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