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 and regional 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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