Fig. 20.1 The GABAA receptor.
The GABAA receptor consists of five transmembrane subunits configured from the 19 possible subunits that have been identified; thus many configurations of the GABA receptor exist, which vary in their sensitivity to benzodiazepines. A common configuration comprises two α1, two β2 and one γ2 subunit. Binding of GABA to the receptor at the interfaces of the α1 and β2 subunits mediates opening of the Cl− channel and an influx of Cl− ions, resulting in hyperpolarisation of the cell. This action is enhanced by drugs stimulating allosteric regulatory sites on the GABA receptor, distinct from the GABA-binding site. Diazepam, lorazepam and other ‘classic’ benzodiazepines (BDZs) bind at the interface of the α1 and γ2 subunits. Compounds such as zolpidem bind with high affinity for the α1-subunits and also enhance Cl− ion influx. The intravenous anaesthetics propofol and etomidate bind to β2– and β3-subunits (Ch. 17).
The GABAA receptor has α, β and γ subunits, arranged in a group of five (usually two α, two β and one γ, although only α and β are essential) around a central pore (see Fig. 20.1 and legend). There are many subtypes of each subunit, and therefore many receptor configurations that show differences in their regional distributions in the brain. Benzodiazepines bind between an α and γ subunit. The presence of an α1– or α5-subunit confers the sedative and amnesic properties of benzodiazepines, while both α2 and α3 appear to be involved in the anxiolytic and muscle relaxant effects. Anticonvulsant activity is conferred by several α subunits. The minority of GABA receptors with only α4 or α6 subunits do not bind benzodiazepines.
The increase in inhibitory neurotransmission produced by benzodiazepines has the following potentially useful effects:
Pharmacokinetics: Benzodiazepines are well absorbed from the gut and their lipid solubility ensures ready penetration into the brain. The pharmacokinetics of individual benzodiazepines determines their major clinical uses. Benzodiazepines that are useful for inducing sleep (e.g. temazepam) are rapidly absorbed from the gut. This produces a fast onset of sedation, then sleep. Metabolism of short-acting benzodiazepines produces inactive derivatives. A brief duration of action is desirable for hypnotics, to avoid hangover sedation in the morning
Long-acting benzodiazepines, such as diazepam, are metabolised in the liver to active compounds (see Fig. 2.12) that contribute to their duration of action through relatively slow elimination from the body. Repeated dosing with long-acting compounds, such as diazepam, increases the risk of accumulation and a prolonged sedative effect. The anxiolytic properties of benzodiazepines are best exploited by using a compound with a long duration of action. Smaller doses can then be used to minimise sedation, and the rebound in anxiety symptoms that can occur between doses of a short-acting drug is avoided.
Diazepam, lorazepam and midazolam can also be given by intravenous injection to provide rapid sedation pre-operatively or before procedures such as endoscopy. Intravenous lorazepam and diazepam are also given for emergency treatment of generalised seizures and status epilepticus (Ch. 23). Long-acting benzodiazepines, such as clobazam, clonazepam, diazepam and lorazepam, are used in the prophylaxis of epilepsy (see Ch. 23).
Potentiation of the sedative effects of other CNS-depressant drugs, such as alcohol. In overdose, such combinations can lead to severe respiratory depression. Flumazenil is a competitive antagonist of benzodiazepines and can be used in acute overdose to reverse respiratory depression (Ch. 53)
Tolerance to the therapeutic effects of benzodiazepines is common. There is widespread concern that their hypnotic effects are lost quite early, although there is little evidence to support this. However, rebound insomnia on withdrawal can perpetuate benzodiazepine use.
Dependence with physical and psychological withdrawal symptoms occurs during long-term treatment. The risk is highest in people with personality disorders, or a previous history of dependence on alcohol or drugs, and is more likely to occur if high doses of benzodiazepines are used. Restricting use to a maximum of 4 weeks will minimise the risk of dependence. With long-acting drugs, withdrawal symptoms may be delayed by up to 3 weeks after stopping. Anxiety is the most frequent symptom, while insomnia, depression and abnormalities of perception, such as altered sensitivity to noise, light or touch, also occur. More severe reactions such as psychosis or convulsions arise occasionally. Some withdrawal symptoms may resemble those for which the drug was originally prescribed, encouraging continued use. Gradual withdrawal of a benzodiazepine over 4–8 weeks is desirable after long-term use, although complete withdrawal may take up to a year. Lorazepam is a potent benzodiazepine with a relatively short duration of action that proves particularly difficult to stop because of the intensity of withdrawal symptoms that begin a few hours after cessation of treatment. Substitution with the longer-acting drug diazepam may be helpful before withdrawal is attempted. There are no proven treatments for reducing symptoms associated with withdrawal. Beta-adrenoceptor antagonists (Ch. 5) are sometimes helpful, or an antidepressant (Ch. 22) if there are depressive symptoms or panic attacks.Azapirones
Mechanism of action and effects: Buspirone is a partial agonist at presynaptic 5-HT1A receptors, producing negative feedback to inhibit serotonin release. It has no effect on GABA receptors. Initial exacerbation of anxiety may occur, possibly caused by postsynaptic 5-HT1A receptor stimulation. The onset of the anxiolytic action of buspirone is slow, beginning after 2 weeks and reaching a maximum effect at approximately 4 weeks. The mechanism of action may involve gradual changes in neural plasticity (enhancement of neural performance or changes in neural connections; Ch. 22). Buspirone has no sedative action, and is ineffective for panic attacks.
Pharmacokinetics: Buspirone is well absorbed from the gut and undergoes extensive first-pass metabolism in the liver. The half-life is short (2–4 h).
Management of anxiety
If substance misuse is identified it should be treated first and may improve symptoms, while comorbid depression may require an antidepressant. Symptoms of anxiety, if mild, often respond to counselling or psychotherapy, using relaxation training or cognitive behavioural therapy without drug therapy.
Generalised anxiety disorder often requires long-term treatment, and there is now considerable evidence that antidepressants (Ch. 22) are useful in this situation. Selective serotonin reuptake inhibitors (SSRIs) such as sertraline are the treatment of choice, or a serotonin and noradrenaline reuptake inhibitor (SNRI) such as venlafaxine if an SSRI is ineffective. Antidepressants can initially exacerbate anxiety, and a benzodiazepine may be necessary for the first 2–3 weeks of treatment to prevent this. The optimal duration of antidepressant treatment in generalised anxiety disorder is uncertain, but similar treatment periods as for depression (Ch. 22) are usually recommended. Pregabalin, which increases inhibitory neurotransmission, is an effective alternative to antidepressants (Ch. 23).
Benzodiazepines can be considered as a short-term measure for anxiety to treat crises, since they have a rapid onset of action over 15–60 min. However, the potential for dependence should limit their use to a maximum of 4 weeks, and the dose should be gradually reduced after the first 2 weeks. Buspirone has similar efficacy to benzodiazepines, but the slow onset of action (3 days) makes it less versatile for managing short-term anxiety. In addition, anxiety that responds well to benzodiazepines often responds less well to buspirone, possibly due to a relative lack of effect of buspirone on somatic symptoms. Somatic symptoms of anxiety (e.g. tremor, palpitations) that are produced by overactivity in the sympathetic nervous system are often helped by a non-selective β-adrenoceptor antagonist such as propranolol (Ch. 5).
Social anxiety disorder responds to monoamine oxidase inhibitors (MAOIs; Ch. 22) better than to most other agents. Moclobemide is the treatment of choice, but phenelzine is also used. Phobic disorders usually need a different approach, and cognitive behavioural therapy is often most effective. Panic disorder is usually treated with tricyclic antidepressants or SSRIs, with MAOIs reserved for people who do not respond.
