Platelet Aggregation Inhibitors Professor Dr MAHMOUD KHATTAB The
![Platelet Aggregation Inhibitors Professor. Dr. MAHMOUD KHATTAB, Platelet Aggregation Inhibitors Professor. Dr. MAHMOUD KHATTAB,](https://slidetodoc.com/presentation_image/d77463527f153978e6093765a8f7298d/image-1.jpg)
Platelet Aggregation Inhibitors Professor. Dr. MAHMOUD KHATTAB,
![The components of a platelet The components of a platelet](http://slidetodoc.com/presentation_image/d77463527f153978e6093765a8f7298d/image-2.jpg)
The components of a platelet
![Platelet Aggregation n Activated platelets undergo three consecutive processes: (a) shape change (b) secretion Platelet Aggregation n Activated platelets undergo three consecutive processes: (a) shape change (b) secretion](http://slidetodoc.com/presentation_image/d77463527f153978e6093765a8f7298d/image-3.jpg)
Platelet Aggregation n Activated platelets undergo three consecutive processes: (a) shape change (b) secretion of platelet granular contents (ADP, fibrinogen & 5 HT) (c) platelet aggregation Platelet aggregation occurs when the receptor (GP IIb/IIIa) binds to fibrinogen GP IIb/IIIa platelet fibrinogen platelet There is 50, 000 GP IIb/IIIa receptors on the surface of each platelet
![Platelet Aggregation ADP Thromboxane a 2 (TXA 2) Collagen thrombin Activation of G-protein TXA Platelet Aggregation ADP Thromboxane a 2 (TXA 2) Collagen thrombin Activation of G-protein TXA](http://slidetodoc.com/presentation_image/d77463527f153978e6093765a8f7298d/image-4.jpg)
Platelet Aggregation ADP Thromboxane a 2 (TXA 2) Collagen thrombin Activation of G-protein TXA 2 Arachidonic acid GP IIb/IIIa undergoes insideout (exposed on the surface of platelet) The receptor binds to fibrinogen COX enzyme TXA 2 • Then TXA 2 acts on its own receptor (act as a positive feedback mediator) • It also has vasoconstriction effect
![ADP n Stored ADP released and acts on its own receptor(positive feedback mediator n ADP n Stored ADP released and acts on its own receptor(positive feedback mediator n](http://slidetodoc.com/presentation_image/d77463527f153978e6093765a8f7298d/image-5.jpg)
ADP n Stored ADP released and acts on its own receptor(positive feedback mediator n ADP activates Gi-coupled P 2 Y 12 receptors. n ADP-ADP receptor complex c. AMP IIb/IIIa exposed GP GP IIb/IIIa It binds to arginine – glycine – asparagine sequence (R – G – D) in fibrinogen molecule or in Von Willebrand factor (v. Wf).
![Overview of antiplatelet drugs Glycoprotein receptor (IIb/IIIa) Fibrinogen mimetics (Tirofiban) TXA 2 receptor TXA Overview of antiplatelet drugs Glycoprotein receptor (IIb/IIIa) Fibrinogen mimetics (Tirofiban) TXA 2 receptor TXA](http://slidetodoc.com/presentation_image/d77463527f153978e6093765a8f7298d/image-6.jpg)
Overview of antiplatelet drugs Glycoprotein receptor (IIb/IIIa) Fibrinogen mimetics (Tirofiban) TXA 2 receptor TXA 2 antagonist (Ridogril) COX inhibitor (Aspirin) 2 - antibody (Abciximab) ADP receptor blocker Gb IIb/IIIa receptor blocker 1 - (R-G-D) mimetics
![Mechanism of action of Aspirin N. B. Aspirin inhibits Thromboxane A 2 & prostacyclin Mechanism of action of Aspirin N. B. Aspirin inhibits Thromboxane A 2 & prostacyclin](http://slidetodoc.com/presentation_image/d77463527f153978e6093765a8f7298d/image-7.jpg)
Mechanism of action of Aspirin N. B. Aspirin inhibits Thromboxane A 2 & prostacyclin too, but the former is more affected because platelets don’t have nuclei can’t synthesize new enzymes TXA 2 remains low for 7 days (platelet lifespan)
![I- ASPIRIN n After oral intake, this action is apparently occurring in the portal I- ASPIRIN n After oral intake, this action is apparently occurring in the portal](http://slidetodoc.com/presentation_image/d77463527f153978e6093765a8f7298d/image-8.jpg)
I- ASPIRIN n After oral intake, this action is apparently occurring in the portal circulation (more action in portal circulation than systemic circulation) Low dose antiplatelet (80 -160 mg) Aspirin High dose analgesic, antipyretic, , ,
![Uses & adverse effect Uses Prophylaxis against unstable angina Adverse effects GI -ulceration Post Uses & adverse effect Uses Prophylaxis against unstable angina Adverse effects GI -ulceration Post](http://slidetodoc.com/presentation_image/d77463527f153978e6093765a8f7298d/image-9.jpg)
Uses & adverse effect Uses Prophylaxis against unstable angina Adverse effects GI -ulceration Post MI Prolonged bleeding time ↑ risk of hemorrhage Post stroke Can not be used in child suffering from viral infection N. B. these are dose dependent
![Aspirin Antiplatelet Efficacy 1 - Dose n Most authorities recommend initial therapy with a Aspirin Antiplatelet Efficacy 1 - Dose n Most authorities recommend initial therapy with a](http://slidetodoc.com/presentation_image/d77463527f153978e6093765a8f7298d/image-10.jpg)
Aspirin Antiplatelet Efficacy 1 - Dose n Most authorities recommend initial therapy with a dose of 160 mg (one half-tablet) to 325 mg (one adult tablet) n Aspirin should be crushed/chewed (to facilitate faster absorption by breaking the enteric-coated delayed release tablet)
![Aspirin Antiplatelet Efficacy A. Efficacy of aspirin in patients with unstable angina q Reduces Aspirin Antiplatelet Efficacy A. Efficacy of aspirin in patients with unstable angina q Reduces](http://slidetodoc.com/presentation_image/d77463527f153978e6093765a8f7298d/image-11.jpg)
Aspirin Antiplatelet Efficacy A. Efficacy of aspirin in patients with unstable angina q Reduces morbid ischemic events B. Efficacy of aspirin in patients following acute MI q Reduces nonfatal MI and nonfatal stroke C. Reduce morbidity and mortality in stroke patients
![II- Glycoprotein IIb/IIIa Receptor Antagonists 1 - Glycoprotein IIb/IIIa murine-derived 7 E 3 Fab II- Glycoprotein IIb/IIIa Receptor Antagonists 1 - Glycoprotein IIb/IIIa murine-derived 7 E 3 Fab](http://slidetodoc.com/presentation_image/d77463527f153978e6093765a8f7298d/image-12.jpg)
II- Glycoprotein IIb/IIIa Receptor Antagonists 1 - Glycoprotein IIb/IIIa murine-derived 7 E 3 Fab monoclonal antibody (Abciximab) n Abciximab is composed of 7 E 3 Fab fragments. n derived from murine (mouse) n Abcixi(m)ab (m): monoclonal antibody. n directed against glycoprotein receptor type GPIIb/IIIa. n Mechanism: The m 7 E 3 Fab binds selectively to the glycoprotein GPIIb/IIIa receptors inhibiting platelet aggregation (see next slide)
![](http://slidetodoc.com/presentation_image/d77463527f153978e6093765a8f7298d/image-13.jpg)
![II- Glycoprotein IIb/IIIa Receptor Antagonists 1 - Glycoprotein IIb/IIIa murine-derived 7 E 3 Fab II- Glycoprotein IIb/IIIa Receptor Antagonists 1 - Glycoprotein IIb/IIIa murine-derived 7 E 3 Fab](http://slidetodoc.com/presentation_image/d77463527f153978e6093765a8f7298d/image-14.jpg)
II- Glycoprotein IIb/IIIa Receptor Antagonists 1 - Glycoprotein IIb/IIIa murine-derived 7 E 3 Fab monoclonal antibody (Abciximab) q Administration and therapeutic use: in angioplasty surgery to prevent ischemic complication (taken IV) o Heparin or aspirin are given along with abciximab
![II- Glycoprotein IIb/IIIa Receptor Antagonists 2 - Synthetic arginine-glycine-aspartic acid (R -G-D) sequence mimetics II- Glycoprotein IIb/IIIa Receptor Antagonists 2 - Synthetic arginine-glycine-aspartic acid (R -G-D) sequence mimetics](http://slidetodoc.com/presentation_image/d77463527f153978e6093765a8f7298d/image-15.jpg)
II- Glycoprotein IIb/IIIa Receptor Antagonists 2 - Synthetic arginine-glycine-aspartic acid (R -G-D) sequence mimetics n Tirofiban (non-peptic) is a synthetic mimetic of the R-G-D sequence of fibrinogen n Hence, it blocks the binding of fibrinogen to glycoprotein GPIIb/IIIa receptors n They are given intravenously for the reduction of thrombotic complications during coronary angioplasty (if they are given orally they are toxic) n Clinical trials showed reductions in the incidence of death and non-fatal MI in response to the use of tirofiban.
![](http://slidetodoc.com/presentation_image/d77463527f153978e6093765a8f7298d/image-16.jpg)
![III- Thromboxane Antagonists q Ridogrel is a combined thromboxane synthase inhibitor and thromboxane A III- Thromboxane Antagonists q Ridogrel is a combined thromboxane synthase inhibitor and thromboxane A](http://slidetodoc.com/presentation_image/d77463527f153978e6093765a8f7298d/image-17.jpg)
III- Thromboxane Antagonists q Ridogrel is a combined thromboxane synthase inhibitor and thromboxane A 2 (TXA 2) receptor antagonist, orally active q It has no effect on the vascular production of prostacyclin but cyclic endoperoxides (PGH 2) may increase q It decreases recurrent ischemic events e. g. (angina, reinfarction, ischemic stroke) more than aspirin. q Used in aspirin intolerant patients.
![IV- Platelet ADP Receptor Antagonists (Thienopyridines) Ticlopidine & Clopidogrel Ø They inhibit irreversibly ADP IV- Platelet ADP Receptor Antagonists (Thienopyridines) Ticlopidine & Clopidogrel Ø They inhibit irreversibly ADP](http://slidetodoc.com/presentation_image/d77463527f153978e6093765a8f7298d/image-18.jpg)
IV- Platelet ADP Receptor Antagonists (Thienopyridines) Ticlopidine & Clopidogrel Ø They inhibit irreversibly ADP binding to receptors inhibit platelet aggregation Ø No effect on PG synthesis Ø Used in aspirin intolerant patients
![](http://slidetodoc.com/presentation_image/d77463527f153978e6093765a8f7298d/image-19.jpg)
![ADVERSE EFFECTS q. Ticlopidine is associated with more side effects than Clopidogrel. Ticlopidine Clopidogrel ADVERSE EFFECTS q. Ticlopidine is associated with more side effects than Clopidogrel. Ticlopidine Clopidogrel](http://slidetodoc.com/presentation_image/d77463527f153978e6093765a8f7298d/image-20.jpg)
ADVERSE EFFECTS q. Ticlopidine is associated with more side effects than Clopidogrel. Ticlopidine Clopidogrel Nausea, dyspepsia, diarrhea (20% of patients) Same Hemorrhage (5%) same Leukopenia in 1% of patients (most serious). (N. B. monitor WBC in the first 3 months of treatment) same Thrombotic thrombocytopenic purpura Same fatal neutropenia nothing
![Antiplatelet Drugs drug mechanism Antiplatelet Drugs drug mechanism](http://slidetodoc.com/presentation_image/d77463527f153978e6093765a8f7298d/image-21.jpg)
Antiplatelet Drugs drug mechanism
![THING TO REMEMBER … n Glycoprotein IIb/IIIa: GP IIb/IIIa Antagonists Antibody tirofiban abciximab n THING TO REMEMBER … n Glycoprotein IIb/IIIa: GP IIb/IIIa Antagonists Antibody tirofiban abciximab n](http://slidetodoc.com/presentation_image/d77463527f153978e6093765a8f7298d/image-22.jpg)
THING TO REMEMBER … n Glycoprotein IIb/IIIa: GP IIb/IIIa Antagonists Antibody tirofiban abciximab n Aspirin: • Inhibits COX 1 enzyme TXA 2 • Is beneficial in prophylaxis of unstable angina and pre/postmyocardial infarction. • Aspirin may cause gastric ulcers and hemorrhage.
![THINGS TO REMEMBER … n Ridogrel: • Is TXA 2 synthetase inhibitor and TXA THINGS TO REMEMBER … n Ridogrel: • Is TXA 2 synthetase inhibitor and TXA](http://slidetodoc.com/presentation_image/d77463527f153978e6093765a8f7298d/image-23.jpg)
THINGS TO REMEMBER … n Ridogrel: • Is TXA 2 synthetase inhibitor and TXA 2 receptor antagonist. n Ticlopidine and clopidogrel: • Bind irreversibly to ADP receptors inhibiting the activation of GP IIb/IIIa. • They are only used in aspirin-intolerant patients because of adverse side effects
![TXA 2 Prostacyclin Aspirin ↓↓↓ ↓ Ridogril ↓↓ Zero Ticlopidine, clopidogrel Zero Remember: TXA TXA 2 Prostacyclin Aspirin ↓↓↓ ↓ Ridogril ↓↓ Zero Ticlopidine, clopidogrel Zero Remember: TXA](http://slidetodoc.com/presentation_image/d77463527f153978e6093765a8f7298d/image-24.jpg)
TXA 2 Prostacyclin Aspirin ↓↓↓ ↓ Ridogril ↓↓ Zero Ticlopidine, clopidogrel Zero Remember: TXA 2: increases platelet aggregation and vasoconstrictor Prostacyclin: decreases platelet aggregation and vasodilator
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