Download - 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