1060

Benzodiazepines remain the most popular prescribed anxiolytics.

CHAPTER 74 However, the recently introduced hypnotics zolpidem, zaleplon, zopi-
clone, and eszopiclone have replaced benzodiazepines as the most com-
SEDATIVE-HYPNOTICS monly prescribed pharmaceutical sleep aids. Melatonin and ramelteon
are emerging as popular sleep aids whose effects are mediated through
melatonin receptor subtypes MT-1 and MT-2 specifically.107,112,127
David C. Lee and Kathy Lynn Ferguson Dexmedetomidine, a central α2-adrenergic agonist, is now increasingly
used in the hospital setting for short-term sedation.5,111

Sedative-hypnotics are xenobiotics that limit excitability (sedation),

and/or induce drowsiness and sleep (hypnosis). Anxiolytics (formerly
PHARMACODYNAMICS/TOXICODYNAMICS
known as tranquilizers) are medications prescribed for their sedative- All sedative-hypnotics induce central nervous system (CNS) depres-
hypnotic properties. There are many different types of medications sion. Most clinically effective sedative-hypnotics produce their physi-
used to induce anxiolysis or sleep. This chapter focuses primarily ologic effects by enhancing the function of GABA-mediated chloride
on pharmaceuticals prescribed for their sedative-hypnotic effects, channels via agonism at the GABAA receptor. These receptors are the
many of which interact with the γ-aminobutyric acid-A (GABAA) primary mediators of inhibitory neurotransmission in the brain (see
receptor (Table 74–1). Specific sedative-hypnotics such as ethanol and Chap. 13). The GABAA receptor is a pentameric structure composed of
γ-hydroxybutyric acid are discussed in more depth in their respective varying polypeptide subunits associated with a chloride channel on the
chapters (Chaps. 77 and 80). postsynaptic membrane. These subunits are classified into families (α,
β, γ, etc.). Variations in the five subunits of the GABA receptor confer
the potency of its sedative, anxiolytic, hypnotic, amnestic, and muscle
relaxing properties. The most common GABAA receptor in the brain
HISTORY AND EPIDEMIOLOGY is composed of α1β2γ2 subunits. Almost all sedative-hypnotics bind to
Mythology of ancient cultures is replete with stories of xenobiotics GABAA receptors containing the α1 subunit. One exception may be
that cause sleep or unconsciousness (Chap. 1). Symptomatic etomidate, which has been shown to produce sedation at the β2 unit
overdoses of sedative-hypnotics were described in the medical and anesthesia at the β3 subunit.24,91,104,150 Low doses of benzodiazepines
literature soon after the commercial introduction of bromide will be effective only at GABAA receptors with the γ2 subunit. Even
preparations in 1853. Other commercial xenobiotics that sub- within classes of sedative-hypnotics, there will be varying affinities for
sequently were developed include chloral hydrate, paraldehyde, differing subunits of the GABA receptor.30,79
sulfonyl, and urethane. Many sedative-hypnotics also act at receptors other than the GABAA
The barbiturates were introduced in 1903 and quickly sup- receptor. Trichloroethanol and propofol, also inhibit glutamate-
planted the older xenobiotics. This class of medications dominated mediated N-methyl-d-aspartate (NMDA) receptors, thereby inhibiting
the sedative-hypnotic market for the first half of the 20th century. excitatory neurotransmission.26,99,116 Some benzodiazepines may also
Unfortunately, because they have a narrow therapeutic-to-toxic ratio inhibit adenosine metabolism and reuptake, thereby potentiating both
and substantial potential for abuse, they quickly became a major A1-adenosine (negative dromotropy) and A2-adenosine (coronary vaso-
health problem. By the 1950s, barbiturates were frequently implicated dilation) receptor-mediated effects.87,124 Benzodiazepines also interact
in overdoses and were responsible for the majority of drug-related with specific benzodiazepine receptors that are not associated with
suicides. As fatalities from barbiturates increased, attention shifted the GABA receptor. These receptors have been labeled ω receptors.
toward preventing their abuse and finding less toxic alternatives.19 Benzodiazepines can also interact with serotonergic pathways. For
The “safer” drugs of that era included methyprylon, glutethimide, example, diazepam modulates morphine analgesia via interactions with
ethchlorvynol, bromides, and methaqualone. Unfortunately, many of serotonin receptors. In addition, the anxiolytic effects of clonazepam
these sedative hypnotics also had significant undesirable effects. After can be partially explained by upregulation of serotonergic receptors,
the introduction of benzodiazepines in the early 1960s, barbiturates specifically 5-HT1 and 5-HT2.8,88,157 Newer sleep aids, such as melatonin
and the other alternatives were quickly replaced as commonly used and ramelteon, do not appear to act at the GABAA receptor. Instead,
sedatives in the United States. they are agonists at melatonin receptor subtypes MT-1 and MT-2 in the
Intentional and unintentional overdoses with sedative-hypnotics suprachiasmatic nucleus of the brain.127 Dexmedetomidine, a central
occur frequently. According to the American Association of Poison α2-adrenergic agonist similar to clonidine, induces a state of “cooperative
Control Centers, sedative-hypnotics is consistently one of the top five sedation.”136
classes of xenobiotics associated with overdose fatalities (see Chap. 135).
With the ubiquitous worldwide use of sedative-hypnotics, they may be PHARMACOKINETICS/TOXICOKINETICS
associated with a substantially higher number of overdoses and deaths
than are officially reported. For example, a recent report described Most sedative-hypnotics are rapidly absorbed via the gastrointestinal
benzodiazepines as being increasingly used in drug-facilitated thefts (GI) tract, with the rate-limiting step consisting of dissolution and
outside the United States.75 dispersion of the xenobiotic. Barbiturates and benzodiazepines are
Chlordiazepoxide, the first commercially available benzodiazepine, primarily absorbed in the small intestine. Clinical effects are deter-
initially was marketed in 1960. Since then, more than 50 benzodiaz- mined by their relative ability to penetrate the blood–brain barrier.
epines have been marketed, and more are being developed. Compared Drugs that are highly lipophilic penetrate most rapidly. The ultrashort-
with barbiturate overdoses, overdoses of benzodiazepines alone account acting barbiturates are clinically active in the most vascular parts of
for relatively few deaths.37 Most deaths associated with benzodiazepines the brain (gray matter first), with sleep occurring within 30 seconds
result from mixed overdoses with other centrally acting respiratory of administration. Table 74–1 lists individual sedative-hypnotics and
depressants.46 some of their pharmacokinetic properties.

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 Chapter 74 Sedative-Hypnotics 1061

TABLE 74–1. Pharmacology of Sedative-Hypnotics

Equipotent Dosing Protein Active Metabolite

Oral Dose (mg)a t1/2 (min.) Binding (%) Vd (L/kg) Important
Benzodiazepines
Agents with full agonist activity at the benzodiazepine site
Alprazolam (Xanax) 1.0 10–14 80 0.8 No
Chlordiazepoxide (Librium) 50 5–15 96 0.3 Yes
Clorazepate (Tranxene) 15 97 0.9 Yes
Clonazepam (Klonopin) 0.5 18–50 85.4 Unclear Yes
Diazepam (Valium) 10 20–70 98.7 1.1 Yes
Estazolam (ProSom) 2.0 8–31 93 0.5 No
Flunitrazepamb (Rohypnol) 1.0 16–35 80 1.0–1.4 Yes
Flurazepam (Dalmane) 30 2.3 97.2 3.4 Yes
Lorazepam (Ativan) 2.0 9–19 90 1–1.3 None
Midazolam (Versed) — 3–8 95 0.8–2 Yes
Oxazepam (Serax) 30 5–15 Unclear Unclear No
Temazepam (Restoril) 30 10–16 97 0.75–1.37 No
Triazolam (Halcion) 0.25 1.5–5.5 90 0.7–1.5 Yes
Nonbenzodiazepines active mainly at the type I (ω1 ) benzodiazepine site
Eszoplicone (Lunesta) ? 6 55 1.3 No
Zaleplon (Sonata) 20 1.0 92 0.54 No
Zolpidem (Ambien) 20 1.7 92 0.5 No
Barbiturates
Amobarbital (Amytal) — 8–42 Unclear Unclear Unclear
Aprobarbitalb (Alurate) — 14–34 Unclear Unclear Unclear
Butabarbital (Butisol) — 34–42 Unclear Unclear Unclear
Barbitalb — 6–12 25 Unclear Unclear
Mephobarbital (Mebaral) — 5–6 40–60 Unclear Yes
Methohexital (Brevital) — 3–6 73 2.2 Unclear
Pentobarbital (Nembutal) 100 15–48 45–70 0.5–1.0 Unclear
Phenobarbital (Luminal) 30 80–120 50 0.5–0.6 No
Primidone (Mysoline) — 3.3–22.4 19 Unclear Yes
Secobarbital (Seconal) — 15–40 52–57 Unclear Unclear
Thiopental (Pentothal) — 6–46 72–86 1.4–6.7 Unclear
Other
Chloral hydrate (Aquachloral) NA 4.0–9.5 35–40 0.6–1.6 Yes
Ethchlorvynolb (Placidyl) NA 10–25 30–40 4 Unclear
Etomidate (Amidate) NA 2.9–5.3 98 2.5–4.5 Unclear
Glutethimideb (Doriden) NA 5–22 47–59 2.7 Unclear
Methyprylonb (Nodular) NA 3–6 60 0.97 Unclear
Meprobamateb (Miltown) NA 6–17 20 0.75 Unclear
Methaqualoneb (Quaalude) NA 19 80–90 5.8–6.0 Yes
Paraldehydeb (Paral) NA 7 Unclear 0.9 Unclear
Propofol (Diprivan) NA 4–23 98 2–10 No
Ramelteon (Rozerem) NA 1–2.6 82 High Yes
Dexmedetomidine (Precedex) NA 2 94 1.5 No

NA = not applicable comparison.

a
This table is an approximation of equipotent doses of xenobiotics affecting the benzodiazepine receptor and several barbiturates. All of the full agonist benzodiazepines have similar amnestic,
anxiolytic, sedative, and hypnotic effects. These effects are a reflection of dose and serum concentration. There can be significant variation of these effects according to age and gender.
b
Not presently available in the United States.

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 1062 Part C The Clinical Basis of Medical Toxicology

After initial distribution, many of the sedative-hypnotics undergo Cl OH

Trichloroacetic
a redistribution phase as they are dispersed to other body tissues,
acid Cl C C
specifically fat. Xenobiotics that are redistributed, such as the lipo-
philic (ultrashort-acting) barbiturates and some of the benzodiazepines Cl O
(diazepam, midazolam), may have a brief clinical effect as the early peak
concentrations in the brain rapidly decline. The clinical activity of many
of them after single doses is determined by their rapid distribution and P450
redistribution (alpha phase) and not by their elimination (beta phase)
(see Chap. 8). Cl H
Many of the sedative-hypnotics are metabolized to pharmaco- Chloral
logically active intermediates. This is particularly true for chloral Cl C C OH
hydrate
hydrate and some of the benzodiazepines. Benzodiazepines can be Cl OH
demethylated, hydroxylated, or conjugated with glucuronide in the
liver. Glucuronidation results in the production of inactive metabolites. ADH H OH
Benzodiazepines, such as diazepam, are demethylated which produces Cl H – Ethanol NADH
H C C
active intermediates with a more prolonged therapeutic half-life than
Cl C C H NAD+ ADH and H O
the parent compound. Because of the individual pharmacokinetics of ALDH
sedative-hypnotics and the production of active metabolites, there is Cl OH – Acetic acid
often little correlation between the therapeutic and biologic half-lives. Trichloroethanol H H
The majority of sedative-hypnotics, such as the highly lipid-soluble
ADH and H C C H
barbiturates and the benzodiazepines, are highly protein bound. These
drugs are poorly filtered by the kidneys. Elimination occurs principally ALDH H OH
by hepatic metabolism. Chloral hydrate and meprobamate are notable – Ethanol
exceptions. Xenobiotics with a low lipid-to-water partition coefficient, Cl OH
such as meprobamate and the longer-acting barbiturates, are poorly
Cl C C Glucuronic acid
protein bound and more subject to renal excretion. Phenobarbital is a
classic example of a drug whose elimination can be enhanced through Cl O
alkalinization. Most other sedative-hypnotics are not amenable to COOH Cl
Trichloroacetic
urinary pH manipulation. acid O O CH2 C Cl
Overdoses of combinations of sedative-hypnotics enhance toxicity
OH Cl
through synergistic effects. For example, both barbiturates and ben-
zodiazepines act on the GABAA receptor, but barbiturates prolong the OH
opening of the chloride ionophore, whereas benzodiazepines increase Urochloralic acid OH
the frequency of ionophore opening.128 Various sedative-hypnotics may (renal elimination)
increase the affinity of another xenobiotic at its respective binding site.
FIGURE 74–1. Metabolism of chloral hydrate and ethanol, demonstrating the inter-
For example, pentobarbital increases the affinity of γ-hydroxybutyrate
actions between chloral hydrate and ethanol metabolism. Note the inhibitory effects
(GHB) for its non-GABA binding site.130 Propofol potentiates the effect
(dotted lines) of ethanol on trichloroethanol metabolism and the converse.
of pentobarbital on chloride influx at the GABA receptor.142 Propofol
also increases the affinity and decreases the rate of dissociation of ben-
zodiazepines from their site on the GABA receptor.18,106 These actions
increase the clinical effect of each xenobiotic and may lead to deeper TOLERANCE/WITHDRAWAL
CNS and respiratory depression.
Another mechanism of synergistic toxicity occurs via alteration of Ingestions of relatively large doses of sedative-hypnotics may not have
metabolism. The combination of ethanol and chloral hydrate, histori- predictable effects in patients who chronically use them. This is due to
cally known as a “Mickey Finn,” has additive CNS depressant effects. tolerance, defined as the progressive diminution of effect of a particular
Chloral hydrate competes for alcohol and aldehyde dehydrogenases, drug with repeated administrations that results in a need for greater
thereby prolonging the half-life of ethanol. The metabolism of ethanol doses to achieve the same effect. Tolerance occurs when adaptive neural
generates the reduced form of nicotinamide adenine dinucleotide and receptor changes (plasticity) occur after repeated exposures. These
(NADH), which is a cofactor for the metabolism of choral hydrate changes include a decrease in the number of receptors (downregulation),
to trichloroethanol, an active metabolite. Finally, ethanol inhibits the reduction of firing of receptors (receptor desensitization), structural
conjugation of trichloroethanol, which in turn inhibits the oxidation of changes in receptors (receptor shift), or reduction of coupling of sedative-
ethanol (Fig. 74–1).16,80,121,122 The end result of these synergistic pharma- hypnotics and their respective GABAA related receptor site (see Chap. 14).
cokinetic interactions is enhanced CNS depression. Tolerance can also be secondary to pharmacokinetic factors. However, in
Multiple drug–drug interactions can occur that may prolong the the majority of cases, tolerance to sedative-hypnotics is caused by phar-
half-life of many sedative-hypnotics and significantly increase their macodynamic changes such as receptor downregulation.129
potency or duration of action. The half-life of midazolam, which Cross-tolerance readily exists among the sedative-hypnotics. For
undergoes hepatic metabolism via cytochrome CYP3A4, can change example, chronic use of benzodiazepines not only decreases the activ-
dramatically in the presence of certain drugs that compete for its ity of the benzodiazepine site on the GABA receptor but also decreases
metabolism, or that induce or inhibit CYP3A4.94,145 For example, the the binding affinity of the barbiturate sites.3,55 Many sedative-hypnotics
half-life of midazolam rises 400-fold when coadministered with itra- are also associated with drug dependence after chronic exposure. Some
conazole.7 Various receptor and metabolic enzyme alterations resulting of these, classically the barbiturates, benzodiazepines, and ethanol, are
in upregulation or downregulation may occur in the setting of acute or associated with characteristic potentially life-threatening withdrawal
chronic exposure to certain sedative-hypnotics. syndromes.

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 Chapter 74 Sedative-Hypnotics 1063

CLINICAL MANIFESTATIONS DIAGNOSTIC TESTING

Patients with sedative-hypnotic overdoses may exhibit slurred speech, When overdose is a primary concern in the undifferentiated comatose
ataxia, and incoordination. Larger doses result in stupor or coma. patient without a clear history laboratory testing, including electrolytes,
In most instances, respiratory depression parallels CNS depression. liver enzymes, thyroid function tests, blood urea nitrogen (BUN), crea-
However, not all sedative-hypnotics cause significant hypoventila- tinine, glucose, venous or arterial blood gas analysis, and cerebrospinal
tion. Oral overdoses of benzodiazepines alone may lead to sedation fluid analysis, may be useful to exclude metabolic abnormalities. With
and hypnosis, but rarely life-threatening hypoventilation. Typically, any suspected intentional overdose, a serum acetaminophen concen-
the patient may appear comatose but have relatively normal vital tration should be obtained. Diagnostic imaging studies, such as head
signs. In contrast, large intravenous doses of benzodiazepines may CT scans, may be warranted on a case-by-case basis.
lead to potentially life-threatening respiratory depression. Single Routine laboratory screening for “drugs of abuse” generally is not
overdoses of zolpidem and its congeners have not been shown to helpful in the management of undifferentiated comatose adult
cause life-threatening respiratory depression in adults.40 patients, although screening may be useful for epidemiologic
Although the physical examination is rarely specific for a particu- purposes in a particular community. These tests vary in type, sensi-
lar sedative-hypnotic, it can sometimes offer clues of exposure based tivity, and specificity. Furthermore, many sedative-hypnotics are not
on certain physical and clinical findings (Table 74–2). Hypothermia included on standard screening tests for drugs of abuse. For example,
has been described with most of the sedative-hypnotics but may be a typical benzodiazepine urine screen identifies metabolites of
more pronounced with barbiturates.56,113 Barbiturates may cause fixed 1,4-benzodiazepines, such as oxazepam or desmethyldiazepam. Many
drug eruptions that often are bullous and appear over pressure-point benzodiazepines that are metabolized to alternative compounds
areas. Although classically referred to as “barbiturate blisters,” this remain undetected and thus may exhibit a false-negative result on the
phenomenon is not specific to barbiturates and has been documented benzodiazepine screening assay. Benzodiazepines that are 7-amino
with other CNS depressants, including carbon monoxide, methadone, analogs, such as clonazepam and flunitrazepam, may not be detected
imipramine, glutethimide, and benzodiazepines. Methaqualone can because they do not have a metabolite with a 1,4-benzodiazepine
cause muscular rigidity and clonus.1 Glutethimide can result in anti- structure. Alprazolam and triazolam are not detected because they
cholinergic signs and symptoms.47 Chloral hydrate use may result in undergo minimal metabolism.33
vomiting, gastritis, and cardiac dysrhythmias.45,71,92,149 Meprobamate Specific concentrations of xenobiotics such as ethanol or pheno-
overdoses may present with significant hypotension due to myocardial barbital may be helpful to confirm or disprove exposure. However,
depression.21 specific concentrations of most other sedative-hypnotics are not
Large or prolonged intravenous doses of sedative-hypnotics may routinely performed in hospital laboratories. Abdominal radiographs
also be associated with toxicities due to their diluents. Propylene glycol may detect chloral hydrate in the gastrointestinal tract because of its
is a classic example of a diluent that may accumulate with prolonged potential radiopacity (see Chap. 5). Although immediate identifica-
infusions of certain medications such as lorazepam. Rapid infusions tion of a particular sedative-hypnotic may be helpful in predicting the
of propylene glycol may induce hypotension. Accumulated amounts length of toxicity, it rarely affects the acute management of the patient.
of propylene glycol may lead to metabolic acidosis and a hyperosmo- One exception is phenobarbital, for which urinary alkalinization and
lar state with elevated serum lactate concentrations.68,72,78,105,146 In one MDAC may enhance elimination.39,102
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 propylene glycol as manifested by hyperosmolar anion gap meta- MANAGEMENT
bolic acidosis6 (see Chap. 55).
Death secondary to sedative-hypnotic overdose usually results from
cardiorespiratory collapse. Careful attention should focus on monitor-
ing and maintaining adequate airway, oxygenation, and hemodynamic
support. Supplemental oxygen, respiratory support, and prevention of
aspiration are the cornerstones of treatment. Hemodynamic instability,
TABLE 74–2. Clinical Findings of Sedative-Hypnotic Overdose although often a secondary or a delayed manifestation of sedative-
hypnotic poisoning, should be treated initially with volume expansion.
Clinical Signs Sedative-Hypnotics Historically, analeptics and other nonspecific arousal xenobiotics
Hypothermia Barbiturates, bromides, ethchlorvynol (see Chap. 1) were used, but their use is no longer recommended.
With good supportive care and adequate early airway/respiratory
Unique odors Chloral hydrate (pear), ethchlorvynol
support as needed, patients with sedative-hypnotic overdoses should
(new vinyl shower curtain)
eventually recover. Patients with meprobamate and chloral hydrate
Cardiotoxicity overdoses, however, may present with both respiratory depression
Myocardial depression Meprobamate and cardiac toxicity. Meprobamate toxicity may be associated with
Dysrhythmias Chloral hydrate myocardial depression and significant hypotension, often resistant to
Muscular twitching GHB, methaqualone, standard intravenous fluid resuscitation.21 Chloral hydrate cardiotoxic
propofol, etomidate effects include lethal ventricular dysrhythmias, resulting from its active
halogenated metabolite trichloroethanol. In the setting of cardiac
Acneiform rash Bromides
dysrhythmias from chloral hydrate, judicious use of β-adrenergic
Fluctuating coma Glutethimide, meprobamate antagonists is recommended.15,45,158
GI hemorrhage Chloral hydrate, methaqualone The use of gastrointestinal decontamination should be decided on
Discolored urine Propofol (green/pink) a case-by-case basis. The benefits of activated charcoal (AC) must be
Anticholinergic signs Glutethimide balanced with the risks of its aspiration and subsequent potential for
pulmonary toxicity. The use of AC should be determined judiciously

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 1064 Part C The Clinical Basis of Medical Toxicology

based upon a patient’s current mental status, potential for further Barbiturates with long side chains tend to have increased lipophilicity,
deterioration, the xenobiotic(s) ingested if known, and the expected potency, and slower rates of elimination. However, the observed clinical
clinical course. Phenobarbital overdose is one particular scenario effects also depend on absorption, redistribution, and the presence of
in which multiple-dose AC (MDAC) may be considered. MDAC active metabolites. For this reason, the duration of action of barbiturates
increases phenobarbital elimination by 50%–80%.9,10,14 However, in (like those of benzodiazepines) does not correlate well with their biologic
the only controlled study, no difference could be demonstrated in out- half-lives.
come measures (time to extubation and length of hospitalization) in Oral barbiturates are preferentially absorbed in the small intestine and
intubated, phenobarbital-poisoned patients who were randomized to are eliminated by both hepatic and renal mechanisms. Longer-acting
single-dose activated charcoal versus MDAC.101 Although inconclusive, barbiturates tend to be more lipid soluble, more protein bound, have
after ensuring an adequately protected airway, activated charcoal may a high pKa, and are metabolized almost completely by the liver. Renal
have potential benefits in certain situations (Antidotes in Depth A2: excretion of unchanged drug is significant for phenobarbital, a long-
Activated Charcoal). acting barbiturate with a relatively low pKa (7.24). Alkalinizing the
Although the efficacy of delayed orogastric lavage is controversial, urine with sodium bicarbonate to a urinary pH of 7.5–8.0 can increase
orogastric lavage may be considered in overdoses with xenobiotics the amount of phenobarbital excreted by 5- to 10-fold. This proce-
that slow GI motility or that are known to develop concretions, dure is not effective for the short-acting barbiturates because they
specifically phenobarbital and meprobamate,21,59,119 Orogastric lavage have higher pKa values, are more protein bound, and are primarily
in the setting of oral benzodiazepine overdoses alone is not rec- metabolized by the liver with very little unchanged drug excreted by
ommended, as the benefits of lavage are minimal compared to the kidneys (see Chap. 9).
the significant risks of aspiration. The use of orogastric lavage in Barbiturates (especially the shorter-acting barbiturates) can accel-
sedative-hypnotic overdose should always be done cautiously as out- erate their own hepatic metabolism by cytochrome P450 enzyme
lined in Chap. 7. No antidote counteracts all sedative-hypnotic over- autoinduction. Phenobarbital is a nonselective inducer of hepatic
doses. Flumazenil, a competitive benzodiazepine antagonist, rapidly cytochromes, the greatest effects being on CYP2B1, CYP2B2, and
reverses the sedative effects of benzodiazepines as well as zolpidem CYP2B10, although CYP3A4 is also affected.65,93,115,126,143 Not surpris-
and its congeners.30,73,156 However, flumazenil has been documented ingly, a variety of interactions are reported following the use of barbitu-
to precipitate life-threatening benzodiazepine withdrawal in benzo- rates. Clinically significant interactions as a result of enzyme induction
diazepine-dependent patients and precipitate seizures, especially in lead to increased metabolism of β-adrenergic antagonists, corticoster-
patients who have overdosed on tricyclic antidepressants41,132,133 (see oids, doxycycline, estrogens, phenothiazines, quinidine, theophylline,
Antidotes in Depth A23: Flumazenil). and many other xenobiotics.
Patients with sedative-hypnotic overdoses rarely require invasive Similar to other sedative-hypnotics, patients with significant
therapy other than respiratory support. Hemodialysis may be con- barbiturate overdoses present with CNS and respiratory depres-
sidered in patients with chloral hydrate overdoses who develop life- sion. Hypothermia and cutaneous bullae (“barb blisters”) are often
threatening cardiac manifestations or in patients who ingest extremely present. These two signs are also described for other patients with
large quantities of phenobarbital and meprobamate who might require sedative-hypnotic overdoses, but they may be more pronounced with
prolonged intubation. barbiturates.11,32 Early deaths caused by barbiturate ingestions result
Because the lethality of sedative-hypnotics is associated with their from respiratory arrest and cardiovascular collapse. Delayed deaths
ability to cause respiratory depression, asymptomatic patients can result from acute renal failure, pneumonia, acute lung injury, cerebral
be downgraded to a lower level of care after a period of observation edema, and multiorgan system failure as a result of prolonged cardio-
with no signs of respiratory depression. Patients with symptomatic respiratory depression.2,48
overdoses of long-acting sedative hypnotics, such as meprobamate and
clonazepam, or drugs that can have significant enterohepatic circula-
tion, such as glutethimide, may require 24 hours of observation (see ■ BENZODIAZEPINES
Chap. 10). Patients with mixed overdoses of various sedative-hypnotics
and CNS depressants also warrant closer observation for respiratory R1
depression due to synergistic respiratory depressant effects. N R2

SPECIFIC SEDATIVE-HYPNOTICS N
R3

R4
■ BARBITURATES
R2′
X O
N Y The commercial use of benzodiazepines began with the introduction
O of chlordiazepoxide for anxiety in 1961 and diazepam for seizures in
N Z 1963. Benzodiazepines are used principally as sedatives and anxiolytics.
O Clonazepam is the only benzodiazepine approved for use as a chronic
anticonvulsant. Benzodiazepines may rarely cause paradoxical psycho-
Barbital became the first commercially available barbiturate in 1903. logical effects, including nightmares, delirium, psychosis, and transient
Although many other barbiturates were subsequently developed, their global amnesia.12,13,34,86 The incidence and intensity of CNS adverse
popularity has greatly waned since the introduction of benzodiaz- events increases with age.81
epines. Barbiturates are derivatives of barbituric acid (2,4,6-trioxo-hexa- Similar to barbiturates, various benzodiazepine side chains influ-
hydropyrimidine), which itself has no CNS depressant properties. The ence potency, duration of action, metabolites, and rate of elimination.
addition of various side chains influence pharmacologic properties. Most benzodiazepines are highly protein bound and lipophilic. They

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 Chapter 74 Sedative-Hypnotics 1065

passively diffuse into the CNS, their main site of action. Because of Acute chloral hydrate poisoning is unique compared with that of
their lipophilicity, benzodiazepines are extensively metabolized via other sedative-hypnotics. Cardiac dysrhythmias are believed to be
oxidation and conjugation in the liver prior to their renal elimination. the major cause of death.45 Chloral hydrate and its metabolites reduce
Benzodiazepines bind nonselectively to “central” benzodiazepine myocardial contractility, shorten the refractory period, and increase
receptors within the brain, termed ω1 and ω2. ω1 receptors are located myocardial sensitivity to catecholamines.17,18,26,158 Persistent cardiac
throughout the brain and contain the GABAA α1 subunit.30 They are dysrhythmias (ventricular fibrillation, ventricular tachycardia, torsades
hypothesized to affect anxiety, sleep, and amnesia. ω2 receptors are de pointes) are common terminal events.45 Standard antidysrhythmics
concentrated predominantly in the hippocampus, striatum, and often are ineffective, and β-adrenergic antagonists are considered
the spinal cord. They are hypothesized to affect muscle relaxation, the treatment of choice.15,17,70,163 In addition to cardiotoxicity, chloral
cognition, memory, and dependence. Peripheral benzodiazepine hydrate toxicity may cause vomiting, hemorrhagic gastritis, and rarely
receptors ω3 are found throughout the body, with the greatest con- gastric and intestinal necrosis, leading to perforation and esophagitis
centrations in steroid-producing cells in the adrenal gland, anterior with stricture formation.71,92 Chloral hydrate is radiopaque and may
pituitary gland, and reproductive organs (Antidote in Depth A24: be detected on radiographs; however, a negative radiograph should
Benzodiazepines). not be used to exclude chloral hydrate ingestion. Few hospital-based
One unique property of the benzodiazepines is their relative safety laboratories have the ability to rapidly detect chloral hydrate or its
even after substantial ingestion, which probably results from their metabolites.
GABA receptor properties.30,95 Unlike many other sedative-hypnotics,
benzodiazepines do not open GABA channels independently at high
concentrations. Benzodiazepines are not known to cause any specific
■ MEPROBAMATE/CARISOPRODOL
systemic injury, and their long-term use is not associated with specific O CH2 O
organ toxicity. Deaths resulting from benzodiazepine ingestions alone
are extremely rare. Most often deaths are secondary to a combination NH2 C O CH2 C CH2 O C NH2
of alcohol or other sedative-hypnotics.46,123 Supportive care is the main- CH2CH2CH3
Meprobamate
stay of treatment.
Tolerance to the sedative effects of benzodiazepines occurs more Meprobamate was introduced in 1950 and was used for its muscle-
rapidly than does tolerance to the antianxiety effects.74,110 Abrupt relaxant and anxiolytic characteristics. Carisoprodol, which was
discontinuation following long-term use of benzodiazepines may introduced in 1955, is metabolized to meprobamate. Both drugs
precipitate benzodiazepine withdrawal, which is characterized by have pharmacologic effects on the GABAA receptor similar to those
autonomic instability, changes in perception, paresthesias, headaches, of the barbiturates. Like barbiturates, meprobamate can directly
tremors, and seizures. Withdrawal from benzodiazepines is common, open the GABA-mediated chloride channel and may inhibit NMDA
manifested by almost one-third of long-term users.66 Alprazolam and receptor currents.108 Both are rapidly absorbed from the GI tract.
lorazepam are associated with more severe withdrawal syndromes Meprobamate is metabolized in the liver to inactive hydroxylated
compared with chlordiazepoxide and diazepam.66,67 This is likely due to and glucuronidated metabolites that are excreted almost exclusively
the fact that both chlordiazepoxide and diazepam have active metabo- by the kidney. Of all the nonbarbiturate tranquilizers, meprobamate
lites. Withdrawal may also occur when a chronic user of a particular most likely will produce euphoria.57,58 Unlike most sedative-hypnotics,
benzodiazepine is switched to another benzodiazepine with different meprobamate has been reported to cause profound hypotension from
receptor activity.76 myocardial depression.21 Large masses or bezoars of pills have been
noted in the stomach at autopsy after large meprobamate ingestions.119
Orogastric lavage with a large-bore tube and MDAC may be indicated
■ CHLORAL HYDRATE for significant meprobamate ingestion; however, the potential benefits
Cl OH of orogastric lavage must be weighed against the risks of aspiration.
Whole-bowel irrigation may be helpful if multiple pills or small con-
Cl C C OH
cretions are noted. It is important to note that patients can experience
Cl H recurrent toxic manifestations as a result of concretion formation with
delayed drug release and absorption. Careful monitoring of the clini-
Chloral hydrate, first introduced in 1832, belongs to one of the oldest cal course is essential even after the patient shows initial improvement
classes of pharmaceutical hypnotics, the chloral derivatives. Although because recurrent and cyclical CNS depression may occur.119
still used fairly commonly in children, its use has substantially
decreased. Chloral hydrate is well absorbed but is irritating to the
GI tract. It has a wide tissue distribution, rapid onset of action, and ■ BROMIDES
rapid hepatic metabolism by alcohol and aldehyde dehydrogenases. Bromides have been used in the past as “nerve tonics,” headache rem-
Trichloroethanol is a lipid soluble, active metabolite that is responsible edies, and anticonvulsants. Although medicinal bromides have largely
for the hypnotic effects of chloral hydrate. It has a plasma half-life of disappeared from the US pharmaceutical market, bromide toxicity still
4–12 hours and is metabolized to inactive trichloroacetic acid by occurs through the availability of bromide salts of common drugs, such
alcohol dehydrogenases. It is also conjugated with glucuronide and as dextromethorphan.89 Poisoning also may occur in immigrants and
excreted by the kidney as urochloralic acid. Less than 10% of trichloro- travelers from other countries where bromides are still therapeutically
ethanol is excreted unchanged. used.38 An epidemic of more than 400 cases of mass bromide poisoning
Metabolic rates in children vary widely because of variable develop- occurred in the Cacuaco municipality of Luanda Province, Angola in
ment and function of hepatic enzymes, in particular glucuronidation.16,80 2007. According to a World Health Organization report, the etiology
The elimination half-life of chloral hydrate and triculoroethanol is of the bromide exposure in these cases was believed to be table salt
markedly increased in children younger than 2 years. This may be contaminated with sodium bromide. Although the majority of persons
especially of concern in neonates and in infants exposed to repetitive affected were children, no actual deaths were attributed to bromide
doses. poisoning in this epidemic.159

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 1066 Part C The Clinical Basis of Medical Toxicology

Bromides tend to have long half-lives and toxicity typically occurs 40 times the therapeutic dose of zolpidem, no biologic or electrocar-
over time as concentrations accumulate in tissue. Bromide and diographic abnormalities were reported.40 Tolerance to zolpidem and
chloride ions have a similar distribution pattern in the extracellular its congeners has also been described. Withdrawal has been reported
fluid. It is postulated that because the bromide ion moves across after abrupt discontinuation following chronic use but typically is
membranes slightly more rapidly than the chloride ion, it is more mild.50,155 Flumazenil may reverse the hypnotic or cognitive effects of
quickly reabsorbed in the tubules from the glomerular filtrate than the these agents.73,156 Deaths have resulted when zolpidem was taken in
chloride ion. Although osmolar equilibrium persists, CNS function large amounts with other CNS depressants (Antidote in Depth A23
is progressively impaired by a poorly understood mechanism, with Flumazenil).40
resulting inappropriateness of behavior, headache, apathy, irritability,
confusion, muscle weakness, anorexia, weight loss, thickened speech,
psychotic behavior, tremulousness, ataxia, and eventually coma.20,164 ■ PROPOFOL
OH
Delusions and hallucinations can occur. Bromide can lead to hyper- H3C CH3
tension, increased intracranial pressure, and papilledema. Chronic use CH CH
of bromides can also lead to dermatologic changes, with the hallmark H3C CH3
characteristic of a facial acneiform rash.53,141 Toxicity with bromides
during pregnancy may lead to accumulation of bromide in the fetus.100
A spurious laboratory result of hyperchloremia with decreased anion
Propofol is a rapidly acting intravenous sedative-hypnotic that is a
gap may result from bromide’s interference with the chloride assay on
postsynaptic GABAA agonist and also induces presynaptic release of
older analyzers161 (Chap. 16). Thus an isolated elevated serum chloride
GABA.117 Propofol is also an antagonist at NMDA receptors.63,64,131
concentration with neurologic symptoms should raise suspicion of
In addition, propofol also interacts with dopamine, promotes nigral
possible bromide poisoning.
dopamine release possibly via GABAB receptors,96,120 and has partial
agonist properties at dopamine (D2) receptors.118 Propofol is used for
■ ZOLPIDEM/ZALEPLON/ZOPICLONE/ESZOPICLONE procedural sedation and either induction or maintenance of general
anesthesia. It is highly lipid soluble, so it crosses the blood–brain
CN barrier rapidly. The onset of anesthesia usually occurs in less than
N 1 minute. The duration of action after short-term dosing is usually less
N than 8 minutes due to its rapid redistribution from the CNS.
CH3 N N
Propofol use is associated with various adverse effects. Acutely,
N O propofol causes dose-related respiratory depression. Propofol may
CH3
CH2 C N decrease systemic arterial pressure and cause myocardial depres-
CH3 CH2CH3 sion. Although short-term use of propofol does not typically cause
N dysrhythmias or myocardial ischemia, atropine-sensitive bradydys-
C CH3
rhythmias have been noted, specifically sinus bradycardia and Mobitz
Zolpidem Zaleplon O type I atrioventricular block.140,154,162 Short-term use of propofol in the
perioperative setting is associated with a myoclonic syndrome mani-
These oral xenobiotics have supplanted benzodiazepines as the most festing as opisthotonus, myoclonus, and sometimes myoclonic seizure
commonly prescribed sleep aid medications.35 Although they are like activity.82,90
structurally unrelated to the benzodiazepines, they bind preferentially Prolonged propofol infusions for more than 48 hours at rates of
to the ω1 benzodiazepine receptor subtype in the brain, specifically 4–5 mg/kg/h or greater are associated with a life-threatening propofol-
the GABAA α1 subunit.30 They have a lower affinity for ω2 receptors infusion syndrome (PIS) involving metabolic acidosis, cardiac dysr-
than benzodiazepines, therefore they have potent hypnotic effects thythmias, and skeletal muscle injury.61 The clinical signs of PIS often
with less potential for dependence.30,52 Each of these xenobiotics begin with the development of a new right bundle branch block and
has a relatively short half-life (≤6 hours), with zaleplon exhibiting ST segment convex elevations in the electrocardiogram precordial
the shortest half-life (1 hour). Unlike benzodiazepines that prolong leads.60 Predisposing factors to the development of PIS include young
the first two stages of sleep and shorten stages 3 and 4 of rapid eye age, severe brain injury (especially in the setting of trauma), respiratory
movement (REM) sleep, zolpidem and its congeners all decrease compromise, concurrent exogenous administration of catecholamines
sleep latency with little effect on sleep architecture. Because of their or glucocorticoids, inadequate carbohydrate intake, and undiagnosed
receptor selectivity, they appear to have minimal effect at other sites mitochondrial myopathy. Some authors propose a “priming” and
on the GABA receptor that mediate anxiolytic, anticonvulsant, or “triggering” mechanism for PIS with endogenous glucocorticoids, cate-
muscle-relaxant effects.69,151 cholamines, and possibly cytokines as “priming” agents, and exogenous
They are hepatically metabolized by various CYP450 enzymes. catecholamines and glucocorticoids in the setting of high-dose propo-
Zolpidem is mainly metabolized by CYP3A4. Zaleplon is primarily fol infusion as “triggering” stimuli.147 Propofol is suggested to induce
metabolized by aldehyde oxidase, but CYP3A4 is also involved in disruption of mitochondrial free fatty acid utilization and metabolism,
parent compound oxidation. Zopiclone is primarily metabolized by causing a syndrome of energy imbalance and myonecrosis similar to
CYP3A4 and CYP2C8, whereas eszopiclone is metabolized mainly other mitochondrial myopathies.22,125,148 Case reports associate propofol
by CYP3A4 and CYP2E1. Various pharmacokinetic interactions with with metabolic acidosis with elevated lactate concentration and fatal
inhibitors or inducers of CYP450 enzymes and these medications have myocardial failure in children and young adults; however, it has been
been reported.51 reported in older adults as well.98 Cases of metabolic acidosis may be
In isolated overdoses, drowsiness and CNS depression are common. associated with an inborn disorder of acylcarnitine metabolism.160
However, prolonged coma with respiratory depression is exception- Caution is advised when prolonged propofol infusions are used in any
ally rare. Isolated overdoses usually manifest with depressed level of patient, especially children, as they may have a previously undiagnosed
consciousness without respiratory depression. For example, even at myopathy that would cause them to be at increased risk for PIS. Despite

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 Chapter 74 Sedative-Hypnotics 1067

the increasing number of reports of PIS in the literature, a direct cause- Dexmedetomidine has no effect at the GABA receptor, and unlike
and-effect relationship remains to be fully elucidated. other sedative-hypnotics, it is not associated with significant respi-
The unique nature of propofol’s carrier base, a milky soybean emul- ratory depression. Although mechanistically similar to clonidine,
sion formulation, is associated with multiple adverse events. It is a fertile dexmedetomidine does not appear to cause as much respiratory
medium for many organisms, such as enterococcal, pseudomonal, staphy- depression as clonidine. Dexmedetomidine is said to induce a state
lococcal, streptococcal, and candidal strains. In 1990, the Centers for Disease of “cooperative sedation,” in which a patient is sedated but yet able to
Control and Prevention (CDC) reported an outbreak of Staphylococcus interact with health-care providers. Dexmedetomidine may also have
aureus associated with contaminated propofol. This carrier base also analgesic effects.23
impairs macrophage function,22 causes hypertriglyceridemia33,55,67,76 and Dexmedetomidine is currently approved for use only for less than
histamine-mediated anaphylactoid reactions,31,62,148 and impairs platelet 24 hours, as safety trials have not yet explored its use beyond 24 hours.
and coagulation function.4,29 Unlike clonidine, rebound hypertension and tachycardia have not been
described upon cessation of dexmedetomidine. Because dexmedeto-
midine decreases central sympathetic outflow, its use should probably
■ ETOMIDATE 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
H3C
the continuous infusion may help to prevent or lessen the hypotensive
CH
O effects.23
N
CH3CH2 O C
N
RAMELTEON/MELATONIN
Etomidate is an intravenous nonbarbiturate, hypnotic primarily used
as an anesthesia induction agent. It is active at the GABAA receptor, Ramelteon is a synthetic melatonin-analog that is FDA approved for
specifically the β2 and β3 subunits.91,104 Only the intravenous formula- the treatment of chronic insomnia. Ramelteon has been proposed to
tion is available in the United States. The onset of action is less than 1 decrease both latency to sleep induction and length of persistent sleep.127
minute and its duration of action is less than 5 minutes. Melatonin (N-acetyl-5-methoxytryptamine) and melatonin-containing
Etomidate is commercially available as a 2 mg/mL solution in a 35% products are sold as dietary supplements. Melatonin is naturally syn-
propylene glycol solution. Propylene glycol toxicity from prolonged thesized from tryptophan by the enzyme 5-hydroxyindole-O-methyl-
etomidate infusions is implicated in the development of hyperosmolar transferase, primarily within the pineal gland in humans. Melatonin
metabolic acidosis.78,144,146 Etomidate has minimal effect on cardiac and ramelteon both act as agonists at MT-1 and MT-2 receptors, which
function, but rare cases of hypotension are reported.42–44,135 Etomidate are G protein–coupled receptors mainly located in the suprachiasmatic
has both proconvulsant and anticonvulsant properties.25,103 Involuntary nucleus of the brain.127 Ramelteon is specific for MT-1 and MT-2
muscle movements are common during induction, and may be caused receptors, whereas melatonin is active at other melatonin receptors that
by etomidate interaction with glycine receptors at the spinal cord are likely not involved in sleep. MT-1 receptors appear to be involved
level.27,84,85 in sleep induction, whereas MT-2 receptors are involved in regulation
Etomidate depresses adrenal production of cortisol and aldosterone of the circadian sleep-wake cycle in humans.134
and has thus been associated with adrenocortical suppression, usually Ramelteon is administered as an oral medication that is rapidly
after prolonged infusions.117,152,153 One prospective randomized trial absorbed but undergoes significant first-pass metabolism. Ramelteon
demonstrated chemical adrenal suppression with decreased serum is metabolized primarily by CYP1A2 hepatic isoenzyme. The half-life
cortisol levels and decreased responses to ACTH stimulation in trauma of ramelteon with therapeutic use is roughly 1.5 hours.
patients even after receiving single-dose etomidate.54 The authors pos- Adverse effects of ramelteon are often mild, and usually include
tulate that this may have been associated with prolonged duration of dizziness, fatigue, headache. The endocrine effects of long-term expo-
hospital and ICU stays, as well as prolonged ventilator requirements. sure to ramelteon seem to be limited to subclinical increases in serum
Other authors question the clinical significance of adrenal suppression prolactin concentration in women, and do not appear to affect adrenal
from single-dose etomidate administration.137 or thyroid function.109 In addition, ramelteon has a low abuse potential
and does not appear to be associated with a withdrawal syndrome or
with rebound insomnia.49,77,83 As of yet, there are no reported cases of
■ DEXMEDETOMIDINE significant toxicity from ramelteon overdose.
Dexmedetomidine is a central α2 adrenergic agonist that decreases cen-
tral presynaptic catecholamine release, primarily in the locus coeruleus.
It was approved by the FDA in 1999 for short-term use in the critical SUMMARY
care setting. It has a terminal half-life of 1.8 hours and its volume of
distribution is less than 1 L/kg. When dexmedetomidine is used to Sedative-hypnotics encompass a wide range of xenobiotics with
help wean patients from ventilators, a better level of desired sedation is varying mechanisms of action. Patients with sedative-hypnotic over-
achieved with less associated delirium.97,136 It is also used for procedural doses often present with the primary manifestation of CNS depres-
sedation in certain settings such as interventional radiology procedures sion; however, death typically results from respiratory depression
and awake fiberoptic intubations. In addition, other authors have and subsequent cardiovascular collapse in the setting of concurrent
described lesser opioid requirements in postoperative patients sedated co-ingestion of other CNS depressants. Careful monitoring, airway
with dexmedetomidine, compared with propofol. Individual case protection, and good supportive care are the cornerstones of treatment.
reports also document the use of dexmedetomidine in benzodiazepine, Specific antidotes such as flumazenil and treatments such as hemodi-
opioid, or ethanol withdrawal.28,36,114,138,139 alysis are rarely indicated.

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 1068 Part C The Clinical Basis of Medical Toxicology

26. Criswell HE, Ming Z, Pleasant N, et al. Macrokinetic analysis of blockade

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