Transcript Anticoagulants, Thrombolytics Agents and Antiplatelet Drugs

Ticlopidine (Ticlid™)
and
Clopidogrel (Plavix™)
Benedict R. Lucchesi, M.D., Ph.D.
Department of Pharmacology
University of Michigan Medical School
Mode of Action of Antiplatelet Agents
CLOPIDOGREL
C
ADP
ADP
GPllb/llla
Activation
(Fibrinogen receptor)
ASA
COX
TXA 2
COX (cyclo-oxygenase)
ADP (adenosine diphosphate)
TXA2 (thromboxane A2)
1. Schafer AI. Am J Med 1996; 101: 199–209.
Collagen thrombin
TXA 2
Ticlopidine (Ticlid™) and Clopidogrel (Plavix™)
• Oral, platelet-aggregation inhibitor structurally
unrelated to any other agent in its class.
• May be more efficacious than aspirin, but more
serious and more frequent adverse effects
• May be used for patients who are intolerant or to
aspirin.
• Interferes with the ADP-induced binding of
fibrinogen to the platelet membrane at specific
receptor sites.
Ticlopidine (Ticlid™)
• Platelet inhibition is
irreversible.
• Platelet-aggregation
inhibition is not significant
until after approximately 4
days of regular dosing.
• Platelet function returns to
normal within 1–2 weeks
as new platelets replace
those affected by
ticlopidine or clopidogrel.
Ticlopidine
Clopidogrel (Plavix™)
•
Selectively inhibits the binding of
adenosine diphosphate (ADP) to its
platelet receptor and the subsequent
ADP-mediated activation of the
glycoprotein GPIIb/IIIa complex,
thereby inhibiting platelet aggregation.
•
Biotransformation of clopidogrel is
necessary to produce inhibition of
platelet aggregation, but an active
metabolite responsible for the activity of
the drug has not been isolated.
•
Clopidogrel also inhibits platelet
aggregation induced by agonists other
than ADP by blocking the amplification
of platelet activation by released ADP.
Clopidogrel does not inhibit
phosphodiesterase activity.
Clopidogrel
Clopidogrel (Plavix™)
• Clopidogrel:
– Inhibits the ADP P2Y12 (P2TAC) platelet receptor.
– Acts by irreversibly modifying the platelet ADP receptor.
Consequently, platelets exposed to clopidogrel are affected for
the remainder of their lifespan.
– ADP-induced activation of the platelet P2Y12 results in the
activation of the GPIIb/IIIa fibrinogen receptor.
• Dose dependent inhibition of platelet aggregation can
•
•
be seen 2 hours after single oral doses..
Repeated doses of 75 mg per day inhibit ADP-induced
platelet aggregation on the first day, and inhibition
reaches steady state between Day 3 and Day 7.
Platelet aggregation and bleeding time gradually return
to baseline values after treatment is discontinued,
generally in about 5 days.
Indications for Clopidogrel
Recent MI, Recent Stroke or Established Peripheral
Arterial Disease
• For patients with a history of recent myocardial infarction
(MI), recent stroke, or established peripheral arterial
disease,
Acute Coronary Syndrome
• For patients with acute coronary syndrome (unstable
angina/non-Q-wave MI) including patients who are to be
managed medically and those who are to be managed with
percutaneous coronary intervention (with or without stent)
or CABG.
Clopidogrel (Plavix™)
• For patients with acute
•
•
coronary syndrome (unstable
angina/non-Q-wave MI),
clopidogrel should be initiated
with a single 300 mg loading
dose and then continued at 75
mg once daily.
Aspirin (75 mg-325 mg once
daily) should be initiated and
continued in combination with
clopidogrel.
Most patients with Acute
Coronary Syndrome also
receive heparin acutely.
Platelet Activation - Arterial Thrombus
Formation
Fibrinogen
Platelet GPIIb/IIIa
(Fibrinogen) Receptor
Release
Platelet
1
Endothelial Cell - Injury
2
3
1=adhesion
2=activation & release
3=aggregation
Platelet Glycoprotein
IIb/IIIa Receptor
Activated
Platelet
Activated
Platelet
Fibrinogen
RGD
Binding
Site
Activated
Platelet
Activated
Platelet
IN TER AC TIO N BE TWEE N F IBR IN OG EN A ND G P II b/ II Ia

G PII b/ GP IIIa



R G D S eq ue nc es
Fibr ino ge n

Bl o o d
Pl at el e t
Bl oo d
Pl a te l et

GP IIb /GP IIIa
C - Te rm i n al 1 2
r es i du es o f th e
 c hain