New Vistas in Neuromuscular Blockers



Fig. 52.1
The chemical structures of gantacurium (a) and CW002 (b). The chlorine (a, red circle) substituted at the olefinic double bond of gantacurium was designed to accelerate the inactivation of the molecule in the presence of l-cysteine. CW002 (b) lacks a halogen substitution at the fumarate component (blue circle) and undergoes l-cysteine adduction and inactivation at a slower rate (Reproduced with permission from Savarese et al. [27])

The inactivation mechanism, l-cysteine adduction at the central fumarate double bond, is unique to this class of neuromuscular-blocking molecules and represents a novel reversal paradigm as well as organ-independent kinetics.

Gantacurium is an ultrashort-acting nondepolarizing neuromuscular-blocking drug whose inactivation is mediated via two principal mechanisms: cysteine adduction [23] and pH-sensitive hydrolysis at the ester linkage of the molecule [24] (Fig. 52.2).

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Fig. 52.2
Degradation of gantacurium. At pH 7.4 and 37 °C (a), the molecule undergoes slow alkaline hydrolysis. In the presence of l-cysteine (b), rapid formation of an adduct intermediate occurs; this adduction product then undergoes slow alkaline hydrolysis (c) (Reproduced with permission from Savarese et al. [27])

In humans, gantacurium has an ED95 of 0.19 mg/kg, representing a relatively modest potency [25] but likely contributing, along with rapid clearance, to its rapid onset of action. Maximum neuromuscular blockade occurred within 90 s following the administration of 1.5xED95 gantacurium and within 60 s following higher doses.

Thus, gantacurium possesses kinetics very similar to those of succinylcholine, the molecule gantacurium was designed to replace. Although transient cardiovascular effects emerged at doses of 3xED95 and histamine release occurred in humans at doses of 4xED95 [25], the propensity of gantacurium to provoke these types of adverse effects was less than that observed with mivacurium [26], another short-duration nondepolarizing drug that has been removed from the clinical market for economic reasons. The inactivation of gantacurium, as mentioned, occurs via both slow pH-sensitive hydrolysis (t ½ 56 min) and rapid l-cysteine adduction (t ½ 0.2 min), the latter resulting in an adduct product of extremely low potency that itself undergoes alkaline hydrolysis to form inactive products (Fig. 52.2).

The antagonism of gantacurium by the addition of exogenous l-cysteine is extremely rapid, with reduction of total duration of neuromuscular block from approximately 10 min with spontaneous recovery to 3 min with 10 mg/kg l-cysteine administered 1 min after a gantacurium dose that completely abolished twitch response [27]. Figure 52.3 depicts the rapidity of blockade antagonism produced by the administration of l-cysteine as measured with mechanomyography.

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Fig. 52.3
Representative mechanomyographic measurements of gantacurium-induced neuromuscular blockade and its antagonism using l-cysteine in an anesthetized rhesus monkey. Panel (a) depicts the neuromuscular blockade produced by 0.5 mg/kg gantacurium (representing approximately 5xED95). Panel (b) One minute after injection of a second dose of 0.5 mg/kg, the administration of 10 mg/kg l-cysteine restored twitch and train-of-four (T) to baseline within 2 min (Reproduced with permission from Savarese et al. [27])

Although gantacurium possessed a rapid speed of onset, an ultrashort duration, and an acceptable side effect profile that was highly attractive to clinical application, problems with production and marketing prevented this molecule from entering the pharmacopeia. Efforts are ongoing to develop other ultrashort-acting fumarate neuromuscular-blocking molecules possessing rapidity of onset and cysteine reversibility with superior side effect profiles to that of gantacurium. This type of molecule would be well positioned to replace the use of succinylcholine in many clinical situations.

The most recent isoquinolinium diester neuromuscular-blocking drug to undergo both nonhuman primate and human testing is CW002 (Fig. 52.1b), which is currently in a phase I human trial. CW002 differs in structure from gantacurium in that its fumarate is symmetrical and lacks halogen substitution. This results in less activation of the olefinic carbon atoms and therefore a slower l-cysteine adduction reaction and inactivation of the molecule.

CW002, as with gantacurium, undergoes both alkaline hydrolysis (t ½ 495 min) and a more rapid l-cysteine adduction reaction (t ½ 11.4 min), although both of these processes are slower than those for gantacurium (Fig. 52.4). The CW002 l-cysteine adduction product (Fig. 52.4) is approximately 70-fold less potent than CW002.

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Fig. 52.4
Degradation of CW002. CW002 undergoes slow alkaline hydrolysis at pH 7.4 and 37 °C (a). In the presence of l-cysteine (b), an adduction intermediate is formed which is approximately 70-fold less potent than CW002. This adduction intermediate itself undergoes alkaline hydrolysis (c) (Reproduced with permission from Savarese et al. [27])

CW002 thus has an approximately threefold longer duration of action than gantacurium (approximately 28 min versus 10 min, respectively) in nonhuman primates and can be classified as an intermediate duration of action neuromuscular blocker [27]. The comparable recovery time for cisatracurium under identical conditions is approximately 58 min [27].

Although longer in duration than gantacurium, CW002 is a more potent molecule, with an ED95 of 0.05 mg/kg in nonhuman primates [28]. This increased potency could be expected to make the onset of action slower than that of gantacurium; however, CW002 at doses of 3xED95 produces complete neuromuscular blockade within 1 min. Thus, CW002 is a potential intermediate duration nondepolarizing drug which might produce conditions for tracheal intubation in humans within approximately 90 s or possibly less. This quality, combined with the ability to rapidly inactivate the molecule at any point during neuromuscular blockade with the administration of l-cysteine, makes CW002 an attractive clinical candidate.

l-cysteine inactivation of CW002 occurs via the same reaction as that for gantacurium, although more slowly due to the lack of an “activating” halogen substitution at the fumarate of CW002. Nevertheless, the administration of l-cysteine 60 s after a 4xED95 dose of CW002 restores neuromuscular function to normal within 3 min (Fig. 52.5) [27]. Thus, as with the ultrashort-acting molecule gantacurium, the duration of action of even an intermediate duration isoquinolinium fumarate like CW002 can be tailored to the clinical duration required via the administration of l-cysteine.

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Fig. 52.5
Representative mechanomyographic measurements of CW002-induced neuromuscular blockade and its antagonism using l-cysteine in an anesthetized rhesus monkey. Panel (a) depicts the neuromuscular blockade produced by injection of 0.15 mg/kg CW002 (approximately 4xED95). One hour following this first dose, injection of 50 mg/kg l-cysteine 1 min after the administration of 0.15 mg/kg CW002 restored twitch and train-of-four (T) to baseline within 2 and 3 min, respectively (Reproduced with permission from Savarese et al. [27])

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Sep 18, 2016 | Posted by in ANESTHESIA | Comments Off on New Vistas in Neuromuscular Blockers
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