Toxicity, Organophosphate ?>

Toxicity, Organophosphate

Toxicity, Organophosphate


Introduction
Background

Organophosphate (OP) compounds are a diverse group of chemicals used in both domestic and industrial settings. Examples of organophosphates include: insecticides (malathion, parathion, diazinon, fenthion, dichlorvos, chlorpyrifos, ethion), nerve gases (soman, sarin, tabun, VX), ophthalmic agents (echothiophate, isoflurophate), and antihelmintics (trichlorfon). Herbicides (tribufos [DEF], merphos) are tricresyl phosphate–containing industrial chemicals.

Organophosphate compounds were first synthesized in the early 1800s when Lassaigne reacted alcohol with phosphoric acid. Shortly thereafter in 1854, Philip de Clermount described the synthesis of tetraethyl pyrophosphate at a meeting of the FrenchAcademy of Sciences. Eighty years later, Lange, in Berlin, and, Schrader, a chemist at Bayer AG, Germany, investigated the use of organophosphates as insecticides. However, the German military prevented the use of organophosphates as insecticides and instead developed an arsenal of chemical warfare agents (ie, tabun, sarin, soman). A fourth agent, VX, was synthesized in England a decade later. During World War II, in 1941, organophosphates were reintroduced worldwide for pesticide use, as originally intended.

Massive organophosphate intoxication from suicidal and accidental events, such as the Jamaican ginger palsy incident in 1930, led to the discovery of the mechanism of action of organophosphates. In 1995, a religious sect, Aum Shinrikyo, used sarin to poison people on a Tokyo subway. Mass poisonings still occur today; in 2005, 15 victims were poisoned after accidentally ingesting ethion-contaminated food in a social ceremony in Magrawa, India.

Nerve agents have also been used in battle, notably in Iraq in the 1980s. Additionally, chemical weapons still pose a very real concern in this age of terrorist activity.
Pathophysiology

The primary mechanism of action of organophosphate pesticides is inhibition of carboxyl ester hydrolases, particularly acetylcholinesterase (AChE). AChE is an enzyme that degrades the neurotransmitter acetylcholine (ACh) into choline and acetic acid. ACh is found in the central and peripheral nervous system, neuromuscular junctions, and red blood cells (RBCs).

Organophosphates inactivate AChE by phosphorylating the serine hydroxyl group located at the active site of AChE. The phosphorylation occurs by loss of an organophosphate leaving group and establishment of a covalent bond with AChE.

Once AChE has been inactivated, ACh accumulates throughout the nervous system, resulting in overstimulation of muscarinic and nicotinic receptors. Clinical effects are manifested via activation of the autonomic and central nervous systems and at nicotinic receptors on skeletal muscle.

Once an organophosphate binds to AChE, the enzyme can undergo 1 of the following 3 processes:
Endogenous hydrolysis of the phosphorylated enzyme by esterases or paraoxonases
Reactivation by a strong nucleophile such as pralidoxime (2-PAM)
Complete binding and inactivation (aging)
Organophosphates can be absorbed cutaneously, ingested, inhaled, or injected. Although most patients rapidly become symptomatic, the onset and severity of symptoms depend on the specific compound, amount, route of exposure, and rate of metabolic degradation.

Frequency
United States

The American Association of Poison Control Centers’ National Incidence Report indicates that pesticide injuries number 102,754 persons annually. Nationally, 4.2% of poisonings are due to insecticides. In 2007, Sudakin et al reported an overall decline in poison center–recorded exposures from 1995 to 2004 because of the United States Environmental Protection Agency phase out of common household and agricultural OP agents (ie, diazinon, chlorpyrifos).1

International

Pesticide poisonings are among the most common modes of poisoning fatalities. In countries such as India, OPs are easily accessible and, therefore, a source of both intentional and unintentional poisonings.
Mortality/Morbidity
Worldwide mortality studies report mortality rates from 3-25%. The compounds most frequently involved include malathion, dichlorvos, trichlorfon, and fenitrothion/malathion.
Mortality rates depend on the type of compound used, amount ingested, general health of the patient, delay in discovery and transport, insufficient respiratory management, delay in intubation, and failure in weaning off ventilatory support.
Complications include severe bronchorrhea, seizures, weakness, and neuropathy. Respiratory failure is the most common cause of death.
Clinical
History

Signs and symptoms of organophosphate poisoning can be divided into 3 broad categories, including (1) muscarinic effects, (2) nicotinic effects, and (3) CNS effects.

Mnemonic devices used to remember the muscarinic effects of organophosphates are SLUDGE (salivation, lacrimation, urination, diarrhea, GI upset, emesis) and DUMBELS (diaphoresis and diarrhea; urination; miosis; bradycardia, bronchospasm, bronchorrhea; emesis; excess lacrimation; and salivation). Muscarinic effects by organ systems include the following:
Cardiovascular – Bradycardia, hypotension
Respiratory – Rhinorrhea, bronchorrhea, bronchospasm, cough, severe respiratory distress
Gastrointestinal – Hypersalivation, nausea and vomiting, abdominal pain, diarrhea, fecal incontinence
Genitourinary – Incontinence
Ocular – Blurred vision, miosis
Glands – Increased lacrimation, diaphoresis
Nicotinic signs and symptoms include muscle fasciculations, cramping, weakness, and diaphragmatic failure. Autonomic nicotinic effects include hypertension, tachycardia, mydriasis, and pallor.
CNS effects include anxiety, emotional lability, restlessness, confusion, ataxia, tremors, seizures, and coma.
Physical

Note that clinical presentation may vary, depending on the specific agent, exposure route, and amount. Symptoms are due to both muscarinic and nicotinic effects. Interestingly, a 2007 retrospective review of 31 OP poisoned children performed by Levy-Khademi et al described that, in contrast to adults, the most common presentations were seizure and coma with relatively less muscarinic or nicotinic findings.2 The authors hypothesized the difference may be due to difficulty in detecting muscarinic findings in infants (eg, crying) and ingestion of contaminated produce instead of OP directly.

Vital signs: Depressed respirations, bradycardia, and hypotension are possible symptoms. Alternatively, tachypnea, hypertension, and tachycardia are possible. Hypoxia should be monitored for with continuous pulse oximetry.
Paralysis
Type I: This condition is described as acute paralysis secondary to continued depolarization at the neuromuscular junction.
Type II (intermediate syndrome): Intermediate syndrome was described in 1974 and is reported to develop 24-96 hours after resolution of acute organophosphate poisoning symptoms and manifests commonly as paralysis and respiratory distress. This syndrome involves weakness of proximal muscle groups, neck, and trunk, with relative sparing of distal muscle groups. Cranial nerve palsies can also be observed. Intermediate syndrome persists for 4-18 days, may require mechanical ventilation, and may be complicated by infections or cardiac arrhythmias. Although neuromuscular transmission defect and toxin-induced muscular instability were once thought to play a role, this syndrome may be due to suboptimal treatment.
Type III: Organophosphate-induced delayed polyneuropathy (OPIDP) occurs 2-3 weeks after exposure to large doses of certain OPs and is due to inhibition of neuropathy target esterase. Distal muscle weakness with relative sparing of the neck muscles, cranial nerves, and proximal muscle groups characterizes OPIDP. Recovery can take up to 12 months.
Neuropsychiatric effects: Impaired memory, confusion, irritability, lethargy, psychosis, and chronic organophosphate-induced neuropsychiatric disorders have been reported. The mechanism is not proven.
Extrapyramidal effects: These are characterized by dystonia, cogwheel rigidity, and parkinsonian features (basal ganglia impairment after recovery from acute toxicity).
Other neurological and/or psychological effects: Guillain-Barré–like syndrome and isolated bilateral recurrent laryngeal nerve palsy are possible.
Ophthalmic effects: Optic neuropathy, retinal degeneration, defective vertical smooth pursuit, myopia, and miosis (due to direct ocular exposure to organophosphates) are possible.
Ears: Ototoxicity is possible.
Respiratory effects: Muscarinic, nicotinic, and central effects contribute to respiratory distress in acute and delayed organophosphate toxicity.
Muscarinic effects: Bronchorrhea, bronchospasm, and laryngeal spasm, for instance, can lead to airway compromise.
Nicotinic effects: These effects lead to weakness and paralysis of respiratory oropharyngeal muscles.
Central effects: These effects can lead to respiratory paralysis.
Rhythm abnormalities: Sinus tachycardia, sinus bradycardia, extrasystoles, atrial fibrillation, ventricular tachycardia, and ventricular fibrillation (often a result of, or complicated by, severe hypoxia from respiratory distress) are possible.
Other cardiovascular effects: Hypotension, hypertension, and noncardiogenic pulmonary edema are possible.
GI manifestations: Nausea, vomiting, diarrhea, and abdominal pain may be some of the first symptoms to occur after organophosphate exposure.
Genitourinary and/or endocrine effects: Urinary incontinence, hypoglycemia, or hyperglycemia are possible.

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