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Platelet Aggregation Inhibitors

Platelet Aggregation Inhibitors. Professor. Dr. MAHMOUD KHATTAB, . The components of a platelet. Platelet Aggregation. Activated platelets undergo three consecutive processes: shape change (b) secretion of platelet granular contents (ADP, fibrinogen & 5-HT) (c) platelet aggregation.

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Platelet Aggregation Inhibitors

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  1. Platelet Aggregation Inhibitors Professor. Dr. MAHMOUD KHATTAB,

  2. The components of a platelet

  3. Platelet Aggregation • Activated platelets undergo three consecutive processes: • 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 There is 50,000GP IIb/IIIa receptors on the surface of each platelet GP IIb/IIIa platelet platelet fibrinogen

  4. Platelet Aggregation ADP Thromboxane a2 (TXA2) Collagen thrombin GP IIb/IIIa undergoes inside-out (exposed on the surface of platelet) Activation of G-protein TXA2 The receptor binds to fibrinogen synthesis COX enzyme Arachidonic acid TXA2 • Then TXA2 acts on its own receptor (act as a positive feedback mediator) • It also has vasoconstriction effect

  5. ADP • Stored ADP released and acts on its own receptor(positive feedback mediator • ADP activates Gi-coupled P2Y12 receptors. • ADP-ADP receptor complex cAMP GP IIb/IIIa exposed GP IIb/IIIa It binds to arginine – glycine – asparagine sequence (R – G – D) in fibrinogen molecule or in Von Willebrand factor (vWf).

  6. Overview of antiplatelet drugs Glycoprotein receptor (IIb/IIIa) Fibrinogen mimetics (Tirofiban) TXA2 receptor COX inhibitor (Aspirin) Gb IIb/IIIa receptor blocker 1- (R-G-D) mimetics TXA2 antagonist (Ridogril) 2- antibody (Abciximab) ADP receptor blocker

  7. Mechanism of action of Aspirin Aspirin N.B. Aspirin inhibits Thromboxane A2 & prostacyclin too, but the former is more affected because platelets don’t have nuclei can’t synthesize new enzymes TXA2 remains low for 7 days (platelet lifespan)

  8. After oral intake, this action is apparently occurring in the portal circulation (more action in portal circulation than systemic circulation) I- ASPIRIN

  9. Uses & adverse effect N.B. these are dose dependent

  10. Aspirin Antiplatelet Efficacy1- Dose • Most authorities recommend initial therapy with a dose of 160 mg (one half-tablet) to 325 mg (one adult tablet) • Aspirin should be crushed/chewed (to facilitate faster absorption by breaking the enteric-coated delayed release tablet)

  11. Aspirin Antiplatelet Efficacy A. Efficacy of aspirin in patients with unstable angina • Reduces morbid ischemic events B. Efficacy of aspirin in patients following acute MI • Reduces nonfatal MI and nonfatal stroke C. Reduce morbidity and mortality in stroke patients

  12. II- Glycoprotein IIb/IIIa Receptor Antagonists1- Glycoprotein IIb/IIIa murine-derived 7E3 Fab monoclonal antibody (Abciximab) • Abciximab is composed of 7E3 Fab fragments. • derived from murine(mouse) • Abcixi(m)ab (m): monoclonal antibody. • directed against glycoprotein receptor type GPIIb/IIIa. • Mechanism: The m7E3 Fab binds selectively to the glycoprotein GPIIb/IIIa receptors inhibiting platelet aggregation (see next slide)

  13. II- Glycoprotein IIb/IIIa Receptor Antagonists1- Glycoprotein IIb/IIIa murine-derived 7E3 Fab monoclonal antibody (Abciximab) • Administration and therapeutic use: in angioplasty surgery to prevent ischemic complication (taken IV) • Heparin or aspirin are given along with abciximab

  14. II- Glycoprotein IIb/IIIa Receptor Antagonists2-Synthetic arginine-glycine-aspartic acid (R-G-D) sequence mimetics • Tirofiban(non-peptic) is a synthetic mimetic of the R-G-D sequence of fibrinogen • Hence, it blocks the binding of fibrinogen to glycoprotein GPIIb/IIIa receptors • They are given intravenously for the reduction of thrombotic complications during coronary angioplasty (if they are given orally they are toxic) • Clinical trials showed reductions in the incidence of death and non-fatal MI in response to the use of tirofiban.

  15. III- Thromboxane Antagonists • Ridogrel is a combined thromboxanesynthaseinhibitor and thromboxane A2 (TXA2) receptor antagonist, orally active • It has no effect on the vascular production of prostacyclin but cyclic endoperoxides (PGH2) may increase • It decreases recurrent ischemic events e.g. (angina, reinfarction, ischemic stroke) more than aspirin. • Used in aspirin intolerant patients.

  16. IV- Platelet ADP Receptor Antagonists (Thienopyridines)Ticlopidine & Clopidogrel • They inhibit irreversibly ADP binding to receptors  inhibit platelet aggregation • No effect on PG synthesis • Used in aspirin intolerant patients

  17. ADVERSE EFFECTS • Ticlopidine is associated with more side effects than Clopidogrel.

  18. Antiplatelet Drugs drug mechanism

  19. THING TO REMEMBER … • Glycoprotein IIb/IIIa: • Aspirin: • Inhibits COX1 enzyme  TXA2 • Is beneficial in prophylaxis of unstable angina and pre/post-myocardial infarction. • Aspirin may cause gastric ulcers and hemorrhage.

  20. THINGS TO REMEMBER … • Ridogrel: • Is TXA2 synthetase inhibitor and TXA2 receptor antagonist. • 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

  21. Remember: TXA2: increases platelet aggregation and vasoconstrictor Prostacyclin: decreases platelet aggregation and vasodilator

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