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Contents • Introduction • Classification • Individual drugs • Newer anti-platelet agents • Summary Introduction • Normal homeostasis • Maintenance of blood in a fluid, clot-free state in normal vessels; and • Formation of haemostatic plug at a site of vascular injury. • Opposite : Thrombosis • Thrombi are lysed and blood is made fluid by fibrinolytic system Coagulation Fibrinolysis Antithrombotic drugs Fibrinolytics Antithrombotic drugs Fibrinolytics Antithrombotic drugs Fibrinolytics Antithrombotic drugs Fibrinolytics Thrombosis • Arterial Thrombosis : • Adherence of platelets to arterial walls - White in color - Often associated with MI, stroke and ischemia • Venous Thrombosis : • Develops in areas of stagnated blood flow (deep vein thrombosis), Red in color- Associated with Congestive Heart Failure, Cancer, Surgery. HOW PLAQUES ARE FORMED? Pathophysiology of the Thrombus Blood Vessel Endothelium Subendothelium INJURY Vasoconstriction Collagen VWF Platelet Adhesion & Secretion Tissue Factor Coagulation Cascade Thrombin Platelet aggregation Fibrin Haemostatic plug • Both hemostasis and thrombosis are regulated by three general components •The vascular wall, •Platelets, and •The coagulation cascade HAEMOSTASISCessation of blood loss from damaged blood Vascular Phase Platelet Phase Coagulation Phase Vascular Phase Vasoconstriction Exposure to tissues activate Tissue factor and initiate coagulation Tissue Factor Platelet Phase WHAT ARE PLATELETS ? White, discoid Smallest element of flowing blood • 1 - 2 microns diameter Lipid bilayer membrane Normal range 150000 – 450000 microlitre blood Formed from cytoplasm of megakaryocytes No nucleus Normal Function of Platelets Haemostasis Integrity and repair of the vessel wall Preventing bleeding from wounds • Receptors on platelets: • • • • • GpIa/IIa: receptors for collagen GpIb: receptor for vWF GpIIb/IIIa: receptor for fibrinogen P2Y1/P2Y12: purinergic receptors for ADP PAR1/PAR4: protease activated receptors for thrombin (IIa) Basic concepts • PGI2- inhibit platelet aggregation • TXA2- platelet aggregation • Elevated c-AMP- inhibit platelet aggregation & vice versa • ADP receptors(P2Y1,P2Y2)-changes shape & platelet aggregation • GPIIb/IIIa receptors- binds fibrinogen & platelets • 5-HT-vasocostriction • Collagen,Thrombin- platelet aggregation agonist • Platelets provide the initial hemostatic plug at sites of vascular injury • They also participate in pathological thromboses that lead to myocardial infarction, stroke, and peripheral vascular thromboses PLATELET AGGREGATORS Collagen Von willebrand factor ADP Thromboxane A2 Stress Thrombin The role of platelets Platelet Activation Pathways Collagen Thrombin Epinephrine ADP Arachidonic acid TxA2 GP IIb/IIIa The role of platelets The role of platelets The role of platelets Platelet adhesion and aggregation Platelet-fibrin clot Damaged blood vessel Activation of platelets Release of collagen Arachidonic acid Release of thrombin Release of ADP COX Cyclic endperoxidase Activates P2Y1 Gq Release of TXA2 Gi Changes in platelet shape inhibits adenylcyclase, Increases phospoinositol Activation of glycoprotein IIB/IIIA receptors Fibrinogen fibrin decrease CAMP ? PGI 2- (Prostacyclins) Naturally occurring potent vasodilator and inhibitor of platelet aggregation. Produced by vessel walls, also present in brain ,gut and kidney. Formed from PG endperoxidase by the action of COX Inhibit platelet aggregation by stimulating adenylcyclase increasing cyclic AMP levels in platelets. Prostacyclins causes hypotension , tachycardia ,headache. intense facial flushing Very unstable ,1/2 life of 3 mins. Prostacyclins (Epoprostananol)-used during haemodialysis. Antiplatelet drugs (Classification) • 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 • Aspirin blocks production of TxA2by acetylating a serine residue near the active site of platelet cyclooxygenase-1 (COX-1) • The action of aspirin on platelet COX-1 is permanent • Anti-thrombotic dose is much lower than doses required for other actions • Higher doses do not improve efficacy • Potentially less efficacious because of inhibition of prostacyclin production • Higher doses also increase toxicity, especially bleeding TXA2 PGI2 • 50-320mg/day • Pro aggregation • Higher doses • Anti aggregation Aspirin Mechanism Of Action Mechanism Of Action Mechanism Of Action Mechanism Of Action Mechanism Of Action ASPIRIN• MOAIn platelets major COX product is TXA2 , a labile inducer of platelet aggregation and potent vasoconstrictor. Aspirin blocks production of TXA2 by covalently acetylating serine residue near the active site of COX, this enzyme produces cyclic endperoxidase precursor of TXA2. Since platelets do not synthesize new proteins hence the action of aspirin on platelets is permanent (7-10 days). For complete inactivation of platelet COX dose of aspirin req. is 160 mg daily. Reason— Higher doses decrease efficacy of aspirin as they inhibit production of prostacyclins which is spared at low doses. (75-150mg) Higher doses also increase toxicity esp.. Bleeding. PHARMACOKINETICS • Rapid absorption in the stomach and upper intestine, • Peak plasma concentration in 15-20 minutes • The peak inhibitory effect on platelet aggregation is apparent approximately one hour post-administration • Aspirin produces the irreversible inhibition of the enzyme cyclooxygenase and therefore causes irreversible inhibition of platelets for the rest of their lifespan (7 days) 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 MAJOR DRAWBACKS • Risk of gastrointestinal adverse events (ulceration and bleeding) • Allergic reactions • Is not a very effective antithrombotic drug but is widely used because of its ease of use • Lack of response in some patients (aspirin resistance) • The irreversible platelet inhibition Phosphodiaster Inhibitors • Dipyridamole • Coronary vasodilator and relatively weak antiplatelet drug MECHANISM • Interferes with platelet function by increasing the cellular concentration of cyclic AMP • This effect is mediated by inhibition of cyclic nucleotide phosphodiesterases and Blockade of uptake of adenosine • cAMPpotentiates PGI2 and interferes with aggregation PHARMACOKINETICS • Incompletely absorbed from the gastrointestinal tract with peak plasma concentration occuring 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 a small amount is excreted in the urine in the bile; USES • Dipyridamole alone has little clinically significant effect • Inhibits embolization from prosthetic heart valves when used in combination with warfarin • May potentiate the action of aspirin in preventing strokes in patients with TIA, • No additional benefit as combination with aspirin in preventing MI MAJOR DRAWBACKS • Is not a very effective antithrombotic drug • Dipyridamole also has a vasodilatory effect and should be used with caution in patients with severe coronary artery disease; chest pain may be aggravated in patients with underlying coronary artery disease who are receiving dipyridamole ADP antagonist: ADP-receptor antagonists – mechanism of action ADP-receptor antagonists – mechanism of action ADP-receptor antagonists – mechanism of action ADP-receptor antagonists – mechanism of action ADP-receptor antagonists – pharmacokinetics • Both currently available ADP-receptor antagonists are thienopyridines that can be administered orally, and absorption is approximately 8090% • Thienopyridines are prodrugs that must be activated in the liver ADP-receptor antagonists – major use • Secondary prevention of ischaemic complications after myocardial infarction, ischaemic stroke and established peripheral arterial disease • Secondary prevention of ischaemic complications in patients with acute coronary syndrome (ACS) without ST-segment elevation ADP-receptor antagonists – major drawbacks • Clopidogrel is only slightly more effective than aspirin • As with aspirin, clopidogrel binds irreversibly to platelets • In some patients there is resistance to clopidogrel treatment Ticlodipine & clopidogrel • ADP antagonists, inhibit binding of ADP to its receptors irreversibly • Also Inhibit fibrinogen induced platelet aggregation with out modifying GPIIb/IIIa • Synergistic action with aspirin • Both are prodrugs have long duration of antiplatelet effect • Clopidogrel a congener of ticlodipine is safer and better tolerated Ticlodipine Vs clopidogrel Ticlodipine • Adverse effects: – Diarrrhoea, vomiting, abdominal pain – Headache, tinnitus, skin rash – Bleeding, neutropenia, thrombocytopenia • dose= 250 mg BD Clopidogrel • Adverse effects – Bleeding most IMP – Less bone marrow toxicity – Diarrhoea, epigastric pain, rashes • Dose = 75 mg OD ADP antagonists- Ticlopidine Ticlopidine blocks Gi coupled ADP receptors It is a prodrug requires conversion to active form by Cyp450. Rapid absorp. ,high bioavailability Maximal inhibition of platelet inhibition it takes 8-11 days after starting therapy. Dose-loading 500mg for rapid onset of action. Usual dose 250mgBD AE- Nausea ,Vomiting, Diarrhea, Neutropenia, Thrombotic Thrombocytopenia Uses- Prevention cerebrovascular events, in 2ndary prevention of stroke Unstable angina Combination –Aspirin + ticlopidine---angioplasty, coronary artery stenting Clopidogrel Less toxic then ticlo. less incidence of leucopenia, thrombocytopenia. Less used than Ticlopidine MOA, PK profile same as Ticlopidine Dose 75mg/day Rest same as Ticlopidine. GP IIb-IIIa Receptor Final common pathway to platelet aggregation White HD. Am J Cardiol. 1997; 80(4A):2B-10B. Platelet GP IIb/IIIa Receptor in Vascular Injury: Adhesion and Activation Adhesion GP IIb/IIIa GP Ib-IX-V Platelet GP Ia/IIa Endothelium von Willebrand factor Collagen Activation GP IIb/IIIa Fibrinogen (or von Willebrand factor) Platelet GP IIb/IIIa Receptor in Vascular Injury: Aggregation Fibrinogen (or von Willebrand factor) GP IIb/IIIa Aggregation ` Inhibition of Platelet Aggregation GP IIb/IIIa Receptor Inhibitor Fibrinogen Resting Platelet Receptors in ligand-unreceptive state Activated Platelet Receptors in ligandreceptive state Aggregating Platelets GP IIb/IIIa receptors occupied by fibrinogen which forms bridges between adjacent platelets Glycoprotein IIb/IIIa inhibitors • Block final step in platelet aggregation induced by any agonist • Abciximab • Eptifibatide • Tirofiban GPIIb/IIIa Antagonist 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 Glycoprotein IIB/IIIA receptors antagonists Platelet surface receptor, receptor for fibrinogen and von willebrand factor,which anchors platelets to foreign surface and each other thereby mediating aggregation. Receptor is activated by TXA2, Collagen, and thrombin to developbinding sites for its ligands. Inhibition of binding to this receptor blocks platelet aggregation induced by the agonist. Abciximab • Fab fragment of Chimeric monoclonal antibody against GP-IIb/IIIa. • Used to prevent platelet aggregation in patients having PCI, administered along with aspirin & heparin or LMW heparin • Most common A/E is bleeding • May cause thrombocytopenia, hypotension, bradycardia • Non antigenic • Dose: 0.25 mg/kg IV before PCI followed by 10 g/min for 12 hrs Eptifibatide • Cyclic peptide inhibitor of the fibrinogen binding site on GpIIb/IIIa receptor • Short duration of action: 6-12 hrs • Given with aspirin and heparin • Use: • Acute coronary syndrome • Angioplastic coronary interventions • Adverse effects: • Bleeding (10%) • Thrombocytopenia (0.5-1%) Tirofiban • Similar to eptifibatide • Value in antiplatelet therapy after acute myocardial infarction is limited • Used in conjunction with heparin GpIIb/IIIa inhibitors Features Abciximab Eptifibatide Tirofiban Description Fab fragment of humanized mouse monoclonal antibody Cyclical heptapeptide Nonpeptide Specific for GPIIb/IIIa No Yes Yes Plasma t1/2 Short Long (2.5h) Long (2.0h) Platelet-bound t1/2 Long (days) Short (sec) Short (sec) Renal clearance No Yes Yes PROSTACYCLINE ANALOGUES • Ex are epoprostenol, iloprost • These group of drugs block all pathway for platelet activation. • They also inhibits the expression of GPIIb/IIIa receptor. • Epoprostenol has a very short half life of 3 mins so it has to be used by iv infusion. • It causes headache and flushing due to vasodilation. • iloprost is similar to epoprostenol but iloprost is longer acting. Newer anti-platelet agents • Cangrelor • Ticagrelor • SCH530348 • E5555 THANK YOU -PHARMA STREET