Janos Szenohradszky

Pharmacokinetics of rocuronium bromide (ORG 9426) in patients with normal renal function or patients undergoing cadaver renal transplantation.

To determine the effect of end-stage renal disease on the pharmacokinetics of reocuronium bromide (ORG 9426), a new nondepolarizing monoquaternary steroidal neuromuscular blocking drug, the authors administered 600 micrograms/kg rocuronium (2 x ED95) intravenously to ten patients undergoing cadaver renal transplantation and ten healthy patients undergoing elective minor surgery (controls). All patients were anesthetized with nitrous oxide (50-70% in oxygen) and isoflurane (end-tidal concentrations of 1.2 +/- 0.5% and 0.8 +/- 0.2%, mean +/- SD, for control and transplant groups, respectively). Plasma concentrations of rocuronium were determined by capillary gas chromatography. A population-based pharmacokinetic analysis (NONMEM) was used to determine typical values, standard errors, and interindividual variability for the pharmacokinetic parameters and to determine whether these values differed between control and renal transplant patients. Total plasma clearance (2.89 +/- 0.25 ml.kg-1.min-1, mean +/- SE) and volume of the central compartment (76.9 +/- 10.6 ml/kg) did not differ between control and renal transplant patients, whereas volume of distribution at steady state was greater in renal transplant patients (264 +/- 19 ml/kg) than in control patients (207 +/- 14 ml/kg). This resulted in a longer elimination half life in renal transplant patients (97.2 +/- 17.3 min) compared to controls (70.9 +/- 4.7 min). The authors conclude that renal failure and renal transplantation alter the distribution but not the clearance of rocuronium.

Temperature-dependent pharmacokinetics and pharmacodynamics of vecuronium.

Background The authors evaluated the influence of temperature on the pharmacokinetics and pharmacodynamics of vecuronium because mild core hypothermia doubles its duration of action. Methods Anesthesia was induced with alfentanil and propofol and maintained with nitrous oxide and isoflurane in 12 healthy volunteers. Train-of-four stimuli were applied to the ulnar nerve, and the mechanical response of the adductor pollicis was measured. Volunteers were actively cooled or warmed until their distal esophageal temperatures were in one of four ranges: < 35.0°C, 35.0–35.9°C, 36.0–36.9°C, and ≥ 37.0°C. With temperature stabilized, vecuronium was infused at 5 &mgr;g · kg−1 · min−1 until the first response of each train-of-four had decreased by 70%. Arterial blood (for vecuronium analysis) was sampled at intervals until the first response recovered to at least 90% of its prevecuronium level. Vecuronium, 20 &mgr;g · kg−1 · min−1, was then infused for 10 min, and arterial blood was sampled at intervals for up to 7 h. Population-based nonlinear mixed-effects modeling was used to examine the effect of physical characteristics and core temperature on vecuronium pharmacokinetics and pharmacodynamics. Results Decreasing core temperature over 38.0–34.0°C decreases the plasma clearance of vecuronium (11.3% per °C), decreases the rate constant for drug equilibration between plasma and effect site (0.023 min−1 per °C), and increases the slope of the concentration–response relationship (0.43 per °C). Conclusions Our results show that reduced clearance and rate of effect site equilibration explain the increased duration of action of vecuronium with reducing core temperature. Tissue sensitivity to vecuronium is not influenced by core temperature.

The pharmacokinetics and neuromuscular effects of rocuronium bromide in patients with liver disease

To determine the effect of liver disease on the pharmacokinetics of rocuronium, the authors administered 0.6 mg/kg (twice the ED95) to 10 patients with liver disease and compared these results to values in 10 healthy surgical patients. Anesthesia was induced with thiopental and maintained with isoflurane (0.9%-1.1% end-tidal concentration) and nitrous oxide (60%). Venous blood samples were obtained for 6 h after rocuronium injection and plasma concentrations were measured using gas chromatography. Pharmacokinetic differences between groups were determined using a population-based pharmacokinetic analysis (NONMEM). Hepatic impairment did not alter the plasma clearance of rocuronium (217 +/- 21.8 mL/min, mean +/- SE, for both groups), but did increase the volume of the central compartment (5.96 +/- 1.01 L for controls, 7.87 +/- 1.33 L for patients with liver disease) and volume of distribution at steady state (16.4 L for controls, 23.4 L for patients with liver disease). In turn, elimination half-life was longer in patients with liver disease (111 min) compared to controls (75.4 min). The authors conclude that liver disease alters the pharmacokinetics of rocuronium by increasing its volume of distribution. The longer elimination half-life might result in a longer duration of action of rocuronium in patients with liver disease, particularly after prolonged administration. (Anesth Analg 1995;80:754-9)

Pharmacodynamic modeling of vecuronium-induced twitch depression : Rapid plasma-effect site equilibration explains faster onset at resistant laryngeal muscles than at the adductor pollicis

Background After bolus doses of nondepolarizing muscle relaxants, the adductor pollicis recovers from paralysis more slowly than the diaphragm and the laryngeal adductors, suggesting that the adductor pollicis is more sensitive than the respiratory muscles to effects of those drugs. In contrast, during onset, the respiratory muscles are paralyzed more rapidly than the adductor pollicis, suggesting that the respiratory muscles are more sensitive than the adductor pollicis. To reconcile these apparently conflicting findings, we determined vecuroniums pharmacokinetics and its pharmacodynamics at both the adductor pollicis and the laryngeal adductors. Methods Six volunteers were studied on two occasions during anesthesia with propofol. Mechanical responses to train‐of‐four stimulation were measured at the adductor pollicis and at the laryngeal adductors. Vecuronium (15–60 micro gram/kg) was given and arterial plasma samples were obtained from 0.5–60 min. Vecuronium doses differed by twofold on the two occasions. A pharmacokinetic model accounting for the presence and potency of vecuroniums 3‐desacetyl metabolite and a sigmoid e‐max pharmacodynamic model were fit to the resulting plasma concentration and effect (adductor pollicis and laryngeal adductors) data to determine relative sensitivities and rates of equilibration between plasma and effect site concentrations. Results The steady‐state plasma concentration depressing laryngeal adductor twitch tension by 50% was approximately 1.5 times larger than that for the adductor pollicis. The equilibration rate constant between plasma and laryngeal adductor concentrations was about 1.5 faster than that between plasma and adductor pollicis concentrations. The Hill factor (gamma) that describes the steepness of the laryngeal adductor concentration‐effect relation was approximately 0.6 times that of the adductor pollicis. Conclusions More rapid equilibration between plasma and laryngeal adductor vecuronium concentrations explains why onset is more rapid at the laryngeal adductors than at the adductor pollicis. During recovery, both rapid equilibration and lesser sensitivity of the laryngeal adductors contribute to earlier recovery.

Central nervous system effects of intrathecal muscle relaxants in rats

&NA; When given for a sufficient time and dose intravenously, neuromuscular blocking drugs eventually can enter the cerebrospinal fluid (CSF). To study the potential pharmacologic consequences of neuromuscular blocking drugs in the CSF, a model was developed in the rat by using an intrathecal infusion of these drugs. A cannula was stereotaxically implanted in a lateral cerebral ventricle of anesthetized male Sprague‐Dawley rats (250‐300 g). Several days later, the effects of an intraventricular infusion (5 μL/min) of atracurium (0.804 μmol/mL), pancuronium (0.172 μmol/mL), and vecuronium (21.978 μmol/mL) were studied in unanesthetized rats. These rats (n = 6 in each group) exhibited dose‐dependent hyperexcitability during drug infusion, with seizures occurring at threshold doses of (mean), 0.12, 0.26, and 0.065 ± 0.010 and 3.32 μmol/kg of atracurium, pancuronium, and vecuronium, respectively. The neuromuscular ED50 (intravenous dose required to produce a 50% depression of twitch tension) in rats determined by other investigators are 0.408, 0.115, and 0.352 μmol/kg for atracurium, pancuronium, and vecuronium, respectively. Therefore, seizure threshold doses were not related to the potencies of these drugs as neuromuscular blocking drugs. Based on these data, central nervous system effects were studied over the subseizure dose range approximating 1/100, 1/10, and 1/5 of the cumulative dose causing seizures for each drug (n = 5 for each dose). At 1/100 of seizure dose, decreased locomotor activity and piloerection occurred. At 1/10 to 1/5 of seizure dose, agitation, shivering, splayed limbs, and whole body shaking resulted. We have demonstrated also that at concentrations similar to those in the CSF at seizure threshold doses, atracurium, pancuronium, and vecuronium produce increases in intracellular calcium in rat cortical brain slices in vitro, suggesting a possible mechanism for seizure activity. We conclude that neuromuscular blocking drugs injected directly into the CSF cause dose‐dependent central nervous system excitation and seizures. Although species and possible dosage differences prevent any clinical applications, we propose that these results in rats indicate that possible central nervous system effects of neuromuscular blocking drugs in patients receiving these drugs for several days deserves exploration. (Anesth Analg 1993;76:1304‐9)

Improving the Design of Muscle Relaxant Studies: Stabilization Period and Tetanic Recruitment

Background The results from studies of muscle relaxants show wide variations among institutions. The authors hypothesized that some of this variability could be explained by differences in duration of nerve stimulation before drug administration (stabilization period). Methods Train‐of‐four stimulation was applied every 12 s to both ulnar nerves and adductor pollicis twitch tension was measured in anesthetized participants given 30 micro gram/kg vecuronium. In phase 1, the stabilization period was > 30 min for both extremities. In phases 2–4, stabilization period was 20 min for one extremity and 2 min for the other. In addition, in phase 3, a 2‐s 50‐Hz tetanus initiated the 2‐min stimulation period; in phase 4, duration of tetanus was 5 s. Twitch recovery was recorded until stable for more than 15 min. Time to 25% recovery (clinical duration) was calculated based on two indices: predrug and final (recovery) twitch tension. Values for onset and clinical duration were compared by paired parametric and nonparametric tests. Results In phase 1, predrug and recovery twitch tension were similar in each extremity, and onset and clinical duration did not differ between extremities, permitting paired comparisons in remaining studies. In phase 2, onset was more rapid with 20‐min of prestimulation. With 20‐min prestimulation, predrug and recovery twitch tension were similar; with 2‐min prestimulation, recovery twitch tension exceeded predrug values. When referenced to predrug twitch tension, clinical duration was shorter with 2‐min, than with 20‐min prestimulation. Initiating stimulation with 2‐s or 5‐s 50‐Hz tetani (phases 3, 4) abolished differences between extremities in onset and recovery. Conclusions With only train‐of‐four stimulation (no tetani), onset and clinical duration vary with duration of prestimulation, suggesting that a brief period of predrug stimulation is inadequate. However, lengthy prestimulation may be impractical in clinical studies. Tetanic stimulation for 2 or 5 s obviates the need for prolonged stabilization during studies of muscle relaxants.

Activation of brain acetylcholine receptors by neuromuscular blocking drugs. A possible mechanism of neurotoxicity.

Background:Neuromuscular blocking drugs cause excitement and seizures when introduced Into the central nervous system. We examined the possibility that these drugs produce paradoxical activation of acetylcholine or glutamate receptors, the chief types of brain receptors involved in excitatory neurotransmission. Methods:Because activation of central glutamate or acetylcholine receptors causes calcium influx into postsynaptic neurons, we measured intracellular calcium concentration ([Ca2+]1) as an index of receptor activation. Changes in [Ca2+], were compared in brain slices exposed to neuromuscular blocking drugs or acetylcholine and glutamate receptor agonists. [Ca2+]1 was measured with the fluorescent dye fura-2. Results:Pancuronium and vecuronium caused sustained increases in [Ca2+]1 in approximately the same potency ratio as for seizure activity in vivo (concentrations at which the Increase in [Ca2+ ]1 was 95% of maximal: 100 and 400 μm, respectively). Atracurium and laudanosine did not increase [Ca2+]1 in cortical slices. Increases in [Ca2+]1 caused by both pancuronium and vecuronium were prevented by the non-subtype-specific nicotinic acetylcholine receptor antagonist D-tubo-curarine and were reduced 44–73% by atropine. Blockade of glutamate receptors or voltage-gated calcium or sodium channels had no effect on calcium influx. Conclusions:The results suggest that the acute excitement and seizures caused by Introduction of pancuronium and vecuronium into the central nervous system is due to accumulation of cytosolic calcium caused by sustained activation of acetylcholine receptor ion channels.

Influence of Chronic Phenytoin Administration on the Pharmacokinetics and Pharmacodynamics of Vecuronium

BackgroundThe duration of action of vecuronium is reduced in patients receiving phenytoin. In this study, the authors examined, simultaneously, the influence of phenytoin on both the pharmacokinetics and the pharmacodynamics of vecuronium. MethodsThis study was approved by the institutional review board of the University of California, San Francisco, and patients gave written informed consent. Twenty-two patients, 11 taking phenytoin and all scheduled to undergo prolonged neurosurgical procedures with general anesthesia, participated in the study. In 12 patients (6 phenytoin, 6 control), vecuronium was infused at 7.5 &mgr;g · kg−1 · min−1 until the first response (T1) of each train-of-four decreased by 50%; in the remaining 10 patients (5 phenytoin, 5 control), 200 &mgr;g/kg vecuronium was infused over 10 min. Arterial blood samples were drawn at intervals over the next 5–7 h. Plasma concentrations of vecuronium and 3-desacetylvecuronium were measured by capillary gas chromatography. Pharmacokinetic and pharmacodynamic modeling was used to characterize the disposition of vecuronium and patient responses to it in the two groups. ResultsClearance was typically increased by 138% (95% confidence interval, 93–183%) in patients taking phenytoin. The effect of vecuronium was well described using a sigmoid Emax model. The concentration of vecuronium giving 50% twitch depression was increased 124% (45–202%) in patients taking phenytoin. ConclusionsChronic phenytoin therapy reduces the effect of vecuronium by mechanisms that include both increased vecuronium metabolism and reduced sensitivity of the patient to circulating concentrations of vecuronium.

The effect of neostigmine on twitch tension and muscle relaxant concentration during infusion of mivacurium or vecuronium.

Background An investigation suggested that neostigmine may not effectively antagonize mivacurium, presumably because neostigmine impairs mivacuriums metabolism. However, the effect of neostigmine on mivacuriums metabolism in vivo has not been reported. Therefore, the effect of neostigmine on neuromuscular function and plasma mivacurium concentrations during constant mivacurium infusion was determined.

Effect of edrophonium and neostigmine on the pharmacokinetics and neuromuscular effects of mivacurium.

Background: Previous studies demonstrated that both edrophonium and neostigmine affect mivacurium’s pharmacokinetics, thereby potentially affecting its recovery profile. However, those studies were not clinically relevant because mivacurium was still infused after the antagonists were given. In the present study, the authors gave antagonists (or placebo) after discontinuing a mivacurium infusion, thereby obtaining data that are more clinically relevant. Methods: In 18 patients, mivacurium was infused at 10 &mgr;g · kg−1 · min−1 for 40 min, the infusion was discontinued for 15 min and then restarted at the same rate for another 40 min. Patients were randomized to receive 500 &mgr;g/kg edrophonium, 50 &mgr;g/kg neostigmine, or saline at discontinuation of the second infusion; all subjects received 1 mg atropine. Plasma was sampled during the final 10 min of each infusion to determine steady state mivacurium concentrations and for 15 min after each infusion. Twitch tension was recorded. Mivacurium concentrations after each of the two infusions were compared. Results: After discontinuation of the second infusion, mivacurium concentrations were larger than those after the first infusion at 2 min with edrophonium and at 2, 4, and 7 min with neostigmine. With both neostigmine and edrophonium, twitch tension recovered after infusion #2 more rapidly than after infusion #1; however, the magnitude of this effect was small. Conclusion: Edrophonium transiently slows the rate at which mivacurium concentrations decrease; this is consistent with our previous findings. Neostigmine has a similar, although longer, effect. Despite altering mivacurium’s elimination characteristics, both drugs facilitate neuromuscular recovery, although their benefit is small.