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

2. COX (cyclo-oxygenase) ADP (adenosine diphosphate) TXA 2 (thromboxane A 2 ) CLOPIDOGREL ASA COX ADP C GPllb/llla (Fibrinogen receptor) Collagen thrombin TXA 2 Activation TXA 2 Mode of Action of Antiplatelet Agents 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 (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. Ticlopidine

5. 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. Clopidogrel

6. Clopidogrel (Plavix™) Clopidogrel: – Inhibits the ADP P2Y 12 (P2T AC ) 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 P2Y 12 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 Endothelial Cell - Injury Platelet 1 23 1=adhesion 2=activation & release 3=aggregation Release

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