Lecture 01 Introduction

Question 1

Define: Personalised Medicine

Answer 1

Customisation of healthcare with decisions and treatments tailored to each individual patient

Question 2

Define: Pharmacogenomics

Answer 2

Part of personalised medicine. The study of how a person’s genes influences their response to medications.

Question 3

Give an example of a genetic polymorphism that influence drug responses

Answer 3

Cytochrome p450 - a drug metabolising enzyme

Question 4

Why is personalised medicine of clinical importance?

Answer 4

Increased importance since the human genome project was completed in 2003.
5% of hospital admissions are due to adverse drug reactions.
Personalised medicine can reduce trial and error prescribing, helping to control costs of health care and improve patient outcomes

Question 5

Give examples of personalised medicine using clinically today

Answer 5

1. Warfarin dosing
2. Familial Hypercholesterolaemia treatment
3. AlloMap Testing to prevent rejection of a heart transplant

Question 6

What is another name for Plavix?

Answer 6

Clopidogrel

Question 7

What does Plavix do? When is it prescribed?

Answer 7

Inhibits platelet aggregation

Given to patients post-MI

Question 8

Why might Plavix not work as well in some people?

Answer 8

1. Genetic factors, cytochrome p450 (cyp2c19) affects the drug metabolism. Low levels of the enzyme cause reduced levels of active drug. Genetic testing for cyp2c19 is required for accurate dosing.
2. Multi-drug interactions, e.g. Omeprazole

Question 9

Define: Inter-individual Variation

What two factors contribute to this?

Answer 9

Variation in concentrations of the drug at the site of action or different responses to the same concentration of drug

Pharmacodynamics and Pharmacokinetics

Question 10

Define: Pharmacokinetics

Answer 10

How fast a drug is metabolised within the body

Question 11

Define: Pharmacodynamic Variation

Answer 11

How an individual responds to a drug and how it is adjusted by monitoring physiological endpoints

Question 12

What are the factors that affect drug concentration?

What are the main causes of variability in drug responses?

Answer 12

1. Age
2. BMI
3. Gender
4. Ethnicity
5. Genetics/Genomics
6. Immunological Factors (drug intolerance)
7. Concomitant Disease
8. Multidrug Interactions
9. Pregnancy
10. Co-existing Medical Conditions

Question 13

How does drug concentration affect newborns?

Answer 13

Less efficient metabolism and elimination

Newborn GFR 20% that of an adult

Question 14

Define: Concomitant Disease

Answer 14

Liver or Kidney Diseases - affect the ability of the body to breakdown or eliminate the drug

Question 15

How does ethnicity affect drug variability?

Answer 15

1. Ethnic variation in genetics

2. Environmental Factors, e.g. diet

Question 16

Give an example of where ethnicity affects drug concentration

Answer 16

Hydralzaine and Nitrate Treatment in heart failure.

More effective in African-Americans over Caucasians

Question 17

Give an example of a genetic mutation that causes a disease

Answer 17

Inherited Thrombophilia - caused by a SNP in Factor V Leiden (a coagulation factor)

Question 18

What are the main causes of drug variability in the elderly?

Answer 18

1. Often less efficient metabolism and excretion

2. Often taking multiple drugs - polypharmacy

Question 19

How do multi-drug interactions cause problems?

Give examples of non-drug compounds that cause adverse-drug problems

Answer 19

e.g. Grapefruit Juice and Herbal Remedies

Can activate the release or molecules or activate enzymes

Question 20

Give two examples of pharmacodynamic (multi-drug) interactions

Answer 20

1. Diretics, used in heart failure to lower plasma potassium, predispose the patient to digoxin toxicity
2. Sildenafil, used as a vasodilator and potentiates the action of organic nitrates. Together leading to severe hypotension

Question 21

How has the Human Genome Project (HGP) affected pharmacogenomics?

Answer 21

10 years after completion of HGP, 104 drugs now have pharmacogenomic information on the label

Question 22

How many % of diabetes patients complain their drugs don’t work?

Answer 22

43

Question 23

What SNPs effect Warfarin metabolism?

Answer 23

CYP2C9 + VKORC genotyping for Warfarin dosing
CYP2C9 - the metabolism of warfarin (2 SNPs)
1* slow metabolisers / 2 or 3* fast metabolisers

VKORC - encodes the enzyme of the warfarin drug-target (1 SNP)
G-to-A mutation sensitises individual to warfarin

Question 24

What is the aim of warfarin treatment?

Answer 24

To keep the INR (International Normalised Ratio), a measure of blood coagulation, within a certain range.
Aim an INR of 2-3

Question 25

What happens if the INR goes outside this range?

Answer 25

Too low - coagulation and blood clotting

Too high - risk of bleeding

Question 26

Why is patient genotyping (CYP2C9 and VKORC) not always integrated into clinical practice?

Answer 26

Often treatment is required to start soon as possible and genotyping results from the lab taking to long