The CNS depressants discussed in this chapter include benzodiazepines, other benzodiazepine receptor agonists (the “Z compounds”), barbiturates, and sedative-hypnotic agents of diverse chemical structure. Older sedative-hypnotic drugs depress the CNS in a dose-dependent fashion, progressively producing a spectrum of responses from mild sedation to coma and death. A sedative drug decreases activity, moderates excitement, and calms the recipient, whereas a hypnotic drug produces drowsiness and facilitates the onset and maintenance of a state of sleep that resembles natural sleep in its electroencephalographic characteristics and from which the recipient can be aroused easily.
Sedation is a side effect of many drugs that are not general CNS depressants (e.g., antihistamines and antipsychotic agents). Although such agents can intensify the effects of CNS depressants, they usually produce more specific therapeutic effects at concentrations far lower than those causing substantial CNS depression. The benzodiazepine sedative-hypnotics resemble such agents; although coma may occur at very high doses, neither surgical anesthesia nor fatal intoxication is produced by benzodiazepines in the absence of other drugs with CNS-depressant actions; an important exception is midazolam, which has been associated with decreased tidal volume and respiratory rate. Moreover, specific antagonists of benzodiazepines exist. This constellation of properties sets the benzodiazepine receptor agonists apart from other sedative-hypnotic drugs and imparts a measure of safety such that benzodiazepines and the newer Z compounds have largely displaced older agents for the treatment of insomnia and anxiety.
The sedative-hypnotic drugs that do not specifically target the benzodiazepine receptor belong to a group of agents that depress the CNS in a dose-dependent fashion, progressively producing calming or drowsiness (sedation), sleep (pharmacological hypnosis), unconsciousness, coma, surgical anesthesia, and fatal depression of respiration and cardiovascular regulation. They share these properties with a large number of chemicals, including general anesthetics (see Chapter 19) and alcohols, most notably ethanol (see Chapter 23).
All benzodiazepines in clinical use promote the binding of the major inhibitory neurotransmitter γ-aminobutyric acid (GABA) to the GABAA receptor, a multi-subunit, ligand-gated chloride channel. GABA binding induces the Cl– current through these channels (see Figure 14–6).
Pharmacological data suggest heterogeneity among sites of binding and action of benzodiazepines; different subunit combinations comprise the GABA-gated chloride channels expressed in different neurons. Receptor subunit composition appears to govern the interaction of various allosteric modulators with these channels, giving hope to efforts to find agents displaying different combinations of benzodiazepine-like properties that reflect selective actions on 1 or more subtypes of GABAA receptors. A number of distinct mechanisms of action are thought to contribute to the sedative-hypnotic, muscle-relaxant, anxiolytic, and anticonvulsant effects of the benzodiazepines, and specific subunits of the GABAA receptor are responsible for specific pharmacological properties of benzodiazepines. While only the benzodiazepines used primarily for hypnosis are discussed in detail, this chapter describes the general properties of the group and important differences among individual agents (see alsoChapters 15 and 21).
Benzodiazepine refers to the portion of the this structure composed of a benzene ring (A) fused to a 7-membered diazepine ring (B). Because all the important benzodiazepines contain a 5-aryl substituent (ring C) and a 1,4-diazepine ring, the term has come to mean the 5-aryl-1,4-benzodiazepines. Numerous modifications in the structure of the ring systems and substituents have yielded compounds with similar activities, including flumazenil (ROMAZICON, in which ring C is replaced with a keto function at position 5 and a methyl substituent is added at position 4), a benzodiazepine receptor antagonist. A large number of nonbenzodiazepine compounds compete with classic benzodiazepines and flumazenil for binding at specific sites in the CNS (e.g., β-carbolines, zolpidem, eszopiclone).
Virtually all effects of the benzodiazepines result from their actions on the CNS. The most prominent of these effects are sedation, hypnosis, decreased anxiety, muscle relaxation, anterograde amnesia, and anticonvulsant activity. Only 2 effects of these drugs result from peripheral actions: coronary vasodilation, seen after intravenous administration of therapeutic doses of certain benzodiazepines, and neuromuscular blockade, seen only with very high doses.
CNS. While benzodiazepines depress activity at all levels of the neuraxis, some structures are affected preferentially. The benzodiazepines do not produce the same degrees of neuronal depression produced by barbiturates and volatile anesthetics. All the benzodiazepines have similar pharmacological profiles. Nevertheless, the drugs differ in selectivity, and the clinical usefulness of individual benzodiazepines thus varies considerably.
As the dose of a benzodiazepine is increased, sedation progresses to hypnosis and then to stupor. The clinical literature often refers to the “anesthetic” effects and uses of certain benzodiazepines, but the drugs do not cause a true general anesthesia because awareness usually persists, and immobility sufficient to allow surgery cannot be achieved. Nonetheless, at “preanesthetic” doses, there is amnesia for events subsequent to administration of the drug. Despite to separate the anxiolytic actions of benzodiazepines from their sedative-hypnotic effects, distinguishing between these behaviors is problematic. Measurements of anxiety and sedation are difficult in humans, and the validity of animal models for anxiety and sedation is uncertain. The existence of multiple benzodiazepine receptors may explain in part the diversity of pharmacological responses in different species.
Tolerance to Benzodiazepines. Studies on tolerance in laboratory animals often are cited to support the belief that disinhibitory effects of benzodiazepines are distinct from their sedative-ataxic effects. Although most patients who ingest benzodiazepines chronically report that drowsiness wanes over a few days, tolerance to the impairment of some measures of psychomotor performance (e.g., visual tracking) usually is not observed. Whether tolerance develops to the anxiolytic effects of benzodiazepines remains a subject of debate. Many patients can maintain themselves on a fairly constant dose; increases or decreases in dosage appear to correspond with changes in problems or stresses. Conversely, some patients either do not reduce their dosage when stress is relieved or steadily escalate dosage. Such behavior may be associated with the development of drug dependence (see Chapter 24).
Some benzodiazepines induce muscle hypotonia without interfering with normal locomotion and can decrease rigidity in patients with cerebral palsy. Clonazepam in nonsedative doses does cause muscle relaxation, but diazepam and most other benzodiazepines do not. Tolerance occurs to the muscle relaxant and ataxic effects of these drugs.
Clonazepam, nitrazepam, and nordazepam have more selective anticonvulsant activity than most other benzodiazepines. Benzodiazepines also suppress photic seizures in baboons and ethanol-withdrawal seizures in humans. However, the development of tolerance to the anticonvulsant effects has limited the usefulness of benzodiazepines in the treatment of recurrent seizure disorders in humans (see Chapter 21).
Although analgesic effects of benzodiazepines have been observed in experimental animals, only transient analgesia is apparent in humans after intravenous administration. Such effects actually may involve the production of amnesia. Unlike barbiturates, benzodiazepines do not cause hyperalgesia.
Effects on the Electroencephalogram (EEG) and Sleep Stages. The effects of benzodiazepines on the waking EEG resemble those of other sedative-hypnotic drugs. Alpha activity is decreased, but there is an increase in low-voltage fast activity. Tolerance occurs to these effects. With respect to sleep, some differences in the patterns of effects exerted by the various benzodiazepines have been noted, but benzodiazepine use usually imparts a sense of deep or refreshing sleep. Benzodiazepines decrease sleep latency, especially when first used, and diminish the number of awakenings and the time spent in stage 0 (a stage of wakefulness). Time in stage 1 (descending drowsiness) usually is decreased, and there is a prominent decrease in the time spent in slow-wave sleep (stages 3 and 4). Most benzodiazepines increase the time from onset of spindle sleep to the first burst of rapid-eye-movement (REM) sleep; the time spent in REM sleep usually is shortened, however, the number of cycles of REM sleep usually is increased, mostly late in the sleep time. Zolpidem and zaleplon suppress REM sleep to a lesser extent than do benzodiazepines and thus may be superior to benzodiazepines for use as hypnotics.
Despite the shortening of stage 4 and REM sleep, benzodiazepine administration typically increases total sleep time, largely by increasing the time spent in stage 2 (which is the major fraction of non-REM sleep). The effect is greatest in subjects with the shortest baseline total sleep time. In addition, despite the increased number of REM cycles, the number of shifts to lighter sleep stages (1 and 0) and the amount of body movement are diminished. Nocturnal peaks in the secretion of growth hormone, prolactin, and luteinizing hormone are not affected. During chronic nocturnal use of benzodiazepines, the effects on the various stages of sleep usually decline within a few nights. When such use is discontinued, the pattern of drug-induced changes in sleep parameters may “rebound,” and an increase in the amount and density of REM sleep may be especially prominent. If the dosage has not been excessive, patients usually will note only a shortening of sleep time rather than an exacerbation of insomnia.
MOLECULAR TARGETS FOR BENZODIAZEPINE ACTIONS IN THE CNS. Benzodiazepines act at GABAA receptors by binding directly to a specific site that is distinct from that of GABA binding (see Figure 14–6). Unlike barbiturates, benzodiazepines do not activate GABAA receptors directly; rather, benzodiazepines act allosterically by modulating the effects of GABA. Benzodiazepines and GABA analogs bind to their respective sites on brain membranes with nanomolar affinity. Benzodiazepines modulate GABA binding, and GABA alters benzodiazepine binding in an allosteric fashion.
Benzodiazepines and related compounds can act as agonists, antagonists, or inverse agonists at the benzodiazepine-binding site on GABAA receptors. Agonists at the binding site increase, and inverse agonists decrease, the amount of chloride current generated by GABAA-receptor activation. Agonists at the benzodiazepine binding site shift the GABA concentration-response curve to the left, whereas inverse agonists shift the curve to the right. Both these effects are blocked by antagonists at the benzodiazepine binding site. In the absence of an agonist or inverse agonist for the benzodiazepine binding site, an antagonist for this binding site does not affect GABAA receptor function. One such antagonist, flumazenil, is used clinically to reverse the effects of high doses of benzodiazepines. The behavioral and electrophysiological effects of benzodiazepines also can be reduced or prevented by prior treatment with antagonists at the GABA binding site (e.g., bicuculline).
Each GABAA receptor is believed to consist of a pentamer of homologous subunits. Thus far 16 different subunits have been identified and classified into 7 subunit families. The exact subunit structures of native GABA receptors still are unknown; most GABA receptors are likely of α, β, and γ subunits that co-assemble with some uncertain stoichiometry. The multiplicity of subunits generates heterogeneity in GABAA receptors and is responsible, at least in part, for the pharmacological diversity in benzodiazepine effects in behavioral, biochemical, and functional studies. An understanding of which GABAAreceptor subunits are responsible for particular effects of benzodiazepines in vivo is emerging from KO animal studies. The attribution of specific behavioral effects of benzodiazepines to individual receptor subunits will, hopefully, aid in the development of new compounds exhibiting fewer undesired side effects.
GABAA Receptor-Mediated Electrical Events. Benzodiazepines exert their major actions by increasing the gain of inhibitory neurotransmission mediated by GABAA receptors. Enhancement of GABA-induced chloride currents by benzodiazepines results primarily from an increase in the frequency of bursts of Cl– channel opening produced by submaximal amounts of GABA. At therapeutically relevant concentrations, benzodiazepines potentiate inhibitory synaptic transmission measured after stimulation of afferent fibers.
The remarkable safety of the benzodiazepines likely relates to the fact that their effects in vivo depend on the presynaptic release of GABA; in the absence of GABA, benzodiazepines have no effects on GABAA receptor function. This is in distinction to barbiturates, which also enhance the effects of GABA at low concentrations, but, in addition, directly activate GABA receptors at higher concentrations, which can lead to profound CNS depression.
The behavioral and sedative effects of benzodiazepines can be ascribed in part to potentiation of GABA-ergic pathways that serve to regulate the firing of monoamine-containing neurons known to promote behavioral arousal and to be important mediators of the inhibitory effects of fear and punishment on behavior. Finally, inhibitory effects on muscular hypertonia or the spread of seizure activity can be rationalized by potentiation of inhibitory GABA-ergic circuits at various levels of the neuraxis. The magnitude of the effects produced by benzodiazepines varies widely depending on such factors as the types of inhibitory circuits that are operating, the sources and intensity of excitatory input, and the manner in which experimental manipulations are performed and assessed. Accordingly, benzodiazepines markedly prolong the period after brief activation of recurrent GABA-ergic pathways during which neither spontaneous nor applied excitatory stimuli can evoke neuronal discharge; this effect is reversed by the GABAA receptor antagonist bicuculline (see Figure 14–5).
Respiration. Hypnotic doses of benzodiazepines are without effect on respiration in normal subjects, but special care must be taken in the treatment of children and individuals with impaired hepatic function. At higher doses, such as those used for preanesthetic medication or for endoscopy, benzodiazepines slightly depress alveolar ventilation and cause respiratory acidosis as the result of a decrease in hypoxic rather than hypercapnic drive; these effects are exaggerated in patients with chronic obstructive pulmonary disease (COPD), and alveolar hypoxia and CO2 narcosis may result. These drugs can cause apnea during anesthesia or when given with opioids. Patients severely intoxicated with benzodiazepines only require respiratory assistance when they also have ingested another CNS-depressant drug, most commonly ethanol.
In contrast, hypnotic doses of benzodiazepines may worsen sleep-related breathing disorders by adversely affecting control of the upper airway muscles or by decreasing the ventilatory response to CO2. The latter effect may cause hypoventilation and hypoxemia in some patients with severe COPD. In patients with obstructive sleep apnea (OSA), hypnotic doses of benzodiazepines may decrease muscle tone in the upper airway and exaggerate the impact of apneic episodes on alveolar hypoxia, pulmonary hypertension, and cardiac ventricular load. Benzodiazepines may promote the appearance of episodes of apnea during REM sleep (associated with decreases in oxygen saturation) in patients recovering from a myocardial infarction; however, no impact of these drugs on survival of patients with cardiac disease has been reported.
Cardiovascular System. The cardiovascular effects of benzodiazepines are minor in normal subjects except in severe intoxication. In preanesthetic doses, all benzodiazepines decrease blood pressure and increase heart rate. With midazolam, effects appear to be secondary to a decrease in peripheral resistance; with diazepam, effects are secondary to a decrease in left ventricular work and cardiac output. Diazepam increases coronary flow, possibly by an action to increase interstitial concentrations of adenosine, and the accumulation of this cardiodepressant metabolite also may explain the negative inotropic effects of the drug. In large doses, midazolam decreases cerebral blood flow and oxygen assimilation considerably.
GI Tract. Benzodiazepines are thought by some gastroenterologists to improve a variety of “anxiety-related” GI disorders. Diazepam markedly decreases nocturnal gastric secretion in humans. Other drug classes are considerably more effective in acid-peptic disorders (see Chapter 45).
ABSORPTION, FATE, AND EXCRETION. All the benzodiazepines are absorbed completely (clorazepate is decarboxylated rapidly in gastric juice to N-desmethyldiazepam [nordazepam], which subsequently is absorbed completely). Drugs active at the benzodiazepine receptor may be divided into 4 categories based on their elimination t1/2:
• Ultra-short-acting benzodiazepines
• Short-acting agents (t1/2 6 h), including triazolam, the non-benzodiazepine zolpidem (t1/2 2 h), and eszopiclone (t1/2 5-6 h)
• Intermediate-acting agents (t1/2 6-24 h), including estazolam and temazepam
• Long-acting agents (t1/2 > 24 h), including flurazepam, diazepam, and quazepam
Flurazepam itself has a short t1/2 (~2.3 h), but a major active metabolite, N-des-alkyl-flurazepam, is long-lived (t1/2 47-100 h); such features complicate the classification of individual benzodiazepines.
The benzodiazepines and their active metabolites bind to plasma proteins. The extent of binding correlates strongly with lipid solubility and ranges from ~70% for alprazolam to nearly 99% for diazepam. The concentration in the cerebrospinal fluid is approximately equal to the concentration of free drug in plasma. The plasma concentrations of most benzodiazepines exhibit patterns that are consistent with 2-compartment models, but 3-compartment models appear to be more appropriate for the compounds with the highest lipid solubility. Accordingly, there is rapid uptake of benzodiazepines into the brain and other highly perfused organs after intravenous administration (or oral administration of a rapidly absorbed compound); rapid uptake is followed by a phase of redistribution into tissues that are less well perfused, especially muscle and fat. Redistribution is most rapid for drugs with the highest lipid solubility. The kinetics of redistribution of diazepam and other lipophilic benzodiazepines are complicated by enterohepatic circulation. The volumes of distribution of the benzodiazepines are large and in many cases are increased in elderly patients. These drugs cross the placental barrier and are secreted into breast milk.
Benzodiazepines are metabolized extensively by hepatic CYPs, particularly CYPs 3A4 and 2C19. Some benzodiazepines, such as oxazepam, are conjugated directly and are not metabolized by these enzymes. Erythromycin, clarithromycin, ritonavir, itraconazole, ketoconazole, nefazodone, and grapefruit juice are inhibitors of CYP3A4 (see Chapter 6) and can affect the metabolism of benzodiazepines. Because active metabolites of some benzodiazepines are biotransformed more slowly than are the parent compounds, the duration of action of many benzodiazepines bears little relationship to the t1/2 of elimination of the parent drug that was administered, as noted above for flurazepam. Conversely, the rate of biotransformation of agents that are inactivated by the initial reaction is an important determinant of their duration of action; these agents include oxazepam, lorazepam, temazepam, triazolam, and midazolam.
Because the benzodiazepines apparently do not significantly induce the synthesis of hepatic CYPs, their chronic administration usually does not result in the accelerated metabolism of other substances or of the benzodiazepines. Cimetidine and oral contraceptives inhibit N-dealkylation and 3-hydroxylation of benzodiazepines. Ethanol, isoniazid, and phenytoin are less effective in this regard. These reactions usually are reduced to a greater extent in elderly patients and in patients with chronic liver disease than are those involving conjugation.
PHARMACOKINETICS AND THE IDEAL HYPNOTIC. An ideal hypnotic agent would have a rapid onset of action when taken at bedtime, a sufficiently sustained action to facilitate sleep throughout the night, and no residual action by the following morning. Among the benzodiazepines that are used commonly as hypnotic agents, triazolam theoretically fits this description most closely. Because of the slow rate of elimination of desalkylflurazepam, flurazepam (or quazepam) might seem to be unsuitable for this purpose. In practice, there appear to be some disadvantages to the use of agents that have a relatively rapid rate of disappearance, including the early-morning insomnia that is experienced by some patients and a greater likelihood of rebound insomnia on drug discontinuation. With careful selection of dosage, flurazepam and other benzodiazepines with slower rates of elimination than triazolam can be used effectively.
The therapeutic uses and routes of administration of individual benzodiazepines that are marketed in the U.S. are summarized in Table 17–1. Most benzodiazepines can be used interchangeably. For example, diazepam can be used for alcohol withdrawal, and most benzodiazepines work as hypnotics. Benzodiazepines that are useful as anticonvulsants have a long t1/2, and rapid entry into the brain is required for efficacy in treatment of status epilepticus. A short elimination t1/2 is desirable for hypnotics. Antianxiety agents, in contrast, should have a long t1/2 despite the drawback of the risk of neuropsychological deficits caused by drug accumulation.
Therapeutic Uses of Benzodiazepines
UNTOWARD EFFECTS. At peak concentration in plasma, hypnotic doses of benzodiazepines cause varying degrees of light-headedness, lassitude, increased reaction time, motor incoordination, impairment of mental and motor functions, confusion, and anterograde amnesia. Cognition appears to be affected less than motor performance. All of these effects can greatly impair driving and other psychomotor skills, especially if combined with ethanol. When the drug is given at the intended time of sleep, the persistence of these effects during the waking hours is adverse. The intensity and incidence of CNS toxicity generally increase with age. Other common side effects of benzodiazepines are weakness, headache, blurred vision, vertigo, nausea and vomiting, epigastric distress, and diarrhea; joint pains, chest pains, and incontinence are much rarer. Anticonvulsant benzodiazepines sometimes increase the frequency of seizures in patients with epilepsy.
ADVERSE PSYCHOLOGICAL EFFECTS. Benzodiazepines may cause paradoxical effects. Flurazepam occasionally increases the incidence of nightmares—especially during the first week of use—and sometimes causes garrulousness, anxiety, irritability, tachycardia, and sweating. Amnesia, euphoria, restlessness, hallucinations, sleep-walking, sleep-talking, other complex behaviors, and hypomanic behavior have been reported to occur during use of various benzodiazepines. Bizarre uninhibited behavior has been noted in some users, whereas hostility and rage may occur in others; collectively, these are sometimes referred to as disinhibition or dyscontrol reactions. Paranoia, depression, and suicidal ideation also occasionally may accompany the use of these agents. Such paradoxical or disinhibition reactions are rare and appear to be dose related. Because of reports of an increased incidence of confusion and abnormal behaviors, triazolam has been banned in the U.K., although the FDA declared triazolam to be safe and effective in low doses of 0.125-0.25 mg.
Chronic benzodiazepine use poses a risk for development of dependence and abuse. Abuse of benzodiazepines includes the use of flunitrazepam (Rohypnol; not licensed for use in the U.S.) as a “date-rape drug.” Withdrawal symptoms may include temporary intensification of the problems that originally prompted their use (e.g., insomnia or anxiety). Dysphoria, irritability, sweating, unpleasant dreams, tremors, anorexia, and faintness or dizziness also may occur, especially when withdrawal of the benzodiazepine occurs abruptly. Despite their adverse effects, benzodiazepines are relatively safe drugs. Ethanol is a common contributor to deaths involving benzodiazepines, and true coma is uncommon in the absence of another CNS depressant. Benzodiazepines can further compromise respiration in patients with COPD or obstructive sleep apnea (OSA).
A wide variety of serious allergic, hepatotoxic, and hematologic reactions to the benzodiazepines may occur, but the incidence is quite low; these reactions have been associated with the use of flurazepam, triazolam, and temazepam. Large doses taken just before or during labor may cause hypothermia, hypotonia, and mild respiratory depression in the neonate. Abuse by the pregnant mother can result in a withdrawal syndrome in the newborn.
Except for additive effects with other sedative or hypnotic drugs, reports of clinically important pharmacodynamic interactions between benzodiazepines and other drugs have been infrequent. Ethanol increases both the rate of absorption of benzodiazepines and the associated CNS depression. Valproate and benzodiazepines in combination may cause psychotic episodes. Pharmacokinetic interactions were discussed earlier.
NOVEL BENZODIAZEPINE RECEPTOR AGONISTS
Hypnotics in this class are commonly referred to as “Z compounds.” They include zolpidem (AMBIEN), zaleplon (SONATA), zopiclone (not marketed in the U.S.), and eszopiclone (LUNESTA), which is the S(+) enantiomer of zopiclone. Although the Z compounds are structurally unrelated to each other and to benzodiazepines, their therapeutic efficacy as hypnotics is due to agonist effects on the benzodiazepine site of the GABAA receptor. Compared to benzodiazepines, Z compounds are less effective as anticonvulsants or muscle relaxants, which may be related to their relative selectivity for GABAA receptors containing the α1 subunit. Over the last decade, Z compounds have largely replaced benzodiazepines in the treatment of insomnia. Z compounds were initially promoted as having less potential for dependence and abuse than traditional benzodiazepines. However, based on postmarketing clinical experience with zopiclone and zolpidem, tolerance and physical dependence can be expected during long-term use of Z compounds, especially with higher doses. Zopiclone and its isomers are classified as schedule IV drugs in the U.S. The clinical presentation of overdose with Z compounds is similar to that of benzodiazepine overdose and can be treated with the benzodiazepine antagonist flumazenil.
Zaleplon and zolpidem are effective in relieving sleep-onset insomnia. Both drugs are FDA-approved for use as long as to 7-10 days at a time. Zaleplon and zolpidem have sustained hypnotic efficacy without occurrence of rebound insomnia on abrupt discontinuation. Zaleplon and zolpidem have similar degrees of efficacy. Zolpidem has a t1/2 of ~2 h, which is sufficient to cover most of a typical 8-h sleep period, and is presently approved for bedtime use only. Zaleplon has a shorter t1/2 ~1 h, which offers the possibility for safe dosing later in the night, within 4 h of the anticipated rising time. Zaleplon and zolpidem differ in residual side effects; late-night administration of zolpidem has been associated with morning sedation, delayed reaction time, and anterograde amnesia, whereas zaleplon does not differ from placebo.
ZALEPLON. Zaleplon (SONATA, generic) is a nonbenzodiazepine and is a member of the pyrazolopyrimidine class. Zaleplon preferentially binds to the benzodiazepine-binding site on GABAA receptors containing the α1 receptor subunit. Zaleplon is absorbed rapidly and reaches peak plasma concentrations in ~1 h. Its bioavailability is ~30% because of presystemic metabolism. Zaleplon is metabolized largely by aldehyde oxidase and to a lesser extent by CYP3A4. Its oxidative metabolites are converted to glucuronides and eliminated in urine. Less than 1% of zaleplon is excreted unchanged in urine. None of zaleplon’s metabolites are pharmacologically active. Zaleplon is usually administered in 5-, 10-, or 20-mg doses.
ZOLPIDEM. Zolpidem (AMBIEN, others) is a non-benzodiazepine sedative-hypnotic drug. The actions of zolpidem are due to agonist effects on GABAA receptors and generally resemble those of benzodiazepines. Zolpidem has little effect on the stages of sleep in normal human subjects. The drug is effective in shortening sleep latency and prolonging total sleep time in patients with insomnia. After discontinuation of zolpidem, the beneficial effects on sleep reportedly persist for up to 1 week, but mild rebound insomnia on the first night also has occurred. Tolerance and physical dependence are rare. Nevertheless, zolpidem is approved only for the short-term treatment of insomnia. At therapeutic doses (5-10 mg), zolpidem infrequently produces residual daytime sedation or amnesia, and the incidence of other adverse effects also is low. As with the benzodiazepines, large overdoses of zolpidem do not produce severe respiratory depression unless other agents (e.g., ethanol) also are ingested. Hypnotic doses increase the hypoxia and hypercarbia of patients with OSA.
Zolpidem is absorbed readily from the GI tract; first-pass hepatic metabolism results in an oral bioavailability of ~70%, but this value is lower when the drug is ingested with food. Zolpidem is eliminated almost entirely by conversion to inactive products in the liver, largely through oxidation of the methyl groups on the phenyl and imidazopyridine rings to the corresponding carboxylic acids. Its plasma t1/2 is ~2 h in individuals with normal hepatic blood flow or function. This value may be increased 2-fold or more in those with cirrhosis and also tends to be greater in older patients; adjustment of dosage often is necessary in both categories of patients. Although little or no unchanged zolpidem is found in the urine, elimination of the drug is slower in patients with chronic renal insufficiency largely owing to an increase in its apparent volume of distribution.
ESZOPICLONE. Eszopiclone (LUNESTA) is the active S(+) enantiomer of zopiclone. Eszopiclone has no structural similarity to benzodiazepines, zolpidem, or zaleplon. Eszopiclone is believed to exert its sleep-promoting effects through its enhancement of GABAA receptor function at the benzodiazepine binding site. Eszopiclone is used for the long-term treatment of insomnia and for sleep maintenance. It is available in 1-, 2-, or 3-mg tablets. Eszopiclone decreases the latency to onset of sleep. In clinical studies, no tolerance was observed; no signs of serious withdrawal, such as seizures or rebound insomnia, were seen on discontinuation of the drug (however, there are such reports for zopiclone, the racemate used outside the U.S.). Mild withdrawal consisting of abnormal dreams, anxiety, nausea, and upset stomach can occur (rate <2%). A minor reported adverse effect of eszopiclone was a bitter taste. Eszopiclone is a schedule IV controlled substance in the U.S.
Eszopiclone is absorbed rapidly after oral administration, with a bioavailability of ~80%; it is metabolized by CYPs 3A4 and 2E1 and has a t1/2 of 6 h.
FLUMAZENIL: A BENZODIAZEPINE RECEPTOR ANTAGONIST
Flumazenil (ROMAZICON, generic), the only member of this class, is an imidazobenzodiazepine that binds with high affinity to specific sites on the GABAA receptor, where it competitively antagonizes the binding and allosteric effects of benzodiazepines and other ligands. Flumazenil antagonizes both the electrophysiological and behavioral effects of agonist and inverse-agonist benzodiazepines and β-carbolines.
Flumazenil is available only for intravenous administration. Flumazenil is eliminated almost entirely by hepatic metabolism to inactive products with a t1/2 of ~1 h; the duration of clinical effects usually is only 30-60 min. Although absorbed rapidly after oral administration, <25% of the drug reaches the systemic circulation owing to extensive first-pass hepatic metabolism; effective oral doses are apt to cause headache and dizziness. The administration of a series of small injections is preferred to a single bolus injection. A total of 1 mg flumazenil given over 1-3 min usually is sufficient to abolish the effects of therapeutic doses of benzodiazepines. Additional courses of treatment with flumazenil may be needed within 20-30 min should sedation reappear.
The primary indications for the use of flumazenil are the management of suspected benzodiazepine overdose and the reversal of sedative effects produced by benzodiazepines administered during either general anesthesia or diagnostic and/or therapeutic procedures. Flumazenil is not effective in single-drug overdoses with either barbiturates or tricyclic antidepressants or in patients who had been taking benzodiazepines for protracted periods and in whom tolerance and/or dependence may have developed. The administration of flumazenil in these settings may be associated with the onset of seizures, especially in patients poisoned with tricyclic antidepressants.
RAMELTEON. Ramelteon (ROZEREM) is a synthetic tricyclic analog of melatonin, approved in the U.S. for the treatment of insomnia, specifically difficulties of sleep onset.
Mechanism of Action. Melatonin levels in the suprachiasmatic nucleus rise and fall in a circadian fashion, with concentrations increasing in the evening as an individual prepares for sleep, and then reaching a plateau and ultimately decreasing as the night progresses. Two GPCRs for melatonin, MT1 and MT2, occur in the suprachiasmatic nucleus, each playing a different role in sleep. Binding of agonists such as melatonin to MT1 receptors promotes the onset of sleep; melatonin binding to MT2 receptors shifts the timing of the circadian system. Ramelteon binds to both MT1 and MT2 receptors with high affinity but, unlike melatonin, it does not bind appreciably to quinone reductase 2, the structurally unrelated MT3 receptor. Ramelteon is not known to bind to any other classes of receptors.
CLINICAL PHARMACOLOGY. Prescribing guidelines suggest that an 8-mg tablet be taken ~30 min before bedtime. Ramelteon is rapidly absorbed from the GI tract. Because of the significant first-pass metabolism that occurs after oral administration, ramelteon bioavailability is <2%. The drug is largely metabolized by hepatic CYPs 1A2, 2C, and 3A4, with t1/2 of ~2 h in humans. Of the 4 metabolites, one, M-II, acts as an agonist at MT1 and MT2 receptors and may contribute to the sleep-promoting effects of ramelteon. Ramelteon is efficacious in combating both transient and chronic insomnia. Studies indicate that the drug is generally well tolerated by patients and does not impair next-day cognitive function. Sleep latency was consistently found to be shorter in patients given ramelteon compared to placebo controls. No evidence of rebound insomnia or withdrawal effects were noted upon ramelteon withdrawal. Unlike most agents mentioned in this chapter, ramelteon is not a controlled substance.
The barbiturates were once used extensively as sedative-hypnotic drugs. Except for a few specialized uses, they have been largely replaced by the much safer benzodiazepines. Table 17–2 lists the common barbiturates and their pharmacological properties.
Major Pharmacological Properties of Selected Barbiturates
Barbiturates are derivatives of this parent structure:
The presence of alkyl or aryl groups at position 5 confers sedative-hypnotic and sometimes other activities. Barbiturates in which the oxygen at C2 is replaced by sulfur sometimes are calledthiobarbiturates. These compounds are more lipid-soluble than the corresponding oxybarbiturates. In general, structural changes that increase lipid solubility decrease duration of action, decrease latency to onset of activity, accelerate metabolic degradation, and increase hypnotic potency.
The barbiturates reversibly depress the activity of all excitable tissues. The CNS is exquisitely sensitive, and even when barbiturates are given in anesthetic concentrations, direct effects on peripheral excitable tissues are weak. However, serious deficits in cardiovascular and other peripheral functions occur in acute barbiturate intoxication.
ABSORPTION, FATE, AND EXCRETION. For sedative-hypnotic use, the barbiturates usually are administered orally (see Table 17–2). Na+ salts are absorbed more rapidly than the corresponding free acids, especially from liquid formulations. The onset of action varies from 10-60 min, and is delayed by the presence of food. Intramuscular injections of solutions of the Na+ salts should be placed deeply into large muscles to avoid the pain and possible necrosis that can result at more superficial sites. The intravenous route usually is reserved for the management of status epilepticus (phenobarbital sodium) or for the induction and/or maintenance of general anesthesia (e.g., thiopental or methohexital). Barbiturates are distributed widely and readily cross the placenta. Uptake into less vascular tissues, especially muscle and fat, leads to a decline in the concentration of barbiturate in the plasma and brain. With thiopental and methohexital, this results in the awakening of patients within 5-15 min of the injection of the usual anesthetic doses (see Chapter 19).
Except for the less lipid-soluble aprobarbital and phenobarbital, nearly complete metabolism and/or conjugation of barbiturates in the liver precedes their renal excretion. The oxidation of radicals at C5 is the most important biotransformation that terminates biological activity. In some instances (e.g., phenobarbital), N-glycosylation is an important metabolic pathway. Other biotransformations include N-hydroxylation, desulfuration of thiobarbiturates to oxybarbiturates, opening of the barbituric acid ring, and N-dealkylation of N-alkyl barbiturates to active metabolites (e.g., mephobarbital to phenobarbital). About 25% of phenobarbital and nearly all of aprobarbital are excreted unchanged in the urine.
The metabolic elimination of barbiturates is more rapid in young people than in the elderly and infants, and t1/2 are increased during pregnancy partly because of the expanded volume of distribution. Chronic liver disease often increases the t1/2 of the biotransformable barbiturates. Repeated administration, especially of phenobarbital, shortens the t1/2 of barbiturates that are metabolized as a result of the induction of microsomal enzymes.
The barbiturates commonly used as hypnotics in the U.S. have t1/2 values such that the drugs are not fully eliminated in 24 h (see Table 17–2). Thus, these barbiturates will accumulate during repetitive administration unless appropriate adjustments in dosage are made. Furthermore, the persistence of the drug in plasma during the day favors the development of tolerance and abuse.
Central Nervous System
Sites and Mechanisms of Action on the CNS. Barbiturates act throughout the CNS; nonanesthetic doses preferentially suppress polysynaptic responses. Facilitation is diminished, and inhibition usually is enhanced. The site of inhibition is either postsynaptic, as at cortical and cerebellar pyramidal cells and in the cuneate nucleus, substantia nigra, and thalamic relay neurons, or presynaptic, as in the spinal cord. Enhancement of inhibition occurs primarily at synapses where neurotransmission is mediated by GABA acting at GABAA receptors. Mechanisms underlying the actions of barbiturates on GABAAreceptors appear to be distinct from those of either GABA or the benzodiazepines. Barbiturates activate inhibitory GABAA receptors and inhibit excitatory AMPA/kainate receptors, These actions can explain their CNS-depressant effects. For details, see the 12th edition of the parent text.
Barbiturates can produce all degrees of depression of the CNS, ranging from mild sedation to general anesthesia (see Chapter 19). Certain barbiturates, particularly those containing a 5-phenyl substituent (e.g., phenobarbital and mephobarbital), have selective anticonvulsant activity (see Chapter 21). The anti-anxiety properties of the barbiturates are inferior to those exerted by the benzodiazepines.
Except for the anticonvulsant activities of phenobarbital and its congeners, the barbiturates possess a low degree of selectivity and a narrow therapeutic index. Pain perception and reaction are relatively unimpaired until the moment of unconsciousness, and in small doses, barbiturates increase reactions to painful stimuli. Hence, they cannot be relied on to produce sedation or sleep in the presence of even moderate pain.
Effects on Stages of Sleep. Hypnotic doses of barbiturates increase the total sleep time and alter the stages of sleep in a dose-dependent manner. Like the benzodiazepines, these drugs decrease sleep latency, the number of awakenings, and the durations of REM and slow-wave sleep. During repetitive nightly administration, some tolerance to the effects on sleep occurs within a few days, and the effect on total sleep time may be reduced by as much as 50% after 2 weeks of use. Discontinuation leads to rebound increases in all the parameters reported to be decreased by barbiturates.
Tolerance. With chronic administration of gradually increasing doses, pharmacodynamic tolerance continues to develop over a period of weeks to months, depending on the dosage schedule, whereas pharmacokinetic tolerance reaches its peak in a few days to a week. Tolerance to the effects on mood, sedation, and hypnosis occurs more readily and is greater than that to the anticonvulsant and lethal effects; thus, as tolerance increases, the therapeutic index decreases. Pharmacodynamic tolerance to barbiturates confers cross-tolerance to all general CNS-depressant drugs, including ethanol.
Abuse and Dependence. Like other CNS depressant drugs, barbiturates are abused, and some individuals develop a dependence on them (see Chapter 24). Moreover, the barbiturates may have euphoriant effects.
Peripheral Nervous Structures. Barbiturates selectively depress transmission in autonomic ganglia and reduce nicotinic excitation by choline esters. This effect may account, at least in part, for the fall in blood pressure produced by intravenous oxybarbiturates and by severe barbiturate intoxication. At skeletal neuromuscular junctions, the blocking effects of both tubocurarine and decamethonium are enhanced during barbiturate anesthesia. These actions probably result from the capacity of barbiturates at hypnotic or anesthetic concentrations to inhibit the passage of current through nicotinic cholinergic receptors. Several distinct mechanisms appear to be involved, and little stereoselectivity is evident.
RESPIRATION. Barbiturates depress both the respiratory drive and the mechanisms responsible for the rhythmic character of respiration. The neurogenic drive is essentially eliminated by a dose 3 times greater than that used normally to induce sleep. Such doses also suppress the hypoxic drive and, to a lesser extent, the chemoreceptor drive. However, the margin between the lighter planes of surgical anesthesia and dangerous respiratory depression is sufficient to permit the ultra-short-acting barbiturates to be used, with suitable precautions, as anesthetic agents. The barbiturates only slightly depress protective reflexes until the degree of intoxication is sufficient to produce severe respiratory depression. Coughing, sneezing, hiccoughing, and laryngospasm may occur when barbiturates are employed as intravenous anesthetic agents.
CARDIOVASCULAR SYSTEM. When given orally in sedative or hypnotic doses, barbiturates do not produce significant overt cardiovascular effects. In general, the effects of thiopental anesthesia on the cardiovascular system are benign in comparison with those of the volatile anesthetic agents; there usually is either no change or a fall in mean arterial pressure (see Chapter 19).
Other cardiovascular changes often noted when thiopental and other intravenous thiobarbiturates are administered after conventional preanesthetic medication include decreased renal and cerebral blood flow with a marked fall in CSF pressure. Although cardiac arrhythmias are observed only infrequently, intravenous anesthesia with barbiturates can increase the incidence of ventricular arrhythmias, especially when epinephrine and halothane also are present. Anesthetic concentrations of barbiturates have direct electrophysiological effects on the heart; in addition to depressing Na+ channels, they reduce the function of at least 2 types of K+ channels. However, direct depression of cardiac contractility occurs only when doses several times those required to cause anesthesia are administered.
GI TRACT. The oxybarbiturates tend to decrease the tone of the GI musculature and the amplitude of rhythmic contractions. A hypnotic dose does not significantly delay gastric emptying in humans. The relief of various GI symptoms by sedative doses is probably largely due to the central-depressant action.
LIVER. The effects vary with the duration of exposure to the barbiturate. Acutely, the barbiturates combine with several CYPs and inhibit the biotransformation of a number of other drugs and endogenous substrates, such as steroids; other substrates may reciprocally inhibit barbiturate biotransformations.
Chronic administration of barbiturates markedly increases the protein and lipid content of the hepatic smooth endoplasmic reticulum, as well as the activities of glucuronyl transferase and CYPs 1A2, 2C9, 2C19, and 3A4. The induction of these enzymes increases the metabolism of a number of drugs and endogenous substances, including steroid hormones, cholesterol, bile salts, and vitamins K and D. This also results in an increased rate of barbiturate metabolism, which partly accounts for tolerance to barbiturates. The inducing effect is not limited to the microsomal enzymes; e.g., there are increases in δ-aminolevulinic acid (ALA) synthetase, a mitochondrial enzyme, and aldehyde dehydrogenase, a cytosolic enzyme. The effect of barbiturates on ALA synthetase can cause dangerous disease exacerbations in persons with intermittent porphyria.
KIDNEY. Severe oliguria or anuria may occur in acute barbiturate poisoning largely as a result of the marked hypotension.
The major uses of individual barbiturates are listed in Table 17–2. As with the benzodiazepines, the selection of a particular barbiturate for a given therapeutic indication is based primarily on pharmacokinetic considerations. Benzodiazepines and other compounds for sedation have largely replaced barbiturates.
After-Effects. Drowsiness may last for only a few hours after a hypnotic dose of barbiturate, but residual CNS depression sometimes is evident the following day, and subtle distortions of mood and impairment of judgment and fine motor skills may be demonstrable. Residual effects also may take the form of vertigo, nausea, vomiting, or diarrhea, or sometimes may be manifested as overt excitement.
Paradoxical Excitement. In some persons, barbiturates produce excitement rather than depression, and the patient may appear to be inebriated. This type of idiosyncrasy is relatively common among geriatric and debilitated patients and occurs most frequently with phenobarbital and N-methylbarbiturates. Barbiturates may cause restlessness, excitement, and even delirium when given in the presence of pain and may worsen a patient’s perception of pain.
Hypersensitivity. Allergic reactions occur, especially in persons with asthma, urticaria, angioedema, or similar conditions. Hypersensitivity reactions include localized swellings, particularly of the eyelids, cheeks, or lips, and erythematous dermatitis. Rarely, exfoliative dermatitis may be caused by phenobarbital and can prove fatal; the skin eruption may be associated with fever, delirium, and marked degenerative changes in the liver and other parenchymatous organs.
DRUG INTERACTIONS. Barbiturates combine with other CNS depressants to cause severe depression; ethanol is the most frequent offender, and interactions with first-generation antihistamines also are common. Isoniazid, methylphenidate, and monoamine oxidase inhibitors also increase the CNS-depressant effects.
Barbiturates competitively inhibit the metabolism of certain other drugs; however, the greatest number of drug interactions results from induction of hepatic CYPs (as described above) and the accelerated disappearance of many drugs and endogenous substances. Hepatic enzyme induction enhances metabolism of endogenous steroid hormones, which may cause endocrine disturbances, as well as of oral contraceptives, which may result in unwanted pregnancy. Barbiturates also induce the hepatic generation of toxic metabolites of chlorocarbons (chloroform, trichloroethylene, carbon tetrachloride) and consequently promote lipid peroxidation, which facilitates periportal necrosis of the liver caused by these agents.
Other Untoward Effects. Because barbiturates enhance porphyrin synthesis, they are absolutely contraindicated in patients with acute intermittent porphyria or porphyria variegata. Hypnotic doses, in the presence of pulmonary insufficiency are contraindicated. Rapid intravenous injection of a barbiturate may cause cardiovascular collapse before anesthesia ensues. Blood pressure can fall to shock levels; even slow intravenous injection of barbiturates often produces apnea and occasionally laryngospasm, coughing, and other respiratory difficulties.
Barbiturate Poisoning. Most of the cases are the result of attempts at suicide, but some are from accidental poisonings in children or in drug abusers. The lethal dose of barbiturate varies, but severe poisoning is likely to occur when b10 times the full hypnotic dose has been ingested at once. The lethal dose becomes lower if alcohol or other depressant drugs also are present. The treatment of acute barbiturate intoxication is based on general supportive measures, which are applicable in most respects to poisoning by any CNS depressant. If renal and cardiac functions are satisfactory, and the patient is hydrated, forced diuresis and alkalinization of the urine will hasten the excretion of phenobarbital. See Chapter 4, Drug Toxicity and Poisoning.
MISCELLANEOUS SEDATIVE-HYPNOTIC DRUGS
Many drugs with diverse structures have been used for their sedative-hypnotic properties, including ramelteon, chloral hydrate, meprobamate, and paraldehyde. With the exception of ramelteon and meprobamate, the pharmacological actions of these drugs generally resemble those of the barbiturates: they all are general CNS depressants that can produce profound hypnosis with little or no analgesia; their effects on the stages of sleep are similar to those of the barbiturates; their therapeutic index is limited, and acute intoxication, which produces respiratory depression and hypotension, is managed similarly to barbiturate poisoning; their chronic use can result in tolerance and physical dependence; and the syndrome after chronic use can be severe and life-threatening.
CHLORAL HYDRATE. Chloral hydrate may be used to treat patients with paradoxical reactions to benzodiazepines. Chloral hydrate is reduced rapidly to the active compound, trichloroethanol (CCl3CH2OH), largely by hepatic alcohol dehydrogenase. Its pharmacological effects probably are caused by trichloroethanol, which can exert barbiturate-like effects on GABAA receptor channels in vitro.
Chloral hydrate is best known in the U.S. as a literary poison, the “knock-out drops” added to a strong alcoholic beverage to produce a “Mickey Finn” or “Mickey,” a cocktail given to an unwitting imbiber to render him malleable or unconscious, most famously Sam Spade in Dashiell Hammett’s 1930 novel, The Maltese Falcon. Now that detectives drink white wine rather than whiskey, this off-label use of chloral hydrate has waned.
MEPROBAMATE. Meprobamate a bis-carbamate ester, was introduced as an antianxiety agent and this remains its only approved use in the U.S. However, it also became popular as a sedative-hypnotic agent. The pharmacological properties of meprobamate resemble those of the benzodiazepines in a number of ways. Meprobamate can release suppressed behaviors in experimental animals at doses that cause little impairment of locomotor activity, and although it can cause depression of the CNS, it cannot produce anesthesia. Large doses of meprobamate cause severe respiratory depression, hypotension, shock, and heart failure. Meprobamate appears to have a mild analgesic effect in patients with musculoskeletal pain, and it enhances the analgesic effects of other drugs.
Meprobamate is well absorbed when administered orally. Nevertheless, an important aspect of intoxication with meprobamate is the formation of gastric bezoars consisting of undissolved meprobamate tablets; hence treatment may require endoscopy, with mechanical removal of the bezoar. Most of the drug is metabolized in the liver, mainly to a side-chain hydroxy derivative and a glucuronide; the kinetics of elimination may depend on the dose. The t1/2 of meprobamate may be prolonged during its chronic administration, even though the drug can induce some hepatic CYPs.
The major unwanted effects of the usual sedative doses of meprobamate are drowsiness and ataxia; larger doses impair learning and motor coordination and prolongation of reaction time. Meprobamate enhances the CNS depression produced by other drugs. The abuse of meprobamate has continued despite a substantial decrease in the clinical use of the drug. Carisoprodol (SOMA), a skeletal muscle relaxant whose active metabolite is meprobamate, also has abuse potential and has become a popular “street drug.”
PARALDEHYDE. Paraldehyde is a polymer of acetaldehyde, basically a cyclic polyether. It has a strong odor and a disagreeable taste. Orally, it is irritating to the throat and stomach, and it is not administered parenterally because of its injurious effects on tissues. Use of paraldehyde has been discontinued in the U.S.
OTHER AGENTS. Etomidate (AMIDATE, generic) is used in the U.S. and other countries as an intravenous anesthetic, often in combination with fentanyl. It is advantageous because it lacks pulmonary and vascular depressant activity, although it has a negative inotropic effect on the heart. Its pharmacology and anesthetic uses are described in Chapter 19. Clomethiazole has sedative, muscle relaxant, and anticonvulsant properties. Given alone, its effects on respiration are slight, and the therapeutic index is high. However, deaths from adverse interactions with ethanol are relatively frequent. Propofol(DIPRIVAN) is a rapidly acting and highly lipophilic diisopropylphenol used in the induction and maintenance of general anesthesia (see Chapter 19), as well as in the maintenance of long-term sedation.
NONPRESCRIPTION HYPNOTIC DRUGS. The antihistamines diphenhydramine and doxylamine are FDA-approved as ingredients in over-the-counter (OTC) nonprescription sleep aids. With eliminationt1/2 of ~9-10 h, these antihistamines can be associated with prominent residual daytime sleepiness when taken the prior evening as a sleep aid.
MANAGEMENT OF INSOMNIA
The “perfect” hypnotic would allow sleep to occur with normal sleep architecture rather than produce a pharmacologically altered sleep pattern. It would not cause next-day effects, either of rebound anxiety or of continued sedation. It would not interact with other medications. It could be used chronically without causing dependence or rebound insomnia on discontinuation. Controversy in the management of insomnia revolves around 2 issues:
• Pharmacological versus nonpharmacological treatment
• Use of short-acting versus long-acting hypnotics
CATEGORIES OF INSOMNIA
• Transient insomnia lasts 3 days and usually is caused by a brief environmental or situational stressor.
• Short-term insomnia lasts from 3 days to 3 weeks and usually is caused by a personal stressor such as illness, grief, or job problems. Hypnotics are best used intermittently during this time, with the patient skipping a dose after 1-2 nights of good sleep.
• Long-term insomnia is insomnia that has lasted for r3 weeks; no specific stressor may be identifiable.
Insomnia Accompanying Major Psychiatric Illnesses. The insomnia caused by major psychiatric illnesses often responds to specific pharmacological treatment for that illness. In major depressive episodes with insomnia, e.g., the selective serotonin reuptake inhibitors, which may cause insomnia as a side effect, usually will result in improved sleep because they treat the depressive syndrome. In patients whose depression is responding to the serotonin reuptake inhibitor but who have persistent insomnia as a side effect of the medication, judicious use of evening trazodone may improve sleep, as well as augment the antidepressant effect of the reuptake inhibitor. However, the patient should be monitored for priapism, orthostatic hypotension, and arrhythmias.
Adequate control of anxiety in patients with anxiety disorders often produces adequate resolution of the accompanying insomnia. The profound insomnia of patients with acute psychosis owing to schizophrenia or mania usually responds to dopamine-receptor antagonists (see Chapters 13 and 16). Benzodiazepines often are used adjunctively in this situation to reduce agitation and improved sleep.
Insomnia Accompanying Other Medical Illnesses. For long-term insomnia owing to other medical illnesses, adequate treatment of the underlying disorder, such as congestive heart failure, asthma, or COPD, may resolve the insomnia. Adequate pain management in conditions of chronic pain will treat both the pain and the insomnia and may make hypnotics unnecessary. Adequate attention to sleep hygiene, including reduced caffeine intake, avoidance of alcohol, adequate exercise, and regular sleep and wake times, often will reduce the insomnia.
Long-Term Insomnia. Nonpharmacological treatments are important for all patients with long-term insomnia. These include education about sleep hygiene, relaxation training, and behavioral-modification approaches, such as sleep-restriction and stimulus-control therapies.
Long-term hypnotic use leads to a decrease in effectiveness and may produce rebound insomnia on discontinuance. Almost all hypnotics change sleep architecture. The barbiturates reduce REM sleep; the benzodiazepines reduce slow-wave non-REM sleep and, to a lesser extent, REM sleep. While the significance of these findings is not clear, there is an emerging consensus that slow-wave sleep is particularly important for physical restorative processes. REM sleep may aid in the consolidation of learning. The blockade of slow-wave sleep by benzodiazepines may partly account for their diminishing effectiveness over the long term, and it also may explain their effectiveness in blocking sleep terrors, a disorder of arousal from slow-wave sleep.
Long-acting benzodiazepines can cause next-day confusion, whereas shorter-acting agents can produce rebound next-day anxiety. Paradoxically, the acute amnestic effects of benzodiazepines may be responsible for the patient’s subsequent report of restful sleep. Anterograde amnesia may be more common with triazolam. Hypnotics should not be given to patients with sleep apnea, especially of the obstructive type, because these agents decrease upper airway muscle tone while also decreasing the arousal response to hypoxia.
Insomnia in Older Patients. The elderly, like the very young, tend to sleep in a polyphasic (multiple sleep episodes per day) pattern rather than the monophasic pattern characteristic of younger adults. This pattern makes assessment of adequate sleep time difficult. Changes in the pharmacokinetic profiles of hypnotic agents occur in the elderly because of reduced body water, reduced renal function, and increased body fat, leading to a longer t1/2 for benzodiazepines. A dose that produces pleasant sleep and adequate daytime wakefulness during week 1 may produce daytime confusion and amnesia by week 3 as the level continues to rise, particularly with long-acting hypnotics.
MANAGEMENT OF PATIENTS AFTER LONG-TERM TREATMENT WITH HYPNOTIC AGENTS. If a benzodiazepine has been used regularly for a2 weeks, it should be tapered rather than discontinued abruptly. In some patients on hypnotics with a short t1/2, it is easier to switch first to a hypnotic with a long t1/2 and then to taper.
PRESCRIBING GUIDELINES FOR THE MANAGEMENT OF INSOMNIA. Hypnotics that act at GABAA receptors, including the benzodiazepine hypnotics and the newer agents zolpidem, zopiclone, and zaleplon, are preferred to barbiturates because they have a greater therapeutic index, have smaller effects on sleep architecture, and have less abuse potential. Compounds with a shorter t1/2 are favored in patients with sleep-onset insomnia but without significant daytime anxiety who need to function at full effectiveness during the day. These compounds also are appropriate for the elderly because of a decreased risk of falls and respiratory depression. Benzodiazepines with longer t1/2 are favored for patients who have significant daytime anxiety. However, longer-acting benzodiazepines can be associated with next-day cognitive impairment or delayed daytime cognitive impairment (after 2-4 weeks of treatment) as a result of drug accumulation with repeated administration.
Older agents such as barbiturates, chloral hydrate, and meprobamate should be avoided for the management of insomnia. They have high abuse potential and are dangerous in overdose.