Organophosphate compounds are type of chemicals used in domestic and agricultural feilds. Many organophosphate compounds able to inhibit the action of acetylcholinesterase (Ache) in neurons. They are a common cause of poisoning worldwide and are frequently used in suicides in agricultural areas. Organophosphates are of main importance due to their usefulness and chemical instability.
Exposure to organophosphates in an attempt toaccomplish suicide is a major problem, mostly in the developing countries, and is a more common cause of poisoning than the chronic exposure faced by farmers and sprayers in contact with pesticides. Estimates of WHO show that each year, 1 million poisonings and 2 million suicide attempts involving pesticides occur around world. Intoxication occurs after absorption through the skin, ingestion via the GI tract or inhalation through the respiratory tract. Early diagnosis and quick treatment is essential to save the patient's life
How poisoning occurs?
Most organophosphates are highly lipid soluble compounds and are well absorbed from skin, oral mucous membranes, conjunctiva and the gastrointestinal and respiratory tracts. They are quickly redistributed to all body tissues. The maximum concentrations are found in the liver and kidneys. This great lipid solubility facilitates crossing the blood/brain barrier and so produces strong effects on the central nervous system. Metabolism occurs mainly by oxidation in the liver with conjugation and esterase hydrolysis producing a half-life of minutes - hours. The oxidative metabolites of malathion and parathion (malaoxon and paraoxon) are active forms and are then hydrolyzed into inactive metabolites. Excretion of organophosphorus compounds and its metabolites occur majorly via urine, bile and faeces.
The situation in Sri Lanka
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Organophosphate poisoning has recently increased in Sri Lanka. Epidemiological studies in Sri Lanka shows that in 1995 there were 15730 cases with 1571 deaths from pesticide poisoning. It is the 6th commonest cause of hospital death in Sri Lanka that time.(1)
The WHO estimates that the yearly death number is around 50 000. (2)
There are more than a 100 organophosphorus compounds in domestic usage. These are classified according to their toxicity and clinical use:
Highly toxic organophosphates- (eg. tetra-ethyl pyrophosphates, parathion).
-used as agricultural insecticides.
Medium toxic organophosphates- (eg. coumaphos, clorpyrifos, trichlorfon).
- used as animal insecticides.
Low toxicity- (eg. diazinon, malathion, dichlorvos).
-used for domestic use and as field sprays.
Action of Acetylcholine
Acetylcholine (ACh) is the neurotransmitter released at all postganglionic parasympathetic nerve endings and at the synapses of both sympathetic and parasympathetic ganglia. That is also released at the skeletal neuromuscular junction and acts as a neurotransmitter in the central nervous system. The acetylcholine, after releasing into the synaptic space, continues to activate the acetylcholine receptors as long as the acetylcholine remains in the space.
Removal of ACh
Most of the acetylcholine is destroyed by the enzyme acetylcholinesterase. This enzyme is attached to the spongy layer of fine connective tissue that fills the synaptic space between the presynaptic nerve terminal and the postsynaptic muscle membrane.
A small amount of acetylcholine diffuse out of the synaptic space and is then no action on the muscle fiber membrane.
The short time that the acetylcholine remains in the synaptic space a few milliseconds normally is enough to excite the muscle fiber. Then the rapid removal of the acetylcholine prevents continued muscle re-excitation after the muscle fiber has recovered from its initial action potential.
What organophosphates do?
Organophosphates inactivate acetyl cholinesterase. Once acetyl cholinesterase has been inactivated, acetylcholine builds up in the nerves, and the nerves turn into over-active due to over muscle re-excitation.
Organophosphate poisoning can happen quickly or build up over a number of days.
Accumulation of acetylcholine causes overstimulation of both muscarinic and nicotinic receptors, and then disrupts the transmission of nerve impulses in both the peripheral and central nervous system.
Reactivation of the inhibited enzyme may happen spontaneously. The rate of reactivation will depend onthe species,
the tissue, and
the chemical group attached to the enzyme.
Reactivation may be improved by hydrolysis of the acid radical enzyme through the use of oximes (i.e. reactivating agents).Response to reactivating agent's fails with time; this procedure is caused by ageing of the inhibited enzyme. Ageing is probably the result of the loss of one alkyl or alkoxy group, leaving a much more stable acetylcholinesterase.
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The aged phosphorylated enzyme cannot be reactivated by oximes.
Clinical features of Organophosphorus Poisoning
Clinical features are depend on type of receptors.
Acetylcholine receptors are divided into two main types on the basis of their pharmacologic properties.Muscarinic and Nicotinic.
Muscarinc receptors are on smooth muscles and glands. The actions of acetylcholine on muscarinic receptors are called muscarinic actions, and the receptors. They are blocked by the drug atropine.
Another type of acetylcholine receptors are called as nicotinic. These actions of acetylcholine are nicotinic. Nicotinic receptors are subdivided as those found in muscle at neuromuscular junctions and as found in autonomic ganglia and the central nervous system.
After exposure to organophosphate compounds, the features are usually appear within 30 min. to 3 hours. This may be delayed in sometimes depending on the rate and amount of absorption at organ level. Toxicity is mainly produced by the rapid absorption of the compound through the gastrointestinal, respiratory tracts and skin.
The clinical symptoms and signs are depending on the specific agent, the quantity and the route of entry.
Some patients present with vomiting, diarrhea and abdominal pain, Someothers may be unconscious on arrival at the hospital. The clinical features can be classified as secondary to the
(a) Muscarinic effects
(b) Nicotinic effects and
(c) Central receptor stimulation. (5)
Early cases present majorly with parasympathetic over-activity, and a characteristic garlic smell. The end result may be a multi-system effect involving the gastrointestinal, respiratory, and cardiovascularand nervous systems, also involvement of skeletal muscle, other organs and metabolic effects such as hyperglycemia.
Most fatalities occur within 24 hours and those who recover usually do so within 10 days.
Symptoms and signs of organophosphorus poisoning:-
Eyes Blurred vision
Ataxia( lack of control of movements)
Dysarthria(difficult in speaking words clearly)
A direct toxic effect on the myocardium
Over activity of cholinergic or nicotinic receptors causing,
Myocardial infarction is a rare case due to exposure to organophosphate compounds.
The commonest cardiac manifestations following poisoning are hypotension (with warm, dilated peripheries), and bradycardia. Patients sometimes present with tachycardia and hypertension due to main nicotinic receptor blockade.
Cardiac manifestations are become the cause of serious complications and fatality.
Electrocardiographic manifestations include prolonged Q-T intervals elevation of the ST segment, inverted T waves and a prolonged PR interval (7). There may also be rhythm abnormalities such as sinus bradycardia, ventricular extra- systoles, ventricular tachycardia and fibrillation.
Respiratory manifestations of acute organophosphorus poisoning include bronchorrhoea, rhinorrhoea, bronchospasm and laryngeal spasm. This is due to the action of the organophosphate on muscarinic receptors. The airway may be occluded by excessive secretions. The nicotinic effects lead to weakness and paralysis of respiratory and oropharyngeal muscles. This increases the likelihood of both airway obstruction and aspiration of gastric contents. Finally, central neurological inactivation may lead to respiratory arrest.
Symptoms resembling gastroenteritis such as vomiting, diarrhea and abdominal cramps are the first to occur after oral ingestion of an organophosphorus compound.
A large number of patients, following exposure to organophosphate compounds, require prolonged ventilatory support in the intensive care unit due to neuromuscular weakness. Three different types of paralysis are recognized based largely on the time of occurrence and their differing pathophysiology:
paralysis or acute paralysis
paralysis or intermediate syndrome
paralysis or organophosphate- induced delayed polyneuropathy
1.Paralysis or acute paralysis is seen initially. This is when large numbers of both muscarinic and nicotinic receptors are occupied by acetylcholine, leading to persistent depolarization at the neuromuscular junction. Clinical features include muscle fasciculation, cramps, twitching and weakness. At this stage the patient may require ventilatory support due to the weakness of the respiratory muscles leading to respiratory depression and arrest.
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2. Paralysis or intermediate syndrome. This syndrome develops 24-96 hours after the poisoning. After recovery from the acute cholinergic crisis, and before the onset of delayed neuropathy, some patients develop a state of muscle paralysis. The cardinal feature of the syndrome is muscle weakness affecting the upper limb muscles and neck flexors. There is a less effect on the distal muscle group. One of the earliest manifestations in these patients is the inability to lift their head from the pillow .This is a useful test to know whether patient is likely to develop respiratory muscle weakness.
Of the cranial nerves, that supply the extra-ocular muscles are mostly affected, with a lesser effect on VII and X. This syndrome remains for about 4-18 days. Most patients will survive if not infection or cardiac arrhythmias complicate the course.
3. Paralysis or organophosphate- induced delayed polyneuropathy is a sensory-motor distal axonopathy due to ingestion of large doses of an organophosphate compound. The neuropathy presents as weakness and ataxia in coming period of 2-4 weeks. Initial stimulation causes excitatory fasciculation, which then progresses to an inhibitory paralysis. The cardinal symptoms are distal weakness of the hands and feet. This is often preceded by calf pain. Delayed CNS signs include tremor, anxiety and coma.
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There are number of measurements to assess early biological effects and organophosphate poisoning. There are no specific clinical features specific to organophosphorus poisoning; diagnosis requires a high suspecting ability. The examination of history and detecting clinical features are effective.
The history of exposure is shown by patients who have attempted suicide. Helpful signs of poisoning include the garlic- like odour of organophosphorus in breath and vomitus, miosis, bradycardia and muscle fasciculation. Excessive salivation, excessive respiratory tract secretions and lacrimation are helpful signs. Some patients may present with the nicotinic effects of tachycardia, hypertension and widening of pupil (expectations are bradycardia and hypotension).
Path to treatment.
Treatment is initiated immediately on clinical suspicion. It takes time to wait for blood investigations
Blood investigations are important, to confirm the diagnosis, and to find out multiple poisonings and other metabolic causes of an affected neurological state. Both true and pseudo cholinesterase levels can be estimated to assess poisoning. These levels are markedly reduced in organophosphorus poisoning. While true cholinesterase correlates with the severity of poisoning at presentation, pseudo cholinesterase levels do not. A 25% or greater reduction in true cholinesterase level is indicative of organophosphorus poisoning.
Metabolites of cholinestereses such as butyrylcholinesterases, neuropathy target esterase in lymphocytes and acetyl cholinesterases.
Management of a organophosphate poisoned person
Management of organophosphorus compounds poisoning
Airway protection if indicated Gastric lavage
Activated charcoal 0.5-1gm/kg every 4hr
Anticholinesterase ( Atropine/glycopyrrolate)
Cholinesterase reactivator ( Pralidoxine)
Airway and respiration
Skin decontamination is very important step that should never be neglected or hurried. The patient should be removed from the site of exposure and their clothes removed. The patient's body should then be thoroughly washed with soap and water to prevent further absorption from the skin. Before treating the patient, staff should be protected from the organophosphate by wearing gloves, gowns and eye protectors. Gastric emptying should then be considered if the patient presents within 1 hour of ingestion. Gastric lavage is the only means of emptying the stomach in unconscious patients in which case the airway needs to be protected. The patient should receive activated charcoal 0.5-1 mg/ kg every four hours to promote adsorption in the gastrointestinal tract. Lavage is preferred to enforced emesis as this may precipitate seizures.
Airway and respiration
The airway should be secured and adequate oxygenation ensured. This is important as atropine can cause ventricular fibrillation in hypoxic patients. Paradoxically, the early use of adequate atropine will dry respiratory secretions, improve muscle weakness and thereby improve oxygenation. Careful observation of the respiratory status is required as these patients are prone to develop respiratory failure during both the acute phase and the intermediate syndrome. The following should be monitored on a regular basis to assess the patient's respiratory status:
Neck muscle weakness
Ocular muscle involvement e.g. diplopia
Arterial blood gas analysis
As mentioned earlier, a wide range of cardiac manifestations can occur and careful hemodynamic and electro cardiac monitoring should be undertaken in all patients. It should be remembered that hypoxaemia, metabolic and electrolyte abnormalities can all contribute to cardiac arrhythmias. Some arrhythmias may require cardiac pacing.
Atropine- Treatment with anticholinergics. These are used to antagonize the muscarinic effects of the organophosphate on the central nervous system, cardio vascular system and gastrointestinal tract. It is still the mainstay of treatment, and should be started as soon as the airway is secured. The recommended starting dose of atropine is a 2mg intravenous to prevent bronchorrhoea .Subsequent doses of 2-5mg every 5-15 minutes should be administered until atropinization is achieved. The signs of adequate atropinization include
Increased heart rate (more than 100 beats per min.),
moderately dilated pupils,
a reduction in bowel sounds,
a dry mouth and a decrease in bronchial secretions.
Complete atropinization is fully dilated pupils, absent bowel sounds, heart rate more than 150 beats per min. These features are no longer necessary. Satisfactory management involves keeping the patient adequately atropinized without the attendant risks of total atropinization includeing hyperexcitability, restlessness, high body temperature [above 41.1°C] and cardiac complications.
Continuous atropine infusions are used in some centresin doses of 0.02-0.08mg/kg/hr(13). The dose of atropine required is maximal on day 1 and tends to decrease over the next few days. Atropine does not reverse the skeletal muscle effects.
Glycopyrolate-glycopyrolate is equally effective. It shows few central nervous system side effects and a better control of bronchial and gastric secretions.
These are Oximes. Oximes are nucleophilic agents that re-activate the phosphorylated acetylcholinesterase by binding to the organophosphorus molecule. The use of oximes in acute organophosphate poisoning wasn't common as there have been very few randomized controlled instances that have addressed the role of pralidoxime (PAM).
Pralidoxime has three main actions:
A direct reaction converting the organophosphate to a harmless compound.
A transient reaction protecting the enzyme from further inhibition.
Reactivation of the inhibited alkyl phosphorylated enzyme to free the active unit (if given early enough)
The reactivating action of pralidoxime is very effective mainly at the nicotinic skeletal neuromuscular junction. It does not reverse the muscarinic manifestations of organophosphorus poisoning.
Pralidoxime should be started as early as possible to prevent permanent binding of the organophosphate to acetylcholinesterase. Once this has occurred, receptor regeneration is required to allow recovery.
The recommended dose of pralidoxime in organophosphorus poisoning is 30 mg/kg by slow intravenous injection 4-hourly or an infusion of pralidoxime 8-10 mg/kg/h(12). Pralidoxime should be continued until adequate spontaneous ventilation is achieved by the patient. The effective plasma concentration is 4mg per liter and the patient should show signs of improvement 10- 40 minutes after its administration. Plasma and pseudo cholinesterase levels should ideally be monitored during treatment.
Side effects of pralidoxime include drowsiness, visual disturbances, nausea, tachycardia and muscle weakness, so treatment should be reserved for potentially fatal cases.
Prevention of organophosphate poisoning
Due to the toxicity of pesticides and the risk involved in treatments one should focus on preventing the risk of poisoning rather than treatments. So there is general agreement that emphasis should be on preventing pesticide poisoning rather relying on treatment.
Make sure that there is always adequate ventilation when using or applying pesticides in the home or on pets.
Don't spray oppose to the direction of wind. Use a face cover to protect from sprays.
Don't use pesticides indoors if they are only designed to be used outdoors.
Pesticides should keep away from children.
Always read and follow the pesticide label's instruction and safety warnings at all times.
Use ready to use products (i.e., no mixing needed) whenever possible. Use gloves for mixing.
Remove all food and water supplies in the home from the area of pesticide application or alternatively keep them sufficiently covered.
Wash all fresh fruits and vegetables adequately before consumption.
Make sure that old pesticide or poison containers are safely discarded, instead of reusing them for storing or transporting drinking water. No matter how well you wash the container, it could still contain remnants of the pesticide.
During agricultural spraying, proper precautions should be taken to prevent inhalation and accidental ingestion of the substance.
Do not transfer pesticides to other containers that children may mistake for cold drink or sweets containers.
Use gloves and other protective clothing when using or applying pesticides.
Always wash your hands after using pesticides.
Make sure regular washing of children's hands throughout the day.
Make sure that all pesticide and poison containers are correctly and adequately labeled as "poison".
Make sure that all pesticides and poisons are stored out of reach of children and other unqualified persons.
Make sure adequate education of children with regard to poisons within the home environment.
Become informed the more you know, the safer your home and environment will be.
Never pour pesticides or household chemicals down the drain, into the toilet or storm water drains, rivers, or lacks.
Sufficient provision of information to the public, regular training of health care providers, better availability of drugs / antidotes and the establishment of poison information centers will facilitate in reducing the morbidity and mortality related to organophosphorus poisoning.
Organophosphates work by inactivating acetyl cholinesterase. Acetyl cholinesterase is an enzyme present in human nervous system. Its job is to break down acetylcholine, which is a chemical that carries signals between the nerves and muscle. Once acetyl cholinesterase is inactivated, acetylcholine is accumulated. Accumulation of acetylcholine causes overstimulation of both muscarinic and nicotinic receptors, and subsequently disrupts the transmission of nerve impulses in both the peripheral and central nervous system.
On arrival a patient who has ingested of an OP compound, usually we can see the patient is drowsy with a garlic-like odour from the frothy secretions in his mouth. Normally he has a heart rate of 60 beats per minute, blood pressure of 100/60mmHg and constricted pupils.
In order to protect the airway, the trachea was intubated immediately after securing intravenous access. Gastric lavage was performed with normal saline and 50mg of activated charcoal introduced via the Ryle's tube. Atropine 2mg was administered intravenously and repeated every 5 minutes until the pupils dilated, HR increased to more than 100beats per minute and secretions from the endotracheal tube decreased. Pralidoxime 1gm was slowly given intravenously. The patient was then transferred to the ICU for ventilatory support and close monitoring.
In the intensive care unit, the patient is sedated with midazolam1mg/hr(a drug used as a sedative for minor surgery, as a premedication, and to induce general anaesthesia) and ventilatory support continued. An atropine infusion is started at 4mg/hour but due to copious secretions from both mouth and respiratory tract was increased to 6-8mg/hour. This is gradually reduced and finally stops. Pralidoxime 1mg intravenous is repeated 6 hourly for a week.