Antiplatelet drugs Prof. Hanan Hagar

Learning objectives By the end of this lecture, students should be able to To describe the role of platelets in clot formation To know the different classes of anti-platelet drugs depending on their target of action. To understand pharmacokinetics, pharmacological effects, clinical applications and side effects of anti-platelet drugs.

 In healthy vasculature, circulating platelets are maintained in an inactive state by:  nitric oxide (NO) and prostacyclin (PGI2) released by endothelial cells lining the blood vessels.  NO & PGI2 → ↑ increases platelet cAMP thus inhibits platelet aggregation. Platelets and blood vessels

Platelet aggregation  An injury to vascular system leads to interaction between blood platelets, endothelial system and coagulation factors which lead to formation of the blood CLOT.

Platelets aggregation & Arterial Thrombosis

Vascular Injury Exposure of collagen and vWF Tissue factor exposure Platelet adhesion and releaseActivation of coagulation Platelet recruitment and activation Thrombin generation Fibrin formation Platelet aggregation Platelet – fibrin thrombus

Plaque rupture CollagenvWF Platelet adhesion and secretion Thrombin generation Platelet aggregation Platelet recruitment and activation X Expression of GPllb / llla receptors TXA2, ADP

Platelets aggregation 1. Platelet adhesion occurs at the site of plaque rupture due to exposure of collagen present in sub-endothelium at site of injury. 2. Platelets recruitment& activation: activated platelets release mediators for attraction and activation of other platelets as thromboxane A2 (TXA2), ADP, PAF and serotonin.  Collagen, thrombin, adenosine diphosphate (ADP), and thromboxane A2 activate platelets by binding to their respective platelet receptors.

Thromboxane A2 (TXA2): –is synthesized from arachidonic acid within platelets –stimulates aggregation & vasoconstriction. Serotonin (5HT): - stimulates aggregation & vasoconstriction. Adenosine diphosphate (ADP): –a powerful inducer of platelet aggregation. Platelet aggregating factor (PAF): –stimulates aggregation. Mediators for platelet activation & aggregation

3. Platelets aggregation: mediators released by activated platelets cause increase in intracellular Ca 2+ and a ctivation of Glycoprotein IIb/IIIa receptors. 4. After activation, GP IIb/IIIa receptors bind with circulating fibrinogen and von Willebrand factor and to each others thus forming platelet aggregate (loose platelet plug). 5. Simultaneously, the coagulation system cascade is activated thrombin formation and a fibrin clot, which stabilizes the platelet plug forming Blood CLOT.

The role of platelets

Consequences of clot formation The formation of unwanted clot whether attached to vessel walls (Thrombi) or float in the blood (emboli) may producing life threatening condition as: –Acute ischemic stroke –Acute myocardial infarction –Deep vein thrombosis –Pulmonary embolism

Drugs used in thrombosis Anticoagulants: drugs which prevent clotting by inhibiting clotting factors (coagulation process) (used in prevention and treatment of thrombosis). Antiplatelets: drugs which prevent and inhibit platelet activation and aggression (used as prophylactic therapy in high risk patients). Thrombolytics or Fibrinolytics: act by dissolving existing or already formed thrombi or emboli and used in the acute treatment of thrombosis.

Drugs used in thrombosis

Classification of antiplatelet drugs  Arachidonic acid pathway inhibitors e.g. aspirin  Phosphodiesterase inhibitors e.g. cilostazol, dipyridamol,  ADP pathway inhibitors e.g. ticlopidine - clopidogrel  Glycoprotein IIb/IIIa inhibitors e.g. Abciximab – Eptifibatide -Tirofiban

Plaque Disruption CollagenvWF Platelet adhesion and secretion Aspirin Ticlopidine & clopidogrel Abciximab Eptifibatide Tirofiban Platelet aggregation Platelet recruitment and activation X COX-1 TXA2 ADP X GPllb / llla activation X Mechanisms of action of antiplatelet drugs

Uses of antiplatelet drugs  Prophylaxis of thromboembolic disorders.  Prevention of myocardial infarction (MI).  Prevention of ischemic stroke.  Following coronary artery bypass grafting.  Following coronary artery angioplasty.  Prosthetic heart valves.

Arachidonic acid pathway inhibitors Aspirin (Acetylsalicylic Acid) Mechanism of action  Antiplatelet action of low dose of aspirin is due to irreversible inhibition of cyclo-oxygenase enzyme selectively (COX-1) in platelets by acetylation thus inhibits thromboxane A 2 (TXA 2 ) production in platelets for their life span (7 days).  Dose: low dose mg / day

Targets of Aspirin in low doses Aspirin inhibits COX-1 present in platelets thus decreasing TXA2 synthesis. Aspirin in low dose does not inhibits PGI2 synthesis by endothelium) Good !!!!

 Low dose of aspirin, spares the protective PGI 2 synthesis.  Large dose of aspirin: inhibits both thromboxane synthesis in platelets (TXA 2 ) and prostacyclin (PGI 2 ) synthesis in endothelium.

Uses of aspirin  Prophylaxis of thromboembolism e.g. prevention of transient ischemic attack, ischemic stroke and myocardial infarction.  Prevention of ischemic events in patients with unstable angina pectoris.  can be combined with other antiplatelet (clopidogrel) or anticoagulant (heparin).

Side effects of aspirin  Risk of Peptic Ulcer.  Increased incidence of GIT bleeding (aspirin prolongs bleeding time)  Aspirin resistance.

ADP pathway inhibitors Ticlopidine & Clopidogrel Mechanism of action  Irreversible inhibition of ADP receptors on platelets thus inhibit platelet activation & aggregation.

ADP pathway inhibitors  are given orally.  have slow onset of action (3 - 5 days).  Pro-drugs, they have to be activated in the liver. Clinical Uses of ADP inhibitors  Secondary prevention of ischemic complications after myocardial infarction, ischemic stroke and unstable angina.

Adverse effects of ADP inhibitors  Sever neutropenia: blood count should be done during treatment.  G.I.T : nausea, dyspepsia, diarrhea.  Bleeding: Prolong bleeding time.  CYT P450 inhibitors: increased plasma levels of drugs as phenytoin, carbamazepine.  Allergic reactions. Precaution: Regular monitoring of WBC count during first three months.

Clopidogrel  is more potent than ticlopidine  Longer duration of action than ticlopidine.  Less frequency of administration.  Less side effects (less neutropenia).  Bioavailability is unaffected by food.  clopidogrel has replaced ticlopidine Ticlopidine: 250 mg twice daily. Clopidogrel: 75 mg once daily

Glycoprotein IIb/ IIIa receptor inhibitors  drugs as: abciximab, tirofiban, Eptifibatide  All are monoclonal antibodies  Acts as GP IIb/ IIIa receptor blockers  GP IIb/IIIa receptor is present on the platelet. –Once activated, the receptor becomes functional and binds fibrinogen, leading to the formation of platelet aggregates. –Glycoprotein IIb/IIIa receptors therefore mediate the final common pathway of platelet aggregation.

 Abciximab:  is a monoclonal antibody directed against glycoprotein IIb/ IIIa receptors.  binds to GPIIb/IIIa and stops platelet aggregation.  Tirofiban and eptifibatide:  inhibit platelets binding to fibrinogen.  Are fibrinogen like mimetic agents: acts by occupancy of the site on glycoprotein IIb/ IIIa receptor that is required to bind the platelet to fibrinogen.

 Glycoprotein IIb/ IIIa receptor inhibitors  Abciximab, Tirofiban and eptifibatide  Available only for intravenous administration  Intravenous administration of a bolus dose followed by continuous infusion.

Uses of Glycoprotein IIb/ IIIa receptor inhibitors Abciximab, Tirofiban and eptifibatide Prevention of ischemic cardiac complications in: – Patients with acute coronary syndrome (ACS) without ST elevation. –During percutaneous coronary interventions (PCI) (coronary angioplasty). Can be used in combination with aspirin and heparin

Cilostazole  Is a phosphodiestrase inhibitor (PDE3) increases cAMP leading to vasodilatation and inhibition of platelet aggregation.  Phosphodiestrase enzyme is required for breakdown of cAMP  Used to prevent intermittent claudication.  Claudication refers to the pain or cramping that is caused by poor circulation due to blockage of the arteries of the lower extremity.

Mechanism of actionDrugROA Inhibition of thromboxane A2 synthesis via inhibiting COX-1 AspirinOral ADP receptor antagonistsClopidogrel Ticlopidine Oral GP IIb / IIIa receptor antagonistsAbciximab Tirofiban Eptifibatide I.V. Phosphodiestrase 3 (PDE) inhibitors Cilostazole Oral SUMMARY