What is the duration of action of lorazepam (Ativan)?

Duration of Action of Lorazepam (Ativan)

Lorazepam has an elimination half-life of approximately 12 hours in adults, with clinical effects typically lasting 6-8 hours after a single dose. 1

Pharmacokinetic Profile

Absorption and Distribution

• Lorazepam is readily absorbed with an absolute bioavailability of 90%
• Peak plasma concentrations occur approximately 2 hours after oral administration
• At clinically relevant concentrations, lorazepam is approximately 85% bound to plasma proteins 1

Metabolism and Elimination

• Primary metabolic pathway: Conjugation at the 3-hydroxy group to form lorazepam glucuronide (inactive)
• Mean half-life of unconjugated lorazepam in human plasma: ~12 hours
• Mean half-life of lorazepam glucuronide: ~18 hours
• 70-75% of the administered dose is excreted as glucuronide conjugate in urine 2
• Complete elimination of active drug and glucuronide conjugate occurs within 1 week following the last dose 2

Duration of Action by Patient Population

Adults

• Elimination half-life: 8-25 hours
• Volume of distribution: 1.0-1.3 L/kg
• Clearance: 0.7-1.2 ml/min/kg 3
• Advanced age does not significantly affect pharmacokinetics, though one study showed a 20% decrease in total body clearance in elderly subjects (60-84 years) compared to younger subjects (19-38 years) 1

Children

• Infants: Half-life of approximately 40.2 hours (range 18-73 hours)
• Children: Half-life of approximately 10.5 hours (range 6-17 hours) 4
• Neonates: Half-life of approximately 40 hours 4

Clinical Implications

Therapeutic Effects

• Onset of action: Within 15-30 minutes of oral administration
• Peak clinical effects: Approximately 2 hours after administration 5
• Duration of anxiolytic and sedative effects: 6-8 hours after a single dose

Withdrawal Phenomena

• Rebound insomnia may occur 3-5 days after discontinuation
• Rebound anxiety may also occur during the withdrawal period 6, 7
• Signs and symptoms of withdrawal from benzodiazepine therapy can be delayed 4

Important Considerations for Clinical Use

Conversion from IV to Oral Administration

When converting from continuous IV midazolam to oral lorazepam (for patients on IV midazolam >7 days):

1. Calculate the 24-hour midazolam dose
2. Divide by 12 (accounting for lorazepam being twice as potent as midazolam and having a sixfold longer half-life)
3. Divide the calculated lorazepam dose by 4 and administer every 6 hours
4. Wean by 10-20% per day, gradually increasing dosage intervals 4

Reversal of Effects

If needed, lorazepam effects can be reversed with flumazenil:

• Initial dose: 0.01 mg/kg (up to 0.2 mg) IV over 15 seconds
• Additional doses: 0.01 mg/kg (up to 0.2 mg) at 60-second intervals
• Maximum total dose: 0.05 mg/kg or 1 mg (whichever is lower)
• Monitor for at least 2 hours after the last dose of flumazenil 8

Cautions

• Flumazenil is contraindicated in patients with seizure history or benzodiazepine dependence
• Duration of action of flumazenil (30-60 minutes) may be shorter than that of lorazepam, requiring close monitoring for resedation 8
• Prolonged use of lorazepam can lead to tolerance and dependence, requiring gradual tapering when discontinuing

Remember that lorazepam's duration of action can vary based on patient factors including age, hepatic function, and concomitant medications. The weaning period should be proportional to the duration of treatment.