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C H A P T E R

Intravenous Anesthetics

KEY CONCEPTS
9
1 Repetitive administration of barbiturates (eg, 4 In contrast to other anesthetic agents,
infusion of thiopental for barbiturate coma ketamine increases arterial blood pressure,
and brain protection) saturates the peripheral heart rate, and cardiac output, particularly
compartments, minimizing any eect of after rapid bolus injections.
redistribution, and rendering the duration 5 Induction doses of etomidate transiently
of action more dependent on elimination. inhibit enzymes involved in cortisol and
This is an example of context sensitivity. aldosterone synthesis. Etomidate was
2 Barbiturates constrict the cerebral often used in the past for ICU sedation
vasculature, causing a decrease in cerebral before reports of its consistent ability to
blood ow, cerebral blood volume, and produce adrenocortical suppression in
intracranial pressure. that circumstance appeared.
3 Although apnea may be relatively 6 Propofol formulations can support the
uncommon after benzodiazepine induction, growth of bacteria, so sterile technique must
even small intravenous doses of diazepam be observed in preparation and handling.
and midazolam have resulted in respiratory Propofol should be administered within 6 h
arrest. of opening the ampule.

General anesthesia began with inhaled agents but feasible with a total intravenous anesthesia (TIVA)
now can be induced and maintained with drugs that technique. This chapter focuses on the intravenous
enter the patient through a wide range of routes. agents used to produce hypnosis, including barbi-
Drug administration can be oral, rectal, transder- turates, benzodiazepines, ketamine, etomidate, and
mal, transmucosal, intramuscular, or intravenous propofol.
for the purpose of producing or enhancing an anes-
thetic state. Preoperative sedation of adults is usu-
ally accomplished by way of oral or intravenous BARBITURATES
routes. Induction of general anesthesia in adults
usually includes intravenous drug administration. Mechanisms of Action
Effective topical anesthesia with EMLA (eutectic Barbiturates depress the reticular activating sys-
mixture of local anesthetic) cream, LMX (plain tem in the brainstem, which controls multiple vital
lidocaine cream 4% and 5%), or 2% lidocaine jelly functions, including consciousness. In clinical con-
has increased the ease of intravenous inductions centrations, barbiturates more potently affect the
in children. Maintenance of general anesthesia is function of nerve synapses than axons. Their primary

175
176 SECTION II Clinical Pharmacology

Barbituric acid
H O
N C
3 4
H
O C2 5 C

H
1 6
N C
H O

Thiamylal Secobarbital Phenobarbital


O O O
H H H
N CH2CH CH2 N CH2CH CH2 N
S O O
N CHCH2CH2CH3 N CHCH2CH2CH3 N CH2CH3
CH3 H CH3 H
H O O O

Thiopental Methohexital Pentobarbital


O O O
H H H
N CH2CH3 N CH2CH CH2 N CH2CH3
S O O
N CHCH2CH2CH3 N CHC CCH2CH3 N CHCH2CH2CH3
CH3 O CH H
H O CH3 O CH3
3

FIGURE 91 Barbiturates share the structure of barbituric acid and dier in the C2, C3, and N1 substitutions.

mechanism of action is believed to be through bind- 2.5% thiopental solution). Concentrations greater
ing to the -aminobutyric acid type A (GABAA) than recommended cause an unacceptable incidence
receptor. Barbiturates potentiate the action of GABA of pain on injection and venous thrombosis.
in increasing the duration of openings of a chloride-
specific ion channel. Pharmacokinetics
A. Absorption
StructureActivity Relationships In clinical anesthesiology, thiopental, thiamylal, and
Barbiturates are derived from barbituric acid methohexital were frequently administered intrave-
(Figure 91). Substitution at carbon C5 determines nously for induction of general anesthesia in adults
hypnotic potency and anticonvulsant activity. A long- and children (prior to the introduction of propofol).
branched chain conveys more potency than does a Rectal thiopental or, more often, methohexital has
short straight chain. Likewise, the phenyl group in been used for induction in children, and intramus-
phenobarbital is anticonvulsive, whereas the methyl cular (or oral) pentobarbital was often used in the
group in methohexital is not. Replacing the oxygen past for premedication of all age groups.
at C2 (oxybarbiturates) with a sulfur atom (thio-
barbiturates) increases lipid solubility. As a result, B. Distribution
thiopental and thiamylal have a greater potency, The duration of sleep doses of the highly lipid-solu-
more rapid onset of action, and shorter durations ble barbiturates (thiopental, thiamylal, and metho-
of action (after a single sleep dose) than pentobar- hexital) is determined by redistribution, not by
bital. The sodium salts of the barbiturates are water metabolism or elimination. For example, although
soluble but markedly alkaline (pH of 2.5% thiopen- thiopental is highly protein bound (80%), its great
tal >10) and relatively unstable (2-week shelf-life for lipid solubility and high nonionized fraction (60%)
CHAPTER 9 Intravenous Anesthetics 177

minimizing any effect of redistribution, and render-


100 ing the duration of action more dependent on elimi-
Plasma
MG nation. This is an example of context sensitivity.
75
C. Biotransformation
% of dose

VRG
50 Barbiturates are principally biotransformed via
hepatic oxidation to inactive water-soluble metabo-
FG lites. Because of greater hepatic extraction, metho-
25
hexital is cleared by the liver more rapidly than
thiopental. Although redistribution is responsible
0.1 1.0 10 100
for the awakening from a single sleep dose of any of
Time (min)
these lipid-soluble barbiturates, full recovery of psy-
chomotor function is more rapid following metho-
hexital due to its enhanced metabolism.
FIGURE 92 Distribution of thiopental from plasma
to the vessel-rich group (VRG; brain, heart, liver, kidney, D. Excretion
endocrine glands), to the muscle group (MG), and Increased protein binding decreases barbiturate glo-
nally to the fat group (FG). (Modied and reproduced, with
permission, from Price HL et al: The uptake of thiopental by body
merular filtration, whereas increased lipid solubility
tissues and its relation to the duration of narcosis. Clin Pharmacol tends to increase renal tubular reabsorption. Except
Ther 1960;1:16.) for the less protein-bound and less lipid-soluble
agents such as phenobarbital, renal excretion is lim-
ited to water-soluble end products of hepatic bio-
account for rapid brain uptake (within 30 s). If the transformation. Methohexital is excreted in the feces.
central compartment is contracted (eg, hypovolemic
shock), if the serum albumin is low (eg, severe liver
disease or malnutrition), or if the nonionized frac-
Eects on Organ Systems
tion is increased (eg, acidosis), larger brain and heart A. Cardiovascular
concentrations will be achieved for a given dose. Intravenous bolus induction doses of barbiturates
Redistribution to the peripheral compartment cause a decrease in blood pressure and an increase in
specifically, the muscle grouplowers plasma and heart rate. Hemodynamic responses to barbiturates
brain concentration to 10% of peak levels within are reduced by slower rates of induction. Depression
2030 min (Figure 92). This pharmacokinetic of the medullary vasomotor center produces vaso-
profile correlates with clinical experiencepatients dilation of peripheral capacitance vessels, which
typically lose consciousness within 30 s and awaken increases peripheral pooling of blood, mimicking
within 20 min. a reduced blood volume. Tachycardia following
The minimal induction dose of thiopental will administration is probably due to a central vagolytic
depend on body weight and age. Reduced induction effect and reflex responses to decreases in blood
doses are required for elderly patients primarily due pressure. Cardiac output is often maintained by an
to slower redistribution. In contrast to the rapid initial increased heart rate and increased myocardial con-
distribution half-life of a few minutes, elimination of tractility from compensatory baroreceptor reflexes.
thiopental is prolonged (elimination half-life ranges Sympathetically induced vasoconstriction of resis-
of 1012 h). Thiamylal and methohexital have similar tance vessels (particularly with intubation under
distribution patterns, whereas less lipid-soluble barbi- light planes of general anesthesia) may actually
turates have much longer distribution half-lives and increase peripheral vascular resistance. However, in
durations of action after a sleep dose. Repetitive situations where the baroreceptor response will be
1 administration of barbiturates (eg, infusion of blunted or absent (eg, hypovolemia, congestive heart
thiopental for barbiturate coma and brain failure, -adrenergic blockade), cardiac output and
protection) saturates the peripheral compartments, arterial blood pressure may fall dramatically due
178 SECTION II Clinical Pharmacology

to uncompensated peripheral pooling of blood equals cerebral artery pressure minus the greater of
and direct myocardial depression. Patients with jugular venous pressure or intracranial pressure.)
poorly controlled hypertension are particularly Barbiturates induce a greater decline in cerebral
prone to wide swings in blood pressure during oxygen consumption (up to 50% of normal) than in
anesthesia induction. The cardiovascular effects of cerebral blood flow; therefore the decline in cerebral
barbiturates therefore vary markedly, depending on blood flow is not detrimental. Barbiturate-induced
rate of administration, dose, volume status, baseline reductions in oxygen requirements and cerebral
autonomic tone, and preexisting cardiovascular dis- metabolic activity are mirrored by changes in the
ease. A slow rate of injection and adequate preopera- electroencephalogram (EEG), which progress from
tive hydration attenuates or eliminates these changes low-voltage fast activity with small doses to high-
in most patients. voltage slow activity, burst suppression, and electrical
silence with larger doses. Barbiturates may protect
B. Respiratory the brain from transient episodes of focal ischemia
Barbiturates depress the medullary ventilatory cen- (eg, cerebral embolism) but probably do not protect
ter, decreasing the ventilatory response to hypercap- from global ischemia (eg, cardiac arrest). Abundant
nia and hypoxia. Deep barbiturate sedation often animal data document these effects but the clinical
leads to upper airway obstruction; apnea often fol- data are sparse and inconsistent. Furthermore, thio-
lows an induction dose. During awakening, tidal pental doses required to maintain EEG suppression
volume and respiratory rate are decreased follow- (most often burst suppression or flat line) are associ-
ing barbiturate induction. Barbiturates incompletely ated with prolonged awakening, delayed extubation,
depress airway reflex responses to laryngoscopy and and the need for inotropic support.
intubation, and airway instrumentation may lead to The degree of central nervous system depres-
bronchospasm (in asthmatic patients) or laryngo- sioninduced by barbiturates ranges from mild seda-
spasm in lightly anesthetized patients. tion to unconsciousness, depending on the dose
administered (Table 91). Some patients relate
C. Cerebral a taste sensation of garlic, onions, or pizza dur-
2 Barbiturates constrict the cerebral vascula- ing induction with thiopental. Barbiturates do not
ture, causing a decrease in cerebral blood impair the perception of pain. In fact, they some-
flow, cerebral blood volume, and intracranial pres- times appear to lower the pain threshold. Small
sure. Intracranial pressure decreases to a greater doses occasionally cause a state of excitement and
extent than arterial blood pressure, so cerebral disorientation that can be disconcerting when seda-
perfusion pressure (CPP) usually increases. (CPP tion is the objective. Barbiturates do not produce

TABLE 91 Uses and dosages of common barbiturates.


Agent Use Route1 Concentration (%) Dose (mg/kg)

Thiopental, Induction IV 2.5 36


thiamylal

Methohexital Induction IV 1 12
Sedation IV 1 0.20.4
Induction Rectal (children) 10 25

Secobarbital, Premedication Oral 5 242


pentobarbital IM 242
Rectal suppository 3
1
IV, intravenous; IM, intramuscular.
2
Maximum dose is 150 mg.
CHAPTER 9 Intravenous Anesthetics 179

muscle relaxation, and some induce involuntary impression that chronic alcohol abuse is associ-
skeletal muscle contractions (eg, methohexital). ated with increased thiopental requirements during
Relatively small doses of thiopental (50100 mg induction lacks scientific proof.
intravenously) rapidly (but temporarily) control
most grand mal seizures. Unfortunately, acute toler-
ance and physiological dependence on the sedative BENZODIAZEPINES
effect of barbiturates develop quickly.
Mechanisms of Action
D. Renal Benzodiazepines bind the same set of receptors in
Barbiturates reduce renal blood flow and glomeru- the central nervous system as barbiturates but bind
lar filtration rate in proportion to the fall in blood to a different site on the receptors. Benzodiazepine
pressure. binding to the GABAA receptor increases the fre-
quency of openings of the associated chloride ion
E. Hepatic
channel. For example, benzodiazepine-receptor
Hepatic blood flow is decreased. Chronic expo- binding facilitates binding of GABA to its receptor.
sure to barbiturates has opposing effects on drug Flumazenil (an imidazobenzodiazepine) is a spe-
biotransformation. Induction of hepatic enzymes cific benzodiazepinereceptor antagonist that effec-
increases the rate of metabolism of some drugs, tively reverses most of the central nervous system
whereas binding of barbiturates to the cytochrome effects of benzodiazepines (see Chapter 17).
P-450 enzyme system interferes with the biotrans-
formation of other drugs (eg, tricyclic antidepres-
sants). Barbiturates promote aminolevulinic acid StructureActivity Relationships
synthetase, which stimulates the formation of The chemical structure of benzodiazepines includes
porphyrin (an intermediary in heme synthesis). a benzene ring and a seven-member diazepine ring
This may precipitate acute intermittent porphyria or (Figure 93). Substitutions at various positions on
variegate porphyria in susceptible individuals. these rings affect potency and biotransformation.
The imidazole ring of midazolam contributes to its
F. Immunological water solubility at low pH. Diazepam and lorazepam
Anaphylactic or anaphylactoid allergic reactions are insoluble in water so parenteral preparations
are rare. Sulfur-containing thiobarbiturates evoke contain propylene glycol, which can produce venous
mast cell histamine release in vitro, whereas oxyba- irritation.
rbiturates do not. For this reason, some anesthesiol-
ogists prefer induction agents other than thiopental
or thiamylal in asthmatic or atopic patients, but Pharmacokinetics
the evidence for this choice is sparse. There is no A. Absorption
question that airway instrumentation with light Benzodiazepines are commonly administered orally,
anesthesia is troublesome in patients with reactive intramuscularly, and intravenously to provide seda-
airways. tion or, less commonly, to induce general anesthe-
sia (Table 92). Diazepam and lorazepam are well
Drug Interactions absorbed from the gastrointestinal tract, with peak
Contrast media, sulfonamides, and other drugs that plasma levels usually achieved in 1 and 2 h, respec-
occupy the same protein-binding sites as thiopental tively. Oral midazolam has not been approved by the
may displace the barbiturate, increasing the amount U.S. Food and Drug Administration, nevertheless
of free drug available and potentiating the organ sys- this route of administration has been popular for
tem effects of a given dose. pediatric premedication. Likewise, intranasal (0.2
Ethanol, opioids, antihistamines, and other 0.3 mg/kg), buccal (0.07 mg/kg), and sublingual (0.1
central nervous system depressants potentiate the mg/kg) midazolam provide effective preoperative
sedative effects of barbiturates. The common clinical sedation.
180 SECTION II Clinical Pharmacology

Diazepam Lorazepam Flumazenil


CH3 N
O O COOC2H5
N N N
OH
N N N
Cl Cl F
CH3
Cl O

Midazolam

CH3 CH3 N
N

N N
pH < 6.0 CH2NH2
N O
Cl pH > 6.0 Cl C
F
F

(lipid-soluble) (water-soluble)

FIGURE 93 The structures of commonly used with permission, from White PF: Pharmacologic and clinical aspects of
benzodiazepines and their antagonist, umazenil, share preoperative medication. Anesth Analg 1986;65:963. With permission
a seven-member diazepine ring. (Modied and reproduced, from the International Anesthesia Research Society.)

Intramuscular injections of diazepam are pain- B. Distribution


ful and unreliably absorbed. In contrast, midazolam Diazepam is relatively lipid soluble and readily
and lorazepam are well absorbed after intramuscu- penetrates the bloodbrain barrier. Although mid-
lar injection, with peak levels achieved in 30 and azolam is water soluble at reduced pH, its imidaz-
90min, respectively. Induction of general anesthesia ole ring closes at physiological pH, increasing its
with midazolam is convenient only with intravenous lipid solubility (see Figure 93). The moderate lipid
administration. solubility of lorazepam accounts for its slower brain
uptake and onset of action. Redistribution is fairly
rapid for the benzodiazepines (the initial distribu-
tion half-life is 310 min) and, like the barbiturates,
TABLE 92 Uses and doses of commonly is responsible for awakening. Although midazolam
used benzodiazepines.
has been used as an induction agent, neither mid-
Agent Use Route1 Dose (mg/kg) azolam nor any other of the benzodiazepines can
Diazepam Premedication Oral 0.20.52 match the rapid onset and short duration of action
Sedation IV 0.040.2 of propofol or even thiopental. All three benzodiaz-
epines are highly protein bound (9098%).
Midazolam Premedication IM 0.070.15
Sedation IV 0.010.1 C. Biotransformation
Induction IV 0.10.4
The benzodiazepines rely on the liver for biotrans-
Lorazepam Premedication Oral 0.05 formation into water-soluble glucuronidated end
1
IV, intravenous; IM, intramuscular. products. The phase I metabolites of diazepam are
2
Maximum dose is 15 mg. pharmacologically active.
CHAPTER 9 Intravenous Anesthetics 181

Slow hepatic extraction and a large volume doses of diazepam and midazolam have resulted in
of distribution (Vd) result in a long elimination respiratory arrest. The steep doseresponse curve,
half-life for diazepam (30 h). Although lorazepam slightly prolonged onset (compared with propofol or
also has a low hepatic extraction ratio, its lower thiopental), and potency of midazolam necessitate
lipid solubility limits its Vd, resulting in a shorter careful titration to avoid overdosage and apnea.
elimination half-life (15 h). Nonetheless, the clini- Ventilation must be monitored in all patients receiv-
cal duration of lorazepam is often quite prolonged ing intravenous benzodiazepines, and resuscitation
due to increased receptor affinity. These differ- equipment must be immediately available.
ences between lorazepam and diazepam illustrate
the low utility of individual pharmacokinetic half- C. Cerebral
lives in guiding clinical practice. Midazolam shares Benzodiazepines reduce cerebral oxygen consump-
diazepams Vd, but its elimination half-life (2 h) is tion, cerebral blood flow, and intracranial pressure
the shortest of the group because of its increased but not to the extent the barbiturates do. They are
hepatic extraction ratio. effective in preventing and controlling grand mal
seizures. Oral sedative doses often produce ante-
D. Excretion grade amnesia, a useful premedication property.
The metabolites of benzodiazepine biotransforma- The mild muscle-relaxing property of these drugs
tion are excreted chiefly in the urine. Enterohepatic is mediated at the spinal cord level, not at the neu-
circulation produces a secondary peak in diazepam romuscular junction. The antianxiety, amnestic,
plasma concentration 612 h following administra- and sedative effects seen at lower doses progress
tion. Kidney failure may lead to prolonged seda- to stupor and unconsciousness at induction doses.
tion in patients receiving larger doses of midazolam Compared with propofol or thiopental, induction
due to the accumulation of a conjugated metabolite with benzodiazepines is associated with a slower
(-hydroxymidazolam). rate of loss of consciousness and a longer recovery.
Benzodiazepines have no direct analgesic properties.
Eects on Organ Systems
A. Cardiovascular Drug Interactions
The benzodiazepines display minimal cardiovascular Cimetidine binds to cytochrome P-450 and reduces
depressant effects even at general anesthetic doses, the metabolism of diazepam. Erythromycin inhib-
except when they are coadministered with opioids its metabolism of midazolam and causes a two- to
(these agents interact to produce myocardial depres- threefold prolongation and intensification of its
sion and arterial hypotension). Benzodiazepines effects. Heparin displaces diazepam from pro-
given alone decrease arterial blood pressure, cardiac tein-binding sites and increases the free drug
output, and peripheral vascular resistance slightly, concentration.
and sometimes increase heart rate. Intravenous mid- As previously mentioned, the combination
azolam tends to reduce blood pressure and peripheral of opioids and benzodiazepines markedly reduces
vascular resistance more than diazepam. Changes in arterial blood pressure and peripheral vascular resis-
heart rate variability during midazolam sedation sug- tance. This synergistic interaction has often been
gest decreased vagal tone (ie, drug-induced vagolysis). observed in patients with ischemic or valvular heart
disease who often receive benzodiazepines for pre-
B. Respiratory medication and during induction of anesthesia with
Benzodiazepines depress the ventilatory response to opioids.
CO2. This depression is usually insignificant unless Benzodiazepines reduce the minimum alveolar
the drugs are administered intravenously or in asso- concentration of volatile anesthetics as much as 30%.
ciation with other respiratory depressants. Although Ethanol, barbiturates, and other central nervous
apnea may be relatively uncommon after ben- system depressants potentiate the sedative effects of
3 zodiazepine induction, even small intravenous
the benzodiazepines.
182 SECTION II Clinical Pharmacology

KETAMINE of phencyclidines psychotomimetic effects. Ket-


amine is used for intravenous induction of anes-
Mechanisms of Action thesia, particularly in settings where its tendency
Ketamine has multiple effects throughout the cen- to produce sympathetic stimulation are useful
tral nervous system, inhibiting polysynaptic reflexes (hypovolemia, trauma). When intravenous access
in the spinal cord as well as excitatory neurotrans- is lacking, ketamine is useful for intramuscular
mitter effects in selected areas of the brain. In con- induction of general anesthesia in children and
trast to the depression of the reticular activating uncooperative adults. Ketamine can be combined
system induced by the barbiturates, ketamine func- with other agents (eg, propofol or midazolam) in
tionally dissociates the thalamus (which relays small bolus doses or infusions for deep conscious
sensory impulses from the reticular activating sys- sedation during nerve blocks, endoscopy, etc. Even
tem to the cerebral cortex) from the limbic cortex subanesthetic doses of ketamine may cause hallu-
(which is involved with the awareness of sensation). cinogenic effects but usually do not do so in clinical
Clinically, this state of dissociative anesthesia may practice, where many patients will have received
cause the patient to appear conscious (eg, eye open- at least a small dose of midazolam (or a related
ing, swallowing, muscle contracture) but unable to agent) for amnesia and sedation. The increased
process or respond to sensory input. Ketamine has anesthetic potency and decreased psychotomi-
been demonstrated to be an N-methyl-d-aspartate metic side effects of one isomer (S[+] versus R[])
(NMDA) receptor (a subtype of the glutamate recep- are the result of stereospecific receptors. The single
tor) antagonist. S(+) stereoisomer preparation is not available in
the United States (but widely available throughout
the world), and it has considerably greater affinity
StructureActivity Relationships than the racemic mixture for the NMDA receptor
Ketamine (Figure 94) is a structural ana- as well as several-fold greater potency as a general
logue of phencyclidine (an anesthetic that has anesthetic.
been used in veterinary medicine, and a drug of
abuse). It is one-tenth as potent, yet retains many Pharmacokinetics
A. Absorption
Ketamine has been administered orally, nasally, rec-
tally, subcutaneously, and epidurally, but in usual
Ketamine Phencyclidine clinical practice it is given intravenously or intra-
muscularly (Table 93). Peak plasma levels are usu-
O
ally achieved within 1015 min after intramuscular
injection.
Cl N
NHCH3
B. Distribution
Ketamine is more lipid soluble and less protein
Etomidate Propofol bound than thiopental. These characteristics,
O N
along with ketamine-induced increase in cere-
OH
CH3CH2OC bral blood flow and cardiac output, lead to rapid
N (CH3)2HC CH(CH3)2
brain uptake and subsequent redistribution (the
CH3CH distribution half-life is 1015 min). Awakening
is due to redistribution from brain to peripheral
compartments.

FIGURE 94 The structures of ketamine, etomidate, C. Biotransformation


and propofol. Note the similarities between ketamine and Ketamine is biotransformed in the liver to several
phencyclidine. metabolites, one of which (norketamine) retains
CHAPTER 9 Intravenous Anesthetics 183

TABLE 93 Uses and doses of ketamine, Eects on Organ Systems


etomidate, and propofol.
A. Cardiovascular
Agent Use Route1 Dose
4 In contrast to other anesthetic agents, ket-
Ketamine Induction IV 12 mg/kg amine increases arterial blood pressure, heart
IM 35 mg/kg rate, and cardiac output (Table 94), particularly
Sedation2 IV 2.515 mcg/kg/min after rapid bolus injections. These indirect cardio-
Etomidate Induction IV 0.20.5 mg/kg vascular effects are due to central stimulation of
the sympathetic nervous system and inhibition
Propofol Induction IV 12.5 mg/kg of the reuptake of norepinephrine after release
Maintenance IV 50200 mcg/kg/min
infusion at nerve terminals. Accompanying these changes
Sedation IV 25100 mcg/kg/min are increases in pulmonary artery pressure and
infusion myocardial work. For these reasons, large bolus
1
IV, intravenous; IM, intramuscular. injections of ketamine should be administered
2
Almost always in combination with propofol. cautiously in patients with coronary artery dis-
ease, uncontrolled hypertension, congestive heart
failure, or arterial aneurysms. The direct myocar-
dial depressant effects of large doses of ketamine,
anesthetic activity. Induction of hepatic enzymes probably due to inhibition of calcium transients,
only partially explains the tolerance that patients are unmasked by sympathetic blockade (eg, spinal
who receive multiple doses of ketamine will develop. cord transection) or exhaustion of catecholamine
Extensive hepatic uptake (hepatic extraction ratio of stores (eg, severe end-stage shock). On the other
0.9) explains ketamines relatively short elimination hand, ketamines indirect stimulatory effects may
half-life (2 h). be beneficial to patients with acute shock.
D. Excretion B. Respiratory
End products of ketamine biotransformation are Ventilatory drive is minimally affected by induction
excreted renally. doses of ketamine, although rapid intravenous bolus

TABLE 94 Summary of nonvolatile anesthetic eects on organ systems.1


Cardiovascular Respiratory Cerebral

Agent HR MAP Vent Bdil CBF CMRO2 ICP

Barbiturates
Thiopental
Thiamylal
Methohexital 0

Benzodiazepines
Diazepam 0/ 0
Lorazepam 0/ 0
Midazolam 0

Ketamine 2 2

Etomidate 0 0

Propofol 0 0
1
HR, heart rate; MAP, mean arterial pressure; Vent, ventilatory drive; Bdil, bronchodilation; CBF, cerebral blood ow; CMRO2, cerebral oxygen
consumption; ICP, intracranial pressure; 0, no eect; 0/, no change or mild increase; , decrease (mild, moderate, marked); , increase (mild,
moderate, marked).
2
Minimal change in CBF and ICP when coadministered with other agents (see text).
184 SECTION II Clinical Pharmacology

administration or combinations of ketamine with -Adrenergic and -adrenergic antagonists


opioids occasionally produce apnea. Racemic ket- (and other agents and techniques that diminish
amine is a potent bronchodilator, making it a good sympathetic stimulation) unmask the direct myo-
induction agent for asthmatic patients; however, cardial depressant effects of ketamine, which are
S(+) ketamine produces minimal bronchodilation. normally overwhelmed by sympathetic stimulation.
Upper airway reflexes remain largely intact, but par- Concurrent infusion of ketamine and propofol, often
tial airway obstruction may occur, and patients at in a fixed infusion rate ratio of 1:10, has achieved
increased risk for aspiration pneumonia (full stom- great popularity for sedation with local and regional
achs) should be intubated during ketamine general anesthesia, particularly in office-based settings.
anesthesia (see Case Discussion, Chapter 17). The
increased salivation associated with ketamine can be
attenuated by premedication with an anticholinergic
ETOMIDATE
agent such as glycopyrrolate Mechanisms of Action
C. Cerebral Etomidate depresses the reticular activating system
The received dogma about ketamine is that it and mimics the inhibitory effects of GABA. Specifi-
increases cerebral oxygen consumption, cerebral cally, etomidateparticularly the R(+) isomer
blood flow, and intracranial pressure. These effects appears to bind to a subunit of the GABAA receptor,
would seem to preclude its use in patients with increasing the receptors affinity for GABA. Unlike
space-occupying intracranial lesions such as occur barbiturates, etomidate may have disinhibitory
with head trauma; however, recent publications effects on the parts of the nervous system that
offer convincing evidence that when combined control extrapyramidal motor activity. This disinhi-
with a benzodiazepine (or another agent acting on bition offers a potential explanation for the 3060%
the same GABA receptor system) and controlled incidence of myoclonus with etomidate induction
ventilation, but not with nitrous oxide, ketamine ofanesthesia.
is not associated with increased intracranial pres-
sure. Myoclonic activity is associated with increased
StructureActivity Relationships
subcortical electrical activity, which is not apparent Etomidate contains a carboxylated imidazole and
on surface EEG. Undesirable psychotomimetic side is structurally unrelated to other anesthetic agents
effects (eg, disturbing dreams and delirium) dur- (see Figure 94). The imidazole ring provides water
ing emergence and recovery are less common in solubility in acidic solutions and lipid solubility at
children and in patients premedicated with benzo- physiological pH. Therefore etomidate is dissolved
diazepines or those in whom ketamine is combined in propylene glycol for injection. This solution often
with propofol in a TIVA technique. Of the nonvola- causes pain on injection that can be lessened by a
tile agents, ketamine comes closest to being a com- prior intravenous injection of lidocaine.
plete anesthetic as it induces analgesia, amnesia,
and unconsciousness. Pharmacokinetics
A. Absorption
Drug Interactions
Etomidate is available only for intravenous admin-
Ketamine interacts synergistically (more than addi- istration and is used primarily for induction of gen-
tive) with volatile anesthetics but in an additive eral anesthesia (see Table 93). It is sometimes used
way with propofol, benzodiazepines, and other for brief production of deep (unconscious) sedation
GABA-receptormediated agents. In animal experi- such as prior to placement of retrobulbar blocks.
ments nondepolarizing neuromuscular blocking
agents are minimally potentiated by ketamine (see B. Distribution
Chapter 11). Diazepam and midazolam attenuate Although it is highly protein bound, etomidate is
ketamines cardiostimulatory effects and diazepam characterized by a very rapid onset of action due to
prolongs ketamines elimination half-life. its great lipid solubility and large nonionized fraction
CHAPTER 9 Intravenous Anesthetics 185

at physiological pH. Redistribution is responsible for in the intensive care unit (ICU) before reports of
decreasing the plasma concentration to awakening its consistent ability to produce adrenocortical
levels. Etomidate plasma kinetics are well explained suppression in that circumstance appeared. Long-
by a two-compartment model. term infusion and adrenocortical suppression
wereassociated with an increased mortality rate in
C. Biotransformation critically ill (particularly septic) patients.
Hepatic microsomal enzymes and plasma esterases
rapidly hydrolyze etomidate to an inactive metabolite. Drug Interactions
D. Excretion Fentanyl increases the plasma level and prolongs
the elimination half-life of etomidate. Opioids
The end products of etomidate hydrolysis are pri-
decrease the myoclonus characteristic of an etomi-
marily excreted in the urine.
date induction.
Eects on Organ Systems
A. Cardiovascular
PROPOFOL
Etomidate has minimal effects on the cardiovascu- Mechanisms of Action
lar system. A mild reduction in peripheral vascular Propofol induction of general anesthesia may
resistance is responsible for a slight decline in arterial involve facilitation of inhibitory neurotransmission
blood pressure. Myocardial contractility and cardiac mediated by GABAA receptor binding. Propofol allo-
output are usually unchanged. Etomidate does not sterically increases binding affinity of GABA for the
release histamine. However, etomidate by itself, even GABAA receptor. This receptor, as previously noted,
in large doses, produces relatively light anesthesia is coupled to a chloride channel, and activation of
for laryngoscopy, and marked increases in heart rate the receptor leads to hyperpolarization of the nerve
and blood pressure may be recorded when etomidate membrane. Propofol (like most general anesthetics)
provides the only anesthetic depth for intubation. binds multiple ion channels and receptors. Propofol
actions are not reversed by the specific benzodiaz-
B. Respiratory epine antagonist flumazenil.
Ventilation is affected less with etomidate than with
barbiturates or benzodiazepines. Even induction StructureActivity Relationships
doses usually do not result in apnea unless opioids
Propofol consists of a phenol ring substituted with
have also been administered.
two isopropyl groups (see Figure 94). Propofol is
C. Cerebral not water soluble, but a 1% aqueous solution (10
Etomidate decreases cerebral metabolic rate, cere- mg/mL) is available for intravenous administration
bral blood flow, and intracranial pressure. Because as an oil-in-water emulsion containing soybean oil,
of minimal cardiovascular effects, CPP is well main- glycerol, and egg lecithin. A history of egg allergy
tained. Although changes on EEG resemble those does not necessarily contraindicate the use of pro-
associated with barbiturates, etomidate increases pofol because most egg allergies involve a reaction
the amplitude of somatosensory evoked potentials. to egg white (egg albumin), whereas egg lecithin
Postoperative nausea and vomiting are more com- is extracted from egg yolk. This formulation will
mon following etomidate than following propofol often cause pain during injection that can be
or barbiturate induction. Etomidate lacks analgesic decreased by prior injection of lidocaine or less
properties. effectively bymixing lidocaine with propofol prior
to injection(2mL of 1% lidocaine in 18 mL propo-
D. Endocrine
6 fol). Propofol formulations can support the
5 Induction doses of etomidate transiently growth of bacteria, so sterile technique must
inhibit enzymes involved in cortisol and aldo- be observed in preparation and handling. Propofol
sterone synthesis. It was used in the past for sedation should be administered within 6 h of opening the
186 SECTION II Clinical Pharmacology

ampule. Sepsis and death have been linked to con- neurosurgical patients has been associated with spo-
taminated propofol preparations. Current formula- radic cases of lipemia, metabolic acidosis, and death,
tions of propofol contain 0.005% disodium edetate the so-termed propofol infusion syndrome.
or 0.025% sodium metabisulfite to help retard the
rate of growth of microorganisms; however, these D. Excretion
additives do not render the product antimicrobi- Although metabolites of propofol are primarily
ally preserved under United States Pharmacopeia excreted in the urine, chronic kidney failure does
standards. not affect clearance of the parent drug.

Pharmacokinetics Eects on Organ Systems


A. Absorption A. Cardiovascular
Propofol is available only for intravenous adminis- The major cardiovascular effect of propofol is a
tration for the induction of general anesthesia and decrease in arterial blood pressure due to a drop in
for moderate to deep sedation (see Table 93). systemic vascular resistance (inhibition of sympathetic
vasoconstrictor activity), preload, and cardiac con-
B. Distribution tractility. Hypotension following induction is usually
Propofol has a rapid onset of action. Awakening reversed by the stimulation accompanying laryngos-
from a single bolus dose is also rapid due to a very copy and intubation. Factors associated with propo-
short initial distribution half-life (28 min). Most fol-induced hypotension include large doses, rapid
investigators believe that recovery from propofol is injection, and old age. Propofol markedly impairs the
more rapid and is accompanied by less hangover normal arterial baroreflex response to hypotension.
than recovery from methohexital, thiopental, ket- Rarely, a marked drop in preload may lead to a vagally
amine, or etomidate. This makes it a good agent for mediated reflex bradycardia. Changes in heart rate and
outpatient anesthesia. A smaller induction dose is cardiac output are usually transient and insignificant
recommended in elderly patients because of their in healthy patients but may be severe in patients at the
smaller Vd. Age is also a key factor determining extremes of age, those receiving -adrenergic blockers,
required propofol infusion rates for TIVA. In coun- or those with impaired ventricular function. Although
tries other than the United States, a device called myocardial oxygen consumption and coronary blood
the Diprifusor is often used to provide target (con- flow usually decrease comparably, coronary sinus lac-
centration) controlled infusion of propofol. The tate production increases in some patients, indicating
user must enter the patients age and weight and some mismatch between myocardial oxygen supply
the desired target concentration. The device uses and demand.
these data, a microcomputer, and standard phar-
macokinetic parameters to continuously adjust the B. Respiratory
infusion rate. Propofol is a profound respiratory depressant that
usually causes apnea following an induction dose.
C. Biotransformation Even when used for conscious sedation in sub-
The clearance of propofol exceeds hepatic blood anesthetic doses, propofol inhibits hypoxic venti-
flow, implying the existence of extrahepatic metabo- latory drive and depresses the normal response to
lism. This exceptionally high clearance rate probably hypercarbia. As a result, only properly educated and
contributes to relatively rapid recovery after con- qualified personnel should administer propofol for
tinuous infusions. Conjugation in the liver results sedation. Propofol-induced depression of upper
in inactive metabolites that are eliminated by renal airway reflexes exceeds that of thiopental, allowing
clearance. The pharmacokinetics of propofol do not intubation, endoscopy, or laryngeal mask placement
appear to be affected by obesity, cirrhosis, or kidney in the absence of neuromuscular blockade. Although
failure. Use of propofol infusion for long-term seda- propofol can cause histamine release, induction with
tion of children who are critically ill or young adult propofol is accompanied by a lower incidence of
CHAPTER 9 Intravenous Anesthetics 187

wheezing in asthmatic and nonasthmatic patients slower recovery than propofol, offering little reason
compared with barbiturates or etomidate. for anesthesiologists to use fospropofol in place of
propofol. The place (if any) of fospropofol relative to
C. Cerebral other competing agents has not yet been established
Propofol decreases cerebral blood flow and intracra- in clinical practice.
nial pressure. In patients with elevated intracranial
pressure, propofol can cause a critical reduction in
CPP (<50 mm Hg) unless steps are taken to support CASE DISCUSSION
mean arterial blood pressure. Propofol and thiopen-
tal probably provide a similar degree of cerebral pro- Premedication of the Surgical Patient
tection during experimental focal ischemia. Unique An extremely anxious 17-year-old woman pres-
to propofol are its antipruritic properties. Its anti- ents for dilation and curettage. She demands to
emetic effects (requiring a blood propofol concen- be asleep before going to the operating room
tration of 200 ng/mL) provide yet another reason for and does not want to remember anything.
it to be a preferred drug for outpatient anesthesia.
Induction is occasionally accompanied by excitatory What are the goals of administering
phenomena such as muscle twitching, spontaneous preoperative medication?
movement, opisthotonus, or hiccupping. Although Anxiety is a normal response to impending sur-
these reactions may occasionally mimic tonicclonic gery. Diminishing anxiety is usually the major goal
seizures, propofol has anticonvulsant properties and of preoperative medication. For many patients, the
has been used successfully to terminate status epi- preoperative interview with the anesthesiologist
lepticus. Propofol may be safely administered to allays fears more eectively than sedative drugs.
epileptic patients. Propofol decreases intraocular Preoperative medication may also provide relief of
pressure. Tolerance does not develop after long-term preoperative pain or perioperative amnesia.
propofol infusions. Propofol is an uncommon agent There may also be specic medical indications
of physical dependence or addiction; however, both for preoperative medication: prophylaxis against
anesthesia personnel and medically untrained indi- postoperative nausea and vomiting (5-HT3s) and
viduals have died while using propofol inappropri- against aspiration pneumonia (eg, antacids), pre-
ately to induce sleep in nonsurgical settings. vention of allergic reactions (eg, antihistamines),
or decreasing upper airway secretions (eg, anticho-
Drug Interactions linergics). The goals of preoperative medication
Fentanyl and alfentanil concentrations may be depend on many factors, including the health and
increased with concomitant administration of pro- emotional status of the patient, the proposed sur-
pofol. Many clinicians administer a small amount of gical procedure, and the anesthetic plan. For this
midazolam (eg, 30 mcg/kg) prior to induction with reason, the choice of anesthetic premedication
propofol; midazolam can reduce the required pro- must be individualized and must follow a thorough
pofol dose by more than 10%. preoperative evaluation.

Do all patients require preoperative medication?

FOSPROPOFOL Nocustomary levels of preoperative anxiety


do not harm most patients. Some patients dread
Fospropofol is a water-soluble prodrug that is
intramuscular injections, and others nd altered
metabolized in vivo to propofol, phosphate, and
states of consciousness more unpleasant than
formaldehyde. It has been released in the United
nervousness. If the surgical procedure is brief, the
States and other countries based on studies show-
eects of some sedatives may extend into the post-
ing that it produces more complete amnesia and
operative period and prolong recovery time. This is
better conscioussedation for endoscopy than mid-
particularly troublesome for patients undergoing
azolam plus fentanyl. It has a slower onset and
188 SECTION II Clinical Pharmacology

ambulatory surgery. Specic contraindications for lorazepam are available orally. Intramuscular mid-
sedative premedication include severe lung dis- azolam has a rapid onset (30 min) and short dura-
ease, hypovolemia, impending airway obstruction, tion (90 min), but intravenous midazolam has an
increased intracranial pressure, and depressed even better pharmacokinetic prole.
baseline mental status. Premedication with sedative Which factors must be considered in selecting
drugs should never be given before informed con- the anesthetic premedication for this patient?
sent has been obtained.
First, it must be made clear to the patient that
Which patients are most likely to benet
in most centers, lack of necessary equipment and
from preoperative medication?
concern for patient safety preclude anesthesia
Some patients are quite anxious despite the being induced in the preoperative holding room.
preoperative interview. Separation of young chil- Long-acting agents such as morphine or loraz-
dren from their parents is often a traumatic ordeal, epam are poor choices for an outpatient proce-
particularly if they have endured multiple prior sur- dure. Diazepam can also aect mental function
geries. Medical conditions such as coronary artery for several hours. One alternative is to establish an
disease or hypertension may be aggravated by intravenous line in the preoperative holding area
psychological stress. and titrate small doses of midazolam using slurred
How does preoperative medication inuence speech as an end point. At that time, the patient
the induction of general anesthesia? can be taken to the operating room. Vital signs
particularly respiratory ratemust be continu-
Some medications often given preoperatively
ously monitored.
(eg, opioids) decrease anesthetic requirements
and can smooth induction. However, intravenous
administration of these medications just prior to
induction is a more reliable method of achieving
the same benets.
SUGGESTED READING
Domino EF: Taming the ketamine tiger. Anesthesiology
What governs the choice among the preoperative 2010;113:678.
medications commonly administered? Garnock-Jones KP, Scott LJ: Fospropofol. Drugs
After the goals of premedication have been 2010;70:469.
determined, the clinical eects of the agents dic- Jensen LS, Merry AF, Webster CS, et al: Evidence-based
strategies for preventing drug administration errors
tate choice. For instance, in a patient experiencing
during anaesthesia. Anaesthesia 2004;59:493.
preoperative pain from a femoral fracture, the anal-
Leslie K, Clavisi O, Hargrove J: Target-controlled infusion
gesic eects of an opioid (eg, fentanyl, morphine, versus manually-controlled infusion of propofol for
hydromorphone) will decrease the discomfort general anaesthesia or sedation in adults. Cochrane
associated with transportation to the operating Database Syst Rev 2008;(3):CD006059.
room and positioning on the operating room table. Raeder J: Ketamine, revival of a versatile intravenous
On the other hand, respiratory depression, ortho- anaesthetic. Adv Exp Med Biol 2003;523:269.
static hypotension, and nausea and vomiting may Short TG, Young R: Toxicity of intravenous anaesthetics.
result from opioid premedication. Best Pract Res Clin Anaesthesiol 2003;17:77.
Benzodiazepines relieve anxiety, often pro- Vanlersberghe C, Camu F: Etomidate and other non-
vide amnesia, and are relatively free of side eects; barbiturates. Handb Exp Pharmacol 2008;(182):267.
Vanlersberghe C, Camu F: Propofol. Handb Exp
however, they are not analgesics. Diazepam and
Pharmacol 2008;(182):227.