Organophosphate poisoning

Organophosphates are used as pesticides in a wide range of settings including agricultural spraying, domestic baits and sprays, termite treatments, and lice and tick products.

They may also be used as chemical weapon nerve agents; however, these are different from pesticides in that they have been specifically selected for their unfavourable characteristics (i.e., relatively high toxicity to humans, high potency, rapid onset of action, high volatility, good absorption via dermal or inhalation exposures, and resistance to antidote effects).

The primary mode of action of organophosphates is to inhibit neuronal acetylcholinesterase (AChE). This leads to excessive acetylcholine at sympathetic, parasympathetic, central nervous system (CNS), and neuromuscular junction sites. Clinical features result from overstimulation of muscarinic and nicotinic receptors.[5]Eddleston M, Buckley NA, Eyer P, et al. Management of acute organophosphorus pesticide poisoning. Lancet. 2008 Feb 16;371(9612):597-607. https://pmc.ncbi.nlm.nih.gov/articles/PMC2493390 http://www.ncbi.nlm.nih.gov/pubmed/17706760?tool=bestpractice.com ​ Effects from muscarinic receptors in the parasympathetic system are predominant early on in most poisonings, causing excessive secretions (bronchorrhoea), bronchospasm, bradycardia, diarrhoea, hypotension and pinpoint pupils. Effects from nicotinic receptors in the sympathetic system may lead to hypertension, tachycardia, and sweating. CNS cholinergic effects are important in severe poisonings, as they may include seizures, confusion, agitation, coma and respiratory failure. Neuromuscular junction stimulation leads to early fasciculations, paralysis and potentially muscle weakness that persists for days to weeks beyond the other features. Delayed-onset CNS and peripheral (predominantly motor) neuropathy are uncommon, but may be severe and can lead to permanent disability. Underlying mechanisms and susceptibility are poorly understood.[6]Lotti M, Moretto A. Organophosphate-induced delayed polyneuropathy. Toxicol Rev. 2005;24(1):37-49. http://www.ncbi.nlm.nih.gov/pubmed/16042503?tool=bestpractice.com

Esterases (such as acetylcholinesterase and neurotoxic target esterase) are inhibited by organophosphorus compounds through phosphorylation. Inhibited acetylcholinesterase reactivates spontaneously at a very slow rate. Over time, phosphorylated acetylcholinesterase may lose an alkyl side chain non-enzymatically, leaving a hydroxyl group in its place (a process known as “ageing”). When this occurs, reactivation of the enzyme is no longer possible.