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The Consultant Pharmacist : the Journal... Sep 2013After more than 50 years of experience with benzodiazepines, the American health care system has a love-hate relationship with them. In 1955, Hoffmann-La Roche chemist...
After more than 50 years of experience with benzodiazepines, the American health care system has a love-hate relationship with them. In 1955, Hoffmann-La Roche chemist Leo Sternbach serendipitously identified the first benzodiazepine, chlordiazepoxide (Librium). By 1960, Hoffmann-La Roche marketed it as Librium, and it pursued molecular modifications for enhanced activity. Valium (diazepam) followed in 1963. Hoffmann-La Roche's competitors also began looking for analogues. Initially, benzodiazepines appeared to be less toxic and less likely to cause dependence than older drugs. A specific improvement was their lack of respiratory depression, a safety concern with barbiturates. Medical professionals greeted benzodiazepines enthusiastically at first, skyrocketing their popularity and patient demand. In the mid-to-late 1970s, benzodiazepines topped all "most frequently prescribed" lists. It took 15 years for researchers to associate benzodiazepines and their effect on gamma-aminobutyric acid as a mechanism of action. By the 1980s, clinicians' earlier enthusiasm and propensity to prescribe created a new concern: the specter of abuse and dependence. As information about benzodiazepines, both raising and damning, accumulated, medical leaders and legislators began to take action. The result: individual benzodiazepines and the entire class began to appear on guidelines and in legislation giving guidance on their use. Concurrently, clinicians began to raise concerns about benzodiazepine use by elderly patients, indicating that elders'lesser therapeutic response and heightened sensitivity to side effects demanded prescriber caution. The benzodiazepine story continues to evolve and includes modern-day issues and concerns beyond those ever anticipated.
Topics: Benzodiazepines; Humans; gamma-Aminobutyric Acid
PubMed: 24007886
DOI: 10.4140/TCP.n.2013.538 -
Handbook of Experimental Pharmacology 2008The actions of benzodiazepines are due to the potentiation of the neural inhibition that is mediated by gamma-aminobutyric acid (GABA). Practically all effects of the... (Review)
Review
The actions of benzodiazepines are due to the potentiation of the neural inhibition that is mediated by gamma-aminobutyric acid (GABA). Practically all effects of the benzodiazepines result from their actions on the ionotropic GABA(A) receptors in the central nervous system. Benzodiazepines do not activate GABA(A) receptors directly but they require GABA. The main effects of benzodiazepines are sedation, hypnosis, decreased anxiety, anterograde amnesia, centrally mediated muscle relaxation and anti-convulsant activity. In addition to their action on the central nervous system, benzodiazepines have a dose-dependent ventilatory depressant effect and they also cause a modest reduction in arterial blood pressure and an increase in heart rate as a result of a decrease of systemic vascular resistance. The four benzodiazepines, widely used in clinical anaesthesia, are the agonists midazolam, diazepam and lorazepam and the antagonist flumazenil. Midazolam, diazepam and flumazenil are metabolized by cytochrome P450 (CYP) enzymes and by glucuronide conjugation whereas lorazepam directly undergoes glucuronide conjugation. CYP3A4 is important in the biotransformation of both midazolam and diazepam. CYP2C19 is important in the biotransformation of diazepam. Liver and renal dysfunction have only a minor effect on the pharmacokinetics of lorazepam but they slow down the elimination of the other benzodiazepines used in clinical anaesthesia. The duration of action of all benzodiazepines is strongly dependent on the duration of their administration. Based on clinical studies and computer simulations, midazolam has the shortest recovery profile followed by lorazepam and diazepam. Being metabolized by CYP enzymes, midazolam and diazepam have many clinically significant interactions with inhibitors and inducers of CYP3A4 and 2C19. In addition to pharmacokinetic interactions, benzodiazepines have synergistic interactions with other hypnotics and opioids. Midazolam, diazepam and lorazepam are widely used for sedation and to some extent also for induction and maintenance of anaesthesia. Flumazenil is very useful in reversing benzodiazepine-induced sedation as well as to diagnose or treat benzodiazepine overdose.
Topics: Anesthetics, Intravenous; Animals; Benzodiazepines; Biotransformation; Central Nervous System; Diazepam; Dose-Response Relationship, Drug; Drug Interactions; Flumazenil; Humans; Lorazepam; Midazolam; Molecular Structure; Receptors, GABA-A; Structure-Activity Relationship
PubMed: 18175099
DOI: 10.1007/978-3-540-74806-9_16 -
Pharmacotherapy 1996Benzodiazepines have a checkered history in the United States; public and professional attitudes about them have ranged from their being wonder drugs in the 1970s to... (Review)
Review
Benzodiazepines have a checkered history in the United States; public and professional attitudes about them have ranged from their being wonder drugs in the 1970s to being virtually purged from many formularies as addictive and dangerous in the 1980s. The attitude today is that they are useful for specific indications. In the last 20 years they have been investigated as adjunctive agents to conventional antipsychotic drugs in the treatment of schizophrenia. Benzodiazepines may be effective in schizophrenia because stress is one mediator of relapse in these patients. In addition, inhibition of dopamine neurotransmission through gamma-aminobutyric acid-enhancing activity may provide a direct antipsychotic effect. As monotherapy or adjuncts to antipsychotic agents, benzodiazepines produced antipsychotic effects in schizophrenia in approximately 50% of controlled trials. Although there is no particular benzodiazepine of choice, low-potency compounds with long elimination half-lives are recommended. Adverse effects of concern include sedation and cognitive impairment, behavioral disinhibition, exacerbation of psychotic symptoms, and the potential for dependence, withdrawal, and abuse. The recent arrival of atypical antipsychotic drugs has significantly slowed research and interest in benzodiazepines in schizophrenia beyond their initial beneficial sedative effects for acute psychotic episodes.
Topics: Antipsychotic Agents; Benzodiazepines; Drug Therapy, Combination; Humans; Schizophrenia; Schizophrenic Psychology
PubMed: 8947998
DOI: No ID Found -
Molecules (Basel, Switzerland) May 2021The synthesis of organometallic compounds with potential pharmacological activity has attracted the attention of many research groups, aiming to take advantage of... (Review)
Review
The synthesis of organometallic compounds with potential pharmacological activity has attracted the attention of many research groups, aiming to take advantage of aspects that the presence of the metal-carbon bond can bring to the design of new pharmaceutical drugs. In this context, we have gathered studies reported in the literature in which psychoactive benzodiazepine drugs were used as ligands in the preparation of organometallic and metal complexes and provide details on some of their biological effects. We also highlight that most commonly known benzodiazepine-based drugs display molecular features that allow the preparation of metallacycles via C-H activation. These organometallic compounds merit further attention regarding their potential biological effects, not only in terms of psychoactive drugs but also in the search for drug replacements, for example, for cancer treatments.
Topics: Benzodiazepines; Metals; Organometallic Compounds; Pharmaceutical Preparations
PubMed: 34068533
DOI: 10.3390/molecules26092796 -
Current Opinion in Anaesthesiology Aug 2020Anaesthesia and sedation are ubiquitous in contemporary medical practice. Developments in anaesthetic pharmacology are targeted on reducing physiological disturbance... (Review)
Review
PURPOSE OF REVIEW
Anaesthesia and sedation are ubiquitous in contemporary medical practice. Developments in anaesthetic pharmacology are targeted on reducing physiological disturbance whilst maintaining or improving titrateability, recovery profile and patient experience. Remimazolam is a new short-acting benzodiazepine in the final stages of clinical development.
RECENT FINDINGS
Clinical experience with remimazolam comprises volunteer studies and a limited number of clinical investigations. In addition, laboratory investigations explore the implications of its 'soft drug' pharmacology.
SUMMARY
Remimazolam provides effective procedural sedation with superior success rates and recovery profile when compared to midazolam. Comparisons with propofol are required. Preliminary studies suggest potential for using remimazolam as the hypnotic component of general anaesthesia. Definitive studies are awaited. As a benzodiazepine, remimazolam could be evaluated as an anticonvulsant and for intensive care sedation.
Topics: Benzodiazepines; Conscious Sedation; Humans; Hypnotics and Sedatives; Midazolam; Propofol
PubMed: 32530890
DOI: 10.1097/ACO.0000000000000877 -
Expert Review of Respiratory Medicine Dec 2014Non-selective benzodiazepines are a class of sedative and anxiolytic medication that are commonly prescribed. Physiology studies and animal studies suggest that...
Non-selective benzodiazepines are a class of sedative and anxiolytic medication that are commonly prescribed. Physiology studies and animal studies suggest that non-selective benzodiazepines may adversely impact respiration through a variety of mechanisms. Several recent, well-designed, population-based observational studies confirm that benzodiazepine-related negative respiratory outcomes are a concern. In this article, the mechanisms and clinical evidence for non-selective benzodiazepine-related adverse respiratory outcomes, as well as the methodological issues relating to the evaluation of adverse drug effects are reviewed.
Topics: Benzodiazepines; Humans; Respiration; Respiratory Tract Diseases
PubMed: 25193249
DOI: 10.1586/17476348.2014.957186 -
The Journal of Clinical Psychiatry 1997Over the past 15 years, benzodiazepines have been used successfully to treat panic disorder with agoraphobia, but not without some controversy. Efficacy and side effect... (Review)
Review
Over the past 15 years, benzodiazepines have been used successfully to treat panic disorder with agoraphobia, but not without some controversy. Efficacy and side effect data from the principal benzodiazepine outcome studies of panic disorder demonstrate that alprazolam, lorazepam, and clonazepam are all clinically effective. Clonazepam has several advantages over other benzodiazepines and can be considered a first-line agent for panic disorder. Benzodiazepines in general are therapeutically effective for a broad range of panic disorder symptoms. Their effect is rapid and maintained without dose increase over a 7- to 8-month period. Discontinuation-related difficulties can occur in a considerable number of patients, but these can be decreased in several ways.
Topics: Alprazolam; Benzodiazepines; Clonazepam; Humans; Lorazepam; Panic Disorder; Treatment Outcome
PubMed: 9078991
DOI: No ID Found -
Drug Safety 1990Benzodiazepines are frequently prescribed for elderly patients living in the community and for those in hospitals and institutions. Their use is more prevalent in women.... (Review)
Review
Benzodiazepines are frequently prescribed for elderly patients living in the community and for those in hospitals and institutions. Their use is more prevalent in women. Prolonged use of benzodiazepines is particularly likely in old age for the treatment not only of insomnia and anxiety, but also of a wide range of nonspecific symptoms. Long term users are likely to have multiple concomitant physical and psychological health problems. The distinction between benzodiazepine anxiolytics and hypnotics is difficult and somewhat arbitrary, since the differences between the compounds are less than their similarities, especially in respect of adverse reactions. Despite their wide therapeutic range, elderly patients are particularly prone to adverse reactions to benzodiazepines. The incidence of unwanted effects, predominantly manifestations of central nervous system depression, has been found to be significantly increased in hospitalised elderly patients, particularly in the frail elderly. Studies on unwanted effects during long term use are scarce, but there is some evidence of tolerance to side effects. However, benzodiazepines have been found to be frequently implicated in drug-associated hospital admissions. There is suggestive evidence that benzodiazepines, especially compounds with long half-lives, may contribute to the falls which are a major health problem in old age. The incidence of benzodiazepine dependence in elderly patients is unknown. The features of benzodiazepine withdrawal in the elderly may differ from those seen in young patients; withdrawal symptoms include confusion and disorientation which often does not precipitate milder reactions such as anxiety, insomnia and perceptual changes. Problems due to both adverse reactions and to benzodiazepine withdrawal may easily be overlooked in multimorbid elderly patients, particularly in those suffering from disorders of the central nervous system. There are numerous studies on benzodiazepine pharmacokinetics indicating that alterations, especially in distribution and elimination of certain compounds, occur in old age. Benzodiazepines with oxidative metabolic pathways and longer half-lives are likely to accumulate with regular administration. However, changes in pharmacodynamics may be more important to explain altered responses to benzodiazepines in the elderly. Although information on pharmacodynamics is still limited, there is convincing evidence of increased pharmacodynamic response in the elderly which may be further accentuated by disease factors. Since the variability of pharmacological response increases with age and is not always predictable, there is good reason at least to start therapy at lower doses and to titrate dosages individually. This may also be appropriate for the newer benzodiazepines, irrespective of advantageous pharmacokinetics.(ABSTRACT TRUNCATED AT 400 WORDS)
Topics: Aging; Benzodiazepines; Humans
PubMed: 2222867
DOI: 10.2165/00002018-199005050-00003 -
Clinical Pharmacokinetics Jan 1996This article reviews the literature on the plasma concentration-effect relationships for benzodiazepines, in humans and in experimental animals. Only literature that... (Review)
Review
This article reviews the literature on the plasma concentration-effect relationships for benzodiazepines, in humans and in experimental animals. Only literature that explicitly links pharmacokinetics to pharmacodynamics is included. The following questions are evaluated. Can concentration-effect relationships be demonstrated? If so, are these relations stable? Are the influences of specific factors such as age and disease on these relationships established? It is clear that, when studies are conducted and interpreted appropriately, relations can be found for a wide range of benzodiazepine effects. These include objective measures such as electroencephalography, semisubjective measures such as psychomotor performance, and subjective measures such as mood/sedation scales. A generally applicable model of the relationship which will allow prediction of effect is, however, not yet established. The relationship appears to be dependent on route and rate of administration, because of factors such as distributional delay, formation of active metabolites and, probably, acute tolerance. Furthermore, intra- and interindividual variability is considerable, probably due to varying experimental conditions and intrinsic interindividual differences. The limited data available on factors influencing the plasma concentration-effect relationships for benzodiazepines demonstrate clear changes in the pharmacodynamics after multiple doses, suggesting the development of tolerance, and a subsensitivity in patients with panic disorder. The influence of factors such as age, disease and drug interactions on the pharmacokinetic-pharmacodynamic relationship remains less clear.
Topics: Animals; Benzodiazepines; Dose-Response Relationship, Drug; Humans
PubMed: 8846627
DOI: 10.2165/00003088-199630010-00004 -
Fundamental & Clinical Pharmacology Jun 2006Benzodiazepines are relatively well-tolerated medicines but can induce serious problems of addiction and that is why their use is regulated. However, in developing... (Comparative Study)
Comparative Study Review
Benzodiazepines are relatively well-tolerated medicines but can induce serious problems of addiction and that is why their use is regulated. However, in developing countries like Senegal, these products are used without clear indications on their prescription, their dispensation or their use. This work focuses on the prescription of these medicines with a view to make recommendations for their rational use. Benzodiazepine prescription was studied with psychiatrists or neurologists and generalists in 2003. Specialist doctors work in two Dakar university hospitals and generalists in the 11 health centres in Dakar. We did a survey by direct interview with 29 of 35 specialists and 23 of 25 generalists. All doctors were interviewed in their office. The questionnaire focused on benzodiazepine indications, their pharmacological properties, benzodiazepines prescribed in first intention against a given disease and the level of training in benzodiazepines by doctors. Comparisons between specialists and generalists were made by chi-square test. Benzodiazepines were essentially used for anxiety, insomnia and epilepsy. With these diseases, the most benzodiazepines prescribed are prazepam against anxiety and insomnia and diazepam against epilepsy. About 10% of doctors do not know that there is a limitation for the period of benzodiazepine use. The principal reasons of drugs choice are knowledge of the drugs, habit and low side effects of drugs. All generalists (100%) said that their training on benzodiazepines is poor vs. 62.1% of specialists, and doctors suggest seminars, journals adhesions and conferences to complete their training in this field. There are not many differences between specialists and generalists except the fact that specialists prefer prazepam in first intention in the insomnia treatment where generalists choose bromazepam. In addition, our survey showed that specialists' training in benzodiazepines is better than that of generalists. Overall, benzodiazepine prescription poses problems particularly in training, and national authorities must take urgent measures for rational use of these drugs.
Topics: Anxiety; Benzodiazepines; Bromazepam; Developing Countries; Drug Prescriptions; Drug Utilization; Education, Medical, Continuing; Health Care Surveys; Health Knowledge, Attitudes, Practice; Humans; Neurology; Physicians, Family; Practice Guidelines as Topic; Practice Patterns, Physicians'; Prazepam; Psychiatry; Senegal; Sleep Initiation and Maintenance Disorders
PubMed: 16671957
DOI: 10.1111/j.1472-8206.2006.00400.x