L1 - Personalised Medicine Flashcards
What is personalised medicine?
Aims to customise healthcare with decisions and treatments tailored to each patient
How many patients do not benefit from the first drug they receive?
43% of diabetic patients
50% arthritis patient
What are the benefits of personalised medicine?
Reduce trial and error prescribing Avoid adverse reactions Increase patient compliance Reveal additional uses Control costs of health care
What is personalised medicine currently useful for?
Guiding cancer therapy
Choosing cardiovascular drugs
What is pharmacogenomics?
The study of how a persons genes influence their response to medication
It is the newer term for pharmacogenetics
What is the common genetic polymorphism in a drug metabolising enzyme?
CYP450
Variations in this account for metabolism of 25% of all drugs
What is pharmacoepidemiology?
Drug effects at a population level or between populations
Increasingly important for health economic decisions
What % of hospital admission are due to adverse drug reactions?
5%
What 3 diseases/drugs are panel tests used for?
Warfarin
Heart transplant –> allomap multi gene expression
Familial hypercholesterolaemia
What is Warfarin used for?
Used to prevent clots
Metabolized by CYP2C9 enzyme
Usually dose is adjusted by trial and error –> FDA have recommended genotyping
What is allomap multi gene expression test used for?
Used in end-myocardial biopsies after heart transplant
What is an example of personalised medicine in cardiology?
Clopidogrel –> drug called Plavix
What does Plavix do?
Anti-platelet medication – stop clot formation
Blocks P2Y12 receptor
Particularly effected by SNPs
What is the guide to taking Plavix?
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
What metabolises Plavix?
Liver enzymes CYP2C9 metabolises Plavix to its active form
Reduced enzyme activity leads to reduced drug effectiveness
What is inter-individual variation?
Variations in concentrations of the drug at the site of action
Different responses to the same concentration of drug
What is pharmacokinetics?
Drug concentrations change with time in different regions of the body in relation to dosing
What is pharmacokinetics dependent on?
Metabolism
Excretion
Absorption `
Distribution in compartments
What is pharmacodynamic variation?
Individualised response (anti-hypertensives, anticoagulants) are adjusted by monitoring physiological endpoints
- Blood pressure
- Platelet function
In results why is it important to look at individual data?
Bar graph suggests no difference but actually there are hidden differences in individuals
May be attributable to age or some other factor
What are the main causes of variability in drug responses?
Age Ethnicity Genomics Immunological factors Concomitant disease Drug interactions Body composition
What is the drug response different in young and old people?
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
How does body composition affect drug response?
Body composition changes with age
- Older and after mostly leading to changes in volume and distribution
GFR is normalised to body surface area
Why is morphine not given in labour?
As transferred to the baby via the placenta –> causes respiratory depression
Why is it risky to give old people heart failure drugs?
Cause postural hypertension more commonly in elderly patients even if plasma concentration is the same as in a younger person
Digoxin half line in young vs old people?
Increases force of heart contraction
½ life in neonate = 200h
½ life in adult = 40h
Why does ethnicity affect the drug response?
Variation in genetics between ethnicities
How does hydrazine differ between different ethnicities?
Hydralazine (vasodilator) used for HF
Hydralazine + nitrate –> prolongs life in African Americans but not in white Americans
The metabolism of what is different in the Chinese population?
Metabolise ethanol to produce a higher concentration of acetaldehyde
- Adverse effects - palpitations and flushing
Propranolol metabolism is also different
What are the two types of genetic mutation?
Heritable change in DNA
Polymorphism
What is an example of a heritable change in DNA?
Slow/fast acetylators - hepatic acetyl transferase
Acetylations important in some drugs but these are not used frequently
What is an example of a polymorphism?
Inherited thrombophilia – SNP in Factor V Leiden (a coagulation factor)
- Increased blood clots
- When they travel deep vein thrombosis
What is a polymorphism?
Alternative sequence at loci within the DNA strand (allele)
SNPs are very common –> C-T most common
What is the possible explanation for difference in propanalol metabolism?
Differences in beta receptors
What is an example of an immunological factor?
Some people form anti-drug antibodies or allergic reaction
What are some examples of concomitant disease?
Disease in kidney or liver
Pregnancy
Some diseases cause gastric stasis
Diseases that influence receptors
How do diseases in the liver to kidney affect drug response?
Metabolise drugs and diseases can affect elimination profiles
Can cause prolonged or intense drug effects
How do some diseases that cause gastric stasis affect drug response?
Stasis in migraine, diabetic neuropathy
Can lead to differences in how we metabolise drugs
How do some diseases influence receptor affect drug response?
Familial hypercholesterolaemia –> lack of function of LDLR receptor
Homozygous form relatively resistant to statins
- Heterozygous form responds well
- New PCSK9 inhibitors useful
What % of ADR are due to drug interaction?
5-20%
What do drugs interact with?
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
What do diuretics do?
Lower plasma K+ and predispose to digoxin toxicity
What does Sildenafil do?
Its mechanism of action potentiates organic nitrates and combination can lead to severe hypotension
What is Warfarin used for?
Used to thin the blood after clots
Balance needed or bleeding/thrombosis
Which three polymorphisms influence Warfarin efficacy?
CYP2C9
VKORC
What is the CYP2C9 polymorphism?
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
What is the VKORC polymorphism?
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
Normal CYP2C9 polymorphism and wildtype VKORC?
5-7mg
If slow metaboliser?
3-4 - 0.5-2mg
If GG–>AA mutation?
More sensitive
0.5-2mg
