Chapter

5 BASIC PHARMACOLOGIC
PRINCIPLES
Steven L. Shafer

PHARMACOKINETICS
Physiologic Basis of Pharmacokinetics
Pharmacokinetic Models
PHARMACODYNAMICS
M edical students are typically asked during their
interviews for residency why they want to become
anesthesiologists. The answer is often a variant of “I like
Transduction of Biologic Signals
pharmacology and physiology.” The answer may seem
Clinical Evaluation of Drug Effects
pedestrian to the practicing anesthesiologist, but it accu-
QUESTIONS OF THE DAY rately reflects the profoundly close linkage between anes-
thesia and pharmacology.
This linkage consists of several components. We give
drugs to patients, who proceed to “dispose” of the drugs
through the processes of absorption, distribution, metab-
olism, and elimination. This process is called pharmaco-
kinetics, and reflects what the body does to the drug.
During its sojourn through the body the drug will interact
with specific receptors in the body, producing the drug
effect. This process is called pharmacodynamics, and
reflects what the drug does to the body.
Our clinical practice teaches fundamental concepts in
pharmacology: steady-state potency, which we call
“MAC” (minimum alveolar concentration) for inhaled
anesthetics (also see Chapter 8); the complex nature of
drug accumulation, which we refer to as “context-sensitive
half-times”; and plasma-effect site hysteresis. In many
countries anesthesia care providers either do or will use
computers to give anesthetic drugs, directly applying the
principles of pharmacokinetics and pharmacodynamics.
New clinical monitors solve the complex mathematics of
drug uptake and distribution, and predict anesthetic drug
concentration and anesthetic drug interactions using
three-dimensional surfaces to help guide the clinician.
This chapter will present the basic pharmacokinetic
and pharmacodynamic principles that govern anesthetic
drug behavior.

PHARMACOKINETICS

Pharmacokinetics describes the processes of absorption,

distribution, and elimination that link drug administra-
tion to drug concentration in the plasma and at the site

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Section II PHARMACOLOGY AND PHYSIOLOGY
of drug effect. Absorption is not relevant to intrave-
nously administered drugs, but is relevant to all other
routes of drug delivery. Distribution includes the instan-
taneous distribution (and dilution) into the blood volume
and the subsequent partitioning of drug into peripheral
compartments. Clearance describes elimination of the
drug, typically through hepatic metabolism, renal elimi-
nation, or (in the case of inhaled anesthetics) removal
via the lungs.
Physiologic Basis of Pharmacokinetics
ABSORPTION
Absorption of drugs is governed by the route of delivery,
the bioavailability, and the possibility of first-pass metabo-
lism. Outside of anesthesia most drugs are given orally.
Orally administered tablets, pills, and liquids exhibit com-
plex behavior, including transit delays, pH effects, food
effects, and first-pass metabolism. These concepts are not
particularly relevant to the practice of anesthesia. Several
drugs, including fentanyl, are administered through the
buccal mucosa. Transmucosal delivery is characterized by
a rapid absorption phase through the buccal mucosa, which
is not affected by food or first-pass metabolism, and a
slower phase for drug swallowed into the stomach. Inhaled
anesthetics are also “absorbed” through the lungs, typically
with very rapid transit. Drug injected into tissues is also
absorbed into the systemic circulation. Absorption from tis-
sue is the process responsible for the offset of local anes-
thetic effect after nerve blocks. The skin may also be a site
of drug absorption, for example with transdermal cloni-
dine, scopolamine, nitroglycerin, and fentanyl. The skin
(by design) presents a considerable barrier to absorption,
and typically several hours are required for clinical effect
to commence following transdermal delivery. The skin also
provides a depot of drug, resulting in continued drug deliv-
ery even after the drug has been removed from the skin.
The fundamental concept of absorption is that the rate
of transfer from the depot (stomach, lung, nerve bundle,
transdermal patch) to the systemic circulation is directly
proportional to the concentration gradient between the
depot and the systemic circulation. When the rate of drug
flow is proportional to the concentration gradient, it is
called “first-order” transfer. A characteristic of first-order
transfer is that the “shape” of the curve does not depend
on the dose. If you double the dose, the curve will look
the same, and peak at the same time, but the concentra-
tions will be exactly twice as high at all times. However,
the absorption rate has a considerable influence on the
magnitude of the peak concentration. Basically, rapid
absorption leads to high peaks, and slow absorption leads
to smaller peaks. This is why nerve blocks at sites with
rapid absorption (e.g., intercostal blocks) of local anes-
thetic drugs result in steeper and higher peaks, and a
more frequent risk of toxicity, than nerve blocks at sites
with slow absorption.
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DISTRIBUTION
Distribution dilutes the drug from the highly concen-
trated solution injected into the body to the highly dilute
concentration in the plasma. It is a process of mixing,
initially with the blood, and then with the tissues of the
body. If we measure the concentration of the drug, then,
we can readily calculate the mixing volume. Concentra-
tion is defined as amount/volume. If we measure concen-
tration, and we know the amount injected, we can solve
this equation for the volume of distribution:
Amountðor doseÞ
Volume ¼ Eq:1
Concentration
Central Volume of Distribution
The central volume of distribution is the apparent volume
immediately after injecting a bolus of drug into the body.
The concept is not exactly right, because there is a time
lag of roughly half a minute between giving an intrave-
nous bolus of drug and the appearance of drug in arterial
blood. This time lag is typically and appropriately
ignored. The central volume reflects the blood and tissue
that the drug has had time to mix with during this rapid
transit. Typically that might include the blood in the
heart and great vessels, as well as drug uptake by the
lungs. The central volume is often used to calculate the
dose of drug that should be administered to obtain a
given concentration by rearranging Equation 1:
Dose ¼ Desired Concentration  Volume Eq:2
Peripheral Volumes of Distribution
Anesthetic drugs are typically highly fat soluble, resulting
in considerable distribution into peripheral tissues. These
tissues comprise peripheral volumes of distribution, which
are linked to the central volume of distribution. The size
of the peripheral volumes of distribution relates to the sol-
ubility of the drug in the tissue, relative to the solubility in
blood (or plasma). If the drug is highly soluble in a tissue,
then it will have a large peripheral volume of distribution.
For example, propofol is highly soluble in fat, resulting in a
huge (>1000 L) peripheral volume of distribution. Rarely
are the actual solubilities of drugs in peripheral tissues
known, but that does not matter. By convention, pharmaco-
kinetic models assume that the solubility of the drug in
every tissue is the same as the solubility in blood or plasma,
and that the tissue is correspondingly large when the drug
is, in fact, highly soluble.
Peripheral volumes of distribution can be characterized
several ways. There are highly detailed physiologic models
for some drugs that account for each organ, the solubility
of drug in each organ, and the flow of drug to organs.1
These models are not particularly useful. A pseudo-
physiologic approach is to approximately divide the body
into several tissue beds: “vessel-rich group” (e.g., brain,
most organs), the muscle group, the fat group, and the
“vessel-poor group” (skin, cartilage, ligaments). This scheme

is often used for inhaled anesthetics. Another approach is to
determine the number of compartments required to accu-
rately predict drug concentration in pharmacokinetic mod-
els. Nearly all anesthetic drugs can be described by a model
with one central compartment of distribution, and two
peripheral volumes of distribution. In this latter approach,
the compartments may be described using terms that sound
physiologic (e.g., the rapidly equilibrating compartment),
but the models are strictly empiric and do not describe
underlying physiology.
CLEARANCE
Clearance is the process that removes drug from a tissue.
Systemic clearance is the permanent removal of drug
from the body, and “intercompartmental” clearance
describes the movement of drug from one tissue to
another. Clearance has units of flow: the volume
“cleared” per unit of time (e.g., liters/minute). For exam-
ple, consider propofol. The liver metabolizes virtually all
of the propofol that enters the liver via the hepatic artery
and portal vein. Thus, the clearance of propofol is liver
blood flow. The liver clears only about half of the fenta-
nyl that enters via the hepatic artery or portal vein, so
fentanyl’s clearance is half the liver blood flow. Simi-
larly, if the kidneys remove every molecule that enters
the kidney, then renal clearance would be the same as
renal blood flow. However, if the kidneys only remove
every molecule that is filtered at the glomerulus, then
plasma clearance is the glomerular filtration rate.
Hepatic Metabolism
Most anesthetic drugs are removed from the body by
hepatic biotransformation. The liver metabolizes drugs
through oxidation and reduction via the cytochrome
P-450 system. The most important cytochrome (CYP)
for anesthetic drugs is CYP 3A4, which metabolizes acet-
aminophen, alfentanil, dexamethasone, fentanyl, lido-
caine, methadone, midazolam, and sufentanil. Propofol
is partly oxidized by CYP 3A4, but mostly by CYP 2B6.
Cytochromes can be induced or inhibited by drugs and
disease. For example, midazolam inhibits CYP 3A4, and
thus might be expected to prolong the effect of drugs
metabolized by CYP 3A4 (alfentanil, fentanyl). Propofol
also inhibits CYP 3A4, although the clinical relevance is
unclear.2 CYP 3A4 is potently inhibited by grapefruit
juice,3 antifungal drugs, protease inhibitors, the “mycin”
antibiotics, and several selective serotonin reuptake in-
hibitors (SSRIs). Conversely, rifampin, rifabutin, tamoxi-
fen, glucocorticoids, carbamazepine, barbiturates, and
the herb St. John’s wort induce CYP 3A4, increasing the
metabolism of 3A4 substrates.
CYP 2D6 is responsible for the conversion of codeine
to morphine, which is the active metabolite of codeine.
Many drugs inhibit CYP 2D6, including quinidine and
the SSRIs. As a result, codeine, oxycodone, and
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Chapter 5 Basic Pharmacologic Principles
hydrocodone are poor analgesic choices for patients
receiving SSRIs.
The liver also metabolizes drugs through conjugation
and hydrolysis. Conjugation transforms hydrophobic
molecules into water-soluble molecules so the kidney
can excrete the molecule. Hydrolysis splits molecules
apart, typically at peptide or ester linkages. The metabo-
lites of most anesthetic drugs are inactive, although mor-
phine and midazolam have metabolites that are as potent
as the parent drug.
Tissue Metabolism
Remifentanil, succinylcholine, and esmolol are cleared in II
the plasma and tissues via ester hydrolysis. These drugs
vanish from the plasma incredibly quick, because
esterases are ubiquitous in tissue and plasma. Addition-
ally, drugs cleared by ester hydrolysis typically have
highly predictable pharmacokinetics, because the esterase
system is very robust. The exception is succinylcholine,
whose metabolism by butycholinesterase (formerly called
“pseudocholinesterase”) is sometimes very slow when a
genetic defect in butylcholinsterase metabolism occurs.
Metabolism and Clearance
Clearance is a fundamental biologic property. For exam-
ple, propofol clearance is almost identical to hepatic
blood flow. What does that say about the rate of drug
removal from the liver? The rate at which propofol
flows into the liver is obviously the propofol concentra-
tion times liver blood flow. If you double the propofol
concentration, then you double the amount of propofol
flowing into the liver. Because the liver removes all
the propofol it detects, the rate of propofol metabolism
must be proportional to propofol concentration as well.
This is a general characteristic of all anesthetic drugs:
the rate of metabolism is proportional to the drug con-
centration. When that is the case, the drug is described
as having “linear” pharmacokinetics, meaning that if
you exactly double the dose, you will double the blood
concentrations as well.
The liver’s metabolic rate to liver blood flow, Q, and
the concentrations of drug flowing into and out of
the liver (Fig. 5-1) can be calculated with a simple
equation:
Rate of drug metabolism ¼ R ¼ QðCinflow  Coutflow Þ
Eq:3
In the case of propofol, Coutflow is nearly 0, so metabo-
lism is the rate of drug flowing into the liver: Q ¼ Cinflow.
Again, the liver metabolizes only about half of the fentanyl
presented to it. In this case, Coutflow is about half of Cinflow.
If we divide both sides of Equation 3 by Cinflow, we get:
 
R Cinflow  Coutflow
¼Q ¼ Q  ER ¼ Clearance
Cinflow Cinflow
Eq:4
37
Section II PHARMACOLOGY AND PHYSIOLOGY
Metabolism (R)
Clearing organ
Conc = Coutflow Conc = Cinflow
Flow = Q
Drug removed via metabolism
R = Q (Cinflow – Coutflow)
Figure 5-1 The rate of metabolism equals liver blood flow
times the difference between the inflowing and outflowing drug
concentrations. (Adapted from Shafer SL, Flood P, Schwinn DA:
Basic Principles of Pharmacology. In Miller RD [ed]. Miller’s
Anesthesia, 7th ed. Philadelphia, Churchill Livingstone Elsevier,
2010, pp 479-513.)
Consider the expression
 
Cinflow  Coutflow
Cinflow
in Equation 4. This is the fraction of drug flowing
into the liver that is removed during the passage. If
Coutflow ¼ 0 (propofol), this is 1. If Coutflow is half of Cinflow
(fentanyl), then this is 0.5. This term is often called the
“extraction ratio,” meaning the fraction (or ratio) of drug
that is “extracted” from the drug flowing into the liver. In
the third term, we have substituted ER for the explicit
ratio. The resulting term, Q  ER, is how clearance is typ-
ically defined.
Let’s now consider the first term and last terms of
Equation 4, but first rearrange by multiplying through
by Cinflow:
R ¼ Clearance  Cinflow
For most drugs used in anesthesia, the rate of metabo-
lism is proportional to concentration. We now see that
proportionality constant is clearance. This is the second
common definition of clearance: the proportionality con-
stant that links drug concentration to metabolic rate. If
the extraction ratio is constant, it follows that the ratio
Coutflow
Cinflow
must also be constant. We can define another term,
“intrinsic clearance,” as the proportionality constant
between the ratio of drug flowing in and flowing out of
the liver:
Coutflow
Cinflow
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and clearance is calculated as:
Coutflow
Clearance ¼ Q  ER ¼  Intrinsic clearance
Cinflow
Eq:6
With a little algebra, one can demonstrate that
Q  ER
Intrinsic clearance ¼ :
1  ER
Intrinsic clearance reflects the metabolic horsepower of
the liver. We can use the concept of intrinsic clearance to
relate extraction ratio, liver blood flow, and clearance, as
shown in Figure 5-2. For drugs such as propofol, with an
extraction ratio that is nearly 1 because the liver removes
nearly all the drug that flows in, changes in liver blood
flow produce proportional changes in clearance. These
drugs are said to be “flow limited,” in that clearance is lim-
ited only by the rate of blood flowing into the liver. An
increase or decrease in liver blood flow produces a propor-
tional increase or decrease in clearance. For drugs with
low extraction ratios (e.g., alfentanil), clearance is limited
by the capacity of the liver to metabolize the drug. Metab-
olism of such drugs is “capacity limited.” For drugs with
capacity limited metabolism, changes in liver blood flow
do not affect clearance. The liver can only metabolize a
fraction of the drug flowing in anyway, so it doesn’t mat-
ter if more or less drug flows into the liver.
The liver does not have infinite capacity to metabolize
drugs. There must be a point at which every cytochrome
in every hepatocyte is working as hard as possible to
metabolize the drug flowing in. At this point, metabolism
is “saturated,” and if additional drug flows into the liver,
it will simply flow out again. If we define Vm as the
maximum metabolic rate, and Km as the concentration
of drug associated with half of the maximum metabolic
rate, we can then modify Equation 4 to account for satu-
rable metabolism:4
Rate of drug metabolism ¼ R ¼ QðCinflow  Coutflow Þ
Eq:5 Coutflow
¼ Vm
Km þ Coutflow
Eq:7
Equation 7 permits calculation of the relationship
among Vm, which measures the hepatic metabolic horse-
power, clearance, and extraction ratio. Figure 5-3 shows
how clearance will respond to changes in Vm, as might
occur with enzyme inhibition, enzyme induction, or liver
disease. Drugs with a high extraction ratio, such as propo-
fol, are insensitive to changes in Vm. The liver has so much
metabolic capacity for propofol that only massive liver
destruction affects clearance. On the other hand, for drugs
with low extraction ratios (e.g., alfentanil), changes in Vm
produce proportional changes in clearance. That is why
even minor induction or inhibition of CYP 3A4 might
affect alfentanil clearance.
 Chapter 5 Basic Pharmacologic Principles

Figure 5-2 The relationship between liver blood

flow (Q), clearance, and extraction ratio (ER), Extraction
showing the response of flow limited drugs (ER > ratio
0.6) versus capacity limited drugs (ER < 0.5) to 3 1.0

Extraction ratio calculated

changes in liver blood flow. (In Miller RD [ed].
Miller’s Anesthesia, 7th ed. Philadelphia, Churchill

at Q = 1.4 L/min
Livingstone Elsevier, 2010, pp 479-513.)
2.5 0.9

•
0.8

Clearance (L/min)
1.5
0.7 II
0.6

1 0.5
0.4
0.5 0.3
0.2
0.1
0
0 0.5 1 1.5 2 2.5 3
Liver blood flow (L/min)

Figure 5-3 The relationship between liver blood

flow (Q), clearance, and extraction ratio (ER),
at Vm = 1 g/min

showing the response of flow limited drugs (ER > 2.00

E.R. calculated

0.6) versus capacity limited drugs (ER < 0.5) to

changes in liver metabolic capacity. (From Miller
RD [ed]. Miller’s Anesthesia, 7th ed. Philadelphia,
Churchill Livingstone Elsevier, 2010, pp 479-513.) Extraction
1.50 ratio
1.0
0.9
Clearance (L/min)

0.8
0.7
0.6
1.00
0.5
0.4
0.3
0.50 0.2

0.1

0.00
0 0.5 1 1.5 2
Liver disease/ Vm Enzyme induction
enzyme inhibition

39
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Section II PHARMACOLOGY AND PHYSIOLOGY
For most drugs used in anesthesia, Coutflow in Equation 5
is much less than Km. When this is the case, metabolism is
proportional to drug concentration, and clearance is con-
stant. Some drugs exhibit saturable pharmacokinetics,
meaning that the concentration of drug exceeds Km. The
clearance of drugs with saturable metabolism (e.g., pheny-
toin) is a function of drug concentration, rather than a
constant.
Renal Clearance
The steroidal muscle relaxants are among the few drugs
used in anesthesia practice that are eliminated by the
renal filtration. The kidneys eliminate about 85% of
administered pancuronium, 20% to 30% of vecuronium,
and 10% to 20% of rocuronium (see Chapter 12).
The kidneys remove drug from plasma by filtration at the
glomerulus and direct transport into the tubules. Creatinine
clearance is a useful approximation of the glomerular filtra-
tion rate, and can be predicted from age and weight accord-
ing to the equation of Cockroft and Gault:5
Men:
Creatinine clearanceðml=minÞ
ð140ageðyrsÞÞ  weightðkgsÞ
¼ Eq:8
72  serum creatinineðmg%Þ
Women: 85% of the above.
Equation 8 shows that age is an independent predictor
of creatinine clearance, which stems in part from the
reduction in renal blood flow with advancing age. The
subtle clinical point is that elderly patients with normal
serum creatinine levels still have decreased creatinine
clearance. Decreased renal clearance will delay the offset
of effect for renally excreted drugs, particularly pancuro-
nium. In general, pancuronium should not be used in
elderly patients because clearance will be decreased, even
if the serum creatinine is normal.
Propofol’s clearance is larger than hepatic blood
flow, which is possible only if there are extrahepatic
sites of propofol metabolism. The kidneys have been identi-
fied as one of the primary sites of extrahepatic propofol
metabolism.6 Renal propofol clearance is about 0.4 L/min,
accounting for approximately a quarter of propofol clear-
ance. Propofol is virtually entirely metabolized, with less
than 1% appearing unchanged in the urine. The kidney is
a metabolic organ for propofol, similar to the liver. Renal
elimination of propofol is not a result of filtration.
Distribution Clearance
Distribution clearance is the transfer of drug between the
blood and the peripheral tissues. Distribution clearance
does not permanently remove drug from the body.
However, it can sequester drug for long periods of time.
Distribution of drug into tissues accounts for the very
rapid decrease in drug concentration observed immedi-
ately following an intravenous bolus of an anesthetic
drug. The rate of drug transfer is proportional to the
40
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concentration of drug in each tissue. At steady state,
the concentration of drug in each tissue is the same,
and there is no net transfer of drug between tissues.
PROTEIN BINDING
Many drugs are bound to plasma proteins, particularly to
albumin and alpha 1-acid glycoprotein. The relationship
between drugs and their binding proteins can be
described as:
½Free drug
kon
þ ½Unbound protein binding sites Ð ½Bound drug
koff
where [Free drug] is the free drug concentration, [Unbound
protein binding sites] is the concentration of the available
unbound protein binding sites, [Bound drug] is the concen-
tration of drug bound to plasma proteins, kon is the rate
constant for binding of drug to plasma protein, and koff is
the rate constant for dissociation of bound drug from the
plasma proteins. This binding occurs almost instantaneously
when drug is administered. Plasma proteins have enormous
capacity to bind anesthetic drugs, so that even for our least
potent drugs (e.g., thiopental) the number of binding sites
greatly exceeds the number of thiopental molecules. In this
setting, the fraction of drug bound to plasma proteins is
purely a function of the concentration of plasma protein.
Will changes in protein concentrations with age or
disease affect the binding of anesthetic drugs? If the drug
is highly bound, (e.g., free fraction is < 10%) then a 50%
reduction in protein concentration will double the free
fraction. This would increase the apparent potency of
the drug, particularly after bolus administration prior
to equilibration of the drug with peripheral tissues.
However, changes in plasma protein concentration have
virtually no effect on the potency at steady state, because
it is the free concentration that equilibrates among
tissues, and plasma proteins contribute very little to the
total body binding capacity of the drug.
Pharmacokinetic Models
FIRST-ORDER PROCESSES
Your interest payment on your home mortgage is usually
proportional to the outstanding balance (e.g., a 6% loan
pays the bank 6% of the outstanding principal each year).
When you drain your bathtub, the water leaves at a rate
that is proportional to the amount (height) of water in
the tub. These are first-order processes, and the rate is
described by an equation of form:
dx
¼ kx,
dt
where x has units of amount, and k has units of 1/time.
We can calculate the amount of x at any point in time
as the integral from time 0 to time t:
xðtÞ ¼ x0 ekt ,
 Chapter 5 Basic Pharmacologic Principles

where x0 is the value of x at time 0. If k > 0, x(t) How long will it take for x to go from some value, x1, to
increases exponentially. If k < 0, x(t) decreases half that value, x½? One can substitute x1, and x½ into the
exponentially. exponential decay equation above and solve for time:
This is the fundamental model for pharmacokinetics,
because drug flows between tissues and is metabolized 0:693
t½ ¼ :
at a rate that is proportional to concentration. The rate k
constant, k, is negative because concentrations decrease This is the fundamental relationship between t½, also
over time. The minus sign is usually explicit, so k is called “half-life,” and the rate constant k.
expressed as a positive number, yielding the basic equa-
tion for drug elimination from a one-compartment model
following bolus injection: COMPARTMENT MODELS
Figure 5-5 shows conventional pharmacokinetic models
xðtÞ ¼ x0 e kt
: of one, two, and three compartments. All of the models II
This relationship is shown in Figure 5-4 in the involve a central volume of distribution, termed V1. The
standard domain (upper graph) and in the log domain two- and three-compartment models have peripheral vol-
(lower graph). ume of distribution, termed V2 and V3, respectively. The
rate constants relate the flow of drug to the amount in
the driving compartment. Thus, the rate of flow from
compartment 1 to compartment 2 is A1  k12, where A1
is the amount of drug in compartment 1. The rate of flow
from compartment 2 to compartment 1 is A2  k21. At
steady state, there is no net rate of flow, and so A1 
10 x0 = 10
k12 ¼ A2  k21.
The rate constant for eliminating drug from the
8
central compartment is k10. Because this is a first-order
k = 0.5 process, the actual rate of drug elimination is A1  k10.
x (amount)

6
What is the clearance of the drug? We know from
Equation 5 that clearance ¼ elimination rate / C. Substi-
4
tuting A1  k10 for the elimination rate, and A1/V1
for the concentration (by definition), we see that
2
clearance ¼ k10  V1. This is a fundamental pharmacoki-
netic identity. It can also be shown that clearance ¼ total
0 systemic dose/area under the concentration versus time
0 2 4 6 8 10
t (time)
curve, often abbreviated as:
Dose
:
10 x0 = 10 AUC
k = 0.5 For the one-compartment model, the bolus dose to
achieve a given target concentration, CT, can be calcu-
lated as CT  V1, where CT is the target concentration.
x (amount)

Similarly, the infusion rate to maintain a given concen-

1 tration is CT  Clearance.
0.1
0 2 4 6
t (time)
Figure 5-4 The top graph shows an exponential decay curve, as
given by xðtÞ ¼ x0 ekt , plotted on standard axes, with x0 ¼ 10
and k ¼ 0.5. The lower graph shows the same exponential decay
curve plotted on a log y axis. (From Miller RD [ed]. Miller’s
Anesthesia, 7th ed. Philadelphia, Churchill Livingstone Elsevier,
2010, pp 479-513.)
Unfortunately, no anesthetic drug is described by a
one-compartment model. The plasma concentrations over
time following an intravenous bolus resemble the curve
in Figure 5-6. In contrast to Figure 5-4, Figure 5-6
is not a straight line even though it is plotted on a log
8 10 Y-axis. For many drugs, three distinct phases can be dis-
tinguished, a “rapid distribution” phase (solid line), a
“slow distribution” phase, and a “terminal phase” (dotted
line) that is log linear. The presence of three distinct
phases following bolus injection is a defining character-
istic of a three-compartment pharmacokinetic model.
The individual phases reflect the peripheral volumes
initially filling with drug (distribution phases), and then
discharging drug back to the plasma (terminal phase).

41
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Section II PHARMACOLOGY AND PHYSIOLOGY

Figure 5-5 One-, two-, and three-

compartment mammillary models. (From
Drug administration Drug administration Miller RD [ed]. Miller’s Anesthesia, 7th ed.
I I Philadelphia, Churchill Livingstone Elsevier,
2010, pp 479-513.)
V V2 k12 V1
Volume of Peripheral Central
distribution compartment k21 compartment

k k10

One compartment Two compartment

Bolus
I

V2 k12 V1 k13 V3
Rapidly equilibrating Central Slowly equilibrating
compartment k21 compartment k31 compartment

k10

Three compartment

Figure 5-6 Concentration versus time

100 relationship showing a very rapid initial
decline after bolus injection. The terminal
log-linear portion is seen only after most of
the drug has left the plasma. This is
characteristic of most anesthetic drugs.
Concentration

Different line types highlight the rapid,

10 intermediate, and slow (log-linear) portions
of the curve. (From Miller RD [ed]. Miller’s
Anesthesia, 7th ed. Philadelphia, Churchill
Livingstone Elsevier, 2010, pp 479-513.)

0 120 240 360 480 600

Minutes since bolus injection

The curve in Figure 5-6 can be described by a sum of
negative exponentials:
CðtÞ ¼ Aeat þ Bebt þ Cegt
where t is the time since the bolus, C(t) is the drug con-
centration following a bolus dose, and A, a, B, b, C,
and g are parameters of a pharmacokinetic model. A, B,
and C are called coefficients, while a, b, and g are
called exponents. The main reason that polyexponential
equations are used is that they describe the plasma con-
centrations observed after bolus injection. One can
convert the parameters A, a, B, b, C, and g, into V1, k10,
k12, k13, k21, and k31 seen in Figure 5-5, but the math is
complicated.*
Eq:9 A steady-state drug concentration cannot be achieved
with a bolus and a simple infusion for drugs described
by multiple compartments. The infusion rate must initially
be high enough to compensate for drug that flows into the
peripheral compartments. Only after these compartments
*See http://www.nonmemcourse.com/convert.xls, last accessed
April 22, 2010.

42
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 Chapter 5 Basic Pharmacologic Principles

have come into equilibration can the infusion be set at CT  which patients received either fentanyl (top figure) or alfen-
Clearance. One can approximate such an infusion with tanil (lower figure).8 The circles show the rapid rise in arte-
various “cookbook” formulae, although the use of “target- rial alfentanil or fentanyl concentrations. The time course
controlled infusions” permits a computer to rapidly achieve, of the electroencephalographic (EEG) response to fentanyl
and sustain, a constant plasma drug concentration.7 clearly lags several minutes behind the changes in arterial
fentanyl concentration, but there is much less “hysteresis”
THE TIME COURSE OF DRUG EFFECT between the rapidly changing arterial concentration and
The plasma is not the site of drug effect for the anesthetic the EEG for alfentanil. The difference shows that alfentanil
drugs except perhaps heparin and methylene blue. Anes- blood-brain equilibration is much faster than fentanyl
thetic drugs must diffuse from the blood into the target tis- blood-brain equilibration.
sue, which produces a delay in the onset of drug effect. For The relationship between plasma concentration and
example, alfentanil has a more rapid onset than fentanyl. drug concentration at the site of drug effect can be
Figure 5-7 shows a study by Stanski and colleagues in described by adding an “effect site,” as shown in II

Figure 5-7 Fentanyl and alfentanil concentrations

in arterial blood (circles) and the concurrent EEG 30 0
(spectral edge) during and after an intravenous Fentanyl
infusion. The time lag between rise and fall in plasma
Arterial level
opioid concentration and EEG effect is much greater
EEG 5
for fentanyl than for alfentanil, reflecting the slower
plasma-effect site equilibration of alfentanil. EEG,

Spectral edge (Hz)

20
Fentanyl (ng/mL)

electroencephalographic. (Modified from Scott JC,

Ponganis KV, Stanski DR. EEG quantitation of
narcotic effect: The comparative pharmacodynamics 10
of fentanyl and alfentanil. Anesthesiology
1985;62:234-241.)
10 15

Infusion 20
0
0 5 10 15 20 25
Time (min)

1500 0
Alfentanil

Arterial level 5
EEG
Spectral edge (Hz)
Alfentanil (ng/mL)

1000 10

15

500
20

Infusion 25

0
0 5 10 15 20 25
Time (min)

43
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Section II PHARMACOLOGY AND PHYSIOLOGY

Figure 5-8 A three-compartment model

with an effect site to account for the
Drug administration
equilibration delay between arterial drug
I concentrations and drug effect. (From Miller
RD [ed]. Miller’s Anesthesia, 7th ed.
V2 k12 V1 k13 V3 Philadelphia, Churchill Livingstone Elsevier,
Rapidly equilibrating Central Slowly equilibrating 2010, pp 479-513.)
compartment k21 compartment k31 compartment
k1e
k10
Effect site
Ve k e0

Figure 5-8. The site of drug effect is connected to the

plasma by a first-order process, with the term ke0 repre-
senting the equilibration rate constant between the plasma
and the site of drug effect; ke0 is most easily understood in
terms of its reciprocal, 0.693/ke0, the half-time for equili-
bration between the plasma and the site of drug effect. 300
Pharmacokinetic models must include ke0 to accurately
predict the time course of drug effect. 240

180
THE OFFSET OF DRUG EFFECT
In medical literature the term “half-life” is often calcu-
120
lated based on the slowest elimination phase (i.e., Morphine
hydromorphone
0.693/smallest exponent). Unfortunately, “half-life” is a Alfentanil
60
useless concept for anesthetic drugs, and should be aban-
doned entirely. A better concept is the context-sensitive Remifentanil
half-time that relates steady-state infusions of given 0
durations to the time required for a 50% decrease in 0 100 240 360 480 600
plasma drug concentration.9 The context-sensitive half- Infusion duration
time does not incorporate the equilibration delay,10 so it
is limited in the ability to characterize the offset of drug 300
effect. The context-sensitive effect site decrement time Morphine
specifically relates the time course of effect site concen- 240
Meperidine
tration with the duration of drug delivery.11 Figure 5-9
shows the context-sensitive half-time (top graph) and 180
the 50% effect site decrement time (lower graph) for the
intravenous opioids used in anesthesia practice. Mor- 120 Hydromorphone

phine has rapid plasma pharmacokinetics, but very slow

blood-brain equilibration. The upper graph suggests that 60
Alfentanil

morphine might be associated with recovery faster than

Remifentanil
alfentanil or sufentanil. The lower graph incorporates 0
the very slow plasma-effect site equilibration of mor- 0 100 240 360 480 600
phine, and suggests that it is not an appropriate drug
for continuous infusion during anesthesia. Infusion duration

Figure 5-9 The top graph shows the context-sensitive half-life

PHARMACODYNAMICS
Pharmacodynamics describes the relationship between
plasma drug concentration and pharmacologic effect.
Although the study of clinically important drug effects
for fentanyl, meperidine, methadone, alfentanil, sufentanil,
morphine, hydromorphone, and remifentanil. The lower graph
shows the 50% effect site decrement curve for these same
opioids. The effect site decrement curve incorporates the
plasma-effect site equilibration delay.

44
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 Chapter 5 Basic Pharmacologic Principles

is multifaceted, we will divide pharmacodynamics into A low Kd indicates tight binding to the receptor, while a
two general areas: transduction of biologic signals high Kd implies weak binding.
(receptor theory and receptor types) and clinical evalua- Full agonists are drugs that activate a receptor to the
tion of drug effects. maximum capacity. Partial agonists are drugs that only
partially activate a receptor, even at very high concentra-
Transduction of Biologic Signals tions. Antagonists block other drugs, but on their own do
not cause activation of the receptor. Inverse agonists
RECEPTOR THEORY have the opposite effect of agonists, which is usually
The binding of a ligand, L, to its receptor, R, follows the thought to result from blockade of endogenous agonists.
laws of mass action: These relationships are shown in Figure 5-10. The differ-
kon ence between full agonists, partial agonists, antagonists,
½L þ ½R > ½LR, and inverse agonists results from differing intrinsic effi-
koff
cacy. Efficacy should not be confused with affinity. Two II
where kon is the rate constant for the ligand binding to drugs can have identical affinity for a receptor (and
the receptor, koff is the rate constant for the ligand disas- therefore bind to the same extent at a given drug concen-
sociating from the receptor, [L] is the concentration of the tration), yet produce different levels of activation, no
ligand, [R] is the concentration of the unbound receptor, activation, or block an endogenous agonist. Antagonists
and [LR] is the concentration of the bound receptor. The can be either competitive, in which case they physically
rate of formation of [LR] is displace an agonist from the receptor site without block-
d½LR ing it, or noncompetitive, in which case they irreversibly
¼ ½L½Rkon  ½LRkoff : bind to the receptor complex.
dt
The binding of an agonist to a receptor has tradition-
At steady state, which is nearly instantaneous, the net ally been thought to change the three-dimensional shape
rate of formation is 0, and thus of the receptor, resulting in the drug effect. It is now
½L½Rkon ¼ ½LRkoff , known that receptors have many conformations, and that
the conformation is in constant flux. It is likely that the
Kd, the dissociation constant, is the ratio of koff to kon: binding of an agonist causes the receptor to favor one
½L½R koff conformation more than when the agonist is not bound,
Kd ¼ ¼ : increasing the amount of time the receptor spends in a
½LR kon
particular conformation. By spending more time in a par-
Kd has units of [L]. When 50% of the receptors are occu- ticular conformation, the protein facilitates a particularly
pied (i.e., [R]¼[LR]), Kd is equal to the drug concentration. biochemical cascade, resulting in the drug effect.

Figure 5-10 Dose or concentration versus

response relationships for a full agonist, a partial 100
agonist, a neutral antagonist, and an inverse
Full agonist
agonist. (From Miller RD [ed]. Miller’s Anesthesia, Partial agonist
7th ed. Philadelphia, Churchill Livingstone Elsevier, Neutral antagonist
80
2010, pp 479-513.) Inverse agonist

60
Effect

40

20

1
Dose, concentration, or
other measure of exposure

45
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Section II PHARMACOLOGY AND PHYSIOLOGY
RECEPTORS TYPES
Receptors are present in cell membranes, cytoplasm, orga-
nelles, and the nucleus. The receptors of most interest to
anesthesiologists are the G protein–coupled receptors,
ligand-gated ion channels, and voltage gated ion channels
on the cell membrane. G protein–coupled receptors are the
most abundant receptors known. Opioids, serotonin, all
vasoactive amines, prostaglandins, and histamine are
examples of drugs whose effects are mediated through
G protein receptors. Ligand-gated ion channels regulate
neural conduction by affecting the flux of sodium, potas-
sium, chloride, or calcium into the cell. Hypnotics (e.g.,
propofol, midazolam, thiopental), ketamine, and muscle
relaxants exert their effects on the ligand-gated ion chan-
nel. Voltage-gated ion channels are responsible for trans-
mission of the action potential down a nerve, and are the
target of local anesthetic action.
Clinical Evaluation of Drug Effects
Figure 5-11 shows the common relationship between
exposure to a drug and the drug effect. This is described
with the sigmoidal relationship:
Cg
Effect ¼ E0 þ ðE max  E0 Þ g :
C50 þ C g
In this equation E0 is the baseline effect in the absence of
drug, and Emax is the maximum possible drug effect.
C is concentration, dose, or another measure of drug ex-
posure. C50 is the concentration associated with 50% of
peak drug effect and is a measure of drug potency.
A drug with a left-shifted concentration versus
100
A B
Effect
Potency
More Less
0
Dose, concentration, or
other measure of exposure
46
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response curve (i.e., lower C50) is more potent, and a
right-shifted concentration versus response curve is
less potent. The exponent g, also called the Hill coeffi-
cient, relates to the sigmoidicity (steepness) of the
relationship.
The ED50 is the dose of a drug required to produce a
specific effect in 50% of individuals. The LD50 is the dose
of a drug required to produce death in 50% of patients
(or, more often, animals). The therapeutic index of a drug
is the ratio between the LD50 and the ED50 (LD50/ED50), as
shown in Figure 5-12. The larger the therapeutic index,
the safer the drug.
DRUG-DRUG INTERACTIONS
There are numerous types of mechanisms by which drugs
can interact pharmacodynamically. The nature of phar-
macodynamic drug-drug interactions is so diverse that
an anesthesiologist can safely assume there will be some
interaction between anesthetic drugs and virtually all
drugs that have action on either the central nervous
system (CNS) or the cardiovascular system.
Some of these drug interactions, such as the interac-
tion between hypnotics and opioids, are fundamental to
the practice of anesthesia. Figure 5-13 shows the interac-
tion between fentanyl and isoflurane MAC (upper
graph),12 and between propofol and alfentanil (lower
graph).13 Typically a small amount of opioid can provide
a huge reduction in the concentration of hypnotic neces-
sary to block responsiveness, but some hypnotic is neces-
sary to assure nonresponsiveness.
Drug-drug pharmacodynamic interactions are frequently
approached using response surfaces.14 The response surface
Figure 5-11 Relationship among efficacy, potency,
Efficacy and individual variability as they relate to a typical
sigmoidal dose or concentration vs. response curve.
(From Miller RD [ed]. Miller’s Anesthesia, 7th ed.
Philadelphia, Churchill Livingstone Elsevier, 2010,
pp 479-513.)
C
 Chapter 5 Basic Pharmacologic Principles

100 1.4
Hypnosis
Percentage of individuals responding

Death 1.2
80

Isoflurane MAC (vol %)

1
60
Therapeutic index
LD50 400 0.8
= =4
ED50 100
40
0.6

20 0.4
II
0.2
0
50 100 200 400 800 1600
ED50 LD1 ED99 LD50 0
Dose (mg) 0 1 2 3 4 5 6
Fentanyl (ng/mL)
Figure 5-12 Relationship among median effective dose (ED50),
median lethal dose (LD50), and therapeutic index. (Adapted from 400
Shafer SL, Flood P, Schwinn DA. (From Miller RD [ed]. Miller’s Intubation
Anesthesia, 7th ed. Philadelphia, Churchill Livingstone Elsevier, Maintenance
Alfentanil concentration (ng/mL)
2010, pp 479-513.) Emergence
300

is the three-dimensional surface that shows the expected

effect of any combination of two drugs. Figure 5-14 shows
typical response surfaces for drugs with additive interac- 200
tions, supra-additive interactions (e.g., synergy), and infra-
additive interactions.
100
QUESTIONS OF THE DAY

1. How are most anesthetic drugs (e.g., opiates and ben-

zodiazepines) removed from the body? 0
0 2 4 6 8 10
2. What are the differences in clearance of a drug that is
flow limited versus a drug that is capacity limited? Propofol concentration (mg/mL)
3. What is the context-sensitive half-time and how does
it compare to the half-life of an anesthetic drug? Figure 5-13 The top graph shows the influence of fentanyl on
4. What is the relationship between a drug’s affinity and the minimum alveolar concentration of isoflurane associated with
its efficacy? 50% probability of movement on incision.(Adapted from McEwan
5. How is the therapeutic index of a drug defined? AI, Smith C, Dyar O, et al. Isoflurane minimum alveolar
concentration reduction by fentanyl. Anesthesiology
1993;78:864-869.) The lower graph shows the influence of
ACKNOWLEDGMENT alfentanil on the concentration of propofol associated with a 50%
probability of response to intubation and incision, as well as a 50%
The editors and publisher would like to thank Dr. Pankaj probability of awakening at the end of surgery. (Adapted from Vuyk
K. Sikka for contributing a chapter on this topic to the J, Lim T, Engbers FH, et al. The pharmacodynamic interaction of
prior edition of this work. It has served as the foundation propofol and alfentanil during lower abdominal surgery in women.
for the current chapter. Anesthesiology 1995;83:8-22.)

47
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Section II PHARMACOLOGY AND PHYSIOLOGY

Figure 5-14 Response

surfaces for potential
1.0 1.0 pharmacodynamic
interactions of anesthetic

Effect
drugs. A, Additive
Effect

0.5 0.5
interaction between two
agonists that have the
0.0 0.0 same mechanism of action
3 3 (e.g., fentanyl and
3 2 3 alfentanil interaction). B,
2 2
Ad 2 Pa 1 Supra-additive interaction
ag ditiv 1 r
ag tia 1
1
on e on l 0 ist between two agonists (e.g.,
ist 0
Agon
ist ist Agon
isoflurane and fentanyl). C,
Infra-additive interaction
A D
between two agonists
(reported for cyclopropane
and nitrous oxide).
1.0 1.0 (Adapted from Minto CF,
Effect Schnider TW, Short TG,
Effect

0.5 0.5 et al. Response surface

model for anesthetic drug
interactions.
0.0 0.0 Anesthesiology
3 3 2000;92:1603-1616.)
2 3 2 3
Su 2 Co 2
pr 1 m 1 1
a 1 an pe
ag -ad nist tag tit 0 nist
on diti
ist ve
0 Ago on ive Ago
ist

B E

1.0 1.0

0.5
Effect

Effect

0.5
0.0
0.0 –0.5
3 3
2 3 2 3
Inf 2 2
ra 1 Inv 1
ag -add 1 ag ers 1
on itiv 0 nist on e 0 nist
ist e Ago ist Ago

C F

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II

49
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