Novel Clinical Toxicology and Pharmacology of Organophosphorus Insecticide Self-Poisoning

Abstract

Organophosphorus insecticide self-poisoning is a major global health problem, killing over 100,000 people annually. It is a complex multi-organ condition, involving the inhibition of cholinesterases, and perhaps other enzymes, and the effects of large doses of ingested solvents. Variability between organophosphorus insecticides-in lipophilicity, speed of activation, speed and potency of acetylcholinesterase inhibition, and in the chemical groups attached to the phosphorus-results in variable speed of poisoning onset, severity, clinical toxidrome, and case fatality. Current treatment is modestly effective, aiming only to reactivate acetylcholinesterase and counter the effects of excess acetylcholine at muscarinic receptors. Rapid titration of atropine during resuscitation is lifesaving and can be performed in the absence of oxygen. The role of oximes in therapy remains unclear. Novel antidotes have been tested in small trials, but the great variability in poisoning makes interpretation of such trials difficult. More effort is required to test treatments in adequately powered studies. Expected final online publication date for the Annual Review of Pharmacology and Toxicology Volume 59 is January 6, 2019. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Organophosphate toxicity: updates of malathion potential toxic effects in mammals and potential treatments

“…AChE acetyl cholinesterase, CNS central nervous system, ICU intensive care unit, OPs organophosphates failure and hypoxemia due to muscarinic effects on the cardiovascular and pulmonary systems (i.e., bronchospasm, aspiration, bradycardia, or hypotension), nicotinic effects on skeletal muscles (weakness and paralysis), loss of central respiratory drive, and seizures (rare). Initial treatment for acute MAL toxicity is mainly concerned with ensuring an adequate airway, oxygenation, and ventilation and stabilizing patient hemodynamics by reversing excessive muscarinic effects, mainly by using atropine (Eddleston et al 2008;Eddleston 2019). Once the patient is stable, the administration of an AChE-reactivating drug, such as pralidoxime or obidoxime, should be considered along with skin and/or gastric decontamination (Roberts and Aaron 2007) (Fig.…”

“…Both preclinical and clinical data suggest that they might be promising adjunct treatments. However, the evidence is currently insufficient to recommend their use, and the precise mechanism of how they might work remains unclear (Brvar et al 2018;Eddleston 2019). Mohammadi et al found that magnetic isotopes of magnesium significantly recovered MAL-induced arrhythmia and cardiac failure in rats (Mohammadi et al 2011).…”

Respiratory failure triggered by cholinesterase inhibitors may involve activation of a reflex sensory pathway by acetylcholine spillover

“…According to the EMA (European Medical Agency) (2003), treating respiratory failure by controlled ventilation after intubation is the immediate therapeutic priority after poisoning by acute doses of organophosphate compounds (OP) (Stone, 2018a). OP and carbamates contribute to pesticide exposure with around 100,000 deaths/year worldwide (Eddleston, 2019). OP chemical warfare nerve agents, such as sarin, have intoxicated people during the Iran-Iraq war (midd-1980) (Stone, 2018a), and in Syria (2013Syria ( , 2017 (Dolgin, 2013).…”

Molecular binding scaffolds increase local substrate concentration enhancing the enzymatic hydrolysis of VX nerve agent

“…Other organophosphate derivatives such as azinphos, chlorpyrifos, and diazinon are used for pest control on food and commodity crops worldwide (Sidhu et al, 2019). Persistence in the environment after agricultural use is limited, but more than 100,000 deaths per year result from organophosphate poisoning, mostly from self‐ingestion (Eddleston, 2019). Paraoxon and parathion also have pesticidal activity and are commonly used as model compounds for chemical warfare agents.…”