3 курс / Фармакология / Essential_Psychopharmacology_2nd_edition

FIGURE 8-23. In this example, both GABA and benzodiazepine (BZ) ligands are binding to their respective receptor sites on the GABA A receptor complex. This causes far more opening of the chloride channel than can be effected by GABA acting alone. Thus, it can be said that benzodiazepine ligands allosterically modulate GABA's ability to open the chloride channel. It is this positive allosteric modulation of the BZ receptor by benzodiazepine drugs that is thought to account for their anxiolytic actions.

8 — 21, can accomplish. Thus, GABA can increase chloride conductance through the chloride channel much more dramatically when a benzodiazepine receptor binding site is helping it allosterically than it can when it is working alone to modulate the chloride channel (Fig. 8 — 23).

In other words, benzodiazepines allosterically modulate GABA neurotransmission by potentiating GABA's ability to increase conductance of chloride through its channel. That is, with GABA plus benzodiazepines, 1 + 1 = 10, not 2. This mechanism greatly expands the scope of the neuron to regulate its fast inhibitory neurotransmission with chemical ligands.

Inverse agonists, partial agonists, and antagonists at benzodiazepine receptors. For a further degree of regulatory control of GABA neurotransmission, the concept of allosteric modulation can be combined with the concept of inverse agonists. Inverse agonists have already been introduced (see Chapter 3). Thus, positive allosteric modulation of benzodiazepines on GABA A receptors occurs because the benzodiazepines are full agonists at the benzodiazepine site (Fig. 8 — 23). However, negative allosteric modulation can occur when an inverse agonist binds to the benzodiazepine site. Instead of increasing the chloride conductance that GABA provokes (Fig. 8 — 22), the inverse agonist decreases it (Fig. 8 — 24).

This can translate into opposite behavioral actions for agonists versus inverse agonists. For example, benzodiazepine full agonists reduce anxiety by increasing chloride conductance, as shown in Figure 8 — 23. However, a benzodiazepine inverse agonist causes anxiety and does this by decreasing chloride conductance, as shown in

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FIGURE 8 — 24. Shown here is what happens when an inverse agonist for the benzodiazepine (BZ) receptor influences GABA binding at the GABA A receptor. In this example, the inverse agonist closes the chloride channel. Thus, an inverse BZ agonist allosterically modulates GABA in the opposite direction from a normal BZ full agonist, such as that shown in Figure 8 — 23. Consequently, a benzodiazepine inverse agonist increases anxiety (i.e., it is anxiogenic, rather than anxiolytic).

Figure 8 — 24. Benzodiazepine inverse agonists would be expected to be not only anxiogenic (creating anxiety) but also proconvulsant (increasing the likelihood of seizures), activating (opposite of sedating) and promnestic (memory promoting, the opposite of amnestic; see Fig. 8 — 25). The latter promnestic actions have even been considered as a possible therapeutic strategy for memory disorders such as Alzheimer's disease (see Chapter 12). However, these agents are potentially dangerous if they can simultaneously promote anxiety and seizures. Indeed, early clinical testing in humans has produced some severe anxiety reactions to inverse benzodiazepine agonists.

Consequently, the pharmacological properties of agonists and inverse agonists reveal that there can be obvious and dramatic clinical and behavioral distinctions across the agonist—antagonist—inverse agonist spectrum (Figs. 3 — 14 and 8-25), which can be explained by the principles of allosteric modulation of receptors.

An intermediate in the agonist spectrum (Fig. 8 — 25) is a partial agonist. Partial agonists have the theoretical possibility of separating the desired (anxiolytic) effects from the undesired effects (daytime sedation, ataxia, memory disturbance, dependency, and withdrawal) (see Fig. 8 — 25). That is, full agonists theoretically exert the full portfolio of benzodiazepine actions, whereas a partial agonist would separate those actions thought to require only partial agonism (anxiolytic effects) from those thought to require full agonism (sedation, and dependency; see Fig. 8—25). A wide variety of partial agonists for the benzodiazepine receptor have been synthesized and tested. The results to date are generally disappointing, since too much partial agonism fails to distinguish such agents from the full agonists already marketed, and too little partial agonism is associated with too little clinical efficacy in anxiety.

FIGURE 8-25. This figure reveals that there is a whole spectrum of agonist activities at the benzodiazepine receptor, ranging from full agonist actions through antagonist actions all the way to inverse agonist actions. These actions have already been introduced in Figure 3 —14. Full agonists (far left of the spectrum) not only have desired therapeutic actions (anxiolytic, sedative-hypnotic, muscle relaxant, and anticonvulsant), but also undesired side effects (amnesia and dependency). Theoretically, a happy medium halfway between a full agonist and an antagonist might be provided by a partial agonist which might be anxiolytic without causing dependency, for example. Antagonists (middle of the spectrum) have no clinical effects by themselves but may reverse the actions of any ligand at the benzodiazepine site, including the actions of both agonists and inverse agonists (see Figs. 8 — 26 and 8 — 27). Full inverse agonists (far right of the spectrum) cause clinical effects essentially opposite to those of full agonists and therefore cause potentially desirable memory-enhancing (promnestic) effects but also the undesirable side effects of increasing anxiety and promoting seizures. Perhaps a happy medium could also be attained here by finding a partial inverse agonist that could still enhance memory without causing anxiety or seizures.

However, this idea of a partial agonist is a conceptually attractive one, based on the promise of such agents from preclinical testing and from theoretical considerations. Pharmacologic manipulations of benzodiazepines have advanced to the point that an antagonist, flumazanil, has been developed that can block the actions of the benzodiazepines and reverse their actions, for example, after anesthesia or after an overdose (Fig. 8 — 26). Interestingly, as predicted from the pharmacology of the agonist spectrum (Fig. 8 — 25), the benzodiazepine antagonist flumazanil is also able to reverse the actions of inverse agonists (Fig. 8 — 27). This underscores the pharmacological principles, developed in Chapter 3, showing how drugs can influence a neu-rotransmitter system over a very broad range when a spectrum of agents can work on the one hand from full agonist through partial agonist to neutral antagonist and

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FIGURE 8 — 26. The benzodiazepine (BZ) receptor antagonist flumazanil is able to reverse a full agonist benzodiazepine acting at the benzodiazepine receptor of the GABA A receptor complex. This may be helpful in reversing the sedative effects of full agonist benzodiazepines when administered for aesthetic purposes or when taken in an overdose by a patient.

on the other hand from neutral antagonist to partial inverse agonist to full inverse agonist (Figs. 3-14 and 8-25).

Benzodiazepines and the treatment of anxiety. Benzodiazepines grew up in an era when the diagnosis and treatment of anxiety was considered to be quite separate from the diagnosis and treatment of depression (Fig. 8 — 7). These agents revolutionized the treatment of anxiety when they were introduced in the 1960s, because they were both less sedating and less dependence-forming than the earlier agents, such as barbiturates and meprobamate, that they replaced. Furthermore, benzodiazepines have other properties, including anticonvulsant, muscle relaxant, and sedativehypnotic actions.

Using benzodiazepines to treat anxiety requires knowledge of how to balance the risks of these agents rationally against their benefits and to compare this with other available therapeutic interventions. For short-term anxiety-related conditions, such as an adjustment disorder with onset after a stressful life event, benzodiazepines can provide rapid relief with little risk of dependence or withdrawal if use is limited to several weeks to a few months. However, for conditions likely to require treatment

FIGURE 8 — 27. The benzodiazepine (BZ) receptor antagonist flumazenil is also able to reverse inverse agonist benzodiazepines acting at the benzodiazepine receptors of the GABA A receptor complex.

for longer than 4 to 6 months, such as GAD, panic disorder, or anxiety associated with depression, the risks of dependence and withdrawal are greatly increased, and long-term use may not be justified in light of the other treatment options.

Short-term stabilization of symptoms in GAD and use as needed for sudden surges in symptoms are usually well justified uses for benzodiazepines. On the other hand, long-term treatment of GAD must encompass consideration of other interventions first before long-term use of benzodiazepines is generally indicated. Thus, life-style changes can be the cornerstone of long-term treatment for this condition, including stress reduction techniques, exercise, healthy diet, appropriate work situation, and adequate management of interpersonal affairs.

Other Drug Treatments for Anxiety

Barbiturates. The very earliest treatments for generalized anxiety were sedating barbiturates. These agents had little in the way of specific antianxiety action; they merely reduced anxiety in direct proportion to their ability to sedate. Because of serious dependency and withdrawal problems (see Chapter 13) and lack of a favorable

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safety profile, especially when mixed with other drugs or in overdose, the barbiturates fell out of favor as soon as the much more selective and less dangerous antianxiety agents of the benzodiazepine class were discovered.

Meprobamate. Meprobamate (Miltown) and tybamate (no longer available in the United States) are members of a chemical class called propanediols, but which are pharmacologically very similar to the barbiturates. No advantage of meprobamate over barbiturates has been demonstrated, and although popular during the 1950s as an antianxiety agent in the United States, it has fallen into disfavor and is infrequently prescribed owing to its liability to abuse and withdrawal symptoms, similar to that of the barbiturates and much more severe than that of the benzodiazepines.

Adjunctive treatments. Numerous adjunctive treatments are available for generalized anxiety disorder. These agents are considered not only to be second-line agents with inferior efficacy but also to work essentially by producing sedation rather than a specific anxiolytic effect. These include the sedating antihistamines, beta adrenergic blockers, and clonidine. The beta blockers may have some efficacy in social phobia (see Chapter 9) and the alpha 2 agonist clonidine may also be helpful in anxiety associated with hyperadrenergic states (Figure 8—13).

New Prospects

Partial agonists at benzodiazepine receptors are under investigation. All of the marketed benzodiazepines are essentially full agonists at the GABA—benzodiazepine receptor complex. It is theoretically possible to improve on the actions of full agonists if a partial agonist of optimal partiality could be identified (Fig. 8 — 20). Animal models predict that a partial agonist would still be anxiolytic but would cause less sedation and have less propensity for dependence and withdrawal. Attempts to identify a partial agonist for use in humans are still underway, using either benzodiazepinetype agents or other unique chemical structures that are not benzodiazepines.

Cholecystokinin (CCK) antagonists are in clinical testing in anxiety disorders, especially panic disorder (see Chapter 9). Corticotropin-releasing factor (CRF) is a neuropeptide, which may mediate some anxiety behaviors in experimental animals. This has led to the proposal that CRF antagonists may be anxiolytic. Numerous CRF antagonists being developed and tested for anxiety are in the very earliest stages of development. Neuroactive steroids are molecules based on a steroid chemical structure, which interact with the GABA —benzodiazepine receptor complex. As some of these agents are naturally occurring, it is hoped that analogues may be effective anxiolytics, with perhaps more "natural" actions than the marketed benzodiazepine anxiolytics. Such agents are in early development.

Clinical Description of Insomnia

Insomnia is a complaint, not a disease. The causes of insomnia are classified both in the DSM-IV for psychiatrists and in the International Classification of Sleep Disorders for sleep experts (Table 8 — 3). Insomnia can be a primary problem, or it can be secondary to medical or psychiatric disorders or to medications. Insomnia can also be due psychophysiological factors such as stress or to circadian rhythm distur-

Table 8 — 3. Classification of insomnia

Primary insomnia, with underlying pathophysiology of sleep Insomnia secondary to a psychiatric disorder Insomnia secondary to a medication or drug of abuse

Insomnia secondary to a general medical condition, especially with painor sleepdisordered breathing Circadian rhythm disturbance Periodic limb movement disorder Restless legs syndrome

bances such as jet lag. The reader is referred to textbooks on the etiology and classification of insomnia and other sleep disorders for details.

Here we will emphasize the use of sedative-hypnotic drugs for the treatment of insomnia. Before prescribing such drugs, however, it is very useful to understand the differential diagnosis of insomnia so that sedative-hypnotic drugs are appropriately used. Thus, if a sleep disorder is secondary to a psychiatric disorder, the ultimate treatment of the sleep disorder is to treat the psychiatric disorder. The same applies to medical disorders that are the primary cause of a sleep disorder. Examples include gastroesophageal reflux, respiratory disorders such as central and obstructive sleep apneas, and medical conditions causing pain. Treating the primary condition often relieves the insomnia, and sedative-hypnotics can be avoided.

If a sleep disorder is due to a medication or to drugs of abuse, changing the medication or stopping the drug of abuse may relieve the problem. If the sleep problem is due to narcolepsy, parasomnias, or a sleep-related movement disorder such as periodic limb movement disorder or restless legs syndrome, treatment aimed at these conditions may alleviate the sleep disturbance. Also, some sleep complaints are due to poor sleep hygiene and amenable to simple behavioral changes such as regular exercise not too late in the day, avoidance of caffeine late in the day, avoidance of naps, and maintaining the bedroom for sleep and sexual activity only.

When these issues are taken into consideration, there is still a high frequency of primary insomnia, as well as secondary insomnia the primary cause of which cannot be satisfactorily treated. Many patients also have both a psychiatric disorder and a primary insomnia. Still others have a psychiatric disorder requiring a sleep-disrupting antidepressant. Here we will discuss the use of sedativehypnotics for these patients.

Insomnia may also be classified according to its duration as a symptom. Thus, transient insomnia occurs in normal sleepers who have traveled to another time zone (jet lag), who are sleeping in an unfamiliar surrounding, or who are under acute situational stress. Often treatment is not required, and insomnia is reversed with time alone. Short-term insomnia can be experienced by one who is generally a normal sleeper but is under a stress that does not resolve within a few days, such as divorce, bankruptcy, or a lawsuit. Such individuals may not meet the criteria for a psychiatric disorder other than an adjustment disorder and yet may require short-term symptomatic relief of their insomnia in order to function optimally.

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Finally, long-term insomnia is not only persistent but disabling. Studies suggest that almost all of these patients have either an associated psychiatric disorder, an associated drug use, abuse, or withdrawal problem, or an associated medical disorder. As mentioned above, treatment of these associated disorders may be sufficient to treat the insomnia as well. However, if the underlying disorder is not treatable or if there is a requirement to relieve the symptom of insomnia before the underlying condition can be relieved, it may be necessary to treat the insomnia symptomatically with a sedative-hypnotic agent.

Product labeling and recommendations from sleep experts suggest that sedativehypnotic drugs be used for a maximum of several weeks. Short-term insomnia should be treated for no more than three weeks, while long-term insomnia should be treated intermittently whenever possible. Chronic treatment can be one night in three for up to 4 months. However, clinical practice suggests that symptoms of clinically significant insomnia can persist for months to years in many patients. Although there is the risk of developing dependence over long periods of time, there is no evidence that sedative-hypnotics lose their efficacy over long periods. Thus, for patients with continuing symptoms of insomnia, treatment may have to be extended beyond 4 months. In such cases, the continuing need for sedative-hypnotics should be reevaluated every few months.

Drug Treatments for Insomnia

Assuming that insomnia cannot be adequately treated by addressing directly an underlying problem responsible for causing the insomnia, then sedative-hypnotic drugs can be used to induce sleep pharmacologically. Such treatments can be controversial if they are overused or abused or if treating insomnia symptomatically removes the impetus to diagnose and relieve any underlying condition(s). One cannot deny, however, the widespread incidence of the complaint of insomnia in the general population, the perceived disruption of functioning and the disability that this symptom produces, and the strength of the demands of patients for drug treatments for this complaint.

Nonbenzodiazepine Short-Acting Hypnotics

The newer sedative-hypnotics that are not benzodiazepines are rapidly becoming the first-line treatment for insomnia. These agents not only have pharmacodynamic advantages over benzodiazepines in terms of their mechanism of action, but perhaps more importantly, pharmacokinetic advantages as well. Three nonbenzodiazepine sedative-hypnotic agents that are now available are zaleplon (a pyrazolopyrimidine), zopiclone (a cyclopyrrolone not available in the United States), and zolpidem (an imidazopyridine) (Figs. 8-28-8-30; Table 8-4).

Zaleplon (Fig. 8-28) and zolpidem (Fig. 8 — 29) act at selectively at omega 1 benzodiazepine receptors involved in sedation but not at omega 2 benzodiazepine receptors concentrated in brain areas regulating cognition, memory, and motor functioning. Thus, such agents should theoretically have less of the unwanted cognitive, memory, and motor side effects of the benzodiazepines that act on both omega 1 and omega 2 receptors. Also, these three agents all share the ideal profile of a sedative-hypnotic agent, namely, rapid onset and short duration. Even before these

FIGURE 8 — 28. The hypnotic agent zaleplon is a rapid-onset, short-acting nonbenzodiazepine which binds to omega sites near benzodiazepine sites on GABA-A receptors.

drugs were available, there was a shift in emphasis to the fast-onset, shorter-duration benzodiazepines in order to obtain a rapid onset of effect and to prevent carryover effects to the next day and accumulation of carryover effects after several days.

Another advantage of these agents over even fast-onset, short-duration benzodiazepines such as triazolam is that the binding of nonbenzodiazepines to the benzodiazepine receptor is different from benzodiazepine binding to this receptor, and may exhibit partial agonist properties (Fig. 8 — 28). Perhaps because of this, rebound insomnia (i.e., insomnia caused by withdrawal of the drug), dependence, withdrawal

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FIGURE 8 — 29. The hypnotic agent zolpidem is relatively short acting nonbenzodiazepine which binds to omega sites near benzodiazepine sites on GABA-A receptors.

FIGURE 8 — 30. The hypnotic agent zopiclone is an intermediate acting nonbenzodiazepine which binds to omega sites near benzodiazepine sites on GABA-A receptors.

symptoms and loss of efficacy over time are uncommon with the nonbenzodiazepine sedative-hypnotics.

Zaleplon. The recently approved agent zaleplon (Fig. 8 — 28) appears to be the ultimate in rapid onset (1-hour peak concentrations) and short duration (1-hour half-life with no active metabolite). The short half-life makes zaleplon ideal for jet lag and for those who require complete drug washout prior to arising. One theoretical concern about a drug with such a short half-life is that its use may be better for patients with sleep onset difficulties than for those with sleep problems in the middle of the night, when zaleplon may have already worn off. In practice, however, the use of a very short acting drug such as zaleplon will treat sleep onset problems and actually facilitate sleep continuity in the middle of the night by allowing natural sleep to unfold. Furthermore, in the case of a patient with middle-of-the-night sleep disruption, zaleplon is short enough in action that taking a first or even a repeat dose on