Anti-Platelet Drugs Flashcards
what are the platelet receptors (2) that bind to collagen and vWF (von Willebrand factor) to cause platelet adhesion to the subendothelium?
thrombus formation begins with glycoprotein VI and Ib (GPVI and GPIb) platelet receptors binding to collagen and vWF, causing platelet adhesion to the subendothelium
what is the function of PAR-1/PAR-4 vs P2Y1/P2Y12 receptors in thrombus formation? (what do they bind and what do they activate)
PAR-1/PAR-4: thrombin (Factor IIa) receptors
P2Y1/P2Y12: ADP receptors
both:
activate COX-1 —> thromboxane A2 (TxA2) production —> recruitment of new platelets
activate GPIIb/IIIa —> fibrinogen binds, platelets aggregate
fill in the blanks regarding thrombus formation:
1. ___ and ____ platelet receptors bind _____ and _____, causing platelet adhesion to subendothelium
2a. ___/____ receptors bind thrombin (Factor IIa), activating _____, which produces thromboxane A2 for the recruitment of new platelets
2b. ____/____ receptors bind ADP, activating ___/____, which binds fibrinogen and promotes platelet aggregation
- GPVI and GPIb platelet receptors bind COLLAGEN and vWF, causing platelet adhesion to subendothelium
2a. PAR-1/PAR-4 receptors bind thrombin (Factor IIa), activating COX-1, which produces thromboxane A2 for the recruitment of new platelets
2b. P2Y1/P2Y12 receptors bind ADP, activating GPIIb/IIIa which binds fibrinogen and promotes platelet aggregation
what is the mechanism of aspirin, and why is this useful for preventing clot formation?
aspirin: irreversibly (covalently) binds COX-1, thereby preventing thromboxane A2 production (which recruits new platelets to thrombus)
used for prevention of CV events in patients with high risk of MI or stroke (given at sub-analgesic doses)
what is the mechanism of Clopidogrel and Ticagrelor, respectively, and what are they used for?
anti-platelet drugs
Clopidogrel: irreversible inhibitor of P2Y12 receptor
Ticagrelor: reversible inhibitor of P2Y12 receptor
therefore, these prevent ADP binding to P2Y12 receptor and subsequent aggregation of platelets (via GPIIb/IIIa)
what are the clinical indications (3) of P2Y12 receptor antagonists such as Clopidogrel and Ticagrelor?
in thrombus formation, ADP binds P2Y12, activating GPIIb/IIIa, which promotes platelet aggregation
indications (used in combination with aspirin):
1. acute coronary syndrome (ACS): STEMI or NSTEMI
2. prevention in patients with history of MI
3. prevention in patients with history of stroke or peripheral vascular disease
what is an extremely important adverse effect to keep in mind with all anti-platelet drugs?
increased risk of bleeding, particularly when in combination!
how are clopidogrel and ticagrelor metabolized that puts use of these drugs at risk for significant drug-drug interactions?
ticagrelor: CYP3A4 metabolized (most common CYP)
clopidogrel: CYP2C19 metabolized (2nd most common CYP)
Clopidogrel: irreversible inhibitor of P2Y12 receptor
Ticagrelor: reversible inhibitor of P2Y12 receptor
prevent ADP binding to P2Y12 receptor and subsequent platelet activation/aggregation
what is the mechanism of action of Vorapaxar and how is it used?
Vorapaxar: competitively inhibits PAR-1 thrombin (Factor IIa) receptor —> prevents COX-1 activation and subsequent thromboxane A2 production (which recruits platelets)
therefore, used in combination therapy for reducing CV events in patients with history of MI or peripheral vascular disease
[voraPARxar inhibits the PAR-1 receptor]
What is the mechanism of action of Eptifibatide and what is it used for?
Eptifibatide: competitive inhibitor of fibrinogen binding site on dimeric glycoprotein GPIIb/IIIa —> prevents platelet aggregation
used in combination with heparin (anticoagulant) to reduce rate of thrombotic events in high-risk patients (with elevated cardiac troponin) undergoing PCI (percutaneous coronary intervention - stent) for NSTEMI
given via IV administration
[eptiFIBatide competitively inhibits FIBrinogen binding]
what is the function of tissue plasminogen activator (t-PA)?
tissue plasminogen activator (t-PA): secreted by endothelial cells at injury site, converts plasminogen to plasmin, which digests fibrin —> dissolves thrombus
inactivated by PAI-1 and PAI-2
what is the function of PAI-1/PAI-2 and alpha2-AP in thrombosis?
PAI-1 and PAI-2 inactivate t-PA (tissue plasminogen activator), which converts plasminogen to plasmin (dissolves fibrin)
alpha2-AP clears away plasmin
these both down-regulate clot dissolving (so you don’t overdo it)
what do all fibrinolytic drugs end in?
“-plase”
examples: Alteplase, reteplase, tenecteplase, Anistreplase
What kind of drug is Alteplase, and considering this, what is it used for?
Alteplase: fibrinolytic drug - human recombinant form of tissue plasminogen activator (t-PA)
t-PA (serine protease) converts plasminogen to plasmin when bound to fibrin —> dissolves thrombus
used for acute MI, acute ischemic stroke, severe DVT, severe pulmonary embolism
What kind of drug is Anistreplase, and what is it used for?
Anistreplase: fibrinolytic drug -
streptokinase (bacterial enzyme) combined with plasminogen (human enzyme) to catalyze conversion of plasminogen to plasmin (which dissolves clots)
IV administration ASAP after onset of MI symptoms
