Chapter 9: Anxiolytic and Hypnotic Drugs




Anxiety is an unpleasant state of tension, apprehension, or uneasiness (a fear that seems to arise from a unknown source). Disorders involving anxiety are the most common mental disturbances. The physical symptoms of severe anxiety are similar to those of fear (such as tachycardia, sweating, trembling, and palpitations) and involve sympathetic activation. Episodes of mild anxiety are common life experiences and do not warrant treatment. However, the symptoms of severe, chronic, debilitating anxiety may be treated with anti-anxiety drugs (sometimes called anxiolytic or minor tranquilizers) and/or some form of behavioral therapy or psychotherapy.

Because many of the anti-anxiety drugs also cause some sedation, the same drugs often function clinically as both anxiolytic and hypnotic (sleep-inducing) agents. In addition, some have anticonvulsant activity. Figure 9.1 summarizes the anxiolytic and hypnotic agents. Though also indicated for certain anxiety disorders, the selective serotonin reuptake inhibitors (SSRIs) will be presented in the chapter discussing antidepressants.

Figure 9.1.Summary of anxiolytic and hypnotic drugs.

Summary of anxiolytic and hypnotic drugs.


Benzodiazepines are the most widely used anxiolytic drugs. They have largely replaced barbiturates and meprobamate in the treatment of anxiety, because benzodiazepines are safer and more effective (Figure 9.2).

Figure 9.2.Ratio of lethal dose to effective dose for morphine (an opioid, see Chapter 14), chlorpromazine (a neuroleptic, see Chapter 13), and the anxiolytic, hypnotic drugs, phenobarbital and diazepam.

Ratio of lethal dose to effective dose for morphine

A. Mechanism of action

The targets for benzodiazepine actions are the ?-aminobutyric acid (GABAA) receptors. [Note: GABA is the major inhibitory neurotransmitter in the central nervous system (CNS).] These receptors are primarily composed of ?, ?, and ? subunit families of which a combination of five or more span the postsynaptic membrane (Figure 9.3). Depending on the types, number of subunits, and brain region localization, the activation of the receptors results in different pharmacologic effects. Benzodiazepines modulate GABA effects by binding to a specific, high-affinity site located at the interface of the ? subunit and the ?2 subunit (see Figure 9.3). [Note: These binding sites are sometimes labeled “benzodiazepine receptors.” Two benzodiazepine receptor subtypes commonly found in the CNS have been designated as BZ1 and BZ2 receptors depending on whether their composition includes the ?1 subunit or the ?2 subunit, respectively.

The benzodiazepine receptor locations in the CNS parallel those of the GABA neurons. Binding of GABA to its receptor triggers an opening of a chloride channel, which leads to an increase in chloride conductance (see Figure 9.3). Benzodiazepines increase the frequency of channel openings produced by GABA. The influx of chloride ions causes a small hyperpolarization that moves the postsynaptic potential away from its firing threshold and, thus, inhibits the formation of action potentials. [Note: Binding of a benzodiazepine to its receptor site will increase the affinity of GABA for the GABA-binding site (and vice versa) without actually changing the total number of sites.] The clinical effects of the various benzodiazepines correlate well with each drug’s binding affinity for the GABA receptor–chloride ion channel complex.

Figure 9.3.Schematic diagram of benzodiazepine–GABA–chloride ion channel complex.

Schematic diagram of benzodiazepine–GABA–chloride ion channel complex.

GABA = ?-aminobutyric acid.

B. Actions

The benzodiazepines have neither antipsychotic activity nor analgesic action, and they do not affect the autonomic nervous system. All benzodiazepines exhibit the following actions to a greater or lesser extent:

1. Reduction of anxiety

At low doses, the benzodiazepines are anxiolytic. They are thought to reduce anxiety by selectively enhancing GABAergic transmission in neurons having the ?2 subunit in their GABAA receptors, thereby inhibiting neuronal circuits in the limbic system of the brain.

2. Sedative and hypnotic actions

All of the benzodiazepines used to treat anxiety have some sedative properties, and some can produce hypnosis (artificially produced sleep) at higher doses. Their effects have been shown to be mediated by the ?1-GABAA receptors.

3. Anterograde amnesia

The temporary impairment of memory with use of the benzodiazepines is also mediated by the ?1-GABAA receptors. This also impairs a person’s ability to learn and form new memories.

4. Anticonvulsant

Several of the benzodiazepines have anticonvulsant activity and some are used to treat epilepsy (status epilepticus) and other seizure disorders. This effect is partially, although not completely, mediated by ?1-GABAA receptors.

5. Muscle relaxant

At high doses, the benzodiazepines relax the spasticity of skeletal muscle, probably by increasing presynaptic inhibition in the spinal cord, where the ?2-GABAA receptors are largely located. Baclofen is a muscle relaxant that is believed to affect GABA receptors at the level of the spinal cord.

C. Therapeutic uses

The individual benzodiazepines show small differences in their relative anxiolytic, anticonvulsant, and sedative properties. However, the duration of action varies widely among this group, and pharmacokinetic considerations are often important in choosing one benzodiazepine over another.

1. Anxiety disorders

Benzodiazepines are effective for the treatment of the anxiety symptoms secondary to panic disorder, generalized anxiety disorder (GAD), social anxiety disorder, performance anxiety, posttraumatic stress disorder, obsessive-compulsive disorder, and the extreme anxiety sometimes encountered with specific phobias such as fear of flying. The benzodiazepines are also useful in treating the anxiety that accompanies some forms of depression and schizophrenia. These drugs should not be used to alleviate the normal stress of everyday life. They should be reserved for continued severe anxiety, and then should only be used for short periods of time because of their addiction potential.

The longer-acting agents, such as clonazepam [kloe-NAZ-e-pam], lorazepam [lor-AZ-e-pam], and diazepam [dye-AZ-e-pam], are often preferred in those patients with anxiety who may require treatment for prolonged periods of time. The anti-anxiety effects of the benzodiazepines are less subject to tolerance than the sedative and hypnotic effects. [Note: Tolerance (that is, decreased responsiveness to repeated doses of the drug) occurs when used for more than 1 to 2 weeks. Cross-tolerance exists among this group of agents with ethanol. It has been shown that tolerance is associated with a decrease in GABA-receptor density.] For panic disorders, alprazolam [al-PRAY-zoe-lam] is effective for short- and long-term treatment, although it may cause withdrawal reactions in about 30 percent of sufferers.

2. Muscular disorders

Diazepam is useful in the treatment of skeletal muscle spasms, such as occur in muscle strain, and in treating spasticity from degenerative disorders, such as multiple sclerosis and cerebral palsy.

3. Amnesia

The shorter-acting agents are often employed as premedication for anxiety-provoking and unpleasant procedures, such as endoscopic, bronchoscopic, and certain dental procedures as well as angioplasty. They also cause a form of conscious sedation, allowing the person to be receptive to instructions during these procedures. Midazolam [mi-DAY-zoe-lam] is a benzodiazepine also used for the induction of anesthesia.

4. Seizures

Clonazepam is occasionally used in the treatment of certain types of epilepsy, whereas diazepam and lorazepam are the drugs of choice in terminating grand mal epileptic seizures and status epilepticus (see Drug Choice). Due to cross-tolerance, chlordiazepoxide [klor-di-az-e-POX-ide], clorazepate [klor-AZ-e-pate], diazepam, and oxazepam [ox-AZ-e-pam] are useful in the acute treatment of alcohol withdrawal and reducing the risk of withdrawal-related seizures.

5. Sleep disorders

Not all benzodiazepines are useful as hypnotic agents, although all have sedative or calming effects. They tend to decrease the latency to sleep onset and increase Stage II of nonrapid eye movement (REM) sleep. Both REM sleep and slow-wave sleep are decreased. In the treatment of insomnia, it is important to balance the sedative effect needed at bedtime with the residual sedation (“hangover”) upon awakening. Commonly prescribed benzodiazepines for sleep disorders include long-acting flurazepam [flure-AZ-e-pam], intermediate-acting temazepam [te-MAZ-e-pam], and short-acting triazolam [trye-AY-zoe-lam].

a. Flurazepam

This long-acting benzodiazepine significantly reduces both sleep-induction time and the number of awakenings, and it increases the duration of sleep. Flurazepam has a long-acting effect (Figure 9.4) and causes little rebound insomnia. With continued use, the drug has been shown to maintain its effectiveness for up to 4 weeks. Flurazepam and its active metabolites have a half-life of approximately 85 hours, which may result in daytime sedation and accumulation of the drug.

Figure 9.4.Comparison of the durations of action of the benzodiazepines.

Comparison of the durations of action of the benzodiazepines.

b. Temazepam

This drug is useful in patients who experience frequent wakening. However, because the peak sedative effect occurs 1 to 3 hours after an oral dose it should be given 1 to 2 hours before the desired bedtime.

c. Triazolam

This benzodiazepine has a relatively short duration of action and, therefore, is used to induce sleep in patients with recurring insomnia. Whereas temazepam is useful for insomnia caused by the inability to stay asleep, triazolam is effective in treating individuals who have difficulty in going to sleep. Tolerance frequently develops within a few days, and withdrawal of the drug often results in rebound insomnia, leading the patient to demand another prescription or higher dose. Therefore, this drug is best used intermittently rather than daily. In general, hypnotics should be given for only a limited time, usually less than 2 to 4 weeks.

D. Pharmacokinetics

1. Absorption and distribution

The benzodiazepines are lipophilic. They are rapidly and completely absorbed after oral administration and distribute throughout the body.

2. Durations of action

The half-lives of the benzodiazepines are very important clinically, because the duration of action may determine the therapeutic usefulness. The benzodiazepines can be roughly divided into short-, intermediate-, and long-acting groups (see Figure 9.4). The longer-acting agents form active metabolites with long half-lives. However, with some benzodiazepines, the clinical durations of action do not always correlate with actual half-lives (otherwise, a dose of diazepam could conceivably be given only every other day or even less often given its active metabolites). This may be due to receptor dissociation rates in the CNS and subsequent redistribution elsewhere.

3. Fate

Most benzodiazepines, including chlordiazepoxide and diazepam, are metabolized by the hepatic microsomal system to compounds that are also active. For these benzodiazepines, the apparent half-life of the drug represents the combined actions of the parent drug and its metabolites. The drugs’ effects are terminated not only by excretion but also by redistribution. The benzodiazepines are excreted in urine as glucuronides or oxidized metabolites. All the benzodiazepines cross the placental barrier and may depress the CNS of the newborn if given before birth. Nursing infants may also become exposed to the drugs in breast milk.

E. Dependence

Psychological and physical dependence on benzodiazepines can develop if high doses of the drugs are given over a prolonged period. Abrupt discontinuation of the benzodiazepines results in withdrawal symptoms, including confusion, anxiety, agitation, restlessness, insomnia, tension, and (rarely) seizures. Because of the long half-lives of some benzodiazepines, withdrawal symptoms may occur slowly and last a number of days after discontinuation of therapy. Benzodiazepines with a short elimination half-life, such as triazolam, induce more abrupt and severe withdrawal reactions than those seen with drugs that are slowly eliminated such as flurazepam (Figure 9.5).

Figure 9.5.Frequency of rebound insomnia resulting from discontinuation of benzodiazepine therapy.

Frequency of rebound insomnia resulting from discontinuation of benzodiazepine therapy.

F. Adverse effects

1. Drowsiness and confusion

These effects are the two most common side effects of the benzodiazepines. Ataxia occurs at high doses and precludes activities that require fine motor coordination, such as driving an automobile. Cognitive impairment (decreased long-term recall and retention of new knowledge) can occur with use of benzodiazepines. Triazolam, one of the most potent oral benzodiazepines with rapid elimination, often shows a rapid development of tolerance, early morning insomnia, and daytime anxiety as well as amnesia and confusion.

2. Precautions

Benzodiazepines should be used cautiously in treating patients with liver disease. These drugs should be avoided in patients with acute narrow-angle glaucoma. Alcohol and other CNS depressants enhance the sedative-hypnotic effects of the benzodiazepines. Benzodiazepines are, however, considerably less dangerous than the older anxiolytic and hypnotic drugs. As a result, a drug overdose is seldom lethal unless other central depressants, such as alcohol, are taken concurrently.

Benzodiazepine Antagonist

Flumazenil [floo-MAZ-eh-nill] is a GABA-receptor antagonist that can rapidly reverse the effects of benzodiazepines. The drug is available for intravenous (IV) administration only. Onset is rapid, but duration is short, with a half-life of about 1 hour. Frequent administration may be necessary to maintain reversal of a long-acting benzodiazepine. Administration of flumazenil may precipitate withdrawal in dependent patients or cause seizures if a benzodiazepine is used to control seizure activity. Seizures may also result if the patient ingests tricyclic antidepressants (TCAs). Dizziness, nausea, vomiting, and agitation are the most common side effects.

Other Anxiolytic Agents

A. Antidepressants

Many antidepressants have proven efficacy in managing the long-term symptoms of chronic anxiety disorders and should be seriously considered as first-line agents, especially in patients with concerns for addiction or dependence or a history of addiction or dependence to other substances. Selective serotonin reuptake inhibitors (SSRIs, such a escitalopram), or selective serotonin and norepinephrine reuptake inhibitors (SNRIs, such as venlafaxine) may be used alone, or prescribed in combination with a low dose of a benzodiazepine during the first weeks of treatment (Figure 9.6). After four to six weeks, when the antidepressant begins to produce an anxiolytic effect, the benzodiazepine dose can be tapered.

SSRIs and SNRIs have a lower potential for physical dependence than the benzodiazepines, and have become first-line treatment for GAD. While only certain SSRIs or SNRIs have been approved by the FDA for the treatment of GAD, the efficacy of these drugs for GAD is most likely a class effect. Thus, the choice among these antidepressants can be based upon side effects and cost. Long-term use of antidepressants and benzodiazepines for anxiety disorders is often required to maintain ongoing benefit and prevent relapse. Please refer to Chapter 12 for a discussion of the antidepressant agents.

Figure 9.6.Treatment guideline for persistent anxiety.

B. Buspirone

Buspirone [byoo-SPYE-rone] is useful for the chronic treatment of GAD and has an efficacy comparable to that of the benzodiazepines. This agent is not effective for short-term or “as-needed” treatment of acute anxiety states. The actions of buspirone appear to be mediated by serotonin (5-HT1A) receptors, although other receptors could be involved, because buspirone displays some affinity for DA2 dopamine receptors and 5-HT2A serotonin receptors. Thus, its mode of action differs from that of the benzodiazepines. In addition, buspirone lacks the anticonvulsant and muscle-relaxant properties of the benzodiazepines and causes only minimal sedation.

However, it does cause hypothermia and can increase prolactin and growth hormone. The frequency of adverse effects is low, with the most common effects being headaches, dizziness, nervousness, and light-headedness. Sedation and psychomotor and cognitive dysfunction are minimal, and dependence is unlikely. It does not potentiate the CNS depression of alcohol. Buspirone has the disadvantage of a slow onset of action. Figure 9.7 compares some of the common adverse effects of buspirone and the benzodiazepine alprazolam.

Figure 9.7.Comparison of common adverse effects of buspirone and alprazolam.

Comparison of common adverse effects of buspirone and alprazolam.

Results are expressed as the percentage of patients showing each symptom.