Clinical Concentrations of Edrophonium Enhance Desensitization of the Nicotinic Acetylcholine Receptor

Abstract

The principal acetylcholinesterase inhibitors used in clinical practice, edrophonium, neostigmine, and pyridostigmine, differ in their abilities to reverse profound neuromuscular block. This difference may reflect differential inhibition of the nicotinic acetylcholine receptor (nAChR) itself. To investigate this possibility, we studied the effects of these drugs on the function of nAChR (alpha 2 beta gamma delta subtype expressed in Xenopus laevis oocytes) using a whole-cell voltage clamp technique. All three drugs produced concentration-dependent inhibition of nAChR currents induced by the nicotinic agonist dimethylphenyl piperazinium iodide (DMPP). However, only with edrophonium did the effective inhibitory concentration overlap with the clinical range, producing 47% inhibition of nAChR current at the peak serum concentration (60 microM) obtained from a 1 mg/kg dose. The inhibition by edrophonium was voltage-dependent, being more potent at hyperpolarized membrane potentials [IC50(-60 mV) = 82.1 +/- 5.0 microM; IC50(-90 mV) = 50.8 +/- 2.7 microM; IC50(-120 mV) = 41.1 +/- 1.3 microM] and implying some degree of channel block within the ion-conducting pore. Edrophonium also enhanced desensitization of the nAChR within the clinically observed range. Edrophonium desensitization of the nAChR was further increased by simultaneous exposure to other drugs known to promote desensitization of the receptor. These two mechanisms, channel block and enhanced desensitization, may provide molecular explanations for the lesser capacity of edrophonium to promote complete reversal of profound neuromuscular block.

Edrophonium effectively antagonizes neuromuscular block at the laryngeal adductors induced by rapacuronium, rocuronium and cisatracurium, but not mivacurium

“…21 Altered kinetics may result in a limited ability of edrophonium to effectively antagonize profound mivacurium-induced block. 21 Edrophoniuminduced desensitization of acetylcholine receptors 22 appears not to be a factor as other neuromuscular blockers in our study could be antagonized.…”

Intravenous regional anesthesia using lidocaine and neostigmine for upper limb surgery

“…However, McCartney et al [18] observed merely a reduced motor block onset time in their neostigmine group. Prolongation of the sensory block may be related to the newly discovered acetylcholine-mediated sensory regulatory mechanism controlled by the motor system [28], and the prolonged motor block may be the result of the nicotinic agonistic effect of neostigmine at the neuromuscular junction [29,30].…”

Paralisia residual pós-operatória

“…ACAs have several limitations: they depend on the degree of neuromuscular blockade 40 (B); they have adverse effects on different organs and systems due to the antimuscarinic action; they have a ceiling effect 41 (D); they can lead to unpredictable reversal of neuromuscular blockade when used in patients with other comorbidities, or in situations such as hypothermia, or when using certain drugs such as calcium-channel blockers, aminoglycosides and magnesium sulphate 37 (D); and they can promote blockade by desensitization, with increased muscle weakness when used at high doses, or when used after complete recovery of neuromuscular blockade or without previous use of NMB 43 (C), 42,44 (D). They can also decrease the activity of the upper airway dilating muscles, if used after recovery of neuromuscular blockade induced by rocuronium 45 (B).…”