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PKPD II > Exam 2 > Flashcards

Exam 2 Flashcards

1
Q

Lecture1: DDI-1: Enzyme inhibitors

what is a drug interaction?

are they intentional?

A

altered drug response produced by admin. of a drug with another substance

can be intentional or intentional

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2
Q

Lecture: DDI-1: Enzyme inhibitors

what is a perpetrator

A

the drug, chemical or food element causing the interaction

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3
Q

Lecture: DDI-1: Enzyme inhibitors

what is a victim

A

drug affected by the interaction

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4
Q

Lecture: DDI-1: Enzyme inhibitors

types of Drug interactions

A
  1. DDI
  2. Drug-herbal
  3. Drug-food/ alcohol interactions
  4. drug-chemical interactions
  5. Drug lab. tests interactions
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5
Q

Lecture: DDI-1: Enzyme inhibitors

PK drug CHANGES due to DDI

A

changes in ADME

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6
Q

Lecture: DDI-1: Enzyme inhibitors

PD changes in DDI

A

affect pd of the drug

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7
Q

Lecture: DDI-1: Enzyme inhibitors

ex. of drugs withdrawn b/c of CYP related ddi’s

A

seldane and ketoconazole- qtc prolongation

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8
Q

Lecture: DDI-1: Enzyme inhibitors

strong CYP3A4 inhibitors

A

intraconazole

clarithromycin

ritonivir

ketoconazole

telithromycin

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9
Q

Lecture: DDI-1: Enzyme inhibitors

cYP3A4 inducers

A

rifampin

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10
Q

Lecture: DDI-1: Enzyme inhibitors

basic expectations of enzyme inhibition

activity vs conc
moa:
onset and reversibility
immediate exposure needed?:
prior exposure needed?
in vitro study:
A

decrease enzyme activity, so increase in drug con.

moa: direct chemical effect on enzyme
onset and reversibility: rapid
immediate exposure: needed
prior exposure: not needed
in vitro study: straightorward
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11
Q

Lecture: DDI-1: Enzyme inhibitors

types of enzyme inhibition

A
  1. Direct inhibition
    a. reversible: competitive, non competitive, uncompetitive
    b. irreversible: mechanism based
  2. indirect inhibition (enzyme metabolism perpetrator and product inhibits enzyme back)
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12
Q

Lecture: DDI-1: Enzyme inhibitors

drug ex of enzyme inhibition

A

theophylline and enoxacin.

enoxacin inhibits cyp1a2, which metabolizes theophylline.

enoxacin raised theophylline conc.

after it was d/c, still exhibited inhibition for more hours

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13
Q

Lecture: DDI-1: Enzyme inhibitors

competitive inhibition extent

A

extent of inhibition directly related to the amount of perpetrator.

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14
Q

Lecture: DDI-1: Enzyme inhibitors

strong inhibitors of cyp1a2

A

fluvoxamine

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15
Q

Lecture: DDI-1: Enzyme inhibitors

strong cyp2d6 inhibitors

A

fluoxetine

paroxetine

quinidine

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16
Q

Lecture: DDI-1: Enzyme inhibitors

route of administration effects

A

oral can have stronger ddi effects because of first pass effect

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17
Q

Lecture: DDI-1: Enzyme inhibitors

time course of inhibition

A

its going to take some time for max inhibition to take place

time course of max con= 5x t 1/2 of inhibitor + 5x t 1/2 of drug

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18
Q

Lecture: DDI-1: Enzyme inhibitors

ketoconozole and itraconazole interaction labeling

A

they have black box warnings due to magnitude of their interactions (etc prolongation)

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19
Q

Lecture: DDI-1: Enzyme inhibitors

ex of benefit of DDI

A

ritonavir and saquinavir
.
both inhibit cyp3a4, increase each others, they increase the conc of eachothers

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20
Q

Lecture: DDI-1: Enzyme inhibitors

paxlovid and ritonavir interaction for covid

A

ritanovir acts as a booster for paxlovid

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21
Q

Lecture: DDI-1: Enzyme inhibitors

explanation of turnover rate

A

turnover rate matters because must wait for body to reproduce enzymes to replace inactivated enzymes

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22
Q

Lecture: DDI-1: Enzyme inhibitors

for ddi involving mechanism-based inhibition, the extent of drug inhibition…

A

a: decreased with increase in natural rate of enzyme degredation
b. increases with increase in the enzyme inactivation rate by the drug

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23
Q

Lecture: DDI-1: Enzyme inhibitors

grape juice fruit food-interaction

A

grape fruit juice inhibits cyp3a4

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24
Q

Lecture: DDI-1: Enzyme inhibitors

polymorphism and DDI

A

severity of inhibitory ddi is greater for extensive metabolizers than normal metabolizers

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25
Q

Lecture: DDI-II: Enzyme inducers

enzymatic DDI general of inducers

A

induction increases enzyme activity, and decreases drug conc.

moa: indirect effect through enhances production of cyp

onset and reversibility: slow

immediate exposure: not needed

in vitro study: dificult

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26
Q

Lecture: DDI-II: Enzyme inducers

onset and onset of induction depends on

what are some risks

A

t 1/2 of inducer, time to make new cyp proteins, and rate of degradation of cyp proteins

risks: risk of tpx failure
toxic conc.
formation of toxic metabolites

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27
Q

Lecture: DDI-II: Enzyme inducers

moa of enzyme induction

A

increased enzyme induction involves increased transcription of cyp450 by nuclear hormone receptors

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28
Q

Lecture: DDI-II: Enzyme inducers

ex of inducers

A

rifampicin induces 2c8, 2c9, 3a4, 2c19, 2b6

phenobarbital: 2c8, 2c9, 3a4,2c19, 2b6
ethanol: 2e1

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29
Q

Lecture: DDI-II: Enzyme inducers

kinetic manifestation

A

if u give 2 drugs and one is an inducer, the conc of other drug css goes down , unless the dosing rate is doubled. if inducer is stopped and other drug not reduced to previous rate, it causes excessive accumulation

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30
Q

Lecture: DDI-II: Enzyme inducers

rifampin induction of quinidine

rifampicin and cyclosporine

A

mean plasma concentration decreased significantly after admin of rifampin

  1. induces cyclosporine. can be dangerous in transplantees because can cause rejection
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31
Q

Lecture: DDI-II: Enzyme inducers

ex. of signifiant ddi due to rifampin induction

A

ethynylestradiol, midazolam, cyclosporine, statins, protease inhibitors

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32
Q

Lecture: DDI-II: Enzyme inducers

st johns wort

A

induces, cyp3a4(nnrti, protease inhibitors, benzos, cab’s, carbamezapine, cyclosporine, digoxin) cyp2c9(warfarin), cyp1a2(warfarin)

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33
Q

Lecture: DDI-II: Enzyme inducers

polymorphism and indution

A

extensive metabolizers: inducing do not have great difference

in poor metabolizers: significant increase in metabolism

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34
Q

Lecture: DDI-III: transporter interactions

apical vs basal side

A

basal side, blood

apical side, lumen

35
Q

Lecture: DDI-III: transporter interactions

ATP-binding cassette (ABC) transporters are influx or efflux

A

efflux

36
Q

Lecture: DDI-III: transporter interactions

Solute-linked carrier(SLC) transporters are influx or efflux

A

influx

37
Q

Lecture: DDI-III: transporter interactions

ex of ABC transporter

A

pgp
mrp1
mrp2..

38
Q

Lecture: DDI-III: transporter interactions

main transporters responsible for limit oral bioavailability of substances clinically

are the efflux or influx

located on apical or basolateral side?

A

pgp
BCRP
efflux transporters tht resin on the apical side (lumen)

increased of pgp or bcrp=> increased substrate bioavailability

39
Q

Lecture: DDI-III: transporter interactions

ex of pgp inhibition by drug

A

oral bioavailability of digoxin is greatly decreased when given w. clarithromycin as apposed to if digoxin given iv. this is because clarithromycin inhibits pgp in gut, decreasing digoxin conc.

40
Q

Lecture: DDI-III: transporter interactions

bbb and transporters

extent of ddi of transporters in bbb

A

pgp and bcrp are highly expressed in bbb to keep harmful drugs out

unbound conc. of marked inhibitors a BBB < in vitro, so theoretical interactions tht can occur don’t happen as much=> low risk for relevant ddi b/c of tight bbb. won’t let perpetrator in.

41
Q

Lecture: DDI-III: transporter interactions

pgp inhibitor cyclosporine effect on verapamil in the brain

A

caused increased conc. of verapamil ( don’t know if it was significantly higher)

42
Q

Lecture: DDI-III: transporter interactions

transporter ddi in the liver

A

if influx transporters such as OATP that are located at the sinusoidal (blood) side are inhibits, drug exposure increases because it is not entering liver to be metabolized.

pgp and bcrp efflux transporters are located at bile canicular side to excrete metabolites in the bile. if inhibited, metabolites accumulate in liver cell, causing DILI (drug induced liver in jury)

43
Q

Lecture: DDI-III: transporter interactions

kidney transporters

A

inhibiting influx transporters in kidney basolateral side, will cause increase toxicity and decreased CL of drug. same if inhibit pgp transporters on tubule lumen apical side, will spill over back into the blood, decrease CL .

44
Q

Lecture: DDI-III: transporter interactions

probenecid inhibition in kidney inhibits influx transporter OATP

A

inhibits influx transporter OATP in kidney

increases t 1/2 of drugs. beneficial for use with benzylpeneckllin

45
Q

Lecture: DDI-III: transporter interactions

DDI of st johns worth and digoxin

A

induction of pgp efflux transporter, which decreases digoxin conc.

46
Q

Lecture: DDI-III: transporter interactions

ddi btw grape fruit and fexofenadine

A

inhibition of influx transporter OATP. prevents uptake of the drug and decreases plasma conc.

47
Q

Lecture: DDI-III: transporter interactions

major ex. of transporter inhibition

A

atorvastatin substrate of oats influx transporter.
cyclosporine inhibits oatp. cases 7 fold increase

altrombopag also an inhibitor of oats influx transporter

48
Q

Lecture: DDI-IV: Protein binding interactions

plasma protein binding generalities

A

changes in protein binding does not alway s necessitate adjustments in dosing

49
Q

Lecture: DDI-IV: Protein binding interactions

conditions favoring drug displacement from protein

A
  1. absence of displacer/ perpetrator for the victim drug must be mostly bound to protein (fu must be low in absence of displacer)
  2. displacer must occupy majority of binding sites( at high enough conc.), lowering the # of sites available for the victim drug to bind
50
Q

Lecture: DDI-IV: Protein binding interactions

diff in pkpd in drugs with low vd and high vd

A

low vd: changes in fu may not matter as much with high vd

51
Q

Lecture: DDI-IV: Protein binding interactions

low cl eq vs high cl eq.

A

low: cl=fu x clint

high cl= q

52
Q

Lecture: DDI-IV: Protein binding interactions

Auc and total exposure in regards to routes of administration

A

changes in fraction unbound effects all orally given drugs, and only low extraction IV drugs (b/c fu is in the equation)

AUC free exposure: AUC=dosexfu/Q. SO iv. IS INFLUENCED by fu

53
Q

Lecture: DDI-IV: Protein binding interactions

free exposure n regards to routes of admin.

A

changes in fu will effect the free exposure of high extraction IV drugs b/c fu is in the equation. will not effect low extraction iv drugs or any oral drugs

54
Q

Lecture: DDI-IV: Protein binding interactions

free Css

A

changes in fu will cause changes in the avg css conc. of high extraction IV drugs

55
Q

Lecture 5: pkpd optimization

dose optimization in interpt. variability

A

dose optimization is only worth while in drugs with high interpt variability and low intrapt variability

56
Q

Lecture 5: pkpd optimization

pk variability

pd variability

A

variability due to diferences in V (body zie, protein binding), differences in cl (renal/ hepatic function), diff. in F/ka

variability due to differences in receptor number and affinity . endogenous substances, effects of disease. (very hard to track pd variability, so we will mostly be dealing with drugs that have high pk variablility and low pd variability)

57
Q

Lecture 5: pkpd optimization

examples of drug that have high pk variability

A

phenytoin

58
Q

Lecture 5: pkpd optimization

reasons why ppl differ

A

genetics

disease (hepatic/ renal)
age

weight

other drugs

gender

environmental factors

non compliance

formulation

food (theophylline dose dumping)

smoking

59
Q

Lecture 5: pkpd optimization

auc eq. of low cl and high cl drugs given IV and oral

A

all oral and low Cl iv drug equation for auc

AUC=Dose/(fu x Cli)

eq. high cl drug AUC eq.
AUC= Dose/Q

60
Q

Lecture 5: pkpd optimization

special population studies

A

tightly controlled studies with small groups of pts/ normal individuals. fix variables, separate pts. based on variably of interest.

61
Q

Lecture 5: pkpd optimization

when is pk based optimization useful?

A
  1. low pd variability
  2. low intra-pt variability in pk
  3. high inter pt variability
62
Q

Lecture 5: pkpd optimization

when is pk based optimization justified?

A
  1. drugs that have a narrow therapeutic index

2. dugs that are very expensive

63
Q

Lecture 5: pkpd optimization

goals of pk optimization

A

enhance drug efficacy

reduce drug toxicity

reduce the expense of drug therapy (drug usage, avoid costly toxicities, hasten cover and decrease duration of hospitalization)

64
Q

Lecture 6: Aminoglycosides (AG) part 1

overview of AG

A

bactericidal

ototoxicity, nephrotoxicity( risk greatly increased if coadministered with her nephrotoxic drugs (like Vanco),

most common agents: amikacin, gentamicin, tobramycin

65
Q

Lecture 6: Aminoglycosides (AG) part 1

AG PK

ADME

variability

A

A: low oral availability. typically given PARENTERALLY

D: css mean= 0.25-0.3 L/kg
AG distributes in fluids like ecf, etc.

high inter pt variability, Vd, and t 1/2

66
Q

Lecture 6: Aminoglycosides (AG) part 1

A

M,E: almost entirely eliminated by kidney.

gentamicin and tobramycin inactivated by some penicillins (carbenicillin, ticarcillin)

67
Q

Lecture 6: Aminoglycosides (AG) part 1

AG pk variability in terms of disease

Distribution (increased and decreased)

Elimination (increased and decrease)

A

distribution:

a. Increased: chf (edema), ascites, post partum, surical pts
b. decreased: sepsis(dehydration)

elimination:
A:increase( burn pts,
cystic fibrosis)

b. decreased(renal insufficiency)

68
Q

Lecture 6: Aminoglycosides (AG) part 1

peak conc related to efficacy:

A

Peak:
therapeutic range: 5-10 mg/L for G&T. 20-30 mg/L for A

Trough:
target trough on 0.5-2 mg/L for G&T, 1-8 mg/L for A

69
Q

Lecture 6: Aminoglycosides (AG) part 1

ag pd

A

concentration-dependent bacterial killing

post-abx EFFECT

adaptive resistance

saturable transport into cells with toxicity

all ld to extended interval dosing

70
Q

Lecture 6: Aminoglycosides (AG) part 1

why shouldpk individualization be used for AG (standard of practice)

A

high interpt varibaility
low TI
association of plasma concentrations to AG efficacy and toxicity

saves money

71
Q

Lecture 6: Aminoglycosides (AG) part 1

what are the 3 thing we need to individualize AG

A
  1. targets
  2. pk model
  3. pk parameters
72
Q

Lecture 6: Aminoglycosides (AG) part 1

pk models for A, G, and T

A

A: one compartment model

g and T: prolongedd use causes accumulation in tissues, so when drug is d/c huge drop in conc occurs, and then another phasee(beta phase) of elimination occurs. to avoid accumulation, make sure pts isn’t on AG for more than 10-14 days

73
Q

Lecture 6: Aminoglycosides (AG) part 1

AG Vd estimation flow chart

A

is 3rd space fluid present?

no=> is TBW>1.2 x IBW?

a. no->V=0.25L/kg x TBW
b. yes->V=0.25L/kg x TBW+0.1L/kg [TBW-IBW]

yes=> Let TBW=TBW-3rd space fluid weight->
is TBW>1.2 x IBW
a. no: V=0.25L/kg x TBW* +1L/kg x 3rd space weight
b. yes: V=0.25L/kg x TBW+0.1L/kg [TBW*-IBW]+1L/kg x 3rd space weight

74
Q

Lecture 6: Aminoglycosides (AG) part 1

pk parameters for pts who haven’t received AG

A
  1. Vd(using IBW)

2. Cl: (CrCl as an estimate for Cl)*note if given conc. info, use that to determine cl, instead of just using Crcl alone

75
Q

Lecture 6: Aminoglycosides (AG) part 1

1 CM peaks and trough times

A

peak: conc. 1/2h following 1/2 hr infusion (1 hr after infusion)
goal: avoid disposition phase for G&T

trough: defined as conc. obtained 1/2 hr prior to initiation of next dose

76
Q

Lecture 6: Aminoglycosides (AG) part 1

calculations required for G-optimization

step 1: prediction of conc.

A

equation

C2=((Dose/tin)/Cl)(1-e^-ktin)(e-kt2)

tin: time of infusion (30 min)
t2: time btw end of infusion and collection of peak conc. (30 min)

this is overall standard

77
Q

Lecture 6: Aminoglycosides (AG) part 1

purpose of loading dose

A

get right to the TI window. AG always get loading doses

78
Q

Lecture 6: Aminoglycosides (AG) part 1

note: when finding loading doses. what # should we round to

A

ROUND UP to th nearest 20mg increment

79
Q

Lecture 7: Aminoglycosides (AG) part 2

calculating maintenance regimens steps

A
  1. determine appropriate interval duration (recommendation: base initial calculation on the highest allowed peak and lowest allowed trough)
  2. adjust tau to reasonable value (q8, q12, q24)
  3. using selected (reasonable tau, calculate dose to “hit” highest allowed peak.
  4. adjust dose to reasonable value (evenly divisible by 20 mg for G & T, evenly divisible by 50 mg for A)
  5. Determine Peak and trough for selected regimen
80
Q

Hartford vs portland
vs AUC24
approach to extended interval dosing

A

hartford: same dos, different frequency
portland: different dose, same frequency

AUC24: auc v. time under curve over a 24 hr interval

81
Q

Lecture: Vancomycin

vanco general decription

A

bactericidal

effective against mrsa and nrsa

nephrotoxic and autotoxic, redmansyndrome (histamine reaction)

package insert dosing recommendation: 250-500mg IVPB q6h

82
Q

Lecture: Vancomycin

vanco ADME

A

A: poor oral bioavailability. administered iv for systemic infections

D: Vss= 0.5-1 L/kg

ME: primarily eliminated unchanged in urine. no dose alterations for hepatic impairment

83
Q

Lecture: Vancomycin

vanco standard Therapeutic window

A

peak <40-50 mg/L

trough: 5-15

AUC: >400
time dependent cell killing

84
Q

does vanco use loading doses ?

A

no because it is a time dependent killer. not concentration dependent killer like aminoglycosides

PKPD II (4 decks)

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