The neuromuscular blocking effects of the new monoquaternary analogue of pancuronium, Org NC 45, have been investigated in anaesthetized patients. In different doses administered as a single i.v. bolus or as an initial bolus followed by several small maintenance doses or by a continuous infusion, Org NC 45 appears to be approximately as potent as pancuronium, but has a more rapid onset of action, considerably shorter duration of action and faster recovery rate than pancuronium. It showed no cumulative effects even after 10 maintenance doses were injected in succession. Doses of 0.08 mg kg−1 provided ideal intubatmg conditions in 90–95 8. Infusions of Org NC 45 provided much smoother control of neuromuscular blockade than did pancuronium. No cardiovascular side-effects were noted even at the greatest dose (0.12 mg kg−1)used. Org NC 45 has clear advantages over pancuronium and represents a potentially valuable addition to the armamentarium of clinically useful muscle relaxants.

The Neuromuscular Blocking Action of ORG NC 45, A New Pancuronium Derivative, in Anaesthetized Patients A pilot study

The fate of pancuronium bromide has been investigated in 20 anaesthetized patients, seven undergoing cholecystectomy with choledochostomy (Group I), seven undergoing cholecystectomy only (Group II) and six undergoing pelvic operations (Group III). A fluorimetric method was used to determine pancuronium bromide and its bis-quaternary derivatives in blood, urine and bile. After a single intravenous injection of 6 mg pancuronium bromide, disappearance of the drug from the plasma proceeded in three phases with half-lives of < 5 min, 7-13 min and 108–147 min, respectively. Renal elimination is suggested as the major excretory pathway in man, but biliary excretion is also significant. Thirty hours after injection, the total recovery of unchanged pancuronium and its metabolite was approximately 37–44% in the urine (Groups I, II, III) and 11% in the bile (Group I). Only one metabolite (3-hydroxy derivative) of pancuronium bromide, accounting in total for about 15% of the administered dose, was identified in urine and 5% in bile by thin-layer chromatography. Renal and hepatic elimination varied widely between patients.



ZUSAMMENFASSUNG

Wir untersuchten das Schicksal von Pancuroniumbromid bei 20 anaesthesierten Patienten, 7 mit Cholecystektomie und Choledochostomie (Gruppe I), 7 mit Cholecystektomie allein (Gruppe II) und 6 mit Operation im Beckenbereich (Gruppe III). Pancuroniumbromid und seine bis-quarternaren Derivate wurden flourimetrisch in Blut, Harn und Galle bestimmt. Nach einer Einzelinjcktion von 6 mg Pancuroniumbromid kam es zum Verschwinden des Mittels aus dem Plasma in drei Phasen mit Halbwertszeiten von weniger als 5 Minuten, bzw. 7–13 Minuten und 108–147 Minuten. Eliminierung durch die Niere scheint beim Menschen der wesentlichste Ausscheidungsweg zu sein, doch ist auch die Ausscheidung Uber die Galle signifikant. 30 Stunden nach der Injektion konnten 37–4 % als unverandertes Pancuronium oder als Metabolit im Harn (Gruppen I, II, III) und 11 % in der Galle (Gruppe I) nachgewiesen werden. Nur ein Metabolit (namlich das 3-Hydroxy-Derivat) des Pancuroniums, verantwortlich fur etwa 15 % der verabreichten Dosis, konnte im Urin und 5 % in der Galle mittels Dunnschichtchromatographie identifiziert werden. Renale und hepatische Ausscheidung variierten stark von Patient zu Patient.

The Fate of Pancuronium Bromide in Man

*Department of Anaesthesia, University of British Columbia, Vancouver, British Columbia, Canada; and the Departments of Anesthesiology, tNorthwestern University, Chicago, Illinois; SUniversity of Miami, Miami, Florida; @tanford University, Stanford, California; and IlColumbia University, New York, New York The purpose of this multicenter, randomized, assessor- blind placebo-controlled study was to determine which of five doses of the new, rapid-onset neuromuscular re- laxant, ORG 9487, provided both good to excellent tra- cheal intubating conditions 60 s after administration and a clinical duration of action ~20 min in 120 younger (aged 18-64 yr) and 61 elderly (aged 65-85 yr) adult patients. Anesthesia was induced with fentanyl (2-5 Fg/kg) and thiopental (3-6 mg/ kg) and main- tained with N,O/O, and a propofol infusion (50- 300 pg * kg-’ * mini’). Neuromuscular train-of-four (TOF) monitoring by electromyography (Datex Relaxo- graph) commenced immediately after anesthetic induc- tion and was followed, within 30 s, by one of five doses of ORG 9487 (0.5, 1.0, 1.5,2.0,2.5 mg/kg) or a placebo. Tracheal intubation was attempted at 60 s and again, in the case of failure, at 90 s. Conditions were assessed with a 4-point scale. Maximum block, clinical duration (time to 25% Tl recovery), and recovery (TOF 2 0.7) were measured. Dose-dependent changes were ob- served in tracheal intubating conditions and neuro- muscular block. Good to excellent intubating condi- tions at 60 s were present in most younger adult (52 of 60) and elderly (26 of 31) patients administered doses 21.5 mg/ kg. Mean clinical durations <20 min were ob- served in adult patients at doses up to 2.0 mg / kg and in geriatric patients up to 1.5 mg/kg. Thus, doses of 1.5- 2.0 mg/ kg ORG 9487 enabled both rapid tracheal intu- bation and a short clinical duration of action in adult and elderly patients. (Anesth Analg 1997;84:1011-8)

Dose-ranging study in younger adult and elderly patients of ORG 9487, a new, rapid-onset, short-duration muscle relaxant.

Drugs which move relatively slowly in and out of body “compartments” thereby confer pharmacokinetic characteristics of a multicompartment system and elicit a considerably different time course of pharmacologic effect than do drugs which are distributed in the body extremely rapidly. The time course of pharmacologiC effects in multicompartment systems is considered here as a function of dose and site of action and duration of repetitive dosings. The durationdose and intensity-time patterns thus obtained are consistent with the results of clinical studies. An appreciation of these relationships should be helpful in designing effective and safe dosage regimens.

Drug distribution and pharmacologic effects

Since the introduction of (+)-tubocurarine (dTc), many new neuromuscular blocking (NMB) agents have been brought into anaesthesia practice. The large molecular size and the quaternary ammonium structure of these compounds are unique among anaesthesia-related drugs. For practical purposes, understanding their structure±activity relationship (SAR) is a rational way to understand their actions and metabolism. A 1994 review by Hill and colleagues summarized contributions by previous reviewers and provided details on several series of compounds. Besides molecular structure, this review will cover molecular conformation and attempt to offer explanations.

Structure, conformation, and action of neuromuscular blocking drugs†

SUMMARY The effects of suxamethonium and tubocurarine were studied in London and New York patients anaesthetized with thiopentone, nitrous oxide and halothane. The action of tha muscle relaxants were assessed by measurement of the twitch respone of the adductor pollicis muscle to supramaximal stimulation of the ulnar nerve. The duration of action of suxamethonium (1 mg/kg) was less in London patients than in a comparable group of New York patients. With tubocurarine (0.1 mg/kg) the magnitude and duration of action was less in London than in New York patients. In a group of Amercian patients at a United States Air Force (USAF) hospital the magnitude and duration of action of tubocurarine (0.1 mg/kg) was similar to that seen in New York patients. It was also observed that the response to tubocurarine (0.1 mg/kg) was affected by the prior administration of suxamethonium (1 mg/kg). Both the magnitude and duartion of action of tuborcurarine were greater in patients who had previously received suxamethonium than in those who had not.

A comparison of the effects of suxamethonium and tubocurarine in patients in london and new york

SUMMARY The neuromuscular blocking action of pancuronium bromide was investigated in anaesthetized patients. Pancuronium resembles tubocurarine in producing a competitive type block but is about five times as potent as tubocurarine. With a small dose (0.02 mg/kg) the onset of action of the drug was slow, with the time to its maximum effect averaging 4.5 minutes. The maximum effect was, on average, a reduction in twitch height of 69 per cent. With larger doses of the agent (0.05 mg/kg and 0.1 mg/kg) the onset was more rapid and usually a complete block was achieved. The recovery from 0.02 mg/kg and 0.05 mg/kg to 50 per cent of the initial twitch height averaged 12.2 minutes and 36.8 minutes respectively. Repeated doses of the drug produced a greater duration of action with a somewhat greater intensity of block. During recovery from the action of the drug a respiratory acidaemia reduced and a respiratory alkalaemia increased the rate of recovery.

R. F. Seed

Papers

A comparison of the effects of suxamethonium and tubocurarine in patients in london and new york

The neuromuscular blocking action of pancuronium in man during anaesthesia

The neuromuscular blocking action of pancuronium in man during anaesthesia

The neuromuscular blocking actions of pancuronium.

A transatlantic study of neuromuscular blockade