Jeffrey R. Strawn, MD Professor of Psychiatry, Pediatrics, and Clinical Pharmacology Director, Anxiety Disorders Research Program
Julia Stimpfl, MD PGY-2 General Psychiatry Resident
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Department of Psychiatry and Behavioral Neuroscience University of Cincinnati College of Medicine Cincinnati, Ohio
Disclosures Dr. Strawn has received research support from Abbvie, the National Center for Advancing Translational Sciences, the National Institutes of Health (NIH), and the Patient-Centered Outcomes Research Institute. He has served as a consultant for Cerevel, the FDA, IntraCellular Therapies, Lundbeck, and Otsuka. He receives royalties from Springer Publishing and UpToDate and received material support from Myriad. He also received honoraria from the American Academy of Child and Adolescent Psychiatry, American Academy of Pediatrics, Medscape Live, and Neuroscience Education Institute. Dr. Strawn is Current Psychiatry’s Section Editor, Child and Adolescent Psychiatry. Dr. Stimpfl reports no financial relationships with any companies whose products are mentioned in this article, or with manufacturers of competing products. Views expressed within this article represent those of the authors and are not intended to represent the position of the NIH, the National Institute of Mental Health, or the Department of Health and Human Services.
Acknowledgments This work was supported by the Yung Family Foundation (Dr. Strawn).
Benzodiazepine pharmacokinetics are intimately linked with the onset of action and duration of clinical effect and vary based on the route of administration, absorption, and distribution/redistribution.31 In this review, we focus on oral administration as opposed to IV, IM, sublingual, or intranasal administration.
Absorption
Benzodiazepines are rapidly absorbed after oral administration and quickly enter the systemic circulation. However, absorption rates vary depending on specific aspects of the gastrointestinal milieu and intrinsic properties of the benzodiazepine. For example, alprazolam is more rapidly absorbed than most other benzodiazepines, with a Tmax of 1.8 hours compared to lorazepam, which has a Tmax of approximately 2 hours. These pharmacokinetic effects instantiate differences in tolerability and efficacy. Thus, following single doses of alprazolam and diazepam, self-rated sedating effects and impairment on a task of working memory suggest that effects have a more rapid onset for alprazolam relative to lorazepam.32 Food and concomitant medications can significantly affect benzodiazepine absorption. A single-dose, 3-way crossover study demonstrated that taking diazepam concomitantly with an antacid (eg, aluminum hydroxide) decreased peak concentrations and prolonged absorption by approximately 30 minutes. However, total absorption of the medication was unaffected.33 Additionally, administration of diazepam with food significantly slows absorption from 1 hour 15 minutes to approximately 2 hours 30 minutes and increases benzodiazepine absorption by 25% (Figure 134); the fat content of the meal appears important in moderating this effect.35 The impact of food on alprazolam varies by formulation. For example, when administered in an extended-release (XR) formulation with a high-fat meal, alprazolam absorption increases by one-third, while absorption for administration of the orally disintegrating tablet with a high-fat meal increases from 1 hour 30 minutes to 2 hours. Similarly, for lorazepam, administration with a meal delays absorption by approximately 2 hours; however, this effect does not appear present with the XR formulation. Administering benzodiazepines with food can be clinically leveraged to either accelerate the onset of action or decrease peak-associated adverse effects. Thus, when a highly lipophilic benzodiazepine is needed to treat acute anxiety or prior to an expected anxiogenic stimuli, administering the medication without food may produce a faster onset of action.
CNS penetration
Benzodiazepines enter the CNS by passive diffusion. Because of this, lipophilicity at physiologic pH influences the rate at which a benzodiazepine crosses the blood-brain barrier. The rate at which benzodiazepines enter the CNS influences their clinical effects and the speed at which both efficacy (ie, anxiolysis) and adverse effects (ie, sedation, slowed cognition) are observed. In general, more lipophilic medications initiate their anxiolytic effect more quickly. However, by quickly leaving the CNS (through the same mechanism that allowed them to enter the CNS at such speed), their effects rapidly cease as they redistribute into fat. Thus, highly lipophilic benzodiazepines produce more intense effects compared to less lipophilic benzodiazepines. For these reasons, lipophilicity is more important than half-life for determining the duration of effect in most patients.
Lipophilicity and duration of effect
Benzodiazepines and their metabolites tend to be highly protein-bound and distributed in fat- and lipid-enriched areas such as the CNS. As a result, the more lipophilic agents generally have the highest rates of absorption and the fastest onset of clinical effects. The duration of action for many benzodiazepines is determined by the rate and extent of distribution (a function of lipophilicity) rather than by the rate of elimination. For example, diazepam has a longer half-life than lorazepam, but its duration of action following a single dose is shorter. This is because diazepam is more lipophilic and therefore more extensively distributed (particularly to adipose tissue). This results in it leaving the brain and blood and distributing to other tissues. In turn, its CNS effect (ie, anxiolytic effects) are more quickly terminated.
By contrast, less lipophilic benzodiazepines maintain their CNS concentrations longer; they have a longer duration of action because of their slower redistribution, which culminates in a shorter half-life, and are less extensively distributed to peripheral tissues. In essence, this means that (other things being equal) a less lipophilic benzodiazepine produces a more sustained anxiolytic effect compared to a highly lipophilic benzodiazepine.36 Lipophilicity is also important in predicting some cognitive adverse effects, including amnesia. Benzodiazepines with high lipophilicity have greater absorption and faster onset of action as well as more rapid amnestic effects.37,38 These effects may relate to overall efficacy differences for oral benzodiazepines. A recent meta-analysis by Stimpfl et al36 found that less lipophilic benzodiazepines produced a greater response compared to more lipophilic benzodiazepines.
