Benzodiazepines are effective in relieving anxiety symptoms and can induce sleep if given in large enough doses. They are also used for their antiepileptic actions, including the reduction of myoclonus, and for their skeletal muscle relaxant and amnesic effects. Their main disadvantage is physical dependence and they can impair performance and affect judgment so that driving and other skilled tasks can be impaired.

Benzodiazepines act by potentiating the action of gamma-aminobutyric acid (GABA) at the GABAA receptor. Interaction with the benzodiazepine receptor results in neuronal inhibition and inhibitory effects on the central nervous system (CNS). Most differences between benzodiazepines are explicable in terms of different pharmacokinetic properties (see Table 8.5).

Pharmacokinetics: Benzodiazepines are generally rapidly and fully absorbed after oral ingestion with peak plasma concentrations occurring from 0.5 to 2 hours after administration. There are some differences in absorption rate between the various drugs. They are metabolised both by oxidation which may produce active compounds, and by glucuronidation which inactivates them. They differ widely in their rate of removal from the body.

Adverse effects, interactions and precautions: Drowsiness is a common initial reaction. Psychomotor performance may be impaired as may some memory functions. Older persons are particularly vulnerable to the adverse effects of ataxia (with consequent falls and injury), confusion, memory loss and cognitive impairment. In younger patients, ataxia, nystagmus, muscle weakness and dysarthria are reported less often. Dry mouth and blurred vision are sometimes troublesome. They can precipitate delirium. The potential for the development of tolerance to some actions, dependence and a withdrawal syndrome are important considerations. Dependence develops rarely in patients taking normal therapeutic doses of these drugs for short periods (eg 1 to 2 weeks). However, about a third of patients who have had long-term treatment may have difficulty in reducing or stopping benzodiazepines

Tolerance, a process of neuroadaptation, occurs more with the sedative and hypnotic effects than with other benzodiazepine actions. The degree of tolerance differs between patients. There is little evidence for the development of tolerance to the anxiolytic effects of benzodiazepines within 6 to 12 months. Even when tolerance develops it is uncommon for patients to increase the dose.

Patients with a history of dependence on alcohol and other drugs are more likely to become dependent or intentionally misuse benzodiazepines. All benzodiazepines can produce symptoms when the drug is withdrawn; these symptoms can be physical and psychological and are related to dose and duration of use. Abrupt discontinuation can result in symptoms of increasing anxiety, sleep disorder, aching limbs, nervousness and nausea. These are promptly relieved by reinstituting any benzodiazepine. Abrupt discontinuation in patients taking high doses, eg greater than 50 mg diazepam daily or equivalent, may be accompanied by seizures. Benzodiazepines should be avoided in patients with myasthenia gravis or severe respiratory impairment.

There are additive effects with alcohol and other CNS depressants (eg opioids). Many interactions with other drugs have been reported but are of dubious clinical significance (see Table 8.14L).