2021B04 Describe the pharmacology of dexmedetomidine.

 

List:

        PC

        PK

        PD

 

Pharmaceutics:

        Dex(tro)-medetomidine = enantiopure

        No additives safe for neuraxial use

 

Pharmacokinetics:

Administration

      IN pre-med: 3mcg/kg paediatrics

      IV loading dose: 0.25-1mcg/kg

      IV infusion: 0.2-1mcg/kg/h

      Spinal and epidural use possible

Time course

      Onset: <5mins IV, 30mins IN

      Peak: <15 mins IV

      Offset: ~2-3 hours ( duration of infusion)

      N.B. CVS effects are faster than the above

Absorption

      Oral bioav: <10%

      Nasal bioav: 65%

Distribution

      Highly lipid soluble

      Crosses BBB

      VD 2L/kg

      Plasma protein binding 90%

Metabolism

      Fully metabolised

      Liver CYP2A6 hydroxylation

      Cl 10ml/kg/min

      t1/2b 2 hours

Excretion

      95% metabolites -> urine

 

Pharmacodynamics:

Receptor

      α2 adrenoceptor full agonist

o  α2 : α1 = 1600:1

o  Central and peripheral

o  Pre- and post-synaptic

      Imidazoline receptor agonist

o  May mediate brainstem effects

Physiology

      Locus coeruleus:

o  Mainly post-synaptic

o  ↓Activity of reticular activating system

o  ↓SNS outflow

o  ↑Descending inhibition of nociceptors

      Dorsal horn:

o  Glutamate/substance P release by nociceptors

o  ↓Activation of WDR projection neurons

      Peripheral nerves

o  Pre-synaptic: ↓NAd release

o  Post-synaptic: similar to α1

CNS

      Anxiolysis and sedation

o   Rousable and co-operative

o   Airway and breathing unaffected

      General anaesthesia

o   Insufficient alone

o   ↓MAC / propofol Cp50

o   ↓CMRO2 / ↓CBF / ↓ICP (mild)

o   EEG quasi NREM 3-4

      Other:

o   Analgesia (opioid-sparing)

o   Augment and prolong neuraxial blockade

o   Neuroprotection (↓NAd, ↓glutamate)

o   Anti-shivering

o   Anti-sialogogue

CVS

Multi-phasic effects:

      At first: ↑SVR, ↑mAP, reflex ↓HR

o  Peripheral post-synaptic α2B

o  May occur after loading dose

      Then: ↓SVR, ↓mAP, ↓HR, CO

o  Central post-synaptic > peripheral pre-synaptic α2A

o  Severe if large bolus

      After cessation: rebound hypertension, agitation

o  α2 receptor upregulation

Use:

      ↓Response to laryngoscopy and surgery

      ↓Myocardial ischaemia (↑supply, ↓demand)

      ↓Opioid withdrawal

 

 

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