Antiplatelet drugs (antithrombotics)

A PowerPoint presentation on Anti-platelet drugs suitable for UG MBBS level .....

1. Dr. D. K. Brahma
Associate Professor
Department of Pharmacology
NEIGRIHMS, Shillong
Antiplatelet Drugs
(Antithrombotic Drugs)

2. Definition
•Drugs which interfere with platelet function
and are useful in prophylaxis of
thromboembolic disorders
–The principal function of platelets is to prevent
bleeding – by THROMBUS formation

3. Background –
Platelet Aggregation
•Glycoprotein (GP) integrin Receptors
•Platelet Activation: Collagen reacts with GPIa and GPIb
receptors via vWF
•Release of TXA2, ADP and 5-HT etc.
•Conformational changes at GPIIb/IIIa – binding of fibrinogen
– cross linkage – Platelet PLUG formation
•Thrombus in arteries – only mass in Arteries; In veins - Red
tail – antiplatelet drugs are useful
•Balance between PGI2 and TXA2 – controls intavascular
Thrombus

4. The role of platelets

5. The role of platelets

6. The role of platelets

7. The role of platelets

8. Available Drugs
•Aspirin and
Dipyridamole
•P2Y12 Receptor
Blockers: Ticlodipine,
Clopidogrel and
Prasugrel
•GPIIb/IIIa Antagonists:
Abciximab, Eptifibatide
and Tirofiban
•TXA
2
synthesis inhibitor:
–Low dose aspirin
•Phosphodiesterase inhibitor:
–Dipyridamole , cilostazole
•Thienopyridine derivatives (ADP
antagonists):
–Ticlodipine, clopidogrel
•Gp-IIb/IIIa receptor antagonists
–Abciximab, eptifibatide,
tirofiban
•Others
–PGI
2
, daltroban, dazoxiben,
clofibrate

9. Aspirin
•MOA: Acetylates COX 1 and TX-synthase – irreversible inactivation -
in portal circulation (Deacetylation of Aspirin)occurs in liver
–TXA2 formation suppressed – fresh enzyme synthesis takes time – at
low doses
–Prolongation of bleeding time for 5 – 7 days
–Cumulative effect – 40 mg/day – max. at 160 mg
–Low doses – only TXA2 but higher doses both TXA2 and PGI2 (Clinically
irrelevant)
–In vessel wall – PGI2 suppression - can synthesize new enzymes
–At low doses (75 – 150 mg/day) – selective suppression of TXA2 –
higher doses – both TXA2 and PGI2
–Also inhibition of ADP – sticking interfered

10. Acetylsalicylic acid – major use
•Secondary prevention of transient ischaemic attack
(TIA), ischaemic stroke and myocardial infarction
•Prevention of ischaemic events in patients with
angina pectoris
•Prevention of coronary artery bypass graft (CABG)
occlusion

11. Dipyridamole -Vasodilator – used in angina
•MOA:
–Phosphodiesterase enzyme inhibitor
– increases cAMP conc.
–Inhibits uptake of Adenosine in
Platelets – increase c AMP
–cAMP - Overall, Potentiates PGI2
–Levels of TXA2 and PGI2 are not
altered – life span increased
•Uses: Used to enhance the action of
Warfarin and Aspirin in TE events –
Risk of stroke in TIA
–To decrease the incidence of
thromboemboism in prosthetic heart
valve
–TIA – risk of stroke reduced
–As vasodilator: myocardial perfusion
imaging (Thallium scanning)
Resistance
vessels

12. Dipyridamole - Kinetics
•Incompletely absorbed from the gastrointestinal tract with
peak plasma concentration occurring about 75 minutes after
oral administration
•More than 90% bound to plasma proteins
•A terminal half-life of 10 to 12 hours
•Metabolised in the liver
•Mainly excreted as glucuronides in the bile; a small amount is
excreted in the urine
•Available as 75 mg and 100 mg preparations

13. Ticlodipine
•Thienopyridine derivative: Alters surface receptors on
Platelets and inhibits ADP and fibrinogen induced platelet
aggregation
•MOA:
1.Gi coupled P2Y12 (P2YAC ) receptor mediates ADP induced adenylyl cyclase
inhibition – blocked – platelet activation interfered
2.Also prevents binding of fibrinogens to platelets – but does not interfere
GPIIb/IIIa receptors
3.TXA2 is not affected – but bleeding time prolonged - platelet survival in
extra-crporeal circulation increased
4.Synergistic action with aspirin
•Kinetics: Well absorbed orally – converts to active metabolite in body –
single dose Half life 8 hrs - cumulates – peak effect 8 – 10 days - lasts for
5-6 days

14. P2Y Receptors

15. Ticlodipine - Uses
•Secondary prevention of Stroke, TIA
•Intermittent claudication
•Unstable angina
•PCI
•Coronary artery bypass surgery
•Prophylaxis of MI
•With aspirin prevents restenosis after PCI and stent
•ADRs: Diarrhoea, vomiting, abdominal pain, headache,
tinnitus, skin rash
–Bleeding, neutropenia, thrombocytopemia and jaundice
–Limited Use

16. Clopidogrel
•Newer and more potent congener of Ticlodipine
•MOA – same with Ticlodipine but safer and better tolerated
•Studies: CAPRIE study - Slightly lower risk of ischaemic events
than aspirin recipients for primary ischemic events –
combination in checking restenosis in stent coronary
•Kinetics: Prodrug – 50% absorption
–Only a fraction is activated in liver by CYP2C19
–CYP2C19 – genetic polymorphism – interindividual variation of action
–Some are non responsive
–Omeprazole - DI
•ADRs: Bleeding – double with aspirin
–neutropenia, thrombocytopenia are rarer than Ticlodipine

17. Prasugrel
•Newer, most potent and faster P2Y12 purinergic receptor blocker
•Preferred in Acute Coronary Syndromes (ACS) and when strong
antiplatelet action required
•Prodrug – but faster and complete absorption – completely activated
•CYP2C19 substrate – but Genetic polymorphism related decrease and DI
with Omeprazole is rare
•Uses: STEMI, ACS to cover angioplasty
–Comparison with clopidogrel in STEMI and NSTEMI – Prasugrel – better in reduction in
death due to CVS causes
–Superior results in reduction of STENT thrombosis
•ADRs: Bleeding complications – severe, Intracranial haemorrhage – in TIA
and stroke patients
•CI: Ischaemic stroke and TIA
•Dose: 10 mg OD (available as 5 and 10 mg tablets)

18. GPIIb/IIIa receptor antagonists
•Newer potent platelet aggregation inhibitor -
Abciximab, eptifibatide and tirofiban
•GPIIb/IIIa is an adhesive receptor aggregation –
antagonists block aggregation -

19. GPIIb/IIIa-receptor antagonists –
mechanism of action

20. GPIIb/IIIa-receptor antagonists –
mechanism of action

21. GPIIb/IIIa-receptor antagonists –
mechanism of action

22. GPIIb/IIIa-receptor antagonists –
mechanism of action

23. GPIIb/IIIa-receptor antagonists –
mechanism of action

24. Abciximab
•Chimeric monoclonal antibody against - GPIIb/IIIa receptor
•But nonspecific – binds to some other proteins also
•Available only in IV form – intravenous bolus dose followed by continuous
IV – with aspirin + heparin during PCI (reduced restenosis – MI and Death)
•After a bolus dose: action remains for 12-24 Hrs, t1/2 – 10 - 30 min
•After continuous infusion: after stoppage – clears rapidly in 6 Hrs – then
slowly – remains in blood for 15 days
•ADRs: Haemorrhage, Thrombocytopenia – should not be repeated 2
nd

time, paralytic ileus, constipation, arrhythmia - nonantigenic
•Drawback: Expensive
•Uses: Unstable angina and as an adjuvant to coronary thrombolysis/PCI
with Stent application

25. Eftibatide
•Synthetic – selective to platelet GPIIb/IIIa
receptor
•Longer plasma half life – but inhibition of
platelet reverses sooner (6 hours)
•Uses: Unstable angina, coronary angioplasty
–Given with aspirin and heparin
•ADR: Bleeding, thrombocytopenia,
anaphylaxis

26. Uses of Antiplatelets
1.Coronary Artery Disease:
•MI: Immediately after MI low dose aspirin
•Aspirin: routinely used after thrombolytic therapy to prevent
reocclusion; to cover PCI with heparin
•Unstable angina: Aspirin reduces risk of MI
•Primary and secondary prevention of MI: Evidence of coronary artery
disease - aspirin
2. Cerebrovascular Disease: Do not have much effect but prevents TIAs
3. Coronary angioplasty, stents etc.: patency of re-canalized artery or implant
bypass vessels improved – re-occlusion reduced
4. Prosthetic Heart Valve and Arteriovenous shunts: reduce formation of
microthrombi in heart valves
5. Venous Thromboembolism
6. Peripheral Vascular Disease

27. Must Know
•Aspirin as antiplatelet agent
•Clopidogrelel
An Aspirin a Day: The Wonder Drug That Could
Save YOUR Life

28. Thank you