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Goldfrank's Toxicologic Emergencies, 11e

Chapter A26: Benzodiazepines

Fiona Garlich Horner; Robert S. Ho man; Lewis S. Nelson; Mary Ann Howland

INTRODUCTION
Benzodiazepines are a class of sedative–hypnotics that share similar chemical structures, receptor
physiology, and clinical e ects. Benzodiazepines are used broadly for a range of clinical indications,
including xenobiotic-induced seizures, xenobiotic-induced psychomotor agitation, withdrawal from ethanol
and other sedative–hypnotics, cocaine-associated myocardial ischemia, chloroquine overdose, and to
induce muscle relaxation in serotonin toxicity, neuroleptic malignant syndrome, strychnine poisoning, and
black widow spider envenomation. This Antidotes in Depth provides a summary of the clinical pharmacology
of benzodiazepines and a review of their use in specific clinical scenarios, with an emphasis on specific drug
selection and safe administration. A discussion of the manifestations and treatment of overdose of
benzodiazepines and similar xenobiotics is found in Chap. 72.

HISTORY
The first benzodiazepine, chlordiazepoxide, was discovered serendipitously in 1957 as part of a quest to
develop safer and more marketable sedatives.70 Before this, the most commonly prescribed sedative–
hypnotics were the barbiturates, which by the 1920s had largely supplanted chloral hydrate, bromides, and
opium as the sedatives of choice.71 Although safer than their predecessors, barbiturates were associated
with dependence, abuse, and numerous overdose deaths, limiting their therapeutic use. Meprobamate,
marketed in the 1950s as the first anxiolytic, was soon withdrawn from the market because of similar
problems. The introduction of chlordiazepoxide in 1960 represented a major breakthrough in the field of
psychopharmacology and ushered in an era of rapid development and widespread use of numerous other
benzodiazepines. The improved safety profile of benzodiazepines as a class allowed them to become, for a
time, the most widely prescribed drugs in the world.70

CHEMISTRY
All benzodiazepines share a common chemical structure, shown in Fig. A26–1. This structure links a benzene
ring with a diazepine ring and gives rise to the name used to describe the drug class. The additional phenyl
ring is present in all clinically important benzodiazepines and serves as a site of substitution that modulates
certain pharmacologic characteristics. Modification of side chains of the ring structures leads to di erences

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in lipophilicity, central nervous system (CNS) penetration, duration of action, potency, and rate of
elimination. The majority of benzodiazepines are highly protein bound and lipophilic, entering the CNS via
passive di usion.48 The nonbenzodiazepine hypnotics (zolpidem, zopiclone, and zaleplon) lack the typical
benzodiazepine structure but have similar pharmacologic e ects.40 A discussion of the manifestations and
treatment of overdose of benzodiazepines and other sedative–hypnotics is found in Chap. 72.

FIGURE A26–1.
Generic structure of benzodiazepines.

γ-AMINOBUTYRIC ACID TYPE A RECEPTORS

Benzodiazepines bind to a specific site on the postsynaptic γ-aminobutyric acid type A (GABAA) receptor. The
GABAA receptor is a ligand-gated chloride channel that, when bound by the inhibitory neurotransmitter
GABA, opens to allow an inward flux of negatively charged chloride ions. This results in membrane
hyperpolarization and subsequent inhibition of neuronal excitability. When benzodiazepines bind to the
GABAA receptor, the frequency of channel opening is increased in the presence of GABA, resulting in

increased chloride ion influx and enhanced neuronal inhibition.112 In the absence of GABA, the
benzodiazepines have no e ect on chloride conductance.

The GABAA receptor is formed by five polypeptide subunits that span the cell membrane in a circular fashion
to create the chloride channel. These subunits are coded as α, β, γ, δ, ε, θ, λ, or ρ, and at least 19 isoforms of
these subunits (eg, α1-5) are identified.106,114 Numerous subunit configurations are possible, but the most
common pentamer is composed of two α subunits; two β subunits; and an additional subunit, most
commonly γ2.100,114 Di erent GABAA receptor subunit isoforms predominate in di erent areas of the CNS

and confer distinct functional e ects and pharmacologic properties.100 Benzodiazepines have no
appreciable binding to GABAB receptors.

BENZODIAZEPINE RECEPTORS

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Rapidly evolving neuroscience has resulted in an exponential expansion in the understanding of

benzodiazepine receptors. As a result, significant evolution in nomenclature has occurred. Older, imprecise
terminology was replaced by more specific characterization of binding sites defined by molecular structure
and function.100

Central

The term “central benzodiazepine receptors” is used to refer to benzodiazepine binding sites on GABAergic
neurons of the nervous system. The benzodiazepine binding site is located at the interface of an α and a γ
subunit; most commonly an α1 and a γ2 subunit.106,114 Anatomical variations in the α isoforms of GABAA

receptors confer distinct pharmacologic response to benzodiazepine binding.80 The α1 isoform, located in
the sensory and motor areas of the brain, mediates sedative and hypnotic e ects. The α2, α3, and α5 isoforms
are dispersed throughout the subcortical and limbic areas of the brain and mediate anxiolytic and
anticonvulsant e ects. γ-aminobutyric acid type A receptors that contain α4 and α6 subunits are insensitive

to benzodiazepines and are of low prevalence in the brain.100

In older nomenclature, GABAA receptors with primarily α1 isoforms were termed benzodiazepine type 1 (BZ1)
receptors or ω1 receptors, and those with predominance of α2, α3, and α5 isoforms were called

benzodiazepine type 2 (BZ2) receptors or ω2 receptors.81 Most typical benzodiazepines have substantial
a inity for the α1, α2, α3, and α5 isoforms, which explains their combined sedative–hypnotic, anxiolytic, and
anticonvulsant e ects. In contrast, the nonbenzodiazepine hypnotics (eg, zolpidem) have high a inity for α1,
intermediate a inity for α2 and α3, and low a inity for α5 isoforms, which explains their lack of antiepileptic

e ects.40 γ-Aminobutyric acid type A receptors are now more simply classified as having high-, low-, or
intermediate-a inity benzodiazepine binding sites.100

Opposite the benzodiazepine binding site, situated at the α–β subunit interface, is the binding site for
neurosteroids such as pregnenolone (Fig. A26–2).53 These neurosteroids are potent modulators of GABAA
receptor function and are important products of the tryptophan-rich sensory protein receptor (see below).

FIGURE A26–2.

The γ-aminobutyric acid type A (GABAA) chloride (Cl–) channel. The figure demonstrates a typical

configuration of the GABAA Cl– channel, which consists of two α, two β, and one γ isoforms. The
benzodiazepine (BZD) receptor is located between an α and a γ subunit. Neurosteroid binding at the
opposite side of the α isoform is a positive allosteric modulator.

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Peripheral (Tryptophan-Rich Sensory Protein)

The term “peripheral benzodiazepine receptor” (PBR) was originally used in the 1970s to define any
benzodiazepine binding sites outside of the nervous system.18 They were also termed BZ3 or ω3 receptors to

distinguish them from the “central receptors” described earlier.63 However, it was subsequently discovered
that this receptor was also expressed in CNS tissues, that it was the binding site for numerous other
nonbenzodiazepine ligands, and that its structure and function were immensely complex and vastly
dissimilar from that expressed in GABAergic neurons.91 The PBR was determined to be an 18-kDa
translocator protein located primarily on the outer mitochondrial membrane, and a member of a family of
proteins involved in transmembrane signaling as part of host defense, stress response, and regulatory
mechanisms in many species.22,35,37,91 This protein is termed tryptophan-rich sensory protein and
abbreviated as TSPO. Although the term PBR remains attractive, for simplicity and consistency, the current
term TSPO will be used in the remainder of this discussion.

The TSPO has a heterotrimer structure that is composed of an isoquinoline binding protein, which is the
actual receptor (TSPO); a voltage-dependent anion channel (VDAC); and an adenine nucleotide transporter
(ANT).91 The TSPO protein and the VDAC span the outer mitochondrial membrane, and the ANT bridges the
outer and inner membranes (Fig. A26–3). Sequencing of TSPOs demonstrates that they are of ancient

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evolutionary origin with DNA from bacteria and fungi having a nearly 50% homology of the isoquinoline
binding domain with human DNA.35,38 This finding suggests that the TSPO performs a “housekeeping
function,” that is, they are involved in a process or processes that are essential for life. In higher life forms,
TSPOs are found in the brain, adrenal glands, heart, and kidney and are especially concentrated in tissues in
which steroids are synthesized.91 Tryptophan-rich sensory proteins are implicated in cholesterol and
protoporphyrin transport required for the synthesis of neurosteroids, heme, and bile salts; ischemia and
reperfusion; regulation of calcium channels; mitochondrial respiration; apoptosis; microglial activation; and
the immune response.38,91,113 More recently, TSPO ligands were investigated as potential targets for a variety
of disorders, including anxiety, cancer, ischemia, and others.24,30,57,59,86,92,107,122 It is hypothesized that the
TSPO has two major roles: opening of the mitochondrial permeability transition pore, leading to calcium
influx and apoptosis,11,37,69 and, as noted earlier, in synthesis of neurosteroids that modulate GABAA

function.90,101

FIGURE A26–3.
The “peripheral benzodiazepine receptor” has three main components: the tryptophan-rich sensory protein
(TSPO; 18-kDa translocator protein), a voltage-dependent anion channel (VDAC), and an adenine nucleotide
transporter (ANT), which are shown on the mitochondrial membrane. Stimulation of the TSPO can trigger
influx of Ca2+ or cholesterol across the mitochondrial membrane. MiPTP = mitochondrial permeability
transition pore; SCC = side chain cleavage.

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PHARMACOKINETICS AND PHARMACODYNAMICS

In the hospital setting, benzodiazepines are usually administered to treat seizures, psychomotor agitation, or
sedative–hypnotic withdrawal. This Antidotes in Depth focuses on the most commonly used parenteral
benzodiazepines: diazepam, lorazepam, and midazolam. Clinically important pharmacologic parameters of
these three benzodiazepines are listed in Table A26–1. Of note, although they are o en used interchangeably
for a variety of indications, the onsets and peak e ects of sedative and antiepileptic activity are distinctly
di erent for each benzodiazepine. Thus, an understanding of pharmacology is crucial in selecting the
optimal benzodiazepine, dose, route, and interval to ensure adequate response and limit adverse reactions.

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TABLE A26–1
Pharmacologic Properties of Select Benzodiazepines

Parameter Diazepam Midazolam Lorazepam

Molecular 284.7 325.78 321.2

weight (g/mol)

Oral >90% 40% >90%

bioavailability

Volume of 0.89 ± 0.18 0.80 ± 0.19 1.28 ± 0.34

distribution
(healthy adults)
(L/kg)

Protein binding 97–99 96 85

(%)

Lipid solubility 3.86 3.68 2.48

(LogD;
octanol/water at
pH 7)

Hepatic Phase 1 Phase 1 Phase 2

metabolism

Active Yes Yes: α-hydroxymidazolam (10% No

metabolites (desmethyldiazepam of parent, but accumulates with
and others) chronic dosing)

Average dose
(mg) in a 70-kg
adulta

Sedation 10 mg IV over 2 min 2 mg IV over >2 min (maximum,
Wait 2 min before 1.5 mg over > 2 min in older
redosing adult or debilitated patients), or
5–10 mg IM
Wait 2 min before IV redosing
2 mg IV over one minute
(dilute with equal volume of
NS or D5W before injection)
Wait 15 min before redosing

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Parameter Diazepam Midazolam Lorazepam

Status 10 mg IV 10 mg IM 4 mg IV
epilepticus
(initial dose)

Diluent(s) Alcohol 10% Benzyl alcohol 1% Benzyl alcohol 2%

Benzyl alcohol 1.5% Sodium edetate 1% Propylene glycol 80%

Propylene glycol
40%

Formulations 5 mg/mL 1 mg/mL 2 mg/mL

5 mg/mL (Rectal gel) 5 mg/mL 4 mg/mL

aAvoid intraarterial administration because severe spasm may occur with resulting ischemia or gangrene. Also avoid

extravasation.

D5W = 5% dextrose in water; IV = intravenous; NS = 0.9% NaCl.

The intravenous (IV) route is preferred in critically ill patients because it guarantees immediate and complete
absorption with a relatively rapid onset of action. Intraosseous delivery of benzodiazepines is equivalent to
IV administration and thus should be used in critically ill patients when IV access cannot be rapidly
established.64 When IV or intraosseous access is unavailable, intramuscular (IM) lorazepam or midazolam is
recommended because they both have good absorptive profiles.43,54,105,118 In contrast, the absorption a er
IM diazepam is best described as slow, incomplete, erratic, and dependent on the site of administration and
the skill of the person administering it.33,54,61 We therefore recommend not to use IM injection of diazepam
unless no other alternatives exist.

Intranasal and rectal administration is occasionally used for benzodiazepine delivery when IV access is not
available, especially in children with seizures. However, both routes are inferior to IV administration. When
rectal diazepam was compared with IV diazepam in children with seizures, the peak concentration was more
variable, was delayed by about 20 minutes, and resulted in higher failure rates.88,96 Similarly, although
midazolam is more rapidly absorbed than diazepam a er both nasal and rectal administration, the kinetic
profile of nasal or rectal midazolam is still inferior to IV administration of either diazepam or midazolam
(Table A26–2).50,75,96

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TABLE A26–2
Relative Pharmacodynamic Properties of Benzodiazepines in Humans

  Diazepam Midazolam Lorazepam

Anticonvulsant      

Onset of action      

IV Rapid (minutes) Rapid (minutes) Rapid

(minutes)

IM Not advisable ∼3 min 9 min

IN 3–5 min 5 min ∼10 min

PR 5–10 min 10–20 min 20 min

Duration of action      

IV 1–2 h 30–80 min Many hours

IM Unpredictable 1–2 h Many hours

Sedative      

Onset of action      

IV 1–2 min 1–2 min 5–20 min

IM Unpredictable 5–10 min 20–30 min

IN 3–5 min 5–10 min ∼10 min

Relative duration      
of action

Single dose Short Short Long

Repeated doses Long (secondary to active Intermediate (secondary to active Long

metabolites) metabolites)

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IM = intramuscular; IN = intranasal; IV = intravenous; PR = per rectum.

A er being absorbed, benzodiazepines distribute into the CNS to produce their sedative and antiepileptic
e ects. The di erences among individual drugs are evaluated in terms of their pharmacokinetics, such as
plasma or cerebral drug concentrations, or their onset and pharmacodynamics, such as changes in either
consciousness or electroencephalographic (EEG) findings. In animal and human studies, whereas diazepam
demonstrates the most rapid onset and time to peak clinical e ects, lorazepam is associated with significant
pharmacodynamic delays.10,44,45 In a cat model, intravenously administered diazepam, midazolam, and
lorazepam all appeared rapidly in the cerebrospinal fluid (CSF), but lorazepam exhibited a slower time to
peak concentration, a slower onset of EEG e ect, and a longer duration of EEG activity.10

In similar human studies, volunteers were given a 1-minute IV infusion of diazepam (0.15 mg/kg), midazolam
(0.1 mg/kg), or lorazepam (low dose, 0.0225 mg/kg; high dose, 0.045 mg/kg).44,45 Electroencephalographic
analysis was used as a surrogate for the pharmacodynamic e ects of sedation. Peak EEG e ects were present
immediately at the end of the diazepam infusion but were delayed for 5 to 10 minutes a er midazolam
administration45 and 30 minutes a er lorazepam administration (Table A26–3).44 The delay to peak e ect
a er lorazepam administration is due to its decreased lipophilicity compared with diazepam and midazolam,
whose greater lipophilicity allows them to rapidly cross the blood–brain barrier.46

TABLE A26–3
Selected Pharmacokinetic and Pharmacodynamic Properties of Intravenous Benzodiazepines 44,45

Diazepam (0.15 Midazolam (0.1 Lorazepam (0.045

Parameter
mg/kg) mg/kg) mg/kg)

Onset of EEG e ect Immediate Immediate Slow

Time to peak EEG e ect 1 5–10 30

(min)

Duration of EEG e ect (h) 5–6 2 8

Elimination half-life (h) 33 ± 5 2.8 ± 0.5 12 ± 2

EEG = electroencephalographic; IV = intravenous.

Benzodiazepines, like many centrally acting xenobiotics, undergo a two-phase elimination in which they
redistribute from the central to the peripheral compartment (represented by the alpha half-life) and then are
eliminated from the body via metabolism and excretion (represented by the β half-life).110 Benzodiazepines

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are classically categorized as long acting (diazepam and chlordiazepoxide), intermediate acting (lorazepam,
alprazolam, clonazepam), and short acting (midazolam) based on their terminal beta elimination half-
lives.47 However, this does not necessarily correlate accurately with their clinical duration of action, which is
more dependent on α redistribution. For example, because of rapid peripheral redistribution, a single dose of
diazepam has a relatively short duration of action despite its long elimination half-life of 20 to 70 hours.
Lorazepam has a much shorter elimination half-life of 10 to 20 hours, but the duration of action a er a single
dose is relatively long.47 These characteristics change a er repeated dosing.

The presence of pharmacologically active metabolites prolongs the duration of action of select
benzodiazepines, especially when repeated doses are administered. All benzodiazepines undergo hepatic
metabolism, either by oxidation (phase I) or by conjugation with glucuronide (phase II).93 Drugs that undergo
phase I oxidation, such as diazepam, midazolam, and chlordiazepoxide, produce active metabolites.
Diazepam is metabolized to nordiazepam (desmethyldiazepam, half-life, 48–72 hours) and temazepam (half-
life, 8–22 hours), which are both subsequently metabolized to oxazepam (half-life, 4–15 hours).47,121 These
long-acting active metabolites e ectively prolong the clinical e ect of diazepam, though because of
redistribution out of the CNS, the duration of clinical e ect is significantly less than the elimination half-life.
Glucuronidation, as in the case of lorazepam, results in the production of pharmacologically inactive
metabolites. Older adult patients and those with hepatic failure have decreased clearance of drugs that
undergo phase I oxidative metabolism.93 As such, administration of diazepam, midazolam, or
chlordiazepoxide in these patients o en results in excessive accumulation of parent drug, a prolonged half-
life, and increased adverse e ects. Lorazepam is o en recommended in patients with cirrhosis for this
reason. The relative pharmacodynamic properties of diazepam, lorazepam, and midazolam are shown in
Table A26–2.

ROLE OF BENZODIAZEPINES IN SELECT CLINICAL SCENARIOS

Many chapters in this text discuss the use of benzodiazepines as GABAA agonists in the management of
poisoned patients (Chaps. 13, 14, 69, 73, 75, 77, 79, and 83). A few commonly encountered clinical scenarios
deserve brief discussion here: xenobiotic-induced seizures, sedative–hypnotic withdrawal, and psychomotor
agitation. There is extensive pharmacologic and clinical evidence supporting the use of GABAA agonists in
these settings, although the choice of agonist is based on many variables. In contrast, the use of
benzodiazepines as modulators of TSPOs for the treatment of poisoned patients is a more speculative but
evolving field. As such, focused discussions of two additional xenobiotics, chloroquine (Chap. 55) and
cocaine (Chap. 75), are warranted.

Xenobiotic-Induced Seizures

Benzodiazepines are well-established as the initial treatment of choice for xenobiotic-induced

seizures.25,31,72,103,104,123,124 Unlike in traumatic or epileptic seizure disorders which arise from a localized
seizure focus, the initiation and propagation of xenobiotic-induced seizures result from a global decrease in
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seizure threshold, either from a decrease in GABAergic tone or an increase in excitatory amino acid
neurotransmission.25 Therefore, non–sedative–hypnotic antiepileptics such as phenytoin are likely to be
ine ective in treating xenobiotic-induced seizures and should be avoided.5,103 Furthermore, there is
evidence that use of non–sedative–hypnotic antiepileptics result in increased toxicity, as occurs with the
enhanced cardiotoxicity of phenytoin in tricyclic antidepressant poisoning.21,103

The selection of a specific benzodiazepine is informed by pharmacokinetic data and clinical studies of
patients with epileptic seizures and status epilepticus. Current data and clinical guidelines indicate that IV
lorazepam or IM midazolam is preferred for rapid seizure cessation. Clinical trials demonstrate that despite
its slower CNS penetration, IV lorazepam is more e ective than other IV benzodiazepines in the cessation of
status epilepticus, with a lower risk of seizure recurrence.2,8,68,94,111 Intravenous midazolam may be as
e ective as IV lorazepam, but it is not as well studied.94 A large multicenter, randomized, double-blind trial
demonstrated that a large dose of IM midazolam (10 mg) was at least, if not more, e ective than IV lorazepam
(4 mg) for seizure cessation in the prehospital setting.105,117 Another study suggests that IM or intranasal
benzodiazepines are superior to the IV route if IV access is not already established.3 Thus, IV lorazepam and
IM midazolam are the recommended first-line antiepileptics for seizures or status epilepticus in the absence
of withdrawal,20,117

If seizure control is not achieved promptly with rapidly escalating doses of benzodiazepines, second-line
sedative–hypnotics such as phenobarbital or propofol are recommended along with appropriate
management of airway, ventilation, and circulation.25 If overdose of isoniazid or other hydrazine-containing
compound is suspected, high-dose pyridoxine should be administered (Chaps. 56 and Antidotes in Depth:
A15).115 Benzodiazepines potentiate the e ect of pyridoxine by acting syngergistically28 but are o en
ine ective as sole treatment for hydrazine-induced seizures because of their upstream blockade of GABA
synthesis.

Sedative–Hypnotic Withdrawal

Benzodiazepines were established almost 50 years ago as the first-line treatment of alcohol withdrawal in a
landmark study in which patients treated with chlordiazepoxide had significantly lower incidence of seizures
and delirium tremens.58 Since then, the benzodiazepines have also been used as the primary management
of withdrawal from benzodiazepines,89 γ-hydroxybutyric acid (GHB)16,109 and GHB precursors 1,4-
butanediol and gamma-butyrolactone,102,120 as well as important adjuncts in the treatment of withdrawal
from baclofen,99,125 gabapentin,14 and the nonbenzodiazepine hypnotics (eg, zolpidem, zopiclone).9,26

Numerous trials have investigated various benzodiazepines, routes, doses, and treatment strategies.
Diazepam has favorable properties that make it a desirable first-line treatment for moderate to severe
sedative–hypnotic withdrawal, in which prolonged agitation is expected. It has the most rapid time to onset
and peak clinical e ect, which limits oversedation when repeated dosing is required. The presence of active

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diazepam metabolites also confers a longer duration of therapeutic e ect and an autotapering e ect at the
end of therapy.121 The delay of lorazepam to onset and peak clinical e ect frequently results in oversedation
when serial doses are administered in rapid succession (“dose stacking”). The relatively short duration of
action of midazolam limits its utility in xenobiotic withdrawal. Oral chlordiazepoxide is commonly used in
early uncomplicated alcohol withdrawal because of its long duration of action and active metabolites (Chap.
77).

Psychomotor Agitation

In patients with extreme psychomotor agitation caused by sympathomimetic or other xenobiotic toxicity, IV
diazepam or midazolam is recommended because of their rapid onset and rapid peak e ects. The relatively
slow onset and delayed peak of lorazepam o en leads to the administration of several doses before the full
e ect of the first dose is appreciated, with resultant oversedation. When a short duration of sedation is
anticipated, such as when treating a patient with toxicity a er IV or inhaled use of cocaine, midazolam is
recommended over diazepam or lorazepam in that the duration of the e ects of midazolam better matches
the duration of e ects of cocaine, thereby limiting oversedation when cocaine is rapidly metabolized. In
some patients with severe psychomotor agitation, obtaining IV access can be di icult or impractical and can
place sta at undue risk. In such cases, we recommend IM midazolam for the treatment of undi erentiated -
agitation.56,60,77 This should be followed, when conditions permit, by IV diazepam or midazolam if agitation
persists (Chaps. 73 and 75).

Chloroquine

Although chloroquine overdose is uncommon, case fatality rates are extremely high, and ingestion of 5 g or
more was once considered universally fatal. However, in 1988, a case series of patients with chloroquine
overdose who survived with the use of an aggressive new regimen was described.97 The protocol, consisting
of early endotracheal intubation, high-dose epinephrine infusion, and IV diazepam (2 mg/kg over 30 min),
resulted in the survival of 10 of 11 patients who ingested at least 5 g of chloroquine. This treatment strategy
was based on observations that patients with mixed chloroquine and diazepam overdoses experienced less
cardiovascular toxicity.29 Subsequent animal studies demonstrated that diazepam mitigated the convulsant
e ect4 as well as the hemodynamic and electrocardiographic manifestations98 of chloroquine poisoning.

The mechanism of the beneficial cardiovascular e ect of diazepam in chloroquine toxicity is unclear, but
peripheral TSPO agonism appears to play a role. In isolated perfused hearts, high-dose diazepam has
positive inotropic e ects that are suppressed by a TSPO antagonist.67 Benzodiazepines, chloroquine, and
experimental TSPO agonists share some structural elements, suggesting a receptor-based mechanism (Fig.
A26–4). Functional similarity is also suggested by evidence that both flurazepam and PK 11195 (a TSPO
agonist) have antimalarial activity.34 Thus, despite the limitations in translating laboratory data to human
poisoning, one could speculate that the beneficial e ects of high-dose diazepam result from competitive
inhibition between chloroquine and TSPOs. Although the ideal regimen has not been defined, for patients

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with severe chloroquine toxicity it is reasonable to administer high-dose diazepam at a dose of 2 mg/kg IV
over 30 minutes followed by 1 to 2 mg/kg/d for 2 to 4 days. Seizures should be treated with diazepam or
another IV benzodiazepine.

FIGURE A26–4.
Comparative structures of flurazepam, PK 11195 (a PBR agonist), and chloroquine. Note the similarity and
particularly the shared isoquinoline rings of chloroquine and PK 11195.

Cocaine-Associated Chest Pain

Patients who use cocaine frequently present to emergency departments with chest pain or signs or
symptoms that could represent myocardial ischemia or infarction.19 Unlike most patients with acute cocaine
toxicity, however, these patients o en present hours a er their last drug use and without the classic
sympathomimetic findings of acute cocaine toxicity.51 Although the pathophysiology of cocaine-induced
myocardial ischemia is complex and multifactorial (Chap. 75), one component of delayed myocardial
ischemia likely results from the vasoconstrictive actions of benzoylecgonine, the principal metabolite of
cocaine.74 Benzoylecgonine is distinct from cocaine in that it has a much longer half-life,6,7 does not produce
CNS stimulation,83,84 and is a direct constrictor vasoconstricts or through modulation of calcium channels.73
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Limited research suggests that chronic cocaine use is associated with an increased number of TSPOs on
human platelets.27 Also in humans, cocaine withdrawal is associated with a decrease in TSPOs on
neutrophils. In the myocardium, TSPOs are either present on mitochondria or coupled to calcium
channels.82 Specifically, TSPO ligands have inhibitory e ects on myocardial L-type calcium channels.23 Also
in experimental models of cardiac ischemia and reperfusion injury, TSPO agonists limit myocardial infarction
size and improve cardiac function.65,122 This e ect most likely occurs through inhibition of the opening of
the mitochondrial permeability transition pore,87 the opening of which is a common final mechanism of cell
death. Additionally, although the exact mechanism is unclear, TSPO agonists directly antagonize the
vasoconstrictive e ects of norepinephrine in rat aortic tissue.41

Benzodiazepines are commonly used to treat the agitation associated with sympathomimetic overdose
(Chaps. 73 and 75). Although it is assumed that the normalization of vital signs results from a decrease in CNS
stimulation and psychomotor agitation, it is reasonable to believe that the e ects on TSPOs are contributory.
In the same isolated perfused hearts described earlier, low-dose diazepam has a negative inotropic e ect
that results from an interaction with calcium currents.66

Two randomized controlled studies evaluated the use of benzodiazepines in patients with cocaine-
associated chest pain.15,52 In the first study, patients were randomized to receive nitroglycerin, diazepam, or
combined therapy.15 Diazepam was equivalent to nitroglycerin in improving chest pain, and combined
therapy appeared to o er no additional benefit. The second study randomized patients to nitroglycerin or
combined nitroglycerin with lorazepam therapy.52 In this trial, combined therapy was better than
nitroglycerin alone. Thus, it is reasonable to administer IV lorazepam or diazepam as an adjunct to
nitroglycerin therapy in patients with chest pain in the setting of recent cocaine use.

ADVERSE EFFECTS AND SAFETY ISSUES

The most common adverse e ects of benzodiazepines are CNS and respiratory depression. Although this is
unavoidable in some cases, it is limited by selecting the optimal drug and the proper dose and dosing
interval. Extra caution is advised in older adult patients because they are more sensitive, particularly to the
sedative and respiratory depressant e ects of midazolam.1 Additionally, patients with hepatic failure are at
increased risk of adverse e ects with diazepam or midazolam because of decreased drug clearance. For this
reason, we recommend lorazepam in patients with cirrhosis. In contrast, paradoxical reactions rarely occur in
which some patients become more agitated a er benzodiazepine administration, particularly
children.76,78,116 These infrequent reactions probably result from disinhibition and typically respond to
larger doses of benzodiazepines. Although paradoxical agitation also responds to flumazenil (Antidotes in
Depth: A25), we recommend against reversal when benzodiazepines are used for most toxicologic
indications.

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Intravenous benzodiazepines produce a mild reduction in heart rate and both systolic and diastolic blood
pressure. The e ects of midazolam are reportedly greater than diazepam,95 but this may merely be based on
an inability to determine an equivalent dosing regimen. Although these reductions result in part from
diminished sympathetic tone, direct myocardial e ects are rarely severe and are o en considered desirable
in the overdose setting.

Whereas respiratory depression is generally not a concern with oral benzodiazepines, parenteral
administration is documented to impair ventilation. Early investigations demonstrated that IM diazepam (10
mg) blunted the hypoxic ventilatory drive in normal subjects.62 Intravenous diazepam impaired the
ventilatory response to a rising PCO2 in normal volunteers.12 The impaired response to a rising PCO2 was
evident almost immediately and lasted for at least 25 minutes a er injection of 0.4 mg/kg of diazepam in
healthy volunteers.49 Studies with midazolam demonstrate similar alterations in respiratory physiology36
that are comparable in magnitude to those reported with diazepam.17 Apnea is reported a er IV midazolam
and is dose and rate related, with doses greater than or equal to 0.15 mg/kg being of particular concern.65
Individuals with preexisting pulmonary disorders, extremes of age, or exposure to other CNS or respiratory
depressants are more susceptible. When IM midazolam is used for the treatment of agitation, some transient
respiratory depression is noted, but the need for ventilatory support is uncommon.56,60,62

Pregnancy and Lactation

Diazepam, lorazepam, and midazolam all cross the placenta and are labeled as US Food and Drug
Administration Pregnancy Category D because of the risk of adverse e ects with chronic use or at the time of
delivery.55,79 Administration of benzodiazepines late in pregnancy or during labor can result in neonatal
flaccidity, respiratory di iculties, and hypothermia, termed the “floppy infant syndrome.” Chronic use late in
pregnancy can result in neonatal withdrawal symptoms. Additionally, an association with congenital
anomalies is suggested with use of prescription benzodiazepines in early pregnancy,32,79 although the bulk
of evidence suggests risk of teratogenicity is very low, if not nonexistent.39,55,119 The risk to a fetus is likely
negligible from short-term benzodiazepine administration in emergent situations, in which the risk of harm
from untreated xenobiotic poisoning vastly outweighs any potential adverse medication e ects. Thus, we
recommend that benzodiazepines not be withheld in critically ill poisoned patients because of pregnancy
status. If delivery is imminent, it is reasonable to select a short-acting benzodiazepine such as midazolam.

Benzodiazepines are excreted into breast milk in very small quanitites.55,79 Although single standard doses
typically do not result in adverse e ects, high doses, repeated administration, or prolonged use may result in
accumulation in the serum of breastfed infants, with a resultant risk of sedation.108 It is thus reasonable to
forgo breastfeeding (by discarding pumped breast milk, ie, “pumping and dumping”) for several hours a er a
single IV dose or for 24 hours a er repeated benzodiazepine dosing (Chaps. 30 and 31).85

DOSING AND ADMINISTRATION

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When selecting a benzodiazepine for a given clinical scenario, the pharmacokinetic and pharmacodynamic
parameters presented in Tables A26–1 and A26–3 should be considered, along with existing clinical data.
Onset of e ect, peak e ect, and duration of e ect should be weighed in the context of the anticipated clinical
course. It is worth noting that each of the three benzodiazepines discussed will likely have some e icacy in
all clinical scenarios for which a benzodiazepine is indicated. Although selection of a specific benzodiazepine
is o en based on availability within the hospital and regional historic preferences, some general
recommendations can be made.

Intravenous dosing is recommended for critically ill patients, although other routes such as IM, intranasal, or
intraosseous are e ective when IV access is unavailable or impractical. Benzodiazepines with rapid onset of
action, such as diazepam or midazolam, are recommended when rapid symptom control is necessary. A
long-acting benzodiazepine with active metabolites, such as diazepam, is recommended in cases of
sedative–hypnotic withdrawal and ethanol withdrawal when prolonged symptoms are anticipated.
Lorazepam is reasonable in patients with hepatic failure because of its relatively preserved clearance and
lack of active metabolites. Intravenous lorazepam or IM midazolam is recommended for seizure cessation.

Common equivalent initial IV doses in adults are: lorazepam 1 mg, diazepam 5 mg, and midazolam 2 mg.13,42
When repeated administration is necessary, appropriate spacing between doses is crucial to avoid
oversedation and respiratory depression. Intravenous diazepam and midazolam can be safely administered
every 2 to 5 minutes, but we recommend delays prior to repeating lorazepam doses of at least 15 minutes to
account for the slower time to peak e ect. It is important to note that switching from one benzodiazepine to
another is rarely indicated and increases the risk of an adverse drug event from unpredictable peak e ects or
improper therapeutic doses or dosing intervals (Chaps. 14, 73, 75, and 77).

FORMULATION AND ACQUISITION

Parenteral benzodiazepines are available from multiple manufacturers in varying concentrations. It is
essential to recognize that some formulations contain several significant and varied diluents, most notably
propylene glycol (Table A26–1). Large doses or prolonged continuous infusions of benzodiazepines may
result in toxicity from these excipients (Chap. 46).

SUMMARY
Although benzodiazepines are commonly used in a variety of medical settings, subtle di erences exist in
their pharmacokinetics and pharmacodynamics. Optimal use of these drugs requires a thorough
understanding of these di erences.

When choosing among di erent benzodiazepines, the desired onset of action, peak e ect, and duration of
action aid in selecting the preferred therapy.

In general, IV administration is preferred in an emergency because of rapid and reliable absorption.

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Because of rapid onset of action and short time to peak e ect, expedient sedation is best achieved with
midazolam when a short duration of action is desirable or diazepam for a longer duration of action.

When IV access is not available, pharmacokinetic and pharmacodynamic parameters favor the use of IM
midazolam for sedation.

When used for control of the agitated patient, the delayed peak e ect of lorazepam (regardless of route of
administration) is undesirable.

Intravenous lorazepam is highly e ective for seizure cessation, with a longer duration of antiepileptic e ect
than IV diazepam or midazolam. Large doses of IM midazolam are e ective for status epilepticus in the
prehospital setting.

Although the use of benzodiazepines as TSPO (peripheral benzodiazepine receptor) agonists may explain
some unique therapeutic e ects of these drugs, existing research is too limited to o er guidance with regard
to choice of drug, dose, or dosing interval required to optimize peripheral benzodiazepine receptor response.

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