Pharmacogenetics Flashcards
The most well-documented examples of differences in drug effects are due to what? What branch is now starting to be heavily researched?
- Metabolism- liver enzymes
2. pharmocodynamic- mechanism of action
Phase I enzymes are associated with what? Phase II?
- CYP-oxidation, hydrolysis, reduction
2. Conjugating enzymes
What variant number is the most clinically important UGT variant?
28
Ultra rapid metabolizers with usually gene multiplication are usually associated with what enzyme?
CYP2D6
The extensive metabolizer is characterized as what?
Normal activity, two copies of normal gene
The intermediate metabolizer is characterized as what?
– Roughly half-normal enzyme activity
– Usually one copy of low activity active gene
The poor metabolizer is characterized as what/
– Little or no enzyme activity
– Two copies of low activity gene
Wat are the 4 most important CYP enzymes?which one does over half of prescription drugs? 25%?
- 2C9, 2C19, 2D6, 3A4
- 3A4
- 2D6
What enzyme converts tomoxifen to active metabolite?
CYP2D6
What converts codeine to morphine
CYP2D6
What are 3 major drug class metabolized by CYP 2 D6
- Anti-depressants (SSRIs, tricyclics)
- Anti-psychotics (aripiprazole, olanzapine)
- -Adrenergic antagonists (carvedilol, metoprolol)
What converts azathioprine and 6 mercaptopurine?
Thiopurine methyltransferase TPMT
What metabolizes irinotecan?
UGT1A1- Gilbert’s syndrome
What metabolizes warfarin and phenytoin?
CYP2C9
What metabolizes isoniazid, hydalazine, procainamide?
N-acetyltransferase
What enzyme converts clopidogrel, carisoprodol, and diazepam?
CYP2C19
Variant 3 for CYP2D6 is what mutation and population percentage? 4? 5?
- frame shift- 2%
- Splicing- 22 %
- gene deletion- 5%
If metabolism of a drug is slower than average, what do we often see?
wanted effects not elicited from certain prodrugs, but toxicity on standard dose
If metabolism of a drug is faster than average, what do we often see?
-no drug response at ordinary dosage
If you are a rapid metabolizer with CYP2D6 multiplication, what happens?
Convert codeine very rapidly to morphine,
sometimes resulting in toxicity
[Tragic cases reported in infants who breast-fed from mothers who were ultra-rapid
metabolizers and had taken codeine Infants died of respiratory arrest from
excess levels of morphine that transferred to
the breast milk]
What protein kinase is important in regards to being mutated for melanoma? What drug is used to inhibit its constitutive activity?
- B-RAF
2. Vemurafenib
What is the importance of vemuradenib?
It was part of the first wave of companion diagnostics specifically targeted at a subset of cancers with a particular molecular alterations
A mutation in VKORC1 causes what?
warfarin resistance in humans and rats
What CYP enzyme metabolizes warfarin? what are the most common variants?
- CYP2C9
2. 2 and 3
if evidence is available to support
the safety and effectiveness of the
drug only in selected subgroups of
the large population with a disease,, what then needs to happen?
identify specific tests
needed for selection or monitoring of
patients who need the drug
How much does genetic variation account for of clinical variation in warfarin effects?
only 1/3
medications, diet, age, weight, and sex
[all included only account for about 50% of effect]
What are the 5 general issues in implementing pharmacogenetics in clinical practice?
- Nomenclature
- Understanding genetic variation in context
- Insurance coverage
- Inertia of status quo
- Establish new standard of care
