Ticagrelor
1. Drug Name
Generic Name: Ticagrelor
Brand Names: Brilinta, Brilique
2. Drug Classification
Class: Antiplatelet Agent
Subclass: P2Y12 Receptor Antagonist (Reversible)
3. Mechanism of Action
Ticagrelor is a direct-acting and reversible P2Y12 receptor antagonist, which inhibits adenosine diphosphate (ADP)-mediated activation of the P2Y12 receptor on platelets. By blocking this receptor, ticagrelor prevents ADP-induced platelet aggregation and thrombus formation. Unlike other P2Y12 inhibitors such as clopidogrel, ticagrelor does not require metabolic activation, allowing for faster onset and greater platelet inhibition.
4. Pharmacokinetics
Absorption: Ticagrelor has a bioavailability of approximately 36%. It reaches peak plasma concentrations within 1.5-3 hours after oral administration.
Distribution: The volume of distribution (Vd) is approximately 88 liters. Ticagrelor is highly protein-bound (99%).
Metabolism: Ticagrelor is metabolized primarily by the CYP3A4 enzyme in the liver to its active metabolite, which also inhibits the P2Y12 receptor.
Excretion: The elimination half-life is 6-12 hours for ticagrelor and around 8-13 hours for its active metabolite. Excretion occurs mainly through the biliary and hepatic routes.
Special Considerations:
Renal Impairment: No dose adjustment is needed for renal impairment, but close monitoring is advised.
Hepatic Impairment: Not recommended in severe hepatic impairment, and caution is advised in mild-to-moderate hepatic impairment.
5. Indications
Primary Indications:
Acute Coronary Syndrome (ACS): For the reduction of thrombotic cardiovascular events in patients with ACS, including those managed medically or with percutaneous coronary intervention (PCI).
Secondary Prevention of Cardiovascular Events: For patients with a history of myocardial infarction to reduce the risk of further cardiovascular events.
Specific Populations: Beneficial in patients with a history of ACS, especially those who may require rapid and reversible platelet inhibition.
6. Dosage and Administration
General Adult Dosing:
Acute Coronary Syndrome: Initial loading dose of 180 mg orally, followed by a maintenance dose of 90 mg twice daily.
Post-MI Secondary Prevention: After the first year following an MI, a dose of 60 mg twice daily may be used for long-term prevention.
Administration: Ticagrelor can be taken with or without food. Avoid concomitant use with high doses of aspirin (>100 mg daily) as it can reduce ticagrelor’s efficacy.
7. Contraindications
Absolute Contraindications:
History of intracranial hemorrhage.
Active pathological bleeding (e.g., peptic ulcer or severe GI bleeding).
Severe hepatic impairment.
Relative Contraindications:
Co-administration with strong CYP3A4 inhibitors or inducers.
High risk of bleeding or undergoing major surgery.
8. Warnings and Precautions
Bleeding Risk: Ticagrelor increases bleeding risk, especially in patients with recent surgery or a history of bleeding. Monitor for signs of bleeding and avoid use in patients with active bleeding conditions.
Dyspnea: Some patients may experience dyspnea as an adverse effect, which is usually mild and transient but may require clinical evaluation.
Bradyarrhythmias: Caution in patients with a history of bradycardia or conduction disturbances, as ticagrelor may cause transient pauses.
9. Adverse Effects
Common Adverse Effects (≥10%):
Dyspnea.
Bleeding, including minor bleeding such as epistaxis and contusions.
Less Common but Clinically Significant Side Effects:
Gastrointestinal bleeding, including peptic ulcers.
Bradycardia or heart block, especially in predisposed individuals.
Rare/Serious Adverse Reactions:
Intracranial hemorrhage, which can be life-threatening.
Significant or severe hypersensitivity reactions, including anaphylaxis.
10. Drug Interactions
Major Drug Interactions:
CYP3A4 Inhibitors (e.g., ketoconazole, ritonavir): These drugs increase ticagrelor plasma levels and bleeding risk. Avoid co-administration or consider alternatives.
CYP3A4 Inducers (e.g., rifampin, carbamazepine): These drugs decrease ticagrelor plasma levels, reducing efficacy.
Aspirin: Use caution with high doses of aspirin (>100 mg daily) as it may decrease ticagrelor effectiveness.
Food-Drug Interactions: None significant, although it can be taken with food to minimize gastrointestinal discomfort.
Interactions with Lab Tests: May affect platelet function tests and coagulation assays, though routine monitoring is not required.
11. Clinical Pharmacology
Pharmacodynamics: Ticagrelor achieves potent and rapid platelet inhibition through direct, reversible inhibition of the P2Y12 receptor. It has a higher efficacy than clopidogrel in reducing major adverse cardiovascular events but has an associated higher risk of bleeding.
12. Special Populations
Pregnancy: Ticagrelor is not recommended during pregnancy due to insufficient data on safety; bleeding risks are a concern for both mother and fetus.
Lactation: Not recommended during breastfeeding due to lack of safety data.
Geriatrics: No specific dose adjustments are required, but careful monitoring for bleeding is essential due to higher bleeding risks in older adults.
Pediatrics: Safety and efficacy have not been established in pediatric patients.
13. Therapeutic Uses
Primary Use: Ticagrelor is primarily used for acute management of ACS and secondary prevention in patients with a history of myocardial infarction.
Combinational Therapy: Often combined with aspirin (dual antiplatelet therapy) to optimize prevention of thrombotic events in high-risk cardiovascular patients.
14. Monitoring and Follow-Up
Bleeding Monitoring: Routine assessment for signs of bleeding, especially gastrointestinal and intracranial bleeding, is essential.
Liver Function Tests: Monitor liver enzymes, especially in patients with hepatic impairment.
Symptom Monitoring: Evaluate for dyspnea and bradyarrhythmic symptoms during therapy.
15. Overdose Management
Symptoms of Overdose: Overdose primarily results in excessive bleeding. Severe overdose may increase the risk of bleeding-related mortality.
Treatment Protocols:
Activated Charcoal: May be administered if the overdose is recent.
Supportive Measures: Includes fluid replacement, blood products, and platelet transfusions if indicated. Ticagrelor’s anticoagulant effect may persist for several days post-discontinuation due to its long half-life.
Reversal Agents: No specific antidote is available for ticagrelor; treatment focuses on supportive care and symptom management.
16. Patient Counseling Information
Key Points:
Inform patients to take ticagrelor exactly as prescribed and not to discontinue abruptly without consulting a healthcare provider, as it may increase cardiovascular risk.
Report any signs of bleeding, including unusual bruising, blood in stools or urine, or prolonged bleeding after cuts.
Notify all healthcare providers, including dentists, of ticagrelor use before any surgical or invasive procedure.
Seek Immediate Medical Attention: Patients should seek prompt care if they experience significant bleeding, severe shortness of breath, or symptoms suggesting an adverse reaction like unusual dizziness or palpitations.