Neuromuscular Blocking Drugs for the New Millennium: Current Practice, Future Trends—Comparative Pharmacology of Neuromuscular Blocking Drugs

Neuromuscular blocking drugs are widely used as adjuvants in anesthesia and intensive care to provide skeletal muscle paralysis for periods ranging from a few minutes to a few days. Because these drugs interfere with the function of the respiratory system, onset time and recovery pattern become crucial safety issues. Since the introduction of d-tubocurarine into clinical practice more than half a century ago, many drugs have been marketed as neuromuscular blocking drugs, none of which is indicated in all cases. Thus, patient safety is best guaranteed by a thorough knowledge of neuromuscular effects and unwanted side effects of the drugs the clinician intends to use. The pharmacology of neuromuscular relaxants should be analyzed by taking into consideration the clinical uses for which these drugs are intended. At present, neuromuscular effects are required to produce immobility during surgery, to improve ventilation in intensive care patients, and to facilitate airway management. In all these cases, four important aspects of the drug action must be known: 1) how much drug is required; 2) how long one must wait for the effect to be manifest; 3) what the duration of this effect is; and 4) what the side effects are. These key elements will be reviewed and compared for the neuromuscular blocking drugs in current use, and the characteristics of the newer nondepolarizing drug rapacuroniurn will be discussed. The clinical situation that has received most attention in the past few years in relation to the use of neuromuscular blocking drugs is tracheal intubation, because this is when expectations are the highest. A perfect setting for tracheal intubation includes a rapid onset to avoid inhalation of gastric contents, profound paralysis to relax all muscles, and a short duration of action, so that the patient’s own respiratory function can be restored should intubation prove to be impossible. These requirements are best met by succinylcholine, which, unfortunately, has many unwanted side effects. However, all the nondepolarizing drugs have longer onset times and durations of action. Rapacuronium has the neuromuscular profile that most closely approaches that of succinylcholine. Dose-Response Relationships The relationship between the dose of a drug and its effect is typically sigmoid. Small doses produce no effect. Then, beyond a certain threshold, effect increases with dose, until a maximum is reached when further increases in dosage produce no increase in effect. This scenario applies to any number of pharmacological (desired) effects and side effects. Dose-response relationships are thus established. They provide information regarding the dose required for a given effect, and comparisons between drugs of a similar class become possible. Each drug is characterized by an ED50, that is, the dose which corresponds to the half-way mark between no effect and maximum effect. A potent drug will have a smaller ED50 than a less potent one. For neuromuscular blocking drugs, dose-response relationships can be obtained by measuring twitch response at a muscle after stimulation of the corresponding nerve. For practical reasons, the mechanical response of the adductor pollicis muscle after stimulation of the ulnar nerve has been adopted as the standard. This setup provides a continuous, as opposed to an all-or-none, response. In other words, each patient given a known dose can have a twitch response which is any number between 0% and 100%. This is in contrast to an all-or-none response, an example of which is the minimal alveolar concentration of inhaled drugs, in which case a patient either does or does not respond. The dose-response relationship at the adductor pollicis is the expression of one of many pharmacological effects of neuromuscular blocking drugs and probably not the most important. In fact, each muscle in the body has its own dose-response curve, and some of these curves differ markedly from each other. For example, the dose-response at the diaphragm is shifted 60%–80% to the right of the adductor pollicis for atracurium, vecuronium or pancuronium, implying that the diaphragm requires 60%–80% more drug for an equivalent degree of blockade (1,2). Although the use of ED50 is pharmacologically correct, it is common usage to quote the ED95, the dose expected to produce 95% twitch depression at the adductor pollicis muscle, as a measure of potency of a given drug. The choice of the 95% level was made because surgical conditions were better than at 50% block, and because intubating conditions were felt to be adequate with an ED95 dose of d-tubocurarine (3). It should be emphasized that not all patients reach 95% block with one ED95 dose, and in some others more than 95% blockade is observed (interpatient variability). Also, different muscles are different, the diaphragm and the laryngeal adductors requiring considerably more than one ED95 at the adductor pollicis for 95% block (2,4). However, the concept of ED95 is also a good pharmacometric tool. For example, drugs can be compared over the range of doses at which they are likely to be clinically effective. For example, knowing that rocuronium has an ED95 of 0.3 mg/kg allows one to deduce that six times as much is required to produce as much effect as vecuronium, with an ED95 = 0.05 mg/kg. For the newer neuromuscular blocking drug rapacuronium, its ED95 has not been determined formally, but it is estimated to be approximately 1.0 mg/kg (5,6). Rapacuronium has approximately 1/20th the potency of vecuronium and, therefore, 20 times as much drug will be required to produce the same effect. This, of course, says nothing about onset and duration, which are separate concepts. Comparisons of dose-response curves can also be used for other purposes. For example, enhancement of neuromuscular effects by volatile anesthetics and synergism between two muscle relaxants were quantified by measurement of ED95 values. Synergism between mivacurium and rocuronium (7), and between cisatracurium and rocuronium (8) were identified by using dose-response curves. Also, women were found to be 25%–30% more sensitive than men to vecuronium (9) or rocuronium (10), as expressed by reduced ED95. Muscle relaxants are commonly classified according to duration of action, which is usually defined as the time from injection until return of 25% twitch height. This definition has been accepted widely because reversal of nondepolarizing drugs is normally rapid when anticholinesterase drugs are given at 25% recovery, which usually corresponds to the return of the fourth twitch in the train-of-four. Duration of action increases as dose increases, so comparisons between muscle relaxants must be made by using equipotent doses. For this purpose, twice the ED95 dose is usually adopted as standard. The recovery index, which is defined as the time between 25% and 75% twitch recovery, is less dependent on dose and is commonly used. Based on duration of action, muscle relaxants can be classified into ultra-short (<8 min), short (8–20 min), intermediate (20–50 min) and long-acting (>50 min) drugs (11) (Table 1).Table 1: Neuromuscular Blocking Drugs According to DurationFor all drugs, neuromuscular recovery occurs when the concentration of the neuromuscular blocking drug at the neuromuscular junction decreases below a certain threshold. This decrease is, in turn, controlled by the decline of plasma concentrations. However, different drugs achieve this decrease in different ways. All long-acting drugs depend on hepatic and renal function for termination of action, and the relative inefficiency of these organs explains the prolonged duration of these drugs. For pancuronium, doxacurium, or pipecuronium, duration of effect is of the same order of magnitude as half-life (1.5–2 h) (12). For all other drugs, termination of effect is via redistribution or breakdown in plasma. Vecuronium (13), rocuronium (14), and rapacuronium (15) have elimination half-lives of 1–2 h, similar to long-acting drugs. However, an extensive redistribution process occurs immediately after injection, so that plasma concentrations of the drug decrease to levels consistent with recovery before the elimination phase begins. Rapacuronium is more extensively redistributed than vecuronium or rocuronium, because it has a more rapid distribution phase. The other drugs (succinylcholine, rnivacurium, atracurium, cisatracurium) depend on enzymatic or spontaneous breakdown for termination of effect. The rate of this breakdown determines the duration of effect. Both types of pharmacokinetics can yield very similar durations of action. This is the case of equipotent doses of vecuronium, rocuronium, cisatracurium, and atracurium, for which duration is 30–45 min. The same is true of mivacurium and rapacuronium, with a duration of 15–20 min. However, drugs that depend on redistribution for termination of action can be converted into longer-acting drugs if the dose is increased. For rapacuronium, another factor must be considered. The drug is metabolized into Org 9488, which is 2.5 times as potent as the parent compound and excreted relatively slowly by the kidney (15). Taken together, these two processes imply that increasing the dose increases the duration of action significantly, from 14 min with 1.5 mg/kg to 25 min with 2.5 mg/kg (6), compared with modest prolongations with mivacurium, 17 min after 0.15 mg/kg to 20 min after 0.25 mg/kg (16). These factors also explain why recovery of rapacuronium after a 1-h infusion is slower than after a single dose (17). Onset Measuring onset of action appears a simple task, but remains elusive. Dose affects onset time, at least for paralyzing doses, i.e., doses producing > 100% block. Clinically relevant doses give > 100% block. Onset is also more rapid in centrally located muscles, such as the muscles of the upper airway and the respiratory system, than in peripheral muscles (4,5). Even if one deals with only one muscle, many confounding factors can be present. Using train-of-four stimulation instead of single twitch can decrease onset time by 50% (5,18). Increasing the duration of stimulation before injecting the drug can also reduce onset time. For example, rocuronium, 0.6 mg/kg, has an onset time of 2.5 min after 1 min of stimulation, and 0.8 min after 20 min (5,19). Mechanical measurements do not yield the same onset time as electromyelography or accelerometry. Thus, it is not surprising that different investigators have obtained very different results after the same dose of the same drug. Particularly, it must be emphasized that onset times reported immediately after the induction of anesthesia, as occurs in clinical practice, might be longer than the values obtained after long stabilization times. For instance, onset times of 3–5 min have been reported for rocuronium, 0. 6 mg/kg, given immediately after the induction drug (20,21), whereas values as short as 0.8 min have been reported for the same drug and dose after several minutes of anesthesia administration (19). However, data between drugs can be compared if doses are equipotent (usually twice the ED95) and the methodology is the same. These comparisons have made possible the confirmation that drugs with fast onset must have a low potency, or a high ED95 (22). Muscle relaxants can be classified according to onset time into ultra-rapid (< 1 min), rapid (1–2 min), intermediate (2–4 min) and slow (> 4 min) drugs (11). Recently, evidence was provided that the key factor in determining onset time was molar potency, that is the ED95 expressed in μmol/kg (23). (Table 1). Not surprisingly, the drugs with the fastest onsets are also the least potent (rocuronium, and especially rapacuronium). Rapacuronium, 1.5–2.0 mg/kg, has an onset time at the adductor pollicis of 1.0–1.5 min (6), and this is even shorter at the laryngeal adductors (5). Endotracheal Intubating Conditions There has been a trend, in recent years, to focus on the clinical end point for which neuromuscular blocking drugs are indicated; that is, the ability to facilitate tracheal intubation, rather than the more traditional measures of onset, potency, and duration. For example, intubating doses of rapacuroniurn were determined before the ED95 was known (6). This type of investigation has been useful in establishing that doses associated with consistently good-to-excellent intubating conditions exceeded the ED95 and were usually closer to twice that value, the actual number being dependent on the time between injection and intubation and on the background anesthetic. The disparity between the ED95 and the dose required for intubation was explained, at least in part, by the relative resistance of some important muscles (laryngeal adductors and diaphragm) (4). The evaluation of intubating conditions has met with problems. There is no accepted standardization of the background anesthetic and time to laryngoscopy, and the evaluation, although blinded, remains subjective. In addition, there are very few comparative studies between drugs and the number of patients required to demonstrate a statistically significant difference is usually large. Nevertheless, when large numbers of patients are studied, it is possible to make useful recommendations. For example, rapacuronium, 1.5 mg/kg, yields good-to-excellent intubating conditions in 79% of patients. With a dose of 2.5 mg/kg, this value may reach 100% (6). In a large multicenter study, rapacuroniurn 1.5 mg/kg was compared with succinylcholine 1.0 mg/kg. When laryngoscopy was started at 50 s, good-to-excellent intubating conditions were seen in 89.4% and 97.4% of cases, respectively (24). Side Effects Among all possible side effects of neuromuscular blocking drugs, cardiovascular effects have received the greatest attention. At present, only doxacurium, cisatracurium, vecuronium, and rocuronium are practically devoid of cardiovascular side effects at clinical doses. Cardiovascular and cutaneous effects of histamine release can be observed with the upper range of recommended doses for atracurium and mivacurium. Unfortunately, cardiovascular side effects and histamine release tend to be more common with low potency drugs, which also have faster onsets. Rapacuroniurn has more cardiovascular effects than most drugs introduced recently. It produces mild dose-related tachycardia and hypotension (24), but these changes are short-lived, and do not seem to be histamine-related. For all neuromuscular blocking drugs, anaphylactic reactions are a rare, but life-threatening possibility. Other side effects are drug specific, such as prolonged paralysis after succinylcholine and mivacurium in patients with abnormal plasma cholinesterase. The depolarizing drug succinylcholine has a long list of unwanted effects, mostly related to its unique mechanism of action on muscle. Concern has been raised with respect to possible respiratory effects of rapacuronium. Bronchospasm or increased airway pressures after tracheal intubation have been reported by several investigators. In one European study, the incidence of such events was 10.7% after rapacuronium compared with 4.1% after succinylcholine (24). However, the overall reported incidence of bronchospasm in preclinical trials of rapacuronium in 1300 subjects was 3.4% (Organon data). Conclusion With the introduction of each new nondepolarizing drug, one gets closer to the perfect drug, which combines rapid onset, short duration, and no side effects in doses used clinically. The newest of these drugs, rapacuronium, has an interesting neuromuscular profile. The onset time approaches that of succinylcholine, but duration is still slightly longer. Cardiovascular side effects are larger than those of most drugs introduced recently into clinical practice, but seem to be acceptable. The respiratory effects still require investigation so recommendations can be made regarding its safe use.

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