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Antiplatelet Therapy in General Overview
Cause of Death by Gender in Europe:
WHO 2008
Plaque Fissure or Rupture
If exposed to subendothelium, platelets activated
Direct and reversible inhibit P2Y12 receptors
Oral
Intravenousl y
180 loading dose and continue treatment with 90 mg twice daily
30 μg per kilogram of body weight followed by an infusion of 4 μg per kilogram per minute for at least 2 hours
There are six putative recognition sites within fibrinogen for GP IIb/IIIa and thus fibrinogen acts as a hexavalent ligand to crosslink GP IIb/IIIa sites on adjacent platelets. Attempts have been made to use fibrinogen fragments and synthetic peptides to define the sequence within fibrinogen which mediates the GP IIb/IIIa-fibrinogen interaction and thus aggregation. The tripeptide sequence arginyl-glycyl-aspartyl (RGD) is believed to represent the minimal sequence necessary for binding to GP IIb/IIIa. RGD occurs four times in fibrinogen twice in each of the two Aa chains, thus contributing four of the six putative recognition sites within fibrinogen. The other two sitesoccur in the C-terminal amino acid segments of the two γ chains.
bleeding dyspnea
The plasma half-life approximately 3 to 5 minutes, and platelet function is restored within 1 hour after cessation of the infusion
ATP analogs & others
ADP receptor antagonists
ADP is an important platelet agonist in vivo, has two types of receptors in the platelet plasma membrane: P2Y1 and P2Y12. The result of ADP signalling through the P2Y1 receptor is Ca2+ mobilization, a change in platelet shape and rapidly reversible platelet aggregation. P2Y12 is a seven-transmembrane domain receptor, but it is linked to a Gi protein and lowering of cyclic AMP levels. The result of ADP signalling through the P2Y12 receptor is the amplification of stable platelet aggregation and secretion
4. GP IIb/IIIa blokers
5. Thrombin receptor antagonists
ASA
Irreversibly acetylates Ser529 of COX1, rendering the catalytic site of COX1 inaccessible to arachidonic acid and therefore inhibiting the generation of prostaglandin H2 and, subsequently, thromboxane A2
12 HR 0.74 (95% CI: 0.66-0.84)
10 p<0.001, NNT 37
8
6
4 HR 1.24
(95% CI: 0.91-1.69)
2
p=0.17, NNH 222
0 0 30
90
180
Days
Clopidogrel 11.0%
来自百度文库Prasugrel 8.3%
TIMI major bleeding
Phosphodiesterase Inhibitors
Dipyridamole stimulates PGI2 synthesis, blocks uptake of adenosine
Clinical trials failed to show efficacy alone, enhances warfarin and ASA
MR form useful for stroke prevention Cilostazol may be useful in claudicatio
and has vasodilatory and antiplatelet effects
Thienopyridines —— irreversibility inhibitors
ATP
Elinogrel
Cangrelor
ticagrelor
Others
Elinogrel, orally or intravenously
Variable Clopidogrel Response
At 5 Days UA Patients* (n = 32)
Nonresponders 22%
Responders 47% Low responders 32%
*Received an oral loading dose of 300 mg of clopidogrel followed by 75 mg daily. Gurbel PA, et al. Circulation. 2003;107(23):2908-2913; Lau WC, et al. Circulation. 2004;109(2):166-171.
Glycoprotein IIb/IIIa Inhibitors
Monoclonal Ab against IIb/IIIa: Abciximab Peptide antagonist: Eptifibatid Nonpeptide antagonist: Tirofiban
Mechanism
No renal/hepatic metabolism to be activated
İv,rapid action, platelets back to normal in 60 minutes
Has additive effects to clopidogrel
Two short term trials discontinued for less than expected efficacy
Ticagrelor
Stable, high affinity inhibitor of ADP induced aggregation
Oral agent acting directly on P2Y12 receptor without transformation
Rapid and greater action Reversibility 180 mg loading ,90 mg bid Higher doses cause dyspnea and
1. COX-1 inhibitors
ASA, Omega 3
2. Phosphodiesterase inhibitors
Dipyrdamole, Cilostazol
3. ADP-P2Y12 interaction blokers
Ticlopidine, Clopidogrel, Prasugrel, Cangrelor, Ticagelor
HO S
O OCH3 N
Cl
O S
O OCH3 N
Cl
ATP analogs—— reversibility inhibitors
ticagrelor Astra Zeneca
Cangrelor The
Medicines Company
Direct and reversible inhibit P2Y12 receptors
Endpoint (%)
TRITON TIMI-38:
Balance of efficacy and safety in patients
< 75 Yrs, ≥ 60 kg, and without prior TIA/Stroke (N=10,804)
16
14
CV death, NF MI, or NF stroke
The plasma half-life of aspirin is only 15-20 minutes, but the platelet inhibitory effect lasts for the lifespan of the platelets because of the irreversible inactivation of COX1
Eptifibatide’s design was based upon a disintegrin, barbourin, which contains the aminoacid sequence Lys-Gly-Asp within a disulphide. Specific for GPIIb/IIIa, this blocker is believed to be an analogue of the sequence at the extreme carboxyterminus of the γ-chain of fibrinogen which mediates the binding of fibrinogen to the receptor. As a competitive inhibitor of fibrinogen binding, it can displace platelet-bound fibrinogen and is efficient at dissociating aggregates to single platelets in whole blood. Tirofiban was designed using the RGD (Arg-Gly-Asp) peptide as starting-point.
Platelet Adhesion
Platelet Activation
Platelet Aggregation
Thrombotic Occlusion
Platelet surface membrane receptors play important role
Different mechanisms of antiplatelet drugs:
Prasugrel 1.9%
Clopidogrel 1.5%
270
360
450
Wiviott SD et al. Circulation 2010;122:394-403
Cangrelor
Potent inhibitor of ADP induced aggregation
ATP analogue that inhibits P2Y12 by 100 %
ventricular pause
PLATO Study
. Lancet. 2002;359:189-198
NEJM 2009; 361:1045
Glycoprotein IIb/IIIa Inhibitors
Block the Common Final Pathway to Platelet Aggregation regardless of the stimulus for activation
Cause of Death by Gender in Europe:
WHO 2008
Plaque Fissure or Rupture
If exposed to subendothelium, platelets activated
Direct and reversible inhibit P2Y12 receptors
Oral
Intravenousl y
180 loading dose and continue treatment with 90 mg twice daily
30 μg per kilogram of body weight followed by an infusion of 4 μg per kilogram per minute for at least 2 hours
There are six putative recognition sites within fibrinogen for GP IIb/IIIa and thus fibrinogen acts as a hexavalent ligand to crosslink GP IIb/IIIa sites on adjacent platelets. Attempts have been made to use fibrinogen fragments and synthetic peptides to define the sequence within fibrinogen which mediates the GP IIb/IIIa-fibrinogen interaction and thus aggregation. The tripeptide sequence arginyl-glycyl-aspartyl (RGD) is believed to represent the minimal sequence necessary for binding to GP IIb/IIIa. RGD occurs four times in fibrinogen twice in each of the two Aa chains, thus contributing four of the six putative recognition sites within fibrinogen. The other two sitesoccur in the C-terminal amino acid segments of the two γ chains.
bleeding dyspnea
The plasma half-life approximately 3 to 5 minutes, and platelet function is restored within 1 hour after cessation of the infusion
ATP analogs & others
ADP receptor antagonists
ADP is an important platelet agonist in vivo, has two types of receptors in the platelet plasma membrane: P2Y1 and P2Y12. The result of ADP signalling through the P2Y1 receptor is Ca2+ mobilization, a change in platelet shape and rapidly reversible platelet aggregation. P2Y12 is a seven-transmembrane domain receptor, but it is linked to a Gi protein and lowering of cyclic AMP levels. The result of ADP signalling through the P2Y12 receptor is the amplification of stable platelet aggregation and secretion
4. GP IIb/IIIa blokers
5. Thrombin receptor antagonists
ASA
Irreversibly acetylates Ser529 of COX1, rendering the catalytic site of COX1 inaccessible to arachidonic acid and therefore inhibiting the generation of prostaglandin H2 and, subsequently, thromboxane A2
12 HR 0.74 (95% CI: 0.66-0.84)
10 p<0.001, NNT 37
8
6
4 HR 1.24
(95% CI: 0.91-1.69)
2
p=0.17, NNH 222
0 0 30
90
180
Days
Clopidogrel 11.0%
来自百度文库Prasugrel 8.3%
TIMI major bleeding
Phosphodiesterase Inhibitors
Dipyridamole stimulates PGI2 synthesis, blocks uptake of adenosine
Clinical trials failed to show efficacy alone, enhances warfarin and ASA
MR form useful for stroke prevention Cilostazol may be useful in claudicatio
and has vasodilatory and antiplatelet effects
Thienopyridines —— irreversibility inhibitors
ATP
Elinogrel
Cangrelor
ticagrelor
Others
Elinogrel, orally or intravenously
Variable Clopidogrel Response
At 5 Days UA Patients* (n = 32)
Nonresponders 22%
Responders 47% Low responders 32%
*Received an oral loading dose of 300 mg of clopidogrel followed by 75 mg daily. Gurbel PA, et al. Circulation. 2003;107(23):2908-2913; Lau WC, et al. Circulation. 2004;109(2):166-171.
Glycoprotein IIb/IIIa Inhibitors
Monoclonal Ab against IIb/IIIa: Abciximab Peptide antagonist: Eptifibatid Nonpeptide antagonist: Tirofiban
Mechanism
No renal/hepatic metabolism to be activated
İv,rapid action, platelets back to normal in 60 minutes
Has additive effects to clopidogrel
Two short term trials discontinued for less than expected efficacy
Ticagrelor
Stable, high affinity inhibitor of ADP induced aggregation
Oral agent acting directly on P2Y12 receptor without transformation
Rapid and greater action Reversibility 180 mg loading ,90 mg bid Higher doses cause dyspnea and
1. COX-1 inhibitors
ASA, Omega 3
2. Phosphodiesterase inhibitors
Dipyrdamole, Cilostazol
3. ADP-P2Y12 interaction blokers
Ticlopidine, Clopidogrel, Prasugrel, Cangrelor, Ticagelor
HO S
O OCH3 N
Cl
O S
O OCH3 N
Cl
ATP analogs—— reversibility inhibitors
ticagrelor Astra Zeneca
Cangrelor The
Medicines Company
Direct and reversible inhibit P2Y12 receptors
Endpoint (%)
TRITON TIMI-38:
Balance of efficacy and safety in patients
< 75 Yrs, ≥ 60 kg, and without prior TIA/Stroke (N=10,804)
16
14
CV death, NF MI, or NF stroke
The plasma half-life of aspirin is only 15-20 minutes, but the platelet inhibitory effect lasts for the lifespan of the platelets because of the irreversible inactivation of COX1
Eptifibatide’s design was based upon a disintegrin, barbourin, which contains the aminoacid sequence Lys-Gly-Asp within a disulphide. Specific for GPIIb/IIIa, this blocker is believed to be an analogue of the sequence at the extreme carboxyterminus of the γ-chain of fibrinogen which mediates the binding of fibrinogen to the receptor. As a competitive inhibitor of fibrinogen binding, it can displace platelet-bound fibrinogen and is efficient at dissociating aggregates to single platelets in whole blood. Tirofiban was designed using the RGD (Arg-Gly-Asp) peptide as starting-point.
Platelet Adhesion
Platelet Activation
Platelet Aggregation
Thrombotic Occlusion
Platelet surface membrane receptors play important role
Different mechanisms of antiplatelet drugs:
Prasugrel 1.9%
Clopidogrel 1.5%
270
360
450
Wiviott SD et al. Circulation 2010;122:394-403
Cangrelor
Potent inhibitor of ADP induced aggregation
ATP analogue that inhibits P2Y12 by 100 %
ventricular pause
PLATO Study
. Lancet. 2002;359:189-198
NEJM 2009; 361:1045
Glycoprotein IIb/IIIa Inhibitors
Block the Common Final Pathway to Platelet Aggregation regardless of the stimulus for activation