Anesth Analg 2002;94:879-885
© 2002 International Anesthesia Research Society
ANESTHETIC PHARMACOLOGY
Neuromuscular Pharmacology of TAAC3, a New Nondepolarizing Muscle Relaxant with Rapid Onset and Ultrashort Duration of Action
Laszlo Gyermek, MD, PhD*,
Chingmuh Lee, MD*,
Young-Moon Cho, PhD*,
N. Nguyen, BS*, and
S. K. Tsai, MD, PhD
*Department of Anesthesiology, Harbor–University of California–Los Angeles Medical Center, Torrance, California; and Department of Anesthesiology, National Taiwan University, Taipei, Taiwan
Address correspondence and reprint requests to Laszlo Gyermek, MD, PhD, Department of Anesthesiology, Harbor–UCLA Medical Center, 1000 W. Carson St., Torrance, CA 90509. Address e-mail to laslogy{at}earthlink.net
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Abstract
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We selected bis [N-(3,4-diacetoxybenzyl) tropanium-3
-yl] glutarate dibromide (TAAC3) from many new tropinyl diester derivatives to evaluate its neuromuscular blocking (NMB) and autonomic side effects on anesthetized rats, rabbits, guinea pigs, cats, pigs, dogs, and monkeys. NMB potency, onset, recovery index, and duration of action were determined. Comparisons of these pharmacologic variables were made between TAAC3 and rocuronium. In the cat, the degrees of train-of-four and tetanic fade, posttetanic potentiation, and pharmacologic antagonism were evaluated. For determination of the NMB maintenance dose, TAAC3 was also given to rabbits and pigs in the initial dose/maintenance infusion mode. Cardiac vagal block was evaluated in the rat, pig, cat, and guinea pig on the basis of the inhibition of the bradycardia to stimulation of the vagus nerve. Sympathetic ganglion block was studied on the superior cervical ganglion-nictitating membrane preparation of the cat. TAAC3 produced nondepolarizing NMB. Its NMB 90% effective doses ranged from 90 to 425 µg/kg, depending on the species. TAAC3 had a faster onset (0.8–1.0 min), shorter recovery index (0.6–1.1 min), and shorter duration of action (1.8–3.5 min) than rocuronium. It produced a slight cumulative effect on infusion, but not on repeated single-dose administration. Cardiac vagal block was present at doses exceeding the NMB 90% effective dose. In the cat and pig at equipotent NMB doses, the degree of cardiac vagal block was similar to that of rocuronium. There was no demonstrable sympathetic ganglion block in the cat. In view of its favorable NMB characteristics, TAAC3 is now undergoing detailed preclinical studies.
IMPLICATIONS: We developed a new nondepolarizing muscle relaxant, TAAC3, and investigated it in several animal models. TAAC3 has shown a very rapid onset and an ultrashort duration of neuromuscular blocking action. A minor degree of cardiac vagal block was observed. TAAC3 is promising for further studies.
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Introduction
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There have been several attempts to produce the "ideal" neuromuscular blocking (NMB) drug. In the past two decades, atracurium, vecuronium, doxacurium, pipecuronium, mivacurium, cisatracurium, rocuronium, and rapacuronium have been introduced to clinical practice (1,2). However, none of these NMB drugs fulfilled all the criteria of an "ideal relaxant," although each satisfied a few of them, still leaving possibilities for new, improved drugs. For some years we have studied a substantial series of bisquaternary tropinyl diester compounds aiming at (a) a high NMB potency, fast onset, and short duration of action; (b) a nondepolarizing type of block; and (c) minimal or no side effects often associated with some NMB drugs (e.g., autonomic ganglion block or peripheral parasympathetic, particularly cardiac vagal, block).
The basic impetus for our study came from earlier findings which showed that the rigid, azabicyclooctane ring system of tropine and pharmacologically potent tropane alkaloids (e.g., atropine and scopolamine) allows stereospecific chemical manipulations that can markedly influence the anticholinergic spectrum of action of these drugs (3,4). Although NMB bisquaternary ammonium derivatives of tropane and tropine have been synthesized and studied, no therapeutically useful drugs have emerged from bisquaternary derivatives of atropine (5,6); mandelyl, benzoyl, and phenylacetyl tropine (7,8); dicarboxylic acid esters of tropine (9–11); or tropane and tropine (12), although some promising features, e.g., a relatively short duration of action of a few of these drugs, were recognized early (9,11).
Since 1986 we have performed systematic structure-activity explorations with bis-tropinyl diester derivatives. We have emphasized the role of the connecting chain that links two terminal onium cationic heads in affecting NMB (13), of the steric position of the 3-OH group of tropine (/trans or ß/cis), and its influence on interonium distances of bis-tropinyl ester derivatives and of quaternary substituents of the N atom (14). Several hundred bisquaternary tropinyl derivatives were synthesized and biologically screened before we focused our interest on the favorable NMB characteristics of bis [N-(3,4-diacetoxybenzyl) tropanium-3-yl] glutarate dibromide (TAAC3).
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Methods
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This study was done with IRB approvals of the Research and Educational Institute of Harbor–University of California–Los Angeles Medical Center, Torrance, CA, and of the National Taiwan University, Taipei. TAAC3 (Fig. 1) has been synthesized by reacting 2 mol of tropine with 1 mol of glutaryl chloride (Aldrich Chemical Co., Milwaukee, WI) (15) followed by quaternization with 3,4-diacetoxybenzyl bromide according to the general method described previously for other tropinyl diesters and quaternizing groups (16). It is a mixture of N quaternary isomers whose nuclear magnetic resonance spectra indicate a 9:1 ratio. With the major isomer, the N-diacetoxybenzyl group is at the equatorial position and the N-methyl group is at the axial position with respect to the six-membered ring part of tropane. The identity of the compound was established by elemental analysis (Galbraith Laboratories, Knoxville, TN) and by nuclear magnetic resonance spectroscopy (17).
TAAC3 was evaluated for NMB actions and for autonomic and cardiovascular side effects in seven different animal species. Rats and guinea pigs were anesthetized with 40–50 mg/kg pentobarbital sodium intraperitoneally, and rabbits were anesthetized with 30–50 mg/kg pentobarbital sodium IV. Adult male and nonpregnant female cats and mongrel dogs were anesthetized with 25–30 mg/kg pentobarbital and 60 mg/kg intraperitoneal -chloralose. The trachea was cannulated, and artificial ventilation was given to maintain normocarbia with continual monitoring of the end-tidal CO2 (except in the rat). Juvenile Duroc pigs (8–12 kg) were first anesthetized with halothane (1%–2%) in a Lucite box, and after orotracheal intubation this was supplemented with 20–30 mg/kg pentobarbital sodium IV. Adult Macaca cyclopis (Swinhoe) monkeys of both sexes and 5.8- to 12-kg body weights were sedated with ketamine IM, were anesthetized with halothane, and were ventilated with a halothane/oxygen mixture. The trachea was intubated; one peripheral vein was cannulated transcutaneously, and an arterial line was established in one extremity through a transcutaneous cannula. Vagus nerve stimulation was not applied to these animals. After the experiments, the monkeys were properly recovered before readmitting them to the holding facility. The dog and monkey experiments were performed by SKT and his associates at the National Taiwan University, Taipei.
Maintenance of anesthesia was provided in most species with additional (5–15 mg/kg) incremental doses of pentobarbital. NMB drugs were given IV within 5 s via an IV catheter inserted into an external jugular or femoral vein. Neuromuscular responses were monitored electromyographically (18), mechanomyographically, or both at the anterior tibial muscle by using supramaximal train-of-four (TOF) stimuli every 12 s. In some experiments, tetanic (50-Hz) stimuli were applied periodically. The stimuli were delivered via bipolar needle electrodes to the sciatic nerve or to its common peroneal branch via a Grass (Quincy, MA) Model S88 Laboratory Stimulator. Arterial blood pressure was transduced via a cannulated common carotid artery, with the exception of monkeys, on which percutaneous arterial lines were established. For monitoring heart rate changes, pulse pressure responses were interfaced with a Beckman Coulter, Inc. (Fullerton, CA) Model 9857-B cardiotachograph. Cardiac vagal block was evaluated in rats, guinea pigs, cats, and pigs on the basis of the inhibition of the bradycardic responses to peripheral stimulation of the cut right vagus nerve with 15- to 20-Hz supramaximal impulses of 0.2 ms duration, for 5–10 s, delivered every 1.5 min. The effect on sympathetic ganglionic transmission was evaluated in two cat superior cervical ganglion-nictitating membrane preparations. The preganglionic portion of the cervical sympathetic nerve was stimulated through bipolar silver electrodes by supramaximal impulses of 0.2 ms, 5–10 V, and 15 Hz for 5 s every 2 min. The resulting contractions of the nictitating membrane were transduced through a Grass Model TF03 force transducer. TAAC3 was given in increasing doses, up to three times the NMB 90% effective dose (ED90). Recordings of all of these responses were made on a Beckman Coulter Model 6011 polygraph.
ED50 and ED90 doses of NMB were determined by plotting the responses to incremental single doses of each animal against the doses. Mean values per group and SEM were calculated. The process of determining individual ED values is illustrated in Figure 2. Onset of action, recovery index (25%–75% twitch recovery time), and duration of NMB (time from drug administration to 90% recovery of the first twitch of the TOF response) were tested in all species. TOF fade (T4 over T1) and, on occasion, tetanic fade and pharmacologic reversibility by edrophonium were determined in the cat. Comparisons of these pharmacologic variables were made between TAAC3 and rocuronium in all species and also between TAAC3 and succinylcholine chloride on three species (pig, cat, and monkey). After full recovery from a single paralyzing bolus dose producing 80%–90% NMB, TAAC3 was administered to pigs and rabbits in an initial dose/maintenance mode of infusion into a vein. For comparison, another group of pigs and rabbits was given the initial NMB ED80 dose and the maintenance mode of infusion of rocuronium, rapacuronium, or both. The infusion was continued for an hour, and thereafter NMB was allowed to spontaneously recover. Maintenance doses (MD80) (the dose per kilogram of the NMB drug that maintains an 80% block of the T1 response during a 1-h long-lasting infusion) for 80% depression of the first twitch of the TOF response were calculated for 10-min epochs; the recovery indices were determined and compared after the initial single dose and during the spontaneous recovery after the infusion. The differences of recovery indices were statistically analyzed by paired Student’s t-tests. Significance was accepted at P 
0.05. The metabolic inactivation of TAAC3 was determined by a sequential reinjection technique in the pig and in the rabbit as follows: First the NMB ED80 dose of TAAC3 was determined, and then the same dose was added to 5 mL (pig) or 3 mL (rabbit) of blood withdrawn from the animal. The blood was heparinized and incubated with agitation in an oxygen-filled syringe at 36°C. The blood samples were reinjected after 5, 10, 15, 20, and 30 min, and the time, in minutes, for 50% loss of potency (and SEM) in the blood was determined by graphic interpolation. Rocuronium (pig and rabbit) and rapacuronium (pig) were tested for comparison under identical conditions.
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Figure 2. Illustration of the method of obtaining 50% and 90% effective dose (ED50 and ED90) values of neuromuscular blocking (NMB) drugs.
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Results
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The results are summarized in Figures 3–5 and in Tables 1 and 2. The type of NMB with TAAC3 was typically nondepolarizing, as illustrated by TOF fade (which was less pronounced during onset than during recovery of the NMB), tetanic fade, posttetanic facilitation during partial block, and reversibility by edrophonium (Fig. 3).
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Figure 3. Demonstration of posttetanic potentiation (top), tetanic fade (middle), and reversibility of action by edrophonium (bottom). Represented are the anterior tibial muscle responses of the cat. Top, mechanomyographic recording (MMG). Bottom, electromyographical (EMG) response. During 50-Hz tetanic contractions, the amplification of the MMG response was reduced, and the paper speed was increased. After TAAC3, train-of-four, tetanic fade, and posttetanic facilitation were present. TS = tetanic stimulation; Ptt = posttetanic twitch.
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Figure 5. Illustration of the breakdown of TAAC3 in the blood of the pig. NMB = neuromuscular blocking drug. *Time of exposure of the drug (amount of an 80% effective NMB dose) to 5 mL of oxygenated blood reinjected IV at different time intervals.
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Table 2. Comparison of the Recovery Indices of TAAC3, Rocuronium, and Rapacuronium Before and After Infusion Administration
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The potency, onset, and duration of action of TAAC3 in seven different animal species are shown in Table 1 (in all species, comparisons were made with rocuronium and in some with succinylcholine). The table shows that the NMB ED50 and ED90 doses of TAAC3 were slightly smaller than those of rocuronium in the cat, guinea pig, and pig. In the other four species, TAAC3 was less potent than rocuronium. In all species, TAAC3 showed a faster onset and shorter duration of action than rocuronium. Comparison of TAAC3 with succinylcholine was made in the cat, pig, and monkey. The onset of action of succinylcholine on these three species was 1.4 (0.1) min (mean [SEM]), 0.6 (0.1) min, and 0.7 (0.2) min, respectively, and its duration of action varied from 4.4 (0.5) min (monkey) to 5.8 (0.6) min (cat). Thus TAAC3 showed a similar or slightly slower onset but an even shorter duration of action than succinylcholine. Lack of cumulative effect in the monkey is demonstrated in Figure 4, which shows no difference in the duration of action pattern upon repeated administration in rapid sequence (e.g., each 3–4 min).
The MD80 has been determined in the rabbit and the pig. The MD80 of TAAC3 was 114 (22) µg · kg-1 · min-1 (n = 4) in the pig and 29 (8) µg · kg-1 · min-1 (n = 4) in the rabbit. The ratios (ED80/MD80 = 3.0 [pig] and 3.2 [rabbit]) suggest that the ED80 dose of TAAC3 can be given at 4- to 5-min intervals to these species without cumulative effect.
Furthermore, we observed fast NMB recovery indices after infusion of TAAC3. These indices were only twice as long after compared with before the infusion, indicating only a slight degree of cumulative effect under these conditions. Comparison of the recovery indices of TAAC3 with those of rocuronium and rapacuronium (in the pig) and with rocuronium (in the rabbit) before and after infusion is shown in Table 2.
The time pattern of the inactivation of TAAC3, as compared with rocuronium, in whole blood samples of the pig indicates significant loss of potency with TAAC3 within 5 min (Fig. 5). Likewise, in the rabbit, more than 50% loss of potency occurred in <10 min. In comparison, the NMB effect of mivacurium (rabbit) and of rocuronium (pig and rabbit) were not measurably affected by identical exposure to oxygenated whole blood up to 20–30 min.
Autonomic side effects ranged from none to moderate, depending on the dose and the species. Significant cardiac vagal block did not occur at the NMB ED50 dose. It was present at doses of ED90 or larger in the cat, the rat, the guinea pig, and, particularly, the pig (Table 1). No significant tachycardia was observed during NMB, and no measurable hypotensive or hypertensive response was observed at the NMB ED90 levels. TAAC3 lacked a blocking effect on sympathetic ganglionic transmission in the cat after up to twice the NMB ED90 doses.
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Discussion
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A new bisquaternary tropine diester derivative, TAAC3, in doses of 90–425 µg/kg (ED90) in seven different animal species, exhibits rapidly developing nondepolarizing NMB, with an ultrashort duration of action that is shorter than that of any clinically used nondepolarizing NMB drug (Figs. 3–5, Table 1). Furthermore, in some species (e.g., the cat and monkey) its onset was equal to and the duration even shorter than those of succinylcholine. Although direct comparison with GW 280430A, a new short-acting nondepolarizing drug, is not available, the onset of NMB action of TAAC3 after the NMB ED90 in the cat, dog, and monkey seems to be 1.0–1.9 times faster, and the duration of action 1.7–3.0 times shorter, than those reported by others on similar species after the NMB ED95 of GW280430A (19–21). Without adequate explanation we can only speculate on the rapid onset of action of TAAC3. Some kinetic factors, such as the access of the TAAC3 to a "prereceptor" compartment, might explain its fast onset of action. Another interesting hypothesis that might be considered in the rapid onset of action of TAAC3 is based on the correlation between dissociation and association kinetics with drugs such as succinylcholine and mivacurium in vivo (22). TAAC3 and its congeners were not studied under similar experimental paradigms. Thus, we do not know whether that hypothesis would be applicable for TAAC3 and similar drugs. We believe, however, that the rapid onset of action of TAAC3 and its congeners cannot be explained by the concept that, within a given series, the less potent a NMB drug is, the more rapidly acting it becomes.
The short duration of action of TAAC3 can be explained by the presence of its rapidly hydrolyzable acetoxy radicals attached to the N-benzyl groups. A spontaneous breakdown of these phenolic acetoxy groups results first in the formation of two hydroxy groups, ionized at physiologic and particularly at alkaline pH. These ionized groups initiate a "1-4 elimination process," which gradually breaks off the benzyl group (Fig. 1). Accordingly, bisquaternary methyl- and tertiary N-methyl glutaryl tropines have been isolated as in vitro breakdown products of TAAC3 (Organon Laboratories, unpublished observations, 2001). Our in vivo results with samples of TAAC3, incubated with whole blood and sequentially reinjected to rabbits and pigs, suggest that the previously mentioned elimination process is catalyzed by nonspecific plasma esterases that seem to preferentially speed up the degradation of the acetoxy ester radicals attached to the benzene ring and not the ester groups of the dicarboxylic acid ester linker component. This assumption is supported by the observation that many other quaternary ammonium derivatives of tropinyl diesters, as well as of some tetrahydroisoquinoline diesters (e.g., mivacurium and doxacurium) lacking acyloxy benzyl groups, show a considerably longer duration of action than the acyloxybenzyl substituted tropinyl diesters. Because of the slower rates of hydrolysis of the dicarboxylic acid ester component and in vitro, nonenzymatic, spontaneous breakdown of the acyloxy benzyl component, we suggest that the rapid inactivation of TAAC3 in vivo largely depends on the elimination of the benzyl groups, starting with the hydrolysis of the acyloxy radicals.
To substantiate this hypothesis, the in vivo isolation of the rapidly forming debenzylated metabolites will be necessary. Regardless of that, however, we already observed that the identified in vitro breakdown products of TAAC3 are practically inactive as NMB drugs (Gyermek et al., unpublished results, 2001).
TAAC3 is representative of a new group of bisquaternary tropinyl diesters (16). These drugs are characterized by an acid diester connecting chain attached to the C3 atom of two tropine molecules, di- or trisubstituted aralkyl quaternary substituents on the tropine N atoms, and varying interonium distances between the terminal ammonium groups measuring from 9 to 34 Å in molecular models. Molecular modeling of TAAC3 with energy minimization with the Sybyl 6 (Tripos Co., St. Louis, MO) and MMP (Chem SW, Fairfield, CA) programs point at a highly flexible structure with a large number of low-energy conformers having interonium distances ranging mostly from 10.2 to 13.5 Å. However, in the receptor-bound conformation and in the solvated form, the interonium distances may be different.
TAAC3 is structurally quite similar to G-1-64, another quaternary glutaryl diester derivative of tropine, reported previously (23). The only difference between these two drugs is in the quaternizing moiety. TAAC3 carries 3,4-diacetoxybenzyl groups, whereas G-1-64 carries 2,6-dichlorobenzyl groups on their N atoms. The introduction of readily hydrolyzable acyloxy radicals into the quaternizing benzyl group of tropinyl diester-type NMB drugs yields NMB drugs with shorter onset and recovery when compared with their dihalo- or dialkoxy benzyl analogs (14,16). The ultrashort duration of action of TAAC3 and similar tropinyl diester-type muscle relaxants may be related primarily to enzymatic cleavage of their acetoxy groups on the quaternary benzyl groups by nonspecific plasma carboxyesterases, which through the previously mentioned 1-4 elimination process can split off the benzyl group. In addition, a similar spontaneous pH-dependent degradation of the acetoxy radicals on the benzyl group may take place. Finally, hydrolysis of the acid diester groups of the connecting chain by plasma pseudocholinesterase is also possible. Because of their possibly slower kinetics and thus lesser in vivo significance, the last two pathways have not been investigated.
In summary, the new neuromuscular relaxant TAAC3 showed typical nondepolarizing NMB in seven different laboratory animal species. The NMB had a rapid onset and an ultrashort duration of action. This drug was practically without any cumulative effect on repeat single-dose administration and showed only a slight cumulative effect on infusion administration. In all these respects, at least in animals, TAAC3 compares favorably with the presently available nondepolarizing NMB drugs. TAAC3 was shown in two species to be rapidly inactivated in the blood. Regarding side effects, TAAC3 exhibited a moderate degree of cardiac vagal block, but it showed no other autonomic nervous system side effects at the NMB ED90. Recent observations, however, indicate that TAAC3 in large doses, e.g., 5–10 times the NMB ED90, produces a significant and fleeting hypotensive response in the dog, and this response was considered to be unrelated to histamine release (Van Egmond et al., personal communication, 2001). The cardiac vagal blocking effect of TAAC3 in equipotent NMB doses is larger than those of atracurium, mivacurium, and vecuronium, is similar to that of rocuronium, and is of a lesser degree than those of pancuronium and rapacuronium. Projected to humans, such a degree of cardiac vagal block may be clinically acceptable, and in certain conditions it may even be desirable (e.g., during large-dose IV narcotic induction of cardiac patients or during the induction of anesthesia in children). On the basis of its favorable NMB characteristics, TAAC3 and some of its analogs are presently undergoing intensive preclinical development by Organon-Teknika, NV, and Organon Laboratories, Ltd.
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Acknowledgments
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Supported by a grant from Organon–Teknika NV, Boxtel, the Netherlands.
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Footnotes
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Presented in part at the 75th Congress of the International Anesthesia Research Society, Ft. Lauderdale, FL, March 16–20, 2001.
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Accepted for publication December 19, 2001.
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Abstract
Introduction
