Esketamine

Esketamine (S-Ketamine)

Introduction

• S(+) enantiomer of racemic ketamine
• Non-barbiturate, non-opioid dissociative anaesthetic
• Produces hypnosis, profound somatic analgesia, amnesia, dissociation
• 2 times more potent than racemic ketamine
• 3 times more potent than R-ketamine
• Available as:
• IV/IM injection anaesthetic use
• Intranasal spray for depression
• Trade names: Ketanest-S, Spravato

Mechanism of action

Anaesthetic and analgesic action

Esketamine

→ Non-selective, non-competitive antagonism of NMDA receptors

→ Blocks glutamate-mediated excitatory neurotransmission

→ Functional dissociation between the thalamocortical and limbic systems

→ Dissociative anaesthesia producing cataleptic state, analgesia, amnesia, loss of environmental awareness

Additional mechanisms contributing to analgesia include:

• Interaction with opioid receptors
• Enhanced descending monoaminergic inhibitory pathways
• Reduced central sensitisation and “wind-up”
• Local anaesthetic action on peripheral nerves and spinal cord

Proposed antidepressant mechanism

NMDA blockade on inhibitory interneurons

→ Transient glutamate release

→ Increased AMPA-receptor activation

→ Activation of BDNF–mTOR signalling

→ Increased synaptic formation and neuronal plasticity

→ Rapid antidepressant effect

The precise antidepressant mechanism is not completely established.

Pharmacological effects

Cardiovascular mechanism

Esketamine stimulates the sympathetic nervous system by:

• Increasing central sympathetic outflow
• Increasing catecholamine release
• Inhibiting catecholamine reuptake

It also has a direct negative inotropic effect, usually masked by sympathetic stimulation.

In catecholamine-depleted patients or prolonged severe shock, the direct myocardial depressant effect may predominate and cause hypotension.

Respiratory effects

• Respiratory drive is generally maintained.
• Bronchodilation makes it useful in:
• Bronchial asthma
• Severe bronchospasm
• Status asthmaticus
• Airway reflexes are only relatively preserved:
• Aspiration remains possible
• Laryngospasm may occur
• Airway and ventilation equipment must be available

Pharmacokinetics

• Highly lipid-soluble
• Rapidly crosses the blood–brain barrier
• Rapid redistribution terminates the anaesthetic effect after a bolus.

Metabolism

• Extensively metabolised in the liver
• N-demethylation by:
• CYP2B6
• CYP3A4
• Minor: CYP2C9 and CYP2C19
• Primary metabolite: noresketamine
• Pharmacologically active
• Lower NMDA-receptor affinity than esketamine
• Further converted to hydroxylated metabolites and glucuronide conjugates

Excretion

• Predominantly excreted in urine as metabolites
• Less than 1% is excreted unchanged
• Reduce the dose in significant hepatic impairment.

Indications

Anaesthetic indications

• Induction and maintenance of general anaesthesia
• Sole anaesthetic for short procedures
• Component of balanced anaesthesia
• Emergency and trauma anaesthesia
• Analgesia in emergency medicine
• Supplementation of regional or local anaesthesia
• Painful procedures and dressing changes
• Anaesthesia in haemodynamically unstable patients
• Severe bronchospasm or status asthmaticus
• Patients in whom spontaneous ventilation is desirable

Psychiatric indications—intranasal Spravato

• Treatment-resistant depression in adults
• As monotherapy or with an oral antidepressant in the USA
• Depressive symptoms in adults with MDD and acute suicidal ideation or behaviour
• Used with an oral antidepressant

Intranasal Spravato is not approved as an anaesthetic. 

Dosage 

Reduce dose in elderly or debilitated patients, multiple trauma, hepatic impairment, shock

Adverse effects

CNS and psychiatric

• Emergence delirium
• Vivid dreams or nightmares
• Hallucinations
• Dissociation
• Dysphoria or euphoria
• Anxiety and agitation
• Disorientation
• Dizziness and vertigo
• Nystagmus
• Increased muscle tone
• Tonic–clonic movements that may resemble seizures

Cardiovascular

• Hypertension
• Tachycardia
• Increased myocardial oxygen consumption
• Arrhythmias
• Bradycardia—rare
• Hypotension in severe/catecholamine-depleted shock

Respiratory and airway

• Transient respiratory depression
• Apnoea after rapid injection or excessive dose
• Increased secretions
• Laryngospasm
• Increased pulmonary vascular resistance

Other effects

• Nausea and vomiting
• Hypersalivation
• Diplopia and blurred vision
• Increased intraocular pressure
• Injection-site pain
• Anaphylaxis—rare
• Hepatotoxicity with prolonged/repeated exposure
• Ulcerative or haemorrhagic cystitis with chronic misuse
• Tolerance, dependence and abuse potential

Emergence reactions are more frequent when esketamine is used alone and may be reduced by a small dose of a benzodiazepine.

Advantages

• Provides anaesthesia, analgesia and amnesia
• More potent than racemic ketamine—requires approximately half the dose
• Rapid onset
• Generally preserves spontaneous ventilation
• Relative preservation of airway reflexes
• Bronchodilator
• Maintains or increases BP and cardiac output
• Useful in trauma, hypotension and bronchospasm
• Minimal adrenal suppression
• Does not trigger malignant hyperthermia
• Rapid antidepressant effect
• May produce:
• Faster recovery
• Less salivation
• Fewer emergence reactions than equipotent racemic ketamine

Limitations

• Poor visceral analgesia
• Does not reliably produce skeletal-muscle relaxation
• Increased secretions
• Sympathetic stimulation may be harmful in cardiac disease
• Emergence reactions and hallucinations
• Risk of laryngospasm and aspiration persists
• Controlled drug with abuse potential
• No specific antagonist

Contraindications

• Hypersensitivity to esketamine or ketamine
• Any condition in which an increase in BP or ICP poses a serious risk
• Uncontrolled hypertension
• Aneurysmal vascular disease or arteriovenous malformation
• Previous intracerebral haemorrhage
• Unstable angina or recent myocardial infarction
• Manifest ischaemic heart disease when used as the sole anaesthetic
• Eclampsia or pre-eclampsia
• Concurrent xanthine derivatives or ergometrine

Use with caution

• Raised ICP or intracranial pathology
• Glaucoma, penetrating eye injury or raised IOP
• Tachyarrhythmia
• Decompensated heart failure
• Hyperthyroidism
• Severe psychiatric illness or psychosis
• Alcohol or substance-use disorder
• Acute intermittent porphyria
• Hepatic impairment
• Upper-respiratory infection
• Procedures involving the pharynx, larynx or bronchi
  

References

1. Peltoniemi MA, et al. Clin Pharmacokinet. 2016;55(9):1059–1077. 
2. Electronic Medicines Compendium. Esketamine: Summary of Product Characteristics. Updated December 2024. 
3. US Food and Drug Administration. SPRAVATO® Prescribing Information. Revised January 2025.