- Coumarin derivatives
- include dicumarol, warfarin sodium, and phenprocoumon.
- warfarin has the best bioavailability and the least severe adverse effects.
- Actions and pharmacologic properties
- indirectly interfere with gamma-carboxylation of glutamate residues in clotting factors II (prothrombin), VII, IX, and X, which is coupled to the oxidation of vitamin K. by vitamin K epoxide reductase is directly inhibited by coumarin derivatives.
- Clotting factors are still synthesized, but at reduced levels, and are undercarboxylated and have greatly reduced biologic activity;
- clotting factors produced before coumarin therapy decline in concentration as a function of factor half-life
- This causes a latency period of 36–48 hours before effects are seen.
- It does not affect established thrombi.
- administered orally
- has 100% bioavailability
- Highly teratogenic and fetotoxic,
- Has a t1/2 of 2.5 days
- warfarin is extensively (99%) bound to plasma albumin
- can displace many other drugs from this site.
- much less well absorbed
- a t1/2 of approximately 2–10 days
- increases the potential for bleeding episodes.
- Therapeutic uses
- treatment and prophylaxis of venous thrombosis and of pulmonary embolism.
- Coumarin derivatives are also indicated to reduce thromboembolism in patients with mechanical heart valves.
- Coumarin derivatives are also used to treat patients with atrial fibrillation, whose risk for a stroke is greatly increased.
- Adverse effects
- Bleeding is a common adverse effect with oral anticoagulants
- prothrombin times should be frequently monitored.
- Warfarin causes hemorrhagic infarction in the breast, intestine, and fatty tissues
- it also readily crosses the placenta and can cause hemorrhage in the fetus
- Warfarin causes defects in normal fetal bone formation
- its teratogenic potential is high.
- Drug interactions
- Amiodarone and sulfinpyrazone inhibit metabolism of the more active warfarin stereoisomer and increase drug activity.
- Aspirin and salicylates increase warfarin action by
- inhibiting platelet function
- displacement of warfarin from plasma-binding sites.
- Antibiotics decrease microbial vitamin K production in the intestine.
- Barbiturates and rifampin decrease warfarin effectiveness by inducing microsomal enzymes.
- Oral contraceptives decrease warfarin effectiveness by increasing plasma clotting factors and decreasing antithrombin III.
Differences Between Heparin and Warfarin
Warfarin medical animation
Vitamin K and Warfarin Correlation