Usage
- Aspirin + Ticlopidine is prescribed for the prevention of thrombotic events like stroke and acute coronary syndrome, particularly in patients who are intolerant to or unresponsive to aspirin alone. It’s specifically indicated for patients with a history of stroke precursors (transient ischemic attack, reversible ischemic neurological deficit) or completed atherothrombotic stroke, and for the prevention of subacute stent occlusion after intracoronary stenting. It has also been studied in unstable angina, intermittent claudication associated with peripheral vascular disease (PVD), and myocardial infarction prophylaxis.
- Pharmacological classification: Antiplatelet agents.
- Mechanism of action: Aspirin inhibits cyclooxygenase-1 (COX-1), thus reducing thromboxane A2 formation and platelet aggregation. Ticlopidine irreversibly inhibits the ADP-induced binding of fibrinogen to the platelet glycoprotein IIb/IIIa receptor, which plays a critical role in platelet activation and aggregation. The combination of aspirin and ticlopidine offers synergistic antiplatelet effects, targeting different pathways of platelet activation.
Alternate Names
- There isn’t a recognized alternate name for this combination other than the names of the drugs.
- Brand Names: Ticlid (for Ticlopidine). Aspirin is widely available generically and under various brand names (e.g. Bayer, Ecotrin). The combination is not typically marketed under a single brand name.
How It Works
- Pharmacodynamics: Aspirin inhibits platelet aggregation through irreversible inactivation of COX-1, thereby reducing thromboxane A2 synthesis. Ticlopidine acts by inhibiting the binding of adenosine diphosphate (ADP) to its platelet receptor, which prevents the activation of the glycoprotein IIb/IIIa receptor complex and subsequent platelet aggregation. The combination leads to a significant reduction in platelet activity.
- Pharmacokinetics:
- Absorption: Both aspirin and ticlopidine are well-absorbed orally, with ticlopidine’s absorption enhanced by food.
- Metabolism: Aspirin is rapidly hydrolyzed to salicylic acid in the liver and other tissues. Ticlopidine is extensively metabolized in the liver via CYP450 enzymes, primarily CYP2C19.
- Elimination: Aspirin metabolites are primarily excreted in the urine. Ticlopidine is excreted in both urine and feces.
- Mode of action: Aspirin irreversibly acetylates the serine residue in the active site of COX-1, preventing thromboxane A2 formation, a potent platelet activator and vasoconstrictor. Ticlopidine selectively and irreversibly blocks P2Y12, a subtype of the ADP receptor on platelets, preventing ADP-mediated platelet activation and aggregation. Neither agent affects the number of circulating platelets; they influence platelet function.
- Receptor binding/enzyme inhibition: Aspirin inhibits COX-1 enzyme. Ticlopidine inhibits the P2Y12 ADP receptor on platelets.
- Elimination pathways: Aspirin is renally excreted. Ticlopidine is excreted in both urine and feces.
Dosage
Standard Dosage
Adults:
- Stroke Prevention: Ticlopidine 250 mg twice daily taken orally with food.
- Coronary Artery Stenting: Ticlopidine 250 mg twice daily taken orally with food along with antiplatelet doses of aspirin (e.g., 75-325 mg daily) for up to 30 days post-procedure.
Children:
- Ticlopidine use is not established in children.
Special Cases:
- Elderly Patients: Clearance of ticlopidine is reduced in elderly patients, so monitoring for adverse events, especially bleeding, is crucial. Dose adjustments are typically made after assessment of creatinine clearance.
- Patients with Renal Impairment: Close monitoring is necessary. Dose adjustments may be required based on creatinine clearance.
- Patients with Hepatic Dysfunction: Ticlopidine is contraindicated in severe hepatic impairment. Caution is advised in mild to moderate hepatic impairment due to increased drug exposure risk.
- Patients with Comorbid Conditions: Use with caution in patients with bleeding disorders, peptic ulcer disease, or a history of thrombotic thrombocytopenic purpura (TTP).
Clinical Use Cases
The primary clinical use cases and dosages are described above (Stroke Prevention and Coronary Artery Stenting). Ticlopidine is not indicated for acute interventions such as intubation, surgical procedures, mechanical ventilation, ICU use, or other emergency situations.
Dosage Adjustments
Dosage adjustments are based primarily on renal and hepatic function. There are no specific dosage adjustments for genetic polymorphisms affecting drug metabolism. For patients with renal impairment, careful monitoring of hematological parameters and signs of bleeding is crucial. For patients with hepatic impairment, ticlopidine should be used with extreme caution or avoided if the impairment is severe.
Side Effects
Common Side Effects
- Diarrhea
- Nausea
- Dyspepsia
- Rash
- Abdominal pain
- Neutropenia
Rare but Serious Side Effects
- Thrombotic thrombocytopenic purpura (TTP)
- Aplastic anemia
- Agranulocytosis
- Neutropenia
- Pancytopenia
- Severe bleeding
- Hepatotoxicity
Long-Term Effects
- Increased risk of bleeding with chronic use, particularly in patients with bleeding diatheses
- Increased cholesterol and triglyceride levels
Adverse Drug Reactions (ADR)
- TTP, Neutropenia/Agranulocytosis, Aplastic anemia.
Contraindications
- Hypersensitivity to ticlopidine or aspirin
- History of TTP or aplastic anemia
- Active pathological bleeding (e.g., peptic ulcer, intracranial hemorrhage)
- Severe hepatic impairment
- Pre-existing neutropenia or thrombocytopenia
- Concomitant use with other anticoagulants (unless specifically indicated, as in coronary stenting for a limited duration)
Drug Interactions
- Aspirin: Synergistic effect on platelet aggregation, increasing bleeding risk. Short term use is acceptable (up to 30 days with coronary stenting).
- NSAIDs: Increased bleeding risk.
- Anticoagulants (Warfarin, Heparin): Increased bleeding risk.
- CYP2C19 inhibitors (e.g., Cimetidine, Omeprazole): Increased ticlopidine levels.
- CYP enzyme inducers (e.g., Phenytoin): Decreased ticlopidine levels.
- Antacids: Decreased ticlopidine absorption.
Pregnancy and Breastfeeding
- Pregnancy Safety Category: B. Aspirin can cause bleeding complications and prolong labor if taken in the third trimester, but ticlopidine is generally considered safe during pregnancy.
- Ticlopidine is not known to be excreted in breast milk. However, aspirin is excreted and can potentially cause adverse effects in a nursing infant. If the combination is essential, breastfeeding should be stopped during treatment or careful monitoring of the infant for effects is recommended.
Drug Profile Summary
- Mechanism of Action: Aspirin inhibits COX-1 and reduces thromboxane A2. Ticlopidine inhibits ADP-mediated platelet aggregation.
- Side Effects: Diarrhea, nausea, rash, bleeding, neutropenia, TTP (rare).
- Contraindications: Hypersensitivity, history of TTP/aplastic anemia, active bleeding, severe hepatic impairment.
- Drug Interactions: Aspirin, NSAIDs, anticoagulants, CYP2C19 inhibitors/inducers, antacids.
- Pregnancy & Breastfeeding: Caution is advised. Monitor infant for potential adverse effects, such as increased bleeding risk. Aspirin is not recommended during the third trimester, and its presence in breastmilk can affect infants.
- Dosage: 250 mg ticlopidine twice daily with or without aspirin (as per clinical indication).
- Monitoring Parameters: Complete blood count (CBC) with differential, especially during the first three months of therapy, liver function tests, signs of bleeding.
Popular Combinations
- Aspirin (for coronary artery stenting)
Precautions
- General Precautions: Monitor CBC, especially during the first three months, due to the risk of neutropenia, agranulocytosis, and TTP. Monitor for signs of bleeding.
- Specific Populations: Same as mentioned in special cases under dosage section.
- Lifestyle Considerations: Alcohol consumption can increase the risk of bleeding.
FAQs (Frequently Asked Questions)
Q1: What is the recommended dosage for Aspirin + Ticlopidine?
A: For stroke prevention: Ticlopidine 250 mg twice daily. For coronary stenting: Ticlopidine 250 mg twice daily plus aspirin (dose as determined by the cardiologist) for up to 30 days post-procedure.
Q2: What are the most serious side effects of Ticlopidine?
A: TTP, aplastic anemia, agranulocytosis, and severe bleeding.
Q3: What is the mechanism of action of Ticlopidine?
A: Ticlopidine irreversibly inhibits ADP-induced platelet aggregation.
Q4: How does aspirin interact with ticlopidine?
A: Aspirin and ticlopidine have a synergistic effect on platelet aggregation, which can enhance the risk of bleeding.
Q5: Can ticlopidine be used during pregnancy?
A: Ticlopidine is generally considered safe during pregnancy, although caution is advised. However, aspirin should be avoided in the third trimester and ticlopidine co-administration should factor in potential drug interaction and subsequent risks.
Q6: Is ticlopidine safe for patients with liver disease?
A: Ticlopidine is contraindicated in patients with severe hepatic impairment and should be used with caution in mild to moderate hepatic impairment.
Q7: What monitoring parameters are important for patients on ticlopidine?
A: Regular CBC with differential (especially during the first three months), liver function tests, and close monitoring for signs of bleeding are essential.
Q8: What are the common drug interactions of ticlopidine?
A: Aspirin, NSAIDs, anticoagulants, CYP2C19 inhibitors (e.g. cimetidine), and antacids.
Q9: What should patients know about taking ticlopidine?
A: Take with food to minimize gastrointestinal discomfort. Report any unusual bleeding or bruising immediately. Inform healthcare provider about all medications and supplements being taken. Regular blood tests are required to monitor for potential side effects.
