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APO611 > Pharmacogenomics and individualised medicine > Flashcards

Pharmacogenomics and individualised medicine Flashcards

1
Q

How do we define pharmacogenomics?

A

The study of how an individual’s genetic makeup affects the drugs responses, eg
- drug transport
- drug metabolism
- drug target

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2
Q

How do we define individualised medicine?

A
  • medical decisions and treatments tailored for an individual patient
  • specific drugs that targets a biomarker in a specific disease - must also consider how an individual responds to specific drug treatments
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3
Q

What do we mean by pharmacokinetic variation? Give 3 examples.

A
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4
Q

What do we mean by pharmacodynamic variation? Give 3 examples

A
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5
Q

Can you relate pharmacogenetics to the intolerance seen in subsets of patients to specific
drugs in terms of pk/pd variation ? e.g. alcohol, codeine ?

A
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6
Q

Why is it important to consider pharmacogenetics in drug design?

A
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7
Q

what are SNPs?

A
  • single nucleotide polymorphisms - single nucleotide changes
  • occur every 300-1000bp means up to ~20million SNPs in diploid genome
  • can occur anywhere
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8
Q

how can SNPs affect proteins?

A

may affect transcription, translation, stability, localisation or activity of protein
can affect activity of metabolic enzyme

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9
Q

what is copy number variation?

A
  • change in number of gene copies - often alters protein expression
  • affects segments of DNA >1000bp long
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10
Q

how to measure gene copy number?

A

oligo array comparative genomic hybridisation

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11
Q

how does CNV analysis work?

A
  • label patient DNA samples and control (reference) samples with
    diff fluorophores (red and green)
  • take equal amounts of DNA samples and mix
  • add to array (array contains probes for whole human genome and can be sorted into chromosomes)
  • control binds to probes
  • patient sample DNA binds to probes if patient has more copies of gene
  • equal copies = yellow spot
  • patient has more = green fluorescence
  • patient has less than control = red fluorescence
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12
Q

what are GWAS?

A

Genome Wide Association Studies
- associations between specific genetic variations and specific physical traits
- compare large populations

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13
Q

how do GWAS work?

A
  • array based technique to look at over a million SNPs
  • probes attached to slide are designed to be complimentary to the genome that is near a particular SNP and ends before the SNP is question
  • short probe strand has a fluorescently tagged nucleotide attach that compliments SNP, colour of nucleotide shows SNP
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14
Q

how are GWAs useful?

A
  • look for particular DNA changes that might be important in a drug response
  • can then tailor treatment of dose of particular drug
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15
Q

what are gene environment interactions?

A
  • the interplay between genes/genotype and the environment
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16
Q

gene-environment interaction example?

A

eg, toxic chemical formaldehyde causes degradation of the BRCA1 tumour suppressor
- BRCA1 heterozygous individuals are more susceptible to breast cancer

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17
Q

what are xenobiotics?

A

chemical that is foreign to body, drugs are an example.

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18
Q

in what ways are xenobiotics modified/metabolised in the body?

A
  • oxidation
  • methylation
  • glutathionalyation
  • glucuronidation
  • reduction
  • acetylation
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19
Q

pharmacogenomics aims (3)

A

aims to
- identify patients that will respond to treatment
- identify patients that will not respond to treatment
- identify patients that will respond adversely to treatment
- make dosing options safer
- decrease health care costs
- improve drug development

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20
Q

G-6-PD pathway, normal vs. deficient

21
Q

common G-6-PD variants

A
  • x-linked (males)
  • more prevalent in countries with high rates of malaria and is potentially protective
  • more prevalent in people with diets rich with oxidants
  • > 200 SNPs cause it
22
Q

define pharmacokinetics

A

what your body does to the drug - absorption, distribution, metabolism and excretion (ADME)

23
Q

define pharmacodynamics

A

what the drug does to your body - the relationship between the concentration of a drug at its site of action and the observed biological effects

24
Q

why is metabolism important in pharmacokinetics?

A

metabolism influences drug concentration at site of action

25
how do genetic polymorphisms affect pharmacokinetics?
genetic variation typically affecting drug metabolism and transport - absorption - distribution - metabolism -excretion
26
how do genetic polymorphisms affect pharmacokinetics?
- receptors (eg binding) - ion channels - enzymes - immune system
27
3 types of genetic variation affecting drug response classed according to stage
1. Variation affecting drug metabolism/transport (ADME) – pharmacokinetic variation (what your body does to the drug) 2. Variation affecting drug targets or associated pathways – pharmacodynamic variation (what the drug does to your body) 3. Variation associated with idiosyncratic adverse drug events – not related to the known pharmacological properties of drug. Rare and unpredictable. Often immune-mediated.
28
pharmacokinetic variation definition
genetic variation typically affecting drug metabolism (eg enzymes) and transport (eg transport proteins)
29
slide 40 not sure
30
what is plasma clearance
measures ability of body and all metabolising systems to remove a drug eg fast/slow metabolism - therapeutic effect will depend on whether active agent is parent drug or metabolite
31
where does most metabolism occur?
in liver
32
phase 1 metabolism
addition of functional groups to the drug, making metabolite more polar - includes oxidation, reduction, hydrolysis - generally inactivates drug, sometimes activates - products of phase 1 often undergo conjugation via phase 2
33
phase 2 metabolism
conjugation - covalent binding to an endogenous substrate - sulphation, glucuronidation, acetylation - produces highly polar molecule to readily be excreted in urine - usually inactivates drug
34
what is SCC? How is it metabolised?
Succinylcholine - muscle relaxant drug. metabolised by butyrylcholinesterase via hydrolysation - inactivates SCC
35
BCHE (butyrylcholinesterase) deficiency issue and cause
- prolonged SCC action, leads to paralysis, respiratory failure -defect is a structurally altered enzyme
36
variants to BCHE (butyrylcholinesterase)
- heterozygous - enzyme with altered affinity or decreased quantity - prolonged response - homozygous - prolonged response of 3-4 hours - silent variant - no cholinesterase activity (very rare)
37
alcohol metabolism
- alcohol (ethanol) is converted to acetaldehyde by alcohol dehydrogenase. - acetaldehyde is toxic - aldehyde dehydrogenase converts acetaldehyde into acetate
38
what does ADH1B*2 do?
- alcohol dehydrogenase mutation - contains a variant beta 2 subunit instead of the usual beta 1 subunit (Arg47His) - alcohol dehydrogenase 1B*2 creates more active enzyme in metabolising alcohol into toxic acetaldehyde. - prevalent in japanese and chinese
39
what is ALDH2*2 mutation?
- aldehyde dehydrogenase mutation of inactivation - loss of activity therefore increase acetaldehyde (toxic) - 50% of japanese and chinese - acetaldehyde is a carcinogen - increased oral cancer and head and neck cancer
40
CYP450 enzymes 3 main families
CYP1, CYP2, CYP3 - CYP3A4 metabolises most drugs but contains fewer SNPs
41
what are CYP450
- chromosome P540 superfamily organised into 18 families and 43 sub families - oxidation of drugs - major class of metabolic enzymes - expressed mainly in liver and GI tract
42
CYP2D6 metabolisers
- poor metabolisers have CYP2D6 variants that code for enzyme with reduced activity or reduced expression - ultra rapid metabolisers are often due to gene amplification - vary in diff populations, eg ultra rapid metabolisers - 21% saudi arabians, 29% ethiopians - ultra-rapid metabolisers may require higher dose of drug, see notes for Nortriptyline
43
what do polymorphisms in CYP2D6 determine?
the success/failure of drug and/or possibility of adverse reaction
44
how to monitor for presence or absence of CYP SNPs?
roche amplichip P450 array. Determines genotypes for alleles of selected CYP genes
45
NAT2 gene has several alleles (variants) - what does this mean? What are they?
affect rate of isoniazid (drug for TB) acetylation (other drugs: hydralazine (hypertensive) and procainamide (antiarrhythmic) - rapid acetylator - allele considered wild-type - slow acetylator (reduced enzyme activity) - alleles have SNPs --> increased levels of parent drug compound - increased levels of parent compound (isoniazid) are toxic - lead to neuropathy and liver damage
46
how do you determine a modified isoniazid dose?
test acetylator status using sulphadimidine (non toxic) something else on slide to understand
47
pharmacodynamic variation definition
genetic variation in target or associated component of signalling pathway eg, polymorphisms in genes encoding drug targets (receptors) may explain some of the variation in drug sensitivity
48
warfarin
49
cover ryanodine receptor

APO611 (5 decks)

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