Antiplatelet Drugs

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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) Irreversible- Clopidogrel,Ticlopidine Reversible – Prasugrel , Ticagrelor , cangrelor III) Phosphodiesterase inhibitors - Dipyridamole PDE-3 inhibitor - Cilostazol IV) Glycoprotein IIb / IIIa inhibitors – Abciximab , Eptifibatide , Tirofiban , Defibrotide

7. Newer antiplatelet Thrombin receptor antagonist- (PAR-1) – Vorapaxar Atopaxar TXA2 receptor antagonist – Teratroban , Picotamide , Ridogrel GP IV receptor antagonist – Revacept GP Ib receptor antagonist, Serotonin receptor antagonist, vWF antagonist Thromboxane synthase inhibitor- Dazoxiben * Prostacycline PGI2 analogue- Epoprostenol iloprost *Miscellaneous- Dextran 70, sulfinpyrazone , clofibrate , tomolol

8. 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

9. MOA Other NSAIDS are r eversible 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

10. 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.

11. Anti- platelet drugs LOW DOSE ASPIRIN

12. 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

13. T iclopidine 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

14. Adverse Effects ticlopidin Sever neutropenia . CBC done monthly Bleeding (Prolong bleeding time). CYT P450 inhibitors G.I.T : Diarrhoea , Nausea, Dyspepsia. Allergic Reactions. Due to ADR use declined over clopidogrel

15. 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

16. 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

17. 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

18. 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

19. 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

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

21. 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.

22. Glycoprotein IIb / IIIa receptor Inhibitors

23. 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 α v β 3 ( vitronectin ) and α m β 2 ( Leucocyte integrin ) Uses: Unstable angina and as an adjuvant to coronary thrombolysis /PCI with Stent application

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

25. 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

26. 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

27. 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

28. Uses of Antiplatelets Aim: Prevent intravascular thrombosis and embolism with minimal risk of bleeding Acute coronary Syndrome: Asprin 325mg oral and LMW heparin sc unstable angina - aspirin, clopidogrel if aspirin cannot be given or combine NSTEMI: asiprin + clopidogrel for 1 yr 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

29. 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

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