Additive inhibition of nicotinic acetylcholine receptors by corticosteroids and the neuromuscular blocking drug vecuronium.
BACKGROUND
Neuromuscular disorders associated with muscular weakness and prolonged paralysis are common in critically ill patients. Acute myopathy has been described in patients receiving a combination therapy of corticosteroids and nondepolarizing neuromuscular blocking drugs for treatment of acute bronchospasm. The cause of this myopathy is not fully established and may involve drug interactions that perturb neuromuscular transmission. To investigate the interaction of corticosteroids with neuromuscular blocking drugs, the authors determined the effects of methylprednisolone and hydrocortisone alone and in combination with vecuronium on fetal (gamma-subunit containing) and adult (epsilon-subunit containing) subtypes of the muscle-type nicotinic acetylcholine receptor.


METHODS
Functional channels were expressed in Xenopus laevis oocytes and activated with 1 microM acetylcholine. The resulting currents were recorded using 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 producing 50% inhibition in the range of 400-600 microM and 1-2 mM, respectively. The corticosteroids produced noncompetitive antagonism of the muscle-type nicotinic acetylcholine receptor at clinical concentrations. Both receptor forms were also inhibited, even more potently, by vecuronium, with a concentration producing 50% inhibition in the range of 1-2 nM. Combined application of vecuronium and methylprednisolone showed additive effects on both receptor forms, which were best described by a two-site model, with each site independent.


CONCLUSIONS
The enhanced neuromuscular blockade produced when corticosteroids are combined with vecuronium may augment pharmacologic denervation and contribute to the pathophysiology of prolonged weakness observed in some critically ill patients.
Kindler
C H
CH
Department of Anesthesia, University of California, San Francisco 94143-0542, USA.
Verotta
D
D
Gray
A T
AT
Gropper
M A
MA
Yost
C S
CS
D000305:Adrenal Cortex Hormones / Q000494:pharmacology*; D000465:Algorithms; D000818:Animals; D004357:Drug Synergism; D005938:Glucocorticoids / Q000494:pharmacology; D006801:Humans; D006854:Hydrocortisone / Q000494:pharmacology; D008775:Methylprednisolone / Q000494:pharmacology; D003473:Neuromuscular Nondepolarizing Agents / Q000494:pharmacology*; D009865:Oocytes / Q000187:drug effects / Q000378:metabolism; D018408:Patch-Clamp Techniques; D011978:Receptors, Nicotinic / Q000187:drug effects*; D014673:Vecuronium Bromide / Q000494:pharmacology*; D014981:Xenopus
D000305:Adrenal Cortex Hormones; D005938:Glucocorticoids; D003473:Neuromuscular Nondepolarizing Agents; D011978:Receptors, Nicotinic; D014673:Vecuronium Bromide; D006854:Hydrocortisone; D008775:Methylprednisolone