forensic toxicology Flashcards
Forensic tox
Forensic - for legal purpose; pertaining to the law.
Deals with the living and the dead:
Impaired driving; drug involved sexual assault
Postmortem cases - cause & manner of death
Workplace drug testing
Sports (e.g. Olympics; horse-racing)
Both criminal and civil cases
Clinical toc=x
emergency screening (e.g. overdose)
Useful only for specific substances, e.g. methanol,
acetaminophen
◦ therapeutic drug monitoring (TDM)
(limited menu of drugs such as immunosuppressants and
some anticonvulsants; defined concentration range)
Testing only done if it is likely to influence treatment
of the patient.
death investigation systems
Medical Examiner
◦ Alberta
◦ Manitoba
◦ Nova Scotia
◦ Newfoundland
Coroner system
◦ British Columbia
◦ Saskatchewan
◦ Ontario
◦ Quebec
◦ New Brunswick, PEI
◦ NWT, Nunavut, Yukon
Medical Examiner system headed by a forensic pathologist
Coroner system may or may not be headed by a physician
They both have the same purpose, and that is to determine the cause and manner of death. The 4 provinces on the the left. including Alberta, obviously, or all medical examiner Systems
Medical Examiner system is normally headed by a. A. An experience to forensic pathologists. the pathologists in Alberta that do the part of the Medical Examiner’s office of both
medical examiners and forensic pathologists. They fulfill both roles
medical exam. The system is normally headed by a forensic pathologist. A coroner system may or may not be headed by a physician. In some situations it is like Ontario.
but you don’t have to be in most provinces and territories a physician in order to be a coroner. and that sounds a little bit weird in some ways, because you can have.
especially in some of the northern areas, You can have somebody that’s a local grocery store manager, the local Funeral Home director. You maybe a paramedic can be a coroner
in British. Sorry in Ontario. You have to be a physician to be a coroner.
Coroners don’t normally perform autopsies. They normally
either have a forensic pathologist on staff, or the
they will contract out to a forensic pathologist.
ab medical examiner
Offices
◦ Edmonton and Calgary
Cases ~6000+ / year
◦ Total Alberta deaths ~33000
Homicides ~80–100 /year
Toxicology
◦ ~5000 cases / year
Cause of Death
Manner of Death
Cause of Death
◦ Immediate MEDICAL cause of
death
◦ NOT circumstances
◦ e.g. “blunt force trauma”
rather than “motor vehicle
accident”
Manner of Death
◦ Specific categories
Homicide ~1.5%
Suicide ~14%
Accident ~44%
Natural ~40%
Undetermined ~2%
Unclassified (MAID deaths)
clin tox: usuually serum or plasma
postmeorten- must use other specimens
Whole blood
Vitreous
Urine (workplace testing; also saliva/oral fluid)
Liver
Stomach contents
Other tissues (sometimes: e.g. decomposition)
Hair (sometimes: e.g. criminal case)
other specimens
Bile, CSF or virtually any fluid
Lungs, kidney, muscle or any solid tissue
Bone, nails, hair
Principle: most drugs are distributed to virtually
all fluids and tissue in the body!!!
why mostmorten tox is dfiiferent
Severe motor vehicle
accident:
Ethanol not detected,
but…
Urine METHANOL 530 mg%
Liver 190, 300 mg%
Spleen 20, 70 mg%
Explanation?
postmortem redistribution
Main mechanism
* Release and diffusion of drugs from the major
structures
* Occurs as cells die, pH changes and protein
binding weakens
* Time and concentration dependent
* Candidates:
* Drugs with a high volume of distribution
typically >5L/kg
* Drugs with ‘Basic’ character (e.g. form HCl
salts)
* Increases of 2 – 10 fold or greater possible
* Order of increasing magnitude of PM
redistribution:
* Cardiac > subclavian > femoral >
antemortem
Case 1
48 y.o. woman with severe heart disease found dead;
also history of depression
Found unresponsive and taken to hospital (but DOA)
Blood taken at hospital by local medical examiner
Blood also taken again at autopsy (12 – 18 h later)
Considerable postmortem redistribution that could
lead to mis-interpretation of toxicology results
Concentrations of amitriptyline and nortriptyline ~10x higher
in blood taken at autopsy than blood collected at the hospital
Cause of death: atherosclerotic C-V disease (MI scars)
Nortrip is active metabolite of amit –> expected to be there
The blood that was taken about 18 h later at autopsy.
the concentrations depending on where you compare them to have gone up about 20 fold for the amit
So those concentrations, if you were to compare them to what you’d expect clinically in somebody, those are considerably higher than you would expect in a clinical patient who’s taken a large overdose.
I’m not going to go into the interpretation in any detail, but that those are fairly low concentrations for liver, ametript, and and nor Tripolin, meaning They’re more consistent with a therapeutic dose somebody that’s taking their medication normally.
Than somebody that’s just swallowed an overdose, and you’ll see some higher numbers in some other cases with different circumstances.
So it turned out, this woman did have very severe a a atherosphereotic, cardiovascular disease, and she also had myocardigal scarring, which indicated she’d, had some previous heart attacks.
Femoral and cardiac blood helped determine not OD
deaths due to impaired metabolism
Such deaths are unusual, but can be due to:
◦ Genetic impairment due to enzyme deficiency
e.g. Cytochrome P4502D6 in 7-10% Caucasians
◦ Drug-Drug impairment of enzyme system
e.g. impairment by SSRIs of CYP4502D6
◦ Impairment due to reduced liver function (age, alcohol)
case 2
7-year-old boy with severe attention deficit disorder
Medications: imipramine (150 mg hs); valproate (250 mg hs).
Collapsed suddenly at school; resuscitation unsuccessful.
Autopsy negative; toxicology indicates “imipramine
poisoning”.
He was prescribed a 150 milligrams of in my room at night.
which is a moderately high dose for a 7 year old, but not excessive val prorate as well.
He was doing well. Once he started taking the amatript Lin. They stabilized him on that. His grades were improving.
and he was actually doing quite a bit better.
The autopsy was negative, meaning. They could find no an atomic cause of death.
and the initial autopsy report indicating he died from imipramine poisoning. which is not totally inaccurate, but it’s a little dramatic in terms of wording.
Des is metabolite
if you look at it doesn’t matter a cardiac blood, femal blood, or the liver, the concentrations of the zip ramen, or about 10 fold or more higher, and the
and that is not normally what you see clinically. the the zip, I mean, maybe anywhere from 50% of the I mean to, maybe at most one and a half times.
* So for some reason this kid is accumulating desipraminee, Like most of the old tricyclic antidepressants are cardio toxic of the high concentrations.
* 0.942 high enough concentration to induce arhythmias, as in pretty much anyone
case 2 mech of imipramine death
- The primary root of metabolism, initially, is demethylation to form that zip remain. and that’s mediated by 3, a 4 cytochrome, P 453, a 4.
- But the Ziprame is also metabolized extensively by a hydroxylation on the ring, one or more rings.
- and that’s mediated by Cytochrome p 45 2d6,
He must have had 2D6 deficiency
because he’s not very efficiently
Hydroxylating imipramine and by inference not the desip either
because it hydroxy metabolites are not being formed, or at least not efficiently.
Therefore, though you can’t form the Glucoseonides, and efficiently excrete those hydroxy metabolites out of the body. so this is likely because of a probably a deficiency in 2D. 6.
What’s surprising about this case is that this kid had
almost nothing in the way of the toxic symptoms.
This the only side effect this kid had was a small amount of urinary retention
case 3 fatal drug accumulation
21 y.o. university student living with parents
History of manic depression, but well controlled
Watching TV with father, but feeling unwell and went
to bed early; 2 h later complained of nausea
4 h later was heard to collapse and taken to hospital;
died en route; resuscitation failed
All medication accounted for (no overdose)
Prescribed: 900 mg chlorpromazine, 125 mg
imipramine, 10 mg amphetamine
No cause of death at autopsy; toxicology…
- Liver levels VERY high (especially metabolite desipramine)
- Very high desipramine (metabolite) to imipramine suggests accumulation
- Likely genetic (P4502D6) and/or drug-drug induced accumulatio
n - All medications accounted for (none missing)
these concentrations are pretty high.
at least for the the ephemeral blood and the liver. There’s nothing much in the stomach
They’re not excessive concentrations. These are maybe a little bit higher, because these are post-mortem samples,
desert remain. The metabolite is at least 5 to 6 times higher.
And what is likely happened in this case, but
that’s relatively high dose of the chlorpromazine. Promising is competitively interfering with metabolism of the imipramine and desipramine
it’s possible that this young woman also had a a, a 2D. 6 deficiency
medication counts
For each important medication determine:
◦ Number prescribed
◦ Date dispensed
◦ Dosage (e.g. tablets per day)
◦ Number remaining at death
◦ Calculate meds “unaccounted for”
Why? Suicide vs. “Build-up”
