Pharmacology_Katzung

Pharmacology_Katzung. 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 FIGURE 22–2 Chemical structures of some benzodiazepines. 1 6 R1: R1: CH2 CH3 R1: CH2 CH CH2 R1: CH2 CH3 25 34 R2: R2: CH CH2 CH2 CH3 R2: CH CH2 CH2 CH3 R2: FIGURE 22–3 Chemical structures of some barbiturates and other sedative-hypnotics.


Pharmacology_Katzung

Pharmacology_Katzung. 1 6 R1: R1: CH2 CH3 R1: CH2 CH CH2 R1: CH2 CH3 25 34 R2: R2: CH CH2 CH2 CH3 R2: CH CH2 CH2 CH3 R2: FIGURE 22–3 Chemical structures of some barbiturates and other sedative-hypnotics. 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). Other classes of drugs that exert sedative effects include anti-psychotics (see Chapter 29), and many antidepressant drugs (see


Pharmacology_Katzung

Pharmacology_Katzung. Other classes of drugs that exert sedative effects include anti-psychotics (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


Pharmacology_Katzung

Pharmacology_Katzung. 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 diaz epam 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.


Pharmacology_Katzung

Pharmacology_Katzung. 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. B. Biotransformation 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 FIGURE 22–4 Chemical structures of newer hypnotics. transformation.


Pharmacology_Katzung

Pharmacology_Katzung. 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


Pharmacology_Katzung

Pharmacology_Katzung. 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, flu-voxamine, tacrine, zileuton) or CYP2C9 (eg, fluconazole). Concur-rent 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.


Pharmacology_Katzung

Pharmacology_Katzung. 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


Pharmacology_Katzung

Pharmacology_Katzung. 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.


Pharmacology_Katzung

Pharmacology_Katzung. The formation of active metabolites has complicated studies on the pharmacokinetics of the benzodiazepines in humans FIGURE 22–5 Biotransformation of benzodiazepines. Boldface, drugs available for clinical use in various countries;*, active metabolite. TABLE 22–1 Pharmacokinetic properties of some benzodiazepines and newer hypnotics in humans. 1Time to peak blood level. 2Includes half-lives of major metabolites.


Pharmacology_Katzung

Pharmacology_Katzung. TABLE 22–1 Pharmacokinetic properties of some benzodiazepines and newer hypnotics in humans. 1Time to peak blood level. 2Includes half-lives of major metabolites. 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).


Pharmacology_Katzung

Pharmacology_Katzung. 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 benzo-diazepines, 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 discontinu-ance. The drug is not effective in blocking the acute withdrawal syndrome resulting from abrupt cessation of use of benzodi-azepines 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


Pharmacology_Katzung

Pharmacology_Katzung. 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 reac-tions 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 dysfunc-tion may slow its clearance. Rifampin, an inducer of cytochrome P450, decreases the half-life of buspirone; inhibitors of CYP3A4 (eg, erythromycin, ketoconazole, grapefruit juice,


Pharmacology_Katzung

Pharmacology_Katzung. and liver dysfunc-tion 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 ben-zodiazepines 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.


Pharmacology_Katzung

Pharmacology_Katzung. 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.


Pharmacology_Katzung

Pharmacology_Katzung. 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


Pharmacology_Katzung

Pharmacology_Katzung. 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.


Pharmacology_Katzung

Pharmacology_Katzung. C. Excretion 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).


Pharmacology_Katzung

Pharmacology_Katzung. 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


Pharmacology_Katzung

Pharmacology_Katzung. 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.


Pharmacology_Katzung

Pharmacology_Katzung. 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


Pharmacology_Katzung

Pharmacology_Katzung. 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).


Pharmacology_Katzung

Pharmacology_Katzung. 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). B. Neuropharmacology 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.


Pharmacology_Katzung

Pharmacology_Katzung. 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.)


Pharmacology_Katzung

Pharmacology_Katzung. 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.


Pharmacology_Katzung

Pharmacology_Katzung. 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


Pharmacology_Katzung

Pharmacology_Katzung. 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.


Pharmacology_Katzung

Pharmacology_Katzung. 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


Pharmacology_Katzung

Pharmacology_Katzung. 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.


Pharmacology_Katzung

C. Benzodiazepine Binding Site Ligands

Pharmacology_Katzung. C. Benzodiazepine Binding Site Ligands


Pharmacology_Katzung

Pharmacology_Katzung. 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,


Pharmacology_Katzung

Pharmacology_Katzung. 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


Pharmacology_Katzung

Pharmacology_Katzung. 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


Pharmacology_Katzung

Pharmacology_Katzung. 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).


Pharmacology_Katzung

Pharmacology_Katzung. 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 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 bind ing sites play a role in the control of states of anxiety, sleep patterns, or any other characteristic behavioral expression of CNS function.


Pharmacology_Katzung

Pharmacology_Katzung. D. Organ Level Effects 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


Pharmacology_Katzung

Pharmacology_Katzung. 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).


Pharmacology_Katzung

Pharmacology_Katzung. 2.


Pharmacology_Katzung

Pharmacology_Katzung. 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


Pharmacology_Katzung

Pharmacology_Katzung. 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.


Pharmacology_Katzung

Pharmacology_Katzung. 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


Pharmacology_Katzung

Pharmacology_Katzung. 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.


Pharmacology_Katzung

Pharmacology_Katzung. 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.


Pharmacology_Katzung

Pharmacology_Katzung. 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.


Pharmacology_Katzung

Pharmacology_Katzung. 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.


Pharmacology_Katzung

Pharmacology_Katzung. 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.


Pharmacology_Katzung

Pharmacology_Katzung. 6. 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.


Pharmacology_Katzung

Pharmacology_Katzung. 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


Pharmacology_Katzung

Pharmacology_Katzung. 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


Pharmacology_Katzung

Pharmacology_Katzung. 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.


Pharmacology_Katzung

Pharmacology_Katzung. 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.


Pharmacology_Katzung

Pharmacology_Katzung. 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


Pharmacology_Katzung

Pharmacology_Katzung. 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.


Pharmacology_Katzung

BENZODIAZEPINE ANTAGONISTS: FLUMAZENIL

Pharmacology_Katzung. BENZODIAZEPINE ANTAGONISTS: FLUMAZENIL


Pharmacology_Katzung

Pharmacology_Katzung. 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.


Pharmacology_Katzung

Pharmacology_Katzung. 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.


Pharmacology_Katzung

Pharmacology_Katzung. The psychological, behavioral, and physiologic responses that characterize anxiety can take many forms. Typically, the psychic awareness of anxiety is accompanied by enhanced vigilance, motor tension, and autonomic hyperactivity. Anxiety is often secondary to organic disease states—acute myocardial infarction, angina pectoris, cancer, etc—which themselves require specific therapy. Another class of secondary anxiety states (situational anxiety) results from circumstances that may have to be dealt with only once or a few times, including anticipation of frightening medical or dental procedures and family illness or other stressful event. Even though situational anxiety tends to be self-limiting, the short-term use of sedative-hypnotics may be appropriate for the treatment of this and certain disease-associated anxiety states. Similarly, the use of a sedative-hypnotic as premedication prior to surgery or some unpleasant medical procedure is rational and proper (Table 22–2).


Pharmacology_Katzung

Pharmacology_Katzung. Excessive or unreasonable anxiety about life circumstances (generalized anxiety disorder, GAD), panic disorders, and agoraphobia are also amenable to drug therapy, sometimes in conjunction with psychotherapy. The benzodiazepines continue to be TABLE 22–2 Clinical uses of sedative-hypnotics. For relief of anxiety For treatment of epilepsy and seizure states As a component of balanced anesthesia (intravenous administration)


Pharmacology_Katzung

Pharmacology_Katzung. For control of ethanol or other sedative-hypnotic withdrawal states widely used for the management of acute anxiety states and for rapid control of panic attacks. They are also used, though less commonly, in the long-term management of GAD and panic disorders. Anxiety symptoms may be relieved by many benzodiazepines, but it is not always easy to demonstrate the superiority of one drug over another. Alprazolam has been used in the treatment of panic disorders and agoraphobia and appears to be more selective in these conditions than other benzodiazepines. The choice of benzodiazepines for anxiety is based on several sound pharmacologic principles: (1) a rapid onset of action; (2) a relatively high therapeutic index (see drug B in Figure 22–1), plus availability of flumazenil for treatment of overdose; (3) a low risk of drug interactions based on liver enzyme induction; and (4) minimal effects on cardiovascular or autonomic functions.


Pharmacology_Katzung

Pharmacology_Katzung. Disadvantages of the benzodiazepines include the risk of dependence, depression of CNS functions, and amnestic effects. In addition, the benzodiazepines exert additive CNS depression when administered with other drugs, including ethanol. The patient should be warned of this possibility to avoid impairment of performance of any task requiring mental alertness and motor coordination. In the treatment of generalized anxiety disorders and certain phobias, newer antidepressants, including selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs), are now considered by many authorities to be drugs of first choice (see Chapter 30). However, these agents have a slow onset of action and thus minimal effectiveness in acute anxiety states.


Pharmacology_Katzung

Pharmacology_Katzung. Orexin A and B are peptides found in specific hypothalamic neurons that are involved in the control of wakefulness and that are silent during sleep. Orexin levels increase in the day and decrease at night. Loss of orexin neurons is associ-ated with narcolepsy, a disorder characterized by daytime sleepiness and cataplexy. Animal studies show that orexin receptor antagonists have sleep-enabling effects. This has prompted the development of a new class of hypnotic drugs, orexin antagonists, which include the drugs almorexant and suvorexant, the latter agent approved by the FDA.


Pharmacology_Katzung

Pharmacology_Katzung. Sedative-hypnotics should be used with appropriate caution to minimize adverse effects. A dose should be prescribed that does not impair mentation or motor functions during waking hours. Some patients may tolerate the drug better if most of the daily dose is given at bedtime, with smaller doses during the day. Prescriptions should be written for short periods, since there is little justification for long-term therapy (defined as use of therapeutic doses for 2 months or longer). The physician should make an effort to assess the efficacy of therapy from the patient’s subjective responses. Combinations of antianxiety agents should be avoided, and people taking sedatives should be cautioned about the consumption of alcohol and the concurrent use of over-the-counter medications containing antihistaminic or anticholinergic drugs (see Chapter 63).


Pharmacology_Katzung

Pharmacology_Katzung. Sleep disorders are common and often result from inadequate treatment of underlying medical conditions or psychiatric illness. True primary insomnia is rare. Nonpharmacologic therapies that are useful for sleep problems include proper diet and exercise, avoiding stimulants before retiring, ensuring a comfortable sleeping environment, and retiring at a regular time each night. In some cases, however, the patient will need and should be given a sedative-hypnotic for a limited period. It should be noted that the abrupt discontinuance of many drugs in this class can lead to rebound insomnia.


Pharmacology_Katzung

Pharmacology_Katzung. Benzodiazepines can cause a dose-dependent decrease in both REM and slow-wave sleep, though to a lesser extent than the barbiturates. The newer hypnotics, zolpidem, zaleplon, and eszopiclone, are less likely than the benzodiazepines to change sleep patterns. However, so little is known about the clinical impact of these effects that statements about the desirability of a particular drug based on its effects on sleep architecture have more theoretical than practical significance. Clinical criteria of efficacy in alleviating a particular sleeping problem are more useful. The drug selected should be one that provides sleep of fairly rapid onset (decreased sleep latency) and sufficient duration, with minimal “hangover” effects such as drowsiness, dysphoria, and mental or motor depression the following day. Older drugs such as chloral hydrate, secobarbital, and pentobarbital continue to be used, but benzodiazepines, zolpidem, zaleplon, or eszopiclone are generally preferred. Daytime


Pharmacology_Katzung

Pharmacology_Katzung. the following day. Older drugs such as chloral hydrate, secobarbital, and pentobarbital continue to be used, but benzodiazepines, zolpidem, zaleplon, or eszopiclone are generally preferred. Daytime sedation is more common with benzodiazepines that have slow elimination rates (eg, lorazepam) and those that are biotransformed to active metabolites (eg, flurazepam, quazepam). If benzodiazepines are used nightly, tolerance can occur, which may lead to dose increases by the patient to produce the desired effect. Anterograde amnesia occurs to some degree with all benzodiazepines used for hypnosis.


Pharmacology_Katzung

Pharmacology_Katzung. Eszopiclone, zaleplon, and zolpidem have efficacies similar to those of the hypnotic benzodiazepines in the management of sleep disorders. Favorable clinical features of zolpidem and the other newer hypnotics include rapid onset of activity and modest day-after psychomotor depression with few amnestic effects. Zolpidem, one of the most frequently prescribed hypnotic drugs in the United States, is available in a biphasic release formulation that provides sustained drug levels for sleep maintenance. Zaleplon acts rapidly, and because of its short half-life, the drug appears to TABLE 22–3 Dosages of drugs used commonly for sedation and hypnosis. have value in the management of patients who awaken early in the sleep cycle. At recommended doses, zaleplon and eszopiclone (despite a relatively long half-life) appear to cause less amnesia or day-after somnolence than zolpidem or benzodiazepines.


Pharmacology_Katzung

Pharmacology_Katzung. Suvorexant is FDA-approved for treatment of both sleep-onset and sleep-maintenance insomnia. The most common adverse effect of suvorexant is next-day somnolence. The drugs in this class commonly used for sedation and hypnosis are listed in Table 22–3 together with recommended doses. Note: The failure of insomnia to remit after 7–10 days of treatment may indicate the presence of a primary psychiatric or medical illness that should be evaluated. Long-term use of hypnotics is an irrational and dangerous medical practice. Table 22–2 summarizes several other important clinical uses of drugs in the sedative-hypnotic class. Drugs used in the management of seizure disorders and as intravenous agents in anesthesia are discussed in Chapters 24 and 25. For sedative and possible amnestic effects during medical or surgical procedures such as endoscopy and bronchoscopy—as well as for premedication prior to anesthesia—oral formulations of shorter-acting drugs are preferred.


Pharmacology_Katzung

Pharmacology_Katzung. Long-acting drugs such as chlordiazepoxide and diazepam and, to a lesser extent, phenobarbital are administered in progressively decreasing doses to patients during withdrawal from physiologic dependence on ethanol or other sedative-hypnotics. Parenteral lorazepam is used to suppress the symptoms of delirium tremens. Meprobamate and the benzodiazepines have frequently been used as central muscle relaxants, though evidence for general efficacy without accompanying sedation is lacking. A possible exception is diazepam, which has useful relaxant effects in skeletal muscle spasticity of central origin (see Chapter 27). Psychiatric uses of benzodiazepines other than treatment of anxiety states include the initial management of mania and the control of drug-induced hyperexcitability states (eg, phencyclidine intoxication). Sedative-hypnotics are also used occasionally as diagnostic aids in neurology and psychiatry.


Pharmacology_Katzung

Pharmacology_Katzung. Many of the common adverse effects of sedative-hypnotics result from dose-related depression of the CNS. Relatively low doses may lead to drowsiness, impaired judgment, and diminished motor skills, sometimes with a significant impact on driving ability, job performance, and personal relationships. Sleep driving and other somnambulistic behavior with no memory of the event have occurred with the sedative-hypnotic drugs used in sleep disorders, prompting the FDA in 2007 to issue warnings of this potential hazard. Benzodiazepines may cause a significant dose-related anterograde amnesia; they can significantly impair ability to learn new information, particularly that involving effortful cognitive processes, while leaving the retrieval of previously learned information intact. This effect is utilized for uncomfortable clinical procedures, eg, endoscopy, because the patient is able to cooperate during the procedure but amnesic regarding it afterward. The criminal use of benzodiazepines in


Pharmacology_Katzung

Pharmacology_Katzung. utilized for uncomfortable clinical procedures, eg, endoscopy, because the patient is able to cooperate during the procedure but amnesic regarding it afterward. The criminal use of benzodiazepines in cases of “date rape” is based on their dose-dependent amnestic effects. Hangover effects are not uncommon following use of hypnotic drugs with long elimination half-lives. Because elderly patients are more sensitive to the effects of sedative-hypnotics, doses approximately half of those used in younger adults are safer and usually as effective. The most common reversible cause of confusional states in the elderly is overuse of sedative-hypnotics. At higher doses, toxicity may present as lethargy or a state of exhaustion or, alternatively, as gross symptoms equivalent to those of ethanol intoxication. The physician should be aware of variability among patients in terms of doses causing adverse effects. An increased sensitivity to sedative-hypnotics is more common in patients with


Pharmacology_Katzung

Pharmacology_Katzung. intoxication. The physician should be aware of variability among patients in terms of doses causing adverse effects. An increased sensitivity to sedative-hypnotics is more common in patients with cardiovascular disease, respiratory disease, or hepatic impairment and in older patients. Sedative-hypnotics can exacerbate breathing problems in patients with chronic pulmonary disease and in those with symptomatic sleep apnea.


Pharmacology_Katzung

Pharmacology_Katzung. Sedative-hypnotics are the drugs most frequently involved in deliberate overdoses, in part because of their general availability as very commonly prescribed pharmacologic agents. The benzodiazepines are considered to be safer drugs in this respect, since they have flatter dose-response curves. Epidemiologic studies on the incidence of drug-related deaths support this general assumption—eg, 0.3 deaths per million tablets of diazepam prescribed versus 11.6 deaths per million capsules of secobarbital in one study. Alprazolam is purportedly more toxic in overdose than other benzodiazepines. Of course, many factors other than the specific sedative-hypnotic could influence such data—particularly the presence of other CNS depressants, including ethanol. In fact, most serious cases of drug overdosage, intentional or accidental, do involve polypharmacy; and when combinations of agents are taken, the practical safety of benzodiazepines may be less than the foregoing would imply.


Pharmacology_Katzung

Pharmacology_Katzung. The lethal dose of any sedative-hypnotic varies with the patient and the circumstances (see Chapter 58). If discovery of the ingestion is made early and a conservative treatment regimen is started, the outcome is rarely fatal, even following very high doses. On the other hand, for most sedative-hypnotics—with the exception of benzodiazepines and possibly the newer hypnotic drugs that have a similar mechanism of action—a dose as low as 10 times the hypnotic dose may be fatal if the patient is not discovered or does not seek help in time. With severe toxicity, the respiratory depression from central actions of the drug may be complicated by aspiration of gastric contents in the unattended patient—an even more likely occurrence if ethanol is present. Cardiovascular depression further complicates successful resuscitation. In such patients, treatment consists of ensuring a patent airway, with mechanical ventilation if needed, and maintenance of plasma volume, renal output, and cardiac


Pharmacology_Katzung

Pharmacology_Katzung. successful resuscitation. In such patients, treatment consists of ensuring a patent airway, with mechanical ventilation if needed, and maintenance of plasma volume, renal output, and cardiac function. Use of a positive inotropic drug such as dopamine, which preserves renal blood flow, is sometimes indicated. Hemodialysis or hemoperfusion may be used to hasten elimination of some of these drugs (see Table 58–2).


Pharmacology_Katzung

Pharmacology_Katzung. Flumazenil reverses the sedative actions of benzodiazepines, and those of eszopiclone, zaleplon, and zolpidem, although experience with its use in overdose of the newer hypnotics is limited. However, its duration of action is short, its antagonism of respiratory depression is unpredictable, and there is a risk of precipitation of withdrawal symptoms in long-term users of benzodiazepines. Consequently, the use of flumazenil in benzodiazepine overdose remains controversial and must be accompanied by adequate monitoring and support of respiratory function. The extensive clinical use of triazolam has led to reports of serious CNS effects including behavioral disinhibition, delirium, aggression, and violence. However, behavioral disinhibition may occur with any sedative-hypnotic drug, and it does not appear to be more prevalent with triazolam than with other benzodiazepines. Disinhibitory reactions during benzodiazepine treatment are more clearly associated with the use of very high doses


Pharmacology_Katzung

Pharmacology_Katzung. not appear to be more prevalent with triazolam than with other benzodiazepines. Disinhibitory reactions during benzodiazepine treatment are more clearly associated with the use of very high doses and the pretreatment level of patient hostility.


Pharmacology_Katzung

Pharmacology_Katzung. Adverse effects of the sedative-hypnotics that are not referable to their CNS actions occur infrequently. Hypersensitivity reactions, including skin rashes, occur only occasionally with most drugs of this class. Reports of teratogenicity leading to fetal deformation following use of certain benzodiazepines have resulted in FDA assignment of individual benzodiazepines to either category D or X in terms of pregnancy risk. Most barbiturates are FDA pregnancy category D. Eszopiclone, ramelteon, suvorexant, zaleplon, and zolpidem are category C, while buspirone is a category B drug in terms of use in pregnancy. Because barbiturates enhance porphyrin synthesis, they are absolutely contraindicated in patients with a history of acute intermittent porphyria, variegate porphyria, hereditary coproporphyria, or symptomatic porphyria.


Pharmacology_Katzung

Pharmacology_Katzung. Depending on the dosage and the duration of use, tolerance occurs in varying degrees to many of the pharmacologic effects of sedative-hypnotics. However, it should not be assumed that the degree of tolerance achieved is identical for all pharmacologic effects. There is evidence that the lethal dose range is not altered significantly by the long-term use of sedative-hypnotics. Cross-tolerance between the different sedative-hypnotics, including ethanol, can lead to an unsatisfactory therapeutic response when standard doses of a drug are used in a patient with a recent history of excessive use of these agents. However, there have been very few reports of tolerance development when eszopiclone, zolpidem, or zaleplon was used for less than 4 weeks.


Pharmacology_Katzung

Pharmacology_Katzung. With the long-term use of sedative-hypnotics, especially if doses are increased, a state of physiologic dependence can occur. This may develop to a degree unparalleled by any other drug group, including the opioids. Withdrawal from a sedative-hypnotic can have severe and life-threatening manifestations. Withdrawal symptoms range from restlessness, anxiety, weakness, and orthostatic hypotension to hyperactive reflexes and generalized seizures. Symptoms of withdrawal are usually more severe following discontinuance of sedative-hypnotics with shorter half-lives. However, eszopiclone, zolpidem, and zaleplon appear to be exceptions to this, because withdrawal symptoms are minimal following abrupt discontinuance of these newer short-acting agents. Symptoms are less pronounced with longer-acting drugs, which may partly accomplish their own “tapered” withdrawal by virtue of their slow elimination. Cross-dependence, defined as the ability of one drug to suppress abstinence symptoms from


Pharmacology_Katzung

Pharmacology_Katzung. drugs, which may partly accomplish their own “tapered” withdrawal by virtue of their slow elimination. Cross-dependence, defined as the ability of one drug to suppress abstinence symptoms from discontinuance of another drug, is quite marked among sedative-hypnotics. This provides the rationale for therapeutic regimens in the management of withdrawal states: Longer-acting drugs such as chlordiazepoxide, diazepam, and phenobarbital can be used to alleviate withdrawal symptoms of shorter-acting drugs, including ethanol.


Pharmacology_Katzung

Pharmacology_Katzung. The most common drug interactions involving sedative-hypnotics are interactions with other CNS depressant drugs, leading to additive effects. These interactions have some therapeutic usefulness when these drugs are used as adjuvants in anesthesia practice. However, if not anticipated, such interactions can lead to serious consequences, including enhanced depression with concomitant use of many other drugs. Additive effects can be predicted with concomitant use of alcoholic beverages, opioid analgesics, anticonvulsants, and phenothiazines. Less obvious but just as important is enhanced CNS depression with a variety of antihistamines, antihypertensive agents, and antidepressant drugs of the tricyclic class. Interactions involving changes in the activity of hepatic drug-metabolizing enzyme systems have been discussed (see also Chapters 4 and 66).


Pharmacology_Katzung

Pharmacology_Katzung. Interactions involving changes in the activity of hepatic drug-metabolizing enzyme systems have been discussed (see also Chapters 4 and 66). Subclass, Drug Mechanism of Action Effects Clinical Applications Pharmacokinetics, Toxicities, Interactions •RamelteonActivates MT1 and MT2 receptors in suprachiasmatic nuclei in the CNS Rapid onset of sleep with minimal rebound insomnia or withdrawal symptoms Sleep disorders, especially those characterized by difficulty in falling asleep •notacontrolledsubstanceOralactivity•formsactivemetaboliteviaCYP1A2•Toxicity:Dizziness•fatigue•endocrinechanges•Interactions:Fluvoxamine inhibits metabolism •Tasimelteon:OrallyactiveMT1 and MT2 agonist, recently approved for non-24-hour sleep disorder


Pharmacology_Katzung

Pharmacology_Katzung. GENERIC NAME AVAILABLE AS BENZODIAZEPINES Alprazolam Generic, Xanax Chlordiazepoxide Generic, Librium Clonazepam Generic, Tranxene Clorazepate Generic, Klonopin Diazepam Generic, Valium Estazolam Generic, ProSom Flurazepam Generic, Dalmane Lorazepam Generic, Ativan Midazolam Generic, Versed Oxazepam Generic, Serax Quazepam Generic, Doral Temazepam Generic, Restoril Triazolam Generic, Halcion BENZODIAZEPINE ANTAGONIST Flumazenil Generic, Romazicon BARBITURATES Amobarbital Amytal Mephobarbital Mebaral (withdrawn) MISCELLANEOUS DRUGS Buspirone Generic, BuSpar GENERIC NAME AVAILABLE AS Pentobarbital Generic, Nembutal Sodium Phenobarbital Generic, Luminal Sodium Secobarbital Generic, Seconal Chloral hydrate Generic, Aquachloral Supprettes Eszopiclone Lunesta Hydroxyzine Generic, Atarax, Vistaril Meprobamate Generic, Equanil, Miltown Paraldehyde Generic Ramelteon Rozerem Suvorexant Belsomra Tasimelteon Hetlioz Zaleplon Sonata Zolpidem Generic, Ambien, Ambien-CR PREP AR A TIONS A V AIL ABLE


Pharmacology_Katzung

Pharmacology_Katzung. Ancoli-Israel S et al: Long-term use of sedative hypnotics in older patients with insomnia. Sleep Med 2005;6:107. Bateson AN: The benzodiazepine site of the GABA A receptor: An old target with new potential? Sleep Med 2004;5(Suppl 1):S9. Chouinard G: Issues in the clinical use of benzodiazepines: Potency, withdrawal, and rebound. J Clin Psychiatry 2004;65(Suppl 5):7. Clayton T et al: An updated unified pharmacophore model of the benzodiazepine binding site on gamma-aminobutyric acid(a) receptors: Correlation with comparative models. Curr Med Chem 2007;14:2755. Cloos JM, Ferreira V: Current use of benzodiazepines in anxiety disorders. Curr Opin Psychiatry 2009;22:90. Da Settimo F et al: GABA A/Bz receptor subtypes as targets for selective drugs. Curr Med Chem 2007;14:2680. Davidson JR et al: A psychopharmacological treatment algorithm for generalized anxiety disorder. J Psychopharmacol 2010;24:3.


Pharmacology_Katzung

Pharmacology_Katzung. Davidson JR et al: A psychopharmacological treatment algorithm for generalized anxiety disorder. J Psychopharmacol 2010;24:3. Drover DR: Comparative pharmacokinetics and pharmacodynamics of short-acting hypnosedatives: Zaleplon, zolpidem and zopiclone. Clin Pharmacokinet 2004;43:227. Drugs for Insomnia. Treatment Guidelines 2012;10:57. Dubey AK et al: Suvorexant: The first orexin receptor antagonist to treat insomnia. J Pharmacol Pharmacother 2015;6:118. Erman M et al: An efficacy, safety, and dose-response study of ramelteon in patients with chronic primary insomnia. Sleep Med 2006;7:17. Gottesmann C: GABA mechanisms and sleep. Neuroscience 2002;111:231. Hanson SM, Czajkowski C: Structural mechanisms underlying benzodiazepine modulation of the GABA(A) receptor. J Neurosci 2008;28:3490. Hesse LM et al: Clinically important drug interactions with zopiclone, zolpidem and zaleplon. CNS Drugs 2003;17:513.


Pharmacology_Katzung

Pharmacology_Katzung. Hesse LM et al: Clinically important drug interactions with zopiclone, zolpidem and zaleplon. CNS Drugs 2003;17:513. Jacobson LH et al: Suvorexant for the treatment of insomnia. Exp Rev Clin Pharmacol 2014;7:711. Kato K et al: Neurochemical properties of ramelteon, a selective MT1/MT2 receptor agonist. Neuropharmacology 2005;48:301. Kralic JE et al: GABA(A) receptor alpha-1 subunit deletion alters receptor subtype assembly, pharmacological and behavioral responses to benzodiazepines and zolpidem. Neuropharmacology 2002;43:685. Krystal AD: The changing perspective of chronic insomnia management. J Clin Psychiatry 2004;65(Suppl 8):20. Lader M, Tylee A, Donoghue J: Withdrawing benzodiazepines in primary care. CNS Drugs 2009;23:2319. McKernan RM et al: Anxiolytic-like action of diazepam: Which GABA(A) receptor subtype is involved? Trends Pharmacol Sci 2001;22:402.


Pharmacology_Katzung

Pharmacology_Katzung. McKernan RM et al: Anxiolytic-like action of diazepam: Which GABA(A) receptor subtype is involved? Trends Pharmacol Sci 2001;22:402. Morairty SR, et al: The hypocretin/orexin antagonist almorexant promotes sleep without impairment of performance in rats. Front Neurosci 2014;8:3. Neubauer DN: New directions in the pharmacologic treatment of insomnia. Primary Psychiatry 2006;13:51. Rapaport MJ et al: Benzodiazepine use and driving: A meta analysis. J Clin Psychiatry 2009;70:663. Rosenberg R et al: An assessment of the efficacy and safety of eszopiclone in the treatment of transient insomnia in healthy adults. Sleep Med 2005;6:15. Sanger DJ: The pharmacology and mechanism of action of new generation, nonbenzodiazepine hypnotic agents. CNS Drugs 2004;18(Suppl 1):9. Silber MH: Chronic insomnia. N Engl J Med 2005;353:803. Walsh JK: Pharmacologic management of insomnia. J Clin Psychiatry 2004;65(Suppl 16):41. Winkelman JW: Insomnia disorder. N Engl J Med 2015;373:1437.


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Pharmacology_Katzung. Walsh JK: Pharmacologic management of insomnia. J Clin Psychiatry 2004;65(Suppl 16):41. Winkelman JW: Insomnia disorder. N Engl J Med 2015;373:1437. Wurtman R: Ramelteon: A novel treatment for the treatment of insomnia. Expert Rev Neurother 2006;6:957. As described in this chapter, nonpharmacologic factors are very important in the management of sleep problems: proper diet (and avoidance of snacks before bedtime), exercise, and a regular time and place for sleep. Avoidance of stimulants is very important, and the large intake of diet colas reported by the patient should be reduced, especially in the latter half of the day. If problems persist after these measures are implemented, one of the newer hypnotics (eszopiclone, zaleplon, or zolpidem) may be tried on a short-term basis. Anthony J. Trevor, PhD* The Alcohols


Pharmacology_Katzung

Pharmacology_Katzung. A 19-year-old college freshman began drinking alcohol at 8:30 pm during a hazing event at his new fraternity. Between 8:30 and approximately midnight, he and several other pledges consumed beer and a bottle of whiskey, and then he consumed most of a bottle of rum at the urging of upperclassmen. The young man complained of feeling nau-seated, lay down on a couch, and began to lose conscious-ness. Two upperclassmen carried him to a bedroom, placed him on his stomach, and positioned a trash can nearby. Approximately 10 minutes later, the freshman was found unconscious and covered with vomit. There was a delay in treatment because the upperclassmen called the college police instead of calling 911. After the call was transferred to 911, emergency medical technicians responded quickly and discovered that the young man was not breathing and that he had choked on his vomit. He was rushed to the hospital, where he remained in a coma for 2 days before ultimately being pronounced dead. The


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Pharmacology_Katzung. discovered that the young man was not breathing and that he had choked on his vomit. He was rushed to the hospital, where he remained in a coma for 2 days before ultimately being pronounced dead. The patient’s blood alcohol concentration shortly after arriving at the hospital was 510 mg/dL. What was the cause of this patient’s death? If he had received medical care sooner, what treatment might have prevented his death?


Pharmacology_Katzung

Pharmacology_Katzung. Alcohol, primarily in the form of ethyl alcohol (ethanol), has occupied an important place in the history of humankind for at least 8000 years. In Western society, beer and wine were a main staple of daily life until the 19th century. These relatively dilute alcoholic beverages were preferred over water, which was known— long before the discovery of microbes—to be associated with acute and chronic illness. Partially sterilized by the fermentation process and the alcohol content, alcoholic beverages provided calories and some nutrients and served as a main source of daily liquid intake. As systems for improved sanitation and water purification were introduced in the 1800s, beer and wine became less important components of the human diet, and the consumption of alcoholic beverages, including distilled preparations with higher concentrations of alcohol, shifted toward their present-day role, in many societies, as a socially acceptable form of recreation.


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Pharmacology_Katzung. Today, alcohol is widely consumed. Like other sedative-hypnotic drugs, alcohol in low to moderate amounts relieves * The author thanks Susan B. Masters, PhD, the previous author of this chapter, for her contributions.


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Pharmacology_Katzung. anxiety and fosters a feeling of well-being or even euphoria. However, alcohol is also the most commonly abused drug in the world, and the cause of vast medical and societal costs. In the United States, approximately 75% of the adult population drinks alcohol regularly. The majority of this drinking population is able to enjoy the pleasurable effects of alcohol without allowing alcohol consumption to become a health risk. However, 8–10% of the general population in the United States has an alcohol-use disorder. Individuals who use alcohol in dangerous situations (eg, drinking and driving or combining alcohol with other medications) or continue to drink alcohol despite adverse consequences related directly to their alcohol consumption suffer from alcohol abuse (see also Chapter 32). Individuals with alcohol dependence have characteristics of alcohol abuse and additionally exhibit physical dependence on alcohol (tolerance to alcohol and signs and symptoms upon withdrawal). They also


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Pharmacology_Katzung. with alcohol dependence have characteristics of alcohol abuse and additionally exhibit physical dependence on alcohol (tolerance to alcohol and signs and symptoms upon withdrawal). They also demonstrate an inability to control their drinking and devote much time to getting and using alcohol, or recovering from its effects. The alcohol-use disorders are complex, with genetic as well as environmental determinants.


Pharmacology_Katzung

Pharmacology_Katzung. The societal and medical costs of alcohol abuse are staggering. It is estimated that more than 600,000 emergency department visits and approximately 85,000 deaths in the USA annually are due to alcohol use. Once in the hospital, people with chronic alcoholism generally have poorer outcomes. In addition, each year, tens of thousands of children are born with morphologic and functional defects resulting from prenatal exposure to ethanol. Despite the investment of many resources and much basic research, alcoholism remains a common chronic disease that is difficult to treat. Ethanol and many other alcohols with potentially toxic effects are used as fuels and in industry—some in enormous quantities. In addition to ethanol, methanol and ethylene glycol toxicity occurs with sufficient frequency to warrant discussion in this chapter.


Pharmacology_Katzung

Pharmacology_Katzung. Ethanol is a small water-soluble molecule that is absorbed rapidly from the gastrointestinal tract. After ingestion of alcohol in the fasting state, peak blood alcohol concentrations are reached within 30 minutes. The presence of food in the stomach delays absorption by slowing gastric emptying. Distribution is rapid, with tissue levels approximating the concentration in blood. The volume of distribution for ethanol approximates total body water (0.5–0.7 L/kg). After an equivalent oral dose of alcohol, women have a higher peak concentration than men, in part because women have a lower total body water content and in part because of differences in first-pass metabolism. In the central nervous system (CNS), the concentration of ethanol rises quickly, since the brain receives a large proportion of total blood flow and ethanol readily crosses biologic membranes.


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Pharmacology_Katzung. Over 90% of alcohol consumed is oxidized in the liver; much of the remainder is excreted through the lungs and in the urine. The excretion of a small but consistent proportion of alcohol by the lungs can be quantified with breath alcohol tests that serve as a basis for a legal definition of “driving under the influence” (DUI) in many countries. In most states in the USA, the alcohol level for driving under the influence is set at 80 mg/dL (0.08%). At levels of ethanol usually achieved in blood, the rate of oxidation follows zero-order kinetics; that is, it is independent of time and concentration of the drug. The typical adult can metabolize 7–10 g (150–220 mmol) of alcohol per hour, the equivalent of approximately one “drink” [10 oz (300 mL) beer, 3.5 oz (105 mL) wine, or 1 oz (30 mL) distilled 80-proof spirits]. A commercial product (“Palcohol”), approved in the USA in 2015, consists of a powder to be mixed to form a drink containing 10% ethanol (approximately equivalent to wine).


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Pharmacology_Katzung. Two major pathways of alcohol metabolism to acetaldehyde have been identified (Figure 23–1). Acetaldehyde is then oxidized to acetate by a third metabolic process. A. Alcohol Dehydrogenase Pathway The primary pathway for alcohol metabolism involves alcohol dehydrogenase (ADH), a family of cytosolic enzymes that catalyze CHAPTER 23 The Alcohols 397 FIGURE 23–1 Metabolism of ethanol by alcohol dehydrogenase and the microsomal ethanol-oxidizing system (MEOS). Alcohol dehydrogenase and aldehyde dehydrogenase are inhibited by fomepizole and disulfiram, respectively. NAD+, nicotinamide adenine dinucleotide; NADPH, nicotinamide adenine dinucleotide phosphate.


Pharmacology_Katzung

Pharmacology_Katzung. the conversion of alcohol to acetaldehyde (Figure 23–1, left). These enzymes are located mainly in the liver, but small amounts are found in other organs such as the brain and stomach. There is considerable genetic variation in ADH enzymes, affecting the rate of ethanol metabolism and also appearing to alter vulnerability to alcohol-abuse disorders. For example, one ADH allele (the ADH1B * 2 allele), which is associated with rapid conversion of ethanol to acetaldehyde, has been found to be protective against alcohol dependence in several ethnic populations, especially East Asians. Some metabolism of ethanol by ADH occurs in the stomach in men, but a smaller amount occurs in women, who appear to have lower levels of the gastric enzyme. This difference in gastric metabolism of alcohol in women probably contributes to the sex-related differences in blood alcohol concentrations noted above.


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Pharmacology_Katzung. During conversion of ethanol by ADH to acetaldehyde, hydrogen ion is transferred from ethanol to the cofactor nicotinamide adenine dinucleotide (NAD+) to form NADH. As a net result, alcohol oxidation generates an excess of reducing equivalents in the liver, chiefly as NADH. The excess NADH production appears to contribute to the metabolic disorders that accompany chronic alcoholism and to both the lactic acidosis and hypoglycemia that frequently accompany acute alcohol poisoning. B. Microsomal Ethanol-Oxidizing System (MEOS) This enzyme system, also known as the mixed function oxidase system, uses NADPH as a cofactor in the metabolism of ethanol (Figure 23–1, right) and consists primarily of cytochrome P450 2E1, 1A2, and 3A4 (see Chapter 4).


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Pharmacology_Katzung. During chronic alcohol consumption, MEOS activity is induced. As a result, chronic alcohol consumption results in significant increases not only in ethanol metabolism but also in the clearance of other drugs eliminated by the cytochrome P450s that constitute the MEOS system, and in the generation of the toxic byproducts of cytochrome P450 reactions (toxins, free radicals, H2O2). C. Acetaldehyde Metabolism Much of the acetaldehyde formed from alcohol is oxidized in the liver in a reaction catalyzed by mitochondrial NAD-dependent aldehyde dehydrogenase (ALDH). The product of this reaction is acetate (Figure 23–1), which can be further metabolized to CO2 and water, or used to form acetyl-CoA.


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Pharmacology_Katzung. Oxidation of acetaldehyde is inhibited by disulfiram, a drug that has been used to deter drinking by patients with alcohol dependence. When ethanol is consumed in the presence of disulfiram, acetaldehyde accumulates and causes an unpleasant reaction of facial flushing, nausea, vomiting, dizziness, and headache. Several other drugs (eg, metronidazole, cefotetan, trimethoprim) inhibit ALDH and have been claimed to cause a disulfiram-like reaction if combined with ethanol. Some people, primarily of East Asian descent, have genetic deficiency in the activity of the mitochondrial form of ALDH, which is encoded by the ALDH2 gene. When these individuals drink alcohol, they develop high blood acetaldehyde concentrations and experience a noxious reaction similar to that seen with the combination of disulfiram and ethanol. This form of reduced-activity ALDH is strongly protective against alcohol-use disorders. Pharmacodynamics of Acute Ethanol Consumption A. Central Nervous System


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Pharmacology_Katzung. Pharmacodynamics of Acute Ethanol Consumption A. Central Nervous System The CNS is markedly affected by acute alcohol consumption. Alcohol causes sedation, relief of anxiety and, at higher concentrations, slurred speech, ataxia, impaired judgment, and disinhibited behavior, a condition usually called intoxication or drunkenness (Table 23–1). These CNS effects are most marked as the blood level is rising, because acute tolerance to the effects of alcohol occurs after a few hours of drinking. For chronic drinkers who are tolerant to the effects of alcohol, higher concentrations are needed to elicit these CNS effects. For example, an individual with chronic alcoholism may appear sober or only slightly TABLE 23–1 Blood alcohol concentration (BAC) and clinical effects in nontolerant individuals.


Pharmacology_Katzung

Pharmacology_Katzung. TABLE 23–1 Blood alcohol concentration (BAC) and clinical effects in nontolerant individuals. 1In many parts of the United States, a blood level above 80–100 mg/dL for adults or 5–20 mg/dL for persons under 21 is sufficient for conviction of driving while “under the influence.” intoxicated with a blood alcohol concentration of 300–400 mg/dL (0.30-0.40%), whereas this level is associated with marked intoxication or even coma in a nontolerant individual. The propensity of moderate doses of alcohol to inhibit the attention and information-processing skills as well as the motor skills required for operation of motor vehicles has profound effects. Approximately 30–40% of all traffic accidents resulting in a fatality in the United States involve at least one person with blood alcohol near or above the legal level of intoxication, and drunken driving is a leading cause of death in young adults.


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Pharmacology_Katzung. Like other sedative-hypnotic drugs, alcohol is a CNS depressant. At high blood concentrations, it induces coma, respiratory depression, and death.


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Pharmacology_Katzung. Ethanol affects a large number of membrane proteins that participate in signaling pathways, including neurotransmitter receptors for amines, amino acids, opioids, and neuropeptides; enzymes such as Na+/K+-ATPase, adenylyl cyclase, phosphoinositide-specific phospholipase C; a nucleoside transporter; and ion channels. Much attention has focused on alcohol’s effects on neurotransmission by glutamate and γ-aminobutyric acid (GABA), the main excitatory and inhibitory neurotransmitters in the CNS. Acute ethanol exposure enhances the action of GABA at GABAA receptors, which is consistent with the ability of GABA-mimetics to intensify many of the acute effects of alcohol and of GABAA antagonists to attenuate some of the actions of ethanol. Ethanol inhibits the ability of glutamate to open the cation channel associated with the N-methyld-aspartate (NMDA) subtype of glutamate receptors. The NMDA receptor is implicated in many aspects of cognitive function, including learning and memory.


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Pharmacology_Katzung. the cation channel associated with the N-methyld-aspartate (NMDA) subtype of glutamate receptors. The NMDA receptor is implicated in many aspects of cognitive function, including learning and memory. “Blackouts”—periods of memory loss that occur with high levels of alcohol—may result from inhibition of NMDA receptor activation. Experiments that use modern genetic approaches eventually will yield a more precise definition of ethanol’s direct and indirect targets. In recent years, experiments with mutant strains of mice, worms, and flies have reinforced the importance of previously identified targets and helped identify new candidates, including a calcium-regulated and voltage-gated potassium channel that may be one of ethanol’s direct targets (see Box: What Can Drunken Worms, Flies, and Mice Tell Us about Alcohol?).


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Pharmacology_Katzung. B. Heart Significant depression of myocardial contractility has been observed in individuals who acutely consume moderate amounts of alcohol, ie, at a blood concentration above 100 mg/dL. C. Smooth Muscle Ethanol is a vasodilator, probably as a result of both CNS effects (depression of the vasomotor center) and direct smooth muscle relaxation caused by its metabolite, acetaldehyde. In cases of severe overdose, hypothermia—caused by vasodilation—may be marked in cold environments. Preliminary evidence indicates that flibanserin augments the hypotensive effects of ethanol and may cause severe orthostatic hypotension and syncope (see Chapter 16). Ethanol also relaxes the uterus and—before the introduction of more effective and safer uterine relaxants (eg, calcium channel antagonists)—was used intravenously for the suppression of premature labor. Consequences of Chronic Alcohol Consumption


Pharmacology_Katzung

Pharmacology_Katzung. Consequences of Chronic Alcohol Consumption Chronic alcohol consumption profoundly affects the function of several vital organs—particularly the liver—and the nervous, gastrointestinal, cardiovascular, and immune systems. Since ethanol has low potency, it requires concentrations thousands of times higher than other misused drugs (eg, cocaine, opiates, amphetamines) to produce its intoxicating effects. As a result, ethanol is consumed in quantities that are unusually large for a pharmacologically active drug. The tissue damage caused by chronic alcohol ingestion results from a combination of the direct effects of ethanol and acetaldehyde, and the metabolic consequences of processing a heavy load of a metabolically active substance. Specific mechanisms implicated in tissue damage include increased oxidative stress coupled with depletion of glutathione, damage to mitochondria, growth factor dysregulation, and potentiation of cytokine-induced injury.


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Pharmacology_Katzung. Chronic consumption of large amounts of alcohol is associated with an increased risk of death. Deaths linked to alcohol consumption are caused by liver disease, cancer, accidents, and suicide. A. Liver and Gastrointestinal Tract


Pharmacology_Katzung

Pharmacology_Katzung. A. Liver and Gastrointestinal Tract Liver disease is the most common medical complication of alcohol abuse; an estimated 15–30% of chronic heavy drinkers eventually develop severe liver disease. Alcoholic fatty liver, a reversible condition, may progress to alcoholic hepatitis and finally to cirrhosis and liver failure. In the United States, chronic alcohol abuse is the leading cause of liver cirrhosis and of the need for liver transplantation. The risk of developing liver disease is related both to the average amount of daily consumption and to the duration of alcohol abuse. Women appear to be more susceptible to alcohol hepatotoxicity than men. Concurrent infection with hepatitis B or C virus increases the risk of severe liver disease. Cirrhosis contributes to elevated portal blood pressure and esophageal and gastric venous varices. These varices may rupture and result in massive bleeding. What Can Drunken Worms, Flies, and Mice Tell Us about Alcohol?


Pharmacology_Katzung

Pharmacology_Katzung. For a drug like ethanol, which exhibits low potency and specific-ity and modifies complex behaviors, the precise roles of its many direct and indirect targets are difficult to define. Increasingly, ethanol researchers are employing genetic approaches to com-plement standard neurobiologic experimentation. Three experi-mental animal systems for which powerful genetic techniques exist—mice, flies, and worms—have yielded intriguing results. Strains of mice with abnormal sensitivity to ethanol were identified many years ago by breeding and selection programs. Using sophisticated genetic mapping and sequencing tech-niques, researchers have made progress in identifying the genes that confer ethanol susceptibility or resistance traits. A more targeted approach is the use of transgenic mice to test hypoth-eses about specific genes. For example, after earlier experiments suggested a link between brain neuropeptide Y (NPY) and etha-nol, researchers used two transgenic mouse models to further


Pharmacology_Katzung

Pharmacology_Katzung. test hypoth-eses about specific genes. For example, after earlier experiments suggested a link between brain neuropeptide Y (NPY) and etha-nol, researchers used two transgenic mouse models to further investigate the link. They found that a strain of mice that lacks the gene for NPY—NPY knockout mice—consume more ethanol than control mice and are less sensitive to ethanol’s sedative effects. As would be expected if increased concentrations of NPY in the brain make mice more sensitive to ethanol, a strain of mice that overexpresses NPY drinks less alcohol than the controls even though their total consumption of food and liquid is normal. Work with other transgenic knockout mice supports the central role in ethanol responses of signaling systems that have long been believed to be involved (eg, GABAA, glutamate, dopamine, opioid, and serotonin receptors) and has helped build the case for newer candidates such as NPY and corticotropin-releasing hormone, cannabinoid receptors, ion channels,


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Pharmacology_Katzung. GABAA, glutamate, dopamine, opioid, and serotonin receptors) and has helped build the case for newer candidates such as NPY and corticotropin-releasing hormone, cannabinoid receptors, ion channels, and protein kinase C. It is easy to imagine mice having measurable behavioral responses to alcohol, but drunken worms and fruit flies are harder to imagine. Actually, both invertebrates respond to ethanol in ways that parallel mammalian responses. Drosophila melanogaster fruit flies exposed to ethanol vapor show increased locomotion at low concentrations but at higher concentrations, become poorly coordinated, sedated, and finally immobile. These behaviors can be monitored by sophisticated laser or video tracking methods or with an ingenious “chromatography” column of air that separates relatively insensitive flies from inebriated flies, which drop to the bottom of the column. The worm Caenorhabditis elegans similarly exhibits increased locomotion at low ethanol concentrations and, at


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Pharmacology_Katzung. insensitive flies from inebriated flies, which drop to the bottom of the column. The worm Caenorhabditis elegans similarly exhibits increased locomotion at low ethanol concentrations and, at higher concentrations, reduced locomotion, sedation, and— something that can be turned into an effective screen for mutant worms that are resistant to ethanol—impaired egg laying. The advantage of using flies and worms as genetic models for ethanol research is their relatively simple neuroanatomy, well-established techniques for genetic manipulation, extensive libraries of well-characterized mutants, and completely or nearly completely solved genetic codes. Already, much information has accumu-lated about candidate proteins involved with the effects of etha-nol in flies. In an elegant study on C elegans, researchers found evidence that a calcium-activated, voltage-gated BK potassium channel is a direct target of ethanol. This channel, which is acti-vated by ethanol, has close homologs in flies and


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Pharmacology_Katzung. researchers found evidence that a calcium-activated, voltage-gated BK potassium channel is a direct target of ethanol. This channel, which is acti-vated by ethanol, has close homologs in flies and vertebrates, and evidence is accumulating that ethanol has similar effects in these homologs. Genetic experiments in these model systems should provide information that will help narrow and focus research into the complex and important effects of ethanol in humans.


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Pharmacology_Katzung. The pathogenesis of alcoholic liver disease is a multifactorial process involving metabolic repercussions of ethanol oxidation in the liver, dysregulation of fatty acid oxidation and synthesis, and activation of the innate immune system by a combination of direct effects of ethanol and its metabolites and by bacterial endotoxins that access the liver as a result of ethanol-induced changes in the intestinal tract. Tumor necrosis factor-α appears to play a pivotal role in the progression of alcoholic liver disease and may be a fruitful therapeutic target. Other portions of the gastrointestinal tract can also be injured. Chronic alcohol ingestion is by far the most common cause of chronic pancreatitis in the Western world. In addition to its direct toxic effect on pancreatic acinar cells, alcohol alters pancreatic epithelial permeability and promotes the formation of protein plugs and calcium carbonate-containing stones.


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Pharmacology_Katzung. Individuals with chronic alcoholism are prone to gastritis and have increased susceptibility to blood and plasma protein loss during drinking, which may contribute to anemia and protein malnutrition. Alcohol also injures the small intestine, leading to diarrhea, weight loss, and multiple vitamin deficiencies. Malnutrition from dietary deficiency and vitamin deficiencies due to malabsorption are common in alcoholism. Malabsorption of water-soluble vitamins is especially severe.


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Pharmacology_Katzung. Malnutrition from dietary deficiency and vitamin deficiencies due to malabsorption are common in alcoholism. Malabsorption of water-soluble vitamins is especially severe. B. Nervous System 1. Tolerance and dependence—The consumption of alcohol in high doses over a long period results in tolerance and in physical and psychological dependence. Tolerance to the intoxicating effects of alcohol is a complex process involving poorly understood changes in the nervous system as well as the pharmacokinetic changes described earlier. As with other sedative-hypnotic drugs, there is a limit to tolerance, so that only a relatively small increase in the lethal dose occurs with increasing alcohol use.


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Pharmacology_Katzung. Chronic alcohol drinkers, when forced to reduce or discontinue alcohol, experience a withdrawal syndrome, which indicates the existence of physical dependence. Alcohol withdrawal symptoms usually consist of hyperexcitability in mild cases and seizures, toxic psychosis, and delirium tremens in severe ones. The dose, rate, and duration of alcohol consumption determine the intensity of the withdrawal syndrome. When consumption has been very high, merely reducing the rate of consumption may lead to signs of withdrawal. Psychological dependence on alcohol is characterized by a compulsive desire to experience the rewarding effects of alcohol and, for current drinkers, a desire to avoid the negative consequences of withdrawal. People who have recovered from alcoholism and become abstinent still experience periods of intense craving for alcohol that can be triggered by environmental cues associated in the past with drinking, such as familiar places, groups of people, or events.


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Pharmacology_Katzung. The molecular basis of alcohol tolerance and dependence is not known with certainty, nor is it known whether the two phenomena reflect opposing effects on a shared molecular pathway. Tolerance may result from ethanol-induced up-regulation of a pathway in response to the continuous presence of ethanol. Dependence may result from overactivity of that same pathway after the ethanol effect dissipates and before the system has time to return to a normal ethanol-free state.


Pharmacology_Katzung

Pharmacology_Katzung. Chronic exposure of animals or cultured cells to alcohol elicits a multitude of adaptive responses involving neurotransmitters and their receptors, ion channels, and enzymes that participate in signal transduction pathways. Up-regulation of the NMDA subtype of glutamate receptors and voltage-sensitive Ca2+ channels may underlie the seizures that accompany the alcohol withdrawal syndrome. GABA neurotransmission is believed to play a significant role in tolerance and withdrawal because (1) sedative-hypnotic drugs that enhance GABAergic neurotransmission are able to substitute for alcohol during alcohol withdrawal, and (2) there is evidence of down-regulation of GABAA-mediated responses with chronic alcohol exposure.


Pharmacology_Katzung

Pharmacology_Katzung. Like other drugs of abuse, ethanol modulates neural activity in the brain’s mesolimbic dopamine reward circuit and increases dopamine release in the nucleus accumbens (see Chapter 32). Alcohol affects local concentrations of serotonin, opioids, and dopamine—neurotransmitters involved in the brain reward system. The discovery that naltrexone, a nonselective opioid receptor antagonist, helps patients who are recovering from alcoholism abstain from drinking supports the idea that a common neurochemical reward system is shared by very different drugs associated with physical and psychological dependence. There is also convincing evidence from animal models that ethanol intake and seeking behavior are reduced by antagonists of another important regulator of the brain reward system, the cannabinoid CB1 receptor. Two other important neuroendocrine systems that appear to play key roles in modulating ethanol-seeking activity in experimental animals are the appetite-regulating system—which uses


Pharmacology_Katzung

Pharmacology_Katzung. CB1 receptor. Two other important neuroendocrine systems that appear to play key roles in modulating ethanol-seeking activity in experimental animals are the appetite-regulating system—which uses peptides such as leptin, ghrelin, and neuropeptide Y—and the stress response system, which is controlled by corticotropin-releasing factor.


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Pharmacology_Katzung. 2. Neurotoxicity—Consumption of large amounts of alcohol over extended periods (usually years) often leads to neurologic deficits. The most common neurologic abnormality in chronic alcoholism is generalized symmetric peripheral nerve injury, which begins with distal paresthesias of the hands and feet. Degenerative changes can also result in gait disturbances and ataxia. Other neurologic disturbances associated with alcoholism include dementia and, rarely, demyelinating disease.


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Pharmacology_Katzung. Wernicke-Korsakoff syndrome is a relatively uncommon but important entity characterized by paralysis of the external eye muscles, ataxia, and a confused state that can progress to coma and death. It is associated with thiamine deficiency but is rarely seen in the absence of alcoholism. Because of the importance of thiamine in this pathologic condition and the absence of toxicity associated with thiamine administration, all patients suspected of having Wernicke-Korsakoff syndrome (including virtually all patients who present to the emergency department with altered consciousness, seizures, or both) should receive thiamine therapy. Often, the ocular signs, ataxia, and confusion improve promptly upon administration of thiamine. However, most patients are left with a chronic disabling memory disorder known as Korsakoff’s psychosis.


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Pharmacology_Katzung. Alcohol may also impair visual acuity, with painless blurring that occurs over several weeks of heavy alcohol consumption. Changes are usually bilateral and symmetric and may be followed by optic nerve degeneration. Ingestion of ethanol substitutes such as methanol (see Pharmacology of Other Alcohols) causes severe visual disturbances. C. Cardiovascular System 1.