Pharmacokinetics Of Vecuronium Research Articles

Vecuronium Pharmacokinetics in Patients With Major Burns

Abstract Background Burn patients develop resistance to non-depolarizing neuromuscular blocking agents (NDNMBAs) and require a significantly large dose to produce a desired clinical response. Pathophysiological changes related to burn injury may alter pharmacokinetics (PK) and pharmacodynamics of NDNMBAs. The purpose of this study was to compare vecuronium PK in burns vs non-burns. Methods Twenty adults, aged 23–58 yr, with 27–81% total body surface area (TBSA) burn, were studied at 4–57 post-burn days and compared with age- and sex-matched, non-burn controls. Vecuronium 0.12 mg kg −1 was given i.v. as a single bolus within 10 s. Blood samples ( n =20) were collected over 12 h at predetermined time points. NONMEM was used to describe plasma drug concentration–time profiles for burns and non-burns. Results A three-compartment model best described vecuronium concentration–time profiles. Burn patients showed enhanced distributional clearance at the terminal phase (0.12 vs 0.095 litre min −1 , P vs 6.6 h, P Conclusions The altered drug distribution between tissues may partially explain the known resistance to vecuronium in patients with major burns.

Vecuronium pharmacokinetics in patients with major burns

BackgroundBurn patients develop resistance to non-depolarizing neuromuscular blocking agents (NDNMBAs) and require a significantly large dose to produce a desired clinical response. Pathophysiological changes related to burn injury may alter pharmacokinetics (PK) and pharmacodynamics of NDNMBAs. The purpose of this study was to compare vecuronium PK in burns vs non-burns. MethodsTwenty adults, aged 23–58 yr, with 27–81% total body surface area (TBSA) burn, were studied at 4–57 post-burn days and compared with age- and sex-matched, non-burn controls. Vecuronium 0.12 mg kg−1 was given i.v. as a single bolus within 10 s. Blood samples (n=20) were collected over 12 h at predetermined time points. NONMEM was used to describe plasma drug concentration–time profiles for burns and non-burns. ResultsA three-compartment model best described vecuronium concentration–time profiles. Burn patients showed enhanced distributional clearance at the terminal phase (0.12 vs 0.095 litre min−1, P<0.0001), which yielded shorter elimination half-life for vecuronium (5.5 vs 6.6 h, P<0.001). BURN was the single most significant covariate that explained the altered vecuronium disposition in burns. ConclusionsThe altered drug distribution between tissues may partially explain the known resistance to vecuronium in patients with major burns.

The Efficacy of Intratracheal Administration of Vecuronium in Rats, Compared with Intravenous and Intramuscular Administration

To investigate the suitability of the intratracheal (IT) route as an alternative route for the administration of vecuronium, we compared the pharmacodynamic parameters for neuromuscular block in three groups of rats given vecuronium via the IT, IM, and IV routes. We also examined the pharmacokinetics of vecuronium in the three groups. The doses for the IT, IV, and IM groups were set at 1.50, 0.300, and 2.25 mg/kg, respectively. The onset of action in the IT group (127 +/- 17 s) was significantly earlier than that in the IM group (267 +/- 62 s), and significantly later than that in the IV group (18 +/- 7 s) (P < 0.05 by analysis of variance and the Tukey-Kramer analysis). The duration of action in the IT group (794 +/- 162 s) was significantly longer than that in the IV group (93 +/- 30 s) but not significantly different from that in the IM group (743 +/- 131 s). The recovery index in the IT group (134 +/- 30 s) was significantly shorter than that in the IM group (222 +/- 47 s) and significantly longer than that in the IV group (32 +/- 12 s). Although IT administration of vecuronium is still slower than IV administration, it appears to be more advantageous as compared with IM administration, given the more rapid absorption and faster onset of action.

Influence of Hypothermia on Pharmacokinetics of Vecuronium in Rat Livers Investigated.

Influence of Hypothermia on Pharmacokinetics of Vecuronium in Rat Livers Investigated.Beaufort et al.(page 270)Beaufort et al. used an isolated perfused rat liver model with a fairly constant perfusion rate to elucidate the influence of hypothermia on the uptake of vecuronium in the intact organ. The researchers divided each perfusion experiment into three phases: (1) a 950-μg bolus of vecuronium was administered, followed by a continuous infusion of vecuronium throughout the experiment; (2) temperature was reduced to 28°C; and (3) temperature was restored to 38°C. In control experiments, temperature was kept constant throughout the perfusion procedure. Concentrations of vecuronium and its metabolites were measured in the perfusion medium, in bile collected from the livers, and in liver homogenate.The team found that hypothermia increased the amount of vecuronium in the perfusion medium and that, when normal temperatures were restored, this amount decreased. Although hypothermia reversibly reduced the net uptake of vecuronium to the liver, biliary excretion remained virtually intact. Hypothermia drastically reduced the biliary excretion rate of 3-desacetyl vecuronium in contrast to that of the parent compound. Researchers were able to measure metabolism of vecuronium in only one of three liver homogenate preparations, and they found in that case that hypothermia reduced the rate of conversion by a factor of 2. Pharmacokinetic analysis showed that the hypothermia-induced changes in the pharmacokinetics of vecuronium could be described adequately only by the combination of reduced hepatic net uptake and reduced metabolism. These results show the need for effective measurement of muscle relaxants during hypothermia to prevent overdosing.

Pharmacokinetics and pharmacodynamics of vecuronium in rats with systemic inflammatory response syndrome: treatment with NG-monomethyl-L-arginine.

Insufficient detoxification caused by nitric oxide-related inhibition of cytochrome P450 may be important for metabolism of numerous drugs, including vecuronium. The present study investigated the pharmacodynamics and pharmacokinetics of vecuronium in rats with inflammatory liver dysfunction. Male Sprague-Dawley rats (n = 56) were randomly allocated into two groups: In the sepsis group, liver inflammation was established by injection of 56 mg/kg heat-killed Corynebacterium parvum; control rats received the solvent. At day 4, groups were subdivided according to treatment with the nitric oxide synthase inhibitor N(G)-monomethyl-L-arginine (250 mg/kg) or placebo. The aminopyrine breath test was performed to assess cytochrome P450 activity. Rats were anesthetized with propofol and mechanically ventilated. Duration of action of vecuronium (1.2 mg/kg) was measured by evoked mechanomyography (stimulation of the sciatic nerve, contraction of the gastrocnemius muscle). In seven rats of each subgroup a 50% neuromuscular blockade was established by a continuous vecuronium infusion. Vecuronium plasma levels were measured and plasma clearance of vecuronium was calculated. Nitric oxide synthesis was assessed by measuring nitrite/nitrate serum levels. In sepsis/placebo rats, vecuronium-induced neuromuscular blockade was prolonged (144% of contro/placebo), vecuronium plasma levels at 50% neuromuscular blockade were increased (122% of control/placebo), and plasma clearance was decreased (68% of control/placebo). N(G)-monomethyl-L-arginine therapy in rats with sepsis improved cytochrome P450 activity and plasma clearance of vecuronium, shortened duration of action of vecuronium, but did not alter the elevated vecuronium plasma levels. A systemic inflammatory response syndrome with liver dysfunction results in decreased sensitivity to and a decreased elimination of vecuronium. Modulation of nitric oxide synthesis may be a strategy that can be used in the future to improve xenobiotic metabolism in sepsis.

Do the Pharmacokinetics of Vecuronium Change During Prolonged Administration in Critically Ill Patients?

Neuromuscular blocking drugs may be administered over several days to patients in the intensive care unit (ICU), but their pharmacokinetics have been studied at only one point in time, or assumed to be constant throughout the period of administration. We sought to determine if, in individual patients, the pharmacokinetics of vecuronium changed over the course of its administration in the ICU. In six critically ill patients, we measured plasma vecuronium concentrations during two periods: first, during initial administration of vecuronium and second, after its administration continuously for 3-6 days. A pharmacokinetic model was fitted to these plasma concentration data, and its parameters permitted to vary between the periods to determine if they had altered. Individual clearance values during the study ranged from 1.4 to 4.4 ml kg-1 min-1. During prolonged administration, vecuronium clearance increased in three and decreased in two patients. This change ranged from a 61% decrease to a 58% increase, and was not linked to any clinical factor. The steady-state volume of distribution (range 368-1765 ml kg-1; median 494 ml kg-1) did not change in any patient during the study. The change in clearance of vecuronium during its prolonged administration in critically ill patients suggests that future studies of neuromuscular blocking drugs in the ICU should take account of their changing pharmacokinetics over the course of administration.

The Pharmacokinetics of Vecuronium in Male and Female Patients

The Pharmacokinetics of Vecuronium in Male and Female Patients

The Pharmacokinetics of Vecuronium in Male and Female Patients

To evaluate the effect of gender on the pharmacokinetics of vecuronium, we studied 30 patients (15 male and 15 female) undergoing elective plastic surgery with anticipated surgical blood loss of <300 mL under general anesthesia.General anesthesia was induced with thiopental 4-6 mg/kg and fentanyl 2-4 [micro sign]g/kg and was maintained with 60% nitrous oxide in oxygen and an end-tidal concentration of 1.5%-2% enflurane. After a 2-min infusion of vecuronium 100 [micro sign]g/kg, a modified fluorometric assay was used to determine the plasma concentrations of vecuronium for 5 h. The results showed that, compared with women, the plasma concentrations of vecuronium in men were significantly lower during the first 20 min and that the disposition kinetics of vecuronium can be best described mathematically by a three-compartment open model in the two groups. The volume of the central compartment and the volume of distribution at steady state were 39.6 +/- 8.6 and 164.8 +/- 29.3 mL/kg, respectively, in women. These values increased significantly to 54.4 +/- 14.4 and 201.4 +/- 75.8 mL/kg in men (P < 0.05). When the data were calculated on the basis of ideal body weight, the volume of distribution of vecuronium was also different between men and women (P < 0.05. The half-lives of fast distribution and distribution, the elimination half-life, mean residual time, area under the plasma-concentration curve, and plasma clearance were not different between the two groups. We conclude that the pharmacokinetics of vecuronium are significantly different between genders and that and men have the greater volume of distribution of vecuronium. Implications: The authors found that, compared with women, men had lower plasma concentrations of vecuronium after the IV administration of vecuronium and a larger volume of distribution of vecuronium. The pharmacokinetic differences may be related to the differences in the sensitivity to vecuronium between genders. (Anesth Analg 1998;86:1322-7)

Do the pharmacokinetics of vecuronium change during prolonged administration in critically ill patients?

Neuromuscular blocking drugs may be administered over several days to patients in the intensive care unit (ICU), but their pharmacokinetics have been studied at only one point in time, or assumed to be constant throughout the period of administration. We sought to determine if, in individual patients, the pharmacokinetics of vecuronium changed over the course of its administration in the ICU. In six critically ill patients, we measured plasma vecuronium concentrations during two periods: first, during initial administration of vecuronium and second, after its administration continuously for 3-6 days. A pharmacokinetic model was fitted to these plasma concentration data, and its parameters permitted to vary between the periods to determine if they had altered. Individual clearance values during the study ranged from 1.4 to 4.4 ml kg-1 min-1. During prolonged administration, vecuronium clearance increased in three and decreased in two patients. This change ranged from a 61% decrease to a 58% increase, and was not linked to any clinical factor. The steady-state volume of distribution (range 368-1765 ml kg-1; median 494 ml kg-1) did not change in any patient during the study. The change in clearance of vecuronium during its prolonged administration in critically ill patients suggests that future studies of neuromuscular blocking drugs in the ICU should take account of their changing pharmacokinetics over the course of administration.

Pharmacokinetics of vecuronium during acute isovolaemic haemodilution

To evaluate the effect of acute isovolaemic haemodilution on the pharmacokinetics of vecuronium, we studied 13 patients undergoing haemodilution during surgery and 13 control patients. General anaesthesia was induced with thiopentone 4-6 mg kg-1 and fentanyl 2-4 micrograms kg-1, and maintained with enflurane and 60% nitrous oxide in oxygen. The haemodilution patients underwent major elective plastic surgery with an anticipated surgical loss of more than 600 ml. Haemodilution was achieved by drainage of venous blood and i.v. infusion of lactated Ringer's solution and 6% dextran, during which the packed cell volume and haemoglobin concentration decreased from 45% to 28.1% and from 14.7 g dl-1 to 9.1 g dl-1, respectively. After administration of a bolus of vecuronium 100 micrograms kg-1, an improved fluorimetric assay was used to measure the plasma concentrations of vecuronium for 5 h. The results showed that the disposition kinetics of vecuronium were best described mathematically by a three-compartment open model in the two groups. The mean volume of the central compartment and volume of distribution at steady state were 42.3 (SD 11.8) ml kg-1 and 168.4 (31.5) ml kg-1, respectively, in control patients, and significantly greater (55.2 (13.4) ml kg-1 and 225.9 (53.3) ml kg-1) in the haemodilution patients (P < 0.05). The elimination half-life was 50.3 (11.5) min in control patients and significantly greater (68.2 (15.1) min) in the haemodilution patients (P < 0.05). The half-lives of fast distribution and distribution, mean residual time, area under the plasma concentration curve and plasma clearance were unchanged in patients who underwent haemodilution compared with the control group.

The use of a PID controller to model vecuronium pharmacokinetics and pharmacodynamics during liver transplantation. Proportional-integral-derivative.

A four-phase proportional-integral-derivative (PID) controller was evaluated under the extremely unstable conditions of liver transplantation. Vecuronium was delivered to achieve 80%-90% neuromuscular blockade as measured by electromyogram (EMG). The first two controller phases delivered boluses and a constant infusion calculated to rapidly achieve setpoint, followed by a proportional-derivative (PD) phase at 35% from setpoint, and PID within 10% of the setpoint. During liver transplantation, the sources of system instability included large blood losses, temperature changes, and loss of hepatic drug metabolism during removal and replacement. During prolonged surgery, and when blood losses were not severe, the EMG remained within 10% of setpoint. Controller performance was more variable during system instability. Plasma sampling and two-compartment modelling of the infusion and response with a weighting factor for blood loss allowed estimation of the sources and degree of instability for improved design of future controllers.

Pharmacokinetics of Rocuronium After Bolus and Continuous Infusion During Halothane Anaesthesia

Comment Intermediate-duration neuromuscular blocking drugs such as vecuronium and atracurium may be administered by IV infusion during long operations or in intensive care settings. The pharmacokinetics of vecuronium and atracurium infusions have been described previously. This investigation characterized the pharmacokinetics of rocuronium when administered by an infusion after a bolus intubating dose. Rather than administering a standardized infusion rate, these investigators targeted the infusion rate to a specific clinical endpoint: maintenance of T1 at 10% of control values. Thus, not only do we obtain a clinically applicable “typical” infusion rate (0.5 mg/kg/hr), but we can appreciate the interpatient variability in the infusion needs (which were relatively constant at 0.45–0.6 mg/kg/hr). Also of practical importance was the determination of the time required for return of neuromuscular function after cessation of the infusion: 30–36 min for return to 90% of T1 and train-of-four of 0.7. In addition to these clinical guidelines for the use of rocuronium infusions, we find that the pharmacokinetic values for rocuronium were similar after bolus and continuous infusion administration. This should aid individuals in designing infusion regimens for this drug. One caveat should be mentioned, however, in interpreting this investigation. Only eight patients were studied, and only two patients received the rocuronium infusion for more than 60 min. Thus, the pharmacokinetic data are based on a very limited number of patients, and the results may not be applicable to infusions of longer duration, such as in intensive care settings.

High-performance liquid chromatography—electrochemical detection of vecuronium and its metabolites in human plasma

A high-performance liquid chromatographic assay coupled with electrochemical detection has been developed for the determination of vecuronium and its three putative deacetylated metabolites in human plasma. A novel solid-phase extraction procedure allowed good recovery of both vecuronium and its metabolites, together with ease and speed of execution. This method was sensitive, reproducible and accurate over the therapeutic range of concentrations of vecuronium and its metabolites, and was applied successfully to a study of the pharmacokinetics of vecuronium in anaesthetized patients.

The Pharmacodynamics and Pharmacokinetics of Vecuronium in Patients Anesthetized with Isoflurane with Normal Renal Function or with Renal Failure

The Pharmacodynamics and Pharmacokinetics of Vecuronium in Patients Anesthetized with Isoflurane with Normal Renal Function or with Renal Failure

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.

Pancuronium and vecuronium pharmacokinetics and pharmacodynamics in younger and elderly adults.

To evaluate the effect of aging on the distribution, metabolism, and neuromuscular junction sensitivity to pancuronium and vecuronium, the authors determined the pharmacokinetics and pharmacodynamics of these drugs in 12 healthy elderly subjects (70-84 yr) and 12 young adults (30-57 yr) during halothane-nitrous oxide anesthesia. Plasma concentrations of the muscle relaxants were determined using a selective ion-monitoring mass spectrometric technique specific for the parent compound. For vecuronium, plasma clearance (3.7 +/- 1.0 and 5.2 +/- 0.8 ml X kg-1 X min-1, respectively), and volume of distribution at steady-state (179 +/- 31 and 244 +/- 38 ml X kg-1, respectively) were lower in the elderly than in young adults; values for distribution half-lives, elimination half-life, and sensitivity of the neuromuscular junction were similar for the two groups. For pancuronium, there were no statistically significant differences between groups for these pharmacokinetic or pharmacodynamic parameters. However, there was a trend toward reduced clearance (20%) and prolonged elimination half-life (16%) in the elderly as compared to the younger patients. The authors conclude that healthy elective surgical patients between the ages of 70 and 84 yr of age do not differ markedly from younger adults in their pharmacokinetic/pharmacodynamic response to vecuronium and pancuronium.

More about the Pharmacokinetics of Vecuronium and Pancuronium

More about the Pharmacokinetics of Vecuronium and Pancuronium