Clinical Concentrations of Edrophonium Enhance Desensitization of the Nicotinic Acetylcholine Receptor

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 (α2βγδ 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 μM) 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 μM; IC50(−90mV) = 50.8 ± 2.7μM;IC50(−120mV) = 41.1 ± 1.3 μM] 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.

[1]  M. Kwatra,et al.  Regulation of Receptor Function by Protein Phosphorylation , 1990, Annals of the New York Academy of Sciences.

[2]  R. Wachtel.  Comparison of anticholinesterases and their effects on acetylcholine-activated ion channels. , 1990, Anesthesiology.

[3]  M. M. White.  Forskolin alters acetylcholine receptor gating by a mechanism independent of adenylate cyclase activation. , 1988, Molecular pharmacology.

[4]  B. S. Pallotta,et al.  Modulation of acetylcholine receptor desensitization by forskolin is independent of cAMP. , 1988, Science.

[5]  A. Mathie,et al.  Nicotinic acetylcholine receptors of nerve and muscle: Functional aspects , 1987 .

[6]  A. Kopman.  Recovery Times Following Edrophonium and Neostigmine Reversal of Pancuronium, Atracurium, and Vecuronium Steady-state Infusions , 1986, Anesthesiology.

[7]  G. Lavery,et al.  A Comparison of Edrophonium and Neostigmine for the Antagonism of Atracurium‐Induced Neuromuscular Block , 1985, Anesthesia and analgesia.

[8]  D. Melton,et al.  Efficient in vitro synthesis of biologically active RNA and RNA hybridization probes from plasmids containing a bacteriophage SP6 promoter. , 1984, Nucleic acids research.

[9]  A. N. Barrett.  Biodata handling with microcomputers , 1984 .

[10]  A Akaike,et al.  The nature of the interactions of pyridostigmine with the nicotinic acetylcholine receptor-ionic channel complex. I. Agonist, desensitizing, and binding properties. , 1984, Molecular pharmacology.

[11]  R. Miller,et al.  Edrophonium: Duration of Action and Atropine Requirement in Humans during Halothane Anesthesia , 1982, Anesthesiology.

[12]  D. Stanski,et al.  Pharmacokinetics of edrophonium in anephric and renal transplant patients. , 1981, British journal of anaesthesia.

[13]  D. Stanski,et al.  Pharmacokinetics of Edrophonium and Neostigmine When Antagonizing d‐Tubocurarine Neuromuscular Blockade in Man , 1981, Anesthesiology.

[14]  W. Bowman.  Pharmacology of neuromuscular function , 1980 .

[15]  L. Sheiner,et al.  Pyridostigmine kinetics with and without renal function , 1980, Clinical pharmacology and therapeutics.

[16]  L. Sheiner,et al.  Renal Function and the Pharmacokinetics of Neostigmine in Anesthetized Man , 1979, Anesthesiology.

[17]  Aaron F. Kopman.  Edrophonium Antagonism of Pancuronium‐induced Neuromuscular Blockade in Man: A Reappraisal , 1979, Anesthesiology.

[18]  D. Bevan.  Reversal of pancuronium with edrophonium , 1979, Anaesthesia.

[19]  B. L. Ginsborg,et al.  Transmission of Impulses from Nerve to Muscle , 1976 .

[20]  W. Riker,et al.  The direct action of prostigmine on skeletal muscle; its relationship to the choline esters. , 1946, The Journal of pharmacology and experimental therapeutics.