Agonists and Antagonists

These agents cause their sedative/hypnotic effect by acting on a specific type of receptor.

Alpha 2 receptors

Alpha 2 receptors have also be classified according to radio-ligand binding studies and pharmacological profiles. 
We cannot however expect to be able to ever fully explain or modulate behaviour at the purely molecular level.

Mechanism of action

  1. Activation of inhibitory G proteins causing a decreasing in cAMP, or
  2. Activation of G proteins that act directly on membrane-bound ion channels, especially potassium channels, or
  3. Activation of the Nitric Oxide, cGMP pathway to cause

Imidazoline receptors

These are receptors that recognise the imidazoline or oxazoline chemical structure. Stimulation leads to a centrally mediated hypotensive and anti-arrhythmogenic action.

Predominant alpha 2 Agonists

  Clonidine Dexmeditomidine Mivazerol
Biokinetics      
Absorption Rapid and complete absorption, peak plasma level in 60-90 minutes Dexmedetomidine alters its own pharmacokinetics!
  • High concentrations cause vasoconstriction which decreases the initial volume of distribution and the intercompartmental clearance, this leads to a transient hypertension
  • Low concentrations allow the central vasodilatation to occur, with a lowering of mean arterial pressure by 10-20% from baseline
 
Onset to action 30 minutes   30 minutes
Distribution 20% protein bound

1.5-2 l/kg volume of distribution

95% protein bound

1.5 l/kg volume of distribution

50% protein binding
Metabolism Liver conjugation
    Minimal inhibition of CYP2D6  
Elimination t 1/2 9-12 hours 2.3 hours initially
Increasing "context sensitive half time" similar to fentanyl with prolonged infusion 		4 hours
Excretion   95% renal excretion of methyl and glucuronide conjugates 40% renal unchanged
Relative Selectivity

Alpha 2:1

220:1 1620:1 120:1

a2: Imidazole

15:1 30:1 215:1
Dose 4 mg/kg to a maximum of 600 mg intravenous or oral dose

0.3 mg/kg/hr infusion

Epidural 1 mg/kg

For sedation in an ICU

1 mg/kg intravenously given as a 10 minute infusion then
0.2-0.7 mg/kg/hr

2.5 mg/kg intravenously given at least over 2 minutes

 0.75-1.5 mg/kg/hr intravenously
Formulation 100 / 250 / 300 mg tablets
100 / 200 / 300 mg/24 hour patches
150 mg/ml solution 		100 mg/ml as 2ml vial and ampoules
Precedex TM (Abbott)		  

Indications and effects

Peri-operatively during general anaesthesia or as an adjunt to regional anaesthesia

  1. Sympatholytic
    1. Improved haemodynamic stability
      • Significant attenuation of the stress response to laryngoscopy.
      • Haemodynamic stability intra-operatively.
      • Slow heart rate helps in reducing intra-operative blood loss.
      • Decrease excessive haemodynamic effects during recovery and extubation.
    2. Prophylactically reduces peri-operative ischaemia
      • Reduction of the peripheral catecholamine levels without the negative inotropic effects associated with beta antagonists.
      • Improved haemodynamic stability
  2. Sedation and anaesthesia
    1. Decreased anaesthetic requirements
      • Clonidine decreases the MAC of halothane by 50%
      • Dexmedetomidine decreases the MAC of isoflurane by 90%
      • Dexmedetomidine decreases opioid and barbiturate requirements.
      • An overzealous reduction in the anaesthetic dose due to suppression of haemodynamic responses to surgical stimulus, may lead to awareness.
      • Dexmedetomidine decreases the MAC of sevoflurane by only 17%
    2. Intrinsic anaesthetic properties which can be selectively reveresed by administering the antagonist atipamezole
      • "Reversible intravenous anaesthetic technique".  Antagonising the sedative/hypnotic effects of dexmedetomidine with atipamezole will permit rapid recovery from anaesthesia, regardless of the duration.  A technique already widely and successfully practiced in veterinary anaesthesia!
  3. Analgesia
    1. Parenteral, epidural and intrathecal placement cause analgesia and synergistically enhance opioid analgesia, decreasing the side effect of respiratory depression.
      • Stimulation of the locus coeruleus with activation of the descending noradrenergic antinociceptive system
      • Stimulation of the alpha 2a receptors in the substantia gelatinosa of the dorsal horn of the spinal cord prevents the firing of nociceptive neurones
  4. Miscellaneous
    1. Cause muscle flaccidity and prevents opioid induced muscle rigidity
      • The muscle relaxant effect is mediated via a central action, not at the neuromuscluar junction.
    2. Reduction in post operative shivering
      • Dexmedetomidine reduces the vasoconstictive threshold by 1.4 o C and the shivering threshold by 2 o C.
    3. Reduction in intraocular pressure
    4. Antisialogue
    5. The reduction of central sympathetic activity by alpha 2 agonists decreases the extent of neuronal damage.

Chronic pain syndromes

  1. Epidural or Intrathecal for neuropathic pain.
  2. Topical for sympathetically maintained pain.
  3. Successful use in the lower back-pain syndromes.

Medical management of angina

  1. Oral mivazerol significantly increases exercise duration and time to onset of angina pain.

Side effects

Other agents that have some alpha 2 agonist activity

  1. Etomidate - Atipamezole partially reverses etomidate induced anaesthesia
  2. Pethidine on alpha 2b receptors- may explain its effectiveness in reducing post anaesthetic shivering

Predominant alpha 2 Antagonists

  1. Atipamezole - The most selective alpha 2 antagonist, has been used to reverse the sedation and hypotension caused by dexmedetomidine. Duration of action of 2 hours is similar to dexmedetomidine
  2. Idazoxan
  3. Yohimbine
  4. Efaroxan
  5. Rauwolscine

Predominant Imidazoline Agonists

Moxonidine

Rilmenidine

Date of First Publication: 2000-6-30 Date of Last Update: 2006/10/24Web page author: Click here