The Toxicokinetics and Toxicodynamics of Organophosphonates versus the Pharmacokinetics and Pharmacodynamics of Oxime Antidotes: Biological Consequences

Abstract

This paper presents basic data on organophosphonate (OP) mechanisms of action, especially by toxicokinetic ⁄ toxicodynamic (TK ⁄ TD) process correlations. It is generally accepted that at least during onset of OP biological systems interaction, blood and tissue cholinesterase's inhibition represents OP exposure marker and initiating mechanisms for toxicodynamic effects, characteristic for cholinergic crisis. OP penetrability of various biological barriers conditioning TK characteristics are determined by a series of physico-chemical properties. Non-cholinergic effects, direct interactions with cellular structures and subsequent effects (excitotoxicity) triggered by cholinergic crisis are also briefly presented. Opposed to these OP TK ⁄ TD characteristics, the authors analysed the pharmacokinetic ⁄ pharmacodynamic (PK ⁄ PD) characteristics and their correlations for oximes, as basic OP antidotes, besides atropine and anticonvulsants. Phosphorilated cholinesterasis reactivators are mono or bispyridinium derivatives with quaternary ammonium atoms, high water solubility, ionized at physiological pH, distribution in extra-cellular space, very low digestive absorption and blood-brain barrier (BBB) penetrability. OP nerve gas acute toxicity is correlated with anti-acetylcholinesterase (AChE) activity and partition coefficient. The toxicity rank seems to be determined by lipophilicity, besides their specific AChE inhibitory property. It has the effect that acute toxicity is the resultant of a TD process closely linked and dependent in vivo upon molecular descriptors determinant for the TK process. For cholinesterasis reactivators, molecular and PK characteristics limit their effects, especially to the peripheral level. The absent or much reduced BBB penetrability allowed some researchers to suggest that reactivators' penetration and presence at central level are not necessary. The study of PK ⁄ PD correlations, molecular descriptors and biological membrane permeability of oximes can better define their antidotal effects mechanisms and, maybe, open a new perspective for field development.

Pharmacokinetics and pharmacodynamics of some oximes and associated therapeutic consequences: a critical review

“…In antidotal intervention, the anticonvulsant effects are of major interest, and the significant efficiency of benzodiazepines (diazepam, midazolam) should be outlined. The fact that other anticonvulsants currently used in the clinical practice are not efficient has led to the experimental analysis of OP convulsion-inducing mechanisms and the major importance of their pharmacodynamics (PD) counteracting action (Shih et al,1999;Shih et al, 2003;Shih et al, 2007;Voicu et al, 2010c). It is generally accepted that atropine together with cholinesterase reactivators potentiate the antidotal effect with respect to separately administered compounds.…”

Efficient Charge Separation in TiO2 Films Sensitized with Ruthenium(II)–Polypyridyl Complexes: Hole Stabilization by Ligand‐Localized Charge‐Transfer States

“…In antidotal intervention, the anticonvulsant effects are of major interest, and the significant efficiency of benzodiazepines (diazepam, midazolam) should be outlined. The fact that other anticonvulsants currently used in the clinical practice are not efficient has led to the experimental analysis of OP convulsion‐inducing mechanisms and the major importance of their pharmacodynamics (PD) counteracting action (Shih et al .,1999; Shih et al ., 2003; Shih et al ., 2007; Voicu et al ., 2010c).…”

Synthesis and in vitro kinetic evaluation of N-thiazolylacetamido monoquaternary pyridinium oximes as reactivators of sarin, O-ethylsarin and VX inhibited human acetylcholinesterase (hAChE)

“…9,17 The reactivation of the inhibited AChE is brought about by the attack of a strong nucleophile in order to break the covalent bond formed between the OP and OH group of the serine residue in the catalytic triad of AChE. For this, ionization of oxime into oximate anion is an essential process under the physiological conditions in the reactivation of OP inhibited AChE.…”

“…Moreover, the intrinsic toxicities of these oximes exert deleterious side effects. 16,17 All these drawbacks strictly underscore the need of a versatile antidotal treatment in the event of acute OP nerve agent and pesticide poisoning. 18 Over past few decades, numerous structurally divergent oxime reactivators were synthesized and evaluated for their efficacies against acute OP poisoning.…”