Sedative Hypnotics zolpidem

A number of compounds that have. structural characteristics broadly related to the benzodiazepines, including neuro-active flavanoids, imidazopyridines. and pyrazolopyriniid-iiKs. can act as positive mc ulators at the benzodiazepine recognition site on one or more of the GABAa receptor mbtypes. Compounds may produce all the characteristic actions of benzodiazepines or be selective, as are. for example, anxiolytic flavanoids or the. sedative-hypnotics zolpidem and zalephun. 

A class of sedative/hypnotic type drug that exert their effects through the benzodiazepine binding site on GABAa receptors. The class consists both of molecules that contain the benzodiazepine moiety, for example diazepam, lorazepam and flunitrazepam, and the newer, non-benzodiazepine compounds such as zolpidem, zopiclone, indiplon and zaleplon. BzRAs are primarily used for the treatment of anxiety, insomnia and to elicit varying levels of sedation. The wide selection of compounds currently available affords the prescribing clinician extensive options in terms of relative efficacies and durations of action. 

One principal difference between the medications is half-life, that is, the time required to metabolize 50% of the compound present in the body. Zolpidem has a half-life of 1.4-4.5 honrs, zaleplon has a half-life of 0.9-1.1 hours, and eszopiclone has a half-life of abont 6 honrs. The key is the markedly shorter half-lives that are displayed by many other sedative-hypnotics, as shown in Eigure 9.1. Only eszopiclone has been shown effective for the long-term (np to 6 months) treatment of chronic insomnia. 

Nevertheless, sedative-hypnotic agents often play a useful role in treatment. In particular, by providing a successful night s sleep, these medications can break the cycle of anxious anticipation and dread that afflicts the insomnia sufferer during the night. We generally prefer using zolpidem or zaleplon as a first-line treatment for early-to-middle insomnia. Late insomnia often responds well to trazodone or eszopiclone, and trazodone often is a first choice in the presence of substance abuse for all insomnias. 

CNS-depressant effects Zolpidem, like other sedative/hypnotic drugs, has CNS-depressant effects. Because of the rapid onset of action, only ingest immediately prior to going to bed. Zolpidem had additive effects when combined with alcohol therefore, do not take with alcohol. 

Respiratory depression Although preliminary studies did not reveal respiratory depressant effects at hypnotic doses in healthy individuals, observe caution if zolpidem is prescribed to patients with compromised respiratory function, since sedative/hypnotics have the capacity to depress respiratory drive. 

Depression As with other sedative/hypnotic drugs, administer zolpidem with caution... 

Drug abuse and dependence Sedative/hypnotics have produced withdrawal signs and symptoms following abrupt discontinuation. These reported symptoms range from mild dysphoria and insomnia to a withdrawal syndrome that may include abdominal and muscle cramps, vomiting, sweating, tremors, and convulsions. Zolpidem does not reveal any clear evidence for withdrawal syndrome. 

Anxiolytics, sedatives, hypnotics (benzodiazepines, barbiturates, chloral derivatives, chlormethiazole, zopiclone, zolpidem)... 

Zolpidem is an imidazopyridine, with a chemical structure of N,N,6-trimethyl-2-(4-methylphenyl)-imidazo [ 1,2-alpha] -pyridine-3-acetamine hemitartrate (Salva and Costa, 1995). This nonbenzodiazepine sedative hypnotic was first released in Europe, and then introduced in the United States in 1993 (Hobbs et ah, 1996). Zolpidem has a strong sedative effect that seems to preclude its use as an anxiolytic. It has only weak anticonvulsant effects (Salva and Costa, 1995 Hobbs et ah, 1996). 

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, a melatonin receptor agonist, is a new hypnotic drug (see Ramelteon). Buspirone is a slow-onset anxiolytic agent whose actions are quite different from those of conventional sedative-hypnotics (see Buspirone). 

The rates of oral absorption of sedative-hypnotics differ depending on a number of factors, including lipophilicity. For example, the absorption of triazolam is extremely rapid, and that of diazepam and the active metabolite of clorazepate is more rapid than other commonly used benzodiazepines. Clorazepate, a prodrug, is converted to its active form, desmethyldiazepam (nordiazepam), by acid hydrolysis in the stomach. Most of the barbiturates and other older sedative-hypnotics, as well as the newer hypnotics (eszopiclone, zaleplon, zolpidem), are absorbed rapidly into the blood following oral administration. 

Some sedative-hypnotics, 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). Muscle relaxation is not a characteristic action of zolpidem, zaleplon, and eszopiclone. 

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 central nervous system (pharmacodynamic tolerance) are of greater importance for most sedative-hypnotics. In the case of benzodiazepines, the development of tolerance in animals has been associated with down-regulation of brain benzodiazepine receptors. Tolerance has been reported to occur with the extended use of zolpidem. Minimal tolerance was observed with the use of zaleplon over a 5-week period and eszopiclone over a 6-month period. 

Blocks actions of benzodiazepines and zolpidem but not other sedative-hypnotic drugs... 

Insomnia is a common comorbid condition with depression, and frequently is made worse by antidepressants, particularly the SSRIs. When insomnia persists despite adequate evaluation and attempts to reduce it by other approaches, it is often necessary to use a concomitant sedative-hypnotic, especially a short-acting nonbenzodiazepine with rapid onset such as zaleplon or zolpidem. At times a benzodiazepine sedative hypnotic such as triazolam or temazepam may be necessary. If anxiety persists during the day and cannot be otherwise managed, it may be necessary to add an anxiolytic benzodiazepine such as alprazolam or clonazepam. Use of sedative-hypnotics and anxiolytics should be short-term whenever possible. 

The fundamental neurobiological importance of the GABA A receptor is underscored by observations that even more receptor sites exist at or near this complex (Fig. 8—20). This includes receptor sites for nonbenzodiazepine sedative-hypnotics such as zolpidem and zaleplon, for the convulsant drug picrotoxin, for the anticonvulsant barbiturates, and perhaps even for alcohol. This receptor complex is hypothetically responsible in part for mediating such wide-ranging CNS activities as seizures, anticonvulsant drug effects, and the behavioral effects of alcohol, as well as the known anxiolytic, sedative-hypnotic, and muscle relaxant effects of the benzodiazepines. 

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). 

Zolpidem (Fig. 8—29). This was the first omega 1 selective nonbenzodiazepine sedative-hypnotic and rapidly replaced benzodiazepines as the preferred agent for many patients and prescribers. It has a somewhat later peak drug concentration (2 to 3 hours) and longer half-life (1.5 to 3 hours) than zaleplon. 

The nonbenzodiazepine sedative-hypnotics zaleplon, zolpidem, and zopiclone are replacing benzodiazepine sedative-hypnotics as first-line treatments for insomnia. Some antidepressants, such as sedating tricyclic antidepressants and trazodone, are also used as sedative-hypnotic agents for the treatment of insomnia. 

Drug combinations Probably the most common combination treatment is concomitant use of an SSRI and a benzodiazepine, especially on initiation of treatment (Fig. 9—6). The benzodiazepines (especially alprazolam and clonazepam) not only appear to act synergistically to increase the onset of therapeutic action and perhaps even boost the efficacy of SSRIs, but they also appear to block the anxiogenic actions of the SSRIs and lead to better tolerability as well as the ability to attain therapeutic dosing levels for the SSRIs. Sometimes sedative-hypnotics such as zale-plon or zolpidem are required in addition to an SSRI, especially on initiation of SSRI treatment. 

Nonbenzodiazepine ligands at benzodiazepine sites This is a variation on the theme of partial benzodiazepine agonists, as these agents act at the same or similar site as benzodiazepines but are not structurally related to them. Thus, the pharmacology of nonbenzodiazepines is that of a partial agonist, but their chemistry is different from that of a benzodiazepine. This is similar to the approach that novel sedative-hypnotics such as zaleplon and zolpidem have taken, and perhaps a less sedating nonbenzodiazepine partial agonist could hold promise for the treatment of panic disorder. 

Nonbenzodiazepine sedative-hypnotics. The non-BZD hypnotic zolpidem (Ambien) is a newer sleeping agent that is thought to work on more specific subdivisions of the GABA receptor complex than, for example, some of the older benzodiazepine agents. It is indicated for short-term insomnia and is generally limited to seven to 10 days of use. 

Several drugs with novel chemical structures have been introduced recently. Buspirone is an anxiolytic agent that has actions different from those of conventional sedative-hypnotic drugs. Zolpidem and zaleplon, while structurally unrelated to benzodiazepines, share a similar mechanism of action. 

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