Postmortem Redistribution In Forensic Toxicology
11/1/2019PostmortemRedistributionin ForensicToxicologyThe Chemistry of DeathLucas ZarwellDarren GriffinChief Toxicologist,DC Medical Examiner's OfficeProfessor of Genetics,University of KentThis ACS Webinar is a special rebroadcast of a past recording, there will be no slides available or interactive Q&A.www.acs.org/acswebinars21
11/1/2019A Review of Postmortem Redistributionin Forensic ToxicologyLucas Zarwell, MFS, D-ABFT-FTChief ToxicologistOffice of the Chief Medical ExaminerWashington, DCDrug movements withinthe body after death whichcause time-dependentvariations in blood andtissue drug concentrationsprior to autopsy2
11/1/2019 Medical Examiners may depend on toxicology results to helpdetermine the cause and manner of death PMR (Postmortem Redistribution) may be misleading,attributing high drug concentrations with a toxic effectTo understand postmortem redistributionin terms of chemistry, pharmacology,and forensic interpretation.3
11/1/201955 year old male is found deceased in bed in a secure residence.There is an antidepressant medication on scene next to the bedincluding the tricyclic antidepressant imipramine.In addition, there is 1/2 full bottle ofwine on the floor. At autopsy, themedical examiner can find noimmediate anatomical cause ofdeath. The medical examinersubmits venous blood, heart blood,vitreous humor and liver to theforensic toxicologist for analysis.MeMe4
11/1/2019Discuss the major contributing elements to PMR Drug Chemistry Drug Pharmacokinetics Distribution Mechanisms5
11/1/2019 Acid / Base Properties (pKa) Lipophilicity Size and StructureWhat is pKa? It is derived from Ka which is the equilibrium constant for thechemical reaction known as dissociation in the context of acidbase reactions pKa - log10KaKa is a quantitative measure of the strength of an acid in solution6
11/1/2019 pKa - log10KaStrong Base pKa is used in practice to avoid the manyorders of magnitude spanned by Ka The value can be assigned to both acidsand bases Essentially: the smaller the pKa thestronger the acid, the higher the pKa, thestronger the base Thus one can determine the degree ofionization at a given pH When we substitute these elements (pH and pKa) in to the HendersonHasselbalch equation we can mathematically determine how much of adrug is ionized at a biological pH The ionization of drug molecules is important with regard to theiradsorption into the circulation and their distribution to different tissues. It's also handy when you are trying to extract on the bench!Strong Acid7
11/1/2019The pKa of Imipramine: 9.5The pKa of Ethanol is 15.9The approximate antemortem pHof the small intestine is 616Audience Survey QuestionANSWER THE QUESTION ON BLUE SCREEN IN ONE MOMENTHow much Imipramine is ionized? 30% 50% 75% 90.1% 99.9%MeMe* If your answer differs greatly from the choices above tell us in the chat!8
11/1/201917Audience Survey QuestionANSWER THE QUESTION ON BLUE SCREEN IN ONE MOMENTHow much Imipramine is ionized? 30% 50% 75% 90.1% 99.9%MeMe* If your answer differs greatly from the choices above tell us in the chat!The nonionized form of the drugtends to be more lipid solubleNormal biological pH is about 7.4Imipramine is highly lipid soluble9
11/1/2019Imipramine:280 Da (Daltons)Formula: ipramine-3D-balls.png10
11/1/2019Calciseptine (mamba venom):7,000 Da (Daltons)Formula: i/File:3Dmodel of calciseptine structure.pngDrug Chemistry Protein Binding Volume of Distribution Storage Depots11
11/1/2019 Passive Transport Filtration (think Kidney) Active Transport (ATP) Facilitated DiffusionAdenosine triphosphate, also known as ATP, is a molecule that carries energy within cells. It is the main energycurrency of the cell, and it is an end product of the processes of photophosphorylation (adding a phosphate groupto a molecule using energy from light), cellular respiration, and fermentation.Drug Chemistry effects drugs ability tobind with plasma proteins and tissues inthe blood Albumin attracts acidic drugs α1-acid glycoprotein attracts basic drugs12
11/1/2019Drug chemistry effects theVolume of Distribution (Vd)Vd is determined experimentally𝑨𝒑𝑽𝒅 𝑪𝒑Imipramine has a Vd of 20 - 40 L/kgEthanol has a Vd of 1 L/kg13
11/1/201928Audience Survey QuestionANSWER THE QUESTION ON BLUE SCREEN IN ONE MOMENTStorage Deposits: What is a good specimen to measure lead? Liver Brain Bone Hair TongueImage Credit: .27/index.s15.html* If your answer differs greatly from the choices above tell us in the chat!14
11/1/201929Audience Survey QuestionANSWER THE QUESTION ON BLUE SCREEN IN ONE MOMENTStorage Deposits: What is a good specimen to measure lead? Liver Brain Bone Hair TongueImage Credit: .27/index.s15.html* If your answer differs greatly from the choices above tell us in the chat!High PMRlow PMR15
11/1/2019These are elements of biochemistry whichinfluence drug blood and tissue concentrationswhether an individual is alive or dead. Digestion stops Breathing stops Decomposition startsMetabolism stopsBlood flow stops16
11/1/2019 Aerobic respiration stops Oxygen is no longer provided (hypoxia) In the mitochondria, oxygen was the final electronreceptor of the electron transport systemresponsible for the synthesis of ATP from NADH Thus we no longer have ATP to run cellularoperations - and cellular death beginsNicotinamide adenine dinucleotide (NAD) is a cofactor that is central to metabolism. Found in all living cells, NAD iscalled a dinucleotide because it consists of two nucleotides joined through their phosphate groups. One nucleotidecontains an adenine nucleobase and the other nicotinamide. NAD exists in two forms: an oxidized and reduced form,abbreviated as NAD and NADH respectively.34Audience Survey QuestionANSWER THE QUESTION ON BLUE SCREEN IN ONE MOMENTCell Death: A decrease in celluar pH is caused by? Water moving out of the cell into the surrounding vessels Anaerobic glycolysis Mitochondrial damage and enzyme activation Tiny Lemons floating in the intracellular space* If your answer differs greatly from the choices above tell us in the chat!17
11/1/201935Audience Survey QuestionANSWER THE QUESTION ON BLUE SCREEN IN ONE MOMENTCell Death: A decrease in celluar pH is caused by? Water moving out of the cell into the surrounding vessels Anaerobic glycolysis Mitochondrial damage and enzyme activation Tiny Lemons floating in the intracellular lycolysisB-v-ug-lumped fig1 294059422* If your answer differs greatly from the choices above tell us in the chat! Build up of lactic acid result in decreases in intercellular pH Na begins to build up in the cell (ATPasepump has failed) Water is osmotically pulled into the cell ANDincreasing catabolites add the intracellularosmotic load Leads to cellular dilation, disruption andlysosomal membrane disruption Lysosomal enzymes leak out, become active, and digest cell components andmembranes18
11/1/2019 Build up of lactic acid result in decreases in intercellular pH Na begins to build up in the cell (ATPase pump has failed) Water is osmotically pulled into the cell AND increasing catabolitesadd the intracellular osmotic load Leads to cellular dilation, disruption and lysosomal membranedisruption Lysosomal enzymes leak out, become active, and digest cellcomponents and membranes “Micro” Redistribution Acidification Passive Diffusion Blood Coagulation and Hypostasis Postmortem “Circulation” Putrefaction19
11/1/2019 Enzymes, proteases, phosphatases, glucosidases all leak intothe cytoplasm - further breaking down cellular components Macromolecules, proteins, and the drugs bound to them (ordetached) drift out into the extracellular space This tends to be higher in tissues rich in enzymes (pancreasand gastric mucosa) and slower in the heart, liver, and kidney Contents of a cell become more acidified after death After a cell lyses, progressively ionized drugs willdistribute more readily as a result of being transportedin the acidic fluid in which they are dissolved20
11/1/201940 mg/LTissue1 mg/LBloodTissueTime Zero20 mg/LTissue10 mg/LBloodTissue4 hours later21
11/1/2019Organs which are close to the heart and major blood vessels Liver (Left Lobe) Stomach / Esophagus Adipose Tissue Small Intestine (Duodenum) Lungs MyocardiumTemperature can effect this Concentration can effect this 22
11/1/2019 Blood sediments and clots unevenly after death This is due to blood clotting and cell lysis happening simultaneously As hours pass, hypostasis occurs when theblood sediments and serum flow, according togravity, to the lower parts of the body Drugs follow according to their respectivechemistries23
11/1/2019 It’s been demonstrated that body position may influence PMR Repositioning of a body after death may also influencemovement of the blood postmortem “New” blood sources may pool near tissues and allow morediffusion to occur Bacteria and microflora can effect drugconcentrations and must be considered. Bacteria can migrate across the intestinal wall toblood vessels and lymph vessels Enteric Bacteria can metabolize drugs andproduce ethanol (as well as yeast) Effect can be decreased in cooler temperatures24
11/1/2019 Rigor mortis can cause blood movement by causing systolicpressure through ventricular contractions Putrefactive processes in the abdomen can move blood due togas swelling These are not strong processes Store and Obtain Autopsy Specimens Properly Understand the Limitations of Interpretation Study and Review Reference Literature25
11/1/2019 Storing decedents between 2 - 8 C prior to autopsy- Slows redistribution- Slows putrefaction Conversely, warmer temperatures have the opposite effect Take blood and tissue from specific sitesduring autopsy Central Blood (Heart, Subclavian) Peripheral Blood (Inferior Vena Cava) Vitreous Humor Tissue (Liver, Brain)26
11/1/20192 Take blood and tissue from specific sitesduring autopsy Central Blood (#1 Heart, #2 Subclavian) Peripheral Blood (#3 Inferior Vena Cava) Vitreous Humor Tissue (Liver, Brain)13(Dinis-Oliveira RJ, Carvalho F, Duarte JA, et al., 1993)27
11/1/2019(Dinis-Oliveira RJ, Carvalho F, Duarte JA, et al., 1993)(Dinis-Oliveira RJ, Carvalho F, Duarte JA, et al., 1993)28
11/1/2019(Dinis-Oliveira RJ, Carvalho F, Duarte JA, et al., 1993) Lung Cerebrospinal fluid Bone Marrow Skeletal Muscle(Dinis-Oliveira RJ, Carvalho F, Duarte JA, et al., 1993)29
11/1/2019Central (Heart) / Peripheral (Venous)Peripheral (Venous) / Tissue (Liver)Central (Heart) / Peripheral (Venous)Peripheral (Venous) / Tissue (Liver)30
11/1/2019Central (Heart) / Peripheral (Venous)methadone 1.0 - 4.0Cocaine 1.3Imipramine 1.8Zolpidem 2.1sold under the brand name Ambien among others, is amedication primarily used for the short term treatmentof sleeping problems.Doxepin 5.5a medication used to treat major depressive disorder,anxiety disorders, chronic hives, and trouble ia/File:Doxepin2DACS.svg1. Basalt R, ed. Disposition of toxic drugs andchemicals in man. 11th ed. Foster City, CA: BiomedicalPublications; 2017.2. Osselton M, Moffat A, Widdop B, eds. Clarke'sanalysis of drugs and poisons. 4th ed. Gurnee, IL:Pharmaceutical Press; 2011. Moffat A., Osselton M., Widdop B. andWatts J., eds.31
11/1/2019reference literatureDrugDescriptionVd (L/kg)ReferenceDigoxinTreats atrial fibrillation5.1 - 7.4Vorphal, 1978MorphineAnalgesic2-5Logan, 1993AmitripylineTricyclic Antidepressant6 - 10Hebb, 1982ImipramineTricyclic Antidepressant20 - 40Jones, 1987EthanolDrinking AlcoholDiphenhydramineAntihistamine0.43 - 0.59 Prouty, 19873 - 14Hargrove, 2008 What does our analysis show us? Show what the reference literature said(basalt and article) Understand the clear differences32
11/1/2019TissueEthanol (g/100mL) Imipramine (mg/L)Heart0.0814IVC0.094Liver0.06 (g/100g)61 (mg/kg)Vitreous Humor0.11N/AImipramine c/p 3.5TissueEthanol (g/100mL) Imipramine (mg/L)Heart0.022IVC0.020.8Liver0.005 (g/100g)18 (mg/kg)Vitreous Humor0.03N/AImipramine c/p 2.533
11/1/2019Reference TissueEthanol (g/100mL)Imipramine (mg/L)PlasmaN/A0.05 - 0.10vsNatural PostmortemReferenceTissueEthanol (g/100mL)Imipramine (mg/L)Blood0.42 - 1.776 - 8.5Liver0.25 - 1.1633 - 381Intoxication FatalityReferenceTissueEthanol (g/100mL)Imipramine (mg/L)Blood0.02 - 0.50 0.5Liver0.01 - 0.351334
11/1/2019DrugImipramineIVC eutic0.05 - 0.10N/AN/AN/AIntoxication6 - 8.533 - 3810.42 - 1.770.25 - 1.16Natural 0.513N/AN/AScenario 14610.090.06Scenario 20.8180.020.00570Audience Survey QuestionANSWER THE QUESTION ON BLUE SCREEN IN ONE MOMENTCase Scenarios: What does our analysis show us? Scenario 1 and 2 are likely intoxications Scenario 1 is likely an intoxication and scenario 2 is likely a natural death We can’t determine if Scenario 2 was drinking wine Scenario 1 is clearly a suicide* If your answer differs greatly from the choices above tell us in the chat!35
11/1/201971Audience Survey QuestionANSWER THE QUESTION ON BLUE SCREEN IN ONE MOMENTCase Scenarios: What does our analysis show us? Scenario 1 and 2 are likely intoxications Scenario 1 is likely an intoxication and scenario 2 is likely a natural death We can’t determine if Scenario 2 was drinking wine Scenario 1 is clearly a suicide* If your answer differs greatly from the choices above tell us in the chat!1. Bynum ND, Poklis JL, Gaffney-Kraft M, Garside D, Ropero-Miller JD. Postmortem distribution of tramadol, amitriptyline, and their metabolitesin a suicidal overdose J Anal Toxicol. 2005;29(5):401-406.2. Dinis-Oliveira RJ, Carvalho F, Duarte JA, et al. Collection of biological samples in forensic toxicology. Toxicol Mech Methods.2010;20(7):363-414.3. Gilliland MG, Bost RO. Alcohol in decomposed bodies: Postmortem synthesis and distribution J Forensic Sci. 1993;38(6):1266-1274.4. Hargrove VM, McCutcheon JR. Comparison of drug concentrations taken from clamped and unclamped femoral vessels J Anal Toxicol.2008;32(8):621-625.5. Hebb JH,Jr, Caplan YH, Crooks CR, Mergner WJ. Blood and tissue concentrations of tricyclic antidepressant drugs in post mortem cases:Literature survey and a study of forty deaths J Anal Toxicol. 1982;6(5):209-216.6. Hilberg T, Ripel A, Slordal L, Bjorneboe A, Morland J. The extent of postmortem drug redistribution in a rat model J Forensic Sci.1999;44(5):956-962.7. Jones GR, Pounder DJ. Site dependence of drug concentrations in postmortem blood--a case study J Anal Toxicol. 1987;11(5):186-190.36
11/1/20198. Langford AM, Pounder DJ. Possible markers for postmortem drug redistribution. J Forensic Sci. 1997;42(1):88-92.9. Leikin JB, Watson WA. Post-mortem toxicology: What the dead can and cannot tell us J Toxicol Clin Toxicol. 2003;41(1):47-56.10. Logan BK, Smirnow D. Postmortem distribution and redistribution of morphine in man. J Forensic Sci. 1996;41(2):221-229.11. O'Sullivan JJ, McCarthy PT, Wren C. Differences in amiodarone, digoxin, flecainide and sotalol concentrations betweenantemortem serum and femoral postmortem blood Hum Exp Toxicol. 1995;14(7):605-608.12. Pelissier-Alicot A-, Gaulier J-, Champsaur P, Marquet P. Mechanisms underlying postmortem redistribution of drugs: A review JAnal Toxicol. 2003;27(8):533 last page 544. doi: 10.1093/jat/27.8.533.13. Pounder DJ. The nightmare of postmortem drug changes Leg Med. 1993:163-191.14. Pounder DJ, Jones GR. Post-mortem drug redistribution--a toxicological nightmare Forensic Sci Int. 1990;45(3):253-263.15. Prouty RW, Anderson WH. The forensic science implications of site and temporal influences on postmortem blood-drugconcentrations J Forensic Sci. 1990;35(2):243-270.16. Prouty RW, Anderson WH. A comparison of postmortem heart blood and femoral blood ethyl alcohol concentrations J Anal Toxicol.1987;11(5):191-197.17. Robertson MD, Drummer OH. Postmortem distribution and redistribution of nitrobenzodiazepines in man. J Forensic Sci. 1998;43(1):9-13.18. Robertson MD, Drummer OH. Postmortem drug metabolism by bacteria J Forensic Sci. 1995;40(3):382-386.19. Vorpahl TE, Coe JI. Correlation of antemortem and postmortem digoxin levels J Forensic Sci. 1978;23(2):329-334.20. Yarema MC, Becker CE. Key concepts in postmortem drug redistribution Clin Toxicol (Phila). 2005;43(4):235-241.37
11/1/2019The Chemistry of DeathLucas ZarwellDarren GriffinChief Toxicologist,DC Medical Examiner's OfficeProfessor of Genetics,University of KentThis ACS Webinar is a special rebroadcast of a past recording, there will be no slides available or interactive Q&A.www.acs.org/acswebinars7638
Medical Examiners may depend on toxicology results to help determine the cause and manner of death PMR (Postmortem Redistribution) may be misleading, attributing high drug concentrations with a toxic effect To understand postmortem redistribution in terms of chemistry, pharmacology, and forensic interpretation.
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