Pharmacogenomics and Drug– Drug Interactions Flashcards
What does the active metabolite of clopidogrel inhibit?
The ADP P2Y12 receptor
This inhibition increases cAMP levels and VASP-P, leading to reduced platelet activation and aggregation.
What are the downstream effects of inhibiting the ADP P2Y12 receptor?
Increase in cAMP levels and VASP-P
This overall inhibits platelet activation and aggregation processes.
What enzyme is involved in the metabolism of clopidogrel and is affected by PPIs?
Cytochrome P450 (CYP) 2C19
Drug interactions with omeprazole and clopidogrel occur due to this common metabolic pathway.
What is the significance of the CYP2C19 isoenzyme in clopidogrel metabolism?
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.
What effect does morphine have on ticagrelor and prasugrel?
Reduces antiplatelet effects and delays onset of action
Particularly significant in ACS patients, especially during STEMI.
What is the prevalence of the 2/2 poor metabolizer status among different ethnic groups?
- Caucasians: ~3%
- African Americans: ~5%
- Asians: ~15%
This status is linked to higher rates of major adverse cardiovascular events.
What are the classifications of CYP2C19 metabolic status?
- 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.
What are the new recommendations regarding platelet function testing according to the 2011 ACCF/AHA update?
Platelet function testing may be considered if it could alter management
This is a Class IIb recommendation with level of evidence B.
What is the recommended daily maintenance dose of aspirin when used with ticagrelor?
75 to 100 mg
Higher doses may decrease the efficacy of ticagrelor.
How does a 60-mg loading dose of prasugrel compare to clopidogrel?
More potent and achieves effects more rapidly
This is true even when clopidogrel is used at high doses.
What is the primary metabolic pathway for ticagrelor?
CYP3A4 system
Strong CYP3A4 inhibitors can significantly increase the risk of bleeding when used with ticagrelor.
True or False: Increasing the dose of aspirin is an effective method to overcome aspirin resistance.
False
Noncompliance is the most important cause of aspirin resistance.
What impact does morphine have on clopidogrel’s pharmacodynamics?
Delays absorption and reduces active metabolite
This results in delayed maximal inhibition of platelet aggregation.
What factors account for inadequate clopidogrel-induced antiplatelet effects?
- Genetic factors
- Cellular factors
- Clinical factors
- Noncompliance and underdosing
Noncompliance seems to play the most important role.
What is the recommendation for patients on dual antiplatelet therapy with a history of GI bleeding?
They can continue or start taking PPIs, including omeprazole
Omeprazole has been shown to significantly reduce the antiplatelet effect of clopidogrel.
What effect does omeprazole have on clopidogrel?
Decreases the antiplatelet effect of clopidogrel
Studies revealed that the interaction between PPIs and clopidogrel is not a class effect.
Which PPI showed significantly better platelet inhibition when combined with clopidogrel?
Pantoprazole
Patients receiving pantoprazole had 44% nonresponders compared to 23% in the omeprazole group.
What does the FDA recommend regarding the use of clopidogrel with omeprazole or esomeprazole?
Avoid simultaneous use
This recommendation addresses potential interactions that may affect efficacy.
What is the ACCF/AHA recommendation for PPI use in patients with a history of prior GI bleeding requiring DAPT?
Class I recommendation for PPI use
Class IIa recommendation for patients at increased risk of GI bleeding.
What is the mechanism through which aspirin exerts its effects?
COX-1 inhibition
Aspirin blocks the platelet’s ability to synthesize thromboxane A2.
What is the recommended dosage of aspirin for achieving full effects quickly?
Chewing 162 to 325 mg
This allows for effect within approximately 15 minutes.
Which azole antifungal is considered a potent inhibitor of CYP3A4?
Ketoconazole
Azole antifungals can interfere with the efficacy of clopidogrel.
What is the role of CYP2C19 in clopidogrel metabolism?
Central role in converting clopidogrel to its active metabolite
Carriers of loss of function alleles have lower active metabolite levels.
What is the significance of genetic variants in ABCB1 regarding clopidogrel?
They can reduce concentrations of the active drug metabolite
Increased rates of adverse clinical outcomes are associated with these variants.
What are the anticoagulant agents mentioned?
UFH, low molecular weight heparin, bivalirudin, warfarin
These agents have varying effects influenced by multiple factors.
What is the target ACT recommended for UFH during coronary angioplasty?
250 to 300 seconds with HemoTec; 300 to 350 seconds with Hemochron
Guidelines recommend a weight-adjusted bolus of heparin.
When should NSAIDs like ibuprofen be avoided in patients with coronary artery disease?
When possible, to prevent adverse cardiovascular outcomes
Ibuprofen can significantly increase all-cause mortality risk.
What interaction occurs between ibuprofen and aspirin?
Competitive inhibition of COX-1
This may reduce the antiplatelet effectiveness of aspirin.
True or False: COX-2 selective agents are less likely to interfere with aspirin’s effectiveness.
True
Examples include celecoxib, diclofenac, and meloxicam.
