BENZODIAZEPINES

Ben Tsutaoka, PharmD

The drug class of benzodiazepines includes many compounds that vary widely in potency,

duration of effect, presence or absence of active metabolites, and clinical use

(Table II–14). Three nonbenzodiazepines—eszopiclone, zaleplon, and zolpidem—

have similar clinical effects and are included here. In general, death from benzodiazepine

overdose is rare unless the drugs are combined with other CNS-depressant

agents, such as ethanol, opioids, and barbiturates. Newer potent, short-acting agents

have been considered the sole cause of death in recent forensic cases.

I. Mechanism of toxicity. Benzodiazepines enhance the action of the inhibitory neurotransmitter

gamma-aminobutyric acid (GABA). They also inhibit other neuronal

systems by poorly defined mechanisms. The result is generalized depression of

spinal reflexes and the reticular activating system. This can cause coma and respiratory

arrest.

A. Respiratory arrest is more likely with newer short-acting benzodiazepines such

as triazolam (Halcion), alprazolam (Xanax), and midazolam (Versed). It has also

been reported with zolpidem (Ambien).

B. Cardiopulmonary arrest has occurred after rapid injection of diazepam, possibly

because of CNS-depressant effects or because of the toxic effects of the diluent

propylene glycol.

C. Pharmacokinetics. Most of these agents are highly protein-bound (80–100%).

Time to peak blood level, elimination half-lives, the presence or absence of active

metabolites, and other pharmacokinetic values are given in Table II–61 (p 412).
II. Toxic dose. In general, the toxic-therapeutic ratio for benzodiazepines is very high.

For example, oral overdoses of diazepam have been reported in excess of 15–20

times the therapeutic dose without serious depression of consciousness. However,

respiratory arrest has been reported after ingestion of 5 mg of triazolam and after

rapid IV injection of diazepam, midazolam, and many other benzodiazepines. Also,

ingestion of another drug with CNS-depressant properties (eg, ethanol, barbiturates,

opioids) probably will produce additive effects.

III. Clinical presentation. Onset of CNS depression may be observed within 30–120

minutes of ingestion, depending on the compound. Lethargy, slurred speech, ataxia,

coma, and respiratory arrest may occur. Generally, patients with benzodiazepineinduced

coma have hyporeflexia and midposition or small pupils. Hypothermia may

occur. Serious complications are more likely when newer short-acting agents are

involved or when other depressant drugs have been ingested.

IV. Diagnosis usually is based on the history of ingestion or recent injection. The differential

diagnosis should include other sedative-hypnotic agents, antidepressants,

antipsychotics, and narcotics. Coma and small pupils do not respond to naloxone

but will reverse with administration of flumazenil (see below).

A. Specific levels. Serum drug levels are often available from commercial toxicology

laboratories but are rarely of value in emergency management. Urine

and blood qualitative screening may provide rapid confirmation of exposure. Immunoassays

are sensitive to the benzodiazepines that metabolize to oxazepam (eg, diazepam, chlordiazepoxide, and
temazepam), but may not detect newer

benzodiazepines or those in low concentrations.

B. Other useful laboratory studies include glucose, arterial blood gases, and

pulse oximetry.

V. Treatment
A. Emergency and supportive measures

1. Protect the airway and assist ventilation if necessary (pp 1–7).

2. Treat coma (p 18), hypotension (p 15), and hypothermia (p 20) if they occur.

Hypotension usually responds promptly to supine position and IV fluids.

B. Specific drugs and antidotes. Flumazenil (p 488) is a specific benzodiazepine

receptor antagonist that can rapidly reverse coma. However, because benzodiazepine

overdose by itself is rarely fatal, the role of flumazenil in routine management

has not been established. It is administered IV with a starting dose

of 0.1–0.2 mg, repeated as needed up to a maximum of 3 mg. It has some

important potential drawbacks:

1. It may induce seizures in patients who have co-ingested medications with

proconvulsant activity.

2. It may induce acute withdrawal, including seizures and autonomic instability,

in patients who are addicted to benzodiazepines.

3. Resedation is common when the drug wears off after 1–2 hours, and repeated

dosing or a continuous infusion is often required.

C. Decontamination (p 46). Consider activated charcoal if the ingestion occurred

within the previous 30 minutes and other conditions are appropriate (see Table

I–38, p 51). Gastric lavage is not necessary after small to moderate ingestions

if activated charcoal can be given promptly.

D. Enhanced elimination. There is no role for diuresis, dialysis, or hemoperfusion.

Repeat-dose charcoal has not been studied.

elevation on ECG, which can be mistaken for acute myocardial infarction. Otherwise

unexplained seizures, coma, hyperthermia, stroke, or cardiac arrest should

raise suspicion of cocaine poisoning.

A. Specific levels. Blood cocaine levels are not routinely available and do not

assist in emergency management. Cocaine and its metabolite benzoylecgonine

are easily detected in the urine for up to 72 hours after ingestion and provide

qualitative confirmation of cocaine use.

B. Other useful laboratory studies include electrolytes, glucose, BUN, creatinine,

creatine kinase (CK), urinalysis, urine myoglobin, cardiac troponin, ECG and

ECG monitoring, CT head scan (if hemorrhage is suspected), and abdominal

radiography (if cocaine-filled condom or packet ingestion is suspected).

V. Treatment

A. Emergency and supportive measures

1. Maintain an open airway and assist ventilation if necessary (pp 1–7).

2. Treat coma (p 18), agitation (p 24), seizures (p 22), hyperthermia (p 21), arrhythmias

(pp 10–15), and hypotension (p 15) if they occur. Benzodiazepines

(p 454) are a good choice for initial management of hypertension and tachycardia

associated with agitation.

3. Angina pectoris may be treated with benzodiazepines, aspirin, nitrates, or

calcium channel blockers. For acute myocardial infarction, thrombolysis has

been recommended but is controversial. Supporting its use is the high prevalence

of acute thrombosis, often superimposed on coronary spasm. Against

its use are the excellent prognosis for patients with cocaine-induced infarction,

even without thrombolysis, and concerns about increased risks for bleeding

caused by intracranial hemorrhage or aortic dissection.

4. Monitor vital signs and ECG for several hours. Patients with suspected coronary

artery spasm should be admitted to a coronary care unit, and because

of reports of persistent or recurrent coronary spasm up to several days after

initial exposure, consider the use of an oral calcium antagonist and/or cardiac

nitrates for 2–4 weeks after discharge.

B. Specific drugs and antidotes. There is no specific antidote.

1. It is widely recommended that beta blockers be avoided in treating acute cocaine

toxicity because propranolol, a nonselective beta blocker, may produce

paradoxical worsening of hypertension because of blockade of beta2-

mediated vasodilation. However, if a beta blocker is needed (eg, for

tachycardia not responsive to benzodiazepines and IV fluids, especially if

associated with myocardial ischemia), it is reasonable to administer a cardioselective

beta blocker such as esmolol (a very short-acting beta blocker

[p 485]) or metoprolol. Beta blockers may be also be used in combination

with a vasodilator such as phentolamine (p 535) for management of hypertension.

2. QRS prolongation caused by sodium channel blockade can be treated with

sodium bicarbonate (p 458). Wide-complex tachyarrhythmias may also respond

to lidocaine (p 503).

C. Decontamination (p 46). Decontamination is not necessary after smoking,

snorting, or IV injection. After ingestion, perform the following steps:

1. Administer activated charcoal orally if conditions are appropriate (see Table

I–38, p 51).

2. Gastric lavage is not necessary after small to moderate ingestions if activated

charcoal can be given promptly.

3. For ingestion of cocaine-filled condoms or packets, give repeated doses of

activated charcoal and consider whole-bowel irrigation (p 52) unless there is

evidence of bowel obstruction, bowel perforation, or severe GI hemorrhage. If

large ingested packets (ie, Ziploc bags) are not removed by these procedures,
laparotomy and surgical removal may be necessary. Surgical intervention to

remove ingested packets may also be required for patients with persistent

severe symptoms of cocaine intoxication or bowel obstruction.