Case Study DDD A 79-year-old man with a history of deep vein thrombosis and pulmonary embolism received anticoagulation

therapy with warfarin 5 mg daily for 8 months. He was diagnosed with osteomyelitis and underwent partial metatarsal resection of his right foot. After surgery, antibiotics were initiated, including ertapenem sodium 1 g intravenously every 24 hours, vancomycin 1400 mg intravenously every 24 hours and rifampicin 300 mg by mouth twice daily. A 5- to 6-fold increase in warfarin dose was prescribed to reach therapeutic INR.

O OH

Warfarin

1. What is INR?
The International Normalised Ratio (INR) is the ratio of the patients prothrombin time (PT) to that of a normal control using standardised reagents. PT is the time needed for clot formation to occur. The following indications and target INRs take into account recommendations of the British Society for Haematology

INR 2.5 for treatment of deep-vein thrombosis and pulmonary embolism INR 3.5 for recurrent deep-vein thrombosis and pulmonary embolism For mechanical prosthetic heart valves, the recommended target INR

depends on the type and location of the valve. Generally, a target INR of 3 is recommended for mechanical aortic valves, and 3.5 for mechanical mitral valves.

If you are given warfarin you will need regular blood tests to check on how

quickly your blood clots. This tests measures the international normalised ratio, or INR. The aim is to get the dose of warfarin and the INR just right so your blood does not clot as easily as normal, but not so much as to cause bleeding problems. An INR of 1 is assigned to the time is takes for normal blood to clot. Blood with an INR of 2 takes twice as long to clot and so on.

This case study was prepared by MPharm student (Farakh Riaz) as part of a project on Contextualisation of Chemistry in Pharmacy

2. Warfarin is administered as the sodium salt. Comment on this considering there is no carboxylic acid functional group in its structure.
Used as sodium salt suggests drug is acidic. The acidic hydrogen is located between two electron withdrawing carbonyl groups. Upon ionisation the negative charge can be delocalised onto each of the electronegative oxygen atoms giving a resonance stabilised anion. Or can consider that when the hydroxyl group is deprotonated, the resulting anion is further stabilised through resonance and hence increasing the acidity of this hydrogen. Warfarin can lose a proton readily and is therefore acidic. In the free acid form warfarin is not very soluble in water so is administered as the sodium salt.
O OH O H O O O O O

3. Warfarin is administered as a racemic drug? Explain from its chemical structure how warfarin is a racemate? Warfarin has an asymmetric carbon. The tetrahedral structure of this carbon and the different arrangement of its four atom substituents give rise to the enantiomeric forms R- and S-warfarin. The R- and S-warfarin enantiomers are a pair of isomers that have the same molecular formula, are nonsuperimposable images and differ in spatial arrangement of their functional groups. Enantiomers have the same physicochemical properties except their ability to rotate the plane of polarised that is equal in magnitude but opposite in direction.
O OH OH O

S-Warfarin

R-Warfarin

4. The enantiomers of warfarin are not equipotent? Why? Although clinically warfarin is administered as a racemate, in the asymmetric environment of the human body, the two enantiomers impart significantly different pharmacokinetic and pharmacodynamic profiles. Consequently, the two enantiomers of warfarin are not equipotent, S-warfarin is at least four-fold more potent as an anticoagulant than R-warfarin (Kaminsky & Zhang, 1997).
This case study was prepared by MPharm student (Farakh Riaz) as part of a project on Contextualisation of Chemistry in Pharmacy

5. What are the metabolites of warfarin?

The different spatial arrangements of the enantiomers impart varying degrees of affinity for different CYP enzymes that results in differing pharmacokinetic profiles as a consequence of stereoselective metabolism. The more potent Senantiomer is metabolised primarily by CYP2C9 to form two metabolites, S-7hydroxywarfarin and S-6-hydroxywarfarin. The relatively less potent Rwarfarin is metabolised primarily by CYP1A2 and CYP3A4 to yield R-6hydroxywarfarin and R-10-hydroxywarfarin respectively. Hence, compounds that affect the metabolism of CYP2C9 that is the principal CYP enzyme that modulates the metabolism of warfarin will inevitably have a greater effect on the pharmacokinetic profile. Hence, the differences in the activities and metabolism of the two enantiomers are important considerations in understanding clinically significant drug-drug interactions.
O
5 6 7 8

OH 10
9

S-Warfarin

6. Why is there a 5- to 6- fold increase in warfarin dose in the case above?

Rifampicin has been shown to be a potent inducer of CYP enzyme. As a consequence of the induction of oxidative metabolism, rifampicin has been shown to reduce the hypoprothrombinaemic response of warfarin by accelerating the clearance of R-warfarin and S-warfarin three-fold and twofold respectively. Hence a large dose increase was required to make adjustments for the accelerated clearance of warfarin.

7. How does the pharmacist ensure patient safety? Find out what the patient already understands about their oral anticoagualation therapy Explain lifestyle changes to ensure good control Importance of adherence Ensure patient is aware of the potential for warfarin to interact with many OTC products including herbal, food and drink Ensure dose in yellow book matches prescribed dose Ask patient for therapeutic indication and ensure target INR is compatible
This case study was prepared by MPharm student (Farakh Riaz) as part of a project on Contextualisation of Chemistry in Pharmacy

Patient should always bring yellow book to pharmacy Its is commonly said that patients on warfarin should refrain from eating leafy green vegetables. What would you advise a patient who asks you this query? The aim of the diet during warfarin therapy is to provide adequate nutrition whilst maintaining a consistent daily intake of vitamin K from dietary sources. Vitamin K is involved in clotting of the blood and warfarin doses are determined in order to control the ability of the blood to clot. Hence, wide fluctuations of vitamin K intake affect the ability of the blood to clot and may affect therapy. Patients should never be advised to reduce vitamin K intake in order to achieve a desirable International normalised ratio (INR) value, but should be encouraged to keep their diet consistent and have routine tests to monitor the INR. If diet does change significantly, for example through illness, the anticoagulant clinic should be notified. Patients should be aware of foods that are high in vitamin K content. These are usually dark green vegetables such as Brussels sprouts, spinach, broccoli, kale, cabbage, parsley and avocado. Patients can be advised to keep a food diary in order to ensure diet remains consistent.

8. What should happen when the antibiotic treatment ceases?

It is imperative that dose reduction is carried out with vigilant monitoring when rifampicin therapy is ceased. In the above case, a 70% dose reduction over a four to five week period was required to ensure the INR value was in the desired range in a safe manner.

Useful Reference on Metabolism and Drug Discovery Gunaratna, C. (2000). Drug Metabolism & Pharmacokinetics in Drug Discovery: A Primer for Bioanalytical Chemists, Part I. Current Separations 19(1), 17-23

This case study was prepared by MPharm student (Farakh Riaz) as part of a project on Contextualisation of Chemistry in Pharmacy