Apple II program to simulate the response-time profile of non-depolarising muscle relaxants.

We have developed a BASIC program for the Apple II microcomputer which can simulate the effect (degree of paralysis) time curve obtained following bolus intravenous administrations of pancuronium. The program is based on a combined pharmacokinetic/pharmacodynamic model and has practical application to the anaesthetist under operating room conditions. Knowing the disease state of the patient and the doses and times of administration of pancuronium the microcomputer can predict the degree of paralysis which exists at any time and so assists in the timing of the next dose of relaxant and in deciding when to effect reversal.

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.

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 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.

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.