Dr. D. K. BrahmaAssociate Professor

Department of PharmacologyNEIGRIHMS, Shillong

Antiplatelet Drugs (Antithrombotic Drugs)

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

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

The role of platelets

The role of platelets

The role of platelets

The role of platelets

Available Drugs

• Aspirin and Dipyridamole

• P2Y12 Receptor Blockers: Ticlodipine, Clopidogrel and Prasugrel

• GPIIb/IIIa Antagonists: Abciximab, Eptifibatide and Tirofiban

• TXA2 synthesis inhibitor:– Low dose aspirin

• Phosphodiesterase inhibitor:– Dipyridamole , cilostazole

• Thienopyridine derivatives (ADP antagonists): – Ticlodipine, clopidogrel

• Gp-IIb/IIIa receptor antagonists– Abciximab, eptifibatide,

tirofiban • Others

– PGI2 , daltroban, dazoxiben, clofibrate

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

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

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

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

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 interfered2. Also prevents binding of fibrinogens to platelets – but does not interfere

GPIIb/IIIa receptors3. TXA2 is not affected – but bleeding time prolonged - platelet survival in

extra-crporeal circulation increased4. 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

P2Y Receptors

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

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

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)

GPIIb/IIIa receptor antagonists

• Newer potent platelet aggregation inhibitor - Abciximab, eptifibatide and tirofiban

• GPIIb/IIIa is an adhesive receptor aggregation – antagonists block aggregation -

GPIIb/IIIa-receptor antagonists – mechanism of action

GPIIb/IIIa-receptor antagonists – mechanism of action

GPIIb/IIIa-receptor antagonists – mechanism of action

GPIIb/IIIa-receptor antagonists – mechanism of action

GPIIb/IIIa-receptor antagonists – mechanism of action

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 2nd

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

with Stent application

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

Uses of Antiplatelets1. 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 - aspirin2. Cerebrovascular Disease: Do not have much effect but prevents TIAs3. Coronary angioplasty, stents etc.: patency of re-canalized artery or implant

bypass vessels improved – re-occlusion reduced4. Prosthetic Heart Valve and Arteriovenous shunts: reduce formation of

microthrombi in heart valves5. Venous Thromboembolism6. Peripheral Vascular Disease

Must Know

• Aspirin as antiplatelet agent• Clopidogrelel

An Aspirin a Day: The Wonder Drug That Could Save YOUR Life

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