1. COX-1 inhibitors 2. ADP receptor inhibitors 3. Blockers of GPIIb/IIIa receptors 4. Phosphodiesterase-3 inhibitors 5. Protease-activated receptor inhibitors (in development)

Coagulation/Antiplatelet Pharmacology Flashcards by Julie Peceny

Hemostasis

arrest of bleeding from a damaged blood vessel

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Coagulation

multi-step process to plus the leaking vessel

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Platelets have organelles and secretory granules but no

nucleus

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The platelet reactions that contact with the ECM initiates

adhesion and shape change
secretion reaction
aggregation

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First step of platelet activation

platelet adhesion and shape change

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Platelet adhesion is mediated by

GPIa binding to collagen; GP1b binding to von Willebrand factor bridged to collagen; shape change facilitates receptor binding

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Intact endothelial cells secret

PGI2 (prostacyclin) to inhibit thrombogenesis (inhibits platelet activation and vasodilation)

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Second step of platelet activation

platelet secretion

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Platelet granules release

ADP, thromboxane A2 (TXA2), serotonin (5-HT)

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ADP, 5-HT, and TXA2 activate and recruit

other platelet

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TXA2 and 5-HT are

potent vasoconstrictors

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Third step of platelet activation

platelet aggregation

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ADP, 5-HT and TXA2 activation induces

conformation of GPIIB/IIIa receptors to bind fibrinogen

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Platelets are cross-linked by

fibrinogen

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Cross-linked platelets forms

temporary hemostatic plug

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Platelets contract to form

irreversibly fused mass

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What does fibrin do?

stabilizes and anchors aggregated platelets and forms surface for clot formation

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Antiplatelet drugs

COX-1 inhibitors
ADP receptor inhibitors
Blockers of GPIIb/IIIa receptors
Phosphodiesterase-3 inhibitors
Protease-activated receptor inhibitors (in development)

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Aspirin is a

COX-1 inhibitor

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MOA of aspirin

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

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The key to anti-platelet activity of aspirin

inhibition of TXA2 synthesis in platelets

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Aspirin is maximally effective at doses of

50-320 mg per day

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Higher doses of aspirin inhibits

prostacyclin production

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Indications for aspirin

prevent coronary thrombosis in unstable angina
adjunct to thrombolytic therapy
reducing recurrence of thrombotic stroke

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Clinical actions of aspirin

prolongs bleeding time, but no increase in PT time | hemostasis returns to normal 36 hr after last dose

ADP receptor inhibitors

P2Y 1 and P2Y 12

P2Y1 is coupled to

Gq-PCL-IP3-Ca2+ pathway

P2Y12 is coupled to

Gi and inhibition of adenylyl cylase

Action of which pathways is required for platelet activation by ADP

both the Gq-PCL-IP2-Ca2+ pathway and the Gi, inhibition of adenylyl cyclase pathway

P2Y12 ADP receptor inhibitors are taken

orally to reduce platelet aggregation

MOA of P2Y12 ADP receptor inhibitors

irreversibly block ADP receptor on platelet and subsequent activation of GPIIb/IIIa complex

Difference between Ticlopidine and Clopidogrel

Clopidogrel has lower toxicity profile

Ticlopidine may induce

thrombotic thrombocytopenis purpura (TTP)

Uses for P2Y12 ADP receptor inhibitors

acute coronary syndrome, recent MI, stroke, established peripheral vascular disease and coronary stent procedures

How long does the action of Ticlodipine and Clopidogrel last

lasts for several days after the last dose

ADAMTS13

protease that cleaves circulating vWF

How often is Ticlopidine (Ticlid) used

isn't used much anymore

Prasugrel

irreversible P2Y12 ADP receptor inhibitor

Prasugrel is approved for the treatment of

acute coronary syndrome, percutaneous coronary intervention

Prasugrel requires

metabolism to an active metabolite (prodrug)

Faster onset of action and increased potency of Prasugrel is due to

rapid metabolism by liver CYP450

Ticagrelor (Brilinta) used in

acute coronary syndrome; PCI - taken orally

MOA of Ticargrelor (Brilinta)

binds to an allosteric site, binding is reversible (plaletlet function comes back more quickly)

Ticagrelor compared to Clopidogrel

Ticagrelor does not require bioactivation by metabolic enzymes and has a faster onset of action compared to clopidogrel

Clopidogrel is activated by

CYP2C19 (enzyme very variable between populations)

Prasugrel is activated by

Hydrolases/CYP3A4/CYP2B6

Eptifibatide is a

Glycoprotein IIb/IIIa receptor inhibitor

MOA of Eptifibatide

inhibits fibrinogen binding to decrease platelet aggretion

Eptifibatide is derived from

cyclic heptapeptide derived from rattlesnake venom

How is Eptifibatide administered

administered by IV bolus, followed by infusion up to 72 hours

Duration of action of Eptifibatide

short duration of action; 6-12 hours

Tirofiban (Aggrastat)

Glycoprotein IIb/IIIa receptor inhibitor

MOA of Tirofiban

reversible inhibitor of fibrinogen binding to the GPIIb/IIIa receptor

How is Tirofiban adminsitered

adminstered IV in dilute solution

Tirofiban combined with heparin is used to treat

Acute coronary syndrome

Abciximab (ReoPro)

Fab fragment of chimeric human-murine monoclonal Ab; binds to GP IIb/IIIa receptor to inhibit platelet aggregation

Administration and duration of action of Abciximab

administered IV bolus, followed by infusion; long duration of action - increased risk of bleeding

Use of Abciximab (ReoPro)

prevent thromboembolism in coronary angioplasty

Abciximab and t-PA is combined for the treatment of

early treatment of acute MI

What do PDE3 inhibitors do

inhibit platelet aggregation

Action of PDE3 inhibitors is related to

related to cAMP PDE inhibition (opposing P2Y12 action) and inhibition of adenosine uptake

PDE inhibitors

Dipyridamole (Persantine) and Cilostazol (Pletal)

Use of Dipyridamole (PDEi)

combined with warfarin to prevent embolization from prosthetic heart valves; used with aspirin to prevent cerebrovascular ischemia

Use of Cilostazol (PDEi)

intermittent claudication

Protease activated receptor (PAR) inhibitors

Vorapaxar and Atopaxar

MOA for protease activated receptor inhibitors

proteolytic cleavage of PAR-1 receptors on platelet surface

PARs are

GPCRs coupled to release of Ca2+ from stores

Thrombin activates

platelets at nanomolar concentrations

Vorapaxar

reversible PAR-1 receptor antagonist; prophylactic to prevent thrombosis in patients with a previous MI or peripheral arterial disease

Vorapaxar is used with

aspirin or clopidogrel

Contraindications for Vorapaxar

history of stroke, TIAs, or intracranial hemorrhage

Half life of Vorapaxar

half life of 3-4 days; antiplatelet effect persists for days after discontinuation

Vorapaxar is metabolized by

CYP3A4

Avoid use of Vorapaxar with

strong 3A4 inhibitors or inducers

Coagulation/Antiplatelet Pharmacology Flashcards

(74 cards)