Lecture 01 Introduction Flashcards
1. Describe what personalised medicine is, give examples of genetics/genomics that influence drug responses and which of these are relevant to the clinic today 2. Give examples of non-genetic reasons for variations in drug responses and explain why these are relevant in the clinic today
Define: Personalised Medicine
Customisation of healthcare with decisions and treatments tailored to each individual patient
Define: Pharmacogenomics
Part of personalised medicine. The study of how a person’s genes influences their response to medications.
Give an example of a genetic polymorphism that influence drug responses
Cytochrome p450 - a drug metabolising enzyme
Why is personalised medicine of clinical importance?
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
Give examples of personalised medicine using clinically today
- Warfarin dosing
- Familial Hypercholesterolaemia treatment
- AlloMap Testing to prevent rejection of a heart transplant
What is another name for Plavix?
Clopidogrel
What does Plavix do? When is it prescribed?
Inhibits platelet aggregation
Given to patients post-MI
Why might Plavix not work as well in some people?
- 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.
- Multi-drug interactions, e.g. Omeprazole
Define: Inter-individual Variation
What two factors contribute to this?
Variation in concentrations of the drug at the site of action or different responses to the same concentration of drug
Pharmacodynamics and Pharmacokinetics
Define: Pharmacokinetics
How fast a drug is metabolised within the body
Define: Pharmacodynamic Variation
How an individual responds to a drug and how it is adjusted by monitoring physiological endpoints
What are the factors that affect drug concentration?
What are the main causes of variability in drug responses?
- Age
- BMI
- Gender
- Ethnicity
- Genetics/Genomics
- Immunological Factors (drug intolerance)
- Concomitant Disease
- Multidrug Interactions
- Pregnancy
- Co-existing Medical Conditions
How does drug concentration affect newborns?
Less efficient metabolism and elimination
Newborn GFR 20% that of an adult
Define: Concomitant Disease
Liver or Kidney Diseases - affect the ability of the body to breakdown or eliminate the drug
How does ethnicity affect drug variability?
- Ethnic variation in genetics
2. Environmental Factors, e.g. diet
Give an example of where ethnicity affects drug concentration
Hydralzaine and Nitrate Treatment in heart failure.
More effective in African-Americans over Caucasians
Give an example of a genetic mutation that causes a disease
Inherited Thrombophilia - caused by a SNP in Factor V Leiden (a coagulation factor)
What are the main causes of drug variability in the elderly?
- Often less efficient metabolism and excretion
2. Often taking multiple drugs - polypharmacy
How do multi-drug interactions cause problems?
Give examples of non-drug compounds that cause adverse-drug problems
e.g. Grapefruit Juice and Herbal Remedies
Can activate the release or molecules or activate enzymes
Give two examples of pharmacodynamic (multi-drug) interactions
- Diretics, used in heart failure to lower plasma potassium, predispose the patient to digoxin toxicity
- Sildenafil, used as a vasodilator and potentiates the action of organic nitrates. Together leading to severe hypotension
How has the Human Genome Project (HGP) affected pharmacogenomics?
10 years after completion of HGP, 104 drugs now have pharmacogenomic information on the label
How many % of diabetes patients complain their drugs don’t work?
43
What SNPs effect Warfarin metabolism?
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
What is the aim of warfarin treatment?
To keep the INR (International Normalised Ratio), a measure of blood coagulation, within a certain range.
Aim an INR of 2-3
What happens if the INR goes outside this range?
Too low - coagulation and blood clotting
Too high - risk of bleeding
Why is patient genotyping (CYP2C9 and VKORC) not always integrated into clinical practice?
Often treatment is required to start soon as possible and genotyping results from the lab taking to long
