Anxiety and Related Disorders Flashcards
Anxiety and fear
Anxiety is a universal human experience and is the most basic of emo- tions. It can be defined as a feeling of apprehension, uneasiness, un- certainty, or dread resulting from a real or perceived threat. Whereas anxiety is a vague sense of dread related to an unspecified or unknown danger, fear is a reaction to a real or perceived specific danger. An- other important distinction between anxiety and fear is that anxiety affects us at a deeper level: it invades the central core of the personal- ity and erodes feelings of self-esteem and personal worth. Physiologi- cally, however, the body reacts to anxiety and fear in similar ways.
Normal anxiety is a healthy reaction necessary for survival. It provides us with energy to carry out everyday tasks and strive toward goals; motivates us to make and survive change; and prompts construc- tive behaviours, such as studying for an examination, being on time for a job interview, preparing for a presentation, and working toward making an individual change.
Drugs Used to Treat Anxiety and Insomnia
GABA is the major inhibitory (calming) neurotransmitter in the cen- tral nervous system (CNS). There are three major types of GABA recep- tors: GABAA, GABAB, and GABAC receptors. The family of GABAA re- ceptors contains several different subtypes (versions) of receptor, each with its own particular drug recognition properties. Specific members of the GABAA receptor family are the targets of benzodiazepines, bar- biturates, and alcohol. Drugs that enhance the actions of GABA at GA- BAA receptors exert a sedative–hypnotic action on brain function. The most commonly used anti-anxiety drugs are the benzodiazepines and, more recently, the selective serotonin reuptake inhibitors (SSRIs) and serotonin–norepinephrine reuptake inhibitors (SNRIs), which were originally introduced for the treatment of depression.
Benzodiazepines
Benzodiazepines enhance the actions of GABA by binding to a specific location on the GABAA receptor complex. They only have an effect if GABA is also bound to its binding sites on the receptor complex. This interaction decreases the probability that the neuron on which the re- ceptors are found will depolarize and thus leads to an overall decrease in neuronal excitability. As shown in Figure 11.11, benzodiazepines, such as diazepam (Valium), clonazepam (Rivotril), and alprazolam (Xanax), bind to GABAA receptors. The receptors are common in the limbic system, the brain’s emotional centre, and enhanced GABA activ- ity is important for decreasing anxiety.
Action of benzodiazepines. Drugs in this group bind to a site that is part of the GABAA receptor complex to which gamma- aminobutyric acid (GABA) itself binds. Clinically useful benzodiaz- epines enhance the inhibitory effects of GABA. Benzodiazepines do not produce an inhibitory effect in the absence of GABA. Both must simultaneously bind to the receptor for any clinical effect to occur.
At higher doses, all benzodiazepines can cause sedation.
The fact that the benzodiazepines promote the ability of GABA to decrease neuronal excitability probably accounts for their efficacy in the treatment of seizures and for their ability to reduce the neuronal overexcitement that is characteristic of alcohol withdrawal. While be- ing efficacious at treating seizures and convulsions, benzodiazepines cannot be used prophylactically due to their tendency to quickly induce tolerance in those that use them.
When combined with other CNS depressants, such as alcohol, opioids, or tri- cyclic anti-depressants (TCAs), the inhibitory actions of the benzodi- azepines can lead to life-threatening respiratory and CNS depression.
Any drug that inhibits electrical activity in the brain can interfere with motor ability, attention, and judgement. A patient taking benzo- diazepines must be cautioned about engaging in activities that could be dangerous if reflexes and attention are impaired, including specialized activities such as working in construction and more common activities such as driving a car. In older persons the use of benzodiazepines may contribute to falls and broken bones. Ataxia is a common adverse ef- fect secondary to the abundance of GABA receptors in the cerebellum.
Short-Acting Sedative–Hypnotic Sleep Drugs
Zopiclone (Imovane) is a member of a newer class of benzodiazepine- like hypnotics. It and the other benzodiazepine-like drugs, zaleplon and zolpidem, have been grouped together into a class colloquially called the Z-drugs. Structurally, zopiclone is not a true benzodiazepine; however, zopiclone displays similar actions as the true benzodiazepines at GABAA receptors. Thus its use also results in a decrease in neuronal excitability. As a result, zopiclone has sedative effects as well as hypnot- ic, anxiolytic, anti-convulsant, and muscle-relaxant effects. The onset of action is faster than that of most benzodiazepines. It is important to inform patients taking non-benzodiazepine hypnotic drugs about the quick onset and advise them to take the drug only when they are ready to go to sleep.
Zopiclone reaches peak plasma concentration within 2 hours and has a short half-life (the amount of time it takes the body to eliminate half of the drug). Zopiclone also has the unique adverse effect of an unpleasant bitter taste upon awakening. Severe drowsiness or impaired
coordination are signs of drug intolerance or excessive doses. Because of the potential for misuse, zopiclone should not be taken for more than 7 to 10 consecutive days and should be used with caution in those who misuse alcohol and other substances.
Buspirone
Buspirone (Bustab) is an anxiolytic drug that is useful for bringing about the short-term relief of excessive anxiety without producing strong sedative–hypnotic effects. Because this drug does not leave the patient sleepy or sluggish, it is often much better tolerated than the benzodiazepines. It is not a CNS depressant, and so the danger of it interacting with other CNS depressants such as alcohol is minimal. Also, there is not the potential for dependence that exists with benzo- diazepines.
Although, at present, the mechanism of action of buspirone is not clearly understood, one possibility is illustrated in Figure 11.12.
Buspirone is a partial agonist (a drug that is unable to fully activate a re- ceptor) at 5-hydroxytryptamine (5-HT1A) receptors. These receptors are known to modulate the release of a number of neurotransmitters, including serotonin and dopamine. Buspirone may also enhance do- pamine release from nerve endings via its action as an antagonist at presynaptic dopamine D2 autoreceptors.
Proposed mechanism of action of buspirone. Top, In a nor- mal state excessive serotonin release is prevented when serotonin binds to the presynaptic 5-HT1A autoreceptors. The inhibitory effect of these autoreceptors on release is indicated by the red arrow. Bottom, Feedback inhibition by serotonin is blocked when buspi- rone binds and occupies 5-HT1A receptors, leading to a loss of inhi- bition on serotonin release from the presynaptic cell as indicated by the dashed red line. This leads to an increase in serotonin levels in the synaptic cleft.
