Hockerman - Antiplatelet Flashcards
Explain the role that platelets play in hemostasis
Hemostasis is defined as the arrest of leaking blood from a damaged blood vessel. There are many phases of hemostasis in order to “plug” the leaking vessel. The first step would be platelet adherence and aggregation which begins the clotting formation.
Explain the three phases of platelet activation
- Adhesion and shape change
- Damage and disruption of the endothelial cells exposes platelets to collagen and vW
- Adhesion is mediated by GP Ia and GP IB which bind to collagen and vW factor (provides stickiness to bind to) respectively
- shape change facilitates receptor binding - secretion reaction
- Platelet secretes ADP, thromboxane A2 (TXA2), and serotonin (5-HT) these will activate and recruit other platelets
- Thromboxane and serotonin are potent vasocontrictors - aggregation
- ADP, TXA2 and 5-HT activation induces conformation of GPIIb/IIIA which will bind to fibrinogen and this binding allows for platelets to be crossed linked which creates a temporary hemostatic plug.
- Fibrin stabilizes and anchors aggregated platelets and forms a surface for clot formation
Explain the role of GP la and GP Ib receptors in platelet activation
distruction to the endothelial wall exposes platelets to collagen and vW factor. GP Ia binds to collagen and GP Ib binds to vWF. this then allows the platelet to have adhesion and release ADP, TXA2, and 5-HT which will recruit and activate other platelets to form a temporary clot formation once platelets are cross-linked by fibrinogen
List three molecules that are secreted by platelets and give their role in hemostasis
ADP, seretonin (5-HT), and thromboxane A2 (TXA2) are released from platelets to recruit and activate other platelets to the area
they also induce the conformation of the GP IIb/IIIa receptor which allows for fibrinogen to bind
Explain the role of Fibrinogen and GP IIb/IIIa receptors in platelet function
GP IIb/IIIa undergoes a conformational change due to the release of 5-HT, ADP, and TXA2. this conformational change allows for fibrinogen to bind and thus platelets are cross-linked by fibrinogen. This cross linking creates a temporary hemostatic plug
Explain the role of aspirin as an antiplatelet drug and why it has a preferential effect on platelets over the endothelium
Aspirin is a COX-1 inhibitor that will inhibit TXA2 synthesis in platelets. This blocks the aggregation of platelets which will prolong bleeding time and prevent arterial thrombi formation
Preferential effect on platelets
- Because it is selective for COX-1 this means it does not effect COX-2. COX-2 produces prostacyclin (PGI2) which is released by the endothelial cells to stop clot formation.
- Another plus to aspirin
Explain the mechanism of clopidogrel
and use
Clopidogrel is a pro-drug that needs activation by easterase and CYP3A4 to active form.
This irreversibly binds to P2Y12 which is one of the ADP receptor on platelets. This will inhibit platelet aggregation and activation. action lasts for several days after last dose
USE:
Coronary syndrome, recent MI, stroke, established peripheral vascular disease and coronary stent procedures
Explain the mechanism of prasugrel
Prasugrel is a prodrug meaning it must be activated by easterase and CYP3A4 to activate form.
Once activated it will irreversibly bind bind to P2Y12 ADP receptor and inhibit aggregation and activation of platelets.
Explain the mechanism of ticagrelor
Reversibly binds to P2Y12 ADP receptor and inhibits platelet aggregation and activation
- Does not require bioactivation
- binds to an allosteric site and binds reversible
What are the different clinical properties between clopidogrel, prasugrel, and ticagrelor
Prasugrel and clopidogrel need to be activated by easterase and CYP enzyme to active form
Prasugrel and clopidogrel have a thiol group that allows for irreversible binding
Ticagrelor does not need metabolism to become active and has a shorter half life because of dephosphorlyation reaction that occurs. It also reversibly binds because of this
Explain the mechanism of action of abciximab and its role in therapy
Abciximab is a GPIIb/IIIa inhibitor that binds to the receptor site which inhibits the cross linking of platelets by blocking binding of fibrinogen to GPIIb/IIIa
USE:
-PREVENT thromboembolism in coronary angioplasty
- Combined with t-PA for early treatment of acute MI
Explain the mechanism of action of eptifibitide and its role in therapy
inhibits fibrinogen binding to decrease platelet aggregation
USE:
to PREVENT thromboembolism in coronary angioplastic procedures and IN UNSTABLE ANGINA
Explain the differences between abciximab and eptifibitide structures
Eptifibitide is a synthetic peptide which selectively blocks GPIIb/IIIa in a reversible manner
- Has a arginine glycine aspart group which binds that binds to the receptor
Abciximab is a chimeric mouse-human monoclonal antibody directed against the human GPIIb/IIa
- has a long duration of action because it binds tightly to the receptor
Explain the mechanism of action of the dipyridamole and cilostazol and differentiate them based on their structures and clinical properties
Dipyridamole and cilostazol are phosphodiesterase-3 inhibitors that inhibit platelet aggregation by inhibition of adenosine uptake
USE FOR DIPYRIDAMOLE:
- combined with warfarin to prevent embolization from prosthetic heart valves
- with ASA to PREVENT cerebrovascular ischemia
USE FOR CILOSTAZOL:
- Intermitten claudication
