Table of Contents
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
- see warfarin
- Once popular but no longer used as occasionally fatal HS reactions.
- A very long acting agent prolongs INR for 20 days - used as a rodenticide
- Similar to warfarin, used in US but no clear advantages.
- The original oral anticoagulant isolated, seldom used as erratic absorption & GIT effects.
- Used in Europe, it had longer half-life (5 days) than warfarin & longer duration of action (7-10D)
factor Xa inhibitors
- introduced in Australia in 2009 as Xarelto
- see rivaroxaban
- 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?
- see 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)
- see dabigatran
Heparin and heparinoids
- 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.
- see heparin
low molecular weight heparins (LMWH)
Low molecular weight glycosaminoglycan:
Anti-thrombin III - independent anti-thrombotics:
- 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.
- 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.
- 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: 2022/11/03 05:06 by wh