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Adv Pharmacogenetics PED3005 > Receptor and other drug target pharmacogenetics > Flashcards

Receptor and other drug target pharmacogenetics Flashcards

1
Q

what is the difference between polymorphisms in receptor and in metabolic proteins

A

you don’t see complete absence of the protein in receptors

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2
Q

what is the two ways that polymorphism can affect G-protein linked receptors

A

Either the receptor or the coupling process of the G-protein

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3
Q

How are polymorphism studied compared to metabolic

A
  • Not able to study phenotype in same way as metabolic
  • scanning genes by sequencing
  • can use knock out mice (maybe?)
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4
Q

How is coding sequences used to study polymorphisms

A

Express variant in suitable cell line and compare function (response to
agonist or antagonist) with wild-type

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5
Q

How are upstream polymorphism used to study polymorphisms

A
  • reporter genes (luciferase) are place in a promoter region and then placed in a vector and transfected into cell line
  • can use alkaline phosphatase (less sensitive, No need to lyse cell as product in released into medium)
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6
Q

What is B2-adrenergic receptor

A

-product of introless gene with coding region of 1239bp

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7
Q

what are the polymorphisms in the coding region of with B2-adrenergic receptors

A

9 known polymorphisms, resulting with 4 amino acid substitutions
Arg16Gly
Gln27Glu
Val34Met
Thr164Ile

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8
Q

what is the polymorphism in the leader peptide of B2-adrenergic receptor

A

Arg19Cys

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9
Q

how many upstream polymorphism are associated with B2-adrenergic receptor

A

7

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10
Q

what is a haplotype

A

combination of alleles on a
particular chromosome. Often will get linkage
with some polymorphisms occurring together

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11
Q

What are the 3 common haplotypes of B2-adrenergic receptor in Europeans

A

2,4 & 6

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12
Q

What haplotypes of B2-adrenergic receptor are seen in African americans

A

1 is also common as well as 4 and 6
2 is rare

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13
Q

What haplotype of B2 adrenergic receptor has the smallest change in FEV when B agonist is administered

A

4/4
both AA at 16 is arginine

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14
Q

What haplotype of B2 adrenergic receptor has the largest change in FEV when B agonist is adminstered

A

4/6
One AA at 16 is arginine and one is glycine

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15
Q

which haplotype of B2-adrenergic receptor responed better to placebo than to salbutamol

A

4 - Arg

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16
Q

where are B1 receptors mainly located and what are the main type of drugs associated

A
  • in the adrenoreceptor in the heart
  • b blockers = Atenolol
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17
Q

what is the main polymorphism associated with B1 adrenoreceptors and what is the frequency of theses variants

A
  • Gly389Arg amino acid
  • Gly variant has frequency of 0.26, Arg 0.74
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18
Q

what is the effect of Gly389Arg polymorphism in B1-adrenorecptors

A

Arg form shows enhanced Gs protein interaction and increased adenyl
cyclase activation

19
Q

what is the pharmacological effect B1 adrenergic receptor polymorphims

A

Patients homozygous for the Arg have a better response to metoprolol

20
Q

what is the gene for the enzyme for coumarin anticoagulants (warfarin)

A

VKORC1

21
Q

what is the protein which is the target for warfarin

A

Vitamin K epoxide reductase

22
Q

True/False - There should be no difference between patients in the dosing of warfarin to achieve good clotting

A

False - individuals have varying doses
there are also some patients who are warfarin resistant

23
Q
A
24
Q

what is the normal dose of warfarin

A
  • 5 mg/day
  • each patients should be titrated to measure clotting though
25
Q

what is the vitamin K cycle

A

-Vitamin K is needed as a cofactor for carboxylase enzyme
- the process to make the clotting factors then generates vitamin K epoxide
- this must be regenerated to Vit K by VKOR

26
Q

what is the two polymorphisms in VKORC1

A

G1639A - in upstream region
C1173T - in the first intron

27
Q

how many exons are in VKORC1 and how

A

3

28
Q

True or false -Polymorphisms in VKORC1 are inherited independently

A

False, due to small size, two polymorphism are almost always inherited together

29
Q

G-1639A and C1173T form part of haplotype associated with __ warfarin dose

A

lower

30
Q

which VKORC1 haplotype has higher expression of VKOR

A

Homologous for wildtype

31
Q

In the overall population, what is most people’s genotype (VKORC1)

A

Heterozygous

32
Q

what is the only group of people who can take more than 8mg warfarin per day

A

homozygous for wildtype

33
Q

what is warfarin resistance

A

patients doesn’t respond to W or needs unusually high dose (>10mg/day)
- Normally its due to non-compliance
- some patients have mutations in coding region of VKORC1
- affects W binding but not Vit K epoxide reduction

34
Q

True or false - due to few mutation which could cause pharmacodynamic warfarin resistance, population frequency is very low

A

False
There are several mutation
This means screening prior to treatment is not considered due to rarity

35
Q

What is the mutation which is more common in Isreal, Egypt and Ethiopia which can cause warfarin resistance

A

D36Y

36
Q

What are the two genes which effects warfarin dose

A

CYP2C9 & VKORC1

37
Q

Which of the two genotypes relating to Warfarin dose, causes a patient to require the highest dose

A

Wildtype - CYP2C9
Wildtype - VKORC1

38
Q

Effects of VKORC1 genotype affecting warfarin dose is seen less in subjects with CYP2C9(2/3) or CYP2C9(3/3) why ?

A

There are less people who have these genotypes therefore less variation

39
Q

All cystic fibrosis patients have defect in __ gene which codes for __ involved in __ transport

A

CFTR
ion channel
Cl-

40
Q

what is the most common genetic defects involved in Cystic fibrosis

A

F508 (single amino acid [phenylalanine] deleted)
so the protein is not inserted into the cell membrane

41
Q

5% of patients have this genetic polymorphism which causes the channel to reach the cell surface but not transport Cl-

A

G551D - channel no longer responds to ligand

42
Q

what is the cellular effect of the Cystic fibrosis polymorphism Class 3 (G551D)

A

missense mutation results of AA substitution which disrupts regulation of teh CRFT channel

43
Q

which drug reverses the G551D mutation in CRFT channel

A

Ivacaftor

Adv Pharmacogenetics PED3005 (11 decks)

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