Pharmacological Functions, Illicit Abuse and Forensic Appraisal of Etomidate and Its Derivatives

doi:10.3969/j.issn.1671-2072.2024.06.006

Abstract

Abstract: Etomidate is a clinical anesthetics that became popular and rapidly spread in 2022, and was quickly listed in October 2023. After listing, the control of etomidate will be carried out according to narcotic standards. Starting from the newly listed etomidate, this review systematically summarizes the pharmacological functions of etomidate and its clinical derivatives, and outlines the clinical testing and analysis of etomidate and its derivatives, as well as the testing technical specifications in forensic practice and forensic appraisal. Responding to the new drug abuse situation as “substituting drugs for narcotics”, work suggestions are proposed from five aspects: tracing the origins of clinical anesthetics and psychotropic drugs, the monitoring of derivatives of narcotics, the filing of raw materials and equipments for narcotics synthesis, the control of new types of narcotics carriers, and the standardization of analyzing methods. The aim is to provide work suggestions and reference for curbing the illegal abuse of clinically legal drugs represented by etomidate, as well as scientific management and effective crackdown on narcotics.

Key words: etomidate, derivative, drug abuse, forensic appraisal

摘要： 依托咪酯是在2022年流行并迅速泛滥的临床麻醉药物，并于2023年10月被迅速列管。列管后，对依托咪酯的管控将按照毒品标准进行。以新列管的依托咪酯为切入点，系统总结了依托咪酯及临床衍生物的药理功能，梳理了依托咪酯及衍生物的临床检测分析及司法实践和司法鉴定中的检测技术规范。针对“以药代毒”这一新的毒情形势，从临床麻醉药物和精神药物的溯源、毒品同系物衍生物的监测、毒品合成原料和设备的备案、新型流毒载体的管控、检测技术和方法的标准化五个方面提出建议，以期为遏制以依托咪酯为代表的临床合法药物被非法滥用及毒品的科学管理和有效打击提供思路和借鉴。

关键词: 依托咪酯, 衍生物, 药物滥用, 司法鉴定

CLC Number:

DF795.1

WANG Peixia, CAO Xintao, WANG Chen, CAO Boyang, ZHANG Lingling. Pharmacological Functions, Illicit Abuse and Forensic Appraisal of Etomidate and Its Derivatives[J]. Chinese Journal of Forensic Sciences, 2024(6): 50-57.

王培霞, 曹鑫涛, 王晨, 曹伯洋, 张令令. 依托咪酯及衍生物的药理功能、非法滥用和司法鉴定[J]. 中国司法鉴定, 2024(6): 50-57.

References

[ 1 ] VALK B I，STRUYS M M R F. Etomidate and its analogs：A review of pharmacokinetics and pharmacodynamics[J]. Clinical Pharmacokinetics，2021，60（10）：1253-1269.
[ 2 ] FORMAN S A. Clinical and molecular pharmacology of etomidate[J]. Anesthesiology，2011，114（3）：695-707.
[ 3 ] JURD R，ARRAS M，LAMBERT S，et al. General anesthetic actions in vivo strongly attenuated by a point mutation in the GABA（A） receptor beta3 subunit[J]. FASEB Journal，2003，17（2）：250-252.
[ 4 ] ZHONG H，RÜSCH D，FORMAN S A. Photo-activated azi-etomidate，a general anesthetic photolabel，irreversibly enhances gating and desensitization of gamma-aminobutyric acid type A receptors[J]. Anesthesiology，2008，108（1）：103-112.
[ 5 ] SNEYD J R，RIGBY-JONES A E. New drugs and technologies，intravenous anaesthesia is on the move （again） [J]. British Journal of Anaesthesia，2010，105（3）：246-254.
[ 6 ] OGLESBY A J. Should etomidate be the induction agent of choice for rapid sequence intubation in the emergency department?[J]. Emergency Medicine Journal，2004，21（6）：655-659.
[ 7 ] 曾因明，邓小明，刘进，等.依托咪酯临床应用指导意见[J].国际麻醉学与复苏杂志，2008，29（4）：382-385.
[ 8 ] JOHNSON K B，EGAN T D，LAYMAN J，et al. The influence of hemorrhagic shock on etomidate：A pharmacokinetic and pharmacodynamic analysis[J]. Anesthesia and Analgesia，2003，96（5）：1360-1368.
[ 9 ] BOVILL J G. Intravenous anesthesia for the patient with left ventricular dysfunction[J]. Seminars in Cardiothoracic and Vascular Anesthesia，2006，10（1）：43-48.
[10] 王玉龙，易琼，徐薇，等.丙泊酚对丘脑室旁核谷氨酸能神经元活性的影响[J].药学学报，2023，58（4）：919-927.
[11] ZUCKERBRAUN N S，PITETTI R D，HERR S M，et al. Use of etomidate as an induction agent for rapid sequence intubation in a pediatric emergency department[J]. Academic Emergency Medicine，2006，13（6）：602-609.
[12] CHERFAN A J，ARABI Y M，AL-DORZI H M，et al. Advantages and disadvantages of etomidate use for intubation of patients with sepsis[J]. Pharmacotherapy，2012，32（5）：475-482.
[13] RAINES D E. The pharmacology of etomidate and etomidate derivatives[J]. International Anesthesiology Clinics，2015，53（2）：63-75.
[14] NYMAN Y，HOFSTEN K V，RITZMO C，et al. Effect of a small priming dose on myoclonic movements after intravenous anaesthesia induction with Etomidate-Lipuro in children[J]. British Journal of Anaesthesia，2011，107（2）：225-228.
[15] DOU X Q，WU B B，LIU J Y，et al. Effect of chirality on cell spreading and differentiation：From chiral molecules to chiral self-assembly[J]. ACS Applied Materials & Interfaces，2019，11（42）：38568-38577.
[16] 张玉婷，魏春燕，张崇敬.青蒿素10位碳取代优势构型的立体选择性合成及不同酸碱性基团对其抗疟活性的影响[J].药学学报，2023，58（12）：3691-3700.
[17] 刘文强，李莉.手性药物及其中间体拆分方法的研究进展[J].药学学报，2018，53（1）：37-46.
[18] 张颖怡，李良，马安德，等. 甲基苯丙胺对映异构体手性分离方法及其毒性作用的研究进展[J]. 法医学杂志，2019，35（3）：337-343.
[19] 汤文川，常靖，王元凤，等. 苯丙胺类、氯胺酮、卡西酮类毒品手性分离的研究进展[J]. 色谱，2021，39（3）：271-280.
[20] AUMATELL A，WELLS R J. Chiral differentiation of the optical isomers of racemethorphan and racemorphan in urine by capillary zone electrophoresis[J]. Journal of Chromatographic Science，1993，31（12）：502-508.
[21] TOMLIN S L，JENKINS A，LIEB W，et al. Stereoselective effects of etomidate optical isomers on gamma-aminobutyric acid type A receptors and animals[J]. Anesthesiology，1998，88（3）：708-717.
[22] COTTEN J F，HUSAIN S S，FORMAN S A，et al. Methoxycarbonyl-etomidate：A novel rapidly metabolized and ultra-short-acting etomidate analogue that does not produce prolonged adrenocortical suppression[J]. Anesthesiology，2009，111（2）：240-249.
[23] PEJO E，COTTEN J F，KELLY E W，et al. In vivo and in vitro pharmacological studies of methoxycarbonyl-carboetomidate[J]. Anesthesia and Analgesia，2012，115：297-304.
[24] PEJO E，GE R，BANACOS B，et al. Electroencephalographic recovery，hypnotic emergence，and the effects of metabolite after continuous infusions of a rapidly metabolized etomidate analog in rats[J]. Anesthesiology，2012，116（5）：1057-1065.
[25] CAMPAGNA J A，POJASEK K，GRAYZEL D，et al. Advancing novel anesthetics：Pharmacodynamic and pharmacokinetic studies of cyclopropyl-methoxycarbonyl metomidate in dogs[J]. Anesthesiology，2014，121（6）：1203-1216.
[26] PEJO E，ZHOU X J，HUSAIN S S，et al. Sedative-hypnotic binding to 11β-hydroxylase[J]. Anesthesiology，2016，125（5）：943-951.
[27] PEJO E，FENG Y，CHAO W，et al. Differential effects of etomidate and its pyrrole analogue carboetomidate on the adrenocortical and cytokine responses to endotoxemia[J]. Critical Care Medicine，2012，40（1）：187-192.
[28] COTTEN J F，FORMAN S A，LAHA J K，et al. Carboetomidate：A pyrrole analog of etomidate designed not to suppress adrenocortical function[J]. Anesthesiology，2010，112（3）：637-644.
[29] DESAI R，MILLER W K，RAINES D E. The pyrrole etomidate analog carboetomidate potently inhibits human 5-HT3A receptor function：Comparisons with etomidate and potential implications for emetogenesis[J]. Anesthesia and Analgesia，2013，116（3）：573-579.
[30] YANG J，KANG Y，WANG B，et al. Metabolite-inactive etomidate analogues alleviating suppression on adrenal function in Beagle dogs[J]. European Journal of Pharmaceutical Sciences，2017，99：343-349.
[31] WANG B，YANG J，CHEN J，et al. An etomidate analogue with less adrenocortical suppression，stable hemodynamics，and improved behavioral recovery in rats[J]. Anesthesia and Analgesia，2017，125（2）：442-450.
[32] WANG B，CHEN S M，YANG J，et al. ET-26 hydrochloride （ET-26 HCl） has similar hemodynamic stability to that of etomidate in normal and uncontrolled hemorrhagic shock （UHS） rats[J]. PLoS One，2017，12（8）：e0183439.
[33] PEJO E，SANTER P，JEFFREY S，et al. Analogues of etomidate：modifications around etomidate’s chiral carbon and the impact on in vitro and in vivo pharmacology[J]. Anesthesiology，2014，121：290-301.
[34] 张宇. 依托咪酯：滥用危害不亚于毒品[N].中国禁毒报，2023-07-21（5）.
[35] 国家药典委员会. 中华人民共和国药典[M]. 北京：化学工业出版社，2005：346.
[36] 宋妍，马爱玲. HPLC法测定依托咪酯脂肪乳注射液中依托咪酯的含量[J].中国医药指南，2013，11（17）：84-85.
[37] 马雅茹，康婷，曹志华，等. HPLC测定甲氧依托咪酯原料药中的有关物质[J]. 华西药学杂志，2021，36（5）：566-569.
[38] O’NEAL L C，CROUCH J D，FATAH A A. Validation of twelve chemical spot tests for the detection of drugs of abuse[J]. Forensic Science International，2000，109（3）：189-201.
[39] CATALAN-CARRIO R，MORENO-SANZ G，BASABE-DESMONTS L，et al. Ionogel based material for the colorimetric detection of Δ9-tetrahydrocannabinol[C]//Proceedings of the 20th IEEE Sensors Conference. Washington，D.C.，USA：IEEE Press，2021：1-4.
[40] 郭畅，周浩，许芳，等.背景荧光猝灭-免疫层析法定量检测唾液中的安非他明[J].化学与生物工程，2020，37（8）：57-62.
[41] 宋朝锦，张大明，郭伟正，等.体液中吗啡类毒品放射免疫分析方法研究[J].中国药物滥用防治杂志，2003（3）：52-54.
[42] 耿莹莹，李亚飞，刘湘祁，等.便携式拉曼光谱仪在毒品和易制毒化学品快速检测中的应用[J]. 散射学报，2015，27（1）：44-48.
[43] DIES H，RAVEENDRAN J，ESCOBEDO C，et al. Rapid identification and quantification of illicit drugs on nanodendritic surface-enhanced Raman scattering substrates[J]. Sensors and Actuators B：Chemical，2018，257：382-388.
[44] 马霞，张志远，张宏，等.基于远红外光谱技术的毒品光谱分析[J].光学仪器，2020，42（2）：20-25.
[45] 张高勤，白冰，乔亚杰，等.红外光谱技术在制毒现场中的应用[J].临床医药文献电子杂志，2018，5（19）：190-191.
[46] 梁辰玮，张凯，苏乐乐，等.拉曼光谱法在毒品检测中的应用[J].中国药物滥用防治杂志，2023，29（10）：1677-1681.
[47] 雷霏，王雅晨，孙其然，等.表面增强拉曼光谱在法庭科学领域的研究进展[J].中国司法鉴定，2019（4）：56-60.
[48] WILLIAMS S F，STOKES R，TANG P L，et al. Detection & identification of hazardous narcotics and new psychoactive substances using Fourier transform infrared spectroscopy （FTIR）[J]. Analytical Methods，2023，15（26）：3225-3232.
[49] HERRERO M，IBÁÑEZ E，CIFUENTES A，et al. Multidimensional chromatography in food analysis[J]. Journal of Chromatography A，2009，1216（43）：7110-7129.
[50] 林楠，周欣蕊，王婷，等.高效液相色谱法在食品安全检测中的应用[J].食品安全质量检测学报，2019，10（6）：1431-1437.
[51] 李重阳，王乐，赵文成.甲卡西酮类新型策划毒品的危害及其检测[J].中国司法鉴定，2014（2）：47-50.
[52] 李双，曹苏仙，杨亮，等.高分辨质谱快速检测人体尿液中常见毒品[J].分析试验室，2017，36（2）：143-146.
[53] 詹绍旭，张强，吕鹏雪，等.质谱技术在文书鉴定中的应用研究进展[J].化学研究与应用，2022，34（7）：1457-1466.
[54] 王霄，刘艳，曹艳萍，等.敞开式离子化质谱在法庭科学中的应用[J].中国司法鉴定，2017（6）：50-55.
[55] HONG Y M，SHARMA V K，CHIANG P C，et al. Fast-target analysis and hourly variation of 60 pharmaceuticals in wastewater using UPLC-high resolution mass spectrometry[J]. Archives of Environmental Contamination and Toxicology，2015，69（4）：525-534.
[56] HERNÁNDEZ F，IBÁÑEZ M，BOTERO-COY A M，et al. LC-QTOF MS screening of more than 1，000 licit and illicit drugs and their metabolites in wastewater and surface waters from the area of Bogotá，Colombia[J]. Analytical and Bioanalytical Chemistry，2015，407（21）： 6405-6416.
[57] SANTOS A D C，DUTRA L M，MENEZES L R A，et al. Forensic NMR spectroscopy：Just a beginning of a promising partnership[J]. TrAC-Trends in Analytical Chemistry，2018，107：31-42.
[58] CASTAING-CORDIER，T，LADROUE V，BESACIER F，et al. High-field and benchtop NMR spectroscopy for the characterization of new psychoactive substances[J]. Forensic Science International，2021，321：110718.
[59] COBAS C. NMR signal processing，prediction，and structure verification with machine learning techniques[J]. Magnetic Resonance in Chemistry，2020，58（6）：512-519.
[60] 中国人民共和国公安部. 法庭科学生物检材中毒物毒品定性定量检验方法通用要求：GA/T 1900—2021[S]. 2021.

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