Sedative-hypnotic drugs

Sedative-hypnotic drugs

The sedative-hypnotics are drugs that depress central nervous system (CNS) function. With some of these drugs, CNS depression is more generalized than with others. The sedative-hypnotics are used primarily for two common disorders: anxiety and insomnia. Agents given to relieve anxiety are known as antianxiety agents or anxiolytics; an older term is tranquilizers. Agents given to promote sleep are known as hypnotics. The distinction between antianxiety effects and hypnotic effects is often a matter of dosage: typically, sedative-hypnotics relieve anxiety in low doses and induce sleep in higher doses. Hence, a single drug may be considered both an antianxiety agent and a hypnotic agent, depending upon the reason for its use and the dosage employed.

There are three major groups of sedative-hypnotics: barbiturates (eg, secobarbital), benzodiazepines (eg, diazepam), and benzodiazepine-like drugs (eg, zolpidem). The barbiturates were introduced in the early 1900s, the benzodiazepines in the 1950s, and the benzodiazepine-like drugs in the 1990s. Although barbiturates were widely used as sedative-hypnotics in the past, they are rarely used for this purpose today, having been replaced by the newer drugs.

Before the benzodiazepines became available, anxiety and insomnia were treated with barbiturates and other general CNS depressants—drugs with multiple undesirable qualities. First, these drugs are powerful respiratory depressants that can readily prove fatal in overdose. As a result, they are “drugs of choice” for suicide. Second, because they produce subjective effects that many individuals find desirable, most general CNS depressants have a high potential for abuse. Third, with prolonged use, most of these drugs produce significant tolerance and physical dependence. And fourth, barbiturates and some other CNS depressants induce synthesis of hepatic drug-metabolizing enzymes, and can thereby decrease responses to other drugs. Because the benzodiazepines are just as effective as the general CNS depressants, but do not share their undesirable properties, the benzodiazepines are clearly preferred to the general CNS depressants for treating anxiety and insomnia.

We begin the chapter by discussing the basic pharmacology of the sedative-hypnotics, and end by discussing their use in insomnia. Use of these drugs for anxiety disorders is addressed in Chapter 35.

Benzodiazepines

Benzodiazepines are drugs of first choice for anxiety and insomnia. In addition, these drugs are used to induce general anesthesia and to manage seizure disorders, muscle spasm, and withdrawal from alcohol.

Benzodiazepines were introduced in the late 1950s and remain important today. Perhaps the most familiar member of the family is diazepam [Valium]. The most frequently prescribed members are lorazepam [Ativan] and alprazolam [Xanax, Xanax XR, Niravam].

The popularity of the benzodiazepines as sedatives and hypnotics stems from their clear superiority over the alternatives: barbiturates and other general CNS depressants. The benzodiazepines are safer than the general CNS depressants and have a lower potential for abuse. In addition, benzodiazepines produce less tolerance and physical dependence and are subject to fewer drug interactions. Contrasts between the benzodiazepines and barbiturates are summarized in Table 34–1.

TABLE 34–1

Contrasts Between Benzodiazepines and Barbiturates

Area of Comparison	Benzodiazepines	Barbiturates
Relative safety	High	Low
Maximal ability to depress CNS function	Low	High
Respiratory depressant ability	Low	High
Suicide potential	Low	High
Ability to cause physical dependence	Low*	High
Ability to cause tolerance	Low	High
Abuse potential	Low	High
Ability to induce hepatic drug metabolism	Low	High

^*Although dependence is low in most patients, significant dependence can develop with long-term, high-dose use.

Since all of the benzodiazepines produce nearly identical effects, we will consider the family as a group, rather than selecting a representative member as a prototype.

Overview of pharmacologic effects

Practically all responses to benzodiazepines result from actions in the CNS. Benzodiazepines have few direct actions outside the CNS. All of the benzodiazepines produce a similar spectrum of responses. However, because of pharmacokinetic differences, individual benzodiazepines may differ in clinical applications.

Central nervous system.

All beneficial effects of benzodiazepines and most adverse effects result from depressant actions in the CNS. With increasing dosage, effects progress from sedation to hypnosis to stupor.

Benzodiazepines depress neuronal function at multiple sites in the CNS. They reduce anxiety through effects on the limbic system, a neuronal network associated with emotionality. They promote sleep through effects on cortical areas and on the sleep-wakefulness “clock.” They induce muscle relaxation through effects on supraspinal motor areas, including the cerebellum. Two important side effects—confusion and anterograde amnesia—result from effects on the hippocampus and cerebral cortex.

Cardiovascular system.

When taken orally, benzodiazepines have almost no effect on the heart and blood vessels. In contrast, when administered intravenously, even in therapeutic doses, benzodiazepines can produce profound hypotension and cardiac arrest.

Respiratory system.

In contrast to the barbiturates, the benzodiazepines are weak respiratory depressants. When taken alone in therapeutic doses, benzodiazepines produce little or no depression of respiration—and with toxic doses, respiratory depression is moderate at most. With oral therapy, clinically significant respiratory depression occurs only when benzodiazepines are combined with other CNS depressants (eg, opioids, barbiturates, alcohol).

Although benzodiazepines generally have minimal effects on respiration, they can be a problem for patients with respiratory disorders. In patients with chronic obstructive pulmonary disease, benzodiazepines may worsen hypoventilation and hypoxemia. In patients with obstructive sleep apnea (OSA), benzodiazepines may exacerbate apneic episodes. In patients who snore, benzodiazepines may convert partial airway obstruction into OSA.

Molecular mechanism of action

Benzodiazepines potentiate the actions of gamma-aminobutyric acid (GABA), an inhibitory neurotransmitter found throughout the CNS. These drugs enhance the actions of GABA by binding to specific receptors in a supramolecular structure known as the GABA receptor–chloride channel complex (Fig. 34–1). Please note that benzodiazepines do not act as direct GABA agonists—they simply intensify the effects of GABA.

Figure 34–1 Schematic model of the GABA receptor–chloride channel complex showing binding sites for benzodiazepines and barbiturates.
The GABA receptor–chloride channel complex, which spans the neuronal cell membrane, can exist in an open or closed configuration. Binding of GABA to its receptor on the complex causes the chloride channel to open. The resulting inward flow of chloride ions hyperpolarizes the neuron (makes the cell highly negative inside) and thereby decreases its ability to fire. Hence GABA is an inhibitory neurotransmitter. Binding of a benzodiazepine to its receptor on the complex increases the frequency of channel opening, thereby increasing chloride influx. Hence, benzodiazepines enhance the inhibitory effects of GABA. In the absence of GABA, benzodiazepines have no effect on channel opening. The benzodiazepine-like drugs (zolpidem, zaleplon, and eszopiclone) have actions much like those of the benzodiazepines. Effects of barbiturates on the chloride channel are dose dependent: at low doses, barbiturates enhance the actions of GABA (by prolonging the duration of channel opening); at high doses, barbiturates directly mimic the actions of GABA.

Figure 34–1 Schematic model of the GABA receptor–chloride channel complex showing binding sites for benzodiazepines and barbiturates.
The GABA receptor–chloride channel complex, which spans the neuronal cell membrane, can exist in an open or closed configuration. Binding of GABA to its receptor on the complex causes the chloride channel to open. The resulting inward flow of chloride ions hyperpolarizes the neuron (makes the cell highly negative inside) and thereby decreases its ability to fire. Hence GABA is an inhibitory neurotransmitter. Binding of a benzodiazepine to its receptor on the complex increases the frequency of channel opening, thereby increasing chloride influx. Hence, benzodiazepines enhance the inhibitory effects of GABA. In the absence of GABA, benzodiazepines have no effect on channel opening. The benzodiazepine-like drugs (zolpidem, zaleplon, and eszopiclone) have actions much like those of the benzodiazepines. Effects of barbiturates on the chloride channel are dose dependent: at low doses, barbiturates enhance the actions of GABA (by prolonging the duration of channel opening); at high doses, barbiturates directly mimic the actions of GABA.

Because benzodiazepines act by amplifying the actions of endogenous GABA, rather than by directly mimicking GABA, there is a limit to how much CNS depression benzodiazepines can produce. This explains why benzodiazepines are so much safer than the barbiturates—drugs that can directly mimic GABA. Since benzodiazepines simply potentiate the inhibitory effects of endogenous GABA, and since the amount of GABA in the CNS is finite, there is a built-in limit to the depth of CNS depression the benzodiazepines can produce. In contrast, since the barbiturates are direct-acting CNS depressants, maximal effects are limited only by the amount of barbiturate administered.

Pharmacokinetics

Absorption and distribution.

Most benzodiazepines are well absorbed following oral administration. Because of their high lipid solubility, benzodiazepines readily cross the blood-brain barrier to reach sites in the CNS.

Metabolism.

Most benzodiazepines undergo extensive metabolic alterations. With few exceptions, the metabolites are pharmacologically active. As a result, responses produced by administering a particular benzodiazepine often persist long after the parent drug has disappeared. Hence, there may be a poor correlation between the plasma half-life of the parent drug and duration of pharmacologic effects. Flurazepam, for example, whose plasma half-life is only 2 to 3 hours, is converted into an active metabolite with a half-life of 50 hours. Hence, giving flurazepam produces long-lasting effects, even though flurazepam itself is gone from the plasma in 8 to 12 hours (about four half-lives).

In patients with liver disease, metabolism of benzodiazepines can decline, thereby prolonging and intensifying responses. Because certain benzodiazepines (oxazepam, temazepam, and lorazepam) undergo very little metabolic alteration, they may be preferred for patients with hepatic impairment.

Time course of action.

Benzodiazepines differ significantly from one another with respect to time course. Specifically, they differ in onset and duration of action, and tendency to accumulate with repeated dosing.

Because all benzodiazepines have essentially equivalent pharmacologic actions, selection among them is based largely on differences in time course. For example, if a patient needs medication to accelerate falling asleep, a benzodiazepine with a rapid onset (eg, triazolam) would be indicated. However, if medication is needed to prevent waking later in the night, a benzodiazepine with a slower onset (eg, estazolam) would be preferred. For treatment of anxiety, a drug with an intermediate duration is desirable. For treatment of any benzodiazepine-responsive condition in the elderly, a drug such as lorazepam, which is not likely to accumulate with repeated dosing, is generally preferred.

Therapeutic uses

The benzodiazepines have three principal indications: (1) anxiety, (2) insomnia, and (3) seizure disorders. In addition, they are used as preoperative medications and to treat muscle spasm and withdrawal from alcohol. Although all benzodiazepines share the same pharmacologic properties, and therefore might be equally effective for all applications, not every benzodiazepine is actually employed for all potential uses. The principal factors that determine the actual applications of a particular benzodiazepine are (1) the pharmacokinetic properties of the drug itself and (2) research and marketing decisions of pharmaceutical companies. Specific applications of individual benzodiazepines are summarized in Table 34–2.

TABLE 34–2

Applications of the Benzodiazepines

	Approved Applications
Generic Name [Trade Name]	GAD*	Insomnia	Seizures	Muscle Spasm, Spasticity	Alcohol Withdrawal	Anesthesia Induction or Preanesthesia	Panic Disorder
Alprazolam [Xanax, Xanax XR, Niravam]
Chlordiazepoxide [Librium]
Clonazepam [Klonopin, Rivotril]
Clorazepate [Tranxene]
Diazepam [Valium, Diastat AcuDial]
Estazolam (generic only)
Flurazepam (generic only)
Lorazepam [Ativan]
Midazolam [Versed]						^†
Oxazepam (generic only)
Quazepam [Doral]
Temazepam [Restoril]
Triazolam [Halcion]

^*GAD = generalized anxiety disorder.

^†Midazolam, in conjunction with an opioid analgesic, is also used to produce conscious sedation, a semiconscious state suitable for minor surgeries and endoscopic procedures.

Anxiety.

Benzodiazepines are drugs of first choice for anxiety. Although all benzodiazepines have anxiolytic actions, only six are marketed for this indication (see Table 34–2). Anxiolytic effects result from depressing neurotransmission in the limbic system and cortical areas. Use of benzodiazepines to treat anxiety disorders is discussed in Chapter 35.

Insomnia.

Benzodiazepines are preferred drugs for insomnia. These drugs decrease latency time to falling asleep, reduce awakenings, and increase total sleeping time. The role of benzodiazepines in managing insomnia is discussed in depth later.

Seizure disorders.

Four benzodiazepines—diazepam, clonazepam, lorazepam, and clorazepate—are employed for seizure disorders. Antiseizure applications are discussed in Chapter 24.

One benzodiazepine—diazepam—is used to relieve muscle spasm and spasticity (see Chapter 25). Effects on muscle tone are secondary to actions in the CNS. Diazepam cannot relieve spasm without causing sedation.

Alcohol withdrawal.

Diazepam and other benzodiazepines may be administered to ease withdrawal from alcohol (see Chapter 38). Benefits derive from cross-dependence with alcohol, which enables benzodiazepines to suppress symptoms brought on by alcohol abstinence.

Perioperative applications.

Three benzodiazepines—diazepam [Valium], lorazepam [Ativan], and midazolam [Versed]—are given IV for induction of anesthesia. In addition, midazolam (in combination with an opioid analgesic) can be used to produce conscious sedation, a semiconscious state suitable for endoscopic procedures and minor surgeries. Benzodiazepines are also used for preoperative sedation. All of these applications are discussed in Chapter 27.

Adverse effects

Benzodiazepines are generally well tolerated, and serious adverse reactions are rare. In contrast to barbiturates and other general CNS depressants, benzodiazepines are remarkably safe.

CNS depression.

When taken to promote sleep, benzodiazepines cause drowsiness, lightheadedness, incoordination, and difficulty concentrating. When these effects occur at bedtime, they are generally inconsequential. However, if sedation and other manifestations of CNS depression persist beyond waking, interference with daytime activities can result.

Anterograde amnesia.

Benzodiazepines can cause anterograde amnesia (impaired recall of events that take place after dosing). Anterograde amnesia has been especially troublesome with triazolam [Halcion]. If patients complain of forgetfulness, the possibility of drug-induced amnesia should be evaluated.

Sleep driving and other complex sleep-related behaviors.

Patients taking benzodiazepines in sleep-inducing doses may carry out complex behaviors, and then have no memory of their actions. Reported behaviors include sleep driving, preparing and eating meals, making phone calls, and having sexual intercourse. Although these events can occur with normal doses, they are more likely when doses are excessive, and when benzodiazepines are combined with alcohol and other CNS depressants. Because of the potential for harm, benzodiazepines should be withdrawn if sleep driving is reported. To minimize withdrawal symptoms, dosing should be tapered slowly, rather than discontinued abruptly.

Paradoxical effects.

When employed to treat anxiety, benzodiazepines sometimes cause paradoxical responses, including insomnia, excitation, euphoria, heightened anxiety, and rage. If these occur, the benzodiazepine should be withdrawn.

Respiratory depression.

Benzodiazepines are weak respiratory depressants. Death from overdose with oral benzodiazepines alone has never been documented. Hence, in contrast to the barbiturates, benzodiazepines present little risk as vehicles for suicide. It must be emphasized, however, that although respiratory depression with oral therapy is rare, benzodiazepines can cause severe respiratory depression when administered intravenously. In addition, substantial respiratory depression can result from combining oral benzodiazepines with other CNS depressants (eg, alcohol, barbiturates, opioids).

Abuse.

Benzodiazepines have a lower abuse potential than barbiturates and most other general CNS depressants. The behavior pattern that constitutes “addiction” is uncommon among people who take benzodiazepines for therapeutic purposes. When asked about their drug use, individuals who regularly abuse drugs rarely express a preference for benzodiazepines over barbiturates. Because their potential for abuse is low, the benzodiazepines are classified under Schedule IV of the Controlled Substances Act. This contrasts with the barbiturates, most of which are classified under Schedule II or III.

Use in pregnancy and lactation.

Benzodiazepines are highly lipid soluble and can readily cross the placental barrier. Use of benzodiazepines during the first trimester of pregnancy is associated with an increased risk of congenital malformations, such as cleft lip, inguinal hernia, and cardiac anomalies. Use near term can cause CNS depression in the neonate. Because they may represent a risk to the fetus, most benzodiazepines are classified in Food and Drug Administration (FDA) Pregnancy Risk Category D. Five of these drugs—estazolam, flurazepam, quazepam, temazepam, and triazolam—are in Category X. Women of child-bearing age should be warned about the potential for fetal harm and instructed to discontinue benzodiazepines if pregnancy occurs.

Benzodiazepines enter breast milk with ease and may accumulate to toxic levels in the breast-fed infant. Accordingly, these drugs should be avoided by nursing mothers.

Other adverse effects.

Occasional reactions include weakness, headache, blurred vision, vertigo, nausea, vomiting, epigastric distress, and diarrhea. Neutropenia and jaundice occur rarely. Rarely, benzodiazepines may cause severe allergic reactions, including angioedema and anaphylaxis.

Drug interactions

Benzodiazepines undergo very few important interactions with other drugs. Unlike barbiturates, benzodiazepines do not induce hepatic drug-metabolizing enzymes. Hence, benzodiazepines do not accelerate the metabolism of other drugs.

CNS depressants.

The CNS-depressant actions of benzodiazepines add with those of other CNS depressants (eg, alcohol, barbiturates, opioids). Hence, although benzodiazepines are very safe when used alone, they can be extremely hazardous in combination with other depressants. Combined overdose with a benzodiazepine plus another CNS depressant can cause profound respiratory depression, coma, and death. Patients should be warned against use of alcohol and all other CNS depressants.

Tolerance and physical dependence

Tolerance.

With prolonged use of benzodiazepines, tolerance develops to some effects but not to others. No tolerance develops to anxiolytic effects, and tolerance to hypnotic effects is generally low. In contrast, significant tolerance develops to antiseizure effects. Patients tolerant to barbiturates, alcohol, and other general CNS depressants show some cross-tolerance to benzodiazepines.

Physical dependence.

Benzodiazepines can cause physical dependence—but the incidence of substantial dependence is low. When benzodiazepines are discontinued following short-term use at therapeutic doses, the resulting withdrawal syndrome is generally mild and often goes unrecognized. Symptoms include anxiety, insomnia, sweating, tremors, and dizziness. Withdrawal from long-term, high-dose therapy can elicit more serious reactions, such as panic, paranoia, delirium, hypertension, muscle twitches, and outright convulsions. Symptoms of withdrawal are usually more intense with benzodiazepines that have a short duration of action. With one agent—alprazolam [Xanax, Xanax XR, Niravam]—dependence may be a greater problem than with other benzodiazepines. Because the benzodiazepine withdrawal syndrome can resemble an anxiety disorder, it is important to differentiate withdrawal symptoms from the return of original anxiety symptoms.

The intensity of withdrawal symptoms can be minimized by discontinuing treatment gradually. Doses should be slowly tapered over several weeks or months. Substituting a benzodiazepine with a long half-life for one with a short half-life is also helpful. Patients should be warned against abrupt cessation of treatment. Following discontinuation of treatment, patients should be monitored for 3 weeks for indications of withdrawal or recurrence of original symptoms.

Acute toxicity

Oral overdose.

When administered in excessive dosage by mouth, benzodiazepines rarely cause serious toxicity. Symptoms include drowsiness, lethargy, and confusion. Significant cardiovascular and respiratory effects are uncommon. If an individual known to have taken an overdose of benzodiazepines does exhibit signs of serious toxicity, it is probable that another drug was taken too.

Intravenous toxicity.

When injected IV, even in therapeutic doses, benzodiazepines can cause severe adverse effects. Life-threatening reactions (eg, profound hypotension, respiratory arrest, cardiac arrest) occur in about 2% of patients.

General treatment measures.

Benzodiazepine-induced toxicity is managed the same as toxicity from barbiturates and other general CNS depressants. Oral benzodiazepines can be removed from the body with gastric lavage followed by ingesting activated charcoal and a saline cathartic; dialysis may be helpful if symptoms are especially severe. Respiration should be monitored and the airway kept patent. Support of blood pressure with IV fluids and norepinephrine may be required.

Treatment with flumazenil.

Flumazenil [Romazicon, Anexate] is a competitive benzodiazepine receptor antagonist. The drug can reverse the sedative effects of benzodiazepines but may not reverse respiratory depression. Flumazenil is approved for benzodiazepine overdose and for reversing the effects of benzodiazepines following general anesthesia. The principal adverse effect is precipitation of convulsions. This is most likely in patients taking benzodiazepines to treat epilepsy and in patients who are physically dependent on benzodiazepines. Flumazenil is administered IV. Doses are injected slowly (over 30 seconds) and may be repeated every minute as needed. The first dose is 0.2 mg, the second is 0.3 mg, and all subsequent doses are 0.5 mg. Effects of flumazenil fade in about 1 hour, hence repeated doses may be required.

Preparations, dosage, and administration

Preparations and dosage.

Preparations and dosages for insomnia are presented later in the chapter. Preparations and dosages of benzodiazepines used for other disorders are presented in Chapter 24 (Drugs for Epilepsy), Chapter 25 (Drugs for Muscle Spasm and Spasticity), Chapter 27 (General Anesthetics), and Chapter 35 (Management of Anxiety Disorders).

All benzodiazepines can be administered orally. In addition, three agents—diazepam, chlordiazepoxide, and lorazepam—may be administered parenterally (IM and IV). When used for sedation or induction of sleep, benzodiazepines are almost always administered by mouth. Parenteral administration is reserved for emergencies, including acute alcohol withdrawal, severe anxiety, and status epilepticus.

Patients should be advised to take oral benzodiazepines with food if gastric upset occurs. Also, they should be instructed to swallow sustained-release formulations intact, without crushing or chewing. Patients should be warned not to increase the dosage or discontinue therapy without consulting the prescriber.

For treatment of insomnia, benzodiazepines should be given on an intermittent schedule (eg, 3 or 4 days a week) in the lowest effective dosage for the shortest duration required. This will minimize physical dependence and associated drug-dependency insomnia.

Intravenous administration is hazardous and must be performed with care. Life-threatening reactions (severe hypotension, respiratory arrest, cardiac arrest) have occurred. In addition, IV administration carries a risk of venous thrombosis, phlebitis, and vascular impairment.

To reduce complications, the following precautions should be taken: (1) inject the drug slowly; (2) take care to avoid intra-arterial injection and extravasation; (3) if direct venous injection is impossible, make the injection into infusion tubing as close to the vein as possible; (4) follow the manufacturer’s instructions regarding suitable diluents for preparing solutions; and (5) have facilities for resuscitation available.

If IM administration is needed, lorazepam is the preferred benzodiazepine to use, owing to consistent absorption from IM sites. Absorption of IM diazepam is erratic and may be delayed. Accordingly, IM diazepam should be avoided.

Benzodiazepine-like drugs

Three benzodiazepine-like drugs are available: zolpidem, zaleplon, and eszopiclone. All three are preferred agents for insomnia. They are not indicated for anxiety. These drugs are structurally different from benzodiazepines, but nonetheless share the same mechanism of action: They all act as agonists at the benzodiazepine receptor site on the GABA receptor–chloride channel complex. Like the benzodiazepines, these drugs have a low potential for tolerance, dependence, and abuse, and are classified as Schedule IV substances.

Zolpidem

Zolpidem [Ambien, Ambien CR, Edluar, Tovalt ODT, Zolpimist], our most widely used hypnotic, is approved only for short-term management of insomnia. However, although approval is limited to short-term use, many patients have taken the drug long term with no apparent tolerance or increase in adverse effects. All zolpidem formulations have a rapid onset, and hence can help people who have difficulty falling asleep. In addition, the extended-release formulation—Ambien CR—can help people who have difficulty maintaining sleep.

Although structurally unrelated to the benzodiazepines, zolpidem binds to the benzodiazepine receptor site on the GABA receptor–chloride channel complex and shares some properties of the benzodiazepines. Like the benzodiazepines, zolpidem can reduce sleep latency and awakenings and can prolong sleep duration. The drug does not significantly reduce time in rapid-eye-movement (REM) sleep and causes little or no rebound insomnia when therapy is discontinued. In contrast to the benzodiazepines, zolpidem lacks anxiolytic, muscle relaxant, and anticonvulsant actions. Why? Because zolpidem doesn’t bind with all benzodiazepine receptors. Rather, binding is limited to the benzodiazepine₁ subtype of benzodiazepine receptors.

Zolpidem is rapidly absorbed following oral dosing. Plasma levels peak in 2 hours. The drug is widely distributed, although levels in the brain remain low. Zolpidem is extensively metabolized to inactive compounds that are excreted in the bile, urine, and feces. The elimination half-life is 2.4 hours.

Zolpidem has a side effect profile like that of the benzodiazepines. Daytime drowsiness and dizziness are most common, and these occur in only 1% to 2% of patients. Like the benzodiazepines, zolpidem has been associated with sleep driving and other sleep-related complex behaviors. At therapeutic doses, zolpidem causes little or no respiratory depression. Safety in pregnancy has not been established. According to the FDA, zolpidem may pose a small risk of anaphylaxis and angioedema.

Short-term treatment is not associated with significant tolerance or physical dependence. Withdrawal symptoms are minimal or absent. Similarly, the abuse liability of zolpidem is low. Accordingly, the drug is classified under Schedule IV of the Controlled Substances Act.

Like other sedative-hypnotics, zolpidem can intensify the effects of other CNS depressants. Accordingly, patients should be warned against combining zolpidem with alcohol and all other drugs that depress CNS function.

Zolpidem is available in five formulations: (1) immediate-release tablets (5 and 10 mg) sold as Ambien, (2) extended-release tablets (6.25 and 12.5 mg) sold as Ambien CR, (3) orally disintegrating tablets (5 and 10 mg) sold as Tovalt ODT, (4) an oral spray (5 and 10 mg) sold as Zolpimist, and (5) sublingual tablets (5 and 10 mg) sold as Edluar. With the immediate-release tablets, sublingual tablets, orally disintegrating tablets, and oral spray, the usual dose is 10 mg. The initial dose should be reduced to 5 mg for elderly and debilitated patients and for those with hepatic insufficiency. With the extended-release tablets, the usual dose is 12.5 mg (or 6.25 mg for elderly or debilitated patients). All formulations have a rapid onset, and hence should be taken just before bedtime. This timing will promote sleep while minimizing daytime sedation.

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Jul 24, 2016 | Posted by admin in NURSING | Comments Off

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