The Impact of Pesticides - Academy Publish

DiazepamBenzodiazepines are CNS depressants, anxiolytics and muscle relaxants. Their mainsite of action is at the gamma-aminobutyric acid (GABA) receptor. The GABAAreceptor is a ligand gated chloride ion channel and part of a superfamily of receptorswhich also includes the nicotinic acetylcholine receptor and the glycine receptor.GABA is the major inhibitory neurotransmitter in the mammalian central nervoussystem. Benzodiazepines, including diazepam, alter GABA binding at the GABAAreceptor in an allosteric fashion but these drugs do not directly activate the receptors(Sellström, 1992; Marrs, 2004).Currently, the most important anticonvulsant is diazepam. The combination ofatropine and diazepam is more effective in reducing mortality than atropine oroxime alone. It was also shown that diazepam enhanced the efficacy of low doses ofatropine. In the cholinergic nervous system, diazepam appears to decrease thesynaptic release of ACh. The main consequence of the action of benzodiazepines inCNS is hyperpolarization of neurons making them significantly less susceptible tocholinergically-induced depolarization. The ultimate result is cessation ofpropagation of convulsions (Sellström, 1992; Marrs, 2004).In patients poisoned with OP, benzodiazepines may have a beneficial effect inreducing anxiety and restlessness, reducing muscle fasciculation, arresting seizures,convulsions, controlling apprehension and agitation and possibly reducing morbidityand mortality when used in conjunction with atropine and an oxime. Diazepamshould be given to patients poisoned with OP whenever convulsions or pronouncedmuscle fasciculation are present. In severe poisoning, diazepam administrationshould be considered even before these complications develop. The recommendeddose of diazepam in cases of OP poisoning is 5-10 mg intravenously in the absenceof convulsions and 10-20 mg intravenously in cases with convulsions, which may berepeated as required (Johnson and Vale, 1992; Jokanović, 2009a). WHOrecommends the dose of diazepam of 5 to 10 mg intravenously slowly over threeminutes which may be repeated every 10 to 15 minutes (maximum 30 mg) in adultsand 0.2 to 0.3 mg/kg intravenously slowly over three minutes in children (maximum5 mg in children up to 5 years old, and 10 mg in children older than 5 years) (IPCS,1998).Pyridinium OximesExtensive studies over the past few decades have investigated the mechanism ofaction of pyridinium oximes. The rate of spontaneous reactivation of phosphorylatedAChE can be accelerated by pyridinium oximes that have a chemical structurewhich ‘fits’ the structure of the inhibited AChE. The oximes can only be of benefitas long as inhibited AChE is not completely converted to the aged form which isresistant to both spontaneous and oxime-induced reactivation. Oximes reactivatephosphorylated AChE by displacing the phosphoryl moiety from the enzyme byvirtue of their high affinity for the enzyme and their powerful nucleophilicity.Phosphorylated oximes are formed during reactivation reaction (Figure 2) and someof them appear to be potent inhibitors of AChE (Luo et al., 1999; Ashani et al.,2003; Worek et al., 2007). It was shown that phosphorylated oximes of 2-substitutedpyridinium compounds (e.g. PAM-2, HI-6) are rather unstable while those of 4-pyridinium aldoximes are markedly stable (Worek et al., 2000; Ashani et al., 2003;Kiderlen et al., 2005).AcademyPublish.org - The Impact of Pesticides48