Antiplatelet Drugs

Question 1

Explain the role that platelets play in hemostatis.

Answer 1

platelets form from megakaryocytes; have organelles and secretory granules but NO nucleus
platelets form a plug to arrest the bleeding (thrombus formation)

Question 2

Explain the three phases of platelet activation.

Answer 2

contact with ECM initiates platelets reactions:
adhesion & shape change
secretion reaction
aggregation

Question 3

Platelet adhesion and shape change

Answer 3

adhesion mediated by GP la and GP lb
shape change facilitates receptor binding
intact endothelial cells secret PGI2 (prostacyclin) to inhibit thrombogenesis

Question 4

Platelet secretion

Answer 4

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

Question 5

Platelet aggregation

Answer 5

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

Question 6

Explain the role of GP la and GP lb receptors in platelet activation.

Answer 6

they mediate adhesion
do this by GP la binding to collagen and GP lb binding to von Willebrand factor bridged to collagen

Question 7

List 3 molecules that are secreted by platelets and give their role in hemostasis.

Answer 7

ADP
TXA2
5-HT
activate and recruit other platelets

Question 8

Explain the role of fibrinogen and GP llb/llla receptors in platelet function.

Answer 8

GP llb/llla receptors bind to fibrinogen, regulate platelet adhesion and aggregation
fibrinogen cross-links platelets

Question 9

Explain the role of aspirin as an antiplatelet drug and why is has a preferential effect on platelets over the endothelium.

Answer 9

inhibition of TXA2 synthesis in platelets is the key to anti-platelet activity of ASA
it is a selective COX inhibitor, selective for platelets

Question 10

Aspirin

Answer 10

COX-1 inhibitor
inhibits platelet COX-1 by acetylation
interferes with platelet aggregation
prolongs bleeding time
prevents arterial thrombi formation

Question 11

Aspirin antiplatelet action

Answer 11

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

Question 12

Selective COX inhibitor

Answer 12

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

Question 13

Explain the mechanisms of action of clopidogrel, prasugrel, and ticagrelor and differentiate between them based on their clinical properties.

Answer 13

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

Question 14

Mechanism of action of P2Y12 receptor antagonists

Answer 14

block adenosine activation of P2Y12 receptor –> suppress cAMP –> inhibit platelet activation –> inhibit platelet aggregation

Question 15

Clopidogrel

Answer 15

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

Question 16

Prasugrel

Answer 16

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

Question 17

Ticagrelor

Answer 17

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

Question 18

Activation of P2Y12 receptor antagonists

Answer 18

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

Question 19

Explain the mechanism of action of abciximab and eptifibitide, their role in therapy, and differences in their structure.

Answer 19

glycoprotein llb/llla receptor inhibitors - inhibits fibrinogen crosslinking of platelets

Question 20

MOA of abciximab

Answer 20

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

Question 21

Abciximab role in therapy

Answer 21

prevent thromboembolism in coronary angioplasty
combined with t-PA for early treatment of acute MI

Question 22

MOA of eptifibitide

Answer 22

synthetic peptide which selectively blocks GPllb-llla in a reversible manner
inhibits fibrinogen binding to decrease platelet aggregation

Question 23

Eptifibitide role in therapy

Answer 23

prevent thromboembolism in unstable angina and angioplastic coronary procedures

Question 24

MOA of tirofiban

Answer 24

nonpeptide tyrosine analogue which is specific for the GPllb-llla and inhibits fibrinogen binding
reversible inhibitor of fibrinogen binding to GP llb/llla receptor

Question 25

Tirofiban role in therapy

Answer 25

combined with heparin to treat acute coronary syndrome

Question 26

Explain the mechanism of action of the dipyridamole and cilostazol and differentiate them based on their structures and clinical properties.

Answer 26

phosphodiesterase-3 inhibitors
platelet aggregation inhibitor
action related to cAMP PDE inhibition (opposing P2Y12 action) and inhibition of adenosine uptake

Question 27

Dipyridamole role in therapy

Answer 27

combined with warfarin to prevent embolization from prosthetic heart valves
with ASA to prevent cerebrovascular ischemia

Question 28

Cilostazol role in therapy

Answer 28

intermittent claudication (decrease in blood flow to lower extremities due to atherosclerosis

Question 29

Protease activated receptor inhibitors

Answer 29

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

Question 30

Vorapaxar

Answer 30

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