Genetic Variations Flashcards
Pharmacokinetics:
what the body does to a drug
- refers to the movement of drug into, through, and out of the body
- time course of its absorption, bioavailability, distribution, metabolism, and excretion.
Pharmacodyamics:
what a drug does to the body
- involves receptor binding, post-receptor effects, and chemical interactions.
- helps explain the relationship between the dose and response, ie, the drug’s effects.
Pharmacogenetics:
- study of inherited differences (variation) in drug metabolism and response.
Pharmacogenetics can influence:
pharmacodynamics and pharmacokinetics
Pharmacogenomics:
- A ‘genomic’ approach to pharmacogenetics – using genomic wide association studies to assess the impact of SNPs on the impact of drug therapy.
Prothrombin time (PT):
- a blood test that measures how long it takes blood to clot.
- normal is 11-13.5 seconds
Drug sensitivity:
- need less of a drug to be within the therapeutic window
Drug tolerance:
- need more of a drug to be within the therapeutic window.
Cytochrome p450s are:
- heme-containing proteins expressed primarily in the liver.
Cytochrome p450s are responsible for:
- detoxifying and exporting both endogenous and external/foreign chemical compounds.
- activating some drugs
How do cytochrome p450s function?
- Accept electrons from donors such as NADPH to catalyze a number of different reactions.
- most important: the addition of oxygen to carbon, nitrogen or sulfur atoms.
- drug binds to heme group, flap closes, reaction occurs and the drug is reduced
How many cytochrome p450s are there?
56
each encoded by a different gene
What do cytochrome p450s do to drugs?
- reduces them.
- adds an oxygen to hydrophobic groups of the drug to increase the drug’s solubility and expedite its clearance from the body
Phase I of drug metabolism:
- addition of a hydroxyl group to a drug
- carried out by CYPs
Phase II of drug metabolism:
- carried out by enzymes other than CYPs
- functionalization of the hydroxyl group, increasing drug solubility, allowing it to be excreted.
How many families of CYPs are there?
20
Tylenol (acetaminophen) is primarily broken down by what CYP?
- CYP3A4 converts acetaminophen to a toxic form
- liver then further modifies drug and excretes it
- if you take too much acetaminophen, the liver cannot keep up with formation of the toxic drug, and irreversible liver damage occurs
Do individual CYPs only react with one specific substrate?
No.
- CYPs interact with a lot of different substrates - fairly promiscuous.
- CYP flap opens, and whatever drug fits into the heme pocket will be reduced once the flap closes.
Warfarin/coumadin is used to:
- prevent abnormal blood clotting:
- thrombosis
- embolism in cases of heart valve prosthesis
- recurrent stroke
- deep vein thrombosis
- pulmonary embolism
How does warfarin function in the body?
- Impairs synthesis of vitamin K dependent clotting factors
- Inhibits vitamin K reductase – key enzyme in vitamin K recycling.
S-warfarin is primarily modified by what CYP?
- CYP2C9
- hydroxylates S-Warfarin, making it more soluble and able to be excreted
What can happen if there is a mutation in CYP2C9 that decreases its activity?
- CYP2C9 will not be able to hydroxylate S-Warfarin.
- S-Warfarin will stay in body longer, have a longer effect on the body.
- patient will be more sensitive to drug.
What can happen if there is a mutation in CYP2C9 that increases its activity?
- CYP2C9 will hydroxylate S-Warfarin faster.
- S-Warfarin will be excreted faster
- patient will be more tolerant to drug.
Is there a standard of cytochrome p450 across individuals?
- no
- each of us have a unique spectrum of cytochrome p450 activity.
- we have multiple CYPs to modify each drug we ingest.
Is CYP2C9 interaction with warfarin considered pharmacokinetics or pharmacodynamics?
pharmacokinetics
“what the body does to a drug”
CYP variants can be classified as:
- poor, normal, or ultrafast metabolizers
What kind of metabolizer is this?
- sawtooth curve = normal metabolizer
- patient stays within the therapeutic window when given normal dosage of the drug.
What kind of metabolizer is this?
- step-wise curve = abnormal metabolizer
- drug is accumulating in body
- poor metabolizer
- patient will be more sensitive to drug; will require a lower dose to stay within the therapeutic window
What will a change in pharmacokinetics do to the curve in this graph?
- the shape of the curve will change
- if the drug is metabolized and excreted faster, the curves will become more steep
What will a change in pharmacodynamics do to the curve in this graph?
- pharcodynamics will affect the drug at the site of action; therapeutic (blue) window will move around.
Mutations in what CYP2C9 alleles make patients more sensitive to warfarin?
- allele 2
- reduced affinity of CYP2C9 for warfarin
- allele 3
- altered substrate specificity
What is one way you can treat a warfarin overdose?
- give a bolus of vitamin K to outcompete warfarin binding to CYPs.
- vitamin K is the natural ligand of CYPs for blood clotting.
What genotypes tend to have the largest therapeutic window for a drug?
wild-type
What genotypes tend to have an intermediate therapeutic window for a drug?
heterozygous
(one allele is mutated)
What genotypes tend to have the smallest therapeutic window for a drug?
homozygous
(both alleles mutated)
What is the target of warfarin?
- vitamin K epoxide reductase (VKORC1)
Inhibition of VKORC1 (vitamin K epoxide reductase) by warfarin:
- prevents regeneration of reduced vitamin K, which is necessary for carboxylation/activation of coagulation factors.
- vitamin K remains oxidized
If a mutation in an enzyme increases the affinity of that enzyme for the drug, will the patient be more sensitive or tolerant to the drug?
- more sensitive
- need less drug to have the same therapeutic effect
If a mutation in an enzyme decreases the affinity of that enzyme for the drug, will the patient be more sensitive or tolerant to the drug?
- patient will be more tolerant
- will need more drug to have the same therapeutic effect
Is the VKORC1 (vitamin K epoxide reductase) interaction with warfarin considered a component of pharmacodynamics or pharmacokinetics?
- pharmacodynamics
- “what the drug does to the body”
- this is the site of drug activity; warfarin inhibits VKORC1
