An effective sedative (anxiolytic) agent should reduce anxiety and exert a calming effect. The degree of central nervous system (CNS) depression caused by a sedative should be the minimum consistent with therapeutic efficacy. A hypnotic drug should produce drowsiness and encourage the onset and maintenance of a state of sleep. Hypnotic effects involve more pronounced depression of the CNS than sedation, and this can be achieved with many drugs in this class simply by increasing the dose. Graded dose-dependent depression of CNS function is a characteristic of most sedative-hypnotics. However, individual drugs differ in the relationship between the dose and the degree of CNS depression. Two examples of such dose-response relationships are shown in Figure 22–1. The linear slope for drug A is typical of many of the older sedative-hypnotics, including the barbiturates and alcohols. With such drugs, an increase in dose higher than that needed for hypnosis may lead to a state of general anesthesia. At still higher doses, these sedative-hypnotics may depress respiratory and vasomotor centers in the medulla, leading to coma and death. Deviations from a linear dose-response relationship, as shown for drug B, require proportionately greater dosage increments to achieve CNS depression more profound than hypnosis. This appears to be the case for benzodiazepines and for certain newer hypnotics that have a similar mechanism of action.
Dose-response curves for two hypothetical sedative-hypnotics.
The benzodiazepines are widely used sedative-hypnotics. All of the structures shown in Figure 22–2 are 1,4-benzodiazepines, and most contain a carboxamide group in the seven-membered heterocyclic ring structure. A substituent in the 7 position, such as a halogen or a nitro group, is required for sedative-hypnotic activity. The structures of triazolam and alprazolam include the addition of a triazole ring at the 1,2-position.
Chemical structures of some benzodiazepines.
The chemical structures of some older and less commonly used sedative-hypnotics, including several barbiturates, are shown in Figure 22–3. Glutethimide and meprobamate are of distinctive chemical structure but are practically equivalent to barbiturates in their pharmacologic effects. They are rarely used. The sedative-hypnotic class also includes compounds of simpler chemical structure, including ethanol (see Chapter 23) and chloral hydrate.
Chemical structures of some barbiturates and other sedative-hypnotics.
Several drugs with novel chemical structures have been introduced more recently for use in sleep disorders. Zolpidem, an imidazopyridine; zaleplon, a pyrazolopyrimidine; and eszopiclone, a cyclopyrrolone (Figure 22–4), although structurally unrelated to benzodiazepines, share a similar mechanism of action, as described below. Eszopiclone is the (S) enantiomer of zopiclone, a hypnotic drug that has been available outside the United States since 1989. Ramelteon and tasimelteon, melatonin receptor agonists, are newer hypnotic drugs (see Box: Ramelteon and Tasimelteon). Suvorexant is an orexin antagonist that improves sleep duration. Buspirone is a slow-onset anxiolytic agent whose actions are quite different from those of conventional sedative-hypnotics (see Box: Buspirone).
Chemical structures of newer hypnotics.
Ramelteon and Tasimelteon
Melatonin receptors are thought to be involved in maintaining circadian rhythms underlying the sleep-wake cycle (see Chapter 16). Ramelteon, a novel hypnotic drug prescribed specifically for patients who have difficulty in falling asleep, is an agonist at MT1 and MT2 melatonin receptors located in the suprachiasmatic nuclei of the brain. Tasimelteon is similar and is approved for non-24-hour sleep-wake disorder. These drugs have no direct effects on GABAergic neurotransmission in the central nervous system. In polysomnography studies of patients with chronic insomnia, ramelteon reduced the latency of persistent sleep with no effects on sleep architecture and no rebound insomnia or significant withdrawal symptoms. The drug is rapidly absorbed after oral administration and undergoes extensive first-pass metabolism, forming an active metabolite with longer half-life (2–5 hours) than the parent drug. The CYP1A2 isoform of cytochrome P450 is mainly responsible for the metabolism of ramelteon, but the CYP2C9 isoform is also involved. Ramelteon should not be used in combination with inhibitors of CYP1A2 (eg, ciprofloxacin, fluvoxamine, tacrine, zileuton) or CYP2C9 (eg, fluconazole). Concurrent use with the antidepressant fluvoxamine increases the peak plasma concentration of ramelteon over 50-fold!
Ramelteon should be used with caution in patients with liver dysfunction. The CYP inducer rifampin markedly reduces the plasma levels of both ramelteon and its active metabolite. Adverse effects of ramelteon include dizziness, somnolence, fatigue, and endocrine changes.
Other classes of drugs that exert sedative effects include antipsychotics (see Chapter 29), and many antidepressant drugs (see Chapter 30). The latter are currently used widely in management of chronic anxiety disorders. Certain antihistaminic agents including hydroxyzine and promethazine (see Chapter 16) are also sedating. These agents commonly also exert marked effects on the peripheral autonomic nervous system. Other antihistaminic drugs with hypnotic effects, eg, diphenhydramine and doxylamine, are available in over-the-counter sleep aids.
A. Absorption and Distribution
The rates of oral absorption of sedative-hypnotics differ depending on a number of factors, including lipophilicity. For example, the absorption of triazolam is extremely rapid, and that of diazepam and the active metabolite of clorazepate is more rapid than other commonly used benzodiazepines. Clorazepate, a prodrug, is converted to its active form, desmethyldiazepam (nordiazepam), by acid hydrolysis in the stomach. Most of the barbiturates and other older sedative-hypnotics, as well as the newer hypnotics (eszopiclone, zaleplon, zolpidem), are absorbed rapidly into the blood following oral administration.
Lipid solubility plays a major role in determining the rate at which a particular sedative-hypnotic enters the CNS. This property is responsible for the rapid onset of the effects of triazolam, thiopental (see Chapter 25), and the newer hypnotics.
All sedative-hypnotics cross the placental barrier during pregnancy. If sedative-hypnotics are given during the predelivery period, they may contribute to the depression of neonatal vital functions. Sedative-hypnotics are also detectable in breast milk and may exert depressant effects in the nursing infant.
Metabolic transformation to more water-soluble metabolites is necessary for clearance of sedative-hypnotics from the body. The microsomal drug-metabolizing enzyme systems of the liver are most important in this regard, so elimination half-life of these drugs depends mainly on the rate of their metabolic transformation.
1. Benzodiazepines—Hepatic metabolism accounts for the clearance of all benzodiazepines. The patterns and rates of metabolism depend on the individual drugs. Most benzodiazepines undergo microsomal oxidation (phase I reactions), including N-dealkylation and aliphatic hydroxylation catalyzed by cytochrome P450 isozymes, especially CYP3A4. The metabolites are subsequently conjugated (phase II reactions) to form glucuronides that are excreted in the urine. However, many phase I metabolites of benzodiazepines are pharmacologically active, some with long half-lives (Figure 22–5). For example, desmethyldiazepam, which has an elimination half-life of more than 40 hours, is an active metabolite of chlordiazepoxide, diazepam, prazepam, and clorazepate. Alprazolam and triazolam undergo α-hydroxylation, and the resulting metabolites appear to exert short-lived pharmacologic effects because they are rapidly conjugated to form inactive glucuronides. The short elimination half-life of triazolam (2–3 hours) favors its use as a hypnotic rather than as a sedative drug.
Biotransformation of benzodiazepines. Boldface, drugs available for clinical use in various countries;*, active metabolite.
The formation of active metabolites has complicated studies on the pharmacokinetics of the benzodiazepines in humans because the elimination half-life of the parent drug may have little relation to the time course of pharmacologic effects. Benzodiazepines for which the parent drug or active metabolites have long half-lives are more likely to cause cumulative effects with multiple doses. Cumulative and residual effects such as excessive drowsiness appear to be less of a problem with such drugs as estazolam, oxazepam, and lorazepam, which have relatively short half-lives and are metabolized directly to inactive glucuronides. Some pharmacokinetic properties of selected benzodiazepines and newer hypnotics are listed in Table 22–1. The metabolism of several commonly used benzodiazepines including diazepam, midazolam, and triazolam is affected by inhibitors and inducers of hepatic P450 isozymes (see Chapter 4).
TABLE 22–1Pharmacokinetic properties of some benzodiazepines and newer hypnotics in humans. ||Download (.pdf) TABLE 22–1 Pharmacokinetic properties of some benzodiazepines and newer hypnotics in humans.
|Drug ||Tmax (hours)1 ||t½ (hours)2 ||Comments |
|Alprazolam ||1–2 ||12–15 ||Rapid oral absorption |
|Chlordiazepoxide ||2–4 ||15–40 ||Active metabolites; erratic bioavailability from IM injection |
|Clorazepate ||1–2 (nordiazepam) ||50–100 ||Prodrug; hydrolyzed to active form in stomach |
|Diazepam ||1–2 ||20–80 ||Active metabolites; erratic bioavailability from IM injection |
|Eszopiclone ||1 ||6 ||Minor active metabolites |
|Flurazepam ||1–2 ||40–100 ||Active metabolites with long half-lives |
|Lorazepam ||1–6 ||10–20 ||No active metabolites |
|Oxazepam ||2–4 ||10–20 ||No active metabolites |
|Temazepam ||2–3 ||10–40 ||Slow oral absorption |
|Triazolam ||1 ||2–3 ||Rapid onset; short duration of action |
|Zaleplon ||< 1 ||1–2 ||Metabolized via aldehyde dehydrogenase |
|Zolpidem ||1–3 ||1.5–3.5 ||No active metabolites |
Buspirone has selective anxiolytic effects, and its pharmacologic characteristics are different from those of other drugs described in this chapter. Buspirone relieves anxiety without causing marked sedative, hypnotic, or euphoric effects. Unlike benzodiazepines, the drug has no anticonvulsant or muscle relaxant properties. Buspirone does not interact directly with GABAergic systems. It may exert its anxiolytic effects by acting as a partial agonist at brain 5-HT1A receptors, but it also has affinity for brain dopamine D2 receptors. Buspirone-treated patients show no rebound anxiety or withdrawal signs on abrupt discontinuance. The drug is not effective in blocking the acute withdrawal syndrome resulting from abrupt cessation of use of benzodiazepines or other sedative-hypnotics. Buspirone has minimal abuse liability. In marked contrast to the benzodiazepines, the anxiolytic effects of buspirone may take 3–4 weeks to become established, making the drug unsuitable for management of acute anxiety states. The drug is used in generalized anxiety states but is less effective in panic disorders.
Buspirone is rapidly absorbed orally but undergoes extensive first-pass metabolism via hydroxylation and dealkylation reactions to form several active metabolites. The major metabolite is 1-(2-pyrimidyl)-piperazine (1-PP), which has α2-adrenoceptor-blocking actions and which enters the central nervous system to reach higher levels than the parent drug. It is not known what role (if any) 1-PP plays in the central actions of buspirone. The elimination half-life of buspirone is 2–4 hours, and liver dysfunction may slow its clearance. Rifampin, an inducer of cytochrome P450, decreases the half-life of buspirone; inhibitors of CYP3A4 (eg, erythromycin, ketoconazole, grapefruit juice, nefazodone) can markedly increase its plasma levels.
Buspirone causes less psychomotor impairment than benzodiazepines and does not affect driving skills. The drug does not potentiate effects of conventional sedative-hypnotic drugs, ethanol, or tricyclic antidepressants; and elderly patients do not appear to be more sensitive to its actions. Nonspecific chest pain, tachycardia, palpitations, dizziness, nervousness, headache, tinnitus, gastrointestinal distress, and paresthesias and a dose-dependent pupillary constriction may occur. Blood pressure may be significantly elevated in patients receiving monoamine oxidase (MAO) inhibitors. Buspirone is a US Food and Drug Administration (FDA) category B drug in terms of its use in pregnancy.
2. Barbiturates—With the exception of phenobarbital, only insignificant quantities of the barbiturates are excreted unchanged. The major metabolic pathways involve oxidation by hepatic enzymes to form alcohols, acids, and ketones, which appear in the urine as glucuronide conjugates. The overall rate of hepatic metabolism in humans depends on the individual drug but (with the exception of the thiobarbiturates) is usually slow. The elimination half-lives of secobarbital and pentobarbital range from 18 to 48 hours in different individuals. The elimination half-life of phenobarbital in humans is 4–5 days. Multiple dosing with these agents can lead to cumulative effects.
3. Newer hypnotics—After oral administration of the standard formulation, zolpidem reaches peak plasma levels in 1–3 hours (Table 22–1). Sublingual and oral spray formulations of zolpidem are also available. Zolpidem is rapidly metabolized to inactive metabolites via oxidation and hydroxylation by hepatic CYP3A4. The elimination half-life of the drug is greater in women and is increased significantly in the elderly. A biphasic extended-release formulation extends plasma levels by approximately 2 hours. Zaleplon is metabolized to inactive metabolites mainly by hepatic aldehyde oxidase and partly by the cytochrome P450 isoform CYP3A4. Dosage should be reduced in patients with hepatic impairment and in the elderly. Cimetidine, which inhibits both aldehyde dehydrogenase and CYP3A4, markedly increases the peak plasma level of zaleplon. Eszopiclone is metabolized by hepatic cytochromes P450 (especially CYP3A4) to form the inactive N-oxide derivative and weakly active desmethyleszopiclone. The elimination half-life of eszopiclone is prolonged in the elderly and in the presence of inhibitors of CYP3A4 (eg, ketoconazole). Inducers of CYP3A4 (eg, rifampin) increase the hepatic metabolism of eszopiclone. The orexin receptor antagonist suvorexant is also a substrate of CYP3A4, and its half-life is prolonged by inhibitors of the enzyme including azole antifungal drugs, clarithromycin, and verapamil.
The water-soluble metabolites of sedative-hypnotics, mostly formed via the phase II conjugation of phase I metabolites, are excreted mainly via the kidney. In most cases, changes in renal function do not have a marked effect on the elimination of parent drugs. Phenobarbital is excreted unchanged in the urine to a certain extent (20–30% in humans), and its elimination rate can be increased significantly by alkalinization of the urine. This is partly due to increased ionization at alkaline pH, since phenobarbital is a weak acid with a pKa of 7.4.
D. Factors Affecting Biodisposition
The biodisposition of sedative-hypnotics can be influenced by several factors, particularly alterations in hepatic function resulting from disease or drug-induced increases or decreases in microsomal enzyme activities (see Chapter 4).
In very old patients and in patients with severe liver disease, the elimination half-lives of these drugs are often increased significantly. In such cases, multiple normal doses of these sedative-hypnotics can result in excessive CNS effects.
The activity of hepatic microsomal drug-metabolizing enzymes may be increased in patients exposed to certain older sedative-hypnotics on a long-term basis (enzyme induction; see Chapter 4). Barbiturates (especially phenobarbital) and meprobamate are most likely to cause this effect, which may result in an increase in their hepatic metabolism as well as that of other drugs. Increased biotransformation of other pharmacologic agents as a result of enzyme induction by barbiturates is a potential mechanism underlying drug interactions (see Chapter 66). In contrast, benzodiazepines and the newer hypnotics do not change hepatic drug-metabolizing enzyme activity with continuous use.
Pharmacodynamics of Benzodiazepines, Barbiturates, & Newer Hypnotics
A. Molecular Pharmacology of the GABAA Receptor
The benzodiazepines, the barbiturates, zolpidem, zaleplon, eszopiclone, and many other drugs bind to molecular components of the GABAA receptor in neuronal membranes in the CNS. This receptor, which functions as a chloride ion channel, is activated by the inhibitory neurotransmitter GABA (see Chapter 21).
The GABAA receptor has a pentameric structure assembled from five subunits (each with four membrane-spanning domains) selected from multiple polypeptide classes (α, β, γ, δ, ε, π, ρ, etc). Multiple subunits of several of these classes have been characterized, eg, six different α, four β, and three γ. A model of the GABAA receptor-chloride ion channel macromolecular complex is shown in Figure 22–6.
A model of the GABAA receptor-chloride ion channel macromolecular complex. A hetero-oligomeric glycoprotein, the complex consists of five or more membrane-spanning subunits. Multiple forms of α, β, and γ subunits are arranged in different pentameric combinations so that GABAA receptors exhibit molecular heterogeneity. GABA appears to interact at two sites between α and β subunits triggering chloride channel opening with resulting membrane hyperpolarization. Binding of benzodiazepines and the newer hypnotic drugs such as zolpidem occurs at a single site between α and γ subunits, facilitating the process of chloride ion channel opening. The benzodiazepine antagonist flumazenil also binds at this site and can reverse the hypnotic effects of zolpidem. Note that these binding sites are distinct from those of the barbiturates. (See also text and Box: The Versatility of the Chloride Channel GABA Receptor Complex.)
A major isoform of the GABAA receptor that is found in many regions of the brain consists of two α1 subunits, two β2 subunits, and one γ2 subunit. In this isoform, the two binding sites for GABA are located between adjacent α1 and β2 subunits, and the binding pocket for benzodiazepines (the BZ site of the GABAA receptor) is between an α1 and the γ2 subunit. However, GABAA receptors in different areas of the CNS consist of various combinations of the essential subunits, and the benzodiazepines bind to many of these, including receptor isoforms containing α2, α3, and α5 subunits. Barbiturates also bind to multiple isoforms of the GABAA receptor but at different sites from those with which benzodiazepines interact. In contrast to benzodiazepines, zolpidem, zaleplon, and eszopiclone bind more selectively because these drugs interact only with GABAA-receptor isoforms that contain α1 subunits. The heterogeneity of GABAA receptors may constitute the molecular basis for the varied pharmacologic actions of benzodiazepines and related drugs (see Box: GABA Receptor Heterogeneity & Pharmacologic Selectivity).
GABA Receptor Heterogeneity & Pharmacologic Selectivity
Studies involving genetically engineered (“knockout”) rodents have demonstrated that the specific pharmacologic actions elicited by benzodiazepines and other drugs that modulate GABA actions are influenced by the composition of the subunits assembled to form the GABAA receptor. Benzodiazepines interact primarily with brain GABAA receptors in which the α subunits (1, 2, 3, and 5) have a conserved histidine residue in the N-terminal domain. Strains of mice, in which a point mutation has been inserted converting histidine to arginine in the α1 subunit, show resistance to both the sedative and amnestic effects of benzodiazepines, but anxiolytic and muscle-relaxing effects are largely unchanged. These animals are also unresponsive to the hypnotic actions of zolpidem and zaleplon, drugs that bind selectively to GABAA receptors containing α1 subunits. In contrast, mice with selective histidine-arginine mutations in the α2 or α3 subunits of GABAA receptors show selective resistance to the antianxiety effects of benzodiazepines. Based on studies of this type, it has been suggested that α1 subunits in GABAA receptors mediate sedation, amnesia, and ataxic effects of benzodiazepines, whereas α2 and α3 subunits are involved in their anxiolytic and muscle-relaxing actions. Other mutation studies have led to suggestions that an α5 subtype is involved in at least some of the memory impairment caused by benzodiazepines. It should be emphasized that these studies involving genetic manipulations of the GABAA receptor utilize rodent models of the anxiolytic and amnestic actions of drugs.
In contrast to GABA itself, benzodiazepines and other sedative-hypnotics have a low affinity for GABAB receptors, which are activated by the spasmolytic drug baclofen (see Chapters 21 and 27).
GABA (γ-aminobutyric acid) is a major inhibitory neurotransmitter in the CNS (see Chapter 21). Electrophysiologic studies have shown that benzodiazepines potentiate GABAergic inhibition at all levels of the neuraxis, including the spinal cord, hypothalamus, hippocampus, substantia nigra, cerebellar cortex, and cerebral cortex. Benzodiazepines appear to increase the efficiency of GABAergic synaptic inhibition. The benzodiazepines do not substitute for GABA but appear to enhance GABA’s effects allosterically without directly activating GABAA receptors or opening the associated chloride channels. The enhancement in chloride ion conductance induced by the interaction of benzodiazepines with GABA takes the form of an increase in the frequency of channel-opening events.
Barbiturates also facilitate the actions of GABA at multiple sites in the CNS, but—in contrast to benzodiazepines—they appear to increase the duration of the GABA-gated chloride channel openings. At high concentrations, the barbiturates may also be GABA-mimetic, directly activating chloride channels. These effects involve a binding site or sites distinct from the benzodiazepine binding sites. Barbiturates are less selective in their actions than benzodiazepines, because they also depress the actions of the excitatory neurotransmitter glutamic acid via binding to the AMPA receptor. Barbiturates also exert nonsynaptic membrane effects in parallel with their effects on GABA and glutamate neurotransmission. This multiplicity of sites of action of barbiturates may be the basis for their ability to induce full surgical anesthesia (see Chapter 25) and for their more pronounced central depressant effects (which result in their low margin of safety) compared with benzodiazepines and the newer hypnotics.
C. Benzodiazepine Binding Site Ligands
The components of the GABAA receptor-chloride ion channel macromolecule that function as benzodiazepine binding sites exhibit heterogeneity (see Box: The Versatility of the Chloride Channel GABA Receptor Complex). Three types of ligand-benzodiazepine receptor interactions have been reported: (1) Agonists facilitate GABA actions, and this occurs at multiple BZ binding sites in the case of the benzodiazepines. As noted above, the nonbenzodiazepines zolpidem, zaleplon, and eszopiclone are selective agonists at the BZ sites that contain an α1 subunit. Endogenous agonist ligands for the BZ binding sites have been proposed, because benzodiazepine-like chemicals have been isolated from brain tissue of animals never exposed to these drugs. Nonbenzodiazepine molecules that have affinity for BZ sites on the GABAA receptor have also been detected in human brain. (2) Antagonists are typified by the synthetic benzodiazepine derivative flumazenil, which blocks the actions of benzodiazepines, eszopiclone, zaleplon, and zolpidem, but does not antagonize the actions of barbiturates, meprobamate, or ethanol. Certain endogenous neuropeptides are also capable of blocking the interaction of benzodiazepines with BZ binding sites. (3) Inverse agonists act as negative allosteric modulators of GABA-receptor function (see Chapter 1). Their interaction with BZ sites on the GABAA receptor can produce anxiety and seizures, an action that has been demonstrated for several compounds, especially the β-carbolines, eg, n-butyl-β-carboline-3-carboxylate (β-CCB). In addition to their direct actions, these molecules can block the effects of benzodiazepines.
The Versatility of the Chloride Channel GABA Receptor Complex
The GABAA-chloride channel macromolecular complex is one of the most versatile drug-responsive machines in the body. In addition to the benzodiazepines, barbiturates, and the newer hypnotics (eg, zolpidem), many other drugs with central nervous system effects can modify the function of this important ionotropic receptor. These include alcohol and certain intravenous anesthetics (etomidate, propofol) in addition to thiopental. For example, etomidate and propofol (see Chapter 25) appear to act selectively at GABAA receptors that contain α2 and α3 subunits, the latter suggested to be the most important with respect to the hypnotic and muscle-relaxing actions of these anesthetic agents. The anesthetic steroid alphaxalone is thought to interact with GABAA receptors, and they may also be targets for some of the actions of volatile anesthetics (eg, halothane). Most of these agents facilitate or mimic the action of GABA. However, it has not been shown that all these drugs act exclusively by this mechanism. Other drugs used in the management of seizure disorders indirectly influence the activity of the GABAA-chloride channel macromolecular complex by inhibiting GABA metabolism (eg, vigabatrin) or the reuptake of the transmitter (eg, tiagabine). Central nervous system excitatory agents that act on the chloride channel include picrotoxin and bicuculline. These convulsant drugs block the channel directly (picrotoxin) or interfere with GABA binding (bicuculline).
The physiologic significance of endogenous modulators of the functions of GABA in the CNS remains unclear. To date, it has not been established that the putative endogenous ligands of BZ binding sites play a role in the control of states of anxiety, sleep patterns, or any other characteristic behavioral expression of CNS function.
1. Sedation—Benzodiazepines, barbiturates, and most older sedative-hypnotic drugs exert calming effects with concomitant reduction of anxiety at relatively low doses. In most cases, however, the anxiolytic actions of sedative-hypnotics are accompanied by some depressant effects on psychomotor and cognitive functions. In experimental animal models, benzodiazepines and older sedative-hypnotic drugs are able to disinhibit punishment-suppressed behavior. This disinhibition has been equated with antianxiety effects of sedative-hypnotics, and it is not a characteristic of all drugs that have sedative effects, eg, the tricyclic antidepressants and antihistamines. However, the disinhibition of previously suppressed behavior may be more related to behavioral disinhibitory effects of sedative-hypnotics, including euphoria, impaired judgment, and loss of self-control, which can occur at dosages in the range of those used for management of anxiety. The benzodiazepines also exert dose-dependent anterograde amnestic effects (inability to remember events occurring during the drug’s duration of action).
2. Hypnosis—By definition, all of the sedative-hypnotics induce sleep if high enough doses are given. The effects of sedative-hypnotics on the stages of sleep depend on several factors, including the specific drug, the dose, and the frequency of its administration. The general effects of benzodiazepines and older sedative-hypnotics on patterns of normal sleep are as follows: (1) the latency of sleep onset is decreased (time to fall asleep); (2) the duration of stage 2 NREM (non-rapid eye movement) sleep is increased; (3) the duration of REM (rapid eye movement) sleep is decreased; and (4) the duration of stage 4 NREM slow-wave sleep is decreased. The newer hypnotics all decrease the latency to persistent sleep. Zolpidem decreases REM sleep but has minimal effect on slow-wave sleep. Zaleplon decreases the latency of sleep onset with little effect on total sleep time, NREM, or REM sleep. Eszopiclone increases total sleep time, mainly via increases in stage 2 NREM sleep, and at low doses has little effect on sleep patterns. At the highest recommended dose, eszopiclone decreases REM sleep. Suvorexant decreases time to persistent sleep and increases total sleep time.
More rapid onset of sleep and prolongation of stage 2 are presumably clinically useful effects. However, the significance of older sedative-hypnotic drug effects on REM and slow-wave sleep is not clear. Deliberate interruption of REM sleep causes anxiety and irritability followed by a rebound increase in REM sleep at the end of the experiment. A similar pattern of “REM rebound” can be detected following abrupt cessation of drug treatment with older sedative-hypnotics, especially when drugs with short durations of action (eg, triazolam) are used at high doses. With respect to zolpidem and the other newer hypnotics, there is little evidence of REM rebound when these drugs are discontinued after use of recommended doses. However, rebound insomnia occurs with both zolpidem and zaleplon if used at higher doses. Despite possible reductions in slow-wave sleep, there are no reports of disturbances in the secretion of pituitary or adrenal hormones when either barbiturates or benzodiazepines are used as hypnotics. The use of sedative-hypnotics for more than 1–2 weeks leads to some tolerance to their effects on sleep patterns.
3. Anesthesia—As shown in Figure 22–1, high doses of certain sedative-hypnotics depress the CNS to the point known as stage III of general anesthesia (see Chapter 25). However, the suitability of a particular agent as an adjunct in anesthesia depends mainly on the physicochemical properties that determine its rapidity of onset and duration of effect. Among the barbiturates, thiopental and methohexital are very lipid-soluble, penetrating brain tissue rapidly following intravenous administration, a characteristic favoring their use for the induction of anesthesia. Rapid tissue redistribution (not rapid elimination) accounts for the short duration of action of these drugs, a feature useful in recovery from anesthesia.
Benzodiazepines—including diazepam, lorazepam, and midazolam—are used intravenously in anesthesia (see Chapter 25), often in combination with other agents. Not surprisingly, benzodiazepines given in large doses as adjuncts to general anesthetics may contribute to a persistent postanesthetic respiratory depression. This is probably related to their relatively long half-lives and the formation of active metabolites. However, such depressant actions of the benzodiazepines are usually reversible with flumazenil.
4. Anticonvulsant effects—Most sedative-hypnotics are capable of inhibiting the development and spread of epileptiform electrical activity in the CNS. Some selectivity exists in that some members of the group can exert anticonvulsant effects without marked CNS depression (although psychomotor function may be impaired). Several benzodiazepines—including clonazepam, nitrazepam, lorazepam, and diazepam—are sufficiently selective to be clinically useful in the management of seizures (see Chapter 24). Of the barbiturates, phenobarbital and metharbital (converted to phenobarbital in the body) are effective in the treatment of generalized tonic-clonic seizures, though not the drugs of first choice. However, zolpidem, zaleplon, and eszopiclone lack anticonvulsant activity, presumably because of their more selective binding than that of benzodiazepines to GABAA receptor isoforms.
5. Muscle relaxation—Certain drugs in the sedative-hypnotic class, particularly members of the carbamate (eg, meprobamate) and benzodiazepine groups, exert inhibitory effects on polysynaptic reflexes and internuncial transmission and at high doses may also depress transmission at the skeletal neuromuscular junction. Somewhat selective actions of this type that lead to muscle relaxation can be readily demonstrated in animals and have led to claims of usefulness for relaxing contracted voluntary muscle in muscle spasm (see Clinical Pharmacology of Sedative-Hypnotics). Muscle relaxation is not a characteristic action of zolpidem, zaleplon, and eszopiclone.
6. Effects on respiration and cardiovascular function—At hypnotic doses in healthy patients, the effects of sedative-hypnotics on respiration are comparable to changes during natural sleep. However, even at therapeutic doses, sedative-hypnotics can produce significant respiratory depression in patients with pulmonary disease. Effects on respiration are dose-related, and depression of the medullary respiratory center is the usual cause of death due to overdose of sedative-hypnotics.
At doses up to those causing hypnosis, no significant effects on the cardiovascular system are observed in healthy patients. However, in hypovolemic states, heart failure, and other diseases that impair cardiovascular function, normal doses of sedative-hypnotics may cause cardiovascular depression, probably as a result of actions on the medullary vasomotor centers. At toxic doses, myocardial contractility and vascular tone may both be depressed by central and peripheral effects, possibly via facilitation of the actions of adenosine, leading to circulatory collapse. Respiratory and cardiovascular effects are more marked when sedative-hypnotics are given intravenously.
Tolerance: Psychological & Physiologic Dependence
Tolerance—decreased responsiveness to a drug following repeated exposure—is a common feature of sedative-hypnotic use. It may result in the need for an increase in the dose required to maintain symptomatic improvement or to promote sleep. It is important to recognize that partial cross-tolerance occurs between the sedative-hypnotics described here and also with ethanol (see Chapter 23)—a feature of some clinical importance, as explained below. The mechanisms responsible for tolerance to sedative-hypnotics are not well understood. An increase in the rate of drug metabolism (metabolic tolerance) may be partly responsible in the case of chronic administration of barbiturates, but changes in responsiveness of the CNS (pharmacodynamic tolerance) are of greater importance for most sedative-hypnotics. In the case of benzodiazepines, the development of tolerance in animals has been associated with down-regulation of brain benzodiazepine receptors. Tolerance has been reported to occur with the extended use of zolpidem. Minimal tolerance was observed with the use of zaleplon over a 5-week period and eszopiclone over a 6-month period.
The perceived relief of anxiety, euphoria, disinhibition, and promotion of sleep have led to the compulsive misuse of virtually all sedative-hypnotics by vulnerable individuals. (See Chapter 32 for a detailed discussion.) For this reason, most sedative-hypnotic drugs are classified as Schedule III or Schedule IV drugs for prescribing purposes. The consequences of abuse of these agents can be defined in both psychological and physiologic terms. The psychological component may initially parallel simple neurotic behavior patterns difficult to differentiate from those of the inveterate coffee drinker or cigarette smoker. When the pattern of sedative-hypnotic use becomes compulsive, more serious complications develop, including physiologic dependence and tolerance.
Physiologic dependence can be described as an altered physiologic state that requires continuous drug administration to prevent an abstinence or withdrawal syndrome. In the case of sedative-hypnotics, this syndrome is characterized by states of increased anxiety, insomnia, and CNS excitability that may progress to convulsions. Most sedative-hypnotics—including benzodiazepines—are capable of causing physiologic dependence when used on a long-term basis. However, the severity of withdrawal symptoms differs among individual drugs and depends also on the magnitude of the dose used immediately before cessation of use. When higher doses of sedative-hypnotics are used, abrupt withdrawal leads to more serious withdrawal signs. Differences in the severity of withdrawal symptoms resulting from individual sedative-hypnotics relate in part to half-life, since drugs with long half-lives are eliminated slowly enough to accomplish gradual withdrawal with few physical symptoms. The use of drugs with very short half-lives for hypnotic effects may lead to signs of withdrawal even between doses. For example, triazolam, a benzodiazepine with a half-life of about 4 hours, has been reported to cause daytime anxiety when used to treat sleep disorders. The abrupt cessation of zolpidem, zaleplon, or eszopiclone may also result in withdrawal symptoms, though usually of less intensity than those seen with benzodiazepines.
BENZODIAZEPINE ANTAGONISTS: FLUMAZENIL
Flumazenil is one of several 1,4-benzodiazepine derivatives with a high affinity for the benzodiazepine binding site on the GABAA receptor that act as competitive antagonists. It blocks many of the actions of benzodiazepines, zolpidem, zaleplon, and eszopiclone, but does not antagonize the CNS effects of other sedative-hypnotics, ethanol, opioids, or general anesthetics. Flumazenil is approved for use in reversing the CNS depressant effects of benzodiazepine overdose and to hasten recovery following use of these drugs in anesthetic and diagnostic procedures. Although the drug reverses the sedative effects of benzodiazepines, antagonism of benzodiazepine-induced respiratory depression is less predictable. When given intravenously, flumazenil acts rapidly but has a short half-life (0.7–1.3 hours) due to rapid hepatic clearance. Because all benzodiazepines have a longer duration of action than flumazenil, sedation commonly recurs, requiring repeated administration of the antagonist.
Adverse effects of flumazenil include agitation, confusion, dizziness, and nausea. Flumazenil may cause a severe precipitated abstinence syndrome in patients who have developed physiologic benzodiazepine dependence. In patients who have ingested benzodiazepines with tricyclic antidepressants, seizures and cardiac arrhythmias may follow flumazenil administration.