1. II. Antiplatelet Drugs

2. 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

3. 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

4. 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

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

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

7. 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:
Tirofiban

8. 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

9. 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

10. 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

11. 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:

12. 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)

13. 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

14. 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

15. 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

16. 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

17. III. Thrombolytic Drugs

18. 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

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

20. 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

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

22. 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