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Mechanism of Action of Antithrombotic Drugs Rabih R. Azar, MD, MSc, FACC Division of Cardiology Hotel Dieu de France Hospital.

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Presentation on theme: "Mechanism of Action of Antithrombotic Drugs Rabih R. Azar, MD, MSc, FACC Division of Cardiology Hotel Dieu de France Hospital."— Presentation transcript:

1 Mechanism of Action of Antithrombotic Drugs Rabih R. Azar, MD, MSc, FACC Division of Cardiology Hotel Dieu de France Hospital

2 Mechanism of Action of Antithrombotic Drugs 1- The coagulation cascade 2- Heparin 3- Low molecular weight heparin 4- Direct thrombin inhibitors 5- Vitamin K antagonists 6- Platelet antagonists 7- Thrombolytics

3 Summary of the coagulation cascade Extrinsic pathway: VII, Tissue factor Intrinsic pathway: XII, XI, IX, VIII Common Pathway: V, X, II (prothrombin) Coagulation occurs when thrombin is formed and transform fibrinogen into fibrin

4 The Central Role of Thrombin in the Coagulation Cascade Thrombin is formed from prothrombin after activation by factor XaThrombin is formed from prothrombin after activation by factor Xa High concentration of thrombin:High concentration of thrombin: –activate fibrinogen into fibrin –activate factor XIII leading to fibrin cross-linking –result in platelets activation and aggregation

5 Site of action of drugs TXA 2 ADP Fibrinogen Fibrin Thrombin Prothrombin IntrinsicExtrinsic Collagen Clopidogrel GP IIb/IIIa antagonists LMWH Heparin–AT-III Hirulog X XaLMWH Vascular Surface TXA 2 = thromboxane A 2 ; ADP = adenosine diphosphate; IIb/IIIa = glycoprotein IIb/IIIa; vWF = von Willebrand factor

6 Mechanism of Action of Antithrombotic Drugs 1- The coagulation cascade 2- Heparin 3- Low molecular weight heparin 4- Direct thrombin inhibitors 5- Vitamin K antagonists 6- Platelet antagonists 7- Thrombolytics

7 Plasma anti-coagulation proteins Anti-thrombin III XIIa, XIa, IXa, Xa, Th Tissue factor inhibitor Still experimental Protein C/S VIIIa, Va Vitamin K dependent VII, IX, X, prothr

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9 Mechanism of Action of Unfractionated Heparin Heparin = indirect thrombin inhibitorHeparin = indirect thrombin inhibitor Stimulate anti-thrombinStimulate anti-thrombin Anti-thrombin binds to thrombin and other activated coagulation factors and forms inactivation complexesAnti-thrombin binds to thrombin and other activated coagulation factors and forms inactivation complexes The rate of formation of these inactivating complexes increases by a factor of several thousand in the presence of heparinThe rate of formation of these inactivating complexes increases by a factor of several thousand in the presence of heparin

10 Mechanism of action of heparin on the thrombin anti- thrombin complex Thrombin and other clotting factors have an active center contained a serine amino acid. This center is inhibited by an arginine on the anti-thrombin (AT) molecule. Heparin binds to a lysine site on the AT molecule and produces a conformational change that converts AT from a slow to a very rapid thrombin inhibitor. Heparin then dissociates from the thrombin/AT complex and can be re-utilized.

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12 Heparin Induced Thrombocytopenia Transient mild-moderate thrombocytopenia in 25% Severe thrombocytopenia in 5% Mild platelet reduction within the first 5 days may result from heparin- induced aggregation that is postulated to be benign and transient A smaller subset of pts may develop an antibody-mediated thrombocytopenia that is associated with paradoxical thrombosis. The antibody is directed against the heparin-platelet factor 4 complex These antigen-antibody complexes bind to Fc receptors on adjacent platelets, causing aggregation and thromboembolism

13 Heparin Dosage and Reversal Therapeutic concentration: anti-Xa units/mL. This will prolong the aPTT by Bolus: units/kg; maintenance: units/kg/h (aPTT ) Reversal of heparin: Protamin combines with heparin as an ion pair to form a stable complex devoid of anticoagulant activity For every 100 units of heparin remaining in the patient, administer 1 mg of protamin sulfate IV The rate of infusion should not exceed 50 mg in any 10 min period

14 Mechanism of Action of Antithrombotic Drugs 1- The coagulation cascade 2- Heparin 3- Low molecular weight heparin 4- Direct thrombin inhibitors 5- Vitamin K antagonists 6- Platelet antagonists 7- Thrombolytics

15 Mechanisms of inhibitory action of unfractionated heparin and low-molecular weight heparin on thrombin and factor Xa Inhibition of thrombin requires binding of heparin through a > 18 saccharide residueInhibition of thrombin requires binding of heparin through a > 18 saccharide residue LMWH do not have that residue and are weak thrombin inhibitorsLMWH do not have that residue and are weak thrombin inhibitors Inhibition of Xa requires binding to AT only (without formation of a ternary complex).Inhibition of Xa requires binding to AT only (without formation of a ternary complex).

16 Mechanism of Action of Low Molecular Weight Heparin (LMWH) Selective Inhibition of factor Xa via Anti-thrombin with a weak effect on thrombinSelective Inhibition of factor Xa via Anti-thrombin with a weak effect on thrombin LMWH anti-Xa/thrombin ratio >> 1LMWH anti-Xa/thrombin ratio >> 1 In contrast, unfract heparin anti-Xa/thrombin ratio = 1In contrast, unfract heparin anti-Xa/thrombin ratio = 1 Depending on the length of LMWH, the effect on thrombin may vary, and the anti-Xa/thrombin ratio variesDepending on the length of LMWH, the effect on thrombin may vary, and the anti-Xa/thrombin ratio varies

17 Low-Molecular-Weight Heparins Anti-Facotr Xa : Anti - Factor IIa Ratios AgentTradeXa:IIaMol Wt (d) EnosaparinLovenox 3.8 : 1 4,200 DalteparinFragmin 2.7 : 1 6,000 ArdeparinNormiflo 1.9 : 1 6,000 NadroparinFraxiparine 3.6 : 1 4,500 Reviparin 3.5 : 1 4,000 Tinzaparin 1.9 : 1 4,500

18 Why are LMWH considered superior to unfractionated heparin 1- Heparin does not inhibit clot bound thrombin or Xa LMWH inhibits clot bound Xa 2-Heparin binds extensively to plasma proteins including acute phase reactants and vascular and blood cells LMWH binds much less to these proteins/cells 3-LMWH are more resistant to neutralization by platelet factor 4 4-The longer half life and more predictable anticoagulant response of LMWH allow their administration at a fixed dose without need for laboratory monitoring

19 Dosing of LMWH Weight-based dosing of the LMW heparins results in predictable pharmcokinetics and plasma levels in patients with normal renal function Levels are determined by anti-Xa units: peak therapeutic levels are unit/mL for twice daily dosing, determined 4 hours after administration, and 1.5 unit/mL for the once daily dosing Neutralization of LMWH by protamin is incomplete. Limited experience suggest that 1 mg of protamin sulfate may be used to partially neutralize 1 mg of enoxaparin. Definite neutralization requires FFP

20 Fondaparinux Is a synthetic pentasachharideIs a synthetic pentasachharide Binds antithrombin with high specific activityBinds antithrombin with high specific activity Inactivates XaInactivates Xa Long half life of 15 hoursLong half life of 15 hours Superior to enoxaparin in preventing DVT following orthopedic surgerySuperior to enoxaparin in preventing DVT following orthopedic surgery

21 Mechanism of Action of Antithrombotic Drugs 1- The coagulation cascade 2- Heparin 3- Low molecular weight heparin 4- Direct thrombin inhibitors 5- Vitamin K antagonists 6- Platelet antagonists 7- Thrombolytics

22 Direct Thrombin Inhibitors: Mechanism of Action

23 Advantages of Direct Thrombin Inhibitors Do not necessitate anti-thrombin for their action Inactivate both free and fibrin-bound thrombin They do not bind to plasma proteins They have a more predictable anticoagulant response Indicated for the treatment of heparin induced thrombocytopenia

24 Direct thrombin inhibitors Hirudin (lepirudin): IV. Short half life Bivalirudin: IV. Rapid onset and offset of action. Argatropan: IV. Short half life. Elevates INR because of test interference, rendering the transition to warfarin difficult. Melgatran: IV but has an oral form: Ximelagatran. Ximelagatran: is a prodrug. Predictable pharmacokinetics and bioavailability allowing for fixed dosing and predictable anticoagulant response. No need for routine coagulation monitoring. Rapid onset and offset of action allowing for immediate anticoagulation and thus no need for overlap with additional anticoagulant drugs.

25 Mechanism of Action of Antithrombotic Drugs 1- The coagulation cascade 2- Heparin 3- Low molecular weight heparin 4- Direct thrombin inhibitors 5- Vitamin K antagonists 6- Platelet antagonists 7- Thrombolytics

26 Mechanism of action of anti-vitamin K drugs - Inhibit Vit K epoxide reductase and quinone reductase -Block the formation of Vit KH2 which is a cofactor for the carboxylation of factors II, VII, IX, X to their active form

27 Plasma anti-coagulation proteins Anti-thrombin III XIIa, XIa, IXa, Xa, Th Tissue factor inhibitor Still experimental Protein C/S VIIIa, Va Vitamin K dependent VII, IX, X, prothr

28 Clinical Use of Anti-vitamin K Vitamin K dependent proteins: VII, IX, X, prothrombin, prot C, S Prot C and S have the shortest half life, followed by factor VII The initial effect of anti-vitamin K drugs is a hypercoagulability effect secondary to a deficiency in protein C and S A large loading dose of anti-vitamin K can decrease factor VII levels without affecting factors IX, X and II. This predisposes to bleeding without protecting against thrombosis because the activity of all 4 factors must be inhibited to achieve a clinically effective anticoagulation

29 Mechanism of Action of Antithrombotic Drugs 1- The coagulation cascade 2- Heparin 3- Low molecular weight heparin 4- Direct thrombin inhibitors 5- Vitamin K antagonists 6- Platelet antagonists 7- Thrombolytics

30 Platelets Activation and Aggregation

31 Coller. Heart Disease, Update Platelet GP IIb/IIIa Receptor in Vascular Injury: Aggregation ` GP IIb/IIIa Fibrinogen (or von Willebrand factor) AggregationAggregation

32 Platelet Activation

33 Oral Antiplatelet Agents Mechanism of Action Collagen Thrombin TXA 2 ADP (FibrinogenReceptor) ADP = adenosine diphosphate, TXA 2 = thromboxane A 2, COX = cyclooxygenase. Schafer AI. Am J Med. 1996;101:199–209. clopidogrel bisulfate TXA 2 ADP dipyridamole phosphodiesterase ADP Gp IIb/IIIa Activation COX ticlopidine HCl aspirin

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35 Effects of aspirin ADP= adenosine diphosphate; GP= glycoprotein Thickness of line indicates strength of activator Adapted from Ohman EM et al Eur Heart J 1995;16(suppl L): ADP Collagen Thrombin Epinephrine Thromboxane A 2 Serotonin Platelet-activating factor Fibrinogen Ticlopidine Clopidogrel ASPIRINASPIRIN GP llb/llla

36 Ticlopidine (ticlid) and clopidogrel (plavix) TiclopidineClopidogrel twice / dayonce / day NeutropeniaNo neutropenia CBC monitoringNo need for CBC monitoring Skin reactions (rash)No skin reactions Delayed onset of effectRapid onset of effect

37 Platelet-fibrinogen interaction

38 GP IIb/IIIa Inhibitors: Chemical Structures AbciximabAbciximab Topol et al. Lancet. 1999;353: EptifibatideEptifibatideTirofibanTirofiban O O O O O O O O OH HN HN S S NH NH N NH HN NHNH H2NH2NH2NH2N H2NH2NH2NH2N H N–SO 2 –C 4 H 9 O COOHCOOHCOOHCOOH HNHNHNHN Chimeric Monoclonal Antibody MW 50,000 D Chimeric Monoclonal Antibody MW 50,000 D Nonpeptide Tyrosine Derivative MW 500 D Cyclic Heptapeptide MW 800 D

39 Type of Chimeric monoclonalNonpeptideCyclic moleculeantibodytyrosine derivativeheptapeptide Affinity for circulating platelets HighModerate Unknown K D (nmol/L) Molecules of drug per receptor 1.5 > Drug clearancet 1/2 = h t 1/2 = 2 ht 1/2 = 2.5 h GP IIb/IIIa NonspecificSpecificSpecific receptor specificity(RGD)(KGD) Type of Chimeric monoclonalNonpeptideCyclic moleculeantibodytyrosine derivativeheptapeptide Affinity for circulating platelets HighModerate Unknown K D (nmol/L) Molecules of drug per receptor 1.5 > Drug clearancet 1/2 = h t 1/2 = 2 ht 1/2 = 2.5 h GP IIb/IIIa NonspecificSpecificSpecific receptor specificity(RGD)(KGD) AbciximabTirofibanEptifibatide Scarborough et al. Circulation. 1999;10: ; Tcheng. Am J Cardiol. 1999;83:7E-11E. Comparative Properties of GP IIb/IIIa Inhibitors

40 Mechanism of Action of Antithrombotic Drugs 1- The coagulation cascade 2- Heparin 3- Low molecular weight heparin 4- Direct thrombin inhibitors 5- Vitamin K antagonists 6- Platelet antagonists 7- Thrombolytics

41 The Fibrinolytic System Plasmin is the key protease enzyme of the coagulation system 2 major activators of plasminogen: tissue-type plasminogen activator (t-PA) and urokinase-type plasminogen activator (u-PA) Both t-PA and plasminogen possess specific affinity for fibrin and thereby bind selectively to clots. In the absence of fibrin, t-PA activates plasminogen to plasmin relatively slowly

42 Thrombolytic Drugs Because indiscriminate plasmin lysis of both fibrin and fibrinogen can produce a sysemic state of fibrin(ogen)olysis, which might cause a serious systemic bleeding tendency, attempts have been made to develop thrombolytic agents that generate plasmin preferentially at the fibrin surface in preformed thrombus Streptokinase and urokinase induce a systemic lytic state In contrast, t-PA activate plasminogen preferentially at the fibrin surface. The risk of hemorrhage is however not reduced, because of the inability of plasmin to discriminate between fibrin in pathological thrombi and fibrin in physiological hemostatic plugs

43 Streptokinase Isolated from hemolytic streptococci Streptokinase itself possesses no enzymatic activity Streptokinase forms a complex with plasminogen and it is the strepto-plasminogen complex that actually possesses enzymatic activity Streptokinase is anti-genic. Most individuals have preexisting antibodies from previous streptococcal infection It can cause allergic reactions: transient hypotension, serum sickness-type syndrome

44 tPA Produced by recombinant DNA technology Fibrin specific It activates plasminogen directly The efficiency of plasminogen activation by t-PA is enhanced in the presence of fibrin Short half life: minutes


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