antplatelets

7/29/2019 antplatelets

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PlateletAggregation

Inhibitors


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The components of a platelet


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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 (GPIIb/IIIa) binds to fibrinogen

platelet platelet

GP IIb/IIIa

fibrinogen

There is50,000GPIIb/IIIa

receptorson the

surface of each

platelet


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Platelet Aggregation

ADPThromboxane a2 (TXA2)Collagenthrombin

Activation of G-protein

GP IIb/IIIaundergoes inside-

out (exposed on thesurface of platelet)

TXA2

Arachidonic acid TXA2

COX enzyme

Then TXA2 acts on its own receptor (act as apositive feedback mediator)

It also has vasoconstriction effect

The receptor binds to

fibrinogen


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Stored ADP released and acts on its ownreceptor(positive feedback mediator

ADP activates G i-coupled P2Y 12 receptors. ADP-ADP receptor complex cAMP GPIIb/IIIa exposed

ADP

GP IIb/IIIa

It binds to arginine glycine asparagine sequence (R G D) infibrinogen molecule or in Von Willebrand factor (vWf).


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Overview of antiplatelet drugs

ADP receptor blocker

COXinhibitor (Aspirin )

Fibrinogenmimetics

(Tirofiban )

Glycoproteinreceptor (IIb/IIIa)

Gb IIb/IIIareceptor blocker

1- (R-G-D)mimetics

2- antibody(Abciximab)

TXA2receptor

TXA2antagonist(Ridogril)


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Mechanism of action of Aspirin

Aspirin

N.B. Aspirin inhibits Thromboxane A2 &prostacyclin too, but the former is moreaffected because platelets dont have

nuclei cant synthesize new enzymes


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I- ASPIRIN

After oral intake, this actionis apparently occurring in theportal circulation (moreaction in portal circulation

than systemic circulation)

Aspirin

Low dose antiplatelet

(80-160 mg)

High dose analgesic,antipyretic,,,


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Uses & adverse effect

Prophylaxisagainstunstable

angina

Post MI

Post stroke

UsesGI -ulceration

Prolongedbleeding time

risk of hemorrhage

Can not beused in childsuffering fromviral infection

Adverseeffects

N.B. these are dosedependent


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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 releasetablet)


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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 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 theglycoprotein GPIIb/IIIa receptors inhibiting platelet

aggregation (see next slide)


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II- Glycoprotein IIb/IIIa Receptor Antagonists 1- Glycoprotein IIb/IIIa murine-derived 7E3

Fab monoclonal antibody (Abciximab)Administration and therapeutic use: in angioplasty surgery toprevent ischemic complication (taken IV)

o 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 theR-G-D sequence of fibrinogenHence, it blocks the binding of fibrinogen to

glycoprotein GPIIb/IIIa receptorsThey 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 incidenceof death and non-fatal MI in response to the useof tirofiban.


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Ridogrel is a combined thromboxane synthase inhibitor and thromboxane A 2 (TXA2 ) receptor antagonist , orallyactiveIt 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 aggregationNo effect on PG synthesis

Used in aspirin intolerant patients


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ADVERSE EFFECTS

Ticlopidine Clopidogrel

Nausea, dyspepsia, diarrhea (20%of patients)

Same

Hemorrhage (5%) same

Leukopenia in 1% of patients (mostserious). ( N.B. monitor WBC in the first 3months of treatment )

same

Thrombotic thrombocytopenicpurpura

Same

fatal neutropenia nothing

Ticlopidine is associated with more side effectsthan Clopidogrel.


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Antiplatelet Drugs

Aspirin Irreversibly inhibitsproduction of TX A2

80-325 mg/d Minutesto h

Up to 1 wk

Ticlopidine Inhibits and antagonizesADP receptor and mayinhibit interactions of GPIIb/IIIa receptor withfibrinogen

250 mg threetimes daily

3-5 d Up to 1 wk

Dipyridamole Phosphodiesteraseinhibitor

25-75 mg threetimes daily

Hours -

c7E3 Fab(Abciximab)

Monoclonal antibodyantagonist of GP IIb/IIIa-ligand binding

0.25 mg/kgbolus, 0.1mg/mininfusion, over12 h

Minutes 12-24 h

Investigational Clopidogrel Similar to ticlopidine 75 mg/d - Up to 1 wk

Ridogrel Thromboxane synthetaseand thromboxane receptorantagonist

300 mg twicedaily

- -

Synthetic R-G-D sequence

mimetics

Antagonist of GP IIb/IIIa-ligand binding

Underinvestigation

Minutes Approximately 4-6 h (longer for

oral compounds)

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.

GP IIb/IIIa

Antagonists

tirofiban

Antibody

abciximab


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THINGS TO REMEMBER

Ridogrel: Is TXA 2 synthetase inhibitor and TXA 2 receptor antagonist.

Ticlopidine and clopidogrel:

Bind irreversibly to ADP receptors inhibiting the activation ofGP IIb/IIIa. They are only used in aspirin-intolerant patients because of

adverse side effects


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ProstacyclinTXA2

Aspirin

ZeroRidogril

ZeroZeroTiclopidine,clopidogrel

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

antplatelets

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