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Hot Topics in Anticoagulation: Warfarin Interactions. Alison M. Walton, PharmD, BCPS Assistant Professor of Pharmacy Practice Butler University College of Pharmacy and Health Sciences Clinical Pharmacy Specialist, St. Vincent Health. Disclosure Statement.
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Hot Topics in Anticoagulation: Warfarin Interactions Alison M. Walton, PharmD, BCPS Assistant Professor of Pharmacy Practice Butler University College of Pharmacy and Health Sciences Clinical Pharmacy Specialist, St. Vincent Health
Disclosure Statement • No conflicts of interest to disclose
Objectives • List mechanisms for interaction with warfarin • Identify clinical significant drug interactions with warfarin • Describe environmental factors that may influence the effect of warfarin
Warfarin Therapy • Most common oral anticoagulant • Vitamin K Antagonist • Inhibits factors II, VII, IX, X • Inhibits protein C and protein S • Racemic mixture of 2 active isomers • S-isomer 5x more potent than R-isomer • Effectiveness and safety dependent on international normalized ratio (INR) values Chest 2008;133(6):160S-198S
Warfarin Metabolism • Rapidly absorbed from GI tract • High bioavailability • Circulates bound to plasma proteins • Accumulates in liver • Hepatic metabolism by cytochrome P450 • S-isomer: CYP450 2C9 • R-isomer: CYP450 3A4 and 1A2 Chest 2008;133(6):160S-198S
Environmental Factors and Drug Interactions Chest 2008;133(6):160S-198S
Systemic literature review: 1993 – 2004 • 181 eligible articles contained original reports on 120 drugs or foods • 72% described potentiation of warfarin’s effect • 84% of poor quality • 86% single case reports Arch Intern Med 2005;165:1095-1106
Rated Reports Arch Intern Med 2005;165:1095-1106
Mechanisms for Interaction • Stereoselective clearance (S-isomer) • Nonstereoselective clearance • Vitamin K pathway • No documented mechanism Arch Intern Med 2005;165:1095-1106
Options to prescribe safely… • Never prescribe or allow another medicine to be given with warfarin • Use system to evaluate interactions among patient’s entire profile of therapies • Group majority of offending interacting drugs into easier-to-remember therapeutic groups Arch Intern Med 2005;165:1095-1106
Common Drug Interactions • Antibiotics: sulfamethoxazole/trimethoprim, azole antifungals, metronidazole, macrolides, quinolones • Cardiovascular agents: lipid-lowering agents, amiodarone, NSAIDs, aspirin • Other: SSRIs, omeprazole, cimetidine, anabolic steroids, rifampin, HIV medications • Herbal supplements: don quai, ginseng, green tea Arch Intern Med 2005;165:1095-1106
Acetaminophen • Considered analgesic of choice for patients using warfarin • Risk of warfarin-associated bleeding with use of NSAIDs and aspirin • Possible potentiating effect with large doses over prolonged periods of time • Variable effect in individuals • Close monitoring with doses >2g/day Pharmacotherapy 2007;27(5):675-683 Pharmacotherapy 2003;23(1):109-112
Menthol Cough Drops • Two documented case reports of potential interaction with warfarin • Clinically significant INR decrease • Potential Mechanism • Affect CYP system as inducer and inhibitor of certain isoenzymes that would potentially interfere with metabolism of warfarin • Menthol derived from peppermint plant Pharmacotherapy 2010;30(1):50e-52e
Influenza Vaccination • Prospective trial evaluated 104 patients • Primary End Points • INR variation • Warfarin weekly dose variation • Follow-up for treatment-related clinical events • Conclusions • No significant effect on INR values or weekly dosage regimens for warfarin; No fatal or major bleeding • Close monitoring not required with stable regimens Arch Intern Med 2010;170(7):609-616
Lifestyle Factors • Diet • Consistency • Social Factors • Activity level • Tobacco use • Alcohol use Chest 2008;133(6):160S-198S
Cranberry Juice • Potential interaction based on case reports • Proposed mechanism for ↑ INR • Flavonoids inhibit warfarin metabolism by CYP2C9 • Antiplatelet effects of salicyclic acid • Small controlled clinical trials do not support potential interaction • Effects of 250-600mL/day of cranberry juice • Unknown effect with supplements and larger amounts or chronic ingestion of juice Pharmacist’s Letter 2007;23(6):230614
Alcohol • Acute consumption • Decrease warfarin metabolism • ↑ warfarin effect • Chronic consumption • Induce warfarin metabolism • ↓ warfarin effect Pharmacist’s Letter 2008;24(1):240106
Disease States • Malabsorption syndromes • Warfarin highly protein bound • Hepatic dysfunction • Potentiates response to warfarin • Impaired synthesis of coagulation factors Chest 2008;133(6):160S-198S
Disease States continued • Heart failure • Decreased clearance of warfarin • Increased catabolism of clotting factors • Hypermetabolic states • Increases warfarin responsiveness • Increased catabolism of vitamin K-dependent coagulation factors Chest 2008;133(6):160S-198S
Summary • Overall poor quality of interaction literature • Translation of drug pharmacology to prediction of interaction far from certain • No drug can be deemed “safe” • Numerous environmental factors influence effect of warfarin • Regular monitoring of INR remains best protection against major harm Arch Intern Med 2005;165:1095-1106
Hot Topics in Anticoagulation: Warfarin Interactions Alison M. Walton, PharmD, BCPS Assistant Professor of Pharmacy Practice Butler University College of Pharmacy and Health Sciences Clinical Pharmacy Specialist, St. Vincent Health