^Includes active metabolites.

+++=marked accumulation; +=some accumulation; ± =?some accumulation; -=no accumulation.

taken benzodiazepines continuously for several years in the UK. The benzodiazepines commonly available are shown in Table 9.1.

The pharmacological properties of all these drugs are essentially similar, despite the fact that they may be prescribed for the treatment of anxiety or for insomnia. There is little objective evidence to suggest that the drugs listed are more specific for the treatment of anxiety or of insomnia; an anxiolytic benzodiazepine given at night is likely to be an effective hypnotic, while a low dose of a hypnotic benzodiazepine given in the morning may be an effective anxiolytic. The reason for the similarity in the pharmacological profile of these drugs lies in the similarity of their mechanism of action and also in their metabolite inter-relationship (see Figure 9.1).

In essence, all of the older benzodiazepines that are structurally related to chlordiazepoxide and diazepam are termed 1,4-benzodiazepines. The chemical structure of some commonly used benzodiazepines is shown in Figure 9.2. They enhance the actions of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) in the brain. As a consequence, they affect the activities of the cerebellum (concerned with balance and coordination), the limbic areas of the brain and the cerebral cortex (thought and decision making, fine movement control).

The half-life of a benzodiazepine is not predictive either of its onset of action or of the therapeutic response of the patient. However, the rate of absorption and distribution within the body are important parameters in determining the pharmacodynamic response. The period for maximal response to treatment may be as long as 6 weeks, and there is no evidence

Figure 9.1. The metabolic pathways for the principal 1,4-benzodiazepines. The major pathway is shown with solid arrows and the minor pathway with broken arrows. Commercially available drugs are underlined.

that prolongation of the treatment, or increasing the dose of the drug, will lead to additional improvement in the response.

Chemical pathogenesis of anxiety

Although different authors have ascribed different meanings to the term ''anxiety'', and have often used the terms ''fear'' and ''anxiety'' interchangeably, it is generally accepted that anxiety is an unpleasant state accompanied by apprehension, worry, fear, nervousness and sometimes conflict. Arousal is usually heightened. An increase in the autonomic sympathetic nervous system is often associated with these psychological changes and may be manifest as an increase in blood pressure and heart rate, an erratic respiratory rate, decreased salivary flow leading to dryness in the mouth and throat, and gastrointestinal disturbances (Figure 9.3). Whilst ''physiological'' anxiety is usually short-lived, often with a rapid onset and abrupt cessation once the aversive event has terminated, ''pathological'' anxiety occurs when the response of the individual to an

Figure 9.2. Chemical structure of some commonly used benzodiazepines. Clobazam differs from the other benzodiazepines shown, being a 1,5- rather than a 1,4-benzodiazepine.

Figure 9.2. Chemical structure of some commonly used benzodiazepines. Clobazam differs from the other benzodiazepines shown, being a 1,5- rather than a 1,4-benzodiazepine.

anxiety-provoking event becomes excessive and affects the ability of the individual to lead a normal life. It has been estimated that 2-4% of the population suffer from pathological anxiety and frequently no causative factor can be identified. The benzodiazepines, and non-benzodiazepine anxiolytics such as buspirone, may be useful in alleviating the symptoms of pathological anxiety. The three neurotransmitters that appear to be most directly involved in different aspects of anxiety are noradrenaline, 5-hydroxytryptamine (5-HT) and GABA (Figure 9.4).

Noradrenaline is the neurotransmitter most closely associated with the peripheral and central stress response (Figure 9.5). There is experimental evidence to show that drugs such as yohimbine that block the noradrenergic autoreceptors (e.g. on cell bodies and nerve terminals) and thereby enhance noradrenaline release cause fear and anxiety in both man and animals. Conversely, drugs that stimulate these autoreceptors (as exemplified by clonidine) diminish the anxiety state because they reduce the release of noradrenaline. Benzodiazepines have been shown to inhibit the fear-motivated increase in the functional activity of noradrenaline in experimental animals, but it is now widely believed that the action of the benzodiazepines on the central noradrenergic system is only short term and may contribute to the sedative effects which most conventional benzo-diazepines produce, at least initially. Nevertheless, altered noradrenergic key peripheral organs areas otthe lira in hypDiralamüSv pupil

^pupils dilate blood vessel

4-increased blood pressure j^aclwa lungs fiyperventlli t Ion skin sweating


^increased heart rare stomach stoma ch secretions fcow^l increased d eta ecatiori bladder

"nrrpan^fl urination


Figure 9.3. Autonomic nervouse system showing typical panic responses in phobia and reflecting increased sympathetic nervous system activity.

function may underlie certain forms of severe anxiety such as that seen in patients with panic attacks or anxiety states associated with major depression. Such forms of anxiety generally respond to treatment with antidepressants or benzodiazepines that also have some mild antidepressant properties (e.g. alprazolam).

Several experimental studies have suggested that a reduction in the activity of 5-HT in the brain results in anxiolysis, and therefore the anxiolytic effects of the benzodiazepines may be at least partly mediated by a reduction in central serotonergic neurotransmission. Other studies have shown that benzodiazepines inhibit the firing of serotonergic neurons in the midbrain raphe region, an area that contains serotonergic cell bodies which send projections to the limbic and cortical regions of the brain (Figure 9.8).

The link between the serotonergic pathways and the control of anxiety has been further strengthened by the introduction of non-benzodiazepine anxiolytics such as buspirone, ipsapirone and gepirone, which decrease central serotonergic function by stimulating a subclass of 5-HT receptors (5-

cingulate cortex cerebellum basal ganglia

locus coeruleus amygdala hippocampus hy pot ha la rrins thalamus dorsal raphe nuclei

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