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Anticoagulant Thaerapy

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					            Anticoagulant Therapy
    Deep venous
     thrombosis            Ischemic Heart
                               Disease
Pulmonary
embolism


                        Open artery if totally
                            occluded
    Prevent Thrombosis    Thrombolysis          Vasodilation
     Anticoagulants   Coronary angioplasty      Nitrates
       Antiplatelets                              CCB
    Coagulation Cascade
 Antiagoagulant therapy is
    aimed at:
   preventing clot in patients at
    risk
   Prevent clot extension/
    embolisation
   Deep venous thrombosis (DVT)
    & pulmonary embolism (PE)
   Prothrombinase complex
    comprises the mixture of FVa/FXa
    in addition to calcium &
    phospholipid
   The presence of phospholipid
    accelerates thrombin formation by
    780-fold
     THROMBIN INHIBITORS
 Thrombin inhibitors can either inactivate
  thrombin directly or block thrombin formation
 Thrombin can be inhibited irreversibly by
  glycosaminoglycans like heparin through an
  antithrombin III-dependent mechanism
 The enzyme can be inhibited reversibly by
  hirudin and hirudin derivatives in an antithrombin
  III-independent manner
 In addition to inhibiting thrombin, the
  glycosaminoglycans also block thrombin
  generation
    Antithrombin-III Dependent
       Thrombin Inhibitors
   Standard Unfractionated Heparin (UFH)
 Heparin is a mixture of glycosaminoglycan
  molecules, which are heterogenous in
  molecular size
 Antithrombin III (ATIII) binding is a necessary
  requirement for its anticoagulant activity
 The mean molecular weight of heparin is
  15,000 D
          Mode of Action of Heparin
                        Antithrombin III (ATIII) is a slow
                           progressive inhibitor of thrombin
                           and other clotting enzymes.
                          Heparin binds to ATIII through a
Heparin
                           unique pentasaccharide (light
                           blue areas) → conformational
                           change in the reactive center of
                           ATIII → accelerating the rate of
                           ATIII-mediated inactivation of the
                           clotting enzymes
                          Heparin also promotes the
                           formation of the thrombin-ATIII
                           complex by serving as a template
                           that binds both thrombin and
                           ATIII
                          ATIII forms a 1:1 irreversible
                           complex with the coagulation
                           enzymes
                          Once this occurs, the heparin
                           dissociates and can be reused
             Heparin inactivates thrombin by binding
                     both ATIII and thrombin

To inactivate thrombin, heparin serves as a template and
  binds both anti-thrombin III (ATIII) and thrombin
 Binding to ATIII is mediated by the unique penta-
  saccharide sequence on heparin
 Binding to thrombin occurs through the heparin-binding
  domain on the enzyme
 Conversely, to inactivate factor Xa, heparin needs only to
  bind to ATIII through its pentasaccharide sequence

Anti-IIa = Anti-Xa activity
     Targets for Heparin-ATIII Complex
 Heparin/ATIII inactivates
  several coagulation enzymes
  including thrombin (factor
  IIa) and factors Xa, IXa, &
  XIa
 The enzyme most sensitive to
  inhibition is factor IIa
 The next most sensitive
  enzyme is factor Xa
 By inhibiting these two
  enzymes heparin inhibits both
  thrombin activity & thrombin
  formation
  Limitations to the Use of Heparin

  LIMITATION                 CAUSE                   CONSEQUENCE

                  - Binding to plasma proteins - Poor bioavailability at low
                                               doses, Marked variability in
Pharmacokinetic   - Binding to endothelium and
                                               dose    response,      Dose-
                  macrophages
                                               dependent clearance

                  - Heparin is unable to         -    Limited efficacy    in
                  inactivate thrombin bound to   preventing         arterial
  Biophysical
                  fibrin or fibrin degradation   thrombosis & reocclusion
                  products and factor Xa bound   after           successful
                  within the prothrombinase      thrombolysis
                  complex

Antihemostatic    - Heparin binds to platelets   Heparin-induced bleeding
                  and inhibits their function
  Low Molecular Weight Heparins
           (LMWHs)
 Low molecular weight heparins (mean molecular
  weight 5000 D), prepared by controlled chemical
  or enzymatic depolymerization of standard
  unfractionated heparin are about one third the
  size of starting material
 Whereas about one third of the molecules of
  unfractionated heparin have the unique
  antithrombin III (ATIII)-binding pentasaccharide,
  only about 20% of low molecular weight heparin
  chains contain the pentasaccharide
 Enoxaparin, dalteparin & tinzaparin are available
  LMWHs products
    Mechanism of Action of Low Molecular
          Weight Heparin (LMWH)
 All LMWH molecules, which contain the unique
   pentasaccharide, can catalyze the inactivation of factor Xa by
   antithrombin III (ATIII)
 In contrast, only 25% to 50% of LMWH molecules that have
   the pentasaccharide sequence also contain at least 13
   additional saccharide units to bind to both ATIII & FIIa
 As a result, the antithrombin (anti-factor IIa)
 activity of LMWH is less than its anti-factor Xa activity
 Standard heparin has equivalent
anti-factor IIa and anti-factor Xa activity
because all of the heparin chains that
contain the pentasaccharide are long
enough to interact with both ATIII & thrombin
          Pharmacokinetic Profile of
                  LMWH
 LMWH has a more favorable pharmacokinetic profile than
    standard heparin because LMWH exhibits less binding to
    plasma proteins & cell surfaces
   The reduced binding to plasma proteins results in
   Better bioavailability (90% vs. 20% for heparin)
   more predictable anticoagulant response
   Laboratory monitoring of LMWH activity is not required
   Heparin resistance is rare for LMWH
   The reduced binding of LMWH to cell surfaces explains
    why it has a longer half-life than heparin (4 hr vs. 2 hr for
    heparin),
   Given at fixed doses once to twice daily by S.C. route
         Biophysical Limitations of
            Heparin and LMWH
 Both heparin and low molecular weight heparin
   preparations have biophysical limitations because they
   are unable to inactivate thrombin bound to fibrin, or to
   subendothelial matrix and to inhibit factor Xa within the
   prothrombinase complex
 Thrombin binds to fibrin where it remains catalytically
   active
 Thrombin bound to fibrin is protected
from inactivation by heparin/antithrombin III
     Other Injectable Antithrombotic Agents

 Fondaparinux, a pentasaccharide, is an AT-III-dependent
    selective factor Xa inhibitor
   It is indicated for the prevention of venous thrombosis
    associated with orthopedic surgery
   Administered >6 hours postoperatively and dose adjusted
    for renal impairment
          Tests for Monitoring Antithrombotic Therapy
   Prothrombin time (PT)/International Normalization Ratio
    (INR), usual target is 2-3 times normal
   Activated partial thromboplastin time (aPTT)- (serum UFH)
   Anti-Xa activity for LMWHs-treatment in cases of
    unexpected bleeding & pregnant women
               Therapeutic Uses
o Heparin should be given either by IV or S.C. injection with
    onset of action of few minutes and 1-2 hr respectively
o   LMWHs is given by S.C. route
o   I.M. injection produces hematoma formation
   Treatment of deep-vein thrombosis & pulmonary embolism
   Prevention of postoperative venous thrombosis in patients
    in acute MI phase or one undergoing elective surgery
   Reduction of coronary artery thrombosis after thrombolytic
    treatment
   Anticoagulant of choice in pregnant women
                  Adverse Effects
 Bleeding: Bleeding time monitoring is essential. Treatment
    involves injection of antidote protamine sulphate (1mg Iv for
    each 100 units of UFH) (reversal of effect)
   Thrombosis: AT-III inactivation may lead to potent
    activation of many clotting factors & hence increasing
    thrombosis risk
   Thrombocytopenia: UFH-induced thrombocytopenia (HIT)
    is a life-threatening immune reaction that occurs in up to 3%
    of patients on heparin therapy for 5-14 days
   It induces platelet activation & endothelial damage with
    enhanced thrombi formation & paradoxical thrombosis
   A non-immunologic reversible HIT may occur in early phase
    of therapy due to direct effect of UFH on platelets
   LMWHs, though of lower risk, are contraindicated with HIT
                  Adverse Effects
 Osteoporosis occurs with large doses of UFH >20,000
    U/day for 6 months or longer
   Hyperkalemia rarely occurs with UFH
   It is attributed to inhibition of aldostetone secretion
   It occurs with both low- & high-dose UFH therapy
   Onset is quick within a week after therapy initiation
   It is reversible by therapy discontinuation
   Diabetic & renal failure patients are at higher risk
   Hypersensitivity: (Antigenicity due to animal source)
   rarely occurring reactions include urticaria, rash, rhinitis,
    angioedema & reversible alopecia
              Contraindications
 Hypersensitivity to heparin
 Active bleeding or hemophilia
 Significant throbocytopenia, purpura
 Severe hypertension
 Intracranial hemrrhage
 Ulcerative GIT lesions
 Active TB
 Recent surgery in CNS, eye
 Advanced hepatic or renal disease
        Direct Thrombin Inhibitors
         Hirudin Hirugen & Hirlug
                             A, Hirudin
 A leech-derived protein, a potent & specific inhibitor of thrombin
 It binds to both the substrate recognition site and the catalytic
  center. The hirudin-thrombin complex slowly dissociates
                            B, Hirugen
 A synthetic peptide analogue of the carboxy terminal of hirudin
 It binds to the substrate recognition site of thrombin
 Direct Thrombin Inhibitors (DTI)
 C, Hirulog is a synthetic bivalent inhibitor of
  thrombin comprised of a catalytic site inhibitor
  linked to hirugen. Thus, hirulog interacts with
  both the substrate recognition site and the
  catalytic center of thrombin.
 D, Catalytic site inhibitors interact with the
  active center of thrombin
  Inhibition of Bound Thrombin
 Neither heparin/ATIII nor LMWH/ATIII are an
  effective inhibitor of fibrin-bound thrombin
  because the heparin-binding site on thrombin is
  masked when the enzyme is bound to fibrin
 In contrast, the ATIII-independent thrombin
  inhibitors are able to inactivate fibrin-bound
  thrombin as well as free thrombin
   In vivo studies with direct thrombin
                 inhibitors
 In experimental animals, hirudin, hirulog, and
  inhibitors of the catalytic site of thrombin are more
  effective than heparin in preventing extension of
  venous thrombosis, preventing platelet-
  dependent arterial thrombosis, and accelerating
  thrombolysis
 Preliminary studies in humans also suggest that
  the direct thrombin inhibitors are more effective
  than heparin in venous thrombosis, in unstable
  angina, and in the setting of thrombolytic therapy
           Clinically Approved Direct
              Thrombin Inhibitors
 Lepirudin, recombinant hirudin-like peptide, has
  been approved for IV anticoagulant use in HIT
  patients, has renal clearance
 It has potential use in unstable angina patients
  (Circulation 2001; 103: 1479)
 Bivaluridin, a bivalent DTI, used by IV route for
  patients undergoing percutaneous coronary
  intervention
 Argatroban, a small monovalent (thrombin active
  site only) molecule, with DTI activity, used similarly
  in HIT patients, has hepatic clearance
 aPTT is used to monitor activity for these agents
           DIRECT FACTOR Xa
              INHIBITORS
 There are two direct factor Xa inhibitors, the tick
  anticoagulant peptide (TAP), originally isolated
  from the soft tick Ornithodoros moubata and
  antistasin, derived from the Mexican leech
 Both inhibitors are now available by recombinant
  technology
 Studies in animals indicate that both TAP and
  antistasin are effective antithrombotic agents in
  experimental models of arterial thrombosis
          DIRECT FACTOR Xa
             INHIBITORS
 Differ from heparin and low molecular weight
  heparins in two ways: 1) they inactivate factor Xa
  independent of antithrombin III (ATIII); and 2) in
  addition to inactivating free factor Xa, there is
  evidence that these agents also are able to inactivate
  factor Xa within the prothrombinase complex
             Oral Anticoagulants
   Vitamin K Antagonists (The Coumarins)
 Vitamin K is crucial co-factor for the hepatic
  synthesis of clotting factors II, VII, IX & X
 Vitamin K catalyses the ɣ-carboxylation of
  glutamic acid residues in the mentioned factors
  via a vitamin K-dependent carboxylase
 The ɣ-carboxyglutamyl residues bind Ca2+ to
  enable interaction with phosphlipids
            Vitamin K Antagonists
                  Warfarin
 The reduced vit K is converted
  into vitamin K epoxide which is
  reduced back by vitamin K
  reductase the target enzyme
  which warfarin inhibits
 This results in the production
  of inactive clotting factors
  lacking ɣ-carboxyglutamyl
  residues
            Vitamin K Antagonists
                  Warfarin
 Onset: Effect of a single dose starts only after 12-
  16 hrs (unlike heparin) & lasts for 4-5 days although
  its quick GIT absorption
 Clinical anticoagulant activity needs several days to
  develop (four half-lives of clotting factors needed to
  elapse before steady state)
o This may be related to the elimination half-lives of
  the concerned clotting factors (6-72 hrs) (Factor II:
  40-72 hrs, X<48hrs)
 Overlap heparin & warfarin therapy to overcome
  delayed warfarin activity & warfarin-inhibition of the
  anticoagulant protein C & S
          Vitamin K Antagonists
                Warfarin
 Warfarin has 100% oral bioavailability,
  powerful plasma protein binding & long plasma
  t1/2 of 36 hrs
 A loading high dose followed by maintenance
  dose is adjusted
 Warfarin is contraindicated with pregnancy as it
  crosses the placental barrier and is teratogenic
  in the first trimester & and induce intracranial
  hemorrhage in the baby during delivery
 Warfarin is metabolized by hepatic Cytochrome
  P450 enzymes with half-life of 40 hrs
        Warfarin Drug Pharmacokinetic &
         Pharmacodynamic Interactions
      Potentiating warfarin               Inhibiting Warfarin
   Inhibitors of hepatic P450        Vitamin K in some
    enzymes (cimetidine, co-           parenteral feed
    trimoxazole, imipramine)          Inducers of hepatic P450
   Platelet aggregation               enzymes (rifampicin,
    inhibitors (NSAIDs, aspirin)       barbiturates, … etc)
   3rd G cephalosporins              Reduction of GIT
   Drugs displacing warfarin          absorption (colestyramine)
    from binding sites (NSAIDs)       Diuretics
   Drugs reducing the                Hypothyroidism
    availability of vitamin K
   Hepatic disease &
    hyperthyroidism
           Warfarin Side-Effects

 Drug-drug interactions
 Bleeding disorder; monitor anticoagulant effect
  by measuring PT or INR, reversal of action:
• Minor bleeding: stop therapy + oral Vitamin K
• Severe Bleeding: stop therapy + I.V. Vitamin K
• Fresh-frozen plasma, recombinant factor VIIa or
  prothrombin complex may be used
 Comparison of UFH & LNWH
          Character                   UFH          LMWH
         Average Mol wt             15,000         5,000
     Anti-Xa/anti-IIa activity        1/1          2-4/1
   aPTT monitoring required          Yes            No
Inactivation of platelet-bound Xa     No            Yes
         Protein binding          Powerful )4+)   Weak (+)
    Endothelial cell binding      Powerful )4+)     No
  Dose-dependent clearence           Yes            No

      Elimination half-life       30-150 min      2-5 times
                                                   longer

				
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