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77 Cards in this Set

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What kind of things do we think about with transplant drugs
large doses early

multidrug regimens

trying to prevent acute allograph rejection
Induction immunosuppression therapy
-how work
-what does
-SE
antibodies against T cells

may decrease acute rejection

risk infections and malignancy
different lvls of immune supression
maintence

rejection
transplant agents classes
Depleting antibodies

IL-2 receptor antibodies

calcineurin antagonists

antiproliferation agents
Depleting antibodies
ATG

OKT3

alemtuzumab

rituximab
IL2 receptior antibodies
daclizumab

basiliximab
calcineurin antagonists
tacrolimus

cyclosporine
antiproliferation agents
azathioprine

mycophenoloic acid
Fuck theres another drug class what is it and what are drugs in it
mTOR inhibitors

Sirolimus

Everolimus
Induction therapy

what, why, length, SE
antibodies for potent immune suppression inital 7-14 days after transplant

decrease reject rate

SE- cytokine release, potential infections, antibodies against antibodies possible
Induction therapy

drug subtypes
Polyclonal antibodies
(ATG, Thymoglobulin)

Monoclonal antibodies
(OKT3, Daclizumab, Basiliximab)

NOTE sum of these are IL2s and sum are depleting... get to that soon
Polyclonal antibodys

info, MOA, where from, SE
MOA-destroy all T cell types, enhanced by steriods

induction or rejection

w/ APAP, cortico, antihistamines

SE- aplastic anemia, nephrotox, thrombocytopenia, pulm edema...infection

ATG-horse
Thymoglobulin-rabbit
Monoclonal antibodies

3 of them 2 still availible... infos
-OKT3
OKT3- mouse
SE- cytokine release syndrome MAJOR

for induction, steroid resist reject, not chronic

MOA-bind CD3 forms complex w/ t cell receptor (TCR)
Monoclonal antibodies

3 of them 2 still availible... infos
-Daclizumab
no longer availible!!!!
Monoclonal antibodies

3 of them 2 still availible... infos
-Basiliximab
INDUCTION only

chimeric

no dose adjust renal or gender

MOA- IL2 antag, comped inhib, note ignores quintesent T cells

40mg day 0 and day 4....

SE constipation, rare thrombosis...
maintenance therapy

whats standard
2 or 3 drugs for life

if no reject attempt to reduce

if reject then up dose or switch class
Maintnenace based off 3 signal model

Each signal and what drugs act there
BOTH 1 and 2 req T cell activation

Signal1- Calcineurin pathway- gen IL2 from T cell seeing antigen
Drugs- inhibitors- Cyclosporine, tacrolimus

S2- Costimulation path- CD40 and CD28 bind with stuff on opposite cells
Drugs-target those- Balacacet (we dont go over it...)

S3- IL2 on CD25 receptor - creates mammalian target of rapamycin(mTOR)
mTOR inhibs- Sirolimus and Everolimus
Calcineuin inhibitors

what are they again?
what signal?
what do they basically do eventully
Cylcosporine and Tacrolimus

signal 1
eventually inhib IL2 production

hepatic metab, P450s watch, NOT DIALIZABLE
Cyclosporin

target
when use
info
target 100-400 mcg/ml

interacts cyclophilin to inactivate calcineurin...no NF-AT

highly protein bound (really thats both)
variable absorb so microemusion (Neoral)

use in borderline diabetics!!!
Tacrolimus

target
when use
specific SE
5-15 mcg/ml

interact FKBP inactivate calcinurin..no NF-AT ...fuck i already wrote this

more predictable absorb

MORE POTENT, CHILD USAGE

SE- gingival hypertrophy, allopecia..worse nephrotox
Calcineurin inhib SE
less IV cuz nephrotox- PO 3x that dose

nephrotox kill kidney- acute tube necro, interstitial fibrosis, all that shit busted

nuerotox- nightmares, some hepato, HTN hyperchol, hypergly

DI- P450s think about it, and avoid nephrotox drugs and NSAIDs, no lovastatin
Antiproliferation agents are...
Azathioprine

Mycophenolate mofetil
Azathioprine

MOA, what is it
SE
watch?
immunosuppressive antimetabolite 6MP formed

nonselective DNA/RNA syn in rapid dividing cells like T and B cells

for renal homotrans

SE-dose depend BMS, reversible hepatotox

watch XO
watch bactrim or ganciclovir or BMSers
Mycophenolic acid

also called
MOA
indication
cellcept- oral or inj

inhib syn IMPDH, block purine syn prevent T B cell proliferation- in S phase i think

for Rebal, liver, cardiac trans
Mycophenolic acid

special?
SE
can use for chronic reject

ENTEROHEPATIC circulation- double peaks
(cyclosporine will prevent this)

SE diarrhea... vomit, leukopenia, sepsis...also BMS
reason to use azathioprine over mycophenolic acid?
there isnt one the studies dont say shit
mTOR inhibitors
are?
what are they basically preventing
Sirolimus aka Rapamycin (macrolide...)

Everolimus

stops signal 3 from recruiting all those immune bastards: cytokines more antibodies and shit
Sirolimus

specific MOA
SE
dose consid
DI
inhib T lympho activation and proliferation via cytokines, also inhib antibody production

1-2g a day, double for AA
follow troughs 8-12

SE CV rxns-HTN, hyperlipid, hyper TG

DI- stagger w/ cyclosporin 4 h, watch p450s major staggering or can get all f'ed (keto specially)
Everolimus

MOA
indication
hyperactivation kinase AKT via inhib mTOR neg feedback loop sum thing sumthin.
.. like Sirolimus

for heart transplant
Corticosteroid use...

when not effective
whatlimits
prevent and tx rejection episodes

not in chronic

inteferes cytokine signals and induce apotposis inflam cells

high dose and taper

SE limit hypo K Na..weakness, BMS...

watch P450 inducers
Tx of acute rejection...

types
cellualr reject

acute humoral reject
Tx of acute rejection...

cellular tx
M/M- methylprednisolone pulse dose

3-5 days high IV dose then taper

S- thymoglobulin IV 1.5mg/kg qd 5 days, or..
OKT 5mg IV qd 5 days (rare)
Tx of acute rejection...

humoral tx
antibody mediated

plasmapheresis (remove antibodies), IVIG infusion or rituxamab
Rituxamab

MOA
dose?
modulate B cell lysis

chimeric monoclonal ab for CD 20

375mg/M2 qwk for 4 wks
Chronic rejection

called diff stuff for diff organs

tx
banishing bile duct sydrim

accellerated atheroscerosis

broncholitis obliterans syndrome

no good tx, can add sirolimus
medical complications from chronic tx and what to do.....
theres a nice chart in my review, look at it.... i think its rather importnat
Organ transplant complication

where it all goes downhill

whats main one... and when happen
infection

usually 1-6 months- viral or fungal maybe
if less than normal easy bacteria
transplant infection tx

bacteria
common agents- 3rd gen ceph,
extended spec PCN
blactamase combo
FQ

use broad spectrum empirically

bascially same as usual tx
Viral complications

whats shitty bout them
which ones
higher reject rate

herpes family :
CMV
HSV
EBV
VZV

also polyoma viruss----BK virus
CMV
disease vs infection

how avoid
dx
disease- symptomatic or tissue invasive

infection usually asymptomatic

if positive host to neg donor give prophlyaxis

dx difficult
CMV tx
prevent w/
ganciclovir
acyclovir
valganciclovir (950mg)

or can use vaccine
immunoglobulin prep- can inactivate liver vaccines...
CMV tx adverse effects
carinogencity

BMS
seizures u know fun stuff
BK virus!!!! neuropathy
in most ppl controled but immunosupress does that

tubulointerstitial nephritis, ureteral stenosis happens

watch for renal issues
BK virus!!!! neuropathy

tx
reduce immunos!!!

leflunomide- pyrimidine syn inhib

cidofovir

IVIG
Tx for...

HSV
VZV
EBV
acyclovir

antivirals

same shit basically...sorta
Fungal infections w/ transplants
tx is poor

surgical debridement

minimize immunosuppress

use antifungals..cyclosporine can increase tox
PCP
use bactrim....
Cancer w/ transplant

which ones increased
how prevent?
and...well
common ones not increase- karposi sarcoma got fuckin huge tho

mimize sun exposure

lymphoma can cuz- cyclosporin, FK, OKT3, ATG, or EBV infection

stop or reduce immunosuppress, consider Rituximab

i think ur gonna die lets be serious about this
Pregnancy and transplant
D/C mycophenolic acid

not that other ones are good for your baby or anything but thats what he said...
Whats a big issue with transplant
noncompliance
Sepsis and its definitions

SIRS
Sepsis
Severe Sepsis
Septic Shock
systemic inflam response syndrome
2 or more: hypo/hyper thermic, HR>90, RR>20, WBC wacked

Sepsis- SIRS w/ infection

Severe Sepsis- SIRS, infection, and organ dysfunction

Shock- all above and PERSISTANT hypotensive despite resuscitation
Pathophysio of sepsis
microbe factors:
high infection burden, superantigen, resistance to opsonization, phagocytosis

Host factors:
proinflammatory (TNF!!)
sum antiinflamm compensatory mechs
histamine release
coagulation factors (PROcoag)
Early vs Late sepsis
in early- compensatory mechs seen
tachy, chills, NnV, myalgias, fever, hyperglycemia, proteinuria, hyperbilirubiemia

late-start to see damage done
lactic acidosis, oliguria, leukopenia, myocardia depress, pulmonary edema, hypotension, hypoglycemia, gI bleed, COMA
Prognosis for sepsis
APACHE II score or

Sequential Organ failure assessment (SOFA)
standards of care in sepsis
initial resuscitation (6 hours)
antibiotic therapy
source control
hemodynaimc support (fluids, vasopressors, inotropes)
-other stuff
sepsis
EDGT
what do we want
Early directed goal therapy
-w/i first 6 hours

CVP 8-12
MAP >65
Urine output >5ml/kg/h
SvO2 >70%
HCT >30%

delay equals organ dysfunc, longer stay etc
Antimicrobials

-where source
-what microbes most liekly
-how start
usually respiratory

usually +ve followed by negative

obtain cultures before initiation w/i first hour
Antimicrobials sepsis empirical choices
one or more drug activity against likely pathogens (combo in pseudomonas)

penetrate source

reassess/ desclate in 48-72 hours

typical duration 7-10 days- stop if noninfectious cause

drain abscesses and remove infected hardware
Hemodynamical issues

what are they
what are ways to fix
CVP down
CO up
SVR (systemic vascular resist way down)

fluid resuscitation and vasopressors and inotropes
Fluid resuscitation
what used and such
done first

6-10 L cyrstalloid fluids
SE-edemas

2-4 L colloids soln (no mortality diff)
SE renal failure and expensive

hourly boluss over 24h, assess after each

remember EDGT goals, CVP, MAP, urine output, SvO2
Vasopressors and ionotropes used why
want perfusion back so organs don fin die
Vasopressors

do?
are?
vasoconstriction--MAP >60-65

adrenergics-
NE, Dopamine, EPI, phenylephrine

Nonadrenergic- vasopressin
Iontropes
are
when
do what
not used as much
will increase CO

Dobutamine
Dopamine
Norepinephrine

acts on
helps
SE
mainly alpha 1

up MAP, up SVR, maybe urine output

1st line!!!!

SE organ ischemia, arrhythmias

preferred over dopamine
Dopamine

acts on
helps
SE
precursor NE

stim DA1, B1, B2, a1

effects dose dependant- alpha 1 >10 mcg/kg/min

1st line

more tachy

low dose is not recommended for renal perfusion
EPI

acts on
doing
when to use
a1, b1, b2

ups MAP, up CO, up HR, up SVR

alpha predominates above 0.05mcg/kg/ml

SE organ ischemia ... elevate serum lactate, tachy from beta

USE: refractory hypotensive
Phenylephrine

acts on
does
when use
a1 exclusive

up MAP and SVR

SE HTN w/ reflex brady cardia

USE: when worried about tachys
Vasopressin

acts
does
when
V1

up MAP, up SVR, maybe urine...maybe

think of it as supplement since naturally depleted in sepsis like stuff

WILL POTENTIATE OTHER VASOPRESSORS- use in refractory septic shock
Dobutamine
B1, B2, minimal a1

up CO, down SVR, up HR

more for cardiogenic shock
combo with NE

USE if inadequate CO
Hypothalamic Pituitary adrenal axis
..
what is is
why do we fuckin care
release of corticotropin releasing hormine if stasis threatened (gets u cortisol)

-this ups glucose, catecholamines, glucagon, BP, vasopressor sens, lipolysis

-with relative adrenal insuff- reversible- we dont have enough cortisol to handle the issues
HPA cortisol def in sepsis

who to tx
suspected adrenal insuff w/ pt on vasopressors despite fluid resus

intermittent 50mg IV q6h, +/- fludrocortisone 50mcg

>7 days then taper

no ACTH stim test

DO NOT USE AT ALL UNLESS SHOCK!!!
Glucose control

tx in spesis and why hapen
hyperglycemia disrupt immune func and promote inflam

use IV insulin to control hyperglycemia in pt w/ severe sepsis following stabilization

try to keep blood glucose <180, provide glucose caloric source and monitor glucose q1-2 h if receiving insulin
Analgesia in sepsis
hemodynamic instability indiction for it

fentanyl, hydromorphone, morphine (careful in RF)

pain scale, FLACC scale, subject assessment
sedation
only after provided aqequate analgesia and physiologic causes, use valid sale and define tx

Propofol, Dexmedetomidine, Benzos

Lorazepam- formulated with propylene glycol- damage kidney pt acidotic (renal issues)

wake up and CNS daily, determine min dose, sedation vacation
NMB- neuro musclualr blocker
surgical relax, mech ventilation, down o2 consumption

Depolarizing-Succinylcholine

Nondepolarizing- the curoniums-- pancuronium, vecuronium, rocuronium

benzylisoquinliums-WTF... tubocurarine, cosatracurium, atracurium

important monitor w/ train of 4 (4 pulses 2 twitches) need baseline
VTE
if anything disposes them to clot

graduated compresion stockings-fit them properly

sequential compression devices- squeezers, cant be ambulatory

risks : low , mod , high

USE low dose UFH or LMWH (preferred) unless CI
if CI mech prop

best to use LMWH and mech
stress ulcer prop
if mech ventilate >48h or coagulopathy INR>1.5

no studys w severe sepsis

H2 or PPI to prevent upper GI bleed- should prolly do it it seems

benefits mut outweight risks.. chance of ventilator associated pneumonia VAP