Pyridostigmine kinetics with and without renal function.

Pyridostigmine kinetics were examined under conditions of clinical use as an antagonist of nondepolarizing neuromuscular blockade in anesthetized patients with and without renal function. Pyridostigmine serum levels were assayed by gas-liquid chromatography, and data were fitted to a 2-compartment kinetic model. Pyridostigmine kinetics following renal transplantation (n = 5) were not different from those in patients with normal renal function. Renal function (n = 5) elimination half-life increased from 112 +/- 12 min (mean +/- SD) to 379 +/- 162 min, and serum clearance decreased from 9 +/- 2 ml/kg/min to 2 +/- 0.6 ml/kg/min in anephric patients (n = 4). We conclude that renal function accounts for 75% of pyridostigmine clearance.

An integrated model for the interaction of muscle relaxants with their antagonists.

An integrated model describing the interaction of nondepolarizing neuromuscular blocking agents with reversible anticholinesterase agents is derived and compared with a naive model using experimental data obtained from four anesthetized dogs. Three consecutive but separate steady-state d-tubocurarine blocks (approximately 50, 70, and 90%) were induced in each of the four dogs and reversed by short edrophonium infusions. Edrophonium arterial concentrations and twitch tension of the anterior tibialis muscle were measured. Both the integrated and the naive model were fit to the twitch tension data using a model with a hypothetical "effect" compartment. The integrated model consistently fit the twitch tension data better than the naive model; the sum of squared deviations was lower by 46, 45, 87, and 69%, respectively, with the integrated model than with the naive model. Also, in contrast to the naive model, the integrated model is capable of describing the interaction of the anticholinesterase agent and the neuromuscular blocking agent when the concentration of either varies with time.

Reversed-phase, ion-pair liquid chromatography of quaternary ammonium compounds: determination of pyridostigmine, neostigmine and edrophionium in biological fluids.

A reversed-phase, ion-pair liquid chromatographic method for the quantitative determination of quaternary acetylcholinesterase inhibitors is described. The method uses an ion-pair extraction to isolate the drugs from biological material prior to liquid chromatographic separation and online UV detection at 214 nm. Quantiation down to 5 ng/ml and within-day precison with coefficient of variation (C.V.) of 1.5% (n = 10, x = 100 ng/ml) for neostigmine, C.V., 1.7% (n = 10, x = 80 ng/ml) for pyridostigmine and C.V., 1.5% (n = 10, x = 100 ng/ml) for edrophonium have been achieved. The assay was designed for pharmacokinetic studies of these drugs in anesthetized patients.

Comparison of thiopental and midazolam on the neuromuscular responses to succinylcholine or pancuronium in humans.

Midazolam (0.3 mg/kg) was compared to thiopental (4.0 mg/kg) for possible interactions with succinylcholine or pancuronium when used for induction of anesthesia. Neuromuscular function was monitored by recording the force of thumb adduction in response to ulnar nerve stimulation. Following induction of anesthesia with either midazolam (N = 10) or thiopental (N = 10), stable muscle-twitch tension was obtained and succinylcholine (1 mg/kg) was given intravenously. The duration of blockade, recovery time, intensity of fasciculations, or adequacy of relaxation for tracheal intubation did not differ between patients receiving midazolam or thiopental. An additional group of patients anesthetized and monitored in the same manner received pancuronium (0.025 mg/kg) in incremental doses until a 99% depression of muscle-twitch tension was obtained. Dose-response curves for pancuronium, duration of blockade, and adequacy of relaxation for tracheal intubation did not differ between patients receiving midazolam (N = 10) or thiopental (N = 10). We conclude that the neuromuscular blockade produced by succinylcholine or pancuronium was no different in patients receiving either midazolam or thiopental for induction of anesthesia.

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

Edrophonium's 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 micrograms/kg of atropine and compared to neostigmine (0.043 mg/kg) and atropine (15 micrograms/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.

Metabolites of neostigmine and pyridostigmine do not contribute to antagonism of neuromuscular blockade in the dog.

The authors sought to determine whether the metabolites of neostigmine and pyridostigmine contribute to antagonism of neuromuscular blockade. Accordingly, the dose-response relationship, onset and duration of action (n = 60), and pharmacokinetics (n = 22) of neostigmine, pyridostigmine, their metabolites 3-hydroxyphenyltrimethylammonium (PTMA) and 3-hydroxy-N-methylpyridinium (MP), and edrophonium were determined in dogs anesthetized with sodium pentobarbital. The force of contraction of the anterior tibialis muscle was maintained at constant 90% depression by infusing pancuronium. Then, a single iv bolus dose of one of the drugs under study was injected while the pancuronium infusion was continued. Venous blood, urine, and bile were sampled for four hours. Concentrations were determined by liquid chromatographic techniques; a three-compartment pharmacokinetic model was fitted to the serum concentration data. The doses producing 50% antagonism were 6.5, 52, 69, and 40 micrograms/kg for neostigmine, pyridostigmine, edrophonium, and PTMA, respectively. MP was inactive as an antagonist. By comparing approximately equipotent doses, time to peak antagonism (onset) and until 30% of peak antagonism remained (duration) were shorter for both edrophonium and PTMA than for neostigmine and pyridostigmine. Slow distribution and elimination half-lives, volume of distribution at steady state (VDss), and total plasma clearance (Cl) were similar for the drugs except for a smaller Vdss and lower Cl for MP. More than 60% of the dose of each drug was recovered unchanged from urine; less than 1% was recovered from bile. Less than 10% of the dose of neostigmine was recovered as PTMA.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacokinetics of edrophonium in anephric and renal transplant patients.

The pharmacokinetics of edrophonium were determined in patients anaesthetized with nitrous oxide and halothane undergoing kidney transplant nephrectomy (n=6) or transplantation of a live related donor kidney (n = 6). Serum concentrations of edrophonium were assayed by high pressure liquid chromatography and pharmacokinetic variables computed using non-compartmental analysis. Patients undergoing transplant nephrectomy had a significant increase in elimination half-life and a significant decrease (67%) in serum clearance when compared with kidney transplant recipients or patients with normal renal function. Pharmacokinetic indices for edrophonium in patients receiving a kidney transplant did not differ from those in patients with normal renal function. We conclude that absence of renal function decrease excretion of edrophonium to an extent similar to that of other acetylcholinesterase inhibitors, neostigmine and pyridostigmine.

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 intravenous (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.

Clinical pharmacology of edrophonium in infants and children.

The dose-response relationship, onset, duration of action, atropine requirement, and pharmacokinetic variables of edrophonium were determined in infants and children during N2O-halothane anesthesia. The technique of steady state infusion of d-tubocurarine anesthesia. The technique of steady state infusion of d-tubocurarine (dTc) was used to determine the ED50 for edrophonium (i.e., the dose producing 50% antagonism of 90% neuromuscular depression) in 4 infants (145 micrograms/kg) and 12 children (233 microgram/kg). The reported values for ED50 for edrophonium (obtained under similar anesthetic conditions) is 128 micrograms/kg for adults. These three dose-response curves do not differ statistically; however, there was greater variability among infants and children than adults. Time to peak antagonism was similar for all three age groups. Duration of antagonism was determined in six infants and six children and did not differ from the reported value for adults. The optimal dose and time of administration of atropine were established by administering edrophonium (1 mg/kg) and atropine (10-20 micrograms/kg) to 24 infants and children. The smallest changes in heart rate and systolic blood pressure occurred when atropine (10 micrograms/kg) was given 30 s before edrophonium. The pharmacokinetics of edrophonium (1 mg/kg) were studied in four infants and four children and were compared with published values for adults: distribution and elimination half-lives and distribution volumes were similar for the three groups. Total clearance (ml.kg-1.min-1) was greatest for infants (17.8 +/- 1.2) compared with children (14.2 +/- 7.3) and adults (8.3 +/- 2.9). The authors conclude that the dose of edrophonium required toantagonize dTc-induced neuromuscular blockade is similar or possibly greater for infants and children than for adults.(ABSTRACT TRUNCATED AT 250 WORDS)

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)

Studies of the neuromuscular blocking effects of BW 403C65 in frog and cat muscle.

BW 403C65, an isoquinolinium bisquaternary compound, was investigated for its neuromuscular blocking properties. In vitro in from preparations, low concentrations induced an increase in miniature endplate potentials (m.e.p.p.) frequency without altering their amplitude. With increasing concentrations m.e.p.p. frequency returned to control value and amplitude started to decrease concomitantly with the decreased sensitivity of the endplate to iontophoretically applied acetylcholine and depression of the twitch tension. Acetylcholine released at the neuromuscular junction was also decreased. In vivo in the cat preparation the intra-arterial injection of low doses of the drug produced an increase in the strength of the muscle twitch, and the development of contracture, as well as the appearance of post-drug repetition at the ventral roots. Greater doses produced a progressive decline in post-tetanic potentiation with prolonged return to control.

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 mass 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 and a prolonged elimination half-life of vecuronium in the renal failure group.

Actions of a new muscle relaxant (AH8165) on neuromuscular transmission.

The effects of a new muscle relaxant, AH8165, on miniature endplate potential (MEPP) amplitude and frequency, endplate sensitivity to acetylcholine, and muscle twitch tension were studied in vitro in the frog sartorius muscle. Nerve terminal effects were studied in vivo in the cat soleus muscle and its ventral root fibers. AH8165 stimulates the nerve terminal, as evidenced by increased MEPP frequency and the appearance of post-drug repetitive activity. In the same concentration range at which MEPP frequency is increased, MEPP amplitude, endplate sensitivity to acetylcholine, and twitch tension are decreased. This suggests that AH8165 produces muscle relaxation by blocking postsynaptic cholinergic receptors. (Key works: Neuromuscular relaxants, AH8165.).

Pharmacokinetics and pharmacodynamics of d-tubocurarine in infants, children, and adults.

The pharmacokinetics and pharmacodynamics of d-tubocurarine (dTc) were determined in neonates (0-2 months, n = 7), infants (2-12 months, n = 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 micrograms/ml in neonates, and 0.27 +/- 0.06 micrograms/ml in infants, both significantly lower than the values of 0.42 +/- 0.14 and 0.53 +/- 0.14 micrograms/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 l/kg in infants, children, and adults, respectively. The elimination half-life (t beta 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 the larger Vdss in younger patients, dose size should not differ with age. In addition, because of the longer t beta 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.

Clinical pharmacology of ORG NC45 (NorcuronTM): a new nondepolarizing muscle relaxant.

To determine the neuromuscular effects of a new muscle relaxant, ORG NC45 (Norcuron), a monoquaternary homologue of pancuronium, 84 ASA Class I or II patients were studied under halothane and nitrous oxide anesthesia. The ED50 (dose of muscle relaxant causing a 50% 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% 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 vecuronium (ORG NC45) and pancuronium in anesthetized humans.

The pharmacokinetics and pharmacodynamics of vecuronium (25-50 micrograms/kg) and pancuronium (25-50 micrograms/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 X kg-1 X min-1; mean +/- SD) and a shorter elimination half-life (71 +/- 20 min) as compared with pancuronium (1.8 +/- 0.4 ml X kg-1 X 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 (Cpss 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.