Platelet Aggregation Inhibitors

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Platelet Aggregation Inhibitors

• Professor. Dr.
• MAHMOUD KHATTAB,

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The components of a platelet
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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
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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

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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).
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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
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Mechanism of action of Aspirin
Aspirin
N.B. Aspirin inhibits Thromboxane A2
prostacyclin too, but the former is more affected
because platelets dont have nuclei? cant
synthesize new enzymes
TXA2 remains low for 7 days (platelet lifespan)
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I- ASPIRIN

• After oral intake, this action is apparently
  occurring in the portal circulation (more action
  in portal circulation than systemic circulation)

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Uses adverse effect
N.B. these are dose dependent
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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)

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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

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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)

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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
  

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II- Glycoprotein IIb/IIIa Receptor Antagonists
2- 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.

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III- Thromboxane Antagonists

• Ridogrel is a combined thromboxane synthase
  inhibitor 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.

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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

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ADVERSE EFFECTS

• 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
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Antiplatelet Drugs
drug mechanism
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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.

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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

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Prostacyclin TXA2
? ??? Aspirin
Zero ?? Ridogril
Zero Zero Ticlopidine,clopidogrel
Remember TXA2 increases platelet aggregation
and vasoconstrictor Prostacyclin decreases
platelet aggregation and vasodilator