Toxicological Evaluation of Psychotropic Drug Overdose in Forensic Practice

INTRODUCTIONDrug overdose is a major public health problem [1, 2]. Poisoning is the second most common cause of unintentional death in the United States, and most of these deaths are due to overdose [3, 4]. There is a large amount of surveillance data from epidemiological studies [5- 9]. It is known that the involvement of drugs differs significantly between countries, states and regions [1-9]. Clinical records [1, 10-13], autopsy records [14-17], and police statistics [18] show that overdose by psychotropic drugs is the most frequently observed cause of poisoning by pharmaceuticals in Japan. Overdose has a high incidence among users of sedatives-hypnotics, especially related to excessive dosage, barbiturate use, and multiple drug use [1, 14, 15, 17, 18].Psychotropic drugs, including hypnotics (benzodiazepines, barbiturates, benzodiazepinereceptor agonists), anxiolytics (benzodiazepines), antipsycho-tics (phenothiazines, butyrophenones, heterocyclic compounds), antidepre-ssants (cyclic antidepressants, selective serotonin reuptake inhibitors (SSRI), serotonin-noradrenaline reuptake inhibitors (SNRI)), and anticonvulsants (hydantoins, iminostilbenes, barbiturates, valproic acid) are widely prescribed in daily medical practice. Overdose by these drugs is a common problem in Japan [1, 10-18]. Forensic pathologists and toxicologists have a role to play in terms of medicolegal investigation. Detailed forensic patho-toxicological analysis in poisoning cases is useful, and data obtained by such studies is indispensable in enacting effective preventive measures. This paper provides an overview of autopsy, pharmacological, and toxicological findings in drug overdose, and may thereby contribute to the development of overdose prevention measures.PHARMACOLOGY OF DRUG OVERDOSE1) Hypnotics and AnxiolyticsMost hypnotics and anxiolytics are well and rapidly absorbed by the small intestine following oral ingestion [19, 20]. Most of these drugs are highly lipophilic. Therefore, clinical symptoms such as ataxia, incoordination, stupor or loss of consciousness are observed rapidly following ingestion [21]. These drugs act as central nervous system (CNS) depressants, due to the enhancement of the γ-aminobutyric acid (GABA)-mediated inhibitory neurotransmission [21]. Overdose can result in death from cardiorespiratory collapse by CNS and respiratory depression [19, 21].2) AntipsychoticsMost antipsychotics are well absorbed by the gastrointestinal (GI) tract following oral ingestion [22]. As several of these drugs have anticholinergic properties, absorption by the intestine may be delayed by the decrease of GI motility, in case of massive ingestion [22, 23]. Overdose of antipsychotics causes a CNS depression, including impaired consciousness. It also causes prolongation of the QRS complex and QT interval in electrocardiogram (ECG). This may develop into fatal arrhythmia [22, 23].3) AntidepressantsMost cyclic antidepressants are fairly well absorbed by the GI tract following oral administration [24]. Blood concentration of most cyclic antidepressants peaks within several hours of ingestion [24]. As several of these drugs have potent anticholinergic properties, absorption by the intestine may be delayed in an overdose by the decrease of GI motility [24, 25]. Most of these drugs are highly lipophilic and have a large distribution volume (Vd: 10- 50L/kg), and are distributed to various organs [24]. Overdose of cyclic antidepressants causes cardiovascular toxicity, such as refractory hypotension, due to myocardial depression or prolongation of the QRS complex and QT interval in ECG [24, 26]. In the case of amoxapine overdose, incidence of seizures is significantly higher than that of other cyclic antidepressants [26-28]. Most SSRI overdoses cause CNS depression and cardiac toxicity, but these are usually not life-threatening [29]. However, since most SSRIs and their metabolites are substrates for, and potent inhibitors of, cytochrome P450 (CYP) enzymes, drug-drug interaction should be considered in cases of multiple drug overdose [24, 29-31]. …