Cardiac toxicity nerve agents

OPs are known to induce time-delayed neurotoxicity. This is due to the inhibition of an esterase in nerve tissue, neuropathy target esterase (NTE), that is also found in muscle and blood cells. The NTE level in the blood is an indicator of the inhibition of the enzyme. Inhibition of NTE and aging, the process of following the OP binding to an active esterase site that prevents the reactivation of the site, is important for selection of an antidote against certain OP nerve agents. It is of primary concern for Novichok agent. There is little information available on OP-caused neurotoxicity and the cardiac toxicity. 

GA, a unitary chemical munition, inhibits AChE, the enzyme responsible for the breakdown of the neurotransmitter ACh. When inhaled, its toxicity is half that of sarin. It depresses plasma and RBC-AChE activities significantly in the blood. At 20-25% of red blood cell AChE baseline, the effect of the nerve agent becomes noticeable. There is no evidence of systemic toxicity other than the cholinesterase activity (Parker et al, 1990 Munro et al, 1994). GA has not been shown to produce OPIDN except at extremely high doses. The cardiac effect of GA conforms to OP-caused arrhythmias and AV block. 

In the open literature little is known about these agents developed in the Soviet Union. They are assessed to be five to ten times more toxic than VX (Ellison, 2008 Smithson et al, 1995). The toxicity of these binary agents does not rely primarily on the inhibition of AChE, but it is thought that it causes permanent neuropathy. Consequently, conventional nerve agent antidotes may not work. Reactive oximes such as potassium 2,3-butanedione monoximate may be use fid in detoxification. No pubhshed information is available on cardiac pathologies caused by Novichok agents. 

The principal nerve agents. Sarin (GB), Soman (GD), Tabun (GA) and V-agents, are all organophosphorus compounds that inhibit the enzyme cholinesterase which is responsible for breaking down acetylcholine, a neurotransmitter. Nerve agents are toxic both by inhalation and by absorption through the skin. Symptoms include droohng, dilated pinhead pupils, headache, involuntary defecation, and a runny nose. Death is caused by cardiac arrest or respiratory failure. 

Magnesium sulfate may be used in an intravenous infusion as a tocolytic agent. Its mechanism of action is to suppress nerve impulses to the uterine smooth muscles by antagonizing intracellular calcium. Maternal side effects are rare but can include pulmonary edema. At toxic levels, hypotension, muscle paralysis, tetany, cardiac arrest, and respiratory depression may occur. ... 

Structure activity correlations for analogs of batrachotoxin have been studied to a limited extent. Toxicity in white mice (Table 4 at the end of this section) (251), effects on nerve-striated muscle preparations (268), cardiac preparations (233), ATPase (79), and eel electroplax (cited in 5) show similar profiles with the different analogs. The substitution pattern on the pyrrole moiety is important. The relative order of activity of certain substituted pyrrole carboxylates in a neuromuscular preparation as depolarizing agents was as follows Batrachotoxin > homobatrachotoxin =... 

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