Antiplatelet Drugs - Principles

Antiplatelet Drugs - Principles

Benedict R. Lucchesi, M.D., Ph.D.Department of Pharmacology

University of Michigan Medical School

Collagen

TissueFactor

Thrombin

Plateletactivation

Prothrombin

ADP

TXA2

PlasmaClottingcascade

THROMBUS

Fibrinogen Fibrin

Plateletaggregation

• Thrombin is a critical mediator in coagulation

• Elicits multiple responses in platelets

Platelet Activation - Arterial Thrombus Formation

Fibrinogen

Platelet GPIIb/IIIa(Fibrinogen) Receptor

Endothelial Cell - Injury

Platelet

1 2 3

1=adhesion2=activation & release3=aggregation

Release

RGD SequencesC-Terminal 12residues of theγ chainFibrinogen

GPIIb/GPIIIa

GPIIb/GPIIIa

βα

γ

αβγBloodPlatelet

BloodPlatelet

INTERACTION BETWEEN FIBRINOGEN AND GPIIb/IIIa

Inhibitors of the Arachidonic Acid Pathway

Cyclooxygenase InhibitorsCyclooxygenase InhibitorsAspirin

Ibuprofen

Indomethacin

SulfinpyrazoneAspirin does impair the aggregation response to epinephrine,

ADP or thrombin and does not affect subendothelial platelet adhesion.

Modifiers of Platelet Cyclic AMPModifiers 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

NitratesNitrates• 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.

Ticlopidine (Ticlid™) Ticlopidine (Ticlid™) Clopidogrel (Plavix™)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.

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™)

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.

Altered Platelet FunctionMechanisms 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.

Altered Platelet FunctionMechanisms 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

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