CHAPTER 5

V O L U M E

T H I R T Y - S I X

PHARMACOKINETICS AND PHARMACODYNAMICS THAT MAKE SENSE

KEN B. JOHNSON, M.D.
ASSOCIATE PROFESSOR LEARNED FAMILY ASSOCIATE PROFESSORSHIP DEPARTMENT OF ANESTHESIOLOGY UNIVERSITY OF UTAH SALT LAKE CITY, UTAH

TALMAGE D. EGAN
PROFESSOR K. C. WONG PRESIDENTIAL ENDOWED CHAIR DEPARTMENT OF ANESTHESIOLOGY UNIVERSITY OF UTAH SALT LAKE CITY, UTAH

EDITOR: MEG A. ROSENBLATT, M.D.

ASSOCIATE EDITORS: JOHN F. BUTTERWORTH IV, M.D. JEFFREY B. GROSS, M.D.

The American Society of Anesthesiologists, Inc.

The ASA Refresher Courses in Anesthesiology CME Program

Beginning with Volume 35, 2007, purchasers of the ASA Refresher Courses in Anesthesiology series are eligible to earn CME credits from the American Society of Anesthesiologists. Please visit www.asa-refresher-cme.asahq.org or see page iv at the beginning of this volume for complete details.

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The American Society of Anesthesiologists is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The American Society of Anesthesiologists designates this educational activity for a maximum of 1 AMA PRA Category 1 Credit. Physicians should only claim credit commensurate with the extent of their participation in the activity. Credit may be claimed in .25 hour increments to a maximum of 1.00 hour.

Author Disclosure Information

Dr. Johnson has disclosed that he receives research funds from Scott Laboratories; has an equity position and receives research funds from Medvis; receives research funds from GE Healthcare; receives consulting fees from ICU Medical; and receives stock options and honoraria from NAPE. Dr. Egan has disclosed that he receives consulting fees from Johnson & Johnson; research funds and consulting fees from Medvis; and consulting fees from MGI Pharma.

2008

The American Society of Anesthesiologists, Inc.

ISSN 0363-471X ISBN 978-0-7817-8953-0

An educational service to the profession under the auspices of The American Society of Anesthesiologists, Inc. Published for The Society by Lippincott Williams & Wilkins 530 Walnut Street Philadelphia, Pennsylvania 19106-3621 Library of Congress Catalog Number 74-18961.
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Pharmacokinetics and Pharmacodynamics That Make Sense

Ken B. Johnson, M.D. Associate Professor Learned Family Associate Professorship Department of Anesthesiology University of Utah Salt Lake City, Utah Talmage D. Egan Professor K. C. Wong Presidential Endowed Chair Department of Anesthesiology University of Utah Salt Lake City, Utah

What Is an Appropriate Dose for My Patient?

Clinical pharmacology is the science of predicting the magnitude and time course of a drug effect. Given that anesthesiologists spend their day administering low therapeutic index agents, clinical pharmacology is perhaps uniquely important to anesthesiologists. From a practical aspect, the ultimate goal of clinical pharmacology is to provide anesthesiologists with the information they need to make rational decisions about the selection and administration of anesthetics. Anesthesia and resuscitation necessitate a standard of precision and accuracy in drug administration not required in most areas of clinical medicine. Anesthesiologists profoundly depress the central nervous system to maintain the anesthetized state but then rapidly re-animate patients after an operation is complete. Although overdosing every patient within the constraints of acceptable hemodynamic variables is one approach to assuring the patient is adequately anesthetized, it comes at the cost of slow emergence from anesthesia, among other costs. Anesthesiologists must therefore target drug concentrations that are within a relatively narrow therapeutic range to achieve the competing clinical imperatives of adequate anesthesia (without toxicity) and rapid emergence. Once an agent is selected, the next challenge is the formulation of a scientically grounded dosing strategy. What does the anesthesiologist need to know? Anesthesiologists have long recognized that conventional, often simplied approaches to describing drug behavior are not useful in answering these questions.1 Anesthesiologists may ask How does the half-life help me deliver a better anesthetic? or Do I care about the plasma concentration? Modern clinical pharmacology techniques and concepts provide the scientic foundation to answer the questions listed in Table 1. Clinical pharmacologists have created tools using principles of pharmacokinetics and pharmacodynamics to construct models that predict drug behavior. Unfortunately, the often puzzling mathematical manipulations involved in estimating pharmacokinetic and pharmacodynamic parameters and the complex mathematics required to build models that predict drug behavior have made these techniques distinctly unpopular among most anesthesiologists. Anesthesiologists are slow
Copyright 2008 American Society of Anesthesiologists, Inc.

45

46
TABLE 1.

JOHNSON AND EGAN

Questions to Consider When Formulating a Dose of Anesthetic

What is the appropriate dose? Should it be a bolus, a continuous infusion, or both? How soon will the intended effect start? How long will it last? For postoperative pain, how do I minimize sedation yet optimize analgesia? Not all patients are alike. How do I account for weight? age?

to integrate the intricacies of kinetics and dynamics into their clinical practice and instead rely on training and experience to determine dosing. Thus, the determination of the proper dose in clinical anesthesia is often little more than a sophisticated guess. So why bother with clinical pharmacology? It is because this discipline provides the core scientic foundation for optimizing doses of intravenous anesthetics and should be a part of every practicing anesthesiologists knowledge base. Fortunately, advances in pharmacologic computer simulation have revolutionized the way we apply complex pharmacokinetic and pharmacodynamic models. Simulations can be used to create meaningful pictures of drug behavior that are useful when considering the questions described in Table 1.

Pharmacokinetics
To develop a pharmacokinetic model, clinical pharmacologists administer a drug and then repeatedly measure drug concentrations in blood over time. The raw data are drug concentrations over time (Fig. 1). For example, considering a 2-mg/kg bolus dose of propofol, measuring the plasma propofol level shortly after infusion may be 9 g/mL and then quickly wane to less than 3 g/mL within 5 minutes. Volume of distribution is a term used to describe the dilution of drug (in this case propofol) into the body. The volume of distribution can be unusual. For example, the volume of distribution for fentanyl, propofol, and pancuronium are 350, 300, and 10 l. At rst glance, some of these do not make sense. How could a drug have a volume of distribution larger than a patients body mass? As it turns out, the volume of distribution is increased in drugs that are lipid-soluble and decreased in drugs that are water-soluble. An important pharmacokinetic feature of an intravenous bolus is that the plasma levels rapidly rise and then decrease. The decline in plasma concentration can be thought of in three different phases. In the rst phase, known as distribution, the plasma concentration rapidly declines. Drug leaves the circulatory system and goes into perfused tissue beds. The rate of distribution is variable and conventionally grouped according to speed of distribution into three tissue types: vessel-rich (fast), muscle (intermediate), and fat (slow) groups. In the second phase, plasma drug levels continue to decline, but at a slower rate. In this phase, propofol that has accumulated in peripheral tissues starts to leach back into the circulating blood volume. In the third phase, drug levels decline at an even slower rate. In this phase, drug is eliminated from the body. However, in vivo, all three processes are present at all times. Mechanisms the body uses to eliminate drug include biotransformation and elimination. Biotransformation includes metabolizing a drug to an inactive state rendering it incapable of readily passing across cell membranes or breaking down drug compounds into inactive metabolites. This is a major function of the liver, but metabolic processes occur in other organs and in blood as well. Elimination refers to the removal of drug from the body. Routes of elimination include exhaled gas from the lungs, urine, and secretion of

PHARMACOKINETICS AND PHARMACODYNAMICS THAT MAKE SENSE

47

Panel A. Raw data

10 9 8 7 Propofol Cp (mcg/mL)

Panel B. Analyzed data

10 9 8 7 Propofol Cp (mcg/mL) 6 5 4 3 2 1 0

6 5 4 3 2 1 0

10

12

14

16

18

20

10 Time (minutes)

15

20

Time (minutes)

Propofol Bolus (2 mg/kg) Panel C: Exponential equation

Cp(t) = Ae-t + Be-t

FIG. 1. Development of a pharmacokinetic model (using propofol as an example). (A) Raw data. Drug Levels (dots) are repeatedly measured over time. (B) Analyzed data. A drug disposition curve (black line) is t to the raw data using an exponential equation based on a computerized nonlinear regression analysis. (C ) The equation is simply a mathematical representation of curves of the general shape that t the data. The curve tting exercise results in a set of parameters (in this example, A, B, , and ) that, when plugged into the equation, reproduce the curve through the data. Cp(t) represents the plasma propofol concentration as a function of time (t). (Reprinted with permission from Longnecker et al.: Anesthesiology, 1st edition. New York: McGraw-Hill, 2008, chapter 39. Copyright 2008 The McGraw-Hill Companies.)

metabolites into the bile. Renal elimination has some interesting features. As drug enters the glomerular ltration system, only nonprotein-bound drug penetrates the renal duct system. From there, nonionized drugs are re-absorbed and only ionized drugs are excreted. Using computerized pharmacokinetic tools, a series of equations are t to the raw data. The equations used are simply a mathematical expression of the shape of the concentration versus time curve. The equations are comprised of parameters like fractional coefcients and rate constants that are not much use to anesthesiologists. To make parameters more meaningful, these equations are often reparameterized (converted) in terms of distribution volumes and clearances or intercompartmental microrate constants. Distribution volumes and clearances are used to create compartmental models that provide a schematic representation of drug behavior (Fig. 2).

Unimportance of Individual Parameters

It is important to point out that it is difcult for anesthesiologists to take advantage of multicompartmental models and the mathematical equations that represent them

48

JOHNSON AND EGAN

IV drug administration

Rapid Peripheral Compartment (V2)

k12

k21

Central Compartment (V1)

k10

k31

k13

Slow Peripheral Compartment (V3)

FIG. 2. Schematic of a three-compartment model. The k parameters represent rate constants. The V parameters represent the compartment volumes. (Reprinted with permission from Longnecker et al.: Anesthesiology, 1st edition. New York: McGraw-Hill, 2008, chapter 39. Copyright 2008 The McGraw-Hill Companies.)

in a clinical setting. Consideration of individual volumes of distribution or clearance parameters in formulating a dose of anesthetic that accounts for the complex interplay of the parameters is impossible for humans to do in real time without the assistance of a computer or a computer-driven infusion pump.

Importance of Simulations
The real power from these pharmacokinetic parameters and compartment models comes through simulation. Because little insight into a drugs pharmacokinetic prole can be gleaned from simple inspection of its multicompartment pharmacokinetic parameters, computer simulation of the expected rise and decrease of drug concentrations using a drugs pharmacokinetic parameters has assumed an important role in modern pharmacokinetic research and analysis. Making use of population pharmacokinetic parameters estimated in research studies, computers can be programmed to simulate the concentration versus time prole that results from any combination of boluses and/or continuous infusions. It is important to recognize that simulations are limited by the quality of the original research from which the pharmacokinetic parameters were estimated and the inherent variability of pharmacokinetic parameters from patient to patient. Simulations are nonetheless a graphic representation of a drugs expected clinical pharmacokinetic prole and provide an excellent framework within which to formulate a rational dosing strategy and within which to pose hypotheses that can be tested with new data.2

Context-sensitive Half-lives
Computer simulation has also been useful in demonstrating how estimating drug behavior based on individual kinetic parameters such as terminal half-lives can be misleading.1 Anesthesiologists have traditionally relied on terminal half-lives as a reection of the duration of drug action when in fact terminal half-life alone is not a very useful pharmacokinetic parameter.3 To that end, techniques have been used to predict the time necessary to achieve a 50% decrease in drug concentration after termination of variable-length continuous infusions. Approaches in simulation have been developed

PHARMACOKINETICS AND PHARMACODYNAMICS THAT MAKE SENSE

49

to provide a context-sensitive half-life or 50% decrement time in which context refers to the duration of a continuous infusion (or to the total dose of a drug given in multiple doses over time).4 Such simulations are intended to provide more clinically useful guidance than half-life or volume of distribution.5 For example, consider simulations of context-sensitive half-lives for a set of sedatives and opioids in Figure 3. Through these simulations, several qualitative differences between drugs can be visualized that may be of use in clinical practice. For the sedatives etomidate, midazolam, propofol, and dexmedetomidine, for infusions of brief duration (less than 30 minutes), the 50% decrement time is rapid (less than 20 minutes) for all drugs. However, for infusions of longer duration (greater than 2 hours), the prole of each drug begins to differ. If the desired goal is to have drug concentrations wane quickly after termination of an infusion, propofol is a good choice. If delayed decline in drug concentration is desirable, dexmedetomidine is a better choice. For the opioids fentanyl, sufentanil, and remifentanil, there is little difference for infusions of brief duration. For long infusions, however, differences emerge. Remifentanil has a very rapid decline, which is essentially independent of infusion duration and is a good choice when rapid decline of drug concentration is desired after termination of an infusion. For long infusions, sufentanil has an attractive prole in that the 50% decrement time approaches 45 minutes with infusions of up to 10 hours. This may provide a more predictable decline in drug level after termination of the infusion. Fentanyl, by contrast, has a prolonged 50% decrement time (greater than 2 hours) for infusions longer than 4 hours. This feature may be desirable after a procedure associated with signicant postoperative pain in a patient with opioid tolerance but less desirable in patients in whom rapid emergence and minimal respiratory depression are anesthetic goals. The 50% decrement time, although an improvement from using terminal half-lives to how anesthetic drugs will behave, is not always relevant. Depending on the dose and pharmacokinetic features of a particular drug, the 50% decrement time may not adequately describe drug behavior that is of clinical interest (i.e., when will the analgesic effect of my intravenous opioid infusion dissipate after the infusion is terminated?). To get beyond this limitation, other decrement times can be used such as the 20% or the 80% decrement time to tailor the pharmacokinetic description of drug behavior to a clinical end point of interest.5,6 These modications of decrement times still do not provide a satisfying response to When will a drug start to have an effect and how long will it last? One feature of pharmacokinetic modeling that is important to consider when interpreting simulations is that models often are based on studies collected in relatively young, healthy volunteers with no comorbidities or patients who have been extrapolated to the population at large. While building these models, clinical pharmacologists acknowledge variability between subjects and that their subject pool may not demographically reect a typical patient population. Hence, there are several reasons why models may not make good predictions of drug concentrations. Model predictions are often illustrated as plots of drug concentration over time. When accounting for the intersubject variability, they probably should be presented as a line with some expression of the variability about that line.

Importance of Biophase
Biophase refers to the equilibration delay between peak drug levels in the blood or plasma and peak drug effect. The time lag (or hysteresis) between peak concentration in the plasma and peak drug effect is a function of drug movement into and action

50

JOHNSON AND EGAN

Sedatives
140 Time Required for plasma levels to drop by 50% (minutes) 120 100 80 60 40 20 0 Etomidate Midazolam Propofol Dexmedetomidine

100

200

300

400

500

600

Duration of infusion (minutes)

Opioids
140 Time Required for plasma levels to drop by 50% (minutes) 120 100 80 60 40 20 0 Sufentanil Fentanyl Remifentanil

100

200

300

400

500

600

Duration of infusion (minutes)

FIG. 3. Simulations of the context-sensitive half-life for selected intravenous sedatives and opioids. (Reprinted with permission from Longnecker et al.: Anesthesiology, 1st edition. New York: McGraw-Hill, 2008, chapter 39. Copyright 2008 The McGraw-Hill Companies.)

PHARMACOKINETICS AND PHARMACODYNAMICS THAT MAKE SENSE

51

within the effect site.79 The effect site represents a theoretical space without any denitive anatomic analog where drug exerts its effect. The lag time represents a summation of events that can impact the onset of pharmacologic effect such as drug diffusion to the effect site, receptor binding, and so on (Fig. 4A). The hysteresis is important to account for when forecasting drug effect. It is particularly important to consider when simulating bolus injections of drug, whereas for long infusions, the time lag assumes less importance because the effect site and plasma are generally closer to equilibrium. Consider a 2-mg/kg bolus of propofol and the observed changes in a processed electroencephalogram parameter such as the Bispectral Index Scale. The maximal decrease in the Bispectral Index Scale lags behind the peak plasma propofol level (Fig. 4B). The time delay, or hysteresis, represents the time required for propofol to go from the plasma to the site where it exerts an effect. In other words, most drugs do not produce their intended clinical effects while remaining in the plasma. For many drugs, including propofol, the equilibration delay between peak concentration in the plasma and peak effect has been characterized by estimating a parameter called the keo. The keo represents the rate constant for elimination of drug from a virtual compartment called the effect site.8,10 When the keo parameter is available for a drug, theoretical effect compartment concentrations can be simulated along with plasma concentrations, thus making the effect of the time lag easily appreciated. In essence, the time course of effect site concentrations leads us closer to accurately predicting the onset and the time course of the drug effect. For example, when using the effect site to model the response to a bolus of midazolam, propofol, and etomidate, differences between drugs can be easily appreciated. Propofol and etomidate reach their peak effect site concentrations within 2 minutes, whereas midazolam requires 9 minutes to reach its peak effect site concentrations. Similarly, simulations of opioid boluses illustrate how remifentanil reaches its peak effect site concentration within 90 seconds, whereas boluses of sufentanil and fentanyl require up to 4 to 5 minutes to reach their peak concentrations (Fig. 5). This may be important to consider when counting on carbon dioxide accumulation to offset respiratory depression associated with opioids. The rapid rise of effect with remifentanil may not allow accumulation of carbon dioxide.

Pharmacodynamics
Pharmacodynamic models have been constructed to describe the relationship between drug effect site levels and drug effect. Some important features of pharmacodynamic models are presented in Figure 6. In this gure, a schematic illustrates how a drug, once it reaches the effect site, interacts with a receptor to produce effect (Fig. 6A). This process is typically characterized graphically using a sigmoidal curve (Fig. 6B). Parameters used to describe the pharmacodynamic model (i.e., the sigmoid curve) include the C50 and gamma (). The C50 represents the effect site concentration at which 50% of the maximal drug effect will be elicited and represents the slope of the concentrationeffect curve. The most important part of the sigmoid curve, the steep section of the curve, represents the dynamic range of drug effect. The dynamic range charts the concentrationeffect relationship from E0 (baseline effect) to Emax (maximal effect). In this region, small changes in drug concentration lead to large changes in drug effect. This is the region of particular interest to anesthesiologists. Increasing effect site concentrations beyond the dynamic range lead to small changes in drug

Panel A.

Capillary

Diffusion

Reaction Effect

Cell Panel B.

10

Time Lag

20

Propofol Cp (mcg/mL)

40 5

Bispectral Index Scale

60

2 80 Plasma Propofol Bispectral Index 1 0 1 2 3 Time (min) 4 5 6 100

Panel C.

dCe dt

= k1eCp - keoCe

FIG. 4. The biophase concept. (A) Schematic of drug (triangles) diffusion from a blood vessel to the site of action (effect site), in this case, a cell membrane. Drug interaction with a cell membrane receptor produces a biochemical reaction that leads to a drug effect. (B) Simulation of plasma propofol levels and Bispectral Index Scale after a 2-mg/kg propofol bolus to a 70-kg person. The solid and dashed lines represent the plasma propofol concentration and Bispectral Index Scale, respectively. The right side vertical axis for Bispectral Index Scale has been reversed. Note the time (hysteresis) lag between the peak propofol plasma level and the peak Bispectral Index Scale value. (C ) The mathematical expression used to compute the effect site concentration. k1e and keo represent the elimination rate constants from the central (Cp) and effect site (Ce) compartments, respectively. (Reprinted with permission from Longnecker et al.: Anesthesiology, 1st edition. New York: McGraw-Hill, 2008, chapter 39. Copyright 2008 The McGraw-Hill Companies.)

Sedatives

1 Normalized Effect Site Concentration

0.5

0.2

Etomidate Propofol Midazolam

0.1 0 1 2 3 4 5 6 7 8 9 10

Time (minutes)

Opioids

1 Normalized Effect Site Concentration

0.5

0.2

Fentanyl Remifentanil Sufentanil

0.1 0 1 2 3 4 5 6 7 8 9 10

Time (minutes)

FIG. 5. Simulations of the effect site after a bolus of selected intravenous sedatives and opioids. The effect site concentrations for each drug have been normalized to 1 on the vertical axis. After a bolus, the peak midazolam effect occurs more than 9 minutes later (left arrow) and the peak remifentanil effect occurs within 90 seconds (right arrow). (Reprinted with permission from Longnecker et al.: Anesthesiology, 1st edition. New York: McGraw-Hill, 2008, chapter 39. Copyright 2008 The McGraw-Hill Companies.)

Panel A

Cell Membrane
Drug Receptor Interaction Panel B
Maximal Effect (Emax)

Drug Effect

Baseline (E0)

C50

C95

Effect Site Drug Concentration (Ce) Panel C

E = E0 +

Emax . Ce C50 + Ce

FIG. 6. A typical pharmacodynamic model. (A) Schematic of the pharmacodynamic process. Drug (triangles) interact with receptors in the effect site to elicit a drug effect. (B) A graphic expression of pharmacodynamic drug behavior. E represents drug effect; C50 represents the effect site concentration necessary to produce 50% of the maximal drug effect. E0 represents the baseline effect (with no drug present) and Emax represents the maximal effect. The vertical axis is on the log scale. The sigmoid shape of the concentration versus effect curve is characteristic of intravenous anesthetics. Gamma () represents the maximal slope of the concentration versus effect curve. The dashed line represents the concentration at which 50% of the maximal effect is achieved. The dashdotdash line represents the concentration at which 95% of the maximal effect is achieved. (C ) Mathematical expression of the pharmacodynamic model used to render the concentration versus effect curve in B. (Reprinted with permission from Longnecker et al.: Anesthesiology, 1st edition. New York: McGraw-Hill, 2008, chapter 39. Copyright 2008 The McGraw-Hill Companies.)

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effect. The mathematical expression that uses the C50 and to estimate drug effect is presented in Figure 6C. A surng analogy is helpful in conceptualizing the application of pharmacodynamic models to rational drug administration.11 Just as a surfer attempts to stay on the crest of a wave, anesthesiologists attempt to maintain their anesthetic drugs at effect site concentrations near the crest of the concentrationeffect relationship (Fig. 6B). In so doing, anesthesiologists maintain a signicant drug effect but can slide down the wave to promote recovery at the end of an anesthetic. From an efcacy and toxicity perspective, there is no advantage of being on the at part of the concentrationeffect relationship near Emax. As an example, consider three bolus doses of propofol (0.5, 2, and 7 mg/kg). The resultant effect site concentrations for each bolus are presented in Figure 7. Using a pharmacodynamic model for propofol, the effect of these boluses is plotted on a sigmoid curve. The C50 for this curve (1.8 g/mL) represents the effect site concentration at which there is a 50% probability of loss of responsiveness.12 Dosing regimens that maintain drug concentrations along the lower left portion of the sigmoid curve (i.e., below the wave) are too low to be effective as illustrated by the low-dose propofol bolus (0.5 mg/kg). Dosing regimens that maintain drug concentrations to the right side of the sigmoid curve (i.e., before the wave breaks) are excessive and may produce unwanted hemodynamic depression or recovery. In this region, increasing drug concentration does not increase drug effect. This phenomenon is illustrated by the 7-mg/kg bolus dose of propofol. The ideal dosing strategy targets the upper portion of the steep part of the concentrationeffect relationship, a concentration that produces a considerable drug effect but from which the drug effect will recover quickly once the drug administration is terminated as illustrated by an intermediate dose of propofol (2 mg/kg). One practical aspect of anesthesia care that makes surng difcult to do is that the concentrationeffect relationship is not consistent across various stimuli. For some stimuli, much less drug is required to achieve a desired effect compared with other stimuli. For example, a skin incision is typically less noxious than laryngoscopy.1315 In an effort to characterize how different stimuli vary, numerous pharmacodynamic models have been built for selected stimuli.

Importance of Combining Kinetic and Dynamic Models

To depict a patients response to a dose of drug, it is necessary to combine pharmacokineticpharmacodynamic models and provide a quantitative description of each. Because most drugs do not act in the blood, the pharmacokinetic and pharmacodynamic models must be linked so that concentrations in the plasma can be translated into effect site concentrations and thus drug effect. One approach to visualize the link between the pharmacokinetic and pharmacodynamic models is to plot a horizontal line on the pharmacokinetic plot of effect site concentrations over time that represents the C50 for a desired drug effect. Two key points of interest are now easily visualized through computer simulation: 1) the time to onset of effect, either desired or potentially toxic; and 2) the duration of the drug effect.3,16,17 Linked pharmacokineticpharmacodynamic models can also provide insight into how drugs behave after termination of continuous infusions. Factors that inuence the duration of effect after termination of an infusion include the infusion rate and the duration of the infusion (or, in other words, the total administered dose of the drug).

Panel A

20

Propofol Ce (mcg/mL)

10 5 2 1 0.5 0.2 0.1

10

Time (minutes)

P anel B

100

Probability of Loss of Consciousness

80

60

40

20

0.1

0.2

0.5

10

20

Propofol Ce (mcg/mL)
FIG. 7. A simulation integrating pharmacokinetic and pharmacodynamic models illustrating the interplay between the doseconcentration (pharmacokinetic) relationship and the concentrationeffect (pharmacodynamic) relationship. (A) Simulation of the propofol effect site concentrations over time for bolus doses of 0.5 mg/kg (squares), 2 mg/kg (circles), and 7 mg/kg (triangles). (B) The corresponding concentration versus effect of the bolus doses in A superimposed over a pharmacodynamic model for propofol. (Reprinted with permission from Longnecker et al.: Anesthesiology, 1st edition. New York: McGraw-Hill, 2008, chapter 39. Copyright 2008 The McGraw-Hill Companies.)

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An example of a combined pharmacokineticpharmacodynamic simulation is presented in Figure 8. To visualize the onset and duration of effect, the 50% probability of loss of responsiveness (C50) is overlaid on the simulations of propofol effect site concentrations. Several investigators have estimated propofol effect site concentrations required for loss of responsiveness with C50s ranging from 1.8 to 2.4 g/mL.12,1820 In this example, the resultant propofol effect site concentrations over time are plotted after bolus doses ranging from 1.0 to 2.5 mg/kg and the horizontal line, representing the C50 for loss of responsiveness, is set at 1.8 g/mL. The onset of effect is quicker (from 80 to 30 seconds) and the duration of effect is longer (from 3 to 10 minutes) with increasing propofol doses. It is important to point out that this C50 for loss of responsiveness, like all pharmacokinetic and pharmacodynamic parameters, is a population estimate for a typical patient and, as such, is subject to intersubject variability and will not perfectly predict unresponsiveness in individuals. Guided by simulations, the clinical implications of a given propofol dosing strategy become apparent. For example, using a larger dose of propofol as part of a rapidsequence induction, if hemodynamically tolerable, may prove useful in minimizing the time in which the airway is unsecured because of a faster onset of effect. By contrast, a lower dose may be useful when providing anesthesia for brief procedures associated with a noxious stimulus such as a retrobulbar block, in which only brief unresponsiveness is required. When using the lower dose, however, practitioners need to recognize that it will take up to 50 seconds longer to achieve loss of responsiveness.
10 2.5 mg/kg 2.0 mg/kg 1.5 mg/kg 1.0 mg/kg

Propofol Effect Site (mcg/mL)

2 50% Probability of Loss of Responsiveness 1

0.5

0.2

10 Time (minutes)

15

20

FIG. 8. Simulations of the propofol effect site concentrations in response to bolus doses ranging from 1 to 2.5 mg/kg for a 70-kg person. The gray horizontal line represents the propofol effect site concentration associated with a 50% probability of loss of responsiveness.12,1820 Note the difference in the onset and duration of effect (loss of responsiveness) for increasing doses. (Reprinted with permission from Longnecker et al.: Anesthesiology, 1st edition. New York: McGraw-Hill, 2008, chapter 39. Copyright 2008 The McGraw-Hill Companies.)

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Summary
Pharmacokinetics and pharmacodynamics are mathematically based disciplines and seem relatively unpopular among anesthesiologists. This unpopularity is ironic given that there is no medical specialty in which the accurate prediction of the timing and magnitude of drug effects is more important than anesthesiology. The clinical implications of pharmacokineticpharmacodynamic models, however, can be most easily understood and described through the use of computer simulation. Using computer simulation, a proposed dosing scheme can be input into a pharmacokineticpharmacodynamic model, producing a picture of the predicted drug concentrations and effects that will be expected to occur. These pictures (computer simulations) are intuitively understandable and are easily applied in clinical situations.

References
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17. Ebling WF, Levy G: Population pharmacodynamics: Strategies for concentration- and effectcontrolled clinical trials. Ann Pharmacother 1996; 30:129. 18. Vuyk J, Mertens MJ, Olofsen E, et al.: Propofol anesthesia and rational opioid selection: Determination of optimal EC50-EC95 propofol-opioid concentrations that assure adequate anesthesia and a rapid return of consciousness. Anesthesiology 1997; 87:154962. 19. Schnider TW, Minto CF, Shafer SL, et al.: The inuence of age on propofol pharmacodynamics. Anesthesiology 1999; 90:150216. 20. Struys MM, Vereecke H, Moerman A, et al.: Ability of the bispectral index, autoregressive modelling with exogenous input-derived auditory evoked potentials, and predicted propofol concentrations to measure patient responsiveness during anesthesia with propofol and remifentanil. Anesthesiology 2003; 99:80212.

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