Pharmacokinetic/pharmacodynamic relationship of benzodiazepines in the direct cortical stimulation model of anticonvulsant effect

The in vivo concentration-anticonvulsant effect relationships of six benzodiazepines, midazolam, clonazepam, oxazepam, flunitrazepam, diazepam and clobazam were quantified in individual rats and correlated with the affinity to the GABAA-benzodiazepine receptor complex. Furthermore the interaction between midazolam and the benzodiazepine antagonist flumazenil was characterized. All benzodiazepines exhibited a nonlinear relationship between concentration and anticonvulsant effect without ceiling of the effect at higher concentration. The potency of most benzodiazepines was similar with values of the EC250, between 0.067 +/- 0.01 mg. l-1 for midazolam and 0.21 +/- 0.03 mg. l-1 for diazepam. The EC250,u of clobazam was 2.8 +/- 0.9 mg. l-1. These values were considerably larger than the Ki for binding at the GABAA-benzodiazepine receptor complex. No correlation was observed between EC250,u and Ki. Antagonism of the anticonvulsant effect of midazolam by flumazenil was associated with a remarkable change in the concentration-anticonvulsant effect relationship. Analysis of these data on basis of a composite model provided evidence for two separate effects of which only one is antagonized by flumazenil. The anticonvulsant effect at low midazolam concentration was characterized on basis of the sigmoid E maximal effect pharmacodynamic model. The value of the EC50,u was 0.0086 +/- 0.0013 mg. l-1 which is similar to the Ki for binding at the GABAA-benzodiazepine receptor complex. The second more pronounced anticonvulsant effect occurred at higher concentration and was described by an exponential function. The findings of this study indicate that the effect of benzodiazepines against seizures induced by cortical stimulation in vivo cannot be fully accounted for by an interaction at the GABAA-benzodiazepine receptor complex.     

Benzodiazepine use in an ambulatory elderly population: a 14-year overview

A survey on use of benzodiazepines was conducted among participants in the Florida Geriatric Research Program. In 1978-79, benzodiazepine use was reported by 14.4% of 1448 women and 9.7% of 855 men; in 1984-85, by 12.0% of 1429 women and 5.9% of 784 men; and in 1991-92, by 13.4% of 1124 women and 6.6% of 497 men. The changes were not significant. During this period the mean ages of the women increased from 74.6 to 78.1 years and the men from 75.0 to 80.2 years. Chlordiazepoxide, diazepam, and flurazepam accounted for 98.1% of all benzodiazepines used in 1978-79 and for 35.5% in 1991-92, when alprazolam, lorazepam, and temazepam accounted for 47.1% of benzodiazepines used.     

Medications and chronic diseases as risk factors for falling injuries in the elderly

Diseases and medications associated with the occurrence of falls leading to medical treatment in elderly Finns (65 yrs or older) during a one-year period are presented. The design was that of a case-control study involving 380 fallers seeking medical treatment and 342 unmatched controls selected randomly from the population register. The occurrence of a fall was shown by logistic regression analysis to be related to advanced age, presence of benzodiazepine in the serum, hypertrophy of the prostate, poor mental capacity, presence of chronic lung disease and asthma, use of analgesics and use of digitalis in the men, and to advanced age, poor mental capacity, presence of benzodiazepine in the serum, use of analgesics and non-occurrence of lower limb arthrosis in the women. The corresponding log-linear models showed advanced age and the presence of benzodiazepine in the serum to be independent risk factors for falling both in the men and women. Furthermore, the use of analgesics was related to falling in the women with normal mental capacities. No disease was independently associated with falls. The results suggest caution in the use of benzodiazepines among the elderly.     

Comparison of different immunoassays and GC-MS screening of benzodiazepines in urine

A total of 53 urine samples were tested by different immunoassay methods and by gas chromatography/mass spectrometry to determine repeatability of the different methods and to assess whether the immunoassays performed on samples obtained from elderly patients of the emergency section could be considered as reliable enough for identifying a benzodiazepine consumption. Repeatability was excellent for GC/MS and good for immunoassays. The specificity was not different for the three immunoassays (96%). The sensitivity varied from 36, 64 to 75% for OnLine, RIA Immunalysis and RIA DPC, respectively. An other difference between immunoassays and GC/MS was the ability of GC/MS to detect lorazepam and low concentrations of benzodiazepines whereas immunoassays did not.     

Benzodiazepines and exposure-based cognitive behavior therapies for panic disorder: conclusions from combined treatment trials

OBJECTIVE: Concurrent use of benzodiazepines and psychotherapy for panic disorder is a prevalent but highly controversial practice. Although there are many rationales for that approach, critics contend that benzodiazepines foster drug abuse and dependence and undermine psychosocial treatments in various ways. The authors examine that controversy in the light of recent empirical findings and offer some tentative conclusions and recommendations. METHOD: Data from studies combining benzodiazepines and the leading psychosocial treatment for panic disorder, exposure-based cognitive behavior therapy, are reviewed, and their application to clinical practice is discussed. RESULTS: The strongest support for combined treatment is for the addition of cognitive behavior therapy to pharmacotherapy for patients with agoraphobia and for those whose benzodiazepine treatment is being discontinued. The greatest problem with combined treatment is relapse after drug discontinuance. CONCLUSIONS: Combined treatment may be advantageous for some patients, but it must be carefully designed to avoid potential problems. Suggestions for that are given.     

Comparative study on benzodiazepine use in Canada and Chile

Benzodiazepines are the most prescribed psychotropic drugs in the world. Comparative international data on benzodiazepine use, specifically among developed and developing countries, are unavailable. To determine the different patterns of benzodiazepine use in two representative countries, use of benzodiazepines in Chile (a developing country) and Canada (a developed country) was undertaken. Wholesale data as provided by the Intercontinental Medical statistics and drug import data were used as databases. Data on trends of benzodiazepine use was determined for 5 years using the methodology recommended by the WHO for drug use research, the defined daily dose/1000 inhabitants/day. Total benzodiazepine use was similar in both countries, but Canadian use had increased slowly. Patterns of use, however, differ widely among the two countries. A linear increase of rapidly eliminated benzodiazepines was observed in Canada, whereas the reverse occurs in Chile: the slowly eliminated benzodiazepines are the ones that have increased use. Hypnotic benzodiazepines are used twice as frequently in Canada than in Chile. Striking differences in the use of individual benzodiazepines are observed. Differences in healthcare systems determine wide differences in the way these drugs are prescribed. Demographic characteristics of the two countries also may account for the differences in benzodiazepine use. The authors conclude that, although total benzodiazepine consumption is similar in the two countries, patterns of benzodiazepine use vary widely. The different patterns of use may determine differences in the morbidity rates associated with the use of these drugs.     

Nonconvulsive status epilepticus in the critically ill elderly

PURPOSE: To describe the electrographic and clinical features of nonconvulsive status epilepticus (NCSE) in the critically ill elderly and to identify potential predictors of outcome. METHODS: We prospectively identified 25 episodes of altered mentation and NCSE in 24 critically ill elderly patients associated with generalized, focal, or bihemispheric epileptiform EEG patterns. Patients with anoxic encephalopathy were excluded. RESULTS: Of 25 hospitalizations, 13 (52%) resulted in death, and 12 (48%) patients survived to discharge. Death was associated with the number of acute, life-threatening medical problems on presentation (survivors, 1.8; fatalities, 2.8; p = 0.013) and with generalized EEG pattern (p = 0.017). Higher doses or greater number of antiepileptic drugs (AEDs) did not improve outcome. Treatment with intravenous benzodiazepines was associated with increased risk of death (p = 0.033). Ten patients with advance directives were managed outside the intensive care unit (ICU). Mean hospitalization was 39 days in the ICU group and 22 for those with advance directives (p = 0.017). CONCLUSIONS: Severity of illness correlates with mortality in critically ill elderly patients with NCSE. Treatment with intravenous benzodiazepines may increase their risk of death. Aggressive ICU management may prolong hospitalization at considerable cost, without improving outcome. It is unclear whether NCSE affects outcome in the critically ill elderly or is merely a marker for severity of disease in predisposed patients. The benefits of aggressive therapy are unclear. Carefully controlled, prospective trials will be necessary to determine the best therapies for NCSE in the critically ill elderly and the appropriate role of the ICU in their management.