NCLEX: Anxiolytic and Hypnotic Drugs

Disorders involving anxiety are among the most common mental disorders. Anxiety is an unpleasant state of tension, apprehension, or uneasiness (a fear that arises from either a known or an unknown source). 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, severe, chronic, debilitating anxiety may be treated with antianxiety drugs (sometimes called anxiolytics) and/or some form of psychotherapy. Because many antianxiety drugs also cause some sedation, they may be used clinically as both anxiolytic and hypnotic  (sleep inducing)agents summarizes the anxiolytic and hypnotic agents. Some antidepressants are also indicated for certain anxiety disorders; however, they are discussed with other antidepressants.

Anxiolytic and Hypnotic Drugs

Anxiolytic and Hypnotic Drugs: BENZODIAZEPINES

Focus topic: Anxiolytic and Hypnotic Drugs

Benzodiazepines are widely used anxiolytic drugs. They have largely replaced barbiturates and meprobamate in the treatment of anxiety and insomnia, because benzodiazepines are generally considered to be safer and more effective. Though benzodiazepines are commonly used, they are not necessarily the best choice for anxiety or insomnia. Certain antidepressants with anxiolytic action, such as the selective serotonin reuptake inhibitors, are preferred in many cases, and nonbenzodiazepine hypnotics and antihistamines may be preferable for insomnia.

A. Mechanism of action

The targets for benzodiazepine actions are the γ-aminobutyric acid (GABAA) receptors. [Note: GABA is the major inhibitory neurotransmitter in the central nervous system (CNS).] The GABAA receptors are composed of a combination of five α, β, and γ subunits that span the postsynaptic membrane. For each subunit, many subtypes exist (for example, there are six subtypes of the α subunit). Binding of GABA to its receptor triggers an opening of the central ion channel, allowing chloride through the pore. The influx of chloride ions causes hyperpolarization of the neuron and decreases neurotransmission by inhibiting the formation of action potentials.

Benzodiazepines modulate GABA effects by binding to a specific, high-affinity site (distinct from the GABA-binding site) located at the interface of the α subunit and the γ subunit on the GABAA receptor. [Note: These binding sites are sometimes labeled “benzodiazepine (BZ) receptors.” Common BZ receptor subtypes in the CNS are designated as BZ1 or BZ2 depending on whether the binding site includes an α1 or α2 subunit, respectively.] Benzodiazepines increase the frequency of channel openings produced by GABA. [Note: Binding of a benzodiazepine to its receptor site increases the affinity of GABA for the GABA-binding site (and vice versa).] The clinical effects of the various benzodiazepines correlate well with the binding affinity of each drug for the GABA receptor–chloride ion channel complex.

Anxiolytic and Hypnotic Drugs

B. Actions

All benzodiazepines exhibit the following actions to some extent:

  • 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 α2 subunit in their GABAA receptors, thereby inhibiting neuronal circuits in the limbic system of the brain.
  • Sedative/hypnotic: All benzodiazepines have sedative and calming properties, and some can produce hypnosis (artificially produced sleep) at higher doses. The hypnotic effects are mediated by the α1-GABAA receptors.
  • Anterograde amnesia: Temporary impairment of memory with use of the benzodiazepines is also mediated by the α1-GABAA receptors. The ability to learn and form new memories is also impaired.
  • Anticonvulsant: Several benzodiazepines have anticonvulsant activity. This effect is partially, although not completely, mediated by α1-GABAA receptors.
  • Muscle relaxant: At high doses, the benzodiazepines relax the spasticity of skeletal muscle, probably by increasing presynaptic inhibition in the spinal cord, where the α2-GABAA receptors are largely located. Baclofen [BAK-loe-fen] is a muscle relaxant that is believed to affect GABA receptors at the level of the spinal cord.
Anxiolytic and Hypnotic Drugs

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.

  • 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 extreme anxiety associated with phobias, such as fear of flying. The benzodiazepines are also useful in treating anxiety related to depression and schizophrenia. These drugs should be reserved for severe anxiety only and not used to manage the stress of everyday life. Because of their addiction potential, they should only be used for short periods of time. 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 that may require prolonged treatment. The antianxiety 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. Tolerance is associated with a decrease in GABA receptor density. Cross-tolerance exists between the benzodiazepines and ethanol.] 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% of patients.
  • Sleep disorders: A few of the benzodiazepines are useful as hypnotic agents. These agents decrease the latency to sleep onset and increase stage II of non–rapid 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 intermediate-acting temazepam [te-MAZ-e-pam] and short-acting triazolam [try-AY-zoe-lam]. Long-acting flurazepam [flure-AZ-e-pam] is rarely used, due to its extended half-life,which may result in excessive daytime sedation and accumulation of the drug, especially in the elderly. Estazolam [eh-STAY-zoe-lam] and quazepam [QUAY-ze-pam] are considered intermediate- and long-acting agents, respectively.

a. 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 bedtime.

b. Triazolam: Whereas temazepam is useful for insomnia caused by the inability to stay asleep, short-acting 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. Therefore, this drug is not a preferred agent, and it is best used intermittently. In general, hypnotics should be given for only a limited time, usually less than 2 to 4 weeks.

  • Amnesia: The shorter-acting agents are often employed as premedication for anxiety-provoking and unpleasant procedures, such as endoscopy, dental procedures, and angioplasty. They 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 used to facilitate amnesia while causing sedation prior to anesthesia.
  • Seizures: Clonazepam is occasionally used as an adjunctive therapy for certain types of seizures, whereas lorazepam and diazepam are the drugs of choice in terminating status epilepticus. Due to cross-tolerance, chlordiazepoxide [klor-di-az-e- POX-ide], clorazepate [klor-AZ-e-pate], diazepam, lorazepam, and oxazepam [ox-AZ-e-pam] are useful in the acute treatment of alcohol withdrawal and reduce the risk of withdrawal-related seizures.
  • 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.
Anxiolytic and Hypnotic Drugs

D. Pharmacokinetics

  • Absorption and distribution: The benzodiazepines are lipophilic. They are rapidly and completely absorbed after oral administration, distribute throughout the body and penetrate into the CNS.
  • Duration of action: The half-lives of the benzodiazepines are 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. The longer-acting agents form active metabolites with long half-lives. However, with some benzodiazepines, the clinical duration of action does not correlate with the actual half-life (otherwise, a dose of diazepam could conceivably be given only every other day, given its active metabolites). This may be due to receptor dissociation rates in the CNS and subsequent redistribution to fatty tissues and other areas.
  • 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. Drug effects are terminated not only by excretion but also by redistribution. The benzodiazepines are excreted in the urine as glucuronides or oxidized metabolites. All benzodiazepines cross the placenta and may depress the CNS of the newborn if given before birth. The benzodiazepines are not recommended for use during pregnancy. Nursing infants may also be 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 for a prolonged period. All benzodiazepines are controlled substances. Abrupt discontinuation of the benzodiazepines results in withdrawal symptoms, including confusion, anxiety, agitation, restlessness, insomnia, tension, and (rarely) seizures. 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.

F. Adverse effects

Drowsiness and confusion are the 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 often shows a rapid development of tolerance, early morning insomnia, and daytime anxiety, as well as amnesia and confusion.

Benzodiazepines should be used cautiously in patients with liver disease. These drugs should be avoided in patients with acute angle closure 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.

Anxiolytic and Hypnotic Drugs

Anxiolytic and Hypnotic Drugs: BENZODIAZEPINE ANTAGONIST

Focus topic: Anxiolytic and Hypnotic Drugs

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 the 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 has a mixed ingestion with tricyclic antidepressants or antipsychotics. Dizziness, nausea, vomiting, and agitation are the most common side effects.

Anxiolytic and Hypnotic Drugs
Anxiolytic and Hypnotic Drugs

Anxiolytic and Hypnotic Drugs: OTHER ANXIOLYTIC AGENTS

Focus topic: Anxiolytic and Hypnotic Drugs

A. Antidepressants

Many antidepressants are effective in the treatment of chronic anxiety disorders and should be considered as first-line agents, especially in patients with concerns for addiction or dependence. Selective serotonin reuptake inhibitors (SSRIs, such as escitalopram or paroxetine) or serotonin/norepinephrine reuptake inhibitors (SNRIs), such as venlafaxine or duloxetine) may be used alone or prescribed in combination with a low dose of a benzodiazepine during the first weeks of treatment. After 4 to 6 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 for the treatment of GAD, the efficacy of these drugs for GAD is most likely a class effect. Thus, the choice among these antidepressants should 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.

B. Buspirone

Buspirone [byoo-SPYE-rone] is useful for the chronic treatment of GAD and has an efficacy comparable to that of the benzodiazepines. It has a slow onset of action and 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 it also displays some affinity for D2 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. The frequency of adverse effects is low, with the most common effects being headaches, dizziness, nervousness, nausea, and light-headedness. Sedation and psychomotor and cognitive dysfunction are minimal, and dependence is unlikely. Buspirone does not potentiate the CNS depression of alcohol.

Anxiolytic and Hypnotic Drugs: BARBITURATES

Focus topic: Anxiolytic and Hypnotic Drugs

The barbiturates were formerly the mainstay of treatment to sedate patients or to induce and maintain sleep. Today, they have been largely replaced by the benzodiazepines, primarily because barbiturates induce tolerance and physical dependence and are associated with very severe withdrawal symptoms. All barbiturates are controlled substances. Certain barbiturates, such as the very short-acting thiopental, have been used to induce anesthesia but are infrequently used today due to the advent of newer agents with fewer adverse effects.

A. Mechanism of action

Focus topic: Anxiolytic and Hypnotic Drugs

The sedative–hypnotic action of the barbiturates is due to their interaction with GABAA receptors, which enhances GABAergic transmission. The binding site of barbiturates on the GABA receptor is distinct from that of the benzodiazepines. Barbiturates potentiate GABA action on chloride entry into the neuron by prolonging the duration of the chloride channel openings. In addition, barbiturates can block excitatory glutamate receptors. Anesthetic concentrations of pentobarbital also block high-frequency sodium channels. All of these molecular actions lead to decreased neuronal activity.

B. Actions

Focus topic: Anxiolytic and Hypnotic Drugs

Barbiturates are classified according to their duration of action. For example, ultra short-acting thiopental [thye-oh- PEN-tal] acts within seconds and has a duration of action of about 30 minutes. In contrast, long-acting phenobarbital [fee-noe-BAR-bital] has a duration of action greater than a day. Pentobarbital [pentoe- BAR-bi-tal], secobarbital [see-koe-BAR-bi-tal], amobarbital [am-oh-BAR-bi-tal], and butalbital [bu-TAL-bi-tal] are short-acting barbiturates.

  • Depression of CNS: At low doses, the barbiturates produce sedation (have a calming effect and reduce excitement). At higher doses, the drugs cause hypnosis, followed by anesthesia (loss of feeling or sensation), and, finally, coma and death. Thus, any degree of depression of the CNS is possible, depending on the dose. Barbiturates do not raise the pain threshold and have no analgesic properties. They may even exacerbate pain. Chronic use leads to tolerance.
  • Respiratory depression: Barbiturates suppress the hypoxic and chemoreceptor response to CO2, and overdosage is followed by respiratory depression and death.

C. Therapeutic uses

Focus topic: Anxiolytic and Hypnotic Drugs

  • Anesthesia: The ultra–short-acting barbiturates, such as thiopental, have been used intravenously to induce anesthesia but have largely been replaced by other agents.
  • Anticonvulsant: Phenobarbital has specific anticonvulsant activity that is distinguished from the nonspecific CNS depression. It is used in long-term management of tonic–clonic seizures. However, phenobarbital can depress cognitive development in children and decrease cognitive performance in adults, and it should be used only if other therapies have failed. Similarly, phenobarbital may be used for the treatment of refractory status epilepticus.
  • Sedative/hypnotic: Barbiturates have been used as mild sedatives to relieve anxiety, nervous tension, and insomnia. When used as hypnotics, they suppress REM sleep more than other stages. However, the use of barbiturates for insomnia is no longer generally accepted, given their adverse effects and potential for tolerance. Butalbital is commonly used in combination products (with acetaminophen and caffeine or aspirin and caffeine) as a sedative to assist in the management of tension-type or migraine headaches.

D. Pharmacokinetics

Focus topic: Anxiolytic and Hypnotic Drugs

Barbiturates are well absorbed after oral administration and distribute throughout the body. All barbiturates redistribute from the brain to the splanchnic areas, to skeletal muscle, and, finally, to adipose tissue. This movement is important in causing the short duration of action of thiopental and similar short-acting derivatives. Barbiturates readily cross the placenta and can depress the fetus. These agents are metabolized in the liver, and inactive metabolites are excreted in urine.

E. Adverse effects

Focus topic: Anxiolytic and Hypnotic Drugs

Barbiturates cause drowsiness, impaired concentration, and mental and physical sluggishness. The CNS depressant effects of barbiturates synergize with those of ethanol.

Hypnotic doses of barbiturates produce a drug “hangover” that may lead to impaired ability to function normally for many hours after waking. Occasionally, nausea and dizziness occur. Barbiturates induce cytochrome P450 (CYP450) microsomal enzymes in the liver. Therefore, chronic barbiturate administration diminishes the action of many drugs that are metabolized by the CYP450 system. Barbiturates are contraindicated in patients with acute intermittent porphyria. Abrupt withdrawal from barbiturates may cause tremors, anxiety, weakness, restlessness, nausea and vomiting, seizures, delirium, and cardiac arrest. Withdrawal is much more severe than that associated with opiates and can result in death. Death may also result from overdose. Severe depression of respiration is coupled with central cardiovascular depression and results in a shock-like condition with shallow, infrequent breathing. Treatment includes supportive care and gastric decontamination for recent ingestions.

Anxiolytic and Hypnotic Drugs
SCREENSHOT

Anxiolytic and Hypnotic Drugs: OTHER HYPNOTIC AGENTS

Focus topic: Anxiolytic and Hypnotic Drugs

A. Zolpidem

Focus topic: Anxiolytic and Hypnotic Drugs

The hypnotic zolpidem [ZOL-pi-dem] is not structurally related to benzodiazepines, but it selectively binds to the benzodiazepine receptor subtype BZ1. Zolpidem has no anticonvulsant or muscle-relaxing properties. It shows few withdrawal effects, exhibits minimal rebound insomnia, and little tolerance occurs with prolonged use. Zolpidem is rapidly absorbed from the gastrointestinal (GI) tract, and it has a rapid onset of action and short elimination half-life (about 2 to 3 hours). It provides a hypnotic effect for approximately 5 hours. [Note: A lingual spray and an extended-release formulation are also available. A sublingual tablet formulation may be used for middle-of-the-night awakening.] Zolpidem undergoes hepatic oxidation by the CYP450 system to inactive products. Thus, drugs such as rifampin, which induce this enzyme system, shorten the half-life of zolpidem, and drugs that inhibit the CYP3A4 isoenzyme may increase the half-life. Adverse effects of zolpidem include nightmares, agitation, anterograde amnesia, headache, GI upset, dizziness, and daytime drowsiness. Unlike the benzodiazepines, at usual hypnotic doses, the nonbenzodiazepine drugs, zolpidem, zaleplon, and eszopiclone, do not significantly alter the various sleep stages and, hence, are often the preferred hypnotics. This may be due to their relative selectivity for the BZ1 receptor. All three agents are controlled substances.

B. Zaleplon

Focus topic: Anxiolytic and Hypnotic Drugs

Zaleplon [ZAL-e-plon] is an oral nonbenzodiazepine hypnotic similar to zolpidem; however, zaleplon causes fewer residual effects on psychomotor and cognitive function compared to zolpidem or the benzodiazepines. This may be due to its rapid elimination, with a half-life of approximately 1 hour. The drug is metabolized by CYP3A4.

C. Eszopiclone

Focus topic: Anxiolytic and Hypnotic Drugs

Eszopiclone [es-ZOE-pi-clone] is an oral nonbenzodiazepine hypnotic that also acts on the BZ1 receptor. It has been shown to be effective for insomnia for up to 6 months. Eszopiclone is rapidly absorbed (time to peak, 1 hour), extensively metabolized by oxidation and demethylation via the CYP450 system, and mainly excreted in urine. Elimination half-life is approximately 6 hours. Adverse events with eszopiclone include anxiety, dry mouth, headache, peripheral edema, somnolence, and unpleasant taste.

D. Ramelteon

Focus topic: Anxiolytic and Hypnotic Drugs

Ramelteon [ram-EL-tee-on] is a selective agonist at the MT1 and MT2 subtypes of melatonin receptors. Melatonin is a hormone secreted by the pineal gland that helps to maintain the circadian rhythm underlying the normal sleep–wake cycle. Stimulation of MT1 and MT2 receptors by ramelteon is thought to induce and promote sleep. Ramelteon is indicated for the treatment of insomnia characterized by difficulty falling asleep (increased sleep latency). It has minimal potential for abuse, and no evidence of dependence or withdrawal effects has been observed. Therefore, ramelteon can be administered long term.Common adverse effects of ramelteon include dizziness, fatigue, and somnolence. Ramelteon may also increase prolactin levels.

E. Antihistamines

Focus topic: Anxiolytic and Hypnotic Drugs

Some antihistamines with sedating properties, such as diphenhydramine, hydroxyzine, and doxylamine, are effective in treating mild types of situational insomnia. However, they have undesirable side effects (such as anticholinergic effects) that make them less useful than the benzodiazepines and the nonbenzodiazepines. Some sedative antihistamines are marketed in numerous over-the-counter products.

F. Antidepressants

Focus topic: Anxiolytic and Hypnotic Drugs

The use of sedating antidepressants with strong antihistamine profiles has been ongoing for decades. Doxepin [DOX-e-pin], an older tricyclic agent with SNRI mechanisms of antidepressant and anxiolytic action, was recently approved at low doses for the management of insomnia. Other antidepressants, such as trazodone [TRAZ-ohdone], mirtazapine [mir-TAZ-a-pine], and other older tricyclic antidepressants with strong antihistamine properties are used off-label for the treatment of insomnia.

Anxiolytic and Hypnotic Drugs
Anxiolytic and Hypnotic Drugs

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