Anticoagulant, Antiplatelet, and Thrombolytic Drugs      Dr. Tharanga Kulathilaka                                 1
Objectives• Normal haemostasis process Plt plug, Clot & Thrombus• Mechanism of action• Indications• Common side effects   ...
Haemostasis• Complex process• Interaction between vessel wall, plt, Coagualtion/  fibrinolytic mechanism.• Vessel wall in ...
Physiology and Pathophysiology        of Coagulation• Hemostasis   – Stage 1—formation of platelet plug      • Platelet ag...
5
• Endothelial injury is caused by  Mechanical stresses (HT)   Biochemical abnormalities ( Modified LDL, DM, Plasma  homocy...
Platelets            7
Platelet plug formation                          8
Clotting pathway                   9
Thrombus           10
Physiological limitations of             coagulation•   Rapid blood flow•   Circulating inhibitors of clotting factors•   ...
Fibrinolysis• Fibrinolysis is the controlled remodeling of a  platelet plug. It is the process that dissolves fibrin  resu...
Overview of Drugs                                                           Therapeutic  Drug Class        Prototype      ...
Antiplatelet Drugs  Two Drugs to        know:  ASPIRIN andCLOPIDOGREL                                      14
Antiplatelet Drugs• Aspirin (ASA)   – Irreversible Inhibition of cyclooxygenase   reducing Txa2   Effect lasts for 7 days....
Cont Anti plt drugs• Clopidogrel – ADP receptor blocker in plt  membrane• Prevents ADP dependent activation of  gpǁb, ǁl a...
Plt llb,llla blockers•   Abciximab•   Eptifibatide•   Tirofiban•   Excessive bleeding•   Its uses yet to indentify•   Duri...
Parenteral Anticoagulants I: Heparin and Related DrugsHeparin (Unfractionated Heparin)• Sources   – Lungs of cattle   – In...
Parenteral Anticoagulants I: Heparin and Related Drugs• Adverse effects   – Hemorrhage   – Heparin-induced thrombocytopeni...
Heparin suppressescoagulation bypromoting the action ofantithrombin (a serineprotease inhbitor)    to inactivatethrombin a...
Low-Molecular-Weight Heparins    Lovenox (enoxaparin)• Heparin preparations composed of molecules that  are shorter than t...
Fondaparinux [Arixtra]• Synthetic subQ anticoagulant – like LMW heparin• Selective inhibition of Factor Xa – see Figure 51...
Parenteral Anticoagulants II:   Direct Thrombin InhibitorsBivalirudin [Angiomax]• Therapeutic use   – Prevent clot formati...
Parenteral Anticoagulants II:   Direct Thrombin InhibitorsBivalirudin [Angiomax]• synthetic peptide,  must be injected IV•...
Warfarin• Oral anticoagulant• Antagonist of vitamin K-dependent reactions• Blocks the biosynthesis of four clotting factor...
Warfarin• Adverse effects   – Hemorrhage   – Fetal hemorrhage and teratogenesis from     use during pregnancy   – Use duri...
Warfarin• Drug interactions  – Drugs that increase anticoagulant effects  – Drugs that promote bleeding  – Drugs that decr...
Thrombolytic Drugs – Clot Busters• Streptokinase [Streptase]   – Binds plasminogen and facilitates plasmin     formation –...
tPA•   Alteplase•   Reteplase•   More specific for clot bound plasminogen•   Fewer bleeding episodes•   Expensive         ...
THANK YOU            30
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Tharanga lecture

  1. 1. Anticoagulant, Antiplatelet, and Thrombolytic Drugs Dr. Tharanga Kulathilaka 1
  2. 2. Objectives• Normal haemostasis process Plt plug, Clot & Thrombus• Mechanism of action• Indications• Common side effects 2
  3. 3. Haemostasis• Complex process• Interaction between vessel wall, plt, Coagualtion/ fibrinolytic mechanism.• Vessel wall in normal condition prevents plt adhesion and thrombin formation by negative charge, PC, NO synthesis, Production of plasminogen activator, Expression of thrombomodulin and heparan sulphate . 3
  4. 4. Physiology and Pathophysiology of Coagulation• Hemostasis – Stage 1—formation of platelet plug • Platelet aggregation – Stage 2—coagulation • Intrinsic coagulation pathway • Extrinsic coagulation pathway – Keeping hemostasis under control – Physiologic removal of clots• Thrombosis – Arterial thrombosis, Venous thrombosis 4
  5. 5. 5
  6. 6. • Endothelial injury is caused by Mechanical stresses (HT) Biochemical abnormalities ( Modified LDL, DM, Plasma homocystein ) Immunological factors Free radicals Inflammation Genetic alteration 6
  7. 7. Platelets 7
  8. 8. Platelet plug formation 8
  9. 9. Clotting pathway 9
  10. 10. Thrombus 10
  11. 11. Physiological limitations of coagulation• Rapid blood flow• Circulating inhibitors of clotting factors• Antithrombin – Heparin• Act protein c (-)V ,viii• Protein S cofactor for protein C 11
  12. 12. Fibrinolysis• Fibrinolysis is the controlled remodeling of a platelet plug. It is the process that dissolves fibrin resulting in the removal of small blot clots. Agents or drugs which promote fibrinolysis are useful therapeutically.• Plasminogen – Plasmin• Tpa• FDP - D dimers 12
  13. 13. Overview of Drugs Therapeutic Drug Class Prototype Drug Action EffectAnticoagulants: Heparin  Fibrin formation Prevention of Parenteral (by promoting venous inactivation of thrombosis clotting factors)Anticoagulants: Warfarin  Fibrin formation Prevention of Oral (by decreasing venous synthesis of thrombosis clotting factors)Antiplatelet Aspirin  Platelet Prevention ofDrugs aggregations arterial thrombosisThrombolytic Streptokinase Promotion of fibrin Removal ofDrugs digestion newly formed thrombi 13
  14. 14. Antiplatelet Drugs Two Drugs to know: ASPIRIN andCLOPIDOGREL 14
  15. 15. Antiplatelet Drugs• Aspirin (ASA) – Irreversible Inhibition of cyclooxygenase reducing Txa2 Effect lasts for 7 days. – Adverse effects • Increase risk of GI bleeding • Hypersensitivity • Bronchospasms • Interstitial nephritis and protenuria • Rayes syndrome 15
  16. 16. Cont Anti plt drugs• Clopidogrel – ADP receptor blocker in plt membrane• Prevents ADP dependent activation of gpǁb, ǁl a complex• Prasugrel - Potent and rapid action• Dipiridamole – Inhibits plt phosphodiesterase activity increses pgi2 action 16
  17. 17. Plt llb,llla blockers• Abciximab• Eptifibatide• Tirofiban• Excessive bleeding• Its uses yet to indentify• During pci 17
  18. 18. Parenteral Anticoagulants I: Heparin and Related DrugsHeparin (Unfractionated Heparin)• Sources – Lungs of cattle – Intestines of pigs• Rapid-acting anticoagulant• Uses – Pulmonary embolism (PE) – Stroke evolving – Massive deep venous thrombosis (DVT) 18
  19. 19. Parenteral Anticoagulants I: Heparin and Related Drugs• Adverse effects – Hemorrhage – Heparin-induced thrombocytopenia – Hypersensitivity reactions• Protamine• Activated partial thromboplastin time (aPTT) 19
  20. 20. Heparin suppressescoagulation bypromoting the action ofantithrombin (a serineprotease inhbitor) to inactivatethrombin and factorXa.Figure 51-3Mechanism of action ofheparin, LMW heparins,and fondaparinux. 20
  21. 21. Low-Molecular-Weight Heparins Lovenox (enoxaparin)• Heparin preparations composed of molecules that are shorter than those found in unfractionated heparin. – Lovenox (enoxaparin)• Therapeutic use – Prevention of DVT following surgery – Treatment of established DVT – Prevention of ischemic complications• Adverse effects and interactions – Bleeding, immune-mediated thrombocytopenia – Cost 21
  22. 22. Fondaparinux [Arixtra]• Synthetic subQ anticoagulant – like LMW heparin• Selective inhibition of Factor Xa – see Figure 51-3• Therapeutic use – Prevention of DVT following surgery – Treatment of acute PE (with warfarin) – Treatment of acute DVT (with warfarin)• Adverse effects – Bleeding is the biggest concern, risk is increased with advancing age and renal impairment – Patients weighting less than 50 kg. low BW increases bleeding risk 22
  23. 23. Parenteral Anticoagulants II: Direct Thrombin InhibitorsBivalirudin [Angiomax]• Therapeutic use – Prevent clot formation (combined with aspirin)• Mechanism of action – Direct, reversible inhibitor of thrombin – Prevents the conversion of fibrinogen into fibrin – Prevents factor XIIIa activation• Adverse effects – Back pain, headache 23
  24. 24. Parenteral Anticoagulants II: Direct Thrombin InhibitorsBivalirudin [Angiomax]• synthetic peptide, must be injected IV• short half-life (25 min)• very expensive 24
  25. 25. Warfarin• Oral anticoagulant• Antagonist of vitamin K-dependent reactions• Blocks the biosynthesis of four clotting factors: Factors VII, IX, X, and prothrombin• Reduces production of clotting factors by 30-50%• Therapeutic uses Long-term prophylaxis of thrombosis • Prevention of venous thrombosis and associated pulmonary embolism • Prevention of thromboembolism (in patients with prosthetic heart valves) • Prevention of thrombosis during atrial fibrillation 25
  26. 26. Warfarin• Adverse effects – Hemorrhage – Fetal hemorrhage and teratogenesis from use during pregnancy – Use during lactation – warfarin enters breast milk 26
  27. 27. Warfarin• Drug interactions – Drugs that increase anticoagulant effects – Drugs that promote bleeding – Drugs that decrease anticoagulant effects – Heparin – Aspirin – Acetaminophen 27
  28. 28. Thrombolytic Drugs – Clot Busters• Streptokinase [Streptase] – Binds plasminogen and facilitates plasmin formation – plasmin digests fibrin of clots – Most effective when therapy is begun within 6 hours of symptom onset – Intended for IV or intracoronary administration• Uses – Acute coronary thrombosis (acute MI) – Deep venous thrombosis (DVT) – Massive pulmonary emboli• Adverse effects – Bleeding, hypotension 28
  29. 29. tPA• Alteplase• Reteplase• More specific for clot bound plasminogen• Fewer bleeding episodes• Expensive 29
  30. 30. THANK YOU 30
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