A Brief History of Propofol and the Introduction of Remimazolam as a Potential Heir Apparent

Propofol (2,6-diisopropylphenol) is an intravenous (IV) sedative-hypnotic agent commonly used for the IV induction and maintenance of general anesthesia.¹ It has a rapid-onset, provides a rapid recovery even after multiple bolus doses or continuous infusion, and has anti-emetic properties which decreases the incidence of post-operative nausea and vomiting.¹ These benefits helped propofol become the most common IV induction agent in hospitals and clinics providing ambulatory anesthesia, where it is utilized as the IV induction agent in almost every modern general anesthetic.¹

Propofol acts on the GABAa receptor, potentiating its neuroinhibitory effect on postsynaptic neurons by hyperpolarizing them and inhibiting the generation of an action potential.^2,3 The GABAa receptor is also potentiated by volatile anesthetic agents and is the receptor target of barbiturates, benzodiazepines, neurosteroids, nonbenzodiazepines (Z-drugs), imidazoles (etomidate), anticonvulsants, and ethanol.³ Depending on the drug and dose, potentiation of the various GABA receptor subtypes produces sedative, anxiolytic, anticonvulsant, amnestic, hypnotic, and/or euphoric effects.¹

First reported in 1973, propofol was the agent selected after John (Iain) Glen, a Veterinary
Anesthesiologist working for Imperial Chemical Industries (ICI, now AstraZeneca) in Cheshire, England, screened a large number of alkyl-substituted phenol compounds for anesthetic properties superior to sodium thiopental and methohexital, the barbiturate IV anesthetics that had been in use since 1934 and 1956, respectively.^{1, 4-6} Pure propofol is a yellowish oil at room temperature. Easily dissolved in organic solvents, propofol’s poor solubility in water (150 mcg/L) required the use of a carrier vehicle to enable IV injection of doses suitable to produce general anesthesia.^7,8 In 1981, clinical trials of propofol which had been ongoing for four years were halted due to anaphylactoid reactions.9 Despite the desire by ICI to discontinue the development of propofol, its discoverer John Glen suspected the adverse reactions were not due to the drug, propofol, but the vehicle carrier, Cremophor EL, which is made from polyethoxylated castor oil.⁹ He began to investigate other suitable vehicle carriers, and after several years of research, and improvements in lipid emulsion technology, produced the current propofol macroemulsion. This lipid emulsion is composed of soybean oil, egg yolk lecithin and glycerol in water.^7,10 Clinical trials began in 1983,⁵ and successful outcomes in these clinical trials led to the approval of Diprivan (propofol) in the United Kingdom and New Zealand in 1986, the USA in 1989, and Canada in 1993.^5,6,11

The lipid emulsion consists of 0.15-0.3 μm droplets of soybean oil which provides the lipid environment in which propofol resides in high concentration. The soybean oil-propofol droplets in water, which would otherwise coalesce into larger droplets of oil and eventually separate into water and oil phases, are stabilized by the egg yolk lecithin, which imparts a net negative charge to the surface of the oil droplets, making an emulsion which is stable for several years.^5,6 It is these oil droplets, which scatter visible light, that give the propofol macroemulsion its white appearance.¹²

Although this propofol emulsion was exceptionally successful as an IV general anesthetic agent, it did have some drawbacks that some believed could be ameliorated by altering the constituents of the emulsion. These included pain on injection in 10-30% of patients,^13,14 and concerns of potential for bacterial growth in the nutrient rich emulsion.^5,15,16 Zeneca Pharmaceuticals (now AstraZeneca) added EDTA to the propofol emulsion in 1996 to inhibit bacterial growth after several postoperative infections were suspected to be caused by propofol. Investigations of these infections though, found the likely source of the postoperative infections to be extrinsic contamination of the propofol resulting from poor (non-sterile) handling technique.^5,15 Many attempts were made at reducing the amount of soybean oil, using alternatives to soybean oil (Lipuro and Aquafol), and eliminating the need for an emulsion by creating a water-soluble prodrug of propofol (Lusedra).^17,18 These attempts were largely unsuccessful, having no clear clinical benefits over the existing formulation, and often having inferior pharmacokinetics.^18-22

Since its introduction, the macroemulsion formulation of propofol, for which several generic versions exist, has maintained its status as the IV anesthetic of choice for the vast majority of both hospital-based and out-of-hospital general anesthetics. John Glen, after persevering through the setbacks of the initial Cremophor EL emulsion to obtain FDA approval of propofol, continued researching and advancing the ability to maintain general anesthesia with propofol for prolonged periods through the creation of target-controlled infusion pumps. He received a Lasker Award (for major contributions to medical science) in 2018, in recognition of his discovery and development of propofol, which had a profound effect on the field of anesthesiology and greatly benefited patients undergoing a large spectrum of medical treatments for which sedation or general anesthesia were required.^1,23

In 2007, reports emerged that an IV anesthetic agent, CNS7056, was undergoing clinical trials.²⁴ ByFavo (remimazolam), produced by Acacia Pharma (Cambridge, England) has recently completed Phase III clinical trials and was approved by the FDA in July 2020 for use in the induction and maintenance of procedural sedation.^25,26 This benzodiazepine has a rapid onset and rapid recovery due to its metabolism by tissue esterases, similar to that of remifentanil. The pharmacokinetic properties of this rapidly metabolized benzodiazepine seem well suited to compliment or challenge the dominance of propofol in the procedural sedation context and may also prove a useful agent for the IV induction and maintenance of general anesthesia.^3,25 Remimazolam appears to be the most promising addition to the repertoire of short-acting IV anesthetic agents since the introduction of the propofol emulsion some 34 years ago. The recent addition of this novel benzodiazepine to the anesthesiologist’s armamentarium will definitely make for an exciting decade in anesthesiology as its utility as a general anesthetic adjunct or induction/maintenance agent are studied, and additional ongoing phase III clinical trials to expand its approved uses are completed.²⁷

Oral Health welcomes this original article.

References

White PF. Propofol–Its Role in Changing the Practice of Anesthesia. Anesthesiology. 2008;109:1132-6.
Griffin III C, Kaye AM, Bueno F, Kaye AD. Benzodiazepine Pharmacology and Central Nervous System–Mediated Effects. The Oschsner Journal. 2013;13:214-23.
Brohan J, Goudra BG. The Role of GABA Receptor Agonists in Anesthesia and Sedation. CNS Drugs. 2017;31(10):845-56.
Lopez-Munoz F, Ucha-Udabe R, Alamo C. The history of barbiturates a century after their clinical introduction. Neuropsychiatr Dis Treat. 2005;1(4):329-43.
Thompson K, Goodale D. The Recent Development Of Propofol. Intensive Care Med. 2000;26:S400-S4.
James R, Glen J. Synthesis, Biological Evaluation, and Preliminary Structure-Activity Considerations of a Series of Alkylphenols as Intravenous Anesthetic Agents. J Med Chem. 1980;23:1350-7.
MacPherson R. Pharmaceutics for the anaesthetist. Anaesthesia. 2001;56:965-79.
Egan TD. Exploring the frontiers of propofol formulation strategy: is there life beyond the milky way? Br J Anaesth. 2010;104(5):533-5.
Briggs L, Clarke R, Watkins J. An adverse reaction to the administration of disoprofol (Diprivan). Anaesthesia. 1982;37:1099-101.
Propofol. [package insert]. Wilmington, Delaware: AstraZeneca; 2002.
Canada H. Diprivan Product Monograph. Drug Product Database. 1993:1-3.
Baker MT, Naguib M. Propofol The Challenges of Formulation. Anesthesiology. 2005;103:860-76.
Picard P, Tramer M. Prevention of Pain on Injection with Propofol. Anesth Analg. 2000;90:963-9.
Jalota L, Kalira V, George E, Shi YY, Hornuss C, Radke O, et al. Prevention of pain on injection of propofol: systematic review and meta-analysis. BMJ. 2011;342:d1110.
Sosis M, Braverman B. Growth of Staphylococcus aureus in four intravenous anesthetics. Anesth Analg. 1993;77:766-8.
Song D, Hamza M, White PF, Klein K, Recart A, Khodaparast O. The pharmacodynamic effects of a lower-lipid emulsion of propofol: a comparison with the standard propofol emulsion. Anesth Analg. 2004;98(3):687-91, table of contents.
Le Guen M, Grassin-Delyle S, Cornet C, Genty A, Chazot T, Dardelle D, et al. Comparisons of the Potency of Different Propofol Formulations. Anesthesiology. 2014;120(2):355-64.
Jung JA, Choi BM, Cho SH, Choe SM, Ghim JL, Lee HM, et al. Effectiveness, safety, and pharmacokinetic and pharmacodynamic characteristics of microemulsion propofol in patients undergoing elective surgery under total intravenous anaesthesia. Br J Anaesth. 2010;104(5):563-76.
Cho J, Cho JC, Lee P, Lee M, Oh E. Formulation and evaluation of an alternative triglyceride-free propofol microemulsion. Arch Pharm Res. 2010;33(9):1375-87.
Terrence L JBL, Lopa Misra T, Rosenfeld DM. Bolus-Dose Fospropofol Disodium (Lusedra): Is 10 mg/Kg Superior To 6.5 mg/Kg for Sedation in Patients Undergoing Regional Anesthesia Blocks Prior to Orthopedic Surgery? Journal of Anesthesia & Clinical Research. 2015;06(08).
Gibiansky E, Struys M, Gibiansky L, Vanluchene A, Vornov J, Mortier E, et al. Aquavan Injection, a Water-soluble Prodrug of Propofol, as a Bolus Injection: A Phase I Dose-escalation Comparison with DIPRIVAN (Part 1). Anesthesiology. 2005;103:718-29.
Calvo R, Telletxea S, Leal N, Aguilera L, Suarez E, De La Fuente L, et al. Influence of formulation on propofol pharmacokinetics and pharmacodynamics in anesthetized patients. Acta Anaesthesiol Scand. 2004;48(8):1038-48.
Wood M, Stark R. John (Iain) Glen Wins 2018 Lasker Prize for Development of Propofol: An Award for All of Anesthesiology. Anesthesiology. 2018;129(6):1055-6.
Kilpatrick G, McIntyre M, Cox R, Stafford J, Pacofsky G, Lovell G, et al. CNS 7056–A Novel Ultra-short-acting Benzodiazepine. Anesthesiology. 2007;107:60-6.
Keam SJ. Remimazolam: First Approval. Drugs. 2020;80(6):625-33.
FDA. NDA 212295–BYFAVO. 2020:1-8.
ClinicalTrials.gov. Efficacy and Safety of Remimazolam (CNS7056) Compared to Propofol for Intravenous Anesthesia During Elective Surgery USA: US National Library of Medicine; 2020 [October 1, 2019:[Available from: https://clinicaltrials.gov/ct2/results?term=remimazolam&Search=Search.

About the Author

Dr. Paul Azzopardi completed his MSc degree in Biochemistry in 2009 and his DDS degree in 2013 at Western University. He subsequently completed a general practice residency at the University of Alberta in 2014. He is currently in his third-year of the Graduate Dental Anaesthesia program at the University of Toronto.