Additive inhibition of nicotinic acetylcholine receptors by corticosteroids and the neuromuscular blocking drug vecuronium

Background Neuromuscular disorders associated with muscular weakness and pr olonged paralysis are common in critically iu patients. Acute myopathy has been described in patients receiving a combination therapy of corticosteroi ds and nondepolarizing neuromuscular blocking drugs for treatment of acute bronchospasm. The cause of this myopathy is not fully established and may i nvolve drug interactions that perturb neuromuscular transmission. To invest igate the interaction of corticosteroids with neuromuscular blocking drugs, the authors determined the effects of methylprednisolone and hydrocortison e alone and in combination with vecuronium on fetal (gamma-subunit containi ng) and adult (epsilon-subunit containing) subtypes of the muscle-type nico tinic acetylcholine receptor. Methods: Functional channels were expressed in Xenopus laevis oocytes and a ctivated with 1 mu M acetylcholine. The resulting currents were recorded us ing a whole cell two-electrode voltage clamp technique. Results: Both forms of the muscle-type acetylcholine receptor were potently inhibited by methylprednisolone and hydrocortisone, with concentrations pr oducing 50% inhibition in the range of 400-600 mu M and 1-2 mM, respectivel y. The corticosteroids produced noncompetitive antagonism of the muscle-typ e nicotinic acetylcholine receptor at clinical concentrations. Both recepto r forms were also inhibited, even more potently, by vecuronium, with a conc entration producing 50% inhibition in the range of 1-2 nM. Combined applica tion of vecuronium and methylprednisolone showed additive effects on both r eceptor forms, which were best described by a two-site model, with each sit e independent. Conclusions: The enhanced neuromuscular blockade produced when corticostero ids are combined with vecuronium may augment pharmacologic denervation and contribute to the pathophysiology of prolonged weakness observed in some cr itically ill patients.