Transcript Antiplatelets-2.ppt

Platelet
Aggregation
Inhibitors
Professor. Dr.
MAHMOUD KHATTAB,
The components of a platelet
Platelets and the Mechanisms
of Arterial Thrombosis
 Platelet adhesion and aggregation occur at the site of plaque
rupture at luminal exposed subendothelium
 ADHESION occurs in response to collagen or vWf followed by a
cascade of further platelets recruitment
 Activated platelets exert pro-coagulant effects and the soluble
coagulation cascade is activated
 Fibrin strands and erythrocytes predominate within the lumen of
the vessel and downstream in the body and tail of the thrombus
Platelet Aggregation
 Activated platelets undergo three consecutive
processes (a) shape change, (b) secretion of
platelet granular contents (ADP, fibrinogen & 5-HT)
and finally (c) platelet aggregation
 The final common pathway in platelet aggregation is
cross-linking of the activated GP IIb/IIIa receptor
(integrin αIIbβ3) with circulating adhesive arginineglycine-asparagine (R-G-D) sequence
macromolecules, predominantly fibrinogen and
von Willebrand factor
 There is ~50,000-80,000 GP IIb/IIIa receptors on the
surface of each platelet
Platelet Aggregation
 GP IIb/IIIa receptors undergo inside-out (low-high
affinity) signalling in order to bind to vWf/fibrinogen
 Main stimuli for full platelet aggregation include:
Collagen, ADP, thromboxane A2 (TXA2), & thrombin
 All except for collagen act through G-protein
coupled receptors activating two transductions
• Phospholipase C
• Phospholipase A2
 Stored ADP & de novo synthesized TXA2 act as
positive feedback mediators
The stimulatory pathway for platelet
secretion
 TXA2 is produced from AA via
3-steps enzymatic process;
PLA2-COX-1/TXA2 synthase
 ADP activates Gi-coupled P2Y12
receptors
 TXA2 & thrombin activate GqPLC-coupled TXA2 & thrombin
receptors respectively
 Ultimately, GP IIb/IIIa receptors
undergo inside-out signalling
bringing platelet aggregation
Platelet Activation
 Activation of membrane-bound G proteins catalyzes the
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intracellular signaling system, predominantly inositol
biphosphate (IP3) and diacyl glycerol (DAG)
IP3 causes the release of intracellular calcium from the SR
& dense granules, phosphorylation of the myosin light
chain, and allows the platelet contractile apparatus to
perform platelet shape changes
DAG activates PKC and in turn the activation of the surface
integrin glycoprotein (GP) IIb/IIIa receptor occurs
Activated receptor undergoes a conformational change and
binds to the arginine-glycine-asparagine (R-G-D)
sequence on circulating macromolecules mainly
fibrinogen & vWf, and is responsible for cross-linking
platelets together
TXA2 provides amplification of the aggregation response &
a significant vasoconstrictor effect
Increased platelet activity implicated
in post-MI reocclusion and ischemia
 Several lines of evidence implicate increased platelet activity in
reocclusion and recurrent ischemia following acute MI
 A, Autopsy data indicate that patients who died after acute MI
are several times more likely to have a platelet-rich thrombus
occluding the coronary infarct-related coronary artery if they had
received thrombolytic therapy than if they had been treated
without it
 B, The production of thromboxane B2 (TXB2), the stable
metabolite of TXA2, is markedly increased, indicating that
platelet activation is stimulated in the early minutes after
thrombolytic therapy is given (The administration of oral aspirin is
able to block this reaction)
 C, Platelet aggregability following thrombolysis with either
streptokinase or tissue-type plasminogen activator is increased,
as measured by responses to either thrombin or ADP added to
platelet-rich plasma
ASPIRIN IN ACUTE ISCHEMIC SYNDROMES
 Low dose of aspirin inhibit TXA2
production by inhibiting
irreversibly COX-1 acetylation
(at serine-530)
 After oral intake, platelets are
exposed to relatively high
concentration of ASA in the
portal circulation
 Antiplatelet activity is achieved
at low dose of ASA than that
required for analgesia or
endothelial PGI2 production?
Aspirin Antiplatelet Efficacy
1- Dose
 Inhibition of 90% to 95% of TXA2 levels is needed to
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abolish in vitro platelet aggregation
Given over a period of days, this level of inhibition can be
achieved with doses as low as 20 mg
In volunteer subjects, a dose of 80 mg can inhibit
aggregation as soon as 15 minutes after ingestion; in the
unstable patient, however, in whom absorption is more
likely to be a problem and in whom circulating platelets are
more likely to be activated
Most authorities recommend initial therapy with a dose of
160 mg (one half-tablet) to 325 mg (one adult tablet)
The aspirin should be crushed/chewed to facilitate
absorption
The frequency of gastrointestinal complications appears to
be dose-dependent
Aspirin prolongs bleeding time, risk of hemorrhage
Aspirin Antiplatelet Efficacy
A, Efficacy of aspirin in patients with unstable angina
 Studies have demonstrated reductions in morbid ischemic events
in patients with unstable angina following the ingestion of aspirin
using varying doses of aspirin and varying periods between the
onset of symptoms and treatment with aspirin
B. Efficacy of aspirin in patients following acute MI
 Analysis of 10 trials of antiplatelet agents (mainly aspirin) for secondary
prophylaxis of vascular events following acute MI, the Antiplatelet
Trialists Collaboration reported striking reductions in nonfatal MI and
nonfatal stroke in patients treated chronically with antiplatelet
therapy (n=18,441) as well as a highly significant reduction in
cardiovascular mortality
 Similar reductions were seen for patients receiving antiplatelet therapy
following stroke. There were no differences in effect between varying
doses of aspirin
II- Glycoprotein IIb/IIIa Receptor Antagonists
1- Glycoprotein IIb/IIIa murine-derived 7E3
Fab monoclonal antibody (Abciximab)
 Abciximab is composed of 7E3 Fab fragments a murine-
derived (m) monoclonal antibody directed against
glycoprotein GPIIb/IIIa.
 Mechanism: The m7E3 Fab binds selectively to the
glycoprotein GPIIb/IIIa receptors inhibiting platelets
binding to fibrinogen and von Willebrand factor, and
consequently inhibiting platelet aggregation
 Clinical Efficacy: In acute MI patients, when the m7E3
Fab antibody was administered 3, 6, or 15 hours after
beginning treatment with rt-PA, the incidence of recurrent
ischemia was lower than expected
II- Glycoprotein IIb/IIIa Receptor Antagonists
1- Glycoprotein IIb/IIIa murine-derived 7E3
Fab monoclonal antibody (Abciximab)
 Administration and therapeutic use: Abciximab is administered
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intravenously as an adjuvant to angioplasty surgery for the prevention of
ischemic complications of angioplasty
Heparin or aspirin is given with abciximab
Blockade of glycoprotein IIb/IIIa receptors following a bolus
injection of c7E3 Fab (0.25 mg/kg):
Although the plasma half-life of this monoclonal antibody is only several
minutes, a potent biologic effect can be measured 2 hours after the
injection
In patients undergoing elective angioplasty, at this point, more than 80%
of receptors are bound by the antibody (and therefore unable to
participate in aggregation). At 6 hours, between 60% and 70% of
receptors are bound, and at 24 hours, 50% are bound
In patients undergoing thrombolysis for acute MI, the return toward
baseline occurs more rapidly. A continuous infusion leads to sustained
blockade of the receptor
II- Glycoprotein IIb/IIIa Receptor Antagonists
2- Synthetic arginine-glycine-aspartic acid
(R-G-D) sequence mimetics
 Eptifibatide (peptidergic) and tirofiban (non-
peptiic) are synthetic mimetics of the R-G-D
sequence of fibrinogen
 Hence, they block the binding of fibrinogen to
glycoprotein GPIIb/IIIa receptors
 They are given intravenously for the reduction of
thrombotic complications during coronary
angioplasty
 Clinical trials showed reductions in incidence of
death and non-fatal MI in response to the use of
both agents
III- Thromboxane
Antagonists
 Ridogrel is a combined thromboxane synthase
inhibitor and thromboxane A2 (TXA2) receptor
antagonist, orally active
 It has no effect on the vascular production of prostacyclin
but cyclic endoperoxides (PGH2) may increase
 In the Ridogrel Aspirin Perfusion Trial (RAPT), patients
received either ridogrel or aspirin (initially given IV then
orally) + IV streptokinase for acute MI
 In both groups of patients inhibition of TXA2 was markedly
inhibited, but recurrent ischemic events (angina,
reinfarction, and ischemic stroke) were observed less
frequently among the ridogrel-treated patients
IV- Platelet ADP Receptor Antagonists
(Thienopyridines)
Ticlopidine & Clopidogrel
 They inhibit irreversibly ADP binding to receptors
 Prevent ADP-mediated activation of the
glycoprotein GPIIb/IIIa & ultimately inhibiting
platelet aggregation
 No effect on PGs synthesis
 In the small percentage of patients who are truly
aspirin-intolerant, ticlopidine should be considered
as an alternative form of therapy
Ticlopidine & Clopidogrel
Adverse Effects
 Ticlopidine is associated with more side effects
than Clopidogrel
 Nausea, dyspepsia, diarrhea (20% of patients)
 Hemorrahge (5%)
 Leukopenia in 1% of patients (most serious),
check WBC in the first 3 months of treatment
 Ticlopidine, but not, clopidogrel can lead to fatal
neutopenia
 Thrombotic thrombocytopenic purpura may occur
with both agents
Other Antiplatelet Agents
 Dipyridamole, inhibits phosphodiesterase
activity and inhibit adenosine uptake
 It is weak antiplatelet vasodilator
 If used, should be combined with aspirin
 Cliostazol is another PD inhibitor used for
intermittent claudication
Antiplatelet Drugs
Aspirin
Irreversibly inhibits
production of TXA2
Ticlopidine Inhibits and antagonizes
ADP receptor and may
inhibit interactions of GP
IIb/IIIa receptor with
fibrinogen
Dipyridamole Phosphodiesterase
inhibitor
c7E3 Fab
Monoclonal antibody
(Abciximab) antagonist of GP IIb/IIIaligand binding
80-325 mg/d
250 mg three
times daily
25-75 mg three
times daily
0.25 mg/kg
bolus, 0.1
mg/min
infusion, over
12 h
Investigational
Clopidogrel Similar to ticlopidine
75 mg/d
Ridogrel
Thromboxane synthetase 300 mg twice
and thromboxane receptor daily
antagonist
Synthetic R-G- Antagonist of GP IIb/IIIa- Under
D sequence ligand binding
investigation
mimetics
Minutes
to h
3-5 d
Up to 1 wk
Hours
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Minutes
12-24 h
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Up to 1 wk
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Up to 1 wk
Minutes Approximately 46 h (longer for
oral compounds)
Overview of Antiplatelets