Platelet Aggregation Inhibitors
Professor. Dr. MAHMOUD KHATTAB,
The components of a platelet
Platelet Aggregation
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
platelet platelet
GP IIb/IIIa
fibrinogen
There is 50,000GP
IIb/IIIa receptors
on the surface of
each platelet
Platelet Aggregation
ADPThromboxane a2 (TXA2)Collagenthrombin
Activation of G-protein
GP IIb/IIIa undergoes inside-
out (exposed on the surface of platelet)
TXA2
Arachidonic acid TXA2 COX enzyme
•Then TXA2 acts on its own receptor (act as a positive feedback mediator)
•It also has vasoconstriction effect
•Then TXA2 acts on its own receptor (act as a positive feedback mediator)
•It also has vasoconstriction effect
The receptor binds to
fibrinogen
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
ADP
GP IIb/IIIa
It binds to arginine – glycine – asparagine sequence (R – G – D) in fibrinogen molecule or in Von Willebrand factor (vWf).
It binds to arginine – glycine – asparagine sequence (R – G – D) in fibrinogen molecule or in Von Willebrand factor (vWf).
Overview of antiplatelet drugs
ADP receptor blocker
COX inhibitor (Aspirin)
Fibrinogen mimetics
(Tirofiban)
Glycoprotein receptor (IIb/IIIa)
Gb IIb/IIIa receptor blocker
1- (R-G-D) mimetics
2- antibody (Abciximab)
TXA2 receptor
TXA2 antagonist (Ridogril)
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
I- ASPIRINI- ASPIRIN
After oral intake, this action is apparently occurring in the portal circulation (more action in portal circulation than systemic circulation)
Uses & adverse effect
N.B. these are dose dependent
Aspirin Antiplatelet EfficacyAspirin Antiplatelet Efficacy1- Dose1- Dose
Most authorities recommend initial therapy with a dose of 160 mg (one half-tablet) to 325 mg (one adult tablet)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)
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
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)
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)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
Tirofiban Tirofiban (non-peptic(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.
III- Thromboxane III- Thromboxane AntagonistsAntagonists
Ridogrel is a combined thromboxanethromboxane synthasesynthase inhibitor and thromboxane A2 (TXA2) receptor antagonist, orally active
It has no effect on the vascular production of prostacyclinprostacyclin 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.
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
ADVERSE EFFECTS
Ticlopidine Clopidogrel
Nausea, dyspepsia, diarrhea (20% of patients)
Same
Hemorrhage (5%) same
Leukopenia 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
Ticlopidine is associated with more side effects than Clopidogrel.
Antiplatelet Drugs
Aspirin Irreversibly inhibits production of TXA2
80-325 mg/d Minutes to h
Up to 1 wk
Ticlopidine Inhibits and antagonizes ADP receptor and may inhibit interactions of GP IIb/IIIa receptor with fibrinogen
250 mg three times daily
3-5 d Up to 1 wk
Dipyridamole Phosphodiesterase inhibitor
25-75 mg three times daily
Hours -
c7E3 Fab (Abciximab)
Monoclonal antibody antagonist of GP IIb/IIIa-ligand binding
0.25 mg/kg bolus, 0.1 mg/min infusion, over 12 h
Minutes 12-24 h
Investigational
Clopidogrel Similar to ticlopidine 75 mg/d - Up to 1 wk
Ridogrel Thromboxane synthetase and thromboxane receptor antagonist
300 mg twice daily
- -
Synthetic R-G-D sequence mimetics
Antagonist of GP IIb/IIIa-ligand binding
Under investigation
Minutes Approximately 4-6 h (longer for
oral compounds)
drug mechanism
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.
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
TXA2 Prostacyclin
Aspirin ↓↓↓ ↓
Ridogril ↓↓ Zero
Ticlopidine,clopidogrel Zero Zero
Remember:TXA2: increases platelet aggregation and vasoconstrictorProstacyclin: decreases platelet aggregation and vasodilator