Paradoxical Excitation Following Intravenous Lorazepam Administration for Alcohol Withdrawal – A Case Presentation and Literature Review

Gonzalez, Jimmy; Upadhyaya, Vandan; Manna, Zachary T; Sharma, Aditya R; Christopher, Jason D.; Douedi, Steven; Sen, Shuvendu

doi:10.1177/08971900221097182

Cited by 7 publications

(4 citation statements)

References 37 publications

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“…In rare cases, benzodiazepines may cause paradoxical excitation which may mimic the symptoms of AWS. 42 AWS refractory to benzodiazepines may be present if severe symptoms are not controlled after 50 mg of diazepam or 10 milligrams of lorazepam in the first hour of treatment, or 200 mg diazepam or 40 mg lorazepam in the first 3 hours of treatment.…”

Section: Discussionmentioning

confidence: 99%

“…Chlordiazepoxide and diazepam have long half-lives as well as active metabolites and should be used with caution in patients with liver failure as the reduction in metabolism may lead to oversedation. In rare cases, benzodiazepines may cause paradoxical excitation which may mimic the symptoms of AWS 42. AWS refractory to benzodiazepines may be present if severe symptoms are not controlled after 50 mg of diazepam or 10 milligrams of lorazepam in the first hour of treatment, or 200 mg diazepam or 40 mg lorazepam in the first 3 hours of treatment.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Prevention of alcohol withdrawal syndrome in the surgical ICU: an American Association for the Surgery of Trauma Critical Care Committee Clinical Consensus Document

Seshadri

Appelbaum

Carmichael

et al. 2022

Trauma Surg Acute Care Open

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Alcohol withdrawal syndrome is a common and challenging clinical entity present in trauma and surgical intensive care unit (ICU) patients. The screening tools, assessment strategies, and pharmacological methods for preventing alcohol withdrawal have significantly changed during the past 20 years. This Clinical Consensus Document created by the American Association for the Surgery of Trauma Critical Care Committee reviews the best practices for screening, monitoring, and prophylactic treatment of alcohol withdrawal in the surgical ICU.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Prevention of alcohol withdrawal syndrome in the surgical ICU: an American Association for the Surgery of Trauma Critical Care Committee Clinical Consensus Document

Seshadri

Appelbaum

Carmichael

et al. 2022

Trauma Surg Acute Care Open

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“…A previous case study ( 147 ) highlighted a 50-year-old male patient undergoing alcohol withdrawal. Treatment with 1 mg lorazepam, a GABA A R positive allosteric modulator, resulted in paradoxical behavioral outcomes that included anxiety, agitation, and eccentric behaviors.…”

Section: Substance Use Disordersmentioning

confidence: 99%

A paradoxical switch: the implications of excitatory GABAergic signaling in neurological disorders

McArdle,

Arnone,

Heaney

et al. 2024

Front. Psychiatry

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Gamma-aminobutyric acid (GABA) is the primary inhibitory neurotransmitter in the central nervous system. In the mature brain, inhibitory GABAergic signaling is critical in maintaining neuronal homeostasis and vital human behaviors such as cognition, emotion, and motivation. While classically known to inhibit neuronal function under physiological conditions, previous research indicates a paradoxical switch from inhibitory to excitatory GABAergic signaling that is implicated in several neurological disorders. Various mechanisms have been proposed to contribute to the excitatory switch such as chloride ion dyshomeostasis, alterations in inhibitory receptor expression, and modifications in GABAergic synaptic plasticity. Of note, the hypothesized mechanisms underlying excitatory GABAergic signaling are highlighted in a number of neurodevelopmental, substance use, stress, and neurodegenerative disorders. Herein, we present an updated review discussing the presence of excitatory GABAergic signaling in various neurological disorders, and their potential contributions towards disease pathology.

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“…Lorazepam [4], a drug approved by the FDA (Food and Drug Administration), is used for short-term (up to 4 months) relief of anxiety symptoms [5,6]. It binds to benzodiazepine receptors located on GABA-A ligand-gated chloride channels within the central nervous system (CNS).…”

Section: Introductionmentioning

confidence: 99%

AI-driven drug design for short-term anxiety disorder

et al. 2024

Preprint

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Anxiety is the most common neurological disorder and results in cognitive, emotional, and somatic behavioral changes. Anxiety may invoke an unpleasant feeling that is strongly associated with apprehension, fear, and disturbance of daily routine life activities. GABA acts as an inhibitory neurotransmitter within the central nervous system, and a decrease in its levels can result in anxiety. Therefore, GABA-A receptor proteins (PDB ID: 4COF) are suitable targets for drug design. Lorazepam is a commonly used drug for the treatment of short-term anxiety. However, Lorazepam causes serious side effects both physically and mentally during treatment for patients. To alleviate the serious side effects of Lorazepam, in this work, in silico studies based on modern artificial intelligence (AI)-based virtual screening were carried out with a series of computational chemistry methods, such as molecular docking (MD), molecular dynamics simulation (MDS) and quantitative structure–activity relationships (QSAR). Initially, using the MolAICal tool, compounds similar to Lorazepam were generated (M1-M12), and based on drug likeliness, 9 compounds were selected (M1, M4-M7, M9-M12). Then, molecular docking was carried out to analyze and visualize their binding scores with the 4COF protein structure. Compound M12 has a greater binding affinity (i.e., a lower binding energy of -8.276 kcal/mol) than Lorazepam. Its applicability was ascertained via QSAR analysis. A molecular dynamics study of M12 and that of Lorazepam showed that M12 has very good binding to the protein 4COF through multiple H-bond interactions, as more than 100% of the simulation times with the ASP 43 residue and 98% of the simulation times with the GLU155 residue. Various protein‒ligand interactions that lasted more than 48% of the simulation time in the selected trajectory were considered. Analysis of these parameters demonstrated the stable binding of M12 within the binding pocket of 4COF, and M12 had more interactions; hence, M12 was proven to be an alternative drug for treating anxiety with high efficacy.

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Paradoxical Excitation Following Intravenous Lorazepam Administration for Alcohol Withdrawal – A Case Presentation and Literature Review

Cited by 7 publications

References 37 publications

Prevention of alcohol withdrawal syndrome in the surgical ICU: an American Association for the Surgery of Trauma Critical Care Committee Clinical Consensus Document

Prevention of alcohol withdrawal syndrome in the surgical ICU: an American Association for the Surgery of Trauma Critical Care Committee Clinical Consensus Document

A paradoxical switch: the implications of excitatory GABAergic signaling in neurological disorders

AI-driven drug design for short-term anxiety disorder

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