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Lab 3 > PK genetic variability > Flashcards

PK genetic variability Flashcards

1
Q

name of study of link between genetic variability + reponse to treatment?

A

PG

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2
Q

PG used to individualise drug selection, give 2 examples

A

HER2+ cancer + Herceptin
ER+ breast cancer + Tamoxifen

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3
Q

Genetic polymorphism can impact the pharmacokinetics (PK) of drugs by affecting ADME.
name 3 gen polymorphism types?

A

enzyme
transporter
receptor

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4
Q

inUK Herceptin (trastuzumab) is licenced for what?

A

breast cancer spread beyond the breast

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5
Q

herceptin: antibody based treatment for which sub group of breast cancer px?

A

those with genetic mutation -> multiple copies of a gene that = overproduction of a tumour GF, HER2

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6
Q

what is HER2?

A

HER2 (human epidermal growth factor receptor 2)

overexpressed in some types of cancer, breast, ovarian, and gastric cancer. this -> uncontrolled cell growth and division, as well as resistance to chemotherapy and other treatments. Therefore, HER2 is an important target for cancer therapy.

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7
Q

2 Drugs that target HER2?

A

trastuzumab and pertuzumab

used to treat HER2-positive breast cancer.

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8
Q

what enzyme responsible for metabolism of 20% drugs, and polymorphism associated w differences in espression?

A

cyp2d6

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9
Q

4 types of cyp2d6 polymorphisms? results

A

complete deficiency
intermediate activity
extensive activity (normal px)
ultrarapid activity

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10
Q

what mutation -> ultrarpid activity of cyp2d6?

A

duplication of gene -> fast metab

more common in middle east and north africa

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11
Q

impact on PK will depend on whether cyp2d6 involved in…. 2

A

metab for ELIM (tricyclic antidepressants, antipsychotics)

metab for ACTIVATION (codeine -> morphine)

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12
Q

what enzyme converts prodrug codeine -> morphine for therapeutic effect?

A

cyp2d6

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13
Q

impact of px w decrease cyp2d6 on codeine -> morphine conversion?

A

little/ no conversion as poor metabolisers

will not experience pain relief but will become nauseated due to higher amounts of codeine in body

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14
Q

whats cyp2c9 responsible for?

A

metab of many NTIs…

  • warfarin
  • phenytoin
  • losartan
  • glipizide
  • NSAIDs
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15
Q

polymorphism of cyp2c9 is linked to various abilities such as

A

WT 1/1 normal

other alloenzymes:
2/2: less metab activity
3/3: no activity

heterozygous genotypes: a mix 1/2 1/3 etc

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16
Q

t/f all other alloenzymes other than WT 1/1 of CYP2c9 are linked to reduced metab to some degree?

A

true
thus require dose adjustment: lower

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17
Q

why do you need lower dose for diff cyp2c9 metab?

A

low activity
high accumulation
lower dose to avoid tox
BUT consider therap window for NTI drugs

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18
Q

what drug metab in liver by CYP2C9, but a variant CYP2C9 gene alters rate of its metab?

A

warfarin

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19
Q

T/F
px with variant gene cyp2c9 break down warfarin slower so need lower doses to get same anticoagulant effect?

A

true

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20
Q

what can having too much anticoagulant eg high/normal dose warfarin in variant cyp2c9 gene px, lead to?

A

potentially dangerous bleesing and inc susceptibility to some drug ints

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21
Q

how is warfarin prescribed/ dosing?

A

start low
monitor blood clotting (INR)
increase slowly until approp lvl reached

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22
Q

whats CYP2C19 responsible for? metabolism of…

A

S-enantiomers of diazepam citalopram propanolol omeprazole

fluoxetine sertraline tricyclic antidepressants

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23
Q

3 types of results of cyp2c19 genetic polymorphism?

A

complete def
intermediate activ
extensive act: normal

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24
Q

there is a potentially higher efficacy of omeprazole, lansoprazole in X metabolisers of CYP2C19?

A

poor

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25
Q

higher risk of ADRs for X metab of CYP2C19 receiving warfarin and phenytoin

A

poor

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26
Q

T/F
lower activity of antimalarial drugs in poor metaboliser cyp2c19
(proguanil)

A

true

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27
Q

DDI + food (grapefruit) interactions seen with what enz?

A

cyp3A4

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28
Q

what does TPMT catalyse?

A

S-methylation of thiopurine rodrugs
eg azathiprine, mercaptopurine

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29
Q

polymorphism of TPMT observed in RBCs why?

A

enz in haematopoietic cells

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30
Q

TMPT ints: dose limiting.
whats low activity of enz linked to?

A

higher risk of haematological ADRs

requires phenotyping and dose adjustment

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31
Q

what does N-acetyltransferase (NAT) catalyse?

A

acetylation of diff drugs to allow elim

eg
isoniazid
hydralazine
phenelzine (MAOI)

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32
Q

NAT
for isoniazid (TB) what do slow acetylators need?

A

low doses to avoid neurological ADRs

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33
Q

NAT
for isoniazid (TB) what do fast acetylators have increased risk of?

A

hepatotoxicity (linked to metabolite conc)

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34
Q

for hydralazine (HTN) what do slow acetylators of NAT have increase risk of?

A

SLE-like syndrome
lupus like

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35
Q

what enz involved in glucoronidation of diff drugs?

A

UDP-glucoronosyltransferase

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36
Q

irinotecan: prodrug metab to SN-38, which is elim following what?

A

glucoronidation by UDP-glucoronosyltransferase

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37
Q

irinotecan can cause severe ADRs like

A

haematological and GI ADRs
diarrhea
sometimes fatal!

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38
Q

low UGT1A1 polymorphism associated w higher/ lower risk of ADRs?

A

higher

39
Q

polymorphism of drugs transporters (ABC, solute) will impact on…

A

risk of disease
response to treatment
ADR risk
plasma concs
…

40
Q

Pgp part of ATP binding treansport and..

A

resistance to therapy

41
Q

Variability and special populations…

factors that can influence PK variability

A

genetics
age body size
disease
environemenatl
diet lifestyle
concomitant drugs (DDIs)

… adherence, pregnancy, alcohol, chronopharmacy (timing of drug admin)

42
Q

2 types of Px variability: intra and inter- patient variability.
whats the difference?

A

intra: same dose same px

inter: same dose diff px

43
Q

standard healthy subject =

A

75kg western male. clinical trials, not representative of whole popn
model not valid for:
paediatric
elderly
liver/ kidney disease

44
Q

Hepatic and renal impairment…

diseases of what organs are responsible for large variations in drug PK?

A

organis of elim

also maybe circulatory system

45
Q

what can diminished perfusion in HF affect in regards to PK parameters?

A

A: if affecting perfusion at absorption sites

D: assed quick in well perfused organs

M,E: if affect perfusion to liver +++ or kidneys.
depending on importance of hepatic metab and excretion for given drug

46
Q

T/F: no single biomarker of hepatic disease?

A

true

47
Q

severe cirrhosis decreases hepatic Cl but what other organs may it also affect?

A

intestine
lung
kidney

48
Q

what PK parameter does liver disease mainly affect?

A

A
increase BA in cirrhosis
reduced FPM

worse for drugs heavily metab by liver

49
Q

what classification system may be used for hepatic disease?

A

child-pugh classification
severe: 10-15

50
Q

what PK parameters 3, can liver disease also affect?

A

D: decrease in protein lvls for protein unbound drugs
displacement/ comp w toxins
- changes in Vd for albumin bound drugs
- changes in Cl

M,E (bile)
CYP450 enz affected

51
Q

how will a drugs BA and Cl change in disease state: cirrhosis?

A

increase
small decrease

52
Q

what drugs should be used with caution in hepatic impairment and px monitored closely?

A

corticosteroids
… + NTI drugs always!

53
Q

high extraction ratio (high liver metabolism) can experience inc/ dec in F?

A

inc (BA)

54
Q

effect of hepatic flow reduced on renal Cl?

A

also reduced

55
Q

how can oedema + ascite change Vd for hydrophilic drugs?

A

increase
as inc in total body water vol

56
Q

for small drugs/ macromols in kidney disease, Cl reduced across the board?

A

small drugs

57
Q

for macormols eg proteins, how does kidney disease affect Cl post metabolism?

A

reduced
but can distribute into interstitial space in inflamm/ cancer

58
Q

in kidney disease are larger proteins mroe or less impacted and why?

A

less and glom filtration not major excretion route

59
Q

reduced Cl -> what to t1/2

A

increases

  • impact Css AND time to reach Css
  • need dose reduction
60
Q

kidney disease redcued protein binding so how is albumin conc changed?

A

decrease. and possible displacement

61
Q

does kidney disease impact hepatic metabolism?

A

yes indirectly

uremic toxins can reduce hepatic enz activity

62
Q

whats renal function measured in?

A

eGFR/ CrCl

63
Q

GFR absolute =

A

eGFR x (BSA/1.73)

64
Q

what is considered a suitable marker for renal func + is used for dosage adaptation?

A

CLcr

65
Q

how much adjustment is needed for renal failure depends on what 2 things?

A

importance of renal excretion

severity of renal disease: larger dose change for more severe

66
Q

Cl change will dpeend on drug, dialysis device properties, px.
more problematic for what type drugs?

A

hydrophilic, low PPB, small Vd
(As likely to be removed from body)

** also consider SA, membrane pore size **

67
Q

why is kidney disease less of a problem for proteins + macromols?

A

similar size to albumin in blood- shouldnt be removed by dialysis

68
Q

T/F
vancomycin is cleared at same rate as creatinine?

A

true

69
Q

Special px populations….

why must anaesthetic drugs be considered in obesity?

A

they are highly lipid soluble thus accumulate in fatty tissue: lots in obesity

70
Q

how is proportion of
- adipose tissue
- water
different in obesity?
and implications for polar drugs eg antipyrine

A

higher
lower

polar drugs will have lower Vd

71
Q

3 parameters different in newborns which mean slower Abdorpiton of drugs in children?

A

low stomach acid levels
delayed gastric emptying
irregular inetstinal peristalsis

72
Q

during first year of life, how does total body water as fraction of body wieght change?

A

decreases
but PPB also reduced

73
Q

why does abilityof newborn to metabolise drugs differ quant and qual than older px?

A

as the avrious pathways of drug metab mature at diff rates

74
Q

after the enzyme system matures at 6 months, what will metabolism depend on?

A

growth of liver
(perfusion, vol, bile function)

75
Q

GFR normalised for BSA slowly increases and reaches adult values when?

A

about 6 months

76
Q

in children, is drug Cl considered to correlate better with BSA or body weight?

A

BSA
thus higher maintenance dose per kg body weight needed the smaller and younger the child

77
Q

what factors change with age/ in elderly that change drug distribution?

A

body fat increases
lean body weight decreases

so distribution of drugs sequestered into fatty tissues will be changed

78
Q

T/F
changes to perfusion + cardiac output cannot also impact distribution rates

A

false they can

79
Q

Vd of hydro/lipophilic drugs may be more effected in elderly?

A

lipophilic

80
Q

how does liver mass and blood flow change with age?

A

decreases
so impacts on metab

81
Q

why must adjustments be made for renally excreted drugs

A

glom filtration
kidney size
func glom
renal blood flow
all reduced

82
Q

in pregnancy what 3 things can reduce absorption rates?

A

delayed gastric emptying
prolonged GI transit
reduced motility

… also elevated gastric pH and nausea, vom

83
Q

preganncy linked w increased blood flow, decreased albumin and alpha-acid glycoprotein.
what will these affect?

A

protein binding.. more unbound drug

84
Q

in pregnancy the inc lvls of unbound drug can affect response and increase risk of what?

A

ADRs

85
Q

what in pregnancy can affect hydrophilic drug distribution?

A

increase in body weight linked to increase extracellular and intravascular volumes

86
Q

what in pregnancy can affect lipophilic Vd?

A

increase in body fat

87
Q

in pregnancy oestrogen and progesterone can cause what in metabolism?

A

induce and inhibit cyp metabolising enzymes

88
Q

in preg, increase in blood flow can ->

A

lower plasma conc of drugs w high extraction ratio which will be metab more extensively

89
Q

T/F in pregnancy, drugs with high extraction ratio will be metabolised more extensively

A

true

90
Q

why does renal excretion of hydrophilic drugs increase in preg?

A

as renal blood flow increasea

91
Q

why may some basic drugs become ionised (cross plasma exc in milk) + unable to transfer abck to plasma, in lactation?

A

as pH more acidic in breast tissue.
7.1

92
Q

drugs are transported in breast milk by passive diffusion, so lipophilic may accumulate more/ less?

A

more

93
Q

are macromols more/ less likley to be excreted in milk?

A

less

94
Q

4 things that affect how much of drug is excreted in milk?

through plasma:milk conc grad?

A

dose
route
freq
time of feeding

Lab 3 (21 decks)

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