Nondepolarizing NMBDs are classified by their duration of action and their chemical composition. The approximate duration of neuromuscular blockade provided by a single dose of these drugs may be short (<20 minutes), intermediate (45-60 minutes), or long (>1 hour). The currently available NMBDs are either benzylisoquinolines (Fig. 34-15) or steroidal molecules (Fig. 34-17). The benzylisoquinolines are based on the structure of D-tubocurarine (curare [dTC]), a naturally occurring substance obtained from the vine Chondodendron tomentosum found in the Amazon jungle. Curare is no longer commercially available. Pancuronium, the parent chemical of the steroidal NMBD, was formulated from the compound malouetine used by African tribesmen as arrowhead poison. Pancuronium is still used in clinical practice.
Chemical structures of the benzylisoquinoline neuromuscular blocking drugs.
A brief discussion of the clinical pharmacology of commonly used nondepolarizing NMBDs is provided, beginning with the benzylisoquinolines in order of the duration of their neuromuscular blockade. Factors associated with either increased resistance and increased sensitivity to nondepolarizing relaxants are summarized in Tables 34-4 and 34-5, respectively. Table 34-6 lists the characteristics of non-depolarizing NMBDs in normal adults.
Table 34-4 Factors Associated with Resistance to Nondepolarizing Neuromuscular Blocking Drugs ||Download (.pdf)
Table 34-4 Factors Associated with Resistance to Nondepolarizing Neuromuscular Blocking Drugs
Presence of extrajunctional receptors
- Trauma (massive)
- Upper motor neuron lesions
- Lower motor neuron lesions
- Demyelinating lesions (end-stage lesions may be very sensitive)
Table 34-5 Factors Associated with the Potentiation of Nondepolarizing Neuromuscular Blocking Drugs ||Download (.pdf)
Table 34-5 Factors Associated with the Potentiation of Nondepolarizing Neuromuscular Blocking Drugs
- Myasthenia gravis
- Muscular dystrophies
Calcium channel blockers
Table 34-6 Characteristics of Non-Depolarizing Neuromuscular Blocking Drugs in Normal Adults ||Download (.pdf)
Table 34-6 Characteristics of Non-Depolarizing Neuromuscular Blocking Drugs in Normal Adults
|Drug||ED95 (mg/kg)||Onset Time (min)||Time to 25% Recovery (min)||Time to 95% Recovery (min)||Volume of Distribution (ml/kg)||Clearance (mL/kg/min)||Elimination Half-Life (min)|
|Rocuronium (0.6 mg/kg)||0.30||1-2b||14-28||23-75||193-221||2.9||66-76|
|Rocuronium (1.2 mg/kg)||0.30||0.7-1.2c||38-150||38-150||193-221||2.9||66-76|
Benzylisoquinolines (Fig. 34-15)
Mivacurium (Short Acting)
Mivacurium is a bisquaternary benzylisoquinoline diester with ED95 = 0.08 mg/kg, onset of 3.5 minutes (Fig. 34-9), recovery time to 25% of baseline twitch of 15 minutes, and total duration of approximately 25 minutes (Fig. 34-10).35,36 It is no longer marketed in the United States but is still widely used in other countries. It is a relaxant with both a high potency and a high clearance rate. Although mivacurium is assumed to have an intermediate potency, its high potency is demonstrable in patients with atypical plasma cholinesterase, and its rapid clearance is partly based on destruction of the compound as well as its distribution. Because these characteristics are antagonistic, mivacurium has a slower onset than expected.
At comparable doses, mivacurium has twice the duration of SCh and half the duration of intermediate drugs such as atracurium and vecuronium (Fig. 34-10). The onset time can be shortened to 2 minutes by increasing the dose threefold. This increases the duration of the block by 20%.35 Mivacurium can cause histamine release when large doses are given by IV bolus.37 In approximately 50% of patients, histamine is released when 3 times the ED95 of mivacurium (0.25 mg/kg) is given within less than 30 seconds. However, when mivacurium was administered in a divided dose regimen of 0.15 mg/kg followed by 0.1 mg/kg 30 seconds later, histamine release did not occur, and good-to-excellent intubation conditions were achieved 90 seconds after the initial dose.21,22 Mivacurium-induced blockade can be maintained by continuous infusion without alteration in its recovery characteristics.
The short duration of block produced by mivacurium (Fig. 34-10) is the result of rapid metabolism by plasma cholinesterase35,38 at approximately 70% to 80% the rate of SCh hydrolysis.38 Biochemical genetic analysis has shown that the K variant of the plasma cholinesterase gene prolongs recovery from mivacurium.39 As a nondepolarizing agent, it is competitively reversed by anticholinesterases by augmenting the concentration of ACh at the neuromuscular junction.35 However, recovery may be slowed after reversal with neostigmine in the presence of a dense block (the absence of a twitch or 1 twitch on TOF stimulation). This delayed recovery is the result of a concomitant inhibition of plasma cholinesterase slowing the hydrolysis of mivacurium by 20 to 60 minutes and markedly prolonging neuromuscular block in patients with low baseline levels of plasma cholinesterase. Therefore, before attempting reversal of mivacurium with anticholinesterases, there should be evidence of recovery manifested by the appearance of at least 2 twitches in response to TOF stimulation. Edrophonium may be a better choice of anticholinesterase to reverse the action of mivacurium because it inhibits plasma cholinesterase to a lesser degree than does neostigmine. The recovery after a mivacurium infusion has been compared to recovery after infusions of atracurium, vecuronium, and SCh. Mivacurium blockade recovers from 5% to 95% approximately 15 minutes after stopping an infusion regardless of the duration of infusion.35 It has half the duration of recovery of atracurium and vecuronium40 and equals the best of phase II–type recoveries of SCh41 given by infusion. Because mivacurium does not depend on organ metabolism for elimination, there is no tendency toward accumulation. It behaves consistently across age groups and in patients with comorbid disease states with normal plasma cholinesterase activity and hepatic synthetic function (Figs. 34-11, 34-12, and 34-13).
Atracurium and cisatracurium (Fig. 34-15) are bisquaternary benzylisoquinoline diesters with similar intermediate durations of action (Figs. 34-9 and 34-10) that produce 95% blockade.42,43 They are unique nondepolarizing blocking drugs that were specifically synthesized to degrade spontaneously and are independent of organ elimination. At physiologic temperature and pH, the Hofmann elimination reaction breaks down both drugs to produce a tertiary amine, laudanosine, and a monoacrylate compound.43,44 Laudanosine at high plasma levels can cause cerebral excitation and seizure activity in animals, but this has not been a clinical problem in humans. Atracurium is additionally metabolized by nonspecific plasma esterases to a quaternary alcohol and acid.45
Atracurium has an elimination half-life of approximately 20 minutes, and its plasma clearance rate is 5 to 6 mL/kg/min46 (Figs. 34-11, 34-12, and 34-13) This elimination half-life is approximately 7 times shorter than that of long-acting relaxants, with a clearance rate approximately 4 times faster. The pharmacodynamics and pharmacokinetics of atracurium are relatively unaltered in patients with renal failure47 or hepatic failure,46 in infants and children,45,48 in elderly adults,49 and when given by continuous infusion50 (Figs. 34-10, 34-11, 34-12, and 34-13). Repeated administration or infusion shows no tendency for accumulation as evidenced by increased recovery times42 (Fig. 34-16). Atracurium causes release of histamine and hypotension when administered at doses greater than 2.5 times its ED95, especially when given as a rapid bolus (<15 seconds). When doses below 0.5 mg/kg are given or when a large dose of atracurium (>0.6 mg/kg) is given slowly over 15 to 75 seconds, few patients elicit histamine release and hypotension (Fig. 34-9).51
Initial dose of atracurium was 0.5 mg/kg, followed by four increments of 0.1 mg/kg every 15 minutes. Note when T1 spontaneously recovered to control height and train-of-four ratio was 0.74 and increased to 0.85 in the next 4 minutes. [From Ali HH, Miller RD. Monitoring of neuromuscular function. In: Miller RD, ed. Anesthesia, vol. 2. 2nd ed. New York, NY: Churchill-Livingstone, 1986, with permission from Elsevier. Copyright 1996.]
Cisatracurium is one of the 1R-cis,1'R-cis configurations of one of the 10 isomers of atracurium and is approximately 4 times as potent as atracurium. The ED95 is 0.05 mg/kg, with an onset time of 7.5 minutes to complete blockade (2 minutes longer than atracurium), a clinical duration of 45 minutes, and a time to greater than 70% TOF ratio of 67 minutes (Figs. 34-9, 34-10, 34-11, 34-12, and 34-13).44 Cisatracurium recovery indices are unaffected by the total dose of relaxant or method of administration. In contrast to atracurium, doses of cisatracurium as great as 8 times the ED95 have been administered rapidly without any evidence of histamine release.
Steroidal Muscle Relaxants (Fig. 34-17)
Chemical structure of steroidal class neuromuscular blocking drugs.
Vecuronium is the monoquaternary analog of the steroidal relaxant pancuronium.52 Vecuronium is a more potent NMBD than pancuronium,53 with half to one-third of its duration of action (Fig. 34-10) by demethylation at the 2 position of the D ring, the position of the steroid nucleus that is responsible for its potency. It is a lipophilic compound that is easily absorbed by the liver and excreted into the bile mostly as the unchanged drug, the predominant method of elimination.53 The action of this drug can be prolonged in patients with liver disease.54 Vecuronium is metabolized in the liver to 3-desacetylvecuronium, 17-desacetylvecuronium, and 3,17-desacetylvecuronium.55 The 3-desacetylvecuronium has neuromuscular blocking properties at approximately half the potency of vecuronium. This metabolite is eliminated by the kidneys (Fig. 34-12), which may account for the prolonged block when vecuronium is given as a continuous infusion to facilitate mechanical ventilation of patients in the intensive care unit (ICU) who have compromised renal function.56,57 Recovery times are increased in infants younger than 1 year of age based on their increased sensitivity to vecuronium and larger volume of distribution and decreased clearance rate.58
Vecuronium does not have effects on heart rate and blood pressure through modification of the A ring of the steroidal nucleus.59 At doses above 0.1 mg/kg, it may inhibit the enzyme histamine-N-methyltransferase,60 which may contribute to occasional reports of histamine-like reactions to vecuronium.61,62 This may be a concern, especially when other drugs that release histamine (eg, the antibiotic vancomycin) are administered or when histamine-rich organs are manipulated during a surgical procedure.60
Rocuronium is the 2-morpholino, 3-desacetyl 16-N-allylpyrrolidino derivative of vecuronium.63 It was developed specifically to have a rapid onset of action (Fig. 34-9). It achieves this effect partly by being approximately 6 times less potent than vecuronium and by having a similar molecular weight.16 This results in a larger number of molecules reaching the neuromuscular junction per circulation time and may contribute to the more rapid development of its neuromuscular blockade. Rocuronium undergoes rapid uptake by the liver because of its relative lipophilicity. Unchanged rocuronium has been found in the urine (8.7%) and in the bile (>50%), indicating dual pathways for its elimination.64 The rapid redistribution of rocuronium from the neuromuscular junction contributes to its intermediate duration of action at lower doses (Fig. 34-10). The pharmacokinetics of this drug have been reported to be altered in patients with major renal65 and hepatic66 disease (Figs. 34-11, 34-12, and 34-13). In both infants and elderly patients, the changes in the pharmacokinetics of rocuronium increases the duration of action.67 Rocuronium does not produce alterations in heart rate and blood pressure.68
The ED95 of rocuronium is 0.3 mg/kg, with a recovery index of 8 minutes and a clinical duration of less than 20 minutes. Mean onset times at 2× ED95 (0.6 mg/kg), 3× ED95 (0.9 mg/kg), and 4× ED95 (1.2 mg/kg) are approximately 90, 75, and 55 seconds, respectively, with ranges of 48 to 156, 48 to 144, and 36 to 84 seconds, respectively.69 These are the most rapid onset times at equipotent doses of any nondepolarizing relaxant currently available. It has been suggested that appropriate doses, this drug in may be useful as an alternative to SCh for rapid intubation of the trachea.69 Because rocuronium depends on organs of elimination for its termination of action,70 it has a dose-related escalation of clinical duration. At 2, 3, and 4 times the ED95 dose, expected durations to 25% recovery are 37 (range, 23-75), 53 (range, 25-88), and 73 (range, 38-150) minutes, respectively (Fig. 34-10).69 In addition, recovery from lengthy rocuronium infusions is markedly slower than from single doses of moderate quantity (eg, 0.6 mg/kg).
Pancuronium (Figs. 34-9 and 34-10) is predominantly eliminated by the kidneys and has a prolonged duration of neuromuscular blockade in patients with renal insufficiency (Fig. 34-12). Whereas clearance of pancuronium is minimally altered in patients with obstructive hepatic disease, the volume of distribution at steady state is increased (Figs. 34-11 and 34-12).71 This implies that in patients with hepatic disease, greater doses may be needed to establish neuromuscular blockade that might be prolonged. In elderly patients, the duration of action is prolonged secondary to compromised clearance of the drug. Approximately 10% to 20% of the injected dose of pancuronium is metabolized in the liver to 3 metabolites: 3-hydroxypancuronium, 17-hydroxypancuronium, and 3,17-dihydroxypancuronium. The 3-hydroxy metabolite is about half as potent as the parent compound and is cleared by the kidneys.
Pancuronium has a tendency to increase heart rate, blood pressure, and cardiac output through a vagolytic action at muscarinic receptors in the autonomic nervous system and via inhibition of catecholamine reuptake at sympathetic nerve terminals.