Anesthetic Agents

C o m m o n l y Us e d by Or a l
a n d M a x i l l o f a c i a l Su r g e o n s
Kyle J. Kramer, DDS, MSa,*, Jason W. Brady, DMDb,c,1

KEYWORDS
 Midazolam  Diazepam  Ketamine  Dexmedetomidine  Propofol  Nitrous oxide
 Anesthetic agents  Inhalational

KEY POINTS
 Thorough knowledge and understanding of an anesthetic agent’s pharmacodynamic and pharma-
cokinetic profile are critical for safe and efficient clinical use.
 Short-acting drugs without active metabolites are ideal for providing the full spectrum of anesthesia
in the unique office-based dental environment.
 To maximize satisfactory outcomes, selected anesthetic agents must match well with the needs of
the patient, anticipated procedure, and surgeon.

INTRODUCTION BENZODIAZEPINES: DIAZEPAM,

MIDAZOLAM, REMIMAZOLAM
The oral and maxillofacial surgeon providing
full-spectrum dental anesthesia services in the Since the discovery of chlordiazepoxide in 1957,
office-based environment currently has a multi- benzodiazepines have had a strong presence in
tude of anesthetic options available. In fact, this dental anesthesia, because of their relatively
may be the dawn of a new “golden age of anes- wide therapeutic index and low risk of producing
thesia” because of the novel agents and tech- unconsciousness and respiratory depression
niques being discovered that can quickly render when administered alone at modest doses. It
a patient unconscious yet also provide an took time for the addictive profile of benzodiaze-
extremely fast and smooth emergence and recov- pines to become apparent, after which rampant,
ery profile ideal for the unique dental environment. unmonitored use was brought under further con-
The multitude of options available today provide trol and scrutiny. Nevertheless, benzodiazepines
practitioners with great flexibility to create an indi- remain popular sedative and anxiolytic agents.
vidualized anesthetic plan, balancing the risks There are currently dozens of available benzo-
inherent with the patient’s medical history and diazepines that may be used for a multitude of pur-
the anticipated surgical plan to achieve maximal poses; however, a select few are more commonly
results. used for anesthesia (Table 1).
oralmaxsurgery.theclinics.com

Disclosure Statement: The authors have nothing to disclose at this time.

a
Department of Oral Surgery and Hospital Dentistry, Indiana University School of Dentistry, 550 North Univer-
sity Boulevard, Room UH3143, Indianapolis, IN 46202, USA; b Department of Dental Anesthesia, NYU Langone
Hospital, 150 55th Street, Brooklyn, NY 11220, USA; c Division of Endodontics, Orthodontics and General Prac-
tice Residency, Herman Ostrow School of Dentistry of USC, 925 West 34th Street, Los Angeles, CA 90089, USA
1
Present address: 3343 East Indigo Bay, Gilbert, AZ 85234.
* Corresponding author.
E-mail address: kjkramer@iu.edu

Oral Maxillofacial Surg Clin N Am 30 (2018) 155–164

https://doi.org/10.1016/j.coms.2018.01.003
1042-3699/18/Ó 2018 Elsevier Inc. All rights reserved.
156 Kramer & Brady

sympathetic outflow. Benzodiazepines cause mini-

Table 1
Benzodiazepines mal depression of the respiratory drive, especially
when given as a solo agent. However, this safe profile
Initial IV dosinga is ablated when used concurrently with other CNS
Diazepam 2.5–5 mg depressant drugs producing synergistic or additive
effects. Benzodiazepines also produce centrally
Midazolam 1–2 mg
mediated skeletal muscle relaxation, which can
Oral dosing
contribute to collapse of the airway musculature, up-
Diazepam 2–10 mg orally per airway obstruction, and loss of airway patency.
Midazolam 0.5 mg/kg; 20 mg maximum
a Pharmacokinetics
Titrated to desired effect.
The pharmacokinetics of benzodiazepines de-
Pharmacodynamics pends not only on the specific agent but also the
route of administration, with the onset speed being
Benzodiazepines all act as gamma-aminobutyric
the fastest in parenteral routes, followed by the
acid (GABA) -positive allosteric modulators, facili-
considerably slower enteral routes. Benzodiaze-
tating the ease at which GABA can bind to its own
pines are metabolized hepatically, typically via a va-
respective twin binding sites on neuronal chloride
riety of agent-specific cytochrome p450 enzymes,
ion channels. What makes benzodiazepines unique
most commonly the 3A4 or 2D6 isozyme variety.1
is not the net increase in GABA activity or inhibitory
Diazepam notoriously has several active byprod-
neuronal activity, but rather the fact that they have
ucts, all of which can significantly extend the dura-
their own binding site, called the benzodiazepine re-
tion of action such that a “hangover” effect may
ceptor, which is found on the gamma subunit of the
persist for days. The longest is desmethyldiazepam,
chloride ion channel. When benzodiazepines bind to
which has an elimination half-life approximating 36
this benzodiazepine binding site, it causes a confor-
to 200 hours.1 Oxazepam and temazepam, 2 of its
mational shift in the spatial alignment of the subunits
other active metabolites, are benzodiazepines as
making up the chloride ion channel. The net result is
well and can persist for considerable lengths
an uncovering of one of the GABAA receptors, which
of time. Midazolam has an active metabolite,
permits GABA neurotransmitters easier access to
a-hydroxymidazolam; however, its short half-life
their binding sites. Once both GABAA receptors
makes it clinically insignificant. Diazepam and mid-
are engaged and activated by GABA, the previously
azolam can be administered enterally or parenter-
closed chloride ion channel opens, permitting the
ally. As enteral agents, they are subject to first
influx of chloride ions into the neuron, negatively
pass hepatic metabolism as well as the modulation
hyperpolarizing the cell. Interestingly, to date there
effects concurrently found with CYP450 isozyme in-
are no other known agonists for the benzodiazepine
hibitors or inducers. Remimazolam is an ultra-short-
binding site; however, several other anesthetic
acting benzodiazepine currently in phase 3 clinical
agents do function in a similar fashion producing
trials, but is likely to play a significant role in office-
GABAA-positive allosteric modulation albeit via
based anesthesia in the near future. It is metabo-
alternative binding sites. In addition, benzodiaze-
lized via tissue esterases, rather than undergoing
pines have the added benefit of a competitive
hepatic metabolism, and has the added benefits
antagonist, flumazenil, which is capable of reversing
of lacking active metabolites or accumulating in
the activity of benzodiazepines.
the peripheral tissues. Its pharmacokinetic profile
All benzodiazepines produce dose-dependent
essentially mimics that of remifentanil, only exerting
central nervous system (CNS) depression ranging
activity for w5 to 10 minutes before all effects begin
from anxiolysis to general anesthesia. Benzodiaze-
to wane completely. Theoretically, such a drug
pines are capable of producing anterograde
could be used to thoroughly sedate a patient, only
amnesia, although this effect can be variable and
to have them recover completely in an extremely
should not be guaranteed. Despite the fact that ben-
short period of time. Remimazolam is worthy of
zodiazepines cause global CNS depression, they
attention with regards to future trends in ambulatory
have also been known to cause paradoxic excitatory
anesthesia.
reactions in some patients, with the highest risk
associated with extremes of age. From a cardiovas-
Clinical Use
cular and respiratory standpoint, benzodiazepines
tend to be rather safe when used alone in modest Diazepam can be given orally to reduce preopera-
doses. A minimal reduction in systemic vascular tive anxiety either the night before or an hour before
resistance may be appreciated, which is mainly the patient’s appointment. Avoidance of any other
attributed to the anxiolytic effects and decreased CNS depressant medications is recommended for
 Anesthetic Agents Commonly Used by Oral and Maxillofacial Surgeons 157

patients in unmonitored settings. Oral midazolam Table 2

has been used primarily for pediatric patients to Propofol
facilitate not only preoperative anxiolysis but also
procedural sedation. One potential drawback of Induction of general anesthesia
the routine use of preoperative oral benzodiazepines IV bolus 1.5–2.5 mg/kg
is the prolonged onset time. Although there is a high Maintenance of sedation/general anesthesia
degree of variability, the onset time approximates 45
Continuous 100–200 mg/kg/min (deep
to 60 minutes, with the peak effect time being highly
infusion sedation/general anesthesia)
variable as well. This delayed onset of enterally 25–50 mg/kg/min (moderate
administered drugs severely hampers accurate sedation)
titration. Clinicians may select alternate routes of Antiemetic/PONV prophylaxis
administration to improve efficiency, reserving
Continuous 15–20 mg/kg/min
enteral benzodiazepines for those patients with
infusion
such significant preoperative anxiety that they may
Bolus 0.5–1 mg/kg; given 15 min
not be otherwise capable of arriving to the office.
before end of case
Diazepam and midazolam both can be readily
titrated to a desired clinical level of sedation/anes- Rescue for active PONV
thesia via the intravenous (IV) route. The onset for Bolus 10–20 mg; titrate slowly to
IV diazepam and midazolam tends to be relatively effect
quick with sedative effects being noted within 1.5
to 2 minutes. However, the peak effect tends to
be more delayed, approximating 3 to 5 minutes. Pharmacodynamics
As such, clinicians should titrate slowly to avoid Propofol is a positive allosteric modulator of GABA,
accidental overdose. Diazepam is not water solu- involving GABAA receptors on chloride ion chan-
ble; hence, the solvent propylene glycol is required nels. The net result is the same as with barbiturates
to render it suitable for IV/intramuscular (IM) and benzodiazepines; however, propofol has its
administration. It can be irritating to patients, who own specific binding site unrelated to the afore-
may complain of burning, and has been associated mentioned anesthetic agents. Propofol’s extremely
with multiple reports of venous thrombosis. Mida- rapid onset produces smooth inductions within 30
zolam does not contain this additive and thus to 60 seconds of IV administration, due to its high
does not carry the same complication risk. There degree of lipophilicity. Propofol has a narrow ther-
is a subtle, yet appreciable difference in the clinical apeutic index capable of causing dose-dependent
profile produced by either agent. Diazepam tends global CNS depression ranging from anxiolysis to
to produce profound anxiolysis and significant general anesthesia. It is notable not only for its anti-
skeletal muscle relaxation; patients often demon- emetic properties but also for its association with
strate the Verrill sign, indicating they remain awake seizurelike phenomenon, which is most commonly
but are extremely relaxed. Midazolam also is appreciated during induction or emergence.3 In
potent anxiolytic, but patients more often demon- addition to its sedative/hypnotic effects, propofol
strate a stronger sedative profile, resting quietly, causes dose- and rate-dependent respiratory and
typically with eyes closed. Similar differences cardiovascular depression, manifesting as hypo-
may be appreciated among other benzodiazepines tension, bradycardia, reduced respiratory rate,
because their clinical profiles are all somewhat tidal volume, and airway muscle tone.4 Similar to
individualized and distinct. Benzodiazepines are most other anesthetic agents, concurrent use
very effective agents for halting seizure activity. with other CNS depressants is known to cause sig-
nificant synergistic or additive effects.
PROPOFOL
Pharmacokinetics
Since its clinical introduction in 1977, propofol
(2,6-diisopropylphenol) has become a mainstay Propofol has a short duration of clinical activity
for IV induction and maintenance.2 Propofol is a due to its large volume of distribution and lipophi-
sedative/hypnotic capable of producing amnesia licity, with a redistribution half-life of 2 to 8 mi-
but notoriously lacking any analgesic properties. nutes.5 Propofol is hepatically metabolized using
It has a very rapid onset, short duration of action, glucuronidation and sulfate conjugation mecha-
and clean emergence profile that has made it an nisms.6 The degree of elimination tends to exceed
especially popular anesthetic agent, particularly hepatic blood flow, which suggests it likely has
for sedation and anesthesia in the ambulatory extrahepatic metabolic pathways, which have
office-based environment (Table 2). not been completely identified as of yet.7 The
158 Kramer & Brady

elimination half-life of propofol is a 3 to 12 hours, Pharmacodynamics/Pharmacokinetics

but it lacks any appreciable active metabolites,
Ketamine is a phencyclidine derivative that acts
which facilitates a smooth recovery free from any
primarily as a noncompetitive glutamate receptor
lingering effects.8–10 The pharmacokinetic profile
antagonist, more specifically involving the re-
of propofol is such that it can easily be titrated to
ceptor subtype N-methyl-D-aspartate (NMDA)
the desired effect without any appreciable concern
(Table 3). However, it has several additional phar-
for prolonged clinical activity.
macodynamic sites of action that are reviewed in
later discussion. Although some reports of keta-
Clinical Use mine precipitating epileptiform or seizure activity
Propofol is extremely popular for IV inductions and have been published, it is generally considered
as a maintenance agent for total intravenous anes- safe for patients with a positive seizure history,
thesia (TIVA) techniques. Propofol is commonly especially if combined with other CNS depres-
mixed with other anesthetic agents, such as remi- sants.12 Ketamine causes very few pulmonary ef-
fentanil or ketamine in one syringe. Although there fects when given alone; however, if administered
is one study suggesting the immiscibility of propo- with other CNS depressants, it can potentiate
fol necessitating the use of separate syringes and depression of the respiratory drive. It is also
pumps to maintain consistency of drug delivery,11 capable of causing bronchial smooth muscle
clinical significance of immiscibility has not been relaxation, which is primarily due to inhibition of
established when drug mixtures are being infused vagal nerve activity more so than beta-
over short periods of time. Propofol’s antiemetic adrenergic action, via inhibition of catecholamine
properties make it an excellent alternative to tradi- reuptake.13 Ketamine causes direct negative
tional inhalational anesthetics. It can be used myocardial inotropic effects; however, this is
to help reduce the risk of postoperative nausea balanced out by dose-dependent direct CNS stim-
and vomiting (PONV), especially when used in ulation that produces a net increase in sympa-
combination with other PONV-reducing strategies, thetic outflow. The end result is that ketamine
such as opioid avoidance. The antiemetic benefits clinically produces mild to modest increases in
of propofol typically last only a few hours after systemic and pulmonary vascular resistance,
discontinuation of the drug; therefore, propofol is heart rate, and overall myocardial workload.
most ideal when used for initial prevention. How- Ketamine is relatively lipophilic and has a fairly
ever, patients who are nauseous or actively vomit- quick onset approximating 30 to 60 seconds with
ing but unresponsive to other PONV modalities a peak effect in 1 to 5 minutes for the IV route
(5-HT3 receptor antagonists, phenothiazines) may and an onset of 2 to 3 minutes with a peak effect
respond well to small boluses of propofol. between 5 and 15 minutes for the IM route.14–16
The duration of the clinical effects following the
initial administration of ketamine depends primar-
KETAMINE ily on the route and the dose. However, ketamine
has a relatively brief redistribution half-life of 11
Ketamine is a dissociative anesthetic that causes
dose-dependent sedation and anesthesia via
uncoupling of the limbic and thalamoneocortical Table 3
systems.10 This rather unique pharmacodynamic Ketamine sites of action
action produces a clinical profile that is markedly
Site of Action Activity
different compared with most other anesthetic
agents. After administration, patients often display NMDA Noncompetitive
a unique cataleptic state or stare, with significantly antagonist
diminished responsiveness and purposeful move- Nicotinic acetylcholine Negative allosteric
ment. Respiratory drive and airway reflexes usually modulator
are unaffected and remain intact. Additional find- Opioid (m, k, d subtypes) Weak/very weak
ings can include nystagmus and increased saliva- agonist
tion. Ketamine has a high degree of bioavailability, Dopamine (D2) Agonist
which permits its use via enteral and parenteral Muscarinic acetylcholine Antagonist
routes, although IV and IM routes are clinically Serotonin, dopamine, Reuptake inhibitor
preferred. It is an ideal agent for IM inductions norepinephrine
for patients who are otherwise unable to tolerate Voltage-gated Channel blockade
placement of a peripheral venous catheter, such Na1 channel
as pre-cooperative pediatric or special needs
L-type Ca11 channel Channel blockade
patients.
 Anesthetic Agents Commonly Used by Oral and Maxillofacial Surgeons 159

to 16 minutes and a terminal half-life of 2 to the dental/oral surgical literature. Investigators

3 hours, both of which may be attributed to its have both supported and denied that use of keta-
very large volume of distribution as well as its rapid mine before the surgical insult helps reduce pain
hepatic clearance, biotransformation, and renal within the first 24 hours for patients following oral
excretion.17,18 As mentioned previously, ketamine surgical procedures.24,25
is metabolized by the liver primarily via N-deme-
thylation by cytochrome p450 enzymes, of which ALPHA-2 AGONISTS (DEXMEDETOMIDINE)
CYP3A4 is the main contributor.19 The breakdown
of ketamine produces several metabolites, the Alpha-2 adrenergic agonists, particularly dexme-
most important being the active byproduct norket- detomidine, have anxiolytic, sedative/hypnotic,
amine, which is w33% as potent as ketamine and analgesic, and sympatholytic properties that
ultimately converted into the inactive metabolite can be used to manage hypertension, attention-
dehydronorketamine.20,21 When administered via deficit disorder, anxiety, migraines, and with-
parenteral routes, ketamine undergoes significant drawal from alcohol and opioids.26 The use of
first-pass hepatic metabolism. alpha-2 agonists for perioperative sedation is
increasing in popularity because of their ability to
Clinical Use reduce anesthetic requirements and minimize pre-
treatment anxiety and emergence delirium, while
Ketamine is quite effective for the induction and maintaining respiratory drive and airway reflexes.
maintenance of anesthesia through a variety of
means, although the most common are IV or IM Pharmacodynamics
administration (Table 4). Special dosing consider-
ations must be given because the risk of postanes- Alpha-2 agonists activate secondary and tertiary
thetic complications is directly related to the total protein messenger systems that ultimately cause
dose of ketamine administered. Significant side ef- the inhibition of adenylyl cyclase, causing
fects, such as postoperative nausea and vomiting, the decreased production of intracellular cyclic
emergence delirium, hallucinations, hypersaliva- adenosine monophosphate, which modulates the
tion, or prolonged nystagmus, are more common synaptic vesicle release of neurotransmitters, pri-
with IM doses greater than 4 mg/kg.22,23 Similar marily norepinephrine (Fig. 1). They act centrally
complications can be appreciated following large to produce hypnotic effects at the locus ceruleus
single boluses or extended continuous infusions of the brain stem and analgesic effects within the
of ketamine. As with all anesthetic drugs, use of spinal cord.27 Hemodynamic alterations stem
the smallest effective dose is recommended to from activation of the central acting a2 adrenocep-
avoid these complications. IV administration of tors within the vasomotor centers of the medulla,
subanesthetic doses of ketamine can be quite reducing sympathetic outflow and inhibiting car-
useful as anesthetic adjuncts for patients with diac output by decreasing chronotropic, inotropic,
higher anesthetic requirements. Patients on and dromotropic effects on the heart as well
chronic opioid medications (eg, chronic pain pa- as causing vasoconstriction and vasodilation. It
tients) often benefit from the addition of a small
subanesthetic bolus of ketamine. The analgesic
effects of the added ketamine are often quite
beneficial in maintaining a “smooth” anesthetic
course. In addition, the use of small boluses of ke-
tamine can help avoid the increased risk of the
aforementioned postanesthetic side effects or
complications. Finally, the use of ketamine as a
preemptive analgesic remains controversial within

Table 4
Ketamine

Induction/procedural sedation
IV bolus 0.5–1.5 mg/kg
IM bolus 3 mg/kg (2–5 mg/kg)
Acute analgesic adjunct Fig. 1. Dexmedetomidine: mechanism of action. cAMP,
cyclic adenosine monophosphate; GTP, guanosine
IV subanesthetic bolus 0.25 mg/kg
triphosphate.
160 Kramer & Brady

elicits a biphasic response causing short-lived avoid hemodynamic changes, and a variable qual-
hypertension and then hypotension. Dexmedeto- ity of sedation among patients. The sedative pro-
midine is one of the most highly selective a2 ago- file produced by dexmedetomidine is similar to
nists available, with an affinity ratio of 1620:1 for that associated with sleep. Constant surgical stim-
a2:a1, and although it shares physiologic similarities ulation, common in many oral surgical procedures,
with clonidine, its affinity for a2 is 7 times higher than can lead to spontaneous arousal. Cost remains a
clonidine.28 The predictable and stable hemody- primary disincentive; however, the US Food and
namic effects without respiratory depression pro- Drug Administration has recently approved a
vide optimal benefits for anesthesia providers. It generic version of Precedex.
also acts as an antisialagogue, has opioid-sparing
effects, and is neuroprotective, but is not as potent OPIOID AGONISTS: MORPHINE,
of an amnesic agent as benzodiazepines. HYDROMORPHONE, FENTANYL CONGENERS

Pharmacokinetics Perioperative administration of opioids has long

been used to provide analgesia, typically in com-
IV dexmedetomidine has a fairly rapid onset within bination with other sedative/hypnotic agents
5 minutes and peak effect within 15 minutes. Dex- facilitating a multimodal or balanced anesthetic
medetomidine is rapidly distributed, with a short approach. Opioids inhibit the upward flow of
redistribution half-life of 6 minutes, and undergoes noxious stimuli from the periphery, thereby reducing
hepatic metabolism, producing inactive metabo- the “pain signal” ultimately received by the brain. In
lites mainly via glucuronidation and hydroxylation, addition, opioids are quite effective at offsetting the
with an elimination half-life of w2 hours. Despite reduction in the pain threshold noted with several
being designed for IV use only, it is well absorbed other sedative/hypnotic agents. There are a multi-
through the nasal and buccal mucosa. Intranasal tude of opioids (endogenous, opium alkaloids,
delivery lacks any burning sensation so pediatric semisynthetic, synthetic); however, morphine,
patients may tolerate intranasal dexmedetomidine hydromorphone, and the fentanyl congeners are
to a higher degree than intranasal midazolam.29,30 most common, with profiles that mesh well with
the needs accompanying oral surgical procedures.
Clinical Use
Dexmedetomidine has a variety of clinical uses, Pharmacodynamics
including preoperative sedation, attenuation of he- Opioids produce analgesia by activating opioid re-
modynamic responses to intraoperative stresses, ceptors within the dorsal horn of the spinal cord,
intensive care unit sedation, controlled hypoten- the medulla, and cortex, and to a lesser degree,
sion, and for procedural sedation. When used as peripheral sensory nerves. This activation inhibits
the sole agent via continuous infusion, the loading afferent noxious neuronal transmission, potenti-
dose is administered over 10 minutes, which facil- ates the modulation of descending inhibitory pain
itates a speedier onset, although avoidance can pathways, and decreases the perception and
minimize hemodynamic alterations (Table 5). It emotional response to pain.31 Several opioid
can also be used to decrease the incidence of receptors have been identified with the m/d/k
emergence delirium in children without prolonging subtypes being the prototypical examples capable
the time to discharge by use of subanesthetic of producing their own clinical effects. The m2 sub-
doses.29 Clinical disadvantages of dexmedetomi- type is particularly notable because it is res-
dine include a relatively slow induction time to ponsible for euphoria, physical dependence,
and constipation. Unfortunately, a m1-selective
Table 5 agonist, which produces supraspinal analgesia
Dexmedetomidine and sedation, has yet to be identified. Opioids
are capable of producing sedation and hypnosis
Procedural sedation at higher doses but do not cause amnesia. They
IV loading dose 0.5–1 mcg/kg, given also activate receptors within the chemoreceptor
slowly over 10 min trigger zone, which can lead to nausea and vomit-
IV infusion 0.6 mcg/kg/h ing. In general, opioids maintain cardiovascular
(0.2–1 mg/kg/h) stability, lacking any significant direct myocardial
Emergence delirium prevention depressant effects. However, bradycardia and
Intranasal 1 mg/kg
hypotension can be noted, likely reflecting a
reduction in general sympathetic tone. Dose-
IV subanesthetic 0.25 mcg/kg
dependent respiratory depression is common
bolus (0.2–0.3 mcg/kg)
with opioid administration, as evidenced by a
 Anesthetic Agents Commonly Used by Oral and Maxillofacial Surgeons 161

decrease in respiratory rate and minute ventilation, as norfentanyl. Remifentanil is unique because it
despite the increase in tidal volume. Opioids undergoes metabolism via nonspecific plasma es-
depress the central respiratory drive by inhibiting terases with an extremely rapid terminal half-life
the medulla’s response to hypercarbia and hypox- approximating 3 to 8 minutes and is devoid of
emia. Higher potency opioids are capable of any active metabolites.36
causing skeletal muscle rigidity when given
rapidly, which can impede ventilation without sub- Clinical Use
sequent neuromuscular blockade. As mentioned previously, these opioid agonists are
most frequently used for analgesia during the peri-
Pharmacokinetics operative period (Table 6). All can be titrated to the
desired effect, often using the patient’s respiratory
Morphine is the prototypical opioid agonist and re- rate as a rough guide to determine adequate anal-
mains the gold standard to which other opioids gesia, with a rate of 10 to 12 breaths per minute be-
are compared. However, morphine has several fea- ing an acceptable target. The extended duration of
tures that may render it less than ideal when action of morphine and hydromorphone can be
compared with hydromorphone. Morphine is rela- useful when prolonged postoperative analgesia is
tively hydrophilic, causing a notoriously delayed desired. Clinicians must be certain, however, that
peak effect (w15–20 minutes) even when given the peak effect of any drug administered is verified
intravenously. Hydromorphone is quite similar but before dismissal of the patient. The fentanyl
somewhat easier to titrate because it is more lipo- congeners can be quite useful for shorter surgical
philic, with a faster peak effect (w5–10 minutes). procedures, especially those where adequacy of
Both undergo hepatic metabolism; however, analgesia can be obtained with local anesthesia.
morphine is converted into the active byproduct A main benefit of these drugs is their shorter dura-
morphine-6-glucuronide metabolites, which hydro- tion of action, which can reduce the risk of compli-
morphone lacks.32 Both agents are renally elimi- cations postoperatively, particularly respiratory
nated with similar elimination half-lives depression. Fentanyl, sufentanil, and alfentanil to
approximating 2 to 4 hours. a lesser degree, can all be given via intermittent bo-
The phenylpiperidine opioid subclass, fentanyl, luses, titrated to the desired clinical effect. Remi-
and its congeners, sufentanil, alfentanil, and remi- fentanil, because of its rapid metabolic profile,
fentanil, have pharmacokinetic profiles that may must be administered via continuous infusion to
be more ideal for shorter surgical procedures maintain surgical analgesia. In fact, if remifentanil
commonly performed in the office-based environ- is used, another opioid agonist is recommended
ment. All of these opioids are more potent than to provide postoperative analgesia and to also
morphine and are quite lipophilic with very rapid help combat postoperative hyperalgesia, which
onset approximating 30 to 60 seconds and peak can occur with remifentanil.
effects within 5 minutes. The duration of action,
primarily dictated by the redistribution half-life, ap- INHALATIONAL AGENTS (NITROUS OXIDE,
proximates 30 minutes for fentanyl, 17 minutes for VOLATILE AGENTS)
sufentanil, and 14 minutes for alfentanil.33–35 With
the noted exception of remifentanil, all undergo The use of inhalational anesthetic agents for
hepatic metabolism to inactive metabolites, such dentistry and oral surgery dates back to the late

Table 6
Opioids

Perioperative Analgesia
Agent Route Dosea
Morphine IV bolus 0.05–0.1 mg/kg
Hydromorphone IV bolus 0.1–0.2 mg
Fentanyl IV bolus 1–2 mg/kg
Sufentanil IV bolus 1–2 mg/kg
Alfentanil IV bolus 5–15 mg/kg
Continuous infusion 0.5 mg/kg/min (0.25–1 mg/kg/min)
Remifentanil Continuous infusion 0.05 mg/kg/min (0.025–0.1 mg/kg/min)
a
Titrated slowly to effect.
162 Kramer & Brady

1800s and the time of Horace Wells, William Mor- benign, causing minimal cardiovascular alter-
ton, and Crawford Long37 and the discovery of ations because of the mild dose-dependent
modern anesthesia. The first inhalational anes- myocardial contractility depression being offset
thetic agent was nitrous oxide, followed almost by a modest increase in sympathetic tone. The
immediately by ether. Although nitrous oxide re- net result is a rather stable cardiovascular profile
mains a popular inhalational anesthetic agent, in otherwise healthy patients. An additional differ-
ether has had many successors, the most recent ence is the potential to trigger malignant hyper-
being the fluorinated hydrocarbons isoflurane, thermia, which is present with all volatile agents
sevoflurane, and desflurane.38 There currently ex- but completely absent with nitrous oxide.
ists no single anesthetic agent that can provide
every desired aspect of anesthesia; however, Pharmacokinetics
these inhalational agents are in all likelihood the As inhaled anesthetics, the uptake, equilibration,
closest, capable of producing hypnosis, anal- and distribution of the volatile agents and nitrous
gesia, amnesia, sedation/unconsciousness, and oxide are primarily dictated by the concentration,
skeletal muscle relaxation.39,40 In addition, the de- flow rate, and solubility (blood:gas partition coeffi-
livery of these drugs via the inhalational route pro- cient) of each gas as well as by the cardiac output
vides an extremely rapid onset of clinical activity, of the patient (Table 7). Once a positive gas
facilitating easy titration to the desired effect, and gradient is established at the alveolar level in rela-
a rapid recovery rivaled by few other anesthetic tion to the blood, the gas begins to saturate the
agents. blood plasma. The same phenomenon occurs be-
tween the blood plasma and the bodily tissues,
Pharmacodynamics with the end result given ample time, and stable
drug delivery being the establishment of an equi-
Nitrous oxide and the other volatile agents all act librium between the anesthetic partial pressures
to cause global CNS depression; however, the at the alveolar, blood plasma, and tissue (brain)
actual mechanism of action by which they produce levels. Isoflurane, sevoflurane, desflurane, and
their clinical effects is yet to be completely under- nitrous oxide all undergo some degree of meta-
stood and identified. Nitrous oxide and the current bolism; however, it is to such a miniscule degree
volatile agents are known to interact with a wide that they are essentially considered unchanged
variety of ion channels present within the central when eliminated. These anesthetic agents are
and peripheral nervous systems.38 In addition, exhaled and eliminated via the lungs, in the reverse
nitrous oxide also acts as an opioid receptor of the same processes that dictated their initial up-
agonist as well as an NMDA receptor antagonist, take and distribution.
similar to ketamine. The minimum alveolar con-
centration (MAC) is a useful means to compare Clinical Use
the potency of the various agents, with a single
MAC being the alveolar concentration in which Nitrous oxide is administered concurrently with
50% of patients fail to respond to a surgical stim- oxygen most commonly via the traditional nasal
ulus. MAC also allows for estimations of anesthetic hood, which is an open system. These systems
depth because MAC values are additive. For can easily incorporate the use of other anesthesia
example, a patient administered 3% desflurane monitors, such as capnography or pulse oximetry,
(w0.5 MAC) plus 50% nitrous oxide/50% oxygen
(w0.5 MAC) is receiving roughly 1 MAC total of
Table 7
inhalational anesthetics. Although the volatile Inhalational agents
agents and nitrous oxide are all associated with
dose-dependent depression of the respiratory Partition Coefficients
drive, increases in respiratory rate, and reductions
Agent MAC % Blood:Gas Fat:Blood
in tidal volume and minute ventilation, the nitrous
oxide effects are minimized when it is used alone Nitrous oxide 104 0.47 2.3
for minimal sedation. Nitrous oxide does not Isoflurane 6 1.4 45
cause, nor break a bronchospasm, because it Sevoflurane 2 0.65 48
lacks the significant bronchodilatory effects noted Desflurane 6 0.42 27
with the volatile agents, specifically sevoflurane.
Comments
Volatile gases cause dose-dependent myocardial
depression and peripheral vasodilation, manifest- MAC awake 0.3%–0.4% (inhaled drug is
sole anesthetic maintenance
ing commonly as bradycardia and significant hy-
agent)
potension. In comparison, nitrous oxide is rather
 Anesthetic Agents Commonly Used by Oral and Maxillofacial Surgeons 163

to verify the presence of fresh gas exchange and permits the delivery of an anesthetic plan tailored
adequacy of oxygenation, respectively. Patient specifically to each individual patient.
dose-responses generally follow a bell-shaped
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