Lec 14 - Personalized Medicine and Pharmacogenetics

Question 1

what factors affect drug response

Answer 1

genetics and environment

Question 2

what is pharmacogenetics

Answer 2

how genetic factors influence response and tox for chemicals

Question 3

what does a high INR mean? WHAT IS INR

Answer 3

international normalised ratio: high = longer time for blood to clot

Question 4

what is the haploid genome? diploid?

Answer 4

haploid: sperm or egg 23 chromosomes, diploid = all 23 pairs

Question 5

the four bases are

Answer 5

a c g t

Question 6

t/f: 90% of dna is organized in genes

Answer 6

false, only 1-2%

Question 7

genes encode for ___

Answer 7

proteins

Question 8

a haplotype is

Answer 8

alleles found on same chromosome

Question 9

what is a rare vs polymorphic variant

Answer 9

rare = variation in less than one percent of pop, polymorphic = cariations occur in more than one percent

Question 10

how does nucleotide variation affect physical traits

Answer 10

variation affects genotype which influences phenotype

Question 11

t/f: variations have the same cause

Answer 11

false; many genetic causes

Question 12

types of large mutatiosn

Answer 12

deletions, insertion, duplication,inversion

Question 13

types of point mutations

Answer 13

substitutions, frameshifts

Question 14

what are SNPs

Answer 14

single nucleotide polymorphism; single substitutions

Question 15

how many snps are in the human genome

Answer 15

10 million

Question 16

frequency of polymorphic nucleotides

Answer 16

about 1 in every 500 nucleotides

Question 17

how can snps be used as mapping markers

Answer 17

use them to mark certain gene differences, see how that influences disease states

Question 18

will all patients with the same diagnosis respond to meds the same

Answer 18

no. non responders and toxic responders should be treated with alternative drugs or doses

Question 19

contrast monogenic vs polygenic

Answer 19

monogenic is mutation in one gene, poly genic is mutation in multiple

Question 20

rare vs polymorphic monogenic , vs polygenic distributions

Answer 20

rare: one normally distributed, small amount of the other phenotype

polymorphic: biomodal

polygenic: one broad distribution

Question 21

how can a polymorphic gene affect drug response

Answer 21

gene has many variants, can make people good or bad metabolizers, can imapct drug levels, response, toxicity

Question 22

when cyp2d6 is mutated debrisoquine leads to

Answer 22

orthostatic hypertension (the opp effect)

Question 23

when cyp2d6 is mutated sparteine leads to

Answer 23

excess uterine contractions (normally oxytocic agent)

Question 24

poor metabolisers of debrisq. had a higher ___ to ___ ratio

Answer 24

debrisq - 4hydroxybrisq

Question 25

codeine, dextromethorphan, and tamoxifen are all affected by polymorphism in CYP____

Answer 25

2d6

Question 26

poor metabolisers of codeine are unable to do what?

Answer 26

convert codeine into morphine

Question 27

how can you use dextromethorphan to predict cyp2d6 metabolism

Answer 27

dex is a safe in vivo probe; by seeing how much of it gets metabolised into des, you can see whether 2d6 is working

Question 28

what is the primary and secondary pathway of tamoxifen metabolism

Answer 28

primary: cyp3a to ndesmethyltam, cyp 2d6 to endoxifen sec: 2d6 to 4hydroxytam, 3a to endoxifen

Question 29

how do poor vs extensive metabolizers by cyp2d6 differ wrt survival rates of breast cancer after being treated w tamoxifen

Answer 29

poor metabolizers: more likely to relapse bc less of the endoxifen is produced em: less likely to relapse bc able to produce endox.

Question 30

what impact does mutated cyp2c9 have on s-warfarin

Answer 30

cant metabolise warfarin, anticoag keeps occuring, excessive bleeding.

Question 31

metabolism by cyp2c19 is an ______ pathway for omeprazole.

Answer 31

inactivation

Question 32

poor metabolizers by cyp2c19 have what outcome (wrt omeprazole)

Answer 32

can better reduce stomach acidity, bc less of the drug gets metabolised, so can act on gastric acidity for longer

Question 33

are poor metabolisers always bad?

Answer 33

no, just depends on whether you have a prodrug or inactivation

Question 34

what role does tmpt play for 6mp? why is this important?

Answer 34

it detoxifies 6mp. without it, it goes onto produce tgn

Question 35

what effect do thioguanine nucleotides have?

Answer 35

cytotoxic effect

Question 36

lower metabolic activity of TMPT has what affect on toxicity in the use of 6mp for leukemia treatment

Answer 36

increases toxicity bc 6mp cant get detoxified

Question 37

contrast toxicity of 6mp in a leukemia patient with m/m vs m/wt vs wt/wt

Answer 37

m/m, least tpmt, least detox, most tox wt/wt, most tpmt, most detox, least tox

Question 38

variation at this amino acid in the ________- receptor affects response to isoproterenol

Answer 38

27, b2 adr recept

Question 39

variation at amino acid 16 in beta ad recep affects response to __________

Answer 39

salbutamol

Question 40

GLN at amino acid 27 on Badrecept leads to _____ blood vessel dilation

Answer 40

less

Question 41

salubutamol is used for. so we want _____ beta 2 receptors for _______

Answer 41

asthma, activated, bronchodilation

Question 42

homozygous arg at amino acid 16 in beta ad receps leads to

Answer 42

large bronchodil response

Question 43

homo or hetero gly at amino acid 16 in beta ad receps leads to

Answer 43

lower bronchodil response

Question 44

wild type mu-opiod recep needs (more/less) m6g at target site to have reduced pupil size

Answer 44

less

Question 45

trastuzumab (herceptin) only works when:

Answer 45

patient has the her2 growth factor

Question 46

how does pharmacogenetics help with deciding if herceptin is good or not

Answer 46

can see whether patient has her2 factor, and whether the treatment is worth it

Question 47

what is the purpose of personalized medicine

Answer 47

medicine tailored to patient, less trial and error

Question 48

t/f: prescribed drugs are effective in the majority of patients

Answer 48

false; 50% ineffective

Question 49

t/f: adverse drug reactions are uncommon

Answer 49

false, 4th leading cause of hosp, 100 000 deaths per year

Question 50

what is the cost of ADRs per year

Answer 50

30-150 billion

Question 51

what (other than cyp2c9) in involved with increased bleeding risk after administering warfarin

Answer 51

vkorc1, cyp4f2, factor v leiden, diet rich in vit k

Question 52

challenges of personalized medicine

Answer 52

polygenic inheirtence and causes of disease technology - not yet at where it needs to be clinical challenges

Question 53

why is polygenic inheritance a challenge for personalized medicine

Answer 53

many different genetic impacts in just one drug met route

Question 54

how do genetics impact metabolism of navoban in liver, brain, and at 5ht receptor

Answer 54

liver: PM leads to high drug levels EM leeds to normal drug levels brain: genetically less p glyco : more drug in brain genetically more p glyco: less drug in brain 5ht: can have variations in SERT (uptake), TPH2 (ser synthesis), serotonin breaker downers

Question 55

technological challenges of personalized medicine

Answer 55

expensive, privacy issues

Question 56

when should pers. med. be used

Answer 56

serious disease, high predictive power, high cost of normal treatment, no alt meds, narrow ther index

Question 57

main ops vs challenges of pers med

Answer 57

improve drug del, improve clinical care, challenging for tech and management

Question 58

t/f: pers med is a good immediate solution for all

Answer 58

False