Oral anticoagulants

[SH4:p511-514]

 

Oral anticoagulants are derivatives of 4-hydroxycoumarin (coumarin)

 

 

Structures

• Essential chemical characteristics is an intact D-hydroxycoumarin residue with a carbon substitution at number 3 position
• Warfarin is the most frequently used anticoagulant because
  * Predictable onset
  * Predictable duration of action
  * Excellent bioavailability after oral administration

Pharmacodynamics

Mechanism of action

• Warfarin inhibits vitamin K epoxide reductase
  --> Blocks conversion of vitamin K epoxide to vitamin K
  --> Depletion of vitamin K-dependent coagulation proteins

NB:

• Platelet activity is not altered by oral anticoagulants

 

Vitamin K-dependent coagulation proteins

• Prothrombin (factor 2)
• Factors 7, 9, 10
• Protein C, Protein S [KB2:p206-207]

Pharmacokinetics

Absorption

• Rapidly and completely absorbed

Distribution

• 97% protein bound (albumin)

Metabolism

• Metabolised to inactive products
  --> Conjugation with glucuronic acid
  --> Excretion in bile and urine
• Prolonged by exposure to trace concentration of inhaled anaesthetics
  * Possibly due to inhibition of warfarin metabolism

Elimination

• Negligible renal excretion

Action profile

• Peak concentration = 1 hour
• Onset of action = 8-12 hours
• Peak effect = 36-72 hours
• Elimination half-time = 24-36 hours

Clinical

Administration

• Dose requirement varies widely among individuals

 

Disadvantages of oral anticoagulants

• Delayed onset of action
• Need for regular laboratory monitoring
• Difficulty in reversal
• Oral administration only

Laboratory evaluation

[SH4:p513]

• Prothrombin time = particularly sensitive to 3 of the 4 vitamin K-dependent clotting factors (2, 7, 10)
• Internatonal normalised ratio --> Used to avoid variable responsiveness of prothrombin time reagents

Special considerations

Pregnancy

[SH4:p513]

• Warfarin crosses the placenta
• Teratogenic

Factors influencing effects of warfarin

[SH4:p513]

• Changes in diet
• Undisclosed drug use
• Poor patient compliance
• Intermittent alcohol consumption

 

Enhanced effects

Preexisting liver disease

Advanced age