The Relationship Between the Pharmacokinetics, Cholinesterase Inhibition and Facilitation of Twitch Tension of the Quaternary Ammonium Anticholinesterase Drugs, Neostigmine, Pyridostigmine, Edrophonium and 3‐hydroxyphenyltrimethylammonium

Abstract

1 The relationship between the concentration of drug in plasma, the inhibition of erythrocyte acetylcholinesterase and the facilitation of neuromuscular transmission has been studied in the rat after the administration of neostigmine, pyridostigmine, edrophonium and 3-hydroxyphenyltrimethylammonium (3-OH PTMA). 2 After the administration of neostigmine or pyridostigmine, acetylcholinesterase activity recovered only slowly due to the covalent nature of the inhibition. In contrast, recovery from the reversible inhibition caused by edrophonium or 3-OH PTMA was rapid and showed a direct relationship to the plasma concentration of these drugs. 3 There was a statistically significant linear correlation between the logarithm of the plasma concentration of the drugs and the increase in the tibialis twitch tension. 4 The relationship between the inhibition of acetylcholinesterase and the facilitation of neuromuscular transmission was complex. When the enzyme was less than 85% inhibited no facilitation occurred.Between 85% and 98% inhibition, facilitation was linearly related to enzyme inhibition. Above 98% inhibition, facilitation was unrelated to inhibition of the enzyme.

Priming with anticholinesterases — the effect of different priming doses of edrophonium

“…1 -3 In priming studies of non-depolarizing muscle relaxants, increasing the size of the priming dose resulted in increasing fade of the TOF ratio, as well as an acceleration of the onset of paralysis following the administration of the second dose) 8'~9 This observation is consistent with a larger"margin of safety" at the neuromuscular junction.2~ In this study, increasing the size of the priming dose of edrophonium from 0.05 mg-kg-i to 0.30 mg,kg -1 resulted in stepwise increase (p < 0.05) in recovery of T 1 and TOF ratio with each increase in the dose up to 0.2 mg-kg-'. This effect is also consistent with the margin of safety in the inhibition of the acetylcholinesterase enzyme, as described by Barber et al 21 However, no further improvement in the recovery TI and TOF was observed with higher doses of edrophonium (0.25 and 0.3 mg'kg-I).…”

Neuromuscular block and current treatment strategies for its reversal in children

“…Neostigmine has two binding sites with an acetylcholinesterase molecule: quaternary ammonium of the neostigmine molecule binds with the negatively charged anionic site of the enzyme and the opposite end of neostigmine creates a covalent binding with the esteratic site of the enzyme (57). This binding is stable and results in slow hydrolysis of neostigmine during which period ACh concentration remains elevated.…”

“…As anticholinesterases have indirect mode of action and increase the concentration of ACh only to a relative maximum, they cannot reverse a profound NMB induced by a high or sustained concentration of muscle relaxants (44,59,(71)(72)(73)(74). Anticholinesterases have to inhibit more than 80% of the cholin esterase enzymes before their effect can be documented (57), and a ceiling effect takes place at muscle relaxant concentrations close to those required for surgical relaxation during clinical anesthesia (75,76). Thus, it is even expected that the use of any anticholinesterase is associated with residual curarization relatively frequently even when intermediate-acting muscle relaxants are used (46,(76)(77)(78)(79)(80).…”

Binding of pyridostigmine bromide, N,N-diethyl- m-toluamide and permethrin, alone and in combinations, to human serum albumin

“…Pharmacokinetics and metabolism of these compounds as individuals have been studied in humans and in animals (Somani et al 1972;Cohan et al 1976;Bloomquist and Thorsell 1977;Chan and Calvey 1978;Barber et al 1979;Aquilonius et al 1980;Anadon et al 1991;Taylor et al 1991;Selim et al 1995;Schoenig et al 1996). PB is metabolized mainly through hydrolysis to N-methyl-3-hydroxypyridinium following administration in rats and humans (Birtley et al 1966;Taylor et al 1991;Abu-Qare and AbouDonia 2000), while metabolism of DEET involves initial oxidative N-deethylation, ring hydroxylation, hydrolysis, and conjugation (Taylor 1986;Taylor et al 1994;Constantino and Iley 1999).…”