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Charleston, SC

jimmy@pharmacyfridaypeals.com

Benzodiazepine Pharmacokinetics and Routes of Administration

Introduction

  1. Benzodiazepines are used for numerous acute states in the emergency department, especially seizures and agitation 
  2. 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 
  3. This handout will focus on the pharmacokinetics of the two most utilized benzodiazepines in the emergency department, lorazepam and midazolam
 Pharmacology  
 Lorazepam Midazolam 
AdministrationIVIMIVIMIN
DoseSedation:  0.5-2 mg   Seizure: 4mgSedation:  5-2mg   Seizure:  0.5 -2mg (not preferred)Sedation:  0.5-2mg   Seizure: 0.2mg/kg  (not preferred)Sedation: 5mg   Seizure:10mg or 0.2mg/kg; max 10mgSedation: 0.1mg/kg   Seizure: 0.2mg/kg; max 10mg
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 hour2-6 hour20-30 min
Bioavailability 100%83-100%100%90%44%
Pros /ConsPro: Fastest onset Pro: No IV access needed    Con: erratic absorptionCon: short duration, potential for recurrence of agitation/seizure Pro: No IV access needed  Pro: Least invasive administration   Con: small volumes (max 1mL each nare), high concentration drug needed
Concentrations available  (at GHS)2mg/mL2mg/mL1mg/mL 5mg/mL1mg/mL 5mg/mL5mg/mL

Jlpruitt@gmh.edu; kmfifer@gmh.edu                                                                                                                           For educational purposes only

 Overview of Evidence
Author, year Design/ sample sizeIntervention & ComparisonOutcome
Nobay 2004Prospective, double-blind, randomized N=95IM 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= 893IM 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    Faster time to drug administration of IM midazolam was offset by the faster onset of IV lorazepam  
Haut 2016Systematic Review N=75 studiesCompared time to administration and time to seizure termination for multiple different benzodiazepines given by various routes Median time to seizure termination IV: 0.3-5.7 min IM: 1.1-7.9 min IN: 2.3-7.5 min   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= 50IV lorazepam vs. IN midazolam for seizureMedian time to seizure termination 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

  1. 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.
  2. 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

  1. Lorazepam. Micromedex [Electronic version].Greenwood Village, CO: Truven Health Analytics. Accessed 2020, February 24. http://www.micromedexsolutions.com/
  2. 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 4. 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.

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