Cardiovascular Disease Flashcards
Active efflux of clopidogrel is thru what?
ABCB1
Degradation of clopidogrel is by what?
Intestinal esterases
How is clopidogrel activated?
Activated to active metabolite via 2 steps
- CYP2C19
- Possibly PON1
What is the target site of clopidogrel?
P2Y12, located on platelets
What is the role of CYP2C19 in the metabolic activation of clopidogrel?
It occurs in both steps of metabolic activation
What are the genetic variations of CYP2C19?
Loss of function alleles (*2 and *3)
Gain of function allele (*17)
In what ancestry flow is there an increase of both intermediate CYP2C19 alleles and poor metabolizers?
Caucasian to AA to Asian
CYP2C19*3 is exclusively in what population?
Asian
What have studies show about the significance of CYP2C19 LOF and GOF alleles?
Increased odds of cardiac events and stent thrombosis
*17 has not shown any regard to efficacy, just increased bleeding risk
PON1 has been shown to be a critical enzyme in activating clopidogrel, what have follow-up studies show?
Failed to replicate any impact on outcome or surrogate clinical markers
What are some factors that can contribute to responses to clopidogrel?
- Diet
- ABCB1/CYP2C19 polymorphism and PON1
- Smoking
- Drug-drug interactions (notably PPIs)
- Intrinsic variation in platelet function
For poor metabolizers of CYP2C19, what must FDA require?
Black box warning regarding diminished effect of clopidogrel
For intermediate metabolizers of CYP2C19, what must FDA require?
They dont address it like poor metabolizers
Why should known CYP2C19 poor and intermediate metabolizers switch from clopidogrel to prasugrel/ticagrelor?
Likelihood of Tx failure
How does warfarin work?
Works thru negative effect on Vit. K epoxide reductase which decreases production of clotting factors (2,7,9,10)
(R or S)-warfarin is more potent
S
(R or S)-warfarin is metabolized via CYP2C9
S
What are the key genetic impacts on warfarin use and which one is race exclusive?
- CYP2C9
- CYP4F2
- VKORC1 (25%)
- CALU**
- Age, body size, RX (15-20%)
**AA only (5.7%)
What does CYP2C9*2 and *3 do w/ warfarin?
Decrease clearance by 40 to 75%
What is the most and least common CYP2C9 allele?
Most common (69%) = Wildtype
Least common (6%) = Homo LOF
Which genotype decreases warfarin clearance by 40 to 75%?
CYP2C9*2 and *3
What are the VKORC1 haplotypes?
Group A and B
Haplotype Group A is associated w/ (lower/higher) dosing of warfarin to achieve INR
lower
Haplotype Group A includes what kind of haplotypes?
H1 and H2
Haplotype Group B is associated with (lower/higher) dosing of warfarin to achieve INR
higher
Haplotype Group B includes what kind of haplotypes?
H2, H8, and H9
What population is CYP4F23/3 allele found in?
What is its significance?
Caucasians, rare in AA
Decrease risk of over-anticoagulation and hemorrhage, more studies are needed
VKORC1 Group A Haplotype is found the most in what population? Lowest in what?
Highest = Asian
Lowest = AA
VKORC1 Group B Haplotype is found the most in what population? Lowest in what?
Highest = European and AA
Lowest = Asian
What variation in AA have been associated w/ an increase in dosing requirements?
CALU (Calumenin)
What specific factors are addressed in the package insert?
CYP2C9 and VKORC1
What codes for OATP1B1, a hepatic transporter?
Which variant results in decreased activity?
SCLO1B1
*15
What are some characteristics of familial hypercholesterolemia?
- High LDL
- Heterozygous
- Mutation in LDL, APOB, or PCSK9
What are some issues with diagnosing familial hypercholesterolemia?
- Hard to test; too many mutations
- Highly under-diagnosed in US
- Higher diagnosis rate in countries performing cascade testing
Adding isosorbide dinitrate/hydralazine benefits who?
Ppl w/ heart failure + AA
CYP11B2 homo and hetero GOF in found mainly in what population? What is its significance?
Caucasian
Associated w/ more heart failure
Mature-onset diabetes of the young is (monogenic/polygenic)
monogenic
What is the most common genetic mutation of mature-onset diabetes of the young?
HNF1A
What has been the treatment of choice (over insulin) for mature-onset diabetes of the young?
Sulphonylureas
Understanding of mature-onset diabetes of the young has led to what kind of theories?
Gene theories of Type II Diabetes mellitus
Which genetic homozygote demonstrates clinically significant outcomes with sulphonylureas?
CYP2C9 LOF
CYP2C9 (LOF vs GOF) is more likely to achieve goal HbA1C, but have a higher risk of what?
LOF
Higher risk of hypoglycemia
What are the non-genetic factors predicting metformin intolerance?
- Increased age
- Females
- OCT1-inhibitor drug interaction
ATM and Metformin
ATM gene codes for what?
Serine/threonine kinase
