Pharmacokinetics, Pharmacodynamics, and Side Effects of Midazolam: A Review and Case Example

Jens-Uwe Peter; Peter Dieudonné; Oliver Zolk

doi:10.3390/ph17040473

journal article Open Access Apr 08, 2024

Pharmacokinetics, Pharmacodynamics, and Side Effects of Midazolam: A Review and Case Example

Jens-Uwe Peter

Peter Dieudonné Oliver Zolk

Pharmaceuticals Vol. 17 No. 4 pp. 473 · MDPI AG

View at Publisher Save 10.3390/ph17040473

Abstract

Midazolam, a short-acting benzodiazepine, is widely used to alleviate patient anxiety, enhance compliance, and aid in anesthesia. While its side effects are typically dose-dependent and manageable with vigilant perioperative monitoring, serious cardiorespiratory complications, including fatalities and permanent neurological impairment, have been documented. Prolonged exposure to benzodiazepines, such as midazolam, has been associated with neurological changes in infants. Despite attempts to employ therapeutic drug monitoring for optimal sedation dosing, its efficacy has been limited. Consequently, efforts are underway to identify alternative predictive markers to guide individualized dosing and mitigate adverse effects. Understanding these factors is crucial for determining midazolam’s suitability for future administration, particularly after a severe adverse reaction. This article aims to elucidate the factors influencing midazolam’s pharmacokinetics and pharmacodynamics, potentially leading to adverse events. Finally, a case study is presented to exemplify the complex investigation into the causative factors of midazolam-related adverse events.

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References

161

[1]

Altamimi "Inter-individual variation in midazolam clearance in children" Arch. Dis. Child. (2015) 10.1136/archdischild-2013-305720

[2]

Lamba "Genetic contribution to variable human CYP3A-mediated metabolism" Adv. Drug Deliv. Rev. (2002) 10.1016/s0169-409x(02)00066-2

[3]

Backman "The area under the plasma concentration-time curve for oral midazolam is 400-fold larger during treatment with itraconazole than with rifampicin" Eur. J. Clin. Pharmacol. (1998) 10.1007/s002280050420

[4]

Ozdemir "Evaluation of the genetic component of variability in CYP3A4 activity: A repeated drug administration method" Pharmacogenetics (2000) 10.1097/00008571-200007000-00001

[5]

Inherited and Acquired Determinants of Hepatic CYP3A Activity in Humans

Johannes Matthaei, Wagner Hugo Bonat, Reinhold Kerb et al.

Frontiers in Genetics 2020 10.3389/fgene.2020.00944

[6]

Miao "Association of genotypes of the CYP3A cluster with midazolam disposition in vivo" Pharmacogenom. J. (2009) 10.1038/tpj.2009.21

[7]

He "Genotype-phenotype associations of cytochrome P450 3A4 and 3A5 polymorphism with midazolam clearance in vivo" Clin. Pharmacol. Ther. (2005) 10.1016/j.clpt.2004.11.112

[8]

Floyd "Genotype-phenotype associations for common CYP3A4 and CYP3A5 variants in the basal and induced metabolism of midazolam in European- and African-American men and women" Pharmacogenetics (2003) 10.1097/00008571-200310000-00003

[9]

Nies "Monitoring of sedation depth in intensive care unit by therapeutic drug monitoring? A prospective observation study of medical intensive care patients" J. Intensive Care (2018) 10.1186/s40560-018-0331-7

[10]

Bremer "Midazolam therapeutic drug monitoring in intensive care sedation: A 5-year survey" Ther. Drug Monit. (2004) 10.1097/00007691-200412000-00010

[11]

Vinks "Pharmacodynamics of midazolam in pediatric intensive care patients" Ther. Drug Monit. (2005) 10.1097/00007691-200502000-00018

[12]

Oldenhof "Clinical pharmacokinetics of midazolam in intensive care patients, a wide interpatient variability?" Clin. Pharmacol. Ther. (1988) 10.1038/clpt.1988.31

[13]

Takano "Interaction with P-glycoprotein and transport of erythromycin, midazolam and ketoconazole in Caco-2 cells" Eur. J. Pharmacol. (1998) 10.1016/s0014-2999(98)00607-4

[14]

Rautio "Midazolam exhibits characteristics of a highly permeable P-glycoprotein substrate" Pharm. Res. (2003) 10.1023/a:1023433502647

[15]

Center for Drug Evaluation and Research (2024, March 17). In Vitro Drug Interaction Studies—Cytochrome P450 Enzyme- and Transporter-Mediated Drug Interactions Guidance for Industry, Available online: https://www.fda.gov/media/134582/download.

[16]

Franke "Influence of solute carriers on the pharmacokinetics of CYP3A4 probes" Clin. Pharmacol. Ther. (2008) 10.1038/clpt.2008.94

[17]

Imanaga "The effects of the SLCO2B1 c.1457C > T polymorphism and apple juice on the pharmacokinetics of fexofenadine and midazolam in humans" Pharmacogenet. Genom. (2011) 10.1097/fpc.0b013e32834300cc

[18]

Jarvinen "The Role of Uptake and Efflux Transporters in the Disposition of Glucuronide and Sulfate Conjugates" Front. Pharmacol. (2021) 10.3389/fphar.2021.802539

[19]

Allonen "Midazolam kinetics" Clin. Pharmacol. Ther. (1981) 10.1038/clpt.1981.217

[20]

Pentikainen "Pharmacokinetics of midazolam following intravenous and oral administration in patients with chronic liver disease and in healthy subjects" J. Clin. Pharmacol. (1989) 10.1002/j.1552-4604.1989.tb03327.x

[21]

Lee "Urinary metabolic markers reflect on hepatic, not intestinal, CYP3A activity in healthy subjects" Drug Metab. Pharmacokinet. (2021) 10.1016/j.dmpk.2020.12.001

[22]

Stoch "Effect of different durations of ketoconazole dosing on the single-dose pharmacokinetics of midazolam: Shortening the paradigm" J. Clin. Pharmacol. (2009) 10.1177/0091270008331133

[23]

Tseng "Relative contributions of cytochrome CYP3A4 versus CYP3A5 for CYP3A-cleared drugs assessed in vitro using a CYP3A4-selective inactivator (CYP3cide)" Drug Metab. Dispos. (2014) 10.1124/dmd.114.057000

[24]

Yu "Effect of the CYP3A5 genotype on the pharmacokinetics of intravenous midazolam during inhibited and induced metabolic states" Clin. Pharmacol. Ther. (2004) 10.1016/j.clpt.2004.03.009

[25]

Greenblatt "Midazolam hydroxylation by human liver microsomes in vitro: Inhibition by fluoxetine, norfluoxetine, and by azole antifungal agents" J. Clin. Pharmacol. (1996) 10.1002/j.1552-4604.1996.tb04251.x

[26]

Seo "Metabolism of 1′- and 4-hydroxymidazolam by glucuronide conjugation is largely mediated by UDP-glucuronosyltransferases 1A4, 2B4, and 2B7" Drug Metab. Dispos. (2010) 10.1124/dmd.110.035295

[27]

Klieber "Contribution of the N-glucuronidation pathway to the overall in vitro metabolic clearance of midazolam in humans" Drug Metab. Dispos. (2008) 10.1124/dmd.107.019539

[28]

Hyland "In vitro and in vivo glucuronidation of midazolam in humans" Br. J. Clin. Pharmacol. (2009) 10.1111/j.1365-2125.2009.03386.x

[29]

Ziegler "Comparison of the effects of intravenously administered midazolam, triazolam and their hydroxy metabolites" Br. J. Clin. Pharmacol. (1983) 10.1111/j.1365-2125.1983.tb02272.x

[30]

Mandema "Pharmacokinetic-pharmacodynamic modeling of the central nervous system effects of midazolam and its main metabolite alpha-hydroxymidazolam in healthy volunteers" Clin. Pharmacol. Ther. (1992) 10.1038/clpt.1992.84

[31]

Bauer "Prolonged sedation due to accumulation of conjugated metabolites of midazolam" Lancet (1995) 10.1016/s0140-6736(95)91209-6

[32]

Stanski "Midazolam pharmacology and pharmacokinetics" Anesth. Rev. (1985)

[33]

Kanto "Midazolam: The first water-soluble benzodiazepine. Pharmacology, pharmacokinetics and efficacy in insomnia and anesthesia" Pharmacotherapy (1985) 10.1002/j.1875-9114.1985.tb03411.x

[34]

Johnson "Contribution of midazolam and its 1-hydroxy metabolite to preoperative sedation in children: A pharmacokinetic-pharmacodynamic analysis" Br. J. Anaesth. (2002) 10.1093/bja/89.3.428

[35]

Franken "Hypoalbuminaemia and decreased midazolam clearance in terminally ill adult patients, an inflammatory effect?" Br. J. Clin. Pharmacol. (2017) 10.1111/bcp.13259

[36]

Beierle "Gender differences in pharmacokinetics and pharmacodynamics" Int. J. Clin. Pharmacol. Ther. (1999)

[37]

Gandhi "Sex differences in pharmacokinetics and pharmacodynamics" Annu. Rev. Pharmacol. Toxicol. (2004) 10.1146/annurev.pharmtox.44.101802.121453

[38]

Lamba "Genetic predictors of interindividual variability in hepatic CYP3A4 expression" J. Pharmacol. Exp. Ther. (2010) 10.1124/jpet.109.160804

[39]

Schmidt "Gender difference in ifosfamide metabolism by human liver microsomes" Eur. J. Drug Metab. Pharmacokinet. (2001) 10.1007/bf03190396

[40]

Wolbold "Sex is a major determinant of CYP3A4 expression in human liver" Hepatology (2003) 10.1002/hep.1840380424

[41]

Yang "Systematic genetic and genomic analysis of cytochrome P450 enzyme activities in human liver" Genome Res. (2010) 10.1101/gr.103341.109

[42]

Gallagher "Sex differences in UDP-glucuronosyltransferase 2B17 expression and activity" Drug Metab. Dispos. (2010) 10.1124/dmd.110.035345

[43]

Meibohm "How important are gender differences in pharmacokinetics?" Clin. Pharmacokinet. (2002) 10.2165/00003088-200241050-00002

[44]

Cotreau "The influence of age and sex on the clearance of cytochrome P450 3A substrates" Clin. Pharmacokinet. (2005) 10.2165/00003088-200544010-00002

[45]

Tsunoda "Differentiation of intestinal and hepatic cytochrome P450 3A activity with use of midazolam as an in vivo probe: Effect of ketoconazole" Clin. Pharmacol. Ther. (1999) 10.1016/s0009-9236(99)70009-3

[46]

Thangavel "Intrinsic sexually dimorphic expression of the principal human CYP3A4 correlated with suboptimal activation of GH/glucocorticoid-dependent transcriptional pathways in men" Endocrinology (2011) 10.1210/en.2011-1274

[47]

Dhir "Sexually dimorphic regulation of hepatic isoforms of human cytochrome p450 by growth hormone" J. Pharmacol. Exp. Ther. (2006) 10.1124/jpet.105.093773

[48]

Hu "Sex-dependent differences in cytochrome P450 3A activity as assessed by midazolam disposition in humans: A meta-analysis" Drug Metab. Dispos. (2010) 10.1124/dmd.109.031328

[49]

Chen "Sex differences in CYP3A activity using intravenous and oral midazolam" Clin. Pharmacol. Ther. (2006) 10.1016/j.clpt.2006.08.014

[50]

Zarezadeh "The effect of obesity, macronutrients, fasting and nutritional status on drug-metabolizing cytochrome P450s: A systematic review of current evidence on human studies" Eur. J. Nutr. (2021) 10.1007/s00394-020-02421-y

Showing 50 of 161 references

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References

Details

Published: Apr 08, 2024
Vol/Issue: 17(4)
Pages: 473
License: View

Authors

J

Jens-Uwe Peter

Institute of Clinical Pharmacology, Immanuel Klinik Rüdersdorf, Brandenburg Medical School, 15562 Rüdersdorf, Germany

P

Peter Dieudonné

Department of Anesthesiology, University Hospital Ulm, 89081 Ulm, Germany

O

Oliver Zolk

Institute of Clinical Pharmacology, Immanuel Klinik Rüdersdorf, Brandenburg Medical School, 15562 Rüdersdorf, Germany

Funding

Brandenburg Medical School publication fund

Cite This Article

Jens-Uwe Peter, Peter Dieudonné, Oliver Zolk (2024). Pharmacokinetics, Pharmacodynamics, and Side Effects of Midazolam: A Review and Case Example. Pharmaceuticals, 17(4), 473. https://doi.org/10.3390/ph17040473

Pharmacokinetics, Pharmacodynamics, and Side Effects of Midazolam: A Review and Case Example

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