Antiplatelets Flashcards
Drugs used in coagulation disorders
-antiplatelets
-anticoagulants
-thrombolytics
-coagulants
Normal homeostasis
-arrest of bleeding from damages blood vessel
1. vasospasm
2. platelet plug formation
3. fibrin clot formation
4. Fibrinolysis
Coagulation
-process to plug leaking blood vessel
Platelet plug formation
-platelet adherence and aggregation
-thanks to fibrin
Fibrin clot formation
-prothrombin
-thrombin
-fibrogen
-fibrin
Fibrinolysis
-plasminogen
-plasmin
-fibrin
-split products
Artherosclerotic plaque and thrombosis
-deadly duo
-coronary plaque rupture
Platelet Formation
-megakaryocytes
1. granules in cell
2. maturation w centrosomal microtubule array
3. pseudopod formation
4. microtubules slide to power proplatelet ELONGATION granules move toward ends (branching amplifies ends also)
5. Platelets realeased from mother cell until naked nucelus
Platelet structure
-organelles
-secretory granules
-NO NUCLEUS = cant make proteins/cant reproduce
Thrombus Formation
-platelet plug/white thrombitis
-3 step process
-initiated by contact with ECM
1.adhesion and shape change
2. Secretion Reaction
3. Aggregation
slide 7
:(
- Adhesion (platelet activation)
-mediated by:
-GO 1a binding collagen (detect wall)
-GP 1b binding vonW factor bridged to collagen (detect wall)
-shape change facilitates receptor binding
How do intact endothelial cells inhibit thrombogenesis
-secrete prostacylin (PGI2)
-barrier to ECM
- Platelet Secretion (release reaction)
-degranulation
-platelet granules release ADP, TXA2, 5-HT
Released from platelet granules
-ADP
-Thromboxane A2*
-Serotonin (5-HT)*
-activate and recruit other platelets
-induces change in GPIIb/IIIa receptors to bind fibrinogen
*vasoconstrictors (restrict blood flow)
- Platelet aggregation
-ADP, 5-HT, TXA2 = GPIIb/GPIIIa receptors bind fibrinogen (aka integrinaIIbB3)
-fibrinogen cross links platelets = hemostatic plug
-contract to form IRREVERSIBLY fused mass
-fibrin stabilizes and anchors aggreggated platelets
=surface for clot formation
Fibrinogen
-binds GPIIb/IIIa receptors
-cross-links platelets during aggregation
Fibrin
-stabilizes aggregated platelets
Antiplatelet drugs
-COX-1 inhibitors
-ADP receptor inhibitors
-GPIIb/IIIa BLOCKERS
-Phosphodiesterase-3 inhibitors
-Protease-Activate Receptor inhibitors
-all inhibitors
Cyclooxygenase-1 inhibitor
-aspirin
-ring w ketone and carboxyl
Asprin Function
-inhibits COX-1 by acetylation
-interferes w platelet aggregation
-prolongs bleeding
-prevents arterial thrombi formation
-inhibition of TXA2 synthesis in platelets is the key of anti-platelet activity of ASA
Aspirin MOA
-IRREVERSIBLE COX-1 inhibition by acetylation
-permanent loss of COX-1 activity
=dec TXA2
-PGI2 production inhibited in tissue by higher doses
Aspirin dose
-max dose 50-320mg/day
-PGI2 production inhibited at higher dose (we dont want that)
Aspirin indications
-prophylaxis
-tx of arterial thromboembolic disorders
-prevent coronary thombosis in unstable angina
-adj to thrombolytic therapy
-reduce recurrence of thrombotic stroke
Aspirin counseling
-prolongs bleeding time but no inc in PT time
-hemostasis returns to normal 36h after last dose
-risk of upper bleeding (age, NSAIDs, alcohol)
Aspirin side effect
-upper GI bleeding
-inhibition of COX-1 mediated PGs needed for mucosa production
-risk inc w age, NSAIDs, alcohol
Acute Aspirin overdose
-can be induced by doses above 150mg/kg
-doses > 500 mg/kg can be fatal
-sx: N/V/D/fever/coma
COX-2 enxyme
-produces prostacyclin (PGI2) in endothelial cells
=vasodilation and inhibition of platelet aggregation
-does not prevent TXA2 tho (inc CV risk!)
-selectively targeting COX-2 blocks prostacyclin
=platelet aggregation
-but TXA2 not inhibited = CV risk
ADP receptor inhibitors
-P2Y1
-P2T12
-activation by BOTH needed to activate platelet by ADP
P2Y1
-ADP receptor
-Gq-PLC-IP3-Ca pathway
P2Y12
-Gi and inhibition of adenylyl cyclase
-target of ADP inhibitors
P2Y12 receptor MOA
-Gi = cAMP = phosphorylation of VASP by PKA = platelet activation
-want to inhibit this
-adenylyl cyclase inhibts aggregation
ADP receptor inhibitor drugs
-P2Y12
-Ticlopidine*
-Clopidogrel*
-Prasugrel*
-Ticagrelor
-Cangrelor
-*prodrug
Thienopyridine class of ADP receptor inhibitors
-Ticlopidine (Ticlid)
-Clopidogrel (Plavix)
-prodrugs
-IRREVERSIBLE block
Ticlopidine and Clopidgrel
-Thienopyridine ADP inhibitors
-prodrugs
-oral
-IRREVERSIBLLY block ADP receptor on platelet
=block GPIIb/IIIa complex
-action lasts several days after last dose (bc irreversible)
-Ticlopidine may induce TTP
Ticlopidine and Clopidgrel use
-acute coronary syndrome
-recent MI, stoke, PVD, coronary stent procedure
Prasugrel (Effient)
-P2Y12 ADP on platelet surface inhibitor
-tx Acute Coronary Syndrome and Percutaneous coronary intervention (PCI)
-take orally
-prodrug
-IRREVERSIBLE binding
-activity lasts several days after last dose
-bleeding risk – not for elderly
Prasugrel (Effient) prodrug
-activated by esterase and CYP 3A4/2B6
-PO
-IRREVERSIBLE P2Y12 binding
-high risk of bleeding (not recommended in elderly or before CABG)
Ticagrelor (Brilinta)
-tx Acute coronary syndrome
-PCl-taken PO
-binds to allosteric site
-REVERSIBLE binding
-CYP3A4 substrate
-faster onset than clopidogrel (7-9h t1/2)
-risk of bleeding
=do NOT use immediately before CABG
Cangrelor (Kangreal)
-P2Y12 ADP inhibitor
-adjunct to PCl – give IV
-REVERSIBLE
-fast onset
-short t1/2 (3-5min)
-activity terminated early which can be good in MI bc it works really quick then the antiplatelet effect is gone before surgery
Activation of P2Y12 ADP receptor antagonists
-clopidogrel activated by CYP2C19
-prasugrel activated by esterases/CYP3A4/CYP2B6
=longer onset and t1/2 than the nonprodrugs
-closed S pentagon opens to SH
Mech of PDE inhibitors
-enhance cAMP levels by inhibiting PDEIII that breaks it down
=maintain platelet activity
- i dont understand
Phosphodiesterase-3 (PDE) inhibitors
-platelet aggregation inhibitor
-oppose P2Y12 action! (cAMP inhibition)
-inhibit adenosine uptake
-Dipyridamole
-Cilostazol
PDE inhibitor drugs
-Dipyridamole (Persantine)
-Cilostazol (Pletal)
Dipyridamole (persantine)
-PDE inhibitor
-combo w warfarin to prevent embolization in prosthetic heart valves
-combo w aspirin to prevent cerebrovascular ischemia
Cilostazol (pletal)
-intermittent claudication (block aggregation in legs)
-PDE inhibitor
Glycoprotein IIb/IIIa receptor inhibitors MOA
-inhibits fibrinogen cross-linking of platelets
GPIIb/IIIa inhibitor drugs
-Abciximab (ReoPro)
-Eptifibitide (integrilin)
-Tirofiban (Aggrastat)
Abciximab (reoPro)
-mAb (Fab fragment) againts GPIIb-IIIa
-inhibits platelet aggregation
-IV bolus then infusion
-long duration (=inc risk of bleeding)
-prevent thromboembolism in coronar angioplasty
-combo w t-PA for early tx of acute MI
Epitifibitide (Integrilin)
-synthetic peptide
-reversibly and selectively blocks GPIIb-IIIa
-inhibits fibrinogen binding to dec platelet aggregation
-admin IV bolus then infusion (upto 72h)
-short duration of action (6-12h)
-prevent thromboembolism in unstable angina and angioplastic coronary procedures
-cyclic heptapeptide derived from rattlesnake venom
Tirofiban (Aggrastat)
-nonpeptide TYROSINE ANALOG
-selective
-REVERSIBLY inhibits fibrinogen binding
-admin IV in dilute solution
->90% inhibition of aggregation after 30 min infusion
-2h t1/2
-combo w heparin to tx acute coronary syndrome
-some structural similarities to RGD
Protease Activated Receptor inhibitor MOA
-slide 32-33
-thombin activates platelets
-proteolytic cleavaage of PAR-1 on platelet surface
-PARs are GPCRs coupled to release of Ca2+ from stores
-Vorapaxar
Vorapaxar (Zontivity)
-reversible PAR-1 antagonist!
-PO qd
-prophylactic to prevent thrombosis in pt w previous MI or PAD
-combo w aspirin or clopidogrel!
-t1/2 of 3-4 days = antiplatelet effect for days after dc!
-CYP3A4 (avoid use w 3A4 inhibitors/inducers)
-do NOT use in history of stroke, TIAs, or intracranial hemorrhage
summary
-slide 35
Prostacyclin
-released in to plasma by endothelium
-binds platelet receptors = camp synthesis
-camp inhibits aggregation
Thromboxane A2
-inhibited by aspirin
RGD motif in glycoprotein IIb/IIIa inhibitors
-arginine, glysine, aspartic acid
-binds receptor
-eptifibatide, tirofiban,
