Background

A new aminosteroidal neuromu scular blocking agent, rocuronium bromide (Figure 1), has recently been introduced into clinical practice. Its main advantage over other currently used drugs of this kind is its fast onset of action, which could render rocuronium the muscle relaxant of choice for rapid facilitation of tracheal intubation. A further advantage of the new compound over vecuronium bromide is the less extensive formation of breakdown products, reducing the contribution of active metabolites to the neuromuscular blocking effects of the parent compound.

Mechanism of action

Rocuronium bromide acts by competing for cholinergic receptors at the motor end-plate. This action is antagonized by acetylcholinesterase inhibitors, such as neostigmine and edrophonium. Rocuronium bromide acts by competitively binding to nicotinic cholinergic receptors. The binding of vecuronium decreases the opportunity for acetylcholine to bind to the nicotinic receptor at the postjunctional membrane of the myoneural junction. As a result, depolarization is prevented, calcium ions are not released and muscle contraction does not occur. Evidence also suggests that nondepolarizing agents can affect ACh release. It has been hypothesized that nondepolarzing agents bind to postjunctional ("curare") receptors and may therefore interfere with the sodium and potassium flux, which is responsible for depolarization and repolarization of the membranes involved in muscle contraction.

Pharmacology and Adverse Effects

Rocuronium bromide is the 2-morpholino-3- hydroxy-16-N-allyl-pyrrolidino analogue of vecuronium. In contrast with the latter it is stable in aqueous solution and 6 times less potent, with a dose to produce 95% depression of troitch tension (muscle force) [ED₉₅] of approximately 0.23 to 0.36 mg/kg. 0.6 mg/kg, A dose that is also used in most pharmacokinetic studies, is usually administered to facilitate tracheal intubation. The onset time (time from injection to development of maximum blockade) ranges between 40 and 180 seconds. Good to excellent intubating conditions, however, are almost always present 60 seconds after the injection of rocuronium because of the fast development of neuromuscular blockade at the laryngeal muscles. The clinical duration of action (time from injection to recovery of 25% of initial twitch height) ranges from 15 to 40 minutes under intravenous anaesthesia, and is slightly longer under inhalational agents.[1-2]

Several clinical studies have demonstrated the absence of cardiovascular adverse effects and the lack of histamine-releasing potential with rocuronium bromide. In children and after higher doses, rocuronium bromide occasionally increases the heart rate by 10 to l5 %, due to slight vagolytic effects.[3] No cases of significant accidental or intentional overdose have been reported. Overdosage with neuromuscular blocking agents may result in neuromuscular block beyond the time needed for surgery and anesthesia.

Elimination Pathways and Metabolism

Of the 3 putative metabolites of rocuronium  bromide, measurable amounts of only the 17-desacetyl derivative have so far been detected in plasma in only 1 study. Due to the very low potency of this metabolite, these concentrations (mean 178 ug/L) of the metabolite are very unlikely to contribute to the neuromuscular blocking effects of the parent compound. As long as no other study reports degradation products, rocuronium should be viewed as a muscle relaxant that undergoes no detectable metabolism.

This may represent a further advantage over vecuronium, whose metabolite s exceed those of rocuronium  bromide both in amount and activity. High plasma concentrations of 3-desacetyl-vecuronium have been implicated in complications such as prolonged paralysis in critically ill patients. After injection of rocuronium  bromide 0.6 mg/kg, 12 to 22 % of the administered dose can be recovered unchanged in the urine in the first 6 to 8 hours after injection, with less than 1% of additional drug being excreted in the following 14 to 16 hours. These values are similar to tho se of vecuronium. After administration of rocuronium  bromide 1.0 mg /kg, Wierda et aL[4] recovered 33% of the do se in the urine. The higher initial plasma concentrations may be the rea son for the greater amount of drug excreted after the larger dose. None of the studies in healthy adult patients analysing the renal excretion of rocuronium detected metabolites in the urine.

Biliary excretion of rocuronium bromide has not been studied in humans so far. In cats, over 50% of an administered dose was eliminated via the bile and another 20 to 30% stored in the liver 6 hours after administration, with no metabolites being detected.[1]

Pharmacodynamics

An inverse relationship between onset and potency has been demonstrated for various aminosteroidal compounds.Therefore, one of the underlying reasons for the fast onset of action of rocuronium bromide is its low potency and relatively high lipophilicity when compared with other muscle relaxants. In addition, onset at the laryngeal muscles, where relaxation is essential for development of good intubating conditions, is faster than onset at the commonly monitored adductor pollicis muscle.This is explained by the significantly shorter half-life of transport between plasma and biophase (effect compartment) at the laryngeal muscles.These muscles also need a higher concentration [mean concentration producing 50% effect (ECso) of 1424 vs 823 ug/L] in the effect compartment for the same degree of neuromuscular blockade, which renders them less sensitive to rocuronium bromide (and other neuromuscular blocking agents) than the adductor pollicis muscle. The context-sensitive half-time approximated 12 to 18 minutes, which equalled the calculated time between stopping infusion and recovery to 75% of control twitch height. A comparison with other aminosteroidal muscle relaxants can be found in table I.[1]

Conclusions

Rocuronium bromide is a new nondepolarising neuromuscular blocking agent with a similar pharmacokinetic behaviour to vecuronium bromide, a structural and pharmacological relative. In contrast with vecuronium, rocuronium is metabolised to a lesser extent and breakdown products therefore probably will not contribute to its neuromuscular blocking effect, representing a possible advantage over vecuronium.

References

[1] Khuenl-Brady KS, Sparr H. Clinical pharmacokinetics of rocuronium bromide. Clin Pharmacokinet. 1996;31(3):174-183

[2] Lambalk LM. DeWit APM. Wierda JMKH. et al. Dose-response relationship and time course of action of Org 9426. Anaesthesia 1991; 46: 907- 911

[3] McCoy P,Maddineni YR. Elliott P. et al. Haemodynamic effects of rocuronium during fentanyl anaesthesia: comparison with vecuronium. Can J Anaesth 1993; 40: 703-708

[4] Wierda JMKH. Kleef UW. Lambalk LM, et al. The pharmacodynami cs and pharmacokinetics of Org 9426. a new nondepolarizing neuromu scular blocking agent, in patients anaesthetized with nitrous oxide. halothane and fentanyl. Can J Anaesth 1991; 38: 430-435