In July 2020, remimazolam, a novel short-acting drug, was approved in the US for procedural sedation in adults (1). Like midazolam (a common anesthetic adjunct), remimazolam is a benzodiazepine and operates by modulating γ-aminobutyric acid (GABA) receptor activity to induce cell membrane hyperpolarization, thereby inhibiting neural activity via an increase in chloride ion influx (2). Its structural and metabolic properties have generated interest in whether, and in what situations, remimazolam is superior to other drugs for intravenous anesthesia and sedation.
Remimazolam was designed to have a carboxylic ester moiety incorporated into its benzodiazepine core. With this structural modification, remimazolam is rapidly hydrolyzed to a pharmacologically inactive metabolite (CNS 7054) via nonspecific tissue esterase activity, which leads to a quick onset and offset of sedation and predictable duration of action (1). Given these pharmacological properties, remimazolam appears to have several advantages over currently available short-acting sedative drugs (1).
The pharmacokinetic properties of intravenous remimazolam were investigated during the first human trial of this drug to determine its safety as a potential anesthesia agent. In the initial phase I study, remimazolam (0.01-0.30 mg/kg administered over 1 min) was compared to midazolam (0.075 mg/kg administered over 1 min). The mean residence times (average time that a drug spends in the body) of remimazolam and midazolam were 0.51 hrs and 3.62 hrs. Additionally, the elimination clearance of remimazolam was approximately three times that of midazolam (70.3 vs. 23.0 L/h) and independent of body weight (3). Furthermore, it was determined that the pharmacokinetic properties of remimazolam were not significantly different between the elderly (median age: 66.0 years) vs. young (median age: 21.0 years) patients, in patients with normal renal function (estimated glomerular filtration rate [eGFR] ≥ 90 ml/min/1.73 m2) vs. those with end-stage renal failure (eGFR < 15 ml/min/1.73 m2), and patients with normal hepatic function vs. those with mild/moderate hepatic dysfunction (Child-Pugh class A and B). However, hepatic clearance was lower in patients with severe hepatic impairment (Child-Pugh class C) than those in normal healthy volunteers. Thus, careful dosage adjustment of remimazolam is recommended in patients with severe hepatic impairment (4).
The ideal characteristics of the anesthetic agents used for procedural sedation include fast onset of action and recovery and few adverse effects. Midazolam, the historical gold standard for procedural sedation, has been highly prized due to its quick onset. However, the active metabolite of midazolam is potent and likely prolongs the effects of sedation (1). In contrast, remimazolam (with its carboxylic ester moiety) produces an inactive metabolite. On a related note, propofol is another agent that is frequently used for procedural sedation. Although it has a rapid onset of action and a very short half-life, it precipitates more adverse events, including hypotension, respiratory depression, bradycardia, and pain upon injection (1). Clinical studies comparing efficacy and safety of remimazolam and propofol for procedural sedation suggest that remimazolam is non-inferior in terms of sedative efficacy and exhibits a better safety profile than that of propofol (1). In summary, it can be seen that remimazolam can be used as a safe and effective alternative to other widely-used sedatives, such as midazolam and propofol, for intravenous anesthesia in patients undergoing various procedures.
- Kim KM. Remimazolam: pharmacological characteristics and clinical applications in anesthesiology. Anesth Pain Med (Seoul). 2022;17(1):1-11. doi:10.17085/apm.21115
- Shimizu T, Takasusuki T, Yamaguchi S. Remimazolam Compared to Propofol for Total Intravenous Anesthesia with Remifentanil on the Recovery of Psychomotor Function: A Randomized Controlled Trial. Adv Ther. 2023;40(10):4395-4404. doi:10.1007/s12325-023-02615-w
- Antonik LJ, Goldwater DR, Kilpatrick GJ, Tilbrook GS, Borkett KM. A placebo- and midazolam-controlled phase I single ascending-dose study evaluating the safety, pharmacokinetics, and pharmacodynamics of remimazolam (CNS 7056): Part I. Safety, efficacy, and basic pharmacokinetics. Anesth Analg. 2012;115(2):274-283. doi:10.1213/ANE.0b013e31823f0c28
- Stöhr T, Colin PJ, Ossig J, et al. Pharmacokinetic properties of remimazolam in subjects with hepatic or renal impairment. Br J Anaesth. 2021;127(3):415-423. doi:10.1016/j.bja.2021.05.027