Side-Effect ‘Tolerance’ in Elderly Long-Term Recipients of Benzodiazepine Hypnotics

Swift, Cameron; Swift, M.R.; Hamley, JG; Stevenson, I. H.; Crooks, J.

doi:10.1093/ageing/13.6.335

Cited by 53 publications

(21 citation statements)

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“…Our observation that withdrawal of thioridazine had no apparent effect on mental function, mobility or balance serves to support the claim that the drug has relatively few side-effects; it may also be that, as with benzodiazepines, old people develop a degree of tolerance to its neurological effects (Swift et al, 1984). A further factor may be that since an audit of drug therapy for hospital patients in the 1970s, psychiatrists have made a deliberate attempt to reduce psychotropic medication in demented patients to the minimum necessary to control symptoms.…”

Section: Discussionsupporting

confidence: 63%

Double‐blind controlled withdrawal of thioridazine treatment in elderly female inpatients with senile dementia

Findlay

Sharma

McEwen

et al. 1989

Int J Geriat Psychiatry

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SUMMARYThirty-six female inpatients with a clinical diagnosis of senile dementia, Alzheimer type, were entered into a doubleblind withdrawal of their established thioridazine. Over a four-week period there were no significant differences between the two study groups in terms of cognitive function, behaviour or physical state. There was no evidence of a withdrawal phenomenon and the use of replacement medication was at a similar low level in the two groups. Although significant differences were not established in terms of side-effects, there was a trend for greater reduction of these for the group in whom treatment was stopped. These data indicated that careful, controlled withdrawal of established thioridazine treatment is a safe procedure which may be useful in circumstances where the contribution of medication is unclear.KEY wom-withdrawal, thioridazine, female inpatients, SDAT.

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Section: Discussionsupporting

confidence: 63%

Double‐blind controlled withdrawal of thioridazine treatment in elderly female inpatients with senile dementia

Findlay

Sharma

McEwen

et al. 1989

Int J Geriat Psychiatry

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“…Peak levels of CHO-FLZ averaged 7.8 ng/ml, and this compound persisted on the average for 8 or more h after FLZ dosage. DA-FLZ, on the other hand, reached peak plasma concentrations considerably later (10.2 h after dosage) and was eliminated very slowly, with a mean half-life of 71.4 h. Because of its long eliminaLion half-life, DA-FLZ will accumulate in plasma during chronic nightly therapy with FLZ in humans (Greenblatt et al 1981 ;Bliwise et al 1984;Swift et al 1984).…”

Section: Relation Of Brain Uptake To Hplc Retentionmentioning

confidence: 99%

Kinetics, brain uptake, and receptor binding characteristics of flurazepam and its metabolites

et al. 1988

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The benzodiazepine derivative flurazepam (FLZ) is widely used as a hypnotic, but the relative contributions of FLZ and its metabolites desalkylflurazepam (DA-FLZ), hydroxyethylflurazepam (ETOH-FLZ), and flurazepam aldehyde (CHO-FLZ) to overall clinical activity remain uncertain. A single 20 mg/kg dose of FLZ.HCl was administered to mice, with plasma and brain concentrations of FLZ and metabolites determined during 5 h after dosage. Brain and plasma concentrations of FLZ were maximal at 0.5 h after dosage, then declined rapidly in parallel, whereas those of DAFLZ were maximal at 2 h, then declined slowly. Concentrations of ETOH-FLZ, the most polar metabolite, were maximal at 0.5 h, and were undetectable after 3 h. Little CHO-FLZ was detected in either brain or plasma. A single 30-mg oral dose of FLZ.HCl was given to 18 human volunteers, with plasma levels determined over 9 days. FLZ was detected in plasma at low concentrations for no more than 3 h after dosage. ETOH-FLZ concentrations were higher and persisted for 8 h after dosage. CHO-FLZ reached intermediate peak levels and was present longer than FLZ or ETOH-FLZ. In contrast, DA-FLZ achieved the greatest peak concentrations, occurring at 10 h after dosage. Levels declined very slowly, with a mean half-life of 71.4 h, and were still detectable 9 days after FLZ dosage. Plasma free fractions (percent unbound) in mice were 40.3, 51.4, and 25.0% for FLZ, ETOH-FLZ and DA-FLZ, respectively; in humans, values were 17.2, 35.2, and 3.5%, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

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“…Enhanced tolerance to the anticonvulsant and sedative/hypnotic versus anxiolytic effects of benzodiazepines (BZD) 1 is an important characteristic of their therapeutic effects (1)(2)(3). Attempts to uncover the molecular mechanism(s) that underlie tolerance to chronic in vivo administration of BZDs began 21 years ago with the discovery that a subsensitivity of allosteric interactions between the GABA and BZD recognition sites occurs after chronic in vivo administration of diazepam to rats (4).…”

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confidence: 99%

GABA Induces Activity Dependent Delayed-onset Uncoupling of GABA/Benzodiazepine Site Interactions in Neocortical Neurons

Gravielle

Faris

Russek

et al. 2005

Journal of Biological Chemistry

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Changes in the function of type A ␥-aminobutyric acid receptors (GABA A Rs) are associated with neuronal development and tolerance to the sedative-hypnotic effects of GABA A R positive modulators. Persistent activation of GABA A Rs by millimolar concentrations of GABA occurs under physiological conditions as GABAergic fast-spiking neurons in neocortex and cerebellum exhibit basal firing rates of 5 to 50 Hz and intermittent rates up to 250 Hz, leaving a substantial fraction of synaptic receptors occupied persistently by GABA. Persistent exposure of neurons to GABA has been shown to cause a down-regulation of receptor number and an uncoupling of GABA/benzodiazepine (BZD) site interactions with a half-life of ϳ24 h. Here, we report that a single brief exposure of neocortical neurons in primary culture to GABA for 5-10 min (t1 ⁄2 ‫؍‬ 3.2 ؎ 0.2 min) initiates a process that results in uncoupling hours later (t1 ⁄2 ‫؍‬ 12.1 ؎ 2.2 h). Initiation of delayed-onset uncoupling is blocked by co-incubation with picrotoxin or ␣-amanitin but is insensitive to nifedipine, indicating that uncoupling is contingent upon receptor activation and transcription but is not dependent on voltage-gated Ca 2؉ influx. Delayed-onset uncoupling occurs without a change in receptor number or a change in the proportion of ␣1 subunit pharmacology, as zolpidem binding affinity is unaltered. Such activity dependent latent modulation of GABA A R function that manifests as delayed-onset uncoupling may be relevant to physiological, pathophysiological, and pharmacological conditions where synaptic receptors are transiently exposed to GABA agonists for several minutes.Enhanced tolerance to the anticonvulsant and sedative/hypnotic versus anxiolytic effects of benzodiazepines (BZD) 1 is an important characteristic of their therapeutic effects (1-3). Attempts to uncover the molecular mechanism(s) that underlie tolerance to chronic in vivo administration of BZDs began 21 years ago with the discovery that a subsensitivity of allosteric interactions between the GABA and BZD recognition sites occurs after chronic in vivo administration of diazepam to rats (4). This was subsequently referred to as uncoupling of allosteric interactions based on experiments in primary cultures of chick brain (5).Surprisingly, a single dose of diazepam results in subsensitivity after only 12 h (6). These results suggest that GABA A R subsensitivity is produced via an interaction of diazepam with GABA-mediated synaptic transmission because BZDs potentiate the GABA A R-mediated response (7).In a similar fashion, a single convulsive dose of pentylenetetrazole causes a reduction in the GABA potentiation of BZD binding in vivo and this is accompanied by selective decreases in subunit-subtype mRNA levels without down-regulation of receptor number (8). These studies suggest that uncoupling between GABA and BZD binding sites can occur in vivo under pharmacologically relevant conditions and without alteration receptor number.Chronic treatment with flurazepam induces tolerance and yields ...

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Side-Effect ‘Tolerance’ in Elderly Long-Term Recipients of Benzodiazepine Hypnotics

Cited by 53 publications

References 0 publications

Double‐blind controlled withdrawal of thioridazine treatment in elderly female inpatients with senile dementia

Double‐blind controlled withdrawal of thioridazine treatment in elderly female inpatients with senile dementia

Kinetics, brain uptake, and receptor binding characteristics of flurazepam and its metabolites

GABA Induces Activity Dependent Delayed-onset Uncoupling of GABA/Benzodiazepine Site Interactions in Neocortical Neurons

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