What are the potential interactions between lorazepam (Ativan) and amiodarone when used concurrently?

Drug Interaction Between Lorazepam and Amiodarone

There is no clinically significant pharmacokinetic interaction between lorazepam and amiodarone, making this a relatively safe combination compared to other benzodiazepines that are metabolized by CYP enzymes. 1

Pharmacological Properties and Metabolism

Lorazepam

• Lorazepam is a benzodiazepine that potentiates GABA-mediated neural inhibition, producing sedation, hypnosis, decreased anxiety, anterograde amnesia, muscle relaxation, and anticonvulsant activity 1
• Unlike other benzodiazepines such as midazolam and diazepam, lorazepam is primarily metabolized through direct glucuronide conjugation rather than through cytochrome P450 enzymes 1
• This metabolic pathway makes lorazepam less susceptible to drug interactions with medications that inhibit CYP enzymes 1

Amiodarone

• Amiodarone is a potent antiarrhythmic agent used to treat ventricular arrhythmias and atrial fibrillation 2
• It is metabolized by CYP3A4 and CYP2C8 to its active metabolite desethylamiodarone 3
• Amiodarone acts as an inhibitor of multiple cytochrome P450 enzymes including CYP3A4, CYP1A2, CYP2C9, and CYP2D6 3
• It also inhibits P-glycoprotein (P-gp) efflux transporter in a reversible manner 3
• Amiodarone has an extremely long half-life (averaging about 58 days), allowing for potential interactions months after discontinuation 2, 3

Interaction Assessment

Minimal Pharmacokinetic Interaction

• Since lorazepam undergoes direct glucuronide conjugation rather than CYP metabolism, it is not significantly affected by amiodarone's inhibition of CYP enzymes 1
• This metabolic pathway difference makes lorazepam a safer choice when combined with amiodarone compared to benzodiazepines like midazolam or diazepam that are metabolized by CYP3A4 1

Potential Pharmacodynamic Interactions

• Both medications can cause cardiovascular effects that might theoretically compound:
  • Amiodarone may cause hypotension, bradycardia, heart block, prolonged QT interval, and torsades de pointes 2
  • Benzodiazepines like lorazepam can cause a modest reduction in arterial blood pressure and an increase in heart rate due to decreased systemic vascular resistance 1
• The combination could potentially enhance sedative effects and respiratory depression, particularly in elderly or critically ill patients 3

Clinical Recommendations

Preferred Benzodiazepine Choice

• Lorazepam is a preferred benzodiazepine option when co-administration with amiodarone is necessary, due to its metabolic pathway that avoids CYP enzymes 1
• This makes it less susceptible to the enzyme inhibition effects of amiodarone compared to midazolam or diazepam 1

Monitoring Requirements

• Monitor for excessive sedation and respiratory depression, particularly when initiating therapy or changing doses 1
• Watch for hemodynamic changes, including hypotension and bradycardia, especially in patients with underlying cardiovascular disease 2, 1
• Elderly patients and those with multiple comorbidities may be at higher risk for adverse effects from potential pharmacodynamic interactions 3

Dosing Considerations

• Consider using lower initial doses of lorazepam when co-administered with amiodarone, particularly in elderly patients or those with compromised cardiovascular function 3, 1
• Unlike some drug combinations with amiodarone (such as statins), there are no specific dose limitations recommended for lorazepam when used with amiodarone 2

Contrast with Other Drug Interactions with Amiodarone

• Amiodarone has well-documented significant interactions with many other medications:
  • Statins: Simvastatin dose should be limited to 20 mg daily when co-administered with amiodarone due to increased risk of myopathy and rhabdomyolysis 2
  • Warfarin: Amiodarone potentiates the anticoagulant effect of warfarin, requiring close monitoring 4
  • Digoxin: Amiodarone increases digoxin levels, necessitating close monitoring 4
  • Quinidine and other antiarrhythmics: Risk of torsades de pointes when combined with amiodarone 4
  • Azole antifungals: Serious cardiovascular events including cardiac arrest have been reported with concurrent use 5