Copyright Material – Provided by Taylor & Francis Special Drug Groups 2 Acetylcholinesterase Inhibitors While acetylcholinesterase inhibitors were historically used as pesticides and herbicides, in recent years they have been used to develop medica- tions to treat Alzheimer’s disease and myasthenia gravis. Commonly, their toxicity is measured by the percentage of acetylcholinesterase (ACh) activ- ity with toxicity beginning 20% below the level of normal activity (or 80% activity level) and becoming pronounced by 50% activity level. Severe tox- icity and death occur at 90% suppression (measured activity level = 10%). Postmortem testing should utilize the red blood cell (RBC), ACh as it better reflects neural ACh activity. Table 2.1 is a non-comprehensive list of common drugs, nerve agents, and insecticide/pesticides that are acetylcholinesterase inhibitors. 3 Copyright Material – Provided by Taylor & Francis 4 Table 2.1 Acetylcholinesterase Inhibitors Drugs—Alzheimer’s disease Drugs—myasthenia gravis Drugs—glaucoma Poisons—nerve agents Donepezil (Aricept) Ambenonium (Mytelase) Demecarium (Humorsol) Cyclosarin Galantamine (Razadyne, Reminyl, Edrophonium (Tensilon, Enlon, Echothiophate (Phospholine iodide) Sarin Nivalin) Reversol) Soman Medical for ExaminersHandbook Toxicology Forensic of Huperzine A Neostigmine (Prostigmin) Tabun Ladostigil Physostigmine (Antilirium) VX Metrifonate Pyridostigmine (Mestinon, VE Rivastigmine (Exelon) Regonol) VG Tacrine (Cognex) VM Insecticides or pesticides Acephate (Orthene) Dichlorvos (DDVP, Vapona) Formetanate (Carzol) Oxydemeton-methyl (Meta Aldicarb (Temik) Dicrotophos (Bidrin) Fenthion (Baytex, Tiguvon, Entex) systox-R) Azinphos-methyl (Guthion) Diisopropyl fluorophosphate Fonofos (Dyfonate) Parathion (Niran, Phoskil) Bendiocarb (Ficam) (Dyflos) Isofenphos (Oftanol, Amaze) Phorate (Thimet) Bufencarb Dimethoate (Cygon, De-Fend) Malathion (Cythion) Phosalone (Zolonc) Carbaryl (Sevin) Dioxathion (Delnav) Methamidophos (Monitor) Phosmet (Imidan, Prolate) Carbofuran (Furadan) Disulfoton (Di-Syston) Methidathion (Supracide) Phosphamidon (Dimecron) Carbophenothion (Trithion) EPN Methiocarb (Mesurol) Pirimicarb (Pirimor) Chlorfenvinphos (Birlane) Ethiofencarb Methomyl (Lannate, Nudrin) Propoxur (Baygon) Chlorpyrifos (Dursban, Lorsban) Ethion Methyl parathion (Penncap-M) Temephos (Abate) Coumaphos (Co-Ral) Ethoprop (Mocap) Mevinphos (Phosdrin) TEPP Crotoxyphos (Ciodrin, Ciovap) Famphur Monocrotophos Terbufos (Counter) Crufomate (Ruelene) Fenamiphos (Nemacur) Naled (Dibrom) Tetrachlorvinphos (Rabon, Demeton (Systox) Fenitrothion (Sumithion) Oxamyl (Vydate) Gardona) Diazinon (Spectracide) Fensulfothion (Dasanit) Trichlorfon (Dylox, Neguvon) Copyright Material – Provided by Taylor & Francis Special Drug Groups 5 Anesthetic Agents General Anesthetics General anesthetic agents are commonly used in the clinical setting to induce or maintain anesthesia. When used for this purpose, in a monitored clinical setting and in ventilated patients, the risk of death due to overdose is minimal. Some anesthetic agents are associated with other toxic effects, such as malignant hyperthermia, liver toxicities, and prolonged QT, but a discussion of these effects is beyond the scope of this book. However, when such agents are abused outside of the monitored clinical setting, even therapeutic concentrations can be lethal. Table 2.2 summarizes lethal concentrations of these medications, which have been reported in the literature. Ketamine and propofol deserve special mention and are described in more detail below. • Ketamine • In addition to being a widely used anesthetic agent, ketamine has become a drug of abuse known as Jet, Special K, Vitamin K, and Special K lube when combined with ethanol and gamma hydroxybutyric acid (GHB). • As ketamine is also used as a recreational drug, its presence alone may not indicate a lethal intoxication. The following nontoxic concentrations have been reported: Blood Liver Kidney Brain Cardiac Muscle Skeletal Muscle (mg/L) (mg/kg) (mg/kg) (mg/kg) (mg/kg) (mg/kg) 0.5–9 0.8 0.6 4 3.5 1.2 Table 2.2 Lethal Concentrations of General Anesthetic Agents Anesthetic Blood Vitreous Liver Kidney Brain Lung Muscle Agent (mg/L) (mg/L) (mg/kg) (mg/kg) (mg/kg) (mg/kg) (mg/kg) Etomidate 0.4 0.3 Halothane 3.4–720 1.7–880 12–14 104–1560 500 Isoflurane 1.8–48 31–1000 27–53 29–307 9–34 9 (skeletal) Ketamine 1.5–38 4.9–6.6 3.2–3.6 3.2–4.3 2.4 (cardiac) Nitrous oxide 11–2030 47–2200 370–2420 Propofol 0.03–5.5 1.4–27 1.8–5.5 2.9–17 222 (skeletal) Sevoflurane 8–26 87 31–269 13–29 Copyright Material – Provided by Taylor & Francis 6 Handbook of Forensic Toxicology for Medical Examiners • Propofol • With high volume of distribution and lipophilicity, it can be found several days following a surgical procedure at low tissue and blood concentrations and may not indicate an acute intoxication. • Can cause propofol infusion syndrome—characterized by metabolic acidosis, bradyarrhythmias, rhabdomyolysis, hypo- tension, and cardiac failure. • Therapeutic/nontoxic concentrations of propofol have been reported from 0.4 to 6.8 mg/L in blood. Local Anesthetics Local anesthetics usually result in toxicity and death by central nervous sys- tem excitation and seizure activity. They can also be cardiotoxic, resulting in arrhythmias and ventricular fibrillation. Tables 2.3 and 2.4 summarize the pharmacokinetic properties and non- lethal and lethal concentrations of several local anesthetic agents. Table 2.3 Pharmacokinetic Parameters and Toxic and Lethal Concentrations of Local Anesthetic Agents Nontoxic Nontoxic Toxic Lethal Lethal Anesthetic Blood Liver Blood Blood Liver Agent ʎ (h) Vd (L/kg) (mg/L) (mg/kg) (mg/L) (mg/L) (mg/kg) Benzocaine Unknown Unknown 0.05–0.5 1.0–5.2a 3.5a Bupivacaine 1–3 0.4–1 0.2–3.5 0.3–20 3.8 Lidocaine 0.7–5 1–4 0.3–5 0.01–4 8–12 12–44 10–96 Mepivacaine 1.5–2 0.5–4 0.1–5 4–9 16b–50 75 Prilocaine 0.5–2.5 0.7–4 0.9–5 0.3–2.8 13–15 14a–49 Procaine 7–8 min 0.3–1 4–43 18–96 Ropivacaine 2–4 0.5–1 0.4–3 1.5–6 2 4.4 a Children. b Mixed with lidocaine 4.9 mg/L. Table 2.4 Additional Tissue Concentrations for Lidocaine and Mepivacaine Nontoxic Concentrations Lethal Concentrations Cardiac Skeletal Cardiac Skeletal Anesthetic Kidney Brain Muscle Muscle Kidney Brain Muscle Muscle Agent (mg/kg) (mg/kg) (mg/kg) (mg/kg) (mg/kg) (mg/kg) (mg/kg) (mg/kg) Lidocaine 0.01–15 0.01–5.9 0.8 0.9–2.9 12–204 6.6–135 9–13 20 Mepivacaine 51–59 51–83 51 51 Copyright Material – Provided by Taylor & Francis Special Drug Groups 7 Lidocaine, benzocaine, and prilocaine deserve special mention and are described in additional detail below. • Benzocaine and prilocaine toxicity can result in methemoglobinemia. • Lidocaine is metabolized by CYP 1A2 and 3A4 to the active metab- olite, monoethylglycinexylidide (MEGX) and has been used as an adulterant in illicit drugs. Neuromuscular Blocking Agents Neuromuscular blocking agents block neuromuscular transmission at the neuromuscular junction, resulting in paralysis. These are most often used in anesthesia to assist in intubation. The use of these agents in the clinical setting, while the patient is being artificially ventilated, should not result in death. The presence of these agents outside of a clinical setting, in a non- ventilated patient, can result in death at any concentration. Common neuromuscular blocking agents include: atracurium, cisatra- curium, doxacurium, gallamine, mivacurium, pancuronium, pipecuronium, rapacurium, rocuronium, succinylcholine, tubocurarine, and vecuronium. Succinylcholine deserves an additional note, because it • Can be difficult to find in postmortem cases due to short half-life. • Absorbs onto glassware during storage. • Is rapidly hydrolyzed to succinylmonocholine, choline, and succinic acid, all of which are found endogenously. Copyright Material – Provided by Taylor & Francis 8 Handbook of Forensic Toxicology for Medical Examiners Metals and Metalloids Humans are exposed to metals and elements through the environment, food and water, smoking, and certain occupations or hobbies. Some metals have also been used not only medicinally but also as poisons, including being components of insecticides or pesticides. The concentrations of metals seen in blood and tissues are often extremely variable due to diet, environment, and occupation, making interpretation of postmortem metal concentrations extremely difficult; it is rec- ommended that such interpretation be done with great skepticism and reflection. Metals tend to be eliminated by and accumulate in the kidneys, so renal tissue is often the preferred tissue when testing for an acute overdose. Chronic exposure can often be delineated by testing of the hair and/or fingernails. Tables 2.5 and 2.6 outline reported metal concentrations. Numerous procedures can be utilized to test for metals, including inductively coupled plasma mass spectrophotometry (ICP), atomic absorption spectros- copy (AAS), atomic emission spectrophotometry (AES), and x-ray defraction. Be certain to contact the testing laboratory for any specific requirements. The following metals deserve special consideration: Aluminum • Classic exposure was through dialysis; no longer common. • Blocks incorporation of calcium into bone. • Associated with elevated calcium concentrations. Arsenic • Is a metalloid. Used medicinally for years. • A known carcinogen. • Elemental arsenic (Aso) is not toxic; can be found in shellfish and seafood. +5 +3 • Arsenate (As ), arsenite (As ), and arsine gas (AsH3) are toxic— +5 +3 As < As < AsH3. • Can cause white lines