The benzodiazepines have been prescribed frequently for the treatment of anxiety and insomnia, and they are especially effective when the anxiety symptoms are severe. Also, they have been used to control overactivity and destructive behavior in children and the symptoms of alcohol withdrawal in adults. The benzodiazepines possess anticonvulsant properties, and the intravenous use of diazepam, lorazepam, and midazolam is an effective means of controlling status epilepticus, as described in Chap. 15. Diazepam in massive doses has been used with considerable success in the management of muscle spasm in tetanus and in the “stiff man” syndrome (see Chap. 45). Alprazolam may have a place in the treatment of panic attacks and other anxiety states, and as an adjunct in some depressive illnesses. It may, however, create more dependence than some of the others in its class.
Other important benzodiazepine drugs are lorazepam (Ativan), flurazepam (Dalmane), triazolam (Halcion), clorazepate (Tranxene), temazepam (Restoril), oxazepam (Serax), alprazolam (Xanax) and other newer varieties, all widely used in the treatment of insomnia (see Chap. 18), and clonazepam (Klonopin), which is useful in the treatment of myoclonic seizures (see Chap. 15) and intention myoclonus (see Chaps. 4 and 46). Midazolam (Versed), a short-acting parenteral agent, is given frequently to achieve the brief sedation required for procedures such as MRI or endoscopy and is also useful in the treatment of status epilepticus. Many other benzodiazepine compounds have appeared in recent years, but a clear advantage over the original ones remains to be demonstrated (Hollister, 1990).
The benzodiazepine drugs, like barbiturates, have a depressant action on the CNS by binding to specific receptors on GABA inhibitory systems. The newer nonbenzodiazepine sleeping medication differs from the benzodiazepines structurally but is pharmacologically similar in binding to similar GABA-ergic receptors. The benzodiazepines act in concert with GABA to open chloride ion channels and hyperpolarize postsynaptic neurons and reduce their firing rate. The primary sites of their action are the cerebral cortex and limbic system, which accounts for their anticonvulsant and anxiolytic effects.
While quite safe in the recommended dosages, they are far from ideal. They frequently cause unsteadiness of gait and drowsiness and at times syncope, confusion, and impairment of memory, especially in the elderly. If taken in large doses, the benzodiazepines can depress the state of consciousness, resembling that of other sedative-hypnotic drugs, but with less respiratory suppression and hypotension.
Flumazenil, a specific pharmacologic antagonist of the CNS effects of benzodiazepines, rapidly but briefly reverses most of the symptoms and signs of benzodiazepine overdose (see Krisanda). It acts by binding to CNS diazepine receptors and thereby blocking the activation of inhibitory GABA-ergic synapses. Flumazenil also may be diagnostically useful in cases of coma of unknown etiology and in hepatic encephalopathy.