2nd Dec - Pharmacogenomics

Question 1

List some factors as to why efficacy of medical treatment varies

Answer 1

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

Question 2

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

Answer 2

Trial and error

Question 3

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

Answer 3

Leads to adverse drug reactions (ADR)s

Question 4

What are ADRs?

Answer 4

Adverse drug reactions

Question 5

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

Answer 5

6-7%

Question 6

What are the most common major ADRs?

Answer 6

Heart Problems
Liver Failure
Dermatological problems
Kidney failure

Question 7

What are the most common minor ADRs?

Answer 7

Minor rash
Abdominal discomfort
Dry mouth
Drowsiness
Headache
Nausea

Question 8

What is pharmacogenetics?

Answer 8

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

Question 9

What is pharmacogenomics?

Answer 9

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

Question 10

When was the human genome project completed?

Answer 10

2003

Question 11

What percentage of DNA is shared between all humans?

Answer 11

99.7%

Question 12

What is a polymorphism?

Answer 12

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

Question 13

What is a mutation?

Answer 13

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

Question 14

What is a haplotype?

Answer 14

Set of associated SNP alleles in a region of a chromosome

Question 15

What can be used to identify these haplotypes?

Answer 15

tag SNPs

Question 16

What is HapMap?

Answer 16

A project to develop a huge haplotide map of sequence variation

Question 17

Why is pharmacogenomics not routinely used in medicine?

Answer 17

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

Question 18

What are the advantages of using pharmacogenomics?

Answer 18

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

Question 19

What are the disadvantages of using pharmacogenomics?

Answer 19

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

Question 20

What is pharmacokinetics?

Answer 20

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

Question 21

Why is cytochrome p450 important in pharmacogenomics?

Answer 21

Involved in the metabolic resistance to xenobiotics

P450 polymorphisms are associated with drug effectiveness of Clopidogrel and codeine

Question 22

What is clopidogrel?

Answer 22

An anti-thrombotic

Question 23

How is clopidogrel metabolised?

Answer 23

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

Question 24

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

Answer 24

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

Question 25

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

Answer 25

Pasugrel - metabolized by alternative pathways | Ticagrelor - direct reversible P2Y12 receptor antagonist

Question 26

What is the clinical use for codeine?

Answer 26

Analgesic Cough Diarrhoea

Question 27

How is codeine metabolised?

Answer 27

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)

Question 28

Why is CYP2D6 mutation important in codeine use?

Answer 28

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

Question 29

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

Answer 29

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

Question 30

What is pharmacodynamics?

Answer 30

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

Question 31

What is salbutamol?

Answer 31

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

Question 32

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

Answer 32

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

Question 33

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

Answer 33

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

Question 34

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

Answer 34

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