Drug-to-Drug Interactions: PowerPoint Presentation Key Points
Slide 1: Definition and Clinical Impact
Drug-drug interactions (DDIs) occur when one drug modifies a patient's pharmacological or clinical response to another drug, either through pharmacokinetic or pharmacodynamic mechanisms. 1
- DDIs cause approximately 2.8% of hospital admissions and account for 26% of all adverse drug events 2, 3
- The highest risk occurs in patients with hepatic or renal impairment, where drug clearance is reduced and interaction effects are magnified 2
- Cancer patients face particularly high DDI risk, with 63% experiencing at least one potential interaction, and co-prescribing rates ranging from 23-74% depending on the drug class 1
Slide 2: Mechanisms of Drug Interactions
Pharmacokinetic Interactions
Pharmacokinetic interactions occur when one drug influences the absorption, distribution, metabolism, or excretion of another drug. 1, 3
- Absorption interactions: Levothyroxine with neutralizing antacids, or colestipol reducing pravastatin absorption by 47% 4, 5
- Distribution interactions: Competition for protein binding sites 6
- Metabolism interactions: The most common and complex mechanism, primarily involving cytochrome P450 enzymes 1
- Elimination interactions: Digoxin with macrolides, or P-glycoprotein transporter interactions 5, 6
Pharmacodynamic Interactions
Pharmacodynamic interactions occur when drugs have additive, synergistic, or antagonistic effects at the site of action. 3, 5
- Additive effects: NSAIDs with phenprocoumon increasing bleeding risk 5
- Antagonistic effects: Aspirin with ibuprofen reducing cardioprotective benefits 5
Slide 3: The Central Role of CYP3A4
CYP3A4 metabolizes over 50% of all drugs in the market and nearly all tyrosine kinase inhibitors, making it the most clinically significant enzyme for DDIs. 2, 1
Strong CYP3A4 Inhibitors (Increase Drug Levels/Toxicity):
- Azole antifungals (ketoconazole, itraconazole) 2
- Macrolide antibiotics (clarithromycin increased pravastatin AUC by 110%) 4
- HIV protease inhibitors (ritonavir, darunavir increased pravastatin by 81%) 4
- Grapefruit juice 2
Strong CYP3A4 Inducers (Decrease Drug Levels/Efficacy):
Other Important CYP Enzymes:
- CYP2D6, CYP2C9, CYP2C19, CYP1A2 also mediate clinically significant interactions 7
Slide 4: High-Risk Cardiovascular Drug Interactions
Statins with CYP3A4 Inhibitors
The American College of Cardiology recommends limiting simvastatin to maximum 20 mg daily when combined with amiodarone, and lovastatin to maximum 40 mg daily. 2
- Statins metabolized by CYP3A4 (simvastatin, lovastatin, atorvastatin) have the highest interaction potential 2
- Prevention strategy: Use pravastatin or rosuvastatin instead, as these are not metabolized by CYP3A4 2
Digoxin Interactions
The American Heart Association recommends reducing digoxin dose by 50% when initiating amiodarone. 2
- Verapamil and other P-glycoprotein inhibitors significantly increase digoxin concentrations 2
- Pravastatin increased digoxin AUC by 23% 4
Warfarin Interactions
The antimicrobials most likely to significantly affect INR in warfarin patients are trimethoprim/sulfamethoxazole, metronidazole, and fluconazole. 8
- Clarithromycin, azole antifungals, and amiodarone are common precipitants 8
- An empiric warfarin dosage reduction of 30-50% is recommended upon initiation of amiodarone therapy 8
Slide 5: Anticoagulant Drug Interactions
Avoid simultaneous strong CYP3A4 and P-glycoprotein inhibitors (ketoconazole, itraconazole, ritonavir) with apixaban and rivaroxaban. 2
- Timing strategy: Administer verapamil 2 hours after dabigatran to minimize interaction 2
- Novel oral anticoagulants are particularly susceptible to interactions affecting both metabolism and transport 2
Slide 6: Antiviral Drug Interactions
Numerous and complex drug-drug interactions occur with HCV direct-acting antivirals (DAAs), requiring thorough assessment prior to starting therapy. 1
Contraindicated Combinations:
- Simeprevir with cyclosporine (significantly increased simeprevir levels due to hepatic uptake transporter inhibition) 1
- Simeprevir with strong CYP3A4 inducers (rifampin, carbamazepine, phenytoin) 1
- Simeprevir with HIV protease inhibitors, efavirenz, etravirine, nevirapine 1
Safe Combinations:
- Raltegravir, maraviroc, rilpivirine, tenofovir, emtricitabine, lamivudine, and abacavir have no interactions with simeprevir 1
Key resource: www.hep-druginteractions.org for regularly updated recommendations 1
Slide 7: Other High-Risk Interactions
CNS Depressant Combinations
Avoid prescribing opioid cough medicines for patients receiving benzodiazepines or other CNS depressants, including alcohol. 8
- Additive CNS depression increases risk of respiratory depression and death 3
Antihypertensive Interactions
Beta blockers should be tapered and discontinued several days before clonidine withdrawal to reduce the risk of rebound hypertension. 8
Electrolyte Disturbances
Limit spironolactone dosages to 25 mg daily when coadministered with potassium supplements. 8
- Risk of life-threatening hyperkalemia 8
Slide 8: Clinical Decision Support Alert Design
Seven core elements should be included in all DDI clinical decision support alerts to improve usability and reduce alert fatigue. 1
Essential Alert Components:
Drugs Involved: Clearly identify interacting drug pairs using both brand and generic names, especially for combination products 1
Seriousness Category: Use consistent terminology across all systems to indicate potential severity 1
Clinical Consequences: Clearly describe potential adverse outcomes (e.g., hyperkalemia, QT prolongation, reduced drug efficacy) with frequency when available 1
Mechanism of Interaction: Explain the mechanism (e.g., CYP3A4 inhibition) to help clinicians choose alternatives 1
Contextual Information/Modifying Factors: Include patient-specific risk factors that may increase interaction severity 1
Recommended Actions: Provide specific guidance such as dose modification, alternative medications, or monitoring strategies 1
Evidence: Present the strength and source of evidence (case report, clinical trial, etc.) 1
Slide 9: Alert Presentation Best Practices
Consistency in alert presentation within and across EHR systems facilitates quick, accurate recognition and action by clinicians. 1
- Use consistent color and visual cues: Most serious (contraindicated) DDIs should be easily distinguished from less serious interactions 1
- Minimize text: Reduce cognitive load while maintaining essential information 1
- All clinicians involved in medication use should be able to view DDI alerts and actions by other clinicians 1
Common Pitfall:
- Clinicians are generally unsatisfied with lack of patient specificity and inappropriate context of DDI alerts 1
- Excessive alerts contribute to alert fatigue and high override rates 1
Slide 10: Prevention Strategies
Systematic knowledge of drug interactions, particularly involving absorption, elimination, transport, and metabolism, helps prevent adverse effects. 5
Key Prevention Strategies:
- Minimize polypharmacy: The probability of interactions increases with the number of drugs taken 5
- Consider therapeutic alternatives: Choose drugs not metabolized by the same pathways when possible 2
- Use drug interaction software: Electronic prescribing systems and databases help identify potential interactions 5, 1
- Adjust administration timing: Separate administration of interacting drugs when interactions cannot be avoided 2
- Monitor for signs of toxicity or effectiveness: Regular re-evaluation of therapy is essential 8
- Adjust dosages when indicated: Proactive dose reduction for known interactions (e.g., warfarin with amiodarone) 8
- Consult clinical pharmacists: Especially when clinical circumstances require use of drugs with high interaction potential 8
Slide 11: Special Populations at Higher Risk
Elderly patients (≥65 years) take an average of 5 drugs, substantially increasing the likelihood of DDIs and drug-related hospitalizations. 5
High-Risk Groups:
- Geriatric patients: Pravastatin AUC was 27-46% higher in elderly patients compared to younger subjects 4
- Hepatic impairment: Pravastatin AUC varied 18-fold in cirrhotic patients versus 5-fold in healthy subjects 4
- Renal impairment: Patients with severe renal impairment had 69% higher pravastatin AUC 4
- Cancer patients: Receive multiple medications for supportive care and toxicity management, with narrow therapeutic windows 1
- HIV/HCV co-infected patients: Require close attention to antiretroviral drug interactions with DAAs 1
Slide 12: Patient Education and Adherence
Patients should be educated on the importance of adherence to therapy, following dosing recommendations, and reporting use of over-the-counter medications, internet-purchased medications, and recreational drugs. 1