The Role of Oximes in the Management of Organophosphorus Pesticide Poisoning

Abstract

The number of intoxications with organophosphorus pesticides (OPs) is estimated at some 3,000,000 per year, and the number of deaths and casualties some 300,000 per year. OPs act primarily by inhibiting acetylcholinesterase (AChE), thereby allowing acetylcholine to accumulate at cholinergic synapses, disturbing transmission at parasympathetic nerve endings, sympathetic ganglia, neuromuscular endplates and certain CNS regions. Atropine is the mainstay of treatment of effects mediated by muscarine sensitive receptors; however, atropine is ineffective at the nicotine sensitive synapses. At both receptor types, reactivation of inhibited AChE may improve the clinical picture. The value of oximes, however, is still a matter of controversy. Enthusiastic reports of outstanding antidotal effectiveness, substantiated by laboratory findings of reactivated AChE and improved neuromuscular transmission, contrast with many reports of disappointing results. In vitro studies with human erythrocyte AChE, which is derived from the same single gene as synaptic AChE, revealed marked differences in the potency and efficacy of pralidoxime, obidoxime, HI 6 and HLö 7, the latter two oximes being considered particularly effective in nerve agent poisoning. Moreover, remarkable species differences in the susceptibility to oximes were revealed, requiring caution when animal data are extrapolated to humans. These studies impressively demonstrated that any generalisation regarding an effective oxime concentration is inappropriate. Hence, the 4 mg/L concept should be dismissed. To antagonise the toxic effects of the most frequently used OPs, pralidoxime plasma concentrations of around 80 mumol/L (13.8 mg/L pralidoxime chloride) should be attained while obidoxime plasma concentrations of 10 mumol/L (3.6 mg/L obidoxime chloride) may be sufficient. These concentrations should be maintained as long as circulating poison is expected to be present, which may require oxime therapy for up to 10 days. Various dosage regimens exist to reach this goal. The most appropriate consists of a bolus short infusion followed by a maintenance dosage. For pralidoxime chloride, a 1 g bolus over 30 minutes followed by an infusion of 0.5 g/h appears appropriate to maintain the target concentrtion of about 13 mg/L (70 kg person). For obidoxime chloride, the appropriate dosage is a 0.25 g bolus followed by an infusion of 0.75 g/24 h. These concentrations are well tolerated and keep a good portion of AChE in the active state, thereby retarding the AChE aging rate. AChE aging is particularly rapid with dimethyl phosphoryl compounds and may thwart the effective reactivation by oximes, particularly in suicidal poisoning with excessive doses. In contrast, patients with diethyl OP poisoning may particularly benefit from oxime therapy, even if no improvement is seen during the first days when the poison load is high. The low propensity to aging with diethyl OP poisoning may allow reactivation after several days, when the poison concentration drops. Rigorous testing of the benef...

Hypotension in severe dimethoate self-poisoning

“…Plasma was separated from an EDTA blood sample and frozen at -20°C. BuChE activity was assayed as described (30,31). The median (IQR) BuChE activity in this population is 4,500 (3,200) mU/mL (Eyer, unpublished).…”

Crystal Structures of Human Carboxylesterase 1 in Covalent Complexes with the Chemical Warfare Agents Soman and Tabun,

“…Atropine, a muscarinic receptor antagonist, blocks cholinergic parasympathetic neurons to maintain capacity for respiration, and is typically administered as soon as possible after an OP exposure (11). Oxime reactivators like pralidoxime (2-PAM) or the Hagedom oxime HI-6 are also typically provided in an attempt to recover AcChE activity (12). Finally, an anticonvulsant like diazepam is commonly administered to treat seizures that can develop, albeit via unknown mechanisms (13).…”

Organophosphorus compounds as chemical warfare agents: a review

“…The treatment regimen with oximes must be rigorously followed in order to maximize the antidote effects, although there are still many doubts about the adequate regimen under certain conditions. 172 Nowadays, it is still discussed even the need of administration of oximes to victims of OPCs intoxication. [173][174][175] Studies have shown that, to be an effective AChE reactivator, a compound should possess some structural properties: it should have a quaternary nitrogen atom, which guides the molecule to the active site by interacting with the anionic subsite.…”