EUROANESTHESIA 2006 BASIC PHARMACOKINETICS FOR THE CLINICIAN INTRODUCTION BASIC PARAMETERS COMPARTMENTAL MODELS. Madrid, Spain, 3-6 June RC2

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1 BASIC PHARMACOKINETICS FOR THE CLINICIAN EUROANESTHESIA 2006 Madrid, Spain, 3-6 June RC2 THOMAS W. SCHNIDER Institute for Anesthesiology Kantonsspital St.Gallen, Switzerland CHARLES F. MINTO Department of Anaesthesia Royal North Shore Hospital Sydney, Australia Saturday June 3, :00-15:45 Room: N107 & N108 INTRODUCTION Pharmacokinetics often seems to intimidate the clinician although most of us are aware that administering anesthetics is applied pharmacokinetics. The basis of understanding modern concepts (some of them are already quite old!) is understanding basic pharmacokinetics. The title of this refresher course is Basic pharmacokinetics for the clinician. This raises the question how basics for the clinician differ from basics for the non-clinician. There is probably no difference but medical students must learn basic pharmacokinetics for examinations! By understanding basic concepts of pharmacokinetics the clinician will use drugs more rationally. Although intuition is important in medicine, new drugs and new technologies can be best applied in daily practice when the underlying pharmacokinetic principles are understood. The title basic pharmacokinetics for the clinician is probably an invitation or even a request for the speaker to cover within one lecture some basics and some application of the basics. Furthermore it is a request not to use (too many) formulae, but to keep it as simple as possible according to Einstein who once said: Keep it simple, as simple as possible, but no simpler! In this lecture we will discuss some basic concepts of pharmacokinetics such as the concept of clearance and volume of distribution. These basic pharmacokinetic parameters, although very important, do not sufficiently describe the behavior of i.v. anesthetics. Compartmental models that describe the initial distribution and redistribution of drugs and how they relate to the basic parameters will be discussed. Concepts which inform better dosing are the concept of time to peak effect and relevant decrement times. Applied to the two most frequently used i.v. anesthetics, propofol and remifentanil, clinically useful conclusions will be drawn. BASIC PARAMETERS Basic non-compartmental description of drugs in terms of volume of distribution, clearance and half-life of the drug is sufficient in the context of steady state dosing. This describes chronic drug administration in internal medicine where, for example, an anti-hypertensive drug is taken at regular intervals over a long period of time. The definition of clearance says that the amount of drug eliminated per unit time is proportional to the concentration of the drug at this time. Clearance is therefore not describing the rate of elimination directly but it is the proportionality constant. When the concentration is double the rate of elimination is double. This is a crucial feature of linear kinetics, which says that the time course of the concentration is always linearly correlated to the dose and infusion rate respectively. Volume of distribution is a parameter that describes how much drug is in the body (at steady state) in relation to the concentration in the blood. The influence of the volume of distribution on the dose required to achieve a desired effect or on speed of recovery from drug effect is complex. Although one is tempted to believe that with a big volume of distribution recovery is faster, this is not necessarily true. The interpretation of the behavior of a drug is more involved and other factors such as intercompartmental distribution are also relevant. Indeed, it is possible that two drugs with identical clearance and volume of distribution have quite different time courses of concentration. COMPARTMENTAL MODELS Compartmental models describe the time course of the initial distribution and the redistribution process. Whereas with the basic parameters only the terminal elimination is described, multi-compartmental models allow description of the early phase of i.v. drug administration. Whether a drug is described with a two or a three compartmental model is based on the observed concentration data. Frequent sampling is necessary, both during the initial phase and long enough after the end of infusion in order to describe the drug s kinetics exactly. The pharmacokinetic model is an abstraction of the real drug behavior, but helpful for exploring the characteristics of a drug by simulation. It is of interest that the dosing recommendations in the package insert for remifentanil is to a considerable extent based on accurate kinetic models. 105

2 EFFECT EFFECT SITE CONCENTRATION, CONCENTRATION EFFECT RELATIONSHIP Compartmental pharmacokinetic models predict that drug concentration is highest immediately after it is injected into the blood stream. Since the site of action of anesthetics is not in the blood, there is time delay between the concentration in the blood and the effect. Therefore, it is clinically more relevant, particularly during induction, to know the time course of the concentration at the site where the drug produces its effect. Based on measurements of the effect of muscle relaxants Sheiner et al.[1] proposed an extension of the compartmental model with an effect compartment. Contemporarily Hull et al.[2] published a model for pancuronium using a similar concept. The effect compartment concept serves as a link between the time course of the blood concentration and the relationship between the concentration and the effect. It is a virtual compartment and as such only a mathematical trick for describing the time delay between the time course of the plasma concentration and the effect. Conceptually and by definition at steady state the concentration in the plasma is equal to the effect site concentration. PREDICTORS OF ONSET OF DRUG EFFECT In the past a lot of argument about the pharmacokinetics and pharmacodynamics of drugs has been based on comparison of parameters. Because anesthesiologists are traditionally impatient, they prefer drugs with a fast onset. For muscle relaxants definitions of the onset of drug effect have been defined by a consensus group [3]. Unfortunately these definitions (e.g. time to 90% twitch depression) are dose dependent. In order to characterize a drug with regard to onset, dose independent predictors are necessary. A dose independent predictor of onset of drug effect is the time to peak effect-site concentration [4]. After a bolus dose the concentration at the effect site steadily increases because of the concentration gradient between the effect site and the plasma. The concentration at the effect site is maximal when the concentration at the effect site equals the plasma concentration. Although this concentration might be higher than the concentration required for a maximal effect (e.g. 100% twitch depression), the time of maximal effect site concentration can be determined from pharmacokinetic / pharmacodynamic data based on the effect compartment concept. Furthermore this predictor of onset is based on all of the parameters of the effect compartment model. Comparing only the equilibration rate constant (ke0) of two drugs is useless for deciding which drug has a faster onset. PREDICTION OF THE RECOVERY TIME (CONTEXT SENSITIVE DECREMENT TIMES) Probably the best recognized pharmacokinetic parameter is the elimination half-life or terminal half-life. It must be noted that half-lives of a drug can be calculated from the volume and clearance values of the compartmental model. Shafer et al. [5] demonstrated more than ten years ago by computer simulations that simply considering pharmacokinetic parameters such as half-lives of different drugs will not predict the relative rates of decrease in effect site concentrations after either an intravenous bolus or a continuous infusion. Drawing on these ideas Hughes et al. [6] showed that elimination half-life is of no value in characterizing disposition of intravenous anesthetic drugs during dosing periods relevant to anesthesia. They coined the expression contextsensitive half-time and proposed it as a useful descriptor of the post-infusion time course of the concentration. The concept evolved to become relevant decrement times. It may be that a 50% decrease of the concentration is not relevant because the relevant clinical recovery from a drug effect might require a 70% decrease of the concentration. Depending on the distribution and elimination characteristics it is possible that one drug compared to another has a faster context sensitive half-time but longer 70% decrement time. PROPOFOL KINETICS AND ITS IMPACT ON DOSING With a constant infusion propofol only slowly approaches its steady state concentration. This has to be considered not only when the infusion rate is increased but also when it is decreased. The time to peak effect of propofol was investigated several years after its introduction. Based on electroencephalographic measurements it was defined as 1.6 minutes [7]. Recently Doufas et al. [8] used the bisprectral index as the measure of propofol effect during increasing target controlled infusion (TCI) using covariate adjusted pharmacokinetic parameters for propofol [9]. They reported a time to peak effect of 2.7 minutes. It seems that the time to peak effect is also slow in children [10]. Because this is a rather slow onset of drug effect, propofol must be relatively overdosed for a fast induction. It is our clinical experience that the dose of propofol must be reduced in the elderly. We also know that the maximal effect occurs later in the elderly. Kazama et al. [11] showed that the elderly are more sensitive to the hemodynamic effects of propofol. A clinically important finding was that the time to peak hemodynamic effect is considerably longer than the time to peak hypnotic effect. This means that despite slow and careful titration of onset of hypnotic drug effect using a TCI device it is likely, particularly in the elderly, that the maximum hemodynamic effect will be observed some time later. With regard to recovery from the hypnotic effect, propofol is more controllable than other intravenous hypnotics. Although the context sensitive halftime for propofol is reasonably constant for target controlled infusions of up to ten hours, the time for greater decrements (e.g., for a 70% decrement) increases significantly for longer infusions

3 Although propofol has many desirable non-hypnotic properties, the controllability of onset is limited. It is best to be cautious and to reduce the induction dose in the elderly substantially. This is likely to lengthen the induction time, making it less suitable for rapid sequence induction. Because recovery from drug effect increases with increasing duration of the infusion it must be administered carefully and adjusted to the individual needs of the patients. Since EEG based objective measure of hypnotic drug effects are available nowadays, sufficiently rapid recovery times can be achieved with propofol by careful monitoring of the drug effect [12]. REMIFENTANIL KINETICS AND THEIR IMPACT ON DOSING The key features of remifentanil are its fast onset and very fast offset. Otherwise remifentanil s pharmacology is comparable to the other anilinopiperidine opioids. With regard to recovery from drug effect, remifentanil is unique. Even after a long duration of infusion, remifentanil s decrement times remain constant. This is a feature very different from fentanyl, sufentanil and alfentanil. Because the kinetics is so fast, for most situations, optimal control of the effect requires a continuous remifentanil infusion. The onset of the remifentanil effect and side effect are fast [13, 14], although the respiratory depressive peak effect occurs somewhat later than the EEG effect. Still, remifentanil is highly controllable because, if infusion is stopped after onset of side effects, recovery occurs rapidly (e.g. from ventilatory depression). When a constant remifentanil infusion is started the concentration and the effect increase until a steady state concentration is reached. 80% of the steady state concentration is reached after 10 minutes. If during surgery or induction of anesthesia an unexpected painful stimulus occurs, it is important that it is immediately treated. In order to have the fastest possible onset of effect, a bolus dose is required. For remifentanil the fastest recommended induction bolus dose is 1 microgram per kilo body weight given over 30 sec. which is the same as a constant infusion of 2 microgram per kilo per minute. Although hemodynamic depression is also observed with high doses of fentanyl and alfentanil, case reports suggested that even moderately high infusion rates can lead to severe bradycardia [15]. Nevertheless, it is pharmacokinetically sound to combine bolus doses of remifentanil together with a constant infusion if a drug effect has to be achieved as rapidly as possible. In volunteers, Egan et al. [16] investigated the safety of bolus injections. In the younger subjects bolus doses up to 200 µg and in the elderly up to 75 µg remifentanil per kilo body weight were well tolerated with no serious side effects. Therefore, if the dose is adjusted to age and other relevant covariates, the combination of bolus doses with constant infusion improves controllability of remifentanil effect. MAKING USE OF PHARMACOKINETIC MODELS WITH TCI With pharmacokinetic models dosing can be rationally optimized. Simple weight-adjusted dosing is often suboptimal but more complex relationships between covariates and required dose cannot be included into manual dosing because the mathematics is complex. When the mathematical model is built into a computer, the required infusion rate can be calculated in real time. Target controlled infusion systems (TCI) control the infusion rate of a syringe pump. Other forms of model-supported drug administration have been explored in the form of online display of the predicted concentration [17]. For adjustment of the PK/PD model based on individual covariates (such as height and weight) the TCI system is very helpful. However, to take full advantage of the PK/PD model, the TCI system should target the effect site concentration rather than the plasma concentration. This method of administration provides the optimal means to rapidly attain and maintain the desired target concentration. Although TCI systems are very helpful we have to be aware that there is big variability between the patients sensitivity to a drug. Therefore dosing has to accommodate for both pharmacokinetic and pharmacodynamic variability. The one size fits all dosing strategy, although still common in medicine, is completely inappropriate in anesthesia. The anesthesiologist has to titrate the anesthetics with the aid of optimized pharmacokinetic models to the desired effect rather than relying on a recommended concentration. TOTAL INTRAVENOUS ANESTHESIA WITH PROPOFOL AND REMIFENTANIL Normally, hypnotics are administered together with opioids. It is well known that one drug can substitute partly for the other. The goal of using interacting drug combinations is to reduce side effects. If the dose of a hemodynamically unstable hypnotic can be reduced by co-administering an opioid that is hemodynamically stable, it is possible that the hypnotic effect is optimized, but the hemodynamic side effects are minimized. Therefore, it is important that studies of drug interaction always explore the effects and the side-effects simultaneously

4 Opioids and propofol are profound respiratory depressants. Spontaneous ventilation is difficult during the combined administration of moderate doses of remifentanil and propofol [18]. In anesthesia slow recovery from drug effect becomes a side effect at the end of surgery; many studies have focused on optimal drug combinations for fast recovery. Nevertheless it is imperative that optimal combinations of hypnotics and opiates for different endpoints are explored. Such endpoints include; suppression of reaction to intubation, adequate intraoperative anesthesia, absence of motor reaction during surgery, adequate level of hypnosis (measured with an EEG based monitor) and, last but not least, the speed of recovery from anesthesia. These endpoints can be conflicting and the significance of each can change during the time course of an anesthetic. For instance, during a relaxant anesthetic it is irrelevant that remifentanil and propofol cause respiratory depression in a synergistic way [18], but during the recovery period this becomes a serious side effect. When using remifentanil in combination with other agents, it seems that recovery is best when relatively more remifentanil and relatively less propofol is used. For good intraoperative anesthesia Mertens et al. [19] suggest a propofol concentration of 2 µg/ml together with 6 ng/ml of remifentanil. It must be noted that these are the concentrations at which 50% of the patients are adequately anesthetized. Therefore higher concentrations must be recommended if the drug is not administered according to a target concentration rather than to some assessment of anesthetic depth. With depth of anesthesia monitoring the hypnotic effect of propofol can be measured. Albertin et al. [20] explored the required remifentanil target concentrations when the propofol is administered according to the measured effect. With a remifentanil target of about 6 ng/ml most patients did not respond to a noxious stimulation when propofol was controlled with the BIS. SUMMARY Optimal control of intravenous drugs depend on mode of administration and on the drug PK/PD characteristics, from which descriptors of onset and recovery from drug effect are derived. Computerized drug administration (with effect site TCI systems) facilitates the inclusion of more complex PK/PD models that incorporate covariate models, which in turn improve individualization of initial drug dosing guidelines. Optimal control is also dependent on how best to achieve the desired effect, while simultaneously minimizing the drug side effects. We are beginning to understand how best we can optimize the interactions occurring between hypnotic and opioid drugs

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