Questions and Answers
What are three factors that can cause thrombosis?
Endothelial injury, abnormal blood flow, hypercoagulability
How can antiplatelet drugs prevent platelet activation?
Prevent TXA2 synthesis, antagonize ADP receptors, antagonize the platelet glycoprotein GPIIb/IIIa, inhibit phosphodiesterase (PDE)
What are the major drug targets for inhibiting platelet function?
ADP receptors (P2Y1 & P2Y12), COX-1 enzyme, fibrinogen receptors (GPIIb/IIIa), phosphodiesterases
Why would antiplatelet drugs target COX-1?
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What are the four clinically used ADP antagonists?
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What patients are ADP antagonists specifically useful for?
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Since Clopidogrel is a prodrug, what enzymes must activate it?
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Can Clopidogrel be combined with aspirin?
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What does Clopidogrel require to achieve a maximal antiplatelet effect rapidly?
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What are side effects of Clopidogrel?
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What are the drug-drug interactions with Clopidogrel?
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If someone is on Clopidogrel and needs to have surgery, what would you do?
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Can Clopidogrel (Plavix) be given in vitro to treat platelets?
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Which antiplatelet drugs are noncompetitive (irreversible) ADP (P2Y12) receptor antagonists?
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Which antiplatelet drugs are prodrugs?
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Which antiplatelet drugs require a loading dose?
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What is the purpose of a loading dose?
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Why is Ticlopidine less safe than Clopidogrel?
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If you are worried about a PPI interaction, which antiplatelet drug should you switch the patient to?
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What is the risk with Prasugrel compared to Clopidogrel?
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Which drug is the one competitive (reversible) ADP (P2Y12) receptor antagonist?
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Which patients would benefit from using Ticagrelor?
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Why shouldn't patients with a CYP2C19 polymorphism take Clopidogrel?
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How do antithromboxane drugs work?
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Which drug is the only irreversible inhibitor of COX-1 and COX-2?
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Chemically, what does Aspirin do to the COX enzymes to inhibit them?
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How long does the effect of Aspirin last?
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Study Notes
Thrombosis Factors
- Thrombosis can occur due to endothelial injury, abnormal blood flow, and hypercoagulability.
- These factors are interconnected and contribute to the formation of occluding thrombi.
Antiplatelet Drug Mechanism
- Antiplatelet drugs prevent platelet activation by inhibiting TXA2 synthesis, antagonizing ADP receptors, blocking GPIIb/IIIa glycoprotein, and inhibiting phosphodiesterase (PDE).
Major Drug Targets
- Key targets for inhibiting platelet function include ADP receptors (P2Y1 & P2Y12), COX-1 enzyme, fibrinogen receptors (GPIIb/IIIa), and phosphodiesterases.
Targeting COX-1
- Antiplatelet drugs target COX-1 because it produces TXA2, which activates new platelets and increases platelet aggregation.
Clinically Used ADP Antagonists
- Major ADP antagonists include Clopidogrel (Plavix), Ticlopidine (Ticlid), Prasugrel (Effient), and Ticagrelor (Brilinta).
Patients Benefiting from ADP Antagonists
- Useful for patients intolerant to aspirin.
Clopidogrel Activation
- Clopidogrel is a prodrug activated by CYP3A4 and CYP2C19 enzymes.
Clopidogrel and Aspirin Combination
- Clopidogrel can be safely combined with aspirin.
Clopidogrel Loading Dose
- A loading dose of 300 mg followed by 75 mg daily is crucial for rapidly achieving maximal antiplatelet effect.
Clopidogrel Side Effects
- Side effects include hemorrhage and serious risk of neutropenia.
Clopidogrel Drug-Drug Interactions
- Interactions with drugs metabolized by CYP3A4 (such as Atorvastatin) and PPIs (like Omeprazole, which inhibit CYP2C19) should be noted.
Surgery Protocol for Clopidogrel Users
- For patients needing surgery, a platelet transfusion is recommended, with a washout period of 5-7 days.
Clopidogrel in Vitro Use
- Cannot be used in vitro to treat platelets as it is a prodrug reliant on metabolic activation.
Noncompetitive ADP Receptor Antagonists
- Clopidogrel, Ticlopidine, and Prasugrel act as noncompetitive (irreversible) ADP (P2Y12) receptor antagonists.
Prodrugs in Antiplatelet Therapy
- Clopidogrel, Ticlopidine, and Prasugrel are all classified as prodrugs.
Antiplatelet Agents Requiring Loading Dose
- Clopidogrel, Prasugrel, and Ticagrelor require a loading dose for effective action.
Purpose of Loading Dose
- A loading dose expedites the achievement of steady state concentration of the drug.
Ticlopidine Safety Profile
- Ticlopidine has a less favorable safety profile than Clopidogrel, causing neutropenia and thrombocytopenia, necessitating frequent blood count monitoring.
Switching from Clopidogrel Due to PPI Interaction
- Switching to Prasugrel is advisable to avoid PPI interactions, as it is metabolized by CYP3A4 and CYP2B6 instead of CYP2C19.
Risk of Prasugrel
- Prasugrel presents a higher risk of bleeding compared to Clopidogrel.
Competitive ADP Receptor Antagonist
- Ticagrelor is the only competitive (reversible) ADP (P2Y12) receptor antagonist and is not a prodrug.
Ticagrelor Usage
- Beneficial for patients with reduced CYP2C19 activity.
CYP2C19 Polymorphism and Clopidogrel
- Patients with CYP2C19 polymorphism should avoid Clopidogrel as they are poor metabolizers, reducing its effectiveness despite increased dosing.
Antithromboxane Drug Mechanism
- Antithromboxane drugs inhibit COX-1, preventing TXA2 formation and subsequent platelet activation.
Aspirin's Role
- Aspirin is the only irreversible inhibitor of COX-1 and COX-2 enzymes.
Aspirin's Mechanism of Action
- Aspirin functionally irreversibly acetylates the serine residue of COX enzymes.
Duration of Aspirin's Effect
- The antiplatelet effect of aspirin lasts the lifetime of the platelets.
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