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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