Warfarin-Drug Interactions among Older Adults
Warfarin-drug interactions are often encountered in the care of older adults. Interactions may be classified as pharmacokinetic, resulting in changes in serum warfarin concentrations, or pharmacodynamic, resulting in changes in hemostasis or platelet function. Knowledge of these mechanisms of warfarin-drug interactions may help identify warfarin interactions, facilitate prescribing decisions, and assist with appropriate monitoring.
Key words: warfarin, drug interactions, anticoagulants, cytochrome P-450 enzyme system, older adults.
Introduction
There is good evidence supporting the use of warfarin for a variety of indications, including the prevention of stroke in patients with atrial fibrillation.1,2 Despite this compelling evidence, warfarin is underutilized, especially among older adults.3 A commonly cited explanation for the underuse of warfarin is the increased risk of bleeding.4,5 Risk factors for bleeding include anticoagulation intensity, increasing age, and drug interactions (Table 1). This article will review the significance and etiology of various drug interactions on the efficacy and safety of warfarin therapy, including practical recommendations to address these interactions, with a focus on older adults.
Types of Drug Interactions
Drug interactions may be categorized as either pharmacokinetic or pharmaco-dynamic. Pharmacokinetic interactions are based on alterations to absorption, distribution, metabolism, and elimination, which all change the effective serum concentration of warfarin. Pharmacodynamic interactions do not affect serum warfarin levels, but either counteract or enhance the pharmacologic effect at its site of action, causing changes in hemostasis or platelet function. These interactions can occur when an interacting medication is either initiated or discontinued.
Pharmacokinetic Interactions
The most common manifestation of pharmacokinetic interactions with warfarin involves the inhibition or induction of its metabolism. Attention should be paid to the relative importance of the warfarin cytochrome P450 (CYP) metabolic pathways. Warfarin is a racemic mixture of its R-isomer (less potent) and S-isomer (more potent).6 S-warfarin is metabolized primarily by the CYP 2C9 isoenzyme whereas R-warfarin is metabolized by CYP 1A2 and 3A4. Depending on the dominant isoenzyme inhibited by the interacting drug, the effect on warfarin may or may not be clinically significant. Consequently, drugs that impact CYP 2C9 metabolism can be expected to have a disproportionate effect on the INR (International Normalized Ratio) compared with other mechanisms.
There are numerous agents, such as metronidazole, trimethoprim/sulfamethoxazole (TMP/SMX), and amiodarone, that are commonly prescribed to older individuals that inhibit the CYP 2C9 pathway These medications, when used in conjunction with warfarin have significant effects on the INR and bleeding risk. In addition, while warfarin clearance is not affected by renal dysfunction, serum levels of interacting drugs (such as ciprofloxacin or TMP/SMX) may increase with renal dysfunction, enhancing the interaction.
The onset and duration of the drug interaction is dependent on serum concentrations of the interacting drug. For example, a drug with a long half-life will have a delayed-onset warfarin interaction while steady state levels are achieved. This interaction will persist well after the discontinuation of the drug due to its prolonged elimination phase. Table 2 highlights some of the more common pharmacokinetic interactions.
Pharmacodynamic Interactions
Pharmacodynamic interactions with warfarin, while not as numerous as pharmacokinetic interactions, may also influence the efficacy and safety of warfarin therapy. The most common type of pharmacodynamic warfarin interaction is the concomitant use of antiplatelet agents (Table 3) including prescription and non-prescription nonsteroidal anti-inflammatory drugs (NSAIDs)7,8 and clopidogrel. These antiplatelet agents can increase bleeding risk without increasing the INR. Acetyl salicylic acid