FRCA Notes

Ketamine

Resources

  • Ketamine is a phencyclidine derivative that exerts its anaesthetic effect predominantly through non-competitive antagonism of the NMDA receptor
  • Does not induce anaesthesia in one arm-brain circuit time
  • It has a molecular weight of 238g/mol
ketamine molecule

Induction of anaesthesia

  • IV (1-2mg/kg) - onset 30-90s and duration 5-10mins

Analgesia

  • Nasal
  • IV via PCA, either alone or mixed with an opioid
  • Epidural

  • Sub-anaesthetic IV dosing
    • 10-20mg single bolus
    • 0.25mg/kg bolus or 0.25mg/kg/hr infusion

Sedation

  • IV e.g. 10-20mg boluses titrated to effect
  • IM (4-10mg/kg) - onset 2-8mins and duration 10-20mins [NB pain on injection]
  • PR (10mg/kg)
  • PO

Other

  • Bronchodilatory properties so may be used in refractory asthma/bronchospasm

Presentation

  • Clear colourless solution with a pH of 4.5
  • Concentrations of 10mg/ml, 50mg/ml or 100mg/ml, stored in glass vials at room temperature
  • Presents as either:

    1. A racemic mixture of the inactive, R(-) enantiomer and the active, S(+) enantiomer
      • Combined with 1-in-10,000 benzethonium chloride preservative, which is neurotoxic

    2. An enantiopure preparation of S(+) ketamine
      • Preservative free therefore safe for use in epidurals
      • Relatively expensive
      • Much greater (4x) affinity for the NMDA receptor and 2-3x more potent than the R(-) enantiomer
      • Responsible for the cardiovascular effects of racemic ketamine (BJA, 2021)

Absorption

  • It has a pKa of 7.5
  • Bioavailability
    • IM: 93%
    • Epidural: 77%
    • Intranasal: 45-50%
    • Sublingual: 25-30%
    • Rectal: 25-30%
    • Oral: 20%

Distribution

  • Volume of distribution is 3L/kg although this is increased in critically ill patients
  • 25% protein binding
  • Described using 2- and 3-compartment models and suitable for use as a TCI e.g. the Domino, Hijazi or Clements models

Metabolism

  • Hepatic metabolism - total body clearance dependent on hepatic blood flow
  • Phase I → CYP450 enzymes (2B6, 3A4) to the weakly active metabolite norketamine (1/3 as potent)
  • Phase II → glucuronidation to inactive metabolites

Excretion

  • Metabolites excreted in the urine (91%)
  • Clearance 17ml/kg/min
  • Elimination half life 2-3hrs

Respiratory

  • Unchanged respiratory drive (BJA, 2025 (1), BJA, 2025 (2))
  • Preserved laryngeal reflexes
  • Is a bronchodilator via histamine antagonism and bronchial smooth muscle relaxation

  • There is increased muscle tone in the jaw that may precipitate obstruction
  • It can cause sialorrhoea and bronchorrhoea, which can predispose children to obstruction/laryngospasm

Cardiovascular

  • Reduces neuronal catecholamine uptake, leading to:
    • Increased heart rate, cardiac output and therefore blood pressure
    • Increased myocardial work and oxygen consumption
    • Raised pulmonary vascular resistance (but not SVR)

  • As such ketamine is relatively contraindicated in those with myocardial ischaemia
  • S(+) ketamine may be preferable in IHD as it produces less cardiac depression (although does induce some direct myocardial depression)
  • Doesn't block ATP-sensitive K+ channels, which is a key mechanism of ischaemic myocardial preconditioning

Neurological

  • Non-competitive NMDA receptor antagonism by binding to the allosteric site
  • Reduces presynaptic glutamate release
  • This produces dissociative anaesthesia
    • Dissociates thalamo-neocortical and limbic systems
    • There is δ and θ activity on EEG; the ɑ-rhythm is abolished

  • Intense analgesia
    • Thought to reduce opioid tolerance by blocking action of PSD-93/-95 proteins
    • Demonstrates some μ-antagonism but κ- and σ- partial agonism

  • Intense amnesia
  • Vivid, unpleasant dreams, hallucinations and delirium (5-30%)
    • Can occur for up to 24hrs post-dose
    • Reduced by concurrent use of opioids or BZD's
    • Same frequency but reduced intensity by using S(+) ketamine
    • Less common in: paediatric, elderly, those less to recover undisturbed

  • Also causes antagonism at nicotinic ACh, muscarinic ACh and mono-aminergic receptors
  • Local anaesthetic activity at high doses via action on neuronal Na+ channels

  • Historically thought to increase cerebral blood flow, CMRO2 and ICP
    • Subsequent work has not replicated this
    • There's a lack of evidence supporting these purported deleterious effects of ketamine in brain injury or increased ICP
  • Increases IOP although not in a clinically meaningful fashion

Gastrointestinal

  • Sialorrhoea
  • Increased frequency of PONV vs. propofol and thiopentone
  • Interstitial cystitis with high-dose, non-prescription use (Class C drug of abuse)
  • Unsafe in porphyria