Biomaterial Database

Clinical concentrations of edrophonium enhance desensitization of the nicotinic acetylcholine receptor. 1994

C S Yost, and E Maestrone

Department of Anesthesia, University of California, San Francisco 94143-0542.

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.

UI	MeSH Term	Description	Entries
D009388	Neostigmine	A cholinesterase inhibitor used in the treatment of myasthenia gravis and to reverse the effects of muscle relaxants such as gallamine and tubocurarine. Neostigmine, unlike PHYSOSTIGMINE, does not cross the blood-brain barrier.	Synstigmin,Neostigmine Bromide,Neostigmine Methylsulfate,Polstigmine,Proserine,Prostigmin,Prostigmine,Prozerin,Syntostigmine,Bromide, Neostigmine,Methylsulfate, Neostigmine
D009469	Neuromuscular Junction	The synapse between a neuron and a muscle.	Myoneural Junction,Nerve-Muscle Preparation,Junction, Myoneural,Junction, Neuromuscular,Junctions, Myoneural,Junctions, Neuromuscular,Myoneural Junctions,Nerve Muscle Preparation,Nerve-Muscle Preparations,Neuromuscular Junctions,Preparation, Nerve-Muscle,Preparations, Nerve-Muscle
D009865	Oocytes	Female germ cells derived from OOGONIA and termed OOCYTES when they enter MEIOSIS. The primary oocytes begin meiosis but are arrested at the diplotene state until OVULATION at PUBERTY to give rise to haploid secondary oocytes or ova (OVUM).	Ovocytes,Oocyte,Ovocyte
D011729	Pyridostigmine Bromide	A cholinesterase inhibitor with a slightly longer duration of action than NEOSTIGMINE. It is used in the treatment of myasthenia gravis and to reverse the actions of muscle relaxants.	Mestinon,Pyridostigmine,Bromide, Pyridostigmine
D011978	Receptors, Nicotinic	One of the two major classes of cholinergic receptors. Nicotinic receptors were originally distinguished by their preference for NICOTINE over MUSCARINE. They are generally divided into muscle-type and neuronal-type (previously ganglionic) based on pharmacology, and subunit composition of the receptors.	Nicotinic Acetylcholine Receptors,Nicotinic Receptors,Nicotinic Acetylcholine Receptor,Nicotinic Receptor,Acetylcholine Receptor, Nicotinic,Acetylcholine Receptors, Nicotinic,Receptor, Nicotinic,Receptor, Nicotinic Acetylcholine,Receptors, Nicotinic Acetylcholine
D002800	Cholinesterase Inhibitors	Drugs that inhibit cholinesterases. The neurotransmitter ACETYLCHOLINE is rapidly hydrolyzed, and thereby inactivated, by cholinesterases. When cholinesterases are inhibited, the action of endogenously released acetylcholine at cholinergic synapses is potentiated. Cholinesterase inhibitors are widely used clinically for their potentiation of cholinergic inputs to the gastrointestinal tract and urinary bladder, the eye, and skeletal muscles; they are also used for their effects on the heart and the central nervous system.	Acetylcholinesterase Inhibitor,Acetylcholinesterase Inhibitors,Anti-Cholinesterase,Anticholinesterase,Anticholinesterase Agent,Anticholinesterase Agents,Anticholinesterase Drug,Cholinesterase Inhibitor,Anti-Cholinesterases,Anticholinesterase Drugs,Anticholinesterases,Cholinesterase Inhibitors, Irreversible,Cholinesterase Inhibitors, Reversible,Agent, Anticholinesterase,Agents, Anticholinesterase,Anti Cholinesterase,Anti Cholinesterases,Drug, Anticholinesterase,Drugs, Anticholinesterase,Inhibitor, Acetylcholinesterase,Inhibitor, Cholinesterase,Inhibitors, Acetylcholinesterase,Inhibitors, Cholinesterase,Inhibitors, Irreversible Cholinesterase,Inhibitors, Reversible Cholinesterase,Irreversible Cholinesterase Inhibitors,Reversible Cholinesterase Inhibitors
D004491	Edrophonium	A rapid-onset, short-acting cholinesterase inhibitor used in cardiac arrhythmias and in the diagnosis of myasthenia gravis. It has also been used as an antidote to curare principles.	Edrophonium Chloride,Edrophonium Bromide,Edroponium,Tensilon,Bromide, Edrophonium,Chloride, Edrophonium
D005260	Female		Females
D000818	Animals	Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA.	Animal,Metazoa,Animalia
D014982	Xenopus laevis	The commonest and widest ranging species of the clawed "frog" (Xenopus) in Africa. This species is used extensively in research. There is now a significant population in California derived from escaped laboratory animals.	Platanna,X. laevis,Platannas,X. laevi