Pharmacodynamic modeling of thiopental anesthesia

We have pharmacodynamically modeled the relationship between the thiopental serum concentration and its effects on the electroencephalogram (EEG). Power spectral analysis was used to calculate the spectral edge, a measure of the underlying EEG frequency that characterizes the progressive slowing of the EEG induced by thiopental. Eight male volunteer subjects had venous thiopental serum concentrations measured, and 10 surgical patients had arterial serum concentrations measured. Thiopental was infused at a rate of 75 to 150 mg/min until a burst suppression EEG pattern was evident. Frequent blood samples were obtained during and after the infusion for measurement of serum thiopental concentrations, and the EEG was recorded for subsequent off-line power spectral analysis to calculate the spectral edge. With venous blood sampling, it was not possible to demonstrate significant hysteresis between the thiopental serum concentration and the spectral edge, allowing thiopental concentrations to be directly related to the spectral edge. With arterial blood sampling, significant hysteresis was present, requiring an effect compartment to relate concentration to effect. The half-time for equilibration (mean ± SD) between concentration and response for the arterial data was 1.2± 0.30min. This value for K_eo is consistent with known values for cerebral blood flow and thiopental brain: blood partition coefficient. Arterialvenous concentration differences cause the apparent lack of hysteresis with venous blood sampling. An inhibitory sigmoid E _max pharmacodynamic model optimally characterized the relationship between thiopental concentrations and the spectral edge. This model allows estimation of the thiopental serum concentration that causes one-half of the maximal EEG slowing (IC₅₀), which is a measure of an individual's sensitivity to thiopental. Except for the hysteresis, there was no statistical difference in the parameters of the inhibitory sigmoid E _max pharmacodynamic model when venous and arterial blood samplings were compared. Arterial blood sampling offers some distinct advantages when pharmacodynamically modeling continuous, rapidly changing measures of drug effect, such as the EEG.This work was supported by NIH Grant R23-GM28032, NIA Grant P01-AG03104, the Veterans Administration Research Service, and the Anesthesiology/Pharmacology Research Foundation of Palo Alto, California. Dr. Hudson was supported by the Medical Research Council of Canada.     

Pharmacodynamic characterization of the electroencephalographic effects of thiopental in rats

We have developed a chronically instrumented rat model that uses changes in electroencephalographic wave forms to estimate continuously the degree of central nervous system (CNS) depression induced by thiopental. Such changes were subject to aperiodic signal analysis, a technique that breaks down the complex EEG into a series of discreet neurologic "events" which are then quantitated as waves/sec. We thus obtained a continuous measure of CNS drug effect. In addition we continuously recorded central arterial blood pressure and heart rate and monitored ventilatory status using arterial blood gas determinations. We also determined, with frequent arterial blood sampling, the distribution and elimination of thiopental in individual animals. The time lag occurring in the curve representing arterial concentration of thiopental vs. EEG effect suggests that arterial plasma is not kinetically equivalent to the EEG effect site. Application of semiparametric pharmacodynamic modeling techniques enabled us to estimate equilibration rate constant (Keo) for concentrations of thiopental between arterial plasma and the effect site. The half-life for equilibration of thiopental with the EEG (CNS) effect was less than 80 sec. Knowledge of the rate of equilibration permitted characterization of the relationship between the steady state plasma concentrations and CNS effect of thiopental, as measured by activation and slowing of the EEG. At concentrations of thiopental below 5 micrograms/ml, EEG activity was 180% higher than during the baseline awake state. Thiopental produced an activated EEG over more than 20% of the concentration-effect relationship. Further increases in the concentration of thiopental at the site of effect depressed EEG activity progressively until complete suppression of the EEG signal occurred (at which time, the concentration was approximately 80 micrograms/ml). This report describes our model and its application to the assessment of the pharmacodynamics of thiopental as manifested by changes on the EEG.     

Pharmacodynamic characterization of the electroencephalographic effects of thiopental in rats

We have developed a chronically instrumented rat model that uses changes in electroencephalographic waveforms to estimate continuously the degree of central nervous system (CNS) depression induced by thiopental. Such changes were subject to aperiodic signal analysis, a technique that breaks down the complex EEG into a series of discreet neurologic events which are then quantitated as waves/sec. We thus obtained a continuous measure of CNS drug effect. In addition we continuously recorded central arterial blood pressure and heart rate and monitored ventilatory status using arterial blood gas determinations. We also determined, with frequent arterial blood sampling, the distribution and elimination of thiopental in individual animals. The time lag occurring in the curve representing arterial concentration of thiopental vs. EEG effect suggests that arterial plasma is not kinetically equivalent to the EEC effect site. Application of semiparametric pharmacodynamic modeling techniques enabled us to estimate equilibration rate constant (K_eo for concentrations of thiopental between arterial plasma and the effect site. The half-life for equilibration of thiopental with the EEG (CNS) effect was less than 80 sec. Knowledge of the rate of equilibration permitted characterization of the relationship between the steady state plasma concentrations and CNS effect of thiopental, as measured by activation and slowing of the EEG. At concentrations of thiopental below 5 gmg/ml, EEG activity was 180% higher than during the baseline awake state. Thiopental produced an activated EEG over more than 20% of the concentration-effect relationship. Further increases in the concentration of thiopental at the site of effect depressed EEG activity progressively until complete suppression of the EEG signal occurred (at which time, the concentration was approximately 80 g/ml). This report describes our model and its application to the assessment of the pharmacodynamics of thiopental as manifested by changes on the EEG.Supported by grant RO1-AGO4594 from the National Institute on Aging, National Institute of Health; and the Anesthesia/Pharmacology Research Foundation.     

Arteriovenous serum cocaine concentration difference after intravenous bolus injection and constant-rate infusions: relation to pharmacodynamic estimates in rats

We characterized the pharmacokinetics of cocaine using both arterial and venous serum data after a bolus dose (2 mg/kg) and two constant-rate infusions (12.24 and 24.48 μg/min) for 2 h in rats. A published behavioral effect was used to investigate the effects of arteriovenous serum concentration differences on pharmacodynamic estimates for the 2 mg/kg dose. Significant temporal arteriovenous serum cocaine and benzoylecgonine (the major metabolite) concentration differences existed after cocaine administrations. The AUCs for arterial serum data were greater than the AUCs for venous data, indicating that cocaine was metabolized more extensively in the venous sampling site. Cocaine’s behavioral effect could be directly related to serum concentrations with no hysteresis observed between the effects and arterial or venous serum concentrations. The pharmacodynamic estimates derived from arterial serum data approximated those from the venous data due to the most decline of cocaine’s effect occurred in the elimination phase during which serum cocaine concentrations were not significantly different between the two sampling sites.     

Do plasma concentrations obtained from early arterial blood sampling improve pharmacokinetic/pharmacodynamic modeling?

In pharmacokinetic/pharmacodynamic (PK/PD) modeling the first blood sample is usually taken 1 to 2 min after drug administration (late sampling). Therefore, investigators have to extrapolate the plasma concentration to Time 0. Extrapolation, however, erroneously assumes instantaneous and complete mixing of drug in the central volume of distribution. We investigated whether plasma concentrations obtained from early arterial blood sampling would improve PK/PD modeling. In 14 pigs, one of five neuromuscular blocking agents (NMBAs) was administered into the right ventricle within 1 sec and arterial sampling was performed every 1.2 sec (1st min). The response of the tibialis muscle was measured mechanomyographically. The influence of inclusion of data from early arterial sampling on PK/PD modeling was determined. Furthermore, the concentrations in the effect compartment at 50% block (EC50) derived from modeling were compared to the measured concentration in plasma during a steady state 50% block. A very high peak in arterial plasma concentration was seen within 20 sec after administration of the NMBA. Extensive modeling revealed that plasma concentrations obtained from early arterial blood sampling improve PK/PD modeling. Independent of the type of modeling, the EC50 and KeO based on data sets that include early arterial blood sampling were, for all five NMBAs, significantly higher and lower respectively, than those based on data sets obtained from late sampling. Early arterial sampling shows that the mixing of the NMBA in the central volume of distribution is incomplete. A parametric PD (sigmoid Emax) model could not describe the time course of effect of the NMBAs adequately.     

The efficiency concept in pharmacodynamics.

The classic approach to describe the pharmacological response to a drug is to analyse its concentration-effect relationship, using a variety of possible models such as maximum effect (Emax) models or sigmoid Emax models. The aim of this review is to discuss an alternative way of describing the pharmacological effect in terms of effect per unit of drug concentration, instead of simple effect. This variable is called efficiency, analogous with concepts used in other fields. The pharmacodynamic model for efficiency is derived from the sigmoid Emax model and is dependent on the same parameters. Since the sigmoid Emax model incorporates 'the law of diminishing returns', requiring ever higher concentrations to increase the effect by a given percentage, efficiency is bound to decrease with increasing concentrations. However, as a mathematical consequence of its derivation from the sigmoid Emax model, efficiency also has a maximum value, which can be expressed as a function of the slope factor (s) and drug concentration associated with half the maximum effect (C50), provided that the slope factor is greater than 1. The efficiency concept is potentially applicable to all drugs and particularly useful for those that follow concentration-effect relationships according to Emax or sigmoid Emax models. Most experience has been obtained with loop diuretics, especially with furosemide (frusemide). Slow administration of furosemide, leading to slow excretion of the drug, has been shown, in many studies, to significantly increase the total diuretic effect per amount of drug recovered in urine. In this review, some examples of the applicability of the efficiency concept to other drugs, such as antibacterials, opioids and antineoplastics, are discussed. In addition to pharmacodynamically varying efficiency, other saturable processes, such as the formation of active metabolites and saturable transport, may form a basis for the application of the efficiency concept. The efficiency of a drug dosage may also be influenced by tolerance and counter-regulation produced by the drug. All these factors contribute to schedule dependency. It is concluded that the shape of the time course of drug presentation to its site of action is an independent determinant of overall response. The possibility of adjusting the drug input profile to maximise therapeutic effect per dose and to separate cumulated therapeutic from cumulated adverse effects should be considered in designing administration schedules and in drug development.     

A pharmacokinetic-pharmacodynamic model for quantal responses with thiopental

The pharmacokinetic-pharmacodynamic model developed here characterizes the relationship between simulated plasma concentrations of thiopental and two dichotomous endpoints determined at induction of anesthesia: loss of voluntary motor power (clinical endpoint), and burst suppression of the electroencephalogram (EEG endpoint). The model incorporated data from two separate thiopental patient studies: a pharmacokinetic study with 21 males, and a pharmacodynamic study with 30 males. In the pharmacodynamic study, cumulative quantal dose-response curves for the clinical and EEG endpoints were developed from observations made during a constant-rate infusion of thiopental. Population mean parameters, derived from the bolus pharmacokinetic thiopental study, were used to simulate concentration-time data for the 150 mg·min¹ thiopental infusion rate used in the dose-response study. A single biophase model incorporating the two endpoints was generated, combining the pharmacokinetic and pharmacodynamic data from the two groups. Estimates of the mean effective thiopental concentrations affecting 50% of the population (EC₅₀s) for the clinical and EEG endpoints were 11.3 and 33.9g·ml^–1, respectively. The half-time for equilibration between arterial thiopental and the effect compartment was 2.6 min. These results are in reasonable agreement with previously described quantal concentration-response data, and with pharmacodynamic models developed for graded EEG responses. Simulation of bolus doses of thiopental with the new model provided ED₅₀s for the clinical and EEG endpoints of 265 mg and 796 mg, respectively; the dose predicted to produce loss of voluntary motor power in 90% of an adult male population was 403 mg. A model combining population pharmacokinetics with cumulative dose-response relationships could prove useful in predicting dosage regimens for those drugs with responses that are categorical.     

厄贝沙坦与氢氯噻嗪联用在肾性高血压大鼠体内药动学-药效学关系研究

目的:应用药动学-药效学结合模型研究厄贝沙坦与氢氯噻嗪联用在肾性高血压大鼠体内单剂量及多剂量用药时的药动学-药效学关系。方法:将SD大鼠制备成2肾1夹型肾性高血压模型,给大鼠单剂量或多剂量灌胃给药,分别于第1天和第8天连续的预定时间点测定血药浓度,同时测定动脉收缩压(SBP)和动脉舒张压(DBP)等药物效应,建立效应室药动学-药效学结合模型并计算相关的药动学和药效学参数。对单用、联用及单剂量、多剂量的药动学-药效学规律进行定量研究。结果:厄贝沙坦的药动学特征呈二室模型,氢氯噻嗪在非稳态和稳态条件下均未改变厄贝沙坦的药动学参数,而在稳态条件下,厄贝沙坦可增高氢氯噻嗪的血药浓度及曲线下面积。厄贝沙坦和氢氯噻嗪联用降压效应优于单用的效应。药物效应和效应室浓度之间符合Sigmoid-Emax药效学模型。单剂量下药物效应与血药浓度间存在滞后现象,多剂量下滞后现象消失。Emax、EC50、Keo等药效学参数在厄贝沙坦组和两药联用组之间的差异有统计学意义。结论:建立了PK-PD定量数学模型研究厄贝沙坦和氢氯噻嗪联用在大鼠体内单剂量和多剂量用药后药动学-药效学(暴露-反应)关系的规律,并提供了相关的药动学和药效学参数,可为临床合理用药提供参考依据。     

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.     

The phenomenon and rationale of marked dependence of drug concentration on blood sampling site. Implications in pharmacokinetics, pharmacodynamics, toxicology and therapeutics (Part I)

At least 42 compounds have been reported to exhibit significant or marked blood sampling site dependence in concentration after dosing in humans and animals. The very high efficiency of uptake of drug by the poorly perfused sampling tissue (e.g. arm or leg) during its very short transit through the capillary (1 to 3 seconds) is mainly responsible for such a universal phenomenon. When marked arteriovenous concentration differences exist, their entire plasma (blood or serum) concentration-time profiles may resemble those obtained from completely different drugs or from different dosing rates. After an intravenous bolus injection, the reported maximal arteriovenous differences were 3240-fold for griseofulvin during the early distribution phase (arterial concentration being higher than venous, and 234% for procainamide during the terminal phase (venous concentration being higher). The reported maximal steady-state arteriovenous difference during infusion was 3.8-fold for glyceryl trinitrate (nitroglycerin), with the arterial level higher, due to metabolism and possible strong binding by sampling tissue. Interestingly, peak arterial plasma concentrations were usually achieved at about 0.5 minutes, while peak venous plasma concentrations generally occurred at 1 to 5 minutes after injection. Thus, the plasma concentration-time profile after an intravenous bolus injection actually resembles that predicted for a short term intravenous infusion, according to the classical instantaneous input hypothesis. Potential factors that may affect the degree of arteriovenous difference are here reviewed in detail. The implications of potential marked arteriovenous differences in pharmacokinetics, in pharmacokinetic/pharmacodynamic correlations or modelling, in toxicology, and in drug therapy are extensively discussed. Clinicians or scientists dealing with the determination and/or use of plasma concentration data should be fully aware of this problem. Many previous studies, based on the commonly accepted assumption that immediately or shortly after dosing plasma (blood) concentrations are essentially uniform throughout the blood circulation or the central (plasma) compartment, may require a reexamination. This is particularly important since the 'driving force' for distribution of a drug to various parts of the body for elimination, for accumulation or for producing a pharmacological or toxic effect, is its concentration in arterial blood, and not in venous blood drained from a poorly perfused tissue (venous blood may more accurately reflect drug concentrations in the poorly perfused sampling tissue itself). The present review probably represents the first of its kind ever reported in the literature. It is hoped that the review will increase the awareness of this very fundamental and important subject matter among our readers, and may also stimulate further studies or discussions.     

Pharmacokinetic/pharmacodynamic modelling of the EEG effects of opioids: The role of complex biophase distribution kinetics

The objective of this investigation is to characterize the role of complex biophase distribution kinetics in the pharmacokinetic-pharmacodynamic correlation of a wide range of opioids. Following intravenous infusion of morphine, alfentanil, fentanyl, sufentanil, butorphanol and nalbuphine the time course of the EEG effect was determined in conjunction with blood concentrations. Different biophase distribution models were tested for their ability to describe hysteresis between blood concentration and effect. In addition, membrane transport characteristics of the opioids were investigated in vitro, using MDCK:MDR1 cells and in silico with QSAR analysis. For morphine, hysteresis was best described by an extended-catenary biophase distribution model with different values for k1e and keo of 0.038+/-0.003 and 0.043+/-0.003 min(-1), respectively. For the other opioids hysteresis was best described by a one-compartment biophase distribution model with identical values for k1e and keo. Between the different opioids, the values of k1e ranged from 0.04 to 0.47 min(-1). The correlation between concentration and EEG effect was successfully described by the sigmoidal Emax pharmacodynamic model. Between opioids significant differences in potency (EC50 range 1.2-451 ng/ml) and intrinsic activity (alpha range 18-109 microV) were observed. A statistically significant correlation was observed between the values of the in vivo k1e and the apparent passive permeability as determined in vitro in MDCK:MDR1 monolayers. It can be concluded that unlike other opioids, only morphine displays complex biophase distribution kinetics, which can be explained by its relatively low passive permeability and the interaction with active transporters at the blood-brain barrier.     

Pharmacokinetics and pharmacodynamics of recombinant human erythropoietin in rats

The pharmacokinetics and pharmacodynamics of recombinant human erythropoietin (rh-EPO; CAS for EPO: 11096-26-7) after repeated intravenous and subcutaneous administrations in rats were studied. Administration of rh-EPO by both routes caused significant increases in hematocrit. The pharmacokinetics of rh-EPO after intravenous and subcutaneous administration exhibited nonlinearity. The pharmacodynamics of rh-EPO was analyzed using the maximum effect (Emax) and sigmoid maximum effect (sigmoid Emax) models. Both models involved the assumption that rh-EPO in plasma would stimulate the proliferation of erythroid progenitor cells. Akaike's information criterion for the Emax model was lower than that for the sigmoid Emax model, suggesting that the Emax model might be an optimal model. The rh-EPO concentration at which the effect is half of the maximum was 0.383 ng/ml. This pharmacodynamic analysis suggests that the maintenance of effective plasma concentration might be important for the efficacy of rh-EPO.     

Pharmacodynamic modeling of the EEG effects of ketamine and its enantiomers in man

The pharmacodynamics of a racemic mixture of ketamine R,S(+/-)-ketamine and of each enantiomer, S(+)-ketamine and R(-)-ketamine, were studied in five volunteers. The median frequency of the electroencephalogram (EEG) power spectrum, a continuous noninvasive measure of the degree of central nervous system (CNS) depression (pharmacodynamics), was related to measured serum concentrations of drug (pharmacokinetics). The concentration-effect relationship was described by an inhibitory sigmoid Emax pharmacodynamic model, yielding estimates of both maximal effect (Emax) and sensitivity (IC50) to the racemic and enantiomeric forms of ketamine. R(-)-ketamine was not as effective as R,S(+/-)-ketamine or S(+)-ketamine in causing EEG slowing. The maximal decrease (mean +/- SD) of the median frequency (Emax) for R(-)-ketamine was 4.4 +/- 0.5 Hz and was significantly different from R,S(+/-)-ketamine (7.6 +/- 1.7 Hz) and S(+)-ketamine (8.3 +/- 1.9 Hz). The ketamine serum concentration that caused one-half of the maximal median frequency decrease (IC50) was 1.8 +/- 0.5 micrograms/mL for R(-)-ketamine; 2.0 +/- 0.5 micrograms/mL for R,S(+/-)-ketamine; and 0.8 +/- 0.4 microgram/mL for S(+)-ketamine. Because the maximal effect (Emax) of the R(-)-ketamine was different from that of S(+)-ketamine and R,S(+/-)-ketamine, it was not possible to directly compare the potency (i.e., IC50) of these compounds. Accordingly, a classical agonist/partial-agonist interaction model was examined, using the separate enantiomer results to predict racemate results. Although the model did not predict racemate results well, its failure was not so great as to provide clear evidence of synergism (or excess antagonism) of the enantiomers.     

Rate of change of blood concentrations is a major determinant of the pharmacodynamics of midazolam in rats.

The objective of this investigation was to characterize quantitatively the influence of the rate of increase in blood concentrations on the pharmacodynamics of midazolam in rats. The pharmacodynamics of midazolam were quantified by an integrated pharmacokinetic-pharmacodynamic modelling approach. Using a computer controlled infusion technique, a linear increase in blood concentrations up to 80 ng ml(-1) was obtained over different time intervals of 16 h, resulting in rates of rise of the blood concentrations of respectively, 1.25, 1.00, 0.87, 0.46, 0.34 and 0.20 ng ml(-1) min(-1). In one group of rats the midazolam concentration was immediately brought to 80 ng ml(-1) and maintained at that level for 4 h. Immediately after the pretreatment an intravenous bolus dose was given to determine the time course of the EEG effect in conjunction with the decline of midazolam concentrations. The increase in beta activity (11.5-30 Hz) of the EEG was used as pharmacodynamic endpoint. For each individual animal the relationship between blood concentration and the EEG effect could be described by the sigmoidal Emax model. After placebo, the values of the pharmacodynamic parameter estimates were Emax = 82+/-5 microV, EC50,u = 6.4+/-0.8 ng ml(-1) and Hill factor = 1.4+/-0.1. A bell-shaped relationship between the rate of change of midazolam concentration and the value of EC50,u was observed with a maximum of 21+/-5.0 ng ml(-1) at a rate of change of 0.46 ng ml(-1) min(-1); lower values of EC50,u were observed at both higher and lower rates. The findings of this study show that the rate of change in plasma concentrations is an important determinant of the pharmacodynamics of midazolam in rats.     

Kinetics and EEG effects of midazolam during and after 1-minute, 1-hour, and 3-hour intravenous infusions

The objective of this study was to evaluate the kinetics and dynamics of midazolam when administered by three different infusion schemes, using electroencephalography to measure pharmacodynamic effects. In a three-way crossover study, 8 volunteers received midazolam (0.1 mg/kg) by constant-rate intravenous infusion. The durations of midazolam infusions for the three trials were 1 minute, 1 hour, and 3 hours. Plasma midazolam concentrations and electroencephalographic (EEG) activity in the 13- to 30-Hz range were monitored for 24 hours. Based on separate analysis of each subject-trial, mean values for volume of distribution and distribution or elimination half-life did not significantly vary. Central compartment volume and clearance differed among the three midazolam infusion trials; however, the magnitude of change was small. EEG activity in the 13- to 30-Hz range significantly increased for all three midazolam infusion trials. Plots of midazolam plasma concentration versus pharmacodynamic EEG effect for the 1-hour and 3-hour infusion trials did not reveal evidence of either counterclockwise or clockwise hysteresis. Plots from the 1-minute infusion trial demonstrated counterclockwise hysteresis, consistent with an equilibration effect-site delay. This was incorporated into a kinetic-dynamic model in which hypothetical effect-site concentration was related to pharmacodynamic EEG effect via the sigmoid E(max) model. Analysis of all three infusion trials together yielded the following mean estimates: maximum EEG effect, 16.3% over baseline; 50% maximum effective concentration, 31 ng/mL; and an apparent rate constant for drug disappearance from the effect compartment which approached infinity. Despite the delay in effect onset during the 1-minute midazolam infusion, midazolam infusions in duration of up to 3 hours produce CNS sedation without evidence of tolerance.     

Estimating the rate of thiopental blood-brain equilibration using pseudo steady state serum concentrations

The equilibration between drug serum concentration and drug effect under non-steady state concentrations has been classically modeled using an effect compartment where the transfer from the serum to the effect compartment is considered to be a first-order process. The purpose of the present study was to examine whether an effect compartment with first-order transfer was adequate for describing thiopental serum concentration-EEG pharmacodynamics. The study has two facets: (i) Successive pseudo steady state serum concentrations of thiopental having a square wave shape were produced and maintained in six human subjects by means of a computer-driven infusion pump. An aperiodic wave form transformation of the electroencephalogram (EEG) was used as a continuous measure of thiopental EEG drug effect. The time course of the EEG effect following each thiopental serum concentration square wave showed an exponential pattern. The first-order rate constant for equilibration of the effect site concentration with the drug serum concentration (keo) was estimated by fitting a monoexponential model to the effect vs. time data resulting from the pseudo steady state thiopental serum concentration profile. (ii) In a second experiment, data were obtained from a classical design, i.e., a zero-order intravenous infusion of thiopental. The same subjects were studied. The keo was estimated by means of a semiparametric iterative method using convolution (effect compartment, transfer of drug from serum to site of action is assumed to be a first-order process). The mean pseudo steady state value for keo of 0.51 min-1 was not different from the mean value of 0.46 min-1 from the semi parametric approach when data from a linear portion of the drug concentration vs. effect curve were examined. The pseudo steady state technique gave inaccurate estimates of keo in the nonlinear portion of the thiopental concentration vs. response curve, i.e., at the peak of the biphasic concentration-effect relationship.