CONTINUING EDUCATION IN HONOR OF NORMAN TRIEGER, DMD, MD

Alpha-2 Adrenergic Receptor Agonists: A Review

of Current Clinical Applications
Joseph A. Giovannitti, Jr, DMD,* Sean M. Thoms, DMD, MS,† and James J. Crawford,
DMD†
*Professor and Chair and †Resident, Department of Dental Anesthesiology, University of Pittsburgh School of Dental Medicine, Pittsburgh,
Pennsylvania

The a-2 adrenergic receptor agonists have been used for decades to treat common
medical conditions such as hypertension; attention-deficit/hyperactivity disorder;
various pain and panic disorders; symptoms of opioid, benzodiazepine, and alcohol
withdrawal; and cigarette craving.1 However, in more recent years, these drugs have
been used as adjuncts for sedation and to reduce anesthetic requirements. This
review will provide an historical perspective of this drug class, an understanding of
pharmacological mechanisms, and an insight into current applications in clinical
anesthesiology.

Key Words: Procedural sedation; General anesthesia; Alpha-2 agonists; Clonidine; Dexmedetomidine.

I n early scientific theory of adrenergic mechanisms, it

was believed that adrenergic receptors were classified
into 2 groups: those whose actions resulted in either
crisis. It was discovered that a-2 agonists produce effects
within both the central and peripheral nervous systems.
Centrally within the locus ceruleus, for example, a-2
excitation or inhibition of effector cells.2 This theory was agonists are able to produce sedation, analgesia, and
the accepted concept until Ahlquist2 demonstrated that euphoric effects and partially block acute withdrawal
there were 2 subtypes of receptors in the class, which he symptoms in chronic opioid users.4 More potent a-2
termed a and b (Table 1). Each had both excitatory and selective drugs, such as dexmedetomidine, have been
inhibitory effects based upon where that receptor was formulated for clinical use as sole sedative agents or as
located.2 Further study led researchers to discover that adjuncts to drastically reduce the patient’s requirement
one of the a receptors inhibited neurotransmitter release for additional sedatives or general anesthetics. Also, a-2
from the presynaptic neuron.3 The a-receptor antago- agonists are gaining popularity in children’s hospitals
nists prazosin and yohimbine were used to further throughout the United States as a preventative measure
subclassify these receptors as a-1 and a-2.4 Later, many of and treatment modality for emergence delirium after
a-2 adrenergic agonists were developed for use in the general anesthesia.6
clinical setting, including their use as anesthesia adjuncts.
The use of a-2 agonists as adjuncts gained popularity
when early reports by Brodsky and Bravo5 found that MECHANISM OF ACTION
withholding a single dose of clonidine prior to anesthesia
caused a patient to experience an acute hypertensive Most studies to differentiate the various subtypes of a-2
receptors have been performed with molecular cloning
Received September 6, 2014; accepted for publication January 20, using rat and human models. Ruffalo et al7 demonstrated
2015. that administering yohimbine, a selective a-2 antagonist,
Address correspondence to Dr Joseph A. Giovannitti, Jr,
Department of Dental Anesthesiology, University of Pittsburgh
can differentiate the types of receptors. He suggested
School of Dental Medicine, 3501 Terrace St, G-89 Salk Hall that blockade of a receptors in bladder tissue is not
Pittsburgh, PA 15261; jag@pitt.edu. competitive, and that more than one type of a-
Anesth Prog 62:31–38 2015 ISSN 0003-3006/15
Ó 2015 by the American Dental Society of Anesthesiology SSDI 0003-3006(15)

31
32 Alpha-2 Adrenergic Receptor Agonists Anesth Prog 62:31–38 2015

Table 1. Adrenergic Receptor Subtypes and Their Physiologic

Functions
Receptor Physiologic Action (Agonism)
a1 Constriction of vascular smooth muscle
Contraction of radial muscle of the eye
Contraction of the vas deferens smooth muscle
a2 Inhibition of norepinephrine release from
presynaptic neuron
Centrally induced sedation via locus ceruleus
Centrally mediated pain modification via dorsal horn
Inhibition of insulin release from pancreatic b cells
b1 Increased cardiac output (increased chronotropy,
dromotropy, inotropy)
Increased renin release from kidney
b2 Bronchial smooth muscle relaxation
Vascular smooth muscle relaxation (vasodilation)
Reduction of mast cell degranulation and histamine
release
b3 Increased adipose tissue lipolysis

adrenergic receptor exists.7 Microbiologists have been

able to subdivide the various classes of a-2 receptors
based upon affinities for agonists and antagonists. The a-
2 receptors constitute a family of G-protein–coupled
receptors with 3 pharmacological subtypes, a-2A, a-2B,
and a-2C. Endogenous agonists, such as norepinephrine
and epinephrine, have similar affinities for all 3 subtypes.
However, prazosin, a selective a-antagonist drug used to
treat high blood pressure, has a 60-fold affinity for the a- Synaptic influences of a-1 and a-2 receptors. Postjunctional a-
2A receptor on rat lung cells.8 1 receptors mediate effects on target tissues whereas prejunc-
The a-2A and -2C subtypes are found mainly in the tional a-2 receptors inhibit neurotransmitter release and
provide negative feedback.
central nervous system. Stimulation of these receptor
subtypes may be responsible for sedation, analgesia, and
sympatholytic effects.9 The a-2B receptors are found is thought that the spinal mechanism produces most of
more frequently on vascular smooth muscle and have the a-2 agonist drugs’ analgesic action.12,13
been shown to mediate vasopressor effects. All 3 Guanabenz, guanfacine, clonidine, tizanidine, mede-
tomidine, and dexmedetomidine are all a-2 agonists that
subtypes have been shown to inhibit adenylyl cyclase,
vary in their potency and affinities for the various a-2
in turn reducing the levels of cyclic adenosine mono-
receptor subtypes. Clonidine, tizanidine, and dexmede-
phosphate and causing hyperpolarization of noradren-
tomidine have received the greatest clinical use and will
ergic neurons in the medial dorsal pons, specifically in
be addressed more thoroughly. Summary data are
the locus ceruleus.10 As cyclic adenosine monophos-
provided in Table 2.
phate is inhibited, potassium efflux through calcium-
activated channels prevents calcium ions from entering
the nerve terminal, leading to a suppression of neural CLONIDINE
firing. This suppression inhibits norepinephrine release
and reduces activity of the ascending noradrenergic Clonidine is the prototypical a-2 agonist, with an affinity
pathways, resulting in hypnosis and sedation.11 Activa- predilection of 200 : 1 for a-2 versus a-1 receptors,
tion of this negative feedback loop may also produce respectively. It was first used as a nasal decongestant, but
reductions in heart rate and blood pressure and is now most frequently used in the management of
attenuation of the sympathetic stress response (Figure). hypertension because it was discovered coincidentally to
Stimulation of a-2 receptors in the dorsal horn of the lower systemic blood pressure through central brainstem
spinal column inhibits nociceptive neurons and reduces adrenergic stimulation. Clonidine is rapidly and almost
the release of substance P. Although there is some completely absorbed after oral administration, and may
evidence for supraspinal and peripheral sites of action, it exhibit transient increases in blood pressure after initial
Anesth Prog 62:31–38 2015 Giovannitti et al. 33

Table 2. Summary of a-2 Receptor Agonists and Pharmacological Properties*

Drug Name Trade Name Pharmacokinetics Clinical Uses Precautions
Clonidine Catapres, Metabolism: liver Treatment of: Transient increases in
Nexiclon XR, (~50%) Hypertension blood pressure after
Kapvay Excretion: 40–60% Anxiety initial dosing (stimulation
unchanged in urine, ADD/ADHD of postsynaptic a1
20% bile/feces Chronic pain receptors)
Half-life: 12–16 h Withdrawal symptoms Rebound hypertension after
Postoperative shivering sudden cessation
Tizanidine Zanaflex Metabolism: Liver Treatment of: Potential for hepatotoxicity
Excretion: 60% urine, Muscle spasm and cramps Fluoroquinolone antibiotics
20% feces associated with CNS increase serum
Half-life: 2.5 h disorders concentration
Myofascial pain disorders of
head and neck
Spasticity of cerebral palsy
Dexmedetomidine Precedex Metabolism: Liver ICU sedation Hypotension, bradycardia
Excretion: 95% urine, Procedural sedation Tachyphylaxis (if infused
4% feces .24 h)
Half-life: 2 h
* ADD indicates attention-deficit disorder; ADHD, attention-deficit/hyperactivity disorder; CNS, central nervous system; and ICU,
intensive care unit.

dosing because of mild stimulation of peripheral post- diazepine, alcohol, cocaine, food, and tobacco with-
junctional a-1 receptors. Sudden withdrawal of clonidine drawal.
after chronic administration has been associated with
rebound hypertension, which may occur up to 20 hours
after cessation of the drug. It should not be withheld prior TIZANIDINE
to dental procedures.
More recently, clonidine has been used as a premed- Tizanidine is another a-2 agonist, similar to clonidine,
icant in patients with significant pretreatment anxiety.14 but with some important differences. Like clonidine, it
It has been shown to improve mask application upon has sedative, anxiolytic, and analgesic properties, but it
induction of anesthesia in the pediatric population, and has a shorter duration of action and less effect on heart
to decrease anesthetic requirements by 40–60%.15 rate and blood pressure. In a study of 70 patients
Clonidine has been used orally for pediatric procedural undergoing general anesthesia, Tabori et al19 evaluated
sedation with success. Cao et al16 evaluated 45 children the effect of tizanidine versus placebo on the hemody-
aged 2–8 years comparing oral midazolam (0.5 mg/kg) namic response to direct laryngoscopy. Subjects received
and oral clonidine (2 or 4 mcg/kg) in providing level of either 4 mg of tizanidine or a placebo 90 minutes prior
sedation, quality of parenteral separation, mask accep- to the induction of general anesthesia with propofol. The
tance, and postoperative analgesia. Both clonidine tizanidine group had less fluctuation in blood pressure
groups achieved better sedation, separation, and mask and heart rate than the control group following direct
acceptance scores than the midazolam group. There was laryngoscopy and intubation. They also found that
less postoperative shivering with clonidine, but the onset tizanidine reduced the propofol requirement by 25%
time was delayed with clonidine, 60 minutes versus 30 and significantly reduced the incidence of postoperative
minutes for midazolam. shivering (11.4 vs 28.6%). They concluded that tizani-
Clonidine and guanfacine may be used to treat dine provides cardiovascular stability during induction of
attention-deficit/hyperactivity disorder in children and general anesthesia, and that it could have utility in
adolescents. The reduced firing of presynaptic neurons attenuating the stress of direct laryngoscopy and
releasing norepinephrine into the prefrontal cortex intubation.
improves the impulsive and hyperactive behavior seen Tizanidine has also been used in the treatment of
in attention-deficit/hyperactivity disorder.17 Adjunctive myofascial pain disorders of the head and neck. It can
effects on serotonin and c-aminobutyric acid receptors reduce spasticity by increasing the presynaptic inhibition
make a-2 agonists the most widely used medications to of motor neurons in the brain and spinal cord, and by
treat insomnia in children with attention-deficit/hyper- reducing painful muscle spasms in the neck and
activity disorder.18 Clonidine is also useful in the shoulder. In a study evaluating its effectiveness in the
treatment of chronic pain disorders and opiate, benzo- treatment of myofascial pain, tizanidine was shown to
34 Alpha-2 Adrenergic Receptor Agonists Anesth Prog 62:31–38 2015

significantly reduce pain and tissue tenderness and to depleted or vasoconstricted or who have a severe heart
improve the quality of sleep. It was rated as good to block.
excellent in relieving pain by 89% of the subjects
studied.20 The reduction in spasticity has also led other
investigators to evaluate the effectiveness of tizanidine in Respiratory Effects
patients with cerebral palsy. In a study of patients with
infantile cerebral palsy, tizanidine was shown to signif- A major advantage of dexmedetomidine compared with
icantly decrease spasticity by 78.8% as compared to other anesthetic drugs is its minimal effect on the
7.6% for placebo.21 It seems apparent that tizanidine respiratory system. In patients with poor airway patency,
may be useful as a sedative premedicant prior to general obesity, and/or limited range of motion, dexmedetomi-
anesthesia and as a management tool for patients with dine produces excellent sedation without compromising
cerebral palsy or other spastic disorders. the airway or depressing respiration.

DEXMEDETOMIDINE
Pharmacokinetic Considerations
Dexmedetomidine is a highly selective a-2 agonist similar
to clonidine but with a greater affinity for the a-2 Dexmedetomidine conforms to a 2-compartment model
receptor. Clonidine has a specificity of 220 : 1 (a-2 : a- of distribution and elimination. It has an elimination half-
1), whereas dexmedetomidine exhibits a specificity of life (T1/2b) of 2 hours, but it is a highly lipophilic drug that
1620 : 1.22 It is the pharmacologically active d-isomer of is rapidly distributed and redistributed, with a distribution
medetomidine, a full agonist of a-2 adrenergic receptors. half-life (T1/2a) of only 6 minutes. This provides a very
rapid onset but a short duration of clinical effect. Its rapid
redistribution and elimination make it an acceptable
Cardiovascular Effects agent for infusion techniques. Dexmedetomidine under-
goes direct glucuronidation and CYP2A6-mediated
Dexmedetomidine exhibits a biphasic blood pressure metabolism. Approximately 80–90% is excreted in the
response in a dose-dependent fashion.23 Intravenous urine, and 5–13% is found in the feces.25 Typically,
infusion of low doses results in a reduction of mean pharmacokinetic-based interactions are unusual. How-
arterial pressure because of selectivity for central and ever, dosage modifications of simultaneously adminis-
peripheral a-2 receptors. The resultant decreases in tered sedatives may need to be made because of drug
heart rate and systemic vascular resistance indirectly potentiation. Adding an a-2 agonist to a sedation
decrease cardiac output and systolic blood pressure. regimen reduces opioid requirement by 50–75% and
These effects aid in modulating the stress response, benzodiazepine requirement by upwards of 80%.26 The
promote stability, and may protect against radical context-sensitive half-time of dexmedetomidine ranges
fluctuations in cardiovascular parameters intraoperative- from 4 minutes after a 10-minute infusion to 250
ly. This may be particularly useful in patients at risk for minutes after an 8-hour infusion.27
cardiac morbidities who could respond adversely to
surgical stressors. Intravenous infusion of high doses or
rapid intravenous bolus administration may result in Clinical Considerations
systemic hypertension due to activation of peripheral
postjunctional a-1 adrenergic receptors. Dexmedetomi- Dexmedetomidine has 3 main clinical applications: (a)
dine loses its a-2 receptor selectivity as the dose is prolonged sedation in hospitalized patients, (b) proce-
increased by intravenous bolus injection or rapid dural sedation and general anesthesia, and (c) obtunding
infusion. This loss in selectivity results in an initial emergence delirium. It is used as a sedative agent for
increase in blood pressure and concomitant decrease in critically ill patients requiring prolonged sedation and
heart rate, which normalizes within 15 minutes.24 mechanical ventilatory support in a critical care setting.
Hypertension can also be observed because of the Dexmedetomidine possesses all of the characteristics of
transient activation of peripheral a-2B receptors upon an ideal sedative for intensive care. It lacks respiratory
rapid bolus injection of the drug. This brief increase in depression, is analgesic and anxiolytic, has a rapid onset,
blood pressure is likely due to an overwhelming effect of is titratable, and produces sedation with hemodynamic
the competition with vasodilatory effects of the central a- stability.
2A receptors.11 Extreme care should be taken when Secondly, dexmedetomidine is used as an adjunctive
using dexmedetomidine on patients who are volume sedative agent for procedural sedation. It can be used
Anesth Prog 62:31–38 2015 Giovannitti et al. 35

Table 3. Guidelines for Use of Dexmedetomidine (Precedex) in Procedural Sedation

Method of Use Dose
Circumstances Loading Dose Maintenance
Infusion*† Adult patients 1 mcg/kg over 10 min 0.6 mcg/kg/h
Titrate to effect with doses from 0.2
to 1 mcg/kg/h
Less invasive procedures 0.5 mcg/kg over 10 min 0.6 mcg/kg/h
Titrate to effect with doses from 0.2
to 1 mcg/kg/h
Patients .65 y 0.5 mcg/kg over 10 min Reduction in maintenance dosage
should be considered
Patients with impaired hepatic A dose reduction should be Reduction in maintenance dosage
or renal function considered should be considered
Bolus 0.25–0.5 mcg/kg in slow divided doses
* Infusion dosing is per manufacturer recommendations.
† ‘‘Precedex Dosing for Procedural Sedation.’’ http://www.precedex.com/wp-content/uploads/2010/02/
Procedural-Sedation-dosing-Card.pdf.28

with agents such as opioids, benzodiazepines, and impaired cognitive functioning, significantly impairing a
propofol to enhance sedation and promote and maintain patient’s ability to process and store information.
hemodynamic stability. Because it does not produce Pediatric patients, patients with special needs, and the
respiratory depression, it is very useful in patients for elderly are particularly prone to emergence delirium
whom this would be a concern. Its rapid distribution half- following anesthesia, especially when benzodiazepines
life (6 minutes) and favorable context-sensitive half-time and potent inhalational agents are used. Patients who
enhance recovery and allow for faster patient discharge. develop delirium are more likely to have poor outcomes
However, recovery could be prolonged in cases where when hospitalized, including increased length of stay, the
infusion of dexmedetomidine continues over several need for subsequent institutionalization, and higher
hours. In these cases, the infusion should be discontinued mortality. Cognitive impairment has been reported to
well in advance of the anticipated discharge time. negatively affect key outcome indicators such as removal
Dexmedetomidine may be given via bolus injection or from the ventilator, pneumonia, and total length of
continuous infusion. A bolus injection of 0.25–0.5 mcg/ hospital stay.29
kg, given slowly in divided doses to avoid a transient Dexmedetomidine has been studied to assess its
increase in blood pressure, produces a noticeable efficacy in reducing the occurrence of emergence
quieting or mellowing effect without respiratory depres- delirium. Riker and others30 compared the efficacy of
sion. As an alternative, sedation may be induced by a dexmedetomidine with midazolam for the maintenance
continuous infusion of dexmedetomidine, 1 mcg/kg over of mechanically ventilated patients, and also examined
10 minutes, followed by a maintenance infusion of 0.2– the incidence of delirium in those patients. Although the
0.7 mcg/kg/h (Table 3). 2 drugs produced comparable levels of sedation,
Finally, dexmedetomidine is very useful in obtunding dexmedetomidine significantly reduced the incidence of
the emergence delirium sometimes seen after general delirium to 54 versus 75% for midazolam. In addition,
anesthesia, especially in the pediatric population. It the duration of delirium was reduced by 48% in the
produces profound calming without respiratory depres- dexmedetomidine group. Patients treated with dexme-
sion. This is a major advantage over other drugs that detomidine had a statistically significant greater ability to
have commonly been used in this situation and deserves communicate and to cooperate than those treated with
further consideration. midazolam. Pandharipande and colleagues31 compared
the efficacy and incidence of delirium of dexmedetomi-
EMERGENCE DELIRIUM dine and lorazepam in mechanically ventilated intensive
care patients. Lorazepam has been recommended by the
Emergence delirium can be a significant problem Society of Critical Care Medicine for the sustained
following outpatient anesthesia because of the potential sedation of mechanically ventilated patients in the
for serious disruption of the office, damage to instru- intensive care unit. However, it has been proposed that
ments and equipment, and injury to the patient or office the gamma-aminobutyric acid effects of lorazepam and
personnel. Delirium is described as a disturbance of other benzodiazepines may alter levels of potentially
consciousness, characterized by the acute onset of deliriogenic neurotransmitters, with negative conse-
36 Alpha-2 Adrenergic Receptor Agonists Anesth Prog 62:31–38 2015

quences. Compared with the lorazepam group, the given intramuscularly, submucosally, buccally, and intra-
dexmedetomidine group had a lower prevalence of coma nasally. In adult volunteers, intramuscular administration
(63 vs 92%) and fewer days with delirium (3 vs 7 days), demonstrated a 73% bioavailability as compared with
and the 12-month time to death was 363 versus 188 intravenous administration. A biphasic hemodynamic
days. response was not observed. Bioavailability following
Emergence delirium is also common in children intranasal administration was 80% and produced seda-
recovering from deep sedation and general anesthesia. tion similar to oral midazolam in pediatric patients.11
Shukry et al32 studied 2 groups of children between the Mason and others37 demonstrated the safety and
ages of 1 and 10 years receiving general anesthesia with efficacy of intramuscular dexmedetomidine in pediatric
sevoflurane. One study group received an infusion of patients aged 0.2–17 years undergoing electroenceph-
dexmedetomidine and the other received saline. The alographic evaluation. Subjects received 1–4.5 mcg/kg
dexmedetomidine group had an emergence delirium intramuscularly based upon the discretion of the
incidence of 26 versus 60% for the saline group. anesthetist and the perceived need. The mean onset to
Another study investigated the incidence of emergence clinical effectiveness occurred within 15 minutes, and the
delirium in children receiving general anesthesia for a clinical duration was almost 1 hour. Dexmedetomidine
nonsurgical procedure.33 One group received an infu- as an oral rinse was studied by Karaaslan and
sion of dexmedetomidine after induction of anesthesia colleagues.38 As a premedicant prior to arthroscopic
and the other group received a placebo infusion. The knee surgery, subjects received either placebo or
children who received dexmedetomidine had a 4.8% intramuscular or buccal dexmedetomidine 2.5 mcg/kg.
incidence of delirium compared with 47.6% for the The buccal dexmedetomidine was administered as an
placebo group. oral rinse in which the subjects swished the solution for
Dexmedetomidine may be used either prophylactically 15 minutes before expectorating. Both routes of
or emergently for the prevention or control of emer- administration provided similarly effective levels of
gence delirium. In patients who are deemed at risk for anxiolysis and sedation, but the buccal administration
emergence delirium, 0.25 mcg/kg of dexmedetomidine provided better analgesia. Alternative routes of adminis-
may be slowly injected intravenously during the mainte- tration of dexmedetomidine offer a rich area for future
nance phase of anesthesia. Should emergence delirium clinical investigation, especially in the pediatric dental
occur, another 0.25 mcg/kg could be administered. In patient.
cases in which no prophylactic dose is given, emergence
delirium may be controlled with the intravenous admin-
istration of 0.5 mcg/kg of dexmedetomidine. REVERSAL AGENTS

Atipamezole is effective in reversing the clinical effects of

PEDIATRIC CONSIDERATIONS
a-2–agonist drugs. This highly selective a-2 antagonist is
widely used in veterinary medicine for the reversal of
Although an off-label use, dexmedetomidine is very
dexmedetomidine sedation in dogs.39 Two similar
useful in providing pediatric sedation for a variety of
studies have demonstrated the effectiveness of atipame-
procedures in the critical care setting and for facilitating
zole in reversing the effects of dexmedetomidine in
computed tomography and magnetic resonance imaging
humans.40,41 Atipamezole provided rapid reversal of
evaluations.34 Dexmedetomidine has been shown to
both the sedative and sympatholytic effects of dexmede-
provide superior sedation to midazolam in children
tomidine. With the increasing use of dexmedetomidine
undergoing computerized imaging.35 Unlike with benzo-
as a sedative agent in critical care and outpatient
diazepines and opioids, dexmedetomidine provides for
anesthesia, further research into the safety and efficacy
an unchanged respiratory rate and end-tidal CO2 during
of this reversal agent is warranted.
spontaneous ventilation anesthesia. Dexmedetomidine is
also useful in the perioperative management of pediatric
cardiac patients.36 Its sympatholytic effects could be
SUMMARY
potentially beneficial for children undergoing cardiac
procedures.
The a-2 adrenergic receptor agonist drugs have estab-
lished a place in the modern anesthetic armamentarium
ALTERNATE ROUTES OF ADMINISTRATION because of their ability to produce a calming effect
without causing respiratory depression, and by promot-
Although intravenous administration is the most popular ing cardiovascular stability while reducing anesthetic
form of administering dexmedetomidine, it has also been requirements. The oral administration of clonidine or
Anesth Prog 62:31–38 2015 Giovannitti et al. 37

tizanidine provides a useful alternative for the premed- 13. Jaakola ML, Salonen M, Lehtinen R, et al. The
ication of difficult patients or to provide prophylactic analgesic action of dexmedetomidine—a novel alpha2-adreno-
cardiovascular protection during laryngoscopy and intu- ceptor agonist in healthy volunteers. Pain. 1991;46:281–285.
bation. In addition, tizanidine may be useful in managing 14. Hall DL, Rezvan E, Tatakis DN, Walters JD. Oral
clonidine pretreatment prior to venous cannulation. Anesth
the spasticity associated with conditions such as cerebral
Prog. 53:34–42, 2006.
palsy. At present, the high cost of dexmedetomidine may
15. Davis PJ, Cladis FP, Motoyama EK. Pharmacology of
limit its use, especially in the doses required for effective pediatric anesthesia. In: Smith’s Anesthesia for Infants and
intramuscular premedication or continuous maintenance Children. 8th ed. Philadelphia, Pa: Elsevier; 2011:206–208.
infusion. However, in the authors’ opinion the advan- 16. Cao J, Shi X, Miao X, Xu J. Effects of premedication of
tages of the drug as a sedation adjunct and for the midazolam or clonidine on perioperative anxiety and pain in
prevention or control of emergence delirium far out- children. Biosci Trends. 2009;3:115–118.
weigh the expense. Furthermore, the subsequent reduc- 17. Nguyen M, Tharani S, Rahmani M, Shapiro M. A review
tion in anesthetic requirements of concomitantly of the use of clonidine as a sleep aid in the child and adolescent
administered drugs results in additional cost contain- population. Clin Pediatr (Phila). 2014;53:211–216.
18. Owens JA. The practice of pediatric sleep medicine:
ment.
results of a community survey. Pediatrics. 2001;108:E51.
19. Tabori M, Alipour M, Esalati H. Evaluation of oral
tizanidine effects on (intraoperative) hemodynamic responses
REFERENCES during direct laryngoscopy under general anesthesia. Iran Red
Crescent Med J. 2013;15:541–546.
1. Moss J, Glick D. The autonomic nervous system. In: 20. Malanga GA, Gwynn MW, Smith R, Miller D. Tizanidine
Miller RD, ed. Miller’s Anesthesia. Vol 1. 6th ed. Philadelphia, is effective in the treatment of myofascial pain syndrome. Pain
Pa: Elsevier; 2005:651. Physician. 2002;5:422–432.
2. Ahlquist RP. A study of the adrenotropic receptors. Am 21. Vasquez-Briceño A, Arellano-Saldaña ME, León-Her-
J Physiol. 1948;153:586–600. nández SR, Morales-Osorio MG. The usefulness of tizanidine.
3. Paton WD, Visi ES. The inhibitory action of noradren- A one-year follow-up of the treatment of spasticity in infantile
aline and adrenaline on acetylcholine output by guinea-pig cerebral palsy. Rev Neurol. 2006;43:132–136.
ilium longitudinal muscle strip. Br J Pharmacol. 1969;35:10– 22. Gertler R, Brown HC, Mitchell DH, Silvius EN.
28. Dexmedetomidine: a novel sedative-analgesic agent. Proc
4. Van Meel JC, DeJonge A, Timmermans PBM, Van (Bayl Univ Med Cent). 2001;14:13–21.
Zwieten, WM. Selectivity of some alpha adrenoceptors in the 23. Ebert TJ, Hall JE, Barney JA, et al. The effects of
normotensive rat. J Pharmacol Exp Ther. 1981;219:760– increasing plasma concentrations of dexmedetomidine in
767. humans. Anesthesiology. 2000;93:382–394.
5. Brodsky JB, Bravo JJ. Acute post-operative clonidine 24. Dyck JB, Maze M, Haack C, et al. The pharmacokinet-
withdrawal syndrome. Anesthesiology. 1976;44:519–520. ics and hemodynamic effects of intravenous and intramuscular
6. Shukry M, Clyde MC, Kalarickal PL, Ramadhyani U. dexmedetomidine hydrochloride in adult human volunteers.
Does dexmedetomidine prevent emergence delirium in chil- Anesthesiology. 1993;78:813–820.
dren after sevoflurane-based general anesthesia? Pediatr 25. Karol MD, Maze M. Pharmacokinetic and interaction
Anesth. 2005;15:1098–1104. pharmacodynamics of dexmedetomidine in humans. Best
7. Ruffalo R, Waddell J, Yaden E. Postsynaptic alpha Pract Res Clin Anaesthesiol. 2000;14:261–269.
adrenergic receptor subtypes differentiated by yohimbine in 26. Venn RM, Grounds RM. Comparison between dexme-
tissues from the rat: existence of alpha-2 adrenergic receptors detomidine and propofol for sedation in the intensive care unit:
in rat aorta. J Pharmacol Exp Ther. 1981;217:235–240. patient and clinician perceptions. Br J Anaesth. 2001;87:
8. Bylund D. Subtypes of a1 and a2-adrenergic receptors. 684–690.
FASEB J. 1992;6:832–839. 27. Kaur M, Singh P M. Current role of dexmedetomidine in
9. Buerkle H, Yaksh T. Pharmacological evidence for clinical anesthesia and intensive care. Anesth Essays Res.
different alpha2-adrenergic receptor sites mediating analgesia 2011;5:128–133.
and sedation in the rat. Br J Anaesth. 1998;81:208–215. 28. Precedex dosing for procedural sedation. Available at:
10. Pichot C, Ghignone M, Quintin L. Dexmedtomidine and http://www.precedex.com/wp-content/uploads/2010/02/
clonidine: from second- to first-line sedative agents in the Procedural-Sedation-dosing-Card.pdf. Accessed August 20,
critical care setting. J Intensive Care Med. 2012;27:219–237. 2014.
11. Carollo DS, Nossaman BD, Ramadhyani U. Dexmede- 29. Ely EW, Shintani A, Truman B, et al. Delirium as a
tomidine: a review of clinical applications. Curr Opin predictor of mortality in mechanically ventilated patients in the
Anaesthesiol. 2008;21:457–461. intensive care unit. JAMA. 2004;291:1753–1762.
12. Virtanen R, Savola JM, Saano V, et al. Characterization 30. Riker RR, Shehabi Y, Bokesch PM, et al. Dexmedeto-
of the selectivity, specificity and potency of medetomidine as an midine vs. midazolam for sedation of critically ill patients: a
a2-adrenoceptor agonist. Eur J Pharmacol. 1988;150:9–14. randomized trial. JAMA. 2009;301:489–499.
38 Alpha-2 Adrenergic Receptor Agonists Anesth Prog 62:31–38 2015

31. Pandharipande PP, Pun BT, Herr DL, et al. Effect of 37. Mason KP, Lubisch N, Robinson F, et al. Intramuscular
sedation with dexmedetomidine vs. lorazepam on acute brain dexmedetomidine: an effective route of sedation preserves
dysfunction in mechanically ventilated patients: the MENDS background activity for pediatric electroencephalograms. J
randomized controlled trial. JAMA. 2007;298:2644–2653. Pediatr. 2012;161:927–932.
32. Shukry M, Mathison C, Kalarickel P, et al. Does
38. Karaaslan D, Peker TT, Alaca A, et al. Comparison of
dexmedetomidine prevent emergence delirium in children after
buccal and intramuscular dexmedetomidine premedication for
sevoflurane-based general anesthesia? Paediatr Anaesth.
2005;15:1098–1104. arthroscopic knee surgery. J Clin Anesth. 2006;18:589–593.
33. Isik B, Arslan M, Tunga AD, et al. Dexmedetomidine 39. Vaha-Vahe T. The clinical effectiveness of atipamezole
decreases emergence agitation in pediatric patients after as a medetomidine antagonist in the dog. J Vet Pharmacol
sevoflurane anesthesia without surgery. Paediatr Anaesth. Ther. 1990;13:198–205.
2006;16:748–753. 40. Karhuvaara S, Kallio A, Salonen M, et al. Rapid reversal
34. Phan H, Nahata MC. Clinical uses of dexmedetomidine of a2-adrenoreceptor agonist effects by atipamezole in human
in pediatric patients. Paediatr Drugs. 2008;10:49–69.
volunteers. Br J Clin Pharmacol. 1991;31:160–165.
35. Tobias JD, Berkenbosch JW. Sedation during mechan-
41. Scheinin H, Aantaa, R, Anttila M, et al. Reversal of the
ical ventilation in infants and children: dexmedetomidine versus
midazolam. South Med J. 2004;97:451–455. sedative and sympatholytic effects of dexmedetomidine with a
36. Mukhtar AM, Obayah, EM, Hassona AM. The use of specific a2-adrenoceptor antagonist atipamezole: a pharma-
dexmedetomidine in pediatric cardiac surgery. Anesth Analg. codynamic and kinetic study in healthy volunteers. Anesthesi-
2006;103:52–56. ology. 1998;89:574–584.

CONTINUING EDUCATION QUESTIONS

1. Stimulation of a-2 receptors in the central and 3. Which of the following is a specific reversal agent for
autonomic nervous systems may produce which of a-2 agonist drugs?
the following effects?
A. atipamezole
(1) sedation (2) analgesia (3) transient hypertension B. caffeine
C. flumazenil
A. 1 and 2 D. naloxone
B. 1 and 3
C. 2 and 3
D. 1, 2, and 3 4. Which of the following has the greatest affinity for the
a-2 adrenergic receptor?

2. Which of the following a-2 agonists has specific A. clonidine

indications for the management of myofascial pain B. dexmedetomidine
disorders and spasticity? C. medetomidine
D. tizanidine
A. dexmedetomidine
B. clonidine
C. guanabenz
D. tizanidine