Anticoagulant Presentation Pharmacology

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					 ANTICOAGULANTS
  MEDPHARM 2010
       PART ONE
HEMOSTASIS & THROMBOSIS
Coagulation Cascade - Secondary Hemostasis

 Series of protease enzymes
 and their cofactors
                                    Extrinsic      Intrinsic


 Takes place on phospholipid
 surface (platelet or
 endothelium)
                                          Common


 Consists of extrinsic, intrinsic
 and common pathways

 Results in formation of
 stable fibrin clot
          The Coagulation and Fibrinolytic Pathways




Kohler H and Grant P. N Engl J Med 2000;342:1792-1801
Hemostasis requires a fine balance between
   procoagulant and regulatory factors


               Coagulation
                Proteins/     PC
                              PS
                                      Thrombosis
  Deficiency    Platelets/
               Vessel wall   ATIII…


                                        Deficiency/
                                        Abnormality

Bleeding
                         Thrombosis
• Definition
   – Formation of a mass of platelets, coagulation
     proteins and RBCs (thrombus) in a blood vessel


• Hemostatic thromboses
   – Self-limited and localized, prevent excessive blood
     loss, represent the body’s natural response to
     acute vascular injury.


• Pathologic thromboses
   – A pathologic process, during which the balance of
     procoagulant and anticoagulant components of the
     coagulation system is lost
   – Clot forms at site free of significant vascular injury
     or there is failure to localize the thrombus, and the
     vessel may be occluded
     Thrombosis - Pathogenesis

• 3 primary influences
  predispose to
  thrombus formation

  Virchow’s Triad (1856):
    1.Endothelial Injury
    2.Stasis
    3.Hypercoagulability
           Fate of the Thrombus
                                                                    Propagation
1) Dissolution (cleared
   by fibrinolysis)

2) Embolization

3) Propagation

4) Organization and
   recanalization         Dissolution   Embolization   Organization and recanalization
 Clinical significance of thrombosis

1. Obstruction of arteries and veins
  – Ischemia or necrosis of downstream tissue


2. Embolization
                Arterial Thrombosis
• Most common cause of death in Western
  industrialized countries
  – Myocardial infarction due to thrombotic occlusion of a
    coronary artery is the #1 cause of death


• Endothelial damage
  – Atherosclerosis
  –   Hypertension
  –   Hypercholesterolemia
  –   Radiation
  –   Endotoxins (in bacterial infection)
Atherosclerotic Plaque Disruption and Platelet Activation




      Mohler E. N Engl J Med 2007;357:293-296
Venous Thrombi
• Most occur in the superficial
  or deep veins of the leg
  (DVT)

• Superficial thrombi
   – Swelling and pain
   – Rarely embolize


• DVT
   – Pain, redness and swelling
   – Asymptomatic in 50%
  Pathophysiology of Pulmonary Embolism




Tapson V. N Engl J Med 2008;358:1037-1052
          Thromboembolism
• Detached fragment from a thrombus is
  carried to a distant site and lodges in the
  vascular system

• Pulmonary

• Systemic
    Pulmonary Thromboembolism
• Definition: a fragment of a thrombus dislodges and then travels
  through the venous circulation to the heart and then lands in the
  pulmonary arterial circulation

• Scope of the problem:
    – Primary cause of death in 100,000/year in US, and a contributing
      cause of death in another 100,000/year

    – Cause of death in 10-15% of hospitalized patients

• Clinical symptoms (most are clinically silent)
    –   Chest pain
    –   Cough
    –   Shortness of breath
    –   Rapid heart rate (tachycardia)
    –   Rapid respirations (tachypnea)
              Pulmonary Thromboembolism
                     OUTCOMES
1.       Most are clinically silent (60-80%)
     •     Small

2.       Sudden death, right heart failure or cardiovascular
         collapse (5%)
     •     Occurs with obstruction of >60% of pulmonary circulation

3.       Pulmonary hemorrhage
     •     From obstruction of medium-sized vessel
     •     Infarction occurs in patients with compromised bronchial
           circulation

4.       Pulmonary hypertension (2-3%)
     •     Multiple small thromboemboli
        Systemic Thromboembolism
      Emboli within the arterial circulation
• Most arise from thrombi in the    • Many others originate from
  cardiac chambers in the setting       thrombi on ulcerated
      of myocardial infarction         atherosclerotic plaques
                   Infarction
• Ischemic necrosis caused by occlusion of
  either the arterial supply or venous
  drainage

  – Ischemia
    • Isch = stop (Greek)
    • Hema = blood
               Infarction
• Scope of the problem
 –More than half of all deaths in the US
  are caused by cardiovascular
  disease
   • Myocardial infarction
   • Cerebral infarction
          Causes of Infarction

• Thrombosis    99% of • Twisting of vessels
• Embolism     infarction (torsion)


• Vasospasm
                       • Compression of blood
                         supply



                       • Rupture of a vessel
      Vulnerability to hypoxia
• The susceptibility of a tissue to hypoxia
  influences the likelihood of infarction

  – Neurons: 3-4 minutes

  – Myocardial cells: 20-30 minutes

  – Fibroblasts in myocardium: several hours
     Oxygen content of blood
• Patients with diminished oxygen content
  are more susceptible
  – Anemia or pulmonary disease

  – Even partial obstruction of a small vessel may
    lead to infarction, whereas under normal
    circumstances it would be without effect
           The Coagulation and Fibrinolytic Pathways




Kohler H and Grant P. N Engl J Med 2000;342:1792-1801
Simplified View of the Coagulation Cascade


        Extrinsic                         Intrinsic



        Common




          Prothrombin Time      Activated Partial
          Extrinsic pathway   Thromboplastin Time
           Monitor warfarin     Intrinsic pathway
                 INR             Monitor heparin
 ANTICOAGULANT & ANTITHROMBOTIC
             DRUGS
Target                       Drug
Activated clotting factors   Heparin
Clotting factors             Warfarin
Thrombin                     Bivalirudin
Platelets                    Aspirin
                             Clopidogrel
                             Abciximab
Blood clot                   r-tissue plasm-
                             inogen activator
HEPARIN FACTORY
                HEPARIN
• Source biological
• Unfractionated(UFH)
• Low molecular
  weight(LMWH)
• Target:activated
  factors
   As heparin enters the circulation, it binds to heparin-binding proteins (ie,
                  other plasma proteins), ECs, Ms, and ATIII




Hirsh, J. et al. Chest 2004;126:188S-203S
                  Molecular weight distributions of LMWHs and heparin




Hirsh, J. et al. Chest 2004;126:188S-203S
          DRUG TARGETS
• Unfractionated
  heparin(UFH)
       DRUG TARGETS



• LOW MOLECULAR
  WEIGHT
  HEPARIN(LMWH)
• Enoxaparin
HEPARINS
              HEPARIN
ABSORPTION       -   NIL

DISTRIBUTION     -   LIMITED

METABOLISM       -   HEPATIC- RE –
                     CELLS


ELIMINATION      -   UNKNOWN
Simplified View of the Coagulation Cascade


        Extrinsic                         Intrinsic



        Common




          Prothrombin Time      Activated Partial
          Extrinsic pathway   Thromboplastin Time
           Monitor warfarin     Intrinsic pathway
                 INR             Monitor heparin
 HEPARIN TEST of CONTROL
ACTIVATED PARTIALTHROMBOPLASTIN
TIME
                OR
         aPTT or PTT
A THERAPEUTIC VALUE, ~ 0.3 u/ml
            REVERSAL
UFH – Protamine
LMWH – Protamine not fully effective
SIDE EFFECTS OF HEPARIN

  Bleeding
  Thrombocytopenia-HIT with
  Arterial & venous thromboembolism
  Hypersensitivity
  Osteoporosis

  Monitor   aPTT & platelet count
Stead L and Judson K. N Engl J Med 2006;355:e7
          HEPARIN
ADVERSE REACTION
   HEMORRHAGE

TREATMENT
   REDUCE THE DOSE
   DISCONTINUE THE DRUG
   PROTAMINE SULFATE
   TRANSFUSION
     HEPARIN-INDUCED
  THROMBOCYTOPENIA-HIT
• A prothrombotic, panvascular disorder
• Venous thromboembolic events/ arterial
  thromboembolic events – 4:1
• The antigen is heparin+platelet factor 4
• The antibody is HIT-IgG
• There is platelet activation and thrombin
  generation
                       Immune-Mediated Thrombocytopenia




Warkentin T. N Engl J Med 2007;356:891-893
A schematic representation of steps that occur during platelet activation in a
                              patient with HIT




                         Kelton, J. G. Chest 2005;127:9S-20S
        HIT (UFH & LMWH)
• Venous thromboembolism
• Arterial thrombosis
• Adrenal vein thrombosis – adrenal
  necrosis
• Skin necrosis
• Anaphylactic reactions
• Disseminated intravascular necrosis
• Warfarin – increases risk of
  microthrombosis
           HIT Rx
    Direct thrombin inhibitor
    Argatroban or Lepirudin
    WARFARIN NOT USED
Warfarin causes venous gangrene
         FONDAPARINUX
Active pentasaccharide moiety of herapin
   Parenteral use
        PE/DVT Treatment and prophylaxis
   Inhibitor of activated factor x (Xa)
   Thrombin unaffected
   Monitoring not required
FONDAPARINUX
DIRECT THROMBIN RECPETOR
     (IIa) ANTAGONISTS
      HEPARIN ALTERNATIVES
  Hirudin     Bivalirudin
  Argatroban
              Thrombin Generation




Di Nisio, M. et al. N Engl J Med 2005;353:1028-1040
Mechanism of Action of Direct Thrombin Inhibitors as Compared with Heparin




                Di Nisio, M. et al. N Engl J Med 2005;353:1028-1040
 CLINICAL PHARMACOLOGY
DRUG           VTE/PE TREATMENT          VTE PROPHYLAXIS
UFH               X monitor with APTT,          X (low dose)
               H/H and platelet count
LMWH               X monitor H/H &              X
               platelet count
FONDAPARINUX      X monitor H/H                 X
ORAL ANTICOAGULANT
WARFARIN A vitamin k antagonist
ROLE of VITAMIN K
WARFARIN – DRUG INTERACTIONS

Diminished warfarin actions
   Ethanol

Enhanced warfarin actions
  Ethanol        Aspirin
  Cimetidine
Simplified View of the Coagulation Cascade


        Extrinsic                         Intrinsic



        Common




          Prothrombin Time      Activated Partial
          Extrinsic pathway   Thromboplastin Time
           Monitor warfarin     Intrinsic pathway
                 INR             Monitor heparin
      PROTHROMBIN TIME
• Reported in real time seconds(pt/control)

With the ratio standardized to the reagents
 used:
 The value reported is the INR or
 International Normalized Ratio
PROTHROMBIN TIME
   WARFARIN MANAGEMENT
INR excessive,not bleeding - adjust dose
BLEEDING
     stop warfarin
     transfuse
     give prothrombin complex(clotting
     factors)
     give vitamin K1


INR subtherapeutic
    increase warfarin dose slowly
  ANTICOAGULANT THERAPY
Heparin(UFH)
 TREATMENT: Full dose,iv
  Deep venous thrombosis (DVT)
  Pulmonary embolism (PE)
  After acute myocardial infarction
 PROPHYLAXIS: Low dose, subcutaneous
   Prevention of DVT & PE
LMWH
   Prevention & treatment DVT/PE
 ANTICOAGULANT THERAPY
Warfarin
 Prevention of thromboembolism
     DVT/PE
     Atrial fibrillation
     w/ Valvular heart disease
     w/ Acute myocardial infarction
     w/ Prosthetic heart valves
     w/ Recurrent systemic embolization
 NOT for stroke or peripheral vascular disease
PLATELET ORIGIN
Atherosclerotic Plaque Disruption and Platelet Activation




      Mohler E. N Engl J Med 2007;357:293-296
             Arterial thrombogenesis


 Anti-
 Platelet
 Drugs




Weitz, J. I. et al. Chest 2004;126:265S-286S
ANTIPLATELET DRUGS

Aspirin       Abciximab
Clopidogrel   Prasurgrel
 Sites of Action of Antiplatelet Therapy on Mechanisms of Platelet
                     Activation and Aggregation




                                    Schulman, S. P. JAMA 2004;292:1875-1882.



Copyright restrictions may apply.
PROSTAGLANDIN SYNTHESIS
Production of prostaglandins from arachidonic acid and their main physiologic
                                   actions




                   Sanderson, S. et. al. Ann Intern Med 2005;142:370-380
The absolute risk of vascular complications is the
  major determinant of the absolute benefit of
            antiplatelet prophylaxis




Patrono, C. et al. Chest 2004;126:234S-264S
       CLOPIDOGREL (Plavix)
Inhibits ADP mediated platelet aggregation
A prodrug that requires 2 step bioactivation
  by cytochrome P-450
Biovalibility ~ 15%
ADRs
 Bleeding
 TTP (thrombotic thrombocytopenic purpura)
                    TTP
•   Thrombocytopenia
•   Microangiopathic hemolytic anemia
•   Fever
•   Neurologic changes
•   Renal abnormalities
•   Case rate 3.7/year/million
•   Mortality 10-20%
             TTP CAUSE
Autoantibody vs a metalloproteinase that
 degrades vonWillebrand factor

The impaired proteolysis leads to binding of
 large multimers of vWF to platelets with
 microthrombi production
ADP block prevents expression of
 glycoprotein IIb/IIIa which binds large
 multimers of vWF
Simplified Model of von Willebrand Factor Functions in Platelet-Plug Formation




                     Mannucci P. N Engl J Med 2004;351:683-694
CLOPIDOGREL
   ANTIPLATELET THERAPY
• Aspirin: Primary prevention of MI in high
  risk persons
  Secondary prevention of MI,TIA & stroke
• Clopidogrel: for persons who can’t take
  aspirin
• Aspirin+clopidogrel: Acute coronary
  syndromes
Sites of Action of Antiplatelet Therapy on Mechanisms of Platelet Activation and Aggregation




                                     Schulman, S. P. JAMA 2004;292:1875-1882.



 Copyright restrictions may apply.
    GLYCOPROTEIN IIb/IIIa
   RECEPTOR ANTAGONISTS

    ABCIXIMAB         Others
    Integrelin

USE: Acute coronary syndromes
The balance between the formation and degradation of FN




Nesheim, M. Chest 2003;124:33S-39S
A 65-year-old woman with chronic atrial fibrillation was admitted for an elective exchange of an
                implanted defibrillator for idiopathic dilated cardiomyopathy




           Ryan R and Brophy D. N Engl J Med 2007;357:2495
A classification of stroke by mechanism with estimates of
   the frequency of various categories of abnormalities




Albers, G. W. et al. Chest 2004;126:483S-512S
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