Prasugrel
1. Drug Name
Generic Name: Prasugrel
Brand Names: Effient
2. Drug Classification
Class: Antiplatelet Agent
Subclass: P2Y12 Receptor Antagonist (Irreversible)
3. Mechanism of Action
Prasugrel is a thienopyridine antiplatelet agent that selectively and irreversibly inhibits the P2Y12 ADP receptor on platelets. This blockade prevents ADP-mediated activation of the glycoprotein GPIIb/IIIa complex, ultimately inhibiting platelet aggregation. Prasugrel is a prodrug that undergoes rapid hydrolysis in the liver to its active metabolite, which provides potent and sustained platelet inhibition compared to other antiplatelets like clopidogrel.
4. Pharmacokinetics
Absorption: Prasugrel is well absorbed, with peak plasma concentrations of the active metabolite occurring within 30 minutes after oral administration. Bioavailability is approximately 79%.
Distribution: The volume of distribution (Vd) of the active metabolite is about 44–68 liters. Prasugrel has high protein-binding capacity (>98%).
Metabolism: Prasugrel is rapidly hydrolyzed in the liver by esterases to its active metabolite, with further metabolism by CYP3A4 and CYP2B6.
Excretion: The elimination half-life of the active metabolite is approximately 7 hours. Prasugrel and its metabolites are excreted primarily via urine (68%) and feces (27%).
Special Considerations:
Renal Impairment: No dose adjustment is required, though careful monitoring for bleeding is recommended.
Hepatic Impairment: Prasugrel should be used cautiously in mild-to-moderate hepatic impairment; contraindicated in severe hepatic dysfunction due to increased bleeding risk.
5. Indications
Primary Indications:
Acute Coronary Syndrome (ACS): Prasugrel is indicated for reducing thrombotic cardiovascular events in patients with ACS who are managed with percutaneous coronary intervention (PCI).
Specific Populations: Especially beneficial in high-risk ACS patients, such as those with diabetes or previous myocardial infarction (MI), as prasugrel provides a faster and more consistent platelet inhibition than clopidogrel.
6. Dosage and Administration
General Adult Dosing:
Acute Coronary Syndrome (ACS): An initial loading dose of 60 mg orally, followed by a maintenance dose of 10 mg once daily. A reduced maintenance dose of 5 mg is recommended for patients weighing <60 kg or those aged ≥75 years (based on clinical risk assessment).
Administration: Prasugrel is administered orally and can be taken with or without food.
7. Contraindications
Absolute Contraindications:
Active pathological bleeding (e.g., peptic ulcer, intracranial hemorrhage).
History of stroke or transient ischemic attack (TIA).
Severe hepatic impairment.
Relative Contraindications:
Age ≥75 years (increased bleeding risk unless high risk of recurrent MI).
Weight <60 kg (consider dose reduction).
8. Warnings and Precautions
Bleeding Risk: Prasugrel carries a significant risk of bleeding, especially in patients with recent trauma, surgery, or with predisposing conditions. Monitor for signs of bleeding.
Thrombotic Thrombocytopenic Purpura (TTP): Although rare, TTP has been reported with prasugrel. Monitor for symptoms such as thrombocytopenia and hemolytic anemia.
Discontinuation Warning: Sudden discontinuation increases the risk of thrombotic events. Avoid abrupt cessation unless medically necessary.
9. Adverse Effects
Common Adverse Effects (≥10%):
Bleeding (including minor bleeding such as epistaxis, hematomas).
Less Common but Clinically Significant Side Effects:
Hypertension.
Hypercholesterolemia.
Rare/Serious Adverse Reactions:
Major bleeding, including life-threatening or fatal hemorrhage.
Hypersensitivity reactions, including angioedema.
Thrombotic Thrombocytopenic Purpura (TTP).
10. Drug Interactions
Major Drug Interactions:
Anticoagulants (e.g., warfarin, heparin): Increased risk of bleeding when used concomitantly.
Nonsteroidal Anti-Inflammatory Drugs (NSAIDs): NSAIDs can enhance bleeding risks when co-administered with prasugrel.
CYP3A4 Inducers/Inhibitors: May affect prasugrel’s metabolism; however, clinical relevance is not established due to prasugrel's direct and extensive hepatic metabolism.
Food-Drug Interactions: None significant.
Interactions with Lab Tests: No known interactions with laboratory tests.
11. Clinical Pharmacology
Pharmacodynamics: Prasugrel achieves potent and irreversible inhibition of the P2Y12 receptor, leading to significant antiplatelet effects and reduced thrombotic risk in high-risk ACS patients. This irreversible inhibition means platelet function remains affected for the lifespan of the platelets (7–10 days), requiring caution with surgical interventions.
12. Special Populations
Pregnancy: Category B; safety during pregnancy is not established, so it is advised to use only if clearly needed.
Lactation: Insufficient data on excretion into human milk; use caution when prescribing to breastfeeding mothers.
Geriatrics: Reduced dose (5 mg) recommended for those ≥75 years to mitigate bleeding risks.
Pediatrics: Safety and efficacy in pediatric populations are not established.
13. Therapeutic Uses
Primary Use: Prasugrel is used in patients with ACS undergoing PCI, specifically for reducing the risk of stent thrombosis and recurrent thrombotic events.
Combinational Therapy: Often administered with aspirin as part of dual antiplatelet therapy (DAPT) to reduce cardiovascular events.
14. Monitoring and Follow-Up
Bleeding Monitoring: Continuous assessment for bleeding, especially gastrointestinal and intracranial, is essential.
Hematologic Monitoring: Consider monitoring platelet count in patients who develop bleeding symptoms or other hematologic abnormalities.
Symptom Monitoring: Evaluate for signs and symptoms of TTP and hypersensitivity reactions.
15. Overdose Management
Symptoms of Overdose: Symptoms primarily include excessive bleeding. Large overdoses may lead to potentially life-threatening hemorrhage.
Treatment Protocols:
Supportive Care: Manage bleeding symptomatically with appropriate supportive measures, including transfusions if necessary.
Reversal Agents: No specific antidote is available. Platelet transfusion may be effective since prasugrel irreversibly inhibits platelet function.
Activated Charcoal: May be administered if the overdose is identified within 1–2 hours of ingestion.
16. Patient Counseling Information
Key Points:
Instruct patients to take prasugrel exactly as prescribed and not to discontinue without consulting their healthcare provider, as this could increase their risk of thrombotic events.
Patients should report any signs of bleeding, including unusual bruising, blood in stools or urine, or prolonged bleeding from cuts.
Patients should inform all healthcare providers, including dentists, that they are taking prasugrel, especially before any surgery or dental work.
Seek Immediate Medical Attention: Patients should seek emergency care if they experience severe bleeding, symptoms suggestive of hypersensitivity, or neurological symptoms that may indicate intracranial bleeding.