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Introduction

  • Benzodiazepines are used for numerous acute states in the emergency department, especially

    • seizures and agitation

  • IV access is often not available for patients with seizures or agitation and alternative routes must be

    • considered; the drug of choice may change depending on the route of administration

  • This handout will focus on the pharmacokinetics of the two most utilized benzodiazepines in the

    • emergency department, lorazepam and midazolam

Clinical Detail

This handout focuses on the pharmacokinetics of the two most utilized benzodiazepines in the emergency department, lorazepam and midazolam, across the routes of administration most relevant when IV access is unavailable.

ParameterLorazepam IVLorazepam IMMidazolam IVMidazolam IMMidazolam IN
DoseSedation: 0.5–2 mg
Seizure: 4 mg		Sedation: 0.5–2 mg
Seizure: 0.5–2 mg (not preferred)		Sedation: 0.5–2 mg
Seizure: 0.2 mg/kg (not preferred)		Sedation: 5 mg
Seizure: 10 mg or 0.2 mg/kg; max 10 mg		Sedation: 0.1 mg/kg
Seizure: 0.2 mg/kg; max 10 mg
Onset2–10 min (longer for anticonvulsant)20–30 min3–5 min15 min10 min
Duration3–6 hours for seizures, up to 8 hours for sedation6–8 hours< 2 hours2–6 hours20–30 min
Bioavailability100%83–100%100%90%44%
Pros / ConsPro: Fastest onsetPro: No IV access needed
Con: Erratic absorption		Con: Short duration, potential for recurrence of agitation/seizurePro: No IV access neededPro: Least invasive administration
Con: Small volumes (max 1 mL each nare), high-concentration drug needed

Evidence

Author, YearDesign / Sample SizeIntervention & ComparisonOutcome
Nobay 2004Prospective, double-blind, randomized
N = 95		IM midazolam vs. IM haloperidol vs. IM lorazepam for agitationMean time to sedation (min)
Lorazepam: 32.3 (±20)
Midazolam: 18.3 (±14)
Haloperidol: 28.3 (±25)
*Lorazepam dropped from study due to significantly longer time to sedation and awakening
Silbergleit 2012Prospective, double-blind, randomized, non-inferiority
N = 893		IM midazolam versus IV lorazepam for seizureSeizures absent at time of arrival to ED
IM midazolam: 73.4%
IV lorazepam: 63.4%
Statistically significant for non-inferiority
Haut 2016Systematic review
N = 75 studies		Compared time to administration and time to seizure termination for multiple different benzodiazepines given by various routesFaster time to drug administration of IM midazolam was offset by the faster onset of IV lorazepam
10 studies showed faster time to administration with IM/IN administration over IV or rectal administration, 7 of which were statistically significant
Owusu 2019Retrospective cohort
N = 50		IV lorazepam vs. IN midazolam for seizureMedian time to seizure termination
IV: 0.3–5.7 min
IM: 1.1–7.9 min
IN: 2.3–7.5 min
IV lorazepam (N = 27): 3.3 min (IQR 1.2–62.4)
IN midazolam (N = 23): 3.2 min (IQR 0.1–28.5)
There was no difference in the number of repeat benzodiazepine doses required or time to administration

Conclusions

  • The initial agent used does not have to be the definitive agent for treatment. Utilizing alternative

    • routes in order to obtain IV access in agitation/convulsing patients is often the safest for both the

    patient and staff members. It may also allow therapy to be initiated faster than waiting to obtain

    IV access.

  • A lack of literature directly comparing all routes of administration for all benzodiazepines should not

    • limit utilization. Important differences exist in pharmacokinetics of each drug and route of

    administration that may be beneficial for specific populations and disease states.

References

    Lorazepam. Micromedex [Electronic version].Greenwood Village, CO: Truven Health Analytics. Accessed 2020, February 24.

    http://www.micromedexsolutions.com/

    Midazolam. Micromedex [Electronic version].Greenwood Village, CO: Truven Health Analytics. Accessed 2020, February 24.

    http://www.micromedexsolutions.com/

    Lorazepam. Lexicomp [online database].Hudson, OH. Woltes Kluwer Clinical Drug Information, Inc. Accessed 2020, February 24. http://www.online.lexi.com

    Midazolam. Lexicomp [online database].Hudson, OH. Woltes Kluwer Clinical Drug Information, Inc. Accessed 2020, February 24. http://www.online.lexi.com

    Nobay, et al. Acad Emerg Med. 2004;11(7):744-49.

    Haut, et al. Epilepsy & Behavior. 2016;63:109-17.

    Silbergleit, et al. NEJM. 2012;366(7):591-600.

    Owusu, et al. Epilepsy & Behavior. 2019;98:161-67.

Tags:benzodiazepine routes seizures agitation

Source PDF

Benzodiazepine Pharmacokinetics and Routes of Administration.pdf