Agonists and Antagonists
These agents cause their sedative/hypnotic effect by acting on a specific type
Alpha 2 receptors
Alpha 2 receptors have also be classified according to radio-ligand binding studies and
We cannot however expect to be able to ever fully explain or modulate behaviour at the
purely molecular level.
- Alpha 2a - Gene found on chromosome 10 - predominant subtype involved in sedation and
- Alpha 2b - Gene found on chromosome 4 - predominant subtype involved in the haemodynamic
- Alpha 2c - Gene found on chromosome 2
- Alpha 2d
Mechanism of action
- Activation of inhibitory G proteins causing a decreasing in cAMP, or
- Activation of G proteins that act directly on membrane-bound ion channels, especially
potassium channels, or
- Activation of the Nitric Oxide, cGMP pathway to cause
- Inhibition of noradrenaline release within neuronal tissue
- In the medullary dorsal motor complex causing hypertension and bradycardia
- In the locus coeruleus leading to sedation and analgesia
- A high density exists in the vagus nerve, intermediolateral column and the substantia
- The dorsal horn of the spinal cord.
- Primary sensory neurons
These are receptors that recognise the imidazoline or oxazoline chemical structure.
Stimulation leads to a centrally mediated hypotensive and anti-arrhythmogenic action.
- Imidazoline 1 receptors have a restricted distribution in the ventrolateral medulla
where they are involved in the blood pressure regulation
- Imadazoline 2 receptors are found on the mitochondrial membrane within a large variety
of cells. They are thought to be involved in neuroprotection.
Predominant alpha 2 Agonists
||Rapid and complete absorption, peak plasma level in 60-90 minutes
||Dexmedetomidine alters its own
- 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
||20% protein bound
1.5-2 l/kg volume of distribution
|95% protein bound
1.5 l/kg volume of distribution
|50% protein binding
||Minimal inhibition of CYP2D6
|Elimination t 1/2
||2.3 hours initially
Increasing "context sensitive half time" similar to fentanyl with prolonged
||95% renal excretion of methyl and glucuronide conjugates
||40% renal unchanged
||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
2.5 mg/kg intravenously given at least over
|0.75-1.5 mg/kg/hr intravenously
||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
- 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.
- Prophylactically reduces peri-operative ischaemia
- Sedation and anaesthesia
- 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%
- Intrinsic anaesthetic properties which can be selectively reveresed by administering the
- "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!
- 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
- Stimulation of the alpha 2a receptors in the substantia gelatinosa of the dorsal horn of
the spinal cord prevents the firing of nociceptive neurones
- Cause muscle flaccidity and prevents opioid induced muscle rigidity
- The muscle relaxant effect is mediated via a central action, not at the neuromuscluar
- Reduction in post operative shivering
- Dexmedetomidine reduces the vasoconstictive threshold by 1.4 o C and the
shivering threshold by 2 o C.
- Reduction in intraocular pressure
- The reduction of central sympathetic activity by alpha 2 agonists decreases the extent
of neuronal damage.
Chronic pain syndromes
- Epidural or Intrathecal for neuropathic pain.
- Topical for sympathetically maintained pain.
- Successful use in the lower back-pain syndromes.
Medical management of angina
- Oral mivazerol significantly increases exercise duration and time to onset of angina
- Initial hypertension
- Pulmonary oedema
- Delayed hypotension
- Nausea and Vomiting
- Pleural effusions
- Muscle jerking
Other agents that have some alpha 2 agonist activity
- Etomidate - Atipamezole partially reverses etomidate induced anaesthesia
- Pethidine on alpha 2b receptors- may explain its
effectiveness in reducing post anaesthetic shivering
Predominant alpha 2 Antagonists
- 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
Predominant Imidazoline Agonists
- Selective I1 agonist
- Decreases central sympathetic tone, causing a decrease in systemic vascular resistance
- Oral administration
- Dose 0.4mg daily
- Less sedation, depression and tiredness than clonidine
- An oxazoline
- Centrally acting anti-hypertensive
- Neuroprotective effects in ischaemic infarction.
- Oral administration
- No withdrawal symptoms.