Succinylcholine produces a depolarisation of the end-plate region which is similar to, but more persistent than, that achieved by acetylcholine. This depolarisation induces desensitisation of the nAChR, inactivation of voltage-gated Na⁺ channels at the neuromuscular junction and increase of the K⁺ permeability in the surrounding membrane. Onset of neuromuscular blockade is characterised by an excitatory state with fasciculations of muscle fibres thought to represent random repetitive neuronal firing. It could be due to the depolarisation of prejunctional receptors; the abolition of fasciculations by d-tubocurarine may represent an action at the presynaptic receptor. The neuromuscular block is characterised by a twitch response to indirect stimulation which is diminished but sustained with repetitive stimulation. It is associated with end-plate depolarisation and development of a surrounding zone of inexcitability through which a muscle action potential evoked by direct stimulation cannot propagate. During prolonged depolarisation, the muscle may gain sodium and chloride and lose significant amounts of potassium, sufficient to raise serum levels of this ion. Following continuous administration, a “phase II block” characterised by fade and post-tetanic facilitation occurs. One of the mechanisms could be an excessive activation of presynaptic nicotinic receptors, which could lead to reduced transmitter output. “Phase II block” could also be associated with a desensitisation of the end plate, which then becomes refractory to chemical stimulation. Succinylcholine depolarises immature receptors more easily, inducing a significant cation flux. Moreover, once depolarised, the immature receptor will stay open for a longer time.

NDMRs competitively bind at the same site as acetylcholine on the α subunit of the nicotinic postjunctional receptor . The binding of one nicotinic antagonist molecule to one of the two α subunits of the receptor prevents opening of the channel because both α subunits need to be bound by acetylcholine for activation of the channel. In a given situation, the proportion of receptors bound to the agonist depends on the affinity of the binding site for the agonist, on its affinity for the antagonist and on the concentration of agonist and antagonist. Some authors have suggested that NDMR could also block the open receptor because they can have access to the mouth of the open channel but cannot pass through, thus preventing further ionic movement. This type of block is non-competitive but its role is probably marginal. Only a small fraction of receptors need to bind to acetylcholine to produce depolarisation. This has been referred to as the “margin of safety” of the neuromuscular transmission. Non-depolarising neuromuscular block is not apparent until a large number of receptors are occupied by the muscle relaxant. Animal studies suggest that 75 % of receptors must be occupied by a NDMR before twitch height decreases. Blockade is usually complete in peripheral muscles when 92 % of receptors are occupied. Peripheral muscles have been found to have a smaller margin of safety than the diaphragm.

There is ample evidence that potent NDMRs have slower onset times than less potent drugs with similar physicochemical properties . These facts can be explained by the concept of the margin of safety. A critical number of receptors at the neuromuscular junction must be occupied before appearance of neuromuscular block, and at least 90 % of the receptors must be occupied before block is complete at the adductor pollicis . When the drug reaches the synaptic cleft, most molecules will bind to receptors which are present with a high density. As the concentration of free drug decreases, more molecules are driven in, and the process will continue until the concentrations of free drug within and outside the synaptic cleft are equal. This process is known as buffered diffusio n [10]. When a potent drug is administered, fewer molecules are given than in a case of a less potent drug, and the onset will be slower compared to onset of weak potency NDMR [11]. This phenomenon is probably what contributes to the slower onset time for cisatracurium than atracurium. Based on theoretical calculations and experimental data, the ED95 to produce a short onset of action might be >0.3–0.5 mg/kg (Fig. 15.2) [9]. However, for very short-acting drugs, the ideal ED95 might be greater (0.5–1.0 mg/kg) because rapid metabolism destroys some of the muscle relaxant given before it reaches the neuromuscular junction [12]. This phenomenon can explain the relatively slow onset time for mivacurium.

Plasma concentrations have only modest influence on onset time. Arterial plasma concentrations peak 25–35 s after administration thus before onset of neuromuscular block. This paradox can be explained by assuming that the site of action, the neuromuscular junction, is represented by the effect compartment in which the concentration of the NMBA is directly related to the magnitude of neuromuscular blockade [13]. As usual the model will include a rate constant for transfer into the effect compartment and another rate constant for transfer out of this compartment. The obtained k_e0 or more appropriately the T_1/2ke0 is related to the time required to fill or empty the effect compartment for a constant plasma concentration. The k_e0 is similar for most intermediate-duration action NMBAs and corresponds approximately to neuromuscular junction blood flow divided by neuromuscular junction/plasma partition coefficient . Whatever muscle relaxant, the limiting factor appears to be the time required for the drug to reach the neuromuscular junction which in turn depends on cardiac output, the distance of the muscle from the central circulation, and muscle blood flow. Therefore in most cases, the onset time will be dependent on blood flow to muscle. It has been demonstrated that in dogs time to maximum blockade was decreased when blood flow increased, whereas recovery was not affected by blood flow [14]. Under normal circumstances, muscle blood flow increases when cardiac output increases, with a direct relationship between speed of onset and cardiac output. This might explain why infants and children have a faster onset of action of NMB and elderly patients have a slower onset than younger individuals. It has been demonstrated that vecuronium-induced onset of NMB was shorter with etomidate than with either thiopental or propofol and onset time was longer if hypotension was present [15].

It is obvious that the intensity of maximum blockade is affected directly by the administered dose. However when the dose increases in the sub-paralysing range, that is, when maximum blockade is between 0 and 100 %, time to reach maximum effect is dose independent. This is because the time to peak concentration at the effect compartment is independent of the dose. When the administered dose is sufficient to obtain complete disappearance of the neuromuscular response, time to maximum blockade becomes dose dependent. For many years, it was believed that shorter-acting NMBA would have a faster onset time than long-acting NMBA. Many studies have shown that atracurium or vecuronium onset times were comparable to that of pancuronium. The lack of effect of elimination of these drugs on onset time is explained by the fact that these NMBAs are eliminated too slowly to see any difference.

Although it is commonly believed that the rate of decline of NMBA plasma concentrations during recovery from neuromuscular blockade determines the duration of action and the rate of recovery, further explanations are needed. It has been suggested that muscle blood flow is, to a certain extent, a limiting factor for the termination of action. For long-acting NMBA, the dominant effect for the recovery from neuromuscular blockade is the rate of decrease of plasma concentration because there is a pseudoequilibrium between concentrations at the neuromuscular junction and the plasma. Therefore changing blood flow will not affect the duration of action. For intermediate-duration action NMBA, after a single bolus dose, plasma concentrations decrease at a rate that differs slightly from the equilibrium half-life with muscle. It can induce a significant concentration gradient between neuromuscular junction and plasma during recovery, but provided that recovery rate is constant, the ratio of concentrations between the neuromuscular junction and plasma will remain relatively constant.

The most important issue is that the rate of decline of plasma concentration during recovery is not always related to the NMBA terminal half-life because after initial administration, plasma concentrations will decrease because of redistribution. It is only when redistribution will be complete that the decrease in plasma concentrations will be dependent of the terminal half-life and will decrease more slowly. For long-acting NMBA such as pancuronium, the recovery time will take place during the terminal half-life. In this situation, the duration of action will be dependent on the rate of decrease of plasma concentrations. It is different for intermediate-duration action NMBA. The terminal half-life of atracurium is around 20 min, whereas the elimination half-lives of both vecuronium and atracurium are between 60 and 120 min. Although such differences can be observed, the duration of action and recovery from neuromuscular block of these three drugs is very similar. These apparent discrepancies can be explained by the fact that the distribution phase is the most important factor and extends for a much longer period than for long-acting NMBA (Fig. 15.3) [16]. If their duration of action and recovery rates are almost identical, it is because plasma concentrations decrease to levels compatible with recovery during the redistribution phase.

These compounds share some structural properties with mivacurium. Gantacurium underwent clinical testing in humans a few years ago. It was shown that following 2–3 times the ED95 at the adductor pollicis, onset time at both the laryngeal muscles and the adductor pollicis was comparable to onset of block following succinylcholine administration. Gantacurium does not exhibit ganglionic blockade or vagolytic properties. However histamine release at 4 times the ED95 and a 17 % reduction in blood pressure in humans has hampered its clinical development [46]. Interestingly, gantacurium is metabolised by a slow pH-sensitive hydrolysis and also by adduction of the naturally occurring amino acid cysteine transforming gantacurium into an inactive compound. Administration of l-cysteine (10 mg/kg), 1 min after administration of gantacurium , results in return of complete neuromuscular function within 1–2 min [47].

CW002 is a gantacurium derivative of intermediate duration of action. Initial dose-finding studies in volunteers did not show any evidence of histamine release or bronchoconstriction. The resulting adduction of cysteine product retains some very low affinity for neuromuscular nAChR with potency for neuromuscular blockade decreased 70–100-fold [47]. CW002 is currently under clinical investigation.

In man, several studies have reported some discrepancies between the level of peripheral paralysis and respiratory depression or intubating conditions. Paton and Zaimis demonstrated in 1951 that some of the muscles of respiration, such as the diaphragm, were more resistant to curare than others. The dose of NDMR needed to block the diaphragm is 1.5–2 times that of the adductor pollicis. Thus, complete paralysis of the diaphragm is not expected with doses of neuromuscular blocking agents used to block neuromuscular transmission at the adductor pollicis [28]. Similarly, the laryngeal adductor muscles are more resistant to NDMR than the more peripheral muscles such as the adductor pollicis, for which all dosing recommendations for neuromuscular blocking agents and their antagonists have been made [29]. The sparing effect on the laryngeal adductor muscles has been documented with vecuronium, rocuronium (Fig. 15.9) [33], cisatracurium and mivacurium. Plaud et al. studied the pharmacokinetic–pharmacodynamic relationship of blocking agents at the adductor pollicis and the laryngeal adductors. They found that the concentration in the effect compartment producing 50 % of the maximum block was significantly greater at the laryngeal adductor muscles (1.5 μg/mL) than that at the adductor pollicis (0.8 μg/ml) (Fig. 15.10) [48]. There is convincing evidence that the EC₅₀ for almost all drugs is 50–100 % higher at the diaphragm or larynx than it is at the adductor pollicis. These differences may be due to any of several factors. Waud and Waud found that following curare administration, neuromuscular transmission occurs when approximately 18 % of the receptors are free at the diaphragm, while it does not occur at the peripheral muscles unless 29 % of receptors are free [49]. This may be due to higher receptor density, greater release of acetylcholine or less acetylcholinesterase activity [50]. The lower density of acetylcholine receptors in slow muscle fibres, such as found in the peripheral muscles, explains, at least in part, the lower margin of safety for neuromuscular transmission when compared to that in the faster muscle fibres in the laryngeal adductors. Interestingly, muscle sensitivity to succinylcholine is different than with other neuromuscular blocking agents [17]. It is the only muscle relaxant that, at equipotent doses, causes greater neuromuscular block at the vocal cords than at the adductor pollicis. Some data suggest that in contrast to NDMR, succinylcholine is more effective in blocking the muscles composed of primarily fast-contracting fibres [51].

In spite of their relative resistance to neuromuscular blockers, the onset of neuromuscular block is significantly faster at the diaphragm and the laryngeal adductors than at the adductor pollicis. Fisher et al. [52] postulated that a more rapid equilibration (shorter t _½k_e0) of the neuromuscular blocking agent between plasma and the effect compartment at these more centrally located muscles was the explanation for this observation. The accelerated rate of equilibrium probably represents little more than differences in regional blood flow. Therefore, muscle blood flow rather than a drug’s intrinsic potency may be more important in determining the onset and offset time of NDMR. Greater blood flow per gram of muscle at the diaphragm or larynx results in them receiving a higher peak plasma concentration of drug in the brief period of time before rapid redistribution occurs. Plaud et al. have confirmed this hypothesis by demonstrating a faster transfer rate constant (t _½k_e0) at the laryngeal adductors (2.7 min) than at the adductor pollicis (4.4 min). Greater resistance to neuromuscular blockade accounts for the more rapid recovery of the respiratory muscles and the muscles of the abdominal wall than at the adductor pollicis. Recovery occurs more rapidly because blood concentration of NMBA has to decrease more in the muscles of respiration than in the adductor pollicis for recovery of neuromuscular function to begin.