Pharmacokinetics and pharmacodynamics of propofol infusions during general anesthesia

The pharmacokinetic and pharmacodynamic properties of propofol were studied in 50 surgical patients. Propofol was administered as a bolus dose, 2 mg/kg iv, followed by a variable-rate infusion, 0-20 mg/min, and intermittent supplemental boluses, 10-20 mg iv, as part of a general anesthetic technique that included nitrous oxide, meperidine, and muscle relaxants. For a majority of the patients (n = 30), the pharmacokinetics of propofol were best described by a two-compartment model. The propofol mean total body clearance rate was 2.09 +/- 0.65 1/min (mean +/- SD), the volume of distribution at steady state was 159 +/- 57 l, and the elimination half-life was 116 +/- 34 min. Elderly patients (patients older than 60 yr vs. those younger than 60 yr) had significantly decreased clearance rates (1.58 +/- 0.42 vs. 2.19 +/- 0.64 l/min), whereas women (vs. men) had greater clearance rates (33 +/- 8 vs. 26 +/- 7 l.kg-1.min-1) and volumes of distribution (2.50 +/- 0.81 vs. 2.05 +/- 0.65 l/kg). Patients undergoing major (intraabdominal) surgery had longer elimination half-life values (136 +/- 40 vs. 108 +/- 29 min). Patients required an average blood propofol concentration of 4.05 +/- 1.01 micrograms/ml for major surgery and 2.97 +/- 1.07 micrograms/ml for nonmajor surgery. Blood propofol concentrations at which 50% of patients (EC50) were awake and oriented after surgery were 1.07 and 0.95 microgram/ml, respectively. Psychomotor performance returned to baseline at blood propofol concentrations of 0.38-0.43 microgram/ml (EC50). This clinical study demonstrates the feasibility of performing pharmacokinetic and pharmacodynamic analyses when complex infusion and bolus regimens are used for administering iv anesthetics.     

Pharmacokinetics and pharmacodynamics of atracurium during isoflurane anesthesia in normal and anephric patients

We compared the pharmacokinetics and pharmacodynamics of atracurium in eight normal and eight anephric patients during isoflurane anesthesia. Plasma concentrations were measured by high performance liquid chromatography after a single injection of 0.5 mg/kg, and neuromuscular effects were evaluated by the single twitch method. With regard to pharmacokinetic or pharmacodynamic parameters, we found no statistically significant differences between normal and anephric patients. We conclude that during isoflurane anesthesia, anephric patients distribute and eliminate atracurium much as normal patients do.     

Pharmacokinetics and pharmacodynamics of doxacurium in young and elderly patients during isoflurane anesthesia

Preliminary disposition studies of the investigational, long-acting muscle relaxant doxacurium chloride (Nuromax) have demonstrated dual elimination by renal and hepatobiliary pathways, as well as slow hydrolysis by plasma cholinesterase. The present study compares the kinetics and dynamics of doxacurium in eight ASA physical status I or II elderly patients (67-72 yr of age) and eight ASA I or II young patients (22-49 yr of age). After institutionally approved written informed consent, kinetic and dynamic measurements were made after a 25-micrograms/kg bolus injection of doxacurium during 1.25 MAC nitrous oxide/oxygen/isoflurane anesthesia. Maximum twitch depression was similar in older patients (96.4% +/- 1.3%) to that in the young patients (96.6% +/- 1.8%). The time to achieve this level of block was significantly longer in the elderly than in the young (11.2 +/- 1.1 min versus 7.7 +/- 1.0 min, respectively). Recovery times to twitch heights of 5% and 25% of control tended to be prolonged and were more variable in the elderly (82.6 +/- 17.2 and 97.1 +/- 20.1 min, respectively) than in the young (54.8 +/- 9 and 67.5 +/- 8.2 min, respectively). Elimination half-life (96 +/- 20 min) and clearance (2.47 +/- 0.69 mL.kg-1.min-1) in the elderly patients were not statistically different from values found in the younger group. Volume of distribution at steady state in the elderly (220 +/- 80.2 mL/kg) was significantly larger than in the young (150 +/- 40.0 mL/kg).(ABSTRACT TRUNCATED AT 250 WORDS)     

Pharmacokinetics of alfentanil and clinical responses during cardiac surgery

This study assessed the pharmacokinetic and pharmacodynamic behaviour of alfentanil during and after coronary artery bypass grafting (CABG). Twenty-eight patients with good ventricular function having CABG were divided into three groups and premedicated with morphine 0.1 mg.kg-1 IM, scopolamine 0.005 mg.kg-1 IM and diazepam 0.1 mg.kg-1 PO. Group I patients received an infusion of 250 micrograms.kg-1 of alfentanil over one hour coincidental with a second infusion at 2.5 micrograms.kg-1.min-1 which was continued to the end of surgery. Patients in group II received 300 micrograms.kg-1 and 3.0 micrograms.kg-1.min-1 and patients in group III 350 micrograms.kg-1 and 3.5 micrograms.kg-1.min-1. The tracheas of all patients were intubated after receiving alfentanil 96 micrograms.kg-1 and pancuronium 0.15 micrograms.kg-1. Haemodynamic responses to intubation and surgical stimuli (greater than or equal to 20 per cent increase in heart rate and/or systolic blood pressure from control) were treated with isoflurane, one to two per cent inspired, until abolished. Blood samples were taken during and after surgery for plasma alfentanil concentrations which were determined by radioimmunoassay. After surgery the times to awakening and extubation, and alfentanil elimination half-life (t1/2B = 0.693/-k) were determined for each patient. Haemodynamic responses occurred in 20 patients. There were no significant differences in any variable among the groups. The times to awakening and extubation for all patients were 3.2 +/- 0.6 and 8.8 +/- 1.2 hr (mean +/- SEM) respectively. The elimination half-life for all patients was 5.1 +/- 1.0 hr (mean +/- SEM).(ABSTRACT TRUNCATED AT 250 WORDS)     

阿芬太尼与芬太尼静吸复合全麻时对血流动力学的影响

对比观察了阿芬太尼与芬太尼对血流动力学的影响。选择ＡＳＡⅠ～Ⅱ级成年患者３６例，随机分成阿芬太尼组（ＡＦ）和芬太尼组（Ｆ）。在诱导和维持时，ＡＦ组静脉泵入阿劳太尼４０μｇ／ｋｇ和每分钟１μｇ／ｋｇ，Ｆ组静脉泵入芬大尼 ４μｇ／ｋｇ和每分钟 ０．１μｇ／ｋｇ，皆吸入 ０．５％～１．５％安氟醚和氧，并辅助维库溴胺维持麻醉。观察入室、给药后１、３、５分钟、静脉注射维库澳铵、硫喷妥钠后、插管后１、５分钟、消毒、切皮、探查、关腹、拔管后１、３分钟的血压、心率变化及给药前后血浆血管紧张素Ⅱ和醛固酮的变化。实验结果发现，ＡＦ组与Ｆ组于各观察点之间均无显著性差异，各参数的变化趋势基本相似。由于阿芬太尼较芬大尼对交感神经系统抑制作用强，临床上血流动力学指标的变化更为稳定些，可以减轻但不能完全消除插管和拔管的应激反应。     

Pharmacokinetics of midazolam and alfentanil in outpatient general anesthesia: A study with concomitant thiopentone, flumazenil or placebo administration

The pharmacokinetics of alfentanil, midazolam and thiopentone used for induction of short general anaesthesia were studied in 55 gynaecological outpatients. All the patients received midazolam as premedication. The patients received intravenous anaesthesia with alfentanil and either thiopentone or midazolam, supplemented with either nitrous oxide or air in oxygen ventilation, reversed by the end of anaesthesia with either placebo or flumazenil. Blood sampling for serum concentration measurements of midazolam, alfentanil and thiopentone was performed regularly for 7 h. The following mean pharmacokinetic parameters (mean ± –s.e.mean) were calculated for midazolam and alfentanil, respectively: elimination half–life 3.9 ± 0.3 h and 1.2 ± 0.05 h, apparent volume of distribution 107 ± 6 1 and 31 ± 1.5 1, total body clearance 20 ± 0.7 1/h and 18 ± 0.8 1/h. No influence of flumazenil on the kinetics of midazolam and no influence of thiopentone, midazolam, flumazenil or nitrous oxide on the kinetics of alfentanil was found. The serum levels of thiopentone were below the detection limit of the assay after 60 min, which made an evaluation of pharmacokinetic parameters impossible. Significant positive correlations were found in the individual patient between midazolam and alfentanil for all pharmacokinetic variables evaluated. For midazolam, an increase in the elimination half–life and the apparent volume of distribution was positively correlated to an increase of body–weight. For alfentanil, a decrease in the total body clearance and an increase in the elimination half–life were positively correlated to an increase of age. A prolonged elimination half–life of alfentanil was positively correlated to use of alcohol. High serum levels of thiopentone were positively correlated to increasing age of the patients.     

阿芬太尼静脉全麻对呼吸的影响

选择在全麻气管插管下行各种择期手术的成年病人 ４０例， ＡＳＡⅠ－Ⅱ 级。第一组为临床组（ｎ＝２０），静脉泵入阿芬太巳，诱导剂量为４０μｇ／ｋｇ，维持剂量为每分钟１μｇ／ｋｇ，第二组为对照组（ｎ＝２０），静脉泵人芬大尼，诱导剂量为４μｇ／ｋｇ，维持剂量为每分钟０．１μｇ／ｋｇ，维持期间皆吸入０．５％～１．５％安氟醚和氧气，酌情使用维库溴铵维持肌肉松弛、观察两组在人室、给药后１～５分钟和拔管０～１０分钟时的血氧饱和度、呼吸频率、潮气量的变化，实验结果发现阿芬太尼和芬太尼都具有呼吸抑制作用，且阿芬太尼的呼吸抑制作用更强。阿芬太尼还可产生迟发性呼吸抑制。因此，我们建议在临床使用阿芬太尼时保证供氧，并常规监测ＳPＯ２，术后２～４小时留恢复室观察。     

Respiratory response to skin incision during anaesthesia with infusions of propofol and alfentanil

Background. The ventilatory response to skin incision duringanaesthesia with enflurane is an increase in tidal volume withouta change in frequency. As opioids affect respiratory frequencyand also affect the processing of pain, we investigated if thebreathing response to a painful stimulus could be differentduring anaesthesia using opioids. Methods. We studied 12 patients during anaesthesia with target-controlledinfusions of propofol (plasma target concentration 4–6 µg ml^–1)and alfentanil (plasma target concentration 40–60 ng ml^–1),having varicose vein surgery. Results. After the initial skin incision, tidal volume increasedpromptly by 17 (4, 81)% (median, quartile values) (P<0.01).Respiratory frequency changed variably with no significant changeoverall [median change 2 (–8, +50)%]. The duration ofinspiration was virtually unaltered, and the duration of expirationdecreased gradually by 5 (–7, 32)%. Patients who showedmore response also showed more change in tidal volume, so thatthere was a significant relationship between increased inspiratoryflow rate and reduced expiratory time (P<0.05). Conclusions. During opioid anaesthesia, the mechanism of ventilatoryincrease after stimulation involves changes in both drive andtiming of breathing. This pattern of response does not resemblethe changes seen during anaesthesia with potent volatile agents. Br J Anaesth 2002; 88: 649–52     

Alcohol consumption alters the pharmacodynamics of alfentanil

Two groups of women, ASA physical status 1, undergoing surgery for primary breast cancer, were studied to assess the effect of alcohol intake on alfentanil pharmacodynamics. Patients in group 1 (n = 6) had an average daily consumption of 20-40 g alcohol. Patients in group 2 (n = 8) were life-long abstainers or drank only occasionally (less than 60 g per year). Anesthesia was induced and maintained with 66% N2O in O2 and alfentanil. Alfentanil was administered by a computer-controlled infusion pump. If during surgery the patient exhibited somatic, hemodynamic, or other autonomic signs of inadequate anesthesia (response), the target alfentanil plasma concentration was increased by 50-100 ng/ml. If there was no response during a 15-min period, the target concentration was decreased by 50-100 ng/ml. Arterial blood samples were taken before any change of the target concentration, 4 min after a new predicted target concentration was achieved, and at extubation. Plasma concentrations were determined by capillary gas chromatography. Alfentanil protein binding was measured by equilibrium dialysis. Plasma alfentanil concentration-effect data were analyzed by nonlinear regression, where effect was either response or no response to surgical stimuli. The average total alfentanil requirement was significantly (P less than 0.005) higher in group 1 (3.7 +/- 1.2 micrograms.kg-1.min-1) than in group 2 (1.9 +/- 0.4 micrograms.kg-1.min-1). The average Cp50 (the plasma concentration for which the probability of no response during surgery is 50%) was significantly (P less than 0.001) higher in group 1 (522 +/- 104 ng/ml) than in group 2 (208 +/- 26 ng/ml).(ABSTRACT TRUNCATED AT 250 WORDS)     

全麻病人静脉注射瑞芬太尼的药代动力学

目的评价全麻下成年病人瑞芬太尼的药代动力学。方法择期手术成年病人10例, ASA Ⅰ或Ⅱ级,在全麻平稳后静脉注射瑞芬太尼5μg·kg~(-1),分别在给药前即刻、给药后1、2、3、5、7、10、 15、20、25、30、45、60、90min 分别取动脉血1.5ml。采用高效液相色谱-质谱联用测定法测定瑞芬太尼血药浓度。结果瑞芬太尼血药浓度-时间曲线变化符合二房室模型。分布半衰期(1.6±0.5)min,消除半衰期(22±10)min,血浆清除率(2.1±0.4)L/min 及表观分布容积(66±29)L。结论本研究瑞芬太尼的药代动力学参数中表观分布容积与国外研究结果存在明显不同,提示不同种族群体间的药代动力学变化可能存在差异。     

维库溴铵按体表面积与按体重给药用于全麻患者药效学的比较

目的 比较维库溴铵按体表面积与按体重给药用于全麻患者的药效学.方法 择期全麻手术患者40例,ASA分级Ⅰ或Ⅱ级,年龄18～64岁,体重40～ 85 kg,采用随机数字表法,将其随机分为2组(n=20):按2倍体重ED95给药组(W组)和按2倍体表面积ED95给药组(S组).麻醉诱导:静脉注射异丙酚2 mg/kg和芬太尼3μg/kg,W组和S组分别静脉注射维库溴铵0.1 mg/kg和2.824mg/m2.T1达最大抑制时行气管插管,机械通气,维持呼气末二氧化碳分压35～45 mm Hg.术中维持BIS值40～50.采用Cooper评分法评估气管插管条件.记录肌松起效时间、T1最大抑制程度、临床作用时间、恢复指数、药理作用时间和维库溴铵用量,计算各指标的变异系数.结果 两组气管插管条件、起效时间、临床作用时间、恢复指数和药理作用时间的变异系数比较差异无统计学意义(P＞0.05).与W组比较,S组T1最大抑制程度和维库溴铵用量的变异系数减小(P＜0.05).结论 按2倍体表面积ED95给予维库溴铵可减少全麻患者药效学的个体差异.     

Plasma concentrations of alfentanil required to supplement nitrous oxide anesthesia for general surgery

To design an efficient infusion regimen from pharmacokinetic data, it is necessary to know the alfentanil plasma concentrations required for satisfactory anesthesia. In 37 patients about to undergo lower abdominal gynecologic, upper abdominal, or breast surgery, anesthesia was induced with alfentanil 150 micrograms/kg iv and 66% N2O in oxygen. Thereafter, N2O anesthesia was supplemented with a continuous infusion of alfentanil that was varied between 25 and 150 micrograms X kg-1 X h-1, as indicated by the patient's responses to surgical stimulation. Small bolus doses of alfentanil 7 or 14 micrograms/kg were administered and the infusion rate increased to suppress precisely defined somatic, autonomic, and hemodynamic responses. Arterial plasma concentrations of alfentanil were measured during the operation when the patient did and did not respond to noxious stimulation. Logistic regression was used to determine plasma concentration-effect curves for different stimuli. Plasma alfentanil concentrations required along with 66% N2O to obtain responses to single episodes of stimulation in 50% of the 37 patients (Cp50 +/- SE) were: 475 +/- 28 ng/ml for tracheal intubation, 279 +/- 20 ng/ml for skin incision, and 150 +/- 23 ng/ml for skin closure. Between skin incision and closure, multiple determinations of response/no response were made for each patient and an individual Cp50 was estimated. The Cp50 (mean +/- SD) for the three surgical procedures were: breast, 270 +/- 63 ng/ml (n = 12); lower abdominal, 309 +/- 44 ng/ml (n = 14); and upper abdominal, 412 +/- 135 ng/ml (n = 11). The Cp50 for satisfactory spontaneous ventilation after the discontinuation of N2O was 223 +/- 13 ng/ml. These data demonstrate that different perioperative stimuli require different alfentanil concentrations to suppress undesirable responses. Thus, the alfentanil infusion rate should be varied according to the patient's responsiveness to stimulation in order to maintain satisfactory anesthetic and operative conditions and to provide rapid recovery of consciousness and spontaneous ventilation.     

Pharmacokinetics and pharmacodynamics of triptorelin

GnRH agonists are derived from the native molecule by substitution of a D-amino acid in position 6 which increases their resistance to enzymatic breakdown and their affinity for LH-RH receptors in comparison with the native hormone. Because of this improved resistance which increases their half-life they have a super-agonistic effect. In 1973, two years only after he characterized LH-RH, A.V. Schally synthesized several GnRH analogs, including D-TRP6-LHRH obtained by substituting the glycine-6 with a D-tryptophan. The biological half life of this agonist injected by the subcutaneous route is 10 times greater than that observed after intravenous injection because of the progressive release of the peptide from the injection site. Pharmaceutical research has led to the development of delayed-release formulations allowing doses to be spaced by intervals of several weeks, or even three months when needed in some indications (Decapeptyl slow release). Triptorelin, as the other GnRH agonists, strongly reduces LH secretion, by preventing the production of the LH-beta subunit. On the opposite, the production of LH-alpha subunit is markedly increased and remains responsive to exogenous GnRH injection, demonstrating that the agonist does not induce actual pituitary desensitization. Compared with LH-RH antagonists which inhibit both LH-alpha and LH-beta subunit secretion, agonists offer the advantage of a sustained efficacy even after one or two days of withdrawal, while the effect of the agonist disappeared as soon as the administration is stopped. On the other hand, GnRH antagonists do not induce the initial hyperstimulation of the gonadotrophs, the so-called flare up, characteristic of the superagonistic effect.     

Awareness during general anesthesia

Canadian Journal of Anesthesia/Journal canadien d'anesthésie -     

Pharmacokinetics of drug infusions

In clinical practice, drugs are given by continuous infusionto maintain a predictable pharmacodynamic action. In anaesthesia,the most common route is by continuous i.v. infusion, but theextradural, subarachnoid and subcutaneous routes are also regularlyused. The effective use of drug infusions requires an understandingof both the pharmacokinetic and pharmacodynamic characteristicsof the drug used. Pharmacokinetics describe how the plasma concentrationof a drug changes over time, with the assumption that plasmawill equilibrate with an effect compartment to produce pharmacodynamicactivity. This article will describe, rather than derive equationsto explain, the pharmacokinetics of i.v. infusions and a basicunderstanding of simple models of pharmacokinetics and the relationshipsbetween parameters is assumed.