Antiplatelet drugs Flashcards
Normal Hemostasis
hemostasis - ___ of bleeding from a damaged blood vessel
Coagulation: multi-step process to ___ the leaking vessel
- arrest
- plug
Phases Hemostasis
- ___ to blood vessel that causes bleeding
- vaso ___
- platelet ___ formation
- ___ clot formation
- fibrinolysis
- injury
- vasospasm
- plug
- fibrin
Platelet formation from Megakaryocytes
- megakaryocytes never really divide, just keep growing and then lil blobs pinch off (pre-platelets)
- platelets have organelles and secretory granules but no ___
nucleus
Thrombus Formation - platelet plug/white thrombus
contact with ___ initiates platelets reactions:
- ___ and shape change
- ___ reaction
- aggregation
ECM
adhesion
secretion
Platelet Adhesion and Shape Change - 1st step of platelet activation
Adhesion mediated by:
- GP ___ binding to collagen
- GP ___ binding to von Willebrand Factor bridged to collagen
- shape change facillitates ___ binding
- intact endothelial cells secrete ___ (prostacyclin) to inhibit ___
- Ia
- Ib
- receptor
- PGI2, thrombogenesis
Platelet Secretion - 2nd step of platelet activation
Secretion (Release reaction):
- degranulation
- Platelet gransules release ___ , thromboxane A2 ( ___ ) , and ___ (5-HT)
- these ___ other platelets
- ___ and ___ are potent vasoconstrictors
- ADP, TXA2, serotonin
- recruit
- TXA2, 5-HT
Platelet Aggregation - 3rd step of platelet activation
- ___ , ___ , and ___ activation induced conforation of GP ___ / ___ receptor to bind ____
- platelets are crosslinked by ___
- this forms a temporary hemostatic ___
- platelets contract to form ___ fused mass
- ___ stabilizes and anchors aggregated platelets
- forms surface for ___ formation
- TXA2, 5-HT, ADP
- IIb/IIIa, fibrinogen
- fibrinogen
- plug
- irreversibly
- fibrin
- clot
COX-1 inhibitors - ASA
- inhibits platelet COX-1 by ___
- interferes with platelet ___
- prolongs ___ time
- Prevents ____ thrombi formation
- inhibition of ___ synthesisi in platelets in the key to anti-platelet activity of ASA
- acetylation
- aggregation
- bleeding
- arterial
- TXA2
Aspirin Antiplatlet Action
- ___ inhibition by acetylation of COX-1
- permanent loss of platelet COX-1 activity - decreased ___
- maximally effective at doses of ___ - ___ mg per day
- prostacyclin ( ___ ) production in tissue inhibitied by higher doses
- irreversible
- TXA2
- 50-320 mg
- PGI2
Aspirin
Indication: ___ and ___ of arterial thromboembolic disorders
- prevent coronary thromosis in unstable ___
- adjunct to thrombolytic therapy
- reduce recurrence of thrombotic ___
Clinical Actions:
- prolongs ___ time, but no increase in PT time
- hemostasis returns to normal after ___ hrs after last dose
- prophylaxis, treatment
- angina
- stroke
- bleeding
- 36 hrs
Side Effects of Aspirin
Upper GI Bleeding
- inhibition of ___ , mediated ___ are needed for gastric mucosa production
- risk increased with age concurrent use of ___ and/or alcohol
Acute Aspirin Overdose
- can be inducd by doses above ___ mg/kg
- doses > ___ mg/kg can be fatal
- N/V, diarrhea, fever, and coma
- COX-1, prostaglandins
- NSAIDs
- 150 mg/kg
- 500 mg/kg
Selective COX Inhibitor?
The Good: COX - ___ produces ___ in endothelial cells. Leads to vaso ___ and inhibition of platelet ____
The Bad: COX - ___ produces ___ in platelets. Leads to vaso___ and platelet ___
The Ugly: Selective COX - ___ inhibitors block synthesis of ___ while not preventing synthesis of ___
INCREASED ___ RISK
- COX-2, prostacyclin, vasodilation, aggregation
- COX-1, TXA2, vasoconstriction, aggregation
- COX-2, prostacyclin, TXA2
- CV
ADP Receptor Inhibitors
2 ADP receptors are involved in activating platelets: ___ and ___
___ - is coupled to Gq - PLC - IP3 -Ca2+ pathwya
___ - is coupled to Gi and inhibition of adenylyl cyclase
Activation of ___ is required for platelet activation by ADP
- P2Y1, P2Y12
- P2Y1
- P2Y12
- BOTH
Examples of ADP inhibibitors - P2Y12 receptor antagonists
Direct Acting (2)
Pro-drugs (2)
direct:
- ticagrelor
- cangrelor
pro-drugs:
- prasugrel
- clopidogrel
ADP Receptor Inhibitors - P2Y12 receptor antagonists
Example: clopidogrel (Plavix)
- ___ class, pro-drug
- taken PO to reduce platelet ___
- ___ block ADP receptor on platelet and subsequent activation of GP ___ / ___ complex
- action lasts for several ___
- Use: acute coronary syndrome, recent MI, stroke, established peripheral vascular disease and coronary stent procedures
- thienopyridine
- aggregation
- irreversibly
- IIb/IIIa
- days
ADP Receptor Inhibitors - P2Y12 receptor antagonists
Example: prasugrel (Effient)
- approved for treatment of acute coronary syndrome; percutaneous coronary intervention (PCI).
- taken PO
- pro-drug: requires ___ + CYP ___ / ___ to generate active metabolite
- ____ binds P2Y12 receptor
- high ___ risk; not recommended in elderly or CABG
- esterases, 3A4/2B6
- irreversibly
- bleeding
ADP Receptor Inhibitors - P2Y12 receptor antagonists
Example: ticagrelor (Brilinta)
- used in acute coronary syndrome, PCI- taken PO
- binds to an allosteric site, binding is ___
- dose not require ___ (not a pro-drug)
- ___ onset compared to clopidogrel, t1/2 = 7-9 hours
- risk of bleeding, dont use immediately before ___
- reversible
- bioactivation
- fast
- CABG
ADP Receptor Inhibitors - P2Y12 receptor antagonists
Example: cangrelor (Kangreal)
- used as an adjunct to PCI - given ___
- ___ inhibits P2Y12 receptors
- does not require ___ (not a prodrug)
- fast onset of action; t1/2 3-5 ___
- IV
- reversibly
- bioactivation
- minutes
T or F: the thiol group on clopidogrel and prasugrel markes binding reversible
F; makes inding irreversible
Glycoprotein IIb/IIIa receptor inhibitors
Mechanism - inhibits fibrinogen ___ of platelets
- abciximab
- eptifibitide
- tirofiban
crosslinking
Glycoprotein IIb/IIIa receptor inhibitors
eptifibatide (Integrilin)
- synthetic peptide derived from ___ venom which selectively blocks GPIIb-IIIa in a ___ manner
- inhibits ___ binding to decrease platelet aggregation
- ___ duration of action: 6-12 hr
- used to prevent thromboembolism in unstable ___ and angioplastic coronary procedures
- rattlesnake, reversibly
- fibrinogen
- short
- angina
Glycoprotein IIb/IIIa receptor inhibitors
tirofiban (Aggrastat)
- non-peptide ___ analogue which is specific for GP ___ / ___ and ___ inhibits fibrinogen binding
- administered ___ in a dilute solution
- >90% inhibition of platelet aggregatio after ___ min infusion, t1/2 = 2 hr
- combined with heparin to treat acute coronary syndrome
- tyrosine, IIb/IIIa, reversibly
- IV
- 30
Glycoprotein IIb/IIIa receptor inhibitors
abciximab (ReoPro)
- ___ fragment of chimeric human-murine monoclonal Ab
- binds to GP ___ / ___ receptor to inhibit platelet aggregation
- administered ____ bolus, followed by infusion
- long duration of action - increases risk of ___
- use: prevent thromboembolism in coronary angioplasty
- combined with t-PA for early treatment of acute ___
- Fab
- IIb/IIIa
- IV
- bleeding
- MI
Phosphodiesterase-3 inhibitors
Examples: dipyridamole (Persantine) and cilostazol (Pletal)
- platelet aggregation inhibitor
- action related to ___ PDE inhibition (opposing ___ action) and inhibition of ___ uptake
- Dipyridamole use: combined with ___ to prevent embolization from prosthetic heart valves. Combined with ___ to prevent cerebrovascular ischemia
- cilostazol use: intermittent claudication
- cAMP, P2Y12, adenosine
warfarin, ASA
Protease Activated Receptor (PAR) Inhibitors
- ___ activates platelets at nanomolar concrentration
- mechanism: proteolytic ___ of PAR-1 receptors on platelet surface
- PARs are ___ coupled to release of Ca2 from stores
- Vorapaxar - inhibitor
- thrombin
- cleavage
- GPCRs
Protease Activated Receptor (PAR) Inhibitors
vorapaxar (Zontivity)
- ____ PAR-1 receptor antagonist
- PO once daily
- ___ to prevent thrombosis in patients with a previous ___ or ___
- used with aspirin or ___
- contraindications - history of ___, TIAs, or intracranial hemorrhage
- t1/2 of 3-4 ___ ; antiplatelet effect persists for ___ after discontinuation
- metabolized by CYP ___; avoid use with strong inducers or inhibitors
- reversible
- prophylactic, MI, PAD
- clopidogrel
- stroke
- days
- CYP3A4
Summary - ASA
mechanism: inhibits ___ preventing formation of ___
indications:
- acute coronary syndrome (with ___)
- acute ___
- primary and secondary prevention of ___ disease
- alternative to anticoagulation in ___
- cyclooxygenase (COX-1), TXA2
- P2Y12
- stroke
- CV
- a-fib
Summary - P2Y12 Inhibitors
examples (3)
mechanism: inhibits the P2Y12 ___ receptor, preventing platelet ___
indications:
- acute coronary syndrom (with ___ and anticoagulation)
- secondary prevention of ____
- as an alternative to ___ in allergic patients
- clopidogrel, prasugrel, ticagrelor
- ADP, activation
- ASA
- stroke
- ASA
Summary - GP IIb/IIIa inhibitors
examples (3)
mechanism: inhibits ___ receptor, preventing platelet ___
indications:
- limited use peri-___ in acute coronary syndrome
- eptifibatide, tirofiban, abciximab
- GP IIb/IIIa, aggregation
- PCI
PCI = percutaneous coronary intervention
Summary - Dipyridamole
mechanism: inhibits ___ and ___ to a lesser extent
indications:
- secondary ___ prevention (usually in combination with ___ )
- use in ___ nuclear imaging
- PDE5, PDE3
- stroke, ASA
- myocardial
Summary - Cilostazol
mechanism: inhibition of ___
indications:
- ___ artery disease
- PDE3
- peripheral
