The pharmacology and mechanisms of action of new generation, non-benzodiazepine hypnotic agents

The new generation hypnotic drugs, zolpidem, zopiclone and zaleplon, are at least as efficacious in the clinic as benzodiazepines and may offer advantages in terms of safety. These drugs act through the BZ binding sites associated with GABAA receptors, but show some differences from benzodiazepines in pharmacological effects and mechanisms of action. Of particular interest is the finding that zolpidem shows a wide separation between doses producing sedative effects and those giving rise to other behavioural actions, and induces less tolerance and dependence than benzodiazepines. Zolpidem also demonstrates selectivity for GABAA receptors containing alpha1 subunits. Recent studies using genetically modified mice have confirmed that receptors containing alpha1 subunits play a particularly important role in mediating sedative activity, thus providing an explanation for the pharmacological profile of zolpidem.     

Specificity within the GABAA receptor supramolecular complex: a consideration of the new omega 1-receptor selective imidazopyridine hypnotic zolpidem

The relative contribution of different recognition sites within the GABAA receptor supramolecular complex (GRSC) to the pharmacological effects of anxiolytic and hypnotic drugs is unknown. The development of the omega 1 (ex BZ1) specific hypnotic zolpidem allows a more direct approach to the problem. In contrast to many benzodiazepine hypnotic/anxiolytics (e.g., flunitrazepam, diazepam), zolpidem shows a specificity for GABAergic function, e.g., selectively reversing isoniazide-induced seizures. Furthermore, zolpidem produces a highly specific hypnotic action as compared to myorelaxant or amnesic effects (ratio of ED50's greater than 4.0 for zolpidem; less than 1 for flunitrazepam). Zolpidem exerts its action within the GRSC as it enhances 35S-TBPS binding, as do mixed omega 1/omega 2 compounds or GABA agonists. Both the in vivo and in vitro actions of zolpidem are reversed by flumazenil and the enhanced 35S-TBPS binding is also bicuculline-sensitive. Thus, omega 1 recognition site stimulation (e.g., by zolpidem) is sufficient to produce potent pharmacological effects and modulation of the GABAA receptor-gated chloride ionophore.     

Comparison of the effects of zaleplon,zolpidem, and triazolam at various GABA(A) receptor subtypes

The pyrazolopyrimidine zaleplon is a hypnotic agent that acts at the benzodiazepine recognition site of GABA(A) receptors. Zaleplon, like the hypnotic agent zolpidem but unlike classical benzodiazepines, exhibits preferential affinity for type I benzodiazepine (BZ(1)/omega(1)) receptors in binding assays. The modulatory action of zaleplon at GABA(A) receptors has now been compared with those of zolpidem and the triazolobenzodiazepine triazolam. Zaleplon potentiated GABA-evoked Cl(-) currents in Xenopus oocytes expressing human GABA(A) receptor subunits with a potency that was higher at alpha1beta2gamma2 receptors than at alpha2- or alpha3-containing receptors. Zolpidem, but not triazolam, also exhibited selectivity for alpha1-containing receptors. However, the potency of zaleplon at these various receptors was one-third to one-half that of zolpidem. Zaleplon and zolpidem also differed in their actions at receptors containing the alpha5 or gamma3 subunit. Zaleplon, zolpidem, and triazolam exhibited similar patterns of efficacy among the different receptor subtypes. The affinities of zaleplon for [(3)H]flunitrazepam or t-[(35)S]butylbicyclophosphorothionate ([(35)S]TBPS) binding sites in rat brain membranes were lower than those of zolpidem or triazolam. Furthermore, zaleplon, unlike zolpidem, exhibited virtually no affinity for the peripheral type of benzodiazepine receptor.     

Zolpidem for insomnia

INTRODUCTION: The imidazopyridine derivative zolpidem , which acts as a benzodiazepine (BZ) receptor agonist, is the most widely prescribed hypnotic drug in the US. AREAS COVERED: This review addresses the neuroreceptor properties of zolpidem; clinical pharmacokinetics, pharmacodynamics and drug interactions; efficacy as a hypnotic; adverse effects; tolerance, dependence and withdrawal; relation to motor vehicle accidents and complex sleep behaviors; and new dosage forms. EXPERT OPINION: Approved doses of zolpidem (10 mg for adults, 5 mg for the elderly) are consistently effective in reducing sleep latency and consequently increasing sleep duration in patients with insomnia. However, favorable effects on sleep maintenance are observed less consistently. Residual daytime effects are unlikely with recommended doses, and provided that at least 8 h elapse prior to arising. Hypnotic efficacy is maintained with repeated nightly use, and the risk of rebound insomnia is low. Dependence and abuse of zolpidem are no more likely to occur than with typical benzodiazepines. Newly available novel dosage forms of zolpidem have increased therapeutic options for patients with insomnia variants such as sleep maintenance insomnia and middle-of-the-night awakening.     

Flunitrazepam a benzodiazepine most used among drug abusers

Flunitrazepam (FZ) is a sedative/hypnotic nitro-benzodiazepine. This drug has been accepted by both patients and physicians and in the last 20 years flunitrazepam has been included and studied in many clinical trials so, in many countries, flunitrazepam is one of the most prescribed hypnotic. Since 1980 it has been found that FZ began to be a popular drug among drug abusers all over the word. However, little is known about the difference between Fz and other Benzodiazepines in capacity to produce physiologic dependence or in ability to produce drug taking or drug seeking behaviour. Flunitrazepam has little risk of abuse by the vast majority of patients; however when the drug is taken i. v. or intranasally, its effect is much faster and risk of abuse is much greater. In this report we examine the reasons why some populations of drug abusers prefer flunitrazepam over the other benzodiazepines.     

A novel clinical pattern of visual hallucination after zolpidem use

BACKGROUND: Zolpidem is a new hypnotic that is supposed to have fewer side effects than traditional benzodiazepines. Some psychotic reactions, such as visual or hypnagogic hallucinations, have been reported to be associated with zolpidem use. CASE REPORT: A young female experienced three episodes of hallucination associated with the use of zolpidem. The visual or hypnagogic hallucination happened after she had stopped zolpidem and then restarted it 2 days later. CONCLUSION: We postulate that hypnagogic or visual hallucinations associated with zolpidem use may be related to rapid withdrawal and restarting of zolpidem. The possible mechanism may be associated with the changes in the GABAA receptor. Avoiding "as needed" use of zolpidem and using the lowest effective dose may prevent these adverse effects.     

Zolpidem: an update of its pharmacology, therapeutic efficacy and tolerability in the treatment of insomnia

Zolpidem is an imidazopyridine agent that is indicated for the short term (< or = 4 weeks) treatment of insomnia (recommended dosage 10 mg/day in adults and 5 or 10 mg/day in the elderly or patients with hepatic impairment). Data have shown that the hypnotic efficacy of zolpidem is generally comparable to that of the benzodiazepines flunitrazepam, flurazepam, nitrazepam, temazepam and triazolam as well as nonbenzodiazepine hypnotic agents such as zopiclone and trazodone in the treatment of elderly and adult patients with insomnia. The comparative efficacy of a recently available nonbenzodiazepine hypnotic zaleplon and zolpidem has yet to be established. There was no evidence of tolerance developing to the hypnotic effects of zolpidem in a number of studies of up to 6 months' duration. However, tolerance has been described in a few patients taking the drug at high dosages for periods of up to several years. Zolpidem is well tolerated in patients with insomnia and the most common adverse events are generally nausea, dizziness and drowsiness. Although zolpidem produced some psychomotor and memory impairment over the first few hours after administration, it had few next-day effects (including effects on daytime well-being and morning coordination). In this respect, it was comparable or superior to flunitrazepam and flurazepam and comparable to other benzodiazepines in patients with insomnia. Zolpidem appears to have a low potential for abuse. Conclusions: Zolpidem is effective and well tolerated in patients with insomnia, including the elderly. Studies have shown that zolpidem generally has similar efficacy to other hypnotics including benzodiazepines and zopiclone. Zolpidem appears to have minimal next-day effects on cognition and psychomotor performance when administered at bedtime. In addition, there is little evidence of tolerance to the hypnotic effects of zolpidem, or rebound insomnia or withdrawal symptoms after discontinuation of the drug when it is given as recommended (10 mg/day for < 1 month) or over longer periods.     

Postnatal development of hippocampal dentate granule cell gamma-aminobutyric acidA receptor pharmacological properties

Postnatal development of hippocampal dentate granule cell gamma-aminobutyric acidA (GABAA) receptor pharmacological properties was studied. Granule cells were acutely isolated from hippocampi of 7- to 14- and 45- to 52-day-old rats, and whole cell patch-clamp recordings were obtained. The sensitivity of GABAA receptors to GABA and modulation of GABAA receptor currents by benzodiazepines (BZ), zinc, furosemide, and loreclezole was studied. Multiple changes in the pharmacological properties of dentate granule-cell GABAA receptors occurred during the first 52 days of postnatal development: GABA-evoked maximal current increased with postnatal age; GABAA receptors changed from BZ type 3 in young rats to BZ type 1 in adult rats; furosemide and zinc inhibited GABAA receptor currents in young rats but not in adult rats; the fraction of cells that expressed loreclezole-sensitive GABAA receptors increased with postnatal age. These findings suggest that dentate granule cells in young and adult animals express pharmacologically distinct GABAA receptors and that the postnatal development of these receptors is prolonged, lasting at least 45 days. Comparison with the previously reported pharmacological properties of GABAA receptors on dentate granule cells acutely isolated from hippocampi of 28- to 35-day-old rats suggests that receptors expressed at that age have properties intermediate between young and adult rats.     

Pharmacologic significance of the structural heterogeneity of the GABAA receptor-chloride ion channel complex.

Gamma-Aminobutyric acidA (GABAA) receptors are heterooligomeric proteins with an apparent high degree of variability in the specific assembly of their component subunits. Although the precise nucleotide and deduced amino acid sequences of many of the various GABAA receptor subunits are known, the exact quaternary structures of the native receptors are unknown. Recombinant expression of receptors with different combinations of subunits produces a variety of structurally different receptors with varying Cl- channel function and sensitivities to modulation by drugs such as benzodiazepines. Differences in the regional distribution of GABAA receptor subtypes in brain, coupled with the observed differences in the relative affinities of various anxiolytic and hypnotic drugs among these receptor subtypes, suggests a new strategy for drug development that is the targeting of drugs to specific subpopulations of GABAA receptors. This is a review of the recent striking progress in understanding the heterogeneity of the GABAA receptors and its possible significance.     

Pharmacological profile and clinical effect of zolpidem (Myslee tablets), a hypnotic agent

Zolpidem is a non-benzodiazepine hypnotic agent with a chemical structure of imidazopyridine. In vitro and in vivo binding studies, zolpidem exhibits selectivity to omega 1 receptors (GABAA-receptor subtypes containing alpha 1 subunits). Unlike benzodiazepines, zolpidem produces sedative effects in preference to anxiolytic, anticonvulsant and myorelaxant effects in behavioral experiments using mice. Double-blind comparative studies with reference drugs such as triazolam and zopiclone show that zolpidem is an effective and highly safe drug for the treatment of insomnia. In addition, zolpidem does not produce next-day residual effects, rebound insomnia and tolerance. This clinical profile of zolpidem may be related to its selectivity and high intrinsic activity for omega 1 receptors.     

Dependence on zolpidem in high dose

There are some indications that zolpidem is open to potential abuse. We present four cases of former drug or alcohol abusers with personality disorders, who all developed dependence on zolpidem in high dose.     

Methods for the analysis of nonbenzodiazepine hypnotic drugs in biological matrices

Zopiclone, zolpidem and zaleplon (Z-drugs) are nonbenzodiazepine hypnotic drugs that are used for the treatment of insomnia. These drugs were developed with the intent to overcome some disadvantages of benzodiazepines, such as dependence and next day sedation. In general, the nonbenzodiazepine hypnotic drugs are administered in oral doses daily and are widely biotransformed in the body. A large number of analytical methods based on chromatographic and electrophoretic techniques for the quantification of Z-drugs and their metabolites in biological matrices have been reported. In this review, the bioanalytical methods for Z-drugs were reviewed with the focus placed on sample preparation procedures and the separation techniques used. Furthermore, as these drugs are also reported as drugs of abuse or in drug-facilitated crime, screening methods that simultaneously cover these drugs and also other drugs of abuse were included in this review.     

Mechanisms of anabolic androgenic steroid modulation of alpha(1)beta(3)gamma(2L) GABA(A) receptors

Modulation of GABA(A) receptors induced by both anabolic androgenic steroids (AAS) and the benzodiazepine (BZ) site agonist, zolpidem, show equivalent dependence upon gamma subunit composition suggesting that both compounds may be acting at a shared allosteric site. Here we have characterized modulation induced by the AAS, 17alpha-methyltestosterone (17alpha-MeT), for responses elicited from alpha(1)beta(3)gamma(2L) GABA(A) receptors and compared it to modulation induced by the BZ site agonists, zolpidem and diazepam. For responses elicited by brief pulses of 20 microM GABA, both the AAS and the BZ site compounds significantly increased the peak current amplitudes and total charge transfer, although 17alpha-MeT was an appreciably weaker agonist than either diazepam or zolpidem at alpha(1)beta(3)gamma(2L) receptors. Neither class of modulator enhanced peak current amplitudes for responses elicited by mM concentrations of GABA. BZ site compounds altered time constants of deactivation, desensitization, and recovery from desensitization, however 17alpha-MeT had no overall effect on these parameters. Experiments in which 17alpha-MeT and BZ site ligands were applied concomitantly indicated that potentiation elicited by 17alpha-MeT and zolpidem were additive and that potentiation by 17alpha-MeT could be elicited in the presence of concentrations of flumazenil that blocked BZ potentiation. Finally, kinetic modeling suggests that while effects of 17alpha-MeT can be simulated by altering receptor affinity, the data for these alpha(1)beta(3)gamma(2L) receptors were best fitted by simulations in which 17alpha-MeT increases transitions into the singly liganded open state. Taken together, our results suggest that 17alpha-MeT does not act at the high-affinity BZ site, but may elicit some of its effects at the low affinity BZ site or at a novel site.     

Differential development of tolerance to the depressant effects of benzodiazepine and non-benzodiazepine agonists at the omega (BZ) modulatory sites of GABAA receptors.

In a previous study, it was found that both the benzodiazepine hypnotic, midazolam, and the imidazopyridine hypnotic, zolpidem, which has selective affinity for a sub-population of omega (benzodiazepine, BZ) modulatory sites of GABA(A) receptors, produced similar decreases in rates of food-reinforced lever pressing in rats. However, during 10 days of repeated administration, marked tolerance developed to the depressant effect of midazolam but little tolerance developed with zolpidem. It was found in the present study that, with a within-subject design similar to that used previously, tolerance developed to the response rate-decreasing activity of the benzodiazepine, triazolam and the cyclopyrrolone, zopiclone but not to that of the triazolopyridazine, CL 218,872. In another experiment, using a between-groups design, tolerance developed to the effect of midazolam, even if the injections were not associated with daily test sessions, providing no evidence for a drug-environment interaction. The lack of tolerance to zolpidem was confirmed in two experiments. There was little indication of tolerance to the depressant effect of zolpidem, even after 19 days administration of daily doses, up to 30 mg/kg, a dose 10 times greater than that which completely suppressed responding. These results showed that the extent to which tolerance develops to the effects of drugs with affinity for omega (BZ) modulatory sites can show wide variations which may be related to differences in mechanisms of action.     

Zolpidem. A review of its pharmacodynamic and pharmacokinetic properties and therapeutic potential

Zolpidem is an imidazopyridine, a chemically novel nonbenzodiazepine hypnotic agent which acts at the benzodiazepine omega 1-receptor subtype in the brain. With a rapid onset of action and short elimination half-life, it reduces the latency to and prolongs the duration of sleep in patients with insomnia, yet has no major effects on sleep stages when given in dosages of 5 to 20 mg nightly. Rebound effects on withdrawal of the drug have not been observed. Unlike benzodiazepines, zolpidem has no myorelaxant or anticonvulsant effects and its effects on anxiety appear to be minor. While zolpidem aids sedation, and may reduce memory or psychomotor function within the first 2 hours after administration of single oral doses, its use as a surgical premedicant remains to be established. Adverse effects are predominantly CNS and gastrointestinal in nature. Altered pharmacokinetics may lead to an increase in dose-proportionate adverse effects in the elderly and in patients with renal dysfunction. Limited evidence to date suggests that the dependence liability of zolpidem is minimal. Thus, zolpidem is an interesting alternative to benzodiazepines in the treatment of insomnia, with properties that potentially offer worthwhile advantages in this therapeutic area if they are confirmed with wider clinical experience.     

Mechanism of action of the hypnotic zolpidem in vivo

Zolpidem is a widely used hypnotic agent acting at the GABA(A) receptor benzodiazepine site. On recombinant receptors, zolpidem displays a high affinity to alpha 1-GABA(A) receptors, an intermediate affinity to alpha(2)- and alpha(3)-GABA(A) receptors and fails to bind to alpha(5)-GABA(A) receptors. However, it is not known which receptor subtype is essential for mediating the sedative-hypnotic action in vivo. Studying alpha1(H101R) mice, which possess zolpidem-insensitive alpha(1)-GABA(A) receptors, we show that the sedative action of zolpidem is exclusively mediated by alpha(1)-GABA(A) receptors. Similarly, the activity of zolpidem against pentylenetetrazole-induced tonic convulsions is also completely mediated by alpha(1)-GABA(A) receptors. These results establish that the sedative-hypnotic and anticonvulsant activities of zolpidem are due to its action on alpha(1)-GABA(A) receptors and not on alpha(2)- or alpha(3)-GABA(A) receptors.     

The discriminative stimulus properties of zolpidem,a novel imidazopyridine hypnotic

Zolpidem is a non-benzodiazepine hypnotic drug which displaces benzodiazepines from their binding sites in different brain structures. Previous work has demonstrated several differences between zolpidem and benzodiazepines, including differences between the stimulus properties of zolpidem and chlordiazepoxide. In the present study the discriminative stimulus properties of zolpidem were analysed by training rats to discriminate between this drug and saline. It was found that stimulus control developed readily with 2 mg/kg but not with 1 mg/kg zolpidem. The effect was dose-related, had a short duration of action and was antagonised by Ro 15-1788. Furthermore, stimulus control produced by zolpidem was associated with marked reductions in rates of responding. Injections of chlordiazepoxide, triazolam, lorazepam, zopiclone, CL 218,872 and pentobarbital produced dose-related responding on the zolpidem-associated lever but haloperidol did not. However, in general, the doses of those drugs which produced drug-lever responding also reduced response rates. It is possible that the above mentioned differences between the discriminative stimulus produced by zolpidem in rats and those produced by other sedatives may be due to a selective action of zolpidem on a sub-type of benzodiazepine binding site. Offprint requests to: D.J. Sanger     

Dependence on zolpidem: two case reports of detoxification with flumazenil infusion

Zolpidem is a hypnotic drug that is chemically distinct from benzodiazepines (BDZ). It has been suggested that it acts selectively on gamma-aminobutyric acid receptors. However, recent evidence has shown that the behavioural effects of zolpidem are generally similar to those of BDZs. Flumazenil is usually considered to be a BDZ antagonist. Nonetheless, in chronic BDZ users, it acts as a partial, bland agonist. We describe two cases of zolpidem dependence that were detoxified by the use of flumazenil infusion. BDZ dependence is usually treated with tapering of the medication. As an alternative, abrupt discontinuation of the medication and rapid detoxification using flumazenil has been used. Flumazenil may represent an alternative to detoxification treatment by employing a tapering approach, or by replacement therapy with BDZs with a long half-life, particularly where patients are hard to treat or have low compliance to treatment.     

Pharmacology of an omega receptor agonist]

It has been suggested that different BZP (omega) receptor subtypes may mediate distinct behavioral effects of BZP receptor ligands. Several studies demonstrated that omega1 selective compounds are characterized by an increase in slow wave deep sleep with rapid onset of hypnotic action, and by reduced muscle relaxation, amnesic liability or tolerance. On the other hand, it is known that many different subtypes of GABAA receptors exist, based on the fact that many different subtypes can go into assembling GABAA receptors. GABAA receptors with alpha1 subunits may mediate sedative action and perhaps amnesia. Those with alpha2 subunits probably mediate anxiolytic actions. GABAA receptors with alpha3 subunits may regulate various neurotransmitters, and those with alpha5 subunits may also contribute to amnesia. Such discoveries could open up new avenues for drug development.     

The effects of repeated zolpidem treatment on tolerance,withdrawal-like symptoms,and GABAA receptor mRNAs profile expression in mice: Comparison with diazepam

Rationale

Zolpidem is a short-acting, non-benzodiazepine hypnotic that acts as a full agonist at α1-containing GABA_A receptors. Overall, zolpidem purportedly has fewer instances of abuse and dependence than traditionally used benzodiazepines. However, several studies have shown that zolpidem may be more similar to benzodiazepines in terms of behavioral tolerance and withdrawal symptoms.

Objectives

In the current study, we examined whether subchronic zolpidem or diazepam administration produced deficits in zolpidem’s locomotor-impairing effects, anxiety-like behaviors, and changes in GABA_AR subunit messenger RNA (mRNA).

Methods

Mice were given subchronic injections of either zolpidem (10 mg/kg), diazepam (20 mg/kg), or vehicle twice daily for 7 days. On day 8, mice were given a challenge dose of zolpidem (2 mg/kg) or vehicle before open field testing. Another set of mice underwent the same injection regimen but were sacrificed on day 8 for qRT-PCR analysis.

Results

We found that subchronic zolpidem and diazepam administration produced deficits in the acute locomotor-impairing effects of zolpidem and increased anxiety-like behaviors 1 day after drug termination. In addition, we found that subchronic treatment of zolpidem and diazepam induced distinct but overlapping GABA_AR subunit mRNA changes in the cortex but few changes in the hippocampus, amygdala, or prefrontal cortex. Levels of mRNA measured in separate mice after a single injection of either zolpidem or diazepam revealed no mRNA changes.

Conclusions

In mice, subchronic treatment of zolpidem and diazepam can produce deficits in the locomotor-impairing effects of zolpidem, anxiety-like withdrawal symptoms, and subunit-specific mRNA changes.