What are the most common drug interactions to be aware of?

Most Common Drug Interactions to Be Aware Of

The most clinically significant drug interactions occur with oral anticoagulants, statins, antibiotics, and medications affecting cytochrome P450 enzymes and P-glycoprotein transporters, requiring careful monitoring and management to prevent serious adverse outcomes. 1

Anticoagulant Interactions

Warfarin Interactions

Warfarin has over 500 reported drug interactions due to its narrow therapeutic index, high protein binding, and dependence on cytochrome P450 metabolism 1:

• Antibiotics:

  • Trimethoprim-sulfamethoxazole (TMP-SMX) with warfarin increases bleeding risk 2
  • Macrolides (excluding azithromycin) with warfarin increases bleeding risk 2
  • Ciprofloxacin with warfarin increases bleeding risk 2

• Cardiovascular medications:

  • Amiodarone is the most common cardiovascular drug interaction with warfarin, requiring an average 25% decrease in warfarin dose 2, 1
  • Dronedarone can increase INR values 2
  • Statins (particularly fluvastatin) can increase INR by approximately 0.3 1

• Other important interactions:

  • NSAIDs and high doses of aspirin increase bleeding risk 2, 3
  • Selective serotonin reuptake inhibitors (SSRIs) increase bleeding risk (OR 2.6) 4
  • Azole antifungals (fluconazole, voriconazole) inhibit CYP2C9, increasing bleeding risk 1

Direct Oral Anticoagulant (DOAC) Interactions

• P-glycoprotein (P-gp) modulators:

  • Dronedarone is a strong P-gp inhibitor that can double dabigatran plasma concentrations 2
  • Verapamil significantly increases dabigatran plasma concentrations 2
  • Amiodarone moderately increases dabigatran levels 2
  • Proton pump inhibitors reduce dabigatran absorption by 20-40% 1

• CYP3A4 inhibitors/inducers:

  • Strong CYP3A4 and P-gp inhibitors should be avoided with apixaban; if unavoidable, reduce apixaban dose by 50% 2
  • Rifampin significantly decreases apixaban and dabigatran exposure 2

Antiplatelet Drug Interactions

• Aspirin interactions:

  • Ibuprofen blocks aspirin's access to platelet cyclo-oxygenase, reducing its antiplatelet effect 5
  • Combined use of warfarin and aspirin increases bleeding risk (OR 4.5) 3

• Clopidogrel interactions:

  • Effectiveness depends on conversion to an active metabolite by CYP2C19 6
  • CYP2C19 inhibitors (omeprazole, esomeprazole) reduce clopidogrel's effectiveness 6, 5
  • Opioids decrease exposure to clopidogrel 6
  • NSAIDs, warfarin, SSRIs, and SNRIs increase bleeding risk when combined with clopidogrel 6

Statin Interactions

• Amiodarone limits simvastatin to 20mg daily and lovastatin to 40mg daily 1
• Strong CYP3A4 inhibitors (ketoconazole, ritonavir) increase statin levels 1

Antibiotic Interactions

• Ciprofloxacin with theophylline increases risk of theophylline toxicity 2
• Rifampin is a strong enzyme inducer that decreases effectiveness of many drugs, including oral contraceptives, methadone, and antiretrovirals 1

Polypharmacy Considerations

• Concurrent use of three or more CNS agents (antidepressants, antipsychotics, benzodiazepines, nonbenzodiazepine hypnotics, antiepileptics, opioids) increases fall risk 2
• Opioids should not be used concurrently with benzodiazepines or gabapentinoids (except when transitioning) 2
• Medications that increase serum potassium should be used cautiously together 2

Clinical Implications and Management

1. For anticoagulant users:

   • Avoid chronic ibuprofen use with aspirin; if necessary, administer aspirin at least 2 hours before ibuprofen 5
   • Consider alternative H2 antagonists instead of PPIs in patients taking clopidogrel 5
   • Monitor INR more frequently when starting or stopping interacting medications with warfarin 2

2. For older adults:

   • Be particularly cautious with drug combinations in patients with reduced kidney function 2
   • Avoid TMP-SMX in patients with reduced kidney function taking ACEIs or ARBs due to hyperkalemia risk 2

3. For patients requiring both antiplatelet and anticoagulant therapy:

   • Carefully assess thrombotic versus bleeding risk for each patient 7
   • Minimize the duration of triple therapy (dual antiplatelet plus anticoagulant) when possible 2

Remember that patients with preexisting hemostatic defects are at particularly high risk when exposed to medications that affect platelet function 8.