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Anti-platelet agents (Donkor) (P2Y12 Antagonist (Thienopyridines…
Anti-platelet agents (Donkor)
Phase II platelet aggregation
Thromboplastic mechanism
release of chemical mediators from platelets that part-take in the coagulation cascade
Phase I platelet aggregation
NO adherence
to undamaged endothelial cells
tissue damage: platelets adhere to the damaged sub endothelial tissues
induce hemostasis via platelet aggregation
forms a mass at the site of damage
Overall,
platelet aggregation promotes
clot formation
inhibitors of platelet aggregation could serve as effective anticoagulants
Inhibitors of PDE3
Dipyridamole
MOA
inhibitions of
adenosine deaminase
and
adenosine reuptake into platelets
increase cAMP and adenosine
vasodilation
due to direct stimulation of adenosine receptors on the smooth m. membrane
pyrimidopyrimidine
derivative
combo use
to prevent blockade of prosthetic heart valves
with
warfarin
with thromboembolic disease
with
aspirin
Cilostazol
MOA
selective
PDE3 inhibitors
inhibits adenosine reuptake
increase adenosine action at A1 and A2
increase cAMP
promotes vasodilation of blood vessels
decrease platelet aggregation
uses
Thromboembolic disease
quinoline
derivative
Inhibitors of Cyclooxygenase
(COX1)
Aspirin
MOA
irreversible
inhibition of COX
derivative of salicylic acid
effect of pH on absorption and excretion
P2Y12 Antagonist
MOA
inhibitors of the ADP-induced fibrinogen-platelet binding
result platelet-platelet itneractions
Purinergic receptors
G protein-coupled
P2Y1
ADP activates - to
initiate
platelet aggregation
P2Y12
ADP activates - to
sustain
platelet aggregation by inhibiting adenyl cyclase
ADP serves as agonist
Thienopyridines
Ticlopidine; Clopido
grel
; Prasu
grel
Prodrugs; Basic drugs
effect of pH on absorption and excretion
acid drug + basic urine = rapidly secreted
MOA
Irreversible
antagonists of
P2Y12
purinergic receptors
Prasu
grel
:
NOT affected by
CYP2C19
polymorphisms
greater potency and rapid onset of action
major bio activation: CYP3A4 and CYP2B6; minor: CYP2C19
Nucleoside analogues
Ticagrelor
a nucleoside analogue with a **cyclopentyl-triazolo-pyrimidine ring
reversible
antagonist of the platelet P2Y12 receptor
Not produce; Not require hepatic activation
effective in patients with
CYP2C19
polymorphism
major active metabolite if formed by via
CYP2A4
O-
de
ethylation (
removal
)
MOA
like Thienopyridines
blocks ADP receptor subtype P2Y12
unlike Thienopyridines
has a binding site different from ADP
aka
allosteric antagonist
GP IIb/IIIa Receptor Antagonists
MOA
reduce thrombus formation through the blockade of key binding sites needed to stabilize the forming platelet aggregate
Inhibition of interaction of fibrinogen with GPIIb/IIIa receptor, which is an activated platelet membrane-bound glycoprotein complex
Abciximab
human-murine chimeric Fab fragment of a monoclonal antibody against the GP IIb/IIIa receptor
Not specific
for the GPIIb/IIIa receptor because
also binds to vitronectin receptors on platelets, vascular endothelial cells, and smooth muscle cells
uses
Acute coronary syndrome aka ACS
ex.
recurrent MI
Eptifibatide
IV
Cyclic peptide inhibitor of the
RGD
binding site on GPIIb/IIIa receptor
Specific
allows compound to present right conformation
more selective drugs
(vs.
Abciximab
- NOT specific)
R = Arg, G = Gly, D= Asp
uses
ACS
- eg.
unstable angina
Tirofiban HCl
IV
tyrosine
derivative
a small molecule inhibitor of the protein-protein interaction between
fibrinogen and the GPIIb/IIIa
Specific
for GPIIb/IIIa receptor
uses
ACS
- eg.
unstable angina and MI