Alpha 2 Agonists

Clonidine and dexmedetomidine are alpha-2 agonists. They inhibit the release of epinephrine and norepinephrine by binding to pre-junctional alpha-2 receptors .

Dexmedetomidine is x8 more selective to alpha-2 compared with alpha-1 receptors than clonidine with higher potency and a shorter duration of action. Therefore, it is more suitable for intra-operative use. Clonidine may have a role in the post-operative period because of its high oral bioavailability, longer half-life, ease of administration, and lower medication cost. However, perioperatively it has mostly been superseded by dexmedetomidine which we will focus on for the remainder of this article.

Dexmedetomidine:

Dexmedetomidine has a unique sedative action mediated via the locus coeruleus to produce natural NREM sleep. When used on its own, this creates “arousable” sedation with much less cognitive impairment. As an anaesthetic adjunct, it will reduce propofol maintained anaesthesia requirements by around 20-50% by acting synergistically to increase GABA receptor sensitivity. A single bolus dose will last for around an hour and, when using an infusion for longer procedures, it should be discontinued 30-60 minutes prior to completion of surgery to avoid delays in recovery.

Uses:

Adult and paediatric sedation, premedication, ICU sedation and intraoperative multimodal anaesthesia. It produces dose-dependent sedation, anxiolysis and analgesia and reduces emergence delirium. There is no respiratory depression. It reduces heart rate and blood pressure by around 20%, although rapid administration will activate alpha-1 receptors and increase blood pressure.

Preparations:

Clear colourless solution 200mcg/ml routinely diluted to 2-4 mcg/ml with NaCl 0.9%. Has been used for nasal administration in its concentrated form as it is non-irritant.

Actions:

• Highly selective alpha 2 agonist
• Sympatholytic effect by decreasing release of catecholamines from sympathetic nerve endings
• Sedative effect from decreased activity in the locus coeruleus (natural sleep)
• Does not act on GABA or NMDA receptors unlike other anaesthetic agents
• Cardiovascular effects depend on the dose
  • low infusion rates: approximately 20% decrease in HR and BP
  • rapid infusion rates: peripheral vasoconstriction can occur (alpha-1 agonist) increasing SVR and BP with reflex bradycardia. Therefore, give the loading dose over 5-10 minutes

Benefits:

• Analgesic and anaesthetic sparing effect
• Anxiolytic
• Decreased postoperative shivering, nausea and vomiting
• Renal protection via diuretic, cytoprotective and anti-inflammatory properties
• Reduced preoperative myocardial ischemia following both cardiac and non-cardiac surgery
• Neuroprotection and reduced postoperative delirium
• Decreased intraocular pressure
• Decreased oral secretions (e.g. suitable for awake intubation procedures)
• Does not cause respiratory depression
• Modest decrease in BP and HR may be helpful in certain surgeries (e.g. maxillofacial, spine)
• Very high therapeutic ratio and safety margin

Dose:

IV loading dose 1 mcg/kg over 5-10 minutes. Best given prior to induction as less propofol will be required to achieve a loss of response during induction.
IV maintenance 0.2 – 0.7 mcg/kg/hr (NB NOT mcg/kg/min – errors have occurred)

Onset of action:

Less than 5 minutes with a peak effect within 15 minutes

Route:

• Intravenous bolus and infusion most established
• Oral absorption is unpredictable and bioavailability is low
• Intranasal is effective as a premedication in children with doses suggested ranging from 1-3 mcg/kg. This will also relieve nasal obstruction
• Epidural, intrathecal and perineural are all strictly off label, experimental and not recommended here

Kinetics:

• Rapid distribution half-life
• High plasma protein binding ~ 94% (mostly albumin)
• Metabolized by the liver (glucuronidation and oxidation)
• Excreted in the urine

Caution:

• Cardiac Failure
• Heart Block
• Hepatic Impairment

Can cause bradycardia and hypotension. Propofol-induced vasodilation and beta-blocker use may worsen this effect. If dexmedetomidine is infused rapidly or in high doses alpha-1 stimulation can lead to increased BP and bradycardia.