| Research Article |
Open Access |
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| Forensic Pharmacokinetics: A New Dimension for Drug Related Medico
Legal Cases |
| Medhi B1*, Pawan K Singh1, Bansal Y S2 and Setia P2 |
| 1Department of Pharmacology, PGIMER, Chandigarh, India |
| 2Forensic Medicine, PGIMER, Chandigarh, India |
| *Corresponding author: |
Dr. Bikash Medh
, Associate Professor
Department of
Clinical Pharmacology Postgraduate Institute of Medical Education & Research,
Chandigarh
Tel: + 91-172- 2755250 (o), +91-9815409652(m)
Fax:+ 91-
1722744401, +91-1722745078
E-mail: drbikashus@yahoo.com |
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| Accepted May 16, 2011; Published May 18, 2011 |
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| Citation: Medhi B, Singh PK, Bansal YS, Setia P (2011) Forensic Pharmacokinetics:
A New Dimension for Drug Related Medico Legal Cases. J Forensic Res 2:128.
doi:10.4172/2157-7145.1000128 |
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| Copyright: © 2011 Medhi B, et al. This is an open-access article distributed under
the terms of the Creative Commons Attribution License, which permits unrestricted
use, distribution, and reproduction in any medium, provided the original author and
source are credited. |
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| Abstract |
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| The incident of drug related medico legal cases are increasing day by day. In Forensic Medicine there is a
need of frequent requirement of estimation of dose size administered or ingested by deceased, based on either
postmortem blood level or concentration of drug in urine. In an ideal situation creatinine clearance should be
evaluated than it is corrected according to age, sex and body surface area. Postmortem changes begin at cellular
level with the onset of ischaemia. Depending on duration of ischaemia structure and function of organs and tissue
gradually deteriorate which influence the distribution of drugs in the body fluids and tissues. For estimation of drug
concentration of deceased, there is need to consider the postmortem redistribution phenomenon. Deceased drug
concentration may not reflect the actual concentration at the time of death, similarly there is possibility that miss
calculation from deceased blood level if it is not judiciously used to simulate the dose versus toxicity relationship. In
this article authors have emphasis on various aspect of co-relation of drugs level following death and different factors
that influence while predicting actual drug concentration for medico legal drugs related cases. |
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| Keywords |
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| Drug concentration; Postmortem; Legal implication |
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| Introduction |
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| The incidence of drug related medico legal cases are increasing
day by day, with the advent of newer drugs on an almost daily basis,
the number of medico legal cases due to complication (accidental or
deliberate) of these drugs are increasing at an alarming rate. Not only
therapeutic agents, the cases of poisoning from know toxicological
agents like organphosphorous compounds, aluminium phosphide etc.
are increasing with each passing day. In such scienerio, the toxicologist
has to determine the amount of the suspected poison in the dead body
from the samples preserved during autopsy. But, are the results that
we get from such samples accurate? Can these results be extrapolated
to the living to get the amount of drug present at the time of death?
Does the time passed since death has any bearing on these value? What
is the correlation we get in blood and various organ? These are many
such question need to be answered before we can use the toxicological
analysis for legal evidence on the basis of these results [1,3]. |
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| All drugs have the potential to be misused, whether legally
prescribed by a doctor, purchased over-the-counter at the local drug
store, or bought illegally on the street. Taken in combination with other
drugs or with alcohol, even drugs normally considered safe can cause
death or serious long term consequences. Accidental drug overdose
may be the result of misuse of prescription medicines or commonly
used medications like pain relievers and cold remedies. Symptoms
differ depending on the drug taken. |
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| While many victims of drug overdose recover without long term
effects, there can be serious consequences. Some drug overdoses cause
the failure of major organs like the kidneys or liver, or failure of whole
systems like the respiratory or circulatory systems. Patients who survive
drug overdose may need kidney dialysis, kidney or liver transplant, or
ongoing care as a result of heart failure, stroke, or coma. Death can
occur in almost any drug overdose situation, particularly if treatment is
not started immediately. |
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| Drugs are generally classified as either |
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| Prescription: These require a doctor's authority to purchase them. Some common examples are; `Valium'(diazepam), `Morphine', and
`Benzodiazepines' (sleeping tablets) etc. |
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| Non-prescription: Are drugs which may be purchased without
prescription. They consist of headache compounds, cough elixirs,
and similar mild medications, and can be purchased at virtually any
chemist or retail outlet. Common examples are; `Panadol', `Aspro',
`Vick's Cough Syrup', alcohol, and nicotine (cigarettes). |
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| Illicit: Are drugs that are imported, grown or manufactured
illegally. All illicit drugs are dangerous and usually imply a degree of
dependence, or in some cases, addiction. Examples are; heroin, cocaine,
amphetamines, `ecstasy', marijuana, meth and LSD. |
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| In a study conduced in Utah between 1991 to 2003, it has been
observed that there is tremendous increase in number of death
caused by use of non-illicit drug poisoning, and most of them was
unintentional in nature. While in 1991, only 50 people died because of
use of non-illicit drug, the number rose to more than 250 by 2001 [29]. |
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| Processes by which the movement of drugs and other chemical
poisons between tissues, organs and body fluids takes place after death
is known as post mortem drug distribution [1]. This phenomenon is
well recognized and was first reported 25 years ago [2]. |
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| Cases of suspected poisoning, either homicidal or suicidal, the role
of drugs in "marginally toxic" cases, such as vehicle accidents, and also
potential toxicological cases of euthanasia or medical negligence might rely upon the toxicological analysis of blood samples and in these
situations one has to consider the role of postmortem drug distribution
for analysis of results of postmortem blood samples [3]. |
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| The timing, method of collection, and source of sample might
influence the interpretation of toxicological analysis. The process of
postmortem distribution results in the migration of drugs between
blood and tissues, the rate and extent of which varies according to
several factors, including the nature of drug and time interval between
death and post mortem specimen collection. |
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| The major organs constitute potential drug pools, and the
gastrointestinal tract might contain considerable quantities of
unabsorbed drug, and thus central blood is subject to redistribution
from these local organs. Peripheral blood, such as femoral blood, is
subject to redistribution influence only from local tissues-muscle and
fat. |
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| So, redistribution into central vessel is greater than that of
peripheral vessels. For these reasons, the blood specimen of choice for
toxicological analysis after death is a femoral venous sample, ideally
collected from a ligated vessel [4,5]. |
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| Often, toxicologists are requested to estimate the amount of drug
present at the time of death. This assumes that the drug concentration
found at the time of post mortem is a reliable estimate of that present at
the time of death. There is lack of evidence that such an extrapolation is
possible, in only a few cases reported, antemortem blood concentration
are available for comparison with values from variety of sites at post
mortem examination [6]. |
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| In cases were intervals between antemortem sampling and death
was known, and an estimate of the plasma concentration at the time
of death was calculated using the following equation to account for the
decline in drug concentration as a result of ongoing metabolism and
elimination during life- |
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| In Nt = In No-Tn2[T/t1/2] |
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| Nt =calculated plasma drug concentration at time of death; No
=plasma drug concentration at time of sampling; T =time interval
between sampling and death; T1/2 =elimination half life of drug in plasma
[7,8]. Drugs with high central to peripheral ratio also tend to have a
high postmortem to antemortem ratio. Overestimation of the ante
mortem drug concentration results in an artificially low postmortem
to antemortem ratio. It can be dangerous to attempt to relate a drug
concentration found at postmortem examination to the antemortem
circulating concentration or the antemortem dose received. It is not
possible to form a general rule regarding the differences between the
antemortem and postmortem drug measurements as variation seen
depends on the nature of drug. |
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| Variables affecting central to peripheral ratio: Increase in
interval between death and postmortem examination affect site specific
postmortem drug concentration to a great extent, and hence the central
to peripheral ratio calculated [9]. It is likely that this interval will also
affect the postmortem to antemortem ratio calculated for the drugs,
although drug concentration in the femoral vein after death appear to
be relatively stable with time, again making any extrapolation using
these ratios unsafe [10,11]. |
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| To determine whether the drug concentration found at post
mortem examination should be attributed to either therapeutic
ingestion or overdose is very difficult because of the influences of post
mortem changes. |
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| Use of postmortem to antemortem ratios, or back extrapolation
from a postmortem concentration, is not recommended. For certain
drugs, it may be more appropriate to consider the parent to metabolite
ratio. It has been shown consistently for several drugs (e.g., tricyclic
antidepressants) that a high ratio is indicative of acute administration,
as seen in overdose, because often in vivo metabolism is saturated or
incomplete and circulating concentration of the parent compound
remains high [12,13,14]. |
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| Postmortem to antimortem blood drug concentration ratios
for both heart blood and blood from vena cava and also the lung to
antemortem blood drug concentration ratio were closely related to the
apparent volume of distribution for the drugs. Accordingly, an apparent
volume of distribution of more than 3-4 L/kg is a good predictor that
a drug is liable to undergo post mortem redistribution with significant
increments in blood levels. Drugs like tricyclic antidepressants;
barbiturate, opiates and others show postmortem concentration
increases in humans [15]. On the other hand, there are substances
that redistribute insignificantly post mortem, as acetaminophen and
zopiclone [16]. |
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| After death, several mechanisms can give rise to artificially increased
blood drug concentration. A drug may be released postmortem from
tissues with high drug concentration and redistribute by means of
diffusion and convection of blood and other fluids in the body. The
lungs have been experimentally verified as a source of post mortem
drug release to the blood [17] but also liver, myocardium, endothelium
and kidney are possible sources. Drug distribute from unabsorbed
from stomach, drug depots to anatomically adjacent tissues like the left
lobe of the liver, left lower lobe of the lung and eventually myocardium
and blood in central compartments [18,19,20]. Agonal or postmortem
reflux of drug-rich material from the stomach into airways followed by
release to the blood can give rise to falsely elevated drug concentration
in heart blood and other central tissues [21]. |
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| Postmortem to antemortem blood drug concentration ratios
for acidic/neutral drugs as Phenobarbital, acetaminophen or
carbamazepine were close to 1.0. For the basic drugs codeine,
amphetamine, verapamil, and trimeprazine, there were significantly
elevated postmortem to antemortem blood drug concentration ratios
[22]. |
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| Calculation of blood alcohol concentration for forensic purposes
are based on several simplified assumption like linear pharmacokinetics
of ethanol, constant value of ethanol elimination, constant rate of
alcohol absorption and constant time to achieve peak blood levels,
which is by convention depends only on type of beverage and quantity
of food consumed. These simplified and idealized assumptions
significantly restrict possibility of back extrapolations of blood alcohol
concentration from the observed values and calculations based on
them exclude the absorption phase of blood alcohol curve. Although
many factors may alter the concentration of alcohol present in autopsy
specimen, postmortem synthesis of alcohol receives most attention.
The microorganisms producing ethanol post mortem can be inhibited
by adding a preservative and storing the sample under refrigeration
[23]. |
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| There did not seem to be any relationship between the postmortem
changes and pharmacological parameters such as acid dissociation
constant (pKa), molecular size, plasma protein binding or lipophilicity.
The basic lipophilic drugs may interact through inhibition of
accumulation in the isolated perfused lung depending on their lipid
solubility [24]. |
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| Lungs function as a reservoir for antidepressants [25]. Addition of
a second antidepressant cause release of the first drug in volunteers,
with an increased risk of toxicity. It has been established that cationic
amphiphilic drugs accumulate in tissues by two major mechanisms,
namely non covalent binding to membrane phospholipids and ion
trapping within acidic cellular compartments like lysosomes [26]. The
tissue to blood drug concentration ratio of the lung was found to be
predictive of the postmortem drug level increase observed in heart
blood. This is in agreement with a previous study in rats showing that
removal of the lungs significantly reduced the postmortem drug level
increase observed in heart blood for amitriptyline. |
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| The apparent volume of distribution is defined as the amount
of drug in the body divided by plasma or blood concentration at
distribution equilibrium. The highly significant co- variation between
the postmortem drug level increase and the volume of distribution
shows that the latter is a very useful measure for assessing drugs for the
possibility of postmortem redistribution. It also correlates the fact that
the apparent volume of distribution of a drug also expresses the average
tissue to blood concentration ratio. It is a measure for the concentration
gradient between tissue and blood. Fick's law of diffusion states that
the rate of diffusion of a substance is proportional to the concentration
gradient across the diffusion barrier. Consequently, the apparent
volume of distribution is a logical measure for the liability of a drug to
redistribute from tissues to blood after death. |
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| Recommendations |
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| Procedure for ideal blood sampling in postmortem cases: A
standard protocol has to be developed for toxicological samples
collection at post mortem examination. Chosen method must be easily
incorporated into routine post mortem practice. Blood for quantitative
analysis (≥5 ml) should be taken from two distinct peripheral sites,
preferably left and right femoral veins. Femoral blood can be taken
by cutting the external iliac vein proximal to inguinal ligament, and
milking the distal cut end into the specimen tube. Early ligation of
this vessel is recommended to avoid mixing with more central blood
during evisceration. An additional larger specimen of blood (≥20ml)
for qualitative screening can be collected from a convenient large vessel
[27,28]. |
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| Following death there can be rapid changes in cellular biochemistry
as autolysis proceeds, and drugs and other poisons may be released
from heir binding sites in tissues and major organs, also unabsorbed
drugs may diffuse from the stomach. Special care should always be
taken in the selection of blood and tissues sampling sites, the method
of collection of samples, and the labeling of sample containers. |
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| In case of liver and lung, recommended sites are right lobe of
liver and apex of the lung. The concentration of drug found in post
mortem blood specimens, even those taken from peripheral sites, will
often much higher than the perimortem plasma drug concentration
particularly if several days have been elapsed between death and
postmortem. It is not scientifically valid to compare the reported
postmortem drug concentration of a drug with literature values of
plasma drug concentrations in cases of drug over dosages. Similarly
the practice of calculating the dose of ingested drug or poison from
the product of the postmortem blood drug concentration [C] and
the reported volume of distribution [Vd] {Dose = C x Vd} is not
recommended. Interpretation of findings can present a problem where
there is little background information concerning the case, or where
specimen collection has been inadequate. Interpretation of findings can also be difficult in drug abusers where the likely degree of "tolerance" to
a drug is unclear because of inadequate history. The recent history, age
and state of health are also important factors to be taken into account
during interpretation. Presently there are very few literature available
on postmortem changes of drugs and there is need for future extensive
research to address various issue on drug related medicolegal cases to
find out the better correlation of drug level with postmortem changes. |
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