Chapter 17: Hypnotics and Sedatives

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 (Chapter 19) and aliphatic alcohols, most notably ethanol (Chapter 23). Only two landmarks on the continuum of CNS depression produced by increasing concentrations of these agents can be defined with a reasonable degree of precision: surgical anesthesia, a state in which painful stimuli elicit no behavioral or autonomic response (Chapter 19), and death, resulting from sufficient depression of medullary neurons to disrupt coordination of cardiovascular function and respiration. The "end points" at lower concentrations of CNS depressants are defined with less precision—in terms of deficits in cognitive function (including attention to environmental stimuli) or motor skills (e.g., ataxia) or of the intensity of sensory stimuli needed to elicit some reflex or behavioral response. Other important indices of decreased CNS activity, such as analgesia and seizure suppression, do not necessarily fall along this continuum; they may not be present at sub-anesthetic concentrations of a CNS depressant drug (e.g., a barbiturate), or they may be achieved with minimal sedation or other evidence of CNS depression (e.g., with low doses of opioids, phenytoin, or ethosuximide).

History. Since antiquity, alcoholic beverages and potions containing laudanum and various herbals have been used to induce sleep. In the middle of the nineteenth century, bromide was the first agent to be introduced specifically as a sedative-hypnotic. Chloral hydrate, paraldehyde, urethane, and sulfonal came into use before the introduction of barbital in 1903 and phenobarbital in 1912. Their success spawned the synthesis and testing of >2500 barbiturates, of which ~50 were distributed commercially. The barbiturates were so dominant that less than a dozen other sedative-hypnotics were marketed successfully before 1960.

The partial separation of sedative-hypnotic-anesthetic from anticonvulsant properties embodied in phenobarbital led to searches for agents with more selective effects on CNS functions. As a result, relatively non-sedating anticonvulsants, notably phenytoin and trimethadione, were developed in the late 1930s and early 1940s (Chapter 21). The advent of chlorpromazine and meprobamate in the early 1950s, with their taming effects in animals, and the development of increasingly sophisticated methods for evaluating the behavioral effects of drugs set the stage in the 1950s for the synthesis of chlordiazepoxide by Sternbach and the discovery of its unique pattern of actions by Randall. The introduction of chlordiazepoxide into clinical medicine in 1961 ushered in the era of benzodiazepines. Most of the benzodiazepines that have reached the marketplace were selected for high anxiolytic potency in relation to their depression of CNS function. However, all benzodiazepines possess sedative-hypnotic properties to varying degrees; these properties are exploited extensively clinically, especially to facilitate sleep. Mainly because of their remarkably low capacity to produce fatal CNS depression, the benzodiazepines have displaced the barbiturates as sedative-hypnotic agents.

Chemistry. The structures of the benzodiazepines in use in the U.S. are shown in Table 17–1, as are those of a few related compounds discussed later.

The term benzodiazepine refers to the portion of the structure composed of a benzene ring (A) fused to a seven-membered diazepine ring (B). Since 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. Various modifications in the structure of the ring systems have yielded compounds with similar activities, including 1,5-benzodiazepines (e.g., clobazam) and compounds in which the fused benzene ring is replaced with heteroaromatic systems such as thieno (e.g., brotizolam). The chemical nature of substituents at positions 1 to 3 can vary widely and can include triazolo or imidazolo rings fused at positions 1 and 2. Replacement of ring C with a keto function at position 5 and a methyl substituent at position 4 is an important structural feature of the benzodiazepine receptor antagonist flumazenil (romazicon).

In addition to various benzodiazepine or imidazobenzodiazepine derivatives, a large number of non-benzodiazepine compounds compete with classic benzodiazepines or flumazenil for binding at specific sites in the CNS. These include representatives from the β-carbolines (containing an indole nucleus fused to a pyridine ring), imidazopyridines (e.g., zolpidem, discussed later), imidazopyrimidines, imidazoquinolones, and cyclopyrrolones (e.g., eszopiclone).

Animal Models of Anxiety. In animal models of anxiety, most attention has focused on the ability of benzodiazepines to increase locomotor, feeding, or drinking behavior that has been suppressed by novel or aversive stimuli. In one paradigm, animal behaviors that previously had been rewarded by food or water are punished periodically by an electric shock. The time during which shocks are delivered is signaled by some auditory or visual cue, and untreated animals stop performing almost completely when the cue is perceived. The difference in behavioral responses during the punished and unpunished periods is eliminated by benzodiazepine receptor agonists, usually at doses that do not reduce the rate of unpunished responses or produce other signs of impaired motor function. Similarly, rats placed in an unfamiliar environment exhibit markedly reduced exploratory behavior (neophobia), whereas animals treated with benzodiazepines do not. Opioid analgesics and antipsychotic drugs do not increase suppressed behaviors, and phenobarbital and meprobamate usually do so only at doses that also reduce spontaneous or unpunished behaviors or produce ataxia.

The difference between the dose required to impair motor function and that necessary to increase punished behavior varies widely among the benzodiazepines and depends on the species and experimental protocol. Although such differences may have encouraged the marketing of some benzodiazepines as selective sedative-hypnotic agents, they have not predicted with any accuracy the magnitude of sedative effects among those benzodiazepines marketed as anxiolytic agents.

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. For example, tolerance to the depressant effects on rewarded or neutral behavior occurs after several days of treatment with benzodiazepines; the disinhibitory effects of the drugs on punished behavior are augmented initially and decline after 3-4 weeks (File, 1985). 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. On the other hand, 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 (Chapter 24).

Some benzodiazepines induce muscle hypotonia without interfering with normal locomotion and can decrease rigidity in patients with cerebral palsy. In contrast to effects in animals, there is only a limited degree of selectivity in humans. Clonazepam in non-sedative 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.

Experimentally, benzodiazepines inhibit seizure activity induced by either pentylenetetrazol or picrotoxin, but strychnine- and maximal electroshock-induced seizures are suppressed only at doses that also severely impair locomotor activity. 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 (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.

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, and 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 (Dujardin et al., 1998).

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.

Although some differences in the patterns of effects exerted by the various benzodiazepines have been noted, their use usually imparts a sense of deep or refreshing sleep. It is uncertain to which effect on sleep parameters this feeling can be attributed. As a result, variations in the pharmacokinetic properties of individual benzodiazepines appear to be much more important determinants of their effects on sleep than are any potential differences in their pharmacodynamic properties.

Molecular Targets for Benzodiazepine Actions in the CNS. Benzodiazepines appear to exert most of their effects by interacting with inhibitory neurotransmitter receptors directly activated by GABA (Chapter 14). The ionotropic GABA_A receptors consist of five subunits that co-assemble to form an integral chloride channel (Figure 14–11). GABA_A receptors are responsible for most inhibitory neurotransmission in the CNS. Benzodiazepines act at GABA_A receptors by binding directly to a specific site that is distinct from that of GABA binding. Unlike barbiturates, benzodiazepines do not activate GABA_A 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 GABA_A receptors. Agonists at the binding site increase, and inverse agonists decrease, the amount of chloride current generated by GABA_A-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 GABA_A 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).

The strongest evidence that benzodiazepines act directly on GABA_A receptors comes from recombinant expression of cDNAs encoding subunits of the receptor complex, which resulted in high-affinity benzodiazepine binding sites and GABA-activated chloride conductances that were enhanced by benzodiazepine receptor agonists (Burt, 2003). The properties of the expressed receptors generally resemble those of GABA_A receptors found in most CNS neurons. Each GABA_A receptor is believed to consist of a pentamer of homologous subunits. Thus far 16 different subunits have been identified and classified into seven subunit families: six α, three β, three γ, and single δ, ∊, π, and θ subunits. Additional complexity arises from RNA splice variants of some of these subunits (e.g., γ2 and α6). The exact subunit structures of native GABA receptors still are unknown, but it is thought that most GABA receptors are composed of α, β, and γ subunits that co-assemble with some uncertain stoichiometry. The multiplicity of subunits generates heterogeneity in GABA_A receptors and is responsible, at least in part, for the pharmacological diversity in benzodiazepine effects in behavioral, biochemical, and functional studies. Studies of cloned GABA_A receptors have shown that the co-assembly of a γ subunit with α and β subunits confers benzodiazepine sensitivity to GABA_A receptors (Burt, 2003). Receptors composed solely of α and β subunits produce functional GABA_A receptors that also respond to barbiturates, but they neither bind nor are affected by benzodiazepines. Benzodiazepines are believed to bind at the interface between α and γ subunits, and both subunits determine the pharmacology of the benzodiazepine binding site (Burt, 2003). For example, receptors containing the α1 subunit are pharmacologically distinct from receptors containing α2, α3, or α5 subunits (Pritchett and Seeburg, 1990), reminiscent of the pharmacological heterogeneity detected with radioligand-binding studies using brain membranes. Receptors containing the α6 subunit do not display high-affinity binding of diazepam and appear to be selective for the benzodiazepine receptor inverse agonist RO 15-4513, which has been tested as an alcohol antagonist (Lüddens et al., 1990). The subtype of γ subunit also modulates benzodiazepine pharmacology, with lower-affinity binding observed in receptors containing the γ1 subunit. Although theoretically ~1 million different GABA_A receptors could be assembled from all these different subunits, constraints for the assembly of these receptors apparently limit their numbers (Sieghart et al., 1999).

An understanding of which GABA_A receptor subunits are responsible for particular effects of benzodiazepines in vivo has emerged. The mutation to arginine of a histidine residue at position 101 of the GABA_A receptor α1 subunit renders receptors containing that subunit insensitive to the GABA-enhancing effects of diazepam (Kleingoor et al., 1993). Mice bearing these mutated subunits fail to exhibit the sedative, the amnestic, and in part the anticonvulsant effects of diazepam while retaining sensitivity to the anxiolytic, muscle-relaxant, and ethanol-enhancing effects. Conversely, mice bearing the equivalent mutation in the α2 subunit of the GABA_A receptor are insensitive to the anxiolytic effects of diazepam (Burt, 2003). The attribution of specific behavioral effects of benzodiazepines to individual receptor subunits will aid in the development of new compounds exhibiting fewer undesired side effects.

Electrophysiological studies in vitro have shown that the enhancement of GABA-induced chloride currents by benzodiazepines results primarily from an increase in the frequency of bursts of chloride channel opening produced by submaximal amounts of GABA (Twyman et al., 1989). Inhibitory synaptic transmission measured after stimulation of afferent fibers is potentiated by benzodiazepines at therapeutically relevant concentrations. Prolongation of spontaneous miniature inhibitory postsynaptic currents (IPSCs) by benzodiazepines also has been observed. Although sedative barbiturates also enhance such chloride currents, they do so by prolonging the duration of individual channel-opening events. Macroscopic measurements of GABA_A receptor-mediated currents indicate that benzodiazepines shift the GABA concentration-response curve to the left without increasing the maximum current evoked with GABA. These findings collectively are consistent with a model in which benzodiazepines exert their major actions by increasing the gain of inhibitory neurotransmission mediated by GABA_A receptors.

GABA_A receptor subunits also may play roles in the targeting of assembled receptors to their proper locations in synapses. In knockout mice lacking the γ2 subunit, GABA_A receptors did not localize to synapses, although they were formed and translocated to the cell surface (Essrich et al., 1998). The synaptic clustering molecule gephyrin also plays a role in receptor localization.

GABA_A Receptor-Mediated Electrical Events: in vivo Properties. The remarkable safety of the benzodiazepines is likely related 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 GABA_A receptor function. Although barbiturates also enhance the effects of GABA at low concentrations, they directly activate GABA receptors at higher concentrations, which can lead to profound CNS depression (discussed later). Further, 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 neurons containing various monoamines (Chapter 14). These neurons are known to promote behavioral arousal and are 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. In most studies conducted in vivo or in situ, the local or systemic administration of benzodiazepines reduces the spontaneous or evoked electrical activity of major (large) neurons in all regions of the brain and spinal cord. The activity of these neurons is regulated in part by small inhibitory interneurons (predominantly GABA-ergic) arranged in feedback and feedforward types of circuits. 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. For example, feedback circuits often involve powerful inhibitory synapses on the neuronal soma near the axon hillock, which are supplied predominantly by recurrent pathways. The synaptic or exogenous application of GABA to this region increases chloride conductance and can prevent neuronal discharge by shunting currents that otherwise would depolarize the membrane of the initial segment. 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 GABA_A receptor antagonist bicuculline (see Figure 14–10).

The macromolecular complex containing GABA-regulated chloride channels also may be a site of action of general anesthetics, ethanol, inhaled drugs of abuse, and certain metabolites of endogenous steroids (Whiting, 2003). Among the latter, allopregnanolone (3α-hydroxy, 5α-dihydroprogesterone) is of particular interest. This compound, a metabolite of progesterone that can be formed in the brain from precursors in the circulation and also synthesized by glial cells, produces barbiturate-like effects, including promotion of GABA-induced chloride currents and enhanced binding of benzodiazepines and GABA-receptor agonists. As with the barbiturates, higher concentrations of the steroid activate chloride currents in the absence of GABA, and its effects do not require the presence of a γ subunit in GABA_A receptors expressed in transfected cells. Unlike the barbiturates, however, the steroid cannot reduce excitatory responses to glutamate (discussed later). These effects are produced very rapidly and apparently are mediated by interactions at sites on the cell surface. A congener of allopregnanolone (alfaxalone) was used previously outside the U.S. for the induction of anesthesia.

Respiration. Hypnotic doses of benzodiazepines are without effect on respiration in normal subjects, but special care must be taken in the treatment of children (Kriel et al., 2000) and individuals with impaired hepatic function, such as alcoholics (Guglielminotti et al., 1999). 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, although benzodiazepines may improve sleep and sleep structure in some instances. 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. Many clinicians consider the presence of OSA to be a contraindication to the use of alcohol or any sedative-hypnotic agent, including a benzodiazepine; caution also should be exercised with patients who snore regularly, because partial airway obstruction may be converted to OSA under the influence of these drugs. In addition, 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; the adverse effects in patients with obstructive sleep disorders or cardiac disease were noted above. In preanesthetic doses, all benzodiazepines decrease blood pressure and increase heart rate. With midazolam, the effects appear to be secondary to a decrease in peripheral resistance, but with diazepam, they 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 (Nugent et al., 1982).

GI Tract. Benzodiazepines are thought by some gastroenterologists to improve a variety of "anxiety related" gastrointestinal disorders. There is a paucity of evidence for direct actions. Benzodiazepines partially protect against stress ulcers in rats, and diazepam markedly decreases nocturnal gastric secretion in humans. Other agents are considerably more effective in acid-peptic disorders (Chapter 45).

Flurazepam itself has a short t_1/2 (~2.3 hours), but a major active metabolite, N-des-alkyl-flurazepam, is long-lived (t_1/2 47-100 hours), which complicates 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. While competition with other protein-bound drugs may occur, no clinically significant examples have been reported.

The plasma concentrations of most benzodiazepines exhibit patterns that are consistent with two-compartment models (Chapter 2), but three-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. In the regimens used for nighttime sedation, the rate of redistribution sometimes can have a greater influence than the rate of biotransformation on the duration of CNS effects (Dettli, in Symposium, 1986a). 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.

The 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 (Tanaka, 1999). Erythromycin, clarithromycin, ritonavir, itraconazole, ketoconazole, nefazodone, and grapefruit juice are inhibitors of CYP3A4 (Chapter 6) and can affect the metabolism of benzodiazepines (Dresser et al., 2000). 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 t_1/2 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.

For benzodiazepines that bear a substituent at position 1 (or 2) of the diazepine ring, the initial and most rapid phase of metabolism involves modification and/or removal of the substituent. With the exception of triazolam, alprazolam, estazolam, and midazolam, which contain either a fused triazolo or a imidazolo ring, the eventual products are N-desalkylated compounds that are biologically active. One such compound, nordazepam, is a major metabolite common to the biotransformation of diazepam, clorazepate, and prazepam; it also is formed from demoxepam, an important metabolite of chlordiazepoxide.

The second phase of metabolism involves hydroxylation at position 3 and also usually yields an active derivative (e.g., oxazepam from nordazepam). The rates of these reactions are usually very much slower than the first stage (t_1/2 >40-50 hours) such that appreciable accumulation of hydroxylated products with intact substituents at position 1 does not occur. There are two significant exceptions to this rule: (1) small amounts of temazepine accumulate during the chronic administration of diazepam and (2) following the replacement of S with O in quazepam, most of the resulting 2-oxoquazepam is hydroxylated slowly at position 3 without removal of the N-alkyl group. However, only small amounts of the 3-hydroxyl derivative accumulate during chronic administration of quazepam because this compound is conjugated at an unusually rapid rate. In contrast, the N-desalkylflurazepam that is formed by the "minor" metabolic pathway does accumulate during quazepam administration, and it contributes significantly to the overall clinical effect.

The third major phase of metabolism is the conjugation of the 3-hydroxyl compounds, principally with glucuronic acid; the t_1/2 of these reactions usually are ~6-12 hours, and the products invariably are inactive. Conjugation is the only major route of metabolism for oxazepam and lorazepam and is the preferred pathway for temazepam because of the slower conversion of this compound to oxazepam. Triazolam and alprazolam are metabolized principally by initial hydroxylation of the methyl group on the fused triazolo ring; the absence of a chlorine residue in ring C of alprazolam slows this reaction significantly. The products, sometimes referred to as α-hydroxylated compounds, are quite active but are metabolized very rapidly, primarily by conjugation with glucuronic acid, such that there is no appreciable accumulation of active metabolites. The fused triazolo ring in estazolam lacks a methyl group and is hydroxylated to only a limited extent; the major route of metabolism involves the formation of the 3-hydroxyl derivative. The corresponding hydroxyl derivatives of triazolam and alprazolam also are formed to a significant extent. Compared with compounds without the triazolo ring, the rate of this reaction for all three drugs is unusually swift, and the 3-hydroxyl compounds are rapidly conjugated or oxidized further to benzophenone derivatives before excretion.

Midazolam is metabolized rapidly, primarily by hydroxylation of the methyl group on the fused imidazo ring; only small amounts of 3-hydroxyl compounds are formed. The α-hydroxylated compound, which has appreciable biological activity, is eliminated with a t_1/2 of 1 hour after conjugation with glucuronic acid. Variable and sometimes substantial accumulation of this metabolite has been noted during intravenous infusion (Oldenhof et al., 1988).

The aromatic rings (A and C) of the benzodiazepines are hydroxylated only to a small extent. The only important metabolism at these sites is reduction of the 7-nitro substituents of clonazepam, nitrazepam, and flunitrazepam; the t_1/2 of these reactions are usually 20-40 hours. The resulting amines are inactive and are acetylated to varying degrees before excretion.

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 (Gillin et al., 1989; Roth and Roehrs, 1992). With careful selection of dosage, flurazepam and other benzodiazepines with slower rates of elimination than triazolam can be used effectively. The biotransformation and pharmacokinetic properties of the benzodiazepines have been reviewed (Laurijssens and Greenblatt, 1996).

Untoward Effects. At the time of peak concentration in plasma, hypnotic doses of benzodiazepines can be expected to 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. These dose-related residual effects can be insidious because most subjects underestimate the degree of their impairment. Residual daytime sleepiness also may occur, even though successful drug therapy can reduce the daytime sleepiness resulting from chronic insomnia (Dement, 1991). The intensity and incidence of CNS toxicity generally increase with age; both pharmacokinetic and pharmacodynamic factors are involved (Monane, 1992).

Other relatively 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 actually increase the frequency of seizures in patients with epilepsy. The possible adverse effects of alterations in the sleep pattern are discussed later.

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. The release of 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. Surveys in the U.K. after the ban found that patients did not have fewer side effects with replacement treatments (Hindmarch et al., 1993), which is consonant with controlled studies that do not support the conclusion that such reactions occur more frequently with any one benzodiazepine than with others (Jonas et al., 1992; Rothschild, 1992).

Chronic benzodiazepine use poses a risk for development of dependence and abuse (Woods et al., 1992), but not to the same extent as seen with older sedatives and other recognized drugs of abuse (Uhlenhuth et al., 1999). Abuse of benzodiazepines includes the use of flunitrazepam (rohypnol; not licensed for use in the U.S.) as a "date-rape drug" (Woods and Winger, 1997). Mild dependence may develop in many patients who have taken therapeutic doses of benzodiazepines on a regular basis for prolonged periods. 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 (Petursson, 1994). Hence, it is prudent to taper the dosage gradually when therapy is to be discontinued. Despite their adverse effects, benzodiazepines are relatively safe drugs. Even huge doses are rarely fatal unless other drugs are taken concomitantly. Ethanol is a common contributor to deaths involving benzodiazepines, and true coma is uncommon in the absence of another CNS depressant. Although overdosage with a benzodiazepine rarely causes severe cardiovascular or respiratory depression, therapeutic doses can further compromise respiration in patients with COPD or obstructive sleep apnea (see "Respiration" earlier in the chapter).

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.

Zaleplon and zolpidem are effective in relieving sleep-onset insomnia. Both drugs have been approved by the FDA for use for up to 7-10 days at a time. Zaleplon and zolpidem have sustained hypnotic efficacy without occurrence of rebound insomnia on abrupt discontinuation (Mitler, 2000; Walsh et al., 2000). Zaleplon and zolpidem have similar degrees of efficacy. Zolpidem has a t_1/2 of ~2 hours, which is sufficient to cover most of a typical 8-hour sleep period, and is presently approved for bedtime use only. Zaleplon has a shorter t_1/2 ~1 hour, which offers the possibility for safe dosing later in the night, within 4 hours of the anticipated rising time. As a result, zaleplon is approved for use immediately at bedtime or when the patient has difficulty falling asleep after bedtime. Because of its short t_1/2, zaleplon has not been shown to be different from placebo in measures of duration of sleep and number of awakenings. 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 preferentially binds to the benzodiazepine-binding site on GABA_A receptors containing the α1 receptor subunit. Zaleplon is absorbed rapidly and reaches peak plasma concentrations in ~1 hour. Its bioavailability is ~30% because of presystemic metabolism. Zaleplon has a volume of distribution of ~1.4 L/kg and plasma-protein binding of ~60%. 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 (usually administered in 5-, 10-, or 20-mg doses) has been studied in clinical trials of patients with chronic or transient insomnia (Dooley and Plosker, 2000), focusing on the drug's effects in decreasing sleep latency. Zaleplon-treated subjects with either chronic or transient insomnia have experienced shorter periods of sleep latency than have placebo-treated subjects.

Although the actions of zolpidem are due to agonist effects on GABA_A receptors and generally resemble those of benzodiazepines, it produces only weak anticonvulsant effects in experimental animals, and its relatively strong sedative actions appear to mask anxiolytic effects in various animal models of anxiety (Langtry and Benfield, 1990). Although chronic administration of zolpidem to rodents produces neither tolerance to its sedative effects nor signs of withdrawal when the drug is discontinued and flumazenil is injected (Perrault et al., 1992), tolerance and physical dependence have been observed with chronic administration of zolpidem to baboons (Griffiths et al., 1992). During U.S. clinical trials, withdrawal effects within 48 hours of drug discontinuation occurred at an incidence of 1% or less. Post-marketing reports of abuse, dependence, and withdrawal have been recorded.

Unlike the benzodiazepines, zolpidem has little effect on the stages of sleep in normal human subjects. The drug is as effective as benzodiazepines 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 (Herrmann et al., 1993), but mild rebound insomnia on the first night also has occurred. Tolerance and physical dependence develop only rarely and under unusual circumstances (Cavallaro et al., 1993; Morselli, 1993). Indeed, zolpidem-induced improvement in sleep time of chronic insomniacs was sustained during as much as 6 months of treatment without signs of withdrawal or rebound after stopping the drug (Kummer et al., 1993). Nevertheless, zolpidem is approved only for the short-term treatment of insomnia. At therapeutic doses (5 to 10 mg), zolpidem infrequently produces residual daytime sedation or amnesia, and the incidence of other adverse effects (e.g., GI complaints or dizziness) 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 (Garnier et al., 1994). Hypnotic doses increase the hypoxia and hypercarbia of patients with obstructive sleep apnea.

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 because of slowed absorption and increased hepatic blood flow. 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 t_1/2 is ~2 hours 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 received FDA approval based on six randomized placebo-controlled clinical trials that showed it has efficacy in treating transient (Rosenberg et al., 2005) and chronic insomnia. In the transient insomnia study subjects receiving the drug showed a decreased latency to attain sleep, increased sleep efficiency, and fewer awakenings, as measured by both polysomnography and a morning questionnaire. There were no observed psychomotor after-effects observed the next day. Eszopiclone also possesses efficacy as a sleep aid when taken chronically, for as long as 12 months (Melton et al., 2005). All chronic studies conducted to date found that eszopiclone decreased the latency to onset of sleep. No tolerance was observed, nor were signs of serious withdrawal, such as seizures or rebound insomnia, seen upon 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%, and shows wide distribution throughout the body. It is 50-60% bound to plasma proteins and has a t_1/2 of ~6 hours. It is metabolized by CYPs 3A4 and 2E1. Eszopiclone is believed to exert its sleep-promoting effects through its enhancement of GABA_A receptor function at the benzodiazepine binding site (Hanson et al., 2008; Jia et al., 2009),

In animal models, the intrinsic pharmacological actions of flumazenil have been subtle; effects resembling those of inverse agonists sometimes have been detected at low doses, whereas slight benzodiazepine-like effects often have been evident at high doses. The evidence for intrinsic activity in human subjects is even more vague, except for modest anticonvulsant effects at high doses. However, anticonvulsant effects cannot be relied on for therapeutic utility because the administration of flumazenil may precipitate seizures under certain circumstances (discussed later).

Flumazenil is available only for intravenous administration. On intravenous administration, flumazenil is eliminated almost entirely by hepatic metabolism to inactive products with a t_1/2 of ~1 hour; the duration of clinical effects usually is only 30-60 minutes. 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 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.

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 minutes usually is sufficient to abolish the effects of therapeutic doses of benzodiazepines; patients with suspected benzodiazepine overdose should respond adequately to a cumulative dose of 1-5 mg given over 2-10 minutes; a lack of response to 5 mg flumazenil strongly suggests that a benzodiazepine is not the major cause of sedation. Additional courses of treatment with flumazenil may be needed within 20-30 minutes should sedation reappear.

Flumazenil is not effective in single-drug overdoses with either barbiturates or tricyclic antidepressants. To the contrary, the administration of flumazenil in these settings may be associated with the onset of seizures, especially in patients poisoned with tricyclic antidepressants (Spivey, 1992). Seizures or other withdrawal symptoms also may be precipitated in patients who had been taking benzodiazepines for protracted periods and in whom tolerance and/or dependence may have developed.

Mechanism of Action. Melatonin levels in the suprachiastmatic 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, are found 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 while melatonin binding to MT₂ receptors shifts the timing of the circadian system (Liu et al., 1997). 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 (Nosjean et al., 2000). Ramelteon is not known to bind to any other classes of receptors, such as nicotinic acetylcholine, neuropeptide, dopamine, or opiate receptors, or the benzodiazepine-binding site on GABA_A receptors.

Clinical Pharmacology. Prescribing guidelines suggest that an 8-mg tablet be taken ~30 minutes before bedtime. Ramelteon is rapidly absorbed from the GI tract and a peak serum concentration is obtained within an hour (Hibberd and Stevenson 2004). Because of the significant first-pass metabolism that occurs after oral administration, ramelteon bioavailability is <2% (Amakye et al., 2004). In the bloodstream, ~80% of ramelteon is protein bound (Takeda Pharmaceuticals North America, 2006). The drug is largely metabolized by the hepatic CYPs 1A2, 2C, and 3A4, with t_1/2 of ~2 hours in humans. Of the four 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. Subjects given 16 or 64 mg of ramelteon in a clinical trial showed a significantly shorter latency to sleep onset, as well as increased total sleep time, compared to placebo controls (Roth et al., 2005); the drug was generally well tolerated by patients and did not impair next-day cognitive function. Ramelteon is also useful in the treatment of chronic insomnia, with no tolerance occurring in its reduction of sleep onset latency even after 6 months of drug administration (Mayer et al., 2009). Sleep latency, evaluated by polysomnography as well as by subject questionnaires, was consistently found to be shorter in patients given ramelteon compared to placebo controls (Erman et al., 2006; Zammit et al., 2007). No evidence of rebound insomnia or withdrawal effects were noted upon ramelteon withdrawal. Ramelteon appears to act by producing a phase advance of the endogenous circadian rhythm (Richardson et al., 2008).

In animals, ramelteon does not produce discriminative stimulus effects similar to those of benzodiazepine receptor agonists, and long-term administration has no effects on spontaneous or operant behaviors, motor activity or posture (France et al., 2006). In addition, ramelteon has no demonstrated positive reinforcing effects in intravenous self-administration experiments performed in rhesus monkeys and there is no indication of abuse liability in humans (Griffiths and Johnson, 2005).

Chemistry. Barbituric acid is 2,4,6-trioxohexahydropyrimidine. This compound lacks central depressant activity, but the presence of alkyl or aryl groups at position 5 confers sedative-hypnotic and sometimes other activities. The general structural formula for the barbiturates and the structures of selected compounds are included in Table 17–4.

The carbonyl group at position 2 takes on acidic character because of lactam–lactim ("keto"–"enol") tautomerization, which is favored by its location between the two electronegative amido nitrogens. The lactim form is favored in alkaline solution, and salts result. Barbiturates in which the oxygen at C2 is replaced by sulfur sometimes are called thiobarbiturates. 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 exert several distinct effects on excitatory and inhibitory synaptic transmission. For example, (−)-pentobarbital potentiates GABA-induced increases in chloride conductance and depresses voltage-activated Ca²⁺ currents at similar concentrations (below 10 μM) in isolated hippocampal neurons; above 100 μM, chloride conductance is increased in the absence of GABA (French-Mullen et al., 1993). Phenobarbital is less efficacious and much less potent in producing these effects, whereas (+)-pentobarbital has only weak activity. Thus, the more selective anticonvulsant properties of phenobarbital and its higher therapeutic index may be explained by its lower capacity to depress neuronal function as compared with the anesthetic barbiturates.

The mechanisms underlying the actions of barbiturates on GABA_A receptors appear to be distinct from those of either GABA or the benzodiazepines for reasons that include the following:

• Like benzodiazepines, barbiturates enhance the binding of GABA to GABA_A receptors in a Cl⁻-dependent and picrotoxin-sensitive fashion; however, barbiturates promote (rather than reduce) the binding of benzodiazepines.

• Barbiturates potentiate GABA-induced Cl⁻ currents by prolonging periods during which bursts of channel opening occur rather than by increasing the frequency of these bursts, as benzodiazepines do.

• Only α and β (not γ) subunits are required for barbiturate action.

• Barbiturate-induced increases in Cl⁻ conductance are not affected by the deletion of the tyrosine and threonine residues in the β subunit that govern the sensitivity of GABA_A receptors to activation by agonists (Amin and Weiss, 1993).

Sub-anesthetic concentrations of barbiturates also can reduce glutamate-induced depolarizations (Macdonald and McLean, 1982) (Chapter 12); only the AMPA subtypes of glutamate receptors sensitive to kainic acid (Figure 14–10) or quisqualic acid appear to be affected (Marszalec and Narahashi, 1993). At higher concentrations that produce anesthesia, pentobarbital suppresses high-frequency repetitive firing of neurons, apparently as a result of inhibiting the function of voltage-dependent, tetrodotoxin-sensitive Na⁺ channels (Figure 11–4); in this case, however, both stereoisomers are about equally effective (Frenkel et al., 1990). At still higher concentrations, voltage-dependent K⁺ conductances are reduced. Taken together, the findings that barbiturates activate inhibitory GABA_A receptors and inhibit excitatory AMPA receptors can explain their CNS-depressant effects (Saunders and Ho, 1990).

Barbiturates can produce all degrees of depression of the CNS, ranging from mild sedation to general anesthesia. The use of barbiturates for general anesthesia is discussed in Chapter 19. Certain barbiturates, particularly those containing a 5-phenyl substituent (e.g., phenobarbital and mephobarbital), have selective anticonvulsant activity (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. Thus, it is not possible to achieve a desired effect without evidence of general depression of the CNS. 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. Pharmacodynamic (functional) and pharmacokinetic tolerance to barbiturates can occur. The former contributes more to the decreased effect than does the latter. 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 (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.

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. Indeed, laryngospasm is one of the chief complications of barbiturate anesthesia.

Apparently, a decrease in cardiac output usually is sufficient to offset an increase in peripheral resistance, which sometimes is accompanied by an increase in heart rate. Cardiovascular reflexes are obtunded by partial inhibition of ganglionic transmission. This is most evident in patients with congestive heart failure or hypovolemic shock, whose reflexes already are operating maximally and in whom barbiturates can cause an exaggerated fall in blood pressure. Because barbiturates also impair reflex cardiovascular adjustments to inflation of the lung, positive-pressure respiration should be used cautiously and only when necessary to maintain adequate pulmonary ventilation in patients who are anesthetized or intoxicated with a barbiturate.

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 two types of K⁺ channels (Nattel et al., 1990; Pancrazio et al., 1993). However, direct depression of cardiac contractility occurs only when doses several times those required to cause anesthesia are administered, which probably contributes to the cardiovascular depression that accompanies acute barbiturate poisoning.

GI Tract. The oxybarbiturates tend to decrease the tone of the GI musculature and the amplitude of rhythmic contractions. The locus of action is partly peripheral and partly central, depending on the dose. 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.

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. Drug interactions may result even when the other substances and barbiturates are oxidized by different microsomal enzyme systems.

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. Many sedative-hypnotics, various anesthetics, and ethanol also are metabolized by and/or induce the microsomal enzymes, and some degree of cross-tolerance therefore can occur. Not all microsomal biotransformations of drugs and endogenous substrates are affected equally, but a convenient rule of thumb is that at maximal induction in humans, the rates are approximately doubled. The inducing effect is not limited to the microsomal enzymes; for example, 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.

Barbiturates are distributed widely, and they readily cross the placenta. The highly lipid-soluble barbiturates, led by those used to induce anesthesia, undergo redistribution after intravenous injection. 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 minutes of the injection of the usual anesthetic doses (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. Oxidation results in the formation of alcohols, ketones, phenols, or carboxylic acids, which may appear in the urine as such or as glucuronic acid conjugates. 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. Their renal excretion can be increased greatly by osmotic diuresis and/or alkalinization of the urine.

The metabolic elimination of barbiturates is more rapid in young people than in the elderly and infants, and t_1/2 are increased during pregnancy partly because of the expanded volume of distribution. Chronic liver disease, especially cirrhosis, often increases the t_1/2 of the biotransformable barbiturates. Repeated administration, especially of phenobarbital, shortens the t_1/2 of barbiturates that are metabolized as a result of the induction of microsomal enzymes.

None of the barbiturates used for hypnosis in the U.S. appears to have an elimination t_1/2 that is short enough for elimination to be virtually complete in 24 hours (Table 17–4). However, the relationship between duration of action and t_1/2 of elimination is complicated by the fact that enantiomers of optically active barbiturates often differ in both biological potencies and rates of biotransformation. All of 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.

CNS Uses. Benzodiazepines and other compounds for sedation have largely replaced barbiturates. Barbiturates, especially butabarbital and phenobarbital, are used sometimes to antagonize unwanted CNS-stimulant effects of various drugs, such as ephedrine, dextroamphetamine, and theophylline, although a preferred approach is adjustment of dosage or substitution of alternative therapy for the primary agents (see Chapter 24).

Untoward Effects

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. For example, a 200-mg dose of secobarbital has been shown to impair performance of driving or flying skills for 10-22 hours. Residual effects also may take the form of vertigo, nausea, vomiting, or diarrhea, or sometimes may be manifested as overt excitement. The user may awaken slightly intoxicated and feel euphoric and energetic; later, as the demands of daytime activities challenge possibly impaired faculties, the user may display irritability and temper.

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 and the accelerated disappearance of many drugs and endogenous substances. The metabolism of vitamins D and K is accelerated, which may hamper bone mineralization and lower Ca²⁺ absorption in patients taking phenobarbital and may be responsible for the reported coagulation defects in neonates whose mothers had been taking phenobarbital. 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. In hypnotic doses, the effects of barbiturates on the control of respiration are minor; however, in the presence of pulmonary insufficiency, serious respiratory depression may occur, and the drugs thus are contraindicated. Rapid intravenous injection of a barbiturate may cause cardiovascular collapse before anesthesia ensues, so the CNS signs of depth of anesthesia may fail to give an adequate warning of impending toxicity. 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. The incidence of barbiturate poisoning has declined markedly, largely as a result of their decreased use as sedative-hypnotic agents. Nevertheless, poisoning with barbiturates is a significant clinical problem, and death occurs in a few percent of cases (Gary and Tresznewksy, 1983). Most of the cases are the result of deliberate 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 >10 times the full hypnotic dose has been ingested at once. If alcohol or other depressant drugs also are present, the concentrations that can cause death are lower.

In severe intoxication, the patient is comatose; respiration is affected early. Breathing may be either slow or rapid and shallow. Eventually, blood pressure falls because the effect of the drug and of hypoxia on medullary vasomotor centers; depression of cardiac contractility and sympathetic ganglia also contributes. Pulmonary complications (e.g., atelectasis, edema, and bronchopneumonia) and renal failure are likely to be the fatal complications of severe barbiturate poisoning.

The treatment of acute barbiturate intoxication is based on general supportive measures, which are applicable in most respects to poisoning by any CNS depressant. Hemodialysis or hemoperfusion is necessary only rarely, and the use of CNS stimulants is contraindicated because they increase the mortality rate. 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. Measures to prevent or treat atelectasis should be taken, and mechanical ventilation should be initiated when indicated. See Chapter 4, Drug Toxicity and Poisoning.

In severe acute barbiturate intoxication, circulatory collapse is a major threat. Often the patient is admitted to the hospital with severe hypotension or shock, and dehydration frequently is severe. Hypovolemia must be corrected, and if necessary, the blood pressure can be supported with dopamine. Acute renal failure consequent to shock and hypoxia accounts for perhaps one-sixth of the deaths. In the event of renal failure, hemodialysis should be instituted.

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.

Chloral Hydrate. Chloral hydrate is formed by adding one molecule of water to the carbonyl group of chloral (2,2,2-trichloroacetaldehyde). 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; significant amounts of chloral hydrate are not found in the blood after its oral administration. Therefore, its pharmacological effects probably are caused by trichloroethanol. Indeed, the latter compound can exert barbiturate-like effects on GABA_A receptor channels in vitro (Lovinger et al., 1993).

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 wine rather than whiskey, this off-label use of chloral hydrate has waned.

Meprobamate. Meprobamate a bis-carbamate ester, was introduced as an anti-anxiety agent and this remains its only approved use in the U.S. However, it also became popular as a sedative-hypnotic drug and is discussed here mainly because of its continued use for such purposes. The question of whether the sedative and anti-anxiety actions of meprobamate differ is unanswered, and clinical proof for the efficacy of meprobamate as a selective anti-anxiety agent in humans is lacking.

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 widespread depression of the CNS, it cannot produce anesthesia. However, ingestion of large doses of meprobamate alone can cause severe or even fatal 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 t_1/2 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 produce considerable impairment of learning and motor coordination and prolongation of reaction time. Like the benzodiazepines, 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" (Reeves et al., 1999). Meprobamate is preferred to the benzodiazepines by subjects with a history of drug abuse. After long-term medication, abrupt discontinuation evokes a withdrawal syndrome usually characterized by anxiety, insomnia, tremors, and, frequently, hallucinations; generalized seizures occur in ~10% of cases. The intensity of symptoms depends on the dosage ingested.

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 13. It also is used in some countries as a sedative-hypnotic drug in intensive care units, during intermittent positive-pressure breathing, in epidural anesthesia, and in other situations. Because it is administered only intravenously, its use is limited to hospital settings. The myoclonus commonly seen after anesthetic doses is not seen after sedative-hypnotic doses.

Clomethiazole has sedative, muscle relaxant, and anticonvulsant properties. It is used outside the U.S. for hypnosis in elderly and institutionalized patients, for preanesthetic sedation, and especially in the management of withdrawal from ethanol (Symposium, 1986b). 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 (Chapter 19), as well as in the maintenance of long-term sedation. Propofol sedation is of a similar quality to that produced by midazolam. Emergence from sedation occurs quickly owing to its rapid clearance (McKeage and Perry, 2003). Propofol has found use in intensive care sedation in adults (McKeage and Perry, 2003), as well as for sedation during gastrointestinal endoscopy procedures (Heuss and Inauen, 2004) and transvaginal oocyte retrieval (Dell and Cloote, 1998). Although its mechanism of action is not understood completely, propofol is believed to act primarily through enhancement of GABA_A receptor function. Effects on other ligand-gated channels and GPCRs also have been reported (Trapani et al., 2000).

Nonprescription Hypnotic Drugs. As part of the ongoing systematic review of over-the-counter (OTC) drug products, the FDA has ruled that diphenhydramine is the only antihistamine that is recognized as generally safe and effective for use in nonprescription sleep aids. Despite the prominent sedative side effects encountered during the use of doxylamine and pyrilamine, these agents subsequently were eliminated as ingredients in the OTC nighttime sleep aids marketed in the U.S.. In 2004, doxylamine regained FDA approval as an OTC sleep aid and re-entered the market as Unisom Nighttime Sleep Aid (doxylamine 25-mg tablets). With elimination t_1/2 of ~9 hours (diphenhydramine) and 10 hours (doxylamine), these antihistamines can be associated with prominent residual daytime sleepiness when taken the prior evening as a sleep aid.

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 (Nierenberg et al., 1994), 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. Sedative use in the anxiety disorders is decreasing because of a growing appreciation of the effectiveness of other agents, such as β adrenergic receptor antagonists (Chapter 12) for performance anxiety and serotonin reuptake inhibitors for obsessive-compulsive disorder and perhaps generalized anxiety disorder. The profound insomnia of patients with acute psychosis owing to schizophrenia or mania usually responds to dopamine-receptor antagonists (Chapters 13 and 16). Benzodiazepines often are used adjunctively in this situation to reduce agitation; their use also will result in 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, including terminal cancer pain, will treat both the pain and the insomnia and may make hypnotics unnecessary.

Many patients simply manage their sleep poorly. 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.

Conditioned (Learned) Insomnia. In those who have no major psychiatric or other medical illness and in whom attention to sleep hygiene is ineffective, attention should be directed to conditioned (learned) insomnia. These patients have associated the bedroom with activities consistent with wakefulness rather than sleep. In such patients, the bed should be used only for sex and sleep. All other activities associated with waking, even such quiescent activities as reading and watching television, should be done outside the bedroom.

Sleep-State Misperception. Some patients complain of poor sleep but have been shown to have no objective polysomnographic evidence of insomnia. They are difficult to treat.

Long-Term Insomnia. Nonpharmacological treatments are important for all patients with long-term insomnia. These include education about sleep hygiene, adequate exercise (where possible), relaxation training, and behavioral-modification approaches, such as sleep-restriction and stimulus-control therapies. In sleep-restriction therapy, the patient keeps a diary of the amount of time spent in bed and then chooses a time in bed of 30-60 minutes less than this time. This induces a mild sleep debt, which aids sleep onset. In stimulus-control therapy, the patient is instructed to go to bed only when sleepy, to use the bedroom only for sleep and sex, to get up and leave the bedroom if sleep does not occur within 15-20 minutes, to return to bed again only when sleepy, to arise at the same time each morning regardless of sleep quality the preceding night, and to avoid daytime naps. Nonpharmacological treatments for insomnia have been found to be particularly effective in reducing sleep-onset latency and time awake after sleep onset (Morin et al., 1994).

Side effects of hypnotic agents may limit their usefulness for insomnia management. The use of hypnotics for long-term insomnia is problematic for many reasons. 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, with a concomitant increase in falls, 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. Triazolam has been postulated to induce cognitive changes that blur the subjective distinction between waking and sleeping (Mendelson, 1993). Anterograde amnesia may be more common with triazolam. While the performance-disruptive effects of alcohol and diphenhydramine are reduced after napping, those of triazolam are not (Roehrs et al., 1993).

Benzodiazepines may worsen sleep apnea. Some hypersomnia patients do not feel refreshed after a night's sleep and so may ask for sleeping pills to improve the quality of their sleep. The consensus is that 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 (Robinson and Zwillich, 1989). These individuals benefit from all-night sleep studies to guide treatment.

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. They may have single or multiple daytime naps in addition to nighttime sleep. This pattern makes assessment of adequate sleep time difficult. Anyone who naps regularly will have shortened nighttime sleep without evidence of impaired daytime wakefulness, regardless of age. This pattern is exemplified in "siesta" cultures and probably is adaptive.

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 t_1/2 for benzodiazepines. A dose that produces pleasant sleep and adequate daytime wakefulness during week 1 of administration may produce daytime confusion and amnesia by week 3 as the level continues to rise, particularly with long-acting hypnotics. For example, the benzodiazepine diazepam is highly lipid soluble and is excreted by the kidney. Because of the increase in body fat and the decrease in renal excretion that typically occur from age 20-80, the t_1/2 of the drug may increase 4-fold over this span.

Elderly people who are living full lives with relatively unimpaired daytime wakefulness may complain of insomnia because they are not sleeping as long as they did when they were younger. Injudicious use of hypnotics in these individuals can produce daytime cognitive impairment and so impair overall quality of life.

Once an older patient has been taking benzodiazepines for an extended period, whether for daytime anxiety or for nighttime sedation, terminating the drug can be a long, involved process. Since attempts at drug withdrawal may not be successful, it may be necessary to leave the patient on the medication, with adequate attention to daytime side effects.

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.