Organophosphates — an overview, ScienceDirect Topics
- 1 Organophosphates
- 2 Related terms:
- 3 Plasmapheresis in Acute Intoxication and Poisoning
- 4 ENVIRONMENTAL TOXINS AND DISORDERS OF THE NERVOUS SYSTEM
- 5 Electrophysiologic Techniques in the Evaluation of Patients with Suspected Neurotoxic Disorders
- 6 Chemical-induced ocular side effects
- 7 Enzymes as Drug Targets
- 8 Drugs and Antidotes in Acute Intoxication
- 9 Environmental Toxins and the Heart
- 10 Toxin-Induced Neurologic Emergencies
- 11 Exogenous Acquired Metabolic Disorders of the Nervous System
- 12 Toxic Exposures
Organophosphates (OPs) are a group of phosphoric acid ester compounds that upon binding to AChE are hydrolyzed, producing phosphorylation of the AChE active site resulting in irreversible inactivation of AChE.
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Plasmapheresis in Acute Intoxication and Poisoning
François Madore, Josée Bouchard, in Critical Care Nephrology (Third Edition) , 2019
Organophosphates are among the most commonly used insecticides in the world. Organophosphates cause a specific and irreversible inhibition of acetylcholinesterase. Treatment of organophosphate poisoning consists of atropine and pralidoxime. 50 Plasmapheresis has been attempted in cases of organophosphate poisonings such as parathion 51 and dimethoate. 52 Plasmapheresis with fresh frozen plasma as replacement fluid has been reported successful in a case unresponsive to atropine and pralidoxime, whose cholinesterase levels were declining despite antidotal therapy. 6 Fresh frozen plasma contains active cholinesterase and may be used to augment plasma cholinesterase levels. 6 Therefore plasmapheresis with autologous plasma as replacement fluid may be beneficial by rapidly increasing cholinesterase levels. Plasmapheresis may allow the rapid administration of fresh frozen plasma without the risk of volume overload. In a recent Chinese meta-analysis including 433 patients, mortality rate was lower with plasmapheresis than without (RR = 0.30, 95% CI [0.19–0.49], p 53 In addition to plasma administration, atropine and pralidoxime may be beneficial in organophosphate poisoning. 54
ENVIRONMENTAL TOXINS AND DISORDERS OF THE NERVOUS SYSTEM
Jean Lud Cadet, Karen I. Bolla, in Neurology and Clinical Neuroscience , 2007
Cause and Pathogenesis
Organophosphates are absorbed through the dermal and respiratory routes, but small amounts may also be ingested with foods that have been sprayed. Organophosphate insecticides are highly toxic to insects but less so to humans and domestic animals. 18 Organophosphates such as triorthocresyl phosphate, mipafox, and trichlorfon compounds can be neurotoxic. Persons at high risk for organophosphate poisoning include factory workers involved in the production of these compounds and agricultural workers who use them to spray crops. Epidemics of organophosphate poisoning have been reported in some developing countries. In 1987, there were reports of 1754 pesticide-related cases in California.
Organophosphates inhibit acetylcholinesterase and pseudocholinesterase. They include chlorpyrifos (Dursban), diazinon, malathion, ethyl and methyl parathion, and trichlorfon. The neurotoxicity of these compounds is related to their ability to inhibit acetylcholinesterase, which is found in the brain, spinal cord, myoneural junctions, and parasympathetic and sympathetic synapses. The resulting increase in acetylcholine overstimulates cholinergic receptors located in various anatomical sites.
Electrophysiologic Techniques in the Evaluation of Patients with Suspected Neurotoxic Disorders
Organophosphate compounds are used as pesticides and herbicides. Acute toxicity relates to anticholinesterase activity and is characterized by both central and peripheral manifestations. The central effects include behavioral disturbances, seizures, and eventually coma or death. Visual inspection of the EEG does not permit central neurotoxicity to be recognized in individual subjects. Quantitative analysis of the EEG recorded 1 year or more after exposure has revealed statistically significant group differences when compared with normal subjects, and similar changes are seen after acute exposure; however, their significance is uncertain. Cognitive processing may be delayed 17 and abnormalities of endogenous potentials have been described after chronic exposure to organophosphate pesticides, 18 but the significance of such findings is uncertain. Organophosphates may affect neuromuscular transmission (p. 827). Certain organophosphates also lead to the development of a delayed polyneuropathy about 2 to 3 weeks after acute exposure (see page 821 ).
Chemical-induced ocular side effects
Organophosphates are a class of chemicals that block cholinesterase in humans, animals and insects, inhibiting the breakdown of acetylcholine, an important neurotransmitter, in the nerve terminal. This makes them effective insecticides. Physostigmine and pyridostigmine are organophosphates used in treating myasthenia gravis.
Ocular side effects
Systemic exposure – acute effects
Systemic exposure – chronic effects
Smooth pursuit – delayed
Visual field defects
Retina – pigmentary degeneration
Color vision deficit
Contrast sensitivity – decreased
Systemic exposure to these compounds mostly occurs in the agriculture industry. Suicide attempts using organophosphates are another means of intoxication. Young children may receive accidental systemic exposure to these toxins from lawn and garden applications. Toxicity from organophosphates leads to a build-up of acetylcholine in nerve synapses, which can cause myriad neurological dysfunctions. In humans poisoning with these agents may cause acute excess secretory activity, including involuntary salivation, lacrimation, urination, emesis, defecation, muscle weakness and seizures.
As with muscarinic compounds such as pilocarpine, miosis and accommodative spasm are part of the symptom complex. Ocular bobbing, opsoclonus and upbeat nystagmus have all been reported as transient effects from toxicity due to organophosphates.
Chronic effects from exposure to organophosphates may include eye findings but these are more controversial. In the 1970s, Japanese researchers identified a symptom complex including myopia, visual field defects, difficulty with ocular pursuit movements and pigmentary changes to the retina occurring in people living in agricultural areas that received heavy organophosphate use. They coined the term ‘Saku disease’ after the name of the region in which a high proportion of the affected patients resided, and they presumed the cause to be chronic exposure to organophosphates. Other work has suggested subclinical effects from chronic exposure to these compounds, including changes in color vision, contrast sensitivity and pupil contractility. There is a well-accepted non-ocular syndrome of peripheral neuropathy resulting from chronic exposure to certain organophosphates. The mechanism of this distal axonal dysfunction seems to be related not to decreased cholinesterase activity but to phosphorylation of a receptor protein, neurotoxic esterase. In any case, there is no consensus on whether long-term systemic exposure to organophosphates causes any type of chronic eye toxicity.
Patients suspected to have acute organophosphate poisoning need emergent evaluation. Care may be best provided in an intensive care setting as seizures and cardiopulmonary arrest are possible. Treatment involves anticholinergic drugs such as atropine and pralidoxime chloride. Ocular symptoms require no special treatment as systemic therapy will reverse the eye findings as well.
Enzymes as Drug Targets
Organophosphates and chemical nerve agents cause lethal toxicity through irreversible inhibition of the enzyme acetylcholinesterase (Acherase). Current therapy relies on pretreatment with a weak reversible Acherase inhibitor pyridostigmine bromide but since this agent is also an Acherase inhibitor, severe side effects can be seen with treatment. A novel approach to the treatment of organophosphate poisoning is to allosterically activate Acherase through binding to a separate site on the enzyme. This would have the effect of reactivating poisoned enzyme and alleviating the severe toxicity. One compound shown to do this is Cmpd II. As shown in the figure, this molecule increases the velocity of the Acherase hydrolysis of acetyl-thiocholine. This also translates to a beneficial diminution of Acherase blockade by organophosphate pesticides such as Paraoxon where the IC 50 value of Paraoxon of 20.4 nM is increased to 42.1 nM in the presence of Cmpd II. However, in keeping with allosteric probe dependence, this reduction does not extend to other organophosphate pesticides such as diisopropyl fluorophosphate and dicrophos  .
Drugs and Antidotes in Acute Intoxication
Organophosphates are agricultural insecticides. These agents inhibit the enzyme acetylcholinesterase, which is responsible for the degradation of acetylcholine. The organophosphate binds to the enzyme, causing it to undergo a conformational change at its binding site to acetylcholine. If the organophosphate does not leave the acetylcholinesterase enzyme within 24 to 48 hours, it is bound irreversibly to the enzyme, which is permanently inactivated; this process is called “aging.” Recovery from poisoning occurs only with resynthesis of new enzyme, a process that takes several weeks. The treatment of organophosphate poisoning is twofold:
Symptomatic treatment with atropine to overcome muscarinic stimulation by acetylcholine. The dose given is that sufficient to “atropinize” the patient—to abolish signs and symptoms (see later).
Reactivation of acetylcholinesterase with an oxime such as pralidoxime. Oximes cleave the organophosphate from acetylcholinesterase and bind circulating free organophosphate. In addition, pralidoxime displays antimuscarinic properties of its own. Because of the aging of the organophosphate-acetylcholinesterase complex, the earlier oximes are administered, the earlier acetylcholinesterase can be re-formed. Resolution of symptoms and a rising acetylcholinesterase level indicate response to therapy.
In military or disaster scenarios, atropine and an oxime are combined in “autoinjectors.” Pralidoxime is discussed here, but in other parts of the world, including the United States, other oximes are used, the most frequent being obidoxime. Oxime effectiveness and dosing have been the subject of much discussion because of the lack of randomized trials evaluating organophosphate treatment. A recently published article by Pawar et al. showed that higher-dose continuous infusion of pralidoxime iodide (1 g/hr of pralidoxime for 48 hours) was superior to intermittent dosing (a bolus of 1 g/hr every 4 hours). 6
Environmental Toxins and the Heart
Sahand Rahnama-Moghadam, . Richard A. Lange, in Heart and Toxins , 2015
Organophosphates and carbamates are used throughout the world as pesticides. Toxicity has occurred following accidental exposure and with chemical warfare. These compounds are lipid soluble, and intoxication may occur via inhalation, absorption from skin contact, or orally, as occurs with ingestion of food recently sprayed with these compounds. Organophosphates and carbamates include more than 50,000 compounds. 276 Organophosphates irreversibly inhibit cholinesterase, whereas carbamates reversibly bind to cholinesterase. Both lead to a massive parasympathetic surge. 277–279 Fat-soluble organophosphates, such as fenthion and chlorfenthion, may lead to cholinergic overactivity for days to weeks due to prolonged systemic release from subcutaneous adipose tissue; this can also manifest as a relapse of toxic symptoms after successful recovery. 279
Classically, three clinical stages of poisoning occur. First, a brief period of sympathetic activity—attributed to an agonist effect on nicotinic receptors—is manifested as hypertension and sinus tachycardia. Second, a period of extreme cholinergic activity ensues, which is characterized by bradycardia, hypotension, and electrocardiographic ST- and T-wave changes, possibly with life-threatening arrhythmias. Finally, prolongation of the QTc interval with an attendant increased risk of sudden death may occur. 277,278,280–282 The severity of systemic poisoning may be estimated by measuring plasma or urine organophosphate concentration, cholinesterase activity, and serum ß-glucuronidase concentration. 279,283
Various life-threatening arrhythmias may occur, including bradycardia, atrioventricular and intraventricular block, atrial fibrillation, and polymorphic ventricular tachycardia (so-called torsades de pointes). 277,280,282,284–286 ST-segment abnormalities may occur acutely and persist for weeks after drug exposure, 280 and life-threatening arrhythmias may occur as late as 20 days after exposure. 279–281 Late-onset arrhythmias may represent healing myocardium or increased free fatty acid levels in the myocardium. 276,280,287 Poor prognostic factors include a combination of ST segment and T-wave changes with concomitant low-voltage complexes. 276
It is difficult to predict which patients are likely to develop the cardiac manifestations of organophosphate poisoning and when after exposure these toxicities may manifest. 279,280,287 Rarely, myocardial infarction may occur as a result of catecholamine release, coronary vasospasm, leukocytosis, hypoxemia, electrolyte disturbances, or possibly a direct toxic effect of the organophosphates. 276–278,280,284,287 Postmortem examination of the heart reveals focal areas of micronecrosis, pericarditis, and separate areas of myocarditis. 276,287 Usually, ventricular function is not affected by organophosphate poisoning 287 ; however, takotsubo cardiomyopathy has been reported. 288
Treatment consists of administering (1) atropine and pralidoxime to antagonize the parasympathetic effects and (2) benzodiazepines to treat seizures induced by the organophosphates. 279,287 Beta blockers, lidocaine, and cardiac pacing have not been found to be effective in the treatment of organophosphate poisoning. 280 Since carbamate reversibly binds to cholinesterase, poisonings with it usually resolve sooner and are associated with less morbidity and mortality than organophosphate poisoning. 289
The evidence of cardiac risk following chronic, low-level exposure to organophosphates is not strong. 290–292 In fact, a recent prospective study of a large number of pesticide applicators chronically exposed to organophosphates and carbamates showed no increased risk of myocardial infarction. 293 Exposure to imidacloprid, a newer organophosphate-related insecticide comprised of neonicotinoid compounds that stimulate the nicotinic acetylcholine receptor, has been linked to reports of fatal ventricular fibrillation. 294
Toxin-Induced Neurologic Emergencies
David Lawrence, . Christopher P. Holstege, in Clinical Neurotoxicology , 2009
Organophosphate poisoning may cause significant morbidity and mortality due to seizure activity. Organophosphates (i.e., nerve agents) induce seizures that progress through three stages. The first 5 minutes of exposure precipitates seizures due to cholinergic overstimulation. During this period, agents with central anticholinergic properties can abort or prevent these seizures. Beyond 5 minutes of exposure, other changes are noted, such as decreased brain norepinephrine levels, increased glutaminergic response, and NMDA receptor activation. In this mixed cholinergic and noncholinergic stage, anticholinergic treatment alone will not terminate seizures. Seizure activity continuing 40 minutes after exposure is mediated by noncholinergic mechanisms and results in structural neuronal injury that is difficult to stop with pharmaceutical agents. 58–60
When dealing with patients poisoned by organophosphates, it is important to remember the effect of nicotinic overstimulation on the neuromuscular junction. Patients may exhibit muscle fasciculations, weakness, and frank paralysis. In this setting, seizures may not be evident. Therefore, patients presenting with unresponsiveness and flaccid paralysis after organophosphate exposure should be assumed to be experiencing seizure activity until proved otherwise. 61 Aggressive management at stopping seizures (atropine and benzodiazepines), electroencephalogram monitoring, and pralidoxime should be initiated immediately in these cases.
Exogenous Acquired Metabolic Disorders of the Nervous System
PATHOGENESIS AND PATHOPHYSIOLOGY
Organophosphates inhibit acetylcholinesterase and pseudocholinesterase. Insecticides that are cholinesterase inhibitors include chlorpyrifos (Dursban), diazinon, malathion, ethyl and methyl parathion, and trichlorofon. 42 The neurotoxicity of these compounds is related to their ability to inhibit acetylcholinesterase, which occurs in the brain, spinal cord, myoneural junctions, pre‐ and postganglionic parasympathetic synapses, and preganglionic and some postganglionic sympathetic nerve endings. The resulting increase in acetylcholine overstimulates the postsynaptic receptors in the cholinergic system, thus differentially stimulating nicotinic receptors (skeletal muscle and autonomic ganglia) and muscarinic receptors (secretory glands and postganglionic fibers in the parasympathetic nervous system).
EPIDEMIOLOGY AND RISK FACTORS
Organophosphate insecticides are highly toxic to insects but are relatively less so to humans and domestic animals. Although specific organophosphates , such as triorthocresyl phosphate, nipafox, and trichlorofon compounds, are obviously neurotoxic, the situation is less clear for other organophosphate pesticides. At risk are factory workers involved in the production of these compounds and agricultural workers who use them to spray crops. The occurrence of organophosphate poisoning in the United States is low, although epidemics have been reported in some Third World countries. It should be noted, however, that 3011 pesticide‐related cases were reported in California and Washington between 1993 and 1998. California accounts for approximately one third of the agricultural workforce in the United States. Organophosphates are absorbed through the skin and respiratory tracts. In addition, small amounts may be ingested by eating foods that have been sprayed with organophosphates.
CLINICAL FEATURES AND ASSOCIATED FINDINGS
Clinically, patients with acute mild symptoms complain of vague fatigue, headache, dizziness, increased salivation, nausea and vomiting, diaphoresis, and abdominal cramps. Symptoms always develop within 24 hours after exposure. Difficulty with speaking or swallowing, shortness of breath, and muscular fasciculations have been reported in patients with more moderate poisoning. With increased severity of poisoning, more intense signs and symptoms can appear. These may include depressed levels of consciousness and marked myosis with no pupillary response. After initial recovery from acute severe intoxication, an organophosphate‐induced delayed polyneuropathy (OPIDP) may develop. OPIDP is a distal dying back axonopathy characterized by cramping muscle pain in the legs, paresthesias, and motor weakness beginning 10 days to 3 weeks after the initial exposure. OPIDP‐associated signs include foot drop, weakness of the intrinsic hand muscles, absent ankle jerk, and weakness of the hip and knee flexors. 43 Chronic low‐level exposure has been associated with weakness, malaise, headache, and lightheadedness. Anxiety, irritability, altered sleep, tremor, numbness and tingling of the extremities, and small pupils may also be observed. 44 Neurobehavioral findings include decreased capacity for information processing, decreased memory and learning abilities, and poor visuoconstructional skills.
A cohort of 90 patients with chronic low‐level exposure to organophosphates were clinically examined and found to have decreased vibratory sense compared to a matched sample group. Nine of these patients underwent electrophysiological testing, and 5 of them were found to have abnormalities consistent with a peripheral neuropathic condition. This study suggests that low‐level organophosphate exposure may be particularly toxic to the PNS. 45 Five cases of acute parkinsonism following acute exposure to organophosphates have been described. Each of these patients resembled the clinical picture of PD but did not respond to levodopa. After the offending agent was removed, 4 of the patients recovered without sequelae. Upon reexposure to the organophosphate, 1 patient had reoccurrence of parkinsonian symptoms. These case reports suggest a causal link between organophosphate exposure and parkinsonism. 46
DIFFERENTIAL DIAGNOSIS AND EVALUATION
Diagnosis depends on exposure history, clinical symptoms, and abnormally low cholinesterase activity in the blood (BEI 70% of baseline level). Serial cholinesterase levels that show a rise after removal from exposure are diagnostic of exposure. Fasciculations with miosis, although not always present, are also diagnostic of organophosphate poisoning. Also, improvement of acute symptoms can be expected after administration of atropine sulfate.
At the time of ingestion, vomiting should be induced. The primary treatment for mild to moderate organophosphate poisoning is the administration of atropine sulfate (1 mg intravenously or intramuscularly) and pralidoxime (Protopam, 2‐PAM, 1 g intravenously). However, potential complications of atropine toxicity include flushed, hot, and dry skin, fever, and delirium. Also, 2‐PAM may cause dangerous increases in blood pressure. 42 In patients with very severe organophosphate poisoning, intravenous administration of pralidoxime will restore consciousness within 40 minutes.
PROGNOSIS AND FUTURE PERSPECTIVES
Prolonged high exposure and the appearance of CNS and PNS symptoms may be associated with an incomplete recovery. However, recovery is complete within weeks to months after lower levels of exposure.
Peter M. Rabinowitz, . Lora E. Fleming, in Human-Animal Medicine , 2010
Pesticides With High Relative Mammalian Toxicity
Organophosphate compounds phosphorylate and inactivate acetylcholinesterase and pseudocholinesterase enzymes that are responsible for breaking down acetylcholine (ACh) in nerve endings, RBCs, and muscle. As a result, ACh accumulates, resulting in disruption of normal nerve stimulus control and excess stimulation of both central and peripheral nerve junctions, including muscarinic and nicotinic receptors. (N ote : Cats have most of their cholinesterases in their plasma rather than RBCs like most other species. Measuring RBCs for cholinesterase activity in cats detects only the pseudocholinesterase activity, which can drop to zero by exposure to subtoxic doses of ACh inhibitors. Plasma ACh activity, not RBC ACh, should therefore be measured in cats to reduce false-positive findings due to the inhibition of RBC pseudocholinesterases.)
N-methyl carbamates cause reversible carbamylation of acetylcholinesterase (AChE) and therefore cause clinical syndromes similar to organophosphates , with muscarinic, nicotinic, and CNS effects. However, inhibition of AChE is more reversible than organophosphate poisoning, resulting in shorter duration of signs and somewhat easier treatment.