Toxicology Flashcards
(122 cards)
1
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Thus, forensic toxicology can be divided into:
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2
Q
Postmortem toxicology
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Q
analysis of tissues and fluids taken from cadavers, either
shortly after death or from decomposed or exhumed bodies.
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Drug samples, drug paraphernalia, and prescription items may also be found at the site of death
and usually become part of the postmortem toxicological examination.
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Q
have limited value because of drug clearance occurring over time prior to death.
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6
Q
analysis of antemortem blood and urine, when available and especially if taken
around the time of hospital admission, may become essential in postmortem protocols when there
has been a prolonged period of survival, or when extensive administration of transfusions occurred
prior to death.
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7
Q
non-
routine procedures to check for the possible presence of certain classes of drugs or poisons that are not
necessarily included in the routine protocols.
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8
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digoxin
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quaternary ammonium muscle
relaxants
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Q
hydroxybutyrate (GHB)],
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11
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Conditions that can alter drug concentration include
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changes resulting from human enzymes,
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bacterial
enzymes, pH, temperature, and hydrolysis.
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14
Q
Postmortem specimens: Blood
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15
Q
sample of postmortem blood is not physiologically or toxicologically
equivalent to a clinical sample.
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The production of gases during decomposition and the resulting pressures can result in the mixing
of blood from different sites.
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Other factors that make interpretation of postmortem blood data difficult
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18
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degree of
hemolysis, or any other changes in the blood matrix.
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19
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The concentration of drug in a blood clot may reflect the concentration in blood at the time of
clotting, if formation occurred at the time of injury.
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20
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Analysis of blood clots, especially after trauma
such as head injury, may be useful for determining drug exposure prior to death, especially in cases
of prolonged surviva
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21
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Postmortem specimens: Urine
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22
Q
useful
for initial screening for the different classes of drugs and for their metabolites.
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presents fewer
problems than blood analysis; for example, urine does not readily support bacterial growth.
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24
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Postmortem specimens: Vitreous Humor
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useful only when bodily decomposition has not set in.
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determination of potassium levels in vitreous humor may be useful in some
cases for approximating the postmortem interval (PMI).
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rise as the interval between death and collection of a sample increases; the correlation,
however, is not always accurate.
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analyze for the presence of many drugs and alcohol.
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little protein compared to blood and tissues.
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Only free drug in blood enters the
vitreous humor, and since most drugs exhibit at least some significant degree of binding to proteins and
other macromolecules in blood
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lower than those in femoral blood.
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protected site; usually, there is little bacterial contamination and therefore little
fermentation. Thus, it may be useful for determining whether the presence of alcohol in tissues was due to
consumption prior to death or formed because of postmortem fermentation.
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good
backup sample for blood ethanol.
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reveal recent use of heroin, as 6-
monoacetylmorphine has a longer half-life in this specimen than that of other fluids.
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Postmortem specimens: Gastric Contents
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should be taken for analysis, and the total weight should be recorded.
Any undigested tablets should be analyzed separately.
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The total amount of drug present in gastric contents, including any undigested material, is of
forensic importance because it may be useful in interpreting the manner of death (i.e., it may be
indicative of suicidal overdose).
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detecting trace amounts of basic drugs in stomach contents
may be due to back diffusion into the stomach as well as representing residual drug following
ingestion.
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Postmortem specimens: Brain
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lipophilic drugs such as anesthetics and hydrocarbons, whereas
many polar compounds are not able to pass the blood–brain barrier in significant amounts.
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enter the brain easily and their levels in brain are useful for determining the
manner of death.
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backup specimen for blood alcohol. At equilibrium, the brain alcohol/blood
alcohol ratio is about 0.85, but this number may be lower if death occurs during the period of a
rising blood alcohol.
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From a few minutes to about
3 h after exposure, the brain/blood ratio for cocaine is approximately 4 to 10.
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The ratio of brain to blood cocaine in cases of death within 3 to 6 h of exposure is approximately 0.4
to 0.8. These ratios may be different, however, in persons who had used cocaine chronically.
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Postmortem specimens: Liver and Bile
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concentrates most parent drugs and metabolites,
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ethanol being the notable exception.
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There is an extensive body of data on the range of hepatic drug levels in therapeutic, toxic, and
lethal cases.
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good source for many drugs and their metabolites, in particular opioids and
benzodiazepines, and because of its storage in the gallbladder, it may be the only specimen where
residual drugs or metabolites may be detected when absent from other tissues.
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prolonged interval elapsed between the last intake of
drug and death.
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contain high concentration of drug in cases of acute overdose where death
occurs while large amounts of drug are still in the gastrointestinal tract and in the portal system.
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SPECIMEN COLLECTION AND STORAGE
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glass containers be used for liquids and glass or plastic containers for tissue and
gastric contents. However, it must be noted that the use of certain types of plastic containers for storage
can result in the loss of THC.
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should be collected in tubes containing at least 1 to 2% sodium fluoride as preservative and stored at
0 to 4◦C. This will inhibit bacterial growth and enzyme activity, which can either produce alcohol or reduce
the concentration of alcohol in alcohol-containing specimens.
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bacterial action at room temperature is likely, and alcohol production by bacteria can
reach concentrations up to 0.10 to 0.15 g/dL.
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also inhibit cholinesterase activity, which can metabolize cocaine and other ester-
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Tissues may be stored for short periods at 0 to 4◦C.
containing substances.
Most drugs are stable at this temperature range, but some drugs (e.g., cocaine) are labile.
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Tissues may also be frozen. However, the freezing and thawing of tissues before processing is not
recommended, as this can rupture cells and cause a loss of drug-containing fluid. Where short- or long-term
•
freezing is utilized, frozen tissues should be rapidly cut and weighed.
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Vitreous humor and urine can be stored at 0 to 4◦C or frozen.
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EXTRACTION PROCEDURES
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requires careful selection of solvent and pH in relation
to the analytes targeted.
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polarity of the extracting solvent, or solvent mixture, should be like the polarity range of the
target analytes.
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pH used for the extraction of acidic and basic compounds should be 2 units below and above,
respectively, the pKa value of the analyte.
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are not dependent on pH. However, when performing a general unknown analysis,
the selection of solvent and pH should be done to obtain satisfactory recovery of a wide range of
possible analytes, keeping in mind such factors as pH-related drug stability, drugs such as
amphetamines that require very high basic pH, and the requirements of amphoteric compound
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requires protein-free extracts. • SPE has a high versatility, owing to the broad range of columns available: polar, nonpolar, ion-
exchange, and mixed-mode.
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high versatility, owing to the broad range of columns available: polar, nonpolar, ion-
exchange, and mixed-mode.
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used for general unknown procedures consist of a combination of nonpolar and
cation-exchange components.
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isolation of highly polar or water-soluble drugs and metabolites. It
should also be noted that the condition or state of the biological matrix being extracted (i.e., “fresh”,
decomposed, or embalmed) can affect the amount recovered, and this needs to be taken into
account when interpreting findings.
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shown that many different types and classes of drugs and toxic metals can be
recovered from exhumed bodies even after long periods of interment. Great caution must be
exercised, however, in the interpretation of all such findings.
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ANALYTICAL TECHNIQUES
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screening techniques, and all presumptive positives
must be confirmed.
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is one or more of the modes of mass spectrometry, usually coupled
with gas chromatography (GC) or liquid chromatography (LC).
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screening technique for basic drugs.
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involves the use of very rapid column heating systems, which provide much faster
increases in temperature, higher carrier gas pressures, and very fast signal acquisition systems.
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necessary for the following reasons: improvement of chromatographic characteristics,
resolution of coeluting compounds, elimination of thermal instability, and in some cases, as with
amphetamines, to produce a derivative with a much more characteristic mass spectral fragmentation
pattern than is found with the underivatized compound.
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this involves the replacement of “active” hydrogen with an alkyl, acyl (
especially polyfluorinated acyls), or silyl group.
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allows for highly sensitive detection
using an electron capture detector. One common application of this procedure is the gas
chromatography–mass spectrometry analysis of cannabinoids
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The interpretation of postmortem findings is becoming increasingly complex. • This is due to such factors as:
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postmortem redistribution,
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significant differences in individual rates of metabolism arising from genetically based polymorphic variations in metabolic
enzymes
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the type and condition of the specimen,
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drug interactions arising from the concurrent use of multiple drugs,
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particular person’s tolerance for a specific drug or class of drugs •
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cross tolerance
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Pharmacogenomics
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interpretation of postmortem drug levels as they relate to cause of death requires careful
assessment of all the particulars of a case.
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should consider genetic influences on the concentration of drug found. The
field of pharmacogenomics attempts to explain a person’s metabolic capabilities for drug
metabolism in relation to the genotype.
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Poisoning, intentional or otherwise, may be the result of genetically influenced altered metabolism.
A person’s genetic makeup may also influence the transport of drugs across membranes and the
interaction of drugs with receptors.
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The use of pharmacogenomics for understanding drug reactions and drug-related deaths has been
termed molecular autopsy.
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person’s genetic makeup has already entered the clinical area and will be utilized increasingly in
the future prior to prescribing medication to better maintain therapeutic levels.
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phase I and phase II pathways.
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oxidation, reduction, and hydrolysis reactions, preparing the metabolite for
conjugation reactions by phase II enzymes. The final product is usually more water soluble than the parent
drug and can easily be eliminated.
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carried out by the cytochrome P450 (CYP450) monooxygenase enzyme system,
located primarily in the liver but also less extensively in other tissues.
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heme-containing proteins are located in the smooth endoplasmic reticulum, and many of the
isoenzymes exhibit genetic polymorphism.
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CYP450 system may play a role in explaining drug-induced deaths by two different mechanisms.
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based on a person’s genomic makeup, one can be a “slow” or a “fast” metabolizer. Another
classification of variants is ultrarapid, extensive, intermediate, or poor metabolizer.
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Those with the slow polymorphic form can accumulate high levels of drug that could result in death, even
from therapeutic doses. About 25 to 30% of all xenobiotics are metabolized by one isoenzyme, CYP2D6 (
debrisoquine hydroxylase); 5 to 10% of
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Caucasians have low levels of CYP2D6 or lack it completely, and doses of medications metabolized by this
isoenzyme must be reduced.
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Metabolism
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metabolized by CYP2D6.
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mutations of the polymorphic gene encoding for this isoenzyme have been identified and may
play a role in oxycodone toxicity.
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metabolized by CYP1A2, CYP3A4, and CYP2D6.
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Oxycodone
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Methadone
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genetic variants of CYP2D6 showed a trend, although it is not statistically significant, toward
poor metabolism of methadone, and higher levels were found in these people than in nonvariant
controls.
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another opioid used for relief of pain and as an anesthetic during surgery, is metabolized
by CYP3A4 and CYP3A5. Variant alleles of the genes encoding these proteins are known and
again may play a role in fentanyl toxicity.
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The response to the anticoagulant warfarin (coumadin) is
dependent on cytochrome metabolism.
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variation in response to warfarin is due to variation in the gene encoding
CYP2C9, and 27% of the variation in response is due to variation in the gene VKORC1 encoding
the warfarin target, vitamin K epoxide reductase.
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metabolic rates of amphetamine and of methamphetamine are dependent on CYP2D6 activity,
and genetic polymorphism for ring hydroxylation of amphetamine has been reported (Miranda-G et
al., 2007).
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Polydrug use can result in additive, synergistic, potentiating, inhibitory, or antagonistic interactions,
and may involve inhibition or induction of metabolic enzymes by one agent affecting the clearance
and effects of others.
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The widespread use of all types of over-the-counter herbal products, domestic and imported, is an
additional, potential complicating factor.
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Drug Stability and Decomposed Tissue
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The postmortem chemical stability (or the lack thereof) of a drug or toxin or of the metabolites is a
function of the combined effects of the chemical’s structure, the length of the postmortem interval,
the conditions of temperature, bacteria, oxygen, water, pH, and so on, to which the body has been
subjected, and the particular matrix containing the agent.
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Decomposed bodies reflect the processes of autolysis and putrefaction. Autolysis, digestion by
natural enzymes, occurs more readily in tissues with a high enzyme content, such as the pancreas
and stomach.
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Tissues with a low content of digestive enzymes, such as heart and liver, are less readily autolyzed.
Autolysis leads to liquefaction of the tissues, which can then mix with blood and result in erroneous
conclusions.
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Putrefaction, destruction of tissue by bacteria, depends on the bacteria that are present, the
temperature and oxygen content of the environment in which the body is located, and the
substrates available for bacterial action.
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susceptible to putrefaction and bacterial fermentation and is not
normally used for postmortem analysis.
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produced because of fermentation in decomposing bodies but can also decrease
from initial antemortem levels due to chemical, microbial, and evaporative processes occurring with
decomposition.
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known to cause a rapid loss of the high levels of cyanide associated with
fatal poisoning, but cyanide is also subject to varying postmortem production, particularly in
deteriorating bodies.
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Artifactual production of cyanide has also been found to occur in some blood samples from fire
death cases, and extreme caution must be exercised in the interpretation of such levels. Cyanide
can be a significant component of some toxic fire gases that cause or contribute to death, but in
such instances, it must be reasonably shown that it derived from pyrolysis of nitrogenous material (e
.g., nitrogen containing plastics) present in the fire environment.
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hydroxybutyrate (GHB) may also be produced
endogenously in postmortem fluids.
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not currently approved for routine use in the United States. It is,
however, available from different sources, and is encountered both as a drug of abuse and as an
agent in drug-facilitated sexual assault. Clearly, very serious misinterpretations can occur unless
the potential ranges of postmortem production are considered.
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