Anticholinesterases and the reversal of neuromuscular blocking agents

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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).

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.

Pharmacokinetics and pharmacodynamics

Edrophonium, neostigmine, and pyridostigmine do not differ in terms of pharmacokinetics. This similarity means that the difference in their potencies is most likely explained on a pharmacodynamic basis.

Because all three drugs are quaternary ammonium ions, they are poorly lipid soluble and do not effectively penetrate lipid cell–membrane barriers, such as the gastrointestinal tract or blood-brain barrier. In contrast, lipid-soluble drugs with AChE activity, such as physostigmine (a tertiary amine) and organophosphates and chemical nerve agents, are readily absorbed from the gastrointestinal tract and other mucous membranes and have predictable central nervous system effects. Neostigmine, pyridostigmine, and edrophonium have very large volumes of distribution because of extensive tissue storage in organs such as the liver and kidneys.

The reported shorter onset of action of edrophonium may reflect a presynaptic (i.e., ACh release) rather than a postsynaptic (i.e., AChE inhibition) action. Neostigmine has been shown to be more rapid and effective than edrophonium in reversing profound neuromuscular blockade, especially when the NMBA being reversed is pancuronium or vecuronium. These differences are decreased if a larger (1.0 mg/kg) dose of edrophonium is administered.

Renal excretion accounts for about 50% of the elimination of neostigmine and about 75% of the elimination of pyridostigmine and edrophonium. All three agents have similar elimination half-lives. The prolongation of their elimination half-lives by renal failure is similar to that affecting clearance of the NMBAs; thus “recurarization” is rarely a problem in patients with renal disease.

Pharmacologic effects

Although the nicotinic effects produced by the increased amounts of available ACh are desirable for reversing neuromuscular blockade, the muscarinic effects of the ACh on the gastrointestinal, pulmonary, and cardiovascular systems can be problematic. The predominant effect on the heart is bradycardia from slowed conduction velocity of the cardiac impulse through the atrioventricular node. Hypotension may result, reflecting decreases in peripheral vascular resistance. AChE drugs enhance secretion of gastric fluid and motility of the entire gastrointestinal tract, probably caused by accumulated ACh at the ganglion cells of the Auerbach plexus and on smooth muscle cells. Bronchial, lacrimal, salivary, gastric, and sweat gland secretion are also increased. These muscarinic effects are blocked by administration of anticholinergic drugs such as atropine or glycopyrrolate.

Clinical uses

Routine use of AChE antagonists is somewhat controversial. The drugs have side effects, as do the anticholinergic medications used with them. The degree of motor blockade by NMBAs is not always accurately assessed; even when the train-of-four response on a peripheral nerve stimulator appears normal, up to 70% of the postjunctional receptors may be occupied by nondepolarizing NMBAs. Because of the latter observation, however, reversal of NMBAs, when they are used, has become the standard of care unless one can demonstrate spontaneous return of the T4:T1 ratio of at least 0.9.

Recommendations for the use of acetylcholinesterase antagonists

Anesthesia providers typically maintain neuromuscular blockade at 70% to 90% twitch depression throughout surgical procedures for which neuromuscular block is indicated. Profound blockade is rarely necessary for surgical procedures and will render antagonists ineffective. At the end of the surgical procedure, AChE reversal agents should be used only after the return of 10% of a control twitch or of T1 that is perceptible using tactile perception of a muscular twitch using a train-of-four monitor.

Neostigmine is the AChE drug most frequently used. If only T1 is present, the maximum dose of neostigmine should be used, 70 μg/kg up to a recommended maximum of 5 mg; if T2 is present, 50 μg/kg should be used; if T3 is present, use 30 μg/kg. (Commonly recommended doses are 30-70 mg/70 kg for edrophonium and 10-20 mg/70 kg for pyridostigmine.)

Clinical assessment should be performed in addition to the use of peripheral nerve stimulators to assess the adequacy of reversal. The maximum inspiratory pressure and sustained head lift of at least 5 sec are recommended clinical guides. A maximum inspiratory pressure of at least −25 cm H₂O is sufficient for adequate ventilation. A maximum inspiratory pressure of −45 cm H₂O approximately correlates with a normal CO₂ response curve and sustained head lift.

Factors that may delay or inhibit antagonism of blockade include hypothermia, respiratory acidosis, presence of certain antibiotics (e.g., aminoglycosides), hypokalemia, and hypocalcemia. The time required to antagonize neuromuscular blockade depends on at least four factors: (1) the degree of blockade, (2) the pharmacokinetics and pharmacodynamics of the NMBA, (3) the specific antagonist used, and (4) the dose of the antagonist.

Another AChE with application for anesthesiologists is physostigmine (Antilirium). Because it is a tertiary amine, not a quaternary amine, it crosses the blood-brain barrier and, therefore, can be useful for treatment of central anticholinergic syndrome. In addition, it has shown utility in treating sedation and somnolence due to general anesthetics, benzodiazepines, phenothiazines, and opioids. It should be used with caution because it can precipitate a seizure if administered intravenously too rapidly.

Finally, no chapter on reversal of NMBAs would be complete without mentioning a new class of selective neuromuscular blocker-binding agents that are capable of rapid reversal of both shallow and profound aminosteroid-induced neuromuscular blockade. Rather than increasing the amount of free ACh available to bind receptor sites, this class of drug forms a tight bond with the NMBA itself, neutralizing it both at the binding site and in peripheral tissues, eliminating the side effect profile of the AChE-anticholinergic reversal model—and minimizing the risk of recurarization. One such drug, sugammadex, is used outside the United States; as of late 2013, the Food and Drug Administration has not approved its use in the United States because of concerns about hypersensitivity and allergic reactions.

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