Ticlopidine (Ticlid™) and Clopidogrel (Plavix™)

1. Ticlopidine (Ticlid™) and Clopidogrel (Plavix™) Benedict R. Lucchesi, M.D., Ph.D. Department of Pharmacology University of Michigan Medical School

2. CLOPIDOGREL C ADP ADP GPllb/llla (Fibrinogen receptor) Collagen thrombin TXA Activation 2 COX ASA TXA 2 Mode of Action of Antiplatelet Agents COX (cyclo-oxygenase) ADP (adenosine diphosphate) TXA2 (thromboxane A2) 1. Schafer AI. Am J Med 1996; 101: 199–209.

3. Ticlopidine (Ticlid™) and Clopidogrel (Plavix™) • Oral, platelet-aggregation inhibitor structurally unrelated to any other agent in its class. • May be more efficacious than aspirin, but more serious and more frequent adverse effects • May be used for patients who are intolerant or to aspirin. • Interferes with the ADP-induced binding of fibrinogen to the platelet membrane at specific receptor sites.

4. Ticlopidine Ticlopidine (Ticlid™) • Platelet inhibition is irreversible. • Platelet-aggregation inhibition is not significant until after approximately 4 days of regular dosing. • Platelet function returns to normal within 1–2 weeks as new platelets replace those affected by ticlopidine or clopidogrel.

5. Clopidogrel Clopidogrel (Plavix™) • Selectively inhibits the binding of adenosine diphosphate (ADP) to its platelet receptor and the subsequent ADP-mediated activation of the glycoprotein GPIIb/IIIa complex, thereby inhibiting platelet aggregation. • Biotransformation of clopidogrel is necessary to produce inhibition of platelet aggregation, but an active metabolite responsible for the activity of the drug has not been isolated. • Clopidogrel also inhibits platelet aggregation induced by agonists other than ADP by blocking the amplification of platelet activation by released ADP. Clopidogrel does not inhibit phosphodiesterase activity.

6. Clopidogrel (Plavix™) • Clopidogrel: • Inhibits the ADP P2Y12 (P2TAC) platelet receptor. • Acts by irreversibly modifying the platelet ADP receptor. Consequently, platelets exposed to clopidogrel are affected for the remainder of their lifespan. • ADP-induced activation of the platelet P2Y12 results in the activation of the GPIIb/IIIa fibrinogen receptor. • Dose dependent inhibition of platelet aggregation can be seen 2 hours after single oral doses.. • Repeated doses of 75 mg per day inhibit ADP-induced platelet aggregation on the first day, and inhibition reaches steady state between Day 3 and Day 7. • Platelet aggregation and bleeding time gradually return to baseline values after treatment is discontinued, generally in about 5 days.

7. Indications for Clopidogrel Recent MI, Recent Stroke or Established Peripheral Arterial Disease • For patients with a history of recent myocardial infarction (MI), recent stroke, or established peripheral arterial disease, Acute Coronary Syndrome • For patients with acute coronary syndrome (unstable angina/non-Q-wave MI) including patients who are to be managed medically and those who are to be managed with percutaneous coronary intervention (with or without stent) or CABG.

8. Clopidogrel (Plavix™) • For patients with acute coronary syndrome (unstable angina/non-Q-wave MI), clopidogrel should be initiated with a single 300 mg loading dose and then continued at 75 mg once daily. • Aspirin (75 mg-325 mg once daily) should be initiated and continued in combination with clopidogrel. • Most patients with Acute Coronary Syndrome also receive heparin acutely.

9. Platelet Activation - Arterial Thrombus Formation Fibrinogen Platelet GPIIb/IIIa (Fibrinogen) Receptor Release Platelet 1 2 3 1=adhesion 2=activation & release 3=aggregation Endothelial Cell - Injury

10. Platelet Glycoprotein IIb/IIIa Receptor Activated Platelet Activated Platelet Activated Platelet Fibrinogen RGD Binding Site Activated Platelet