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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

A
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
Q

how do genetic polymorphisms affect pharmacokinetics?

A

genetic variation typically affecting drug metabolism and transport
- absorption
- distribution
- metabolism
-excretion

26
Q

how do genetic polymorphisms affect pharmacokinetics?

A
  • receptors (eg binding)
  • ion channels
  • enzymes
  • immune system
27
Q

3 types of genetic variation affecting drug response classed according to stage

A
  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
Q

pharmacokinetic variation definition

A

genetic variation typically affecting drug metabolism (eg enzymes) and transport (eg transport proteins)

29
Q

slide 40 not sure

A
30
Q

what is plasma clearance

A

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
Q

where does most metabolism occur?

A

in liver

32
Q

phase 1 metabolism

A

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
Q

phase 2 metabolism

A

conjugation - covalent binding to an endogenous substrate
- sulphation, glucuronidation, acetylation
- produces highly polar molecule to readily be excreted in urine
- usually inactivates drug

34
Q

what is SCC? How is it metabolised?

A

Succinylcholine - muscle relaxant drug.
metabolised by butyrylcholinesterase via hydrolysation - inactivates SCC

35
Q

BCHE (butyrylcholinesterase) deficiency issue and cause

A
  • prolonged SCC action, leads to paralysis, respiratory failure
    -defect is a structurally altered enzyme
36
Q

variants to BCHE (butyrylcholinesterase)

A
  • 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
Q

alcohol metabolism

A
  • alcohol (ethanol) is converted to acetaldehyde by alcohol dehydrogenase.
  • acetaldehyde is toxic
  • aldehyde dehydrogenase converts acetaldehyde into acetate
38
Q

what does ADH1B*2 do?

A
  • 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
Q

what is ALDH2*2 mutation?

A
  • 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
Q

CYP450 enzymes 3 main families

A

CYP1, CYP2, CYP3
- CYP3A4 metabolises most drugs but contains fewer SNPs

41
Q

what are CYP450

A
  • 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
Q

CYP2D6 metabolisers

A
  • 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
Q

what do polymorphisms in CYP2D6 determine?

A

the success/failure of drug and/or possibility of adverse reaction

44
Q

how to monitor for presence or absence of CYP SNPs?

A

roche amplichip P450 array. Determines genotypes for alleles of selected CYP genes

45
Q

NAT2 gene has several alleles (variants) - what does this mean? What are they?

A

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
Q

how do you determine a modified isoniazid dose?

A

test acetylator status using sulphadimidine (non toxic)

something else on slide to understand

47
Q

pharmacodynamic variation definition

A

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
Q

warfarin

A
49
Q

cover ryanodine receptor

A

APO611 (5 decks)

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