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PubMed1992

Lipid solubility of sedative-hypnotic drugs influences hypothermic and hypnotic responses of long-sleep and short-sleep mice.

The anesthetic potency of many agents, including alcohols, barbiturates and other sedative-hypnotic drugs, is influenced by lipid solubility. Previous studies from our laboratory, however, have demonstrated that genetic factors influence this relationship. We have reported that mouse lines selectively bred for differences in duration of ethanol-induced anesthesia, the long-sleep (LS) and short-sleep (SS) mice, differ in sleep-time response to water-soluble, but not lipid-soluble, sedative-hypnotic drugs. The studies described here sought to determine whether this same relationship exists for the hypothermic response produced by 17 sedative-hypnotic drugs in the LS and SS mice. Dose-response and time course relationships for hypothermic actions were determined and were compared with the dose-related anesthetic effects of the drugs. Hypothermic potencies increased along with lipid solubility for both the LS and SS mouse lines, but the rate of change differed for the two mouse lines. LS mice were more responsive to ethanol and other water-soluble drugs whereas the SS were more responsive to lipid-soluble drugs; significant correlations were obtained between lipid solubility (log P-octanol-water partition coefficient) and relative LS-SS responsiveness to both the hypothermic and hypnotic actions of the 17 test drugs. Thus, both hypnotic and hypothermic actions of sedative-hypnotic drugs are correlated with lipid solubility. Possible explanation for these correlations include greater LS central nervous system sensitivity to water-soluble drugs and LS-SS differences in distribution of lipid-soluble drugs.

Animals↗

PubMed1978

A retrospective analysis of analgesics and sedative-hypnotics in hospitalized obstetrical and gynecological patients.

In a retrospective analysis, the dose per patient day (DPPD) of controlled analgesics and sedative-hypnotics dispensed to inpatients at a women's hospital in the United States were studied from October 1974 through September 1975. Obstetric patients received as many analgesics (1.872 DPPD) as did gynecologic patients (1.945 DPPD). Percodan and meperidine were the most frequently dispensed oral and parenteral analgesics (0.673 and 0.526 DPPD) respectively. Obstetric patients received greater quantities of sedative-hypnotics (0.453 DPPD) than did gynecologic patients (0.311 DPPD). Secobarbital and pentobarbital were the most frequently dispensed oral and parenteral sedative-hypnotics (0.161 and 0.015 DPPD), respectively. A decline in the use of barbiturates was observed toward the end of the study year, with a corresponding increase in the use of the non-barbiturate sedative-hypnotics. It is recommended that intrapartum administration of analgesics and sedatives be carefully evaluated in view of their possible depressant effects on the fetus/newborn.

Analgesics, Opioid↗

PubMed2000

Agranulocytosis induced by pyrithyldione, a sedative hypnotic drug.

OBJECTIVE: Pyrithyldione, a sedative-hypnotic drug with a poor clinical pharmacological development, was associated with anecdotal cases of agranulocytosis in the 1940s in the USA, in the 1960s and 1970s in the ex-Democratic Republic of Germany and in the 1980s in Japan. We describe the estimation of the risk of agranulocytosis associated with its use in Spain, which led to its withdrawal from the market. METHODS: In collaboration with the haematology units of all the hospitals in a defined area (3.3-3.9 x 10(6) inhabitants), all cases of agranulocytosis meeting strict diagnostic criteria were identified. Each case - defined as an episode of agranulocytosis - was reviewed by a haematologist without knowledge of previous drug exposures. Cases and age-, gender- and hospital-matched controls were interviewed with a structured questionnaire about previous drug exposures. In addition, in order to estimate the risk of pyrithyldione-associated agranulocytosis through a case-population approach, its consumption among the cases was compared with its consumption among the general population. RESULTS: After a follow-up of 66.5 x 10(6) person-years, 330 cases of agranulocytosis (230 community cases) were assembled. Reliable information on previous exposures was obtained for 204 cases. They were compared with 1314 controls. Eleven patients (14 cases, 6.9%) and zero controls had been exposed to pyrithyldione. The adjusted OR was 200.11 (CI 95% 22. 62-infinity). All patients were female; none had a fatal outcome; three exhibited positive rechallenge; and all had concomitantly taken other drugs. Although pyrithyldione was a prescription-only medicine, only 8% had been dispensed with medical prescriptions. Assuming the worst case, i.e. that all the exposed cases could be attributed to pyrithyldione, the incidence was 35.6 cases per 100, 000 patient-years (95% CI, 18.9-60.9), which gives a risk ratio estimate of 109.6 (57.5-191.5) if compared with the incidence of agranulocytosis among the non-exposed population [3.26 cases (CI 95% 2.83-3.71) per 10(6) inhabitants and per year]. DISCUSSION: Pyrithyldione was viewed by pharmacists as a mild hypnotic, and apparently this had conferred to this drug an unjustified image of safety. The National Commission of Pharmacovigilance recommended to the Ministry of Health its withdrawal from the market when eight cases of agranulocytosis had been identified. However, it took more than 2 years to withdraw it, and six additional cases occurred in the study area. This illustrates the need for quick regulatory action when pharmacoepidemiological data suggest an unfavourable benefit/risk ratio.

Adult↗

PubMed1986

History and current status of sedative-hypnotic drug use and abuse.

Sedative-hypnotic drug use and abuse increased in Europe after World War II and peaked about 1972. Clinical and follow-up descriptions of abusers support the concept of a psychiatric addiction syndrome, different from a low-dose withdrawal syndrome. Although these drugs may be prescribed unnecessarily, large portions of the general population with pathological psychic distress and insomnia do not receive psychotropic treatment, in spite of findings pointing to genetic and biochemical factors in the genesis of these. Research on underlying mechanisms and the rationale for maintenance therapy is needed.

Anti-Anxiety Agents↗

PubMedDate not supplied

Conformational analysis and pharmacophore design for selected 1-(2-pyrimidinyl)piperazine derivatives with sedative-hypnotic activity.

The conformational of selected 1-(2-pyrimidinyl)piperazine derivatives with high sedative-hypnotic activity was analysed and the model bioactive conformations were suggested. Subsequently, the pharmacophores of analysed compounds were designed. It was suggested that the pharmacophore of bioactive derivatives should be composed of 11 features that characterise the binding model of pyrimidinylpiperazine ligands to the binding site at the hypothetic receptor. This 11 feature pharmacophore was compared to three other pharmacophores designed for the selected anxiolytics (benzodiazepines and buspirone analogues) and the sedative-hypnotic agents (benzodiazepines and barbiturates). Several substantial differences between the pharmacophores were found: the number of pharmacophoric features and their distribution in 3-D space were unique for selected groups of compounds that exhibit sedative-hypnotic or anxiolytic activity.

Hypnotics and Sedatives↗

PubMed2006

A method for screening for various sedative-hypnotics in serum by liquid chromatography/single quadrupole mass spectrometry.

A screening method for the detection of sedative-hypnotics in serum is described. The target drugs, which include practically all the sedative-hypnotics distributed in Japan, consisted of 5 barbiturates, 30 benzodiazepine-related drugs and 11 other sedative-hypnotics (i.e., apronalide, bromisovalum, chloral hydrate, triclofos, chlorpromazine, promethazine, diphenhydramine, hydroxyzine, zopiclone, zolpidem and tandospirone). Thirty-nine analytes, selected in terms of the pharmacokinetics of the target drugs, in human serum were screened using a combination of mixed-mode solid-phase extraction and liquid chromatography/electrospray-ionization single-quadrupole mass spectrometry. The detection limits (non-basic analytes, 1-50 ng/ml; basic analytes, 0.1-5 ng/ml) were sufficient to permit the screening of a single therapeutic administration of a target drug.

Female↗

PubMed1996

The impact of sedative-hypnotic use on sleep symptoms in elderly nursing home residents.

OBJECTIVE: To determine the frequency of sleep-related complaints among institutionalized elderly subjects and to assess the relationship between perceived sleep quality and the use of sedative-hypnotic agents and other psychoactive medications. METHODS: In 12 nursing homes in Massachusetts, we conducted observational, cross-sectional, and longitudinal studies of 145 institutionalized elderly subjects (average age, 83.0 years; age range, 65 to 105 years). We recorded the patients' demographic characteristics and all medication use (both scheduled and as needed) during a 1-month baseline period. A research assistant who was blinded to diagnoses and medication use performed detailed neuropsychologic testing and administered a series of standardized questions concerning difficulty sleeping, early morning awakening, and time spent awake in bed. Medication use and patient assessments were repeated after a 6-month interval. RESULTS: One or more sleep-related complaints were present at baseline in 94 (65%) of the residents studied. Using logistic regression to adjust for potential confounding, we found no relationship in the baseline month between use of sedative-hypnotic agents and the presence or absence of sleep complaints. After 6 months of follow-up, 27 (19%) of the residents had decreased their use of sedative-hypnotic agents and 23 (16%) had increased their use. However, there was no relationship between decreased use of sedative-hypnotic agents and worsened sleep (p > 0.20) or between their increased use and improved sleep reports (p > 0.10). Improvement in functional status was significantly associated with improved sleep at follow-up (p < 0.005). CONCLUSIONS: Sleep complaints occur in the majority of institutionalized elderly persons. Neither cross-sectional nor longitudinal analyses showed a relationship between patterns of sedative-hypnotic use and the presence, absence, or change in sleep complaints.

Aged↗

PubMed1991

Outpatient use of prescription sedative-hypnotic drugs in the United States, 1970 through 1989.

Data from two pharmaceutical marketing research databases, the National Prescription Audit and the National Disease and Therapeutic Index, were used to study outpatient use of prescription sedative-hypnotic drugs in the United States from 1970 through 1989. Retail pharmacies dispensed an estimated 62.5 million prescriptions for sedative-hypnotic drugs in 1970. This number declined by half to 31.6 million in 1978. This decline has continued, so that in 1989 there were 20.8 million dispensed prescriptions. From 1970 to 1989, barbiturate and nonbarbiturate-nonbenzodiazepine prescriptions decreased 24-fold and 18-fold, respectively, and benzodiazepine prescriptions increased 26-fold. By 1989, the ultrashort-acting benzodiazepine drug triazolam was the leading sedative hypnotic, with about 40% of the total sedative-hypnotic market in the 6 years since its marketing. Data also indicate shifts from longer to shorter acting, and from higher to lower dose, benzodiazepine prescriptions, increasing use of antidepressant drugs for insomnia, female predominance of use, and increasing use with age.

Ambulatory Care↗

PubMed2006

Fine mapping of a sedative-hypnotic drug withdrawal locus on mouse chromosome 11.

We have established that there is a considerable amount of common genetic influence on physiological dependence and associated withdrawal from sedative-hypnotic drugs including alcohol, benzodiazepines, barbiturates and inhalants. We previously mapped two loci responsible for 12 and 9% of the genetic variance in acute alcohol and pentobarbital withdrawal convulsion liability in mice, respectively, to an approximately 28-cM interval of proximal chromosome 11. Here, we narrow the position of these two loci to a 3-cM interval (8.8 Mb, containing 34 known and predicted genes) using haplotype analysis. These include genes encoding four subunits of the GABA(A) receptor, which is implicated as a pivotal component in sedative-hypnotic dependence and withdrawal. We report that the DBA/2J mouse strain, which exhibits severe withdrawal from sedative-hypnotic drugs, encodes a unique GABA(A) receptor gamma2 subunit variant compared with other standard inbred strains including the genetically similar DBA/1J strain. We also demonstrate that withdrawal from zolpidem, a benzodiazepine receptor agonist selective for alpha1 subunit containing GABA(A) receptors, is influenced by a chromosome 11 locus, suggesting that the same locus (gene) influences risk of alcohol, benzodiazepine and barbiturate withdrawal. Our results, together with recent knockout studies, point to the GABA(A) receptor gamma2 subunit gene (Gabrg2) as a promising candidate gene to underlie phenotypic differences in sedative-hypnotic physiological dependence and associated withdrawal episodes.

Animals↗

PubMedDate not supplied

Sedative-hypnotic use of diphenhydramine in a rural, older adult, community-based cohort: effects on cognition.

OBJECTIVE: The authors sought to identify patterns and associations of prescription and over-the-counter sedative-hypnotic use in an older, rural, blue-collar, community-based cohort in southwestern Pennsylvania over 10 years. METHODS: A group of 1,627 individuals age 65 and over were recruited and assessed during 1987-1989 and re-assessed during approximately biennial waves. Data included sleep medications, demographics, depressive symptoms, sleep complaints, and cognitive functioning (Mini-Mental State Exam [MMSE]). RESULTS: At Waves 1 through 5, the mean age of the cohort increased from 73.4 to 80.5 years. Use of prescription sedative-hypnotics (primarily benzodiazepines) increased from 1.8% to 3.1%, and over-the-counter sedative-hypnotic use (primarily diphenhydramine) increased from 0.4% to 7.6%. At Wave 5 (1996-1998), 8.17% of the sample reported using diphenhydramine as a sleep aid. After adjusting for age and sex, diphenhydramine use was associated with higher education and more depressive symptoms, the latter becoming nonsignificant after controlling for initial insomnia. MMSE became significantly associated with diphenhydramine use when 143 subjects with dementia were excluded from the analysis. CONCLUSION: As the cohort aged, prescription sedative-hypnotic use remained relatively stable, whereas over-the-counter sedative use, principally diphenhydramine, increased substantially. The association of this drug with cognitive impairment in persons without dementia highlights its potential for causing adverse reactions in older adults.

Aged↗

PubMed2003

Pharmacokinetics and drug interactions of the sedative hypnotics.

Sleep complaints are common among patients and may be associated with mild to severe clinical symptoms. The use of hypnotic agents to improve the onset and quality of sleep has a history dating back centuries. Currently, several benzodiazepines and nonbenzodiazepines are widely used as sedative hypnotic drugs. The pharmacokinetic and pharmacodynamic profiles of these agents vary substantially, allowing them to be chosen for different clinical situations and tailored to specific sleep complaints. The short-acting benzodiazepines and benzodiazepine agonists have become the most widely prescribed sedative hypnotics because of their short to ultrashort half-life, and low tendency to impair cognitive and psychomotor performance on the day following nighttime use. In the current review, we summarize the pharmacokinetic and drug interaction profiles of the Food and Drug Administration-approved benzodiazepine sedative hypnotics: estazolam, flurazepam, quazepam, temazepam, and triazolam. In addition, alprazolam is included because of its popularity for this use, and 2 benzodiazepine receptor agonists, zolpidem and zaleplon, are reviewed. The presented data will provide clinicians with insight into the pharmacokinetic profiles of several popular sedative hypnotic agents, and provide guidelines to help them recognize or avoid drug interactions.

Benzodiazepines↗

PubMed2000

Sedative, hypnotic, and antianxiety medication use in an aging cohort over ten years: a racial comparison.

OBJECTIVES: Prescriptions of sedatives, hypnotics, and antianxiety medications have decreased over the past 15 years. However, racial differences have not been well investigated in controlled analyses. DESIGN: A prospective cohort study. SETTINGS AND PARTICIPANTS: The authors analyzed data from a community-based, biracial cohort of older adults (n = 4,000 at baseline) followed for 10 years to determine sociodemographic and health characteristics associated with the use of these medications between 1986 and 1996. MAIN OUTCOME MEASURES: Information about sedative, hypnotic, and antianxiety medication use and demographic and health characteristics was obtained from a race-stratified, probability-based sample of black and white community-dwelling older adults in the Piedmont region of North Carolina during four in-person interviews spanning 10 years. Descriptive statistics were calculated. Logistic regression was used for the final models. RESULTS: A total of 13.3% of the subjects were taking these medications in 1986, with the frequency of use declining only to 11.8% in 1996 despite the cohort aging 10 years. Correlates of use at baseline were female gender, white race, depressive symptoms, poor self-rated health, impaired physical function, and health services use. These correlates persisted for each of the three follow-up waves of the survey. In 1996, the odds for being white and using these medications was 4.70 in controlled analyses. CONCLUSIONS: Despite the overall decline in the use of sedative, hypnotics, and antianxiety agents in the general population in recent years, over the 10 years of this survey, an aging cohort continued to use these medications at a frequency greater than the general population and did not demonstrate a significant decline in use. Factors unrelated to health status, specifically being white, were among the strongest correlates of use throughout the years of follow-up.

Activities of Daily Living↗

PubMed1998

Synthesis and sedative-hypnotic effects of N3-allyl- and N1-allyl-5,6-substituted 2-thiouracil derivatives in mice.

Twenty four thiouracil derivatives, including N3-allyl- (19) and N1-allyl-2-thiouracil (20) were synthesized and their pharmacological effects [sedative-hypnotic activity (loss of righting reflex and spontaneous activity), convulsant activity, effect on pentobarbital (PB)-induced sleep and mortality] were evaluated in mice at doses of 320 mg/kg, i.p. and 2 mumol/mouse by intracerebroventricular (i.c.v.) injections, respectively. N3-Allyl-6-propyl-2-thiouracil (3), N3-allyl-5,6-dimethyl-2-thiouracil (10), N3-allyl-1,2,3,4,5,6,7,8,9-nonahydro-4-oxo-2-thiocyclohepta [d]pyrimidine (16) and N3-allyl-5-methyl-2-thiouracil (18) exhibited sedative-hypnotic activity, whereas N3-allyl-6-ethyl-5-methyl-2-thiouracil (11), N1-allyl-5-methyl-2-thiouracil (21), N1-allyl-1,2,3,4,5,6,7,8,9-nonahydro-4-oxo-2-thiocyclohepta[ d]pyrimidine (23) and N1-allyl-5,6-dimethyl-2-thiouracil (24) conversely displayed clonic- and/or tonic-convulsant seizures. N3-Allyl-6-propyl-2-thiouracil (3) and N3-allyl-5-methyl-2-thiouracil (18) decreased spontaneous activity. Other compounds examined were inactive, or only slightly active in the sedative-hypnotic assay even at high doses. Fifteen compounds (1-4, 7, 10, 11, 14-16, 18-21, and 23) significantly prolonged the PB-induced sleeping time. Interestingly, only N1-allyl-5,6-dimethyl-2-thiouracil (24) shortened the PB-induced sleeping time. These results showed that these thiouracils possessed many different effects such as sedative-hypnotic, anticonvulsant and/or convulsant, and that N3-allyl-5-methyl-2-thiouracil (18) and N1-allyl-5,6-dimethyl-2-thiouracil (24) had the most potent hypnotic activity and antagonistic effect against PB, respectively.

Animals↗

PubMed2001

No effect of albinism on sedative-hypnotic sensitivity to ethanol and anesthetics.

BACKGROUND: Studies using the long-sleep (LS) X short-sleep (SS) (LSXSS) recombinant inbred mice and inbred long-sleep (ILS) by inbred short-sleep (ISS) intercrosses have found genetic linkage between Tyr albinism (c/c) and differential sensitivity to sedative-hypnotic doses of ethanol and general anesthetics. This linkage could be due to a gene or genes near Tyr or Tyr itself. With regard to the latter possibility, the absence of tyrosinase activity (encoded by Tyr) in albinos could alter tyrosine availability and thus the rate-limiting step in catecholamine synthesis. In addition, albinism is associated with altered brain development that could have pleiotropic effects on behavior. Therefore, in this study, we asked whether albinism affects sedative-hypnotic sensitivity. METHODS: Loss of righting reflex (LORR) duration was measured using doses of ethanol (4.1 g/kg), pentobarbital (70 mg/kg), isoflurane (2 g/kg), and etomidate (20 mg/kg) that were previously associated with differential sensitivity of albino versus nonalbino mice. Tyr transgenics (c/c, Tg(Tyr+)) were backcrossed to ISS (c/c) to compare pigmented (c/c, Tg(Tyr+)) and albino (c/c) mice in the context of an ISS-like background. ISS was also crossed with C57BL/6 (B6) mice heterozygous for a spontaneous albino mutation (c2j) to compare pigmented (c/+) and albino (c/c2j) mice. Pigmented B6 (c2j/+ and +/+) and albino B6 (c2j/c2j) mice were also compared (pentobarbital). RESULTS: For each sedative hypnotic, albinism had no effect on LORR duration. Each expected difference was ruled out at the 95% or 99% confidence level. For each sedative hypnotic, males were more sensitive than females even though the effect size was usually smaller than the expected albino effect size, arguing empirically that the inability to detect an albino effect was not due to systematic error or an insufficient number of mice. CONCLUSION: We conclude that the differential sensitivity associated with albinism is most likely due to a gene or genes near Tyr rather than Tyr itself.

Albinism↗

PubMed1983

Sedative-hypnotic drug use and ageing.

Behavioural disadvantages associated with the use of sedative-hypnotic drugs in the elderly are considered in relation to four aspects of drug usage reported in the epidemiological literature between 1960 and 1982, viz. (1) the prevalence of drug usage; (2) the type of drug, and the dose used; (3) the typical duration of usage; and (4) the typical frequency of usage. Demographic characteristics of elderly hypnotic users are also examined. The pattern and prevalence of usage over the past 20 yr show many consistent features. In particular, the prevalence of drug usage among the elderly has remained relatively high, especially within institutional settings. Sex differences in the prevalence of sleeping drug usage, frequently reported for elderly populations, appear to be related to bereavement, health status, and age. The advanced age of hypnotic drug users, however, does not appear to influence the choice of hypnotic drug prescribed. Moreover, drugs and dosages typically prescribed, and the duration and frequency of use typically reported, do not reflect a consistent approach to the problem of minimizing some of the adverse behavioural consequences associated with sedative-hypnotic drug use in the elderly.

Aged↗

PubMed1993

Phenobarbital versus clonazepam for sedative-hypnotic taper in chronic pain patients. A pilot study.

A randomized, double-blind controlled trial is reported comparing phenobarbital and clonazepam for the purpose of sedative-hypnotic taper in inpatients with chronic, nonmalignant pain. After receiving the Minnesota Multiphasic Personality Inventory (MMPI) and a standardized psychiatric diagnostic interview, patients' baseline sedative-hypnotic use was assessed over 48 hours. Baseline use was converted into phenobarbital or clonazepam equivalents and administered in four doses daily using a blinded liquid pain cocktail. Baseline dose was maintained for two days and then tapered by 10% per day. Over the first week of taper, differences in mean and maximum Beck Anxiety and Benzodiazepine Withdrawal scores were not significant. However, when scales 1, 3, or 8 of the MMPI were taken as covariates, differences on the Withdrawal Scale only increased to a trend level for mean scores and to a significant level for maximum scores. These findings support the superiority of benzodiazepines over barbiturates for sedative-hypnotic taper for symptoms of withdrawal but not of recurrent or rebound anxiety.

Adult↗

PubMedDate not supplied

A role for valproate in the treatment of sedative-hypnotic withdrawal and for relapse prevention.

In the human central nervous system, the gamma-aminobutyric acid (GABA) type A receptor complex undergoes changes with both acute and chronic exposure to sedative-hypnotic drugs. These changes contribute to both the acute effects of these drugs as well as the chronic effects of sedative-hypnotic dependence, withdrawal, and drug craving. Clinically these chronic effects are difficult to treat in patients dependent on ethanol or benzodiazepines. Valproate may return the GABA type A receptor function to a state more closely resembling its normal function. By this mechanism, it is possible to reduce the symptoms of sedative-hypnotic withdrawal and relapse.

Chronic Disease↗

PubMed1992

A recombinant inbred strain analysis of sleep-time responses to several sedative-hypnotics.

The results of previous studies suggested that the sleep-time differential between long-sleep (LS) and short-sleep (SS) mice decreases for a series of sedative-hypnotic drugs as lipid solubility increases. Using the LS x SS recombinant inbred (RI) strains, we have tested whether this relationship arises because of common genetic influences on the sleep-time responses or was simply a fortuitous difference between LS and SS mice. Mice were sleep-time tested after intraperitoneal injections of a variety of sedative-hypnotic drugs that vary in lipid solubility including alcohols, barbiturates, chloral hydrate, and urethane. Sleep-time values from each of these drugs were compared with ethanol-induced sleep times in the LS x SS RI strains. Significant genetic correlations were observed between ethanol-induced sleep time and those responses elicited by butanol, propanol, and chloral hydrate, but not by pentobarbital or secobarbital. When the partition coefficient (log P) values were compared with the genetic correlations, a significant relationship (r = -0.85) was observed. These data suggest that common genes mediate sedative-hypnotic reactions to ethanol and some drugs resembling it in log P value, and that anesthetic agents with low lipid solubility may be working through different mechanisms than drugs with greater lipid solubilities.

1-Butanol↗