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Learn about the impact, toxicity, and clinical features of organophosphorus compounds in pesticides on human health. Understand the principles of disease and potential complications associated with exposure.
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PERSPECTIVE • Pesticides, a generic term used to refer to all pest-killing agents, include numerous chemicals intended for use as insecticides, herbicides, rodenticides, fungicides, and fumigants. • Many of these chemicals are general protoplasmic poisons affecting a wide range of organisms, including humans. • Organophosphate insecticides some of the most common pesticides for home and industrial use
Principles of Disease • Organophosphorus insecticides are highly lipid soluble and are readily absorbed via dermal, GI, and respiratory routes. • This lipid solubility results in the storage of organophosphorus compounds in body fat, making toxic systemic levels possible from gradual or rapid accumulation from repeated low-level exposures.
Principles of Disease • The parent compound and its metabolites are acetylcholinesterase inhibitors • Many parent organophosphorus compounds are less potent than their metabolites (e.g., parathionto paraoxon), which may result in delayed onset of clinical toxicity.
Principles of Disease • They work by persistently inhibiting the enzyme acetylcholinesterase, the enzymatic deactivator of the ubiquitous neurotransmitter acetylcholine.
Principles of Disease • Inhibition of cholinesterase results in the accumulation and subsequent prolonged effect of acetylcholine at a variety of neurotransmitter receptors, including the sympathetic and parasympathetic ganglionic nicotinic sites, postganglionic cholinergic sympathetic and parasympathetic muscarinic sites, skeletal muscle nicotinic sites, and central nervous system sites.
Principles of Disease The autonomic nervous system (ANS) comprises the sympathetic and parasympathetic nervous systems. The sympathetic nervous system is also known as the thoracolumbar outflow, where the cell body lies in the spinal cord and the first synapse occurs in the sympathetic ganglia. The neurotransmitter in this first synapse is acetylcholine (ACh) (preganglionic), and the neurotransmitter in the postganglionic neuron with the target organ is norepinephrine (NE). In the parasympathetic nervous system (craniosacral outflow), nerves from the medulla and sacrum use ACh as the neurotransmitter in preganglionic and postganglionic target organs. The ANS is divided further into the muscarinic and nicotinic receptors, where atropine can block the muscarinic receptors but not the nicotinic receptors. The neuromuscular junction uses ACh as the effector neurotransmitter. In the brain, ACh is just one of several active neurotransmitters.
Clinical Features Signs and Symptoms • The accumulation of acetylcholine results in a classic cholinergic syndrome, manifested by hyperactivity of cholinergic responses at the receptor sites indicated previously. • The clinical syndrome of muscarinic acetyl cholinesterase inhibition is commonly called the SLUDGE syndrome.
Clinical Features Signs and Symptoms • Bradycardia is a classic sign of the cholinergic syndrome, but the increased release of norepinephrine from postganglionic sympathetic neurons precipitated by excess cholinergic activity at sympathetic ganglia may result in normal or even tachycardic heart rates (nicotinic effect).
Clinical Features Signs and Symptoms • The most lethal components of acetylcholinesterase inhibition occur in the brain and neuromuscular junction. • A combination of sympathetic stimulation, involvement of the N-methyl-d-aspartate receptor, and enhanced acetylcholine concentrations can lead to seizures.
Clinical Features Signs and Symptoms • At the neuromuscular junction, excess acetylcholine causes hyper stimulation of the muscles with secondary paralysis. • Because the diaphragm is affected, cholinesterase poisoning leads to respiratory arrest
Clinical Features Signs and Symptoms • The patients with chronic poisoning commonly exhibit vague confusion or other central nervous system complaints; mild visual disturbances; or chronic abdominal cramping, nausea, and diarrhea.
Complications • Seizures and pulmonary hypersecretion, or bronchorrhea and bronchoconstriction, are prominent mechanismsof early morbidity • Bronchorrhea is often incorrectly called non cardiogenic pulmonary edema because the origin of the excessive pulmonary fluids is from airway secretions and not transudation of fluid across the alveolar-capillary membrane.
Complications • The obstruction of upper and lower airways and broncho constriction produce hypoxia
Complications • Muscle hyperactivity eventually gives way to muscle fatigue and paralysis, including the respiratory musculature and particularly the diaphragm. • Respiratory insufficiency may be delayed and result in death if not anticipated and corrected by mechanical or pharmacologic means.
Complications • A unique effect of organophosphorus insecticides results from “aging,” the irreversible conformational change that occurs when the organophosphorus agent is bound to the cholinesterase enzyme for a prolonged time. • On average, for commercial organophosphorus agents some aging will occur by 48 hours, but aging may take longer. • Once the enzyme has aged, an oxime antidote cannot regenerate the cholinesterase.
Diagnostic Strategies • Known or suspected exposure to cholinesterase inhibitors should be confirmed by ordering plasma and erythrocyte (RBC)cholinesterase levels. • In acute exposures, the plasma cholinesterase levels decrease first, followed by decreases in RBC cholinesterase levels. • .
Diagnostic Strategies • Patients with chronic exposures may show only reduced RBC cholinesterase activity, with a normal plasma cholinesterase level. • The true reflection of depressed cholinesterase activity is found in the RBC activity, and even a mild acute exposure may result in severe clinical poisoning. • RBC cholinesterase levels recover at a rate of 1% per day in untreated patients and take approximately 6 to 12 weeks to normalize, whereas plasma cholinesterase levels may recover in 4 to 6 weeks.
Diagnostic Strategies • Other studies should focus on the evaluation of pulmonary, cardiovascular, and renal function and fluid and electrolyte balance. • Patients presenting with no acidosis, or only a metabolic acidosis on the arterial blood gas, have lower mortality than those presenting with a respiratory or mixed acidosis
Management Treatment is directed toward four goals: • (1) decontamination • (2) supportive care • (3)reversal of acetylcholine excess at muscarinic sites • (4) reversal of toxin binding at active sites on the cholinesterase molecule. • Decontamination should start in the out-of-hospital phase
Management • Decontamination is particularly important in cases of dermal exposure; removal and destruction of clothing and thorough flushing of exposed skin may limit absorption and subsequent toxicity. • Care givers are at risk for contamination from splashes or handling of contaminated clothing. • Should use universal precautions, including eye shields, protective clothing, and nitrile or butyl rubber gloves.
Management • In the case of ingestion, GI decontamination procedures are of questionable benefit because of the rapid absorption of these compounds. • Profuse vomiting and diarrhea are seen early in ingestion and may limit or negate any beneficial effect of additional GI decontamination.
Management • supportive care should be directed primarily toward airway management, including suctioning of secretions and vomitus, oxygenation, and, when necessary, ventilatory support.
Management • The definitive treatment of acetylcholinesterase inhibition starts with atropine. • A competitive inhibitor of acetylcholine at muscarinic receptor sites, atropine reverses the clinical effects of cholinergic excess at parasympathetic end organs and sweat glands. • Large doses of atropine may be required. • Data suggest that the more rapid the atropinization, the faster control is obtained
Management • Suggested dosing is 1 or 2 mg of atropine (0.02–0.05 mg/kg) IV, with doubling of each subsequent dose every 5 minutes until there is control of mucous membrane hypersecretion and the airway clears. • If IV access is not immediately available, atropine may be administered IM. • Patients may require 200 to 500 mg of atropine IV during the first hour, followed by prolonged continuous infusions of 5 to 100 mg/hr to maintain adequate secretion control.
Management • Tachycardia and mydriasis may occur at these doses, but they are not indications to stop atropine administration. • The endpoint of atropinization is drying of respiratory secretions, easing of respiration, and a mean arterial pressure greater than 60 mm Hg. • Animal evidence suggests that early rapid atropinization may limit seizure propagation and, in conjunction with diazepam, prevent status epilepticus.
Management • Atropine is not active at nicotinic sites and does not reverse the skeletal muscle effects (e.g., muscle fatigue and respiratory failure). • Other anticholinergic medications such as diphenhydramine or ophthalmic agents may have benefit if atropine is scarce or unavailable; however, optimal IV dosing is not known
Management • The second part of acetyl cholinesterase inhibition treatment is the use of an oxime, such as pralidoxime (2-PAM, Protopam) or obidoxime (Toxigonin), to regenerate the organophosphate-acetylcholinesterase complex and restore cholinesterase activity at muscarinic and nicotinic sites. • There are various dosing regimens; the most common dose of pralidoxime is 1 or 2 g intravenously (pediatric dose, 25–50 mg/kg); • additional doses may be given based on clinical response and serial cholinesterase levels.
Management • Indications for oxime therapy include respiratory depression/apnea, fasciculations, seizures, arrhythmias, cardiovascular instability, and use of large amounts of atropine. Oxime therapy can be used whenever the patient requires more than a limited amount of atropine (2–4 mg) to completely reverse the signs and symptoms of intoxication or in any patient who requires repeated doses of atropine. Oxime therapy and atropine are synergistic.
Management • Many organophosphates are highly lipid soluble and slowly leach out of fat stores for up to 6 weeks, resulting in newly formed complexes with excellent reversal of the cholinesterase inhibition by pralidoxime clinically and by measurements of cholinesterase activity. Pralidoxime can also combine with unbound organophosphates and prevent their subsequent binding to nerve terminals. Even with optimal treatment, seriously intoxicated patients may require long-term supportive care, including ventilator support.
Management • In conjunction with atropine and oxime pralidoxime, patients with agitation, seizures, and coma should be treated with adequate doses of a benzodiazepine after the airway has been secured.
Management • Sarin, soman, tabun, and VX are nerve agents that might be used in a terrorist attack. These agents have important differences from the common household or commercial organophosphorous insecticides. These agents tend to age very quickly, with tabun (GA) aging in 14 hours, sarin (GB)in 5 hours, soman (GD)in 5 or 6 minutes, and VX in 48 hours. Due to this rapid aging, reversal of nerve agent poisoning is very time sensitive.
Management • New therapies for treatment of organophosphorus poisoning, including the use of N-acetylcysteine and exogenous acetylcholinesterase, show promise in research studies.
Disposition • Because of the prolonged effects of acetylcholinesterase inhibition, most patients with significant exposures require hospital admission. Occasionally, a person with chronic exposure, depressed cholinesterase levels, and mild visual or GI symptoms may be followed on an outpatient basis.
Plasma cholinesterase levels are available, they may be useful for treatment and disposition decisions. Asymptomatic or minimally symptomatic patients with normal or minimally depressed levels may be discharged after 4 to 6 hours with close outpatient follow-up to ensure that progressive toxicity does not occur.
Patients with severely depressed levels (usually associated with significant symptoms) require admission and close monitoring, usually in a high-intensity care unit. Patients may develop rebound toxicity several days after apparently satisfactory response to initial treatment. Rebound toxicity may occur for many reasons, including persistent release of organophosphates from lipid stores.
A secondary syndrome, the intermediate syndrome (IMS), occurs 24 to 96 hours after exposure and consists of proximal muscular weakness specifically of the respiratory muscles. It is believed to be an abnormality at the neuromuscular junction. Patients with IMS present with respiratory failure several days after the acute cholinergic symptoms have resolved and may require several weeks of ventilatory support.
It is theorized that this may occur as a result of in adequate initial oxime treatment or premature discontinuation of oxime therapy. Oximes may be beneficial for IMS; however, this is controversial. Finally, organophosphorus-delayed neuropathy has been reported as a different entity and affects an axonal enzyme, neurotoxic esterase, and leads to a peripheral sensorimotor neuropathy 7 to 21 days after exposure.
True/False Following are the clinical features of organophosphorus poisoning 1- Salivation 2- Lacrimation 3- Urination 4- Defecation 5- Emesis
Clinical features of organophosphorus poisoning 1- Miosis 2- Bradycardia 3- Bronchorea 4- Bronchospasm 5- Diaphoresis
Following are True regarding organophosphorus poisoning 1- Decontamination can be delayed until late 2- It acts by inhibiting enzyme acetylcholinesterase 3- In acute poisoning serum level of cholinesterase is low 4- Atropine and pralidoxime are used in the treatment 5- Betablockers are very useful in the treatment
CARBAMATE INSECTICIDES • Carbamate insecticides are another class of acetylcholinesterase inhibitors and are differentiated from the organophosphorus compounds by their relatively short duration of toxic effects. Carbamates inhibit acetylcholinesterase for minutes to 48 hours, and the carbamate-cholinesterase binding is reversible. Although the clinical picture of acute carbamate poisoning may be identical to that of organophosphate poisoning,
the toxic effects are limited in duration and patients may require only decontamination, supportive care, and treatment with adequate doses of atropine. Although the duration is limited in scope, patients may become just as sick and require assisted ventilation and seizure therapy. The use of pralidoxime is controversial in carbamate poisoning; an animal study suggests that pralidoxime administration may produce. Zohair Al Aseri MD,FRCPC EM & CCM
greater toxicity in cases of carbaryl (Sevin) poisoning, although the author has used pralidoxime in carbaryl-poisoned humans without adverse events. Nevertheless, if doubt exists as to whether a severe poisoning is due to a carbamate or organophosphate, pralidoxime should be administered. It is the author's practice to use oximes when patients present with a cholinergic toxindrome and a history of exposure of organophosphorus or carbamate insecticides. Zohair Al Aseri MD,FRCPC EM & CCM
CHLORINATED HYDROCARBON INSECTICIDES • DDT, the prototype of chlorinated hydrocarbon insecticides (sometimes referred to as organochlorine insecticides), was first used extensively during World War II for the successful control of typhus and malaria and was used widely in the United States as a general insecticide after the war. Because of the effectiveness of DDT, many other chlorinated hydrocarbon insecticides were developed. Zohair Al Aseri MD,FRCPC EM & CCM
These insecticides were used extensively in agricultural, commercial, and residential pest control. However, although these insecticides were very effective, their widespread use, long half-life, and persistence had negative ecologic repercussions. Many of these insecticides have been targeted as persistent organic pollutants by international agencies, leading to their restricted use. Zohair Al Aseri MD,FRCPC EM & CCM
Although chlorinated hydrocarbon insecticides are no longer used in the United States for agricultural use, γ-hexachlorobenzene, better known as lindane (Kwell), is still used as a topical medicinal agent for the treatment of head lice and scabies. As a result, lindane is probably the most common cause of toxicity from an organochlorine compound in the United States. Given its toxicity, lindane is no longer a first-line agent for the treatment of scabies. In 2001, California issued a ban on the use and sale of lindane, and other states are considering a ban on lindane. Zohair Al Aseri MD,FRCPC EM & CCM
Principles of Disease • Chlorinated hydrocarbon pesticides are highly lipid soluble. They are readily absorbed through dermal, respiratory, and GI routes.Dermal and GI exposures account for most clinical poisonings, including inappropriate external use of lindane or other compounds and the occasional accidental oral administration of lindane. Because they are so lipid soluble, these compounds are stored in fatty tissues, and repeated small exposures result in accumulation and eventual clinical toxicity Zohair Al Aseri MD,FRCPC EM & CCM
