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BS3054 > 2nd Dec - Pharmacogenomics > Flashcards

2nd Dec - Pharmacogenomics Flashcards

1
Q

List some factors as to why efficacy of medical treatment varies

A 
Disease
Age
Gender
Smoking
Genetic Factors
Lifestyle
Body mass
Co-medication
Environmental agents
Diet
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2
Q

How do most physicians currently optimise a dosage regime for an individual patient?

A

Trial and error

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3
Q

What is the major disadvantage of using trial and error to optimise a dosage regime?

A

Leads to adverse drug reactions (ADR)s

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4
Q

What are ADRs?

A

Adverse drug reactions

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5
Q

What percentage of hospital admissions in the UK are due to ADRs?

A

6-7%

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6
Q

What are the most common major ADRs?

A

Heart Problems
Liver Failure
Dermatological problems
Kidney failure

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7
Q

What are the most common minor ADRs?

A 
Minor rash
Abdominal discomfort
Dry mouth
Drowsiness
Headache
Nausea
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8
Q

What is pharmacogenetics?

A

The study of the relationship between individual gene variants and drug effects

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9
Q

What is pharmacogenomics?

A

The study of the relationship between variation in a large collection of genes and variable drug effects

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10
Q

When was the human genome project completed?

A

2003

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11
Q

What percentage of DNA is shared between all humans?

A

99.7%

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12
Q

What is a polymorphism?

A

Any difference in DNA that occurs in >1% of the population

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13
Q

What is a mutation?

A

Difference in DNA that occurs in <1% of the population

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14
Q

What is a haplotype?

A

Set of associated SNP alleles in a region of a chromosome

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15
Q

What can be used to identify these haplotypes?

A

tag SNPs

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16
Q

What is HapMap?

A

A project to develop a huge haplotide map of sequence variation

17
Q

Why is pharmacogenomics not routinely used in medicine?

A

Limited data in the public domain
Market fragmentation would not be attractive to Big Pharma
Many genetic variations are not of clinical significance
Test expense is high about £10 000 per patient
Ethical issues as it would be difficult to prevent discrimination
Issue of information delivery to the GP

18
Q

What are the advantages of using pharmacogenomics?

A

Personlised medicine allows focused treatment, minimises ADRs, allows the use of drugs in an ADR free group (for drugs that were previously excluded due to ADRs), reduction of medical costs due to wasted medication

19
Q

What are the disadvantages of using pharmacogenomics?

A

Ethical issues, i.e. it being used for discrimination

Big Pharma may chose only to invest in more frequent genetic variations or in those belonging to the rich

20
Q

What is pharmacokinetics?

A

What the body does to the drug, i.e. how the drug is absorbed, distributed, metabolized and eliminated

21
Q

Why is cytochrome p450 important in pharmacogenomics?

A

Involved in the metabolic resistance to xenobiotics

P450 polymorphisms are associated with drug effectiveness of Clopidogrel and codeine

22
Q

What is clopidogrel?

A

An anti-thrombotic

23
Q

How is clopidogrel metabolised?

A

15% –> Active metabolite (Part of which is metabolized by CYP450 family enzyme CYP2619)
85% –> inactive metabolite

24
Q

Why are 20-40% of patients unresponsive to clopidogrel?

A

Due to varying degrees of CYP2619 mutations which lead to cardiovascular accidents

25
Q

What is the alternative treatment to clopidogrel for patients with mutations in CYP2619?

A

Pasugrel - metabolized by alternative pathways

Ticagrelor - direct reversible P2Y12 receptor antagonist

26
Q

What is the clinical use for codeine?

A

Analgesic
Cough
Diarrhoea

27
Q

How is codeine metabolised?

A

10-15% to Narcodeine by a CYP450 protein
50-70% to Codeine-6-glucorinide (active)
0-15% to Morphone (active) by CYP2D6 (a CYP450 protein)

28
Q

Why is CYP2D6 mutation important in codeine use?

A

As the active metabolites codeine, narcodeine and codeine-6-glucorinide all have the same affinity for mu1 opiod receptors, however morphine has a 200x greater affinity, which is catalysed by CYP2D6.

Thus a mutation in CYP2D6 could cause ineffective pain relief or morphine intoxication

29
Q

How can one prevent morphine intoxication by the administration of codeine and ineffectiveness of clopidogrel?

A

An array chip has been developed to determine genotypes of alleles of selected CYP2D6 (Codeine) genes and CYP2C19 (Clopidogrel) genes, to give predictive genotyping.

30
Q

What is pharmacodynamics?

A

What the drug does to the body i.e. modification of the drug target

31
Q

What is salbutamol?

A

A short acting beta 2 adrenergic receptor agonist that mediates vasodilation, lipolysis and bronchodilation

32
Q

How can mutations in Beta 2 adrenergic receptor alter salbutamol function?

A

Altered response to salbutamol - heterozygotes for Gly16 appear to be more responsive to salbutamol than homozygotes

Adverse effects of salbutamol - Arg16 homozygotes have decreased lung function with regular salbutamol administration compared to as needed administration

33
Q

How was it identified that the in vivo response to salbutamol is dependent on beta 2 adrenergic receptor halotypes?

A

Measured FEV1’s before and after salbutamol inhalation and found the response was significantly related to beta 2 adrenoceptor genotype

34
Q

How does the beta1 adrenergic receptor genotype effect survival after Bucinolol treatment?

A

Performed a beta blocker evaluation of survival test (BEST)

Arg389 Homozygous had increased survival with bucinolol
Gly 389 had no effect on survival with bucinolol

Used site directed mutagenesis to recreate Arg389 SNP. Found that Arg389 had higher basal activity and 3x increase in agonist stimulated activity –> arg 289 provides enhances stabilisation of the active conformation

BS3054 (25 decks)

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