Tranquilizer Drug Forensics

CE ARTICLE: 3 CE CREDITS By Jonathan J. Lipman, PhD, DABFE, DABFM, DABPS TRANQUILIZER Addiction, dependence, withdrawal syndromes, memory disturbances, amnesia, disinhibited behavior, violence, impulsivity, automatistic and somnambulistic states, and cognitive and neuropsychological impairments result at least in part from activation of receptors in the brain for the neurotransmitter Gama Aminobutyric Acid (GABA) This mechanism is responsible for many of the common, shared, and similar actions of various tranquillizing drugs used for relief of anxiety, for night-time sedation, as anticonvulsants, as a muscle-relaxant, and for surgical anesthetic purposes. These tranquillizing drugs of superficially very different chemical classes share this GABA mechanism, and they produce effects similar to beverage alcohol, ethanol. These drug effects, alone and in interaction with other drugs, combine with idiosyn- cratic neurobiological vulnerabilities to bring the user’s behavior to forensic notice in a wide variety of criminal and civil cases. The recent death of singer Michael Jackson availability and prevalence of illicit (non- has focused popular attention on the drug prescribed) or non-medical use of tranquil- propofol (Diprivan) that is relatively un- izing drugs has paralleled their emergence known outside of hospital anesthesiology. into medical markets and constitutes a ma- This drug shares many pharmacological jor problem in drug abuse. This review ad- similarities with a number of tranquilizing dresses a common mechanism, and certain drugs that are widespread and common common effects, shared by the majority of in use and abuse and form the bulk of the currently-available tranquilizing drugs of pharmaceutical money train. The relative widely different chemical families’ action This article is approved by the following for continuing education credit: (ACFEI) The American College of Forensic Examiners International provides this continuing education credit for Diplomates. After studying this article, participants should be better able to do the following: 1. Understand the common pharmacological mechanisms and effects of tranquilizing drugs acting at the brain’s GABA-A receptors. 2. Understand how drug adverse effects of different tranquillizer classes can be involved in forensically- relevant behavior. 3. Appreciate the growth of illicit drug abuse that parallels the ethical, licit, market. KEY WORDS: sedative, anxiety, tranquillizer, benzodiazepene, barbiturate, zolpidem (Ambien), gamma aminobutyric acid (GABA) receptor, automatism, amnesia, disinhibition, hostility, rage TARGET AUDIENCE: Behavioral scientists, forensic examiners, pharmacologists PROGRAM LEVEL: Basic DISCLOSURE: The authors have nothing to disclose. PREREQUISITES: None www.acfei.com DRUG FORENSICS at the brain’s GABAA receptors (described lepsy treatment (anticonvulsants), night- tion of GABA at the “Type A” GABA re- more fully below). Notwithstanding these time insomnia relief (hypnotics), conscious ceptor (the GABAA receptor). They share mechanistic similarities or commonalities, surgical sedation (sedation and amnesia), this mechanism with ethanol, also known however, different members of the class and complete surgical anesthesia (uncon- as beverage alcohol. also exert actions at non-GABAA sites and sciousness, insensibility). Given in deliber- Like beverage alcohol, the acute effects mechanisms in addition. ate overdose, they are used for pest control of tranquilizing drugs may be forensical- The purpose of this article is to provide and animal euthanasia and—in the United ly relevant in criminal and civil law cases an understanding and appreciation of the States—for prisoner execution, either as a involving driving or operating machin- shared and common GABAA mechanisms component of a serial drug mixture, or, as ery or other intoxicated, dis-coordinated and effects that tranquilizing drugs medi- recently adopted by the state of Ohio and or disinhibited or impulsive behavior or ate on brain, mind, and behavior in cir- perhaps in other states to come, as a sin- misbehavior or in poisoning, homicide cumstances of forensic relevance. Although gle drug injection (thiopentone). In many or suicide issues. When chronically used the incidence rate of disabling psychotox- cases, the same drug is used for more than (repeatedly taken over time) other com- ic effects caused by GABAA stimulation is one such intended purpose and most of plex forensic neuropharmacological is- relatively rare in the general population of these tranquilizing drugs—at least in a sues emerge, including dependence and therapeutically-prescribed users, it is higher portion of their pharmacological spec- withdrawal states resulting from changes in the drug abuser population, and in both trum—have in common a shared or closely in brain biochemistry caused by repeated populations of users and abusers, the crimi- related mechanism of action at the recep- use of the tranquilizer. In addition, the nal and civil justice systems act as a sieve to tors on nerve cells in the brain and spi- adaptive changes wrought by these drugs select and concentrate these cases of forensic nal cord for the neurotransmitter GABA. in the brain over time and their interac- interest. Therefore, regardless of the tranquilizing tions with other drugs taken or co-admin- Tranquilizing drugs are used for a vari- drugs’ structural class (barbiturate or car- istered typically need to be accounted for ety of medical purposes: relief of muscle bamate or benzodiazepine or imidazopyri- and understood in neuro-behavioral terms spasm (spasmolytics), anxiety relief, treat- dine etc.), they all, to some extent and in (see below) in order to evaluate their fo- ment of panic attacks (anxiolytics), epi- part, act in the brain to facilitate the ac- rensic relevance. (800) 592-1399 Spring 2010 THE FORENSIC EXAMINER® 17 ta and rho, α, β, γ, δ and ρ subunits) sur- rounding a central pore or channel in the nerve membrane through which chloride ions pass (Levitan et al 1988, cited in Crews (2004)1. In different parts of the brain, and on different nerves, different assemblies of these subunits allow a wide variety of different types of GABAA receptor-linked ionophores to be formed by varying the type and number of subunits. The receptor complex spans the postsynaptic membrane as illustrated schematically in Fig 1, and receptors—neurotransmitter recognition patches for various chemicals or ligands— are formed either on the subunits, or where subunits meet or within the chloride pore itself. In this article, the chloride pore as- sembly responsive to GABA or drug stimulation is referred to as the “GABAA receptor complex.” In contrast to the barbiturates, benzodi- azepines cannot directly open the chloride channel, but they facilitate GABA’s ability to do so. Chloride influx at the GABAA receptor complex hyperpolarizes the cell membrane, making it more negatively charged on the interior relative to the ex- Figure 1 terior, which renders it less likely to conduct Schematic representation of the GABAA receptor complex comprised of α, β and γ, subunits forming the chloride an action potential, and thus the effect of ion pore, spanning the nerve cell membrane. Flow of chloride ion (Cl¯) is from outside to inside the cell when GABA binds to its receptor. Receptors are schematically shown for steroid, barbiturate, benzodiazepine, ω = any ligand binding (GABA or ethanol or omega, ethanol (alcohol), picrotoxin and GABA (Gamma Aminobutyric Acid) ligands. drug) is inhibitory on the nerve. Tranquilizing drug effects on cognitive ticipation of the likely drug effects, and in Common mechanisms, function can influence alleged cognitive either case drug interactions may be para- cross-tolerance disability as relevant to brain injury claims mount in an interpretation and understand- The different types of sedative tranquilizers or compensation issues, or employment ing of consequences on the mind, brain and discussed here each exert a similar facilitato- disability claims, and can interfere with behavior of the consumer. ry effect on the GABAA receptor complex, performance in the neuropsychological but when the tranquilizers are used in com- tests used to evaluate such brain function. Shared mechanisms of different bination, their interaction is multiplicative Under certain circumstances and in certain tranquilizer types: the GABAA (either additive or potentiated, synergistic, individuals—described more fully below receptor complex see below for discussion). It follows, too, —tranquilizer intoxication can influence Gamma Aminobutyric Acid (GABA) is from their shared and common site of ac- “competence at the time of the crime” or the most abundant neurotransmitter in the tion that there is functional cross-tolerance “competence to be tried” and drug-influ- central nervous system, and GABA recep- between these different drugs. Thus a with- enced memory or the absence of this (am- tors are widely distributed throughout the drawal syndrome resulting from discon- nesia) may enter into insanity and legal brain, with high concentrations in the cor- tinuation of ethanol (beverage alcohol) in competence considerations. Where guilt is tex and limbic system. There are two types a dependent alcoholic (“delirium tremens”) not at issue in a criminal case, the effects of GABA receptor (“A” and “B”) of which can be arrested by administering a benzo- of these drugs may nevertheless bear upon the B-type is a metabotropic G-protein cou- diazepine such as diazepam

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