CHAPTER I

INTRODUCTION

General anesthesia began with inhaled agents but now can be induced and
maintained by drugs that enter the patient through a wide range of routes. Drug
administration can be oral, rectal, transdermal, transmucosal, intramuscular, or
intravenous for the purpose of producing or enhancing an anesthetic state.
Preoperative sedation of adults is usually accomplished by way of oral or intravenous
routes. Induction of general anesthesia in adults usually includes intravenous drug
administration.1
In 1952 Gray and Rees examined the components of anaesthesia, and put
forward the Triad Concept of hypnosis, analgesia, and muscular relaxation. These
effects could be achieved selectively by the judicious use of specific agents to
produce balanced anaesthesia.2
The concept of anesthesia with three basic components as described by Gray,
is essential for a sound anesthetic technique. These components have been expanded
through the years. Nevertheless, they continue to revolve around the three
fundamental components: hypnosis, analgesia, and relaxation. Understanding the
interaction among these basic components paves the way to a clear understanding of
the range of responses elicited when administering anesthetic agents.3

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 CHAPTER II
LITERATURE REVIEW

2.1 Hypnotics
2.1.1 Benzodiazepines
Benzodiazepines are drugs that exert, in slightly varying degrees, five
principal pharmacologic effects: anxiolysis, sedation, anticonvulsant actions, spinal
cord–mediated skeletal muscle relaxation, and anterograde amnesia. The amnestic
potency of benzodiazepines is greater than their sedative effects resulting in a longer
duration of amnesia than sedation. Benzodiazepines do not produce adequate skeletal
muscle relaxation for surgical procedures nor does their use influence the required
dose of neuromuscular blocking drugs. The frequency of anxiety and insomnia in
clinical practice combined with the efficacy of benzodiazepines has led to widespread
use of these drugs. 4
Midazolam is the most commonly used benzodiazepine in the perioperative
period. Furthermore, the context-sensitive half-time for diazepam and lorazepam are
prolonged; therefore, only midazolam is likely to be used for prolonged
administration when prompt recovery is desired. However, the longer context-
sensitive half-time of lorazepam makes this drug an attractive choice to facilitate
sedation of patients in critical care environments. Structurally, benzodiazepines are
similar and share many active metabolites.4

2.1.1.1 Mechanisms of Action

Benzodiazepines appear to produce all their pharmacologic effects by
facilitating the actions of GABA. Benzodiazepines do not activate the GABA A
receptors but rather enhance the affinity of the receptors for GABA. As a result of
increased affinity for GABA, there are more frequent channel openings, resulting in
increased chloride conductance and hyperpolarization of the postsynaptic cell
membrane. The postsynaptic neurons are thus rendered more resistant to excitation.
This resistance to excitation is presumed to be the mechanism by which

2
benzodiazepines produce anxiolysis, sedation, anterograde amnesia, alcohol
potentiation, and anticonvulsant and skeletal muscle relaxant effects.4

2.1.1.2 Pharmacokinetics
A. Absorption
Benzodiazepines are commonly administered orally, intramuscularly, and
intravenously to provide sedation or, less commonly, to induce general anesthesia
(Table 1). Diazepam and lorazepam are well absorbed from the gastrointestinal tract,
with peak plasma levels usually achieved in 1 and 2 hour, respectively. Oral
midazolam has not approved by the U.S. Food and Drug Administration, nevertheless
this route of administration has been popular for pediatric premedication. Likewise,
intranasal (0.2– 0.3 mg/kg), buccal (0.07 mg/kg), and sublingual (0.1 mg/kg)
midazolam provide effective preoperative sedation.1

Table 1. Uses and doses of commonly used benzodiazepines

Intramuscular injections of diazepam are painful and unreliably absorbed. In

contrast, midazolam and lorazepam are well absorbed after intramuscular injection,
with peak levels achieved in 30 and 90 minutes, respectively. Induction of general
anesthesia with midazolam is convenient only with intravenous administration.1

B. Distribution
Diazepam is relatively lipid soluble and readily penetrates the blood–brain
barrier. Although midazolam is water soluble at reduced pH, its imidazole ring closes

3
at physiological pH, increasing its lipid solubility. The moderate lipid solubility of
lorazepam accounts for its slower brain uptake and onset of action. Redistribution is
fairly rapid for the benzodiazepines (the initial distribution half-life is 3–10 minutes).
Although midazolam has been used as an induction agent, neither midazolam nor any
other of the benzodiazepines can match the rapid onset and short duration of action of
propofol or even thiopental. All three benzodiazepines are highly protein bound (90–
98%).1

C. Biotransformation
The benzodiazepines rely on the liver for biotransformation into water-soluble
glucuronidated end products. The phase I metabolites of diazepam are
pharmacologically active.1
Slow hepatic extraction and a large volume of distribution (Vd) result in a

long elimination half-life for diazepam (30 hour). Although lorazepam also has a low
hepatic extraction ratio, its lower lipid solubility limits its Vd, resulting in a shorter

elimination half-life (15 hour). Nonetheless, the clinical duration of lorazepam is

often quite prolonged due to increased receptor affinity. These differences between
lorazepam and diazepam illustrate the low utility of individual pharmacokinetic half-
lives in guiding clinical practice. Midazolam shares diazepam’s Vd, but its

elimination half-life (2 hour) is the shortest of the group because of its increased
hepatic extraction ratio.1

D. Excretion
The metabolites of benzodiazepine biotransformation are excreted chiefly in
the urine. Enterohepatic circulation produces a secondary peak in diazepam plasma
concentration 6–12 hour following administration. Kidney failure may lead to
prolonged sedation in patients receiving larger doses of midazolam due to the
accumulation of a conjugated metabolite (α-hydroxymidazolam).1

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2.1.1.3 Effects on Organ Systems
A. Cardiovascular
The benzodiazepines display minimal cardiovascular depressant effects even
at general anesthetic doses, except when they are coadministered with opioids (these
agents interact to produce myocardial depression and arterial hypotension).
Benzodiazepines given alone decrease arterial blood pressure, cardiac output, and
peripheral vascular resistance slightly, and sometimes increase heart rate. Intravenous
midazolam tends to reduce blood pressure and peripheral vascular resistance more
than diazepam. Changes in heart rate variability during midazolam sedation suggest
decreased vagal tone.1

B. Respiratory
Benzodiazepines depress the ventilatory response to CO2. This depression is

usually insignificant unless the drugs are administered intravenously or in association

with other respiratory depressants. Although apnea may be relatively uncommon after
benzodiazepine induction, even small intravenous doses of diazepam and midazolam
have resulted in respiratory arrest. The steep dose–response curve, slightly prolonged
onset (compared with propofol or thiopental), and potency of midazolam necessitate
careful titration to avoid overdosage and apnea. Ventilation must be monitored in all
patients receiving intravenous benzodiazepines, and resuscitation equipment must be
immediately available.1

C. Cerebral
Benzodiazepines reduce cerebral oxygen consumption, cerebral blood flow,
and intracranial pressure but not to the extent the barbiturates do. They are effective
in preventing and controlling grand mal seizures. Oral sedative doses often produce
antegrade amnesia, a useful premedication property. The mild muscle-relaxing
property of these drugs is mediated at the spinal cord level, not at the neuromuscular
junction. The antianxiety, amnestic, and sedative effects seen at lower doses progress
to stupor and unconsciousness at induction doses. Compared with propofol or

5
thiopental, induction with benzodiazepines is associated with a slower rate of loss of
consciousness and a longer recovery. Benzodiazepines have no direct analgesic
properties.1

2.1.1.4 Drug Interactions

Cimetidine binds to cytochrome P-450 and reduces the metabolism of
diazepam. Erythromycin inhibits metabolism of midazolam and causes a two-to-
threefold prolongation and intensification of its effects. Heparin displaces diazepam
from protein-binding sites and increases the free drug concentration.1
As previously mentioned, the combination of opioids and benzodiazepines markedly
reduces arterial blood pressure and peripheral vascular resistance. This synergistic
interaction has often been observed in patients with ischemic or valvular heart disease
who often receive benzodiazepines for premedication and during induction of
anesthesia with opioids.1
Benzodiazepines reduce the minimum alveolar concentration of volatile
anesthetics as much as 30%. Ethanol, barbiturates, and other central nervous system
depressants potentiate the sedative effects of the benzodiazepines.1

2.1.2. Ketamine
2.1.2.1 Mechanisms of Action
Ketamine has multiple effects throughout the central nervous system,
inhibiting polysynaptic reflexes in the spinal cord as well as excitatory
neurotransmitter effects in selected areas of the brain. Ketamine functionally
“dissociates” the thalamus (which relays sensory impulses from the reticular
activating system to the cerebral cortex) from the limbic cortex (which is involved
with the awareness of sensation). Clinically, this state of dissociative anesthesia may
cause the patient to appear conscious (eg, eye opening, swallowing, muscle
contracture) but unable to process or respond to sensory input. Ketamine has been
demonstrated to be an N-methyl-d-aspartate (NMDA) receptor (a subtype of the
glutamate receptor) antagonist.1

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2.1.2.2 Structure–Activity Relationships
Ketamine is a structural analogue of phencyclidine (an anesthetic that has
been used in veterinary medicine, and a drug of abuse). Ketamine is used for
intravenous induction of anesthesia, particularly in settings where its tendency to
produce sympathetic stimulation are useful (hypovolemia, trauma). When intravenous
access is lacking, ketamine is useful for intramuscular induction of general anesthesia
in children and uncooperative adults. Ketamine can be combined with other agents
(eg, propofol or midazolam) in small bolus doses or infusions for deep conscious
sedation during nerve blocks, endoscopy, etc. Even subanesthetic doses of ketamine
may cause hallucinogenic effects but usually do not do so in clinical practice, where
many patients will have received at least a small dose of midazolam (or a related
agent) for amnesia and sedation.1

2.1.2.3 Pharmacokinetics
A. Absorption
Ketamine has been administered orally, nasally, rectally, subcutaneously, and
epidurally, but in usual clinical practice it is given intravenously or intramuscularly
(Table 2). Peak plasma levels are usually achieved within 10–15 minutes after
intramuscular injection.1

Table 2. Uses and doses of ketamine, etomidate, and propofol

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B. Distribution
Ketamine is more lipid soluble and less protein bound than thiopental. These
characteristics, along with ketamine-induced increase in cerebral blood flow and
cardiac output, lead to rapid brain uptake and subsequent redistribution (the
distribution half-life is 10–15 minutes). Awakening is due to redistribution from brain
to peripheral compartments.1

C. Biotransformation
Ketamine is biotransformed in the liver to several metabolites, one of which
(norketamine) retains anesthetic activity. Induction of hepatic enzymes only partially
explains the tolerance that patients who receive multiple doses of ketamine will
develop. Extensive hepatic uptake (hepatic extraction ratio of 0.9) explains
ketamine’s relatively short elimination half-life (2 hours).1

D. Excretion
End products of ketamine biotransformation are excreted renally.1

2.1.2.4 Effects on Organ Systems

A. Cardiovascular
In contrast to other anesthetic agents, ketamine increases arterial blood
pressure, heart rate, and cardiac output, particularly after rapid bolus injections. These
indirect cardiovascular effects are due to central stimulation of the sympathetic
nervous system and inhibition of the reuptake of norepinephrine after release at nerve
terminals. Accompanying these changes are increases in pulmonary artery pressure
and myocardial work. For these reasons, large bolus injections of ketamine should be
administered cautiously in patients with coronary artery disease, uncontrolled
hypertension, congestive heart failure, or arterial aneurysms. The direct myocardial
depressant effects of large doses of ketamine, probably due to inhibition of calcium
transients, are unmasked by sympathetic blockade (eg, spinal cord transection) or

8
exhaustion of catecholamine stores (eg, severe end-stage shock). On the other hand,
ketamine’s indirect stimulatory effects may be beneficial to patients with acute
shock.1

B. Respiratory
Ventilatory drive is minimally affected by induction doses of ketamine,
although rapid intravenous bolus administration or combinations of ketamine with
opioids occasionally produce apnea. Racemic ketamine is a potent bronchodilator,
making it a good induction agent for asthmatic patients. Upper airway reflexes remain
largely intact, but partial airway obstruction may occur, and patients at increased risk
for aspiration pneumonia should be intubated during ketamine general. The increased
salivation associated with ketamine can be attenuated by premedication with an
anticholinergic agent such as glycopyrrolate.1

C. Cerebral
The received dogma about ketamine is that it increases cerebral oxygen
consumption, cerebral blood flow, and intracranial pressure. These effects would
seem to preclude its use in patients with space-occupying intracranial lesions such as
occur with head trauma; however, recent publications offer convincing evidence that
when combined with a benzodiazepine (or another agent acting on the same GABA
receptor system) and controlled ventilation, but not with nitrous oxide, ketamine is
not associated with increased intracranial pressure. Myoclonic activity is associated
with increased subcortical electrical activity, which is not apparent on surface EEG.
Undesirable psychotomimetic side effects (eg, disturbing dreams and delirium)
during emergence and recovery are less common in children and in patients
premedicated with benzodiazepines or those in whom ketamine is combined with
propofol in a TIVA technique. Of the nonvolatile agents, ketamine comes closest to
being a “complete” anesthetic as it induces analgesia, amnesia, and unconsciousness.1

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2.1.2.5 Drug Interactions
Ketamine interacts synergistically (more than additive) with volatile
anesthetics but in an additive way with propofol, benzodiazepines, and other GABA-
receptor–mediated agents. In animal experiments nondepolarizing neuromuscular
blocking agents are minimally potentiated by ketamine. Diazepam and midazolam
attenuate ketamine’s cardiostimulatory effects and diazepam prolongs ketamine’s
elimination half-life.1
α-Adrenergic and β-adrenergic antagonists (and other agents and techniques
that diminish sympathetic stimulation) unmask the direct myocardial depressant
effects of ketamine, which are normally overwhelmed by sympathetic stimulation.
Concurrent infusion of ketamine and propofol, often in a fixed infusion rate ratio of
1:10, has achieved great popularity for sedation with local and regional anesthesia,
particularly in office-based settings.1

2.1.3 Propofol
2.1.3.1 Mechanisms of Action
Propofol induction of general anesthesia may involve facilitation of inhibitory
neurotransmission mediated by GABAA receptor binding. Propofol allosterically
increases binding affinity of GABA for the GABAA receptor. This receptor, as
previously noted, is coupled to a chloride channel, and activation of the receptor leads
to hyperpolarization of the nerve membrane. Propofol (like most general anesthetics)
binds multiple ion channels and receptors.1

2.1.3.2 Structure–Activity Relationships

Propofol consists of a phenol ring substituted with two isopropyl groups.
Propofol is not water soluble, but a 1% aqueous solution (10 mg/mL) is available for
intravenous administration as an oil-in-water emulsion containing soybean oil,
glycerol, and egg lecithin. A history of egg allergy does not necessarily contraindicate
the use of propofol because most egg allergies involve a reaction to egg white (egg
albumin), whereas egg lecithin is extracted from egg yolk. This formulation will often

10
cause pain during injection that can be decreased by prior injection of lidocaine or
less e ectively by mixing lidocaine with propofol prior to injection (2 mL of 1%
lidocaine in 18 mL propofol). Propofol formulations can support the growth of
bacteria, so sterile technique must be observed in preparation and handling. Propofol
should be administered within 6 h of opening the ampule. Sepsis and death have been
linked to contaminated propofol preparations. Current formulations of propofol
contain 0.005% disodium edetate or 0.025% sodium metabisulfite to help retard the
rate of growth of microorganisms; however, these additives do not render the product
“antimicrobially preserved” under United States Pharmacopeia standards.1

2.1.3.3 Pharmacokinetics
A. Absorption
Propofol is available only for intravenous administration for the induction of
general anesthesia and for moderate to deep sedation (Table 2).1

B. Distribution
Propofol has a rapid onset of action. Awakening from a single bolus dose is
also rapid due to a very short initial distribution half-life (2–8 min). Most
investigators believe that recovery from propofol is more rapid and is accompanied
by less “hangover” than recovery from methohexital, thiopental, ketamine, or
etomidate. This makes it a good agent for outpatient anesthesia. A smaller induction
dose is recommended in elderly patients because of their smaller Vd. Age is also a

key factor determining required propofol infusion rates for TIVA.1

C. Biotransformation
The clearance of propofol exceeds hepatic blood flow, implying the existence
of extrahepatic metabolism. This exceptionally high clearance rate probably
contributes to relatively rapid recovery after continuous infusions. Conjugation in the
liver results in inactive metabolites that are eliminated by renal clearance. The
pharmacokinetics of propofol do not appear to be affected by obesity, cirrhosis, or

11
kidney failure. Use of propofol infusion for long-term sedation of children who are
critically ill or young adult neurosurgical patients has been associated with sporadic
cases of lipemia, metabolic acidosis, and death, the so-termed propofol infusion
syndrome.1

D. Excretion
Although metabolites of propofol are primarily excreted in the urine, chronic kidney
failure does not affect clearance of the parent drug.1

2.1.3.4 Effects on Organ Systems

A. Cardiovascular
The major cardiovascular effect of propofol is a decrease in arterial blood
pressure due to a drop in systemic vascular resistance (inhibition of sympathetic
vasoconstrictor activity), preload, and cardiac contractility. Hypotension following
induction is usually reversed by the stimulation accompanying laryngoscopy and
intubation. Factors associated with propofol-induced hypotension include large doses,
rapid injection, and old age. Propofol markedly impairs the normal arterial baroreflex
response to hypotension. Rarely, a marked drop in preload may lead to a vagally
mediated reflex bradycardia. Changes in heart rate and cardiac output are usually
transient and insignificant in healthy patients but may be severe in patients at the
extremes of age, those receiving β-adrenergic blockers, or those with impaired
ventricular function. Although myocardial oxygen consumption and coronary blood
flow usually decrease comparably, coronary sinus lactate production increases in
some patients, indicating some mismatch between myocardial oxygen supply and
demand.1

B. Respiratory
Propofol is a profound respiratory depressant that usually causes apnea
following an induction dose. Even when used for conscious sedation in subanesthetic
doses, propofol inhibits hypoxic ventilatory drive and depresses the normal response

12
to hypercarbia. As a result, only properly educated and qualified personnel should
administer propofol for sedation. Propofol-induced depression of upper airway
reflexes exceeds that of thiopental, allowing intubation, endoscopy, or laryngeal mask
placement in the absence of neuromuscular blockade. Although propofol can cause
histamine release, induction with propofol is accompanied by a lower incidence of
wheezing in asthmatic and nonasthmatic patients compared with barbiturates or
etomidate.1

C. Cerebral
Propofol decreases cerebral blood flow and intracranial pressure. In patients
with elevated intracranial pressure, propofol can cause a critical reduction in CPP
(<50 mm Hg) unless steps are taken to support mean arterial blood pressure. Propofol
and thiopental probably provide a similar degree of cerebral protection during
experimental focal ischemia. Unique to propofol are its antipruritic properties. Its
antiemetic effects (requiring a blood propofol concentration of 200 ng/mL) provide
yet another reason for it to be a preferred drug for outpatient anesthesia. Induction is
occasionally accompanied by excitatory phenomena such as muscle twitching,
spontaneous movement, opisthotonus, or hiccupping. Although these reactions may
occasionally mimic tonic–clonic seizures, propofol has anticonvulsant properties and
has been used successfully to terminate status epilepticus. Propofol may be safely
administered to epileptic patients. Propofol decreases intraocular pressure. Tolerance
does not develop after long-term propofol infusions. Propofol is an uncommon agent
of physical dependence or addiction; however, both anesthesia personnel and
medically untrained individuals have died while using propofol inappropriately to
induce sleep in nonsurgical settings.1

2.1.3.5 Drug Interactions

Fentanyl and alfentanil concentrations may be increased with concomitant
administration of propofol. Many clinicians administer a small amount of midazolam
(eg, 30 mcg/kg) prior to induction with propofol; midazolam can reduce the required

13
propofol dose by more than 10%.1

2.2 Opioid Analgetics

2.2.1 Mechanisms of Action
Opioids bind to specific receptors located throughout the central
nervous system and other tissues. Four major opioid receptor types have been
identified (Table 3): mu (μ, with subtypes μ1 and μ2), kappa (κ), delta (δ), and
sigma (σ). All opioid receptors couple to G proteins; binding of an agonist to
an opioid receptor causes membrane hyperpolarization. Acute opioid effects
are mediated by inhibition of adenylyl cyclase (reductions in intracellular
cyclic adenosine monophosphate concentrations) and activation of
phospholipase C. Opioids inhibit voltage-gated calcium channels and activate
inwardly rectifying potassium channels. Opioid effects vary based on the
duration of exposure, and opioid tolerance leads to changes in opioid
responses.1
Although opioids provide some degree of sedation and (in many
species) can produce general anesthesia when given in large doses, they are
principally used to provide analgesia. The properties of specific opioids depend
on which receptor is bound (and in the case of spinal and epidural
administration of opioids, the location in the neuraxis where the receptor is
located) and the binding affinity of the drug. Agonist–antagonists (eg,
nalbuphine, nalorphine, butorphanol, and pentazocine) have less efficacy than
so-called full agonists (eg, fentanyl) and under some circumstances will
antagonize the actions of full agonists.1
The opioid drugs mimic endogenous compounds. Endorphins,
enkephalins, and dynorphins are endogenous peptides that bind to opioid
receptors. These three families of opioid peptides differ in their amino acid
sequences, anatomic distributions, and receptor a nities.1

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 Table 3. Classification of opioid receptors

Opioid receptor activation inhibits the presynaptic release and

postsynaptic response to excitatory neurotransmitters (eg, acetylcholine,
substance P) from nociceptive neurons. The cellular mechanism for this action
was described at the beginning of this chapter. Transmission of pain impulses
can be selectively modified at the level of the dorsal horn of the spinal cord
with intrathecal or epidural administration of opioids. Opioid receptors also
respond to systemically administered opioids. Modulation through a
descending inhibitory pathway from the periaqueductal gray matter to the
dorsal horn of the spinal cord may also play a role in opioid analgesia.
Although opioids exert their greatest effect within the central nervous system,
opiate receptors have also been identified on somatic and sympathetic
peripheral nerves. Certain opioid side effects (eg, depression of gastrointestinal
motility) are the result of opioid binding to receptors in peripheral tissues (eg,

15
the wall of the gastrointestinal tract), and there are now selective antagonists
for opioid actions out- side the central nervous system (alvimopan and oral
naltrexone). The distribution of opioid receptors on axons of primary sensory
nerves and the clinical importance of these receptors (if present) remains
speculative, despite the persisting practice of compounding of opioids in local
anesthetic solutions applied to peripheral nerves.1

2.2.2 Pharmacokinetics
A. Absorption
Rapid and complete absorption follows the intramuscular injection of
hydromorphone, morphine, or meperidine, with peak plasma levels usually reached
after 20–60 min. Oral transmucosal fentanyl citrate absorption provides rapid onset of
analgesia and sedation in patients who are not good candidates for conventional oral,
intravenous, or intramuscular dosing of opioids.1
The low molecular weight and high lipid solubility of fentanyl also favor
transdermal absorption (the transdermal fentanyl “patch”). The amount of fentanyl
absorbed per unit of time depends on the surface area of skin covered by the patch
and also on local skin conditions (eg, blood flow). The time required to establish a
reservoir of drug in the upper dermis delays by several hours the achievement of
effective blood concentrations. Serum concentrations of fentanyl reach a plateau
within 14–24 h of application (with peak levels occurring after a longer delay in
elderly than in younger patients) and remain constant for up to 72 h. Continued
absorption from the dermal reservoir accounts for persisting measurable serum levels
many hours after patch removal. Fentanyl patches are most often used for outpatient
management of chronic pain and are particularly appropriate for patients who require
continuous opioid dosing but cannot take the much less expensive, but equally
efficacious, oral agents such as methadone.1
A wide variety of opioids are effective by oral administration, including
oxycodone, hydrocodone (most often in combination with acetaminophen), codeine,

16
tramadol, morphine, hydromorphone, and methadone. These agents are much used
for outpatient pain management.1
Fentanyl is often administered in small doses (10–25 mcg) with local
anesthetics for spinal anesthesia, and adds to the analgesia when included with local
anesthetics in epidural infusions. Morphine in doses between 0.1 and 0.5 mg and
hydromorphone in doses between 0.05 and 0.2 mg provide 12–18 hours of analgesia
after intrathecal administration. Morphine and hydromorphone are commonly
included in local anesthetic solutions infused for postoperative epidural analgesia.
Extended-release epidural morphine (DepoDur) is administered as a single epidural
dose (5–15 mg), the effects of which persist for 48 h.1

B. Distribution
Table 4 summarizes the physical characteristics that determine distribution
and tissue binding of opioid analgesics. After intravenous administration, the
distribution half-lives of all of the opioids are fairly rapid (5–20 min). The low fat
solubility of morphine slows passage across the blood–brain barrier, however, so that
its onset of action is slow and its duration of action is prolonged. This contrasts with
the increased lipid solubility of fentanyl and sufentanil, which are associated with a
faster onset and shorter duration of action when administered in small doses.
Interestingly, alfentanil has a more rapid onset of action and shorter duration of action
than fentanyl following a bolus injection, even though it is less lipid soluble than
fentanyl. The high nonionized fraction of alfentanil at physiological pH and its small
volume of distribution (Vd) increase the amount of drug (as a percentage of the

administered dose) available for binding in the brain.1

17
 Table 4. Physical characteristics of opioids that determine distribution

Significant amounts of lipid-soluble opioids can be retained by the lungs

(first-pass uptake); as systemic concentrations fall they will return to the bloodstream.
The amount of pulmonary uptake is reduced by prior accumulation of other drugs,
increased by a history of tobacco use, and decreased by concurrent inhalation
anesthetic administration. Unbinding of opioid receptors and redistribution (of
drug from effect sites) terminate the clinical effects of all opioids. After
smaller doses of the lipid-soluble drugs (eg, fentanyl or sufentanil),
redistribution alone is the driver for reducing blood concentrations, whereas
after larger doses biotransformation becomes an important driver in reducing
plasma levels below those that have clinical effects. Thus, the time required for
fentanyl or sufentanil concentrations to decrease by half is context sensitive; in
other words, the half-time depends on the total dose of drug and duration of
exposure.1

C. Biotransformation
With the exception of remifentanil, all opioids depend primarily on the liver
for biotransformation and are metabolized by the cytochrome P (CYP) system,
conjugated in the liver, or both. Because of the high hepatic extraction ratio of

18
opioids, their clearance depends on liver blood flow. The small Vd of alfentanil

contributes to a short elimination half-life (1.5 h). Morphine and hydromorphone

undergo conjugation with glucuronic acid to form, in the former case, morphine 3-
glucuronide and morphine 6-glucuronide, and in the latter case, hydromorphone 3-
glucuronide. Meperidine is N-demethylated to normeperidine, an active metabolite
associated with seizure activity, particularly after very large meperidine doses. The
end products of fentanyl, sufentanil, and alfentanil are inactive. Norfentanyl, the
metabolite of fentanyl, can be measured in urine long after the native compound is no
longer detectable in blood to determine chronic fentanyl ingestion. This has its
greatest importance in diagnosing fentanyl abuse.1
Codeine is a prodrug that becomes active after it is metabolized by CYP to
morphine. Tramadol similarly must be metabolized by CYP to O-desmethyltramadol
to be active. Oxycodone is metabolized by CYP to series of active compounds that
are less potent than the parent one.1
The ester structure of remifentanil makes it susceptible to hydrolysis (in a
manner similar to esmolol) by nonspecific esterases in red blood cells and tissue,
yielding a terminal elimination half-life of less than 10 min. Remifentanil
biotransformation is rapid and the duration of a remifentanil infusion has little
effect on wake-up time. The context-sensitive half-time of remifentanil
remains approximately 3 minutes regardless of the dose or duration of infusion.
In its lack of accumulation remifentanil differs from other currently available
opioids. Hepatic dysfunction requires no adjustment in remifentanil dosing.
Finally, patients with pseudocholinesterase deficiency have a normal response
to remifentanil (as also appears true for esmolol).1

D. Excretion
The end products of morphine and meperidine biotransformation are
eliminated by the kidneys, with less than 10% undergoing biliary excretion.
Because 5–10% of morphine is excreted unchanged in the urine, kidney failure

19
prolongs morphine duration of action. The accumulation of morphine
metabolites (morphine 3-glucuronide and morphine 6-glucuronide) in patients
with kidney failure has been associated with prolonged narcosis and
ventilatory depression. In fact, morphine 6-glucuronide is a more potent and
longer-lasting opioid agonist than morphine. As previously noted,
normeperidine at increased concentrations may produce seizures; these are not
reversed by naloxone. Renal dysfunction increases the likelihood of toxic
effects from normeperidine accumulation. However, both morphine and
meperidine have been used safely and successfully in patients with kidney
failure. Metabolites of sufentanil are excreted in urine and bile. The main
metabolite of remifentanil is eliminated in urine, is several thousand times less
potent than its parent compound, and thus is unlikely to produce any clinical
opioid effects.1

2.2.3 Effects on Organ Systems

A. Cardiovascular
In general, opioids have few direct effects on the heart. Meperidine tends to
increase heart rate (it is structurally similar to atropine and was originally synthesized
as an atropine replacement), whereas larger doses of morphine, fentanyl, sufentanil,
remifentanil, and alfentanil are associated with a vagus nerve-mediated bradycardia.
With the exception of meperidine (and only then at very large doses), the opioids do
not depress cardiac contractility provided they are administered alone (which is
almost never the circumstance in surgical anesthetic settings). Nonetheless, arterial
blood pressure often falls as a result of bradycardia, venodilation, and decreased
sympathetic reflexes, sometimes requiring vasopressor support. These effects are
more pronounced when opioids are administered in combination with
benzodiazepines, in which case drugs such as sufentanil and fentanyl can be
associated with reduced cardiac output. Bolus doses of meperidine, hydromorphone,
and morphine evoke histamine release in some individuals that can lead to profound

20
drops in systemic vascular resistance and arterial blood pressure. The potential
hazards of histamine release can be minimized in susceptible patients by infusing
opioids slowly or by pretreatment with H1 and H2 antagonists, or both. The end
effects of histamine release can be reversed by infusion of intravenous fluid and
vasopressors.1
Intraoperative hypertension during large- dose opioid anesthesia or
nitrous oxide–opioid anesthesia is common. Such hypertension is often
attributed to inadequate anesthetic depth, thus it is conventionally treated by
the addition of other anesthetic agents (benzodiazepines, propofol, or potent
inhaled agents). If depth of anesthesia is adequate and hypertension persists,
vasodilators or other antihypertensives may be used. The inherent cardiac
stability provided by opioids is greatly diminished in actual practice when
other anesthetic drugs, including nitrous oxide, benzodiazepines, propofol, or
volatile agents, are typically added. The end result of polypharmacy can
include myocardial depression.1

B. Respiratory

Opioids depress ventilation, particularly respiratory rate. Thus, monitoring of

respiratory rate provides a convenient, simple way of detecting early respiratory
depression in patients receiving opioid analgesia. Opioids increase the partial pressure
of carbon dioxide (Paco2) and blunt the response to a CO2 challenge, resulting in a
shift of the CO2 response curve downward and to the right (Figure 1). These effects
result from opioid binding to neurons in the respiratory centers of the brainstem. The
apneic threshold—the greatest Paco2 at which a patient remains apneic—rises, and
hypoxic drive is decreased. Morphine and meperidine can cause histamine-induced
bronchospasm in susceptible patients. Rapid administration of larger doses of opioids
(particularly fentanyl, sufentanil, remifentanil, and alfentanil) can induce chest wall
rigidity severe enough to prevent adequate bag-and-mask ventilation. This centrally

21
mediated muscle contraction is effectively treated with neuromuscular
blocking agents. This problem is rarely seen now that large-dose opioid
anesthesia is less often used in cardiovascular anesthesia practice. Opioids can
effectively blunt the bronchoconstrictive response to airway stimulation such
as occurs during tracheal intubation.1

Figure 1. Opioid depress ventilation

C. Cerebral
The effects of opioids on cerebral perfusion and intracranial pressure
must be separated from any effects of opioids on Paco2. In general, opioids
reduce cerebral oxygen consumption, cerebral blood flow, cerebral blood
volume, and intracranial pressure, but to a much lesser extent than barbiturates,
propofol, or benzodiazepines. These effects will occur during maintenance of
normocarbia by artificial ventilation; however, there are some reports of
mild— but transient and almost certainly unimportant— increases in cerebral
artery blood flow velocity and intracranial pressure following opioid boluses in
patients with brain tumors or head trauma. If combined with hypotension, the
resulting fall in cerebral perfusion pressure could be deleterious to patients

22
with abnormal intracranial pressure–volume relationships. Nevertheless, the
important clinical message is that any trivial opioid-induced increase in
intracranial pressure would likely be much less important than the much more
likely large increases in intracranial pressure associated with intubation that
might be observed in an inadequately anesthetized patient (from whom opioids
were withheld). Opioids usually have almost no effects on the
electroencephalogram (EEG), although large doses are associated with slow δ-
wave activity. There are curious sporadic case reports that large doses of
fentanyl may rarely cause seizure activity; however, some of these apparent
seizures have been retrospectively diagnosed as severe opioid-induced muscle
rigidity. EEG activation and seizures have been associated with the meperidine
metabolite normeperidine, as previously noted.1
Stimulation of the medullary chemoreceptor trigger zone is responsible
for opioid-induced nausea and vomiting. Curiously, nausea and vomiting are
more common following smaller (analgesic) than very large (anesthetic) doses
of opioids. Prolonged oral dosing of opioids or infusion of large doses of
remifentanil during general anesthesia can produce the phenomenon of opioid-
induced tolerance. Repeated dosing of opioids will reliably produce tolerance,
a phenomenon in which larger doses are required to produce the same response.
This is not the same as physical dependence or addiction, which may also be
associated with repeated opioid administration.1
Prolonged dosing of opioids can also produce “opioid-induced
hyperalgesia,” in which patients become more sensitive to painful stimuli.
Infusion of large doses of (in particular) remifentanil during general anesthesia
can produce acute tolerance, in which much larger than usual doses of opioids
will be required for postoperative analgesia. Relatively large doses of opioids
are required to render patients unconscious (Table 5). Regardless of the dose,
however, opioids will not reliably pro- duce amnesia. Parenteral opioids have

23
been the mainstay of pain control for more than a century. e relatively recent
use of opioids in epidural and intrathecal spaces has revolutionized acute and
chronic pain management. Unique among the commonly used opioids,
meperidine has minor local anesthetic qualities, particularly when administered
into the subarachnoid space. Meperidine’s clinical use as a local anesthetic has
been limited by its relatively low potency and propensity to cause typical
opioid side effects (nausea, sedation, and pruritus) at the doses required to
induce local anesthesia. Intravenous meperidine (10–25 mg) is more effective than
morphine or fentanyl for decreasing shivering in the postanesthetic care unit and
meperidine appears to be the best agent for this indication.1

Table 5. Uses and doses of common opioids

D. Gastrointestinal
Opioids slow gastrointestinal motility by binding to opioid receptors in the gut
and reducing peristalsis. Biliary colic may result from opioid-induced contraction of
the sphincter of Oddi. Biliary spasm, which can mimic a common bile duct stone on

24
cholangiography, is reversed with the opioid antagonist naloxone or glucagon.
Patients receiving long-term opioid therapy (eg, for cancer pain) usually become
tolerant to many of the side effects but rarely to constipation. This is the basis for the
recent development of the peripheral opioid antagonists methylnaltrexone and
alvimopan, and for their salutary effects in promoting motility in patients with
opioid bowel syndrome, those receiving chronic opioid treatment of cancer
pain, and those receiving intravenous opioids after abdominal surgery.1

E. Endocrine
The neuroendocrine stress response to surgical stimulation is measured
in terms of the secretion of specific hormones, including catecholamines,
antidiuretic hormone, and cortisol. Large doses of opioids (typically fentanyl
or sufentanil) block the release of these hormones in response to surgery more
completely than volatile anesthetics. Although much discussed, the actual
clinical outcome benefit produced by attenuating the stress response, even in
high-risk cardiac patients, remains speculative (and possibly nonexistent).1

2.2.4 Drug Interactions

The combination of meperidine and monoamine oxidase inhibitors should be
avoided as it may result in hypertension, hypotension, hyperpyrexia, coma, or
respiratory arrest. The cause of this catastrophic interaction is incompletely
understood. (The results of failure to appreciate this drug interaction in the celebrated
Libby Zion case led to changes in work rules for house officers in the United States.)1
Propofol, barbiturates, benzodiazepines, and other central nervous system depressants
can have synergistic cardiovascular, respiratory, and sedative effects with opioids.1
The biotransformation of alfentanil may be impaired following treatment with
erythromycin, leading to prolonged sedation and respiratory depression.1

2.3 Muscle Relaxation

25
 Neuromuscular blocking agents are divided into two classes: depolarizing and
nondepolarizing (Table 6). This division reflects distinct differences in the
mechanism of action, response to peripheral nerve stimulation, and reversal of block.1

Table 6. Depolarizing and nondepolarizing muscle relaxants

2.3.1 Depolarizing Muscle Relaxants

Depolarizaing muscle relaxants acts like acetylcholine, but in the synaptic
cleft it is not destroyed by acetylcholinesterase so that it lasts long enough to cause
depolarization that characterized by fasciculation followed by striated muscle
relaxation. Drugs that included in this class are succinylcholine (diacetylcholine) and
decamethonium. In vein, succinylcholine is metabolized by plasma cholinesterase,
pseudocholinesterase into succinylmonocolin. Anti-cholinesterase (prostigmine)
drugs are contraindicated because they inhibit pseudocolinesterase.5 The only
depolarizing muscle relaxant in clinical use today is succinylcholine.1

2.3.1.1 Physical Structure

Succinylcholine—also called diacetylcholine or suxamethonium—consists of
two joined ACh molecules. This structure underlies succinylcholine’s mechanism of
action, side effects, and metabolism.1

2.3.1.2 Metabolism & Excretion

26
 The popularity of succinylcholine is due to its rapid onset of action (30–60
second) and short duration of action (typically less than 10 minutes). Its rapid onset
of action relative to other neuromuscular blockers is largely due to the relative
overdose that is usually administered. Succinylcholine, like all neuromuscular
blockers, has a small volume of distribution due to its very low lipid solubility, and
this also underlies a rapid onset of action. As succinylcholine enters the circulation,
most of it is rapidly metabolized by pseudocholinesterase into succinylmonocholine.
This process is so efficient that only a small fraction of the injected dose ever reaches
the neuromuscular junction. As drug levels fall in blood, succinylcholine molecules
di use away from the neuromuscular junction, limiting the duration of action.
However, this duration of action can be prolonged by high doses, infusion of
succinylcholine, or abnormal metabolism. The latter may result from hypothermia,
reduced pseudocholinesterase levels, or a genetically aberrant enzyme. Hypothermia
decreases the rate of hydrolysis. Reduced levels of pseudocholinesterase (measured as
units per liter) accompany pregnancy, liver disease, renal failure, and certain drug
therapies, such as neostigmine, esmolol, and pancuronium. Reduced
pseudocholinesterase levels generally produce only modest prolongation of
succinylcholine’s actions (2–20 minutes).
 One in 25-30 patients of European
extraction is a heterozygote with one normal and one abnormal (atypical)
pseudocholinesterase gene, resulting in a slightly prolonged block (20–30 minutes).
Even fewer (1 in 3000) patients have two copies of the most prevalent abnormal gene
(homozygous atypical) that produce an enzyme with little or no affinity for
succinylcholine. In contrast to the doubling or tripling of blockade duration seen in
patients with low enzyme levels or heterozygous atypical enzyme, patients with
homozygous atypical enzyme will have a very long blockade (eg, 4–8 hours)
following administration of succinylcholine. Of the recognized abnormal
pseudocholinesterase genes, the dibucaine-resistant (variant) allele, which produces
an enzyme with 1/100 of normal affinity for succinylcholine, is the most common.
Other variants include fluoride-resistant and silent (no activity) alleles.1
Dibucaine, a local anesthetic, inhibits normal pseudocholinesterase activity by

27
80%, but inhibits atypical enzyme activity by only 20%. Serum from an individual
who is heterozygous for the atypical enzyme is characterized by an intermediate 40%
to 60% inhibition. The percentage of inhibition of pseudocholinesterase activity is
termed the dibucaine number. A patient with normal pseudocholinesterase has a
dibucaine number of 80; a homozygote for the most common abnormal allele will
have a dibucaine number of 20. The dibucaine number measures
pseudocholinesterase function, not the amount of enzyme. Therefore, adequacy of
pseudocholinesterase can be determined in the laboratory quantitatively in units per
liter (a minor factor) and qualitatively by dibucaine number (the major factor).
Prolonged paralysis from succinylcholine caused by abnormal pseudocholinesterase
(atypical cholinesterase) should be treated with continued mechanical ventilation and
sedation until muscle function returns to normal by clinical signs. Such unsedated
patients do not appreciate unnecessary, repetitive use of nerve stimulation when all
members of a department come by to confirm the diagnosis.1

2.3.1.3 Drug Interactions

The effects of muscle relaxants can be modified by concurrent drug therapy
(Table 7). Succinylcholine is involved in two interactions deserving special comment.

Table 7. Potentiation () and resistance () of neuromuscular blocking

28
agents by other drugs

A. Cholinesterase Inhibitors
Although cholinesterase inhibitors reverse non-depolarizing paralysis, they
markedly prolong a depolarizing phase I block by two mechanisms. By inhibiting
acetylcholinesterase, they lead to a higher ACh concentration at the nerve terminal,
which intensi es depolarization. They also reduce the hydrolysis of succinylcholine
by inhibiting pseudocholinesterase. Organophosphate pesticides, for example, cause
an irreversible inhibition of acetylcholinesterase and can prolong the action of
succinylcholine by 20–30 min. Echothiophate eye drops, used in the past for
glaucoma, can markedly prolong succinylcholine by this mechanism.1

B. Nondepolarizing Relaxants
In general, small doses of nondepolarizing relaxants antagonize a depolarizing
phase I block. Because the drugs occupy some ACh receptors, depolarization by
succinylcholine is partially prevented. If enough depolarizing agent is administered to
develop a phase II block, a nondepolarizer will potentiate paralysis.1

29
2.3.1.4 Dosage
Because of the rapid onset, short duration, and low cost of succinylcholine,
many clinicians believe that it is still a good choice for routine intubation in adults.
The usual adult dose of succinylcholine for intubation is 1–1.5 mg/kg intravenously.
Doses as small as 0.5 mg/kg will often provide accept- able intubating conditions if a
defasciculating dose of a nondepolarizing agent is not used. Repeated small boluses
(10 mg) or a succinylcholine drip (1 g in 500 or 1000 mL, titrated to effect) can be
used during surgical procedures that require brief but intense paralysis (eg,
otolaryngological endoscopies). Neuromuscular function should be frequently
monitored with a nerve stimulator to prevent overdosing and to watch for phase II
block. The availability of intermediate-acting nondepolarizing muscle relaxants has
reduced the popularity of succinylcholine infusions. In the past, these infusions were
a mainstay of ambulatory practice in the United States.1
Because succinylcholine is not lipid soluble, it has a small volume of
distribution. Per kilogram, infants and neonates have a larger extracellular space than
adults. Therefore, dosage requirements for pediatric patients are often greater than for
adults. If succinylcholine is administered intramuscularly to children, a dose as high
as 4–5 mg/kg does not always produce complete paralysis.1
Succinylcholine should be stored under refrigeration (2–8°C), and should
generally be used within 14 days after removal from refrigeration and exposure to
room temperature.1

2.3.1.5 Side Effects & Clinical Considerations

Succinylcholine is a relatively safe drug—assuming that its many potential
complications are under- stood and avoided. Because of the risk of hyperkalemia,
rhabdomyolysis, and cardiac arrest in children with undiagnosed myopathies,
succinylcholine is considered relatively contraindicated in the routine management of
children and adolescent patients. Most clinicians have also abandoned the routine use
of succinylcholine for adults. Succinylcholine is still useful for rapid sequence
induction and for short periods of intense paralysis because none of the presently

30
available nondepolarizing muscle relaxants can match its very rapid onset and short
duration.1
A. Cardiovascular
Because of the resemblance of muscle relaxants to ACh, it is not surprising
that they affect cholinergic receptors in addition to those at the neuromuscular
junction. The entire parasympathetic nervous system and parts of the sympathetic
nervous system (sympathetic ganglions, adrenal medulla, and sweat glands) depend
on ACh as a neurotransmitter.1
Succinylcholine not only stimulates nicotinic cholinergic receptors at the
neuromuscular junction, it stimulates all ACh receptors. The cardiovascular actions of
succinylcholine are therefore very complex. Stimulation of nicotinic receptors in
parasympathetic and sympathetic ganglia, and muscarinic receptors in the sinoatrial
node of the heart, can increase or decrease blood pressure and heart rate. Low doses
of succinylcholine can produce negative chronotropic and inotropic effects, but
higher doses usually increase heart rate and contractility and elevate circulating
catecholamine levels. In most patients, the hemodynamic consequences are
inconsequential in comparison to the effects of the induction agent and laryngoscopy.
Children are particularly susceptible to profound bradycardia following
administration of succinylcholine. Bradycardia will sometimes occur in adults when a
second bolus of succinylcholine is administered approximately 3–8 min after the first
dose. The dogma (based on no real evidence) is that the succinylcholine metabolite,
succinyl-monocholine, sensitizes muscarinic cholinergic receptors in the sinoatrial
node to the second dose of succinylcholine, resulting in bradycardia. Intravenous
atropine (0.02 mg/kg in children, 0.4 mg in adults) is normally given prophylactically
to children prior to the first and subsequent doses, and usually before a second dose
of succinylcholine is given to adults. Other arrhythmias, such as nodal bradycardia
and ventricular ectopy, have been reported.1

B. Fasciculations

31
 The onset of paralysis by succinylcholine is usually signaled by visible motor
unit contractions called fasciculations. These can be prevented by pretreatment with a
small dose of nondepolarizing relaxant. Because this pretreatment usually
antagonizes a depolarizing block, a larger dose of succinylcholine is required (1.5
mg/kg). Fasciculations are typically not observed in young children and elderly
patients.1

C. Hyperkalemia
Normal muscle releases enough potassium during succinylcholine-induced
depolarization to increase serum potassium by 0.5 mEq/L. Although this is usually
insignificant in patients with normal baseline potassium levels, it can be life-
threatening in patients with preexisting hyperkalemia. The increase in potassium in
patients with burn injury, massive trauma, neurological disorders, and several other
conditions can be large and catastrophic. Hyperkalemic cardiac arrest can prove to be
quite refractory to routine cardiopulmonary resuscitation, requiring calcium, insulin,
glucose, bicarbonate, and even cardiopulmonary bypass to support the circulation
while reducing serum potassium levels.1
Following denervation injuries (spinal cord injuries, larger burns), the
immature isoform of the ACh receptor may be expressed inside and out- side the
neuromuscular junction (up-regulation). These extrajunctional receptors allow
succinylcholine to effect widespread depolarization and extensive potassium release.
Life-threatening potassium release is not reliably prevented by pretreatment with a
nondepolarizer. The risk of hyperkalemia usually seems to peak in 7–10 days
following the injury, but the exact time of onset and the duration of the risk period
vary. The risk of hyperkalemia from succinylcholine is minimal in the first 2 days
after spinal cord or burn injury.1

D. Muscle Pains
Patients who have received succinylcholine have an increased incidence of
postoperative myalgia. The efficacy of nondepolarizing pretreatment is controversial.

32
Administration of rocuronium (0.06–0.1 mg/kg) prior to succinylcholine has been
reported to be effective in preventing fasciculations and reducing postoperative
myalgias. The relationship between fasciculations and postoperative myalgias is also
inconsistent. The myalgias are theorized to be due to the initial unsynchronized
contraction of muscle groups; myoglobinemia and increases in serum creatine kinase
can be detected following administration of succinylcholine. Perioperative use of
nonsteroidal antiin ammatory drugs may reduce the incidence and severity of
myalgias.1

E. Intragastric Pressure Elevation

Abdominal wall muscle fasciculations increase intragastric pressure, which is
o set by an increase in lower esophageal sphincter tone. Therefore, despite being
much discussed, there is no evidence that the risk of gastric reflux or pulmonary
aspiration is increased by succinylcholine.1

F. Intraocular Pressure Elevation

Extraocular muscle differs from other striated muscle in that it has multiple
motor endplates on each cell. Prolonged membrane depolarization and contraction of
extraocular muscles following administration of succinylcholine transiently raise
intraocular pressure and theoretically could compromise an injured eye. However,
there is no evidence that succinylcholine leads to worsened outcome in patients with
“open” eye injuries. The elevation in intraocular pressure is not always prevented by
pretreatment with a nondepolarizing agent.1

G. Masseter Muscle Rigidity

Succinylcholine transiently increases muscle tone in the masseter muscles.
Some difficulty may initially be encountered in opening the mouth because of
incomplete relaxation of the jaw. A marked increase in tone preventing laryngoscopy
is abnormal and can be a premonitory sign of malignant hyperthermia.1

33
H. Malignant Hyperthermia
Succinylcholine is a potent triggering agent in patients susceptible to
malignant hyperthermia, a hypermetabolic disorder of skeletal muscle (see Chapter
52). Although some of the signs and symptoms of neuroleptic malignant syndrome
(NMS) resemble those of malignant hyperthermia, the pathogenesis is completely
different and there is no need to avoid use of succinylcholine in patients with NMS.1

I. Generalized Contractions
Patients afflicted with myotonia may develop myoclonus after administration
of succinylcholine.1

J. Prolonged Paralysis
As discussed above, patients with reduced levels of normal
pseudocholinesterase may have a longer than normal duration of action, whereas
patients with atypical pseudocholinesterase will experience markedly prolonged
paralysis.1

K. Intracranial Pressure
Succinylcholine may lead to an activation of the electroencephalogram and
slight increases in cerebral blood flow and intracranial pressure in some patients.
Muscle fasciculations stimulate muscle stretch receptors, which subsequently increase
cerebral activity. The increase in intracranial pressure can be attenuated by
maintaining good airway control and instituting hyperventilation. It can also be
prevented by pretreating with a nondepolarizing muscle relaxant and administering
intravenous lidocaine (1.5–2.0 mg/kg) 2–3 minutes prior to intubation. The effects of
intubation on intracranial pressure far outweigh any increase caused by
succinylcholine, and succinylcholine is not contraindicated for rapid sequence
induction of patients with intracranial mass lesions or other causes of increased intra-
cranial pressure.1

34
L. Histamine Release
Slight histamine release may be observed following succinylcholine in some
patients.

2.3.2 Nondepolarizing Muscle Relaxants

Available nondepolarizing neuromuscular blockers can be classified
according to chemical class (the steroidal, benzylisoquinolinium, and other blockers)
or according to rapidity of onset of action or duration of action (long-acting,
intermediate-acting, or short-acting) of equipotent doses (Table 8).6

Table 8. Classification of commonly used and new nondepolarizing

neuromuscular blockers according to duration of action

2.3.2.1 Atracurium
2.3.2.1.1 Physical Structure
Like all muscle relaxants, atracurium has a quaternary group; however, a
benzylisoquinoline structure is responsible for its unique method of degradation. The
drug is a mixture of 10 stereoisomers.1

2.3.2.1.2 Metabolism & Excretion

Atracurium is so extensively metabolized that its pharmacokinetics are
independent of renal and hepatic function, and less than 10% is excreted unchanged
by renal and biliary routes. Two separate processes are responsible for metabolism.1
A. Ester Hydrolysis

35
 This action is catalyzed by nonspecific esterases, not by acetylcholinesterase
or pseudocholinesterase.1
B. Hofmann Elimination
A spontaneous nonenzymatic chemical breakdown occurs at physiological pH
and temperature.1

2.3.2.1.3 Dosage
A dose of 0.5 mg/kg is administered intravenously for intubation. After
succinylcholine, intraoperative relaxation is achieved with 0.25 mg/kg initially, then
in incremental doses of 0.1 mg/kg every 10–20 minutes. An infusion of 5–10
mcg/kg/min can effectively replace intermittent boluses. Although dosage
requirements do not significantly vary with age, atracurium may be shorter acting in
children and infants than in adults.1
Atracurium is available as a solution of 10 mg/ mL. It must be stored at 2–8°C,
as it loses 5% to 10% of its potency for each month it is exposed to room temperature.
At room temperature, it should be used within 14 days to preserve potency.1

2.3.2.1.4 Side Effects & Clinical Considerations

Atracurium triggers dose-dependent histamine release that becomes
significant at doses above 0.5 mg/kg.1
A. Hypotension and Tachycardia
Cardiovascular side effects are unusual unless doses in excess of 0.5 mg/kg
are administered. Atracurium may also cause a transient drop in systemic vascular
resistance and an increase in cardiac index independent of any histamine release. A
slow rate of injection minimizes these effects.1

B. Bronchospasm
Atracurium should be avoided in asthmatic patients. Severe bronchospasm is
occasionally seen in patients without a history of asthma.1

36
C. Laudanosine Toxicity
Laudanosine, a tertiary amine, is a breakdown product of atracurium’s
Hofmann elimination and has been associated with central nervous system excitation,
resulting in elevation of the minimum alveolar concentration and even precipitation
of seizures. Concerns about laudanosine are probably irrelevant unless a patient has
received an extremely large total dose or has hepatic failure. Laudanosine is
metabolized by the liver and excreted in urine and bile.1

D. Temperature and pH Sensitivity

Because of its unique metabolism, atracurium’s duration of action can be
markedly prolonged by hypothermia and to a lesser extent by acidosis.1

E. Chemical Incompatibility
Atracurium will precipitate as a free acid if it is introduced into an intravenous
line containing an alkaline solution such as thiopental.1

F. Allergic Reactions
Rare anaphylactoid reactions to atracurium have been described. Proposed
mechanisms include direct immunogenicity and acrylate-mediated immune activation.
IgE-mediated antibody reactions directed against substituted ammonium compounds,
including muscle relaxants, have been described. Reactions to acrylate, a metabolite
of atracurium and a structural component of some dialysis membranes, have also
been reported in patients undergoing hemodialysis.1

2.3.2.2 Vecuronium
2.3.2.2.1 Physical Structure
Vecuronium is pancuronium minus a quaternary methyl group (a
monoquaternary relaxant). This minor structural change beneficially alters side
effects without affecting potency.1

37
2.3.2.2.2 Metabolism & Excretion
Vecuronium is metabolized to a small extent by the liver. It depends primarily
on biliary excretion and secondarily (25%) on renal excretion. Although it is a
satisfactory drug for patients with renal failure, its duration of action is somewhat
prolonged. Vecuronium’s brief duration of action is explained by its shorter
elimination half-life and more rapid clearance compared with pancuronium. Long-
term administration of vecuronium to patients in intensive care units has resulted in
prolonged neuromuscular blockade (up to several days), possibly from accumulation
of its active 3-hydroxy metabolite, changing drug clearance, and in some patients,
leading to the development of a polyneuropathy. Risk factors seem to include female
gender, renal failure, long-term or high-dose corticosteroid therapy, and sepsis. Thus,
these patients must be closely monitored, and the dose of vecuronium carefully
titrated. Long-term relaxant administration and the subsequent prolonged lack of ACh
binding at the postsynaptic nicotinic ACh receptors may mimic a chronic denervation
state and cause lasting receptor dysfunction and paralysis. Tolerance to
nondepolarizing muscle relaxants can also develop after long- term use. Fortunately,
the use of unnecessary paralysis has greatly declined in critical care units.1

2.3.2.2.3 Dosage
Vecuronium is equipotent with pancuronium, and the intubating dose is 0.08–
0.12 mg/kg. A dose of 0.04 mg/kg initially followed by increments of 0.01 mg/kg
every 15–20 minutes provides intraoperative relaxation. Alternatively, an infusion of
1–2 mcg/kg/min produces good maintenance of relaxation.1
Age does not affect initial dose requirements, although subsequent doses are
required less frequently in neonates and infants. Women seem to be approximately
30% more sensitive than men to vecuronium, as evidenced by a greater degree of
blockade and longer duration of action (this has also been seen with pancuronium and
rocuronium). The cause for this sensitivity may be related to gender-related
differences in fat and muscle mass, protein binding, volume of distribution, or
metabolic activity. The duration of action of vecuronium may be further prolonged in

38
postpartum patients due to alterations in hepatic blood flow or liver uptake.1

2.3.2.2.4 Side Effects & Clinical Considerations

A. Cardiovascular
Even at doses of 0.28 mg/kg, vecuronium is devoid of significant
cardiovascular effects. Potentiation of opioid-induced bradycardia may be observed
in some patients.1

B. Liver Failure
Although it is dependent on biliary excretion, the duration of action of
vecuronium is usually not significantly prolonged in patients with cirrhosis unless
doses greater than 0.15 mg/kg are given. Vecuronium requirements are reduced
during the anhepatic phase of liver transplantation.1

39
 CHAPTER III
CONCLUSION

In 1952 Gray and Rees examined the components of anaesthesia, and put
forward the Triad Concept of hypnosis, analgesia, and muscular relaxation. These
effects could be achieved selectively by the judicious use of specific agents to
produce balanced anaesthesia.
The most common hypnotics used in general anesthesia are benzodiazepine,
ketamine, and propofol. Midazolam is the most commonly used benzodiazepine in
the perioperative period and can be used as premedication, sedation, and induction
agent. Ketamine is used for intravenous induction of anesthesia, particularly in
settings where its tendency to produce sympathetic stimulation are useful, such as in
hypovolemia and trauma. Ketamine can be combined with other agents like propofol
or midazolam. Propofol has a rapid onset of action and is available only for
intravenous administration for the induction of general anesthesia and for moderate to
deep sedation.
Opioids provide some degree of sedation and when given in large doses
can produce general anesthesia in many species, but principally opioid use to
provide analgesia. Opioid that usually used are fentanyl, tramadol, morphine,
and others. The distributions half-lives of all of the opioids are fairly rapid.
Neuromuscular blocking agents are divided into two classes, depolarizing and
nondepolarizing agents. The only depolarizing muscle relaxant use today is
succinylcholine. Nondepolarizing agents divided into short acting, intermediate
acting, and long acting agents. The most common used muscle relaxant is atracurium
that have shorter acting in children and infants than in adults.

40
 REFERENCES

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