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CHAPTER 2-29: BENZODIAZEPINES

Ben Tsutaoka

INTRODUCTION

The drug class of benzodiazepines includes many compounds that vary widely in potency, duration of effect, the 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.

TABLE II–14.BENZODIAZEPINES
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TABLE II–14. BENZODIAZEPINES
Drug Half-life (h) Active Metabolite Oral Adult Dose (mg)
Alprazolam 6.3–26.9 No 0.25–0.5
Bromazepam 8–30 Yes 3–30
Chlordiazepoxide 18–96a Yes 5–50
Clobazam 10–50 Yes 5–40
Clonazepam 18–50 No 0.5–2
Clorazepate 40–120a Yes 3.75–30
Diazepam 40–120a Yes 5–20
Estazolam 8–28 No 1–2
Eszopiclonec 6 No 2–3
Flunitrazepam 9–30 No 1–2
Flurazepam 47–100a Yes 15–30
Lorazepam 10–20 No 2–4
Midazolam 2.2–6.8 Yes 1–5b
Oxazepam 5–20 No 15–30
Phenazepam 15–60 Yes 0.5–2
Quazepam 70–75a Yes 7.5–15
Temazepam 3.5–18.4 No 15–30
Triazolam 1.5–5.5 No 0.125–0.5
Zaleplonc 1 No 5–20
Zolpidemc 1.4–4.5 No 5–10

aHalf-life of active metabolite, to which effects can be attributed.

bIM or IV.

cNot a benzodiazepine, but similar mechanism of action and clinical effects, which may be reversed with flumazenil.

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.

  1. 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).

  2. 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.

  3. 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–66.

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.

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, ...

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