Anticholinesterases and the reversal of neuromuscular blocking agents

Published on 07/02/2015 by admin

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Last modified 07/02/2015

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Anticholinesterases and the reversal of neuromuscular blocking agents

Claudia C. Crawford, MD

Classification

Acetylcholinesterase (AChE) inhibitors (neostigmine, pyridostigmine, physostigmine, and edrophonium) are reversible inhibitors and are commonly administered to accelerate the reversal of nondepolarizing neuromuscular blockade of nicotinic receptors in the neuromuscular junction. AChE the enzyme that metabolizes acetylcholine (ACh) into choline and acetic acid, is one of the most efficient enzymes known; a single molecule has the capacity to hydrolyze an estimated 300,000 molecules of ACh per minute. When the enzyme is inhibited, the concentration of ACh in the neuromuscular junctional cleft is increased, allowing ACh to compete for ACh receptor sites from which neuromuscular blocking agents (NMBAs) have dissociated (Figure 82-1).

image
Figure 82-1 The physiology of the neuromuscular junction. (Netter illustration from www.netterimages.com. © Elsevier Inc. All rights reserved.)

Structure

The active center of the AChE molecule consists of a negatively charged subsite that attracts the quaternary group of choline through both coulombic and hydrophobic forces, and an esteratic subsite, where nucleophilic attack occurs.

Unlike physostigmine, neostigmine, pyridostigmine, and edrophonium are quaternary ammonium ions that do not cross the blood-brain barrier. Neostigmine and pyridostigmine bind to the AChE molecule through formation of a carbamyl-ester complex at the esteratic site of the enzyme. Edrophonium has neither a carbamate nor an ester group but, instead, binds to the AChE molecule by virtue of its electrostatic attachment to the anionic site of the molecule and is further strengthened by hydrogen bonding at the esteratic site. This blockade is of brief duration; it is the duration of the drug in the body, rather than the duration of molecular action, that is important for edrophonium’s duration of action. Individual edrophonium molecules leave the enzyme rapidly but are immediately replaced by another molecule as long as the drug is present in the body.

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