FRCA Notes

Dexmedetomidine

Resources

  • Dexmedetomidine is an imidazole compound with action at ɑ2-adrenoreceptors and central imidazole receptors
  • It is only licensed for sedation on intensive care, although may be used by sneaky intensivists/anaesthetists intra-operatively too

Intensive Care

  • Sedation:
    • As a sole agent or adjunct
    • May be used as a bridge to extubation
    • May be associated with reduced risk of delirium compared to other studies
    • May be associated with reduced duration of mechanical ventilation and reduced length of ICU stay
    • Associated with increased mortality in patients >65yrs when used for sedation in critical care (SPICE III trial, 2019 )

Anaesthesia

  • Sedative premedication (paediatrics) at an intranasal dose of 1mcg/kg
  • Adjunct during general anaesthesia for anaesthetic- and opioid-sparing effects
  • Smooth extubation and reduce incidence of emergence phenomena
  • Neurosurgical procedures requiring intra-operative awakening e.g. awake craniotomy, deep brain stimulator implantation
  • Sympatholysis
  • Post-operative analgesia

  • Highly selective α2-adrenoceptor agonist demonstrating an α2:α1 selectivity ratio of 1620:1
  • It is more potent than clonidine, with a higher affinity for the ɑ2-adrenoreceptor and exhibits full agonist properties

Sedation and anxiolysis

  • Agonism of α2-receptors in the locus coeruleus of the pons
  • This leads to dose-dependent inhibition of noradrenaline release, disinhibition of the ventrolateral pre-optic nucleus and then release of inhibitory neurotransmitters
  • This pathway is part of the complex natural sleep circuitry, resulting in a sedative quality closer to actual sleep than from GABAergic sedatives
  • Indeed, EEG evidence suggests dexmedetomidine sedation mimics stage 2 non-REM sleep
  • Features of the sedation include:
    • Preserved muscle tone
    • Preserved ventilation
    • Spontaneous and evoked movements
    • Awakening by external stimuli
    • Return to previous level of sedation once external stimulus discontinued

Analgesia

  • Main site of action at α2-receptor in the substantia gelatinosa of the dorsal horn
  • This reduces release of nociceptive neurotransmitters such as substance P

Presentation

  • Medetomidine is a racemic mixture but only the D-isomer is active
  • Dexmedetomidine is an enantiopure preparation of the S-enantiomer
  • The formulation in the UK (Dexdor) presents as a clear, colourless solution of 100μg/ml in ampules or vials of 2 - 10ml
  • Diluted before administration in glucose or normal saline to a concentration of 4μg/ml
  • Can be administered centrally or peripherally

Dosing (anaesthetics)

  • Load with 0.5 - 1μg/kg over 10mins
  • Maintenance infusion of 0.6μg/kg/hr titrated down or up to between 0.2 - 1.0μg/kg/hr

Absorption

  • Unpredictable oral absorption; oral bioavailability only 15%
  • Relatively good nasal (65%) and buccal (82%) bioavailability

Distribution

  • 94% protein bound; primarily albumin and also α1-acid glycoprotein
  • Unbound drug crosses BBB to exert central effect
  • Highly lipophilic drug; undergoes rapid distribution
  • Steady state volume of distribution 118L; increased in low plasma albumin concentration
  • Fits a two-compartment model with first order elimination
  • Exhibits linear pharmacokinetics

Metabolism

  • Hepatic metabolism via:
    • Oxidation via CYP2A6 and other CYP450 enzymes
    • Glucuronidation (34%)
    • N-methylation
    • Hydroxylation
  • Metabolites are inactive
  • Dose reduction in hepatic impairment due to reduced protein binding and metabolism

Excretion

  • Inactive metabolites are 95% excereted in the urine
  • Does not require dose adjustment in renal impairment
  • Clearance 39L/hr
  • Elimination half-life is 2hrs

  • Dexmedetomidine displays essentially the same pharmacodynamic properties as clonidine, with exceptions that are detailed below

Cardiovascular

  • Biphasic cardiac effects:
    • At higher infusion rates including during loading doses, there is hypertension due to activation of α2B-receptors on vascular smooth muscle
    • There is subsequent hypotension and bradycardia due to inhibited sympathetic outflow
  • Cardiac effects likely to be more pronounced in patients with hypovolaemia, chronic hypertension, high vagal tone, elderly or diabetes mellitus
  • Bradycardia may be so profound so as to cause asystole
  • Therefore relatively contraindicated in patients with hypotension or heart block

Neurological

  • Reduces intra-operative propofol maintenance infusion doses by 20-50%
  • No protective effect on post-operative agitation or emergence delirium in paediatric patients
  • No reduction in rate of post-operative delirium in patients undergoing cardiac surgery (BJA, 2022)
  • Increased length of stay in recovery

  • Rebound agitation, hypertension, and tachycardia can occur after cessation of a prolonged infusion

  • Decreased cerebral blood flow in animal models but maintenance of flow-metabolism coupling in humans i.e. decreased CBF and decreased CMRO2
  • No effect on evoked potentials
  • Neuroprotective effect in animal models of hypoxia-ischaemia and traumatic brain injury

Gastrointestinal

  • Decongestant
  • Anti-sialagogue
  • Reduces bowel motility

Renal

  • Diuretic effect by inhibiting action of ADH at the collecting duct
  • Mitigates renal ischaemia-reperfusion injury (BJA, 2025)