Brainscape's Knowledge GenomeTM

Browse over 1 million classes created by top students, professors, publishers, and experts.


See full index

Genetics of Complex Disease > Pharmacogenetics > Flashcards

Pharmacogenetics Flashcards

You may prefer our related Brainscape-certified flashcards:
Biology 101 flashcards
0
Q

how is pharmacogenomics defined?

A

a study of the effect of drugs on gene expression

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
1
Q

how is pharmacogenetics defined?

A

the study of inherited genetic variation to drug response

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
2
Q

what are three examples of polymorphisms?

A

minisatellites, microsatellites and SNPs

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
3
Q

what is a minisatellite?

A

tandem repeats of 14-100 base pairs

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
4
Q

what are microsatellites?

A

short sequences of tandem repeats of 2-5 base pairs, e.g. CA repeats

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
5
Q

what are variable number tandem repeats (VNTRs)?

A

variable numbers of minisatellite and microsatellite repeats

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
6
Q

give three consequences of polymorphisms in drug responses

A

alterations to toxicity, efficacy and disease susceptibility

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
7
Q

what effect can polymorphisms have on drug toxicity?

A

exaggerated effect or effect on inappropriate target

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
8
Q

which drugs are influenced by the TPMT protein?

A

TPMT influences the metabolism of two anti-cancer drugs: 6-mercaptopurine and azathioprine

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
9
Q

what does TMPT stand for?

A

thiopurine s-methyltransferase

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
10
Q

what is 6-mercaptopurine?

A

a purine antimetabolite prodrug that produces active 6-thioguanine nucleotides that are incorporated into DNA to trigger cell apoptosis

(therefore is used as a chemotherapy drug)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
11
Q

what is azathioprine?

A

a 6-mercaptopurine prodrug used as an immunosuppressant

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
12
Q

which endogenous body molecule does 6-mercaptopurine closely resemble?

A

hypoxanthine

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
13
Q

what is the action of TPMT on 6-mercaptopurine?

A

TPMT is a methyltansferase enzyme that methylates 6-mercaptopurine to inactivated 6-methylmercaptopurine

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
14
Q

what is the effect of high TPMT activity?

A

increased 6-MP inactivation therefore decreased 6-MP therapeutic effect

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
15
Q

what is the result of decreased TPMT activity?

A

increased activity of 6-MP and therefore increased 6-MP therapeutic effect - may potentially induce 6-MP activity in all cells and not just rapidly diving cancerous cells

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
16
Q

what polymorphism is associated with low TMPT activity?

A

TMPT*3A null allele

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
17
Q

why is the TMPT*3A alle associated with decreased TMPT activity?

A

the allele contains two SNPs (Ala154Thr and Tyr240Cys) associated with TMPT protein instability

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
18
Q

which three groups result from varying TMPT activity? why is this?

A

LOW activity = TPMT3A/TPMT3A
MEDIUM activity = TPMT1A/TPMT3A
HIGH activity = TPMT1A/TPMT1A

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
19
Q

how many caucasians have the TPMT*3A null allele and therefore lack TPMT?

A

1 in 300 (compared to 1 in 2500 asians)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
20
Q

how do TPMT*3A homozygotes fare when given 6-mercaptopurine?

A

due to low levels/absent TPMT, they experience high thiopurine toxicity (due to high levels of 6-MP and therefore 6-thioguanine nucleotides) and may experience life-threatening myelosuppression

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
21
Q

what is myelosuppression?

A

bone marrow suppression - i.e. a decrease in leukocytes, erythrocytes and thrombocytes
(is a serious side effect of chemotherapy)

22
Q

how do TMPT1A/TMPT1A homozygotes fare when given 6-mercaptopurine?

A

high TPMT activity results in increased 6-MP metabolism and decreased therapeutic effect

23
Q

is TPMT gene testing currently carried out before treatment with 6-mercaptopurine?

A

yes, in 2003 the FDA recommended TPMT testing and dosing recommendations for 6-MP

24
Q

what effect can polymorphisms have on drug efficacy?

A

polymorphisms can create unresponsive drug targets, stop the activation of a prodrug or induce too rapid metabolism/excretion of the drug

25
Q

what is the cytochrome P450 family of enzymes?

A

a multigene family of enzymes that oxidise drugs and other foreign compounds, highly expressed in the liver

26
Q

what is a debrisoquine?

A

an antihypertensive drug

27
Q

which enzyme metabolises debrisoquine?

A

the cytochrome P450 enzyme CYP2D6

28
Q

how many CYP2D6 polymorphisms have now been identified?

A

> 70

29
Q

what are four common CYP2D6 polymorphisms?

A 
CYP2D6*3 = base (A) deletion
CYP2D6*4 = altered splice site
CYP2D6*5 = entire CYP2D6 gene deletion
30
Q

what two types of metabolism are related to CYP2D6 metabolism?

A

“poor metabolisers” and “ultrarapid metabolisers”

31
Q

what are “poor metabolisers” with relation to cytochrome P450 enzymes?

A

individuals who poorly metabolise drugs oxidised by the CYP2D6 enzyme due to a recessive trait requiring the inheritance of two defective CYP2D6 gene copes

32
Q

what are “ultrarapid metabolisers” with relation to cytochrome P450 enzymes?

A

individuals that demonstrate high metabolism of drugs oxidised by CYP2D6 due to extra copies (between 2 and 13 copies possible) of the CYP2D6 gene adjacent to the wt CYP2D6 and therefore increased levels of CYP2D6

33
Q

how do CYP2D6 polymorphisms influence metabolism of nortryptyline?

A

1 CYP2D6 gene copy = high [nortryptyline] and therefore high therapeutic efficacy (though may get drug toxicity)
13 CYP2D6 gene copies = low [nortryptyline] and therefore very low therapeutic efficacy

34
Q

how do poor metabolisers of CYP2D6-metabolised drugs fare when given these drugs?

A

decreased metabolism of drugs results in high drug levels and an increased risk for an adverse drug reaction
OR
if the drug is a prodrug requiring metabolic activation by CYP2D6 then the drug will have no therapeutic effect

35
Q

how do ultrarapid metabolisers of CYP2D6-metabolised drugs fare when given these drugs?

A

very high drug metabolism results in decreased therapeutic effect of drugs at normal drug dose

36
Q

is CYP2D6 gene testing currently carried out before treatment with CYP2D6-metabolised drugs?

A

no, as few studies have shown a clear benefit of CYP2D6 genotyping in a clinical setting

37
Q

what effect can polymorphisms have on disease susceptibility with relation to drugs?

A

the existence of polymorphisms in many drug targets, bio transforming enzymes or transporters may effect susceptibility to disease

38
Q

what is MDR1?

A

an ATP-dependent efflux pump (of the ATP-binding cassette ABC transporter family) with broad substrate specificity, expressed in the colon, liver, kidney and blood brain barrier

39
Q

what common MDR1 polymorphism is associated with inflammatory bowel disease?

A

an Ala893 variant

40
Q

why is the Ala893 variant in MDR1 associated with inflammatory bowel disease?

A

the Ala839 variant is associated with decreased MDR1 activity when compared to the 839Ser variant, resulting in decreased removal of harmful substances and therefore increased risk of IBD

41
Q

when are you likely to see an adverse drug reaction?

A

when the drug has a narrow therapeutic window or when the drug is metabolised by a single enzyme pathway (i.e. there is a lack of redundancy)

42
Q

an adverse drug reaction to which drug can clinically resemble primary biliary cirrhosis?

A

augmentin

43
Q

what is augmentin?

A

i.e. amoxicillin/clavulanic acid or co-amoxiclav = an antibiotic useful in the treatment of bacterial infections

44
Q

what are the adverse toxic effects associated with augmentin?

A

hepatotoxicity - reversible cholestatic jaundice with lymphocyte infiltrates and immune damage to interlobular bile ducts

45
Q

an adverse drug reaction to augmentin is often fatal: true or false?

A

false - an adverse drug reaction to augmentin is rarely fatal

46
Q

what is thought to occur in patients with a genetic predisposition to an adverse drug reaction to augmentin?

A

they develop an immune-allergic reaction to augmentin, possibly due to the production of a novel metabolite with structural similarity to a self-antigen

47
Q

what are the 3 major drug-induced causes of liver toxicity?

A

augmentin, diclofenac and flucloxacillin

48
Q

what is flucloxacillin?

A

an antibiotic used in the treatment of staphylococcus infections

49
Q

what adverse drug reaction is associated with flucloxacillin?

A

cholestatic hepatitis (and therefore jaundice)

50
Q

1 in ___ cases of flucloxacillin are fatal without a liver transplant

A

20

51
Q

what is the primary risk allele associated with susceptibility to flucloxacillin drug-induced liver injury (DILI)?

A

the HLA*B5701 allele

52
Q

there is an ___-fold increased risk of flucloxacillin drug-induced liver injury if an individual has the HLA-_____ risk allele

A

there is a 80-fold increased risk of flucloxacillin drug-induced liver injury if an individual has the HLA-B*5701 risk allele

53
Q

the HLA-B*5701 is also a risk allele for an adverse drug reaction to which drug?

A

abacavir, a HIV-1 antiviral

Genetics of Complex Disease (6 decks)

Brainscape helps you reach your goals faster, through stronger study habits.
© 2024 Bold Learning Solutions. Terms and Conditions