Poisoning by medicines

Dr David Chumba
MBcHB, MMED (Human
Pathology), Dip. For Med (SA)
• Factors affecting toxicity in poisoning:
– Administration: Mainly by ingestion, inhalation, injection and absorption
through the skin or mucus membrane
– Absorption: This refers to the process where the drugs move from the
site of administration to a fluid medium mainly blood. The mechanisms
for this include:
• passive diffusion for those that are water soluble,
• lipid diffusion through cells,
• facilitated diffusion where carrier molecules transport the drugs across the
epithelial cells through cells
• and pinocytosis this is where large molecules are engulfed by cell
membranes and dispersed into the blood
– Distribution: This is the process of transportation of the drug from site of
absorption to various parts of the body, site of metabolism, target organ,
site of elimination, the medium is usually blood or plasma
– Elimination occurs in two methods, metabolism and excretion
• Metabolism: This chemical conversion of drug to another molecule, this
occurs in the liver epithelial cells, this occurs by one of the following,
oxidation, reduction, hydrolysis or conjugation methods and result in an in
active drug. The first three are named as phase I reaction and conjugation is
referred to as phase II reaction
• The reactions in the liver is catalysed by cytochrome
450 enzymes located in the cytoplasmic reticulum and
the amount, activity and structure are genetically
controlled. The following are the consequences of
drug metabolism in the body:
– The toxic effects of drugs and poisons is removed, and most
therapeutic drugs are removed in this manner
– Prodrugs are converted into active forms and this may lead
to delay in therapeutic effect
– Poisonous metabolites may be the outcome of metabolism
e.g. methanol is metabolised in the lver to form formic acid
which highly toxic
– Knowledge of metabolic pathways has led to development of
innovative drugs that block or accelarate to the benefit of
humans e.g. ethanol is used for treatment of methanol
poisoning
– Enzyme induction has been used in treatment of jaundice
using phenobabitone
• Excretion: This refers to irreversible loss of unchanged or
chemically changed drug in the body. The main routes are
urine, faeces, airway, saliva or skin
• Factors affecting the action of the drug:
– Drug related factors
• Physical state of the drug
• Chemical nature and composition
• Dose of the drug, all drugs are poisons the right dose differentiates a poison
from a remedy
• Route of administration
– Patient related characteristics:
• Genetic factors: e.g. slow acetylation of isoniazid in treatment of tb may result
in toxicity
• Age infants and the elderly are more prone to toxic effects of drugs
• Sex: some drugs have toxic effects on the ovary or the testis
• Allergy anaphylactic type I due to penicillin, cytotoxic type II SLE induced by
hydralazine or procainamide, type III immune comlex stephen Johnson
syndrome induced by salphonamides and type IV delayed seen in contact
dermatitis
– Concurrent food adminstration this reduces the amount of drug absorbed
– Concurrent drug administration can increase toxicity by synergistic
effects, antagonistic with less toxicity, increased metabolism and
inhibition
• General considerations: This is more common in developed world and is
mainly for self destruction and may be due to ease of availability of this
medicines, third world countries have general lack of medicines hence
poisoning is much more rare
• Autopsy in such cases require some clinical history and even then no
morphological features may be found requiring full toxicological screen. The
gut is rarely eroded as the current medicines are specific to the target organ
• Laboratory testing: This is usually done in collaboration between the
pathologist and the toxicologist. The pathologist rules out trauma, natural
disease, and provides tissue for analysis. The lab runs technical assays and
produces qualitative and quantitative results, this is interpreted by the
pathologist based on history and post mortem findings
• The autopsy investigation of medicinal poisoning may be very difficult due
the following reasons;
– The nature of the substance is uncertain or unknown
– More than one substance may be involved
– There may be delay in ingestion and death and concentrations may be far below
fatal and therapeutic levels
– No characteristic autopsy findings in these cases
– The original substance may be metabolized into breakdown products which may
be very difficult to analyze
• Specific poisons
• Poisoning by analgesics: This include paracetamol and aspirin
• Aspirin: Therapeutic does is 1-3 tablest or 325 mg to 975 mg,
mean blood concentration is between 30-100 mg/l
• Apart from those react death is usually caused by intake of at
least 50 tablets (16g)
• At autopsy: Externally there is nothing to see except if there has
been vomiting where the vomitus is seen to be blood stained
• Internal examination: The stomach may contain a mass of
fused unabsorbed tablets. The stomach mucosa may show
ulceration by the acidic irritative substance, may also show
petechie and echymosis. This petechie is usually seen in all the
organs
• Post mortem toxicology need blood, urine, stomach contents
and the liver.
• Toxic levels measured as total salicylate is 300-500 mg/l, the
liver concentration 2.5-1000 mg/kg
• Cardiac arrest can occur in with no toxic symptoms, this is the
main cause of death in patients who have been discharged
from the hospital with no symptoms, hence need to admit the
patient in the hospital for at least two days for observation
•
• Paracetamol or acetominophen has no anti inflammatory
properties and no gastric irritation.
• Normal does is 500 g to 1000g. Levels of 20 g are lethal.
• The drug is a potent liver poison and this is due to conversion
to N-acetyl-p-benzoquinone. This is usually detoxified by
glutathione but overdoes exhausts this chemical causing severe
centri lobular necrosis
• The concurrent administration of phenorbabitone, phenytoin,
alcohol, worsen the toxicity because these drugs activate P450
enzyme. Most deaths are delayed for 2-4 days
• At autopsy there is nothing specific. The liver may or may not
be enlarged but histologically shows massive centrilobular
necrosis
• Renal changes include tubular necrosis with histological
evidence of myocardial fiber damage
• Typical blood levels in overdose is 100-400 mg/l
• Antidepressant drugs: This are tricyclic antidepressants including
amitryptyline, dothiepin, doxepin and trimipramine also have sedative
properties
• Tetracyclic antidepresant like maprotiline and mianserin and monodidase
inhibitors
• Most of these drugs are frequently involved in self poisoning
• Benzodiazepines: They are widely used for sedative and tranquilizer effects,
both short acting and long acting cpds. Long acting include flurozepam,
diazepam, intermediate include loprazolam lorazepam and short acting
include triazolum. The fatal concentration of diazepam is 5-10 mg/l
• Phenothiazines: These are tranquilisers and includes haloperidol.
• In all the above cases, the autopsy findings are non specific and toxicology
is needed
• Barbiturates: These are still available in the illicit market either alone or in
combination with amphetamine otherwise the need for this drug in medical
practice has totally been replaced by benzodiazepines
• Classification
– Long acting barbitone, phenobrbitone and phenytoin
– Intermediate pentobarbitone, allobarbitoen
– Short acting: thiopentone, cyclobarbitone and secobarbital. Much lower
concentrations are found in these group in fatal cases
• Autopsy findings: Signs of respiratory failure seen as
cyanosis, congestion of the conjuntiva.
• The lungs show intense congestion
• The organs may be almost black due deoxygenated
blood
• There may be barbiturate blisters seen on the
dependent areas of the skin the buttocks, back of
thighs
• The stomach may show areas of erosion as a result of
the drug itself and show edematous nad hemorrhagic
mucosa
• The mouth, oesophagus and the stomach may show
characteristic traces appearing as turguoise-blue, can
also be red, yellow.
• Smell of alcohol which speeds the toxic effects are
common
• Insulin poisoning: This is commonly used by medical people to
commit suicide as insulin is otherwise not available to non
medics
• Fatal toxicity is suicidal, homocidal or accidental medical error
• At autopsy: The needle marks may be seen, this may be dificult
as diabetics use fine needles
• Blood is usually taken and serum separated emediately frozen.
Whole blood can also be used but must be send straight away
to the public health laboratories for analysis
• Skin and tissue samples are also send but not in formalin
• Porcine or povine insulin is easier to detect but human insulin
cannot be distinguished hence C-peptide which is produced 1:1
with insulin will help distinguish
• Very low levels of glucose in the vitrous humour may suggest
hypoglyceamia but cannot be used as a confirmatory test