Zolpidem and Zaleplon

Zolpidem and zaleplon are hypnotics that act at the omega-1 receptor of the central GABA receptor complex. This selectivity is hypothesized to be associated with a lower risk of dependence. Unlike benzodiazepines, zolpidem and zaleplon do not appear to have significant anxiolytic, muscle relaxant, or anticonvulsant properties. However, amnestic effects may occur. 

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Both zolpidem and zaleplon are available in 5- and 10-mg tablets for oral administration. The maximum recommended dose for adults is 10 mg/day and 20 mg/day, respectively, administered at night. The initial dose for elderly persons should not exceed 5 mg. Caution is advised in patients with hepatic dysfunction. In general, hypnotics should be limited to short-term use, with reevaluation for more extended therapy (see below under Treatment of Specific Conditions ). 

In general, side effects of zolpidem and zaleplon are similar to those of short-acting benzodiazepines. These agents should not be considered free of abuse potential. 

Both zolpidem and zaleplon appear to be nonfatal in overdose. However, overdoses in combination with other central nervous system (CNS) depressant agents pose a greater risk. Recommended treatment consists of general symptomatic and supportive measures, including gastric lavage. Use of flumazenil may be helpful. 

Research on drug interactions with zolpidem and zaleplon is limited, but any drug with CNS depressant effects could potentially enhance the CNS depressant effects of zolpidem and zaleplon through pharmacodynamic interactions. In addition, zolpidem is primarily metabolized by CYP 3A3/4, and zaleplon is partially metabolized by CYP 3A3/4. Thus, inhibitors of these enzymes may increase blood levels and the toxicity of zolpidem. 

Ramelteon is a hypnotic with melatonin receptor agonist activity targeting melatonin MTj and MT2 receptors. It has not been proven to induce dependence. As with zolpidem and zaleplon, no known anxiolytic properties have been elicited. No appreciable activity on serotonin, dopamine, GABA, or acetylcholine is present with the parent compound, but in vitro studies report that its primary metabolite M-II has weak 5-HT2g receptor agonist activity. 

More recently, non-BZD anxiolytics, such as buspirone, and nonbarbiturate, non-BZD hypnotics, such as zolpidem and zaleplon, have been developed. The more recent anxiolytics and hypnotics offer equal efficacy, fewer serious adverse effects, and less risk of a fatal consequence due to accidental or intentional overdose. Unfortunately, these compounds have not entirely eliminated the hazards of tolerance, dependency, and withdrawal syndromes, although they do have a lower abuse potential than their predecessors. 

Hesse LM et al Clinically important drug interactions with zopiclone, zolpidem and zaleplon. CNS Drugs 2003 17 513. [PMID 12751920]... 

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 manner and severity of withdrawal symptoms varies according to the type of drug and the extent of physical dependence.50 Withdrawal after short-term benzodiazepine use may be associated with problems such as sleep disturbances (i.e., so-called rebound insomnia).34 62 As discussed earlier, withdrawal effects seem to be milder with the newer nonbenzodiazepine agents (zolpidem and zaleplon).34,62 Newer agents, however, are not devoid of these problems and care should be taken with prolonged use, especially in people with psychiatric disorders or a history of substance abuse.26... 

Terzano MG, Rossi M, Palomba V, Smerieri A, Parri-no L. New drugs for insomnia comparative tolerability of zopiclone, zolpidem and zaleplon. Drug Saf. 2003 26 261-282. 

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. 

The benzodiazepine hypnotics midazolam, triazolam, and brotizolam, together with zopiclone, eszopiclone, zolpidem, and zaleplon are short-acting derivatives. The benzodiazepines flunitrazepam and temazepam are intermediate-acting hypnotics,... 

A range of medications is available to treat insomnia, ranging from herbal preparations such as valerian to the recently introduced z compounds, zopiclone, zolpidem and zaleplon. Many drugs used for other primary purposes have sedative and sleep-inducing properties as side effects these include many tricyclic antidepressants and antihistamines. 

Anonymous. Zopiclone, zolpidem and zaleplon. Get your zzz s without affecting performance the next day. Drugs Ther Perspect 2004 20(2) 16-8. 

Zopiclone, zolpidem, and zaleplon have made major inroads in capturing significant market shares of the sedative-hypnotic market segment. 

Zolpidem and zaleplon are nonbenzodiazepines that bind to the BZ, receptors and therefore are more specific hypnotics. Buspirone is an anxiolytic that does not work through the GABA system. It is nonsedating and does not cause dependence but takes a week or two to show antianxiety effects. 

Most benzodiazepines decrease sleep latency, especially when first used, and diminish the number of awakenings and the time spent in stage 0 (a stage of wakefulness). Time in stage I (descending drowsiness) usually is decreased and there is a prominent decrease in the time spent in slow-wave sleep (stages 3 and 4). Most benzodiazepines increase the time from onset of spindle sleep to the first burst of rapid-eye-movement (REM) sleep. The time spent in REM sleep usually is shortened but the number of cycles of REM sleep cycles usually is increased mostly late in the sleep time. Zolpidem and zaleplon suppress REM sleep to a lesser extent and thus may be superior to benzodiazepines for use as hypnotics. 

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