WARFARINDarya Osman HusseinNile College May, 2014

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)

SYNTHESIS OF WARFARIN

MOLECULAR STRUCTURE

• A cyclic tautomer (left) and cyclic hemiketal tautomer (right)

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

WARFARIN SODIUM & WARFARIN SODIUM CLATHRATE

• 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

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

IMPURITIES• Three main impurities can be found:• (5RS)-3-(2-hydroxyphenyl)-5-phenylcyclohex-2-enone

• 4-hydroxy-2H-1-benzopyran-2-one (4-hydroxycoumarin)

• (3E)-4-phenylbut-3-en-2-one (benzalacetone)

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

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

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

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

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