Effect Compartment Concentration Research Articles

Paracetamol (acetaminophen) pharmacodynamics: interpreting the plasma concentration

Interpretation of analgesic and antipyretic responses documented after paracetamol administration is confused because response is not directly related to concentration in the blood, but rather to an effect compartment. The...

Use of a target-controlled infusion system for propofol does not improve subjective assessment of anaesthetic depth by inexperienced anaesthesiologists*

Target-controlled infusion, via the calculated effect compartment concentrations, may help anaesthesiologists to titrate anaesthetic depth and to shorten recovery from anaesthesia. In this prospective, randomized clinical study, we compared the performance of six inexperienced anaesthesiologists with <1 yr of training when using target- or manually controlled infusion of propofol, combined with manual dosing of fentanyl. Ninety-two premedicated ASA I-III patients undergoing minor elective urological or gynaecological surgery were assigned to the manual- or target-controlled infusion group. Bispectral index was recorded in a blinded manner. Subjective assessment of anaesthetic depth on a 10 point numerical scale (1 = very deep anaesthesia, 10 = awake) was asked at regular intervals and the correlation with the blinded bispectral index was analysed using the prediction probability, PK. The propofol concentration profile was calculated post hoc. Propofol administration was similar in both groups with no significant difference for the administered amount and concentrations of propofol. Recovery times were also not different. In both groups, a large percentage of the bispectral index data points recorded during surgery showed bispectral index values below the recommended value of 40, but in the target-controlled infusion group there were significantly less bispectral index values above the recommended upper limit of 60 (2.5% vs. 5.1%). A target-controlled infusion system does not help inexperienced anaesthesiologists to assess anaesthetic depth or to shorten recovery times, but may reduce episodes of overly light anaesthesia and thus help to prevent awareness.

Pharmacokinetics/Pharmacodynamics of Acetaminophen Analgesia in Japanese Patients with Chronic Pain

Acetaminophen (APAP) is a popular analgesic. In the present study, we characterized the pharmacokinetics and pharmacodynamics of APAP in the Japanese. Five healthy volunteers were administered 1000 mg of APAP orally. Five patients with chronic pain were administered the optimal oral dose of APAP ranging from 600 to 1000 mg to allow for an adequate analgesic effect. Plasma APAP and APAP metabolite concentrations were measured in the volunteers, plasma APAP concentrations and pain scores using a visual analog scale were measured in the patients with chronic pain. Patient data were fitted to a first-order absorption one-compartment model with delayed effects accounted for by an effect compartment. A sigmoid Emax model was used as the pharmacodynamic model. Acetaminophen-cysteine metabolites, which are conjugates of the toxic metabolite N-acetyl-p-benzoquinone-imine, were detected in the plasma at levels lower than 0.2 microg/ml, but no side effects were observed. The pharmacokinetic and pharmacodynamic parameter (mean+/-S.D.) estimates were as follows: clearance, 18.7+/-4.7 l/h; distribution volume, 30.9+/-6.8 l; absorption rate constant, 2.4+/-1.3 h(-1); rate constant for the elimination of APAP from the effect compartment, 1.3+/-0.5 h(-1); maximum pain relief score, 4.6+/-2.2 units; effect compartment concentration at 50% maximum, 2.0+/-1.2 microg/ml; and sigmoid factor, 1.3+/-0.7. These results suggest that these parameters can be used to determine an effective APAP dosage regimen for Japanese patients with chronic pain.

PK-PD modeling of irbesartan in healthy Chinese adult volunteers under non-steady-state conditions

The purpose of this study was to construct a pharmacokinetic/pharmacodynamic model (PK-PD model) of irbesartan in healthy Chinese adult volunteers under non-steady-state conditions and provide relevant PK/PD parameters for use in clinical practice. Thirty-six healthy Chinese adult male volunteers received 150 or 300 mg irbesartan orally in tablet form (2 groups; n = 18 per group). Plasma concentrations were determined by HPLC and pharmacological effects, including effects on systolic (SBP) and diastolic blood pressure (DBP) were measured simultaneously. The experimental data were quantitatively analyzed according to the PK-PD model construct. PK/PD parameters were calculated. Blood pressure remained almost unchanged at an irbesartan dose of 150 mg under non-steady-state conditions. After a single dose of 300 mg, the pharmacokinetic profiles of irbesartan conformed to a two-compartment model. There were hysteresis loops between drug effects and plasma concentrations. The relationship between effects and effect compartment concentrations (Ce) could be represented by the sigmoid-Emax model. The Emax values for the inhibitory effects on SBP and DBP of irbesartan were 14.8 +/- 1.5 and 9.8 +/- 2.1 mmHg respectively, the EC50 values were 0.29 +/- 0.11 and 0.18 +/- 0.07 microg x ml(-1), while the K(eo) values were 0.62 +/- 0.09 and 0.68 +/- 0.07 h(-1), respectively. The PK-PD model of irbesartan was developed in healthy Chinese adult male volunteers, and may provide a more rational basis for dosage individualization.

Effect-compartment equilibrium rate constant (keo) for propofol during induction of anesthesia with a target-controlled infusion device

The effect-compartment concentration (C(e)) of a drug at a specific pharmacodynamic endpoint should be independent of the rate of drug injection. We used this assumption to derive an effect-compartment equilibrium rate constant (k(eo)) for propofol during induction of anesthesia, using a target controlled infusion device (Diprifusor). Eighteen unpremedicated patients were induced with a target blood propofol concentration of 5 microg x ml(-1) (group 1), while another 18 were induced with a target concentration of 6 microg x ml(-1) (group 2). The time at loss of the eyelash reflex was recorded. Computer simulation was used to derive the rate constant (k(eo)) that resulted in the mean C(e) at loss of the eyelash reflex in group 1 being equal to that in group 2. Using this population technique, we found the k(eo) to be 0.57 min(-1). The mean (SD) effect compartment concentration at loss of the eyelash reflex was 2.39 (0.70) microg x ml(-1). This means that to achieve a desired C(e) within 3 min of induction, the initial target blood concentration should be set at 1.67 times that of the desired C(e) for 1 min, after which it should revert to the desired concentration.

A-Line, Bispectral Index, and Estimated Effect-Site Concentrations: A Prediction of Clinical End-Points of Anesthesia

Autoregressive modeling with exogenous input of middle-latency auditory evoked potentials (A-Line AEP index, AAI) has been developed for monitoring depth of anesthesia. We investigated the prediction of recovery and dose-response relationship of desflurane and AAI or bispectral index (BIS) values. Twenty adult men scheduled for radical prostatectomy were recruited. To minimize opioid effects, analgesia was provided by a concurrent epidural in addition to the general anesthetic. Electrodes for AAI and BIS monitoring and a headphone for auditory stimuli were applied. Propofol and remifentanil were used for anesthetic induction. Maintenance of anesthesia was with desflurane only. For comparison to AAI and BIS monitor parameters, pharmacokinetic models for desflurane and propofol distribution and effect-site concentrations were used to predict clinical end-points (Prediction probability P(K)). Patients opened their eyes at an AAI value of 47 +/- 20 and a BIS value of 77 +/- 14 (mean +/- sd), and the prediction probability for eye opening was P(K) = 0.81 for AAI, P(K) = 0.89 for BIS, and P(K) = 0.91 for desflurane effect-site concentration. The opening of eyes was best predicted by the calculated desflurane effect-site concentration. The relationship between predicted desflurane effect-site concentration versus AAI and BIS was calculated by nonlinear regression analysis (r = 0.75 for AAI and r = 0.80 for BIS). The correlation between BIS and clinical end-points of anesthesia or the desflurane effect-compartment concentration is better than for the AAI.

Pharmacokinetics and Pharmacodynamics of a 0.1 mg/kg Dose of Cisatracurium Besylate in Children During N2O/O2/Propofol Anesthesia

We studied the pharmacokinetics and pharmacodynamics of cisatracurium in 9 children (mean weight, 17.1 kg) aged 1-6 yr (mean, 3.75 yr) during propofol-nitrous oxide anesthesia. Neuromuscular monitoring was performed. Venous samples were taken before injection of a 0.1 mg/kg dose of cisatracurium and then at 2, 5, 10, 30, 60, 90, and 120 min. Cisatracurium plasma concentrations were determined by high performance liquid chromatography. Onset time was 2.5 +/- 0.8 min, recovery to 25% of baseline twitch height was 37.6 +/- 10.2 min, and the 25%-75% recovery index was 10.9 +/- 3.7 min. Distribution and elimination half-lives were 3.5 +/- 0.9 min and 22.9 +/- 4.5 min, respectively. Steady-state volume of distribution (0.207 +/- 0.031 L/kg) and total body clearance (6.8 +/- 0.7 mL/min/kg) were significantly larger than those published for adults. Pharmacodynamic results were comparable to those obtained in pediatric studies during halothane or opioid anesthesia with the exception of a longer recovery to 25% baseline. Although the plasma-effect compartment equilibration rate constant was twofold faster (0.115 +/- 0.025 min(-1)) than that published for cisatracurium in adults, the effect compartment concentration corresponding to 50% block was similar (129 +/- 27 ng/mL).

Pharmacokinetic–pharmacodynamic relationship of rocuronium under stable nitrous oxide–fentanyl or nitrous oxide–sevoflurane anesthesia in children

The aim of this study was to compare pharmacokinetics and pharmacokinetic-pharmacodynamic (PK-PD) relationship of rocuronium in children anesthetized with nitrous oxide (N2O) and fentanyl or with N2O and sevoflurane. Twenty-four children (3-11 years old, ASA PS I or II) were randomized to receive N2O/O2-fentanyl or N2O/O2-sevoflurane (one MAC) anesthesia. Neuromuscular transmission was monitored electromyographically. Initial bolus dose of rocuronium, 0.6 mg x kg(-1) was followed by continuous infusion, targeting at steady-state 95% T1 depression. Neuromuscular transmission was allowed to recover spontaneously. Plasma samples were collected at the moment of discontinuation of infusion, and 10, 20, 30, 50, 60 and 75 min afterwards. Concentrations of rocuronium were measured using high-performance liquid chromatography with electrochemical detection (HPLC-EC). Rocuronium PK was described by a two-compartment model and PD parameters were estimated using effect compartment and sigmoidal E(max) models. No differences in rocuronium PK parameters were observed between study groups. Clearance was 3.91 +/- 2.07 and 3.62 +/- 0.80 ml x min(-1) x kg(-1) in sevoflurane and fentanyl groups, respectively (P < 0.65). Effect compartment concentrations corresponding to 50% inhibition of T1 (EC50) were 1.41 +/- 0.45 and 2.32 +/- 1.00 microg x ml(-1) (P < 0.02), and rate constants for equilibration between plasma and effect compartment (k(e0)) values were 0.10 +/- 0.04 and 0.24 +/- 0.14 min(-1) (P < 0.009) in sevoflurane and fentanyl groups, respectively. Disposition of rocuronium was similar under stable N2O-fentanyl and N2O-sevoflurane anesthesia. Sevoflurane reduced rocuronium requirements as well as decreased EC50 relevant to inhibition of T1 and rocuronium transfer to effect compartment. Therefore, the potentiating effect of sevoflurane seems to be mainly of PD origin, probably due to an increased sensitivity of the neuromuscular junction.

Comparison of entropy and narcotrend indexes during TCI of propofol

Objective To compare the entropy with narcotrend indexes during the period of propofol induction and tracheal intubation. Methods Eighteen patients of ASA Ⅰ-Ⅱ were inducted by target-controlled infusion (TCI) of propofol, target was set according to the effect compartment concentration (Ce), stepwise increasing (0.5 mg/L) method was used, after the final Ce (6 mg/L) was achieved, orotracheal intubation was performed. Observer’s assessment of alertness/sedation scale (OAA/S) was used to detect the changes of consciousness. Response entropy (RE), state entropy (SE), stages and values of narcotrend (NT), MAP and HR were recorded at each step of Ce, and the time-point of before, immediately, and 1min to 10min after tracheal intubation. Results Scores of OAA/S scale were decreased with the increases of Ce of propofol. Ce according to OAA/S score of 2 and 0 were 2.0±0.6 mg/L and 2.2±0.6 mg/L, respectively. Values of RE, SE, and NT were decreased gradually with the increases of Ce, especially the NT values. The Spearman rank correlation coefficient between Ce and RE, SE, NT values were -0.83,-0.80 and -0.86 (P0.01), respectively. RE, SE, and NT values at the point of 2.0 mg/L of Ce were significantly lower than those of baseline. Compared to the values of before intubation, RE and SE of immediately after intubation were significantly increased (P0.05), MAP and HR at the time-point of 1min and 2min after intubation were also increased(P0.05), however, values and stages of NT had no statistically significant changes during the period of intubation. Conclusions Both Entropy and Narcotrend indexes can reflect promptly the changes of consciousness during the induction of propofol, and they have a close correlation with the effect compartment concentration of propofol, especially the stages and values of NT. Entropy index (RE and SE) and hemodynamic indictors (MAP and HR), but Narcotrend index (stages and values), can reflect the stimulation of tracheal intubation.

Pharmacokinetic and Pharmacodynamic Interaction Between Irbesartan and Hydrochlorothiazide in Renal Hypertensive Dogs

Combined irbesartan/hydrochlorothiazide (HCTZ) formulations are often used clinically. Pharmacokinetic-pharmacodynamic (PK/PD) modeling was applied to investigate the pharmacokinetic and pharmacodynamic interaction between irbesartan and HCTZ in renal hypertensive dogs at non-steady-state and steady-state. The renal hypertensive dogs were treated with oral irbesartan alone, or HCTZ alone, or the combination of irbesartan and HCTZ for 8 days. Blood pressure and plasma concentrations were measured and pharmacokinetic-pharmacodynamic parameters were analyzed. Irbesartan showed a two-compartment model pharmacokinetic profile. The concentration-time course of irbesartan was not changed by HCTZ, but irbesartan increased the peak plasma concentration and area under the curve of HCTZ at steady-state. HCTZ had no blood pressure lowering effect at non-steady-state. Irbesartan plus HCTZ had greater blood pressure lowering action than irbesartan alone. HCTZ increased actions of irbesartan. Hysteresis loops were found between effect and plasma concentrations of irbesartan after a single dose. However, hysteresis loops disappeared at steady state with more rapid realization of maximum concentration and effects. The relationship between effects and effect-compartment concentrations of the drugs was represented by a sigmoid Emax model. The results suggest synergistic pharmacodynamic interaction between irbesartan and HCTZ in renal hypertensive dogs and some differences of pharmacokinetic-pharmacodynamic properties between irbesartan and irbesartan/HCTZ combinations at non-steady-state and steady state.

Impact of peripheral elimination on the concentration–effect relationship of remifentanil in anaesthetized dogs

This study elucidates the impact of sampling site when estimating pharmacokinetic-pharmacodynamic (PK-PD) parameters of drugs such as remifentanil that undergo tissue extraction in the biophase. The interrelationship between the concentrations of remifentanil predicted for the effect compartment and those measured in arterial, venous, and cerebrospinal fluid were investigated under steady-state conditions. Following induction of anaesthesia with pentobarbital, an arterial cannula (femoral) and two venous catheters (jugular and femoral) were inserted. Electrodes were placed for EEG recording of theta wave activity. Each dog received two consecutive 5-min infusions for the PK-PD study and a bolus followed by a 60-min infusion was started for the steady-state study. Cerebrospinal fluid, arterial and venous blood samples were drawn simultaneously after 30, 40, and 50 min. At the end of the infusion, arterial blood samples were collected for pharmacokinetic analysis. Remifentanil PK-PD parameters based on theta wave activity were as follows: apparent volume of distribution at steady-state (V(ss)) (231+/-37 ml kg(-1)), total body clearance (Cl) (63+/-16 ml min(-1) kg(-1)), terminal elimination half-life (t(1/2 beta)) (7.71 min), effect compartment concentration at 50% of maximal observed effect (EC(50)) (21+/-13 ng ml(-1)), and equilibration rate constant between plasma and effect compartment (k(e0)) (0.48+/-0.24 min). The mean steady-state cerebrospinal fluid concentration of 236 ng ml(-1) represented 52 and 74% of that in arterial and venous blood, respectively. Our study re-emphasizes the importance of a sampling site when performing PK-PD modelling for drugs undergoing elimination from the effect compartment. For a drug undergoing tissue elimination such as remifentanil, venous rather than arterial concentrations will reflect more exactly the effect compartment concentrations, under steady-state conditions.

Pharmacokinetic and pharmacodynamic of irbesartan in renal hypertensive dogs under non-steady-state and steady-state conditions

The aim of this study was to investigate the pharmacokinetic and pharmacodynamic properties of irbesartan in renal hypertensive dogs under non-steady-state and steady-state conditions using pharmacokinetic-pharmacodynamic (PK/PD) modeling. Drugs were administered intragastrically to renal hypertensive dogs, plasma drug concentration was determined by HPLC method and Pharmacologic effects, including SBP, DBP, dp/dtmax and LVSP, were measured simultaneously. AT II, Aldosterone (ALD) and Endothelin (ET) were also used as measurement of effect. The PK and PD data were quantitatively analyzed according to the PK/PD model theory. The pharmacokinetic profiles of irbesartan conformed to a two-compartment open model. There was hysteresis loops between effects and plasma concentrations under non-steady-state condition. The relationship between effects and effect compartment concentrations (Ce) could be represented by the Sigmoid-Emax model. The Hysteresis loops disappeared under steady-state condition with more rapidly attainment of maximum concentration and effect. There were certain difference of pharmacokinetic and pharmacodynamic properties between non-steady-state and steady-state condition.

Application of Bispectral Index and Narcotrend index to the measurement of the electroencephalographic effects of isoflurane with and without burst suppression.

The Narcotrend monitor (MonitorTechnik, Bad Bramstedt, Germany) has recently been introduced as an intraoperative monitor of anesthetic state, based on a classification scheme originally developed for visual assessment of the electroencephalogram. The authors compared the performance of the Narcotrend index (software version 4.0) to the Bispectral Index (BIS, version XP; Aspect Medical Systems, Natick, MA) as electroencephalographic measures of isoflurane drug effect during general anesthesia. The authors observed 15 adult patients scheduled to undergo radical prostatectomy with a combined epidural-isoflurane general anesthesia technique. At least 45 min after induction of general anesthesia, during a phase of constant surgical stimulation, end-tidal isoflurane concentrations were varied between 0.5 and 2.0 multiples of minimum alveolar concentration, and the BIS and the Narcotrend index were recorded. The prediction probability (PK) was calculated for the BIS and the Narcotrend index to predict isoflurane effect compartment concentration for each measure. The correlation analysis of the BIS and the Narcotrend index with the isoflurane effect compartment concentration was obtained by pharmacodynamic modeling based on two sigmoidal curves to account for the discontinuity in both indices with the onset of burst suppression. The prediction probabilities were indistinguishable (BIS PK = 0.72 +/- 0.07 (mean +/- SD); range, 0.61-0.84; Narcotrend index PK = 0.72 +/- 0.10; range, 0.51-0.87), as were the correlations between the electroencephalographic measures and isoflurane effect compartment concentrations (BIS R = 0.82 +/- 0.12; Narcotrend index R = 0.85 +/- 0.09). The pharmacodynamic models for the BIS and the Narcotrend index yielded nearly identical results. The BIS and the Narcotrend index detected the electroencephalographic effects of isoflurane equally. Combining two fractional sigmoid Emax models adequately described the data before and after the onset of burst suppression.

A novel method of deriving the effect compartment equilibrium rate constant for propofol

Calculation of the effect compartment concentration (Ce) in non-steady-state conditions requires the equilibrium rate constant, keo. Most studies of propofol derive the keo using EEG measurements. This study investigated an alternative method. Starting from a predicted concentration-time profile, a keo value was included so that the predicted Ce at a specific pharmacodynamic end-point was the same when using three different methods of injection. Seventy-five patients were given propofol for induction of anaesthesia. Twenty-five patients received a single bolus, 25 patients received an infusion, and 25 patients received a bolus followed by an infusion. Computer simulation was used to derive the central compartment concentration. The keo that brought about the same value for Ce at loss of the eyelash reflex using the three methods of injection was derived. Keo was found to be 0.80 min(-1). Mean (SD) Ce at loss of the eyelash reflex was 2.27 (0.69) microg ml(-1). The effect compartment equilibrium rate constant and concentration at loss of the eyelash reflex can be derived without the use of electronic central nervous system monitors.

Concentration-effect relation of succinylcholine chloride during propofol anesthesia.

The pharmacokinetics and pharmacodynamics of succinylcholine were studied simultaneously in anesthetized patients to understand why the drug has a rapid onset and short duration of action. A quantitative model describing the concentration-effect relation of succinylcholine was proposed. The correlation between hydrolysis in plasma and elimination was also examined. Before induction of anesthesia, blood was drawn for analysis in seven adults. Anesthesia was induced with propofol and remifentanil. Single twitch stimulation was applied at the ulnar nerve every 10 s, and the force of contraction of the adductor pollicis was measured. Arterial blood was drawn frequently after succinylcholine injection to characterize the front-end kinetics. Plasma concentrations were measured by mass spectrometry, and pharmacokinetic parameters were derived using compartmental and noncompartmental approaches. Pharmacokinetic-pharmacodynamic relations were estimated. The mean degradation rate constant in plasma (1.07 +/- 0.49 min(-1)) was not different from the elimination rate constant (0.97 +/- 0.30 min(-1)), and an excellent correlation (r2 = 0.94) was observed. Total body clearance derived using noncompartmental (37 +/- 7 ml x min(-1) x kg(-1)) and compartmental (37 +/- 9 ml x min(-1) x kg(-1)) approaches were similar. The plasma-effect compartment equilibration rate constant (k(eo)) was 0.058 +/- 0.026 min(-1), and the effect compartment concentration at 50% block was 734 +/- 211 ng/ml. Succinylcholine is a low-potency drug with a very fast clearance that equilibrates relatively slowly with the effect compartment. Its disappearance is greatly accountable by a rapid hydrolysis in plasma.

Application of semilinear canonical correlation to the measurement of the electroencephalographic effects of volatile anaesthetics.

The common parameters of the electroencephalogram quantify a shift of its power spectrum towards lower frequencies with increasing anaesthetic drug concentrations (e.g. spectral-edge frequency 95). These ad hoc parameters are not optimized for the content of information with regard to drug effect. Using semilinear canonical correlation, different frequency ranges (bins) of the power spectrum can be weighted for sensitivity to changes of drug concentration by multiplying their power with iteratively determined coefficients, yielding a new (canonical univariate) electroencephalographic parameter. Electroencephalographic data obtained during application of volatile anaesthetics were used: isoflurane (n = 6), desflurane (7), sevoflurane (7), desflurane during surgical stimulation (12). Volatile anaesthetic end-tidal concentrations varied between 0.5 and 1.6 minimum alveolar concentration (MAC). The canonical univariate parameter and spectral-edge frequency 95 were determined and their correlation with the volatile anaesthetic effect compartment concentration, obtained by simultaneous pharmacokinetic-pharmacodynamic modelling, were compared. The canonical univariate parameter with individually optimized coefficients, but not with mean coefficients, was superior to the spectral-edge frequency 95 as a measure of anaesthetic drug effect. No significant differences of the coefficients were found between the three volatile anaesthetics or between the data with or without surgical stimulus. The coefficients for volatile anaesthetics were similar to the coefficients for opioids, but different from coefficients for propofol and midazolam. The canonical univariate parameter calculated with individually optimized coefficients, but not with mean coefficients, correlates more accurately and consistently with the effect site concentrations of volatile anaesthetics than with spectral-edge frequency 95.

Predicted effect compartment concentration of thiopental at loss of eyelash reflex

We derived the predicted effect compartment concentration of thiopental, at loss of the eyelash reflex, following three different injection regimens. Sixty patients were given thiopental for induction of anaesthesia. Twenty patients received multiple small boluses, 20 patients received a single bolus and 20 patients received an infusion. Computer simulation was then used to derive the effect compartment concentration. The median concentration was not significantly different between the three groups. EC50, derived after combining all three groups was 11.3 microg ml(-1). The EC05-EC95 range was 6.9-18.3 microg ml(-1), suggesting wide inter-individual variation.

Isoflurane, nitrous oxide, and fentanyl pharmacodynamic interactions in surgical patients as measured by effects on median power frequency

Study Objective: To identify and quantify the simultaneous interactions of isoflurane, nitrous oxide (N2O), and fentanyl during surgical procedures. The slowing of the EEG to a median power frequency of 2 Hz to 3 Hz was chosen as the measure of pharmacodynamic drug effect.Design: Prospective, randomized, open label.Setting: Operating room of a university hospital.Patients: 65 ASA physical status I and II patients undergoing gynecological laparatomies.Interventions: 25 patients received no fentanyl. 20 patients received a loading dose of 100 μg fentanyl and a continuous infusion of 70 μg · h−1 fentanyl. Calculated effect compartment concentrations were 0.7 ng · ml−1 between the first and second hours after induction of anesthesia. Another 20 patients received a loading dose of 200 μg fentanyl and a continuous infusion of 150 μg · h−1 fentanyl; the respective effect compartment concentrations were 1.5 ng · ml−1. N2O was randomly administered in concentrations of 0, 20, 40, and 60 vol%; in the group that did not receive fentanyl, we additionally investigated 75 vol% N2O. Each patient received two different N2O concentrations, with each combination of N2O and fentanyl finally applied to ten patients. Isoflurane vaporizer settings were chosen so that the median power frequency was held between 2 Hz and 3 Hz. The type and degree of interaction among the three anesthetic drugs was analyzed based on a generalized isobole approach.Measurements and Main Results: The interaction of isoflurane, N2O, and fentanyl is compatible with additivity. A model with regard to the relative potencies and age dependency is given by:Isoflurane conc.c0,iso·10a·(age−35)+N2O conc.c0,N2O·10a·(age−35)+Fentanyl conc.c0,fen·10a·(age−35)=1.0

Pharmacokinetic-pharmacodynamic modeling of risperidone effects on electroencephalography in healthy volunteers.

CNS-active drugs produce specific electroencephalographic changes and the concentration-effect relationship of antipsychotics may be elucidated by adopting electroencephalography (EEG) as an effect measurement tool. The purpose of the present study was to determine the concentration-effect relationship of risperidone by assessing the EEG effect after oral administrations of single dose risperidone in healthy young males. Nine healthy male volunteers received a 1 mg single oral dose of risperidone according to a placebo controlled crossover design. Plasma levels of risperidone and its active metabolite 9-hydroxyrisperidone were measured by radioimmunoassay. Quantitative EEG parameters were obtained for each of four frequency bands through spectral EEG analysis. The difference in the absolute power in the delta frequency band for the F3 lead between risperidone and placebo was used as a drug effect parameter. For pharmacokinetic-pharmacodynamic modeling, the hypothetical effect compartment kinetically linked to plasma by a first-order process was postulated. All curve fittings were done with the non-linear curve-fitting program NONLIN. Our results showed that absolute powers in delta and theta frequency bands were higher for risperidone administration than for placebo at all EEG leads, and the maximum effects were detected at about 3 h after administration of the drug. The hysteresis loop was observed in the plot of plasma concentration of risperidone or sum of risperidone and 9-hydroxyrisperidone (Cp) versus EEG effect for each subject. A linear model adequately described the relationship between the effect compartment concentrations (Ce) and EEG effects, and the two limbs of hysteresis in the Cp-effect plot were collapsed in the Ce-effect plot for risperidone or risperidone plus 9-hydroxyrisperidone. The increases of absolute power for delta and theta frequency bands of EEG were induced by single oral administration of risperidone. The linear PK-PD model fit well with the relationship between effect compartment concentrations (Ce) and EEG effects of risperidone.

Deep sedation and mechanical ventilation without paralysis for 3 weeks in normal beagles: exaggerated resistance to metocurine in gastrocnemius muscle.

Patients in the intensive care unit may have muscle weakness in the recovery phase, and disuse atrophy may play a role in this weakness. To assess this problem, the authors measured changes in the potency of the nondepolarizing neuromuscular blocking agent metocurine in a canine model that involved 3 weeks of intensive care, nonparalyzing anesthesia with pentobarbital, and positive-pressure ventilation. Six dogs were anesthetized with pentobarbital to a sufficient depth that spontaneous and reflex muscle movements were absent. Their tracheas were intubated, their lungs were mechanically ventilated, and they received round-the-clock intensive medical and nursing care for 3 weeks. Transduced gastrocnemius muscle responses to metocurine were determined weekly. A 4- to 15-min infusion of 148-4,300 microg/min (longer durations and greater concentrations on progressive weeks) yielded more than 80% paralysis. Serial metocurine plasma concentrations during the onset of the block and recovery provided data to determine pharmacokinetics using NONMEM. Metocurine plasma concentrations and the degree of paralysis were used to model the effect compartment equilibration constant, and the Hill equation was used to yield the slope factor and potency within the effect compartment. The metocurine effect compartment concentration associated with a 50% diminution of twitch height after 3 weeks was 1,716+/-1,208 ng/ml (mean +/- SD), which was significantly different from 257+/-34 ng/ml, the value on day 0. There were no pharmacokinetic differences. The absence of muscle tone and reflex responsiveness for 3 weeks was associated with exaggerated resistance to the neuromuscular blocker metocurine.