Lorazepam Metabolism in Liver Impairment
Lorazepam does not rely on the cytochrome P450 system for metabolism, making it a safer option for patients with impaired liver function compared to other benzodiazepines. 1
Metabolism of Lorazepam
- Lorazepam undergoes direct glucuronide conjugation in the liver, bypassing the cytochrome P450 enzyme system that metabolizes most other benzodiazepines 2, 3
- The primary metabolite is lorazepam glucuronide, which is pharmacologically inactive 3, 4
- Approximately 70-75% of the administered dose is excreted as the glucuronide conjugate in urine 3
Comparison with Other Benzodiazepines
- Unlike lorazepam, midazolam and diazepam are extensively metabolized by cytochrome P450 enzymes (particularly CYP3A4 and CYP2C19) 1, 2
- Midazolam and diazepam produce active metabolites that can accumulate with prolonged administration, especially in patients with renal dysfunction 1
- The clearance of midazolam and diazepam is significantly reduced in patients with hepatic dysfunction, while lorazepam's metabolism is less affected 1
Clinical Implications for Liver Impairment
- Lorazepam's elimination half-life is still increased in patients with hepatic dysfunction, but to a lesser extent than other benzodiazepines 1, 5
- For patients with liver cirrhosis, lorazepam may be preferred over benzodiazepines that rely heavily on CYP450 metabolism 1, 2
- Despite bypassing the CYP450 system, dose adjustments are still necessary for patients with severe liver impairment 5
Important Considerations and Precautions
- Parenteral formulations of lorazepam contain propylene glycol as a diluent, which can cause toxicity in critically ill patients, manifesting as metabolic acidosis and acute kidney injury 1
- Total daily IV doses as low as 1 mg/kg of lorazepam can cause propylene glycol toxicity 1
- The elimination half-life and duration of clinical effect of lorazepam are increased in patients with renal failure 1
- Elderly patients are significantly more sensitive to the sedative effects of all benzodiazepines, including lorazepam 1
Monitoring Recommendations
- Monitor serum osmol gap as a screening tool for propylene glycol accumulation; an osmol gap greater than 10-12 mOsm/L may indicate significant propylene glycol accumulation in patients receiving lorazepam 1
- For patients with both hepatic and renal impairment, more careful dose adjustments and monitoring are required 1, 5
- Watch for signs of excessive sedation, respiratory depression, and systemic hypotension, especially when administered with other cardiopulmonary depressants 1