REVIEW ARTICLE

Drugs 44 (2): 182-199, 1992 0012,6667/92/0008-0182/$09.00/0 © Adis International Limited. All rights reserved. DRUl179

Newer Neuromuscular Blocking Drugs

An Overview of their Clinical Pharmacology and Therapeutic Use Rajinder K. Mirakhur Department of Anaesthetics, The Queen's University, Belfast, Northern Ireland

Contents 183 184 184 184 186

187 J88 J88 J88 188 189 190 190 190

191 191 191 193 193 194 194 194 194 194 195 195 196 196 196 196

Summary I. Pipecuronium Bromide 1.1 Neuromuscular Effects 1.2 Cardiovascular Effects 1.3 Pharmacokinetics 1.4 Effect of Age 1.5 Interactions 1.6 Clinical Use 2. Doxacurium Chloride 2.1 NeuromuScular Effects 2.2 Cardiovascular Effects 2.3 Pharmacokinetics 2.4 Effect of Age 2.5 Interactions 2.6 Clinical Use 3. Mivacurium Chloride 3.1 Neuromuscular Effects 3.2 Cardiovascular Effects 3.3 Pharmacokinetics 3.4 Effect of Age 3.5 Interactions 3.6 Clinical Use 4. Org 9426 (Rocuronium) 4.1 Neuromuscular Effects 4.2 Cardiovascular Effects 4.3 Pharmacokinetics 4.4 Effect of Age 4.5 Interactions 4.6 Clinical Use 5. Conclusion

Newer Neuromuscular Blockers

Summary

183

Four new nondepolarising muscle relaxants, pipecuronium bromide, doxacurium chloride, mivacurium chloride and Org 9426 (rocuronium) offer alternatives to the established agents atrilcurium ~esilate and vecuronium bromide. Pipecuronium and Org 9426 are steroidal compounds, the latter being a monoquaternaryagent, whereas doxacurium and mivacurium are bisquaternary benzylisoquinolinium compounds. Pipecuronium and doxacurium have a relatively slow onset and a long duration of action. Pipecuronium produces maximum block in 3 to 6 min when given in a dose of 45 to 80 J.lg/kg, and a duration of clinical relaxation of between 40 and 110 min. Doxacurium is more potent, but is the least rapid and the longest acting relaxant currently available. When administered in doses of 37 to 80 J.lg/kg, it produces maximum block within 3.5 to 10 min, with a duration of clinical relaxation of 77 to 164 min. The advantage of both pipecuronium and doxacurium istheir cardiovascular stability. Both agents are primarily eliminated via the kidneys and both have now been licensed for use in the US. Mivacurium is a muscle relaxant with a short duration of action. When administered in doses of 0.1 to 0.25 mg/kg it produces maximum block in 2 to 4 min, but the duration of clinical relaxation is less than 20 min. Higher doses which could induce a faster neuromuscular block are unfortunately associated with some histamine liberation. The drug is metabolised by plasma cholinesterase. Mivacurium has also been licensed for use in the US. Org 9426 is an agent with a rapid onset but an intermediate duration of aCtion. A dose of 0.5 to 0.6 mg/kg induces maximum block in about 1.5 min and has a duration of clinical relaxation of about 30 min. The rapid onset of effect could be useful for early intubation as an alternative to suxamethonium chloride. However, much more clinical experience is needed with this agent, particularly with regard to duration of action of larger doses and occurrence of side effects. The drug is mainly eliminated via the liver.

Ever since the introduction of tubocurarine (cu- . rare) in 1942 (Griffith & Johnson 1942), the use of neuromuscular blocking agents has become commonplace in anaesthetic practice. However, many of the currently used nondepolarising relaxants have side effects, particularly on the cardiovascular system. In addition, all have a relatively slow onset of action. An ideal muscle relaxant has been defined by Savarese and Kitz (1975) as an agent with a brief, noncumulative nondepolarising neuromuscular blocking action, with rapid onset and recovery, easy reversibility by an appropriate antagonist, and lack of any cliniCally important cardiovascular and other side effects. They also suggested that there was a need for 3 different types of neuromuscular blockers, all nondepolarising: (a)a rapid and shortacting drug to replace suxamethonium; (b) an intermediate-duration agent for procedures lasting about an hour and without cumulative properties; and (c) a long-acting agent for longer procedures. Absence of side effects, particularly cardiovascular, would also be a desirable feature of all types of

compounds. It is in the context of these requirements that the recent developments in the field of neuromuscular blockade have taken place. Following a large amount of investigation, the early 1980s marked the introduction of atracurium besilate and vecuronium bromide into clinical practice, and these are currently the moS-t frequently used neuromuscular blocking agents in the UK and perhaps the rest of Europe (Mirakhur 1990). Both possess the profile of the intermediateacting relaxant according to the definition of Savarese and Kitz (1975). flowever, neither approached the speed of onset or the duration of action of suxamethonium and the search has thus continued for the development of a rapid and shortacting nondepolarising neuromuscular blocking drug. More recently, work has been in progress with 4 new compounds, pipecuronium bromide, doxacurium chloride, mivacurium chlorjde andOrg 9426 (rocuronium), which will be discussed in the present review.

Drugs 44 (2) 1992

184

1. Pipecuronium Bromide This bisquaternary neuromuscular blocking agent is based on a steroidal structure like pancuronium and vecuronium, the main difference being the greater distance between the quaternary nitrogen moieties (fig. I). Pipecuronium was originally used in Hungary (Boros et al. 1980) but has since been investigated and evaluated in Western Europe and the US. It has now been approved for clinical use in the US. 1.1 Neuromuscular Effects Dose-response studies in adults under balanced anaesthesia and using mechanomyography and single twitch stimulationat 0.1 Hz have shown pipecuronium to be about 20 to 25% more potent than pancuronium, with an ED95 (dose effectively producing 95% inhibition of evoked response, or twitch) of approximately 45 J.Lg/kg (Boros et al. 1983; Stanley & Mirakhur 1989; Wierda et al. 1989). Potency studies using electromyography and a trainof-four (TOF) method of stimulation applied every 20 sec however showed the ED95 to be 59 J.Lg/kg (pittet et al. 1989). The anaesthetic protocols were otherwise generally similar in these studies. Several workers have examined the neuromuscular blocking effects of pipecuronium in humans (table I) [Foldes et al. 1990; Pittet et al. 1989; Stanley et al. 1991 b; Wierda et al. 1989]. The time to onset of maximum block is dose-dependent, as is commonly observed with other muscle relaxants. When administered in a dose of 45 to 50 J.Lg/kg, the time to onset of block with pipecuronium was between 3.5 and 5 min and the duration of clinical relaxation (time to 25% recovery of first twitch of theTOF response) varied from 29 to 41 min. The recovery index (time to recovery of twitch from 25 to 75% of control) following a 45 J.Lg/kg dose was reported to be 31 min by Stanley et al. (1991 b), similar to that observed with an equipotent dose (60J.Lg/kg) of pancuronium. A duration of clinical relaxation of only 29 min in one of the groups in the study of Wierda et al. (1989) may have been due to the administration of the total dose of 50

ltg/kg ofpipecuronium over a longer period and in smaller increments. A dose of 70 to 85 J.Lg/kg produces complete block in 2 to 2.5 min (Larijani et al. 1989; Stanley et al. 1991 b). The duration of clinical relaxation however approaches 1.5 to 2 hours with these doses (Caldwell et al. 1988). It appears that there is a wide variation in the duration of action and thus a need for careful monitoring of effect. Administration of up to 3 repeated doses of pipecuronium resulted in similar durations of effect (Foldes et al. 1990). However, this study was too small to clearly define the potential of pipecuronium to accumulate. Intubating conditions have been described as good or excellent at 3 min following administration of pipecuronium in doses of 70 J.Lg/kg or more (Larijani et al. 1989). Adequate antagonism of pipecuronium-induced neuromuscular block [T4 divided by T1 ~ 0.75 (TOF ratio), where T4 is the last and T1 the first twitch] with the anticholinesterase neostigmine 60 J.Lgjkg was achieved in an average time of just over 8 min when spontaneous recovery of Tl was 20% or more (Abdulatif & Naguib 1991). However, 5 of 15 patients in this study required an additional 20 J.Lg/kg of neostigmine. The speed of reversal of block is related to the degree of spontaneous recovery present prior to the administration of the anticholinesterase agent (Larijani et al. 1989). Sometimes adequate antagonism may take longer than 10 min and further doses of neostigmine may be required; antagonism is particularly delayed during isoflurane anaesthesia (Meistelman et al. 1990). .Edrophonium is an unreliable .and ineffective antagonist (Abdulatif & Naguib 1991; Wierda et al. 1989). 1.2 Cardiovascular Effects One of the main virtues of pipecuronium is its lack of cardiovascular side effects (Stanley et al. 1991 a; Tassonyi et al. 1988). While observing a 22% increase in.heart rate from 54 to 66 beats/min after administering pancuronium in patients undergoing coronary artery bypass surgery under high dose fentanyl-oxygen-air anaesthesia, Stanley and col-

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Pipecuronium

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WOCH3 h / . OCH3

+N-(CH2l3-0~-(CH2)2-~0-(CH2l3-W 'CH

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Fig. 1.

~

0-C-CH3 ~/CH3 +N N CH 3

Mivacurium

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oc~

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Structural formulae of mivacurium, pipecuronium, doxacurium and Org 9426.

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00 Vl

Drugs 44 (2) 1992

186

Table I. Neuromuscular effects of pipecuronium Reference

Foldes et al. (1990) Larijani et al. (1989)

Stanley et al. (1991b)

Wierda et al. (1989)

Anaesthesia

Narcotic Narcotic Narcotic Narcotic Narcotic Halothane Halothane Isoflurane Halothane Narcotic

Dosage

Maximum

Time to

Duration of clinical

(ltg/kg)

block (%)

maximum block (min)

relaxation (min)

80 70 85 100 45 45 70

99.3 100 100 100 96 99 100

3.6 3.7 3.2 3.0 5.7 4.3

110.5 69.9 98.3 94.6 41 54

2.5

50 50

98 96.8

5.4 5.5

50

93

6.3

95 50 36 29

leagues (l99Ia) found little change in heart rate following pipecuronium. Mean arterial pressure, cardiac index and rate pressure product also increased significantly following administration of pancuronium whereas there were only minimal and insignificant changes following pipecuronium. Even doses as high as 200 J.Lg/kg had no significant effect on heart rate (I % reduction) in 10 patients undergoing coronary artery surgery under anaesthesia with etomidate and sufentanil, although sufentanil was not administered until 10 min afterpipecuronium administration (Wierda et al. 1990a). Many of these patients were receiving fj-adrenoceptor blocking agents and calcium antagonists. There was however a reduction in cardiac output of 19%, and mean arterial pressure decreased from 124/69.Smm Hg to 107/61.4mm Hg after pipecuronium administration. This was accompanied by a reduction in central venous pressure from 9.1 to 6.6mm Hg but without any significant change in systemic vascular resistance. Dubois et al. (1991) reported bradycardia occurring within 2 min of administration of pipecuronium 80 J.Lg/kg both with and without prior suxamethonium, but neither the degree of decrease in heart rate nor the number of affected patients was described. These episodes were thought to be due to prior administration of suxamethonium, or to the unopposed cardiovascular effects of thio-

pental and fentanyl, since similar observations were made in the placebo group. 1.3 Pharmacokinetics Initial pharmacokinetic studies in dogs revealed an elimination half-life (t,/,) of 44.8 min, with a clearance rate ofO.3S L/kg/h and a mean residence time of Sl.l min (Khuenl-Brady et al. 1989). 77% of the administered dose was recovered from the urine, suggesting that renal elimination is the primary route of elimination of pipecuronium. When the renal pedicles were clamped, t./, increased to 196.7 min, plasma clearance decreased to O.OS L/ kg/h, and mean residence time increased to 221 min. These findings have been confirmed in humans by Caldwell and colleagues (1988, I 989a) who compared the kinetics of pancuronium and pipecuronium in subjects with normal renal function and also studied the kinetics of pipecuronium in patients with compromised renal function (table II). They observed in those with normal renal function that t./" mean residence time, and the time taken to 2S% recovery were similar after equipotent doses of pipecuronium and pancuronium (0.07 and 0.Ql mg/kg, respectively). The steady-state volume ofdistribution was larger with pipecuronium (0.309 vs 0.199 L/kg), but so was its plasma clearance (0.14 vs 0.09 L/kg/h). There was hence no great difference in the t./, (137 vs lIS min) or

Newer Neuromuscular Blockers

187

the meal). residence times (140 vs 134 min) of the two drugs. The volume of distribution of pipecuronium was significantly increased and the plasma clearance significantly decreased in patitmts with renal failure (Caldwell et al. 1989a). The t'l2 was 137 min in patients with normal renal function compared with 263 min in patients with end-stage renal failure. It would thus appear that renal dysfunction exerts a marked influence on the pharmacokinetics of pipecuronium in humans. The time to 25% reco\'ery of twitch tension was, however, similar in patients with and without adequate renal function (98 and 103 min respectively), but patients with renal dysfunction showed large interpatient variability. The authors suggested that pipecuronium may thus be less suitable for use in patients with renal failure. Recently, the liver has been shown to be important for elimination of pipecuronium in the pig, where a reduction of 80% was found in the dosage requirements after clamping the hepatic vessels in contrast to a reduction of 25% after clamping the renal pedicles (pittet et al. 1990b). Although studies such as this are not yet available in humans, it appears that a reduction in pipecuronium dosage is indicated in patients with marked liver disease. Preliminary data suggest that pharmacokinetic parameters are unchanged in the elderly (Matteo et al. 1991).

1.4 Effect of Age Age-related changes in both potency and the duration of action are observed following administration of pipecuronium. Pittet et al. (1989) observed an almost 33% increase in the ED95 using electromyography and TOF stimulation in children aged 1.7 to 11.5 years in comparison with adults during anaesthesia with nitrous oxide, oxygen and fentanyl (79.3 vs 59.4 ~g/kg) . Halothane did not appear to influence the ED95. The same workers in a subsequent study observed that young infants were more sensitive to pipecuronium; the ED95 was 46.5 ~g/kg in infants up to 3 months of age, 48.7 ~g/kg in 3- to 12-month-old infants, and 70.5 ~g/ kg in 2- to 9-year-oldchildren (pittet et al. I 990a). During halothane anaesthesia the ED95 values were reported to ,be 33, 38, 47 and 49 ~g/kg at 3 to 6 months, 6 to 12 months, 1 to 3 years and 3 to 6 years of age, respectively (Sarnet et al. 1990). The duration of clinical relaxation (25% recovery) is shorter in both infants and children by about 25%. Older children and adults show no significant differences in the neuromuscular effects of pipecuronium (Hollinger et al. 1990; Pittet et al. 1990a). TheED95 in 26 elderly patients aged 66 to 79 years has been reported to be 35 ~g/kg using mechanomyography (Azad et al. 1989). These authors also showed that antagonism of pipecuronium

Table II. Comparative pharmacokinetic parameters (means ± SD) for pancuronium and pipecuronium (from Caldwell et al. 1988. 1989a)

Parameter

Pancuronium

Pipecuronium renal failureb,c

normal Vdss (L/kg) CL (L/kg/h) tV2~ (min) MRT (min)

0.2 0.09 115 134

± ± ± ±

0.05 a 0.02 a 40 26

0.31 0.14 137 140

± ± ± ±

O.la 0.04 a 68 63

0.44± 0.1 ± 263 ± 329 ±

0.16 0.04 168 198

Vdss and CL significantly different (p < 0,005 and p < 0.0005. respectively) between pancuronium and pipecuronium in patients with normal renal function . b All parameters significantly different between patients with normal and impaired renal function (p < 0.05). c Patients with renal failure undergoing cadaveric transplantation. Abbreviations: Vd ss = volume of distribution at steady-state; CL = total plasma clearance; tV2~ = elimination half-life; MRT = mean residence time . a

Drugs 44 (2) 1992

188

neuromuscular block was easily achieved, provided the spontaneous recovery was greater than 13%. 1.5 Interactions Administration of suxamethonium prior to pipecuronium significantly reduced the mean time taken for onset of maximum block from 2.8 to 1.6 min when pipecuronium was given in a dose of 80 /-tg/kg following 75% recovery from 1.0 mg/kg of suxamethonium (Dubois et al. 1991). There was however no significant increase in the duration of clinical relaxation (107 min without vs 81 min with prior suxamethonium). However, I patient in the latter group exhibited prolonged blockade requiring postoperative ventilation for I hour. Among the volatile agents, halothane has been shown not to prolong the duration of action of pipecuronium significantly; however isoflurane increased the duration of clinical relaxation from 29 to 50 min in one study following pipecuronium 50 /-tg/kg (Wierda et al. 1989). Administration of cephalosporin antibiotics or metronidazole has no effect on the duration of action of pipecuronium, but the effect may be prolonged by the concurrent administration of the aminoglycoside antibiotic netilmicin, clindamycin and, to a smaller extent, colistin (de Gouw et al. 1991; Stanley et al. 1990). Patients receiving chronic carbamazepine therapy show a reduced duration of action with pipecuronium (Modica et al. 1991). Acute respiratory and metabolic acidosis, and metabolic alkalosis increased the intensity of steadystate pipecuronium block by 11, 11 and 21 %, respectively, in the cat whereas respiratory alkalosis reduced it by 10% (Biro 1988). The duration of neuromuscular block was increased by 40% during metabolic alkalosis and reduced by 50% during acidosis. However, neither influenced the antagonism of pipecuronium block by neostigmine. The clinical significance of these data is not clear. 1.6 Clinical Use Pipecuronium thus appears to be an agent which resembles pancuronium in its neuromuscular profile. It posesses a relatively slow onset of action and

duration of clinical relaxation of about 45 min to 1 hour following administration of 45 to 50 /-tg/kg. The main advantage of using this drug appears to be its cardiovascular stability.

2. Doxacurium Chloride Doxacurium is a bisquaternary benzylisoquinolinium compound (fig. 1) which has been undergoing clinical trials in the US for sometime and has recently been approved for use there. The agent has recently been reviewed (Faulds & Clissold 1991). 2.1 Neuromuscular Effects Doxacurium is the most potent neuromuscular blocking agent currently available, with an estimated ED95 of 25 to 30 /-tg/kg (Basta et al. 1988; Katz et al. .1989; Murray et al. 1988), compared to approximately 60 /-tg/kg for pancuronium, 500 /-tg/ kg for tubocurarine, 40 /-tg/kg for vecuronium, 225 /-tg/kg for atracurium and 45 /-tg/kg for pipecuronmm. Doxacurium is a drug with a slow onset and a long duration of action (table III) [Scott & Norman 1989]. A dose of 23 /-tg/kg was reported to produce maximum block in a mean of 10.3 min with a duration of clinical relaxation of 57.1 min, while a 40 /-tg/kg dose achieved maximum block in 7.6 min with a duration of clinical relaxation of 77.4 min (Murray et al. 1988). Doses of 40 to 60 /-tg/kg produced complete block within about 4.5 min and a duration of clinical relaxation of about 75 to 100 min (Basta et al. 1988; Murray et al. 1988; Scott & Norman 1989). A dose of 80 /-tg/kg has been shown to produce complete block in 3.5 min, and a duration of clinical relaxation of over 2.5 hours (Lennon et al. 1989). Complete spontaneous recovery to 95% of control values occurred after 74 to 204 min with doses of doxacurium ranging from 23 to 50 '/-tg/kg; Murray et al. (1988) observed the time to 95% recovery following 40 /-tg/kg to be over 2 hours. In view of the wide individual variations in respoq,se to doxacurium, it is essential that the effect is carefully monitored.

Newer Neuromuscular Blockers

189

Table III. Neuromuscular effects of doxacurium

Reference

Lennon et al. (1989) Murray et al. (1988)

Scott & Norman (1989)

Anaesthesia

Enflurane a Enfluranea Narcotic Narcotic

Dosage (I'g/kg)

50 80 40 50

Maximum block (%)

95.7 97.7 99.1 100 100

Narcotic

60

Halothane a Halothane a

37.5

83.6

62.5

97.6

a

Administered after occurrence of maximum block.

b

Time to 90% block only.

The cumulative potential of doxacurium is difficult to define as few patients require repeated administration of a drug with a long duration of action. Although repeat administration of up to 3 additional doses of doxacurium did not result in increasing duration of action, 5 to 25% recovery time increased with increasing doses (Basta et al. 1988; Murray et al. 1988). While intubating conditions 3 to 4 min after 60 ~g/kg of doxacurium were described as generally good, they were not ideal (Scott & Norman 1989). Others have found the conditions for tracheal intubation to be good at 5 min following a dose of 50 ~g/kg, or 4 mIn after a larger dose of 80 pg/kg (Lennon et al. 1989). The antagonism of doxacurium-induced neuromuscular blockade by anticholinesterases has been reported to be satisfactory, provided adequate and considerable spontaneous recovery perhaps in excess of 25% of control has taken place. With lower levels of spontaneous recovery antagonism takes considerably longer (Basta et al. 1988). Adequate antagonism with neostigmine required 45 min if it was attempted at 99% block, but only 4 to 5 min if the spontaneous recovery was greater than 25% (Murray et al. 1988). Lennon et al. (1989) observed that while the first twitch in the TOF attained a value equivalent to 95% of baseline within 5 to 10 min of administration of antagonists at 25% recovery, the TOF ratio lagged, recovering to a mean

Time to maximum block (min)

Duration of clinical relaxation (min)

5.4 b 3.5 b

84.7 164.4

7.6 4.5

124.8

4.4

122.8

77.4

10.5 9.85

101.7

of only 0.6 at 20 min. This was irrespective of whether neostigmine 45 ~g/kg or 60 ~g/kg oredrophoniuml mg/kg were administered for antagonism of neuromuscular block. 2.2 Cardiovascular Effects Preliminary studies assessing neuromuscular blockade suggested that there were no significant cardiovascular effects observed with the administration of doxacurium although a gradual onset of bradycardia Was observed in 12 of 27 patients in one study (Scott & Norman 1989). More detailed haemodynamic studies have, however, been carried out recently (Emmott et al. 1990; Reich et al. 1989; Stoops et al. 1988). Stoops et al. (1988) administered doxacurium in doses of 25, 50 or 80 ~g/ kg to patients undergoing coronary artery bypass surgery, and 50 or 80 I-'g/kg to patients undergoing valvular surgery during sufentanil anaesthesia. Except for a decrease in heart rate of I to 5 beats/ min in some groups and a statistically significant increase in the pulmonary artery. occlusion pressure in another, there were no changes of any clinical or statistical significance in any of the other measured or derived haemodynamic variables. In a comparative study of the cardiovascular effects of equipotent doses of doxacurium, pancuronium and vecuronium (0.037, 0.09 and 0.075mg/ kg, respectively) in 9 patients each anaesthetised

190

with thiopental and fentanyl, no significant changes were observed in mean arterial pressure, heart rate or cardiac index with doxacurium in contrast to a significant increase following pancuronium and a small but significant decrease following vecuronium in these parameters (Emmott et al.1990). Central venous, pulmonary arterial and pulmonary capillary wedge pressures decreased significantly in all groups by 10 to 20%. Doxacurium 0.075 mg/kg resulted in .a statistically significant decrease in mean heart rate, but the actual decrease was only 4 beats/min. There is no elevation of plasma histamine levels following administration of doxacurium in doses of up to 2.7 times the ED95 (Basta et al. 1988), although transient systemic arterial hypotension and cutaneous flushing has been reported (Reich 1989). 2.3 Pharmacokinetics The elimination t'/2 of doxacurium was reported to be 86 min, the rate of clearance 0.13 L/kg/h, and the steady-state volume of distribution 0.15 L/kg in adult subjects following a dose of 25 ~g/kg administered during isoflurane anaesthesia (Dresner et al. 1990). The same authors reported that the elderly displayed a significantly higher volume of distribution ' (0.22 L/kg) but no significant difference in the rate of clearance (0.15 L/kg/h) or elimination t'/2 (96 min). Renal elimination accounted for 31 % of the administered dose in the young and 24% in the elderly. The volume of distribution of doxacurium is slightly increased in patients with hepatic and renal failure, with significant decreases in plasma clearance (Cook et al. 1991). The mean residence time and the elimination t'/2 are also markedly increased in patients with renal disease (Cook et al. 1991). From these studies it appears that the duration of action of doxacurium would show only mild prolongation in patients with liver disease but would be quite markedly prolonged in patients with significant renal disease (table IV). These findings have been confirmed in patients with renal disease by Cashman et al. (1990), who reported a time of 120.8

Drugs 44 (2) 1992

min to 25% recovery of twitch height in patients with end-stage renal failure compared to 66.7 min in patients with normal renal function following administration of doxacurium 25 ~g/kg. 2.4 Effect of Age The maximal twitch depression following a dose of 25 ~g/kg of doxacurium during nitrous oxideoxygen-isoflurane anaesthesia has been reported to be similar in young adults and elderly patients (Dresner et al. 1990). However, the onset time for the occurrence of maximal block was significantly longer in the elderly (11.2 vs 7.7 min), may be because of a larger volume of distribution. Although the times to the start of recovery were similar in the young and the elderly (40.5 vs 44.8 min), the time to 25% recovery was prolonged in the elderly (67.5 vs 97.1 min). The ED95 of doxacurium in children was 27.3 ~g/kg using electromyography (Sarner et al. 1988), and 29.4 ~g/kg using mechanomyography (Goudsouzian et al. 1989b), marginally higher than in the adults. Recovery to 25% of control twitch height occurred in 27.8 min following 27 ~g/kg and in 50.6 min following 50 /-Lg/kg (Sarner. et al. 1988). This is considerably shorter than in adults under comparable anaesthesia and has been observed by others (Goudsouzian et al. 1989b; Katz et al. 1989). Antagonism of the residual block at this stage with neostigmine 60 ~g/kg was achieved readily. 2.5 Interactions Administration of doxacurium 23 ~g/kg at 95% . recovery from suxamethonium 1 mg/kg was found not to alter the degree of maximal block attained with doxacurium, but the time to onset of maximal block decreased from 10.3 to 7.6 min and the time to 95% recovery increased from 73.7 to 104.9 min (Forbeset al. 1987). A subsequent study however showed that prior administration of suxamethonium 1 mg/kg did not significantly affect either the degree or the duration of neuromuscular block when doxacurium 24 ~g/kg was administered at 95% recovery from suxamethonium, although the degree

191

Newer Neuromuscular Blockers

Table IV. Pharmacokinetic parameters (means ± SO) for doxacurium in patients with and without hepatic and renal failures (from Cook et al. 1991) Parameter

Normal hepatic and renal function

Vd ss L/kg) CL (L/kg/h) t'l2p (min) MRT(min)

0.22 0.16 99 95.2

± ± ± ±

0.11 0.09 b 54 57 b

Hepatic failure

0.29 0.14 115 129.4

± ± ± ±

0.06 0.02 31 30

R~nal

0.27 0.07 221 270

failure

± ± ± ±

0.130 0.04b 156 210 b

a b

Patients with hepatic and renal failure undergoing cadaveric liver and kidney transplantations. MRT and CL significantly different between patients with normal and impaired renal function. Abbreviations: see table II.

of block was lower if the same dose of doxacurium was administered at only 10% recovery from suxamethonium(90 vs 98 min) [Katz et al. 1988]. The time to 25% recovery was also reduced from 81 to 43 min but this was not considered to be a significant difference. The degree of block produced by doxacurium and the duration of action are prolonged in the presence of volatile anaesthetics, enflurane and isoflurane being more potent in this respect than halothane. The ED95 during nitrous oxide-oxygenisoflurane anaesthesia has been reported to be 16 JLg/kg in contrast to 24 JLg/kg when no volatile supplement is used (Katz et al. 1989). Phenytoin and carbamazepine both antagonise the neuromuscular blocking effects of doxacurium (Ornstein et al. 1988, 1989). 2.6 Clinical Use Doxacurium, like pipecuronium, would thus appear to be an agent which is similar to, or longeracting than, pancuronium but with a considerably slower onset of action, the main advantage being absence of cardiovascular side effects. It appears that doses useful for carrying out tracheal intubation would be too long-acting for surgery lasting less than 2 hours. Long surgical procedures requiring cardiovascular stability would be the main indication for doxacurium use. Both pipecuronium and doxacurium have prob-

ably little to offer over high dose vecuronium, and are likely to be expensive.

3. Mivacurium Chloride Mivacurium is a new nondepolarisingmuscle relaxant with a bisquaternary benzylisoquinolinium structure resembling atracurium and doxacurium (fig. 1). Following extensive clinical trials mostly in the US, the drug has now been licensed for use there. 3.1 Neuromuscular Effects Dose-response studies carried out by various workers have shown the potency of mivacurium in terms ofits' ED95 to be between 0~06 and 0.08 mg/ kg (Caldwell et al. 1989c; Choi et al. 1989; From et al. 1990; Pearson et al. 1990; Savarese et al. 1988; Weber et al. 1988). The time to onset of maximum block following mivacurium administration is dose-dependent, varying between just under 4 min following 0.1 mg/ kg and 2.3 min after 0.25 mg/kg (Savarese et al. 1988). Caldwell et al. (1989b) observed onset times of 2.4 to 2.7 min after administration of mivacurium 0.15 to 0.25 mg/kg, which are similar to that of atracurium 0.5 mg/kg and significantly longer than the 1.1 min taken for onset of maximum block following suxamethonium 1 mg/kg. The time to onset of maximum block with mivacurium does not approach that of suxamethonium until 3 to 4

Drugs 44 (2) 1992

192

times the ED95 doses are administered (table V). The duration of clinical relaxation (time to recovery of twitch height to 25% of control) is 15 to 20 min following doses of 0.1 to 0.2 mg/kg. This is approximately half to one-third of the duration of action after comparable doses of atracurium and vecuronium (Caldwell et al. 1989b). The recovery index (time for 25 to 75% recovery) is relatively rapid, ranging between 6 and 10 min. The duration of action is. dose-related, 95% recovery taking between 12.5 to 36.7 min as the dose of mivacurium is increased from 0.03 to 0.3 mg/ kg (Savarese et al. 1988). Caldwell et al. (1989b) similarly reported an increase in the time to 10% recovery from 15.6 to 18.0 to 20.6 min as the dose of mivacurium was increased from 0.15 to 0.2 to 0.25 mg/kg. Intubating conditions were described as good within 90 to 120 sec following mivacurium 0.25 mg/kg in one of the early studies (Savarese et al. 1986). Administration of the same total dose in divided doses did not make any significant difference. The conditions 2 min after administration of mivacurium 0.2 or 0.25 mg/kg were subsequently

observed to be excellent in 7 of 10 patients and good in the remaining 3 with either dose (Goldberg et al. 1989). These results were not significantly different from those achieved 1 min after suxamethonium 1 mg/kg, where conditions were judged 'excellent' in 8 of 9 patients. Similarly, intubating conditions were deemed to be excellent or good in 30 of 36 and in 34 of 36 patients 2 min after administration of mivacurium 0.15 and 0.25 mg/ kg, respectively (Shanks et al. 1989). However, conditions were poor or intubation impossible in 6 and 2 patients, respectively. Brandom et al. (1989) also reported similar intubating conditions following suxamethonium 1 mg/kg and mivacurium 0.25 mg/kg, although intubation in the mivacurium group was carried out 0.75 to 1.3 min later. Because mivacurium is metabolised by plasma cholinesterase, antagonism of residual neuromuscular block is seldom indicated (Savarese et al. 1988). However, it can be achieved easily by administration of neostigmine 45 to 60 ~g/kg (Goldberg et al. 1989; Savarese et al. 1988). Adequate recovery of neuromuscular . transmission (TOF ratio .~ 0.7) is quicker after administration

.Table V. Neuromuscular effects of mivacurium Reference

Anaesthesia

Dosage (mg/kg)

Maximum block (%)

Time to maximum block (min)

Duration of clinical· relaxation (min)

Caldwell et al. (1989b)

Narcotic Narcotic

0.20 0.25

100 100

2.4 2.7

21.3 24.1

From et al. (1990)

Narcotic Halothane

0.15 0.15

99.7 100

3.3 2.8

15.5 18.6

Savarese et al. (1988)

Narcotic Narcotic Narcotic Narcotic Narcotic

0.1 0.15 0.2 0.25 0.3

95.7 100 100 100 100

3.8 3.3 2.5 2.3 1.9

14.2 16.8 19.7 20.3 25.0

Shanks et al. (1989)

Narcotic Narcotic Enflurane Enflurane

0.15 0.25 0.15 0.25

Narcotic

0.15

Isoflurance Isoflurance

0.05 0.10

Weber et al. (1988)

14 23 14 21 93 97 95

3.8 4.5 4.4

15.9 13.0 15.0

Newer Neuromuscular Blockers

of neostigmine 0.04 mg/kg or edrophonium 0.75 mg/kg compared to when recovery is allowed to take place spontaneously from a residual twitch height of 10% or less after stopping mivacurium infusion (8 to II vs 17 min) [Shanks et al. 1989]. With a relatively rapid onset of effect similar to that of atracurium . and vecuronium, but with a duration which is much shorter than either of these, mivacurium is a suitable agent for use by a continuous infusion. In a comparative study of the use of infusions, Ali et al. (1988) observed that mivacurium 8.3~g/kg/min, atracurium 7.9 ~g/kg/min and vecuronium 1.2 ~g/kg/min were required to maintain a 95% twitch suppression. Shanks et al. (1989) found adosage of 6 to 6.5 ~g/kg/min was adequate for maintaining a 95% block during nitrous oxide-oxygen and narcotic anaesthesia but the dosage was lower (4 ~g/kg/min) during steadystate enflurane anaesthesia. The mean dosage requirement reported by Goldhill et al. (1991) was 6.6 ~g/kg/min during anaesthesia with enflurane but showed a nearly 5-fold interpatientvariability. Mivacurium dosages are also lower during isoflurane anaesthesia (Choi et al. 1989). Some investigators did not find any difference in the recovery index (25 to 75% recovery) achieved with infusions or single bolus doses ofmivacurium (Ali et al. 1988; Caldwell et al. 1989b; Choi et al. 1989; Savarese et al. 1988). However, Shanks et al. (1989) observed the recovery to be slower after infusions in comparison to bolus doses. The recovery times in any case are roughly half those of vecuronium and atracurium and any small prolongation of recovery with increasing the total dose of mivacurium in healthy patients is likely to be of minimal clinical significance. A convenient way is to commence the infusion following administration of a bolus dose. Mivacurium does not differ all that much from atracurium in this respect. A preliminary study has suggested that anephric patients may be more sensitive to the effects of mivacurium (Phillips & Hunter 1991). 3.2 Cardiovascular Effects Initial studies of heart rate during steady-state anaesthesia and in the absence of any surgical stimulation showed a change of less than 7% after

193

doses of 0.03 to 0.3 mg/kg of mivacurium (Savarese et al. 1989). Similar changes were observed in the mean arterial pressure with doses of mivacurium up to 0.15 mg/kg. However, patients administered doses higher than this demonstrated decreases in arterial pressure lasting a few minutes. This is due to histamine liberation as shown by the presence of facial erythema and the good correlation between the decrease in arterial pressure and increase in plasma histamine levels. Signs of histamine liberation are accentuated by rapid administration of larger doses of mivacurium. However, slow administration of moderate doses of mivacurium of up to 0.25 mg/kg are associated with relatively small changes in heart rate, arterial pressure and histamine levels. Savarese and colleagues (1989) showed that while 0.25 mg/kg of mivacurium administered over 10 to 15 seconds resulted in a 13% decrease in the mean ·arterial pressure, the same dose given over 30 and 60 sec resulted in a decrease in the mean arterial pressure of only 7.6 and 1.5%, respectively. Initial detailed cardiovascular studies carried out in patients undergoing coronary bypass grafting during oxygen-sufentanil anaesthesia showed, in general, no important or significant changes in the mean arterial pressure, coronary artery pressure, systolic or pulmonary vascular resistance or cardiac index (Stoops et al. 1989). Ho~ever, significant hypotension was observed in 2 patients after 0.2 and 0.25 mg/kg ofmivacurium, respectively. Other workers have also observed transient decreases in arterial pressure following administration of mivacurium, in doses greater than 0.15 to 0.2 mg/kg (Caldwell et al. 1989b; Choi et al. 1989; From et al. 1990). It appears that hypotension due to histamine liberation with doses which are only just larger than would be normally used is a disadvantage of an otherwise useful drug from a neuromuscular blocking point of view. Although muscle relaxants in general cause less histamine liberation in children, cutaneous flushing and a decrease in arterial pressure (32% in I child) were observed in 3 of 18 children after administration of mivacurium 0.25 mg/kg (Samer

Drugs 44 (2) 1992

194

et al. 1989). The changes were however short-lived and resolved spontaneously within 2 min. 3.3 Pharmacokinetics Mivacurium undergoes hydrolysis in vitro by purified human plasma cholinesterase at approximately 88% of the rate of hydrolysis of suxamethonium (Cook et al. 1987). Plasma cholinesterase activity is an important factor in the pharmacodynamics of mivacurium. There is a negative correlation between plasma cholinesterase activity and the duration of action of mivacurium (Ostergaard et al. 1989). The duration of action of mivacurium is prolonged in patients with homozygous atypical and heterozygous plasma cholinesterase genes (Ostergaard et al. 1989, 1991). The elimination t'/2 of mivacurium has been reported to be 16.9 min, with a clearance rate of 3.3 L/kg/h (deBros et al. 1987). 3.4 Effect of Age Dose-response studies in children indicate some resistance to the effects of mivacurium in those aged 2 to 12 years, with an estimated ED95 of 0.11 mg/ kg under balanced anaesthesia and 0.095 mg/kg under halothane anaesthesia (Goudsouzian et al. 1989a; Sarner et al. 1989). The duration of action is also shorter in this group, 25% recovery after a dose of 0.2 mgjkg occurring within 11 min and 95% recovery after 18 min. The dose requirements of mivacurium for steady-state relaxation in children is higher than in adults, whether calculated on the basis of bodyweight at 13 ~g/kg/min or on the basis of body surface area at 375 ~g/m2/min(Alifimoff & Goudsouzian 1989; Brandom et al. 1990). The requirements are slightly lower during anaesthesia with volatile agents. A limited study in 9 elderly patients showed no significant differences either in the neuromuscular effects or in pharmacokinetic parameters when compared to adult patients (Basta et al. 1989). However more data need to be available to confirm these findings.

3.5 Interactions The apparent potency of mivacurium is increased and its ED95 significantly reduced when volatile agents such as isoflurane and enflurane are used concurrently (Caldwell et al. 1989c; Choi et al. 1989; Weber et al. 1988). The potency however did not show any significant difference in the presence of approximately 1 MAC (minimal alveolar concentration) of halothane (From etal. 1990). The duration of action of single bolus doses was not prolonged by concomitant administration of enflurane, although the dosage requirements were lower when the drug was administered by a continuousinfusion (Shanks et al. 1989). 3.6 Clinical Use It appears that mivacurium is a muscle relaxant which has a shorter duration of action and a more rapid recovery than atracurium and vecuronium even after continuous infusions, but is similar to them in the speed of its action. Good to excellent intubating conditions prevail about 2 min after a dose 9( 0.1 ;5 to 0.2 mg/kg. Higher doses such as 0.25 mg/kg may act more rapidly but may be associated with some histamine liberation unless administered ,over a period ,of 1 min. Currently it would . appear to be an agent suitable for use by continuous infusion or where .antagonism of neuromuscular block would be considered undesirable. Tht; agent may ·be useful in the Intdhsive Care Unit once it is established that the metabolites have no significant effects.

4. Org9426 (Rocuronium) Following investigation of several steroid compounds, Bowman and colleagues (1988) suggested that de-acetoxy analogues of pancurbnium and vecuronium may provide agents with a more rapid onset of neuromuscular block. This led to .the investigation in animals of three ne~ steroid compounds, Org 9616, Org 7617 and Org 9426. Although both Org 9616 and Org 7617 produced neuromuscular blockade of a rapid onset and short

Newer Neuromuscular Blockers

duration in anaesthetised cats and pigs, both also caused a decrease in arterial pressure (Muir et al. 1989b). Org 9616 was in addition associated with significant tachycardia. Studies have thus centred on Org 9426 (fig. I), and the agent is now under extensive investigation in humans. 4.1 Neuromuscular Effects Studies in isolated neuromuscular preparations and in anaesthetised cats and pigs have shown that Org 9426 is approximately 20% as potent as vecuronium and exhibits a typical nondepolarising neuromuscular block (Muir et al. 1989a). Its onset of action is twice as rapid as that of vecuronium in the cat (Muir et al. 1989a). The duration of action is however similar to that of vecuronium in cats, pigs and dogs (Cason et al. 1990; Muir et al. 1989a). Studies with Org 9426 in humans have suggested an ED95 of approximately 250 to 305 !!g/kg (Cooper et al. 1992; Foldes et al. 1991; Nagashima et al. 1989; Wierda et al. 1990b). Cooper et al. (1992) also observed that the ED95 was significantly lower with a TOF mode of stimulation in comparison to single twitch at 0.1 Hz, The onset of action is relatively rapid with this relaxant, although smaller doses may show an initial rapid effect followed by a slower phase (Quill et al. 1991). These authors noted that while the time to 80% block after a dose of 240 !!g/kg was 1.9 min, the time to attain a maximum block of 90% was 4.6 min. Doses of 570 to 850 !!g/kg are associated with onset of maximal block and good to excellent intubating conditions in about 90 to 110 sec, and a duration of clinical relaxation of between 27 and 45 min (Foldes et al. 1991; Lapeyre et al. 1990; Mirakhur et al. 1992). A dose of I mg/kg resulted in maximum block in 1.7 min, a clinical relaxation lasting 53 min and a recovery index of 20 min during halothane anaesthesia (Wierda et al. 1991). Use of the 'priming' or the divided dose technique did not confer any advantage in terms of the onset of action of Org 9426 (Foldes et al. 1991). No significant accumulation has been observed following up to 7 repeat doses of Org 9426 75, 150

195

or 225 !!g/kg (Khuenl-Brady et al. 1991). The dosage for infusion is between 5.1 and 8 !!g/kg/min during enflurane and isoflurane anaesthesia and 10.2 to 12.5 !!g/kg/min during balanced anaesthesia (Shanks et al. 1991). More data, however, are needed regarding drug accumulation and about administration by continuous infusion. Intubating conditjons at the vocal cords were considered to be good to excellent 60 sec after administration of Org 9426 500 !!g/kg, although diaphragmatic coughing was sometimes observed (Wierda et al. 1990b). In another study, the intubating conditions after 0.6 mg/kg were reported to be excellent or good in 19 of 20 patients at 60 sec and in all 20 patients at 90 sec (Mirakhur et al. 1992). Vandenbrom et al. (1991) also noted that the intubation conditions after Org 9426 0.6 mg/ kg were similar to suxamethonium 1.5 mg/kg (pretreated with gallamine) at 60 sec. The agent has been shown to be easily antagonised by edrophonium (Foldes et al. 1991). Detailed studies of antagonism are lacking at this stage, although no particular difficulties have been reported so far. 4.2 Cardiovascular Effects Vagal and ganglion-blocking effects have been observed in cats and pigs after Org 9426 administration only at very high doses (Muir et al. 1989b). Studies in dogs further confirmed it to be free of any significant cardiovascular effects up to 3 times the ED95 dose (Cason et al. 1990). Doses of 5 times the ED95 however increased the heart rate significantly by about 13%. Routine cardiovascular measurements carried out during the course of neuromuscular blocking studies in humans have suggested no significant cardiovascular effects with dose ranges of 0.5 to 0.6 mg/kg. The agent has also been observed to be free of cardiovascular effects in a limited number of patients when used in larger doses (Booij & Knape 1991), although another recent study reported a significant dose-dependent effect on heart rate with 2.5 times the ED95 dose (Mellinghoff et al. 1991). However, this study did not specify the type of

196

change in heart rate, nor did it give either the baseline heart rate or the extent of change. Detailed cardiovascular studies in humans are thus still awaited. No significant histamine release was observed with doses of up to t..2 mg/kg (4 x ED95) of Org 9426 (Davis et al. 1991). 4.3 Pharmacokinetics

Pharmacokinetic studies carried out in the cat have shown that the bulk of the drug is excreted into the bile, with less than 10% excreted in the urine (Khuenl-Brady et al. 1990). Plasma clearance of Org 9426 is lower in cats after ligation of their renal pedicles. The amount of drug that can be recovered from the liver in cats increases when the renal pedicles are ligated. The duration of the neuromuscular blockade of Org 9426 was, however, not altered in the presence of ligated renal pedicles in the cat. Initial pharmacokinetic studies in humans revealed a steady-state .volume of distribution of 0.28 L/kg, a rate of clearance of 0.17 L/kg/h and an elimination tlh of 203 min following administration of Org 9426 0.6 mg/kg administered during isoflurane anaesthesia (Szenohradszky et al. 1991), and 0.27 L/kg, 0.24 L/kg/h and 131 min, respectively, where 1 mg/kg of Org 9426 was administered during halothane anaesthesia to normal patients (Wierda et al. 1991). These parameters and the onset and duration of clinical relaxation of Org 9426 were not significantly different in patients with end-stage renal failure (Szenohradszky et al. 1991). 33% of the unchanged drug was recovered in the urine after 24 hours (Wierda et al. 1991). The elimination tIll and the volume .of distribution of Org 9426 following a dose of 0.6 mg/kg were significantly increased in patients with marked hepatic dysfunction in comparison to those with normal hepatic function (173 vs 79 min; 0.32 vs 0.17 L/kg) [Magorian et al. 1991]. The duration of clinical relaxation ·was more variable . in patients with liver disease and on average increased by about 140% (114 vs 47 min).

Drugs 44 (2) 1992

4.4 Effect of Age

The onset of action was slower in the elderly (236 vs 181 sec) in a study containing 17 young and 6 elderly subjects after administration of a total dose of 0.3 mg/kg of Org 9426 (Fiset et al. 1990). The clinical duration was also prolonged in this age group (16 vs 9.5 min). Another study using Org 9426 0.6 mg/kg showed that the duration of clinical relaxation (43 vs 26 min) as well as the recovery index (21 vs 13 min) were both significantly longer in older compared with younger patients (Matteo et aL 1991). This was associated with a lower rate of clearance (0.2 vs 0.35 L/kg/h) and a prolonged elimination tIll (137 vs 56 min) in the elderly. The ED95 of Org 9426 is higher in children, at 0.403 mg/kg (Bikhazi et al. 1991). FoiIowing a dose of 0.8 mg/kg, the time to development of maximal block (28.2 sec), duration of clinical relaxation (32.3 min), recovery index (8.6 min) and time to 90% recovery (46.9 min) were all shoI1er than with comparable doses in the adults (O'KeHy et al. 1991; Wierda et al. 1991). 4,5 Interactions

Like other neuromuscular blocking agents, the effects.ofOrg 9426 are potentiated by volatile agents such asenflurane resulting in ED95 1values of 214 and 195 ~g/kg, respectively, with 1 and 2% enflurane (Bartkowski et al. 1990). Halothane in low concentrations has no significant effect (Tullock et al. 1990). 4.6 Clinical Use

Org 9426 has a duration of action which is similar to that of vecuronium. However, it has the advantage of a more rapid onset of blpck and being stable in solution which obviates t~e necessity of mixing the drug prior to administration. Its use is limited to clinical trials at this stage~ Our own experience has confirmed a relatively rapid onset of complete block about 90 sec after a dose of 0.6 mg/ kg during narcotic anaesthesia with ia duration of clinical relaxation of about 30 min. If detailed

Newer Neuromuscular Blockers

studies in humans confirm a lack of cardiovascular side effects, it is likely that Org 9426 will replace vecuronium in clinical use and appears likely to be suitable for facilitating rapid tracheal intubation.

5. Conclusion Pipecuronium and doxacurium are relatively slow- and long-acting drugs. Their main advantage is a lack of significant cardiovascular effects. Their application may be mainly in prolonged surgery and in cardiothoracic surgery. Mivacurium and Org 9426 (rocuronium) are 2 agents with different profiles of action, unlike atracurium and vecuronium which were similar in many ways. Mivacurium is a drug with an onset of action similar to that of vecuronium and atracurium, but with an approximately 50% shorter duration of action, and a rapid rate of recovery. It will have to be used by infusion except in very short surgical procedures. Org 9426 is a drug with a duration of action similar to that of vecuronium and atracurium, but with an approximately 3-fold more rapid onset. It could be used in place of these drugs and as part of the rapid sequence induction.

References Abdulatif M, Naguib M. Neostigmine and edrophonium for re. versal of pipecuronium neuromuscular blockade. Canadian Journal of Anaesthesia 38: 159-163, 1991 Ali HH, Savarese JJ, Embree BD, Basta SJ, Stout RG, et aI. Clinical pharmacologyofmivacurium chloride (BW B1090U) infusion: comparison with vecuronium and atracurium. British lournal of Anaesthesia 61 : 541 -546, 1988 Alifimoff AK, Goudsouzian NG. Continuous infusion of mivacurium in children. British Journal of Anaesthesia 63: 520-524, 1989 Azad SS, Larijani GE, Goldberg ME, Beach CA, Marr AT, et al.. A dose-response evaluation of pipecuronium bromide inelderly patients under balanced anaesthesia. Journal of Clinical Pharmacology 29: 657-659, 1989 Bartkowski RR, Witkowski T A, Azad SS, Epstein RH, Marr A et al. Dose-response and recovery of Org 9426 under enflurane anesthesia. Anesthesiology 73: A902, 1990 Basta SJ, Dresner DL, Shaff LP, Lai AA, Welch R. Neuromuscular effects and pharmacokinetics of mivacurium in elderly patients under isoflurane .anesthesia. Anesthesia Analgesia 68: S18, 1989 BaSta SJ,' Saverese JJ, Ali HH, Embree BB, Schwartz AF, et al.. Clinical pharmacology of doxacurium chloride, a new longacting nondepolarising muscle relaxant. Anesthesiology 69: 478486, 1988 Bikhazi GB, Marin F, Mouhanna J, Halliday NJ, Foldes FF. The

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dose response of Org 9426 in children anesthetized with halothane. Anesthesiology 75: A1067, 1991 Biro K. Effects of respiratory-and metabolic alkalosis and acidosis on pipecuronium neuromuscular block. European Journal of Pharmacology 154: 329-333, 1988 Booij LHDJ, Knape HDA. The neuromuscular blocking effect of Org 9426, a new intermediately acting nondepolarising muscle relaxant in man. Anaesthesia 46: 341-343, 1991 Boros M, Szenohradszky J, Marosi '0, Toth I. Comparative clinical study of pipecuronium ,bromide and pancuronium bromide. Arzneimittel Forschung 30: 389-393, 1980 Boros M, SzenohradszkyJ, Kertiesz A, Morosi G, Tutsek L. Clinical experiences with pipecuronium bromide. Acta Chirurgica Hungarica 24: 207-214, 1983 Bowman WC, Rodger IW, Houston J, Marshall RJ, McIndewai I. Structure-action relationship among some desacetoxy analogues of pancuroniumand vecuronium in the anaesthetised cat. Anesthesiology 69: 57-62, 1988 Brandom BW, Woelfel SK, Cook DR, Weber S, Powers OM, Weakly IN. Comparison of mivacurium and suxamethonium administered by bolus and infusion. British 10urnal of Anaesthesia 62: 488-493, 1989 Brandom BW, Sarner JB, Woelfel SK, Dong ML, Horn MC, et al. Mivacurium infusion requirements in pediatric surgical patients during nitrous oxide-halothane and during nitrous oxide-narcotic anesthesia. Anesthesia and Analgesia 71: 16-22, 1990 Caldwell JE, Castagnoli AP, Canfell DC, Filhey MR, Lynam DP, et al. Pipecuronium and pancuronium:' comparison of pharmacokinetics and duration of action. British Journal of Anaesthesia 61: 693-697, 1988 Caldwell JE, Canfell PC, Castagnoli KP, Lynam DP, Fahey MR, et al. The influence of renal failure on the pharmacokinetics and duration of pipecuronium bromide in patients anaesthetized with halothane and nitrous oxide. Anesthesiology 70: 712, 1989a Caldwell JE, Hieir T, Kitts IB, Lynam DP, Fahey MR, et al. Comparison of the neuromuscular block induced by mivacurium, suxamethonium or atrilcurium during nitrous oxide-fentanyl anaesthesia. British Journal of Anaesthesia 63: 393-399, 1989b Caldwell JE, Kitts JB, Heier T, Fahey MR, Lynam DP, et al. The dose-response relationship of mivacurium chloride in humans during nitrous oxide-fentanyl or nitrous oxide-enflurane anesthesia. Anesthesiology 70: 31-35, 1989c Cashman IN, Luke JJ; Jones RM. Neuromuscular block with doxacurium (BW A938U) in patients with normal or absent renal function, British Journal of Anaesthesia 64: 186-192, 1990 Cason B, Baker. DG, Hickey RF, Miller RD, Agoston S. Cardiovascular and neuromuscular effects of -three steroidal neuromuscular blocking drugs in dogs (ORG 9616, ORG 9426, ORG 9991). Anesthesia and Analgesia 70: 382-388, 1990 Choi WW, Mehta MP, Murray OJ, Sokoll MD, Forbes RB, et al. Neuromuscular and cardiovascular effects of mivacurium chloride in surgical patients receiving nitrous oxide-narcotic or nitrous oxide-isoflurane anaesthesia. Canadian Journal of Anaesthesia 36: 641-650, 1,989 Cook DR, Freeman lA, Lai AA, Robertson KA, Kang Y, et al. Pharmacokinetics and pharmacodynamics of doxacurium in normal patients and in those with hepatic or renal · failure. Anesthesia and Analgesia 72: 145"1'50, 1991 Cook DR, Stiller RL, Chakravorti S, Welch RM, Brandom BW. In vitro metabolism ofBW B1090U. Anesthesiology 67: A61O, 1987 Cooper AR, Mirakhur RK,Elliott P, McCarthy G. EstimatiOn of the potency of ORG 9426 using two different modes of nerve stimulation. Canadian Journal of Anaesthesia 39: 139-142, 1992 Davis GK, Szlam F, Lowdon JD, Levy JH. Evaluation of histamine release following Org' 9426 administration' using a new radioimmunoassay. Anesthe'siology 75: A818; 1991 deBros F, Basta SJ, Ali HH, Wargin W, Welch R. Pharmacokinetics and pharmacodynamics of BW B1090U in healthy sur-

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gical patients receiving N20j02 isoflurane anesthesia. Anesthesiology 67: A609, 1987 de Gouw N , Crul JF, Vandermeersch E, Mulier JP, Van Aken H. Interaction of antibio.tics on pipecuronium induced neuromuscular blockade. Anesthesiology 75: A776, 1991 Dresner DL, Basta SJ, Ali HH, Schwartz AF, Embree BB, et al. Pharmacokinetics and pharmacodynamics of doxacuriu,m in young and elderly patients during isoflurane anesthesia. Anesthesia and Analgesia 71: 498-502, 1990 Dubois R, Fleming NW, Lee E. Effects of succinylcholine on the pharmacodynamics ofpipecuronium and pancuronium. Anesthesia and Analgesia 72: 364-368, 1991 Emmott RS, Bracey BJ, Goldhill DR, Yate PM, Flynn PJ.,Cardiovascular effects of doxacurium, pancuronium and vecuronium in anaesthetised ,patients presenting for coronary artery bypass surgery. British Journal of Anaesthesia 65: 480-486, 1990 Faulds D, Clissold SF. Doxacurium. A review of its pharmacology and clinical potential in anaesthesia. Drugs 42: 673-689, 1991 Fiset P, Balendran P, Bevan DR. Onset, duration, and recovery from Org 9426 in the elderly. Anesthesiology 73: A881, 1990 Foldes FF, Nagashima H, Nguyen HD, DuncalfD, Goldiner BL. Neuromuscular and cardiovascular effects of pipecuronium. Canadian Journal of Anaesthesia 37: 549-555, 1990 Foldes FF, Nagashima H, Nguyen HD, Schiller WS, Mason MM, Ohta Y. The neuromuscular effects of ORG 9426 in patients receiving balanced anesthesia. Anesthesiology 75: 191-196, 1991 Forbes RB, Mehta MP, Murray DJ, Choi WW, Sokoll MD et al. Effect of succinylcholine on subsequent neuromuscular blockade with BW A938U. Anesthesiology 67: A363, 1987 From RP, Pearson KS, Choi WW, Abou-Donia M, Sokoll MD. Neuromuscular and cardiovascular effects of mivacurium chloride (BW B 1090U) during nitrous oxide-fentanyl-thiopentone and nitrous oxide-halothane anaesthesia. British Journal of Anaesthesia 64: 193-198, 1990 Goldberg ME, Larijani GE, Azad SS,SosisN, Seltzer JL, et al. Comparison of tracheal intubating conditions and neuromuscular blocking profiles after intubating doses of mivacurium chloride or succinylcholine in surgical outpatients. Anesthesia and Analgesia 69: 93-99, 1989 Goldhill DR, Whitehead JP, Emmott RS, GriffithAP, Bracey BJ, Flynn PJ. Neuromuscular and clinical effects of mivacurium chloride in healthy adult patients during nitrous oxide-enflurane anaesthesia. British Journal of Anaesthesia 67: 289-295, 1991 Goudsouzian NG, Alifimoff JK, Everly C, Smeets R, Griswold J, et al. Neuromuscular and cardiovascular effects of mivacurium in children. Anesthesiology 70:237-242, 1989a Goudsouzian NG, Alifimoff JK, LiuLM, Foster R, McNulty B, et al. Neuromuscular and cardiovascular effects of doxacurium in children anaesthetised with halothane. British Journal of Anaesthesia 62: 263-268, 1989b Griffith HR, Johnson GE. The use of curare in general anesthesia. Anesthesiology 3: 418-420, 1942 Hollinger I, Nagashima H,Nguyen HD, Bikhazi OB, Foldes FF. The cumulative dose-response of pipecuronium bromide in children. Anesthesia and Analgesia 70: S163, 1990 Katz JA, Fragen RJ, Shanks CA, Dunn K,'McNulty V, et al. The effects of succinylcholine ,on doxacurium-ihduced neuromuscular blockade. Anesthesiology 69: ,604-607, 1988 Katz JA, Fragen RJ, Shanks CA, Dunn K, McNulty V, et al. Dose-response relationships of doxac,\Irium chloride, in humans during anesthesia with nitrous oxi~e and fentanyl, enflurane, isoflurane or halothane. Anesthesiology 70: 432-436, 1989 Khuenl-Brady KS, Puhringer F, KollerJ, Mitters~hiffthaler G. Evaluation of the . cumulative properties ' of Org 9426. Anesthesiology 75: A1064, 1991 Khuenl-Brady KS,Sharma M, Chung K, Miller RD, Agoston S, et al. Pharmacokinetics and disposition of pipecuronium bromide in dogs, with and without ligated renal p~dicles. Anesthesiology 71: 919-922, 1989 Khuenl-Brady K, Castagnoli KP, Canfell PC, Caldwell JE, Agos-

Drugs 44 (2) 1992

ton S, et al. The neuromuscular blocking effects and pharmacokinetics of Org 9426 and Org9616 in the cat. Anesthesiology 72: 669-674, 1990 Khuenl-Brady KS, Mair P, Koller J. Antagonism ofvecuronium by one of its metabolites in vitro. Anesthesiology 75: A800, 1991 Lapeyre G, Dubois M,Lea D, Kataria B, Tran D. Effects of 3 intubating doses of Org 9426 in humans. Anesthesiology 73: A906, 1990 Larijani GE, Bartkowski RR, Azad SS, Seltzer JL, Weinberger MJ et al. Clinical pharmacology of pipecuronium bromide. Anesthesia and Analgesia 68: 734-739, 1989 Lennon RL, Hosking MP, Houck BC, Rose SH, Wedel DJ, et al. Doxacurium chloride for neuromuscular blockade before tracheal intubation and surgery during nitrous oxide-oxygen-narcotic-enflurane anesthesia. Anesthesia and Analgesia 68: 255260, 1989 Magorian T, Wood P, Caldwell JE, SzenohradszkyJ, Segredo V, et al. Pharmacokinetics, onset, and duration of action of rocuronium in humans: normal vs ' hepatic dysfunction. Anesthesiology 75: A1069, 1991 Matteo RS, Ornstein E, Schwartz AE, Stone JG, Ostapkovich N et al. Pharmacokinetics and pharmacodynamics of Org 9426 in elderly surgical patients. Anesthesiology 75: AI065, 1991 Matteo RS, Schwartz AE, Ornstein E, Jamdar S, Diaz J et iiI. Pharmacokinetics and pharmacodynamics of pipecuronium in elderly surgical patients. Anesthesia and Analgesia 72: S 172, 1991 Meistelman C, Plaud B, Lira E, Donati F. Effects of the concentration of isoflurane on the recovery of pipecuronium neuromuscular blockade following neostigmine administration. Anesthesiology 73: A886, J 990 Mellinghoff H, Diefenbach Ch, Buzello W. Neuromuscular and cardiovascular properties ofOrg 9426. Anesthesiology 75: A807, 1991 Mirakhur RK. Drug usage byanaesthetists. Anaesthesia 45: 500501,1990 Mirakhur R, Cooper R, McCarthy G, Elliott P. Comparison of the intubating conditions and some neuromuscular effects following administration of ORG 9426 and succinylcholine. Anesthesia and Analgesia 74: S21O, 1992 Modica P, Tempelhoff R, Jellish W, Williams EL. Accelerated recovery from pipecuronium in neurosurgical patients treated with chronic carbamazepine therapy. Anesthesiology 75: A187, 1991 Muir AW, Houston J; Green KL, Marshall RJ, Bowman WC, et al. Effects of a new neuromuscular blocking agent, ORG 9426, in anaesthetised cats and pigs and in isolated nerve-muscle preparations. British Journal of Anaesthesia 63.: 400-410, 1989a Muir AW, Houston J, Marshall RJ, Bowman WC, Marshall IG. A comparison of neuromuscular blocking arid autonomic effects of twonewshort,acting muscle relaxants with those of succinylcholil)e in the anaesthetized cat and pig. Anesthesiology 70: 533-540, 1989b , , , Murray DJ, Mehta MP, Choi W, Forbes RB, Sokoll MD, et al. The neuromuscular blocking and cardiovascular effects of doxacurium chloride in patients receiving nitrous oxide-narcotic anesthesill. Anesthesiology 69: 472-477, 1988 Nagashima H, Nguyen HD, Kinsey A, Rosa M, Hollinger I et al. The human dose response of Org 9426. Anesthesiology 71: A773,1989 O'Kelly B, Brossard J, Meistelman C, Ecoffey C. Neuromuscullir blockade following Org 9426 in chi.ldren during N20-halothane anesthesia. Anesthesiology 75: A787, 1991 Ornstein E, MatteO RS, Halevy JD, Young WL, Abou-Donia M. Accelerated recovery from doxacurium in carbamazepine treated Patients. Anesthesiology 71: A784, 1989 Ornstein E, Matteo RS, Weinstein JA, Halevy JD, Young WL. Accelerated recovery from doxacurium chloride induced neuromllscular blockade in patients receiving chronic phenytoin therapy. Anesthesiology 69: A488, 1988 Ostergaard D, knsen fS, Jensen E, Viby Mogensen J. Mivacurium induced ,neuromuscular blockade (NMB) in patients het-

Newer Neuromuscular Blockers

erozygous for the atypical gene for plasma cholinesterase. Anesthesiology 71 : A782, 1989 Ostergaard D, Jensen E, Jensen FS, Viby Mogensen J. The duration of action of mivacurium-induced neuromuscular block in patients homozygous for the atypical plasma cholinesterase gene. Anesthesiology 75: A774, 1991 Pearson KS, From RP, Choi WW, Abou-Donia M, Sokoll MD. Neuromuscular and cardiovascular effects of mivacurium chloride (BW B1090U) during nitrous oxide-narcotic, nitrous oxide-halothane and nitrous oxide-isoflurane anaesthesia in surgical patients. Middle East Journal of Anesthesiology 10: 469-478, 1990 Phillips BJ, Hunter JM. Use of mivacuriurn chloride by constant' infusion in the anephric patient. British Journal of Anaesthesia 67: 653P-654P, 1991 Pittet JF, Tassonyi I, Morel DR, Gemperle G, Richter M, et al. Pipecuronium-induced neuromuscular blockade during nitrous oxide-fentanyl-isoflurane and halothane anesthesia in adults and children. Anesthesiology 71 : 210-213, 1989 Pittet JF, Tassonyi E, Morel DR, Gemperle G, Rouge Je. Neuromuscular effect of pipecuronium bromide in infants and children during nitrous oxide-alfentanilanesthesia. Anesthesiology 72: 432-435, 1990a Pittet JF, Tassonyi E, Schopfer C, Morel DR, Leemann P et al. Dose requirements and plasma concentrations of pipecuronium during bilateral renal exclusion and orthoptic liver transplantation in pigs. British Journal of Anaesthesia 65: 779-785, 1990b Quill TJ, Begin M, Glass PSA, Ginsberg B, Gorback MS. Clinical responses to Org 9426 during isoflurane anesthesia. Anestl1esia ' and Analgesia 72: 203-206, 1991 Reich DL. Transient systemic arterial hypotension and cutaneous flushing in response to doxacurium chloride. Anesthesiology 71: 783-785, 1989 Reich DL, Constadt SN, Thys DM, Hillel Z, Raymond R, et al. Effects of doxacurium chloride on biventricular cardiac function in patients with cardiac disease. British Journal of Anaesthesia 63: 675-681 , 1989 Sarner JB, Brandom DW, Cook DR, Dong NL, Horn MC, et al. Clinical pharmacology of doxacurium chloride (BW A938U) in children. Anesthesia and Analgesia 67: 303-306, 1988 Sarner JB, Brandom DW, Dong ML, Pickle D, Cook DR, et al. Clinical pharmacology of pipecuronium in infants and children during halothane anesthesia. Anesthesia and Analgesia 71 : 362-366, 1990 Sarner JB, Brandom DW, Woelfel SK, Dong ML, Horn MC, et al. Clinical pharmacology of mivacurium chloride (BW B1090U) in children during nitrous oxide-halothane and .nitrous oxide-narcotic anesthesia. Anesthesia and Analgesia 68: 116-121 , 1989 Savarese JJ, Ali HH , Basta SJ, Embree PB, Schwartz A et al. Ninety and 120-second tracheal intubation with BW BI090U: Clinical conditions with and without priming after fentanylthiopental induction. Anesthesiology 65: A283, 1986 Savarese JJ, Ali HH, Basta SJ, Embree PB, Scott RP, et al. The clinical neuromuscular pharmacology of mivacurium chloride (BW B1090U) a short-acting nohdepolarising'ester neuromuscular blocking drug. Anesthesiology 68: 723-732; 1988 Savarese JJ, Ali HH, Basta SJ, Scott RP,Embree PB, et al. The cardiovascular effects of mivacurium chloride (BW B1090U) in patients receiving nitrous oxide~opiate-barbiturate anes1 . thesia. Anesthesiology 70: 386-394, 1989 Savarese JJ, Kitz RJ . Does clinical anaesthesia heed new neuromuscular blocking agents? Anes'thesiology 42; 236-239, 1975 Scot~ RP, ~orman 1. Doxacuriurn ~hl.oride, a pr~liminary clinical tnal. Bntlsh Journal of Anaesthesia 62,: 373-377, 1989 Shanks CA, Fragen RJ, Pemberton iD Katz JA Risner ME. Mivacurium-induced neuromuscular bl~ka4efojiowing single bolus doses and with continuous infusion during, either balanced or enflurane anesthesia. Anesthesidiogy7l: 362-366, 1989

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Shanks CA, Fragen RJ, Ling D, Pemberton D, Dunn K, Howard K. Infusion requirements of Org 9426 in patients receiving balanced, enflurane or isoflurane anesthesia. Anesthesiology 75: AI068, 1991 Stanley JC, Carson IW, Gibson FM, McMurray TJ, Elliott P, et al. Comparison of the haemodynamic effects of pipecuronium and pancuronium during fentanyl anaesthesia. Acta Anaesthesiologica Scandinavica 35: 262-266, 1991a Stanley JC, Mirakhur RK. Comparative potency ofpipecuronium bromide and pancuronium bromide. British Journal of Anaesthesia 63: 754-755, 1989 Stanley IC, Mirakhur RK, Bell PF, Sharpe TDE, Clarke RSJ. Neuromuscular effects Of pipecuroniufn bromide. European Journal of Anaesthesiology 8: 151-156, 1991 b Stanley JC, Mirakhur RK, Clarke RSJ. Study of pipecuroniumantibiotic interaction. Anesthesiology 73: A898 1990 Stoops CM, Curtis CA, Kovach DA, McCammo~ RL, Stoelting RK, et al. Hemodynamic effects of doxacurium chloride in patients receiving oxygen-sufentanil anesthesia for coronary artery bypass grafting or valve replacement. Anesthesiology 69: 365-370, 1988 . Stoops CM, Curtis CA, Kovach DA, McCammon RL, Stoelting RK, et al. Hemodynamic effects of mivacurium chloride administered to patients during oxygen-sufentanil anesthesia for coronary artery bypass grafting or valve replacement. Anesthesia and Analgesia 68: 333-339, 1989 Szenohradszky J, Segredo V, Caldwell JE, Sharma M, Gruenke LD et al. Pharmacokinetics, onset and duration of action of Org 9426: normalvs. absent renal function . Anesthesia and Analgesia 72: S290, 1991 Tassonyi E, Neidhard E, Pittet JF, Morel DR, Gemperle M. Cardiovascular effects of pipecuronium and pancuronium in patients undergoing coronary artery bypass:grafting. Anesthesiology 69: 793-796, 1988 Tullock WC, Wilks DH, Brandom BW, Diana P, Cook DR. Org 9426:Smgle-dose response, onset, and duration with halothane anesthesia. Anesthesiology 73: A877, 1990 Vandenbrom RHG, Wierda JMKH, Huizinga ACT; Hennis PJ. Intubation conditions and time-course of action of ORG 9426. Anesthesiology 75: A788, 1991 Weber S,. Brandom BW, Bowres DM, Sarner JB, Woelfel SK, et al. Mlvacurium chloride (BW BI090U)-induced neuromuscular blockade during nitrous oxide-isoflurane and nitrous oxide-narcoti~ anesthesia in adult surgical patients. Anesthesia , and Analgesia 67:495-499, 1988 Wierda JM, Cafliczek GF, Van den Brom RH,:Pinto I, KerstenKleef UW, et al. Pharmacokinetics and cardi()vascular dynamics of pipecuroniurn bromide during c;oron;try artery surgery. CanadIan Journal of Anaesthesia 37: 183-19'1, 1990a Wierda JM, De-Wit AP, Kuizenga K, Agoston S. Clinical observations of the neuromuscular blocking action of Org 9426, a new steroidal nondepolarising agent. British Journal of Anaesthesia 64: 521-523, 1990b Wi erda JMKH, Kleef UW, Lambalk LM, Kloppenburg WD, Agoston S. The pharmacodynamics and pharmacokinetics of Org 94.26, a new nondepolari~ing ~euromuscular blocking agent, m patIents anaesthetIzed wIth ' mtrous oxide, halothane. Canadian Journal of Anaesthesia 38: 430-435, 1991 Wierda JM, Richardson ,F}, Agpston S. Dose-response relation and tIme course of action ofpipecuronium bromide in humans anaesthetised with nitrous oxide and isoflurane halothane or droperidol and fentanyL Anesthesia and Analgesia 68: 208-213 1989 '

Correspondence and reprints: Dr Rajinder K. Mirakhur, Department of Anaesthetics, The Queen's University of Belfast, Whitla Medical Building, 97 Lisburn Road, Belfast BT9 7BL, Northern Ireland.

Newer neuromuscular blocking drugs. An overview of their clinical pharmacology and therapeutic use.

Four new nondepolarising muscle relaxants, pipecuronium bromide, doxacurium chloride, mivacurium chloride and Org 9426 (rocuronium) offer alternatives...
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