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Perspectives on Premeds – Alpha-2 Agonists

Perspectives on Premeds is a series of articles touching on different pharmacological, physiological and clinical aspects of pre-anaesthetic medication. This first article aims to provide a refresher on α2 agonists. 

Background

Alpha-2 agonists have been the subject of significant discussion within the veterinary literature.  Since their initial introduction onto the veterinary market they frequently received ‘bad press’ and were associated with a number of negative user experiences. A likely explanation for this was unfamiliarity with α2 agonists together with the high dose rates initially recommended. However, as user experience and confidence has grown, the beneficial sedative and analgesic effects of α2 agonists have become extensively recognised and their use in small animal veterinary medicine is now wide spread.

Available Formulations

α2 agonists are currently available on the UK market, namely: medetomidine, dexmedetomidine and xylazine. Xylazine has an approximately 10 times less affinity for the α2 receptor than medetomidine and dexmedetomidine, and as a result is associated with a wider range of undesirable effects in the most commonly treated small animals.  

Medetomidine is a 50:50 mix of dexmedetomidine and levomedetomidine.  Dexmedetomidine is the active isomer and levomedetomidine has traditionally been considered to be the inactive component. However, a recent study3 has suggested very high doses of levomedetomidine may actually reduce the sedative and analgesia effects of dexmedetomidine and enhance bradycardia.  Further studies need to be performed to determine the clinical effects of the levomedetomidine isomer in the practice setting. Additionally, dexmedetomidine has a reduced hepatic metabolic requirement as only one isomer is delivered to the liver for processing. 

This article will focus on medetomidine and dexmedetomidine.

Clinical Indications

α2 agonists are widely used for their sedative and analgesic properties and are regularly incorporated into premedication protocols prior to general anaesthesia. When used for this purpose they elicit several desirable effects, these include:

  • Sedation
  • Analgesia
  • Drug sparing effects – the doses of other premedicants, induction and maintenance agents may be reduced. This effect should be considered when determining the doses of other concomitantly administered CNS depressant drugs
  • Minimal respiratory depression at clinical doses

Pharmacological Effects of Alpha-2 Agonists

The α2 agonists, medetomidine and dexmedetomidine, provide profound, dose related sedation which plateaus at higher doses. 

α2 agonists afford profound analgesia, effected at spinal cord level via the α2 receptors. This can help produce a smooth and stable induction, maintenance and recovery with a reduction in “swings”.   The analgesic effects are short lived and generally persist for approximately 1 hour at clinical doses although sedation may continue for longer.  

Peripheral vasoconstriction occurs following administration.  This can initiate a biphasic alteration to blood pressure

  • Phase 1. There is an initial increase in blood pressure lasting approximately 20 minutes resulting in a compensatory decrease in heart rate and cardiac output.  Cardiac output can reduce by up to 50%.  This should not be an issue in healthy animals but must be considered in animals with a reduced organ reserve when blood flow to the vital tissues may be compromised.
  • Phase 2. After approximately 20 minutes there is a decrease in central sympathetic tone and a reduction in peripheral vasoconstriction.  As a result, blood pressure returns to normal or just below, with a normal or reduced heart rate.

Although peripheral vasoconstriction will limit heat loss there is also depression of the thermoregulatory centre giving rise to a reduction in body temperature.  Animals should be closely monitored following administration of α2 agonists and warming provided where necessary.

There are significant drug sparing effects4 following the administration of α2-agonists, some authors reporting up to a 70% dose sparing effect.2 This should always be considered when administering multiple products, during intravenous induction of anaesthesia and during maintenance.  The doses of concomitant drugs should be reduced accordingly.

Blood flow to the liver and the hepatic metabolism of drugs is reduced following the administration of α2 agonists.  In patients with liver disease α2 agonists should be avoided if possible.

The reduction in cardiac output increases circulation time and this, together with the reduced metabolic capacity of the liver, means intravenous induction agents should be given slowly and to effect. The dose of both induction and maintenance agents may be lower than expected.

There are minimal effects on the respiratory system. However, in brachycephalics, the profound sedation can potentially lead to upper airway obstruction and caution should be exercised.

A reduction in vasopressors and renin secretion following the administration of α2-agonists causes an increased urine output.  This class of drug should therefore be avoided in “blocked cats” and attention must be paid to bladder care in all patients receiving α2-agonists (and all premedicants).

A transient hyperglycaemia may be observed as a consequence of reduced insulin production.

Emesis may be observed in some individuals due to activation of the central α2 receptors. This class of drug should therefore be avoided in gastrointestinal foreign body patients.

Antagonism of alpha-2 agonists

α2 agonist sedation and analgesia are readily antagonised with atipamezole (an α2 antagonist).  

Antagonism of α2 agonists will not only “reverse” the sedative effects of the drug but also the analgesic effects, so it is essential to consider administering an alternative class of analgesic to maintain pain relief.

Antagonism may be considered in some patients during the recovery period as studies have demonstrated this to be a time of high risk for anaesthetic complications.1 If atipamezole is administered intramuscularly the recovery should be smooth and uneventful although this can be dependent on the timing of antagonism and on the concomitant use of other drugs e.g. ketamine. 

Antagonism is not recommended less than 45 minutes after α2 agonist administration if used in combination with ketamine, as excitable recoveries are more likely than if antagonism occurs at a later stage.2

Intravenous administration of atipamezole is “off licence” (see appropriate SPC) and may result in very rapid and excitable recoveries. Routine intravenous administration is not recommended.2, 5

The selectivity of dexmedetomidine for the alpha 2 receptor is superior to that of medetomidine suggesting it would be the drug of choice but clinical evidence is sparse, and its use is currently the preference of the individual prescribing the drug. 

Summary of alpha-2 agonists

  • Profound sedation (dose dependent) 
  • Profound analgesia (duration approximately 1 hour)
  • Peripheral vasoconstriction
  • Biphasic alterations to blood pressure
    • Increased blood pressure (approx. 20 minutes duration)
    • Followed by normal or slightly reduced blood pressure
  • Significant dose sparing. Adjust the doses of concomitant drugs, induction & maintenance agents accordingly
  • Potential for hypothermia (resetting of thermoregulatory centre)
  • Reduced hepatic blood flow (and therefore metabolism)
  • Increased circulation time and reduced cardiac output – administer intravenous agents more slowly
  • May increase urine output. Care in urinary disease/“blocked” animals
  • Transient hyperglycaemia
  • May cause emesis. Care in GI disease/foreign bodies
  • Antagonisable.  Both sedation and analgesia are “reversed”.  Consider alternative and multimodal pain management

Coming soon within the Perspectives on Premeds series:

  • Opioids
  • Phenothiazines
  • Benzodiazepines
  • Anticholinergics
  • Timing and route of administration for optimal results
  • ASA Physical Status
  • Downloadable pre-meds characteristics table
  • Which premed? – Choosing the most appropriate combination for each ASA Physical Status category (dogs and cats)
Article by
Karen Heskin
BVSc CertSAO MRCVS

Veterinary Technical Manager

Originally published: Friday, 4th May 2018
Last updated: Thursday, 17th May 2018

References

  1. Broadbelt DC, Blisset KJ et al (2008).  The risk of death: the confidential enquiry into perioperative small animal fatalities. Veterinary Anaesthesia & Analgesia 35, 365-373
  2. BSAVA Manual of Canine and Feline Anaesthesia and Analgesia.  3rd edition. (2016)
  3. Kuusela E et al (2001).  Sedative, analgesic, and cardiovascular effects of levomedetomidine alone and in combination with dexmedetomidine in dogs.  American Journal of Veterinary Research 62, 616-621
  4. Dugdale A (2010). Veterinary Anaesthesia, Principles to Practice. Wiley-Blackwell.
  5. BSAVA Small Animal Formulary. 9th Edition (2017).

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