Benzodiazepines

Gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the CNS and activates ionotropic GABA_A receptors on postsynaptic neurons (Fig. 3.35.2). The overstimulation of these receptors can result in sedation, amnesia and ataxia, while insufficient stimulation can lead to arousal, anxiety, insomnia and seizures. GABA_A receptors are multimeric complexes that gate the movement of Cl⁻ into neurons, evoking fast inhibitory synaptic potentials and reducing neuronal excitability in postsynaptic neurons. Benzodiazepines bind to a regulatory site (α-subunit) on the GABA_A receptor that is distinct from the GABA-binding site (β-subunit) and increase the frequency of channel opening, thereby enhancing the inhibitory actions of GABA throughout the CNS (e.g. cortex, hippocampus and amygdala).

Fig. 3.35.2 Control of the GABA_A receptor.

Benzodiazepines are used for short-term treatment of severe anxiety, insomnia (hypnotics), epilepsy, acute alcohol withdrawal and preoperative sedation. They are being increasingly replaced with selective serotonin reuptake inhibitors (SSRIs) for the treatment of anxiety, as these are safer. Longterm use of benzodiazepines as sleeping pills is best avoided because of undesirable effects. The benzodiazapines are orally bioavailable. Diazepam is converted to active metabolites in the liver (e.g. N-desmethyldiazepam), which have a considerably longer duration of action. In contrast, lorazepam and alprazolam are more rapidly inactivated and have shorter plasma half-lives. Benzodiazepines may be administered i.v. for the emergency treatment of epilepsy (diazepam) or as a premedication for surgery (midazolam).

This drug class is associated with a number of important adverse effects. Drowsiness and impaired motor coordination are important side-effects, particularly if patients need to drive or operate machinery. Overdose with benzodiazepines alone will prolong sleep but does not lead to respiratory or CNS depression, although the effects can be life threatening if administered in combination with alcohol, barbiturates or antihistamines. The GABA_A receptor antagonist flumazenil can be useful in acute overdose but can cause seizures.

The major shortcomings of benzodiazepines are hangover, tolerance and drug dependence; the mechanism of these effects is not entirely known but will involve adaptive changes within the CNS. Tolerance develops with chronic use and, therefore, short-term treatment is advisable. Tolerance to the sedative effects of these drugs may be beneficial when treating anxiety. Drug dependence, is a major problem and cessation can give rise to rebound anxiety, tremor, insomnia and loss of appetite. These symptoms appear more slowly with benzodiazepines with long plasma half-life and more abruptly with the shorterduration benzodiazepines.