6.16 - Section VI: Selected Neurotoxic Agents – Pesticides: Anticholinesterase Insecticides

Abstract

Anticholinesterase insecticides exert their toxicity by inhibiting acetylcholinesterase (AChE) in the nervous system. The resulting increase in concentration of the neurotransmitter acetylcholine (ACh) in cholinergic synapses causes hyperstimulation of many cholinergic receptors and eventual fatigue of some of them. The two main classes of anticholinesterases are organophosphorus (OP) and carbamate esters. These chemicals acylate the active site serine of AChE, thus preventing access by the normal substrate, ACh. Potency of inhibition by OP and carbamate esters can be assessed by measuring the bimolecular rate constant of inhibition (ki) or the fixed-time IC50, the concentration of inhibitor required to decrease the enzyme activity by half after a specified time of preincubation with the enzyme. Although OP and carbamate compounds can be highly potent, carbamates undergo relatively rapid spontaneous reactivation, so that inhibition is much shorter lived. Biotransformation of OP esters can result in activation or detoxification, whereas carbamates are mainly detoxified. The main adverse effect of both classes of insecticides is acute cholinergic toxicity. Some OP compounds can produce the intermediate syndrome and others can cause OP compound-induced delayed neurotoxicity (OPIDN), but this effect is now extremely rare, seen mainly after attempted suicides. Human blood contains serine esterases whose decreased activity or presence of chemical modifications can serve as biomarkers of exposure. Therapy for acute cholinergic toxicity consists of atropine to counteract muscarinic effects of excess ACh and pralidoxime to reactivate OP-inhibited AChE. Pralidoxime is not used in carbamate poisoning. There are no antidotes or specific therapies for intermediate syndrome or OPIDN.