Biochemical Studies of the Neuroparalysis of Acute Organophosphate Poisoning

Abstract

Severe muscle weakness or Type II neuroparalysis is a major consequence of OPP. This results in need for prolonged mechanical ventilation and intensive care leading to significant morbidity and mortality of poisoned patients. The clinical determinants of Type II paralysis are the dose of organophosphate ingested and the severity of the clinical syndrome. Laboratories studies have shown that the muscle is severely injured in OPP and the severity of injury determines the occurrence of neuroparalysis. What are the mechanisms underlying neuroparalysis and muscle weakness of OPP? While AChE inhibition is the primary and initiating reaction, this mechanism does not account for all aspects of the clinical syndrome. Despite severe AChE inhibition not all patients develop neuroparalysis. In the phase of delayed paralysis there is the absence of muscarinic signs. This suggests that there is sufficient AChE to maintain acetylcholine at normal levels in the synapse. These observations suggest that the inhibition of AChE initiates other non-cholinergic pathways that may contribute to the prolonged weakness of OPP. newlineSeveral critical reactions that are initiated in the early phase of OPP continue for the duration of poisoning and may contribute to the development of muscle weakness. These reactions are 1) increased NO production 2) inhibition of mitochondrial Ca2+ uptake 3) oxidative stress 4) structural disorganization of the muscle membrane 5) inhibition of AChE in the brain. newlineA productive interplay of biochemical mechanisms that lead to cellular toxicity of organophosphates in the muscle and those that protect the organ are seen in OPP. In the animal this balance appears to facilitate rapid recovery and prevent the development of prolonged paralysis. Studying how these toxic and protective mechanisms play out their roles in severe OPP in humans, may be a productive line of enquiry. This understanding could potentially be channelled towards development of therapeutic strategies for improved patient management of acute organophosphate poisoning.