PK genetic variability

Question 1

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

Answer 1

PG

Question 2

PG used to individualise drug selection, give 2 examples

Answer 2

HER2+ cancer + Herceptin
ER+ breast cancer + Tamoxifen

Question 3

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

Answer 3

enzyme
transporter
receptor

Question 4

inUK Herceptin (trastuzumab) is licenced for what?

Answer 4

breast cancer spread beyond the breast

Question 5

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

Answer 5

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

Question 6

what is HER2?

Answer 6

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.

Question 7

2 Drugs that target HER2?

Answer 7

trastuzumab and pertuzumab

used to treat HER2-positive breast cancer.

Question 8

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

Answer 8

cyp2d6

Question 9

4 types of cyp2d6 polymorphisms? results

Answer 9

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

Question 10

what mutation -> ultrarpid activity of cyp2d6?

Answer 10

duplication of gene -> fast metab

more common in middle east and north africa

Question 11

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

Answer 11

metab for ELIM (tricyclic antidepressants, antipsychotics)

metab for ACTIVATION (codeine -> morphine)

Question 12

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

Answer 12

cyp2d6

Question 13

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

Answer 13

little/ no conversion as poor metabolisers

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

Question 14

whats cyp2c9 responsible for?

Answer 14

metab of many NTIs…

• warfarin
• phenytoin
• losartan
• glipizide
• NSAIDs

Question 15

polymorphism of cyp2c9 is linked to various abilities such as

Answer 15

WT 1/1 normal

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

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

Question 16

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

Answer 16

true
thus require dose adjustment: lower

Question 17

why do you need lower dose for diff cyp2c9 metab?

Answer 17

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

Question 18

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

Answer 18

warfarin

Question 19

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

Answer 19

true

Question 20

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

Answer 20

potentially dangerous bleesing and inc susceptibility to some drug ints

Question 21

how is warfarin prescribed/ dosing?

Answer 21

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

Question 22

whats CYP2C19 responsible for? metabolism of…

Answer 22

S-enantiomers of diazepam citalopram propanolol omeprazole

fluoxetine sertraline tricyclic antidepressants

Question 23

3 types of results of cyp2c19 genetic polymorphism?

Answer 23

complete def
intermediate activ
extensive act: normal

Question 24

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

Answer 24

poor

Question 25

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

Answer 25

poor

Question 26

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

Answer 26

true

Question 27

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

Answer 27

cyp3A4

Question 28

what does TPMT catalyse?

Answer 28

S-methylation of thiopurine rodrugs eg azathiprine, mercaptopurine

Question 29

polymorphism of TPMT observed in RBCs why?

Answer 29

enz in haematopoietic cells

Question 30

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

Answer 30

higher risk of haematological ADRs requires phenotyping and dose adjustment

Question 31

what does N-acetyltransferase (NAT) catalyse?

Answer 31

acetylation of diff drugs to allow elim eg isoniazid hydralazine phenelzine (MAOI)

Question 32

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

Answer 32

low doses to avoid neurological ADRs

Question 33

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

Answer 33

hepatotoxicity (linked to metabolite conc)

Question 34

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

Answer 34

SLE-like syndrome lupus like

Question 35

what enz involved in glucoronidation of diff drugs?

Answer 35

UDP-glucoronosyltransferase

Question 36

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

Answer 36

glucoronidation by UDP-glucoronosyltransferase

Question 37

irinotecan can cause severe ADRs like

Answer 37

haematological and GI ADRs diarrhea sometimes fatal!

Question 38

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

Answer 38

higher

Question 39

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

Answer 39

risk of disease response to treatment ADR risk plasma concs ...

Question 40

Pgp part of ATP binding treansport and..

Answer 40

resistance to therapy

Question 41

Variability and special populations... factors that can influence PK variability

Answer 41

genetics age body size disease environemenatl diet lifestyle concomitant drugs (DDIs) ... adherence, pregnancy, alcohol, chronopharmacy (timing of drug admin)

Question 42

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

Answer 42

intra: same dose same px inter: same dose diff px

Question 43

standard healthy subject =

Answer 43

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

Question 44

Hepatic and renal impairment... diseases of what organs are responsible for large variations in drug PK?

Answer 44

organis of elim also maybe circulatory system

Question 45

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

Answer 45

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

Question 46

T/F: no single biomarker of hepatic disease?

Answer 46

true

Question 47

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

Answer 47

intestine lung kidney

Question 48

what PK parameter does liver disease mainly affect?

Answer 48

A increase BA in cirrhosis reduced FPM worse for drugs heavily metab by liver

Question 49

what classification system may be used for hepatic disease?

Answer 49

child-pugh classification severe: 10-15

Question 50

what PK parameters 3, can liver disease also affect?

Answer 50

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

Question 51

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

Answer 51

increase small decrease

Question 52

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

Answer 52

corticosteroids ... + NTI drugs always!

Question 53

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

Answer 53

inc (BA)

Question 54

effect of hepatic flow reduced on renal Cl?

Answer 54

also reduced

Question 55

how can oedema + ascite change Vd for hydrophilic drugs?

Answer 55

increase as inc in total body water vol

Question 56

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

Answer 56

small drugs

Question 57

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

Answer 57

reduced but can distribute into interstitial space in inflamm/ cancer

Question 58

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

Answer 58

less and glom filtration not major excretion route

Question 59

reduced Cl -> what to t1/2

Answer 59

increases - impact Css AND time to reach Css - need dose reduction

Question 60

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

Answer 60

decrease. and possible displacement

Question 61

does kidney disease impact hepatic metabolism?

Answer 61

yes indirectly uremic toxins can reduce hepatic enz activity

Question 62

whats renal function measured in?

Answer 62

eGFR/ CrCl

Question 63

GFR absolute =

Answer 63

eGFR x (BSA/1.73)

Question 64

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

Answer 64

CLcr

Question 65

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

Answer 65

importance of renal excretion severity of renal disease: larger dose change for more severe

Question 66

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

Answer 66

hydrophilic, low PPB, small Vd (As likely to be removed from body) ***** also consider SA, membrane pore size *****

Question 67

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

Answer 67

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

Question 68

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

Answer 68

true

Question 69

Special px populations.... why must anaesthetic drugs be considered in obesity?

Answer 69

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

Question 70

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

Answer 70

higher lower polar drugs will have lower Vd

Question 71

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

Answer 71

low stomach acid levels delayed gastric emptying irregular inetstinal peristalsis

Question 72

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

Answer 72

decreases but PPB also reduced

Question 73

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

Answer 73

as the avrious pathways of drug metab mature at diff rates

Question 74

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

Answer 74

growth of liver (perfusion, vol, bile function)

Question 75

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

Answer 75

about 6 months

Question 76

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

Answer 76

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

Question 77

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

Answer 77

body fat increases lean body weight decreases so distribution of drugs sequestered into fatty tissues will be changed

Question 78

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

Answer 78

false they can

Question 79

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

Answer 79

lipophilic

Question 80

how does liver mass and blood flow change with age?

Answer 80

decreases so impacts on metab

Question 81

why must adjustments be made for renally excreted drugs

Answer 81

glom filtration kidney size func glom renal blood flow all reduced

Question 82

in pregnancy what 3 things can reduce absorption rates?

Answer 82

delayed gastric emptying prolonged GI transit reduced motility ... also elevated gastric pH and nausea, vom

Question 83

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

Answer 83

protein binding.. more unbound drug

Question 84

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

Answer 84

ADRs

Question 85

what in pregnancy can affect hydrophilic drug distribution?

Answer 85

increase in body weight linked to increase extracellular and intravascular volumes

Question 86

what in pregnancy can affect lipophilic Vd?

Answer 86

increase in body fat

Question 87

in pregnancy oestrogen and progesterone can cause what in metabolism?

Answer 87

induce and inhibit cyp metabolising enzymes

Question 88

in preg, increase in blood flow can ->

Answer 88

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

Question 89

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

Answer 89

true

Question 90

why does renal excretion of hydrophilic drugs increase in preg?

Answer 90

as renal blood flow increasea

Question 91

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

Answer 91

as pH more acidic in breast tissue. 7.1

Question 92

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

Answer 92

more

Question 93

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

Answer 93

less

Question 94

4 things that affect how much of drug is excreted in milk? through plasma:milk conc grad?

Answer 94

dose route freq time of feeding