The major inhibitory (calming) neurotransmitter in the central nervous system (CNS) is GABA. The most commonly used antianxiety agents are the benzodiazepines.
Benzodiazepines
Benzodiazepines potentiate, or promote, the activity of GABA by binding to a specific receptor on the GABA receptor complex. This binding results in an increased frequency of chloride channel opening causing membrane hyperpolarization, which reduces the cellular excitation. If cellular excitation is decreased, the result is a calming effect. Fig. 3.10 shows that benzodiazepines, such as diazepam (Valium), clonazepam (Klonopin), and alprazolam (Xanax), enhance the effects of GABA.
All benzodiazepines can cause sedation at higher therapeutic doses. There are five
benzodiazepines approved by the FDA for treatment of insomnia with a predominantly hypnotic (sleep-inducing) effect: flurazepam (Dalmane), temazepam (Restoril), triazolam (Halcion),
estazolam (ProSom), and quazepam (Doral). Other benzodiazepines, such as lorazepam (Ativan) and alprazolam (Xanax), reduce anxiety without being as sleep-producing when used at lower therapeutic doses.
The fact that the benzodiazepines inhibit neurons probably accounts for their usefulness as anticonvulsants and for their ability to reduce the neuronal overexcitement of alcohol withdrawal.
When used alone, even at high dosages, these drugs rarely inhibit the brain to the degree of respiratory depression, coma, and death. However, when combined with other CNS depressants, such as alcohol, opiates, or tricyclic antidepressants, the inhibitory actions of the benzodiazepines can lead to life-threatening CNS depression.
Any drug that inhibits electrical activity in the brain can interfere with motor ability, attention, and judgment. Healthcare providers must caution a patient taking benzodiazepines 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 adults, the use of benzodiazepines may contribute to falls and bone fractures. Ataxia is a common side effect secondary to the abundance of GABA receptors in the cerebellum.
Short-Acting Sedative-Hypnotic Sleep Agents
The Z-hypnotics include zolpidem (Ambien), zaleplon (Sonata), and eszopiclone (Lunesta). They have sedative effects without the antianxiety, anticonvulsant, or muscle relaxant effects of
benzodiazepines. They are selective for GABAA receptors containing alpha-1 subunits. The drugs’
affinity to alpha-1 subunits confers the potential for amnestic and ataxic side effects, and their onset of action is faster than that of most benzodiazepines. It is important to inform patients taking nonbenzodiazepine hypnotic agents about the quick onset of action and to take them when they are ready to go to sleep.
FIG. 3.10 Action of the benzodiazepines. Drugs in this group attach to receptors adjacent to the receptors for the neurotransmitter γ-aminobutyric acid (GABA). Drug attachment to these receptors results in a strengthening of the inhibitory effects of GABA. In the absence of GABA there is no inhibitory effect of
benzodiazepines.
Most of these drugs have short half-lives, which determine the duration of action. Eszopiclone has the longest duration of action (an average of 7 to 8 hours of sleep per therapeutic dose) while the other two are much shorter. Eszopiclone also has a unique side effect of an unpleasant bitter taste upon awakening. Although tolerance and dependence are reportedly less than with
benzodiazepines, the Z-hypnotics are categorized as schedule IV, similar to the benzodiazepines, by the US Drug Enforcement Administration (DEA). There have been reports of sleepwalking, eating, and even driving after the use of Z-hypnotics. These CNS adverse effects have been reported with other hypnotics as well. Doses for immediate-release zolpidem are now lower for women and the elderly.
Melatonin Receptor Agonists
Melatonin is a naturally occurring hormone that is only excreted at night as part of the normal circadian rhythm. Ramelteon (Rozerem) is a melatonin (MT) receptor agonist and acts much the same way as endogenous melatonin. It has a high selectivity and potency at the MT1 receptor site—
which regulates sleepiness—and at the MT2 receptor site—which regulates circadian rhythms. This is one of two hypnotic medications approved for the treatment of insomnia not classified as a scheduled substance, lacking abuse potential, by the DEA. Side effects include headache and dizziness. Long-term use of ramelteon above therapeutic doses can lead to increased prolactin and associated side effects (e.g., sexual dysfunction).
Doxepin
Doxepin (Silenor) is the low-dose formulation (3-mg and 6-mg tablets) of an old tricyclic
antidepressant. Doxepin is indicated for the treatment of insomnia characterized by difficulty in maintaining sleep. The mechanism of action for its sedative effect is most likely from a strong histamine-1 receptor blockade.
Patients with severe urinary retention or on MAOIs should avoid this medication. The use of other CNS depressants and sedating antihistamines should also be avoided. Doxepin was mainly studied in the geriatric population where it showed an improvement in total sleep duration with no significant decrease in time of sleep onset.
Suvorexant
The orexins are neurotransmitters produced in the hypothalamus that promote normal wakefulness. Suvorexant (Belsomra) is an orexin receptor antagonist. It selectively blocks the binding of orexin to suppress wakefulness. There are some important precautions including:
• Daytime impairment (e.g., falling asleep while driving)
• Additive CNS depression when used together with other CNS depressants
• Abnormal thinking and behavioral changes
• Hypnagogic and hypnopompic hallucinations
• Cataplexy-like symptoms associated with the higher doses Buspirone
Buspirone (BuSpar) is a drug that reduces anxiety without having strong sedative-hypnotic
properties. Because this agent does not leave the patient sleepy or sluggish, patients tolerate it better than the benzodiazepines. It is not a CNS depressant and, therefore, does not have as great a danger of interaction with other CNS depressants such as alcohol.
Although the mechanism of action of buspirone is not clear, one possibility is illustrated in Fig.
3.11. Buspirone seems to act as a partial serotonin-1A agonist (booster). It also has a moderate affinity for D2 receptors, and side effects include dizziness and insomnia.
Refer to Chapter 15 on anxiety disorders for a discussion of the adverse reactions, dosages, nursing implications, and patient and family teaching points for the antianxiety drugs. Refer to Chapter 19 on sleep disorders for a more detailed discussion on medications to promote sleep.
Treating Anxiety Disorders with Antidepressants
The symptoms, neurotransmitters, and circuits associated with anxiety disorders overlap
extensively with those of depressive disorders (refer to Chapters 14 and 15). Many antidepressants have proven to be effective treatments for anxiety disorders. Selective serotonin reuptake inhibitors (SSRIs) are often used to treat obsessive-compulsive disorder (OCD), social anxiety disorder (SAD), generalized anxiety disorder (GAD), panic disorder (PD), and posttraumatic stress disorder (PTSD).
The selective serotonin norepinephrine reuptake inhibitor (SNRI), venlafaxine (Effexor XR), is used to treat GAD, SAD, and PD. Another drug in that classification, duloxetine (Cymbalta), has FDA approval for GAD.
FIG. 3.11 Action of buspirone. A proposed mechanism of action of buspirone is that it blocks feedback inhibition by serotonin. This leads to increased release of serotonin by the presynaptic cell. 5-HT1,
Serotonin.
FIG. 3.12 Possible effects of receptor binding of the antidepressant medications.