Properties of Heparins and warfarin
Heparin
- 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
- 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.
- 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.