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anticoagulants

anticoagulants

traditional oral anticoagulants

Mechanism of action:

  • orally active agents that block the reductive re-activation of vitamin K epoxide back to its active hydroquinone form which is needed for the gamma-carboxylation of several glutamate residues in the formation of the serine protease factors VII, IX, X & II which are involved in the clotting cascade, as well as the formation of Protein C & Protein S which are anti-thrombotic factors.
  • this results in partially inhibited synthesis of these vit-K dependant factors whose half-lives are 6, 24, 40 & 60hrs for factors VII, IX, X & II respectively, hence there is a 8-12hr delay in onset of anticoagulation effect & a 1-3day delay from peak drug level to peak INR.
  • prothrombin time (INR) is prolonged by reduction in functional levels of fibrinogen, factor V, or the vit-K dependant factors II, VII or X.
  • it is NOT affected by reductions in levels of factor IX, or proteins C or S.

Examples of oral anticoagulants

warfarin (coumadin)
Phenindione:
  • Once popular but no longer used as occasionally fatal HS reactions.
Diphenadione:
  • A very long acting agent prolongs INR for 20 days - used as a rodenticide
Anisindione:
  • Similar to warfarin, used in US but no clear advantages.
Dicoumarol:
  • The original oral anticoagulant isolated, seldom used as erratic absorption & GIT effects.
Phenprocoumon:
  • Used in Europe, it had longer half-life (5 days) than warfarin & longer duration of action (7-10D)

factor Xa inhibitors

LMW heparin

rivaroxaban

  • introduced in Australia in 2009 as Xarelto
  • an orally active Factor Xa inhibitor marketed as Xarelto as an option in the prevention and Rx of DVT & PE
  • onset of action ~3hrs after dose and lasts 8-12hrs but factor Xa activity does not return to normal within 24hrs allowing once daily dosing
  • usual dose in adults 10mg once daily orally
  • C/I in severe liver or renal disease as partly metabolised and partly excreted in urine unchanged
  • appears to prevent more DVTs than enoxaparin but major bleeding post THR was 0.3% in the rivaroxaban group vs 0.1% in the enoxaparin group
  • no anticoagulant effect monitoring required in short term use
  • no antidote for overdosage
  • current trials underway for use in Mx of AF - will these reveal hepatotoxicity in longer term use as was the case with ximelagatran (another oral anticoagulant) or will we at last be able to offer patients a useful substitute for warfarin?

apixaban

  • oral reversible factor Xa inhibitor although there is no antidote to Mx bleeding complications
  • introduced in Australia on PBS in 2011 as Eliquis 2.5mg film-coated tablets for prevention of post-op DVT, and in Sept 2013 for prevention of stroke in patients with non-valvular AF.

thrombin inhibitors (factor IIa)

Dabigatran

anti-platelet agents

Heparin and heparinoids

pharmacology

unfractionated heparin

  • Heparin was discovered in 1915 by Jay McLean, searching for a pure procoagulant in dog liver & heart, but finding anticoagulants instead. McLean's insight & perserverence in pursuing this strange lead resulted in the discovery of heparin which became the standard Rx for a variety of thrombotic disorders in the 1940's.

low molecular weight heparins (LMWH)

pharmacology
  • does not inhibit clot-bound thrombin, but safer than heparin.
  • inhibit factors Xa & IIa
  • given s/c
  • therapeutic monitoring not required
  • immediate onset
  • protamine only partially reverses bleeding effect
  • high cross reactivity with heparin
  • can cause thrombocytopenia
enoxaparin (Clexane)

Low molecular weight glycosaminoglycan:

  • as for LMW heparins BUT:
    • low cross-reactivity with heparin
    • minimal effect on platelets
    • bleeding effects not reversed by protamine
danaparoid

Anti-thrombin III - independent anti-thrombotics:

Hirudin:

  • A powerful & specific thrombin inhibitor derived from the leech & now prepared by recombinant DNA technology. Its action is independent of antithrombin III which means it can reach & inactivate fibrin-bound thrombin in thrombi.
  • It has little effect o platelets or bleeding time.
  • Like heparin it must be given parenterally & is monitored by APTT. Its half-life is 90mins.

Hirulog:

  • Is a 20 AA synthetic peptide inhibitor of thrombin designed using hirudin as a model.
  • It inhibits free & clot-bound thrombin & thus prevents clot formation & extension.
  • It may also facilitate clot lysis. It has a half life of 30min.
  • It has comparable potency to hirudin, but being a synthetic molecule has less risk of antigenicity. It may be a better inhibitor of clot-bound thrombin due to its size.

Bivalirudin:

  • direct inhibitor of thrombin related to hirudin that reversibly binds to thrombin stopping the conversion of fibrinogen to fibrin.
  • introduced in Australia in 2005 for use in cardiac angioplasties but still controversial cost:benefit over heparin.
  • effects begins within a few minutes of IV dose, increasing clotting time, APTT, prothrombin time & thrombin time.
  • half life 25min thus given as bolus followed by infusion
  • 20% is renally excreted so renal impairment prolongs half-life.
  • REPLACE-II trial showed it reduced major bleeding in coronary angioplasties from 4.1% when using heparin + glycoprotein inhibitor + aspirin, to 2.5% when using bivalirudin + glycoprotein inhibitor + aspirin
anticoagulants.txt · Last modified: 2014/05/29 15:48 (external edit)