1999A16 Describe the effects of alpha 2 adrenoceptor agonists relevant to anaesthesia.

 

List:

·      Receptor effects

·      CNS effects

·      CVS effects

·      Other effects

 

Receptor effects:

 

Clonidine

Dexmedetomidine

Adrenoceptors

·  Partial agonist

·  α2:α1 = 200:1

·  α2A > α2B > α2C

·  Pre-synaptic α2: ↓norad release

·  Post-synaptic α2: activation, like α1

·  Full agonist

·  α2:α1 = 1600:1

Imidazoline receptors

·  Agonist

·  May account for many/most effects!

·  Same

 

Central nervous system:

 

Clonidine

Dexmedetomidine

Effects

·  Mainly post-synaptic

·  Locus coeruleus:

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

·  Brainstem (imidazoline)

o ? May mediate many effects

·  Same

Use

·  Oral pre-medication, anxiolysis (bioav ~100%)

·  Sedation

·  Adjunct to GA; MAC and propofol-sparing

·  Analgesia, opioid-sparing

·  ↓CMRO2 -> ↓CBF

·  Augment and prolong neuraxial blockade

 

·  *Note slower CNS than CVS effects

·  IV only (bioav poor)

·  Anxiolysis

·  Sedation: rousable, co-operative

·  General anaesthesia, often with propofol (EEG quasi NREM 3-4)

·  Analgesia, opioid-sparing

·  Manage hyperactive delirium in ICU

 

·  *Note not for neuraxial use

·  *Note fast CNS and CVS effects

 

Cardiovascular:

 

Clonidine

Dexmedetomidine

Effects

Biphasic:

1.    ↑SVR, ↑mAP +/- reflex ↓HR

o Peripheral post-synaptic α2B

o Seen with IV bolus

2.    ↓SVR, ↓mAP +/- reflex ↑HR

o Central post-synaptic

o Peripheral pre-synaptic α2A

o Hypotension may be prolonged

 

·  *Note minimal effect on cardiac output

·  +/-Induction loading dose -> ↓HR, ↓mAP

·  +/- Cessation -> rebound hypertension

o Upregulation of adrenoceptors

Use

·  Antihypertensive

·  Obtund pressor response to laryngoscopy

·  ↓Risk peri-op myocardial ischaemia

o ↓SNS outflow and ↓HR protective

o Rebound changes deleterious

 

Other:

 

Clonidine

Dexmedetomidine

Effects

·  Minimal respiratory depression

·  Minimal effect on airway reflexes

·  ↓Platelet activation

·  ↓Salivation

·  ↓Renovascular resistance

·  ↓Shivering*

·  ↓Intra-ocular pressure

·  ↓SNS activation in opioid withdrawal*

·  Same

 

Addit: compare the pharmacokinetics of clonidine and dexmedetomidine

 

 

Clonidine

Dexmedetomidine

Admin:

IV, PO epidural, intrathecal,
peripheral nerve with local anaesthetic

IV only

Loading dose 1mcg/kg

(may cause ↓HR ↓mAP)

Infusion 0.2-1mcg/kg/h

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% (hence PO pre-med)

Poor

Distribution:

 

 

-Lipid solubility

High

High

-VDSS

2L/kg

2L/kg

-Plasma protein binding

20%

90%

Metabolism:

 

 

-Extent

50%

100%

-Mode

Liver 2D6 -> inactive metabolites (note polymorphism)

Liver CYP2A6 hydroxylation

-Speed

Cl 2-4mL/kg/min

t1/2β 12-24 hours

(slow!)

Cl 100mL/kg/min

t1/2β 2 hours

(fast!)

-Active metabolites

Nil

 

Excretion:

 

 

 

50% parent and near 100% metabolites

95% metabolites -> urine

 

 

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