What medications can cause an elevated Prothrombin Time (PT) and International Normalized Ratio (INR)?

Medications Associated with Elevated PT and INR

Numerous medications can cause elevated PT and INR values, with warfarin being the most common, but many other drugs can increase PT/INR through various mechanisms including affecting vitamin K metabolism, inhibiting clotting factor synthesis, or interfering with warfarin metabolism. 1

Primary Medications That Increase PT/INR

Anticoagulants

• Warfarin - directly inhibits vitamin K epoxide reductase, preventing synthesis of clotting factors II, VII, IX, and X 2
• Direct thrombin inhibitors (e.g., argatroban) - can artificially elevate INR when transitioning to warfarin 3

Medications That Potentiate Warfarin Effects

Medications that inhibit warfarin metabolism through CYP450 enzyme inhibition:

1. Antibiotics:

   • Sulfonamides (sulfamethoxazole/trimethoprim) - nearly doubles bleeding risk 2
   • Metronidazole - requires 33% warfarin dose reduction 2
   • Fluoroquinolones (ciprofloxacin, norfloxacin, ofloxacin) 2, 1
   • Macrolides (erythromycin, clarithromycin) - inhibit CYP3A4 2, 1
   • Doxycycline, neomycin 1

2. Cardiovascular Medications:

   • Certain statins (fluvastatin, lovastatin, rosuvastatin, simvastatin) - can increase INR by ~0.3 2
   • Amiodarone - potent CYP2C9 inhibitor 1
   • Propafenone 1
   • Amlodipine - inhibits CYP3A4 2

3. Psychotropic Medications:

   • SSRIs (especially fluvoxamine and fluoxetine) - inhibit CYP2C9 and CYP3A4 2
   • Quetiapine, valproic acid 2

4. Cancer Chemotherapy:

   • Fluoropyrimidines (fluorouracil, capecitabine) - may require 20-70% warfarin dose reduction 2
   • Gemcitabine, paclitaxel 2
   • Imatinib - when combined with CYP3A4 inhibitors 2

5. Anti-inflammatory Drugs:

   • NSAIDs (diclofenac, naproxen) - doubles bleeding risk 2, 1
   • Acetaminophen - dose-dependent effect, significant with >9.1g/week 2

6. Tyrosine Kinase Inhibitors:

   • Gefitinib - inhibits metabolism of warfarin via CYP1A2, CYP2C9, and CYP3A4 2

7. Other Medications:

   • Disulfiram, omeprazole, esomeprazole 1
   • Fibrates (fenofibrate, gemfibrozil) 2
   • Fish oil (1-2g/day) 2

Medications That Decrease PT/INR

1. Enzyme Inducers:

   • Carbamazepine - can require 50% increase in warfarin dose 2
   • Phenytoin - biphasic effect (initial increase then decrease) 2
   • Rifampin 1
   • Barbiturates (phenobarbital, butalbital) 1

2. Other Medications:

   • Cholestyramine - interferes with warfarin absorption 2, 1
   • Vitamin K-containing supplements 1
   • St. John's wort 1

Endogenous Factors Affecting PT/INR

• Liver disease - impairs synthesis of clotting factors 2
• Hyperthyroidism - increases metabolism of clotting factors 1
• Lupus anticoagulant - can cause variable INR results 4
• Cancer - can affect coagulation pathways 1

Clinical Approach to Elevated PT/INR

Assessment Algorithm:

1. Determine if patient is on warfarin or other anticoagulants
2. Review medication list for potential interacting drugs
3. Assess for endogenous factors (liver disease, malnutrition, etc.)
4. Consider laboratory factors (sample collection issues, reagent variability)

Management Pearls:

• When initiating potentially interacting medications in patients on warfarin, monitor INR more frequently (2-3 times weekly initially) 2
• For patients with lupus anticoagulant, consider chromogenic factor X assay as an alternative monitoring method 4
• Be aware that the same INR value may represent different coagulation profiles in different clinical contexts 5

Common Pitfalls and Caveats

• Laboratory variability: Different thromboplastin reagents have varying sensitivities, affecting INR results 6
• Citrate concentration: Higher citrate concentrations (3.8%) lead to higher INR values; underfilling collection tubes causes falsely elevated INR 2
• Point-of-care testing: May be unreliable in patients with lupus anticoagulant 4
• Antibiotic effect: All antibiotics can alter gut microbiome (source of vitamin K), potentially affecting INR beyond direct drug interactions 2
• Botanical supplements: Many herbal products (garlic, ginkgo biloba, dong quai) can increase INR and bleeding risk 1

Remember that the clinical significance of an elevated PT/INR depends on the magnitude of elevation, the patient's baseline, and the presence of bleeding. Monitoring should be individualized based on the specific medication interaction and patient risk factors.