rapacuronium and Kidney-Failure--Chronic

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

Because renal function affects the elimination of muscle relaxants, each new muscle relaxant must be evaluated in patients with renal failure. Accordingly, the neuromuscular effects and pharmacokinetics of rapacuronium were identified in patients with renal failure.. Rapacuronium (1.5 mg/kg) was administered to 10 healthy volunteers and 10 patients with renal failure who were undergoing non-transplant surgery, were 18-45 yr old, and were anesthetized with propofol. The adductor pollicis muscle twitch tension was monitored. Plasma samples were obtained frequently for a period of 8 h to measure the concentrations of ORG9487 and its metabolite, ORG9488. Pharmacokinetic parameters were determined using mixed-effects modeling.. One patient was excluded from analysis because he was taking phenytoin chronically. Twitch depression at 1 min was less in patients than in healthy volunteers (median values: 92% in patients, 99% in volunteers). The times to 90% and peak twitch depression; to 10%, 25%, and 75% twitch recovery; and to 70% and 80% train-of-four ratios were similar in volunteers and patients. Rapacuronium's clearance was 32% less in patients with renal failure; in both groups, clearance decreased 0.909% per year of age compared with the value in a 30 yr old. The steady state distribution volume was 14% less in women than in men and 16% less in patients than in volunteers. For ORG9488, clearance was 85% less in patients than in volunteers.. The neuromuscular effects of a single dose of rapacuronium are affected minimally by renal failure. However, the decreased clearance of rapacuronium and its potent metabolite in renal failure suggests that repeated dosing of rapacuronium may lead to prolonged effects in patients with renal failure.

Topics: Adolescent; Adult; Female; Humans; Infusions, Intravenous; Kidney Failure, Chronic; Male; Middle Aged; Models, Biological; Muscle Contraction; Muscle, Skeletal; Neuromuscular Nondepolarizing Agents; 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