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Pharmacology > Pharmacogenomics > Flashcards

Pharmacogenomics Flashcards

1
Q

people can have the same diagnosis and symptoms but

A

response to drugs differently

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2
Q

what are the 3 rights

A

need to provide the RIGHT treatment to the RIGHT patient at the RIGHT dose

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3
Q

pharmacogenomics

A

describes the interaction between drugs and the whole genome

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4
Q

pharmacogenetics (Vogel in 1959)

A

Study of genetically determined variations that are revealed solely by the effects of drugs

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5
Q

pharmacogenetics now

A

influence of genes on the efficacy and side effects of drugs

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6
Q

what does genetic variation effect

A

pharmacokinetics and pharmacodynamics and also cause idiosyncratic reactions

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7
Q

are introns or axons larger

A

introns (displayed as the same size in models - inaccurate)

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8
Q

what are the 3 types of structural variations?

A

copy number variation, inversion and translocation

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9
Q

what is copy number variation?

A

where there is an increase or decrease in the amount of DNA
•deletion: where an entire block of DNA is missing
• insertion: where a block of DNA is added in
• duplication: where there are additional copies of a section of DNA.

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10
Q

What is inversion?

A

when a chromosome breaks in two places and the resulting piece of DNA is reversed and reinserted back into the chromosome (the opposite way round).

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11
Q

what is translocation?

A

when genetic material is exchanged between two different chromosomes.

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12
Q

which is the most common type of genetic variation in the human genome

A

SNP

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13
Q

what is an SNP

A

change in a single nucleotide base

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14
Q

how often would an SNP occur

A

1/300 bases

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15
Q

what type of SNPs are there in non-coding regions?

A

spliced, promotor activity or and unknown/no change

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16
Q

what type of SNPs are there in coding regions?

A

synonymous - no change - same AA

non-synonomus - miscense and non-sense

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17
Q

what does HGVS stand for

A

human genome variation society

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18
Q

what do g, c and p stand for in HGVS stand for

A

g - genomic sequence
c - cDNA sequence (complementary DNA/RNA)
p - protein sequence (AA’s)

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19
Q

what do SNP cluster IDs do

A

all SNPs have a unique rs number - used be researchers to refer to them

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20
Q

what is the star allele nomenclature used in?

A

pharmacogenetics only

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21
Q

what star is used for the WT

A

1*

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22
Q

what do 2/3/4* represent

A

allele with altered fractionally which may lead to profiles of increased or reduced drug metabolism

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23
Q

one single star allele one can identify

A

not just a single variant, but even a group of variants.

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24
Q

consequences of genetic variation on proteins can be

A

No change
• No function
• Diminished function
• Altered/gain of function

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25
Q

estimated hospital patients that will have adverse drug reactions

A

15%

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26
Q

what helps to identify genetic profiles of patients who are more likely to suffer adverse events

A

PGx

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27
Q

Examples of drugs that can cause adverse events include

A

soniazid, Codeine Diclofenac, Statins, Warfarin, Carbamazepine
(anticonvulsant), Flucloxacillin etc

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28
Q

Adverse drug reactions can be

A

idosyncratic or caused by changes in the pharmacokinetics, pharmacodynamics of drug

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29
Q

what is abacavir and what is it used for?

A

a reverse transcriptase inhibitor which is used to treat HIV

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30
Q

% patients that show fatal hypersensitivity to abacavir?

A

5%

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31
Q

idiosyncratic reaction

A

Cannot relate to how it is metabolised in the body

does not occur in most patients at any dose and does not involve the known pharmacological properties of the drug

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32
Q

in 2002 which allele was found to have a strong association with abacavir hypersensitivity

A

HLA-B*57:01

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33
Q

where would you find whether you needed testing for a drug

A

on an information label

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34
Q

Pharmacokinetics

A

absorption, distribution, metabolism, excretion

what body does to the drug

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35
Q

pharmacodynamics

A

drug action and mechanism

what the drug does to the body

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36
Q

absorption

A

the process of a substance entering the blood circulation

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37
Q

distribution

A

the dispersion or dissemination of substances throughout the fluids and
tissues of the body

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38
Q

metabolism

A

the recognition by the organism that a foreign substance is present and the irreversible transformation of parent compounds into daughter metabolites.

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39
Q

excretion

A

the removal of substances from the body

40
Q

which part of pharmacokinetics is th focus for pharmacogenetics

A

metabolism

41
Q

phase 1 metabolism

A

hydrolysis or most commonly oxidation. Oxidation by cytochrome P450 enzymes

42
Q

phase 2 metabolism

A

conjugation - that is, the attachment of an ionised group to the drug - include glutathione, methyl, Sulfyl or acetyl groups.

43
Q

CYP2D6 (Cytochrome P450 D6)

A

in phase 1 metabolism

Beta-blockers Tricyclic antidepressants Codeine metabolism

44
Q

CYP2C9 (Cytochrome P450 D9)

A

oxidation i phase 1 metabolism of warfarin

45
Q

NAT2 (N-acetyltransferase2)

A

acetylation in phase 2 of metabolism - isoniazid (Tuberculosis)

46
Q

what are the types of metabolisers?

A

Ultra rapid metaboliser
• Extensive metaboliser
• Intermediate metaboliser
• Poor metaboliser

47
Q

what are the 2 types of drugs?

A

Prodrugs– eg Codeine

• Active drugs – eg Warfarin

48
Q

which enzyme metabolises codine

A

CYP2D6

49
Q

CYP2D6 gene is

A

highly polymorphic, with more than 100 star (*) alleles described

50
Q

why would pain relief in poor metabolisers of codine be inadequte

A

they don’t have the enzyme/enough to convert codine-morphine which is the active comound

51
Q

what may ultra metabolisers of coding experience?

A

morphine overdose symptoms

52
Q

what are thiopurine methyltransferases?

A

Cytoplasmic enzyme that methylates THIOPURINES to an inactive, non toxic form.

53
Q

examples of thiopurine methyltransferases

A
  • 6-mercaptopurine
    – 6-thioguanine
    – azothipurine
54
Q

what are thiopurine methyltransferases used for?

A

treatment of inflammatory and autoimmune disease, leukaemia and to prevent rejection post organ transplant

55
Q

what are the side effect of thiopurine methyltransferases?

A
  • life threatening bone marrow suppression - neutropenia
  • hepatotoxicity
  • nausea and vomitting
  • pancreatitis
56
Q

what affect would you get if you ultrametaboliser of warfarin?

A

no effect - metabolise the active drug to quikcly

57
Q

what % of the population has normal TPMT enzyme activity?

A

89%

58
Q

what % of the population has low TPMT enzyme activity?

A

11%

59
Q

what % of the population has undetectable TPMT enzyme activity?

A

0.3%

60
Q

The TPMT*3A allele (low activity allele) is

A

bsent in the Chinese population, however its frequency in

Caucasians is approximately 4%. (Low activity)

61
Q

genotype specific dosing can allow

A

similar (and non-toxic) levels to be achieved for a drug

62
Q

what is recommended for dosing azothiopurine?

A

genotyping - DNA test

isn’t mandatory

63
Q

when would you consider alternative medication to azothiopurine?

A

Homozygous for low activity variant – consider alternative medication or 10% of standard dose

64
Q

what % of british people have low activity alleles for TPMT?

A

10%

65
Q

Patients with undetectable TPMT activity are generally

A

not treated with these drugs

66
Q

Those with low activity usually receive

A

a reduced dose

67
Q

Normal enzyme levels have

A

standard dose

68
Q

Genotyping in some circumstances…

A

Deficient TPMT activity
– Recent blood transfusion
– Previous severe reaction to thiopurine drugs
– Change in TPMT status on repeat testing

69
Q

TMPT levels do not predict

A

all adverse reactions to thiopurines

70
Q

Phenotype versus genotype - TPMT

A 
Enzyme test (phenotype), can be affected by blood transfusions and
other drugs
– Genotype test – quick and easy but rare variants can be missed.
71
Q

what do statins do?

A

reduce cholesterol levels

72
Q

adverse affect to statin

A

1-5% of patients exposed experience skeletal muscle toxicity.
-Myalgias (pain)
• Myopathy (pain with evidence of muscle degradation)
• Rhabdomyolysis (severe muscle damage with acute kidney injury)

73
Q

OATP1B1 transporter

A

facilitates the hepatic uptake of statins

encoded by the SLCO1B1 gene

74
Q

what kind of genetic variation can effect drug targets?

A

enzymes, receptors and ion channels, and their associated pathways

75
Q

what is malignant hyperthermia?

A

an autosomal dominant disorder of the skeletal muscle

Characterized by muscle rigidity and a hyper-metabolic state (high temperature)
• Can cause death if not treated promptly

76
Q

what triggers malignant hyperthermia

A

volatile anaesthetics (e.g.halothane) and depolarizing muscle relaxants

77
Q

what causes 50-70% of malignant hyperthermia?

A

mutation of the ryanodine receptor (type 1) (RYR1)

78
Q

how would you test for malignant hyperthermia?

A

muscle biopsy
n-vitro contracture test (IVCT).
– Living muscle tissue is exposed to halothane and caffeine following a standard protocol

79
Q

normal muscle v MH muscle

A

Normal muscle will relax when exposed to halothane whereas MH muscle will contract and this can be measured.
– MH muscle is more sensitive to caffeine and will contract at much lower concentrations than normal muscle.

80
Q

MH genetic testing

A

available in leeds

Positive genetic test = no muscle biopsy • Safe anaesthesia
• No scar, no discomfort, cheaper test,
– Negative genetic test = muscle biopsy still required

81
Q

what is neonatal diabetes

A

A form of diabetes that is diagnosed under the age of nine months (not an autoimmune condition)
• Some patients have neurological problems: – Developmental delay
– Epilepsy (<12 months)

82
Q

how would you treat neonatal diabetes?

A

First line treatment is insulin, however in certain individuals sulphonylureas can be used

83
Q

insulin is released through which receptor in response to

A

though the GLUT2 receptor in response to glucose

84
Q

insulin secretnion

A

ATP generated causes KATP channel on the cell membrane to close
• Membrane depolarisation
• Ca2+ influx
• Insulin release through GLUT2 receptor

85
Q

what causes neonatal diabetes?

A

a mutation in the Katp gene

86
Q

what are the benefits of identifying Katp in NDM

A

95% of patients with Katp channel mutations can be treated with sulphonylureas

Glucose values fluctuate less as well as being lower
• Neurological function may improve
• Sulphonylureas = tablets
• Insulin =injection

87
Q

what are the benefits of identifying Katp in NDM

A

95% of patients with Katp channel mutations can be treated with sulphonylureas

Glucose values fluctuate less as well as being lower
• Neurological function may improve
• Sulphonylureas = tablets
• Insulin =injection

88
Q

what pedigree of disease is cystic fibrosis?

A

autosomal recessive

89
Q

cystic fibrosis is fatal among

A

caucasian populations

90
Q

CF is caused by a mutation in

A

CFTR gene on chromosome 7

91
Q

what is the phenotype for CF?

A

malfunctioning epithelial ion channel - CF transmembrane conductance regulator protein

92
Q

what does the CFTR usually do?

A

regulated the absorption and secretion of salt and water in various tissues

93
Q

what do type 3 mutation in th CFTR gene/protein do? which drugs treat this?

A

impaired normal channel gating activity

vacaftor / Kalideco / VX-770 ameliorates the gating defect

94
Q

Ivacaftor

A

Effective therapy for patients with type 3 CFTR mutations including the p.Gly551Asp mutation

In trials when compared with placebo:
– Ivacaftor significantly improved FEV1 by 10.6% over 48 weeks
– Subjects also were 55% less likely to have a pulmonary exacerbation
– gained more weight

95
Q

what do Lumicaftor/Orkambi treat

A

cystic fibrosis

Effective therapies for patients bearing p.Phe508 mutation (type 2) would act to improve protein folding, channel gating and cell surface stability.
– Lumicaftor / VX-809 partially rescues processing defect
– Lumicaftor / Kalideco / VX-770 then can ameliorate the gating defec

Pharmacology (18 decks)

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