Antiplatelet drugs (antithrombotics)

Antiplatelet drugs (antithrombotics)

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  Dr. D. K.Brahma Associate Professor Department of Pharmacology NEIGRIHMS, Shillong Antiplatelet Drugs (Antithrombotic Drugs)
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  Definition • Drugs whichinterfere with platelet function and are useful in prophylaxis of thromboembolic disorders – The principal function of platelets is to prevent bleeding – by THROMBUS formation
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  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
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  The role ofplatelets
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  The role ofplatelets
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  The role ofplatelets
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  The role ofplatelets
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  Available Drugs • Aspirinand 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
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  Aspirin • MOA: AcetylatesCOX 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
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  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
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  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
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  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
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  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
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  P2Y Receptors
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  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
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  Clopidogrel • Newer andmore 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
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  Prasugrel • Newer, mostpotent 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)
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  GPIIb/IIIa receptor antagonists •Newer potent platelet aggregation inhibitor - Abciximab, eptifibatide and tirofiban • GPIIb/IIIa is an adhesive receptor aggregation – antagonists block aggregation -
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  GPIIb/IIIa-receptor antagonists – mechanismof action
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  GPIIb/IIIa-receptor antagonists – mechanismof action
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  GPIIb/IIIa-receptor antagonists – mechanismof action
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  GPIIb/IIIa-receptor antagonists – mechanismof action
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  GPIIb/IIIa-receptor antagonists – mechanismof action
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  Abciximab • Chimeric monoclonalantibody 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
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  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
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  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
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  Must Know • Aspirinas antiplatelet agent • Clopidogrelel An Aspirin a Day: The Wonder Drug That Could Save YOUR Life
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  Thank you