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

2. The components of a platelet

3. There is 50,000GP IIb/IIIa receptors on the surface of each platelet
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 synthesis 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 activates Gi-coupled P2Y12 receptors.
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
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. I- ASPIRIN
After oral intake, this action is apparently occurring in the portal circulation (more action in portal circulation than systemic circulation)
Aspirin
Low dose  antiplatelet
( mg)
High dose  analgesic,antipyretic,,,

9. N.B. these are dose dependent
Uses & adverse effect
Uses
Prophylaxis against unstable angina
Post MI
Post stroke
Adverse
effects
GI -ulceration
Prolonged bleeding time  ↑ risk of hemorrhage
Can not be used in child suffering from viral infection
N.B. these are dose dependent

10. Aspirin Antiplatelet Efficacy 1- 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
الكلام اللي هنا مدري ايش يبغى
It’s mean aspirin not like thromblytic drug
Thrombolytic drugs depend on time after the attack, but aspirin not
الجملة غامضة شوي

12. II- Glycoprotein IIb/IIIa Receptor Antagonists 1- 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)

14. II- Glycoprotein IIb/IIIa Receptor Antagonists 1- 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

15. 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.

17. 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.

18. 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

20. 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)
Thrombotic thrombocytopenic purpura
fatal neutropenia
nothing

21. Antiplatelet Drugs
drug mechanism

22. 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.
GP IIb/IIIa
Antagonists
tirofiban
Antibody
abciximab

23. THINGS TO REMEMBER … Ridogrel: Ticlopidine and clopidogrel:
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

24. Ticlopidine,clopidogrel
Prostacyclin
TXA2 ↓
↓↓↓
Aspirin
Zero ↓↓
Ridogril
Ticlopidine,clopidogrel
Remember:
TXA2: increases platelet aggregation and vasoconstrictor
Prostacyclin: decreases platelet aggregation and vasodilator