Antiplatelet Drugs Hockerman Flashcards
What is hemostasis?
Arrest of bleeding from a damaged blood vessel
Phases of hemostasis
-Vasospasm
-Platelet plug formation
-Fibrin clot formation
-Fibrinolysis
Why is it important that platelets do not have nuclei?
They cannot replace proteins that have been irreversibly inhibited
What does GP Ia bind to?
Collagen
What does GP Ib bind to?
von Willebrand Factor bridged to collagen
What do endothelial cells secrete?
PGI2 (prostacyclin) which inhibits thrombogenesis
Why does the disruption of the endothelial layer cause platelet aggregation?
Exposes collagen and van Willebrand factor to the clotting factors
What granules are secreted by the platelet through degranulation?
-ADP
-TXA2
-5-HT
What do the granules released by the platelet during degranulation do?
-ADP, 5-HT, and TXA2 activate and recruit other platelets
-TXA2 and 5-HT are also potent vasoconstrictors
What do GPIIb/IIIa receptors bind to?
These receptors bind to fibrinogen after ADP, 5-HT and TXA2 activation
How do platelets recruit other platelets during platelet aggregation?
-Platelets are cross-linked by fibrinogen which is a bivalent molecule
-Platelets then contract to form an irreversibly fused mass called a fibrin which stabilizes and anchors aggregated platelets
What are the COX-1 inhibitors?
Aspirin
COX-1 inhibitor mechanism of action
Irreversible inhibition by acetylation of COX-1 leading to a permanent loss of platelet COX-1 activity (decrease in TXA2)
At what dose is aspirin maximally effective?
AT 50-320mg per day
Why is it important to not go too high in dosing of aspirin?
PGI2 production in tissue inhibited by higher doses
What are the indications for aspirin?
“prophylaxis and treatment of arterial thromboembolic disorders”
-Prevent coronary thrombosis in unstable angina
-Adjunct to thrombolytic therapy
-Reducing recurrence of thrombotic stroke
What are two key clinical actions for aspirin?
-Prolong bleeding time, but no increase in prothrombin time
-Hemostasis returns to normal after 36 hours after last dose
Side effects of aspirin
-Upper GI bleed (risk increases with age, concurrent use of NSAIDs and/or alcohol)
-Acute aspirin overdose (above 150 mg/kg)
At what dose of aspirin can be fatal?
Over 500 mg/kg
Symptoms of acute aspirin overdose
-Nausea
-Vomiting
-Diarrhea
-Fever
-Coma
What are the two ADP receptors involved in activating platelets?
-P2Y1
-P2Y12
-Activation of both is required for platelet activation by ADP
What are the ADP receptor inhibitors?
-Clopidogrel (Plavix)
-Ticlopidine (Ticlid) (Not on the market anymore so probably not on exam)
-Prasugrel (Effient)
-Ticagrelor (Brilinta)
-Cangrelor (Kangreal)
What is the pharmacophore for ADP receptor inhibitors?
Thienopyridine group
Clopidogrel mechanism of action
-Irreversibly block ADP receptor on platelet and subsequent activation of GPIIb/IIIa complex
-Action lasts for several days
What is the only ADP receptor inhibitor not given orally?
Cangrelor is given IV
Use of Clopidogrel
-Acute coronary syndrome
-Recent MI
-Stroke
-Established peripheral vascular disease
-Coronary stent procedures
Why does Prasugrel work more dependably in more people compared to Clopidogrel?
Clopidogrel is activated by the enzyme CYP2C19 while Prasugrel is activated by esterase and CYP3A4/CYP2B6
What is a warning to consider in Prasugrel?
High risk of bleeding so it is not recommended in the elderly or before CABG
What is Prasugrel approved for treating?
-Acute coronary syndrome
-Percutaneous coronary intervention (PCI)
What is Ticagrelor used to treat?
-Acute coronary syndrome
-PCI
What is a warning to consider in Ticagrelor?
Risk of bleeding- do not use immediately before a CABG
What is Cangrelor used for?
An adjunct to PCI
Which ADP receptor inhibitors are prodrugs?
-Clopidogrel
-Pasugrel
Which ADP receptor inhibitors are not prodrugs?
-Ticagrelor
-Cangrelor
Which ADP receptor inhibitors are reversible?
-Ticagrelor
-Cangrelor
Which ADP receptor inhibitors are irreversible?
-Clopidogrel
-Prasugrel
What are the GPIIb/IIIa receptor inhibitors?
-Abciximab
-Eptifibatide
-Tirofiban
What is the same motif that is present in eptifibatide that is also present in the GPIIb/IIIa receptors?
-Arginine
-Glycine
-Aspartic acid
How are GPIIb/IIIa receptor inhibitors given?
Through IV
Which GPIIb/IIIa receptor inhibitor has the longest duration of action?
Abciximab which means it has an increased risk of bleeding
Which GPIIb/IIIa receptor inhibitor has the shortest onset?
Tirofiban inhibits over 90% of platelet aggregation after just 30 minutes of infusion
What is Eptifibatide used for?
To prevent thromboembolism in unstable angina and angioplastic coronary procedures
Is Tirofiban reversible or irreversible?
Reversible
What is Tirofiban used for?
Combined with heparin to treat acute coronary syndrome
What is Abciximab used for?
-Prevent thromboembolism in coronary angioplasty
-Combined with t-PA for early treatment of acute MI
Is Abciximab reversible or irreversible?
Reversible but it binds very tightly giving it a long half-life
Use of Dipyridamole
-Combined with warfarin to prevent embolization from prosthetic heart valves
-Used with ASA to prevent cerebrovascular ischemia
Use of Cilostazol
Intermittent claudication
