Ciprofol in Intravenous Anesthesia

Among intravenous agents used in general anesthesia, propofol has long been the standard drug of choice due to its rapid onset, short duration, and favorable recovery profile. Its mechanism enhances inhibitory GABAergic transmission, producing reliable sedation and anesthesia. However, propofol is not without drawbacks, as adverse reactions ranging from minor events like injection-site pain to serious complications like propofol infusion syndrome can limit propofol usage.¹ To address these challenges, researchers have pursued alternatives with improved safety and tolerability profiles. In 2017,² ciprofol was first introduced as a next-generation intravenous anesthesia agent that shows potential to replace propofol in clinical practice.

Ciprofol builds on the traditional 2,6-disubstituted phenol structure shared by classic intravenous anesthetics such as propofol but features the addition of a cyclopropyl group that modifies the agent’s chemical and pharmacological properties. This substitution reduces lipophilicity and breaks the symmetry of the parent molecule, which creates a chiral center and produces stereoselective activity at the GABA_A receptor. These structural changes enhance receptor binding affinity and production. This results in a higher receptor affinity for ciprofol over propofol, as confirmed by radioligand-binding assays.³ Additionally, the R-enantiomer of ciprofol demonstrates greater stereoselectivity for the GABA_A receptor than propofol’s S-enantiomer. Together, these results indicate ciprofol has stronger target selectivity and higher action intensity.

Mechanistically, ciprofol functions as both a positive allosteric modulator and direct agonist of the GABA_A receptor. Electrophysiological studies, such as competitive binding assays and whole-cell patch-clamp experiments, confirm that ciprofol facilitates chloride influx by binding to butylbicyclophosphorothionate and t-butylbicycloorthobenzoate targets (two extremely potent GABA receptor antagonists) in the chloride channels of GABA_A receptors through receptor-associated pathways.⁴ The influx of chloride can cause hyperpolarization of nerve cell membranes by increasing the intracellular chloride concentration and further activating GABAergic neurons to achieve central nerve inhibition, producing sedative and anesthetic effects.

In a 2022 preclinical study, both ciprofol and propofol were administered to rats via intravenous injection to assess hypnotic potency and safety. Loss of righting reflex was used as a behavioral marker of anesthesia, with the effective dose (ED₅₀) values calculated based on the proportion of animals losing reflex at different doses. To evaluate safety, the lethal dose (LD₅₀) value was determined by monitoring mortality after escalating doses, and the therapeutic index was then derived from the LD₅₀/ED₅₀ ratio. They found ciprofol has approximately 4–5 times higher hypnotic potencythan propofol and exhibits ahigher therapeutic index, indicative of a wider safety margin.⁵

A prospective, double-blind, single-center RCT enrolled 120 female patients undergoing general anesthesia for gynecological surgery. There were no significant differences between patients who received propofol or ciprofol in terms of induction success rate, duration of successful induction, time to induction (as measured by the loss of eyelash reflex), and tracheal intubation. However, the overall incidence of adverse events was significantly lower in the ciprofol group than in the propofol group (20% vs. 48%, respectively).⁶

Current evidence suggests ciprofol offers certain pharmacological and clinical advantages over propofol. Its structural modifications enhance stereoselectivity and receptor affinity, translating to stronger potency at lower dosage levels. Preclinical studies in murine models demonstrated a higher therapeutic index, supporting a wider safety margin over propofol. Early clinical trials further confirmed the agent’s comparable anesthetic efficacy while reducing the incidence of adverse events. These findings indicate that ciprofol has potential as a next-generation intravenous anesthesia agent to become widely used in the operative setting.

References

1. Mashour G. A., Sanders R. D., and Lee U., Propofol Anesthesia: A Leap Into the Void? Anesthesiology. (2022) 136 (3), 405-407, https://doi.org/10.1097/ALN.000000000000411035120194
2. Zhang C., Li F., Yu Y., et al. Design, Synthesis, and Evaluation of a Series of Novel Benzocyclobutene Derivatives as General Anesthetics. Journal of Medicinal Chemistry. 2017;60(9):3618-3625. https://doi.org/10.1021/acs.jmedchem.7b00253
3. Qin L., Ren L., Wan S., et al. Design, Synthesis, and Evaluation of Novel 2,6-Disubstituted Phenol Derivatives as General Anesthetics. Journal of Medicinal Chemistry. 2017;60(9):3606-3617. https://doi.org/10.1021/acs.jmedchem.7b00254
4. Lu M, Liu J, Wu X, Zhang Z. Ciprofol: A Novel Alternative to Propofol in Clinical Intravenous Anesthesia? BioMed Research International. 2023;2023:1-12. https://doi.org/10.1155/2023/7443226
5. Liao J., Li M., Huang C., et al. Pharmacodynamics and Pharmacokinetics of HSK3486, a Novel 2,6-Disubstituted Phenol Derivative as a General Anesthetic. Frontiers in Pharmacology. 2022;13. https://doi.org/10.3389/fphar.2022.830791
6. Chen B., Yin X., Jiang L., Liu J., Shi Y., Yuan B., The Efficacy and Safety of Ciprofol Use for the Induction of General Anesthesia in Patients Undergoing Gynecological Surgery: A Prospective Randomized Controlled Study. BMC Anesthesiology. 2022;22(1). https://doi.org/10.1186/s12871-022-01782-7