· Effects
· Comparison
|
Receptor |
· α2 adrenoceptor agonist o α2 >> α1 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 |
· Effects o During use: ↓SVR, ↓mAP, ↓HR, ↔CO § Central post-synaptic > peripheral pre-synaptic α2A § Severe if large bolus o After cessation: ± rebound ↑mAP, agitation § α2 receptor upregulation · Use: o ↓Response to laryngoscopy and surgery o ↓Myocardial ischaemia (↑supply, ↓demand) o ↓Opioid withdrawal |
|
|
Clonidine |
Dexmedetomidine |
|
PC |
· So cheap |
· So expensive |
|
PK |
· 100% oral bioavailability o Oral pre-med · t1/2β 12-24h o Bolus only o Risk prolonged hypotension · 50% metabolised o Accumulate in AKI |
·
Poor oral bioavailability · t1/2β 2h
o
Bolus and/or infusion · 100% metabolised |
|
PD |
· Partial agonist (ceiling effect) · α2:α1 = 200:1 · ? No phasic response |
· Full agonist · α2:α1 = 1600:1 · Loading dose -> ↑SVR, ↑mAP
|
|
|
Clonidine |
Dexmedetomidine |
|
Admin: |
IV, PO, neuraxial, regional |
IV, neuraxial, regional |
|
Time course: |
|
|
|
-Onset |
<5 min |
<5 min |
|
-Peak |
10 min |
<15 mins |
|
-Duration |
3-7 hours (for bolus only) |
2-3 hours (suitable for long infusion) |
|
Absorption: |
|
|
|
-Oral bioavailability |
Near 100% |
Poor |
|
Distribution: |
|
|
|
-Lipid solubility |
High |
High |
|
-VDSS |
2L/kg |
2L/kg |
|
-Plasma protein binding |
20% |
90% |
|
Metabolism: |
|
|
|
-Extent |
50% |
100% |
|
-Mode |
Liver CYP2D6 N.B. polymorphism |
Liver CYP2A6 hydroxylation |
|
-Speed |
Cl 2-4mL/kg/min t1/2β 12-24 hours |
Cl 10mL/kg/min t1/2β 2 hours |
|
-Active metabolites |
Nil |
Nil |
|
Excretion: |
|
|
|
-Urine |
50% parent 100% metabolites |
95% |
|
-Faeces |
|
5% |
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