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Pharmacogenomics: Pharmacogenetics in Hypertension & Heart Failure (EXAM 2)

Terms in this set (44)

Which of the following is TRUE regarding hypertension?
A. Its persistently elevated arterial blood pressure due to force exerted by the blood against the vessel walls
B. Affects 34% of adults in the US
C. BP >120/80 mmHg
D. Stage 2 HTN is BP >140/90 mmHg
E. All the above
E
There are 2 types of HTN. Match the following description to the correct type.

1. HTN of unknown cause, highly heritable & is polygenic, most common type
2. HTN caused by renal, endocrine or other disorders

A. Primary/essential
B. Secondary
1. A
2. B
52% of HTN patients do not achieve adequate BP control and this can be attributed to?
A. Genetic factors (family history)
B. Genetic susceptibility + lifestyle factors
C. Drug targets (ex: β receptors) & drug metabolizing
enzymes (ex: CYP2D6)
D. All the above
D
Hypertension treatments include:
1. β-blockers
2. Thiazide Diuretics
3. ACE Inhibitors
4. ARBs
5. Direct Renin Inhibitors
6. Aldosterone antagonists
7. Calcium Channel Blockers
8. Loop Diuretics
9. Vasodilators
10. Centrally-acting agents (i.e.: clonidine)

ACEIs, ARBs, DRIs & Aldosterone antagonists are RAAS modulators
Heart Failure (HF) is characterized by:
A. SOB
B. Fatigue
C. Fluid retention
D. All the above
D

family history increases risk
HF treatments include:
1. β-blockers
2. Diuretics
3. ACE Inhibitors
4. ARBs
5. Aldosterone antagonists
6. ARNIs
7. If channel blocker
8. Digoxin
9. Isosorbide dinitrate
10. Hydralazine

ACEIs, ARBs, Aldosterone antagonists & ARNIs are RAAS modulators
B-blockers such as metoprolol, propanolol, carvedilol & atenolol prevent
catecholamine action by antagonizing:

1. B₁ adrenergic receptors in the?
A. Heart
B. Kidney
C. Adipose tissue
D. All the above


2. B₂ adrenergic receptors in the?
A. Bronchial smooth muscle
B. Vascular smooth muscle
C. Both A & B
1. D
2. C

Widely used for HTN, HF, ACS
B-blockers in HF improve ejection fraction by inhibiting sympathetic nervous system activation of β-adrenergic receptors.

B-blockers currently used in HF include:
A. Metoprolol succinate
B. Bisoprolol
C. Carvedilol
D. All the above
D
Match the following B-blocker genes to their targets.

1. ADRB1
2. ADRB2
3. GNAS1, GNB3, GRK5
4. CYP2D6

A. B₁ adrenergic receptor
B. B₂ adrenergic receptor
C. G-proteins in the adrenergic signaling pathway
D. Drug metabolism
1. A
2. B
3. C
4. D
ADRB1 gene encodes for B₁ adrenergic receptor that is highly polymorphic.

The 2 most studied polymorphisms are Gly389 → Arg AND Ser49 → Gly.

Match the following polymorphisms to their description:

1. Gly389 → Arg (Arg389)
2. Gly49 allele
3. Ser49

A. Higher β1 activity and may improve β-blocker response
B. Lower number of β1-receptors following β-agonist exposure
C. May improve β-blocker response
1. A
2. B
3. C

Gly49 is more prevalent in African Americans

Arg389 is prevalent in all populations
Which of the following ADRB1 genotypes showed the largest
decrease in DBP when taking metoprolol?
A. Ser49Ser/Arg389Arg
B. Ser49Gly/Arg389Arg
C. Ser49Ser/Arg389Gly
D. Ser49Gly/Arg389Gly
A
Which of the following is TRUE regarding the INVEST trial?
A. It compared CV outcomes in HTN pts w/ CAD who received either atenolol-based or verapamil-based treatment
B. Ser49/Arg389 increased mortality
C. Ser49/Arg389 derived survival benefit from atenolol compared to verapamil
D. All the above
D


This survival benefit was not seen in non-Ser49/Arg389 carriers
Which of the following is TRUE regarding the Arg389 allele in HF?
A. Arg389 allele has higher β1 activity and may improve β-blocker response
B. Arg389 allele is associated with greater improvements in left
ventricular ejection fraction & remodeling w/ metoprolol succinate
C. Arg389 carriers had less need for additional heart failure medications after titration of β-blocker
D. Arg389 carriers had better survival on high-dose β-blocker therapy vs.
low-dose (Not seen w/ Gly389)
E. All the above
E
Which of the following is TRUE regarding the Ser49 allele in HF?
A. Ser49 may improve β-blocker response
B. Ser49 carriers had better survival on high-dose β-blocker therapy vs. low-dose (Not seen w/ Gly389)
C. Both A & B
C
β-blockers may be a better choice for
Caucasian and Asian patients in HTN.
A. True
B. False
A
There is currently no literature related to ADRB1 & ADRB2
polymorphisms and impact on ________ for HTN or HF.
A. Toxicity
B. Product selection
C. Dosing selection
D. All the above
D

ADRB1 & ADRB2 genetic tests are unavailable & NOT recommended by any organization
The 2 most studied polymorphisms in ADRB2 gene (β2-adrenergic receptor) are:
A. Arg16 → Gly16
B. Gln27 → Glu27
C. Gly389 → Arg389
D. Gly49
E. Ser49
A & B

Glu27 has a greater agonist-mediated receptor down-regulation

Glu27 & Gly16 are both more common in caucasians
Match the following:

1. GNAS2
2. GNB3


A. Encodes G protein α-subunit
B. Encodes G protein β3-subunit
1. A
2. B
Match the following:

1. FokI+ allele (GNAS2)
2. Cys825 → Thr825 (GNB3)

A. Associated w/ higher β-blocker response in HTN
B. Associated w/ greater BP reduction during β-blocker therapy
1. A
2. B
Which of the following is TRUE regarding Leu41 (GRK5)?
A. Its associated with decreased risk of death, MI & stroke
B. Its not associated with BP response to β-blockers
C. Leu41 carriers did not benefit from β-blocker therapy in HF
D. Leu41 has a high frequency in African American population
E. All the above
E
CYP2D6:
Match the following CYP2D6 phenotypes to their alleles.

1. Gene duplication in the absence of inactive or decreased activity alleles
2. "Normal"; 2 active alleles
3. 2 decreased activity alleles OR
1 active and 1 inactive allele OR
1 decreased activity and 1 inactive allele
4. 2 inactive alleles


A. Ultrarapid metabolizers (UM)
B. Extensive metabolizers(EM)
C. Intermediate metabolizers (IM)
D. Poor metabolizers (PM)
1. A
2. B
3. C
4. D
CYP2D6 poor metabolizers have 6-fold _________ metoprolol plasma concentrations compared to extensive metabolizers.
A. Higher
B. Lower
A

more BP lowering but increased risk of AEs
1. FDA label for metoprolol mentions CYP2D6 but does not outline dosing plan for the phenotypes.
A. True
B. False

2. Royal Dutch Pharmacists Association - Pharmacogenetics Working Group (DPWG) has given specific recommendations on the various genotypes.
A. True
B. False
1. A
2. A
-HF: select alternative medication (e.g. bisoprolol, carvedilol) or reduce dose by 75%
-HTN/other indications: be alert to AEs (bradycardia, cold extremities) or select alternative medication (e.g. atenolol, bisoprolol)

These are DPWG guidelines for:
A. PM
B. IM
C. UM
A
-HF: select alternative medication (e.g. bisoprolol, carvedilol) or reduce dose by 50%
-HTN/other indications: be alert to AEs (bradycardia, cold extremities) or select alternative medication (e.g. atenolol, bisoprolol)

These are DPWG guidelines for:
A. PM
B. IM
C. UM
B
-HF: select alternative medication (e.g. bisoprolol, carvedilol) or titrate dose to a maximum of 250% of the normal dose in response to efficacy and AEs
-HTN/other indications: select alternative medication (e.g. atenolol, bisoprolol) or titrate dose to a maximum of 250% of the normal dose in response to efficacy and AEs


These are DPWG guidelines for:
A. PM
B. IM
C. UM
C
KNOW

For patients taking propanolol, metoprolol or nebivolol;

1. _______ may not receive as much benefit from the medications
A. UM
B. IM/PM

2. _______ may have enhanced benefit but also increase risk fo adverse effects.
A. UM
B. IM/PM
1. A
2. B
Thiazide diuretics (hydrochlorothiazide & chlorthalidone) work by inhibiting sodium-chloride transporter in the distal tubule thereby promoting sodium & chloride?
A. Excretion
B. Retention
A
ADD1 (α-adducin) regulates signal
transduction within the cell.
A. True
B. False
A
Which of the following is TRUE regarding Trp460?
A. Associated with renal sodium retention & salt sensitive HTN
B. Enhanced BP lowering response from thiazide diuretics
C. Lower risk of MI & stroke when thiazide or loop diuretic is used for HTN (not present in Gly460)
D. All the above
D
RAAS modulators include:
A. ACEIs
B. ARBs
C. Direct renin inhibitors
D. Aldosterone antagonists
E. All the above
E
Match the following drug classes with their MOA:

1. ACEIs (ex: lisinopril, trandolapril, benazepril)
2. ARBs (ex: irbesartan, losartan, valsartan)
3. Direct renin inhibitors (ex: Tekturna/aliskiren)
4. Aldosterone antagonists (ex: spironolactone, eplerenone)

A. Competitive inhibitor of angiotensin-converting enzyme which prevents angiotensin I conversion to angiotensin II
B. Antagonizes the angiotensin II receptor
C. Decreases plasma renin activity and inhibits conversion of angiotensinogen to angiotensin I
D. Blocks aldosterone activity thereby inhibiting sodium reabsorption in the kidney
1. A
2. B
3. C
4. D
Which of the following is TRUE regarding the ACE gene?
A. 267 base pair deletion (D)/insertion (I) polymorphism in intron 16
B. D allele: associated w/ ↑ ACE levels
C. D/I does not influence ACE Inhibitor/ARB response (GenHAT)
D. ACE D allele associated with worse clinical outcomes
E. Risk was higher in D allele pts on low-dose ACE inhibitor, high-dose ACE inhibitor in D allele carriers had better outcomes
F. All the above
F
Polymorphism in the REN gene (encodes renin) can increase gene transcription of renin which converts angiotensinogen to angiotensin I
A. True
B. False
A
1. AGT encodes angiotensinogen.
A. True
B. False

2. AGTR1 encodes angiotensin II type I receptor, the target receptor for ARBs
A. True
B. False
1. A
2. B
There is currently no recommendation for
genetic testing to guide CCB, ACEI, ARB or direct renin inhibitor therapy.
A. True
B. False
A


Includes - product, dosing selection or toxicity avoidance
DHP CCBs (ex: amlodipine, nifedipine) & Non-DHP CCBs (ex: verapamil, diltiazem) work by?
A. Inhibiting calcium ions from entering "slow channels"
B. Produce relaxation of coronary vascular smooth muscle & vasodilation
C. Both A & B
C
CACNA1C encodes α1c-subunit of "slow channel".

Match the following: (rs1051375)

1. Wild-type (AA)
2. Variant (GG)

A. Showed better CV outcomes with verapamil vs. atenolol
B. Showed worse CV outcomes with verapamil vs atenolol (INVEST trial)
1. A
2. B
Isosorbide dinitrate + hydralazine (BiDil) is indicated for ___________ patients with HF that remains symptomatic despite optimal guideline-directed therapy OR patients who cannot tolerate ACEI & ARB.
A. African American
B. Asian
C. Caucasian
D. Hispanic
A
1. Isosorbide dinitrate MOA:
A. Vascular smooth muscle dilation via cyclic-GMP stimulation
B. Direct vasodilation of arterioles

2. Hydralazine MOA:
A. Vascular smooth muscle dilation via cyclic-GMP stimulation
B. Direct vasodilation of arterioles
1. A
2. B
CYP11B2 encodes aldosterone
synthase.
A. True
B. False
A
Which of the following is TRUE regarding CYP11B2 T-allele?
A. T allele is more frequent in African American patients
B. T allele is associated w/ higher aldosterone levels and worse outcomes in HF
C. T allele homozygotes had a better response to isosorbide dinitrate/hydralazine in HF
D. All the above
D
EASYGENERATOR Q

1. Which of the following is NOT a gene that may influence metoprolol efficacy?
A. ADRB1
B. ADRB2
C. CYP2D6
D. CYP2C9

2. CYP2D6 poor metabolizers taking Bystolic (nebivolol) may?
A. Experience less efficacy
B. Have an increased risk of side effects
C. Experience less benefit and increased risk of adverse effects
D. None of the above because nebivolol is not metabolized by CYP2D6

3. The ACE gene 267 base pair deletion (D allele) is associated with increased ACE levels and worse outcomes in HF.
A. True
B. False


4. Patients who carry the CYP11B2 T-allele are more likely to receive benefit from BiDil
A. True
B. False
1. D
2. B
3. A
4. A
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