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PubMed1986

The use of hypnotics and anxiolytics in the elderly.

Anxiety and insomnia are prevalent conditions in the elderly, and anxiolytics and hypnotic drugs are commonly used. Pharmacokinetic variables--absorption, distribution, metabolism and elimination--are all altered to a greater or lesser extent. As a general rule, the elderly are more sensitive to psychotropic drug actions than younger patients. This is particularly so in the over 80s. The elderly tend to suffer from physical conditions which may cause insomnia and anxiety, and medication for those physical complaints may interact with psychotropic medication. In the treatment of insomnia, short- or intermediate-acting benzodiazepines are preferable to long-acting compounds which tend to accumulate and produce confusional states and ataxia. Similarly, the benefit/risk ratio for anxiolytics is least in the elderly. Compounds of intermediate half-life and no active metabolites, such as oxazepam, are preferable. Anxiety syndromes occurring in other contexts, e.g. dementia may be better treated with low doses of antipsychotic drugs.

Aged↗
PubMed1980

Aspiration after overdosage of sedative or hypnotic drugs.

We have reviewed the charts of 329 patients admitted to our hospital because of overdosage from sedative or hypnotic agents. Of this population 11.2% were believed to have aspirated. Included in this group were 13 patients who were observed to aspirate and 24 who were suspected of aspiration because of the appearance of radiographic infiltrates associated with compatible microbiologic studies. In the observed group, seven became febrile, four were hypotensive, eight had radiographic infiltrates, three had complications, and one died. In the group suspected of aspiration, 23 became febrile, ten became hypotensive, five had complications, and none died. We believe the low mortality from aspiration in this setting justifies caution in the use of steroids and antibiotics.

Adult↗
PubMed1999

Inhibition of nitric oxide metabolism enhances the hypnotic-anesthetic action of the alpha2-adrenoceptor agonist dexmedetomidine in vivo.

Nitric oxide (NO) synthase inhibitors have been demonstrated to increase the anesthetic action of volatile and intravenous anesthetics. This study was designed to test the hypothesis that, comparable to other general anesthetics, the hypnotic-anesthetic action of dexmedetomidine is increased after administration of the NO synthase inhibitor nitro-L-arginine methyl ester (L-NAME). With approval of the local animal care committee, the anesthetic potency of dexmedetomidine or a combination of dexmedetomidine plus 1 mM L-NAME was determined in Xenopus laevis larvae. Anesthesia was defined as loss of righting reflex. Concentration-response curves were calculated by a logistic approach. Additional experiments were performed that exposed the animals to dexmedetomidine in the presence of L-NAME plus L-arginine, as well as D-NAME. In the dexmedetomidine and the dexmedetomidine plus L-NAME groups, the fraction of anesthetized animals increased with increasing concentrations of dexmedetomidine. Calculation of the half-maximal effective concentration (EC50) resulted in a value of 7.8+/-0.6 microM for dexmedetomidine and 3.8+/-0.2 microM for dexmedetomidine plus L-NAME (p<0.05). Addition of L-arginine reversed the potentiating effect of L-NAME. Administration of D-NAME did not affect the EC50 of dexmedetomidine. In a manner comparable to that of other general anesthetics, the anesthetic effect of dexmedetomidine was increased by about 51% by an acute inhibition of the NO metabolism. Together with recent findings that alpha2-adrenoceptor agonists decrease the NO mediated synthesis of cGMP similar to volatile and intravenous anesthetics, the results suggest that the NO/cGMP pathway is an important mediator of the anesthetic action of these compounds.

Adrenergic alpha-Agonists↗
PubMed2003

Chronic intermittent injections of high-dose ethanol during adolescence produce metabolic, hypnotic, and cognitive tolerance in rats.

BACKGROUND: Many humans are first exposed to ethanol during adolescence, the time at which they are most likely to binge drink ethanol. Chronic intermittent ethanol (CIE) exposure produces ethanol tolerance in adolescent rodents. Recent studies suggested that adolescent animals administered CIE experienced increased cognitive impairment following an ethanol challenge. These studies further explore development of ethanol tolerance caused by CIE in adolescence, and whether CIE during adolescence leads to altered ethanol response in adulthood. METHODS: Beginning postnatal day (P) 30, adolescent rats were administered 5.0 g/kg ethanol or saline every 48 hours for 20 days. In experiment I, animals were tested for differential weight gain. In experiment II, loss of righting reflex (LORR) was observed after each injection, then at completion of pretreatment all animals were tested with 5.0 g/kg ethanol and LORR was observed. In experiment III, blood ethanol levels were observed and elimination rates calculated after the first and fifth pretreatments. All animals were tested with 5.0 g/kg at completion of pretreatment and elimination rates were recalculated. In experiment IV, animals were trained on the spatial version of the Morris Water Maze Task (MWMT) on non-treatment days. Following completion of pretreatment and training, animals were tested after receiving an ethanol (1.0, 1.5, or 2.0 g/kg), or saline. Tests for experiments II, III, and IV were repeated in the same animals following 12 ethanol-free days. RESULTS: Chronic intermittent ethanol exposure during adolescence caused differential weight gain (experiment I). Adolescent rats developed tolerance to ethanol-induced LORR (experiment II) and metabolic tolerance to ethanol (experiment III). This tolerance was seen after 12 ethanol-free days. CIE also attenuated ethanol-induced spatial memory deficits in the MWMT (experiment IV). This effect was not long-lasting. CONCLUSIONS: Following CIE pretreatment during adolescence, tolerance developed to the hypnotic and cognitive impairing effects of ethanol, along with increased metabolic rate and decreased weight gain. These results further emphasize the ability of CIE to produce a variety of effects during adolescence, some having long-lasting consequences.

Age Factors↗
PubMed2006

Rifampicin markedly decreases plasma concentration and hypnotic effect of brotizolam.

The purpose of the present study was to examine the effects of rifampicin on the single oral dose pharmacokinetics and pharmacodynamics of brotizolam. Thirteen healthy male volunteers received rifampicin 450 mg/day, or matched placebo, for 7 days in a double-blind randomized crossover manner. On the sixth day they received a single oral 0.5-mg dose of brotizolam, and blood sampling was performed for 24 hours, together with an assessment of psychomotor function using the Digit Symbol Substitution Test and the Stanford Sleepiness Scale. Rifampicin treatment significantly (P<0.001) decreased the peak plasma concentration (69%), total area under the plasma concentration-time curve (90%) and elimination half-life (79%) of brotizolam. Rifampicin significantly increased the area under the score-time curve of the Digit Symbol Substitution Test (P<0.01), and decreased that of the Stanford Sleepiness Scale (P<0.05). The present study suggests that rifampicin markedly decreases plasma concentration and hypnotic effect of brotizolam and, therefore, this combination is not recommended in clinical practice.

Adult↗
PubMed1983

Profile of etomidate. A hypnotic, anticonvulsant and brain protective compound.

A review of the hypnotic, anticonvulsant and brain protective action of etomidate in animals shows that when given as a single injection in different animal species recovery from hypnosis is quick and that the safety margin is large. In dogs a bolus or infusion produces high amplitude theta activity on the electroencephalogram (EEG). During infusion burst suppression is seen. After high doses, behaviour and EEG changes returned to normal within 3 hours. The wide spectrum of anticonvulsant activity suggests that etomidate may be useful in the treatment of status epilepticus. Studies in various animal models show that etomidate might have brain resuscitative properties. In hypoxic-ischaemic conditions etomidate has some protective effects, where its anticonvulsant action is probably important. Lowering of the cerebral metabolic rate of oxygen consumption, and reducing the rise of intracranial pressure, coupled with immobilisation and prevention of hyperactivity enables animals to resist a hypoxic insult.

Anesthesia, Intravenous↗
PubMed1990

Effects of hypnotics on sleep and psychomotor performance. A double-blind randomised study of lormetazepam, midazolam and zopiclone.

Lormetazepam, midazolam and zopiclone were compared as night medication in patients scheduled for elective surgery the next morning. Sixty patients divided at random into three groups, received double-blind lormetazepam 1 mg, midazolam 15 mg or zopiclone 7.5 mg, by mouth at 2200 hours. The quality of sleep was assessed at 0700 hours from responses to a questionnaire, and psychomotor function by comparing paper and pencil (p-deletion) and Maddox Wing tests with reference values from the day before. The three hypnotics were equally effective as sleep medication for time until onset of sleep, duration of sleep and condition upon awakening, whereas zopiclone provided significantly fewer (p less than 0.05) spontaneous awakenings. The p-deletion test did not differ in any of the three groups from the reference values. The ocular imbalance test in all three groups was significantly different (p less than 0.01) from control. The lormetazepam group scored significantly better (p less than 0.05) than the zopiclone group. No side effects were seen.

Adolescent↗
PubMed1982

Hypnotic activity and effects on performance of lormetazepam and camazepam--analogues of temazepam.

1 The effects of lormetazepam and camazepam on sleep electroencephalography, visuo-motor coordination, digit symbol substitution and subjective assessments of mood and sleep quality were compared with placebo in six young adult males (18-27 years). The study was double blind. 2 Over the dose range 0.5, 1.0 and 2.0 mg, lormetazepam increased total sleep time (P less than 0.05), reduced wakefulness (P less than 0.05) and drowsy sleep (linear effect P less than 0.05). With 2.0 mg there were increases in stage 3 (P less than 0.05) and reduction in rapid eye movement sleep (P less than 0.01). Overnight ingestion of 2.0 mg, was followed by impaired visuo-motor coordination and fewer substitutions with the digit symbol test. 3 The hypnotic effect of 10-20 mg camazepam was limited to reduced awake activity (P less than 0.05), and with 20 mg there were increased substitutions on the digit symbol test. After 40 mg overnight stage 4 sleep was reduced (P less than 0.001) and performance at the digit symbol test was impaired (P less than 0.05 at 9.75 h). Morning ingestion of 20 mg camazepam did not alter performance, and the subjects assessed themselves to be more relaxed. 4 Lormetazepam is not specially indicated for those involved in skilled activity, but may prove useful for patients with insomnia resistant to other drugs. Camazepam would appear to be a promising anxiolytic with minimal effects on performance.

Adolescent↗
PubMed1983

Pharmacokinetic and clinical considerations in the choice of a hypnotic.

Not only has insomnia become much more frequent in the last hundred years but its causes have also changed considerably. In the treatment of insomnia, benzodiazepines--because of their additional anxiolytic effect--offer substantial advantages over other sleep-inducing agents. The residual fraction--the quotient of plasma concentration at 12 h after drug intake to maximum plasma concentration--makes it possible to differentiate between the benzodiazepines according to their suitability as anxiolytics or hypnotics. Midazolam has the lowest residual fraction of all known benzodiazepines and thus, administered in the appropriate dosage, also has the shortest duration of activity.

Anti-Anxiety Agents↗
PubMed1983

Midazolam and triazolam in out-patients: a double-blind comparison of hypnotic efficacy.

The hypnotic efficacy and the effect on the condition after morning awakening of midazolam 15 mg and of triazolam 0.5 mg were studied in a multicentre, double-blind cross-over study in 198 out-patients with sleeping difficulties of various origin. The subjects received each drug for two consecutive nights, and completed a questionnaire each day on awakening. Both midazolam and triazolam significantly shortened the sleep-onset latency, reduced the number of awakenings, and increased the total sleep time. The state on awakening was also significantly improved after both compounds for several self-rated items. There was a difference only with regard to the patients' feeling of being under drug influence, which was reported as being significantly more marked after triazolam. In conclusion, both compounds were effective and well tolerated in the doses used, only a few side-effects being reported.

Adult↗
PubMed1983

Hypnotic activity of brotizolam: a study in general practice.

A double-blind, crossover study was carried out in general practice on the hypnotic activity of 0.25 mg brotizolam in patients aged between 18 and 70 years complaining of insomnia (11 men, 28 women). Patients reported that they slept better, that they awoke less frequently and that they slept longer with brotizolam than with placebo. Overall the patients preferred brotizolam to placebo, and subjective assessments of well-being after brotizolam did not differ from those after placebo. Brotizolam was well tolerated and there were no incidents of note.

Adolescent↗
PubMed1984

The effect of posture at the time of administration on the central depressant effects of the new hypnotic zopiclone.

Nine healthy volunteers swallowed 7.5 mg zopiclone in the standing and lying positions on different occasions. Plasma concentrations of zopiclone and psychometric tests, including simple and complex reaction time, and critical flicker fusion threshold, were performed at regular intervals after drug administration. The results show that when the drug was swallowed in the supine position, there was a significant delay in the onset of the impairment of psychomotor function, with prolongation in time to peak impairment by 30-40 min (P less than 0.02). The overall impairment in psychomotor performance was found to be significantly less after administration of the drug in the supine position (P less than 0.005). Pharmacokinetic analysis revealed a prolongation in lag time of greater than 20 min before absorption began (P less than 0.002) after supine drug administration, with a significantly lower rate constant of absorption (P less than 0.02). Area under the plasma concentration-time curve extrapolated to infinity and rate constant of elimination were not significantly different between the two modes of administration. We conclude that to obtain a rapid and complete effect from the hypnotic zopiclone, the tablet should be swallowed in the standing position.

Adult↗
PubMed1986

The hypnotic effects of an antihistamine: promethazine.

Twelve volunteer poor sleepers of mean age 59 years took placebo on one night, promethazine 20 mg on one night and promethazine 40 mg on one night, in a double-blind balanced order study. Sleep in the EEG laboratory was increased by nearly 1 h after either dose of promethazine, and sleep interruptions were reduced. Slow-wave sleep was unaffected, but the larger dose reduced the percentage of sleep spent as REM sleep. Sleep was improved subjectively by both doses of promethazine which appears to be an effective hypnotic.

Aged↗
PubMed1987

Assessment of a new hypnotic imidazo-pyridine (zolpidem) as oral premedication.

1 A new imidazo-pyridine hypnotic (zolpidem 10 mg and 20 mg) was compared with placebo as premedication before general anaesthesia in female patients undergoing minor gynaecological surgery. Efficacy and tolerance before and after anaesthesia were assessed. Psychomotor testing was used to study recovery from anaesthesia. 2 Both doses of zolpidem produced good sedation pre-operatively but only the higher dose was associated with anterograde amnesia. 3 Premorbid anxiety scores were low in the group of patients studied and were unaffected by either dose of zolpidem. 4 There were no significant effects on the course of anaesthesia. However, postoperatively there was a tendency for wake-up to be delayed in those patients who received either dose of zolpidem. 5 Postoperative recovery, as indicated by tests of psychomotor performance, was noticeably delayed with a dose of 20 mg compared with placebo whilst psychomotor performance had returned towards baseline levels 3 h after wake-up in those patients who had received placebo. The zolpidem 10 mg group was intermediate. 6 Zolpidem may be a suitable premedicant when hypnosis and amnesia only are required.

Adult↗
PubMed1991

Hospital prescribing and usage of hypnotics and anxiolytics.

In-patient prescribing and usage of hypnotic and anxiolytic drugs were surveyed in a teaching hospital for 4 to 6 weeks. Twenty-one percent of admissions were prescribed these drugs which were predominantly benzodiazepines. Few patients (1.6%) were discharged with such prescriptions and subsequent usage in the community was similar to that before admission to hospital (6.1% and 6.4% respectively). In-patient consumption increased with patient age and both prescriptions and consumption were greater in women than men.

Anti-Anxiety Agents↗
PubMed1996

A multicenter study of sleep-wake rhythm disorders: therapeutic effects of vitamin B12, bright light therapy, chronotherapy and hypnotics.

One hundred and six subjects with primary sleep-wake rhythm disorders [13 non-24 hour sleep-wake syndrome (non-24), 76 delayed sleep phase syndrome (DSPS), 11 irregular sleep-wake pattern (irregular) and six long sleepers] were treated with vitamin B12, bright light, chronotherapy and/or hypnotics. These therapies caused moderate or remarkable improvement in 32% of the non-24, 42% of DSPS, 45% of irregular and 67% of long sleepers. A lack of adequate sleep, unpleasant feelings at waking and daytime drowsiness were also improved in DSPS.

Adolescent↗
PubMed1978

Reversal of the action of amino acid antagonists by barbiturates and other hypnotic drugs.

1 The effects of pentobarbitone (PB) and other sedative/hypnotic drugs have been examined in relation to gamma-aminobutyric acid (GABA) in vitro on the superfused isolated superior cervical ganglion of the rat and in vivo on single units in the brain stem of the anaesthetized rat.2 PB, and other barbiturates, depolarized the ganglion in a dose-dependent manner (threshold concentration 100-300 muM, cf. GABA depolarization threshold 1 muM). The depolarization was reduced in the presence of the selective GABA antagonist (+)-bicuculline methochloride (Bic). Other non-barbiturate sedatives e.g. chlordiazepoxide, amitriptyline, promethazine at concentrations up to 2mM produced no depolarization.3 PB, tested at concentrations up to 80 muM, produced variable effects on the dose-response curve to GABA. On most occasions a slight potentiation occurred in responses to low concentrations of GABA (below 10 muM) coupled with a depression in the responses to concentrations of GABA greater than 10 muM.4 Superfusion with PB in the presence of Bic reversed the depression in the response to GABA produced by Bic. This reversal phenomenon occurred at concentrations of PB too low to depolarize the ganglion and was dependent not only on the concentration of PB but also on that of Bic.5 The reversal potency within an homologous series of barbiturates increased with the size of the alkyl substituent (R2) at C5 on the barbiturate ring. The most potent occurred when the substituent contained 5 carbon atoms (pentobarbitone and amylobarbitone); above this, activity decreased.6 PB reversed the effects of the other GABA antagonists, tetramethylenedisulphotetramine and isopropyl bicyclophosphate and also the non-selective antagonism produced by strychnine. A concomitant reduction by strychnine of responses to the cholinomimetic, carbachol, was not reversed by PB.7 Non-barbiturate sedative/hypnotics also reversed the GABA antagonism produced by Bic. The benzodiazepines were effective at lower concentrations than PB (chlordiazepoxide threshold concentration 0.5 muM, cf. PB 5 muM), however, they only produced a partial reversal even at concentrations much higher than the maximally effective concentration of PB.8 The Bic reversal effect of chloridazepoxide (and other benzodiazepines) lasted many hours after removal from the superfusion solution. By contrast the effect of PB lasted only 15-30 min after its removal.9 Chlordiazepoxide (30 muM) applied in the absence of Bic did not affect the response to GABA but did reduce the depression produced by the subsequent application of Bic even though the chlordiazepoxide had been removed 40 min earlier.10 In the rat brain stem in vivo PB, applied iontophoretically in amounts which neither decreased the spontaneous neuronal firing rate nor affected the response to GABA or glycine, reversed the GABA antagonism induced by iontophoretic application of Bic (in all 23 neurones tested). PB also reversed the antagonism produced by strychnine of responses to glycine although this was less readily observed (5 out of 14 neurones tested).11 Iontophoretic application of other barbiturates and chlordiazepoxide also reversed the effect of Bic. Chlordiazepoxide only produced a partial reversal, as in the isolated ganglion, and no reversal could be demonstrated with flurazepam.12 Intravenous administration of thiopentone (1.3 mg/kg) pentobarbitone (0.4-5.5 mg/kg) hexobarbitone (0.4-0.8 mg/kg) and clonazepam (0.1-0.2 mg/kg) also reversed the effect of iontophoretically applied Bic. The reversal by clonazepam was of much longer duration than that produced by the barbiturates.13 It is suggested that the reversal exhibited by PB and the other hypnotics may be explained by assuming that the amino acids and their antagonists bind to the membrane at separate sites. If the reversal agent has particular affinity only for the antagonist binding site then it may displace the antagonist without affecting the receptor.

Aminobutyrates↗