MOA in Hemostasis (Finished)

• Vasodilation causes inflammation (which allows the body to fight infection)
• Vasoconstriction activates the coagulation process
• A clot must be degraded before wound healing can occur
• Vitamin K dependent clotting factors:

  • Factor II
  • Factor VII
  • Factor IX
  • Factor X
• If you were to develop a new medication to prevent blood clotting, you would consider that the drug should:

  • Deplete vitamin K
  • Interfere with vitamin K
• Heparin: a complex mixture of sulfated mucopolysaccharides that is the most commonly given anticoagulant for short-term use
• Sources of heparin:

  • Bovine lung
  • Porcine intestinal mucosa
• You cannot inject heparin IM - IV or deep subcutaneous only
• Heparin half-life: 1-5 hrs
• Heparin monitors actived partial thrombopoastin time (aPTT/PTT) in patient receiving unfactionated heparin (UFH)
• Adverse effect of heparin: hemorrhage
• Antidote to heparin: potamine sulfate

  • Is easy to manufacture
  • Useful to soak up drugs
• UFH stands for unfractionate heparin (aka HWM)
• UFH/HMW actions:

  • Enhances action of antithrombin III (AT-III),a plasma protease inhibitor, by 1000 fold
  • Heparin binds to AT-III to active it by changing AT-III's conformation
• AT-III inhibits clotting factor proteases like thrombin IIa, IXa, Xa, XIa, and XIIa

  • Inhibition by forming equimolar stable complexes
• Low molecular weight heparin (LMWH) is a derivative that is more specific and predominantly inhibits factor Xa

  • Is more precise than HMWH
• Heparin doesn't affect thrombin

  • Thrombin is already bound to fibrin (factor X bound to platelets)
• Heparin can be used for:

  • Clotting
  • Allergic reactions
  • Thrombocytopenia
• Pentasaccharide sequence of LMWH binds to antithrombin
• Unfractioned heparin binds to thrombin, which is bound to factor Xa
• UFH can hit many kinds of targets

  • The pentasaccharide sequence is derived from LMW and can only bind to Xa
• Examples of direct thrombin Inhibitors (DTIs)

  1. Hiradin
  2. Lepirudin
  3. Bivalirudin
• Direct thrombin Inhibitors (DTIs) will inhibit fibrin from binding to thrombin -> inhibits thrombin activity
• Direct thrombin inhibitors (DTIs) is an approved treatment for heparin induced thrombocytopaenia (HIT)
• Advantages of DTIs over Heparin:

  1. Anticoagulant action is AT III-independent
  2. Increased safety
  3. Hemorrhage
  4. Little effect on platelets (except Bivalirudin)
• Warfarin sodium, phytonadione (vitamin K1), dicumarol, phenndione are all oral anticoagulant drugs that are structurally similar
• Warfarin is an example of a coumarin that is structurally related to vitamin K
• Half-life of warfarin is 36 hours and its delay onset is 8-12 hours

  • Because of its large half-life, warfarin is great for dosing
• Warfarin overdose treatments:

  • IV vitamin K
  • 4-factor prothrombin complex concentrate
  • Fresh frozen plasma
• Warfarin will deplete vitamin K stores
• Vitamin K can cross the placenta, so it is recommended that Warfarin not be taken during pregnancy
• Heparins are large polymers that are given IV. Its sight of action is in the blood
• The antidote of heparin is protamine sulfate that can work for UFH but not for LMWH
• Heparin's sight of action is in the blood. Warfarin's sight of action is in the liver
• Drugs that also hit factor Xa: rivaroxaban

  • Xarelto
  • Eliquis
• Drug that also hits thrombin: dabigatran etexilate

  • Pradaxa
• Intrinsic and extrinisic activation in the clotting cascade all converges to the common pathway - this is why drugs usually hit factor Xa and thrombin
• Anti-platelet drugs can affect:

  • PAR-1
  • GPIIbIIIa
  • GPVI
  • von Willebrand Factor
  • P2Y12
  • Thromboxane
• Antiplatelet drugs that are PAR-1 antagonists:

  • Atopaxar
  • Vorapaxar
• Antiplatelet drugs that inhibit GPVI and vWF activation:

  • Revacept (PR-15)
  • Anfebatide
  • Caplacizumab
  • ARC-1779