Benzodiazepines became available in the late 1950s and rapidly replaced the barbiturates as preferred sedative–hypnotics. Their wide acceptance resulted from their greater safety, including lower risks associated with overdose and abuse compared with those of the barbiturates and related sedative–hypnotics such as methaqualone, ethchlorvynol, meprobamate, and chloral hydrate; benzodiazepines also are less likely to induce hepatic metabolism of other drugs. Yet, like barbiturates and related sedative–hypnotics, benzodiazepines and related drugs bind to and facilitate the functioning of GABAA receptors. Their mechanisms of action and general pharmacology are discussed in greater detail in Chapters 5 and 15. The chemical structures of representative benzodiazepines used as sedative–hypnotics are shown in 13–9.
Chemical structures of representative benzodiazepines and other drugs used to treat insomnia.
Benzodiazepines promote the onset of sleep and sleep continuity in the treatment of insomnia. They also are commonly used as anxiolytics (Chapter 15). Much of the clinical art of benzodiazepines and other treatments for insomnia involves an understanding of the importance of drug half-life in determining appropriate drug therapy and minimizing adverse effects 13–2. Long-acting benzodiazepines, such as flurazepam and chlordiazepoxide, have active metabolites with half-lives in excess of 200 hours; their use often interferes with daytime alertness and is associated with more errors while driving an automobile compared with the use of shorter-acting agents. In contrast, benzodiazepines with extremely short half-lives (2–4 hours), such as triazolam, are useful for promoting the onset of sleep, but may be of less benefit to those who have difficulty maintaining sleep. Such short half-life agents can cause rebound insomnia during the latter half of the night, which can be viewed as a mild withdrawal syndrome that occurs in response to a single dose of the benzodiazepine. Repeated use of these agents can lead to more significant rebound insomnia and anxiety; however, the slow tapering of these agents can minimize the occurrence of a discontinuation syndrome. For these reasons, compounds with intermediate half-lives (eg, temazepam) are optimal for most individuals. Benzodiazepines are also associated with anterograde amnesia, especially if used in high doses or taken with alcohol. The drugs suppress the total amount of REM sleep and alter the time spent in stages 1 to 4; consequently, sleep produced by a sedative–hypnotic may not be as physiologically useful as normal sleep. Also, tolerance can develop to the sleep-promoting effects of benzodiazepines with daily use. Although zaleplon, zolpidem, and eszopiclone are not chemically classified as benzodiazepines 13–9, they act on the benzodiazepine site of the GABAA receptor with virtually equivalent results. They have the same benefits and liabilities of short-to-intermediate half-life benzodiazepines.
13–2Comparison of Representative Benzodiazepines for Insomnia Therapy ||Download (.pdf) 13–2 Comparison of Representative Benzodiazepines for Insomnia Therapy
|Drug ||Half-Life ||Advantages ||Disadvantages|
|Estazolam ||Intermediate || ||Some daytime sedation and performance decrements |
|Flurazepam ||Long ||Delayed rebound insomnia ||Daytime sedation; high risk of falls and driving errors |
|Temazepam ||Intermediate || ||Some daytime sedation and performance decrements |
|Triazolam ||Short ||No daytime sedation ||Rebound insomnia |
|Zolpidem1 ||Short ||No daytime sedation ||Rebound insomnia |
Attempts to improve the long-term treatment of insomnia have addressed the various liabilities of drugs that act at the benzodiazepine site of the GABAA receptor. One strategy, which remains speculative, might involve the use of partial agonists at this site; such drugs might be designed to cause sedation without producing tolerance. Another strategy might be to take advantage of the molecular diversity of GABAA receptor subunits. Because the sedative effects of benzodiazepines appear to be mediated predominantly by one particular GABAA receptor α subunit, the α1 subunit (Chapters 5 and 15), drugs might be developed that are selective for this subunit and therefore unlikely to cause the deleterious cognitive effects of previously mentioned agents. Certain currently available drugs (eg, zolpidem and eszopiclone) show some preference for this subunit, but true subunit-selective benzodiazepine-like drugs are not yet available.
Nonbenzodiazepine Sedative–Hypnotic Agents
Several nonbenzodiazepine classes of drugs are currently used to promote sleep. Antihistamines, specifically the first-generation H1 receptor inverse agonists—commonly referred to as antagonists—are frequently used and in fact are the active ingredients in most over-the-counter sleep remedies. They are able to penetrate the blood–brain barrier because of their lipophilicity, relatively low molecular weight, and lack of recognition by the P-glycoprotein efflux pump (Chapter 2). Examples of these medications include diphenhydramine 13–9, dimenhydrinate, chlorpheniramine, hydroxyzine, and promethazine. However, these drugs are less effective than benzodiazepines and are associated with more adverse daytime effects. Antihistamines also can adversely affect memory and psychomotor performance, even after the drugs are no longer detectable in the general circulation. Many people report the sensation of being “in a fog” for as many as 24 hours after taking an antihistamine.
As H1 inverse agonists, antihistamines combine with and stabilize the inactive form of the H1 receptor, shifting the equilibrium toward the inactive state. However, because the histaminergic neurons of the TMN of the hypothalamus are quiescent during sleep, antihistamines may cause more sedation during waking hours than promotion of sleep during the sleep cycle. Several tricyclic antidepressants and antipsychotic drugs block H1 receptors, which contributes to the sedative effects of these agents. Another strategy for promoting sleep may involve the use of an H3 receptor agonist. As described in Chapter 6, H3 receptors are inhibitory autoreceptors on histaminergic neurons of the TMN. An agonist at these receptors, for example, R -α-methylhistamine, would be expected to reduce the activity of the neurons and thereby promote sleep. This approach has not yet been tested in humans.
Sodium oxybate (γ-hydroxybutyrate [GHB]) is a naturally occurring central nervous system (CNS) metabolite. It is found in highest concentration in the hypothalamus and basal ganglia. GHB is given to consolidate sleep, increase total nocturnal sleep time, and decrease sleep paralysis, hypnagogic hallucinations, and nightmares. Patients report progressive restfulness on awakening. Patients with narcolepsy report a decrease in cataplexy frequency. GHB is often referred to as a date rape drug, used to induce sleep in unsuspecting victims. The mechanism of action of GHB is poorly understood. It may be an agonist at GABAB receptors; it also may be metabolized into GABA and thereby activate other GABA receptors. Another date rape drug, flunitrazepam (also known as Rohypnol or roofies), is a benzodiazepine agonist with a long half-life.
Trazodone is marketed as an antidepressant but is less effective in the treatment of depression than many other available agents. However, trazodone is sedating and is sometimes used to promote sleep. It improves sleep continuity and also subjective sleep quality. Although it is frequently recommended because of a putative lack of associated tolerance, data regarding its long-term efficacy have not been obtained. Trazodone is an agonist at several 5HT receptors; however, its mechanism of action in promoting sleep remains undetermined. Mirtazapine is another antidepressant known clinically for its sedative effect, which is thought to be related to the blockade of serotonin 5HT2 receptors.
The melatonin system has been examined as a potential target for new sedative–hypnotic agents. Endogenous melatonin is synthesized exclusively in the pineal gland from tryptophan and serotonin (Chapter 6). Its physiologic role in the control of circadian rhythms and sleep remains uncertain. Exogenous melatonin has been shown to help reset the circadian clock in some experimental situations 13–1. It is commonly used to treat jet lag in individuals who travel across multiple time zones. Moreover, it has been used to help shift workers better adjust to new work hours, although its efficacy when used for these purposes has not been established in well-designed clinical trials. Its efficacy in the treatment of noncircadian insomnia also has not been supported by convincing evidence. Moreover, the safety of over-the-counter melatonin preparations in the United States has yet to be determined; indeed, even the composition of most of these preparations remains unknown because of the lack of regulatory oversight by the US Food and Drug Administration (FDA). The dose commonly available in health food stores has been determined to produce a level of melatonin that is 10 times greater than peak physiologic levels. Elevated concentrations of melatonin have been associated with endocrine disturbances such as amenorrhea in females and hypogonadism in males. Melatonin also can lead to the asynchrony of circadian physiology if used frequently at different times of the day. Melatonin produces its effects in mammals via activation of two Gi/o-linked receptors, termed MT1 and MT2, and knockout mice are now being used to determine their selective physiologic functions. The pharmaceutical industry currently is attempting to develop agonists that are selective for these melatonin receptors, such as the recently marketed ramelteon. However, studies of the efficacy of these agents to date have been disappointing.
There is considerable enthusiasm toward the recent development of orexin receptor antagonists for the treatment of insomnia. Several clinical trials have demonstrated that so-called dual orexin receptor antagonists, which block OX1 and OX2 receptors, as well as selective OX2 antagonists, are highly effective at inducing and maintaining sleep. Suvorexant 13–9 is an example of a dual antagonist; it was approved by the FDA in August 2014 for treatment of insomnia. An interesting theoretical difference between orexin antagonists versus GABAA-acting sedative–hypnotics is that the former suppress mechanisms of natural arousal while the latter suppress CNS activity globally. Given that most cases of insomnia involve hyperarousal and not a failure of CNS inhibition, it is possible that orexin antagonists may prove more effective in treating insomnia with fewer side effects. However, such speculation must be viewed with caution until extensive clinical experience with orexin-based agents becomes available.
Drugs That Increase Alertness
The drugs used most commonly to promote wakefulness are caffeine—for example, in coffee, soda, and over-the-counter stimulants—and related substances such as theophylline in tea and theobromine in chocolate. Although these drugs have several mechanisms of action, their stimulant properties are most closely associated with antagonism of adenosine receptors, particularly that of A1 and possibly A2A receptors as stated earlier (Chapter 8). The medicinal use of these drugs is limited by side effects such as nausea, headache, and tremulousness, which are common at clinically relevant doses. More selective antagonists of adenosine receptors, which have yet to be developed, may offer the clinical benefits of these agents without such unpleasant side effects.
The most potent agents that promote wakefulness are amphetamine-like psychostimulants, including D-amphetamine, methamphetamine, methylphenidate, mazindol, and pemoline. These drugs increase the synaptic levels of dopamine, serotonin, and norepinephrine primarily by blocking their reuptake or promoting their release (Chapters 6, 15, and 16). Actions on the dopamine system are believed to be most important for the stimulant effects of these drugs. Amphetamines remain the treatment of choice for narcolepsy. Although these drugs offer important symptomatic improvement in many patients, their use is associated with complications such as nighttime insomnia, tolerance, dependence, and in some cases addiction.
Modafinil, a (diphenyl-methyl)-sulfinyl-2-acetamide derivative, is another wakefulness-promoting drug approved by the FDA. It increases alertness and vigilance in normal individuals and in patients with narcolepsy, although it is clearly less efficacious than amphetamines. However, modafinil shows fewer cardiovascular side effects and less abuse potential compared with amphetamines. Of note, modafinil reduces subjective sleepiness and improves wakefulness, but—unlike amphetamine—does not reduce cataplexy. The mechanism of action of modafinil is not yet established with certainty. The drug inhibits the dopamine transporter, to which it binds with micromolar affinity, and its stimulant actions are lost in mice lacking this transporter. However, modafinil’s pharmacologic effects in humans are sufficiently distinct from those of amphetamine and other psychostimulants to raise questions about its underlying mechanisms. One possibility is that modafinil exerts a distinct effect on the dopamine transporter protein compared with the psychostimulants, resulting in different functional consequences. It is also possible that modafinil has additional direct actions on other neurotransmitter systems, although this remains speculative.
Several antidepressants alter the sleep–wake cycle. Some of these drugs exhibit strong antagonism of H1 histamine and muscarinic cholinergic receptors, which mediates the ability of these drugs to promote sleep independently of their antidepressant actions. However, several antidepressants such as fluoxetine and bupropion, which have an amphetamine-like structure (Chapter 15), exert the opposite effect in some patients and can lead to insomnia. Why some serotonin-acting antidepressants, such as trazodone, promote sleep while others, for example, fluoxetine, disrupt sleep in a subset of patients remains unknown but may be related to the different groups of 5HT receptors that are activated by these medications.
H3 antagonists or inverse agonists have been considered as wake-promoting and procognitive agents. These drugs, by opposing the activity of inhibitory H3 autoreceptors on histaminergic neurons, would be expected to promote histamine release throughout the CNS. However, clinical trials that have examined the ability of H3 antagonists/inverse agonists to promote wakefulness have generally been disappointing.
Many distinct but interdependent neural pathways regulate the sleep–wake cycle. Because each of these pathways is subserved by distinct neurotransmitters, many pharmacologic agents can influence sleep patterns. The cellular and molecular mechanisms involved in the regulation of sleep and circadian rhythms require more investigation, but it is anticipated that the elucidation of these mechanisms will lead to new targets for the effective pharmacologic treatment of sleep disorders.
Despite nearly two centuries of widespread use, the mechanisms through which drugs produce a state of anesthesia remain poorly understood. Initial hypotheses revolved around the discovery that an anesthetic drug’s potency correlated with its solubility in olive oil. This finding, coupled with the low potency of most general anesthetics (micromolar to millimolar), slowed identification of specific molecular targets and led to the lipid theory of anesthetic action, in which anesthetic effects were thought to be mediated by nonspecific interactions within lipid membranes. This lipid theory of anesthetic action dominated thinking for more than 80 years until the 1980s when anesthetics were shown to interact directly with the firefly luciferase protein in a lipid free preparation. Rapidly thereafter, researchers focused on ion channels as potential molecular targets of general anesthetic agents.
At clinically relevant concentrations, general anesthetics (including all volatile ether-based anesthetics—isoflurane, sevoflurane, desflurane, and enflurane—as well as the halogenated volatile alkane anesthetic, halothane) act as positive or negative allosteric modulators of many ligand-gated ion channels, for example, GABAA, NMDA and AMPA glutamate, nicotinic acetylcholine, and glycine receptors (Chapters 5 and 6). The anesthetics also regulate several types of ion channels, such as two-pore K+ channels, voltage-gated Na+ channels, and the hyperpolarization-activated, cyclic nucleotide-modulated (HCN) channels (Chapter 2). The net effect of anesthetics is to hyperpolarize resting membrane potentials (mainly by activating two-pore K+ channels) and to enhance synaptic inhibition and inhibit excitation. For example, at GABAA receptors, most volatile and intravenous anesthetics (eg, propofol and etomidate) prolong the channel open time by enhancing the gating of the receptor by GABA. At glutamatergic synapses, volatile anesthetics act presynaptically to decrease glutamate release. Other nonhalogenated inhaled anesthetics (xenon, nitrous oxide, and cyclopropane) and the intravenous dissociative anesthetic ketamine (Chapters 15 and 16) depress glutamatergic transmission postsynaptically by blocking NMDA glutamate receptors; some also activate two-pore K+ channels.
While the molecular targets of anesthetic action have been the focus of intense investigation over the past two decades, the critical neuroanatomic substrates on which anesthetic drugs act have received relatively less attention. General anesthesia is a state defined by a collection of specific behavioral end points including amnesia, analgesia, immobility, and unconsciousness. We focus here on anesthetic-induced unconsciousness as an example of how the behavioral features of general anesthesia are being understood neurobiologically, although parallel efforts are under way to understand other features of anesthesia.
The hypnotic component of general anesthesia (defined experimentally as a lack of perceptive awareness of nonnoxious stimuli) shares many similarities to that of NREM sleep 13–3. However, one crucial difference is that even the deepest sleeper can be awakened by external stimuli, while the anesthetized individual will not reawaken until the anesthetic drugs are discontinued. Nonetheless, similarities led to the hypothesis that anesthetic drugs may exert their hypnotic effects via specific actions on NREM sleep–promoting circuits. When given in hypnotic doses, anesthetic drugs cause a breakdown in cortical–cortical communication as occurs in NREM sleep. Additionally, although sensory information continues to flow forward along lateral-parietal and mesial-temporal pathways, selective disruption of cortical feedback is a newly recognized feature of anesthetic-induced unconsciousness. This disruption of cortical feedback occurs with anesthetics as diverse as sevoflurane, propofol, and ketamine. However, controversy remains as to whether anesthetic-induced unconsciousness occurs directly as a result of a top-down cortical failure or whether impairing subcortical sleep–wake, bottom-up systems is the initiating event, which subsequently alters cortical function to cause loss of consciousness.
13–3Comparison Between Non-REM Sleep and General Anesthesia ||Download (.pdf) 13–3 Comparison Between Non-REM Sleep and General Anesthesia
| ||NREM Sleep ||General Anesthesia|
|Arousal state ||Transient unconsciousness ||Transient unconsciousness |
|Cerebral metabolic rate ||Decreased globally ||Decreased globally |
|Cerebral blood flow ||Decreased globally with more specific reductions in thalamic and midbrain reticular formation activity ||Decreased globally with more specific reductions in thalamic and midbrain reticular formation activity |
|EEG pattern ||Increased delta power ||Increased delta power |
|EEG entropy (measure of disorder) ||Decreased ||Decreased |
|EMG activity ||Decreased ||Decreased to totally absent |
|Thalamic sensory relay ||Impaired ||Impaired |
|Effect of agents that promote sleep (such as adenosine) ||Promote sleep ||Potentiate general anesthesia |
|Cardiac output ||Decreased ||Decreased |
|Minute ventilation ||Decreased ||Decreased |
|Core body temperature ||Decreased ||Decreased|
Anesthetics clearly alter function at multiple sites of the ARAS, where they may quench conscious wakefulness in part by disrupting signaling from the noradrenergic neurons of the LC, the histaminergic neurons of the TMN, and the orexinergic neurons of the lateral and posterior hypothalamus. Moreover, systemic delivery of anesthetics as structurally distinct as propofol, barbiturates (eg, pentobarbital), dexmedetomidine (an α2-adrenergic agonist), and the volatile anesthetics (eg, isoflurane and sevoflurane) activates endogenous sleep-promoting neurons of the VLPO. Nevertheless, we also know that not every anesthetic uses these same ARAS systems en route to unconsciousness as highlighted by ketamine.
Unraveling the mysteries of how anesthetic drugs reliably and reproducibly cause a loss of consciousness, along with their other many effects, remains an area of active investigation.