPA axis =
20adrenal insuff = req stress dosing for surgery, infxn, trauma
Cushingoid appearance: truncal obesity, facial adipose tissue (moon face), dorsocervical adipose tissue, striae, acne, hirsutism
CV: HPTN, dyslipidemia, fluid retention, ↓K+, ↑Na+, arrhythmias (intx with cyclosporin, mTOR inhibitors)
Endocrine: hyperglycemia (intx w/ tacrolimus and antidiabetics)
Neuromuscular and skeletal: osteoporosis, bone fractures, myopathy, osteonecrosis
GI: PUD, gastritis, esophagitis
Infxns: viral, bacterial, opportunistic (causes leukocytosis)
↓ growth rate in children

144
Q

prednisone interacts with _______ and _______

A

CYP3A4 and P-gp

145
Q

prednisone can potentially induce phase ___enzymes- this results in ___________________ for other transplant drugs

A

1+2 = increased CL of tacrolimus, cyclosporin, sirolimus, mycophenolate

446- ID and transplant (18 decks)

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