Pharmacokinetics: Warfarin Allie Punke (apunke@uthsc.edu)

The Basics Most of the anticoagulant activity of warfarin is due to which isomer? S What clotting factors does warfarin inhibit? 7, 9, 10, 2 Protein C +S Which factor is reflected in the measurement of PT/INR? 7 Which factor is responsible for the antithrombotic effect? 2 and 10

The Basics When do we recommend loading doses of warfarin? And what is the dose? Healthy, young patients: 10 mg X 2 doses (2 days) How is the interaction with tube feedings avoided? Hold tube feedings 1 hour before and 1 hour after warfarin is given Which enzymes metabolize warfarin? R: 1A2, 2C19, 3A4 S: 2C9 and 3A4

True OR False A patient taking Cefdinir may experience a lowering of her INR due to the gut flora being altered. False (INR would be increased) The interaction of aspirin and warfarin is due to warfarin being displaced from protein binding sites causing an increased INR. False (It doesn’t displace binding sites) Low Extraction Drug: Css,u= D/Clint A chronic alcoholic can be expected to have consistently decreased INR. True Patients who smoke may require less warfarin, since they are more “sensitive” to it. False False True

Application Warfarin, a highly protein bound drug, is added on to a patient’s medication regimen along with a drug that displaces warfarin from albumin. How should we handle this? A. Because warfarin is a High E drug, the dose should be reduced to prevent excess free warfarin. B. Because warfarin is a Low E drug, the dose should be increased to ensure therapeutic INR. C. Because warfarin is a Low E drug, the dose should be reduced to prevent excess free warfarin. D. Because warfarin is a Low E drug, no change needs to be made.

Application A patient is being managed on warfarin for atrial fibrillation. Additionally, her physician wants to start her on amiodarone. The physician asks you how to manage the interaction. A. The interaction usually occurs after being on amiodarone for 3 months and the dose of warfarin does not depend on the dose of amiodarone. B. The interaction usually occurs after being on amiodarone for about 2 weeks and the dose of amiodarone can be used to guide the dosing of warfarin. C. The interaction time is variable, but the dose of amiodarone can be used to guide the dosing of warfarin. D. The interaction time is variable and the dose of warfarin does not depend on the dose of amiodarone. C. Peak effect is 1 week to 5 months. What is the interaction due to? CYP2C9, 1A2, 3A4.

Application The patient is started on 200 mg of amiodarone. How should the dose of warfarin be adjusted if she takes 5 mg of warfarin daily?

Application A patient needs to be started on a bile acid sequestrant. Which would be best to recommend to avoid a documented interaction with warfarin? Welchol How can we tell the patient to take cholestyramine or colestipol with warfarin? Take 1 hour before or 4-6 hours after

Application—To Load or Not to Load MB, 24 YO woman, was diagnosed with a DVT and needs to be initiated on warfarin. Should we give her a LD or not? Yes JP, 75 YO, needs to be started on warfarin. Actual Body Weight= 58 kg. PMH=history of liver disease. Home medications= lisinopril and hydrochlorthiazide, amiodarone. Should we give him a LD or not? No (elderly, liver disease, weight)

Application-Drug Interactions Match each drug with Increased or Decreased INR Garlic Increased Barbiturates Decrease Ginseng Procoagulant Metronidazole Increase St. John’s Wort Decreased Fluoroquinolones Increased Amiodarone Increased Rifampin Decreased Septra Increase Black cohosh Antiplatelet Carbamazepine Decreased Fab 5: Increase INR: - Flagyl, FQ, fluconazole, aminodarone, bactrim

Application-Drug Interactions How do we manage these drug interactions? Rifampin: Onset of interaction: 5-10 days Dosage change: Increase warfarin by 100-200% Offset of interaction: Decrease warfarin by 50% 1-2 weeks after rifampin is D/C Rifampin (5-10 day delay in interaction onset) and may require 100-200% increase. OFFSET is difficult to predict. Should decrease warfarin dose by 50% 1-2 weeks after rifampin is discontinued.

Application BA, a 85 year old patient, is taking warfarin correctly, but she has been taking double of her levothyroxine dose chronically for the past 1.5 months. How (if at all) does this affect INR? A. Her INR will be elevated due to the levothyroxine inhibiting the metabolism of warfarin B. Her INR will be decreased due to impaired metabolism of clotting factors C. Her INR will be elevated due to rapid metabolism of clotting factors D. Her INR will be decreased due to the excess levothyroxine stimulating metabolism of warfarin C

Summary Always check for drug interactions if a patient is taking warfarin. Know when a LD is appropriate. Know how certain disease states and medications can affect the dose of warfarin. Always counsel on the effects of Vitamin K foods and recommend to maintain a consistent diet of these.

Questions?