The Effects of Organophosphate Poisoning on the Human Body and What You Should Do.
Introduction
Around the world, pesticides have played a significant role in deterring any vertebrates and macro-invertebrates. The core idea is to protect any field crops, vegetable and fruit crops and produce a maximum yield. Organophosphates are the most known and used pesticide and are very effective at what they do.
In a 2016 study, Kushwaha et al mentioned that Profenofos, a moderately hazardous organophosphate, have been found as residues on vegetables, mint leaves, gooseberries and other. Ingestion is the main exposure pathway to humans and, to this date, no complete biodegradation pathway has been established. Exposure to this compound can result in cell death, chromosome aberrations and red blood cell necrosis. This compound has been used in countries such as Australia, United States, China, India, South Africa, Brazil, Vietnam, Japan, Iran and a few others just to mention. Kushwaha et al also indicates the long term effects and the contamination within the environment of various countries and should be an environmental concern. Inevitably, humans are exposed to these organophosphate and its residues. Worryingly, Gotoh et al have confirmed in finding organophosphate with its residues in human plasma and urine.
The most vulnerable groups to organophosphate exposure and poisoning are:
Farmers,
Children,
Agricultural workers who have low education and/or with a language barrier,
Rural and remote farms with difficult access to a hospital,
Lack of proper safety equipment and standard operating procedures (SOPs).
Two children are playing on the fields of a farm. One sees this really cool equipment resembling a flamethrower with a container filled with a liquid held like a backpack. The child puts it on, grab the flamethrower-like gun and starts squirting the clear and fruity liquid on his friend as a game, not realising that it contains organophosphate (but who would know that?). There shouldn’t be any harm as his friend is wearing clothes and has no apparent cuts or ways for this chemical to get in. They laugh and have a fun time. His friend starts to realise the muscles on his arms and legs are twitching without his control until the muscles twitch so much that it is now paralysed. Fear slowly creeps in, and he vomits for the first time. He notices that his breathing is slowing down, his lungs are getting full of mucous, and simultaneously he urinates himself. Struggling to move, he falls. He salivates and drools uncontrollably, his eyes are watery, and he defecates. His vision is blurry. He cannot focus or see anymore. His friend becomes scared, panics and leaves as he runs back to the farmhouse. He lies there on the floor, struggling to breathe, confused and drowning in his own mucous.
As seen in this scenario, organophosphate poisoning is lethal and may cause death. The mortality of such exposure is between 3-25%; however, this depends on many factors such as the rurality/remote of the location, age/weight of the patient, dose/exposure to the chemical, respiratory management, discovery and transport, the compound used, general health of this patient and any co-morbidity such as asthma.
A quick revision of what happens between neuron synapses
The anticholinesterase or cholinesterase inhibitor (AChE Inh.) drugs, as the name suggests, block the essential enzyme called acetylcholinesterase (AChE). This enzyme is specific for acetylcholine (ACh), a neurotransmitter that is released between neurons and neurons to muscle groups. Acetylcholinesterase is responsible for the rapid hydrolysis of acetylcholine into its inactive product called acetate anion and choline. This makes sense as when the neurotransmitters have finished initiating an all-or-nothing response, ACh needs to be deactivated immediately. Otherwise, the communication would not stop and there would be an uncontrollable response which may result in severe side effects and death. These reactions occur at the cholinergic synapses, whereas butyrylcholinesterase (BuChE) occurs in the plasma and in the tissues. Figure 1 below demonstrates what happens to the ACh with and without the anticholinesterase compounds.
Acetylcholine (ACh): the neurotransmitter that will go onto its allocated receptors.
Acetylcholine Esterase (AChE): the enzyme that breakdown ACh to stop its action.
Anticholinesterase/cholinesterase inhibitor (AChE Inh): the compound that blocks the AChE enzyme. They are utilised as a medication, pesticide/insecticide as well as chemical warfare.
Figure 1. Demonstrates the cholinergic synapse between two neurons. In (A) we can see that ACh is being broken down naturally by the AChE into choline and acetate. In (B) the AChE enzyme has been blocked, no by-products are made, which leads to an increase of ACh at the synapse. An increase in ACh will evidently increase a response, which causes neurological and neuromuscular side effects.
The figure has been modified and changed from its original state. Original illustration from Smedlib, Wikipedia Commons.
What is the rationale of blocking an acetylcholinesterase enzyme?
The net effect of blocking the acetylcholinesterase enzyme is simply an increase in the neurotransmitter at the cholinergic synapse, which is acetylcholine. In a controlled environment, scientists have decided to take this as an advantage and apply to relevant pathology.
Ultimately, there is an enhancement of cholinergic transmission at the neuromuscular junction and at the cholinergic autonomic synapse. It is important to note that anticholinesterase or cholinesterase inhibitor that travels through the blood-brain barrier affects the central nervous system.
There are different types of anticholinesterase, and these are short-acting, medium-duration and irreversible. The short-acting helps the healthcare staff to diagnose myasthenia gravis as an improvement in muscle strength should be seen. If there is no improvement, then we can deduce the muscle weakness must come from something else. A drug example is Edrophonium. In the short-acting acetylcholinesterase, the bond is readily reversible and the action of the drug is brief.
The medium-duration anticholinesterase works in the minutes as the medication is hydrolysed much slower than ACh or the short-acting acting anticholinesterase. The reason for slower hydrolysis is due to the carbamyl group that Neostigmine, Pyridostigmine and Physostigmine contain. Neostigmine is mainly used to reverse competitive neuromuscular block, an oral treatment for myasthenia gravis and visceral side effects. Pyridostigmine is also used for myasthenia gravis and has a longer duration of action. Physostigmine is utilised for glaucoma. Donepezil, Rivastigmine and Galantamine are the approved anticholinesterase medications used to improve Alzheimer’s disease. The rationale is to increase the ACh neurotransmitter at the synapse and has been shown to improve certain patient’s life, see ‘An Introduction to Alzheimer's Disease with Its Normal Anatomy and Its Pathophysiology’.
Irreversible anticholinesterase phosphorylates the enzyme active site by adding a pentavalent phosphorus compound. These compounds are generally described as organophosphate, which is an organic compound with a pentavalent phosphorus group. There are some exceptions, such as using a labile group such as fluoride instead of an organic compound. This bond is very stable, with no hydrolysis activity to remove the phosphate group. The enzyme (AChE) is completely inactivated and becomes redundant as the only way to recover is to wait for more AChE enzymes to be produced. This may take up to weeks! Certain organophosphates are volatile, non-polar and highly lipid-soluble. This means that these compounds can enter intact and unbroken skin, absorb through the mucous membrane and enter insect cuticles. The rationale is to kill insects or humans by causing severe side effects, which will eventually at a high dose cause death.
What happens at the AChE enzyme site of action?
The acetylcholinesterase active site contains two distinct sites of action, that is the anionic and the esteratic site. The glutamate carboxylate residue (seen as the anion carboxyl group) will electrostatically attract the positive groups such as quaternary ammonium or tertiary amine compounds. which is the choline part of ACh. The esteratic site (catalytic site) compromises of histidine and serine. Essentially the histidine helps the serine to bond its hydroxyl group to the acetyl moiety of ACh. The serine is now acetylated, and the choline leaves to be reabsorbed/transported back into the neuron and be made into ACh with Acetyl-CoA. Histidine, along with water, removes the acetyl group from serine. The acetate/acetic acid is now free.
Figure 2 and 3 demonstrate how ACh is naturally broken down. Did you know that the turnover of AChE is extremely high? It has been noted that 10 000 molecules of ACh are hydrolysed per second by a single active site!
Figure 4 demonstrates how a medium-duration medication work and the irreversible anticholinesterase pathway.
Figure 2. Demonstrates how the Acetylcholine fits precisely within the active site right before the acetylation reaction. Figure from Kushwaha M, Verma S, Chatterjee S.
Figure 3. Demonstrates the acetylation which removes the choline, and also shows the de-acetylation reaction (from spontaneous hydrolysis), which eliminates the acetate. Figure from Kushwaha M, Verma S, Chatterjee S.
Figure 4. Demonstrates on the left-hand side how a medium-acting AChE Inh would behave as the AChE Inh is slowly hydrolysed, hence blocking all function of AChE. The right-hand side demonstrates how a pentavalent phosphorus compound completely blocks the AChE irreversibly. Notice the organophosphate blocks the catalytic area of the active site and phosphorylate the serine hydroxyl group. To recover Pralidoxime must be used or the body has to make new AChE, which could be weeks. Figure from: Rang H. Rang & Dale's Pharmacology, 7th ed.
The pharmacology of Pralidoxime
An acetylcholinesterase that has been phosphorylated has an extremely slow spontaneous hydrolysis reaction, which explains why an organophosphate is successful as a potent poison. So how can AChE recover without having the body to make new ones? This where the use of Pralidoxime make sense. Pralidoxime contains an oxime group, which is described as a double bond between the carbon and nitrogen with a hydroxyl group that is attached to the nitrogen. Pralidoxime also has a quaternary ammonium cation, which is simply a positive nitrogen. As mention before, that positive part of Pralidoxime will settle near the anionic site of the active site, leaving the oxime group to interact with the phosphorylated serine. The oxime group act as a strong nucleophile and in a way kidnaps the phosphate group from the serine hydroxyl group. This liberates the esteratic site (catalytic site) and in turn, the Pralidoxime-phosphate compound now leaves the active site. The AChE is now reactivated and can start reducing immediately the already high concentration of ACh at the synapse. Figure 4 demonstrates how Pralidoxime interacts at the active site and the phosphate compound.
However, there are some serious limitations. Pralidoxime does not cross the blood-brain barrier; hence another compound must be given to treat the central effect of an organophosphate. After a few hours to an organophosphate poisoning, the AChE that has been irreversibly blocked and unfortunately becomes redundant. This is called ‘ageing’, and nothing can be done. Hence Pralidoxime must be given immediately or relatively early for the medication to work. Figure 5 below demonstrates the usefulness of Pralidoxime given intravenously to a patient that had an organophosphate poisoning. It is not a total recovery, but it is definitely life-saving.
Figure 5. ChE represents Cholinesterase. Figure from: Rang H. Rang & Dale's Pharmacology, 7th ed, who redrew from Sim V M 1965 JAMA 192: 40.
The signs and symptoms from organophosphate poisoning
After being poisoned from an organophosphate compound, the following symptoms should occur. Think ‘wet’ such as vomiting, salivation, increased mucous secretion, urination, diarrhoea and defecation. The symptoms would be the opposite of what adrenaline or any sympathomimetics should be doing. Hence we get:
Autonomic - Muscarinic
Bradycardia (languid/plodding heartbeats),
Hypotension (low blood pressure),
Excessive secretions such as saliva, watery eyes, sweating
Gastrointestinal hypermotility such as urination/defecation,
Bronchoconstriction, bronchospasm, cough,
Decrease of intraocular pressure,
Blurred vision, miosis.
Medscape utilises a simple mnemonic on remembering these symptoms, these are:
SLUDGE: salivation, lacrimation, urination, diarrhoea, GI upset, emesis.
DUMBELS: diaphoresis and diarrhoea, urination, miosis, bradycardia, bronchospasm, bronchorrhea, emesis, excess lacrimation and salivation.
Neuromuscular - Nicotinic
Muscle fasciculation (small, local, involuntary muscle contraction),
Increased twitch tension, cramping, weakness,
Eventually, a depolarisation block causing paralysis.
An increase in muscle twitching is due to that initial increase in ACh concentration and duration, which increase the endplate potential (EPP) and gets closer to the firing threshold. When the ACh has reached a specific build-up in the plasma and tissue fluid, paralysis may be seen as a depolarisation block.
Central Nervous System
Anxiety,
Seizures,
Ataxia,
Disorientation/confusion,
Collapsing,
Coma.
What to do — think fast and do first aid
Think of DRS ABCD: Danger, Response, Send help, Airway, Breathing, Cardio-Pulmonary Resuscitation (CPR) and Defibrillator. Having a defibrillator may always be handy, so do put it on your victim if you can. Remember that a DRS ABCD or any CPR attempt is always better than no attempt at all but do not put your life in danger as we don’t want two severely contaminated victims. However, I believe in some risk-taking decisions if it will improve your victim’s situation dramatically. Do judge the situation carefully and think so that a sound decision can be made. The main goal is to keep the victim breathing, alleviate pain where possible and reduce the consequences in further exposure to organophosphate.
DRS ABCD
(D)anger
If something happened to someone there is most likely a cause present, which could be harmful and dangerous. Hence, look out for the danger that is present. In organophosphate poisoning this could include: harmful liquid spoilage, the container including the pesticide that is open, et cetera.
Look for the source of the danger.
Stop touching any pesticide/liquid/gas and get away from its exposure.
Think for your life. If you are going to risk yourself to save someone, then do it fast with decisive thinking.
If there is pesticide liquid on the person, remove it with a cloth and minimise the exposure to you and your victim. The use of mild soap and water is acceptable and try to wear protective equipment. Be careful with the equipment as hydrocarbons can penetrate latex and vinyl, instead use neoprene or nitrile gloves.
(R)esponse
In short: is the person responding? Are they conscious? There are a few techniques to see if the victim is responsive or if the victim is unconscious. You can talk to them by calling out their name, squeeze their hands, instruct them to open their eyes, rub on their chest/sternum area (the chest plate) and squeeze their shoulders.
(S)end help
If the person has been exposed to organophosphate or any pesticide/insecticide, it is considered as an emergency, especially if they are children. Remember that these are compounds that have been utilised in warfare and are used to kill animal. Hence these are dangerous compounds that can kill a human being.
Depending on the country you are in, it is always a good idea to know the emergency number. For example, in Australia triple zero (000) is the emergency number.
What to do with the operator? The most likely course of action or the first questions should be:
What is your name?
Give us your phone number.
Where are you, address, co-ordinate if available.
What is happening/reason for calling
Based on this information they will judge if help is necessary, what type of vehicle to send you, and what services you need. Depending on where you are, for example, being on a farm at a rural town, the operator may send an ambulance, a helicopter or an aeroplane.
(A)irway
Figure 6. Demonstrates the recovery position.
Before checking the breathing, we first need to see if the victim has vomited or has anything stuck in their mouth/trachea. Quickly check if there is anything in their mouth and if there is, scoop it out with your fingers and roll them to their side. If there is nothing, you have to check their airway for breathing, and that is by tilting their head backwards gently. If they immediately breath again put them into the recovery position. Do not give them food or water. The recovery position is when the person lies on their side, with one arm supporting their heads, an arm stretched out and a bent leg seen in figure 6. Now many sources indicate how to check the airway thoroughly and in steps but in a situation where there will be stress and panic, it is easier to remember to get rid of any content that is blocking the airways. This is especially true with organophosphate poisoning as it is unlikely that the victim has a spinal fracture unless caused by a fall. Do be careful when handling the victim’s head.
(B)reathing
Kneel down next to the victim and put your head near their mouth. Look/listen for breathing.
Check if they are breathing, do you feel breathing on your ear?
Place your hand on their chest, do you see their chest rise and fall?
Look and feel for at least 10 seconds.
If they are breathing and unconscious, put them into the recovery position and wait for help to arrive.
(C)PR and (D)efribulator
Be present with the victim and do not let them be on their own, they may stop breathing, and CPR may be required to be started whilst waiting for the emergency to arrive. Essentially the person aiding the victim, who is unconscious and not breathing, has to press one hand firmly on the victim’s chest and the other hand on top. Compressions must be made of a depth of one-third and should be made 30 times before giving two breaths. The rate should be 100 beats per minute (almost but not quite 2 beats per second). The breaths are not mandatory as giving only compressions is at a standard level, especially if the victim is unknown to the person giving CPR and/or has no CPR breathing barrier protection. The person could also contaminate themselves.
Regarding organophosphate poisoning, the airway, breathing and the slowing heart rate will be the major problems. Arrhythmia could be present, so it is always a good idea to put in place the defibrillator. There should be instructions given with pictograms on how to set up a defibrillator on a human being. Generally, it is automatic and a voice should be guiding the person that is helping.
For more detail information, see BetterHealth from the Victoria State Government on how to put on a defibrillator.
Medication used for treatment
Essentially, what we need to do is to remove the irreversible block on the AChE enzyme, to reduce the ACh concentration and to improve the unwanted symptoms, especially the bronchoconstriction and bradycardia. It has been mentioned in Medscape the most prominent and crucial symptom to treat is breathing or managing breathing. The lungs will have an increase in mucous secretion as well as bronchoconstriction, which decrease the ability to increase the surface area for oxygen/carbon dioxide exchange. The muscles of the diaphragm may also be affected and could be paralysed, which results in the lungs not being able to fully expand.
Techniques and Medication used:
Before Atropine administration, optimise use of airway control and oxygenation. Intubation may be required and consider administrating oxygen.
Atropine: limits the parasympathomimetic effects. Its mode of action is to binds and inhibit muscarinic acetylcholine receptors. This will cause an anticholinergic effect.
Glycopyrrolate can be used as an alternative to Atropine. However, it does not cross the blood-brain barrier and cannot treat central cholinergic toxicity.
Pralidoxime: as seen earlier, it is used to remove the strong phosphate bond at the AChE active site.
Benzodiazepines may be given if seizures are present or if there is evident muscle paralysis. It is mainly used as an anxiolytic, anticonvulsant, sedative and skeletal muscle relaxant activity.
Blood-gas measurement should be made, establish oximetry and an electrocardiogram (ECG).
Magnesium sulfate has been reported as beneficial.
Intraosseous administration has been found to add Atropine and Pralidoxime in a patient quickly; this should be considered in times of an emergency.
Conclusion
Awareness is crucial to prevent any organophosphate poisoning and is especially needed in rural and remote farms. Quick thinking and doing first aid to stabilise the victim can reduce the mortality rate. Education and prevention is the best solution for organophosphate poisoning, hence be sure to get on that!
The following could be done to decrease the likelihood of organophosphate poisoning or exposure:
Do first aid if someone has been exposed to an organophosphate compound. This includes looking for danger, responsiveness and sending help immediately. Protect yourself whilst doing so with the right equipment.
Check the first aid kit yearly for any damage and expiry dates.
Awareness and education are essential - teach any staff members that works on the farm about pesticides and how to handle these chemicals. Teach on how to give proper first aid through professionals and the procedures of what to do in case of an exposure.
Have a location that is easy to reach and that contains a first aid kit as well as emergency numbers and co-ordinates of the farm. They may send a plane or a helicopter.
Stay indoors when the organophosphates are being used and wash your hands before eating, drinking and going to the toilet.
Install pictograms with clear warnings and carefully store any pesticides.
Have standardised and approved safety equipment when handling any sorts of pesticide/chemicals.
Published 30th January 2020. Last reviewed 1st December 2021.
Reference
BetterHealth Authors. First aid basics and DRS ABCD. BetterHealth Victoria Government website. https://www.betterhealth.vic.gov.au/health/conditionsandtreatments/first-aid-basics-and-drsabcd. Updated August, 2014. Accessed January 20, 2020.
Drugbank Authors. Atropine. Drugbank website. https://www.drugbank.ca/drugs/DB00572. Updated January 28, 2020. Accessed January 29, 2020.
Drugbank Authors. Pralidoxime. Drugbank website. https://www.drugbank.ca/drugs/DB00733. Updated January 2, 2020. Accessed January 29, 2020.
Gotoh M, Sakata M, Endo T, Hayashi H, Seno H, Suzuki, O. Profenofos metabolites in human poisoning. Forensic Sci. Int. 2001;116: 221-226. DOI: https://doi-org.elibrary.jcu.edu.au/10.1016/S0379‐0738(00)00377‐7. Accessed January 29, 2020.
Jenna Fletcher, Medically reviewed by Deborah Weatherspoon. What are the symptoms of organophosphate poisoning? Medical News Today website. https://www.medicalnewstoday.com/articles/320350.php#signs-and-symptoms. Reviewed December 19, 2017. Accessed January 29, 2020.
Kenneth D Katz. Organophosphate Toxicity. Medscape website. https://emedicine.medscape.com/article/167726-medication. Reviewed September 22, 2018. Accessed January 29, 2020.
Kushwaha M, Verma S, Chatterjee S. Profenofos, an Acetylcholinesterase-Inhibiting Organophosphorus Pesticide: A Short Review of Its Usage, Toxicity, and Biodegradation. J Environ Qual. 2016;45(5): 1478-1489. https://www.ncbi.nlm.nih.gov/pubmed/27695768. Accessed January 27, 2020.
Ritter J, Flower R, Henderson G, Loke YK, MacEwan D, Rang H. Rang & Dale's Pharmacology. 7th ed. London: Elsevier; 2019. eBook ISBN: 9780702074462.
Figures
Figure 1. Smedlib. Acetylcholine. Wikipedia. https://commons.wikimedia.org/wiki/User:Smedlib. Updated January 23, 2020. Accessed January 26, 2020.
ADDITIONAL SOURCE OF INFORMATION:
South African Medicine Formulary (SAMF),