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).
Regarding cytochrome P450 (CYP) metabolism, polymorphic CYP2C19 and CYP3A4/5 are involved in the metabolism of several benzodiazepines39 and CYP2B6 has been recognized as a contributor to diazepam metabolism. CYP3A5 gene polymorphisms may produce variation in alprazolam metabolism; however, the predominant cytochrome involved in the metabolism of nonoxidatively metabolized benzodiazepines (lorazepam, oxazepam, and temazepam) is primarily CYP3A4, and most effects on CYP3A4 activity are related to concomitant medications and other nongenetic factors.
Drug-drug interactions
Apart from lorazepam,40,41 oxazepam,42,43 and temazepam, most benzodiazepines are metabolized through oxidative mechanisms that involve CYP3A4 (Figure 220).39 As such, their metabolism is influenced by medications that impact CYP3A4, including antifungals (eg, ketoconazole), calcium channel blockers (eg, verapamil, diltiazem), nefazodone, some protease inhibitors, and macrolide antibiotics. Research has examined the impact of low-dose estrogen oral contraceptives (OCPs) on exposure (eg, plasma concentrations) of several benzodiazepines. The mechanism for this interaction is likely complex and putatively involves multiple pathways, including inhibition of CYP3A4 by OCPs. The effects of OCPs on benzodiazepine pharmacokinetics vary based on the metabolism of the benzodiazepine. In general, medications oxidized and nitroreduced (eg, chlordiazepoxide, alprazolam, diazepam, and nitrazepam) have decreased clearance in patients treated with OCPs. Regarding nonoxidatively metabolized benzodiazepines, data are mixed. Research found no OCP-related effects on the pharmacokinetics of nonoxidatively metabolized benzodiazepines44; another study suggested that clearance of these medications—through increased glucuronidation—may be increased.31 The effect of smoking on benzodiazepine concentration has been well documented. Smoking increases the clearance of orally administered diazepam,45 but not IV diazepam, midazolam, or lorazepam, suggesting that this represents a first-pass effect.46 For alprazolam, plasma concentrations are reduced by 15% to 30% in smokers and total body clearance is 24% greater compared to nonsmokers, which results in an approximately 50% increase in half-life in nonsmokers compared to smokers.47 The most notable interaction between benzodiazepines and SSRIs is seen with fluvoxamine. Because fluvoxamine moderately inhibits CYP2C19 and CYP3A4 and potently inhibits CYP1A2,48 the clearance of oxidatively metabolized benzodiazepines is reduced.49 Additionally, the effects of grapefruit juice—a potent inhibitor of CYP3A4—has been evaluated for several benzodiazepines. Yasui et al50 found grapefruit juice did not alter alprazolam plasma concentrations. However, in separate research, grapefruit juice tripled diazepam exposure, increased peak concentrations 1.5-fold, and prolonged absorption.51
Hepatic disease
Exposure to benzodiazepines—other than lorazepam, oxazepam, and temazepam—is influenced by intrinsic hepatic disease and requires dose adjustment in individuals with significant hepatic impairment. The impact of hepatic disease on the clinical pharmacology of benzodiazepines may relate to 2 factors: protein binding and metabolism. In a study of individuals with cirrhosis, lorazepam binding was decreased, although its metabolism and clearance were largely unaffected.40
Aging and benzodiazepine metabolism/clearance
Aging is associated with myriad physiologic changes (eg, decrease in renal clearance after age 40, changes in body fat distribution, changes in activity of cytochromes) that are relevant to benzodiazepine pharmacology. They may underlie differences in the tolerability of benzodiazepines and other clinically relevant characteristics (eg, duration of action, accumulation).
Several studies have evaluated the impact of aging on the clearance and disposition of selected benzodiazepines. The respective half-lives of chlordiazepoxide and diazepam increase from 4- to 6-fold from age 20 to 80. Further, with chronic dosing, highly lipophilic benzodiazepines may require additional attention in geriatric patients. In a study that included individuals up to age 78, steady-state plasma concentrations of diazepam and its metabolite, desmethyldiazepam (DMDZ), were 30% to 35% higher in older patients compared to younger individuals.52 In this study, the half-lives for the young and older patients were 31 hours and 86 hours, respectively, for diazepam, and 40 hours and 80 hours, respectively, for the active metabolite. The half-life of diazepam is increased by “1 hour for each year of age beginning with a half-life of 20 hours at 20 years of age, as the volume of distribution is increased, and clearance is decreased.”52 Clinically, this implies that in older adults, clinicians should expect lower peak concentrations (Cmax), higher trough concentrations (Cmin), and that diazepam will take longer to reach steady-state concentrations. Taken together, these findings raised concern that “slow accumulation and delayed washout of diazepam and DMDZ is probable.”52 These findings—which may have more clinical relevance than those of single-dose studies—suggest that the effects related to diazepam would also take longer to resolve in older patients. Finally, lorazepam clearance or distribution does not appear to be affected by aging, at least in patients age 15 to 73.40 Alprazolam is more slowly cleared in geriatric patients and its effects may be potentiated by reduced protein binding.
