Sedative-Hypnotic and Anxiolytic Drugs

Sedative-Hypnotic and Anxiolytic Drugs

Classification of Sedative-Hypnotic and Anxiolytic Drugs

Benzodiazepines

• Alprazolam (XANAX)

• Chlordiazepoxide (LIBRIUM)

• Clonazepam (KLONOPIN)

• Diazepam (VALIUM)

• Lorazepam (ATIVAN)

• Midazolam (VERSED)

• Triazolam (HALCION)^a

• Flumazenil (ROMAZICON)^b

• Amobarbital (AMYTAL)

• Pentobarbital (NEMBUTAL)

• Phenobarbital (LUMINAL)

• Thiopental (PENTOTHAL)

• Diphenhydramine (BENADRYL)

• Doxepin (SILENOR)

• Hydroxyzine (ATARAX)

Other Sedative-Hypnotic Drugs

• Zolpidem (AMBIEN)

• Zaleplon (SONATA)

• Eszopiclone (LUNESTA)

• Ramelteon (ROZEREM)

Nonsedating Anxiolytic Drugs

• Buspirone (BUSPAR)

• Propranolol (INDERAL)

^a Also estazolam (PROSOM), flurazepam (DALMANE), oxazepam (SERAX), temazepam (RESTORIL), and clorazepate (TRANXENE).

^b Benzodiazepine antagonist.

Overview

Sedative-hypnotic drugs are among the most widely used pharmaceutical agents in the world. The sedative part of their name refers to the ability of these agents to calm or reduce anxiety, known as an anxiolytic effect. The hypnotic part of their name describes the ability of these agents to induce drowsiness and promote sleep. This latter action is caused by a greater depression of central nervous system (CNS) activity; most sedative-hypnotic drugs will first cause sedation, then at higher doses produce hypnosis, the medical term for sleep. A few agents, however, exert anxiolytic effects without causing sedation or hypnosis.

This chapter describes the pharmacologic properties of benzodiazepines, barbiturates, and other sedative-hypnotic and anxiolytic drugs that are used in the treatment of anxiety and sleep disorders. Because of their greater safety, fewer adverse effects, and the availability of an antagonist, the benzodiazepines have largely replaced the older barbiturates for these indications. Although ethanol (alcohol) has sedative-hypnotic effects, it is not used therapeutically for these purposes; its pharmacologic effects are described in Chapter 25.

Anxiety Disorders

Anxiety is normally an adaptive response that prepares a person to react to the challenges of life. Anxiety is characterized by changes in mood (apprehension and fear), sympathetic nervous system arousal, and hypervigilance. When anxiety becomes chronic, it can impair a person’s ability to perform the activities of daily living. Moreover, chronic anxiety often leads to visceral organ dysfunction and unpleasant symptoms. For example, patients with chronic anxiety may develop gastrointestinal, cardiovascular, and neurologic problems, including diarrhea, tachycardia, sweating, tremors, and dizziness. Ultimately, anxiety can contribute to heart disease and other disorders, including self-medication, which may lead to substance abuse.

Neurologic Basis of Anxiety

The neuronal pathways involved in anxiety disorders include the sensory, cognitive, behavioral, motor, and autonomic pathways. Sensory systems, cortical processing, and memory are involved in interpreting a stimulus to be dangerous and creating a state of heightened arousal. Motor systems and autonomic processing participate in the exaggerated responses to an anxiety state.

Growing evidence indicates that the amygdala, an almond-shaped structure in the temporal lobe, plays a central role in mediating most of the manifestations of anxiety, including the conditioned avoidance reaction (conditioned fear reaction) that underlies anxiety states. In experimental protocols, this reaction can be induced in animals by teaching them that a cue (e.g., a flashing light) will be followed by a noxious stimulus (e.g., a shock to the foot). During the anticipatory period, the animals conditioned in this manner will exhibit signs of anxiety, such as autonomic and behavioral arousal. Electrical stimulation of the amygdala induces signs of anxiety, whereas lesioning the amygdala or the administration of anxiolytic drugs prevents the behavioral and physiologic manifestations of anxiety during the anticipatory period. It is believed that long-term potentiation in amygdala neurons establishes the memory of adverse events underlying anticipatory anxiety.

Classification and Treatment of Anxiety Disorders

The appropriate management of anxiety disorders requires an accurate diagnosis, and treatment may involve the use of pharmacologic agents, psychotherapy, or both.

Acute Anxiety

Acute anxiety may develop in response to various factors, such as illness, separation from loved ones, or the anticipation of stressful events. Acute anxiety is often self-limiting and may resolve in a few weeks to a few months without drug treatment. A benzodiazepine might provide short-term relief from more severe acute anxiety conditions.

Panic Disorder

Panic disorder is characterized by acute episodes of severe anxiety with marked psychological and physiologic symptoms. During a panic attack, an individual may feel an impending sense of doom that is often accompanied by sweating, tachycardia, tremor, and other visceral symptoms. Patients with panic disorder often respond to drug therapy with a benzodiazepine or an antidepressant drug, such as a selective serotonin reuptake inhibitor (SSRI; see Chapter 22). Benzodiazepines may provide immediate relief from panic attacks during the early phase of therapy, and alprazolam and clonazepam are benzodiazepines that have been particularly useful in this regard. For long-term treatment, an SSRI antidepressant, such as fluoxetine, is often prescribed.

Phobic Disorders

Phobic disorders can be grouped into specific phobia, social anxiety disorder (social phobia), or agoraphobia. Phobias are conditions in which an individual is overly fearful about a particular situation or condition, such as a fear of spiders or traveling in an airplane. Panic disorder can coexist with agoraphobia, an intense fear of being in a public place from which it might be difficult or embarrassing to cope with a panic attack. Patients with panic disorder and agoraphobia often show the best outcomes when treated with a combination of psychotherapy and drug therapy. As with panic disorder, phobic disorders are treated with a benzodiazepine or an antidepressant drug. Benzodiazepines provide acute relief of symptoms and enable patients to more easily benefit from psychotherapy, whereas antidepressants are usually the most effective long-term drug therapy for agoraphobia and social phobia. Propranolol is useful in the prevention of stage fright, or acute situational or performance anxiety.

Obsessive-Compulsive Disorder

Obsessive-compulsive disorder (OCD) is characterized by obsessions, which are recurring or persistent thoughts and impulses, and compulsions, defined as repetitive behaviors in response to obsessions. OCD can be treated effectively with an antidepressant drug (see Chapter 22) and psychotherapy.

Generalized Anxiety Disorder

Generalized anxiety disorder (GAD) is characterized by chronic worry and apprehension concerning future events. Short-term therapy with a benzodiazepine may relieve acute symptoms and provide a useful bridge to psychotherapy. The severity of the disorder often fluctuates over time, and benzodiazepines may be effectively used on an intermittent basis to help patients deal with exacerbations of the disorder. Buspirone, a nonsedating anxiolytic, provides a useful alternative to benzodiazepines for the treatment of chronic anxiety states, because it produces little sedation and is not associated with tolerance or dependence. It must be taken for 3 or 4 weeks, however, before its anxiolytic effects are felt. SSRIs, such as paroxetine, and the serotonin and norepinephrine reuptake inhibitors (SNRIs) venlafaxine and duloxetine (see Chapter 22), are also used in the treatment of GAD.

Posttraumatic Stress Disorder

Posttraumatic stress disorder (PTSD) may develop after exposure to a traumatic event, such as sexual assault or military combat. SSRIs are used in the treatment of PTSD. Other medications, such as benzodiazepines, may also be used to treat associated symptoms, such as an exaggerated startle response and flashbacks.

Sleep Disorders

Sleep is a reversible state of reduced consciousness that is accompanied by characteristic changes in the EEG. Five distinct patterns of brainwave activity occur during sleep, grouped into the four stages of non-rapid eye movement (NREM) sleep, and a pattern characterized by paralysis of voluntary muscles and quick, saccadic movement of the eye called rapid eye movement (REM) sleep.

As an individual falls asleep, the high-frequency and low-amplitude activity of the alert state gradually diminishes during stages 1 and 2 and is replaced by the low-frequency and high-amplitude activity of slow-wave sleep (stages 3 and 4). Over time, the individual returns to stage 1 and eventually to the REM stage. REM sleep is also known as paradoxical sleep because the EEG pattern is similar to that in the awake state. A normal adult cycles through the sleep stages about every 90 minutes (Box 19-1).

Box 19-1 Effect of Sedative-Hypnotic Drugs on Sleep Architecture Terminology

Patterns on the electroencephalogram (EEG) vary with the stage of sleep. When a person falls asleep, the high-frequency and low-amplitude pattern of the awake state is gradually replaced by the progressively lower-frequency and higher-amplitude patterns of stages 1 through 4, which collectively are called non–rapid eye movement sleep (NREM sleep). Stages 3 and 4 are called slow-wave sleep. Another stage, called rapid eye movement sleep (REM sleep), is characterized by rapid, jerky eye movements. REM sleep is also called paradoxical sleep because it is during this stage that the pattern on the EEG returns to the pattern seen during the awake state.

Normal and Abnormal Sleep Patterns

The normal sleep pattern in adults consists of about five cycles, each of which lasts approximately 90 minutes. During each cycle, an individual progresses from stage 1 to stage 4 and then returns to stage 1, followed by a period of REM sleep. As the cycles progress through the night, they become shorter, and the amount of slow-wave sleep decreases.

Effects of Drugs on Sleep Architecture

The sleep patterns of patients with insomnia vary widely but are often characterized by reduced amounts of slow-wave sleep and by one or more awakenings during the night. The time required to fall asleep (sleep latency) is usually prolonged, and the total sleep time is decreased in most patients with insomnia. Elderly adults often have a similar sleep pattern.

Benzodiazepines and most other hypnotics suppress stage 3 and REM sleep. In contrast, zolpidem, zaleplon, eszopiclone, and ramelteon (new agents) have little effect on sleep architecture. Therefore the use of these new agents may better restore the sleep pattern to normal.

State	Rapid Eye Movements	Pattern on EEG	Effect of Benzodiazepines	Effect of New Agent
Awake	No	High-frequency, low-amplitude pattern	Induce sleep	Induces sleep
Stages 1 and 2 sleep	No	Lower-frequency, higher-amplitude pattern than awake state	Increase length of stages	Little change
Stages 3 and 4 sleep	No	Lower-frequency, higher-amplitude pattern than stages 1 and 2	Decrease length of stages	Little change
REM sleep	Yes	High-frequency, low-amplitude pattern	Decrease length of stage	Little change

Sleep patterns change with age and are altered by sedative-hypnotic and other CNS drugs.

Neurologic Basis of Sleep

The neuronal systems involved in sleep include the basal forebrain nuclei and the reticular formation. Projecting from the basal forebrain to the cortex are cholinergic fibers that are believed to be involved in the induction of sleep. The basal forebrain is the only region of the brain that is active during slow-wave sleep and quiescent at other stages. The reticular formation facilitates the flow of sensory information from the thalamus to the cortex. When reticular nuclei are quiescent, the thalamus does not transfer information to the cortex, and this facilitates the onset of sleep.

Classification and Treatment of Sleep Disorders

Insomnia

Some patients with insomnia find it difficult to go to sleep or to stay asleep during the night, whereas others awaken too early in the morning. In general, the management of insomnia depends on whether the sleep disorder is caused by physiologic, psychological, or medical conditions. As shown in Box 19-1, the patterns of sleep stages in patients with insomnia are irregular and include longer latency to fall asleep and frequent awakenings.

Occasional sleeplessness caused by acute stress or a minor illness is usually self-limiting and may not require treatment. More severe insomnia caused by medical conditions whose symptoms interfere with sleep is effectively treated with benzodiazepines or other sedative-hypnotic drugs, such as zolpidem and zaleplon, whereas insomnia related to psychological and psychiatric disturbances is best managed with a combination of psychotherapy and sedative-hypnotic drugs. Benzodiazepines and most other hypnotic drugs decrease sleep latency (the time required to go to sleep) and increase sleep duration. The newest agents, zolpidem, zaleplon, eszopiclone, and ramelteon, have the advantages of not significantly affecting sleep architecture and not causing as much tolerance and dependence as do the older drugs. For these reasons, zolpidem, zaleplon, eszopiclone, and ramelteon have become the drugs of choice to treat most types of insomnia.

Other Sleep Disorders

Other sleep disorders include hypersomnia (difficulty in awakening), narcolepsy (sleep attacks), enuresis (bedwetting during sleep), somnambulism (sleepwalking), sleep apnea (episodes of hypoventilation during sleep), and nightmares and night terrors. Most of these disorders are managed with a combination of psychotherapy and antidepressant drugs or CNS stimulants. Sodium oxybate (XYREM), a form of the abused drug γ-hydroxybutyrate, was recently approved for the treatment of cataplexy associated with narcoleptic attacks. CNS stimulants used to treat narcolepsy and other sleep disorders are discussed in Chapter 22.

Sedative-Hypnotic Drugs

The sedative-hypnotic drugs include benzodiazepines, barbiturates, some antihistamines, and a few nonbenzodiazepine agents, such as zolpidem, zaleplon, eszopiclone, and ramelteon. The properties of these drugs are summarized in Table 19-1, and their adverse effects and drug interactions are listed in Table 19-2.

TABLE 19-1

Pharmacokinetic Properties and Clinical Uses of Sedative-Hypnotic and Anxiolytic Drugs

DRUG	ONSET OF ACTION*	DURATION OF ACTION*	ACTIVE METABOLITES	MAJOR CLINICAL USES
Benzodiazepines
Alprazolam	Fast	Medium	Yes	Anxiety, including panic disorder
Chlordiazepoxide	Fast; very fast (IV)	Long	Yes	Alcohol detoxification; anxiety
Clonazepam	Fast	Medium	No	Anxiety, including panic disorder; seizure disorders
Diazepam	Fast; very fast (IV)	Long	Yes	Alcohol detoxification; anxiety; muscle spasm; seizure disorders; spasticity
Estazolam	Fast	Medium	Yes	Insomnia
Flurazepam	Fast	Long	Yes	Insomnia
Lorazepam	Fast; very fast (IV)	Medium	No	Anxiety; seizure disorders
Midazolam	Very fast (IV)	Short (IV)	Yes	Anesthesia
Oxazepam	Fast	Short	No	Anxiety
Temazepam	Fast	Medium	No	Insomnia
Triazolam	Fast	Short	Yes	Insomnia
Barbiturates
Amobarbital	Fast	Medium	No	Insomnia
Pentobarbital	Fast	Short	No	Insomnia
Phenobarbital	Slow	Long	No	Seizure disorders
Thiopental	Very fast (IV)	Short (IV)	No	Induction of anesthesia
Antihistamines
Diphenhydramine	Fast	Medium	No	Insomnia
Hydroxyzine	Fast	Long	No	Anxiety; sedation
Other Sedative-Hypnotic Drugs
Zolpidem	Fast	Short	No	Insomnia
Zaleplon	Fast	Very short	No	Insomnia; midsleep awakenings
Eszopiclone	Fast	Short	No	Insomnia
Ramelteon	Slow	Short	Yes	Sleep-onset insomnia
Nonsedating Anxiolytic Drugs
Buspirone	Very slow	Long	No	Chronic anxiety
Propranolol	Fast	Medium	Yes	Situational or performance anxiety

< div class='tao-gold-member'>

Only gold members can continue reading. Log In or Register to continue

Related

Tags: Pharmacology with STUDENT CONSULT Online Access

Jul 23, 2016 | Posted by admin in PHARMACY | Comments Off

Full access? Get Clinical Tree

Get Clinical Tree app for offline access

Get Clinical Tree app for offline access

%d bloggers like this: