antiplatelets, anti-thrombotics Flashcards
event in platelet activation & aggregation
1 (normal). intact endothelium releases PGI2 into plasma, which binds to platelet membrane –> synthesis of cAMP –> inhibit release of granules containing aggregating agents
2 (inhibited by aspirin). thrombin, TXA2 (also synthsized in platelet), exposed collagen –> release of arachidonic acid from platelet membrane –> platelet synthesize more TXA2
- TXA2 binds to receptors on toher platelets –> initiate release of additional aggregating agents (propagation)
balance b/w PGI2 and TXA2 influences whether platelets aggregate or circulate freely
serotonin, ADP increases platelet aggregation
aspirin
anti-platelet NSAID
irreversible inhibitor of COX –> effect lasts the life of platelet –> 7-10 days
uses:
- prophylactic tx of transient cerebral ischemia
- reduce incidence of recurrent myocardial infarction
- decrease mortality of post-MI pt
AE: bleeding (PGI2 > TXA2), gastric ulcer (PGE2 v), GI bleeding
platelet GPIIB/IIIA receptor blockers
antiplatelet
- used to prevent restenosis after coronary angioplasty, acute coronary syndromes
abciximab – monoclonal Ab (IV route) directed against IIb/IIIa complex –> reversibly inhibits binding of fibrinogen and other ligands to GPIIB/IIIA
eptifibatide –> analog of part of fibrinogen –> competitive inhibitor
tirofiban –> small molecule (oral route) blocker of GPIIB/IIIA
GP IIB/IIIA receptor
platelet membrane glycoprotein complex involved in platelet cross-linking
receptor for fibrinogen, fibronectin, vitronectin, von willebrand factor (clotting factors)
ADP receptor blocker
ticlopidine
antiplatelet
prevents release of ADP which increases platelet aggregation
PDE inhibitor
dipyridamole
antiplatelet
inhibits conversion of cAMP to 5’ AMP
increase intra-platelet [cAMP], increased effect of cAMP to prevent degranulation of granules containing ADP and serotonin
actions of thrombin (factor IIa)
-activated upstream proteins –> further thrombin generation
cleaves fibrinogen –> fibrin
activates factor XIII, a fibrinoligase –> strengthen fibrin-to-fibrin links
causes platelet aggregation
stimulate cell proliferation
modulate smooth muscle contraction
antithrombin III (ATIII)
endogenous anticlotting protein
irreversibly inactivates clotting factor proteases (esp thrombin, IXa, Xa)
forms stable complexes
heparin
anticoagulant
PK: IV, subcutaneous
CANNOT GIVE IM –> haematoma
family of sulfated GAG (mucopolysaccharides)
low m.w. heparins –> longer duration of action, but only increases action of ATIII on Xa, not thrombin
uses
- deep vein thrombosis, pulm embolism, acute MI
- when MUST use an anticoagulant in pregnancy
- in combi w thrombolytics for revascularisation (restore blood flow in aa/vv)
- in combi w GPIIb/IIIa inhibitors during angioplasty, placement of coronary stents
AE:
haemorrhage –> stop heparin, use protamin sulfate (bind to heparin)
thrombosis (blood clot), thrombocytopenia (low platelet count) –> immune mediated response
action of heparin
heparin binds to ATIII –> ATIII active site exposed –> more rapid interaction w proteases
heparin need bind to ATIII and thrombin to inhibit thrombin
only need to bind to ATIII to inhibit factor X (LMWHs)
vit K
-fat soluble vitamin essential for formation of clotting factors 2, 7, 9, 10
reduced vit K essential co-factor in gamma carboxylation of glutamate residues
- reduced vit K regenerated by vit K reductase
uses:
- tx/prevention of bleeding from anticoagulant drug use eg warfarin, prevent haemorrhagic disease in newborns
- vit k deficiency
warfarin
anticoagulant
pk: small, lipid soluble – oral route
- small vol of distribution – >99% bound to plasma albumin
- elimination depends on metab by CYP450 (drug interactions)
vit k reductase inhibitor
- reduced vit K cannot regenerate –> less clotting factors
uses: same as heparin BUT CANNOT USE IN PREGNANCY
AE: bleeding
PREGNANCY: crosses placenta – hemorrhagic disorder in fetus
fetal proteins in bone and blood may be affected
thrombolytic agents
IV, intracoronary injection
t-PA, urokinase, streptokinase, anistreplase
all increases conversion from plasminogen to plasmin –> dissolve fibrin
uses: emergency tx of coronary aa thrombosis (intracoronary inj), peripheral aa thrombosis, emboli
ischaemic stroke (<4.5h window)
AE: bleeding
Contraindication: delayed wound healing, pregnancy
