POSTMORTEM REDISTRIBUTION

DEFINITION;
Phenomena whereby increased concentration of some drugs are observed in
postmortem samples and/or site dependent differences in drug concentration may be
observed.
Typically, central blood samples are more prone to postmortem changes (will have greater
drug concentrations than peripheral blood samples).

 Coping with the problem of postmortem redistribution:

 Analysis of both central blood and peripheral blood in Case where postmortem
redistribution may be a factor.

 Compilation of tablets to determine average and range of postmortem

redistribution factors for drugs.

POSSIBLE MECHANISMS OF POSTMORTEM

REDISTRIBUTION;
 Diffusion from specific tissue sites of higher concentration (i.e., liver,

myocardium, lungs) to central vessels in close proximity.

 Diffusion of unabsorbed drugs in the stomach to the heart and inferior

vena cava

 Diffusion of drugs from the trachea, associated with agonal aspiration

of vomitus.

1. REDISTRIBUTION FROM THE LIVER;

Postmortem redistribution (PMR) from the liver is complex, as it involves different
mechanisms. Drugs sequestered in the liver at the time of death could be
redistributed via the hepatic veins to the inferior vena cava and then into the right
cardiac chamber and pulmonary vessels or to peripheral venous blood.
 The liver is also the target of redistribution from the gastrointestinal tract the
anatomical relationships between the digestive tract and liver are of great importance
for the understanding of these mechanisms. The greatest part of the inferior surface
of the left liver lobe is in contact with the stomach, and the pylorus and proximal
duodenum rest against the right lobe of the liver and the gall bladder. Finally, taking
into account the close anatomical proximity between the liver and the stomach, the
xenobiotic contained in the latter at the time of death can enter the hepatic
parenchyma either by passive diffusion or through the portal vein .

2. REDISTRIBUTION FROM MYOCARDIUM;

the living, many cardiac drugs are concentrated in the myocardium. One of the best
examples is digoxin, with in vivo myocardia concentrations 30 times higher than that
in heart blood. This is also the case for calcium channel blockers and quinidine.
Rapidly, these drugs are redistributed into cardiac blood, in which concentrations
rise dramatically. A moderate in- crease has also often been described in the
subclavian venous blood, which cannot, for this reason, be considered as a peripheral
blood specimen. Such redistribution from the myocardium into heart blood has also
been described for other drugs such as morphine; amphetamine; methamphetamine;
propoxyphene and nor- propoxyphene; imipramine and desipramine; and
amitriptyline, doxepin, maprotiline, and metoprolol. Because the dramatic
concentration increase observed in cardiac blood may result from redistribution
from the stomach, lungs, or liver, proof of redistribution from the myocardium as the
primary mechanism responsible for this increase would be demon- striated by higher
concentrations of the drug in both the left and right cardiac chambers

3. REDISTRIBUTION FROM LUNGS;

In vivo, the lungs receive the entire blood flux from the right ventricle and so
accumulate many drugs, particularly weak lipophilic bases with pKa values greater
than 8, such as imipramine, amitryptiline, methadone, or chlorpromazine. PMR
from the lungs begins within the first two hours after death, inducing a rise in drug
concentrations in cardiac chambers and thoracic vessels, and seems to be more
intense than redistribution from the gastrointestinal tract. In all the cases reported,
the concentrations in the aorta and left cardiac chambers were higher than in the
superior vena cava and right cardiac chambers. The two previously described
mechanisms are probably involved in this redistribution.
First, the drugs can be redistributed via the pulmonary vessels. The earlier
postmortem increase in drug levels in pulmonary veins than in the arteries could
result from the fact that diffusion through the thinner-walled veins occurs more
rapidly. On the other hand, drugs sequestered in lung parenchyma and vessels could
be redistributed directly into surrounding tissues, including thoracic vessels and
cardiac chambers.
 The fact that concentrations in the aorta and the superior vena cava were
higher than in the left and right cardiac chambers, respectively, suggests direct
redistribution into both the aorta and inferior vena cava from surrounding tissues,
that is, from the left lung, left primary bronchus, and carina for the aorta and from
veins adjacent to the trachea for the superior vena cava that is, from the left lung, left
primary bronchus, and carina for the aorta and from veins adjacent to the trachea for
the superior vena cava

EXAMPLE;
DIGOXIN
A 33-year-old white female is admitted to hospital after taking 60 tablets, an
Antemortem blood sample collected 01 hour prior to her death indicates a blood
digoxin level of 18ng/ml.
Heart blood digoxin concentration obtained at autopsy is 36nm/ml.
Postmortem increases in blood digoxin concentration are suspected to be due
to the release of the drug from the myocardium.

 Postmortem levels > Antemortem levels.

 Heart blood levels > femoral blood levels.

TABLE;
DRUG RESERVOIRS;
 Many drugs are sequestered antemortem in organs qualified as "drug

reservoirs”.

 After death, they are redistributed to the surrounding tissues. Hollow organs,

such as different parts of the gastrointestinal tract, or viscera with a high

concentrating power, such as the liver and lungs (the myocardium also), can

be classed as drug reservoirs.

 PMR from these organs can occur by two different mechanisms:

 Diffusion through blood vessels and

 Transparietal diffusion towards the surrounding organs.

 Redistribution into central vessels is greater than redistribution into

peripheral vessels. The difference between the two sites is known as the

central to peripheral (C/P) ratio. Femoral blood is widely accepted as the most

reliable postmortem specimen for drug analysis in forensic toxicology

EXAMPLE;
Clozapine, an anti-psychotic drug redistribution following death may result in
an over calculation of three times the actual concentration in serum only 12
hours after death.

PHARMACOKINETIC PROPERTIES OF DRUGS;

The postmortem changes in pharmacokinetics are probably more complex, and
modifications may occur at each pharmacokinetic stage, that is, absorption,
distribution, metabolism, and elimination.
Postmortem changes in the human body begin at the cellular level with the onset of
ischemia. As the length of time of ischemia increases and death ensues, more
changes occur and lead to deterioration in tissue and organ function. These changes
may affect the pharmacokinetic and distribution behavior of certain drugs.
Drugs particularly affected are those whose distribution is dependent on molecular
size, lipophilicity, pH, energy-dependent transport, and tissue binding.
Such drugs include the tricyclic antidepressants, digoxin, and cimetidine. Other
drugs with similar characteristics, such as procainamide, may also demonstrate like
changes in distribution and pharmacokinetics.
During the elimination phase, the venous concentrations of drugs such as
furosemide, procainamide, and propranolol are higher than the arterial
concentrations.

PRACTICAL CONSEQUENCES;
 It is very important in postmortem testing to be able to compare

concentrations in several blood and tissue samples.

 Blood samples must be taken at central (cardiac) and peripheral sites.

 Femoral blood appears to be the specimen of choice for postmortem

toxicological analysis due to the following reasons:

1. It is the least subject to PMR.

2. `Femoral blood concentrations were less affected by the postmortem time

delay than the concentrations in central blood

CONCLUSIONS AND PERSPECTIVES;

PMR of drugs may complicate the interpretation of the results in forensic toxicology.
The competing processes of diffusion from drug reservoirs, cell-lysis and
putrefaction, and the particular pharmacokinetic properties of certain drugs
contribute to the differences in drug concentrations observed between sites and
sampling intervals.
These redistribution phenomena put into perspective the reliability of the
databases of therapeutic/toxic/lethal blood levels, built from published data often
reported with no mention of sampling sites, postmortem delay, or autopsy
conditions. This is particularly important because a large number of toxic drugs are
lipophilic weak bases with a large Vd, prone to PMR, More surprisingly, there is little
information on the metabolic activity in the first hours postmortem or on the real
influence of drug physicochemical properties or pharmacokinetic parameters on the
redistribution phenomena.
 MCQ’s
01; PMR stands for_________
a) Postmortem redistribution. b) postmortem distribution. c) postmortem
design. d) postmortem research.
ANSWER (A).
02; Diffusion of unabsorbed drugs in the stomach to the _______ and inferior vena
cava.
a) Lungs. b) heart. c) liver. d) brain.
ANSWER (B).
03; Many ______ drugs are concentrated in the myocardium.
a) Anti-depressants. b) psychotics. c) cardiae. d) hepatic.
ANSWER (C).
04; Diffusion from specific tissue sites of higher concentration.
a) Liver. b) Myocardium. c) Lungs. d) All the above.
ANSWER (D).
05; Calcium channel blockers and quinidine rapidly redistributed into____.
a) Cardia blood. b) liver. c) Stomach. d) All the above.
ANSWER (A).
06; In vivo, the lungs receive the entire blood flux frim the ______ ventricle.
a) Right. b) Left. c) Both. d) None of the above.
ANSWER (A).
07; In vivo, myocardium concentrations ___ times higher than heart blood.
a) 30. b) 40. c) 20. d) 10.
ANSWER (A).
08; Concentration in the aorta and the superior vena cava were _______than in the
left and right cardiae chambers.
a) Low. b) Medium. c) Higher. d) None of above.
ANSWER (C).
09; Drugs in lungs parenchyma and vessels could be redistributed _______into
surrounding tissues.
a) Indirectly. b) Directly. c) Both. d)None.
ANSWER (B).
10; Blood digoxin concentration is suspected to be due to release of the drug from
the _______.
a) Myocardium. b) Liver. c) Stomach. d) Kidney.
ANSWER (A).
11; postmortem redistribution from the liver is _____.
a) Easy. b) Complex. c) Difficult. d) Both b & c.
ANSWER (B).
12; Drugs in the liver at the time of death could be redistributed through______.
a) Hepatic veins. b) Inferior vena cava. c) Cardiac chamber. d) All of
above.
ANSWER (D).
13; The liver is the target of redistribution from the_______.
a) Stomach. b) Gastrointestinal. c) Bile duct. d) All of the
above.
ANSWER (B).
14; Weak lipophilic bases pKa value is greater than____.
a) 02. b) 04. c) 08. d) 06
ANSWER (C).
15; Diffusion of the drugs from the trachea, associated with________ aspiration of
vomitus.
a) Mouth. b) Stomach. c) Agonal. d) None.
ANSWER (C).
16; Redistribution from myocardium to heart also described for other drugs such
as_______
a) Morphine. b) Imipramine. c) Desipramine. d) All of above.
ANSWER (D).
17; In lungs redistribution first the drug redistributed_______.
a) Capillary. b) Pulmonary vessels. c) Both. d) None.
ANSWER (B).
18; Redistribution from the gastrointestinal tract and digestive tract and ____ are of
great importance.
a) Liver. b) Lungs. c) Heart. d) All of above.
ANSWER (A).
19; At the time death xenobiotic is enter in ______ either by passive diffusion.
a) Portal vein. b) hepatic parenchyma. c) Both. d) None.
ANSWER (B).
20; Best example of myocardium redistribution is _______.
a) Digoxin. b) NSAIDS. c) Calcium channel blockers. d)
β-blockers.
ANSWER (A).