Nondepolarizing neuromuscular blocking agents

Published on 07/02/2015 by admin

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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

Agent	Intubating Dose (mg/kg)	Infusion Rate (μg • kg⁻¹ • min⁻¹)	Onset (sec)*	Duration of Action	Vagolysis	Histamine Release	Elimination	Comments
Succinylcholine	1.5	NA	30-90	Very short	Variable	Slight	Butyrylcholinesterase	Depolarizing muscle relaxant
Mivacurium	0.15	3-12	90-150	Short	No	Yes	Butyrylcholinesterase	No longer available in U.S.
Rapacuronium	1.5	NA	45-90	Short	Yes	Yes	Kidney, ester hydrolysis	No longer available
Rocuronium	0.9-1.2	9-12	60-90	Intermediate	Yes	No	Liver, kidney
Cisatracurium	0.15-0.2	1-3	90-120	Intermediate	No	No	Hofmann degradation
Atracurium	0.5	3-12	90-150	Intermediate	No	Yes	Hofmann degradation, ester hydrolysis
Vecuronium	0.08-0.12	1-2	90-150	Intermediate	No	No	Liver, kidney
Pancuronium	0.08-0.12	NA	Slow	Long	Yes	No	Kidney, liver
Gantacurium	0.4-0.6	NA	90-120	Very short	No	Yes	Cysteine adduction, ester hydrolysis	Still investigational

NA, not applicable.

^*Time to intubation.

Nonrelaxant side effects

Nonrelaxant side effects of nondepolarizing NMBAs include histamine release and cardiovascular and autonomic effects. Such side effects are detailed in Chapter 79.

Commonly used nondepolarizing neuromuscular blocking agents

Vecuronium

Vecuronium is a monoquaternary aminosteroid NMBA. At an ED₉₅ of 0.05 mg/kg, its onset of action is 3 to 5 min and its duration of action is 20 to 35 min. The drug is supplied in powder form because it is unstable in solution. Vecuronium is metabolized by the liver and cleared by the kidney. Biliary excretion also plays a role in its elimination. Repeated dosing of vecuronium causes a cumulative effect that is less than that of pancuronium but greater than that of atracurium. Vecuronium has minimal, if any, cardiovascular effects.

Atracurium

Atracurium is an intermediate-acting NMBA, which is a mixture of 10 stereoisomers. At an ED₉₅ dose of 0.2 mg/kg, its onset and duration of action are 3 to 5 min and 20 to 35 min, respectively. Atracurium is metabolized and eliminated independent of the liver and kidney. It undergoes spontaneous nonenzymatic in vivo degradation (Hofmann elimination) at normal body pH and temperature. The drug also undergoes hydrolysis by nonspecific plasma esterases, unrelated to butyrylcholinesterase. One third of administered atracurium is degraded by Hofmann elimination and two thirds by ester hydrolysis. Both pathways produce laudanosine, which, although not active as an NMBA, may cause central nervous system excitation at high doses in animals. At doses of atracurium used clinically in humans, laudanosine does not appear to have significant effects. Repeated supplemental doses of atracurium do not produce a significant cumulative drug effect because of the rapid clearance of the drug from plasma. Accordingly, there is consistency of time to recovery of neuromuscular function. Atracurium causes a dose-dependent histamine release, which is significant at doses greater than 0.5 mg/kg. The use of atracurium should be avoided in patients with asthma.

Cisatracurium

One of the 10 stereoisomers of atracurium, the 1R-cis, 1R’-cis form, makes up approximately 15% of the atracurium mixture. The purified preparation, known as cisatracurium, is an NMBA that is four times more potent than the parent compound. Cisatracurium does not cause histamine release; hence, it has minimal cardiovascular effects. Metabolism is by the Hofmann degradation, but nonspecific esterases have no role in its elimination.

Pancuronium

Pancuronium, a bisquaternary aminosteroid, is the most commonly administered long-acting NMBA. It has an ED₉₅ of 0.07 mg/kg, with an onset of action of 3 to 5 min and duration of action of 60 to 90 min. The drug is mainly excreted unchanged in the urine, although there is a small component of hepatic metabolism. Renal failure may increase its duration of action. Pancuronium causes a vagolytic effect, leading to a modest increase in heart rate, blood pressure, and cardiac output. For this reason, it may be a good choice in patients undergoing cardiac operations, especially when a high-dose opioid technique is being used.

The search for a replacement for succinylcholine

Although the depolarizing NMBA succinylcholine is widely used, its significant side effects have led to the search for an NMBA with an equivalent rapid onset and short duration of action.

Rocuronium

Rocuronium is a monoquaternary aminosteroid with a structure similar to that of vecuronium. When administered at three times ED₉₅, rocuronium has an onset of action similar to that of succinylcholine, although the laryngeal muscles are relatively more resistant to the effects of rocuronium. Doses used for rapid tracheal intubation (0.9 to 1.2 mg/kg) typically cause neuromuscular blockade that may last for an hour or more. Sugammadex, a modified γ-cyclodextrin, is not a muscle relaxant but, instead, is the first selective relaxant binding agent. It is capable of reversing any depth of neuromuscular blockade induced by rocuronium and, to a lesser extent, vecuronium. The drug does not yet have U.S. Food and Drug Administration approval for general use, but it has the potential to change rocuronium from an intermediate-acting NMBA to a short-acting NMBA.

Rapacuronium and mivacurium

Rapacuronium, a monoquaternary synthetic steroid NMBA that has a rapid onset of action, was introduced as a replacement for succinylcholine. However, its tendency to cause life-threatening bronchospasm led to its withdrawal from clinical use. Mivacurium also has a rapid onset of action and is hydrolyzed by plasma cholinesterase at 80% of the rate of succinylcholine metabolism. Histamine-induced bronchospasm was also problematic with mivacurium, and it is no longer available in the United States, though it is still used elsewhere.

Gantacurium

Gantacurium, an NMBA currently under investigation, represents a new class of nondepolarizing NMBAs known as the asymmetrical mixed-onium chlorofumarates. It is degraded by two nonenzymatic chemical reactions, cysteine adduction and ester hydrolysis. Gantacurium has a pharmacodynamic profile similar to that of succinylcholine. Gantacurium has undergone phase 1 and 2 trials but has not been approved by the Food and Drug Administration at present.

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