Under the Microscope: Too Much Drug Will Kill You With No Doubt
In most countries, especially those
with advanced economies and relatively sophisticated medical services,
poisoning with medicinal compounds is common. In many such counties, poisoning
with therapeutic substances exceeds deaths from other types of toxic agents,
especially in suicidal and accidental poisoning. This is explained by the ease
of access of such substances, whether they are obtainable from a doctor on
prescription or on demand across the counter of a pharmacy. Where state-
sponsored health services exist, the cost to the recipient may be minimal or
absent and this ease of access contributes to opportunities for self-poisoning,
whether it be deliberate self-destruction, suicidal gestures or accidental
ingestion - the latter especially in children. Unfortunately, overprescribing
or the supply of too great a quantity of drugs at one time allows excessive
stocks of drugs to be easily available to the public. Though only a minority of
victims of medicinal poison- ing fail to recover, there are still an
appreciable number of deaths. These come to the attention of the investigative
authorities and hence to pathologists. The autopsy investigation of a fatality
from a therapeutic substance can be difficult, for a number of reasons:
-
The
nature of the substance may be uncertain or unknown.
-
There
may be more than one such substance involved.
-
There
may be a delay between ingestion and death sufficient to allow blood, urine and
tissue concentrations to decline below fatal, toxic or even therapeutic levels.
-
Analysis
may be difficult to arrange because of lack of facilities.
-
Information
about fatal levels may be unobtainable.
-
Most
medicinal poisons leave virtually no characteristic features at autopsy, so
diagnosis depends upon laboratory findings.
-
Post-mortem
changes may make analysis difficult, inaccurate or impossible.
-
Where
death is delayed after taking the substance, none may be recoverable from the
stomach (which has emptied) or even from the intestine.
-
The
original substance may be rapidly metabolized into one or more breakdown products,
adding to difficulties in identification and interpretation.
The lack of characteristic autopsy
appearances is often very frustrating for the pathologist. Unless there is an
indicative or suggestive history as to which drug was taken - a matter for the
investigators in respect of circumstances and recovery of containers - then an
autopsy may have to be performed 'blind'. Where no significant morphological
lesions can be discovered, then a full toxicology screen must be considered,
which in some jurisdictions may be difficult or impossible to obtain, or be
extremely expensive. The majority of modern medicinal substances are, by
design, bland and non-irritant to the tissues and gastro- intestinal tract.
Most of those met with in forensic practice are taken orally and, though the
active constituents may be potent in their pharmacological effect on target
organs and tissues, the medicine will cause no erosion or damage to the
alimentary tract. Thus little or no physical evidence can be obtained from a
gross or even microscopic examination of the gastrointestinal tract or other organs.
Much of the physical bulk of modern tablets or capsules is merely the vehicle
for introducing the active component into the body and is thus unlikely to have
any adverse effect. When a medicinal compound causes death, the mode of death
is most often some form of cardiorespiratory failure, often secondary to
depressive effects on the central nervous system. This mode of death causes
only non-specific changes discernible at autopsy, which are usually of no use
in indicating the basic reason for the death. Acute congestive cardiac failure,
pulmonary oedema, sometimes cerebral oedema, generalized organ congestion,
scattered petechiae on serous membranes - none of these is of any real use to
the pathologist, who has to rely on the results of toxicological analysis for a
definitive answer. The toxicology laboratory conducts the technical assays, and
produces qualitative and quantitative results. The toxicologist analyst
interprets those results to the pathologist, by providing an indication of the
therapeutic, toxic and fatal ranges of concentrations in various body fluids
and tissues, and by pointing out problems such as decline from post- ingestion
survival, conversion to metabolites and many others. The pathologist then
collates this information with his own knowledge of the history and autopsy
findings to offer the best interpretation of the investigation for judicial authorities.
Most problems arise either because the information about the medicine
(especially if it is newly developed or where its toxicity is low) is
incomplete in terms of toxic blood and tissue levels - because post-ingestion
survival has allowed the originally lethal levels to have subsided to
therapeutic or even lower limits. What is offered in the remainder of this
chapter is a digest of information about such potentially lethal levels, culled
from a variety of sources. The ranges are often wide as most of the data are of
necessity derived anecdotally, and the problems of uncertainty of dosage,
variation in post- ingestion survivals and wide individual biological variation
make it impossible to lay down strict thresholds between therapeutic, toxic and
fatal concentrations. Wherever possible, the advice of the analytical toxicologist
should be taken about each case - but where this is impracticable, then the
following data and similar material, which is constantly being updated in
forensic and toxicological publications, may be of assistance. The choice of
substances is arbitrary, but represents the most common medicines seen in
suicidal and accidental poisoning.
Aspirin is the most widely used
therapeutic drug, being analgesic, antipyretic and anti-inflammatory. It was
formerly very common as an agent of self-poisoning, both accidental in children
and suicidal in adults. In Britain in the last two decades, its use as a
self-poisoning agent has declined remarkably, so that fatalities are now rarely
seen. The therapeutic dose is usually 325-975.mg, that is, 1-3 tablets. Rarely,
persons with an aspirin hypersensitivity may become ill or even die after
therapeutic doses, suffering urticaria, angioneurotic oedema, hypotension,
vasomotor disturbances and laryngeal and glottal oedema.
Patients on long-term salicylate
therapy for arthritic or rheumatic diseases may take 3-5 g/day and slowly reach
blood concentrations which would be in the lethal range if caused by acute
overdoses. Those on 3gIday have blood levels varying between 44 and 330 mg/l.
Apart from deaths caused by hypersensitivity, death in an adult is unlikely
with the ingestion of fewer than about 50 tablets, that is, about 16g. The
blood concentration - (measured as total salicylate), from a medicinal dose of
975 mg, ranges from about 30 to 100 mg/l (with a mean of 77) 2 hours after
ingestion. There is a rapid fall to around 25 mg/l some 8 hours later. At
autopsy, aspirin is one of the few medicines that may cause some gross
abnormalities, though they are not particularly specific. Externally there is
nothing to see, unless vomiting has taken place, when dark or even red, bloody
gastric contents may be expelled. Rarely, there may be some haemorrhagic
manifestations in the form of skin petechiae.
Post-mortem toxicology requires the usual samples of blood, urine, stomach contents and liver. The mass of aspirin in the stomach may remain for several days in life, forming a partly insoluble concretion that may retard the absorption of the drug. This is why it is always worth washing out the stomach of a live victim, as a large proportion of the aspirin may be removed before it can cause systemic effects. With the advent of soluble aspirin or effervescent preparations, this aspect is lost as no such insoluble bolus forms. At autopsy, part of such a mass can be sent for analysis, whilst quick 'spot' tests can be carried out on another part. Such quick chemical confirmation may be performed in the autopsy room itself, by using a 10 per cent solution of ferric chloride. If a small quantity is added to a urine sample or to the surface of the tablet mass, an immediate purple-blue colour suggests aspirin. This is by no means specific, but is merely suggestive. If negative, however, then aspirin can be virtually discounted. These are only rapid screening methods and by no means replace proper laboratory analysis. Toxic blood levels (measured as total salicylate) begin at about 300-500 mg/l, though both death and survival are consistent with far higher or lower levels. Blood concentrations in fatal cases may range from about 60 to 7300 mg/l, some authorities suggesting that 500mgll is an average minimum level. The liver concentration in fatalities varies from 2.5 to 1000 mg/kg and urine salicylate from 20 to 1350 mg/l, emphasizing the wide levels that are compatible with life. Salicylate has a rather slow clearance rate from the blood, the half-life being up to a day in some massive overdoses. Aspirin poisoning is dangerous in that sudden cardiac arrest can occur in the absence of any toxic symptoms. This accounts for the deaths that take place after patients have been discharged fit from the emergency departments of hospitals. They may have seemed quite well and symptom free, but suffer a fatal collapse up to a day or so later. Fatal cardiac arrhythmias can supervene without warning and make it advisable, where possible', to admit patients with aspirin overdoses for observation for a day or so.
The tricyclic antidepressants are
frequently involved in self-poisoning, partly associated with the type of
patient for whom they are prescribed. Amitriptyline, dothiepin, doxepin and
trimipramine have additional sedative properties. Those with little or no
sedating action include protriptyline, nortriptyline, imipramine, clomipramine,
iprindole, loperamide, desipramine and butriptyline. Tetracyclic
antidepressants include maprotiline and mianserin. Other types include the
monoamine oxidase inhibitors, which are well known to have dangers related to
the concurrent ingestion of other drugs and foods, especially those with
sympathomimetic action and tyramine content, such as rich cheese, yeast
extracts, red wine and beans. Dangerous hypertension may ensue with the risk of
cerebrovascular haemorrhage. Drugs of this class include phenoxypropazine,
tranylcypromine, isocarboxazid and phenelzine. These widely used drugs are
employed for their sedative and tranquillizing effects. A large number of both
1,4- and 1,5-benzodiazepines are available, divided into short-acting,
intermediate-acting and long-acting compounds. Long-acting benzodiazepines
include: flurazeparn, nitrazepam, diazepam, ketazalam, chlordiazepoxide,
clobazam, chlorazepate, medazepam and alprazolarn. Intermediate- acting
benzodiazapines include: loprazolam, lormetazepam, ternazepam, flunitrazeparn,
lorazepam, bromazepam and oxazepam. A shortacting benzodiazepine is triazolam. This
group of tranquillizer drugs includes: haloperidol (butyrophenone),
chlormethiazole, chlorpromazine, fluphenazine, diphenylbutylpiperidine,
promazine, trifluoperazine and prochlorperazine. The autopsy appearances are
non-specific and toxicology may resolve any diagnostic problems if the death
has occurred fairly soon after ingestion - which may often not be the case,
when history and ante-mortern investigations can provide the only answer.
The massive problem posed by
therapeutic administration of barbiturates until about 20 years ago has largely
abated in countries with a responsible medical profession, which voluntarily
refrained from the prescription of these drugs except where specifically
indicated. Their use as sleeping tablets and general soporific sedative agents
led to widespread abuse, so that at one time they were easily the most common
agent of drug addiction. The development of non-barbiturate hypnotics, such as
the benzodiazepines, helped to remove the need for the older and more lethal
compounds. Unfortunately, barbiturates are still widely available on the
illicit market, either alone or in combination with other substances such as
amphetamines. Much lower blood levels will be found in fatal poisonings in the
short-acting group as death may occur more quickly from the usual mode of
action, a central depression of the respiratory centres.
At autopsy, the signs are of general
cardiorespiratory failure, with often a cyanotic, congestive appearance.
Though non-specific, probably the congested lungs in acute barbiturate
poisoning are more intense than in any other condition. These organs may be
almost black and the whole venous system is engorged with dark, deoxygenated
blood. There may be 'barbiturate blisters' on dependent parts of the skin
surface, especially buttocks, backs of thighs, calves and forearms, though as
discussed in the chapter on carbon monoxide poisoning, these blisters are
common to all states of deep coma. Internally there may be local signs of
erosion from the drug itself. The gastric mucosa may be badly damaged from the
alkaline attack of drugs such as sodium amytal which, being the sodium salt of
a weak organic acid, hydrolyses in the stomach. The fundus may be thickened,
granular and haemorrhagic. The cardia and lower oesophagus may be eroded from
reflux and, if the victim regurgitates, then black, altered blood may appear at
the nose and mouth. The capsules of certain barbiturates also leave characteristic
traces in the mouth, oesophagus and stomach. The colour varies with the
manufacturer, but the turquoise- blue of sodium amytal capsules may stain the
stomach contents and even be visible through the wall of the intestine when
the abdomen is opened. Other pigmented gelatine capsules can be red, yellow or
blue.
Fatal insulin toxicity may be
accidental, suicidal or homicidal. The accidental fatalities are usually
examples of medical error, mostly from misreading the label on the box or
ampoule. Insulin is, of course, inactive orally and has to be given by
injection to perform its hypoglycaemic effect. At autopsy, where either from
the circumstances or the finding of needle marks, insulin is a possibility,
peripheral blood samples and skin and underlying tissue from the injection site
should be carefully preserved, together with control skin from another site.
The fine needles usually used by diabetics may leave virtually no mark on the
skin.
Attempting to prove insulin-induced
hypoglycaemia by measuring glucose levels in human post-mortem fluids is
impracticable, due to the unreliability of such estimations after death. Very
low vitreous humour glucose levels may strongly suggest hypoglycaemia, but are
not absolutely acceptable.
Acknowledgements:
www.aived.nl AIVD – @Erik Akerboom ©
www.politie.nl Politiekorpschef @Janny Knol©
www.politie.nl WEB Politie - @Henk van Essen©
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