Properties of Heparins and warfarin

Heparin

  1. Chemistry—Heparin is a large sulfated polysaccharide polymer obtained from animal sources. Each batch contains molecules of varying size, with an average molecular weight of 15,000–20,000. Heparin is highly acidic and can be neutralized by basic molecules (eg, protamine).
Properties of Heparins and warfarin.
Property
Heparins
Warfarin
Structure
Large acidic polysaccharide polymers
Small lipid-soluble molecule
Route of administration
Parenteral
Oral
Site of action
Blood
Liver
Onset of action
Rapid (minutes)
Slow (days); limited by half-lives of preexisting normal
factors
Mechanism of action
Activates antithrombin III, which proteolyzes
coagulation factors including thrombin and factor Xa
Impairs post-translational modification of factors II, VII,
IX and X
Monitoring
aPTT for unfractionated heparin but not LMW heparins
Prothrombin time
Antidote
Protamine for unfractionated heparin; protamine
reversal of LMW heparins is incomplete
Vitamin K1, plasma, prothrombin complex concentrates
Use
Mostly acute, over days
Chronic, over weeks to months
Use in pregnancy
Yes
No

Heparin is given intravenously or subcutaneously to avoid the risk of hematoma associated with intramuscular injection. Low-molecular-weight (LMW) fractions of heparin (eg, enoxaparin) have molecular weights of 2000–6000. LMW heparins have greater bioavailability and longer durations of action than unfractionated heparin; thus, doses can be given less frequently (eg, once or twice a day). They are given subcutaneously. Fondaparinux is a small synthetic drug that contains the biologically active pentasaccharide present in unfractionated and LMW heparins. It is administered subcutaneously once daily.

 

Warfarin and Other Coumarin Anticoagulants

  1. Chemistry and pharmacokinetics

Warfarin and other coumarin anticoagulants are small, lipid-soluble molecules that are readily absorbed after oral administration. Warfarin is highly bound to plasma proteins (>99%), and its elimination depends on metabolism by cytochrome P450 enzymes.

  1. Mechanism and effects

Warfarin and other coumarins interfere with the normal post-translational modification of clotting factors in the liver, a process that depends on an adequate supply of reduced vitamin K. The drugs inhibit vitamin K epoxide reductase (VKOR), which normally converts vitamin K epoxide to reduced vitamin K. The vitamin K-dependent factors include thrombin and factors VII, IX, and X (Figure 34–1). Because the clotting factors have half-lives of 8–60 h in the plasma, an anticoagulant effect is observed only after sufficient time has passed for elimination of the normal preformed factors. The action of warfarin can be reversed with vitamin K, but recovery requires the synthesis of new normal clotting factors and is, therefore, slow (6–24 h).

More rapid reversal can be achieved by transfusion with fresh or frozen plasma that contains normal clotting factors. The effect of warfarin is monitored by the prothrombin time (PT) test.

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