II. Antiplatelet Drugs

Introduction The vascular endothelial cell layer lining blood vessels has an anticoagulant phenotype, and circulating blood platelets and clotting factors do not normally adhere to it to an appreciable extent Following disruption of the endothelial lining and exposure of blood to the subendothelial vessel wall, platelets adhere to and virtually cover the exposed collagen of the subendothelium This triggers a complex series of chemical reactions, resulting in platelet activation

Introduction Activation of platelets results: Activation of thromboxane A2 synthesis, from arachidonic acid within platelets, that causes platelets to change shape, release their granules, and aggregate The release of platelet granules containing mediators, such as ADP and serotonin (5-HT), which stimulate aggregation Conformational change in the IIb/IIIa receptor, enabling it to bind fibrinogen, which cross-links adjacent platelets, resulting in aggregation and formation of a platelet plug

Platelet Aggregation Inhibitors Platelets provide the initial hemostatic plug at sites of vascular injury They also participate in pathological thromboses that lead to MI, stroke, and peripheral vascular thromboses These drugs decrease the formation or the action of chemical signals that promote platelet aggregation These drugs act by discrete mechanisms, and thus in combination their effects are additive or even synergistic

Platelet Aggregation Inhibitors Antiplatelets include: Aspirin Glycoprotein IIb/IIIa receptor inhibitor Antagonist of ADP receptors

Sites of Action of Antiplatelet Therapy on Mechanisms of Platelet Activation and Aggregation Copyright restrictions may apply. Schulman, S. P. JAMA 2004;292:1875-1882.

Sites of Action of Antiplatelet Therapy Clopidogrel Ticlopidine ADP Receptor (P2Y12) ADP Prasugrel ADP GP IIb/IIIa receptor Collagen Thrombin TXA2 Activation Fibrinogen COX TXA2 Abciximab Aspirin Eptfibatide ADP = adenosine diphosphate, TXA2 = thromboxane A2, COX = cyclooxygenase. Adapted from Schafer AI. Am J Med. 1996;101:199-209. Tirofiban

Aspirin It inhibits the synthesis of thromboxane A2 by irreversible acetylation of the enzyme cyclooxygenase-1 (COX-1) Since platelets do not synthesize new proteins, the action of aspirin on platelet cyclooxygenase is permanent, lasting for the life of the platelet (7 to 10 days) Repeated doses of aspirin produce a cumulative effect on platelet function

Aspirin Clinical uses: Prophylactic treatment of transient cerebral ischemia To reduce the incidence of recurrent MI To decrease mortality in pre- and post-myocardial infarct patients Aspirin is frequently used in combination with other drugs having anticlotting properties (e.g. heparin and clopedogril) ADRs: increased incidence of hemorrhagic stroke as well as GIT bleeding, especially at higher doses

Ticlopidine, Clopidogrel, & Prasugrel These drugs irreversibly block the ADP receptor on platelets and thereby prevent ADP-mediated platelet aggregation Ticlopidine, clopidogrel, & prasugrel are used in combination with aspirin following coronary stent implantation to decrease the incidence of stent thrombosis

Ticlopidine, Clopidogrel, & Prasugrel inhibit the P2Y12 receptor ADP Receptor (P2Y12) ADP Prasugrel ADP GP IIb/IIIa receptor Collagen Thrombin TXA2 Activation Fibrinogen COX TXA2 ADP = adenosine diphosphate, TXA2 = thromboxane A2, COX = cyclooxygenase. Adapted from Schafer AI. Am J Med. 1996;101:199-209.

Ticlopidine, Clopidogrel, & Prasugrel Ticlopidine ADRs: GIT: nausea, dyspepsia, and diarrhea Hemorrhage Leukopenia: detected by regular monitoring of the WBC count during the first 3 months of treatment Thrombotic thrombocytopenic purpura (TTP)

Ticlopidine, Clopidogrel, & Prasugrel Clopidogrel ADRs: Clopidogrel has fewer ADRs than ticlopidine: less frequent thrombocytopenia and leukopenia Clopidogrel is preferred over ticlopidine Prasugrel ADRs: the main side effect is bleeding which can be fatal

Blockade of Platelet Glycoprotein IIb/IIIa Receptors Agents: abciximab, eptfibatide, & tirofiban These drugs target the platelet IIb/IIIa receptor complex By binding to GP IIb/IIIa, these drug reversibly block the binding of fibrinogen and von Willebrand factor; consequently, aggregation does not occur

GP IIb/IIIa receptor antagonist Inhibition of platelet aggregation GP IIb/IIIa receptors bound by antagonists Agonist ADP, thrombin, epinephrine, TXA2, collagen, & others Resting platelet GP IIb/IIIa receptors in unreceptive state Fibrinogen Activated platelet GP IIb/IIIa receptors in ligand-receptive state Processes of Platelet Activation and Aggregation and Inhibition of Platelet Aggregation by Inhibitors of Glycoprotein IIb/IIIa Receptors Aggregation of platelets GP IIb/IIIa receptors are bound to fibrinogen, forming bridges between adjacent platelets

Blockade of Platelet Glycoprotein IIb/IIIa Receptors These agents are administered parenterally (IV) Clinical uses: to prevent restenosis after coronary angioplasty and to decrease the incidence of thrombotic complications associated with acute coronary syndromes Major ADRs: bleeding

III. Thrombolytic Drugs

Introduction During plug formation, the fibrinolytic pathway is locally activated Plasminogen is enzymatically processed to plasmin (fibrinolysin) by plasminogen activators in the tissue Plasmin is a relatively nonspecific protease; it digests fibrin clots and other plasma proteins, including several coagulation factors

Plasminogen Plasmin Fibrinogen degradation products Fibrinogen Fibrin Thrombin Fibrinogen degradation products Fibrinogen Fibrin Fibrin degradation products Clot dissolution Lytic state

Thromoblytic/Fibrinolytic Drugs Fibrinolytic agents include: Tissue plasminogen activator: alteplase, erteplase, and tenecteplase Streptokinase Urokinases Either directly or indirectly lyse thrombi by catalyzing the formation of the serine protease plasmin from its precursor zymogen, plasminogen

Plasminogen Fibrinolytic Agents Plasmin Fibrinogen Thrombin Fibrinogen degradation products Fibrinogen Fibrin Fibrin degradation products Clot dissolution Lytic state

Fibrinolytic agents Uses: PE, DVT, acute MI, arterial thrombosis, and occluded access shunts The greatest benefit of appears to be achieved by early administration (within 4 hrs) Major ADR: bleeding complications : Aminocaproic acid inhibits streptokinase-plasminogen activator complex formation and can be used in the rare instances of life-threatening hemorrhage