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]

Side effects

• Haemorrhage
• Skin necrosis
  * Occurs within 3 - 8 days of therapy
  * Due to extensive thrombosis of venules and capillaries in subcutaneous fat
• Foetal abnormality
  * CNS abnormality when warfarin is used at any stage
  * Embryopathy (only when used in first trimester)
  * Foetal bleeding
  * Heparin should be used instead for anticoagulation during pregnancy

Pharmacokinetics

Absorption

• Rapidly and completely absorbed orally

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
• Effects are affected by dietary vitamin K intake

Laboratory evaluation

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• 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

Reversal

• Withhold oral anticoagulants 1 to 3 days before operation
  * Can restart 1 - 7 days post-op

In emergencies,

• Oral or IV administration of vitamin K (1 - 2 mg)

If immediate reversal is needed, consider

• FFP
• Recombinant factor 7a (very expensive though) (e.g. novoseven)
• Prothrombin complex concentrate (e.g. prothrombinex)

Novoseven

Consists of

• 600mcg/mL(30,000 IU/mL) Recombinant factor 7a
• NaCl
• Glycylglycine
• Polysorbate 80
• Mannitol 30mg/mL

Dose = 35 - 120 mcg/kg every 2 to 3 hours

Prothrombinex-VF

Consists of

• 500IU of Factor 2, 9, and 10
• 25 IU of Antithrombin III
• 192IU of Heparin (porcine)
• Some human plasma proteins (<500mg)
  * May include low levels of factor 5 and 7

Side effects

• Risk of infection (though rare)
• Risk of allergy (though rare)

Drug interaction

Clearance of warfarin is inhibited by

• Phenylbutazone
• Amiodarone
• Cimetidine
• Omeprazole

NB:

• Cimetidine and omeprazole decrease clearance of the less active D-isomer

 

Absorption can be inhibited by

• Cholestyramine

 

Clearance can be increased by

• Enzyme inducers
  * Barbiturates
  * Rifampicin
  * Carbamazepine

Others

• Cephalosporin can increase warfarin effect by inhibiting cyclic interconversion of vitamin K
• Increased risk of bleeding when used with heparin, aspirin, and other NSAIDs

Special considerations

Pregnancy

[SH4:p513]

• Warfarin crosses the placenta
• Teratogenic

Factors influencing effects of warfarin

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• Changes in diet
• Undisclosed drug use
• Poor patient compliance
• Intermittent alcohol consumption
• Advanced age
  * Enhanced effects
• Pre-existing liver disease
  * Enhanced effects