Nondepolarizing neuromuscular blocking agents

Published on 07/02/2015 by admin

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Last modified 07/02/2015

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Nondepolarizing neuromuscular blocking agents

Mark T. Keegan, MB, MRCPI, MSc

The introduction of nondepolarizing neuromuscular blocking agents (NMBAs) into clinical practice marked a significant advance in anesthesia and surgery. The past 20 years have seen a significant evolution in nondepolarizing NMBAs, with the appearance of new drugs, free from many of the undesirable side effects of their predecessors. Some of these new agents have threatened the position of succinylcholine as the drug of choice for rapid-onset, short-acting muscle relaxation.

Mechanism of action

By competing with acetylcholine (ACh) for binding to nicotinic receptor α subunits, nondepolarizing NMBAs cause receptor inhibition, thus resulting in skeletal muscle relaxation. The nondepolarizing NMBAs may also be capable of directly blocking the ion channel, stopping the flux of Na⁺ through the ion pore. Some nondepolarizing NMBAs block Na⁺ channels on prejunctional nicotinic ACh receptors, interfering with mobilization of ACh from sites of synthesis. Calcium-dependent release of ACh is not affected.

Characteristics of neuromuscular nondepolarizing blockade

Muscle relaxation caused by nondepolarizing NMBAs is characterized clinically by a train of four T4:T1 ratio less than 1 (with <0.7 representing adequate surgical relaxation), tetanic “fade,” post-tetanic potentiation, absence of fasciculations, potentiation by other nondepolarizing NMBAs, and antagonism of the block by acetylcholinesterase inhibitors. Blockade by nondepolarizing NMBAs occurs more rapidly in laryngeal adductors, diaphragm, and masseter than in the adductor pollicis. The ED₉₅ is the dose needed to produce 95% suppression of a single-twitch response evoked by a peripheral nerve stimulator in the presence of NO₂-barbiturate-opioid anesthesia and is used as a measure of potency. Administration of one to three times the ED₉₅ allows tracheal intubation. The speed of onset of blockade is inversely proportional to the potency of the NMBA.

Alterations in sensitivity

Enhanced NMBA effects occur with administration of inhalation anesthetics, local anesthetics, diuretics, antiarrhythmics, aminoglycosides, magnesium, and lithium. Hypothermia, acidosis, and hypokalemia also increase the potency of nondepolarizing NMBAs. Patients with myasthenia gravis are very sensitive to the effects of nondepolarizing NMBAs. In contrast, patients with burn injuries are resistant to the effects owing to proliferation of nicotinic receptors (upregulation). Administration of 10% of the intubating dose of an NMBA 2 to 4 min before the full intubating dose is given is known as priming. Priming may accelerate the onset of muscle relaxation to approximately 60 sec.

Chemical structure and pharmacokinetics

Currently used nondepolarizing NMBAs are benzylisoquinolinium and aminosteroid compounds, both of which have one or more positively charged quaternary ammonium groups (Tables 78-1 and 78-2). (ACh has a single quaternary ammonium.) The presence of a quaternary ammonium group on nondepolarizing NMBAs means that they are highly ionized water-soluble compounds at physiologic pH. Lipid solubility is limited, so nondepolarizing NMBAs do not easily cross lipid-membrane barriers such as the blood-brain barrier. After a single dose, the volume of distribution is similar to the extracellular fluid volume; the volume of distribution, plasma clearance, and elimination may be affected by patient age or the presence of renal or hepatic dysfunction. Although many nondepolarizing NMBAs rely on hepatic or renal clearance, or both, some are eliminated in an unusual fashion (see following discussion).

Table 78-1

Nondepolarizing Neuromuscular Blocking Agents by Duration of Action

Structural Class	Short-Acting Agent	Intermediate-Acting Agent	Long-Acting Agent
Benzylisoquinolinium	Mivacurium*	Atracurium Cisatracurium	d-Tubocurarine* Metocurine* Doxacurium*
Aminosteroid	Rapacuronium*	Vecuronium Rocuronium	Pancuronium
Asymmetrical mixed-onium chlorofumarate	Gantacurium*

^*Not available in the United States.

Table 78-2

Characteristics of Commonly Used Neuromuscular Blocking Agents

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Agent	Intubating Dose (mg/kg)

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