Flashcards in Pharmakogenetics Deck (12):
Describe the difference between pharmacokinetics and pharmacodynamics.
Pharmacokinetics - refers to how a drug is handled by the body, how levels are maintained, how it is transported, distribution throughout the body.
Pharmacodynamics: is the mechanism of action of the drug itself. How well it interacts with the target (binding affinity, what is too high a dosage and too low a dosage, therapeutic window.
What is warfarin, PT and INR?
Warfarin (primarily S warfarin) is a blood thinner, used to slow the formation of clots so it is used to treat thrombosis and embolisms (blood clots)
It impairs the synthesis of vitamin K dependent clotting factors and inhibits vitamin K reductase (VKORC1), which takes NADH and reduces Vitamin K
-Inhibition of VKORC1 prevents regeneration of reduced vitamin K which is a cofactor for GGCX, glutamyl carboxylation of clotting factors which is normally on standby to activate clotting factors.
Warfarin inhibits VKORC1, no reduced vitamin K, no GGCX activation, no activated clotting factors.
Pharmokinetically: the warfarin is modified, becomes more soluble and excreted although if any member of the pathway has a mutation, you will have difficulty metabolizing warfarin (intolerant/sensitive)
The enzyme is CYP29.
Pharmodynamically: how well the warfarin binds will affect sensitivity. SNPs in VKORC1 will likely reduce binding, therefore requiring a higher dose of warfarin.
So everyone varies in CYT levels and drug efficacy.
PT is prothrombin time, how quickly blood clots
So INR is expected to be higher than 1 if you use warfarin.
Generally what are CYPs and what do they generally do for drugs?
Cytochrome P450s, they are heme containing and expressed primarily in the liver. They detoxify and get rid of endogenous and xenobiotic compounds. They can activate drugs or accept electrons to make a drug more soluble (by addition of oxygen) for easier excretion.
Phase 1: they add a hydroxyl group to the molecule
Phase 2: they modify the hydroxyl group into something else increasing drug solubility.
Describe the metabolism of Tylenol and drug toxicity.
The enzyme is CYP3A4 and CYP2D6.
(it is the primary one but there are 8 others inferring a lack of substrate specificity)
It metabolizes acetaminophen into N-acetyl-p-benzoquinone which is toxic. But that is removed from the liver.
Clearance of benzoquinone takes days, but accumulation can occur in hours.
If you take too much tylenol that leads to toxic environment and liver damage.
Alcohol is an inducer which accelerates the process.
Describe the different metabolizers
For metabolism of a drug, you want ideally the drug levels to stay in the therapeutic window for as long as possible. Extensive metabolizer is the normal.
An intermediate metabolizer is a single mutation on a CYP gene.
A poor metabolizer is homozygous for a mutation on the CYP gene and so drug levels would accumulate with each repeated dose.
On the other spectrum, there is increased enzyme speed so fast metabolizer and ultrafast metabolizer
What three things can happen to ultrafast metabolizers?
If the cyp activates the drugs: 1. toxic buildup of medications
2. hypersensitivity to a medication
If it excretes the medication:
3. underdosing on medication.
What is all that is needed for effective use of pharmacogenomics in predicting outcomes of drug therapy?
for a GWAS study to be effective, all that is required is a statistically valid correlation between a SNP, or set of genetic variations, and the clinical assessment. This GWAS might suggest new target genes or loci that were previously not known to be associated with a disease/treatment. These could then lead to more in-depth studies of metabolism, PK or PD.
Answer: a high positive predictive value for the test.
A patient is heterozygous for a mutation that affects drug sensitivity. What do you expect from this patient?
This patient would have reduced ability to metabolize the drug so you would see persistance of the drug compared to the normal.
A drug interferes with warfarin's blood thinning activity and with acetaminophen, leads to liver toxicity. What is likely the effect of this drug?
This drug likely induces CYP production in the liver leading to...
1. faster metabolism of the warfarin to be excreted
2. faster conversion of acetaminophen to the toxic benzoquinone leading to its buildup.
A GWAS is a study on genetic factors that affect drug metabolism. What three things do you need?
1. A large population size to make statistically significant correlations
2. A reliable measure of clinical response to a drug.
3. A second repeat population to validate associations from the primary study.
You do not need a list of candidate genes because you can use this study to identify new genes that modulate drug response. (genetic linkage) just measure responses, sequence and find patterns.
A null mutation for CYPdan leads to resistance to a drug that inhibits platelet activation. What is the likely reason for this?
CYPdan is responsible to activating clopidogrel.
As a result with only half the normal activity, clopidogrel is not being activated fast enough and is instead being removed from the body faster than it needs to be.
Need higher dosage.