Benzodiazepines: Their Use Either As Essential Medicines Or As Toxics Substances
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toxics Review Benzodiazepines: Their Use either as Essential Medicines or as Toxics Substances Edilma Sanabria 1 , Ronald Edgardo Cuenca 1, Miguel Ángel Esteso 2,3 and Mauricio Maldonado 4,* 1 Grupo GICRIM, Programa de Investigación Criminal, Universidad Manuela Beltrán, Avenida Circunvalar No. 60-00, 111321 Bogotá, Colombia; [email protected] (E.S.); [email protected] (R.E.C.) 2 Universidad Católica Santa Teresa de Jesús de Ávila, Calle los Canteros s/n, 05005 Ávila, Spain; [email protected] 3 U.D. Química Física, Universidad de Alcalá, 28805 Alcalá de Henares, Spain 4 Departamento de Química, Facultad de Ciencias, Universidad Nacional de Colombia, Sede Bogotá, Cr. 30 No. 45-03, 111321 Bogotá, Colombia * Correspondence: [email protected] Abstract: This review highlights the nature, characteristics, properties, pharmacological differences between different types of benzodiazepines, the mechanism of action in the central nervous system, and the degradation of benzodiazepines. In the end, the efforts to reduce the benzodiazepines’ adverse effects are shown and a reflection is made on the responsible uses of these medications. Keywords: benzodiazepines; medical uses; toxicology 1. Introduction According to the World Health Organization (WHO), benzodiazepines are essential medicines used in the treatment of many clinical disorders, including different kinds Citation: Sanabria, E.; Cuenca, R.E.; of epileptic attacks, panic, phobias, depression, excitation, aggressiveness, anxiety, and Esteso, M.Á.; Maldonado, M. insomnia, among others. Fast starting of action, efficiency, a minor number of collateral Benzodiazepines: Their Use either as effects, and minimum acute toxicity are some of the advantages of using these medicines. Essential Medicines or as Toxics However, these can also show serious adverse effects when they are used improperly. Some Substances. Toxics 2021, 9, 25. examples of this are: consumption times longer than prescribed; when they are consumed https://doi.org/10.3390/toxics9020025 mixed with other stimulants substances like Opium; consumption of chemically modified benzodiazepines which have not been approved as medicaments; overdose; if during the Received: 6 January 2021 Accepted: 19 January 2021 treatment both driving and heavy machinery handling is not restricted; and, used for Published: 1 February 2021 criminal purposes, when they are administered masked in drinks or food in order to steal or sexually abuse victims. Publisher’s Note: MDPI stays neutral 2. Benzodiazepines with regard to jurisdictional claims in published maps and institutional affil- The Benzodiazepines (BDZs) are a group of components that receive their name iations. because in their chemical structure have a benzene ring joined to other seven-members heterocyclic ring called Diazepine (Figure1). There is a wide range of medicines that belong to these types of substances. The type of BDZ depends on the component present in the basic nucleus of the compound. As an Copyright: © 2021 by the authors. example of it, Figure2 shows several BDZ structures, in which the termination, lam, pam, Licensee MDPI, Basel, Switzerland. etc., indicate which is its active principle. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). Toxics 2021, 9, 25. https://doi.org/10.3390/toxics9020025 https://www.mdpi.com/journal/toxics Toxics 2021, 9, x FOR PEER REVIEW 19 of 19 R1 R2 Toxics 2021, 9, 25 N 2 of 18 Toxics 2021, 9, x FOR PEER REVIEW 19 of 19 R3 R7 N R1 R2 R2' N R3 R7 N Figure 1. Benzodiazepines basic structure. R2' There is a wide range of medicines that belong to these types of substances. The type of BDZ depends on the component present in the basic nucleus of the compound. As an example of it, Figure 2 shows several BDZ structures, in which the termination, lam, pam, Figureetc., indicate 1. Benzodiazepines which is its basic active structure. principle. Figure 1. Benzodiazepines basic structure. N There is a wideO range of medicinesN that belongH toO these types of substances.H O The type of BDZ dependsN on the componentN present in theN basic nucleusO of the compound.N As an example of it, Figure 2 shows several BDZ structures, in which the termination, lam,O pam,H etc.,Cl indicate whichN Clis its active principle.N Cl N OH Cl N Cl N O N H O H O N N N O N Diazepam Alprazolam Clorazepate Lorazepam OH Cl F3C N Cl N Cl NN OH Cl N O O N Cl O N N N N Cl DiazepamN AlprazolamN Cl ClorazepateN Cl LorazepamN O Cl F3C N O O N O N N N N Halazepam Clobazam Triazolam Prazepam Cl N N Cl N Cl N FigureFigure 2. 2.Chemical Chemical structures structures of of some some benzodiazepines. benzodiazepines. O Cl 3. Synthesis of Benzodiazepines 3. Synthesis of Benzodiazepines Within the BDZs group, several families of these compounds can be found differing Within the BDZs group, several families of these compounds can be found differing in the positionHalazepam and presenceClobazam of functional groups. Triazolam Some of the Prazepam great importance are 1,4- benzodiazepines,in the position and 1,5-benzodiazepines, presence of functional 1,4-benzodiazepines-2-ones, groups. Some of the andgreat 1,4-benzodiazepines- importance are 1,4- 3-ones.Figurebenzodiazepines, 2. The Chemical synthesis structures 1,5-benzodiazepines, of 1,5-benzodiazepines of some benzodiazepines. 1,4-benzodiazepines-2-ones, includes the reactions of phenylendiamines and 1,4-benzodiaze- with ketonespines-3-ones. in the presenceThe synthesis of catalysts of 1,5-benzodiazepines [1–4] by condensation includes with theα, reactionsβ-unsaturated of phenylendia- carbonyl compounds3.mines Synthesis with [ 5 ketonesof]. TheBenzodiazepines reactions in the presence can also beof carriedcatalysts out [1–4] under by solvent-free condensation conditions with α, [ 6β,7-unsatu-] or by rated carbonyl compounds [5]. The reactions can also be carried out under solvent-free meansWithin of procedures the BDZs under group, microwave several families conditions of these [8,9]. compounds can be found differing conditions [6,7] or by means of procedures under microwave conditions [8,9]. in theMethods position for and preparing presence 1,4-benzodiazepineof functional groups. derivatives Some of the include great importance an aromatic are elec- 1,4- Methods for preparing 1,4-benzodiazepine derivatives include an aromatic electro- trophilicbenzodiazepines, substitution 1,5-benzodiazepines, from N-substituted anilines1,4-benzodiazepines-2-ones, [10]. It is also possible and via 1,4-benzodiaze- a condensation philic substitution from N-substituted anilines [10]. It is also possible via a condensation reactionpines-3-ones. between Theo synthesis-substituted of 1,5-benzodiazepines benzylamines with activatedincludes the aziridines reactions by of ring-opening phenylendia- reaction between o-substituted benzylamines with activated aziridines by ring-opening reactionsmines with [11 ketones–13], among in the others. presence 1,4-Benzodiazepin-3-ones of catalysts [1–4] by condensation are synthesized with α by, β the-unsatu- con- reactions [11–13], among others. 1,4-Benzodiazepin-3-ones are synthesized by the conden- densationrated carbonyl of 2-bromobenzylamines compounds [5]. The withreactions amino can acids also [ 14be], carried as well out as byunder intramolecular solvent-free sation of 2-bromobenzylamines with amino acids [14], as well as by intramolecular nucle- nucleophylicconditions [6,7] aromatic or by substitutionmeans of proced [15]; otherures under alternate microwave methods conditions include cyclization [8,9]. process ophylic aromatic substitution [15]; other alternate methods include cyclization process by by UgiMethods reaction for [16 preparing,17]. The synthesis 1,4-benzodiazepine of 1,4-benzodiazepin-2-ones derivatives include includes an aromatic the previous electro- synthesisphilic substitution of the intermediate from N-substituted amino-ketone anilines [18]. Moreover,[10]. It is also cyclization possible processes via a condensation involving anreaction Ugi reaction between as o a-substituted first step [ 19benzylamines,20]. Finally, with other acti methodsvated aziridines include the by cascadering-opening cou- pling/ condensation process of 2-bromobenzylamines with amino acids [21] and Buchwald reactions [11–13], among others. 1,4-Benzodiazepin-3-ones are synthesized by the conden- reaction [22] (Figure3). sation of 2-bromobenzylamines with amino acids [14], as well as by intramolecular nucle- ophylic aromatic substitution [15]; other alternate methods include cyclization process by Toxics 2021, 9, x FOR PEER REVIEW 19 of 19 Ugi reaction [16,17]. The synthesis of 1,4-benzodiazepin-2-ones includes the previous syn- thesis of the intermediate amino-ketone [18]. Moreover, cyclization processes involving Toxics 2021, 9, 25 an Ugi reaction as a first step [19,20]. Finally, other methods include the cascade coupling/3 of 18 condensation process of 2-bromobenzylamines with amino acids [21] and Buchwald reac- tion [22] (Figure 3). FigureFigure 3. 3.Some Some synthesis synthesis routes routes toward toward benzodiazepines. benzodiazepines. 4.4. Benzodiazepines Benzodiazepines Action Action Mechanism Mechanism on on the the Central Central Nervous Nervous System System DueDue to to its its high high solubility solubility in in lipids, lipids, BDZ BDZ can can penetrate penetrate the the brain brain and and cause cause rapid rapid and and effectiveeffective