pharmacology

1. Antiplatelet agents

2. NO, PG I2, ADP
dephosphatase
HS, TM
t – PA
P P
H S
3
TM
T
Plasminogen
Plasmin
Fibrin → Fibrin split
products
Platelet adhesion
2, 9, 10, 11, 12
5, 8

3. Vasospasm Platelet plug
formation
(Primary)
Coagulation
cascade
Thrombin
Fibrinogen
Fibrin monomers
Cross linked Fibrin
XIIIa ← XIII
Thrombus
(Secondary)
• Platelets
• Blood
cells
• Fibrin
P P
P P
P
P

4. Platelet
Platelet Platelet Platelet Platelet
Platelet Adhesion

5. Platelet adhesion
• Platelet binding to non - platelet surface
• GP Ib complex via vWF  Collagen
• GP Ia / IIa & GP VI  Collagen
Platelet
Platelet Platelet

6. Platelet
Platelet Platelet Platelet Platelet
Platelet Adhesion
PL
Arachidonate
TxA2
PLA2
COX
COX
PGI2
COX
TxA2 PGI2

7. Platelet
Platelet Platelet Platelet Platelet
Platelet Adhesion
PL
Aa
TxA2
PLA2
COX
5 – HT
ADP
Calcium
CF I & V
vWF
PDGF
Platelet Activation
Delta Alpha
Arachidonate

8. Platelet activation & release reaction
• TXA2 bind to TP receptor: Platelet activation
• 5 – HT: Vasoconstriction
• ADP bind to P2Y12 receptor: Platelet activation
• Calcium: Helps the clotting factor to stick to each other
• PDGF: Smooth muscle mitosis, Collagen synthesis
PL
Aa
TxA2
PLA2
COX
5 – HT
ADP
Calcium
CF I & V
vWF
PDGF
Delta Alpha

9. Platelet
Platelet Platelet Platelet Platelet
Platelet Adhesion
Platelet Activation
GP II b / IIIa
Platelet
Platelet Platelet Platelet Platelet

10. Platelet
Platelet Platelet Platelet Platelet
Platelet Adhesion & Activation
Platelet Aggregation
GP II b / IIIa
Glanzmann’s
thrombasthenia

11. Platelet aggregation
• Platelet binding to other platelet surface
• Fibrinogen & vWF bridge between GP IIb / IIIa receptors
of neighboring platelets: Platelet aggregation
• Primary hemostatic plug (loose)

12. Primary triggers
• TxA2 : TP receptor
• Collagen
• ADP : P2Y12 receptor
• Thrombin : PAR receptor

13. COX inhibitor
ADP receptor
blockers
GP IIb / IIIa
receptor blockers

14. ASPIRIN
• Most superior antiplatelet agent
• Mechanism of action
Aspirin (low dose)
Acetylates the COX - 1 enzyme (Irreversible)
Selective inhibition of TxA2 synthesis
Antiplatelet effect
(Inhibition of platelet aggregation)

15. ASPIRIN
• Antiplatelet effect : 8 – 10 days
 Discontinued 1 week before surgery
 Contraindicated: Hemophiliacs
• > 2 g/day: Loss of antiplatelet effect
TxA2
PGI2
Low dose
(40 to 325 mg/day)
Inhibit aggregation
Facilitate aggregation
-
Aspirin dose
(> 2g/day)
-
-

16. ASPIRIN
• Uses
 Post –
Myocardial
infarction
 Post – Stroke

17. ADP receptor blockers
• Irreversible
 Ticlopidine
 Clopidogrel
 Prasugrel
• Reversible
 Ticagrelor
 Cangrelor

18. TICLOPIDINE
• Prodrug
• Mechanism of action
Ticlopidine
Active metabolite
ADP receptor blockade (Irreversible)
Antiplatelet effect

19. TICLOPIDINE
• Uses
 Prevention of stroke (h/o of TIAs)
 Prevention of coronary stent thrombosis
(Aspirin + Ticlopidine)
• ADRs
 20 %: Nausea, dyspepsia, diarrhea
 5% : Hemorrhage
 1% : Leukopenia (Most serious) {WBC count}
 TTP: Thrombotic thrombocytopenic purpurea

20. CLOPIDOGREL
• Uses: Preferred over ticlopidine
 NSTEMI (Aspirin)
 STEMI (Aspirin)
 Stroke
 PVD
• ADRs: Few compared to ticlopidine
 Rarely neutropenia
TTP: Thrombotic thrombocytopenic purpurea

21. GP-IIb / IIIa receptor blockers
• All are given by IV route.
• Mechanism of action
GP-IIb/IIIa receptor blockers
Block the receptor (GP – IIb/IIIa)
Prevent fibrinogen from binding with activated platelets
Inhibition of platelet aggregation to any platelet agonist
(Thrombin, TxA2, Collagen, ADP)

22. ABCIXIMAB
• Chimeric monoclonal antibodies
• Mechanism of action
o Block GP – IIb/IIIa receptor for fibrinogen on
platelets
o Also block GP – IIb/IIIa receptor for vitronectin on
platelets

23. ABCIXIMAB
• Uses
 Percutaneous coronary intervention (PCI)
 Acute coronary syndrome (ACS)
• ADRs
 Bleeding
 Thrombocytopenia

24. GP-IIb/IIIa receptor blockers
• Eptifibatide & Tirofiban
• Mechanism of action
 Only block GP – IIb/IIIa receptor for fibrinogen on
platelets
 Do not inhibit GP – IIb/IIIa receptor for vitronectin
on platelets
 Less effective antiplatelet effect than Abciximab

25. Prostacyclin (PGI2)
5’AMP
PG I2
ADP
Inhibit platelet activation and aggregation
PDE - 3
-
Platelet
ATP
↑ cAMP

26. Phosphodiesterase inhibitors
5’AMP
PG I2
ADP
Inhibit platelet activation and aggregation
PDE - 3
-
Platelet
ATP
↑ cAMP

27. DIPYRIDAMOLE
• Mechanism of action
 Inhibit PDE-3 enzyme
 Increase cAMP level
 Inhibit ADP release and platelet activation
• Uses
 Warfarin + Dipyridamole: Primary prophylaxis of
thromboembolism (Prosthetic heart valve)
 Aspirin + Dipyridamole: Secondary prophylaxis of
cerebrovascular disease

28. CILOSTAZOL
• Mechanism of action
 Inhibit PDE-3 enzyme
 Increase cAMP level
 Inhibit ADP release and platelet activation
• Uses
 Peripheral vascular disease: To prevent
intermittent claudication.

29. Uses of Antiplatelet agents
T : Transient ischemic attacks (TIAs)
H : Heart valves (Prosthetic)
R : Reverse
O : Occlusion of veins & Arteries (Venous TE and PVD)
M : Myocardial infarction
B : Bypass implants or Angioplasty with stent
U : Unstable angina
S : Shunts (Arterio-venous)