Antithrombotic drugs heparins

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Antithrombotic drugs Heparins These
slides were kindly provided by AstraZeneca
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Antithrombotic drugs
Fibrinolytics
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Antithrombotic drugs
Fibrinolytics
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Antithrombotic drugs
Fibrinolytics
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Antithrombotic drugs
Fibrinolytics
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Anticoagulant drugs
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Anticoagulants historical development
Dabigatran Rivaroxaban Apixaban AZD0837
Oral
Spoiled sweet clover
Warfarin clinical use
High / low dose Warfarin / INR
Ximelagatran clinical trials
Dicoumarol discovered
Warfarin / Vitamin K mechanism
Warfarin clinical trials
1916
1924
1936
1940
1950s
2006
1970s
1976
1980s
1990s
2001
Heparin clinical use
LMWH discovered
Pentasaccharide clinical trials
LMWH clinical trials
Heparin discovered
Continous heparin infusion/ aPTT
Injection
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Heparins - history
1912 Doyon Homogenate from dog
liver 1916 McLean Extract from the liver which
strongly inhibits coagulation 1918 Howell named
the agent - Heparin 1933 Purification of heparin
from various organs by Charles and
Scott 1937 Chemical characterisation of heparin
by Jorpes and Best 1970 Depolymerisation LMWH
(optimal molecular weight not defined) 1980 Clini
cal trials with LMWH 1981 Choay Synthesis of the
pentasaccharide sequence 2001 Pentasaccharide
clinical trials
William H. Howell
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Heparin is a polymer composed of heterogenous
polysaccharide units
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Unfractionated heparin
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Low molecular weight heparin
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Fondaparinux
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Heparins mechanism of action
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Heparins mechanism of action
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Heparins mechanism of action
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Heparins mechanism of action
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Heparins mechanism of action
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Heparins mechanism of action
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Heparins mechanism of action
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Heparins mechanism of action
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Heparins mechanism of action
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Heparins mechanism of action
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Heparins mechanism of action
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Heparins mechanism of action
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Heparin and the coagulation cascade
Tenase complex
FIXaFVIIIa
Pentasaccharide
Antithrombin
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Low molecular weight heparin and the coagulation
cascade
Tenase complex
FIXaFVIIIa
Pentasaccharide
Antithrombin
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Fondaparinux and the coagulation cascade
Tenase complex
FIXaFVIIIa
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Unfractionated heparin pharmacokinetics

• Administered by continous intravenous infusion or
  subcutaneous injection
• The clearance involves a rapid, saturable
  mechanism and a slower, unsaturable mechanism.
• A renal pathway is primarily responsible for the
  slow, unsaturable component
• Once in the blood stream, UFH binds to plasma
  proteins, endothelial cells and macrophages
  (accounts for the rapid, saturable phase of
  heparin clearance)
• The complex kinetics explains the non-linear
  relationship between dose and plasma half-life
  and the variable anticoagulant effect
• The apparent biological half-life of heparin
  increases with increasing doses

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Unfractionated heparin major use

• Treatment of thromboembolic diseases, mainly as
  induction of vitamin K antagonists
• Prevention of postoperative VTE
• Prevention of thrombosis after MI
• Prevention of coagulation during extracorporal
  circulation e.g. during renal dialysis or cardiac
  surgery
• Treatment of disseminated intravascular
  coagulation (DIC)

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Unfractionated heparin major drawbacks

• Inconvenience of administration by injection and
  the need for regular monitoring, which delays
  hospital discharge and therefore increases the
  demand on hospital resources

• Risk of heparin-induced thrombocytopenia (HIT)
• A relatively high risk of bleeding compared to
  more recently developed alternatives
• Sometimes associated with osteoporosis in chronic
  use
• The drawbacks above are reduced with LMWH and UFH
  has now largely been replaced by LMWH for
  prevention and treatment of thrombosis

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Low molecular weight heparin pharmacokinetics

• Typically administered by subcutaneous injection
• More predictable dose-response relationship, a
  2-4 times longer plasma half-life, and improved
  bioavailability after subcutaneous administration
  compared to UFH, due to reduced binding to plasma
  proteins, macrophages and endothelial cells
• Clearance is mostly via a renal pathway, thus the
  half-life can be prolonged in patients with renal
  failure
• Regular coagulation monitoring is not required.
  However, in certain situations (if needed)
  anti-factor Xa activity is measured, as LMWH has
  less effect on the activated partial
  thromboplastin time (aPTT)

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Low molecular weight heparin major use

• Treatment of VTE
• Prevention of postoperative VTE and prolonged
  prophylaxis of VTE after elective hip surgery
• Prevention of VTE in patients with acute medical
  diseases
• Acute coronary syndrome (ACS)
• Prevention of coagulation during extracorporal
  circulation during renal dialysis

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Low molecular weight heparin advantages over
unfractionated heparin

• Effective subcutaneous administration
• No need for regular coagulation monitoring due to
  more predictable dose-response relationship
• Improved bioavailability
• Longer plasma half life allows for once-daily
  dosing
• Reduced risk of toxic effects, such as
  heparin-induced thrombocytopenia (HIT) and
  osteoporosis

LMWH has largely replaced UFH as a front-line
therapy
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Low molecular weight heparin major drawbacks

• Can only be administered by injection
• Risk of thrombocytopenia, while lower than with
  UFH, is still a concern due to the severity of
  this condition

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Fondaparinux pharmacokinetics

• After subcutaneous injection, peak plasma
  concentrations are achieved after approximately
  two hours
• Long plasma half-life, which allows a once-daily
  regimen
• Exclusively eliminated by the kidneys
• Regular coagulation monitoring is not required.
  However, in certain situations if needed,
  anti-factor Xa activity is measured, as
  fondaparinux has less effect on the activated
  partial thromobplastin time (aPTT)

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Fondaparinux major use

• Prevention of venous thromboembolism (VTE) after
  major orthopaedic surgery such as hip and knee
  replacement or hip fracture repair

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Fondaparinux major drawbacks

• Fondaparinux, like all heparins also carries the
  disadvantage of only being available in an
  injectable formulation
• Lack of sufficient information in clinical
  practice on efficacy and safety
• Fondaparinux has a long plasma half-life and
  this, taken together with the increased risk of
  bleeding seen in some studies, raises concerns

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Some important features of heparins
UFH LMWH Penta- saccharide
Mass 5000-30000 1500-6000 1400 Half-life 1-5
h 3-7 h 15 h Monitoring test aPTT Anti-FXa Anti-F
Xa Dosing Fixed Fixed Fixedalternatives Adjust
ed by Weight- Adjusted in severe monitoring
adjusted renal impairment