Ciprofol, chemically known as (R)-2-[(1-cyclopropyl)ethyl]-6-(propan-2-yl)phenol or HSK3486, is a short-acting intravenous anesthetic agent and sedative-hypnotic that functions as a positive allosteric modulator of the γ-aminobutyric acid type A (GABA_A) receptor, facilitating chloride ion influx to inhibit neuronal activity and induce rapid sedation or anesthesia.[1] As a 2,6-disubstituted phenol derivative structurally modified from propofol, it exhibits 4- to 5-fold higher binding affinity to GABA_A receptors, enabling lower effective doses while providing a quick onset (T_max of 2-3 minutes) and metabolism primarily via CYP2B6 and UGT enzymes, with a half-life of approximately 2.09 hours and predominant renal excretion.[1][2]Developed by China's Haisco Pharmaceutical Group and first reported in 2017, ciprofol received initial approval from the National Medical Products Administration (NMPA) on December 15, 2020, for sedation during gastrointestinal endoscopic procedures such as painless bronchoscopy and gastroscopy.[1] Subsequent expansions in 2022 broadened its indications to include induction and maintenance of general anesthesia in surgical settings and sedation for mechanically ventilated patients in intensive care units, positioning it as a versatile option for procedural and perioperative care primarily in China, with approvals limited to China as of November 2025 while investigational internationally.[1][3] Ongoing clinical trials continue to evaluate its efficacy in diverse populations, including pediatrics and obese patients, with phase III studies demonstrating its potential for broader applications.[4][5]In clinical practice, ciprofol offers advantages over propofol, including significantly reduced injection pain (incidence of 4.9% versus 52.4%), lower rates of respiratory depression (2.8% versus 5.5%), and enhanced hemodynamic stability with minimal cardiovascular effects, while achieving comparable sedation depths and higher patient satisfaction scores in procedures like gastroscopy.[1][6] Its higher potency allows for dose reductions of up to 50-70%, potentially mitigating common propofol-related adverse events such as hypotension and apnea, though it may involve slightly longer recovery times in some contexts.[7][8] These properties have spurred interest in ciprofol as a safer alternative for short-duration anesthesia and sedation, particularly in high-risk patients, with research emphasizing its favorable safety profile in non-operating room settings.[9][10]
Chemical properties
Structure
Ciprofol, chemically known as 2-[(1R)-1-cyclopropylethyl]-6-(propan-2-yl)phenol, has the molecular formula C14H20O and a molar mass of 204.31 g/mol.[11][12]It is an optically active 2,6-disubstituted alkylphenol derivative, characterized by a cyclopropylethyl side chain at the 2-position that introduces chirality and enhances steric hindrance compared to its precursor.[13] This structural feature contributes to greater stereoselectivity in its interactions with biological targets.[13]Ciprofol shares a phenolic core with propofol, a 2,6-diisopropylphenol, but features a targeted replacement of one isopropyl group with the cyclopropylethyl moiety, which modifies its lipophilicity and overall pharmacological profile for potentially improved potency and fewer side effects.[13] This design leads to a higher bindingaffinity to relevant receptors.[13]
Physical characteristics
Ciprofol, in its pure form, is a liquid substance.[12] Due to its high lipophilicity, indicated by a calculated logP value of approximately 4.37, ciprofol exhibits poor solubility in water but is soluble in organic solvents such as DMSO (up to 100 mg/mL).[14][12] This lipophilicity, greater than that of propofol (logP 3.93), necessitates its formulation as an oil-in-water emulsion for intravenous administration, incorporating medium- and long-chain triglycerides.[14][15]The commercial emulsion formulation of ciprofol appears as a white, opalescent, uniform liquid with no visible precipitation or phase separation under standard conditions.[16] It maintains physical stability, with mean particle size below 200 nm and relative standard deviation less than 1.0%, when stored at room temperature (25°C) or refrigerated (4°C) for up to 24 hours, and even at 37°C.[16] The emulsion's pH is approximately 7.76, fluctuating minimally (≤0.07 units) over time, while osmotic pressure remains around 321 mOsm/kg.[16] Protection from light is recommended during storage to preserve stability, consistent with guidelines for similar lipid emulsions.[12]
Clinical uses
Approved indications
Ciprofol (also known as HSK3486) received approval from the China National Medical Products Administration (NMPA) on December 15, 2020, for use as a short-acting intravenous anesthetic agent specifically for sedation during endoscopic procedures, including gastrointestinal endoscopy (such as gastroscopy and colonoscopy) and bronchoscopy, in adults.[1] This initial indication targets moderate sedation to facilitate painless examination and intervention, allowing for rapid onset and recovery suitable for outpatient settings.[10]In 2021, the NMPA expanded the approved indications to include induction and maintenance of general anesthesia in surgical settings (approval number H20210007), with typical dosing of 0.4 mg/kg bolus for induction followed by maintenanceinfusion as needed.[17] In July 2022, the NMPA further expanded approval to include sedation for intensive care unit (ICU) patients requiring mechanical ventilation, addressing the need for prolonged sedation in critically ill individuals while minimizing hemodynamic instability.[18] For procedural sedation in endoscopy, such as gastroscopy, colonoscopy, and bronchoscopy, ciprofol is typically administered as a single intravenous bolus dose of 0.4–0.5 mg/kg, achieving effective sedation within 1–2 minutes.[19][20] In ICU settings, dosing involves an initial loading infusion of 0.1–0.2 mg/kg over 0.5–5 minutes, followed by a maintenanceinfusion starting at 0.3 mg/kg/h, titrated to maintain a target sedation level (e.g., Richmond Agitation-Sedation Scale of –2 to 0).[21]Clinical studies supporting these approvals demonstrate that ciprofol provides comparable sedation efficacy to propofol but with advantages in recovery profiles, including shorter times to full alertness and orientation after gastrointestinal procedures, attributed to its higher potency and favorable pharmacokinetics as a GABA_A receptor agonist.[22]
Investigational applications
A multicenter phase III trial in China demonstrated ciprofol's non-inferiority to propofol for sedation and anesthesia in outpatient gynecological procedures, such as hysteroscopy, achieving high success rates with reduced injection pain and adverse events.[23] Additionally, clinical studies have explored its use in kidney transplantation, where ciprofol provided effective induction and maintenance of anesthesia with stable hemodynamics and a 100% sedation success rate, comparable to propofol.[24]Research into ciprofol's neuroprotective potential focuses on its combination with mild therapeutic hypothermia following cardiac arrest. Preclinical studies in rat models showed that ciprofol, when paired with hypothermia, improved survival rates and neurological outcomes by reducing brain injury markers, supporting its hypothesis as an adjunct for post-arrest neuroprotection in humans.[25]Investigational applications in special populations include pediatric and elderly patients. In children aged 3–12 years, trials established the median effective dose (ED50) of ciprofol for anesthesia induction at approximately 0.35 mg/kg without premedication, demonstrating rapid onset, stable circulation, and low incidence of injection pain during procedures like adenotonsillectomy.[26] For elderly patients undergoing thoracic surgery, randomized controlled trials indicated that ciprofol reduced the incidence of postoperative delirium compared to propofol, with lower rates of cognitive fluctuations and improved recovery profiles in major procedures.[27]Comparative studies from 2024–2025 highlight ciprofol's advantages over propofol in obese patients, particularly for hemodynamic stability during induction. In randomized trials involving obese individuals undergoing gastrointestinal endoscopy or laparoscopic surgery, ciprofol-remifentanil combinations maintained superior blood pressure and heart rate stability, with fewer respiratory adverse events and better overall safety profiles than propofol equivalents.[28][29]
Adverse effects
Common reactions
Common adverse reactions to ciprofol are generally mild to moderate and include hypotension, bradycardia, and mild respiratory depression, which occur dose-dependently and resolve quickly due to the drug's short half-life of approximately 2-3 hours.[30] In clinical trials for anesthesiainduction, hypotension has been reported in 19-26% of patients receiving ciprofol, typically manifesting as a transient decrease in mean arterial pressure without requiring intervention in most cases.[31][32]Bradycardia, defined as heart rate below 60 beats per minute, occurs in 8-39% of patients, with higher rates at induction doses compared to maintenance sedation.[31][33] Mild respiratory depression, such as transient desaturation, is observed in less than 10% of cases, often self-limiting and less frequent than with propofol.[34]Injection site reactions are minimal with ciprofol, with pain on injection reported in under 5% of patients—significantly lower than the 30-50% incidence seen with propofol due to ciprofol's modified chemical structure.[5][35] Other common effects include transient dizziness and nausea, affecting 1-5% of patients postoperatively, which typically resolve within minutes to hours owing to the drug's rapid metabolism.[36][37]Management of these reactions is primarily supportive and dose-related; lower infusion rates for sedation (e.g., 0.4-0.8 mg/kg/h) result in reduced incidence compared to bolus induction doses (e.g., 1.5-2 mg/kg), allowing for safer use in outpatient procedures.[38] Overall, the profile of common reactions supports ciprofol's tolerability in clinical settings, with adverse event rates often comparable or lower than propofol in randomized trials.
Serious risks
Ciprofol administration carries risks of respiratory arrest or apnea, particularly during high-dose induction for general anesthesia, though the incidence remains low at approximately 3% in procedural sedation contexts, significantly less than the 10% observed with propofol.[39] These events necessitate close monitoring of respiratory function and readiness for ventilatory support, as they can lead to hypoxia if unmanaged.[40]Cardiovascular collapse, manifesting as severe hypotension or arrhythmias, poses a serious risk, especially in patients with pre-existing cardiac conditions such as heart failure or severe valvular disease.[41] Ciprofol is contraindicated in cases of known hypersensitivity to the drug or its components, and extreme caution is advised in severe cardiac impairment to avoid exacerbating hemodynamic instability.[42] Studies indicate a lower overall incidence of hypotension with ciprofol compared to propofol, but vulnerable patients may still require dose titration and cardiovascular monitoring.[43]Allergic reactions, including rare anaphylaxis, can occur due to the lipid emulsion formulation containing soybean oil and egg lecithin, similar to propofol-related hypersensitivity.[44] Such reactions demand immediate intervention with epinephrine and supportive care, underscoring the need for pre-administration allergy screening.[44]In special populations, caution is warranted. Elderly patients exhibit heightened sensitivity, necessitating a reduced induction dose of 0.3 mg/kg to minimize risks of respiratory and hemodynamic adverse effects.[45] For pregnant individuals, data are limited, and use is recommended only if benefits outweigh potential risks, with no established safety profile.[42] In cases of mild renal or hepatic impairment, no dose adjustment is required, as ciprofol's pharmacokinetics remain unaffected; however, monitoring is advised for moderate to severe cases.[46]
Pharmacology
Pharmacodynamics
Ciprofol, the R-enantiomer, acts primarily as a positive allosteric modulator of γ-aminobutyric acid type A (GABAA) receptors, enhancing the binding of the endogenous neurotransmitterGABA to these ligand-gated ion channels. This potentiation increases chloride ion influx into neurons, resulting in membrane hyperpolarization and subsequent inhibition of neuronal excitability, which underlies its sedative and anesthetic effects.[47]Compared to propofol, ciprofol demonstrates 4- to 5-fold greater potency, attributed to its higher binding affinity for GABAA receptors containing the β3 subunit, as evidenced by molecular dynamics simulations showing stronger interactions of the R-enantiomer of ciprofol with GABRB3.[48] This enhanced affinity contributes to its efficacy at lower doses while maintaining a favorable safety profile.Ciprofol exhibits high selectivity for GABAA receptors, with minimal interaction at non-GABAA targets such as sodium, potassium, or calcium channels, which reduces the incidence of cardiovascular and respiratory depression relative to propofol.[47] In dose-response studies, the median effective dose (ED50) for sedation is approximately 0.4 mg/kg.[49]Preclinical models have revealed mild anti-inflammatory properties of ciprofol, including attenuation of NLRP3inflammasome activation in Parkinson's disease mouse models and reduction of pro-inflammatory cytokines in ischemia-reperfusion injury.[50][51]
Pharmacokinetics
Ciprofol is administered exclusively via intravenous injection or infusion, achieving complete bioavailability due to this route. Its high lipophilicity facilitates rapid onset of action, typically within 30 to 60 seconds following administration, allowing quick penetration into the central nervous system.[52][53]Following administration, ciprofol exhibits extensive distribution throughout the body, characterized by a large volume of distribution of approximately 3 to 4 L/kg, reflecting its partitioning into tissues such as the brain and adipose tissue. It rapidly redistributes from the brain to peripheral compartments, contributing to its short duration of effect. Plasma protein binding is high, around 95% to 99%, primarily to albumin, which influences its free fraction availability.[1][2][54]Ciprofol undergoes primary hepatic metabolism through phase II conjugation, predominantly via the enzyme UDP-glucuronosyltransferase 1A9 (UGT1A9), forming inactive glucuronide metabolites such as M4. The glucuronidation pathway via UGT1A9 accounts for the majority (~54%) of biotransformation, with CYP2B6 contributing ~24.5%.[55][2][54][56] The metabolites lack hypnotic activity, ensuring that pharmacological effects are attributable to the parent compound.Elimination of ciprofol is characterized by a terminalhalf-life of 2 to 3 hours, supporting its suitability for short procedures without prolonged recovery. The drug and its metabolites are primarily excreted via the kidneys, with over 80% of the dose recovered in urine as the glucuronide conjugate M4 within 24 hours and negligible amounts of unchanged parent drug. No significant accumulation occurs with repeated or continuous dosing, owing to its efficient clearance.[54][1][57]
Development and regulation
History
Ciprofol (HSK3486) was developed by Haisco Pharmaceutical Group Co., Ltd., based in Chengdu, China, and first reported in 2017, as a structural analog of propofol intended to address key limitations such as injection site pain and hemodynamic instability.[52][1] This innovation stemmed from efforts to create a short-acting intravenous anesthetic with enhanced selectivity for the GABA_A receptor while minimizing cardiovascular and respiratory depression.[1]Preclinical studies evaluated ciprofol in animal models including rats and dogs, confirming its sedative and hypnotic effects through metrics like loss of righting reflex (LORR). These investigations revealed that ciprofol exhibited approximately 4- to 6-fold greater potency compared to propofol (ED50 for LORR in rats: 0.88 mg/kg versus 5.05 mg/kg for propofol) alongside a more favorable safety profile, including reduced cardio-depressive effects and no injection pain.[1] Initial pharmacokinetic data from these studies supported rapid onset and offset, paving the way for clinical advancement.[58]Early human trials commenced with Phase I studies in Australia in 2018, which assessed safety, tolerability, and pharmacokinetics in healthy volunteers across doses up to 0.81 mg/kg without reaching dose-limiting toxicity.[19] Phase III trials in China, conducted from 2018 to 2019, focused on sedation efficacy for procedures like colonoscopy and demonstrated non-inferiority to propofol with fewer adverse reactions.[59]Regulatory milestones accelerated thereafter: Haisco submitted a new drug application to China's National Medical Products Administration (NMPA) in 2020, leading to initial approval on December 15, 2020, for sedation during gastrointestinal endoscopy (approval H20200013).[60] Approval for induction and maintenance of general anesthesia followed in 2021 (approval H20210007).[17] An extension for sedation in intensive care unit patients requiring mechanical ventilation was granted in July 2022.[3] As of 2025, a phase III trial in the United States (NCT05486416, completed in 2024) supports further regulatory pursuits, with ongoing evaluations in surgical and procedural settings.
Approval status
Ciprofol, also known as HSK3486, received approval from the National Medical Products Administration (NMPA) in China for sedation during gastrointestinal endoscopy on December 15, 2020.[60] In July 2022, the NMPA expanded its approval to include sedation for patients requiring mechanical ventilation in intensive care units.[3] It is marketed in China exclusively as Sishuning (Ciprofol Injection), a 2 mg/mL lipidemulsion formulation developed and commercialized by Haisco Pharmaceutical Group Co., Ltd.[61] No generic versions of ciprofol are currently available worldwide.[62]Outside of China, ciprofol remains investigational and has not received regulatory approval as of November 2025. In the United States, phase III clinical trials are ongoing for indications such as sedation and general anesthesia in outpatient procedures, with no FDA approval granted to date.[60] Phase I trials were conducted in Australia in 2018, while phase III trials continue in the United States (e.g., NCT05486416, completed in 2024). Ciprofol is not approved in any other countries, including Japan or India, despite market interest in the Asia-Pacific region.[63]Access to ciprofol is limited to approved clinical use within Chinese hospitals for the specified indications, where it is administered intravenously under medical supervision.[1] Globally, availability is restricted to investigational settings through ongoing clinical trials, and it holds no over-the-counter status anywhere.[64] In trial contexts, it is commonly referred to by its developmental code HSK3486 or the generic name ciprofol.[1]