rapacuronium and Liver-Cirrhosis

Rapacuronium is an aminosteroidal nondepolarising neuromuscular blocking agent (NMBA). Its neuromuscular blocking effects have a different time course to those of most currently available agents. It also has lower potency than many of the other NMBAs. In doses consistent with short to medium duration of action, rapacuronium has rapid and complete onset. In some doses it gives tracheal intubating conditions that compare favourably with those produced by suxamethonium (succinylcholine) during rapid sequence induction of anaesthesia. Tracheal intubating conditions improve as dose increases, but adverse effects (including potentially severe bronchospasm) become more prominent. Rapacuronium has an active metabolite that is at least as potent as the parent compound and is eliminated much less efficiently. Consequently, the time course of action of rapacuronium is prolonged after multiple doses or an infusion. Its potency is similar across age ranges and its time course after single doses is little altered in patients with hepatic or renal insufficiency. At least in part because of its active metabolite, rapacuronium is highly cumulative in renal failure. In keeping with its rapid onset and short to medium duration of action, rapacuronium has a more rapid clearance than most other NMBAs. Values for clearance are in the range 0.26-0.67 L/h/kg, with most studies giving a value of approximately 0.45 L/h/kg. There is some evidence that clearance declines marginally with advanced age, and it is also reduced in children. A typical value for steady-state volume of distribution is 0.3 L/kg. This is similar to that of many other NMBAs, but is small compared with many other drugs, as expected with a highly polar compound. Pharmacokinetic parameters do not appear to differ markedly in hepatic insufficiency, but clearance is reduced by approximately 30% in renal failure. Rapacuronium equilibrates very rapidly between the plasma and the site of effect. This is the principal explanation behind its unusually rapid onset. It also appears to have a similar potency at the larynx compared with the adductor pollicis; most other NMBAs are less effective at the larynx. Because it gives rapid onset in a dose consistent with brief duration of action, it was hoped that rapacuronium might be a suitable alternative to suxamethonium. It does not have the problems associated with suxamethonium, but its use is associated with bronchospasm, the incidence of which is dose-related. Rapacuronium

Topics: Age Factors; Anesthesia Recovery Period; Child; Clinical Trials as Topic; Dose-Response Relationship, Drug; Humans; Intubation, Intratracheal; Kidney Failure, Chronic; Liver Cirrhosis; Neuromuscular Nondepolarizing Agents; Vecuronium Bromide

Delayed elimination kinetics of steroidal neuromuscular blocking agents have been observed in patients with cirrhosis. Like other steroidal muscle relaxants, rapacuronium may, in part, be eliminated by the liver. To determine the influence of liver disease on its neuromuscular blocking effect, we studied the pharmacokinetics and pharmacodynamics of rapacuronium in patients with cirrhosis.. Sixteen patients undergoing elective surgery or endoscopy with general anesthesia, eight with cirrhosis and eight with normal liver function, were studied. Anesthesia was induced with fentanyl 2 microg/kg and thiopental 5-7 mg/kg and maintained with 60% nitrous oxide and 0.6-0.8% isoflurane in oxygen and repeated doses of fentanyl 1 microg/kg. Rapacuronium 1.5 mg/kg was administered intravenously before tracheal intubation. Thumb adduction force evoked by supramaximal ulnar nerve stimulation was recorded in 16 patients. Venous blood was sampled at frequent intervals for 8 h. Rapacuronium and its breakdown product Org 9488 were measured in plasma by high-pressure liquid chromatography. Values are reported as median (range).. The central volume of distribution was increased to 131 (104-141) ml/kg in patients with cirrhosis (P < 0.01), compared with 75 (47-146) ml/kg in controls. The total apparent volume of distribution was also increased (P < 0.05) to 331 (284-488) ml/kg in patients with cirrhosis, compared with 221 (124-285) ml/kg in controls. The elimination half-life was 88 (77-102) min in controls and 90 (76-117) min in patients with cirrhosis. Plasma clearance was increased (P < 0.05) to 6.9 (6.1-8.9) ml x min(-1) x kg(-1) in patients with cirrhosis, compared with 5.3 (4.2-8.4) ml x min(-1) x kg(-1) in controls. Rapacuronium neuromuscular blocking effect was similar between the two groups. Onset time was 65 (40-110) s in controls and of 60 (52-240) s in patients with cirrhosis. Time to return to 90% of thumb adduction force control value was of 49 (28-80) min in controls and 47 (28-71) min in patients with cirrhosis.. The neuromuscular blocking effect of a single bolus dose of rapacuronium in patients with cirrhosis is not different from that of patients with normal hepatic function. No decrease in plasma clearance of rapacuronium was observed in patients with cirrhosis.

Topics: Adult; Aged; Anesthesia, General; Chromatography, High Pressure Liquid; Electric Stimulation; Female; Half-Life; Humans; Liver Cirrhosis; Liver Function Tests; Male; Mass Spectrometry; Middle Aged; Neuromuscular Nondepolarizing Agents; Ulnar Nerve; Vecuronium Bromide

Recent trials indicate that rapacuronium's pharmacokinetic characteristics are influenced by both renal failure and cirrhosis but the time course of a single bolus dose of 1.5 mg/kg is affected minimally. The authors reassessed these pharmacokinetic findings and examined the time course of the same bolus dose followed by a 30-min infusion.. During nitrous oxide-isoflurane anesthesia, patients with normal renal and hepatic function (n = 25), those with renal failure (n = 28), and those with cirrhosis (n = 6) received a bolus dose of rapacuronium (1.5 mg/kg) followed by a 30-min infusion adjusted to maintain 90-95% twitch depression. At 25% recovery, neostigmine was administered. Blood was sampled until 8 h after the infusion to determine concentrations of rapacuronium and its active metabolite ORG9488. Rapacuronium's pharmacokinetic parameters were determined using mixed-effects modeling.. Onset and facilitated recovery of twitch depression were similar in the three groups. Patients with renal failure required 22% less rapacuronium to maintain target twitch depression during the infusion. Rapacuronium's plasma clearance was 24% smaller in renal failure and decreased 0.5%/yr of age; rapid distribution clearance was 51% smaller in men than in women. After the infusion, ORG9488 concentrations decreased markedly more slowly in patients with renal failure. Cirrhosis did not alter the pharmacokinetics of rapacuronium.. Rapacuronium's plasma clearance and infusion requirement were decreased by renal failure. By dosing to maintain target twitch depression, recovery was not prolonged. Cirrhosis does not affect the pharmacokinetics or neuromuscular effects of rapacuronium. Persistence of ORG9488 in patients with renal failure might prolong recovery after rapacuronium if target twitch depression is not maintained or with administration of rapacuronium for more than 30 min.

Topics: Adolescent; Adult; Age Factors; Aged; Anesthetics, Inhalation; Female; Humans; Kidney Failure, Chronic; Liver Cirrhosis; Male; Middle Aged; Neuromuscular Junction; Neuromuscular Nondepolarizing Agents; Nitrous Oxide; Time Factors; Vecuronium Bromide