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Antiplatelet drugs (antithrombotics)
Dr. D. K. Brahma discusses antiplatelet drugs, which interfere with platelet function and are useful for preventing thromboembolic disorders. The document defines antiplatelet drugs and describes the role of platelets in thrombosis formation. It then discusses the mechanisms of various antiplatelet drugs including aspirin, dipyridamole, ticlodipine, clopidogrel, prasugrel, and GPIIb/IIIa receptor antagonists like abciximab. The uses of these antiplatelet drugs for conditions like heart attacks, strokes, angioplasty and stents are summarized.
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Antiplatelet drugs (antithrombotics)
- 1. Dr. D. K.Brahma Associate Professor Department of Pharmacology NEIGRIHMS, Shillong Antiplatelet Drugs (Antithrombotic Drugs)
- 2. 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
- 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 ofplatelets
- 5. The role ofplatelets
- 6. The role ofplatelets
- 7. The role ofplatelets
- 8. 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
- 9. 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
- 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
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- 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 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
- 17. 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)
- 18. 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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- 24. 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
- 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 • Aspirinas antiplatelet agent • Clopidogrelel An Aspirin a Day: The Wonder Drug That Could Save YOUR Life
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Editor's Notes
- #5 Following vascular injury, von Willebrand factor binds to collagen in the exposed subendothelium at the site of injury. The other site of the “rod-formed” von Willebrand factor binds to the platelet receptor GPIb and platelets are thereby anchored to the site of the injured entothelium. This is called adhesion.
- #6 Following adhesion, agonists such as collagen, thrombin, adenosine diphosphate (ADP), and thromboxane A2 activate platelets by binding to their respective platelet receptors.
- #7 As a result of agonist binding, platelets undergo a shape change and new structures such as phospholipids and GPIIb/IIIa receptors are exposed on the cell membrane. This is called activation.
- #8 The third step of platelet response is aggregation. After activation, fibrinogen binds to GPIIb/IIIa to connect platelets together into a loose platelet plug.
- #20 The glycoprotein IIb/IIIa receptor is exposed on the platelet membrane after activation and is responsible for mediating platelet aggregation.
- #21 Once activated, the receptor becomes functional and binds fibrinogen, leading to the formation of platelet aggregates. Glycoprotein IIb/IIIa receptors therefore mediate the final common pathway of platelet aggregation.
- #22 GPIIb/IIIa antagonists hava a high affinity for the fibrinogen receptor…
- #23 …and when binding is completed…
- #24 …they will prevent fibrinogen from binding to the receptors.