Pharmacogenomics and Drug– Drug Interactions

Question 1

What does the active metabolite of clopidogrel inhibit?

Answer 1

The ADP P2Y12 receptor

This inhibition increases cAMP levels and VASP-P, leading to reduced platelet activation and aggregation.

Question 2

What are the downstream effects of inhibiting the ADP P2Y12 receptor?

Answer 2

Increase in cAMP levels and VASP-P

This overall inhibits platelet activation and aggregation processes.

Question 3

What enzyme is involved in the metabolism of clopidogrel and is affected by PPIs?

Answer 3

Cytochrome P450 (CYP) 2C19

Drug interactions with omeprazole and clopidogrel occur due to this common metabolic pathway.

Question 4

What is the significance of the CYP2C19 isoenzyme in clopidogrel metabolism?

Answer 4

It is involved in both oxidation steps required for clopidogrel prodrug to generate its active metabolite

Genetic polymorphisms or drugs affecting this enzyme can influence clopidogrel’s efficacy.

Question 5

What effect does morphine have on ticagrelor and prasugrel?

Answer 5

Reduces antiplatelet effects and delays onset of action

Particularly significant in ACS patients, especially during STEMI.

Question 6

What is the prevalence of the 2/2 poor metabolizer status among different ethnic groups?

Answer 6

• Caucasians: ~3%
• African Americans: ~5%
• Asians: ~15%

This status is linked to higher rates of major adverse cardiovascular events.

Question 7

What are the classifications of CYP2C19 metabolic status?

Answer 7

• Ultrarapid: 1/17, 17/17
• Extensive: 1/1
• Intermediate: 1/2-8, 17/2-8
• Poor: 2-8/2-8

The wild-type allele is indicated as *1.

Question 8

What are the new recommendations regarding platelet function testing according to the 2011 ACCF/AHA update?

Answer 8

Platelet function testing may be considered if it could alter management

This is a Class IIb recommendation with level of evidence B.

Question 9

What is the recommended daily maintenance dose of aspirin when used with ticagrelor?

Answer 9

75 to 100 mg

Higher doses may decrease the efficacy of ticagrelor.

Question 10

How does a 60-mg loading dose of prasugrel compare to clopidogrel?

Answer 10

More potent and achieves effects more rapidly

This is true even when clopidogrel is used at high doses.

Question 11

What is the primary metabolic pathway for ticagrelor?

Answer 11

CYP3A4 system

Strong CYP3A4 inhibitors can significantly increase the risk of bleeding when used with ticagrelor.

Question 12

True or False: Increasing the dose of aspirin is an effective method to overcome aspirin resistance.

Answer 12

False

Noncompliance is the most important cause of aspirin resistance.

Question 13

What impact does morphine have on clopidogrel’s pharmacodynamics?

Answer 13

Delays absorption and reduces active metabolite

This results in delayed maximal inhibition of platelet aggregation.

Question 14

What factors account for inadequate clopidogrel-induced antiplatelet effects?

Answer 14

• Genetic factors
• Cellular factors
• Clinical factors
• Noncompliance and underdosing

Noncompliance seems to play the most important role.

Question 15

What is the recommendation for patients on dual antiplatelet therapy with a history of GI bleeding?

Answer 15

They can continue or start taking PPIs, including omeprazole

Omeprazole has been shown to significantly reduce the antiplatelet effect of clopidogrel.

Question 16

What effect does omeprazole have on clopidogrel?

Answer 16

Decreases the antiplatelet effect of clopidogrel

Studies revealed that the interaction between PPIs and clopidogrel is not a class effect.

Question 17

Which PPI showed significantly better platelet inhibition when combined with clopidogrel?

Answer 17

Pantoprazole

Patients receiving pantoprazole had 44% nonresponders compared to 23% in the omeprazole group.

Question 18

What does the FDA recommend regarding the use of clopidogrel with omeprazole or esomeprazole?

Answer 18

Avoid simultaneous use

This recommendation addresses potential interactions that may affect efficacy.

Question 19

What is the ACCF/AHA recommendation for PPI use in patients with a history of prior GI bleeding requiring DAPT?

Answer 19

Class I recommendation for PPI use

Class IIa recommendation for patients at increased risk of GI bleeding.

Question 20

What is the mechanism through which aspirin exerts its effects?

Answer 20

COX-1 inhibition

Aspirin blocks the platelet’s ability to synthesize thromboxane A2.

Question 21

What is the recommended dosage of aspirin for achieving full effects quickly?

Answer 21

Chewing 162 to 325 mg

This allows for effect within approximately 15 minutes.

Question 22

Which azole antifungal is considered a potent inhibitor of CYP3A4?

Answer 22

Ketoconazole

Azole antifungals can interfere with the efficacy of clopidogrel.

Question 23

What is the role of CYP2C19 in clopidogrel metabolism?

Answer 23

Central role in converting clopidogrel to its active metabolite

Carriers of loss of function alleles have lower active metabolite levels.

Question 24

What is the significance of genetic variants in ABCB1 regarding clopidogrel?

Answer 24

They can reduce concentrations of the active drug metabolite

Increased rates of adverse clinical outcomes are associated with these variants.

Question 25

What are the anticoagulant agents mentioned?

Answer 25

UFH, low molecular weight heparin, bivalirudin, warfarin

These agents have varying effects influenced by multiple factors.

Question 26

What is the target ACT recommended for UFH during coronary angioplasty?

Answer 26

250 to 300 seconds with HemoTec; 300 to 350 seconds with Hemochron

Guidelines recommend a weight-adjusted bolus of heparin.

Question 27

When should NSAIDs like ibuprofen be avoided in patients with coronary artery disease?

Answer 27

When possible, to prevent adverse cardiovascular outcomes

Ibuprofen can significantly increase all-cause mortality risk.

Question 28

What interaction occurs between ibuprofen and aspirin?

Answer 28

Competitive inhibition of COX-1

This may reduce the antiplatelet effectiveness of aspirin.

Question 29

True or False: COX-2 selective agents are less likely to interfere with aspirin’s effectiveness.

Answer 29

True

Examples include celecoxib, diclofenac, and meloxicam.