Antiplatelet Drugs Flashcards
Explain the role that platelets play in hemostatis.
platelets form from megakaryocytes; have organelles and secretory granules but NO nucleus
platelets form a plug to arrest the bleeding (thrombus formation)
Explain the three phases of platelet activation.
contact with ECM initiates platelets reactions:
adhesion & shape change
secretion reaction
aggregation
Platelet adhesion and shape change
adhesion mediated by GP la and GP lb
shape change facilitates receptor binding
intact endothelial cells secret PGI2 (prostacyclin) to inhibit thrombogenesis
Platelet secretion
degranulation - platelet granules release ADP, thromboxane A2 (TXA2), and serotonin (5-HT)
these bind to ADP receptor –> important pharmacological target to prevent platelet aggregation
ADP, 5-HT, & TXA2 activate and recruit other platelets; TXA2 & 5-HT are potent vasoconstrictors
Platelet aggregation
ADP, 5-HT, & TXA2 activation induces conformation of GPllb/IIIa receptors (AKA-integrin alphaIIbbeta3) to bind fibrinogen –> fibrinogen cross-links platelets –> forms temporary hemostatic plug –> platelets contract to form irreversibly fused mass –> fibrin stabilizes and anchors aggregated platelets –> forms surface for clot formation
Explain the role of GP la and GP lb receptors in platelet activation.
they mediate adhesion
do this by GP la binding to collagen and GP lb binding to von Willebrand factor bridged to collagen
List 3 molecules that are secreted by platelets and give their role in hemostasis.
ADP
TXA2
5-HT
activate and recruit other platelets
Explain the role of fibrinogen and GP llb/llla receptors in platelet function.
GP llb/llla receptors bind to fibrinogen, regulate platelet adhesion and aggregation
fibrinogen cross-links platelets
Explain the role of aspirin as an antiplatelet drug and why is has a preferential effect on platelets over the endothelium.
inhibition of TXA2 synthesis in platelets is the key to anti-platelet activity of ASA
it is a selective COX inhibitor, selective for platelets
Aspirin
COX-1 inhibitor
inhibits platelet COX-1 by acetylation
interferes with platelet aggregation
prolongs bleeding time
prevents arterial thrombi formation
Aspirin antiplatelet action
irreversible inhibition by acetylation of COX-1
permanent loss of platelet COX-1 activity - decrease TXA2
prostacyclin (PGI2) production in tissue inhibited by higher doses
Selective COX inhibitor
the good: COX-2 produces prostacyclin in endothelial cells –> vasodilation and inhibition of platelet aggregation
the bad: COX-1 produces TXA2 in the platelets –> vasoconstriction and platelet aggregation
the ugly: selective COX-2 inhibitors block synthesis of prostacyclin while not preventing synthesis of TXA2 –> increased cardiovascular risk (balance b/w levels of prostacyclin and TXA2 influences whether platelet aggregates or circulates freely
Explain the mechanisms of action of clopidogrel, prasugrel, and ticagrelor and differentiate between them based on their clinical properties.
all are ADP receptor inhibitors
2 ADP receptors are involved in activating platelets: P2Y1 - coupled to Gq-PLC-IP3-Ca2+ - pathway and P2Y12 - coupled to Gi and inhibition of adenylyl cyclase
activation of both is required for platelet activation by ADP
ticagrelor is direct acting
prasugrel and clopidogrel are pro-drugs
Mechanism of action of P2Y12 receptor antagonists
block adenosine activation of P2Y12 receptor –> suppress cAMP –> inhibit platelet activation –> inhibit platelet aggregation
Clopidogrel
P2Y12 ADP receptor on platelet surface
thienopyridine class of ADP receptor inhibitors
irreversibly block ADP receptor on platelet and subsequent activation of GPllb/llla complex
has lower toxicity profile
use: acute coronary syndrome, recent MI, stroke, established vascular disease, coronary stent procedures
Prasugrel
P2Y12 ADP receptor on platelet surface
prodrug requiring esterases + CYP 3A4/2B6 to generate active metabolite
IRREVERSIBLY binds P2Y12 receptor
high risk of bleeding - not recommended in elderly or before coronary artery bypass graft
use: acute coronary syndrome, percutaneous coronary intervention
Ticagrelor
REVERSIBLE binding to allosteric site
does not require bioactivation by metabolic enzymes - CYP 3A4 substrate
fast onset of action compared to clopidogrel
risk of bleeding - don’t use before coronary artery bypass graft
use: acute coronary syndrome, percutaneous coronary intervention
Cangrelor is the same
Activation of P2Y12 receptor antagonists
clopidogrel - CYP2C19; thiol group makes binding irreversible
prasugrel - esterases CYP3A4/CYP2B6; thiol group makes binding irreversible
ticagrelor/cangrelor - non metabolism necessary, binds directly to receptors, short T1/2 due to dephosphorylation
Explain the mechanism of action of abciximab and eptifibitide, their role in therapy, and differences in their structure.
glycoprotein llb/llla receptor inhibitors - inhibits fibrinogen crosslinking of platelets
MOA of abciximab
chimeric mouse-human monoclonal antibody directed against the human GPllb-llla
Fab fragment of chimeric human-murine monoclonal Ab
binds to GP llb/lla receptor to inhibit platelet aggregation
long duration of action - increased risk of bleeding
Abciximab role in therapy
prevent thromboembolism in coronary angioplasty
combined with t-PA for early treatment of acute MI
MOA of eptifibitide
synthetic peptide which selectively blocks GPllb-llla in a reversible manner
inhibits fibrinogen binding to decrease platelet aggregation
Eptifibitide role in therapy
prevent thromboembolism in unstable angina and angioplastic coronary procedures
MOA of tirofiban
nonpeptide tyrosine analogue which is specific for the GPllb-llla and inhibits fibrinogen binding
reversible inhibitor of fibrinogen binding to GP llb/llla receptor
Tirofiban role in therapy
combined with heparin to treat acute coronary syndrome
Explain the mechanism of action of the dipyridamole and cilostazol and differentiate them based on their structures and clinical properties.
phosphodiesterase-3 inhibitors
platelet aggregation inhibitor
action related to cAMP PDE inhibition (opposing P2Y12 action) and inhibition of adenosine uptake
Dipyridamole role in therapy
combined with warfarin to prevent embolization from prosthetic heart valves
with ASA to prevent cerebrovascular ischemia
Cilostazol role in therapy
intermittent claudication (decrease in blood flow to lower extremities due to atherosclerosis
Protease activated receptor inhibitors
thrombin activates platelets
mechanism: proteolytic cleavage of PAR-1 receptors on platelet surface; thrombin binds + cleaves PAR1 –> cleavage of amino terminus, receptor now in active form
PARs are GPCRs coupled to release of Ca2+ from stores
ex. vorapaxar - inhibits interaction of thrombin with protease thrombin receptor
Vorapaxar
reversible PAR-1 receptor antagonist
prophylactic to prevent thrombosis in pts with previous MI or peripheral arterial disease
used with aspirin or clopidogrel
contraindications: history of stroke, TIAs, intracranial hemorrhage
antiplatelet effect persists for days after discontinuation
metabolized by CYP3A4 - avoid concomitant use with strong 3A4 inhibitors or inducers
