Ciprofol - 10 Marks (MD Anaesthesia)

Introduction

Chemical Structure

• Full name: 2-[(1R)-1-(2-methylphenoxy)ethyl]-4-(propan-2-yl)phenol (also called (R)-2-(1-(2,6-dichlorophenoxy)propyl)-1H-imidazole in older nomenclature - this is incorrect; correct IUPAC: (R)-2-(1-cyclopropylethyl)-6-isopropylphenol)
• A phenol derivative, like propofol, but with a cyclopropyl methyl substituent replacing the simple isopropyl group at the 2-position
• Formulated as a lipid emulsion at a concentration of 10 mg/mL (similar to propofol 1% emulsion)
• White milky appearance; soluble in fat

Mechanism of Action

1. Ciprofol competitively binds to the TBPS (t-butylbicyclophosphorothionate) and TBOB (t-butylbicycloorthobenzoate) binding sites within the chloride channel of the GABA-A receptor
2. This binding potentiates GABAergic inhibitory neurotransmission
3. Chloride ion influx increases into the neuron
4. The resulting intracellular chloride accumulation hyperpolarizes the neuronal membrane
5. GABAergic neurons are further activated, producing central nervous system depression - yielding sedation, hypnosis, and anaesthesia

Pharmacokinetics

Pharmacodynamics

CNS Effects

• Produces dose-dependent sedation, hypnosis, and unconsciousness
• Bispectral Index (BIS) monitoring confirms dose-dependent suppression (target BIS 40-60 for surgical anaesthesia)
• No intrinsic analgesic properties (requires supplemental opioid/regional anaesthesia)
• Antiemetic properties (similar to propofol)
• Dreaming during anaesthesia: RCT data shows ciprofol is associated with dreaming in ~10-15% of patients undergoing endoscopy - comparable to propofol

Cardiovascular Effects

• Causes dose-dependent reduction in blood pressure (vasodilation + mild negative inotropy)
• Incidence of hypotension lower than propofol: Meta-analysis (Akhtar et al., 2024, 13 RCTs, n=1998) - RR 0.82 (95% CI: 0.68-0.98, p=0.03)
• Heart rate changes: comparable to propofol (no significant bradycardia difference)

Respiratory Effects

• Dose-dependent respiratory depression
• Phase III RCT (Liang et al., 2023, Eur J Anaesthesiol) showed incidence of respiratory depression in endoscopy sedation: 2.8% (ciprofol) vs 5.5% (propofol) - significantly lower
• Apnoea risk exists, particularly in elderly, paediatric patients, and those with cardiovascular disease or hypovolaemia
• Airway reflexes are suppressed - requires monitoring

Clinical Uses

1. Induction of general anaesthesia - dose: 0.4 mg/kg IV (vs propofol 2 mg/kg); non-inferior success rate (100% in phase III trial)
2. Maintenance of general anaesthesia - infusion adjusted to BIS 40-60
3. Procedural sedation (NORA - Non-Operating Room Anaesthesia):
   • Gastroscopy, colonoscopy, bronchoscopy
   • Gynaecological outpatient procedures
4. ICU sedation - multicentre RCT (Liu et al., 2023, Crit Care Med) demonstrated non-inferiority to propofol in mechanically ventilated ICU patients
5. Non-tracheal intubation surgeries (laryngeal mask airway cases)

Comparison with Propofol

Adverse Effects

1. Muscle fasciculation - most notable unique adverse effect; dose-dependent (incidence 33.3% at 0.4 mg/kg, up to 83.3% at 0.9 mg/kg in phase I trials); mechanism unclear
2. Hypotension - less frequent than propofol but still occurs
3. Respiratory depression / apnoea - dose-dependent; less than propofol
4. Bradycardia - comparable to propofol
5. Injection site pain - markedly reduced compared to propofol (major advantage)
6. Nausea and vomiting - possible, though antiemetic properties reduce PONV
7. Transient QT prolongation - comparable to propofol; requires monitoring
8. Hiccups - reported in some endoscopy trials

Special Populations

• Elderly: Requires dose reduction; higher risk of hypotension and respiratory depression; RCT (Liang et al., 2024, J Clin Anesth) showed non-inferior postoperative quality of recovery compared to propofol in elderly laparoscopic surgery patients
• Paediatric: Dose-dependent respiratory depression - use with caution; limited data
• Cardiovascular disease / Hypovolaemia: Increased risk of haemodynamic compromise
• Hepatic impairment: Use cautiously; hepatic metabolism may be prolonged

Advantages over Propofol (Summary)

1. Far lower incidence of injection pain (major patient comfort benefit)
2. More haemodynamically stable (less hypotension)
3. Less respiratory depression in procedural sedation
4. Smaller volume required (lower lipid load due to 4-5x potency)
5. Comparable onset, recovery, and anaesthetic success rates
6. Potential cardioprotective effect - emerging animal data shows ciprofol may reduce myocardial ischaemia-reperfusion injury by inhibiting ferroptosis via HIF-1α upregulation (Ding et al., 2024)

Current Evidence Base

• Meta-analysis (Akhtar et al., 2024, J Clin Anesth, PMID: 38412619): 13 RCTs, n=1998 - ciprofol non-inferior to propofol, with significantly less injection pain and hypotension
• Phase III RCT (Liang et al., 2023, Eur J Anaesthesiol, PMID: 36647565): 10-centre trial - 100% anaesthetic maintenance success, non-inferiority confirmed
• ICU sedation RCT (Liu et al., 2023, Crit Care Med, PMID: 37272947): Non-inferior to propofol for mechanically ventilated ICU patients
• Network meta-analysis (Zhou et al., 2025, BMC Anesthesiol, PMID: 40340730): In endoscopy, ciprofol, remimazolam, and propofol compared - ciprofol shown favourable on multiple safety outcomes

Limitations and Future Directions

• Currently approved only in China; FDA/EMA approval trials ongoing
• Limited paediatric data
• Long-term safety unknown; PRIS equivalent not yet described but cannot be excluded
• Muscle fasciculation mechanism requires further study
• Comparative data against remimazolam and dexmedetomidine still limited
• Cost-effectiveness vs generic propofol remains a barrier to widespread adoption

Conclusion