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    Platelet Aggregation Inhibitors: Professor. Dr. Mahmoud Khattab

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    frabzi
    Platelets play a key role in thrombosis through aggregation. Several drugs target different pathways of platelet aggregation. Aspirin irreversibly inhibits the COX enzyme, blocking thromboxane A2 production. Abciximab is a monoclonal antibody that binds the GP IIb/IIIa receptor, inhibiting fibrinogen binding. Tirofiban is a small molecule that mimics fibrinogen, blocking the GP IIb/IIIa receptor. Ridogrel inhibits thromboxane synthesis and antagonizes its receptor. Ticlopidine and clopidogrel bind irreversibly to ADP receptors to inhibit platelet aggregation. These drugs are used to prevent thrombosis in conditions like heart attacks, strokes, and angioplasty.

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    Platelet Aggregation Inhibitors: Professor. Dr. Mahmoud Khattab

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    frabzi
    57 views24 pages
    Platelets play a key role in thrombosis through aggregation. Several drugs target different pathways of platelet aggregation. Aspirin irreversibly inhibits the COX enzyme, blocking thromboxane A2 production. Abciximab is a monoclonal antibody that binds the GP IIb/IIIa receptor, inhibiting fibrinogen binding. Tirofiban is a small molecule that mimics fibrinogen, blocking the GP IIb/IIIa receptor. Ridogrel inhibits thromboxane synthesis and antagonizes its receptor. Ticlopidine and clopidogrel bind irreversibly to ADP receptors to inhibit platelet aggregation. These drugs are used to prevent thrombosis in conditions like heart attacks, strokes, and angioplasty.

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    Platelets play a key role in thrombosis through aggregation. Several drugs target different pathways of platelet aggregation. Aspirin irreversibly inhibits the COX enzyme, blocking thromboxane A2 production. Abciximab is a monoclonal antibody that binds the GP IIb/IIIa receptor, inhibiting fibrinogen binding. Tirofiban is a small molecule that mimics fibrinogen, blocking the GP IIb/IIIa receptor. Ridogrel inhibits thromboxane synthesis and antagonizes its receptor. Ticlopidine and clopidogrel bind irreversibly to ADP receptors to inhibit platelet aggregation. These drugs are used to prevent thrombosis in conditions like heart attacks, strokes, and angioplasty.

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    Download as ppt, pdf, or txt
    57 views24 pages

    Platelet Aggregation Inhibitors: Professor. Dr. Mahmoud Khattab

    Uploaded by

    frabzi
    Platelets play a key role in thrombosis through aggregation. Several drugs target different pathways of platelet aggregation. Aspirin irreversibly inhibits the COX enzyme, blocking thromboxane A2 production. Abciximab is a monoclonal antibody that binds the GP IIb/IIIa receptor, inhibiting fibrinogen binding. Tirofiban is a small molecule that mimics fibrinogen, blocking the GP IIb/IIIa receptor. Ridogrel inhibits thromboxane synthesis and antagonizes its receptor. Ticlopidine and clopidogrel bind irreversibly to ADP receptors to inhibit platelet aggregation. These drugs are used to prevent thrombosis in conditions like heart attacks, strokes, and angioplasty.

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    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 & 5HT) (c) platelet aggregation
    Platelet aggregation occurs when the receptor (GP IIb/IIIa) binds to fibrinogen GP IIb/IIIa fibrinogen

    platelet

    platelet

    There is 50,000GP IIb/IIIa receptors on the surface of each platelet

    Platelet Aggregation
    ADP Thromboxane a2 (TXA2) Collagen thrombin Activation of G-protein GP IIb/IIIa undergoes insideout (exposed on the surface of platelet)

    TXA2

    The receptor binds to fibrinogen


    COX enzyme

    Arachidonic acid

    TXA2

    Then TXA2 acts on its own receptor (act as a positive feedback mediator) It also has vasoconstriction effect

    ADP

    Stored ADP released and acts on its own

    receptor(positive feedback mediator ADP activates Gi-coupled P2Y12 receptors. ADP-ADP receptor complex cAMP IIb/IIIa exposed
    GP IIb/IIIa

    GP

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

    Overview of antiplatelet drugs


    Glycoprotein receptor (IIb/IIIa)

    TXA2 receptor

    Fibrinogen mimetics (Tirofiban)


    COX inhibitor (Aspirin)
    2- antibody (Abciximab)

    TXA2 antagonist (Ridogril)

    Gb IIb/IIIa receptor blocker 1- (R-G-D) mimetics

    ADP receptor blocker

    Mechanism of action of Aspirin

    Aspirin

    N.B. Aspirin inhibits Thromboxane A2 & prostacyclin too, but the former is more affected because platelets dont have nuclei cant synthesize new enzymes

    I- ASPIRIN
    After oral intake, this action

    is apparently occurring in the portal circulation (more action in portal circulation than systemic circulation)
    Low dose antiplatelet (80-160 mg) Aspirin High dose analgesic,antipyretic,,,

    Uses & adverse effect


    Uses
    Prophylaxis against unstable angina

    Adverse effects
    GI -ulceration

    Post MI

    Prolonged bleeding time risk of hemorrhage

    Post stroke

    Can not be used in child suffering from viral infection


    N.B. these are dose dependent

    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)

    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 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)

    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) 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 (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 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.

    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 is associated with more side effects than Clopidogrel.
    Ticlopidine Nausea, dyspepsia, diarrhea (20% of patients) Hemorrhage (5%) Leukopenia in 1% of patients (most serious). (N.B. monitor WBC in the first 3 months of treatment) Thrombotic thrombocytopenic purpura fatal neutropenia Same Clopidogrel

    same same

    Same nothing

    Antiplatelet Drugs
    drug
    Aspirin

    mechanism
    80-325 mg/d 250 mg three times daily Minutes to h 3-5 d Up to 1 wk Up to 1 wk

    25-75 mg three times daily 0.25 mg/kg bolus, 0.1 mg/min infusion, over 12 h Investigational Clopidogrel Similar to ticlopidine 75 mg/d Ridogrel Thromboxane synthetase 300 mg twice and thromboxane receptor daily antagonist Synthetic R-G- Antagonist of GP IIb/IIIa- Under D sequence ligand binding investigation mimetics

    Irreversibly inhibits production of TXA2 Ticlopidine Inhibits and antagonizes ADP receptor and may inhibit interactions of GP IIb/IIIa receptor with fibrinogen Dipyridamole Phosphodiesterase inhibitor c7E3 Fab Monoclonal antibody (Abciximab) antagonist of GP IIb/IIIaligand binding

    Hours Minutes

    12-24 h

    Up to 1 wk -

    Minutes Approximately 46 h (longer for oral compounds)

    THING TO REMEMBER
    Glycoprotein IIb/IIIa:
    GP IIb/IIIa

    Antagonists

    Antibody

    tirofiban

    abciximab

    Aspirin: Inhibits COX1 enzyme TXA2 Is beneficial in prophylaxis of unstable angina and pre/postmyocardial 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 Ticlopidine,clopidogrel

    Zero

    Zero Zero

    Remember: TXA2: increases platelet aggregation and vasoconstrictor


    Prostacyclin: decreases platelet aggregation and vasodilator

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