Personalized Medicine and Pharmacogenomics Flashcards
1
Q
Human Genome Project
A
- laid the groundwork for understanding the similarities and differences between individuals
- 36 complete eukaryotic and 1117 prokaryotic genomes also sequenced
- the most important outcome was to generate a sequence for most human DNA
- the next step is to determine what it means
- research is ongoing to identify genes and determine their function
- Online Mendelian Inheritance in Man (OMIM)
2
Q
Number of genes
A
- the total number of human genes is much smaller than expected 20,500
- only slightly larger than zebra fish
- and smaller than the genome complements of C. elegans (round worm) and the purple sea urchin genome
- two individuals- 99.5%
3
Q
Evidence of Personalized Medicine
A
- drug therapy
- idiopathic disease
- cancer diagnosis, prognosis, treatment
- prenatal testing and newborn screening
4
Q
Pharmacogenetics
A
-this relates heritable variation to inter-individual variation in drug response
5
Q
Pharmacogenomics
A
- the field of new drug development based on our rapidly increasing knowledge of all genes in the human genome
- Pharmacogenomics = pharmacogenetics for profit
6
Q
Pharmacokinetics
A
-the study of the mechanisms of absorption and distribution of an administered drug, the rate at which a drug action begins and the duration of the effect, the chemical changes of the substance in the body (e.g by enzymes) and the effects and routes of excretion of the metabolites of the drug
7
Q
Why some drugs don’t work in some patients
A
- their genotypes are different
- one is able to metabolize the drug and receive its benefits
- drug metabolism in the other patients results in a toxicity
- not everyone reacts in the same way
- right now, we know the genotype-phenotype connection for very few drugs
- drugs go through clinical testing and will be marketed as long as there are very ASR during the trials
- because we don’t know what is causing the problem, the drugs get prescribed to all individuals with the disorder for which the drug was developed
- toxic reactions to drugs are well known. ADRs are the fourth or fifth leading cause of death among adults
- the overall incidence of ADRs in US hospitals is 6.7%. The frequency of fatal ADRs is 0.3%
- per year, there are more than 2 million serious adverse reactions to FDA approved drugs
- about 100,000 Americans die each year from adverse drug reactions
- the system is supposed to work one way, with all the pieces fitting together and generating a positive response: CYP P450
8
Q
Mutation in pathway
A
- variant alleles result in poor-metabolizer status
- if there is a mutation such that one part of the pathway is changed, then the outcome is likely to be different
- in this case, a mutation in the gene for CYP2C18 changes the protein structure which modifies a binding site
- the mutant protein is unable to interact with the drug which negatively impacts the drug function
9
Q
Pharmagenomics for the future
A
- it is imperative that we know what genes are involved in drug metabolism, and the effects of different mutations
- if the patient’s genotype can be determined, it will then be possible to individualize drug therapy such that each patient gets exactly the right medication for his/her situation
- this will benefit drug companies as well
- right now, a drug may be beneficial for some individuals but fail clinical trials because of a relatively high frequency of adverse drug reactions in test subjects
- if a connection can be made between the ADR and a particular genotype, the drug could be marketed to the population that benefits and not used for those patients with the known drug reaction genotype
10
Q
Cytochrome P450 Family of Genes
A
- family includes a variety of different enzymes involved in drug metabolism (as well as metabolism of other substances such as lipids and hormones)
- mutations in the genes result in a change in that enzyme’s ability to perform its function
11
Q
Variation in CYP2D6
A
- the ability of an individual to metabolize certain drugs depend on their genotype with respect to CYP2D6
- classes are ultra, extensive, intermediate, poor
- normal condition is extensive- 2 functional alleles, most drugs are targeted to those individuals
- a poor metabolizer has no functional allele for this gene and thus has difficulty converting the drugs to their useable forms. There may be a very low level of enzyme activity in which case the conversion process would be very slow. This results in the accumulation of chemicals in the body which may be toxic, these people require smaller doses
- an ultra metabolizer has duplicate copies of functional allele and the drug degrades rapidly so it is eliminated before therapeutic levels can be reached. Higher doses or other drugs
- intermediate metabolizers are heterozygotes with one functional and one mutant allele. These individuals can utilize the drug but at a slow rate than normal, thus, these individuals generally require a lower than normal dose to avoid a toxic build up
12
Q
Pharmacogenetics and Warfarin
A
- anticoagulant
- first notice when a series of cows died of hemorrhage following relatively minor procedures- moldy silage containing anticoagulant
- subsequent studies isolated the substance, called Coumadin, which is present in many different plants. The synthetic form of the drug is known as warfarin
- proved to work in rodent poisons
- good thing in proper concentration
13
Q
Mechanism of Warfarin
A
- it inhibits the enzyme epoxide reductase resulting in inhibition of vitamin K metabolism
- Vit K is essential for the function of many of the clotting factors
- the pathway generating the functional cofactors only works if the reduced form of VitK can be converted to the oxidized form
- to complete the cycle, the oxidized VitK is changed back to the reduced form by the enzyme VitK reductase
- warfarin inhibits the VKOR, limiting the presence of the functional cofactors, resulting in loss of the ability to coagulate the blood
14
Q
Downsides of Warfarin
A
- it reacts with many common medicines such as aspirin, ibuprofen, acetaminophen which increases the risk of bleeding. Antibiotics have a similar affect
- some foods contain a large concentration of VitK and can reduce the effectiveness of the drug (spinach, kale, broccoli, Brussel sprouts) whereas other foods increase the risk of bleeding (ginger and garlic)
- excessive use of alcohol may also change the effect of the drug
- genetic: some individuals are very sensitive while others are relatively unresponsive
- if initial dose is too high, the neg effects can be counteracted by treatment with Vitamin K
15
Q
Genes affect warfarin metabolism
A
- VKORC1 allele of the VKOR gene accounts for approximately 30% of the variation. There are low dose (more sensitive to the drug- Asians) and high dose groups (more resistant so require higher dosage- common in African America)
- CYP2C9 allele of cytochrome P450 explains about 10% of variability. These polymorphisms are most common in Caucasian and rare in African Americans and Asians
