Cough syrups containing paracetamol are generally safe for consumption by children but the recent deaths of more than 300 children in Africa and Asia from contaminated cough medicines, has led to calls for closer scrutiny of these over-the-counter paediatric medicines, notes MedicalBrief.
The recent deaths of more than 300 children in Africa and Asia have prompted the World Health Organisation (WHO) to warn about the use of “substandard and falsified” medicine, with toxicologists Winston Morgan and Shazma Bashir writing in The Conversation that manufacturers and regulatory authorities also have a responsibility to protect children.
The WHO has issued three alerts over the past five months, warning people not to use specific over-the-counter paediatric medicine, after the children’s deaths in various countries including The Gambia, Indonesia and Uzbekistan.
The agency issues these warnings only when independent laboratory analysis has confirmed the product is substandard or falsified and that it poses a significant threat to public health. The threat must also extend beyond one country.
The children – some as young as five – died after consuming cough syrup contaminated with ethylene glycol and diethylene glycol. Cases were reported in at least seven countries.
What are ethylene glycol and diethylene glycol?
Ethylene glycol and diethylene glycol are toxic alcohols with a slightly sweet taste, widely used in windscreen wiper fluids and engine coolants.
These compounds are sometimes also found at very low levels as contaminants in many food ingredients and medical solvents (including propylene glycol, polyethylene glycol, sorbitol and glycerin/glycerol). This happens when there are poor standards of manufacturing and testing.
Medical solvents are commonly used to dissolve the ingredients of a medicine. Ethylene glycol and diethylene glycol contamination poisonings over the years have mainly been associated with solutions containing paracetamol.
Paracetamol in cough syrups is good and safe for children with infections; a pain killer good at reducing fever, without causing gastric irritation as aspirin or ibruprofen might do.
Are they dangerous?
Both ethylene glycol and diethylene glycol are seen as toxic. A fatal oral dose is about 1 000-1 500mg per kilogram. For a small child weighing 20kg a fatal single dose would be about 28ml or about six teaspoons of pure ethylene glycol.
However, it is also possible to cause toxicity by consuming much lower doses over several days and weeks. That is why the WHO safe level for these chemicals is only 0.5mg per kilogram daily. That’s the equivalent of 1/15th of a teaspoon per day.
What makes these glycols potentially so dangerous is that toxicity comes from the consumption of relatively large amounts before symptoms of contamination appear.
The additional danger from cough syrups is that symptoms of ethylene glycol and diethylene glycol contamination, such as drowsiness, are sometimes observed in children who have not taken contaminated medicine, and can be misinterpreted as normal in a child with a cough or fever. Guardians and medical professionals may not notice what’s wrong until it’s too late.
What’s the role of paracetamol?
To understand the potential role of paracetamol in these poisonings, we need to understand what happens to ethylene glycol and diethylene glycol in the body.
To be toxic, these glycols must be converted to a compound called glycoaldehyde, and then to glyoxylic acid. Glyoxylic acid can concentrate in and damage the kidneys, leading to death from renal failure.
The conversion is triggered by a certain concentration of a coenzyme called nicotinamide adenine dinucleotide (NAD+). NAD+ is regulated by mitochondria – small structures in human cells which regulate many chemical reactions in the body.
In a recent study, we demonstrated that at the normal dose required to treat fever, paracetamol inhibits mitochondria. Thus it affects the level of NAD+ and, in turn, the conversion of glycols to toxins. Children taking paracetamol preparations contaminated with the glycols could potentially be in danger.
We believe that the combination of medicines containing paracetamol and glycols, even when the contamination is relatively low but above the WHO acceptable limit of 0.5 mg/kg of body weight per day, could be lethal.
Unlike other medications or food products which do not disrupt mitochondrial function, preparations containing standard levels of paracetamol are more likely to lead to adverse outcomes for children, because of the increased metabolism of ethylene glycol and diethylene glycol.
Other medicines and foods contaminated with low levels of ethylene glycol and diethylene glycol probably go unnoticed because they don’t contain paracetamol.
How to prevent future deaths?
If spotted early enough, ethylene glycol and diethylene glycol poisoning can be treated. The two most common antidotes for overdose are fomepizole and ethanol. Both reduce the amount of toxic ethylene glycol and diethylene glycol metabolite produced in the body.
Incidents of mass poisonings highlight the need for greater vigilance in monitoring preparations containing paracetamol.
Medications containing paracetamol are normally very safe for children. But to avoid deaths related to cough syrup, both parents and medical professionals should consider glycol poisoning as a possibility if children start to display symptoms of intoxication and drowsiness after taking the medicine.
These incidents generally happen in countries categorised as the global south. Manufacturers and regulatory authorities in these countries also have a responsibility to protect children.
Study details
Inhibition of mitochondrial function: An alternative explanation for the antipyretic and hypothermic actions of acetaminophen
Shazma Bashir, Winston A Morgan.
Published in Life Sciences on 1 January 2023
Abstract
Aims
Acetaminophen is the medication of choice when treating fever because of its limited anti-inflammatory effects. However, at overdose it can cause mitochondrial dysfunction and damage, often associated with metabolism to N-acetyl-p-benzoquinone imine (NAPQI). What has never been investigated is whether the inhibition of mitochondrial function, particularly fatty acid uptake and oxidation could be the key to its antipyretic and hypothermic properties.
Methods
Mitochondrial function and fatty acid oxidation (FAO) was determined by measuring oxygen consumption rate (OCR) in isolated mitochondria and in 3T3-L1 adipocytes using the XFp Analyser. Basal fatty acids and adrenergic stimulated OCR of mitochondria and 3T3-L1 adipocytes were assessed with acetaminophen and compared to NAPQI, etomoxir, and various mitochondrial stress compounds.
Key findings
Using the XFp Analyser, acetaminophen (10 mM) decreased FAO by 31 % and 29 % in basal and palmitate stimulated adipocytes. NAPQI (50 μM) caused a 63 % decrease in both basal and palmitate stimulated FAO. Acetaminophen (10 mM) caused a 34 % reduction in basal and adrenergic stimulated OCR. In addition acetaminophen also inhibited complex I and II activity at 5 mM. NAPQI was far more potent at reducing mitochondrial respiratory capacity, maximum respiratory rates and ATP production than acetaminophen.
Significance
These studies demonstrate the direct inhibition of mitochondrial function by acetaminophen at concentrations which have been shown to reduce fever and hypothermia in mammals. Understanding how antipyretics directly affect mitochondrial function and heat generation could lead to the development of new antipyretics which are not compromised by the anti-inflammatory and toxicity of the current medications.
Winston Morgan is a professor of Toxicology, Equity and Inclusive Practice, Director of Impact and Innovation, University of East London, England.
Shazma Bashir is a postdoctoral fellow, University of East London, England.
See more from MedicalBrief archives:
WHO probes raw materials link in lethal cough syrups
Indonesia families launch lawsuit over contaminated cough syrup
Indonesia revokes firms’ licences after 150 deaths from toxic meds