Definition; Platelet plug formation; Platelet Aggregation; coagilation cascade; classification of Antiplatelet drugs.

1. ANTI-PLATELET
DRUGS
RVS Chaitanya Koppala

2. Antiplatelet drugs
• An antiplatelet drug is a member of a class of drugs that decreases
platelet aggregation and inhibits thrombus formation.

3. Platelet and vessels
• Nitric oxide & Prostacycline (endothelial cell)
– Inhibit platelet aggregation
• Injury – platelet, endothelial system and coagulation factors
form clot
• Thrombus- clot adheres to vessel
• Embolus – clot float in blood
• Thrombosis- Formation of unwanted clot in blood vessel producing
life threatening conditions-AMI Stroke DVT PE

4. Role of platelet
• Many Glycoprotein (GP) integrin Receptors
• Platelet Activation: Collagen reacts with GPIa and GPIb receptors
via vWF - Release of TXA2, ADP, Thrombin and 5-HT etc.
• Conformational changes at GPIIb/IIIa – binding of fibrinogen –
cross linkage – Platelet PLUG formation
• Thrombus in arteries – platelet mass in Arteries; antiplatelet
drugs are more useful
• In veins – sluggish blood flow fibrinous tail with trapped RBC -
Red tail
• Balance between PGI2 and TXA2 – controls intavascular
Thrombus

5. Role of platelet

7. Antiplatelet drugs
I) Cyclooxygenase/TX2 synthase inhibitors: Aspirin
II)Adenosine di phosphate(ADP) receptor inhibitors(P2Y12)
1) Irreversible: Clopidogrel, Ticlopidine
2) Reversible: Prasugrel, Ticagrelor, cangrelor
III)Phosphodiesterase inhibitors: Dipyridamole, PDE-3 inhibitor -
Cilostazol
IV) Glycoprotein IIb/IIIa inhibitors: Abciximab, Eptifibatide, Tirofiban,
Defibrotide

8. Newer antiplatelet
I) Thrombin receptor antagonist- (PAR-1): Vorapaxar Atopaxar
II) TXA2 receptor antagonist: Teratroban, Picotamide, Ridogrel
III) GP VI receptor antagonist: Revacept
IV) GP Ib receptor antagonist, Serotonin receptor antagonist,
vWF antagonist
V) Thromboxane synthase inhibitor: Dazoxiben
* Prostacycline PGI2 analogue: Epoprostenol iloprost
*Miscellaneous: Dextran 70, sulfinpyrazone, clofibrate, tomolol

11. Aspirin
Mechanism ofAction
•Irreversible inhibition of cyclooxygenase enzyme via acetylation.
•Platelet exposed to aspirin in portal circulation before first pass
metabolism (deacetylation)
•Small dose (75-325 mg/d)inhibits thromboxane synthesis in platelets
(TXA2) but not prostacyclin (PGI2) synthesis in endothelium (larger
dose > 1000 mg)
• larger dose increase toxicity e.g. GI bleeding
•So higher doses are less efficacious

12. Mechanism of action
•Other NSAIDS are reversible COX1 inhibitor may interfere with
aspirin binding to COX1
•Aspirin inhibits Thromboxane A2 & prostacyclin too, but the former
is more affected because platelets don’t have nuclei and can’t synthesize
new enzymes
•TXA2 remains low for 7 days (platelet lifespan)
•Aspirin inhibit release of ADP fromplatelet
•No effect on platelet survival time and their adhesion to damaged vessel
wall
•Dose- low 40mg maximal effect at 75 to 150 mg (81mg) high dose
325mg per day

13. ASPIRIN:
• Irreversible inactivation of TXA2
synthetase in the platelets.
• Low dose spares endothelial
synthesis of PGI-2 and thus better
anti-platelet activity.
• Gastric bleeding is a
disadvantage.

14. Anti-platelet drugs
LOW DOSE
ASPIRIN

15. ADP(P2Y12) antagonist
1) Irreversible: Ticlopidine, clopidogrel , Prasugrel
• They inhibit irreversibly ADP (P2Y1/P2Y12) receptors
inhibit platelet aggregation
• No effect on PG synthesis
• Used in aspirin intolerant patients
Mechanism ofAction
•Alters surface receptors on Platelets and inhibits
ADP and fibrinogen induced platelet aggregation.
•P2Y12 are purinergic Gi coupled receptor

17. Ticlopidine
PK: oral.
• Extensively bound to plasma proteins.
• Prodrug Metabolized in the liver to give active metabolites.
• cumulative effect Slow onset of action
(3-5 days). 250 mg twice daily .
Platelet Survival time increased extracorporeal Synergistic effect
with aspirin

18. Adverse Effects
Ticlopidine
1. Sever neutropenia. CBC done monthly
2. Bleeding (Prolong bleeding time).
3. CYT P450 inhibitors
4. G.I.T : Diarrhoea, Nausea, Dyspepsia.
5. Allergic Reactions.
Due to ADR use declined overclopidogrel

19. Clopidogrel
Replace ticlopidine
1. Clopidogrel is more potent.
2. Less side effects ( less neutropenia).
3. Less Frequency (75 mg once daily).
4. Bioavailability is unaffected by food.
5. Longer acting
Clinical Uses
Alternative prophylactic therapy to aspirin in secondary prevention of
stroke and myocardial infarction and unstable angina

20. Clopidogrel…
.
• Drug Interaction: Prodrug 50% absorbed, small activated
slowly in liver by CYP2C19. Genetic polymorphism of
CYP2C19 -high interindividual veriation - some pt non
responsive
• Omeprazole: inhibitor of CYP2C19 decrease activation ans
antiplatelet action
• S/E: Bleeding, Rare neutropenia, Diarrhoea epigastric pain, rash
• Combination with aspirin synergistic – prevention of MI and
Checking restenosis of stented coronary

21. Prasugrel
• More potent rapid onset of action than clopidogrel
• Rapid absorption and activation- fast action
• Prodrug though CYP2C19 activation – genetic polymorphism and
omeprazole interference is not prominent
• Use STEMI, ACS. 19% decrease death CVS causes increase outcome
decrease stent thrombosis
• S/E: Bleeding more frequent serious.

22. Reversible P2Y12 antagonist
Ticagrelor: Direct reversible P2Y12 antagonist
• ATP—cAMP dephosphorylation of vasodilator stimulated
phosphoprotein phosphatidyl inositol 3 kinase inhibition
• Oral, rapid onset of action, acceptable safety profile, dyspnoea
• Greater reduction in CVS death in ACS compare to clopidogrel
Cangrelor: IV used adjunct to PCI Elinogrel : IV

23. Dipyridamole
•Phosphodiestrase inhibitor thus cAMP in the blood platelets
•Blocks uptake of adenosine acts on A2 receptor
stimulate platelate adenylyl cyclase. This potentiate PGI2
inhibition of platelet aggregation.
•Primary prophylaxis of thromboembolism in patients with prosthetic
heart valves ( in combination with warfarin ).
•As prophylactic therapy TIA & MI in combination with aspirin .
•Disadvantages: Headache Advantage: oral, No excess risk of bleeding

24. Cilostazol
• Phosphodiesterase 3 inhibitor
• Approve for intermittent claudication dilation of arteries
of leg and inhibit platelet aggregation
• Increase death in CHF pt

25. GP IIb/IIIa receptors Antagonists
• block a key receptor on the platelet for fibrinogen and von
Willebrand factor through which agonists like thrombin TXA2 ADP
etc finally induce platelet aggregation.
• They are known as “super aspirins”. They are the most
effective antiplatelet drugs marketed.
• The mechanism of action is reversible blockade of platelet GP
IIb/IIIa receptors
• Used only IV.

26. GP IIb/IIIa
Antagonists
Tirofiban
Eptifibatide
Antibody
abciximab

27. Glycoprotein IIb/ IIIa receptor Inhibitors

28. Abciximab
• Chimeric monoclonal antibody against - GPIIb/IIIa
• Nonspecific
• IV form – with aspirin + heparin during PCI (reduced restenosis – MI
and Death)
• Iv bolus: action remains 12-24 Hrs, t1/2 – 10 - 30 min
• ADRs: Haemorrhage, Thrombocytopenia, paralytic ileus, constipation,
arrhythmia Expensive Nonantigenic
• Antiinflammatory and antiproliferative: Inhibit αvβ3 (vitronectin) and
αmβ2 (Leucocyte integrin)
• Uses: Unstable angina and as an adjuvant to coronary
thrombolysis/PCI with Stent application

29. Eptifibatide and Tirofiban
• Eptifibatide- Peptide and Tirofiban- nonpeptide
• Longer plasma half life – but inhibition of platelet reverses sooner
(6 hours)
• ADR: Bleeding, thrombocytopenia, anaphylaxis

30. Abciximab Eptifibatide Tirofiban
Specificity
for
GPIIb/IIIa
No Yes Yes
T1/2 Short 10-30
min
Long 2.5 hr Long 2hr
Platelet
bound T1/2
Long (days) Short Short
Renal
clearence
No Yes Yes

31. Vorapaxar
• Thrombin Receptor Antagonist PAR1(Protease activated
receptor)
• Oral
• Inhibit thrombin and thrombin receptor activating peptide induced
platelet aggregation
• Not affect PT/APTT
• Use : Pt with MI and peripheral artery diseases
• Atopaxar: PAR-1 antagonist increase BT in Guinea pig

32. Prostacycline analogue
• Prostacycline blocks all pathways of platelet activation inhibit GP
IIb/IIIa activation directy inhibit platelet aggregation
• Epoprostenol: Limit use as T1/2 is 3 min iv
iv infusion- decrease platelet loss during dialysis. Potent vasodilator –
headache flushing
• ILOPROST: Longer acting
Thrombaxane synthase inhibitor dazoxiben used in raynaud’s syndrome

33. Uses of Antiplatelets
Aim: Prevent intravascular thrombosis and embolism with minimal risk of
bleeding
1. Acute coronary Syndrome:
a) Asprin 325mg oral and LMW heparin sc unstable angina- aspirin,
clopidogrel if aspirin cannot be given or combine
b) NSTEMI: asiprin + clopidogrel for 1 yr
c) STEMI: Primary PCI with oe without stent placement within 12 hr-
Prasugrel + aspirin
-GPIIb/IIIa antagonist + aspirin- high risk pt PCI with LMWH –decrease
incidence of restenosis
- Aspirin + clopidogrel – ACS t/t withthrombolysis
- CABG- aspirin + GPIIb/IIIa antagonist /Prasugrel
- dual antiplatelet after stent
- Stent thrombosis with clopidogrel- use Prasugrel

34. 2) Prophylaxis of coronary artery disease: Post MI – decrease mortality
and reinfarction 75-150 mg asprin. primary prevention- no proven
benefit decrease incidence of MI but increase risk of cerebral
hemorrhage
3) Cerebrovascular Disease: Do not have much effect but prevents TIAs
4) Prosthetic Heart Valve and Arteriovenous shunts: reduce formation
of microthrombi in heart valves and embolism. Dipyridamole +
Warfarin. Aspirinincrease risk of bleeding
5) Venous Thromboembolism: DVT PE anticoagulants used value of
antiplatelet not established
6) Peripheral Vascular Disease: Aspirin/clopidogrel improve
intermittent claudication and decrease thromboembolosm

36. END