ANESTHESIOLOGY

Dexmedetomidine and Anesthesia

Sudivya Sharma*, Prashast Jain**

Abstract
The α2-adrenoceptors (ARs) by virtue of their sedative, analgesic, sympatholytic, anesthetic-sparing and hemodynamic-
stabilizing properties, have been used as an adjunct to local anesthetics for prolongation of effect. Dexmedetomidine a
stereoisomer of medetomidine a highly selective α2-adrenergic receptor (AR) agonist with a relatively high ratio of α2/ α1-activity
(1620:1 as compared to 220:1 for clonidine). It has recently been introduced in anesthesia practice. It is currently being
used for continuous intravenous sedation in the intensive care setting and procedural sedation in nonintubated patients.
Keywords: Dexmedetomidine, α2-2 adrenergic receptor agonist, adjuvant, analgesic

D
exmedetomidine is a stereoisomer of
CH
medetomidine, with chemical formula 4-[(1S)- CH
H
1-(2, 3-dimethylphenyl) ethyl]-1H-imidazole. N CH
It is a highly selective α2-adrenergic receptor (AR) O H
agonist with a relatively high ratio of α2/ α1-activity
N
(1620:1 as compared to 220:1 for clonidine).1 H

Pharmacokinetics Figure 1. Chemical formula of dexmedetomidine.

Dexmedetomidine undergoes almost complete
hydroxylation through direct glucuronidation and
cytochrome P450 metabolism in liver. Metabolites
are excreted in the urine (about 95%) and feces
(4%). The elimination half-life is approximately two
hours. The average protein binding is 94%. Effects
of dexmedetomidine can be antagonized easily by
administering the α2-AR antagonist atipamezole.
Uses
The α2-adrenoceptors (ARs) by virtue of their sedative,
analgesic, sympatholytic, anesthetic-sparing and
hemodynamic-stabilizing properties, have been used
as an adjunct to local anesthetics for prolongation of
*PGIMS, Rohtak
**Dept. of Anesthesia
PGIMS, Rohtak, Haryana
Address for correspondence
Dr Sudivya Sharma
Flat No-77, B-Wing, Mahavir Krupa Building
TJ Road, Sewari (W), Mumbai - 400 015
E-mail: drsudivyasharma@gmail.com
effect. Clonidine, an α2-AR agonists has been used with
local anesthetics in peripheral nerve block, though the
results have been somewhat less impressive.2,3
Dexmedetomidine, a highly selective α2-AR agonist has
recently been introduced in anesthesia practice. It is
currently being used for continuous intravenous sedation
in the intensive care setting and procedural sedation
in nonintubated patients. Its potential benefit as an
adjuvant to local anesthetics in peripheral nerve blocks
has been emphasized in few experimental studies.1
Mechanism
There have been four proposed mechanisms of action
of α2-AR agonists in peripheral nerve blocks. These
mechanisms include:
ÂÂ Direct action on the peripheral nerve
ÂÂ Centrally mediated analgesia
ÂÂ α-2B-AR2 mediated vasoconstrictive effects
ÂÂ Attenuation of the inflammatory response.4
Despite the fact that there is no α2-AR representation
on peripheral nerves, there is prolongation of action
by perineural administration of α2-AR agonist as

Indian Journal of Clinical Practice, Vol. 24, No. 3, August 2013 223
ANESTHESIOLOGY
an adjuvant to local anesthetics. They prolong the
duration of analgesia by blocking the so-called
hyperpolarization-activated cation current (Ih current).
This is the most well-defined mechanism of α2-AR
agonists. After an action potential (AP) has occurred,
the nerve will have to repolarize to be able to produce
new APs. The early repolarization phase will result in
a hyperpolarized state that will make the generation of
new APs virtually impossible, and the nerve is, during
this period, judged to be refractory to stimulation.
Thus, blocking the Ih current will result in prolonged
hyperpolarization of the nerve, which in turn will result
in an analgesic action. Blocking the Ih current may also
have the potential to produce a selective sensory effect
as this effect appears to be more pronounced in C fibers
(pain) than in A alpha fibers (motor). Dexmedetomidine
has more pronounced effect on inhibition of nerve fiber
action potentials as compared to clonidine.5
Centrally, α2-AR agonists cause analgesia and sedation
by inhibition of substance P release in the nociceptive
pathway at the level of the dorsal root neuron and by
activation of α2-AR in the locus coeruleus. Suppression
of activity in the descending noradrenergic pathway,
which modulates nociceptive neurotransmission,
terminates propagation of pain signals leading to
analgesia.1
Apart from above mechanisms, clonidine may reduce
systemic uptake of the perineurally deposited local
anesthetic-clonidine mixture by means of a1-receptor-
mediated vasoconstriction. As dexmedetomidine has a
very limited effect on a1-ARs, it is unlikely that a nerve
block by a local anesthetic-dexmedetomidine mixture
may prolong the block duration by this mechanism,
despite being able to cause time limited vasoconstriction
by stimulation of α2-ARs.5
The upcoming anti-inflammatory effects of α2-AR
agonists has been highlighted by a series of animal
studies by Brummett and colleagues who reported that
large doses of dexmedetomidine or clonidine prolonged
the duration of sciatic nerve block when added to local
anesthetics like bupivacaine or ropivacaine in rats.
In addition, histopathological examinations of sciatic
nerves at 24 hours and 14 days showed that the nerve
axon and myelin were unaffected after perineural
application of dexmedetomidine. There was decrease
in proinflammatory products from immune cells
recruited to the site of injury and an increase in anti-
inflammatory cytokines. Hence, there was decrease
in perineural inflammation as compared to sole
use of local anesthetic. These findings reinforce the
neuroprotective role of dexmedetomidine. Because of
224 Indian Journal of Clinical Practice, Vol. 24, No. 3, August 2013
the safety profile of dexmedetomidine, it is now being
used intrathecally without apparent toxicity.4,6
Other useful effects of activation of α2-ARs include
decreased salivation, increased glomerular filtration,
decreased intraocular pressure and increased seizure
threshold.1
Adjuvant
Dexmedetomidine exhibits synergism with local
anesthetics, prolonging their duration of action. So far,
the clinical evidence for the use of dexmedetomidine
as an adjuvant to local anesthetic for peripheral nerve
blocks is limited to few animal studies and three human
studies.3,4,6-8
In the spinal cord, activation of both a-2C and a2-
ARs, situated in the neurons of superficial dorsal horn
especially lamina II, directly reduces pain transmission
by reducing the release of pronociceptive transmitter,
substance P and glutamate from primary afferent
terminals and by hyperpolarizing spinal interneurons
via G-protein-mediated activation of potassium
channels. Postsynaptic activation of central a2-ARs
results in sympatholytic effect leading to hypotension
and bradycardia, an effect judiciously used to attenuate
the stress response of surgery.9-13
The greater a2-ARs selectivity of dexmedetomidine
enhances the therapeutic window of dexmedetomidine
in the treatment of pain. Its opiate sparing effect has
important implications for the management of acute
postoperative pain and chronic pain states, including
disorders involving spasticity or myofascial pain,
neuropathic pain, sympathetically maintained pain
such as complex regional pain syndrome (CRPS) and
chronic daily headaches. It is evolving as an adjuvant
analgesic, both as intravenous and intrathecal infusion,
in cancer pain refractory to multiple treatment
modalities.14-16
Conclusion
Dexmedetomidine has evolved as a panacea for various
applications/procedures with multiple promising
delivery routes. Its clinical applications in adults and
children include premedication, as part of multimodal
anesthetic regimen, regional anesthesia, sedation
monitored anesthesia care, procedural sedation,
prevention/treatment of emergence delirium, alcohol
withdrawal and shivering, and the list continues to
grow.
 ANESTHESIOLOGY

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■■■■

Cardiac Surgery Success Hinges on Teamwork

Better communication is the key to improving patient outcomes after cardiac surgery, according to a new scientific
statement from the American Heart Association.
A wide-ranging review of evidence, led by Joyce Wahr, MD, of the University of Michigan Ann Arbor, called for
such things as checklists, preoperative and postoperative briefings, and team training in communication skills.
But the review, published online in Circulation, also cautioned that “research in this area is nascent but informative.”
The investigators noted that cardiac surgical operating rooms form ‘a complex environment’ that includes many
highly trained people working together and using sophisticated equipment to treat people with severe disease.
“Preventable errors are often not related to failure of technical skill, training or knowledge,” they wrote, “but
represent cognitive, system or teamwork failures.”
Key to improvement of patient safety, they argued, are the “nontechnical skills” of communication, cooperation,
coordination and leadership.

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