What are some common drug interactions?

Common Drug Interactions in Clinical Practice

The most clinically significant drug interactions involve warfarin with antibiotics, direct oral anticoagulants (DOACs) with P-glycoprotein inhibitors, and combinations of CNS depressants, all of which substantially increase morbidity and mortality through bleeding complications, toxicity, or respiratory depression. 1

Warfarin Interactions (Over 500 Documented)

High-Risk Antibiotic Combinations

Warfarin has the most extensive interaction profile of commonly prescribed medications, with particular concern for antibiotics that affect multiple metabolic pathways 1:

• Sulfonamides (trimethoprim-sulfamethoxazole): Nearly double bleeding risk compared to warfarin alone and require 25% pre-emptive dose reduction 1, 2
• Metronidazole: Requires 33% warfarin dose reduction when co-administered 1, 3
• Fluoroquinolones (especially ciprofloxacin): Inhibit CYP1A2, elevating R-warfarin concentrations and significantly increasing bleeding risk 1
• Macrolides (clarithromycin, erythromycin): Strong to moderate CYP3A4 inhibitors that potentiate warfarin effects, requiring 25% dose reduction 1, 2
• All antibiotics: Can alter gut microbiome (a rich vitamin K source), potentiating anticoagulant effects regardless of enzyme interactions 1, 3

Critical Monitoring Strategy

The timing of drug initiation matters significantly 1:

• Adding antibiotics to stable warfarin therapy causes more INR variability than simultaneous initiation
• Monitor INR closely whenever any antibiotic is started or stopped 1, 2
• Higher antibiotic doses exponentially increase interaction risk 2, 3

Direct Oral Anticoagulant (DOAC) Interactions

P-Glycoprotein and CYP3A4 Modulators

Avoid strong P-glycoprotein inducers in all DOAC patients unless proven safe 1:

• Dronedarone: Strong P-gp inhibitor that doubles dabigatran plasma concentrations; generally avoid with all DOACs 1
• Verapamil: Potent P-gp inhibitor requiring 2-hour spacing after dabigatran administration; avoid if renal impairment present 1
• Amiodarone: Moderate P-gp inhibitor; can co-administer if no other risk factors for DOAC accumulation exist 1
• Simultaneous strong CYP3A4 and P-gp inhibitors: Absolutely avoid in patients taking apixaban and rivaroxaban 1

Anticoagulant-Antiplatelet Combinations

Minimize duration of concomitant therapy to reduce bleeding risk while maintaining thrombotic protection 1:

• Bioprosthetic valve patients: Warfarin plus aspirin (≤100mg) for 3-6 months with PPI, then anticoagulation alone 1
• Mechanical valve patients: Lifelong aspirin (75-100mg/day) plus warfarin only (never DOAC) 1
• Post-TAVR: Consider triple therapy (warfarin + aspirin + clopidogrel) only in exceptionally high-risk patients, maximum 6 months 1

Drug-Drug Interactions in Older Adults

The 2019 AGS Beers Criteria identifies critical combinations to avoid 1:

CNS Depressant Combinations

Avoid concurrent use of three or more CNS agents (antidepressants, antipsychotics, benzodiazepines, antiepileptics, opioids) due to dramatically increased fall risk 1:

• Opioids + benzodiazepines: Absolutely contraindicated due to respiratory depression risk 1
• Opioids + gabapentinoids: Avoid except when transitioning from opioids to gabapentinoids 1

Electrolyte-Altering Combinations

Trimethoprim-sulfamethoxazole + ACE inhibitor/ARB: Use with extreme caution in reduced kidney function due to hyperkalemia risk 1:

• TMP-SMX + phenytoin: Increases phenytoin toxicity risk 1
• Avoid combinations of three or more medications that increase serum potassium 1

Additional High-Risk Combinations

• Macrolides (excluding azithromycin) or ciprofloxacin + warfarin: Significantly increases bleeding risk 1
• Ciprofloxacin + theophylline: Increases theophylline toxicity risk 1

Pharmacokinetic Interaction Mechanisms

Understanding enzyme systems prevents predictable interactions 1:

• CYP2C9 inhibitors: Affect S-warfarin (5x more potent than R-warfarin), causing most clinically significant warfarin interactions 1
• CYP3A4 inhibitors/inducers: Affect R-warfarin and rivaroxaban/apixaban metabolism 1
• CYP1A2 inhibitors: Affect R-warfarin clearance (ciprofloxacin) 1
• P-glycoprotein: Primary transporter affecting dabigatran and edoxaban; secondary effect on apixaban/rivaroxaban 1

Common Pitfalls to Avoid

• Don't assume all antibiotics in the same class have identical warfarin interaction profiles 3
• Recognize that enzyme induction effects take 2-4 weeks to fully develop and persist 2-4 weeks after discontinuation 2, 3
• Never ignore topical formulations: Miconazole oral gel interacts with warfarin; use nystatin oral solution instead 2
• Remember that 80% of atrial fibrillation patients will receive a medication that interacts with their oral anticoagulant over their lifetime 1