Stereospecificity of Antidotes and Their Mechanism of Action in Intoxications with Organophosphorus Anticholinesterases

In intoxications by organophosphates conventional prophylaxis and therapy by atropine and oximes have shown to benefit from the addition of diazepam treatment. The implication of the cholinergic system in such intoxications prompted us to study the direct effects of diazepam on this system. In this context acetylcholine (ACh) turnover in mouse brain in vivo is a suitable cholinergic model. Turnover of ACh was studied by following the incorporation of Ch into ACh after i.v. injection of deuterated Ch. To study the functional muscarinic receptor pool, we have developed a method utilizing the pharmacologically 'active' antipode of atropine, l-hyoscyamine. By injecting this compound and measuring its concentration in the brain of mice, it is possible to study specific receptor binding. The concentration of l-hyoscyamine after equilibration is assumed to correspond to the size of the functional muscarinic receptor pool. At this concentration, l-hyoscyamine prevented oxotremorine (OT)-induced tremor, confirming its physiological relevance. The effects of diazepam on the ACh dynamics are consistent with diazepam's known potentiation of gamma-aminobutyric acid's inhibitory function in nerve transmission, with a decreased turnover rate of ACh and increased levels of ACh and Ch as results. The modulating effect of diazepam on the binding properties of muscarinic receptors is probably one of the mechanisms responsible for its profound effects in treatment of intoxications with anticholinesterases. Keywords: Antidotes, Cholinesterase inhibitors.