Warfarin

Pharmacology of Warfarin

1. Warfarin Darya Osman Hussein Nile College May, 2014

2. Brief Introduction and History Anticoagulant Used in prevention of thrombosis and thromboembolism Synthetic derivative of dicoumarol (a 4-hydroxycoumarin derived mycotoxin anticoagulant) Name comes from acronym of organization that funded the research and discovery of the drug (Wisconsin Alumni Research Foundation – WARF and –arin to indicate its link with coumarin)

3. Synthesis of Warfarin

4. Molecular structure A cyclic tautomer (left) and cyclic hemiketal tautomer (right)

5. General Properties Appearance White or almost white crystalline powder Solubility Very soluble in water, freely soluble in ethanol, soluble in acetone, very slightly soluble in methylene chloride Appearance and pH of Solution clear colourless solution with pH of 7.6 – 8.6

6. Warfarin Sodium & Warfarin sodium Clathrate

7. Pure Warfarin Sodium or mixture , in form of clathrate (i.e. salt) , of Warfarin Sodium and Propan-2-ol in molecular proportions2:1 Clathrate salt should contain approximately 98 – 102% warfarin sodium Assay method – Infrared absorption spectrophotometry

8. Assay Procedure Dissolve 0.100 g in 0.01M NaOH and dilute to 100.0 mls with the same solvent. Dilute 10.0 mls of solution to 100.0 ml with 0.01M NaOH (X2) Measure absorbance at absorption maximum of308nm Using specific absorbance of 431, calculate the percent content

9. Impurities Three main impurities can be found: (5 RS )-3-(2-hydroxyphenyl)- 5-phenylcyclohex-2-enone 4-hydroxy-2 H -1-benzopyran-2-one (4-hydroxycoumarin ) (3E)-4-phenylbut-3-en-2-one (benzalacetone )

10. Dosage Form Oral Tablet Available in 1mg, 3mg and 5mg doses Usually coloured to ease identification Can contain Warfarin Sodium or Warfarin Sodium Clathrate Content % = 95 – 105% of stated amount

11. Physiological action Warfarin decrease blood coagulation by inhibiting vitamin K epoxide reductase, an enzyme that recycles  oxidized vitamin K1 to its reduced form after it has participated in the carboxylation  of several blood coagulation proteins, mainly  prothrombin and  factor VII Despite being labeled a vitamin K antagonist,  warfarin does not antagonize the action of vitamin K1 Warfarin antagonizes vitamin K1 recycling, depleting active vitamin K1 and the pharmacologic action may always be reversed by fresh vitamin K1

12. contra-indications Indications: Prophylaxis of embolization in rheumatic heart disease and atrial fibrillation Prophylaxis after insertion of prosthetic heart valve Prophylaxis and treatment of venous thrombosis and pulmonary embolism Transient ischemic attacks Contra-indications : Peptic ulcer Severe hypertension

13. Additional information Hepatic impairment: Should be avoided in severe impairment Renal Impairment: Should be used with caution in mild to moderate impairment and avoided in severe impairment Should be used with prophylactic vitamin K for the infant

14. Pregnancy and breastfeeding Pregnancy: Teratogenic (should not be given in first trimester) Can cross placenta and causes congenital malformations, placental fetal or neonatal haemorrhage Breastfeeding: Not present in significant amounts and appears safe