L1 - Personalised Medicine

Question 1

What is personalised medicine?

Answer 1

Aims to customise healthcare with decisions and treatments tailored to each patient

Question 2

How many patients do not benefit from the first drug they receive?

Answer 2

43% of diabetic patients

50% arthritis patient

Question 3

What are the benefits of personalised medicine?

Answer 3

Reduce trial and error prescribing
Avoid adverse reactions
Increase patient compliance
Reveal additional uses
Control costs of health care

Question 4

What is personalised medicine currently useful for?

Answer 4

Guiding cancer therapy

Choosing cardiovascular drugs

Question 5

What is pharmacogenomics?

Answer 5

The study of how a persons genes influence their response to medication
It is the newer term for pharmacogenetics

Question 6

What is the common genetic polymorphism in a drug metabolising enzyme?

Answer 6

CYP450

Variations in this account for metabolism of 25% of all drugs

Question 7

What is pharmacoepidemiology?

Answer 7

Drug effects at a population level or between populations

Increasingly important for health economic decisions

Question 8

What % of hospital admission are due to adverse drug reactions?

Answer 8

5%

Question 9

What 3 diseases/drugs are panel tests used for?

Answer 9

Warfarin
Heart transplant –> allomap multi gene expression
Familial hypercholesterolaemia

Question 10

What is Warfarin used for?

Answer 10

Used to prevent clots
Metabolized by CYP2C9 enzyme
Usually dose is adjusted by trial and error –> FDA have recommended genotyping

Question 11

What is allomap multi gene expression test used for?

Answer 11

Used in end-myocardial biopsies after heart transplant

Question 12

What is an example of personalised medicine in cardiology?

Answer 12

Clopidogrel –> drug called Plavix

Question 13

What does Plavix do?

Answer 13

Anti-platelet medication – stop clot formation
Blocks P2Y12 receptor
Particularly effected by SNPs

Question 14

What is the guide to taking Plavix?

Answer 14

Clopidogrel bisulfate tablets
Plavix may not work as well in people who
- Have certain genetic factors that affect how the body breaks down Plavix
– May do genetic tests to make sure Plavix is right for you
– Take certain medicines - especially omeprazole

Question 15

What metabolises Plavix?

Answer 15

Liver enzymes CYP2C9 metabolises Plavix to its active form

Reduced enzyme activity leads to reduced drug effectiveness

Question 16

What is inter-individual variation?

Answer 16

Variations in concentrations of the drug at the site of action
Different responses to the same concentration of drug

Question 17

What is pharmacokinetics?

Answer 17

Drug concentrations change with time in different regions of the body in relation to dosing

Question 18

What is pharmacokinetics dependent on?

Answer 18

Metabolism
Excretion
Absorption `
Distribution in compartments

Question 19

What is pharmacodynamic variation?

Answer 19

Individualised response (anti-hypertensives, anticoagulants) are adjusted by monitoring physiological endpoints

• Blood pressure
• Platelet function

Question 20

In results why is it important to look at individual data?

Answer 20

Bar graph suggests no difference but actually there are hidden differences in individuals
May be attributable to age or some other factor

Question 21

What are the main causes of variability in drug responses?

Answer 21

Age 
Ethnicity 
Genomics 
Immunological factors 
Concomitant disease 
Drug interactions 
Body composition

Question 22

What is the drug response different in young and old people?

Answer 22

Drug elimination less efficient
GFR in newborns is 20% of the adult value
Drug metabolising enzymes are altered in newborns
More drugs in the elderly so more interactions

Question 23

How does body composition affect drug response?

Answer 23

Body composition changes with age
- Older and after mostly leading to changes in volume and distribution
GFR is normalised to body surface area

Question 24

Why is morphine not given in labour?

Answer 24

As transferred to the baby via the placenta –> causes respiratory depression

Question 25

Why is it risky to give old people heart failure drugs?

Answer 25

Cause postural hypertension more commonly in elderly patients even if plasma concentration is the same as in a younger person

Question 26

Digoxin half line in young vs old people?

Answer 26

Increases force of heart contraction ½ life in neonate = 200h ½ life in adult = 40h

Question 27

Why does ethnicity affect the drug response?

Answer 27

Variation in genetics between ethnicities

Question 28

How does hydrazine differ between different ethnicities?

Answer 28

Hydralazine (vasodilator) used for HF | Hydralazine + nitrate --> prolongs life in African Americans but not in white Americans

Question 29

The metabolism of what is different in the Chinese population?

Answer 29

Metabolise ethanol to produce a higher concentration of acetaldehyde - Adverse effects - palpitations and flushing Propranolol metabolism is also different

Question 30

What are the two types of genetic mutation?

Answer 30

Heritable change in DNA | Polymorphism

Question 31

What is an example of a heritable change in DNA?

Answer 31

Slow/fast acetylators - hepatic acetyl transferase | Acetylations important in some drugs but these are not used frequently

Question 32

What is an example of a polymorphism?

Answer 32

Inherited thrombophilia – SNP in Factor V Leiden (a coagulation factor) - Increased blood clots - When they travel  deep vein thrombosis

Question 33

What is a polymorphism?

Answer 33

Alternative sequence at loci within the DNA strand (allele) | SNPs are very common --> C-T most common

Question 34

What is the possible explanation for difference in propanalol metabolism?

Answer 34

Differences in beta receptors

Question 35

What is an example of an immunological factor?

Answer 35

Some people form anti-drug antibodies or allergic reaction

Question 36

What are some examples of concomitant disease?

Answer 36

Disease in kidney or liver Pregnancy Some diseases cause gastric stasis Diseases that influence receptors

Question 37

How do diseases in the liver to kidney affect drug response?

Answer 37

Metabolise drugs and diseases can affect elimination profiles Can cause prolonged or intense drug effects

Question 38

How do some diseases that cause gastric stasis affect drug response?

Answer 38

Stasis in migraine, diabetic neuropathy | Can lead to differences in how we metabolise drugs

Question 39

How do some diseases influence receptor affect drug response?

Answer 39

Familial hypercholesterolaemia --> lack of function of LDLR receptor Homozygous form relatively resistant to statins - Heterozygous form responds well - New PCSK9 inhibitors useful

Question 40

What % of ADR are due to drug interaction?

Answer 40

5-20%

Question 41

What do drugs interact with?

Answer 41

Other drugs Chemicals - grapefruit juice or herbal remedies - Grapefruit juice regulate sCYP3A4 in the gut Pharmacodynamic interactions – usually predictable - E.g. diuretics (heart failure) lower plasma K+ and predispose to digoxin toxicity - E.g. Sildenafil (vasodilator) mechanism of action potentiates organic nitrates and combination can lead to severe hypotension

Question 42

What do diuretics do?

Answer 42

Lower plasma K+ and predispose to digoxin toxicity

Question 43

What does Sildenafil do?

Answer 43

Its mechanism of action potentiates organic nitrates and combination can lead to severe hypotension

Question 44

What is Warfarin used for?

Answer 44

Used to thin the blood after clots | Balance needed or bleeding/thrombosis

Question 45

Which three polymorphisms influence Warfarin efficacy?

Answer 45

CYP2C9 | VKORC

Question 46

What is the CYP2C9 polymorphism?

Answer 46

Enzyme in liver Encodes an enzyme that metabolises warfarin allele 2 and 3 - Both slow and fast metabolisers Metabolise it slower therefore drug concentration is higher so the warfarin dose needs to be lowered

Question 47

What is the VKORC polymorphism?

Answer 47

Protein target Encodes the drug target of warfarin the vit K epoxide reductase enzyme Those with G --> A in the promoter are more sensitive to warfarin - GG is wildtype --> AA needs a lower dose

Question 48

Normal CYP2C9 polymorphism and wildtype VKORC?

Answer 48

5-7mg

Question 49

If slow metaboliser?

Answer 49

3-4 - 0.5-2mg

Question 50

If GG-->AA mutation?

Answer 50

More sensitive | 0.5-2mg