JOURNAL CLUB

ROOPA KRISHNAN
JR II
DEPT. OF FORENSIC MEDICINE
GMCT
•Mechanisms Underlying
Postmortem Redistribution
of Drugs: A Review
• Journal of Analytical Toxicology, Vol. 27, November/December 2003

• Journal of Analytical Toxicology, Vol. 27, November/December 2003

OVERVIEW

• INTRODUCTION
• MECHANISMS FOR PMR
• SOURCES OF PMR
• AGONIC AND CADAVERIC CHANGES
• PHARMACOKINETICS, ABSORPTION, METABOLISM AND
ELIMINATION
• PRACTICAL CONSEQUENCES AND CONCLUSION
 INTRODUCTION
• Lethality of any intoxication
• Evaluation in the postmortem period.
• Do not necessarily reflect blood concentrations at the time of
death.

• Variations: sampling site, the interval between death and

sampling.

• These variations: "postmortem redistribution" (PMR).

MECHANISMS FOR
PMR
MECHANISMS FOR POSTMORTEM
REDISTRIBUTION
MECHANISMS OF PMR

• "DRUG RESERVOIRS”.
• Redistributed after death.
• Two mechanisms:1) diffusion through blood vessels
2)transparietal diffusion towards the
surrounding organs.
SOURCES OF POSTMORTEM
REDISTRIBUTION

• Redistribution from the gastrointestinal tract

• Redistribution from the lungs
• Redistribution from the liver
• Redistribution from the myocardium
• Redistribution into body fat.
REDISTRIBUTION FROM THE
GASTROINTESTINAL TRACT

• Unabsorbed drugs in the stomach : mediastinal vessels and

surrounding organs
• left cardiac chambers, aorta, right cardiac chambers, and
inferior vena cava.
• begin within hours after death
• The pericardial fluid and myocardium are also affected.
• Because of close anatomical apposition of the fundus against
the diaphragm.
• Reported for ethanol, amitriptyline, methanol, and lithium .
• Contamination of airways - pulmonary vessels , cardiac
blood.
• Associated with an increase in the drug blood concentration
• Drug concentrations higher in blood from the aorta and
superior vena cava than from the left and the right cardiac
chambers, respectively
• suggesting direct diffusion than diffusion via the pulmonary
and cardiac blood.
• This phenomenon was described for ethanol, paracetamol,
and propoxyphene .
REDISTRIBUTION FROM THE LUNGS

• Lungs receive the entire blood flux from right ventricle.

• Accumulate, particularly weak lipophilic bases.
• Eg imipramine, amitryptiline, methadone, or chlorpromazine.
• PMR from the lungs begins within the first two hours after
death.
• Rises drug concentrations in cardiac chambers and thoracic
vessels.
• Intense than redistribution from the gastrointestinal tract.
REDISTRIBUTION FROM THE LIVER

• PMR from the liver is complex

• the hepatic veins to the inferior vena cava
• drugs could be redistributed directly into adjacent organs.
• but this is not as important as the redistribution via the
hepatic vessels.
REDISTRIBUTION FROM THE
MYOCARDIUM

• In the living, many cardiac drugs are concentrated in the

myocardium.
• Eg digoxin, calcium channel blockers.
• redistributed into cardiac blood, in which concentrations rise
dramatically
• as morphine, amphetamine,methamphetamine ,
propoxyphene.
AGONIC & CADAVERIC CHANGES

• Cell death
• Postmortem hypostasis and coagulation
• Blood movements
• Putrifactive changes
CELL DEATH

• Release of basic drugs from solid tissues into the blood

compartment.
• Hypoxia during the agonic processes is the first stage
• Anaerobic glycolysis and accumulation of lactic acid
• Neutral or acidic drugs are less affected
• “ enzymes into the extracellular space could be used as an
indicator for PMR”
• disintegration of physiological and anatomical barriers
• postmortem vascular permeation
• Researches
BLOOD COAGULATION & HYPOSTASIS

• Postmortem blood sediments and clots unevenly in the body

• The clot entraps a large number of red blood cells
• unequal distribution between red blood cells and serum
• Hypostasis induces variations in the percentage of
erythrocytes by volume
• Researches
BLOOD MOVEMENTS

• Movements of blood within the vessels occur early after

death
• responsible for physical redistribution of drugs
• influenced by pressure and fluidity changes
• Rigor mortis
• induces systolic ventricular contractions with small
movement of blood
• Increase in intra-abdominal pressure
PUTREFACTIVE PROCESS

• Bacteria transmigrate throughout the body

• could produce and/or metabolize many compounds in the
postmortem blood
• Eg ethanol
• Vitreous humor is considered an ideal specimen
• Postmortem degradation by bacteria
• cyanide degradation by bacteria during the putrefactive process.
VITREOUS HUMOR

• (1) it contains no glucose or microorganisms

• (2) it is protected from putrefaction or trauma
• (3) the concentration of ethanol in this medium reflects (is
not equal because of differences in water content) the
antemortem blood concentrations
PHARMACOKINETICS

• The PMR process influenced by pharmacokinetic behavior of

dru
• Arterial concentrations higher than venous concentrations
during the absorption.
• whatever the mode of administration, as has been described
for ethanol, diazepam.
ABSORPTION

• different processes by which a drug can cross the lipidic membranes

of cells.
• Most drugs cross membranes by passive diffusion, ruled by Fick's law,
• depending on the concentration gradient of the molecule
• pH on both sides of the membrane
• molecular size & lipid solubility,
• ionization state of the molecule
DISTRIBUTION

• After absorption, drugs reach the circulation in order to be

distributed throughout the body and reach their site(s) of
action.
• Blood transport ofxenobiotics.
• The first stage of distribution is the transport of xenobiotics in
the bloodstream.
• In the circulating blood, drugs can be (1) dissolved in the
plasma water, (2) bound to the plasma proteins, and/or (3)
bound to the mem
• Only water-soluble molecules can be completely or almost
completely dissolved in plasma water.
• This is the case for ethanol, for example, which is dissolved in
total body water and whose PMR is not influenced by
changes in blood proteins or red cells.
METABOLISM

• The drug-metabolizing system may persist several hours

after death
• inducing the breakdown of a drug and the synthesis of its
metabolites.
• all studies concerning this problem -metabolism of cocaine
• cocaine and its metabolites present PMR
• hypothesis of a postmortem, residual cocaine metabolism
has been raised
• spontaneous hydrolysis of cocaine to benzoylecgonine
• hydrolysis is inhibited by the acidification after death
• The hypothesis of a residual esterase activity was then
formulated
ELIMINATION

• As for absorption, to the best of our knowlegde no study has

been dedicated to the possible persistance of an elimination
process after death.
PRACTICAL CONSEQUENCES IN FORENSIC
TOXICOLOGY
• Central (cardiac) and peripheral sites.
• Femoral vein.
• Least subject to PMR
• cross-clamping the iliac vein and the inferior vena cava
• Right lobe of the liver, the right kidney, and the right lung should be
sampled.
• No precise recommendation concerning brain sampling is given in the
literature.
• The skeletal muscle has been suggested as an alternative
specimen
• for postmortem toxicology because
• it is present in large amounts and
• is affected by decomposition later than blood or viscera
CONCLUSIONS AND PERSPECTIVES

• PMR 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
• The most common problem is a difference in drug
concentration between the different sampling sites
• The pharmacokinetics of the drugs concerned must be taken
into account, as well as, if possible, the autopsy findings,
which in many cases give useful information
• autopsy findings, which in many cases give useful
information. The position of the corpse and regurgitation of
the gastric contents into the airways or thoracic trauma may,
for example, explain differences in blood concentrations from
• 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. Further studies
are thus warranted.
REFERENCES
PROS AND CONS

• Very informative
• Validated studies
• Most aspects covered
• Drawback of the studies also mentioned.
THANK YOU