72 SEDATIVE–HYPNOTICS
Payal Sud and David C. Lee
HISTORY AND EPIDEMIOLOGY
Sedative–hypnotics are xenobiotics that limit excitability (sedation) and or
induce drowsiness and sleep (hypnosis). Anxiolytics (formerly known as
minor tranquilizers) are medications prescribed for their sedative–hypnotic
properties. Mythology of ancient cultures is replete with stories of xenobiotics
that cause sleep or unconsciousness (Chap. 1). Sedative–hypnotic overdoses
were described in the medical literature soon after the commercial intro-
duction of bromide preparations in 1853. Other commercial xenobiotics that
subsequently were developed include chloral hydrate, paraldehyde, sulfo-
nyl, and urethane.
Barbiturates were introduced in 1903 and quickly supplanted older xeno-
biotics. Barbiturates dominated the sedative–hypnotic market for the first
half of the 20th century. Because of their narrow therapeutic index and sub-
stantial potential for abuse, they quickly became a major health problem. By
the 1950s, barbiturates were frequently implicated in overdoses and were
responsible for the majority of drug-related suicides. As fatalities from bar-
biturates increased, attention shifted toward preventing their abuse and
finding less toxic alternatives.19 After their introduction in the early 1960s,
benzodiazepines quickly became the most commonly used sedatives in the
United States.
Intentional and unintentional overdoses with sedative–hypnotics occur
frequently. According to the American Association of Poison Control Centers,
sedative–hypnotics is consistently one of the top five classes of xenobiotics
associated with overdose fatalities (Chap. 130). With the ubiquitous world-
wide use of sedative–hypnotics, they may be associated with a substan-
tially higher number of overdoses and deaths than are officially reported.
Compared with barbiturate overdoses, overdoses of benzodiazepines alone
account for relatively few deaths.29,36,43 Most deaths associated with benzodi-
azepines result from mixed overdoses with other respiratory depressants.36,112
Chlordiazepoxide, the first commercially available benzodiazepine, was
initially marketed in 1960. Since then, more than 50 benzodiazepines have
been marketed, and more are being developed. Although the benzodiazepines
remain the most popular prescribed anxiolytics, several benzodiazepine-
receptor agonists were developed in 1989 in an attempt to circumvent some
of the side effects of benzodiazepines. These drugs include zolpidem, as
zaleplon, zopiclone, and eszopiclone.6,107 Newer formulations of zolpidem
tartrate such as Intermezzo are now available, which is a low-dose sublingual
tablet form (1.75 mg and 3.5 mg compared with 5 mg and 10 mg). Ramelteon
and tasimelteon are newer sleep aids that function as melatonin receptor
(MT1 and MT2) agonists rather than benzodiazepine-receptor agonists.112,134
Dexmedetomidine, a central α2-adrenergic agonist, is now increasingly used
in the hospital setting for short-term sedation.143 An additional medication
is suvorexant, a dual orexin receptor antagonist that inhibits the action of
orexin, a neuropeptide that promotes wakefulness.30
This chapter focuses primarily on pharmaceuticals prescribed for their
sedative–hypnotic effects, many of which interact with the γ-aminobutyric
acid-A (GABAA) receptor (Table 72–1). Specific sedative–hypnotics such as
ethanol and γ-hydroxybutyric acid (GHB) are discussed in more depth in
their respective chapters (Chaps. 76 and 80).
PHARMACODYNAMICS AND TOXICODYNAMICS
All sedative–hypnotics induce central nervous system (CNS) depression.
Most clinically effective sedative–hypnotics produce their physiologic effects
by enhancing the function of GABA-mediated chloride channels via agonism
at the GABAA receptor. These receptors are the primary mediators of inhibi-
tory neurotransmission in the brain (Chap. 13). The GABAA receptor is a
1084
pentameric structure composed of varying polypeptide subunits associated
with a chloride on the postsynaptic membrane. These subunits are classified
into families (eg, α, β, γ). Variations in the five subunits of the GABA receptor
confer drug selectivity and clinical effects such as sedation, anxiolysis, hypnosis,
amnesia, and muscle relaxation.133 The most common GABAA receptor in
the brain is composed of α1β2γ2 subunits. Almost all sedative–hypnotics
bind to GABAA receptors containing the α1 subunit. One exception may be
etomidate, which produces sedation at the β2 unit and anesthesia at the
β3 subunit.24,94 Benzodiazepines are effective only at GABAA receptors with
the γ2 subunit. Even within classes of sedative–hypnotics, there are varying
affinities and actions for differing subunits of the GABA receptor.33,78 The α1
subunit is responsible for sedation and amnesia, the α2 subunit is respon-
sible for anxiolysis, and the α4 and α6 subunits are completely insensitive to
benzodiazepines. Nonbenzodiazepine sedative–hypnotics such as zolpidem,
zaleplon, and zopiclone selectively bind the α1 subunit and thus cause pri-
marily sedation and not anxiolysis at therapeutic doses.
The role of GABA receptors in the peripheral nervous system has
been increasingly recognized, especially in the gastrointestinal (GI) tract.
γ-Aminobutyric acid agonism is involved in modulation of GI visceral
pain processing.7 Furthermore, GABAB agonism by baclofen was found to
reduce duodenal ulcer formation.64
Many sedative–hypnotics also act at receptors other than the GABAA
receptor. Trichloroethanol and propofol also inhibit glutamate-mediated
N-methyl-d-aspartate (NMDA) receptors, thereby inhibiting excitatory
neurotransmission.26,102,121 Certain benzodiazepines inhibit adenosine
metabolism and reuptake, thereby potentiating both A1-adenosine (negative
dromotropy) and A2-adenosine (coronary vasodilation) receptor-mediated
effects.90,131 Benzodiazepines can also interact with serotonergic pathways.
The anxiolytic effects of clonazepam can be partially explained by upregula-
tion of serotonergic receptors, specifically 5-HT1 and 5-HT2.9 Sleep aids such
as melatonin, ramelteon, and tasimelteon are agonists at melatonin receptor
subtypes MT1 and MT2 in the suprachiasmatic nucleus of the brain.116,134,140,146
Dexmedetomidine is a central α2-adrenergic agonist similar to clonidine.143
PHARMACOKINETICS AND TOXICOKINETICS
Most orally administered sedative–hypnotics are rapidly absorbed via the GI
tract, with the rate-limiting step consisting of dissolution and dispersion of
the xenobiotic. Barbiturates and benzodiazepines are primarily absorbed in
the small intestine. Clinical effects are determined by their relative ability to
penetrate the blood–brain barrier. Xenobiotics that are highly lipophilic pen-
etrate most rapidly. The ultrashort-acting barbiturates are clinically active in
the most vascular parts of the brain (gray matter first), with sleep occurring
within 30 seconds of administration. Table 72–1 lists individual sedative–
hypnotics and some of their pharmacokinetic properties.
After initial distribution, many of the sedative–hypnotics undergo a
redistribution phase as they are dispersed to other body tissues, specifically
adipose tissue. Xenobiotics that are extensively redistributed, such as the
lipophilic (ultrashort-acting) barbiturates, have a brief clinical effect as the
early peak concentrations in the brain rapidly decline.
Many of the sedative–hypnotics are metabolized to pharmacologi-
cally active intermediates. This is particularly true for chloral hydrate and
some of the benzodiazepines. The benzodiazepines can be demethylated,
hydroxylated, or conjugated with glucuronide in the liver. Glucuronidation
results in the production of inactive metabolites. Benzodiazepines such as
diazepam and chlordiazepoxide are demethylated, which produces active
intermediates with a more prolonged half-lives than the parent compound
 CHAPTER 72 • SEDATIVE–HYPNOTICS 1085

TABLE 72–1 Sedative-Hypnotics: Duration of Action and Active Metabolites and benzodiazepines increase the frequency of ionophore opening.135
Various sedative–hypnotics increase the affinity of another xenobiotic at
Active Metabolite
its respective binding site. For example, pentobarbital increases the affinity of
Duration of Actiona Important
γ-hydroxybutyric acid (GHB) for its non–GABA binding site.137 Propofol poten-
Benzodiazepines tiates the effect of pentobarbital on chloride influx at the GABAA receptor.111
Propofol also increases the affinity and decreases the rate of dissociation of
Alprazolam S No
benzodiazepines from their site on the GABAA receptor.18,150 These actions
Chlordiazepoxide I Yes increase the clinical effect of each xenobiotic and lead to deeper CNS and
Clonazepam L Yes respiratory depression when they are used concomitantly.
Clorazepate L Yes Another mechanism of synergistic toxicity occurs via alteration of
Diazepam Single dose: S Yes metabolism. The combination of ethanol and chloral hydrate, historically
Multiple doses: L known as a “Mickey Finn,” has synergistic CNS depressant effects. Chloral
Estazolam I No hydrate competes for alcohol and aldehyde dehydrogenases, thereby prolong-
Flunitrazepam L Yes ing the half-life of ethanol. The metabolism of ethanol generates the reduced
Flurazepam L Yes form of nicotinamide adenine dinucleotide (NADH), which is a cofactor for
Lorazepam I No the metabolism of choral hydrate to trichloroethanol, an active metabolite.
Midazolam S Yes Finally, ethanol inhibits the conjugation of trichloroethanol, which in turn
Oxazepam I No inhibits the oxidation of ethanol (Fig. 72–1).1,80,128,129 The end result of these
Temazepam I No synergistic pharmacokinetic interactions is enhanced CNS depression.
Triazolam S No Multiple drug–drug interactions prolong the half-life of sedative–
Eszopiclone S No hypnotics and significantly increase their potency or duration of action
(Chap. 9). The half-life of midazolam, which undergoes hepatic metabo-
Zaleplon S No
lism via cytochrome CYP3A4, can change dramatically in the presence of
Zolpidem S No
Barbiturates
Trichloroacetic Cl OH
Amobarbital I Yes
Butabarbital I Unknown acid Cl C C
Mephobarbital S Yes Cl O
Methohexital S No
Pentobarbital Single dose: S No
Multiple doses: I P450
Phenobarbital L No
Primidone I Yes Cl H
Secobarbital I Unknown Chloral
Cl C C OH
hydrate
Other
Cl OH
Chloral hydrate I Yes
ADH H OH
Dexmedetomidine S No
Cl H – Ethanol NADH
H C C
Etomidate US Unclear
Propofol US No Cl C C H NAD+ ADH and H O
Ramelteon S Yes ALDH
Cl OH – Acetic acid
Tasimelteon S No
Trichloroethanol H H
Suvorexant I No
a ADH and H C C H
The duration of action usually approximates the half-life (t½); some lipophilic xenobiotics have a short
duration of action with a single dose because of redistribution from the central nervous system but with ALDH H OH
multiple doses become longer acting. – Ethanol
I = intermediate acting t½ = 6–24 h; L = long acting t½ >24 h (a long-acting metabolite may contrib- Cl OH
ute to a long duration of action); S = short acting t½ <6 h; US = ultrashort acting t½ <1 h.
Cl C C Glucuronic acid
(Table 72-1). Because of the individual pharmacokinetics of sedative– Cl O
COOH Cl
hypnotics and the production of active metabolites, there is often little Trichloroacetic
correlation between the duration of effect and biologic half-lives. acid O O CH2 C Cl
Most sedative–hypnotics, such as the highly lipid-soluble barbiturates OH Cl
and the benzodiazepines, are highly protein bound. These drugs are
OH
poorly filtered by the kidneys. Elimination occurs principally by hepatic
metabolism. Chloral hydrate and meprobamate are notable exceptions. Urochloralic acid OH
Xenobiotics with a low lipophilicity and limited protein binding are more (renal elimination)
subject to renal excretion. FIGURE 72–1. Metabolism of chloral hydrate and ethanol demonstrating
Overdoses as well concomitant therapeutic usage of combinations of the interactions between chloral hydrate and ethanol metabolism. Note the
inhibitory effects (dotted lines) of ethanol on trichloroethanol metabolism
sedative–hypnotics enhance toxicity through additive and synergistic effects. and the converse. ADH = alcohol dehydrogenase; ALDH = aldehyde
For example, both barbiturates and benzodiazepines act on the GABAA dehydrogenase; NAD+= Nicotinamide adenine dinucleotide; NADH =
receptor, but barbiturates prolong the opening of the chloride ionophore, nicotinamide adenine dinucleotide.
1086 PART C • THE CLINICAL BASIS OF MEDICAL TOXICOLOGY
certain xenobiotics that compete for its metabolism or that induce or inhibit
CYP3A4 (Table 11–2).96,153 For example, the half-life of midazolam rises
400-fold when coadministered with itraconazole.8,136
TOLERANCE AND WITHDRAWAL
Ingestions of typical doses of sedative–hypnotics have less predictable effects
in patients who chronically use them. This is due to tolerance, defined as the
progressive diminution of effect of a particular drug with repeated admin-
istrations that results in a need for greater doses to achieve the same effect.
Tolerance occurs when adaptive neural and receptor changes (plasticity)
occur after repeated exposures. These changes include a decrease in the
number of receptors (downregulation), reduction of firing of receptors (receptor
desensitization), structural changes in receptors (receptor shift), or reduc-
tion of coupling of sedative–hypnotics and their respective GABAA-related
receptor site (Chap. 14). Tolerance can also be secondary to pharmacokinetic
factors, such as increased metabolism after repetitive doses. However, in
most cases, tolerance to sedative–hypnotics is caused by pharmacodynamic
changes such as receptor downregulation.136
Cross-tolerance readily exists among the sedative–hypnotics. For
example, chronic use of benzodiazepines not only decreases the activity of
the benzodiazepine site on the GABA receptor but also decreases the bind-
ing affinity of the barbiturate sites.2,54 Many sedative–hypnotics are also
associated with drug dependence after chronic exposure. Some of these—
classically, the barbiturates, benzodiazepines, and ethanol—are also associ-
ated with life-threatening withdrawal syndromes.
CLINICAL MANIFESTATIONS
Patients with sedative–hypnotic overdoses exhibit slurred speech, ataxia,
and incoordination. Larger doses result in stupor or coma. In most instances,
respiratory depression parallels CNS depression. However, not all sedative–
hypnotics cause significant hypoventilation. Although oral overdoses of
benzodiazepines alone produce sedation and hypnosis, they rarely produce
life-threatening hypoventilation. Typically, the patient appears comatose but
with normal vital signs. In contrast, large intravenous (IV) doses of benzodi-
azepines occasionally lead to potentially life-threatening respiratory depression.
Single overdoses of zolpidem and its congeners do not typically cause life-
threatening respiratory depression in adults.127,162
Although the physical examination is rarely specific for a particular
sedative–hypnotic, it can sometimes offer clues of exposure based on certain
physical and clinical findings (Table 72–2). Hypothermia is described with
most of the sedative–hypnotics but is more pronounced with barbiturates.55,119
TABLE 72–2 Clinical Findings of Sedative–Hypnotic Overdose
Clinical Signs Sedative–Hypnotics
Acneiform rash Bromides
Cardiotoxicity
Hypotension from myocardial depression Meprobamate
Dysrhythmias Chloral hydrate
Coma (fluctuating) Glutethimide, meprobamate
GI hemorrhage Chloral hydrate
Hypothermia Barbiturates, bromides, ethchlorvynol
Muscular twitching γ-Hydroxybutyric acid, γ-butyrolactone,
1,4-butanediol, γ-valerolactone, propofol,
etomidate
Odors (Unique) Chloral hydrate (pear), ethchlorvynol
(new vinyl shower curtain)
Urine (discolored) Propofol (green/pink)
GI = gastrointestinal.
Fixed drug eruptions that are often bullous can appear over pressure-point
areas. Although classically referred to as “barbiturate blisters,” this phenom-
enon is not specific to barbiturates because other CNS xenobiotics, including
carbon monoxide, methadone, imipramine, benzodiazepines, and several
others, can lead to the same finding.
Large single doses or prolonged duration of IV dosing of sedative–
hypnotics can also cause toxicities due to their diluents. Propylene glycol
accumulates with prolonged infusions of certain medications such as
lorazepam. Rapid infusions of propylene glycol induce hypotension.
Accumulated amounts of propylene glycol lead to metabolic acidosis and
a hyperosmolar state with elevated lactate concentrations.101,110,152,154 In one
study, two-thirds of critical care patients given high doses of lorazepam
(0.16 mg/kg/h) for more than 48 hours had significant accumulations of pro-
pylene glycol as manifested by hyperosmolarity and an anion gap metabolic
acidosis5 (Chap. 46).
DIAGNOSTIC TESTING
When overdose is a primary concern in an undifferentiated comatose
patient without a clear history, laboratory testing is useful to exclude meta-
bolic abnormalities. This includes electrolytes, liver function tests, thyroid
function tests, blood urea nitrogen, creatinine, glucose, venous blood gas
analysis, and cerebrospinal fluid analysis as clinically indicated. With any
suspected intentional overdose, a serum acetaminophen concentration
should be obtained. Diagnostic imaging studies, such as neuroimaging of the
head, are warranted on a case-by-case basis.
Routine laboratory screening for “drugs of abuse” generally is not helpful
in the management of undifferentiated comatose adult patients. However,
screening may be useful for epidemiologic purposes in a particular com-
munity or in psychiatric patients. These tests vary in type, sensitivity, and
specificity. Furthermore, many sedative–hypnotics are not included on
standard screening tests for drugs of abuse. For example, a typical benzo-
diazepine urine screen identifies metabolites of 1,4-benzodiazepines, such
as oxazepam or nordiazepam (desmethyldiazepam). Many benzodiazepines,
including the commonly used lorazepam and clonazepam, are metabolized
to alternative compounds and remain undetected, thus exhibiting a false-
negative result on the benzodiazepine-screening assay. Alprazolam and
triazolam are not detected because they undergo minimal metabolism.34
Specific concentrations of xenobiotics such as ethanol or phenobarbi-
tal, although readily available at most hospitals, are rarely crucial in clinical
decision making. Concentrations of most other sedative–hypnotics are not
routinely performed in hospital laboratories. Because of its radiopacity, large
ingestions of chloral hydrate are evident on abdominal radiography (Chap. 8).
Although immediate identification of a particular sedative–hypnotic may
be helpful in predicting the length of toxicity, it rarely affects the acute
management of the patient. One exception is phenobarbital, for which uri-
nary alkalinization and multiple-dose activated charcoal (MDAC) enhance
elimination.38,73,106,117 The EXtracorporeal TReatments in Poisoning (EXTRIP)
workgroup recommends intermittent hemodialysis for severe barbiturate
poisoning, and hemoperfusion and continuous renal replacement therapy
are viable alternatives.74
MANAGEMENT
Death secondary to sedative–hypnotic overdose usually results from cardiore-
spiratory collapse. Careful attention should focus on monitoring and maintain-
ing adequate airway, oxygenation, and hemodynamic support. Supplemental
oxygen, respiratory support, and prevention of aspiration are the cornerstones
of treatment. Hemodynamic instability should be treated initially with volume
expansion. With proper supportive care and adequate airway and respiratory
support as needed, patients with sedative–hypnotic overdoses should eventu-
ally recover. Patients with meprobamate and chloral hydrate overdoses occa-
sionally present with both respiratory depression and cardiac toxicity. In 40%
of cases, meprobamate toxicity was found to be associated with myocardial
depression and significant hypotension, often resistant to IV fluid resuscita-
tion.21 The cardiotoxic effects of chloral hydrate include lethal ventricular

dysrhythmias resulting from its active halogenated metabolite trichloroetha-
nol causing myocardial sensitization to catecholamines. In the setting of car-
diac dysrhythmias from chloral hydrate, use of β-adrenergic antagonists such
as propranolol is reported to cause resolution of the dysrhythmia.15,17,166,175 We
recommend administering IV β-adrenergic antagonists in patients with chlo-
ral hydrate–induced dysrhythmias resistant to standard therapy.
The use of GI decontamination should be decided on a case-by-case
basis. The benefits of activated charcoal (AC) must be balanced with the
risks of its aspiration and subsequent potential for pulmonary toxicity. The
use of AC should be determined based on the current mental status of the
patient, the potential for further deterioration, the xenobiotic(s) ingested,
and the expected clinical course. Phenobarbital overdose is one particu-
lar scenario in which MDAC increases elimination by 50% to 80%.10,11,14 In a
prospective study of 10 comatose patients after phenobarbital overdose, the
serum half-life of phenobarbital was significantly decreased after multiple
dose activated charcoal (MDAC) administration (36 ± 13 hours) compared
with the group treated with single dose activated charcoal (SDAC) (93 ± 52
hours) (Antidotes in Depth: A1).105
Although the efficacy of orogastric lavage is controversial, orogastric
lavage is reasonable in overdoses with xenobiotics that slow GI motility
or that are known to develop concretions, specifically phenobarbital and
meprobamate.21,59,125 Orogastric lavage in the setting of oral benzodiaz-
epine overdoses alone is not recommended because the benefits of lavage
are minimal compared with the significant risks of aspiration (Chap. 5). No
antidote counteracts all sedative–hypnotic overdoses. Flumazenil, a com-
petitive benzodiazepine antagonist, rapidly reverses the sedative effects of
benzodiazepines as well as zolpidem and its congeners.71,123,165,172 However,
flumazenil can precipitate life-threatening benzodiazepine withdrawal in
benzodiazepine-dependent patients. Flumazenil use is also associated with
seizures, especially in patients who have overdosed on tricyclic antide-
pressants (Antidotes in Depth: A25).56,139 Because the lethality of sedative–
hypnotics is associated with their ability to cause respiratory depression,
asymptomatic patients can be downgraded to a lower level of care after a
period of observation when there are no signs of respiratory depression.
The exact length of the observation period will vary based on the patient’s
clinical presentation, age, and the type and amount of xenobiotic(s) ingested.
Patients with symptomatic overdoses of long-acting sedative–hypnotics,
such as meprobamate and clonazepam, or drugs that have significant
enterohepatic circulation may require 24 hours of observation in the inten-
sive care unit. Patients with mixed overdoses of various sedative–hypnotics
and CNS depressants also warrant closer observation for respiratory depres-
sion because of synergistic respiratory depressant effects.
SPECIFIC SEDATIVE–HYPNOTICS
Barbiturates
X O
N Y
O anxiety in 1961 and diazepam for seizures in 1963. Benzodiazepines are used
N Z
O epine approved for use as a chronic anticonvulsant. Benzodiazepines rarely
The general structure of barbiturates is shown above. Barbital became the
first commercially available barbiturate in 1903. Although many other bar-
biturates were subsequently developed, their popularity has greatly waned
since the introduction of benzodiazepines. Barbiturates are derivatives of
barbituric acid (2,4,6-trioxo-hexa-hydropyrimidine), which itself has no CNS
depressant properties. The addition of various side chains influences the
pharmacologic properties. Barbiturates with long side chains tend to have
increased lipophilicity and potency and slower rates of elimination. However,
the observed clinical effects also depend on absorption, redistribution, and
the presence of active metabolites. For this reason, the duration of action
of barbiturates (like those of benzodiazepines) does not correlate well with
their biologic half-lives.
CHAPTER 72 • SEDATIVE–HYPNOTICS 1087
Oral barbiturates are preferentially absorbed in the small intestine and
are eliminated by both hepatic and renal mechanisms. Shorter acting barbi-
turates tend to be more lipid soluble, more protein bound, have a higher pKa,
and are metabolized almost completely by the liver. Longer acting barbitu-
rates such as phenobarbital accumulate less extensively in tissues and are
excreted renally as the parent drug. An example of this is phenobarbital, with
a relatively low pKa (7.24). Alkalinizing the urine with sodium bicarbonate
to a urinary pH of 7.5 to 8.0 can increase the elimination of phenobarbital
by 5- to 10-fold. This procedure is not effective for the short-acting barbitu-
rates because they have higher pKa values, are more protein bound, and are
primarily metabolized by the liver with very little unchanged drug excreted
by the kidneys (Antidotes in Depth: A5 and Chap. 6). Urinary alkalinization is
utilized to decrease the serum half-life of phenobarbital. The clinical benefits
are supported in a prospective controlled trial and few case reports.117 Given
the pharmacokinetic properties of barbiturates, the EXTRIP Workgroup
recommends dialysis for cases of severe long-acting barbiturate poisoning
presenting with prolonged coma, respiratory depression requiring mechani-
cal ventilation, shock, persistent toxicity or persistently elevated or rising
serum concentrations despite MDAC. Intermittent hemodialysis and con-
tinuation of MDAC during dialysis is recommended.74
Barbiturates (especially the shorter acting barbiturates) can accelerate
their own hepatic metabolism by cytochrome P450 enzyme autoinduction.
Phenobarbital is a nonselective inducer of hepatic cytochromes, the greatest
effects being on CYP2B1, CYP2B2, and CYP2B10, although CYP3A4 is also
affected.120,151 Not surprisingly, a variety of interactions are reported after the
use of barbiturates. Clinically significant interactions as a result of enzyme
induction lead to increased metabolism of β-adrenergic antagonists, corti-
costeroids, doxycycline, estrogens, phenothiazines, quinidine, theophylline,
and many other xenobiotics.
Early deaths caused by barbiturate ingestions result from respiratory
arrest and cardiovascular collapse. Delayed deaths result from acute kidney
failure, pneumonia, acute respiratory distress syndrome, cerebral edema,
and multiorgan system failure as a result of prolonged cardiorespiratory
depression.3,42
Benzodiazepines
R1
R2
N
R3
N
R4
R2′
The general structure of benzodiazepines is shown above. The commercial
use of benzodiazepines began with the introduction of chlordiazepoxide for
principally as sedatives and anxiolytics. Clonazepam is the only benzodiaz-
cause paradoxical psychological effects, including nightmares, delirium,
psychosis, and transient global amnesia.83,86,176 The incidence and intensity of
CNS adverse events increase with age.81
Similar to barbiturates, variations of the benzodiazepine side chains
influence potency, duration of action, metabolites, and rate of elimination.
Most benzodiazepines are highly protein bound and lipophilic. They passively
diffuse into the CNS, their main site of action. Because of their lipophilicity,
benzodiazepines are extensively metabolized via oxidation and conjugation
in the liver before their renal elimination.
Benzodiazepines bind nonselectively to “central” benzodiazepine sites
located throughout the brain. These sites contain the GABAA α and γ
subunits.33,161 The binding of the benzodiazepine to its particular site changes
the GABA receptor to “lock” into a position that promotes GABA binding to
1088 PART C • THE CLINICAL BASIS OF MEDICAL TOXICOLOGY
the GABA receptor. Whereas benzodiazepines that are active at the α1 sub-
unit affect anxiety, sleep, and amnesia, those that are active in the α2 and α3
subunits tend to have greater anxiolytic properties. “Peripheral” benzodiaz-
epine sites are found throughout the body, with the greatest concentrations
in steroid-producing cells in the adrenal gland, anterior pituitary gland, and
reproductive organs. These sites are not affiliated with the GABA receptor
(Antidotes in Depth: A26).
One unique property of the benzodiazepines is their relative safety even
after substantial ingestion, which probably results from their GABA receptor
properties.33,97 Unlike many other sedative–hypnotics, benzodiazepines do
not open GABA channels independently at high concentrations. Benzodiaz-
epines do not cause any specific systemic injury, and their long-term use is
not associated with specific organ toxicity. Most often deaths are secondary
to a combination of alcohol or other sedative–hypnotics.130,168,170 Supportive
care is the mainstay of treatment.
Flumazenil is a competitive benzodiazepine receptor antagonist that is
ideal for either benzodiazepine-naïve patients with a sole benzodiazepine
overdose or benzodiazepine-naïve patients who develop respiratory depres-
sion after IV administration of benzodiazepines (Antidotes in Depth: A25).
Caution should be exercised if flumazenil is administered to patients with an
unknown overdose because seizures and dysrhythmias are reported to occur
from the effects of the coingestant after the effect of the benzodiazepine has
been reversed. Similarly, chronic benzodiazepine users are at risk of develop-
ing withdrawal symptoms, including seizures, after receiving flumazenil. The
duration of effect of flumazenil is shorter than that of most benzodiazepines,
and resedation can occur.118
Tolerance to the sedative effects of benzodiazepines occurs more
rapidly than does tolerance to the antianxiety effects.73,115 Abrupt discon-
tinuation after long-term use of benzodiazepines precipitates benzodi-
azepine withdrawal, characterized by autonomic instability, changes in
perception, paresthesias, headaches, tremors, and seizures.13 Withdrawal
from benzodiazepines is common, manifested by almost one-third of
chronic users.66 Alprazolam and lorazepam are associated with more severe
withdrawal syndromes compared with chlordiazepoxide and diazepam.66,67
This is likely because both chlordiazepoxide and diazepam have active
metabolites, accumulation of which prolongs the clinical effect of the drug
and results in a gradual tapering effect. This leads to delayed presentation
of withdrawal from benzodiazepines with active metabolites. Withdrawal
may also occur when a chronic user of a particular benzodiazepine is
switched to another benzodiazepine with a greater affinity for different
receptor subunits.76
Chloral Hydrate
Cl OH
Cl C C OH
Cl H hallmark characteristic of a facial acneiform rash.49,149 Toxicity with bromides
First introduced in 1832, chloral hydrate belongs to one of the oldest classes
of pharmaceutical hypnotics, the chloral derivatives. Although still used
sporadically in children, its use has substantially decreased.1,75,93,103 Chloral
hydrate is well absorbed but is irritating to the GI tract. It has extensive tissue
distribution, rapid onset of action, and rapid hepatic metabolism by alco-
hol and aldehyde dehydrogenases. Trichloroethanol is a lipid-soluble, active
metabolite that is responsible for the hypnotic effects of chloral hydrate. It
has a serum half-life of 4 to 12 hours and is metabolized to inactive trichloro-
acetic acid by alcohol dehydrogenases. It is also conjugated with glucuronide
and excreted by the kidney as urochloralic acid. Less than 10% of trichloro-
ethanol is excreted unchanged.
Metabolic rates in children vary widely because of variable develop-
ment and function of hepatic enzymes, in particular those achieving
glucuronidation.16,80 The elimination half-life of chloral hydrate and trichlo-
roethanol is markedly increased in children younger than 2 years. This is
especially concern in neonates and in infants exposed to repetitive doses.
Acute chloral hydrate poisoning is unique compared with that of other
sedative–hypnotics because of the production of toxic metabolites. Cardiac
dysrhythmias are the major cause of death.41 Chloral hydrate and its meta-
bolites reduce myocardial contractility, shorten the refractory period, and
increase myocardial sensitivity to catecholamines. Persistent cardiac dys-
rhythmias (ventricular fibrillation, ventricular tachycardia, torsade de
pointes) are common terminal events.79 β-Adrenergic antagonists such as
propranolol mitigate this myocardial sensitivity and are recommended in
patients with chloral hydrate–induced dysrhythmias resistant to standard
therapy.15,17,166,175
In addition to cardiotoxicity, chloral hydrate toxicity causes vomiting,
hemorrhagic gastritis, and rarely gastric and intestinal necrosis, leading to
perforation and esophagitis with stricture formation.69,157 Although large inges-
tions of chloral hydrate are evident on abdominal radiographs because of its
radiopacity, a normal radiograph should not be used to exclude chloral hydrate
ingestion. Few hospital-based laboratories have the ability to rapidly detect
chloral hydrate or its metabolites.
Bromides
Bromides were used in the past as “nerve tonics,” headache remedies, and
anticonvulsants. Although medicinal bromides have largely disappeared
from the US pharmaceutical market, bromide toxicity still occurs through
the availability of bromide salts of common drugs, such as dextrometho-
rphan hydrobromine, in large overdoses.91 There is also documentation of
bromism from excessive consumption of cola with brominated vegetable
oils.52 Poisoning may also occur in immigrants and travelers from other
countries where bromides are still therapeutically used.37 An epidemic of
more than 400 cases of mass bromide poisoning occurred in the Cacuaco
municipality of Luanda Province, Angola, in 2007. According to a World Health
Organization report, the etiology of the bromide exposure in these cases was
believed to be table salt contaminated with sodium bromide. Although the
majority of persons affected were children, no actual deaths were attributed
to bromide poisoning in this epidemic.167
Bromides tend to have long half-lives, and toxicity typically occurs over-
time as concentrations accumulate in tissue. Bromide and chloride ions
have a similar distribution pattern in the extracellular fluid. It is postu-
lated that because the bromide ion moves across membranes slightly more
rapidly than the chloride ion, it is more quickly reabsorbed in the tubules
from the glomerular filtrate than the chloride ion. Although osmolar equi-
librium persists, CNS function is progressively impaired by a poorly under-
stood mechanism, with resulting inappropriateness of behavior, headache,
apathy, irritability, confusion, muscle weakness, anorexia, weight loss,
thickened speech, psychotic behavior, tremulousness, ataxia, and eventu-
ally, coma. Delusions and hallucinations occur. Bromides lead to hyperten-
sion, increased intracranial pressure, and papilledema.20,37,149 Chronic use of
bromides also produces dermatologic changes called bromoderma, with the
during pregnancy causes accumulation of bromide in the fetus and resul-
tant CNS depression.104 A spurious laboratory result of hyperchloremia with
decreased or negative anion gap results from the interference of bromide
with the chloride assay on some analyzers109,171 (Chap. 12). Thus, an isolated
elevated serum chloride concentration with neurologic symptoms should
raise suspicion of possible bromide poisoning.
Carisoprodol and Meprobamate
O CH2 O
NH2 C O CH2 C CH2 O C NH2
Meprobamate CH2CH2CH3
Meprobamate was introduced in 1950 and was used for its muscle-relaxant
and anxiolytic characteristics. Carisoprodol, which was introduced in 1955,
is metabolized to meprobamate. Both drugs have pharmacologic effects
on the GABAA receptor similar to those of the barbiturates. Similar to the

barbiturates, meprobamate can directly open the GABA-mediated chloride
channel and inhibits NMDA receptor currents.113 Both are rapidly absorbed
from the GI tract. Meprobamate is metabolized in the liver to inactive
hydroxyl and glucuronide metabolites that are excreted almost exclusively
by the kidney. Of all the nonbarbiturate tranquilizers, meprobamate is most
likely to produce euphoria; the exact mechanism of this is unknown.57,58
Unlike most sedative–hypnotics, meprobamate causes profound hypo-
tension from direct myocardial depression.21 Adherent masses or bezoars
of pills are reported in the stomach at autopsy after large meprobamate
ingestions.125 Orogastric lavage with a large-bore tube and MDAC is reason-
able for patients with a significant meprobamate ingestion while keeping in
mind the risk of aspiration. Whole-bowel irrigation is also reasonable if mul-
tiple pills or small concretions are suspected. Patients can experience recur-
rent toxic manifestations as a result of concretion formation with delayed
drug release and absorption. Careful monitoring of the clinical course is
essential even after the patient shows initial improvement because recurrent
and cyclical CNS depression can occur.125
Zolpidem, Zaleplon, Zopiclone, and Eszopiclone
CN
N
N CH3 N N
N O
CH3
CH2 C N
CH3 CH2CH3
N Propofol use is associated with various adverse events. Acutely, propo-
C CH3
Zolpidem Zaleplon
O
These oral hypnotics have supplanted benzodiazepines as the most com-
monly prescribed sleep aid medications.35 Although they are structurally
unrelated to the benzodiazepines, they bind preferentially to the benzo-
diazepine site subtype in the brain that contains the GABAA α1 subunit.33
They have a lower affinity for benzodiazepine sites that contain the other
α isoforms; therefore, they have potent hypnotic effects with less potential
for dependence and antiepileptics properties.48 Each of these xenobiotics
has a relatively short half-life (6 hours or less), with zaleplon exhibiting the
shortest half-life (1 hour). Unlike benzodiazepines that prolong the first two
stages of sleep and shorten stages 3 and 4 of rapid eye movement sleep,
zolpidem and its congeners all decrease sleep latency with little effect on
sleep architecture. Because of their receptor selectivity, they appear to have
minimal effect at other sites on the GABAA receptor that mediate anxiolytic,
antiepileptic, or muscle-relaxant effects.68,158 A low-dose sublingual tablet
of zolpidem tartrate (Intermezzo) was recently approved for middle of the
night awakenings. An unusual side effect of these drugs, even during thera-
peutic dosing, is somnambulism, transient anterograde global amnesia, with
the majority of these reports involving zolpidem.45
They are hepatically metabolized by various CYP450 enzymes. Zolpidem
is mainly metabolized by CYP3A4. Zaleplon is primarily metabolized by alde-
hyde oxidase, but CYP3A4 is also involved in parent compound oxidation.
Whereas zopiclone is primarily metabolized by CYP3A4 and CYP2C8, eszopi-
clone is metabolized mainly by CYP3A4 and CYP2E1. Various pharmacoki-
netic interactions with inhibitors or inducers of CYP450 enzymes and these
medications are reported.47
In isolated overdoses, drowsiness and CNS depression are common.
However, prolonged coma with respiratory depression is exceptionally
rare. Isolated overdoses usually manifest with depressed level of conscious-
ness without respiratory depression. For example, even at 40 times the
therapeutic dose of zolpidem, no biologic or electrocardiographic abnor-
malities were reported.40 Zopiclone overdoses are rarely associated with
methemoglobinemia.39 Tolerance to zolpidem and its congeners occurs,
and as expected, withdrawal follows abrupt discontinuation of chronic use.
CHAPTER 72 • SEDATIVE–HYPNOTICS 1089
The withdrawal syndrome is typically mild.46,164 Flumazenil reverses the
hypnotic and cognitive effects of these xenobiotics, and given the lack of
antiepileptic effects of these xenobiotics, flumazenil reversal may be safer
here than in the case of benzodiazepines (Antidotes in Depth: A25).71,172
Because of increasing prevalence of these xenobiotics, they have been asso-
ciated with increasing hospitalizations especially when ingested with other
sedative-hypnotics.179 Deaths result when zolpidem is taken in large amounts
with other CNS depressants.40
Propofol
OH
H3C CH3
CH CH
H3C CH3
Propofol is a rapidly acting IV sedative–hypnotic that is both a postsynaptic
GABAA agonist and induces presynaptic release of GABA.95,150 Propofol is also
an antagonist at NMDA receptors.63,138,177 In addition, propofol interacts with
dopamine, promotes nigral dopamine release possibly via GABAB receptors,98,126
and has partial agonist properties at dopamine (D2) receptors.124 Propofol
is used for procedural sedation and either induction or maintenance of
general anesthesia, as well as an antiepileptic to manage status epilepticus. It
is highly lipid soluble, so it crosses the blood–brain barrier rapidly. The onset
of anesthesia usually occurs in less than 1 minute. The duration of action
after short-term dosing is usually less than 8 minutes because of its rapid
redistribution from the CNS.
fol causes dose-related respiratory depression. Propofol decreases systemic
arterial pressure and causes myocardial depression. Although short-term
use of propofol does not typically cause dysrhythmias or myocardial ischemia,
atropine-sensitive bradydysrhythmias are noted, specifically sinus brady-
cardia and Mobitz type 1 atrioventricular block.148,163,174 Short-term use of
propofol in the perioperative setting is associated with a myoclonic syndrome
manifesting as opisthotonus, myoclonus, and sometimes myoclonic seizure–
like activity.84,92
Prolonged propofol infusions, typically more than 48 hours at rates of
4 to 5 mg/kg/h or greater, are associated with a life-threatening propofol-
infusion syndrome involving metabolic acidosis, cardiac dysrhythmias, and
skeletal muscle injury.60,61 The clinical signs of propofol infusion syndrome
often begin with the development of a new right bundle branch block and ST-
segment convex elevations in the electrocardiogram precordial leads.60 Pre-
disposing factors to the development include young age, severe brain injury
(especially in the setting of trauma), respiratory compromise, concurrent
exogenous administration of catecholamines or glucocorticoids, inad-
equate carbohydrate intake, and undiagnosed mitochondrial myopathy.
Some authors propose a “priming” and “triggering” mechanism for propofol
infusion syndrome with endogenous glucocorticoids, catecholamines, and
possibly cytokines as “priming” agents and exogenous catecholamines and
glucocorticoids in the setting of high-dose propofol infusion as “triggering”
stimuli.155 Propofol disrupts mitochondrial free fatty acid utilization and
metabolism, causing a syndrome of energy imbalance and myonecrosis simi-
lar to mitochondrial myopathies.22,132,156 Most case reports associate propofol
with metabolic acidosis, elevated lactate concentration, and fatal myocar-
dial failure in both children and young adults. However, this syndrome is also
reported in older adults.100 Some cases of metabolic acidosis are associated
with an inborn disorder of acylcarnitine metabolism.169 Prolonged propofol
infusions unmask previously undiagnosed myopathy that would cause them
to be at increased risk for propofol infusion syndrome, especially in children.
The unique nature of the carrier base of propofol, a milky soybean emul-
sion formulation, is associated with multiple adverse drug events such as
impairment of macrophage function,22 hypertriglyceridemia,65,72,156 histamine-
mediated anaphylactoid reactions,33,62,156 and impairment of platelet and
coagulation function.3,31 Additionally, the carrier base is a fertile medium
1090 PART C • THE CLINICAL BASIS OF MEDICAL TOXICOLOGY
for many organisms, such as enterococcal, pseudomonal, staphylococcal,
streptococcal, and candidal species. In 1990, the US Centers for Disease
Control and Prevention first reported an outbreak of Staphylococcus aureus
associated with contaminated propofol.87 Since then, 20 propofol-related
outbreaks have been reported, which have affected 144 patients and caused
10 deaths.178
Etomidate
H3C
CH
O cycle.53 Melatonin, ramelteon, and tasimelteon act as agonists at MT1 and
N
CH3CH2 O C
N
Etomidate is an IV nonbarbiturate, hypnotic primarily used for an anesthe-
sia induction. It is active at the GABAA receptor, specifically the β2 and β3
subunits.24,94 Only the IV formulation is available in the United States. The
onset of action is less than 1 minute, and its duration of action is less than
5 minutes.
Etomidate is commercially available as a 2-mg/mL solution in a 35%
propylene glycol solution. Propylene glycol toxicity from prolonged etomi-
date infusions is implicated in the development of hyperosmolar metabolic
acidosis (Chap. 46).70,152,154 Etomidate has minimal effect on cardiac function,
but rare cases of hypotension are reported because of adrenal suppression.142
Etomidate has both proconvulsant and antiepileptic properties.25,108 Involun-
tary muscle movements are common during induction and are caused by
etomidate interaction with glycine receptors at the spinal cord level.28,88,89
Etomidate depresses adrenal production of cortisol and aldosterone;
therefore, it is associated with adrenocortical suppression, usually after
prolonged infusions.122,159,160 Etomidate is associated with increased mor-
bidity and mortality in critically ill and trauma patients.27,50 However, the
clinical significance of adrenal suppression from etomidate administration
is disputed.51,144,145 In the appropriate setting, etomidate does not appear
to have any greater risk of significant adverse events compared with its
counterparts.
Dexmedetomidine
Dexmedetomidine is a central α2-adrenergic agonist that decreases central
presynaptic catecholamine release, primarily in the locus ceruleus. When
dexmedetomidine is used to help wean patients from ventilators, sedation
is achieved with less associated delirium compared with other agents.99,143
It is also used for procedural sedation in certain settings such as interven-
tional radiology procedures and awake fiberoptic intubations. Compared
with propofol, dexmedetomidine sedation lessens opioid requirements in
postoperative patients.
Dexmedetomidine has minimal effect at the GABAA receptor. Unlike
other sedative–hypnotics, it is not associated with significant respiratory
depression. Although mechanistically similar to clonidine, dexmedetomi-
dine does not appear to cause as much respiratory depression as clonidine.
Dexmedetomidine is said to induce a state of “cooperative sedation” in
which a patient is sedated but yet able to interact with health care providers.
Dexmedetomidine also has analgesic effects.23
Dexmedetomidine is currently only approved for use for less than
24 hours. Extensive safety trials have not yet explored its use beyond 24 hours.
Unlike clonidine, rebound hypertension and tachycardia have not been
described upon cessation. Because dexmedetomidine decreases central
sympathetic outflow, its use should probably be avoided in patients whose
clinical stability is dependent on high resting sympathetic tone. The most
common adverse effects from its use are nausea, dry mouth, bradycardia,
and varying effects on blood pressure (usually hypertension followed by
hypotension). Slowing of the continuous infusion may help to prevent or
lessen the hypotensive effects.23 In one case, a 60-fold overdose in a child was
associated with hypoglycemia.12
Melatonin, Ramelteon, and Tasimelteon
Melatonin (N-acetyl-5-methoxytryptamine) and melatonin-containing prod-
ucts are sold as dietary supplements. Melatonin is naturally synthesized
from tryptophan by the enzyme 5-hydroxyindole-O-methyltransferase,
primarily within the pineal gland in humans. Ramelteon is a synthetic
melatonin-analog that is FDA approved for the treatment of chronic insomnia.
Ramelteon is thought to decrease both latency to sleep induction and length
of persistent sleep.134 Tasimelteon, the newest melatonin receptor agonist,
is the only FDA-approved drug used to treat non–24-hour sleep–wake dis-
order that occurs in blind individuals in whom light cues do not reach the
suprachiasmatic nucleus of the brain to allow for a normal sleep–wake
MT2 receptors, which are G protein–coupled receptors mainly located in the
suprachiasmatic nucleus of the brain.127 Whereas MT1 receptors are involved
in sleep induction, MT2 receptors are involved in regulation of the circadian
sleep–wake cycle in humans.140
Ramelteon administered orally is rapidly absorbed but undergoes
significant first-pass metabolism primarily by CYP1A2.
Adverse effects of ramelteon are mild and usually include drowsiness,
dizziness, fatigue, and headache. The endocrine effects of long-term expo-
sure to ramelteon seem to be limited to subclinical increases in serum pro-
lactin concentration in women and do not appear to affect adrenal or thyroid
function.114 In addition, ramelteon appears to have a low abuse potential and
does not appear to be associated with a withdrawal syndrome or rebound
insomnia.44,77,85 A retrospective review of 222 poison control center calls of
ramelteon overdose reported no significant clinical effect in 88.3% of cases.
Isolated cases of bradycardia, hypotension, and seizures did occur.147 There
are no published reports of tasimelteon toxicity from overdose.
Suvorexant
Suvorexant is a newly approved dual orexin receptor antagonist. Orexin
(also known as hypocretin) promotes wakefulness; as an orexin antagonist,
suvorexant induces and maintains sleep. This is the first drug in this class of
sedative–hypnotics.141,173 Preliminary studies have shown that patients tak-
ing this drug have a shorter sleep latency and stayed asleep longer than the
control group taking placebo. There are no reports of physical dependence
on this drug or withdrawal upon its cessation. There are no trials comparing
suvorexant with other drugs for noninferiority or efficacy. The most com-
monly reported side effect with overdose is somnolence after awakening.82
SUMMARY
■ Sedative–hypnotics encompass a wide range of xenobiotics that
predominantly interact with the GABAA receptor but can also have
varying mechanisms of action.
■ Patients with sedative–hypnotic overdoses often present with the
primary manifestation of CNS depression; however, death typically
results from respiratory depression and subsequent cardiovascular col-
lapse in the setting of concurrent coingestion of other CNS depressants.
■ Treatment is largely supportive, including careful monitoring, airway
protection, and proper supportive care, with a rare need for GI decon-
tamination in select severe cases.
■ Specific antidotes such as flumazenil and hemodialysis are rarely
indicated.
Acknowledgment
Kathy Lynn Ferguson, DO, contributed to this chapter in previous editions.
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3. Aoki H, et al. In vivo and in vitro studies of the inhibitory effect of propofol on human
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