Influence of chronic phenytoin administration on the pharmacokinetics and pharmacodynamics of vecuronium

BACKGROUND: The 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. METHODS: This 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 microg x kg(-1) x 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 microg/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. RESULTS: Clearance 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. CONCLUSIONS: Chronic 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.     

Pharmacokinetics and pharmacodynamics of vecuronium bromide

The pharmacokinetics and pharmacodynamics of vecuronium bromide were studied in patients under general anesthesia of enflurane and nitrous oxide in oxygen. Eighteen patients were randomly divided into two groups which received either 0.05mg·kg^–1 (low dose group) or 0.20mg·kg^–1 (high dose group) of vecuronium intravenously. The plasma concentration of vecuronium was determined by high performance liquid chromatography. The neuromuscular blocking effect was assessed by measuring the twitch tension of the adductor pollicis muscle elicited by supramaximal electrical stimulation. Pharmacokinetic analysis was carried out using a two compartment model.The relationship between the T4/T1 and T1/ control T1 ratios differed during onset and spontaneous offset of the blockade; the T4/T1 ratios were significantly higher during onset than during offset, although there were large variations of fade in the train-of-four response in each patient during offset. These results suggest that it is difficult to estimate the T1/control T1 ratio by the T4/T1 ratio during offset.Pharmacokinetic analysis revealed that the high dose group had a shorter elimination half-life than did the low dose group. A shorter elimination half-life at a high dose may be to some extent due to hepatic clearance. The pharmacokinetic parameters bore no fixed relationship to the pharmacodynamics in each patient.(Nomura T: Pharmacokinetics and pharmacodynamics of vecuronium bromide. J Anesth 6: 28–37, 1992)     

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.     

Pharmacokinetics and pharmacodynamics of vecuronium and pancuronium in anesthetized children

The pharmacokinetics and pharmacodynamics of vecuronium and pancuronium were determined in 12 children (3-6 yr) undergoing minor surgery under 60% nitrous oxide, 1 MAC halothane anesthesia. When the level of anesthesia and the electromyograph (EMG) recording of the adductor pollicis were stable, an intravenous bolus of vecuronium (100 micrograms/kg) or pancuronium (100 micrograms/kg) was administered. Plasma concentrations of the two muscle relaxants were determined for 6 hr after the administration by means of a fluorimetric assay followed by a thin layer chromatography. Plasma concentrations of vecuronium and pancuronium declined biexponentially in children and no metabolites could be detected in plasma. The elimination half-lives of vecuronium and pancuronium did not differ significantly. The volume of distribution at steady state (Vdss) was greater (P less than 0.05) after vecuronium (320 +/- 181 ml/kg; mean +/- SD) than after pancuronium (203 +/- 36 ml/kg). Plasma clearance of vecuronium (2.8 +/- 0.9 ml X min-1 X kg-1) was greater than that of pancuronium (1.7 +/- 0.2 ml X min-1 X kg-1; P less than 0.05). Plasma concentrations measured at 10%, 50%, or 90% recovery of the EMG response did not differ significantly for vecuronium and pancuronium. Thus the shorter duration of action of vecuronium is probably due to its greater apparent volume of distribution, as well as to its higher plasma clearance. Thus although the elimination half-lives are comparable, the plasma disappearance of vecuronium is more rapid than that of pancuronium.     

Pharmacokinetics and pharmacodynamics of vecuronium in the obese surgical patient.

The effect of obesity on the disposition and action of vecuronium was studied in 14 surgical patients. After induction of anesthesia with thiopental and maintenance of anesthesia by inhalation of nitrous oxide and halothane, seven obese patients (93.4 +/- 13.9 kg, 166% +/- 30% of ideal body weight, mean +/- SD) and seven control patients (60.9 +/- 12.3 kg, 93% +/- 6% of ideal body weight) received 0.1 mg/kg of vecuronium. Plasma arterial concentrations of muscle relaxant were determined at 1, 3, 5, 10, 15, 20, 30, 45, 60, 90, 120, 150, 180, 210, 240, 300, and 360 min by a spectrofluorometric method. Simultaneously, neuromuscular blockade was assessed by stimulation of the ulnar nerve and quantification of thumb adductor response. Times to 50% recovery of twitch were longer in the obese than in the control patients (75 +/- 8 versus 46 +/- 8 min) as were 5%-25% recovery times (14.9 +/- 4.0 versus 10.0 +/- 1.7 min) and 25%-75% recovery times (38.4 +/- 13.8 versus 16.7 +/- 10.3 min). However, vecuronium pharmacokinetics were similar for both groups. When the data were calculated on the basis of ideal body weight (IBW) for obese and control patients, total volume of distribution (791 +/- 303 versus 919 +/- 360 mL/kg IBW), plasma clearance (4.65 +/- 0.89 versus 5.02 +/- 1.13 mL.min-1.kg IBW-1), and elimination half-life (119 +/- 43 versus 133 +/- 57 min) were not different between groups.(ABSTRACT TRUNCATED AT 250 WORDS)     

影响丙泊酚药代动力学及药效学的因素

丙泊酚为一种较理想的静脉麻醉药,广泛应用于临床.但影响其药物代谢动力学及药效学的凶素较多,如年龄、性别、体重、血液稀释、复合用药等,因此临床应用时应综合考虑患者生理、病理特点及其他因素,个体化用药.     

A comparison of the pharmacodynamics of rocuronium and vecuronium during halothane anaesthesia

Thirty healthy patients were randomised to receive either a single bolus dose of rocuronium 0.6 mg.kg-1 or vecuronium 0.1 mg.kg-1 during halothane anaesthesia. Onset time, duration 25, duration 75 and train-of-four 70 were measured. The onset of neuromuscular blockade following rocuronium was more rapid than vecuronium (p = 0.0001). All other pharmacodynamic parameters were similar. During the first minute following injection of the neuromuscular blocking agent, the heart rate increased by 36% in the rocuronium group but remained stable in those patients who received vecuronium (p = 0.0008). No adverse effects were noted in either group.     

Midazolam pharmacodynamics and pharmacokinetics during acute hypovolemia

This study was designed to test the hypothesis that acute hypovolemia would compromise the compensatory hemodynamic mechanisms to midazolam and decrease its metabolic clearance. Experiments were performed on seven chronically instrumented female beagle dogs. Animals received a single intravenous dose of midazolam, 10 mg/kg, 4 days apart during normovolemic (N) and hypovolemic (H) states in a random sequence. Hypovolemia was achieved by the withdrawal of 26 ml/kg of blood, equivalent to one-third of the calculated blood volume. Midazolam plasma concentrations were determined at 0.25, 0.5, 1, 2, 3, 4, 5, 6, 8, 10, and 12 h after midazolam injection. Elimination half-life (t 1/2 beta) was significantly longer and total clearance was significantly lower during H than during N. Initial distribution half-life, central compartment volume, total volume of distribution, and plasma protein binding were similar in both N and H states. Midazolam caused a significant decrease in systolic blood pressure (SBP) and an increase in heart rate (HR) during N, and produced significant decreases in SBP, diastolic blood pressure (DBP), and mean arterial pressure (MAP) during H. Midazolam led to similar per cent decreases in blood pressure and cardiac output in states N and H; however, the absolute values of blood pressure and cardiac output were significantly (P less than 0.001) lower in the hypovolemic state than in the normovolemic state. These data suggest that the hypotensive effects of midazolam, like those of other intravenous induction agents, could be potentiated by volume depletion.     

Mechanisms of drug interactions: pharmacodynamics and pharmacokinetics

The classification of drug interactions is first considered in this article, with an explanation of the terminology. Emphasis is placed on the importance of the topic in relation to the polypharmacy employed in anaesthesia and critical care. Pharmacodynamic interactions are then discussed. Further classification of these interactions is explained using examples of drugs in everyday use in anaesthesia and critical care medicine. Non-specific pharmacodynamic interactions are considered at some length, being the largest group of drug interactions that occur in anaesthesia. Synergy and summation are extremely relevant to anaesthetic practice and are employed in both induction and maintenance of anaesthesia everyday. The article then explains pharmacokinetic interactions under the headings of absorption, distribution, metabolism and elimination. Again, emphasis is placed on drugs used in current practice to highlight the relevance of each type of interaction to the reader.     

Mechanisms of drug interactions: pharmacodynamics and pharmacokinetics

The classification of drug interactions is first considered in this article, with an explanation of the terminology. Emphasis is placed on the importance of the topic in relation to the polypharmacy employed in anaesthesia and critical care. Pharmacodynamic interactions are then discussed. Further classification of these interactions is explained using examples of drugs in everyday use in anaesthesia and critical care medicine. Non-specific pharmacodynamic interactions are considered at some length, being the largest group of drug interactions that occur in anaesthesia. Synergy and summation are extremely relevant to anaesthetic practice and are employed in both induction and maintenance of anaesthesia everyday. The article then explains pharmacokinetic interactions under the headings of absorption, distribution, metabolism and elimination. Again, emphasis is placed on drugs used in current practice to highlight the relevance of each type of interaction to the reader.     

The pharmacodynamics and pharmacokinetics of mivacurium in children

BACKGROUND: In children, onset time and duration of action of mivacurium are shorter than in adults. Some suggest that this is due to differences in plasma cholinesterase (pChe), whereas others indicate that there is no difference. The purpose of this study was to evaluate the pharmacodynamics and pharmacokinetics of mivacurium in phenotypically normal children aged 3-6 and 10-14 years old, respectively. METHODS: Ten children aged 3-6 years and 10 children aged 10-14 years were studied during halothane anaesthesia. Before induction of anaesthesia, a blood sample was drawn to measure the pChe activity and phenotype. The neuromuscular block was monitored at the thumb using train-of-four (TOF) nerve stimulation every 12 s and mechanomyography. The times to different levels of neuromuscular recovery following mivacurium 0.2 mg/kg were recorded. The concentrations in venous blood of the three isomers and the metabolites of mivacurium were measured. RESULTS: No statistically significant difference was found in pChe activity or in the pharmacodynamics of mivacurium. The onset time was 1.4 min (0.8-1.9) median (range) and 1.3 min (1.1-1.9) and the time to first response to TOF nerve stimulation was 9.6 min (6.5-12.6) and 10.5 min (7.0-14.0) in young and older children, respectively. The pharmacokinetic data were too sparse to allow analysis of the two age groups separately (8 and 8 patients), hence the data were pooled. The median clearances of the cis-cis, the cis-trans, and the trans-trans isomer were 5.5, 51.0 and 30.5 ml/kg/min, respectively. CONCLUSION: Our data indicate that there are no major differences in pharmacodynamics or pharmacokinetics of mivacurium between young (3-6 years) and older (10-14 years) children.     

Mechanisms of drug interactions: pharmacodynamics and pharmacokinetics

The classification of drug interactions is first considered in this article, with an explanation of the terminology. Emphasis is placed on the importance of the topic in relation to the polypharmacy employed in anaesthesia and critical care. Pharmacodynamic interactions are then discussed. Further classification of these interactions is explained using examples of drugs in everyday use in anaesthesia and critical care medicine. Non-specific pharmacodynamic interactions are considered at some length, being the largest group of drug interactions that occur in anaesthesia. Synergy and summation are extremely relevant to anaesthetic practice and are employed in both induction and maintenance of anaesthesia everyday. The article then explains pharmacokinetic interactions under the headings of absorption, distribution, metabolism and elimination. Again, emphasis is placed on drugs used in current practice to highlight the relevance of each type of interaction to the reader.     

Comparative pharmacokinetics and dynamics of vecuronium and pancuronium in anesthetized patients

Plasma concentrations and the degree of neuromuscular blockade after a 2-min infusion of 0.1 mg/kg of vecuronium bromide or pancuronium bromide (equipotent doses) were studied in 12 gynecologic patients. The plasma concentrations of both drugs declined in a triphasic manner. The difference between the intercepts and rate constants of the two drugs was not significant. Vecuronium was removed faster from the plasma than pancuronium; this was reflected in a significantly larger plasma clearance rate for vecuronium (4 ml X min-1 X kg-1 vs 1.1 ml X min-1 X kg-1 for pancuronium). The effective plasma concentrations at 50% recovery of the twitch height were 0.11 +/- 0.02 (vecuronium) and 0.2 +/- 0.03 microgram/ml (pancuronium). The disposition kinetics were adequately described by a three-compartment model. An effect compartment was added to the model to correlate the neuromuscular effects and plasma concentrations of both drugs. The ratio between concentrations of vecuronium and pancuronium in the effect compartment at 50% twitch height was 0.83. In spite of its greater potency, vecuronium has a shorter duration of action than pancuronium.     

Mechanisms of drug interactions II: pharmacokinetics and pharmacodynamics

This article complements that of Corrie and Hardman (2011) as it dwells specifically on drug interactions in pharmacokinetics. It emphasizes how pharmacokinetics is influenced by drug–drug and drug–disease interactions. Common examples, in anaesthesia and intensive care settings, are illustrated. It then concludes in reaffirming pharmacodynamic interactions in the article cited.     

氯普鲁卡因硬膜外阻滞时的药效学和药代动力学

目的通过对氯普鲁卡因（2-CP）在硬膜外阻滞时药效学和药代动力学的研究,探讨不同年龄因素及加入肾上腺素的2-CP进入硬膜外腔后在人体的吸收、分布和消除规律。方法选择ASAⅠ或Ⅱ级、在连续硬膜外阻滞下行择期下腹部手术患者30例,根据年龄和用药的不同随机分为三组,每组10例。青壮年组（C组）,年龄为30-55岁,以3％2-CP 6mg／kg行硬膜外阻滞;肾上腺素组（CE组）,青壮年患者,以3％2-CP6mg／kg加入1：200000肾上腺素行硬膜外阻滞;老年组（CO组）,年龄65岁以上,以3％2-CP6mg／kg行硬膜外阻滞。分别观察局麻药起效时间、运动阻滞起始时间和运动阻滞程度;用高效液相色谱仪测定注药后3、6、9、11、13、15、17、20、30、45、60、90min血浆2-CP浓度。用药代动力学计算程序（3p97）进行血药浓度数据处理,计算药代动力学参数。结果三组的局麻药起效时间、运动阻滞起始时间和运动阻滞程度差异均无统计学意义。三组的血浆药物浓度峰值（Cmax）分别为：（0．47±0．31）、（0．32±0．22）、（0．58±0．39）mg／L;血药浓度达峰时间（Tmax）分别为：（8．71±3．45）、（7．84±3．42）、（6．42±4．84）min;血浆药物浓度-时间曲线下面积（AUC）分别为：（9．16±4．09）、（8．66±3．47）、（7．71±3．82）μg·min^-1·ml^-1;清除速率常数（K）分别为：（0．53±0．48）、（0．45±0．42）、（0．52±0．42）／min。以上参数三组间比较差异均无统计学意义。结论1：200000肾上腺素和年龄对3％2-CP行硬膜外阻滞的药代动力学和药效学无明显影响。     

Pharmacokinetics and pharmacodynamics of vecuronium (ORG NC 45) in patients with cirrhosis

To evaluate the effect of liver cirrhosis on the pharmacokinetics and the pharmacodynamics of vecuronium, 12 patients with cirrhosis, aged (mean +/- SD) 52 +/- 12 yr, and 14 control patients, 42 +/- 15 yr, undergoing elective surgery under general anesthesia were studied. The simultaneous time courses of the plasma concentration of vecuronium and of the neuromuscular blockade were studied after the administration of a bolus dose of 0.2 mg X kg-1. Vecuronium plasma concentration declined biexponentially in both groups. Vecuronium plasma clearance was reduced significantly (P less than 0.01) from 4.26 +/- 1.38 ml X min-1 X kg-1 in the controls to 2.73 +/- 1.19 ml X min-1 X kg-1 in the patients with cirrhosis. The elimination half-life was 58 +/- 19 min in the controls and was prolonged significantly to 84 +/- 23 min (P less than 0.01) in the patients with cirrhosis. The total apparent volume of distribution was unchanged in patients with cirrhosis (0.253 +/- 0.086 1 X kg-1 vs. 0.246 +/- 0.092 1 X kg-1 in the controls). Cirrhosis caused a prolongation of the neuromuscular blockade induced by vecuronium: the duration of effect from injection to 50% recovery of the twitch height was prolonged by 100% (P less than 0.01) from 62 +/- 16 min in the controls to 130 +/- 52 min in patients with cirrhosis. The recovery rate (TH 25-75) also was prolonged (P less than 0.05) from 21 +/- 7 min in the controls to 44 +/- 18 min in patients with cirrhosis.(ABSTRACT TRUNCATED AT 250 WORDS)     

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.