Antiplatelets, & fibrinolytics

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  • 1. Antiplatelets & Fibrinolytics HARSHIT SHETH
  • 2. 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.
  • 3. HOW PLAQUES ARE FORMED?
  • 4. 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
  • 5. ANTIPLATELETS: Classification • Aspirin • Phospodiesterase inhibitors- Dipyridamol, - Cilostazole • ADP antagonist- Clopidogrel,Ticlopidine • GPIIb/IIIa Antagonist- Abciximab,Eptifibatide,Tirofiban , Lamifiban • Synthetic PGI2- Epoprostenol
  • 6. Aspirin(ASA):Mechanism
  • 7.  Vascular endothelial cells can synthesize new PGI2 but platelets cannot synthesize new TXA2.  Thus action of aspirin on platelet is permanent lasting for the lifetime of platelet i.e. 7-10 days.  Balance between TXA2 (promoter of aggregation) & PGI2 ( inhibitor of aggregation)
  • 8. As higher doses of aspirin are needed to inhibit COX in vascular endothelium than in platelets, antiplatelet effect can be achieved at low doses ( 75- 150 mg per day orally)  Other NSAIDs are reversible inhibitors.
  • 9. Limitations of Aspirin •Multiple pathways of platelet activation in vivo Thrombin, collagen, high shear stress activate platelets via non-cyclooxygenase pathways Catecholamines can overcome antiplatelet effect Platelet adhesion and thrombus formation not blocked Prothrombotic effect at higher doses Inhibition of vascular prostacyclin generation Inhibition of tPA (at doses >300 mg)
  • 10. Adverse effects • At lower dose mainly GIT adv. Effect: A)GI mucosa damage B)High risk of bleeding C)Suppression of GI protective action of PGs
  • 11. Phosphodiaster Inhibitors: • Dipyridamol: • It inhibits Phosphodiasterase & blocks uptake of adenosine to increase cAMP which potentiate PGI2 & interfere with aggregation • Dipyridamol+Aspirin-used in TIA
  • 12. ADP antagonist:
  • 13. Clopidogrel • Pro Drug • Slow onset of action • Fewer side effects than Ticlodipine • Dose dependent action – within 5 hrs of oral loading dose 80% of platelet activity inhibited. • Duration of antiplatelet effect 7- 10 days.
  • 14. Ticlodipine • Pro Drug • 8-11 days to show maximal effect. • Nausea, vomiting, diarrhoea. • Thrombocytopenia • Neutropenia • Thrombotic Thrombocytopenic Purpura – rare. • Due to distinct MOA combo with aspirin has additive or synergistic effect. • Used for sec. prevention of stroke
  • 15. GPIIb/IIIa Antagonist
  • 16. Abciximab • Human murine chimeric monoclonal antibody Fab fragment • Binds with high affinity and slow dissociation rate. • Immediate and profound inhibition of platelet activity extending for 12-36 hrs after termination of infusion. • 0.25mg/kg bolus followed by 0.125μg/kgper min for 12hrs
  • 17. Eptifibatide/ Tirofiban • • Prevent binding of fibrinogen to • the receptor complex • • Used to treat unstable angina • • Used for angioplastic coronary • interventions. • • ADRs • - Haemorrage • - Thrombocytopenia
  • 18. Clinical uses of antiplatelet drugs  The main drug is aspirin. Other drugs with distinct actions (e.g. dipyridamole, clopidogrel) can have additive effects, or be used in patients who are intolerant of aspirin.  Uses of antiplatelet drugs relate mainly to arterial thrombosis and include uses in:  acute myocardial infarction high risk of myocardial infarction, including a history of myocardial infarction, angina – unstable Angina (clopidogrel is added to aspirin)
  • 19. following coronary artery bypass grafting
  • 20. – following coronary artery angioplasty (PCI) – abciximab(I.V), are used in some patients in addition to aspirin) – transient cerebral ischaemic attack ('ministrokes') or thrombotic stroke, to prevent recurrence (dipyridamole can be added to aspirin) – atrial fibrillation, if oral anticoagulation is contraindicated. • epoprostenol [PGI2]; have specialised clinical applications in haemodialysis or haemofiltration in cases in which heparin is
  • 21. FIBRINOLYTICS • These drugs dissolve the Thrombi in blood vessel(mainly coronary artery) by activating fibrinolytic system
  • 22. Fibrinolytics Agents 1st GEN: • Streptokinase • Urokinase 2nd GEN • Alteplase 3rd GEN • Reteplase • Tenecteplase
  • 23. Streptokinase :1st GEN: • Streptokinase is a protein • synthesized by streptococci that • combines with proactivator • plasminogen. Caution in patients • with previous history of fibrinolytic • therapy due to formation of • antibodies. • • Streptokinase- loading dose of • 250,000 units followed by • 100,000 units/hr for 24-72 hrs. • • It is antigenic & can cause hypersensitivity rxn when used
  • 24. Urokinase • Urokinase is a human enzyme synthesized by the kidney that directly converts plasminogen to plasmin. • Plasminogen can be activated endogenously by t-PA. Preferentially activate plasminogen bound to fibrin  Non-antigenic Indicated in pts. With sensitivity to strepokinase
  • 25. FIBRINOLYTICS • 2ND GEN: ALTEPLASE (TPA) – Cleaves plasminogen plasmin fibrinolysis – Specific activity in thrombus, less systemic fibrinolysis – Weight-based IV infusion over 60-90min – Half-life<5 min – Heparin commonly administered shortly after • 2ND GEN: ALTEPLASE (TPA) – Cleaves plasminogen plasmin fibrinolysis – Specific activity in thrombus, less systemic fibrinolysis – Weight-based IV infusion over 60-90min – Half-life<5 min – Heparin commonly administered shortly after  DOSE- 60 mg i.v. over the first hour followed by 40 mg at a rate of 20 mg/hr.
  • 26. Adv.Of alteplase in TIA(mini stroke)
  • 27. Comparision
  • 28. FIBRINOLYTICS • 3RD GEN: modifications of TPA – RETEPLASE • Half-life= 18 min • Double bolus regimen – TENECTEPLASE (TNK) • Half life= 20 min • Single-weight tiered bolus dosing over 5-10s *bolus-doses fewer med errors * No absol mortality benefit in AMI
  • 29. FIBRINOLYTICS: Clinical uses • The main use is in acute myocardial infarction, with ST segment elevation on the ECG within 12 hours of onset (the earlier the better!) • Other uses include: – acute thrombotic stroke within 3 hours of onset (tPA), in selected patients – clearing thrombosed shunts and cannulae – acute arterial thromboembolism – life-threatening deep vein thrombosis and pulmonary embolism (streptokinase, given promptly).
  • 30. Adv. Effect : These agents do not distinguish b/w pathological thrombi & fibrin deposit at site of vascular injury
  • 31. Books To Be Referred: • Lippincott • F.s.k Barar • Rang & Dale • Goodman & Gillman • K D Tripathi • H L Sharma • R K Goyal • Photographs from Medical books • Internet
  • 32. Good ideas are not adopted automatically. They must be driven into practice with courageous patience. --Hyman Rickover US Admiral(1900-1986) 37