Remimazolam

Remimazolam 

Introduction

• Ultra-short-acting intravenous benzodiazepine
• Structurally related to midazolam
• Rapid, predictable metabolism resembles the pharmacokinetic concept of remifentanil
• Available as remimazolam besylate
• Water-soluble formulation
• Trade name: Byfavo

Chemistry

• Imidazobenzodiazepine containing a metabolically labile carboxylic ester linkage
• Molecular formula: C₂₁H₁₉BrN₄O₂
• Molecular weight: approximately 439.3 Da
• The ester linkage permits rapid hydrolysis to an inactive metabolite

Mechanism of action

Remimazolam

→ Binds to the benzodiazepine site on GABA-A receptors

→ Positive allosteric modulation of GABA-A receptor

→ Increases the frequency of GABA-mediated chloride-channel opening

→ Increased Cl⁻ influx and neuronal hyperpolarization

→ Reduced neuronal excitability

→ Anxiolysis → sedation → hypnosis, depending on dose

It has no analgesic action; an opioid or another analgesic is usually required for painful procedures.

Pharmacological effects

Pharmacokinetics

• Onset of sedation: approximately 1–2 minutes
• Rapid recovery after discontinuation
• Short context-sensitive half-time, with limited accumulation
• Elimination half-life: approximately 37–53 minutes in current regulatory pharmacokinetic data
• Clearance: approximately 1 L/min
• Metabolised predominantly by hepatic carboxylesterase-1 (CES1)
• Converted to an essentially inactive carboxylic-acid metabolite: CNS7054
• Metabolism is independent of the cytochrome P450 system
• Therefore, fewer CYP-mediated drug interactions are expected

Organ impairment

• Renal impairment: generally no dose adjustment required
• Mild–moderate hepatic impairment: usually no formal adjustment; titrate clinically
• Severe hepatic impairment: clearance may be reduced and effects prolonged—use careful, slower titration

The older statement that metabolism is completely “organ-independent” is inaccurate. CES1 is located predominantly in the liver, although metabolism is not dependent on renal clearance or CYP450 enzymes.

Current approved indications

Approval varies between countries:

• United States: procedural sedation in adults undergoing procedures lasting 30 minutes or less
• European Union/United Kingdom:
• Procedural sedation in adults
• Intravenous induction and maintenance of general anaesthesia in adults
• Paediatric safety and efficacy remain insufficiently established for routine labelled use.

Remimazolam received its initial US FDA approval in July 2020

Dosage

Premedication: 0.075mg/kg

Induction: 0.1-0.3mg/kg

Infusion: 0.72-3mg/kg/h to titrate based on sedation  surgical anaesthesia 

Adverse effects

• Hypotension
• Bradycardia
• Hypoxia
• Respiratory depression or apnoea
• Airway obstruction
• Headache
• Somnolence
• Nausea and vomiting
• Anterograde amnesia
• Hypersensitivity reactions, including rare anaphylaxis
• Paradoxical agitation may occur, as with other benzodiazepines

Advantages

• Rapid onset and offset
• Short context-sensitive half-time
• Limited accumulation during infusion
• Rapid metabolism by CES1
• No CYP450-dependent metabolism
• Generally greater haemodynamic stability than propofol
• Usually less injection pain than propofol
• Can be used in renal impairment without routine dose adjustment
• Effects can be reversed with flumazenil

Important precautions

• Must be administered with continuous respiratory and cardiovascular monitoring.
• Airway equipment, assisted ventilation and resuscitation drugs must be immediately available.
• Combining it with opioids, alcohol or other CNS depressants can cause profound sedation, respiratory depression, coma or death.
• Flumazenil reverses sedation, but the patient must still be observed for re-sedation and respiratory depression.

References

1. Goudra BG, Singh PM. Saudi J Anaesth. 2014;8(3):388–391. 
2. Doi M, et al. J Anesth. 2020;34(4):491–501. 
3. Kim KM. Anesth Pain Med (Seoul). 2022;17(1):1–11.