Roy Cronnelly

Clinical Pharmacology of ORG NC45 (NorcuronTM)A New Nondepolarizing Muscle Relaxant

To determine the neuromuscular effects of a new muscle relaxant, ORG NC45 (NorcuronTM), a monoquaternary homologue of pancuronium, 84 ASA Class I or II patients were studied under halothane and nitrous oxideanesthesia. The ED50 (dose of muscle relaxant causing a 50 per cent depression of twitch tension) of pancuronium and ORG NC45 was 0.022 mg/kg (r = 0.90) and 0.015 mg/kg (r = 0.80), respectively, for a potency ratio of 1.5 (0.022/0.015). The duration of action (time from injection to 90 per cent recovery of control twitch tension) was 27 ± 5 min with ORG NC45, 0.02 mg/kg, and 65 ± 16 min with pancuronium in an equivalent dose of 0.03 mg/kg. The increase in duration of neuromuscular blockade from repetitive doses was greater with pancuronium than with ORG NC45. Reversal of an ORG NC45 neuromuscular blockade was accomplished with doses of neostigmine slightly less than those required for pancuronium. Under thiopental-nitrous oxide anesthesia, endotracheal intubation was easily performed using ORG NC45, 0.07–0.14 mg/kg. The duration of action of ORG NC45, 0.07 mg/kg, was about one-third that of pancuronium (0.1 mg/kg). It was concluded that ORG NC45 is more potent and has a shorter duration of action with both initial and repetitive doses than does pancuronium. With these characteristics and the reported lack of cardiovascular effects, the authors believe further clinical trials are warranted.

Pharmacokinetics and Pharmacodynamics of d-Tubocurarine in Infants, Children, and Adults

&NA; The pharmacokinetics and pharmacodynamics of d‐tubocurarine (dTc) were determined in neonates (0–2 months, n = 7), infants (212 months, a = 7), children (1–12 years, n = 9), and adults (12–30 years, n = 8) during 70% nitrous oxide, 0.58 MAC halothane anesthesia. dTc was administered by infusion, while blood for determination of plasma dTc concentrations was obtained, and the EMG of the adductor pollicis recorded. The plasma dTc concentration at which 50% depression of EMG twitch height occurs (Cpss(50)) was 0.18 ± 0.09 &mgr;g/ml in neonates, and 0.27 ± 0.06 &mgr;g/ml in infants, both significantly lower than the values of 0.42 ± 0.14 and 0.53 ± 0.14 &mgr;g/ml for children and adults, respectively. The steady‐state distribution volume (Vdss) was 0.74 ± 0.33 l/kg in neonates, significantly greater than the values of 0.52 ± 0.22, 0.41 ± 0.12, and 0.30 ± 0.10 1/kg in infants, children, and adults, respectively. The elimination half‐life (t&bgr;1/2) was 174 ± 60 min in neonates, significantly longer than the values of 90 ± 23 and 89 ± 18 min in children and adults, respectively. Plasma clearance did not differ with age. We also determined D50, the product of Vdss and Cpss(50). D50, the quantity of drug present at steady‐state to produce 50% paralysis, did not differ between groups. The authors conclude that during comparable nitrous oxide‐halothane anesthesia, neonates and infants have an increased sensitivity to dTc, as determined by Cpss(50). However, because of he larger Vdss in younger patients, dose size should not differ with age. In addition, because of the longer t&bgr;1/2 in neonates, second and subsequent doses should be required at less frequent intervals.

Clinical Pharmacology of Vecuronium and Atracurium

Vecuronium and atracurium provide addition flexibility to the clinician using neuromuscular blocking drugs. The shorter duration of action, lack of significant cardiovascular effects, and the lack of dependence on the kidney for elimination provide clinical advantages over, or alternatives to, currently available nondepolarizing neuromuscular blocking drugs.

Edrophonium: duration of action and atropine requirement in humans during halothane anesthesia.

Edrophoniums onset and duration of antagonism (n = 26) and atropine requirement (n = 24) were determined under conditions of d-tubocurarine (dTc) neuromuscular blockade and halothane, nitrous oxide anesthesia. Results are compared with previous work in our laboratory on neostigmine and pyridostigmine under similar conditions. dTc was administered by continuous infusion to maintain a 90% depression of muscle twitch tension. Edrophonium (0.03–1.0 mg/kg) was injected as an iv bolus in combination with atropine (0.5 mg). dTc infusion was continued until a stable 90% depression of muscle twitch tension was reestablished. Time-to-peak effect (onset of action), duration, and magnitude of antagonism were recorded. The atropine requirement was determined during spontaneous recovery from dTc (0.3 mg/kg) and stable halothane, nitrous oxide anesthesia. Edrophonium (0.5 mg/kg) was mixed with 7, 15, or 30 μg/kg of atropine and compared to neostigmine (0.043 mg/kg) and atropine (15 μg/kg). Blood pressure, heart rate, and rhythm were recorded for 60 min following edrophonium administration. The time-to-peak antagonism for edrophonium (0.8–2.0 min) was far more rapid than neostigmine (7–11 min) or pyridostigmine (12–16 min). The ED50 for edrophonium was 0.125 mg/kg, however, the dose-response curve was not parallel to those for neostigmine or pyridostigmine. In equiantagonistic doses, the duration of antagonism by edrophonium (66 min) did not differ from neostigmine (76 min), but was shorter than pyridostigmine. Edrophonium required one-half the amount of atropine as did neostigmine to prevent bradycardia. The authors concluded that edrophonium has a more rapid onset than neostigmine and an equivalent duration of antagonism, and requires less atropine to prevent bradycardia.

The pharmacodynamics and pharmacokinetics of vecuronium in patients anesthetized with isoflurane with normal renal function or with renal failure.

The duration of action and the pharmacokinetics of vecuronium were compared in patients with and without renal function. Twenty patients were studied: 12 with renal failure who were to receive kidney transplants from cadaveric donors, and eight with normal renal function. After oral premedication with diazepam, 10 mg, anesthesia was induced with thiopental, 4 mg/kg iv, and maintained with the inhalation of 60% nitrous oxide and 0.9–1.1% isoflurane, end-tidal concentration, in 40% oxygen. The force of thumb adduction in response to supramaximal ulnar nerve stimulation was monitored and recorded. An intravenous bolus of vecuronium, 0.1 mg/kg, was administered after 15 min of a stable end-tidal isoflurane concentration, as measured by mean spectrometry. Venous blood was then sampled at frequent intervals for 4 h following the bolus. Vecuronium concentrations in plasma were quantified by a sensitive and specific gas chromatographic assay. Data were analyzed by nonlinear least squares regression and described by a two-compartment model. The duration of neuromuscular blockade was longer in patients with renal failure than in those with normal renal function. This increased duration may be related to both a decreased plasma clearance duration may be related to both a decreased plasma clearance and a prolonged elimination half-life of vecuronium in the renal failure group.

Renal function and the pharmacokinetics of neostigmine in anesthetized man.

The pharmacokinetics of neostigmine in patients with normal renal function (n = 8) were determined and compared with those of patients undergoing renal transplantation (n = 6) or bilateral nephrectomy (n = 4). All patients were anesthetized with nitrous oxide and halothane. d-Tubocurarine was infused at a rate sufficient to maintain 90 per cent depression of twitch tension. Ten to 15 minutes prior to the end of operation and anesthesia, the d-tubocurarine infusion was terminated and neostigmine, 0.07 mg/kg, and atropine, 0.03 mg/kg, were given by infusion over a 2-min period. Concentrations of neostigmine in blood drawn periodically during the following four hours were determined by gas-liquid chromatography and the data fitted to a two-compartment pharmacokinetic model. In anephric patients elimination half-life (181 ± 54 min, mean ± SD) was significantly prolonged when compared with comparable values for patients with normal renal function (80 ± 48 min). Total serum clearance was significantly decreased from 16.7 ± 5.4 ml/kg/min in patients with normal renal function to 7.8 ± 2.6 ml/kg/min in anephric patients. Neostigmine pharmacokinetics following renal transplantation were not different from those in patients with normal renal function. It is concluded that renal excretion accounts for 50 per cent of neostigmine clearance and, in the absence of renal function, the serum half-life of neostigmine is prolonged, similar to that of d-tubocurarine.

Pharmacokinetics and Pharmacodynamics of Vecuronium (ORG NC45) and Pancuronium in Anesthetized Humans

The pharmacokinetics and pharmacodynamics of vecuronium (25–50 μg/kg) and pancuronium (25–50 μg/kg) were determined in nine ASA class I or II patients anesthetized with nitrous oxide and halothane. Force of thumb adduction in response to supramaximal stimulation of the ulnar nerve was quantified and recorded. Serum concentrations of the muscle relaxants were determined for eight hours after their administration using a mass spectrometry assay. Data were analyzed by nonlinear regression and fit to a three-compartment pharmacokinetic model and a four-compartment pharmacodynamic model. Vecuronium had a more rapid clearance (5.2 ± 0.7 ml · kg-1 min-1; mean ± SD) and a shorter elimination half-life (71 ± 20 min) as compared with pancuronium (1.8 ± 0.4 ml · kg-1 · min-1; 140 ± 25 min). No other pharmacokinetic differences were found between the drugs. Pharmacodynamic analysis showed that the plasma concentration at steady state which produced a 50% neuromuscular blockade (Cp, 50) was similar for vecuronium and pancuronium. The authors conclude that the drugs are equivalent in their onset and potency; however, the more rapid clearance and shorter elimination half-life for vecuronium provides a kinetic basis for its shorter duration of neuromuscular blockade as compared with pancuronium.

Neostigmine and edrophonium antagonism of varying intensity neuromuscular blockade induced by atracurium, pancuronium, or vecuronium.

To compare the time course of neostigmine and edrophonium antagonism of varying intensity neuromuscular blockade induced by atracurium, pancuronium, or vecuronium, the authors studied 98 patients anesthetized with nitrous oxide (60%) and halothane or enflurane. Neuromuscular blockade, as monitored by single stimulus-induced twitch tension (TT), was antagonized at varying degrees of spontaneous recovery (2-80% of control TT). Time to antagonism (time from injection of neostigmine or edrophonium to 90% recovery of control TT) was not different between edrophonium, 0.5 mg/kg, and neostigmine, 0.04 mg/kg, when spontaneous recovery had been allowed to occur to at least 11% of control TT prior to antagonist administration (P greater than 0.05). For profound neuromuscular blockade (TT less than or equal to 10% of control) induced by pancuronium or vecuronium, time (mean +/- SD) to antagonism with neostigmine, 0.04 mg/kg, was 7.0 +/- 2.2 min and 5.6 +/- 1.7 min, respectively, while the same for edrophonium, 0.5 mg/kg, was 20.0 +/- 8.0 min and 15.0 +/- 12.5 min, respectively (P less than 0.05). Time to antagonism of profound atracurium-induced neuromuscular blockade was 8.5 +/- 3.3 min for neostigmine, 0.04 mg/kg, and 9.8 +/- 7.0 min for edrophonium, 0.5 mg/kg, (P less than 0.05). For profound vecuronium-and pancuronium-induced neuromuscular blockade, time to antagonism by edrophonium, 1.0 mg/kg, was 4.6 +/- 3.0 min and 3.9 +/- 1.6 min respectively. The authors conclude that neostigmine, 0.04 mg/kg, antagonizes neuromuscular blockade within 12 min when TT is greater than 2% of control at time of reversal. When TT is greater than 10% of control, edrophonium, 0.5 mg/kg, produces similar time to antagonism.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacokinetics of edrophonium and neostigmine when antagonizing d-tubocurarine neuromuscular blockade in man.

The pharmacokinetics and effectiveness of edrophonium antagonism of d-tubocurarine neuromuscular blockade were compared with that of neostigmine in surgical patients anesthetized with halothane and nitrous oxide. After an intranveous (iv) injection of d-tubocurarine (0.3 mg/kg), the single twitch tension was allowed to return to five per cent of the control level. Edrophonium, 0.5 or 1.0 mg/kg (n = 12), or neostigmine, 0.07 mg/kg (n = 6), was then given iv in combination with atropine, 1.0 mg, as a 2-min controlled infusion. Train-of-four and single twitch tension were followed for 60 min in all patients. Twelve patients were monitored for 90 min, six patients for 120 min, four patients for 150 min, and two patients for 240 min. Blood was sampled intermittently for four hours and assayed for edrophonium or neostigmine using high-pressure liquid chromatography. Edrophonium was found to promptly antagonize the d-tubocurarine blockade. Twitch tension rapidly increased to a plateau (a rate of increase in twitch tension of less than 2 per cent of control per min) which was sustained in all cases. The mean time to plateau for edrophonium was 2.9 ± 0.21 (±SE) min as compared to 6.1 ± 0.75 min for neostigmine. Neuromuscular blockade did not reappear in any patient. The degree of antagonism of the neuromuscular blockade by neostigmine and edrophonium was not significantly different. Except for a longer distribution half-life, the pharmacokinetic variables for edrophonium did not differ significantly from those for neostigmine. The elimination half-lives of edrophonium and neostigmine were 110 ± 34 min (mean ± SD) and 77 ± 47 min, respectively. The authors therefore conclude that edrophonium, 0.5–1.0 mg/kg, has pharmacokinetic variables comparable to neostigmine and produces prompt, sustained, and effective antagonism of d-tubocurarine neuromuscular blockade.

Potency Determination for Vecuronium (ORG NC45)Comparison of Cumulative and Single-dose Techniques

To compare two methods of estimating the potency of neuromuscular relaxants of medium duration, the authors determined the potency of vecuronium (ORG NC45) using cumulative dose-response (CDR) techniques, and compared these data with published values from our group obtained using the single bolus technique. During 60% N2O-halothane anesthesia, patients received 10 micrograms/kg vecuronium; additional incremental doses of vecuronium, 5 micrograms/kg, were given when no change occurred in the height of three successive twitches. Using these dose-response data, the authors determined least-squares regression lines and ED20, ED50, and ED80. These results were compared to values obtained by the single bolus technique under comparable conditions. The CDR and single bolus technique yielded ED50 values of 19.9 and 15.0 micrograms/kg, respectively. All potency estimates by CDR were larger than those obtained by the single bolus dose technique. It was concluded that, for vecuronium, a medium duration neuromuscular relaxant, CDR yields potency estimates which are larger than those obtained by the traditional single bolus dose technique. Because the single bolus dose technique is the accepted method for construction of dose-response curves, the authors recommended that CDR not be used for potency determination of muscle relaxants of medium and short duration such as vecuronium.