Antiplatelet Drugs - Principles

1. Antiplatelet Drugs - Principles Benedict R. Lucchesi, M.D., Ph.D. Department of Pharmacology University of Michigan Medical School

2. Plateletactivation Plateletaggregation Thrombin ADP Collagen TXA2 Fibrinogen Fibrin Prothrombin THROMBUS PlasmaClottingcascade TissueFactor • Thrombin is a critical mediator in coagulation • Elicits multiple responses in platelets

3. 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

5. Inhibitors of the Arachidonic Acid Pathway • Cyclooxygenase Inhibitors • Aspirin • Ibuprofen • Indomethacin • Sulfinpyrazone • Aspirin does impair the aggregation response to epinephrine, ADP or thrombin and does not affect subendothelial platelet adhesion.

6. Modifiers of Platelet Cyclic AMP • Agents that increase cyclic AMP will inhibit platelet aggregation. Increases in cyclic AMP are achieved in two ways: • stimulation of adenylate cyclase • inhibition of phosphodiesterase • Prostacyclin and Derivatives -Increases cAMP • Therapeutic use limited by side effects • Dipyridamole - PDE inhibitor • Therapeutic efficacy is questionable

7. Nitrates • Nitrates (nitroglycerin, isosorbide dinitrate, etc.) undergo conversion in the platelet to yield nitric oxide (NO). • NO activated platelet guanylate cyclase (cGMP) resulting in an inhibition of platelet aggregation • Nitrates may also increase synthesis of prostacyclin by the endothelial cells • The full potential of nitrates as antiplatelet drugs is relatively unexplored.

8. Ticlopidine (Ticlid™) • Clopidogrel (Plavix™) • Prolongs bleeding time • Inhibits platelet aggregation in response to ADP, but not to epinephrine, arachidonic acid, 5-HT, thrombin, etc. • Antiplatelet effects develop slowly - 24 to 48 hours from initial dosing. • Onset of action may be increased with large oral dose.

9. Antiplatelet Therapy in Patients with Ischemic Heart Disease • Acetylsalicylic Acid (Aspirin) • Ticlopidine (Ticlid™) • Clopidogrel (Plavix™) • Dipyridamole (Persantin™) • Aspirin+ Dipyridamole(Aggrenox™) • Abciximab (7E3 Antibody; ReoPro™) • Eptifibatide (Integrilin™) • Tirofiban (Aggrestat™)

10. Ischemic Heart Disease and Platelet Function • Patients with ischemic heart disease and abnormal coronary artery anatomy are at an increased risk for: • activation of circulating blood platelets • platelet vessel wall interactions • platelet adhesion and intravascular aggregation • episodic, transient interruptions in coronary artery blood flow - transient ischemic events • occlusive thrombus formation - prolonged regional myocardial ischemia - infarction.

11. Altered Platelet Function Mechanisms associated in arterial thrombus formation 1. exposure of the circulating blood to a thrombo-genic surface • injured endothelial surface and exposure of subendothelial structures - collagen • atheromatous lesions on vessel wall - leading to turbulent flow • rupture of the fibrous cap of the atheromatous lesion and exposure of lipids, collagen, thrombogenic contents.

12. Altered Platelet Function Mechanisms associated in arterial thrombus formation (continued) 2. A sequence of platelet related events, involving, • platelet adhesion • platelet aggregation • release of platelet components that promote • further aggregation • vasoconstriction • activation of the coagulation cascade

13. Altered Platelet Function Mechanisms associated in arterial thrombus formation (continued) 3. Activation of the clotting mechanism with an important role for thrombin.... • formation of fibrin • stabilization of platelet aggregate/thrombus • activation of the platelet to enhance aggregation • activation of thrombomodulin/ProteinC/ inhibi-tion of fVIIIa and fVa