Clinical pharmacokinetics of the non-depolarising muscle relaxants.

Muscle relaxants are of great benefit to the anaesthetist as adjuncts to anaesthesia. These drugs are used to facilitate endotracheal intubation and to reduce muscle tone during surgery, and may also find application in assisting ventilator care in the intensive care situation. The pharmacological effect of the relaxants may be readily assessed by the anaesthetist by means of a variety of techniques to quantify muscular activity in response to electrical stimulation. A number of factors may modify the effects of the muscle relaxants including anaesthetic agents, hypothermia, patient age and disease status and a variety of drugs. The disposition kinetics of the muscle relaxants have been well characterised although information on protein binding and placental transfer is somewhat scanty. A common characteristic of their pharmacokinetics is multicompartmental behaviour. Clearance of the relaxants ranges from total elimination by the kidneys (gallamine) to substantial hepatic clearance (fazadinium), and thus their clearance may be adversely affected by renal or hepatic disease. Dosage regimens have been designed using knowledge of the disposition kinetics of the relaxants to provide for continuous adequate relaxation during prolonged surgical procedures. With the use of sophisticated pharmacokinetic and pharmacodynamic models good relationships have been demonstrated between plasma concentrations of the relaxants throughout the entire range of relaxant response.

Simulating the time-course of clinical paralysis.

This computer program depicts the concentration-time curves for the nondepolarizing neuromuscular blocking agents. It simulates their administration by single and multiple iv injections, and with continuous infusion, alone and in combination. It provides the plasma concentrations related to 75% and 25% depression of the twitch response, using these to calculate clinically useful pharmacodynamic values, such as the duration of surgical relaxation, and the recovery index. These simulations allow the user to contrast the time-course of relaxation to be expected with various dosage regimens.

Dose-response curves for alcuronium and pancuronium alone and in combination.

Simultaneous administration of pancuronium and alcuronium was used in surgical patients during nitrous oxide-narcotic-barbiturate anaesthesia in order to determine the intensity of neuromuscular blockade. When compared with the results obtained when each of the drugs was given alone, the effect was not greater than the additive. The mean effective dose of pancuronium to produce 95% paralysis was 76 micrograms per kg for the mechanical twitch response and 70 micrograms per kg for the electrical response. The respective mean doses of alcuronium producing that degree of paralysis were 285 and 244 micrograms per kg. Usually the curve derived for the mechanical twitch response was to the right of, and roughly parallel to, that for the electrical response.

Neuromuscular recovery after laparoscopy.

Vecuronium bromide, 0.045 mg X kg-1, was compared with pancuronium, 0.07 mg X kg-1, when used to provide muscle relaxation for tracheal intubation and abdominal relaxation for outpatient gynecologic laparoscopy. Both drugs provided adequate intubating conditions within 5 min and satisfactory abdominal relaxation. Because spontaneous recovery from vecuronium was more rapid, either with inhalational or nitrous oxide-narcotic techniques, pharmacological reversal with edrophonium and atropine was either not necessary or more easily accomplished after vecuronium, as shown by the train-of-four. All patients receiving pancuronium required reversal of the blockade, and in a few patients reversal was difficult. Tests of muscle power and coordination performed 30 and 60 min postoperatively showed no difference between the drugs. There were no postoperative complications related to muscle relaxants and all patients met our discharge criteria the day of surgery. Given the conditions observed at the end of the procedure, we would choose vecuronium for muscular relaxation in laparoscopic surgery.

Clinical pharmacokinetics of pancuronium bromide.

Plasma concentrations of pancuronium bromide have been studied in seven surgical patients following a 6 mg intravenous bolus injection of the drug for neuromuscular blockade. Concurrently, evoked muscle twitch response was monitored for each patient as a measure of the pharmacodynamic effect of the drug. The plasma decay curve for pancuronium was found to be biphasic and after rigorous statistical analysis the data were interpreted according to a 2-compartment open model. The half-life of the beta-phase varied between 89.5 and 161.5 min. The apparent volume of distribution of the central compartment ranged from 62.9 to145.5 ml/kg and the plasma clearance from 57.6 to 187.3 ml/min. At the first sign of recovery from neuro-muscular blockade the mean pancuronium plasma level was found to be 0.218 mcg/ml. The mean duration of action as measured from time of onset of paralysis to 20% recovery was 83.4 min with the plasma level at 20% being 0.169 mcg/ml corresponding to 45.4% of dose remaining to be eliminated from the body.

Plasma concentrations of pancuronium during predetermined intensities of neuromuscular blockade.

The plasma concentrations of pancuronium were monitored during i.v. infusions of the relaxant in dogs. Pancuronium was administered at rates which maintained the degree of neuromuscular blockade at three predetermined levels. The concentrations of the drug in the blood were consistent for any one animal but showed considerable overlap for the three levels of paralysis between animals. Concentrations obtained during infusion and which maintained the twitch response at 20% and 80% of control were compared, in the same dogs, with concentrations obtained during recovery from a bolus injection of pancuronium. When the infusion maintained the twitch response at 20% of the control value, the mean plasma concentration of pancuronium was 0.152 microgram ml-1. That measured after the bolus injection was 0.156 microgram ml-1. The concentrations at 80% of control were 0.094 microgram ml-1 and 0.083 microgram ml-1 respectively. The agreement between these results suggests a relationship between the plasma concentration of the relaxant and its effect during the termination of the action after a large bolus injection of the drug. As this occurs chiefly during the postdistribution equilibrium, the relatively slow decrease in plasma concentration would appear to become the rate-limiting factor in recovery from paralysis.

Dose-response and plasma concentration-response relationships of pancuronium in man.

The dose-response and plasma concentration-response relationships for pancuronium in man were studied during its intravenous administration to eight patients at a rate of 1.62 microgram/kg/min. The (log) dose-response relationships resulted in a sigmoid curve that was linear in its central range. At 20, 50 and 80 per cent paralysis the cumulative dosages (mean +/- SEM) were 0.04 (+/- 0.01), 0.06 (+/- 0.01), and 0.08 (+/- 0.02) mg/kg, respectively. Administration of pancuronium, 56 microgram/kg, to another 12 patients at a more rapid rate resulted in a maximum intensity of blockade of more than 50 per cent. The (log) plasma concentration-response curve was not parallel to the dose-response curve, with mean (+/- SEM) concentrations at 20, 50 and 80 per cent paralysis of 0.21 (+/- 0.04), 0.25 (+/- 0.04), and 0.30 (+/- 0.04) microgram/ml, respectively during the onset of paralysis. Following cessation of the infusion, plasma concentrations of pancuronium were usually lower for the same intensity of paralysis. Using data for the entire response range during recovery from paralysis, the mean effective plasma concentration of pancuronium for a 50 per cent response was 0.20 microgram/ml. Recovery from blockade to 95 per cent paralysis (5 per cent of control twitch height) was associated with a plasma concentration of 0.25 microgram/ml, a value in agreement with plasma concentrations obtained following a single bolus administration of pancuronium, 6 mg, to 30 patients. For 27 patients the rate of decline of paralysis from 80 to 20 per cent showed a highly statistically significant relationship to the apparent rate of decline in the plasma concentrations of pancuronium.

The effect of renal failure on the disposition and neuromuscular blocking action of pancuronium bromide.

Plasma concentrations of pancuronium following single dose administration in six patients, and following multiple dose administration in four patients, all undergoing renal transplantation surgery, were measured using a fluorimetric method. A two-compartment open model was used in the pharmacokinetic analysis of the data. Comparison of the pharmacokinetic findings with data previously obtained for patients undergoing elective surgery but having normal renal function indicated that the clearance of the drug was reduced significantly in the patients with renal failure, and that in these individuals the half-life was increased significantly. Measurement of the evoked mechanical twitch response concurrently with plasma concentration monitoring of pancuronium confirmed that the prolongation of half-life in the patients with renal failure was often but not always associated with an extended duration of neuromuscular blockade and furthermore that the rate of recovery from block might also be prolonged. The clinical implications of these findings are discussed.

Disposition kinetics of pancuronium bromide in patients with total biliary obstruction.

Plasma concentrations of pancuronium were measured in nine patients undergoing surgery because of total biliary obstruction. When compared with the averaged model-independent pharmacokinetic parameters obtained for normal patients, the terminal half-life of 270 min was more than twice normal (132 min, P less than 0.001); the plasma clearance of 59 ml min-1 was less than half the normal rate for pancuronium (123 ml min-1, P less than 0.003). These significant alterations to the pharmacokinetics of pancuronium were associated with prolongation of neuromuscular blockade. Following a bolus injection of pancuronium 6 mg, there was a mean time of 114 min (normals 70 min, P less than 0.05) before the evoked twitch response had returned to 5% of the control value. The pattern of urinary excretion of the drug and its metabolites did not differ from that of normal patients. To avoid excessive dosage during prolonged surgery for total biliary obstruction, it is recommended that supramaximal nerve stimulation be used to indicate the need for the administration of further doses of pancuronium.

Pharmacokinetic and pharmacodynamic modelling with pancuronium.

The pharmacokinetics and pharmacodynamics of pancuronium were studied following intravenous infusion in eleven patients undergoing surgical anaesthesia. Measurement of the plasma concentrations (Cp) of the neuromuscular blocking agent ( NMBA ) and the concomitant intensities of paralysis allowed their simultaneous modelling. The pharmacokinetic parameters derived for pancuronium were in the range of previously reported values, except that the mean total systemic plasma clearance (0.79 +/- 0.28 ml X min-1 X kg-1) was reduced and the mean terminal phase half-life (169 min) was longer in these patients. Plasma concentration and % paralysis data were successfully fitted to a previously proposed pharmacodynamic model. This model assumes a separate effect compartment which exchanges drug directly with the central kinetic compartment (integrated effect model). The 'steady-state' Cp necessary to produce 50% paralysis ( ECpss (50] was estimated to be 0.21 +/- 0.08 micrograms X ml-1 (mechanical response) and 0.18 +/- 0.05 micrograms X ml-1 (EMG response). An analysis using the Hill equation of the Cp-response relationship, during and after the constant-rate infusion of pancuronium bromide, resulted in effective plasma concentrations for 50% paralysis ( ECp50 ) of 0.35 +/- 0.06 micrograms X ml-1 and 0.20 +/- 0.09 micrograms X ml-1, respectively, for mechanical twitch response. The corresponding values for EMG response were 0.32 +/- 0.06 micrograms X ml-1 and 0.17 +/- 0.06 micrograms X ml-1. Using this latter approach, the ECp50 estimated during onset of paralysis was significantly higher than that estimated during offset of paralysis (p less than 0.05); no such difference was apparent between this latter parameter and the ECpss (50) of the integrated effect model (p greater than 0.05). No significant differences were observed between any of the pharmacodynamic parameter estimates generated from the data obtained from the two methods of assessment of neuromuscular function (mechanical vs. EMG response) (p greater than 0.05).

Calculation of an effect compartment rate constant using recovery indices obtained with an isolated arm technique.

We have examined the implications of the theoretical single pharmacokinetic compartment associated with blocker-induced paralysis, in relation to the isolated arm technique. It is assumed that the blocker concentration-effect relationship can be characterized by a sigmoid curve, which incorporates an exponent, s. After tourniquet release, the concentration gradient between the effect compartment and plasma should be large, and elimination related to the rate constant, keo. The major measurement of spontaneous recovery with the isolated arm is the time interval between 75% and 25% twitch depression, T25-T75. The general equation relating these three variables is developed: keo = 2.2/(s x (T25-T75)). Insertion of published values for T25-T75 with isolated arm studies into this equation gave estimates for an intrinsic keo for atracurium, vecuronium, rocuronium and pancuronium.

Tubocurarine and pancuronium: a pharmacokinetic view.

This review is an attempt to bring together the pharmacokinetic data on d-tubocurarine and pancuronium with clinical observations on relaxant dosage and effect. The modelling techniques used here represent an oversimplification of the relationships between relaxant plasma concentration and response as they do not predict either the time of onset of paralysis or its peak intensity. However, they do enable calculation of a bolus dose of relaxant required to achieve a particular intensity of paralysis for the average patient once pseudo-distribution equilibrium has been achieved. This has been further extended to predict the cumulation of the relaxants with subsequent dosage in average patients. Suggested regimens incorporating bolus and infusion doses of the relaxants to achieve continuous neuromuscular blockade have been calculated also. Averaged pharmacokinetic parameters derived from patients with renal or hepatic dysfunction have been used to predict the likely duration and intensities of paralysis for the relaxants.

Dose-response curves for four neuromuscular blockers using continuous i.v. infusion.

Cumulative dose-response curves were constructed in man for tubocurarine, pancuronium, gallamine and alcuronium from data obtained during barbiturate-narcotic-nitrous oxide anaesthesia. Fifty-six adult patients received one of these drugs, administered by constant-rate infusion, a technique enabling response levels and results pooled to derive a composite dose-response curve for each drug. Using the mechanical twitch response, the ED50 for each neuromuscular blocking drug was: tubocurarine 0.236 mg kg-1, pancuronium 0.048 mg kg-1, gallamine 1.3 mg kg-1 and alcuronium 0.161 mg kg-1. The slopes of the composite curves for pancuronium and alcuronium were significantly steeper than those for tubocurarine and gallamine. In the alcuronium studies the simultaneous compound electromyogram was recorded, and usually this was more depressed than the mechanical twitch response, giving an ED50 of 0.135 mg kg-1.