This ppt is important for UG MBBS, PG Pharmacology and any other healthcare person interested in Antiplatelet drugs.

1. ANTIPLATELET DRUGS
Dr. CHANDANE R. D.
Associate Professor
Dept. Of Pharmacology
Lady Hardinge Medical College
New Delhi

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

6. 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

7. Newer antiplatelet
I) Thrombin receptor antagonist- (PAR-1) – Vorapaxar
Atopaxar
II) TXA2 receptor antagonist – Teratroban, Picotamide,
Ridogrel
III) GP IV 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

9. Aspirin
Mechanism of Action
• 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

10. MOA
•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 can’t synthesize new enzymes
•TXA2 remains low for 7 days (platelet lifespan)
•Aspirin inhibit release of ADP from platelet
•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

11. 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.

12. Anti-platelet drugs
LOW DOSE
ASPIRIN

13. 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 of Action
•Alters surface receptors on Platelets and inhibits
ADP and fibrinogen induced platelet aggregation.
•P2Y12 are purinergic Gi coupled receptor

15. 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

16. Adverse Effects ticlopidin
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 over clopidogrel

17. 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

18. 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

19. 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. So C/I in pt with
H/O TIA Stroke elderly >75yrs – intracranial bleeding

20. 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

21. 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

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

23. 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.

24. GP IIb/IIIa
Antagonists
Tirofiban
Eptifibatide
Antibody
abciximab

25. Glycoprotein IIb/ IIIa receptor Inhibitors

26. 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

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

28. 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

29. Vorapaxar
• Thrombin Receptor Antagonist PAR 1(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

30. Prostacycline anologue
• 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

31. 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 with thrombolysis
- CABG- aspirin + GPIIb/IIIa antagonist /Prasugrel
- dual antiplatelet after stent
- Stent thrombosis with clopidogrel- use Prasugrel

32. 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. Aspirin increase
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