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Mechanism of Action of Antithrombotic Drugs

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Presentation on theme: "Mechanism of Action of Antithrombotic Drugs"— 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 Xa 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 Vascular Surface TXA2 ADP Fibrinogen Fibrin
Clopidogrel TXA2 ADP Fibrinogen Fibrin GP IIb/IIIa antagonists Thrombin Prothrombin LMWH X Xa LMWH Slide I.9 Drugs used for the prevention of cardiac ischemic events in patients with UAP/NSTEMI act at various steps in the process of thrombus formation. Aspirin blocks formation of the platelet agonist TXA2 by irreversibly inhibiting the platelet cyclooxygenase pathway.20 The thienopyridine clopidogrel inhibits platelet activation by interfering with the mechanism mediated by ADP,20 another platelet agonist. Heparin primarily augments the activity of circulating antithrombin III, thereby enhancing its inhibitory effect on thrombin.21 Hirulog, a direct thrombin inhibitor, can block the activity of both free (circulating) and clot-bound thrombin.10 Low molecular weight heparin principally inhibits factor Xa, with a lesser effect on antithrombin III.22 Glycoprotein IIb/IIIa receptor antagonists act by preventing binding of fibrinogen to these receptors, the final common pathway for platelet aggregation.15,23 Heparin–AT-III Hirulog Intrinsic Extrinsic Collagen Vascular Surface TXA2 = thromboxane A2; 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


9 Mechanism of Action of Unfractionated Heparin
Heparin = indirect thrombin inhibitor Stimulate anti-thrombin Anti-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 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.


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 2-2.5 Bolus: units/kg; maintenance: units/kg/h (aPTT 2-2.5) 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 residue LMWH do not have that residue and are weak thrombin inhibitors 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 thrombin LMWH anti-Xa/thrombin ratio >> 1 In 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 varies

17 Agent Trade Xa:IIa Mol Wt (d)
Low-Molecular-Weight Heparins Anti-Facotr Xa : Anti - Factor IIa Ratios Agent Trade Xa:IIa Mol Wt (d) Enosaparin Lovenox 3.8 : ,200 Dalteparin Fragmin 2.7 : ,000 Ardeparin Normiflo 1.9 : ,000 Nadroparin Fraxiparine 3.6 : ,500 Reviparin : ,000 Tinzaparin : ,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 pentasachharide
Binds antithrombin with high specific activity Inactivates Xa Long half life of 15 hours Superior 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 Platelet GP IIb/IIIa Receptor in Vascular Injury: Aggregation
Fibrinogen (or von Willebrand factor) GP IIb/IIIa Aggregation Platelet activation causes changes in the shape of platelets and conformational changes in GP IIb/IIIa receptors, transforming the receptors from a ligand-unreceptive to a ligand-receptive state. Ligand-receptive GP IIb/IIIa receptors bind fibrinogen molecules, which form bridges between adjacent platelets and facilitate platelet aggregation. Inhibitors of GP IIb/IIIa receptors also bind to GP IIb/IIIa receptors, blocking the binding of fibrinogen and thus preventing platelet aggregation. ` Coller. Heart Disease, Update Coller B. Unstable angina. In: Braunwald E, ed. Inhibitors of Platelet Aggregation: GP IIb/IIIa Antagonists. Heart Disease, Update 4. Philadelphia, Pa: WB Saunders; 1995.

32 Platelet Activation

33 clopidogrel bisulfate
Oral Antiplatelet Agents Mechanism of Action clopidogrel bisulfate ADP dipyridamole ticlopidine HCl ADP phosphodiesterase ADP Collagen Thrombin TXA2 Gp IIb/IIIa Activation (Fibrinogen Receptor) COX TXA2 aspirin ADP = adenosine diphosphate, TXA2 = thromboxane A2, COX = cyclooxygenase. Schafer AI. Am J Med. 1996;101:199–209.


35 Effects of aspirin  Ticlopidine Clopidogrel ADP ASPIRIN Collagen
Thrombin Epinephrine Thromboxane A2 Serotonin Platelet-activating factor ASPIRIN GP llb/llla Slide I.10 Multiple platelet agonists are involved in thrombus formation. Aspirin, a standard therapy for UAP and acute MI,24 interferes with the action of various agonists by inhibiting cyclooxygenase within platelets.20 By inhibiting platelet cyclooxygenase, aspirin prevents the actions of epinephrine, serotonin, and TXA2. Not all agonists are inhibited by aspirin, however.13,25 The thienopyridines ticlopidine and clopidogrel interfere with ADP receptors on the platelet surface to produce an antiplatelet effect,13,20,25,26 but, like aspirin, these agents interfere with only one of many intracellular pathways. Fibrinogen 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):50-55.

36 Ticlopidine (ticlid) and clopidogrel (plavix)
Ticlopidine Clopidogrel twice / day once / day Neutropenia No neutropenia CBC monitoring No need for CBC monitoring Skin reactions (rash) No skin reactions Delayed onset of effect Rapid onset of effect

37 Platelet-fibrinogen interaction
Platelet aggregation Blood vessel wall Platelet IIb/IIIa Fibrinogen Ib receptor Site of injury Platelet adhesion IIb/IIIa receptor blockers Ib Slide I.13 The combined effect of platelet adhesion and platelet recruitment by agonists such as thrombin exposes the integrin platelet glycoprotein IIb/IIIa receptor,13,15 which is present in as many as 50,000 copies on the surface of each platelet.32 Like other members of the integrin family, platelet glycoprotein IIb/IIIa receptors are specific for the amino-acid sequence arginine-glycine-aspartic acid, or RGD.32 Thus, adhesive proteins, such as fibrinogen, that contain an RGD sequence can bind to the glycoprotein IIb/IIIa receptor.23 Indeed, the primary function of this receptor is to provide a binding site for fibrinogen. Activated platelets form aggregates by cross-linking through fibrinogen's multiple glycoprotein IIb/IIIa receptor binding sites.23 Once platelets begin cross-linking with fibrinogen, they rapidly join together into doublets, triplets, and multiple groups. These aggregates enlarge at the site of vessel damage.33 Following atherosclerotic plaque rupture, large platelet aggregates can potentially lead to a critical occlusion of the diseased vessel.16 Elucidation of the pathophysiology of thrombus formation has shown that the binding of fibrinogen to the platelet glycoprotein IIb/IIIa receptor is the final, obligatory pathway to platelet aggregation.15 By preventing the binding or interaction of the receptor with fibrinogen, glycoprotein IIb/IIIa receptor antagonists help prevent platelet aggregation and subsequent thrombus formation.15

38 GP IIb/IIIa Inhibitors: Chemical Structures
Abciximab Tirofiban Eptifibatide Chimeric Monoclonal Antibody MW  50,000 D Nonpeptide Tyrosine Derivative MW  500 D Cyclic Heptapeptide MW  800 D O OH HN S N H NH H2N H N–SO2–C4H9 O COOH HN Regardless of the stimulus that leads to platelet aggregation, the GP IIb/IIIa receptor—1 of a group of adhesion receptors known as integrins—plays a key role in the process. Although the 3 GP IIb/IIIa inhibitors currently in clinical use differ in their chemical structures, all 3 target this receptor and have a similar mechanism of action: inhibition of ligand binding to the receptor. Abciximab, the first GP IIb/IIIa blocker to be tested and used clinically, is the Fab fragment of a chimeric murine- and human-derived monoclonal antibody altered to reduce immunogenicity. With a molecular weight of approximately 50,000 daltons, abciximab is about 2 orders of magnitude larger than the other 2 agents. Eptifibatide, a peptide specific for the GP IIb/IIIa receptor, is an analog of the sequence at the extreme carboxyterminus of the -chain of fibrinogen, which mediates the binding of fibrinogen to the receptor. Tirofiban, a tyrosine derivative, was based on the Arg-Gly-Asp (RGD) recognition peptide for the GP IIb/IIIa receptor. The design of the molecule provided for GP IIb/IIIa specificity, high affinity for the target receptor, and elimination of peptide bonds. Topol et al. Lancet. 1999;353: Topol EJ, Byzova TV, Plow EF. Platelet GP IIb-IIIa blockers. Lancet. 1999;353:

39 Comparative Properties of GP IIb/IIIa Inhibitors
Abciximab Tirofiban Eptifibatide Type of Chimeric monoclonal Nonpeptide Cyclic molecule antibody tyrosine derivative heptapeptide Affinity for circulating platelets High Moderate Unknown KD (nmol/L) Molecules of drug per receptor 1.5 >100  Drug clearance t1/2 = h t1/2 = 2 h t1/2 = 2.5 h GP IIb/IIIa Nonspecific Specific Specific receptor specificity (RGD) (KGD) Among the properties that define GP IIb/IIIa inhibitor efficacy and safety are receptor specificity, antagonist affinity, and reversibility. These differ for the 3 agents currently approved for clinical use: the chimeric monoclonal antibody abciximab, the cyclic heptapeptide eptifibatide, and the nonpeptide tyrosine derivative tirofiban. While all 3 agents share a biologic target, they are different in other respects, including the physical binding site on the receptor (which regulates specificity), dissociation kinetics (governing affinity), stoichiometry for inhibition, clearance mechanisms, and plasma and biologic half-lives. Tirofiban and eptifibatide are both small molecules that fit into the binding pocket of the GP IIb/IIIa receptor, assuring high specificity. In contrast, abciximab is too large to enter the ligand-binding pocket; instead, it covers the receptor and interferes with a secondary fibrinogen-binding site. It thus binds less selectively than either of the other inhibitors. Abciximab also interferes with the function of several other ligand-binding sites, including the MAC-1 and vitronectin receptors; it is unknown whether this property of abciximab confers clinical benefit. Tirofiban and eptifibatide are competitive antagonists with a concentration-dependent antiplatelet effect. Both agents are cleared as active drug with lesser concentrations of inactive metabolites. There is no contribution to platelet blockade from metabolites of either drug. With abciximab, there is a slow loss of receptor blockade over time after termination of an infusion, with a concomitant prolongation of bleeding time. With tirofiban and eptifibatide, physiologic platelet aggregation and normal hemostasis generally return within 4 hours after the end of an infusion. Scarborough et al. Circulation. 1999;10: ; Tcheng. Am J Cardiol. 1999;83:7E-11E. Scarborough RM, Kleiman NS, Phillips DR. Platelet glycoprotein IIb/IIIa antagonists: what are the relevant issues concerning their pharmacology and clinical use? Circulation. 1999;100: Tcheng JE. Differences among the parenteral platelet glycoprotein IIb/IIIa inhibitors and implications for treatment. Am J Cardiol. 1999;83:7E-11E.

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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