Year: 2019
Type: article
Abstract: "Designer drugs," also referred to as Novel Psychoactive Substances, represent a public health issue of emerging importance. In general, designer drugs are synthetic analogues or derivatives of potentially abusable psychotropic substances.1-4 Most are manufactured illicitly outside the United States in countries with high production capabilities and low labor costs. The chemical structures of many of these drugs have been available in the scientific literature for decades, and many originated as investigational pharmaceuticals for which patents have been filed. Designer drugs allow manufacturers and sellers to evade regulatory constraints and law enforcement in the United States and Western Europe. The chemical isolation, cataloging, and legal scheduling of new compounds is time-consuming. By the time a given compound becomes known to law enforcement and corresponding legislation is enacted, some other similar compound may be synthesized and disseminated.1, 2 Designer benzodiazepines (BZs) constitute a major class of designer drugs.5-8 They have similar chemical structures and clinical effects to "traditional" BZs such as lorazepam, alprazolam, and diazepam.9, 10 Unlike traditional BZs, designer BZs have no approved medical uses in the United States or Western Europe. Some have never been formally studied prior to their sale and consumption. The first novel BZs to appear in Western Europe in the 2000s, phenazepam and etizolam, were not technically considered "designer" BZs due to their approved medical use in Russia and Japan, respectively. Between 2010 and 2015 the first true designer BZs were identified that had never been licensed for medical use anywhere in the world.6 As of November 2018, at least 24 different designer BZs have been identified.7, 8 They can be classified according to their basic chemical structure as either 1,4-benzodiazepines (a structure shared by most traditional BZs), triazolobenzodiazepines, or thienotriazolodiazepines (Figure 1).6, 7 Slight alterations of chemical substituents at various positions can yield a large number of different compounds (Table 1). Among the 1,4-benzodiazepines, whether traditional or designer, all have an electronegative substituent (such as a halogen or a nitro moiety) at the R7 position, and many have electronegative groups at R2' as well.9, 10 Of the triazolobenzodiazepines, all have electronegative groups at R8 and in many cases at R2' in addition. No systematic data exists regarding the precise pharmacodynamic or receptor binding profiles of designer BZs. Given their chemical structures and observed effects, it is inferred that they are allosteric modulators at type-A γ-aminobutyric acid (GABAA) receptors, similar to traditional BZs. Quantitative structure-activity relationship models have been used to estimate the potencies of individual designer BZs based on their chemical structures. From this analysis, the triazolobenzodiazepines were in general the most potent group,11 but these findings have not been replicated in vivo. Metabolic profiles of a number of the designer BZs have been characterized by mass spectrometric analysis of human urine samples.7, 12-15 Some are metabolized in vivo to traditional BZs. For example, the designer BZ diclazepam is metabolized to lorazepam, and the designer compound cloniprazepam is metabolized to clonazepam.7, 16 Conversely, the designer BZs nifoxipam and fonazepam are known active metabolites of the traditional BZ flunitrazepam.7, 14 Norflurazepam, also named desalkykflurazepam, is the principal active metabolite of flurazepam,10, 17, 18 a BZ hypnotic used in the United States since 1970.19, 20 In clinical practice, BZs are most often classified by their pharmacodynamic duration of action and/or their pharmacokinetic properties, including elimination half-life.10, 21 The principal determinants of elimination half-life are lipid solubility, volume of distribution, and clearance.22-24 Traditional BZs with very similar chemical structures may have differing half-lives, and there is no evident relationship between structure and half-life. Only a few estimates of elimination half-lives of individual designer BZs have been published. Notably, elimination half-life data for the newer compounds pyrazolam, flubromazepam, flubromazolam, deschloroetizolam, and diclazepam derives from single-volunteer studies in which one of the authors ingested a dose of the specific designer BZ.7, 16, 25-27 From this limited information, there is no apparent structure-disposition relationship among designer BZs. For example, diclazepam has an estimated half-life of 46 hours, whereas flubromazepam, which has slightly different substituents at the R1, R7, and R2' positions, has an estimated half-life of 106 hours.7, 16, 26 This variation represents a potential hazard for recreational users, especially since new compounds with scant data emerge frequently. If a compound with a very long half-life is inadvertently dosed too frequently, unintended drug accumulation might result in clinical toxicity.10 This scenario is not difficult to envision if a user is not familiar with a particular compound, or ingests an impure mixture of multiple compounds. Clinical toxicity patterns associated with designer BZs have been described in case reports and case series, and are similar to those associated with the traditional BZs: slurred speech, somnolence, lethargy, ataxia, psychomotor impairment, slowed reaction time, and impaired memory.6, 28-31 In cases of overdose, some designer BZs can be detected with adequate sensitivity by immunoassay-based urine drug screening.32-35 However, not all designer BZs will necessarily cross-react with commercially used immunoassays, and the detectability of many designer BZs remains unknown.36 In an urgent care setting, a negative urine drug screening result based on an immunoassay does not exclude the possibility of BZ intoxication. Identification of a specific designer BZ requires confirmatory mass spectrometry analysis, results of which are usually not available quickly enough to guide clinical management. Case reports suggest that the effects of designer BZs, when taken alone in overdose, are reversible (at least partly) by the BZ antagonist flumazenil.29, 31 In an appropriate patient, empiric administration of flumazenil may be reasonable even if the urine drug screening is negative. As in traditional BZ intoxication, the use of flumazenil carries a theoretical risk of precipitating discontinuation symptoms in highly BZ-tolerant patients. The available literature suggests that designer BZs are rarely the sole agents involved in drug abuse and dependence. Records of police confiscations and toxicology testing of apprehended drivers exist, mostly from Western Europe. Among 141 samples from apprehended drivers in Finland containing phenazepam, only 7 revealed phenazepam as the only psychoactive substance. The same study reported 17 cases in which phenazepam was detected in autopsy specimens. In none of these cases was phenazepam considered the sole cause of death or the most relevant toxicologic finding.37 Assuming this pattern of use applies to other designer BZs, these compounds are usually identified in the context of polysubstance use. Among all confirmed cases of designer BZ use, the proportion of lethal ingestions (known as the Index of Fatal Toxicity) appears to be the lowest of any class of designer drugs.38 Although the addiction potential of designer BZs is not clearly established, it is likely that the risk is low and comparable to that of traditional BZs. Mortality or serious morbidity associated with misuse or overdosage with designer BZs occurs almost exclusively when they are combined with other psychoactive substances. However, the existence of numerous compounds with differing and unknown pharmacokinetic properties and durations of action may exaggerate the risks beyond those of traditional BZs. Impure or adulterated drug preparations are prevalent on the recreational scene, and patient or collateral history might not establish exactly what has been ingested. Emergency and urgent care physicians should be aware of the heterogeneity of available designer drugs and the high likelihood of multiple substance ingestion.
DOI: 10.1002/cpdd.667
Authors: H. Karl Greenblatt, David J. Greenblatt
Institutions: University of Cincinnati, Tufts University
Language: English
Subfield: Toxicology
Domain: Life Sciences
Open Access status: bronze
OpenAlex ID: W2913050467