Anesth Prog 35:87-101 1988
REVIEW ARTICLES
Principles of Pharmacotierapy:
This paper and the ensuing series present the
principles guiding and affecting the ability of drugs
to produce therapeutic benefit or untoward harm.
The principles of pharmacodynamics and
pharmacokinetics, the physiologic basis of adverse
drug reactions and suitable antidotal therapy, and
the biologic basis of drug allergy, drug-drug
interactions, pharmacogenetics, teratology and
hematologic reactions to chemicals are explored.
These principles serve to guide those administering
and using drugs to attain the maximum benefit and
least attendant harm from their use. Such is the
goal of rational therapeutics.
"The desire to take medicine is perhaps the greatest
feature which distinguishes man from animals.
Sir William Osler
D rugs are chemicals that modify the physiologic
activities of living tissue. These living systems may
range from a single cell and its subcellular constituents to
various organ systems on to a single human being or a
population of such individuals. Pharmacotherapeutics is
the application of drugs in the prevention and treatment
of disease. Pharmacodynamics is the study of the bio-
chemical and physiologic effects of drugs, their mecha-
nisms of action, and the interaction of host tissues with
such chemicals. Pharmacokinetics is the study of the
processes of absorption, distribution, metabolism, and
excretion that determine the amount of drug present at
various times at its site of action within the physiologic
Received December 15. 1987; accepted for publication January 22.
1988.
Address correspondence to Dr. Thomas J. Pallasch, Associate Profes-
sor of Pharmacology and Periodontics and Chairman. Pharmacology
Section, University of Southern California, School of Dentistry, Univer-
sity Park MC-0641, Los Angeles, CA 90089-0641.
© 1988 by the American Dental Society of Anesthesiology
87
I. Phannacodynamics
Thomas J. Pallasch, DDS, MS
Pharmacology Section, School of Dentistry,
University of Southem Califomia, Los Angeles, Califomia
system. Toxicology is the determination of the harmful
effects of chemicals in biologic systems and the mecha-
nisms involved in such activity.
Ours is a chemical society. The American populace
spends 200 billion dollars annually on chemicals (illegal
drugs of abuse, nonprescription nostrums, caffeine, nico-
tine, and ethyl alcohol) by self-administration in an
attempt to alter mood and thereby the perception of
reality. At one time (1977), 8000 tons of benzodiazepines
were manufactured annually for use in the United States
(7.6 trillion ten milligram tablets).1 Approximately three
million persons are hospitalized in the United States
annually for community-acquired infections while two
million patients experience a nosocomial (hospital-
acquired) infection each year.2 These nosocomial infec-
tions extend hospital stay by 7-17 days,3 cost additional
billions of dollars, and result in 60,000-150,000 deaths.2
Many of these nosocomial infections are due to highly
antibiotic-resistant microbes selected out by the promis-
cuous use of antibiotics (45-65% of antibiotic use in
hospitals may be unwarranted or inappropriate4). Ap-
proximately 16 per million (400-800) persons exposed
to penicillin annually in the United States die from
penicillin-induced anaphylaxis; some in a misguided at-
tempt to treat or prevent a microbial infection.5 Dentistry
is well aware that patients die in dental offices (possi-
bly 4 or so each year in California) from pharmacose-
dation poorly applied. It appears that we have some-
thing to leam about what drugs can and cannot do
for us.
Yet chemicals have added immeasureably to our
health and wellbeing. The control of infection (immuniza-
tion, surgical asepsis, sanitation, and the elimination of
the animal vectors of infection, antibiotics) and the
blessed advent of anesthesia (the ability to surgically
operate within the body without pain and surgical shock)
have been principally and primarily responsible for the
doubling of the human lifespan in developed societies in
the past century. It appears that the good or ill derived
from drugs rests in our hands.
ISSN 0003-3006/88/$3.50
88 Principles of Pharmacotherapy
DRUG ACTION AND DRUG EFFECT
All drugs act by producing alterations in the known
physiologic function(s) of the living tissues to which they
are applied and their effects can only be detected by
these changes. A drug is capable of altering the rate or
magnitude at which these physiologic processes proceed
(slower or faster, more or less) but are incapable of
confering (creating) new functions on or in a cell, tissue or
organ system. Therefore the effects of drugs are always
quantitative rather than qualitative.6'
The consequences resulting from drug application to a
physiologic system occur when a drug reaches and
interacts with its receptor. Such receptors are macro-
molecular components of a physiologic system for which
the drug has affinity and, when the drug and receptor
interact, result in an alteration in physiologic activity, the
intrinsic activity of the drug. Drug action is the conse-
quence of drug-receptor interaction (the site of the drug
action and the changes in receptor configuration due to
drug-receptor interaction) and drug effect is the ensuing
physiologic event resulting from drug-receptor interac-
tion. The site of action of a drug is the location (physiolo-
gic system) where the drug locates and acts to induce a
series of events culminating in physiologic change. The
mechanism of action of a drug is the biochemical pro-
cess(es) used by the drug to alter its receptor site or
receptor function to induce change.
CHEMICALS AS DRUGS
For any chemical to function as a drug it must possess at
least four properties: selectivity, reversibility, biologic
activity, and potency.
All drugs are selective for only a few receptor sites
within the organism (penicillin indeed may have only
one). These receptors usually include the single receptor
for therapeutic action and possibly a few other receptors
not associated with its primary effect (secondary recep-
tors or nonspecific binding). Otherwise the drug would
possess a multiplicity of action that would render it
therapeutically useless and maximally harmful. The se-
lectivity of the drug for its receptor is intimately depen-
dent upon the complementary chemical properties of
these two entities.
Most useful drugs possess reversibility of action. Drug
activity is usually terminated by liver metabolism and, or
renal excretion. An irreversibile drug would possess the
probable undesireability of a very long or ever permanent
action (a local anesthetic that lasted for days or longer).
Occasionally a permanent effect might be desirable as in
the case of alcohol destruction of nerve tissue in trigemi-
nal neuralgia. Pharmacokinetics entails the use of the
Anesth Prog 35:87-101 1988
factors that determine drug reversibility of action to
achieve a proper concentration of the drug at its receptor
site for a suitable period of time.
Biologic activity is the inherent ability of the chemical to
interact with biologic systems. Such interaction is deter-
mined by the water and lipid solubility of the drug and its
chemically-reactive components which are attracted to
and complementary to its biologic host receptor site and
as such are capable of inducing physiologic change.
Since the human body is 70% water, a drug must be, to
some extent, water-soluble and, because membranes are
composed of lipids, must also be fat-soluble to traverse
these membranes to its site of action. If a drug has no
receptor site it is biologically inactive: if a drug cannot
reach its receptor site it is likewise inactive.
Potency is the biologic activity of a drug per unit
weight and is usually measured in milligram amounts. A
more potent drug produces a biologic response at a dose
lower than a less potent drug. It is important to delineate
between drug potency and drug efficacy. Drug potency is
simply the milligram amount of the drug necessary to
elicit varying degrees of biologic response. It is per se a
relatively unimportant drug characteristic. Whether a
drug is effective at 10 or 50 mg is immaterial as long as
the organism can assimilate both doses. Potency only
becomes significant if a drug is so impotent as to require
massive amounts for efficacy or if a drug is so potent as to
be seriously harmful in minute amounts. Drug efficacy is
the inherent quantitative ability of the drug to alter a
physiologic system. A more efficacious drug is inherently
superior to a less efficacious chemical because it produces
a superior therapeutic effect. Due to its chemical proper-
ties, penicillin is more efficacious against most gram-posi-
tive microorganisms than tetracycline. Barbiturates are
inherently more able to depress respiration than the
benzodiazepines. Drug efficacy is a measure of drug
affinity for its receptor and its intrinsic activity during
drug-receptor interaction. Drug potency and efficacy are
not per se related. A more potent drug is not necessarily
or even commonly more efficacious whereas a more
therapeutically efficacious drug is a significant biologic
advance.
BASIC SCHEME OF DRUG ACTION
Any drug possess three phases in its function as a
modifier of biologic activity: 1) pharmaceutical, 2) phar-
macokinetic, and 3) pharmacodynamic. The pharmaceu-
tical phase constitutes the processes governing the re-
lease of active drug from its particular dosage form
(solution. tablet, capsule) to present drug concentrations
available for passage through membranes and into the
blood. The pharmacokinetic phase entails all the various
Anesth Prog 35:87-101 1988
processes which determine the absorption. distribution.
metabolism and excretion of the drug and its subsequent
concentrations in blood and at receptor sites. The phar-
macodynamic phase results from drug-receptor interac-
tion and the resulting cascade of physiologic events.
To induce a therapeutic or toxic biologic response, a
drug must enter into a series of events: drug administra-
tion, drug absorption and distribution, drug-receptor
interaction, production of a pharmacologic response and
eventual detoxification within, and elimination from the
organism. A drug must somehow be introduced to the
physiologic system (administration), generally be taken
up into the blood (absorption). move through extracellu-
lar fluid and membranes (distribution), interact with its
site of action (receptor interaction), to induce a physiolo-
gic change (response), and eventually have its action
terminated (detoxification and elimination). No drug
escapes this sequence of events.
THE DRUG RECEPTOR
The drug receptor is that specific portion of the biologic
system with which the drug interacts to produce an effect
and subsequent physiologic change. The concept of the
drug receptor originated with J.N. Langley's (1905)
"receptor substance" of muscle acted upon by nicotine
and curare and Paul Ehrlich's (1913) " receptor" concep-
tualized to denote the specific chemical groupings of
"protoplasm" upon which drugs act and explain the
specificity of antigens and antibodies.7
Most drug receptors are macromolecules such as en-
zyme proteins, glycoproteins of cell membranes and. in
the case of hormones, the DNA apparatus. Most drug
receptors are located on or within cell membranes. The
receptor substance is the chemical component of the
macromolecule directly involved in the initial action of a
drug. The receptor site (group) is the adjacent portion of
the receptor that enhances or hinders the access of the
drug to the active receptor substance. The basic function
of the receptor is to bind the drug and to convey a
biologic message that induces physiologic change.
The mutual molding of the drug and receptor by
intermolecular forces (ionic, hydrogen or covalent
bonding, and Van de Waals forces) produces a con-
formational change (shape alteration) in the receptor to
effect drug-receptor coupling and receptor site alterations
resulting in a physiologic effect.8 The "lock and key"
analogy is still somewhat appropriate for drug-receptor
attraction if, in addition, dynamic spatial and confi-
gurational changes are visualized.9 The complementary
chemical structures of drug and receptor are often highly
specific; often optical isomers of a drug are inactive or
have significantly different pharmacologic effects.
The drug-receptor interaction itself may be sufficient to
Pallasch 89
induce the drug effect or the consequences of this union
may be so specific and localized as to require "amplifi-
cation".: the formation and/or release of many additional
chemicals (second or third messengers) that are them-
selves responsible for the physiologic change. The effects
of epinephrine, a /-adrenergic receptor stimulant, on the
f3-adrenergic receptor illustrates this concept. Epineph-
rine stimulates adenylate cyclase (possibly the beta re-
ceptor) to convert adenosine triphosphate (ATP) to cyclic
AMP. The proliferation and release of cAMP is responsible
for the ensuing vasodilation, bronchial relaxation and
cardiac stimulation (the beta response) not the epineph-
rine itself. The calcium ion and its intracellular increase
may also be a "second messenger at muscarinic,
a-adrenergic, platelet thrombin and vasopressin recep-
tors. "() More recent evidence indicates that poly-
phosphoinositides and their active products, inositol tri-
phosphate, and diacylglycerol, may be responsible for
this calcium release therefore calcium may be in effect a
"third messenger. The ultimate goal of second messen-
gers such as cAMP and cGMP (guanosine mono-
phosphate) may be the phosphorylation of cellular pro-
teins.
The processes involved in drug-receptor interaction
can best be understood by the Occupational (Occu-
pancy) Theory as formulated by Clark (1927) and Gad-
dum (1936) with a few modifications. This theory holds
that: 1) the magnitude of the drug effect is proportional to
the number of receptors occupied, 2) drug effects occur
according to the law of mass action, 3) only a small
portion of the total number of drug molecules in the body
combine with the receptor, 4) the maximum effect occurs
when all receptors are occupied, and 5) as long as a
minimum number of receptors are occupied, some effect
will be discernible.
In general these tenets still hold true however more
recent evidence indicates that: 1) when amplifier mecha-
nisms are active, only a fraction of receptors need be
occupied to achieve a maximal effect,8 2) some drugs
may never induce a maximum system response no
matter how high the drug concentration,7 and 3) receptor
"downregulation" and "upregulation" may alter classic
mass action kinetics.7 In some situations, a prolonged
exposure to a drug particularly in high concentrations
may induce the receptor to adjust by reducing its number
or its affinity for or sensitivity to the drug (receptor
downregulation). Such is the decrease in receptor sensi-
tivity seen with exposure to insulin and dopamine and
may be useful in explaining the concept of tolerance.
Conversely, the application of antagonists to the receptor
or some other means of depriving the receptor of its
normal activating chemical may result in an increase in
receptor number and/or sensitivity (receptor upregu-
lation, receptor supersensitivity).11 This increase in recep-
90 Principles of Pharmacotherapy
tor activity or number may explain the withdrawl or
abstinence syndrome seen upon discontinuance of ad-
dicting central nervous system depressants such as nar-
cotics and ethyl alcohol. The depressant drug may
interfere with or substitute for an endogenous neuro-
chemical allowing for receptor upregulation. When the
drug is withdrawn, an abnormal receptor number or
activity is present resulting in central nervous system
hyperactivity. There then appears to be some ability of
the receptor to regulate its own activity.
The Occupation Theory has also led to the useful
concepts of affinity and intrinsic activity and agonists,
antagonists, and partial agonists. Affinity is the inherent
chemical ability of the drug and receptor to combine and
depends upon suitable pharmacokinetics and the com-
plementary fit of drug and receptor. Intrinsic activity is
the inherent ability of the drug to produce a given
response. In essence it is the chemical or physicoche-
mical ability of the drug to alter the receptor configuration
and induce an effect. Both affinity and intrinsic activity
are fundamental properties of the drug and its comple-
mentary relationship to the receptor. The affinities and
intrinsic activities of drugs even those within the same
pharmacologic group can vary enormously and dictate
the therapeutic efficacy and toxicity of a given chemical.
An agonist drug is one that combines both affinity and
intrinsic activity. The drug reaches its receptor site satis-
factorily and once attached induces the conformational
change that ellicits an observable effect. These dual
abilities of a drug can vary among congeners (similar
drugs). Most useful drugs are agonists. An antagonist drug
as classically portrayed has affinity for the receptor but
not intrinsic activity. It attaches to the receptor but
produces no change in the receptor and hence no effect.
Current evidence indicates that this simple explanation
may not hold for some antagonists of adrenergic, cho-
linergic, dopaminergic, and serotonergic receptors.8 In
these situations the agonist and antagonist bind to differ-
ent (allosteric) sites on the receptor which are mutually
exclusive.8 The antagonist may then alter the receptor
site so as not to allow agonist-receptor fit. The difference
between these two concepts is one receptor site for both
agonist and antagonist versus different activity sites for
each; the end result may be the same. A partial agonist
drug is one that has affinity for the receptor but less
intrinsic activity than an agonist. Even at full saturation of
the receptor, a partial agonist will never produce the
maximum effect seen with an agonist.12 If the partial
agonist displaces the agonist from the receptor it acts as
an antagonist as it has less intrinsic activity than the
displaced agonist. This antagonism is not complete be-
cause the partial agonist by definition has intrinsic activity.
Partial agonists have intrinsic activity intermediate be-
tween agonist and antagonist. Nalorphine (Nalline) is a
Anesth Prog 35:87-101 1988
partial agonist of the opioid receptor; some new
,8-adrenergic blocking drugs have antagonist properties
but also possess adrenergic stimulant effects (intrinsic
sympathomimetic activity).
In most situations the intensity of the generated
response is proportional to the number of receptors
occupied. A maximal effect may occur when only a
critical portion of receptors are occupied. For some drugs
there may be a "functional occupancy threshold" so that
no effect is seen until a certain number of receptors
(threshold) are activated. It is possible that receptors
exist in two forms: the nonactivated (R) and the activated
(R*) configurations.8 Agonists have affinity for the R*
form and antagonists for the R form; an agonist shifts the
equilibrium to the R* type and an antagonists to the R
configuration.8 Partial agonists have affinity for both R
and R* but allow for only a small percentage to be in the
active R* state.
Drugs may also have affinity for areas of the organism
where they may selectively concentrate without the
presence of effector receptors and therefore induce no
pharmacologic effect. This nonspecific binding usually
occurs with plasma proteins and adipose tissue.
There is at present no satisfactory unifying hypothesis
to explain all the observed drug-receptor interactions.
The drug receptor concept is still undergoing evolution
and comprehension of this concept can be difficult.
Possibly a brief description of four important receptors
(those for general anesthetics, local anesthetics, ben-
zodiazepines, narcotic opioids) can add to our under-
standing.
The Local Anesthetic Receptor
Local anesthetics interfere with the initial processes ess-
ential for the generation and conduction of the nerve
action potential. The inward sodium current necessary for
nerve depolarization and "firing" are blocked and the
nerve membrane remains polarized. The current theory
regarding the mechanism of action of tertiary amine local
anesthetics (lidocaine, mepivacaine, prilocaine) is depic-
ted in Figure 1. These anesthetics interact with specific
receptors (R-LA) located in or near the sodium channels
(pores) and probably within the nerve membrane. The
neutral (uncharged form of the molecule) anesthetic
passes through the membrane while the charged form of
the anesthetic molecule is primarily but not exclusively
responsible for receptor activation. 13
The sodium channels exist in several configurations
with two "gates" within each channel: the activation (m)
and the inactivation (h) gate.'13"4 When the gates are in
the open (0) position, sodium ions are allowed entry and
depolarization occurs. Sodium entry is blocked when the
gates are in the closed (C) or inactivated (I) confi-
Anesth Prog 35:87-101 1988 Pallasch 91

Na+ J
(SODIUM CHANNEL)

LOCAL
TETRODOTOXIN ANESTHETIC
SAXITOXIN

CENTRUROIDES
AXOPLASM LEIURUS SCORPION VENOM
SCORPION VENOM SEA ANEMONE VENOM

Figure 1. The local anesthetic receptor. Tertiary local anesthetics inhibit sodium
influx during nerve conduction by binding to a receptor within the sodium channel
(R-LA) to block the normal activation mechanism (O gate configuration) and also to
promote movement of activation (m) and inactivation (h) gates to a position
resembling the inactivated (I) state. Biotoxins (R-T) block sodium influx at an outer
surface receptor, benzocaine (R-B) by membrane expansion, and various venoms by
altering the activity of the m and h gates (as adapted from Strichartz" and Ritchie'4).
Reprinted by permission of the Dental Drug Service Newsletter.
0 = channel in open configuration (depolarization); C = channel in closed
configuration; I = channel in inactivation configuration; m activation gate; h
inactivation gate.

guration. Tertiary amine local anesthetics interact with the
open channel state to promote gate alignment resembling
that seen during the inactivation (I) configuration.13'14
The normal inactivation process is enhanced and the
activation mechanism responsible for keeping the chan-
nel in the open position is immobilized. 1314 Both the "h"
and "m" gates must be in the open position to allow the
anesthetic to reach the receptor. The drug then diffuses to
the receptor and interacts with it to produce some change
in the configuration of channel proteins or negatively-
charged phospholipids (local anesthetics are positively-
charged) that promotes closure of the inactivation gate.
Biotoxins such as tetrodotoxin (from the Japanese
Puffer fish) and saxitoxin (from marine organisms conta-
minating some shellfish) block the sodium channels by
attaching to receptors at the outer surface of the nerve
membrane (R-T).14 The venom of the sea anemone and
the scorpion, Leiurus sculpturatus, interact with the
inactivation gate (h) whereas the venom of the scorpion,
Centuroides sculpturatus, interacts with the activation
gate (m). The benzocaine-type of local anesthetics locate
within the nerve membrane (R-B) to increase the
freedom of lipid molecules thereby promoting membrane
expansion, lateral membrane pressures, constriction of
the sodium channel, and blockade of nerve depolari-
zation. 14
The Inhalation Anesthetic Receptor
Specific receptors for inhalation general anesthetics have
yet to be identified. Most theories of anesthesia concen-
trate on the lipid phase of nerve membranes although
lipids are rarely considered to be potential drug receptors.
The Meyer-Overton Theory'5 holds that the potency of an
anesthetic agent is proportional to its oil/water partition
coefficient; That is generally true but says little about
specific receptors. The Critical Volume Theory visualizes
mechanical rather than chemical mechanism: the gas
a
anesthetic molecules fit into the lattice structure of mem-
branes and eventually achieve a critical volume that
blocks ion channels necessary for nerve excitability.16
The Perturbation Theory states that anesthetic molecules
produce a series of perturbation changes in nerve mem-
branes that induce nonfunctional nerve elements. The
Phase-Transition Hypothesis or Lateral-Phase Separa-
tion Theory maintain that lipids in membranes are in a
"gel" phase (more solid) and inhalation anesthetics cause
membranes to become more "fluid" or "liquid" thereby
closing the channels. Somewhat similarly, the "Fluidi-
zation Theory" holds that inhalation anesthetic gases
alter the order in membrane structure that prevents the
lateral diffusion of molecular components. 16 Such "fluid-
ization" of the membrane allows for expansion to alter
92 Principles of Pharmacotherapy Anesth Prog 35:87-101 1988

protein function or channel pores involved in nerve
excitability.'6 Current research is focusing on the protein
membrane components as anesthetic gases are known to
produce conformational changes in the protein receptors
for acetylcholine, dopamine, opioids, and adrenergic
agents. 17
Inhalation gas anesthetics most probably act at nerve
synapses to somehow interfere with the normal physiolo-
gic order of nerve membranes through perturbation,
fluidization, volume changes, or consistency alterations to
depress nerve excitability. Due to the highly varied
chemical structures of the diverse chemicals that induce
general anesthesia, a single inhalation anesthetic receptor
or a unifying theory of anesthetic-receptor interaction
may not be possible.
The Benzodiazepine Receptor
Most if not all of the pharmacologic effects of the ben-
zodiazepines occur as a result of their facilitation of the
actions of y-aminobutyric acid (GABA), the major inhibi-
tory neurotransmitter in the central nervous system
(CNS). GABA is a neurotransmitter at 30-40% of brain
synapses and functions to increase chloride ion conduc-
tance, probably by increasing the frequency of chloride
channel openings, and promote neuronal cell hyperpo-
larization.'8 There may be two GABA receptor subtypes:
GABAA associated with the chloride channels (Figure 2)
and GABAB with no effect on chloride conductance.
The benzodiazepine receptor is an allosteric site loca-
ted on GABA (GABAergic) neurons. Benzodiazepine
binding is greatest in the cerebral cortex, less in the
hippocampus, amygdala, hypothalamus and thalamus,
and least in the brain stem and spinal cord.20 "Periph-
eral" benzodiazepine receptors also are present in non-
neuronal cells of the CNS and other tissues unrelated to
the GABA-chloride channel complex.20 The ben-
zodiazepine receptor may exist in two forms both coupled
to the GABA receptor: BZ1 and BZ2. The BZ, receptor
may modulate antianxiety effects at the GABAA sites and
BZ2 may be associated with drowziness, ataxia, and drug
dependence.19'2' It is also possible that only one ben-
zodiazepine receptor exists with three attachment posi-
tions: A (high affinity), B (anxiogenic drugs), and C
(anxiolytic agents).22 The evidence to support single or
multiple benzodiazepine receptors has been reviewed.23
Also located on the GABA neuron is a receptor for both
barbiturates and picrotoxin.23,24
The benzodiazepine receptor is available for three
ligands (chemicals that bind to specific receptors):
agonists, inverse agonists, and antagonists. The classic
benzodiazepine agonists bind to the receptor and act
through three possible mechanisms: 1) to increase the
affinity of GABA for its receptor, 2) to enhance or
facilitate the changes induced in the GABA receptor by
GABA, or 3) to enhance the binding between the GABA
receptor and the chloride ion channel. Chloride channel
openings are enhanced.20 Inverse agonists (,3-carboline)
induce GABA receptor changes opposite those of ben-
zodiazepine agonists and reduce the gating function of
GABA.25 The resultant clinical effects are anxiety, ner-
vousness, and convlusions. Flumazenil (RO 15-1788,
Anexate) is a complete antagonist of both agonists and
inverse agonists at the benzodiazepine receptor25 and has

Figure 2. The GABA-benzodiazepine-chloride receptor. The benzodiazepines may

function to: 1) increase the affinity of GABA fbr its receptor, 2) facilitate changes in the
GABA receptor by GABA, or 3) enhance the binding between the GABA receptor and
the chloride ion channel. GABA facilitates 4) benzodiazepine agonist binding to the BZ
receptor. Inverse benzodiazepine agonists 5) reduce the gating function (chloride
conductance) of GABA and its receptor.23'24'27

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Anesth Prog 35:87-101 1988 Pallasch 93

Table 1. The Various Opioid Receptors and Agonist, expanded to include the delta and epsilon and possibly
Antagonist, and Partial Agonist Drugs30 the iota and lambda receptors."9 Subclasses of the mu
Receptor Agonist Antagonist Partial agonist and kappa receptors may also exist.29
Mu Morphine Naloxone Butorphanol
Agonist, antagonist, and agonist-antagonist opioids
Fentanyl Nalbuphine have differing affinities for these various receptors (Table
Enkephalins 1). Morphine is a classic agonist of the mu receptor but
Beta-Endorphins also interacts with the kappa receptor. Pentazocine is an
Peptide E agonist of the sigma receptor whereas butorphanol is a
Proenkephalin A partial agonist of both the mu and sigma receptor.30
Kappa Morphine Naloxone
Fentanyl The interaction of opioid agonists with these various
Ketocyclazocine receptors results in different pharmacologic effects (with
Butorphanol highly varied species differences) and dictates the proper-
Nalbuphine ties of each drug (Table 2).30 Mu receptor activation
Prodynorphin results in euphoria, analgesia, respiratory depression, and
Proenkephalin A
Proenkephalin B drug dependence, all clasically attributed to morphine-
Dynorphin A like opioid agents. Sigma receptor activation ellicits the
Sigma Pentazocine Naloxone Butorphanol unwanted properties of dysphoria and hallucinations
Fentanyl (psychotomimetic effects) seen with pentazocine.
Delta Beta-endorphin This discussion of receptors is not academic. As more is
Proenkephalin B
known about drug receptors and the physiologic effects
of their activation, it may be possible to alter drug-recep-
tor affinity and intrinsic activity so as to create strong
been successful in reversing benzodiazepine intoxi- analgesics with no respiratory depressant or drug abuse
cation.26 RO 16-6028 is a partial agonist of the ben- potential and anxiolytic agents free of sedative or motor
zodiazepine receptor with full anticonvulsant and anxioly- incoordination properties.
tic activity but devoid of sedative, ataxic, muscle relaxant,
and drug dependence properties.26
TYPES OF DRUG EFFECTS
The Opioid Receptor
Drug-receptor interaction and the subsequent pharmaco-
Martin and coworkers (1976)28 first proposed a theory of logic response(s) can be broadly classified into four types
multiple receptors for opioid agonist drugs. These various that can occur simultaneously: 1) primary, 2) secondary,
receptors interact with agonist morphine-like agents, 3) toxic, and 4) abnormal.
opioid antagonists (naloxone), opioid agonist-antagonists A primary drug effect is the intended response of the
(nalbuphine), and endogenous opioids such as pro- target organ system. It is usually a predictable therapeu-
opiomelanocortin (containing f8-endorphin), proen- tic effect (digitalis increasing the efficiency of the heart)
kephalin A (pepfides E and F, met-enkephalin, leu- although in some situations it may be a harmful or lethal
enkephalin) and proenkephalin B (dynorphin, leumor- acfion on an undesireable physiologic activity or entity
phin, neoendorphin). Martin's original proposal of three (bactericidal action of penicillin on microorganisms).
separate opioid receptors (mu, kappa, sigma) has been A secondary drug effect is commonly termed a "side

Table 2. Physiologic Responses Attributed to Various Opioid Receptors30

Mu Kappa Sigma Delta
Euphoria Sedation Dysphoria Sedation
Supraspinal analgesia Spinal analgesia Hallucinations Euphoria
Miosis Limited respiratory depression Catatonia
Respiratory depression Depressed flexor relfexes Mydriasis
Catalepsy Tachycardia
Bradycardia Respiratory stimulation
Locomotion Vasomotor stimulation
Hypothermia
Muscular rigidity
Dependence
94 Principles of Pharmacotherapy
effect." Since drug action is never totally specific for only
a single receptor or physiologic system, it is anticipated
that drugs will affect systems not related to the primary
action of the drug (no drug ever exerts a single action).
Such secondary effects may not always be harmful. In
some cases they can be used theraputically (sleep in-
duction from a benzodiazepine used primarily for its
anxiolytic effect). Sometimes these secondary actions are
unwanted but only annoying (nausea from codeine). In
these cases the secondary effects may be impossible to
dissociate from primary effects. It is also possible for
secondary drug actions to be definitely harmful (ben-
zodiazepine-induced sedation resulting in an auto ac-
cident).
A toxic drug effect is by any definition harmful to the
recipient. The resultant effect is usually some degree of
cellular damage or serious system disruption that may or
may not be reversible. Peptic ulceration from aspirin,
digitalis-induced ventricular fibrillation, and diazepam-
induced vasculitis are toxic drug effects. The line between
secondary and toxic drug effects may admittedly be
narrow hence the generic terms "adverse drug reactions"
or "adverse drug effects" to include both types of
untoward drug responses.
An abnormal drug effect is a rare event that does not fit
into any of the above categories and takes one of three
possible forms: 1) hypersensitive, 2) hyposensitive, or 3)
idiosyncratic. Such an unusual response may be related
to the unique genetic characteristics of the drug recipient
(pharmacogenetics) or more commonly reflect a small
segment of a population of individuals responding with a
primary, secondary, or toxic effect at an unusual dose or
in a bizarre manner.
A hypersensitive (hyperreactive) drug effect is either an
anticipated response to a drug from its known pharmaco-
logic profile at a very low dose or an exaggerated drug
response to an average or normal dose. Hypersensitive
individuals represent the small percent of persons at the
left "tail" of a normal distribution (bell-shaped) curve
(Figure 3). A two milligram oral dose of diazepam
inducing sleep would probably be a hypersensitive re-
sponse. True pharmacologic hypersensitivity should not
be confused with the misnomer "hypersensitivity reac-
tions" commonly misapplied to antibody-antigen (aller-
gic) situations. It is not possible to be "hypersensitive" to
an allergen since this is an all or none reaction. One is
either allergic or not; there are no gradations of sensitivity
and hypersensitivity. Hypersensitivity should denote an
anticipated reaction at low dose of a drug and "sensitiza-
tion reactions" the clinical manifestations of antibody-
antigen union.
A hyposensitive (hyporeactive) drug effect is a predic-
table drug action occurring at a dose well below average.
It represents the right "tail" of the normal distribution
Anesth Prog 35:87-101 1988
MEAN
0
4n
S.D.aStanardw
Dgwiat.on
*<
a
w
0 Hyp.r
. . . .~~~~~~~~~~~
1
L 1 Su.B"%
2 SD.= 95
3 SOD99.7 X
I
Figure 3. The normal (frequency) distribution curve. Most
responding units gather around the mean or average drug dose.
A much smaller percentage respond either at very low (hyper-
sensitive) or very high doses (hyposensitive).
curve (Figure 3). A lack of clinical response to an
intravenous dose of 300 mg of pentobarbital would
constitute hyposensitivity. The hyposensitive response
may reflect a simple unexplained unresponsiveness to the
drug, genetic differences (a genetically-altered receptor
site), or tolerance due to heightened drug liver metabo-
lism or adaptation of the CNS. Both hypersensitive and
hyposensitive drug effects are quantitative in nature.
An idiosyncratic drug effect is one that is qualitatively
different from the known pharmacology of the drug and
as such is far less predictable than the above quantitative
differences. The excitement, agitation, and irritability
occasionally seen upon administration of a CNS de-
pressant agent (alcohol, barbiturates, benzodiazepines)
might be idiosyncratic in nature. In this situation the
basis for such a reaction is known (release of anxiety-
bound hostility) whereas in other cases the underlying
mechanism may defy current understanding.
TYPES OF DRUG MECHANISMS
Drugs may induce pharmacologic effects by a variety of
mechanisms and at various sites within physiologic sys-
tems: 1) direct, 2) reflex, 3) enzyme induction or inhibi-
tion, 4) control of protein synthesis, 5) alterations in
membrane activity, 6) control of metabolic processes, 7)
antimetabolite activity, and 8) release of endogenous
substances.
A direct drug mechanism usually signifies that a drug
interacts with specific drug receptors in a physiologic
system (nitroglycerin acts directly on vascular smooth
Anesth Prog 35:87-101 1988
muscle) but also usually implies a lack of precise knowl-
edge regarding specific receptor sites and biochemical
mechanism of action. A drug may initiate reflex activity
within an organ system. The veratrum alkaloids stimulate
aortic pressoreceptors to mimic increased blood pressure
that the body reflexively reduces by activation of the
parasympathetic nervous system. Enzymes are a major
site of drug activity. Enzyme induction (stimulation) is
responsible for the action of many drugs within the
autonomic nervous system. Enzyme inhibition is also
involved in the actions of many cardiovascular and
autonomic agents and explains the ability of penicillin to
inhibit microbial cell wall synthesis. Many endogenous
hormones control protein synthesis by acting on DNA
and the tetracyclines inhibit microbial protein synthesis at
the RNA level. Via their action at membrane-associated
receptors, many drugs, such as local and general
anesthetics, alter neuron and other membrane activity.
Some chemicals, most notably endogenous hormones
and neuromodulators, control metabolic activity by an
action on enzymes, the process of enzyme synthesis, or
the substrate levels available for enzyme activity. An
antimetabolite is a drug chemically similar to a required
endogenous substance that produces a deficiency of that
endogenous chemical within an essential biologic system.
The sulfonamides compete with para-aminobenzoic acid
in the enzymatic synthesis of vital folic acid in bacteria
and in so doing induce a deficiency of folic acid incom-
patible with microbial viability. In the end it may not be
the drug itself that is responsible for the effect but rather it
may function to release an endogenous chemical which is
the true effector of change. Tyramine and amphetamine
release norepinephrine at the adrenergic nerve terminal
to interact with the adrenergic receptor. In a sense
release mechanisms are in effect when amplification takes
place. Beta-adrenergic agonists via adenylate cyclase
promote the release of cAMP as the second messenger
and the eventual entity responsible for 3-adrenergic
responses.
FACTORS MODIFYING DRUG ACTION
A number of variable factors can modify the action of a
drug once it is introduced to the physiologic system: 1)
pharmacokinetics, 2) repeated administration, 3) pres-
ence of other drugs, 4) dosage, and 5) biological vari-
ation.
The pharmacokinetics of a drug (absorption, distribu-
tion,metabolism, and excretion) determine the amount
of drug available for drug-receptor interaction and the
time course of drug action assuming proper doses are
used. Pharmacokinetic variables include a drug's dosage,
absorption characteristics, ability to traverse membranes,
Pallasch 95
rate of liver metabolism and the type of metabolites
formed, and the route by which the drug is excreted and
its rate of loss from the body. Individual drug pharmaco-
kinetics greatly dictate and control the effects of repeated
drug administration and its modification of action when
other drugs are already present in the system or are later
added to it. The second paper in this series will discuss
pharmacokinetics as it affects drug action.
DRUG DOSAGE
"All substances are poisons; there is none which is not.
The right dose differentiates a poison from a remedy."
Paracelsus (1493-1541)
Few concepts have been better expressed. All drugs can
be harmful if improperly employed. No drug is totally
"safe." The amount of drug applied to the physiologic
system to a great extent dictates the therapeutic or toxic
response of that system. The harm or benefit from a
chemical rests primarily in the hands of the user.
Drug dosage is the milligram amount administered per
unit time to achieve a particular biologic response. It is
the drug amount necessary to produce an appropriate
drug concentration at its site of receptor action with a
particular time course of activity as dictated by the
pharmacokinetic properties of the chemical. The proper
dose of a drug is "enough:" that which produces a
suitable therapeutic response with the least attendant
toxicity.
The concept of drug dosage can best be illustrated by
dose-response (dose-effect) curves. According to the
Occupational Theory of drug-receptor interaction, the
intensity of the drug effect is directly proportional to the
number of receptors occupied by the drug. The magni-
tude of the drug responseis a faithful indicator of the
number of receptors occupied6 and as such dictates
dosage. There are two basic types of dose-response
curves: 1) graded (quantitative) and 2) quantal (all or
none). These curves are usually presented logrithmically
rather than arithmetically for better graphic representa-
tion. These two curves depict four variables: 1) drug
efficacy, 2) drug potency, 3) rate of maximum effect
(slope), and 4) individual variation in a population.
The graded dose-response curve (Figure 4) relates a
given drug dose to the magnitude of response produced
in a single biologic unit. As the dose is increased, the
response of the organism increases (a progressively
greater effect as the concentration of the drug increases).
The efficacy of the drug is determined by the height of the
curve attained as measured along the response axis. At
some point the curve begins to flatten where increasing
dose results in little or no greater response. At this
96 Principles of Pharmacotherapy
DE
OF
M-i
* DOSE
Figure 4. The graded dose-response (effect) curve. As the
dose increases in a single biologic unit, the response will also
increase until a plateau (ceiling dose or maximum effect) is
reached where no further response is detected. A threshold
dose is always present that induces the first discernible response
(there are always doses below or to the left that produce no
effect). The position of the curve along the dose axis determines
potency and the height of the curve along the response axis
determines efficacy.
"plateau" level, "ceiling dose" or "maximum effect
level" the organism can no longer respond further. The
system may be at its maximum efficiency level, an
enzyme system may be depleted or fully responsive or
the organ system may be so impaired (if intended toxicity
is the desired effect) as to be nonviable. The location of
the dose-response (effect) curve along the dose axis is a
measure of the potency of the drug. A drug with a
dose-response curve further to the left is more potent
than a curve further to the right (Figure 5). As depicted in
these curves, drug potency does not imply greater drug
efficacy. The slope of the curve indicates receptor affinity,
the rate of attainment of maximum effect (as measured
by the dose increases necessary to achieve the ceiling
dose), and also the margin of safety between the thresh-
old and maximum dosages. A more vertical curve indica-
tes a narrow dose range between effect onset and
maximum intensity whereas a more horizontal curve
allows for a wider dose range between onset of effect and
maximum efficacy or toxicity.
The threshold dose is that dose that induces the first
discemible effect (response) in the biologic system. It is
always to the right of the response axis and indicates that
there is always a dose(s) that are incapable of inducing
detectable effect, either therapeutic or toxic, in a physio-
logic system. If such were not so, there might exist a
chemical that could induce harm even at the most minute
of doses.
The quantal dose-response (percent) curve measures
the effects of varying drug doses in a population of
biologic entities. It is not a measure of the intensity of a
Anesth Prog 35:87-101 1988
drug effect in a single unit but rather the frequency of
occurence of a predetermined response in a population
of individuals (Figure 6). It is "all or none:" either the
biologic unit responds with a given effect at a certain dose
or it does not. At each dose increment along the dose
axis, a certain percentage of the units will respond and
more will respond with increasing dose until virtually all
have responded at the far right of the curve (actually the
tail of the curve stretches to infinity). Each drug has at least
two quantal dose-response curves: therapeutic and toxic.
Quantal dose-response curves can be expressed as the
normal frequency distribution (normal distribution curve)
as depicted in Figure 3 or as sigmoid curves (as with the
graded response in Figure 5). The normal (frequency)
distribution curve indicates that in a given population of
units some will manifest the response at a very low dose
(hypersensitive), some only at high doses (hyposensitive)
and the majority at or near the average (mean) dose.
Both quantal and graded dose-response curves are at the
heart of the principle of titration of doses in intravenous
sedation. As the dose of the drug increases, the response
of the patient will increase but there is no assurance as we
begin where the patient resides under the bell-shaped
normal distribution curve. With dosage titration we avoid
the mistakes of starting with a dose too high on the
Figure 5. Drug potency and drug efficacy. Drug X is more
potent than drug Y because its threshold dose is further to the
left on the dose axis. However, drug Y is more efficacious than
drug X because its maximum effect attains a higher position
along the response axis. Potency is not related to efficacy. The
slope of the dose-response curve (more horizontal or more
vertical) indicates receptor affinity and sometimes intrinsic
activity but more importantly the rate of attainment of the
maximum effect and the margin of safety (dose range, DR)
between the onset of the effect and the maximum response. In
this situation, drug Y might be safer to use because, even
though its maximum effect is greater, the flatter slope of its
dose-response curve allows for greater safety because increas-
ing doses induce a less precipitous rise (slower) to the maximum
effect.
DOSE
DEGA
OF
RESPONSE
DOSE
Anesth Prog 35:87-101 1988
100
PERCENT
Of
ANIMALS
so
50
-TERAPEUTIC INX ( LDS _
EDso
graded curve and of applying an average or hyposen-
sitive dose to patients to the left of the mean dose.
The quantal dose-response curve can be used to
compare the efficacy of a drug to its toxicity and the
express its margin of safety (Figure 6). This relationship is
commonly expressed as the therapeutic index (TI). The
therapeutic index is usually determined by comparing the
dose at which 50% of the test animals or human
population respond therapeutically (the effective dose in
one-half or the ED50) to the dose at which 50% of the
biologic units die (the lethal dose in one-half or the LD50).
The TI is then expressed as the ratio: LD50/ED50. The
further apart the LD and ED curves, the greater the
margin of safety of the drug. The TI for a given drug will
vary with the effect measured and also among drugs in
the same group or used for the same purpose. If the
average oral adult sedative dose for pentobarbital is 100
mg and the average acute lethal oral dose is 2000 mg,
then the TI for sedation is 20. If the average oral adult
hypnotic dose of pentobarbital is 200 mg then its TI for
hypnosis is only 10 (one-half that for sedation). If the
average adult hypnotic dose of flurazepam is 30 mg and
the average lethal dose (if one exists) is 3000 mg, then
the TI of flurazepam for hypnosis is 100 (about 100
times the dose to produce death as to induce sleep). If
pentobarbital is used for hypnosis however its TI is only
10 (about 10 times the dose to produce death as to
induce sleep). All chemicals are potentially toxic; the dose
determines whether a drug produces harm or benefit.
BIOLOGICAL VARIATION
All drugs produce different pharmacologic effects. The
frequency distribution curve amply illustrates that individ-
Pallasch 97
Figure 6. The therapeutic index and margin of safety.
The quantal dose-response curve for a drug depends on
the effect measured (therapeutic or toxic) and can illus-
trate the therapeutic index (TI). As the curves move
farther apart (the LD50 moves further to the right), the
margin of safety increases but decreases as the LD50
moves closer to the ED50 (further to the left). The
therapeutic index compares the LD50 to the ED50. The
lower the number, the more potentially toxic the drug.
ual biologic units vary in their response to drugs depend-
ing upon dose. It is equally obvious that all individual
animals or humans are genetically distinct. Therefore
three distinct variables exist that control all drug activity:
1) the inherent pharmacologic properties of the drug
(affinity and intrinsic activity), 2) drug dosage and its
attendant pharmacokinetics, and 3) the biologic variation
inherent in the drug recipient. Biologic variation can
depend upon age, body weight, sex, species differences,
presence of pathology, diet, and mental attitude and
environment.
Age
The extremes of age pose special problems in drug
therapy. Age not size is the more dominant factor in drug
action in the infant and young child.6 Newborns may
have immature liver drug metabolizing systems that take
1-8 weeks to achieve adult levels of activity.6 During this
time liver oxidation and glucuronide systems are usually
deficient.6 Infants have a greater percentage of body
water than adults with therefore greater drug distribution
and reduced receptor interaction.32 Renal drug excretion
rates may be decreased in neonates due to reduced renal
blood flow.6
The incidence of adverse drug reactions increases from
8-12% at age 41 to 50, to 21-25% at age 70 to 79.33
Others estimate the prevalence of adverse reactions in
patients age 70 to 90 at 12-17% versus 3% in persons
age 10 to 30.34 Higher estimates indicate a seven-fold
greater incidence of adverse drug reactions in the elderly
than at age 20 to 29. This age-dependent increase in
adverse drug reactions may be the result of: 1) pharma-
codynamic changes in the quality and/or quantity of
98 Principles of Pharmacotherapy
receptors, and 2) the pharmacokinetic alterations in drug
absorption, distribution, metabolism, and excretion.36
Present evidence is scant for actual alterations in
receptor sensitivity in the elderly. Older persons appear
more sensitive to the CNS depressant effects of a given
dose of diazepam and nitrazepam but more resistant to
cardiac actions of propranolol.37 Age-related alterations
in pharmacokinetics have far greater implications. 37
Splanchnic blood flow is reduced which might delay or
reduce drug absorption.36'37 Blood flow to the liver and
kidneys decreases with age and its concomitant reduction
in cardiac output.37 Serum albumin levels decrease with
age allowing more free drug in the blood.37 Both liver
function and lean body mass decrease with age.37 Re-
duced renal blood flow (up to 50%) in the elderly may
restrict drug excretion.36 Four of five persons above age
65 have at least one chronic disease and such individuals
are commonly taking three to 12 drug medications.37
Additionally, cardiovascular disorders, malnutrition, de-
hydration, and altered mental status may be present.37
Altered pharmacodynamic and pharmacokinetic drug
activity along with the potential for adverse drug interac-
tions dictate that the drug regimens for the elderly be
individualized as much as possible.37
Body Weight
Drug doses are ordinarily calculated on the basis of
milligrams per kilogram of body weight but as measured
by lean body weight (or total body water) rather than
total body mass (water plus fat). In obese persons body
water is usually about 50% of body weight versus 70% in
lean individuals.6 Since drugs are distributed according to
total body water rather than total body mass, obesity may
give a distorted representation of body weight (body
water as a percent of total body mass) and therefore
require a reduction of dosage versus a relatively lean
person of the same body weight. Highly fat-soluble drugs
(benzodiazepines, halothane), however, may be readily
distributed to body fat in obese individuals requiring
greater dosages.38 The renal elimination of triazolam is
impaired in obese persons.39
Sex
The difference between drug responses in males and
females is ordinarily not great even though little data
exists except in regard to the incidence of adverse
reactions. Alcoholism is more prevalent in males although
changing lifestyles and social pressures in females is
tending to close this disparity. Women have a greater
predeliction for tardive dyskinesia and akathisia associ-
ated with neuroleptic antipsychotic agents and the hepa-
Anesth Prog 35:87-101 1988
titis seen with halothane.40'41 Conversely, halothane-
induced malignant hyperthermia is more common in
males, particularly those age 14 and under.42 Since the
total body mass of females contains a greater percentage
of adipose tissue (less body water) than males, pharma-
cokinetics may be altered.6
Species Variation
Pharmacodynamic and pharmacokinetic drug activity
can vary widely among animal species and becomes
critical when animal data is extrapolated to the human.
Any drug that induces gross structural damage in physio-
logical systems will probably do so similarly in lower
animals and man. However the rates of liver drug
metabolism in various animal species can vary 10-20
fold.43 The types and potential toxicity of metabolites
formed can also vary considerably. The tragedy of
thalidomide lay in the inability to detect the teratologic
effects of the drug in commonly used laboratory animals.
The birth defects caused by thalidomide were only
apparent at reasonable doses in rabbits and humans and
at very high doses only in rats. It is also likely that rabbits
and man were the only two species to convert thalido-
mide to the active metabolite responsible for phocomelia
(seal-like limbs). Humans generally metabolize drugs less
rapidly than other animals.44 The metabolism of drugs in
lower animals can be affected by diet, altitude, light,
temperature, oxygen tension, climate, atmospheric wa-
ter, food contamination, and even the type and composi-
tion of bedding placed in animal cages.45 Very substantial
differences in drug metabolism are apparent in different
ethnic human populations.46 The metabolism of the
benzodiazepines varies greatly among different animal
species and there is no one animal species like any other
in the metabolism of caffeine.47 All in vitro studies carry
the potential for distorting drug concentrations because
such systems are lacking the usual liver and kidney drug
detoxifying mechanisms (calling forth the old pharmaco-
logic adage: "Take the drug to the intact animal").
Lysergic acid diethylamide (LSD) caused great concern
regarding its teratogenic potential until it was determined
that the study indicting the drug (damage to chromo-
somes in tissue culture) used doses 17,000 times those
occurring in the human blood. Any purported toxic effect
of chemicals in lower animals must control for drug
concentrations equivalent to those seen or used during
human use. The blood concentration in the intact animal
must be similar to that seen in man. The human must also
form the same therapeutic or toxic metabolites as the
experimental animal. Any animal or in vitro study claim-
ing a direct relationship to humans should be scrutinized
Anesth Prog 35:87-101 1988
very carefully and interpreted with great caution and
suitable skepticism.
Presence of Pathology
Liver and kidney impairment can significantly alter drug
blood levels and the intensity and duration of drug action.
The influence of hepatic disease on drug disposition in
the body is not consistent and may be highly variable
even for drugs in the same pharmacologic category.48
Reduced liver function due to disease or reduced liver
blood flow (congestive heart failure) generally leads to an
increased blood level of a drug that has a high liver
extraction (metabolism) rate (morphine, meperidine, li-
docaine, and pentazocine), but less so with drugs that are
poorly extracted due to a much slower metabolism rate
or greater excretion of the intact drug (e.g., diazepam,
thipental, hexobarbital).48 A reduction in hepatic blood
flow more seriously affects the metabolism of drugs that
rely significantly on liver metabolism for their detoxi-
fication (high extraction rates).49 Generally, the effects of
drugs acting on the CNS are more pronounced in
persons with liver impairment.50 Both renal and hepatic
failure may decrease the plasma protein binding of drugs
leading to increased blood concentrations.51 For most
drugs the rate of renal excretion is proportional to the
renal glomerular filtration rate. Therefore impaired renal
function most commonly affects drug action by reduced
renal excretion.52 Such situations may require a reduction
in drug dosage or a lengthening of drug dosing intervals.
Also the drug itself may not rely on renal excretion for its
detoxification but the same may not be true for its
metabolites.53
Diet
The presence of food in the stomach may increase,
decrease, or have no effect on the eventual amount of
the drug reaching the blood. Generally only the rate of
absorption of a drug is slowed by food in the gastric
contents (delayed gastric emptying). Drug metabolism
may be altered by nutritional factors. Drug clearance
(metabolism) in the liver is decreased by low protein-high
carbohydrate diets and in children by protein malnutri-
tion.54 Fasting or anorexia in humans has little effect of
drug metabolism54 but may reduce the renal elimination
of some chemicals.55 Charcoal-broiled meat, cabbage,
and brussel sprouts may stimulate the liver drug metabo-
lizing enzymes.54
Mental Attitude and Environment
The mood or mental attitude of a patient towards
medication may significantly dictate drug effects. That
Pallasch 99
which is expected or not expected of a drug may have
substantial influence on its resultant therapeutic or toxic
effects. Collectively this influence of the CNS on drug
action can be termed the "placebo effect:" any effect
attributed to a pill, potion, or procedure but not to its
pharmacodynamic or specific properties.' Most medical
personnel unwisely underestimate or fail to grasp the role
of placebos in pain management.57 That placebos are
powerful medicine should never be forgotten.
Beneficial effects of placebos have been detected in
clinical situations of anxiety, depression, pain, headache,
fever, cough, insomnia, asthma, seasickness, the com-
mon cold, osteoarthritis, rheumatoid arthritis, peptic ul-
cer, angina pectoris, hypertension, and more objective
entities such as blood counts, pupillary size, and adrenal
gland secretions.58'59 In his classic study, Beecher60 re-
ported an average effectiveness of placebos of 35.2% in
over 1000 patients studied as well as 35 different "toxic
effects" from placebos. A placebo effect occurs more
commonly in certain disease states (e.g., emotional,
gastrointestinal, cardiovascular), in situations associated
with anxiety and pain, in settings where patient expecta-
tions of relief are high, and where the doctor or the
therapist conveys sincere empathy for the patient and
enthusiasm for and confidence in the medication or
procedure.
The placebo response is dependent upon two essential
factors: 1) a disease of variable intensity, and 2) a real or
implied doctor-patient relationship.61 Diseases commonly
amenable to placebos have associated symptoms that
fluctuate in amplitude and degree; there are good days
and bad. Cancer or cardiac arest will not respond to
placebos. Some type of authority must also be present.
Usually this takes the form of medical or therapeutic
personnel but the patient may also function as the "doc-
tor" via a strong belief in the rectitude of their own
judgement regarding the value of the pill or procedure.
There may be no such thing as a "placebo reactor" with
definable personality traits that predispose to the placebo
effect.5859'61 It is generally agreed that a placebo re-
sponse will occur in 30-50% of patients with suitable
diseases if the requirements of variable intensity and
authoritarian direction are present. However it does not
follow that the same 30-50% of subjects will be placebo
reactors in a subsequent clinical situation either identical
or different in nature.59
Whatever the basis for the placebo response, the wise
practitioner refrains from a callous disdain for placebos.
This is particularly true with the management of pain and
anxiety where the empathetic understanding of and
concem for the patient's plight has much to do with the
eventual resolution of their difficulties. Placebos work and
work well.
100 Principles of Pharmacotherapy
REFERENCES
1. Tallman JF, Paul SM, Skolnick P, Gallager DW: Recep-
tors for the age of anxiety: Pharmacology of the ben-
zodiazepines. Science 207:274-281, 1980.
2. Dixon RE: Effect of infections on hospital care. Arch Int
Med 89:749-753, 1978.
3. Brachman PS, Dan BB, Haley RW, et al: Nosocomial
surgical infections: Incidence and cost. Surg Clin NA 60:15-
25, 1980.
4. Pallasch TJ: Antibiotics: Past, present and future. J Calif
Dent Assoc 14:65-68, 1986.
5. Pallasch TJ: A critique of antibiotic prophylaxis. J Calif
Dent Assoc 14:28-36, 1986.
6. Levine RR: Pharmacology: Drug Actions and Reactions.
3rd ed, Boston/Toronto, Little Brown & Company, pp. 249-
251, 1983.
7. DeMetys P, Rousseau GG: Receptor concepts: A century
of evolution. Circulation Res 46 (Suppl 1):I-3-I-9, 1980.
8. Ariens EJ: Receptors: From fiction to fact. Trends Phar-
macol Sci 1:11-15, 1979.
9. Ariens EJ: Receptors: Perspectives in pathology and
clinical medicine. J Receptor Res 4:1-17, 1984.
10. Marx JL: A new view of receptor actions. Science
224:271-274, 1984.
11. Friedhoff AJ, Miller JC: Chemical implications of receptor
sensitivity modification. Ann Rev Neuroscience 6:121-148,
1983.
12. Ariens EJ: Intrinsic activity: Partial agonists and partial
antagonists. J Cardiovasc Pharmacol 5 (Suppl 1 ):S8-S15,
1983.
13. Strichartz GR: Current concepts of the mechanism of
acfion of local anesthetics. J Dent Res 60:1460-1467, 1981.
14. Ritchie JM: A pharmacological approach to the structure
of sodium channels in myelinated axons. Ann Rev Neuro-
science 2:341-362, 1979.
15. Bumie JP: Molecular mechanisms of general anesthesia.
Anesthesiol 36:1027-1039, 1981.
16. Roth SH: Mechanisms of anaesthesia: A review. Canad
Anaes Soc J 27:433-439, 1980.
17. LaBella FS: The general anesthesia receptor. Perspect
Biol Med 25:322-331, 1982.
18. Tallman JF, Gallager, DW: The GABA-ergic system: A
locus of benzodiazepine action. Ann Rev Neuroscience 8:21-
44, 1985.
19. McCabe RT, Wamsley JK: II. Autoradiographic locali-
zation of subcomponents of the macromolecular GABA recep-
tor concept. Life Sci 39:1937-1945, 1986.
20. Miller LG, Greenblatt DJ, Shader RI: Benzodiazepine
receptor binding: Influence of physiologic and pharmacologic
factors. Biopharmaceutics Drug Disp 8:103-114, 1987.
21. Barnett A, Iorio LC, Billard W: Novel receptor specific-
ity of selected benzodiazepines. Clin Neuropharmacol 8 (Suppl
1): S8-S16, 1985.
22. Davis LG, Manning RW, Dawson WE: Putative endoge-
nous ligands to the benzodiazepine receptor: What can they tell
us? Drug Devel Res 4:31-37, 1984.
23. Bergman SA: The benzodiazepine receptor. Anesthesia
Progress 33:213-220, 1986.
Anesth Prog 35:87-101 1988
24. Braestrup C, Nielson M: Benzodiazepine receptors. Clin
Neuropharmacol (Suppl 1):S2-S7, 1985.
25. Haefely WE: The benzodiazepine receptor and its cli-
nically useful ligands. Clin Neuropharmacol 9 (Suppl 4): 398-
400, 1986.
26. Hofer P, Scollo-Lavizzari G: Benzodiazepine antagonist
RO-15-1788 in self-poisoning: Diagnostic and therapeutic use.
Arch Int Med 145:663-664, 1985.
27. Richards JG, Mohler H: Benzodiazepine receptors. Neu-
ropharmacol 23:233-242, 1984.
28. Martin WR, Eades CG, Thompson JA, et al: The effects
of morphine and nalorphine-like drugs in nondependent and
morphine-dependent chronic spinal dog. J Pharmacol Exp
Therap 197:517-532, 1976.
29. Kitchen I: Endogenous opioid nomenclature: Light at
the end of the tunnel. Gen Pharmacol 16:79-84, 1985.
30. Pallasch TJ, Gill CJ: Butorphanol and nalbuphine: A
pharmacologic comparison. Oral Surg Oral Med Oral Path
59:15-20, 1985.
31. Council Conference: Notes on the package insert. JAMA
207:1335-1338, 1969.
32. Rane A, Wilson JT: Clinical pharmacokinetics in infants
and children. Clin Pharmacokinetics 1:2-24, 1976.
33. Bender AD: Pharmacodynamic principles of drug ther-
apy in the aged. J Am Geriat Soc 22:296-303, 1974.
34. Hurwitz M: Predisposing factors in adverse reactions to
drugs. Br Med J 1:536-539, 1969.
35. Hollister LE: Prescribing drugs for the elderly. Geriatrics
32:71-73, 1977.
36. Schmucker DL: Aging and drug disposition: An update.
Pharmacol Rev 37:133-148, 1985.
37. Ouslander JG: Drug therapy in the elderly. Ann Int Med
95:711-722, 1981.
38. Abemethy DR, Greenblatt DJ: Pharmacokinetics of
drugs in obesity. Clin Pharmacokinetics 7:108-124, 1982.
39. Abemethy DR, Greenblatt DJ, Divoll M, et al; The
influence of obesity on the pharmacokinetics of oral alprazolam
and triazolam. Clin Pharmacokinetics 9:177-183, 1984.
40. Black JL, Richelson E, Richardson JW: Antipsychotic
agents: A clinical update. Mayo Clin Proc 60:777-789, 1985.
41. Stock JGL, Strumin L: Unexplained hepatitis following
halothane. Anesthesiol 63:424-439, 1985.
42. Brockhouse RT: Malignant hyperthermia. J Am Dent
Assoc 98:581-583, 1970.
43. Conney AH, Coutinho C, Keochlin B, et al: From
animals to man: Metabolic considerations. Clin Pharmacol
Therap 16:176-182, 1974.
44. Dedrick RL, Bischoff, KB: Species similarities in pharma-
cokinetics. Fed Proc 39:54-59, 1980.
45. Sanvordeker DR, Lambert HJ: Environmental modifica-
tion of mammalian drug metabolism and biologic response.
Drug Met Rev 3:201-229, 1974.
46. Kalow W: Ethnic differences in drug metabolism. Clin
Pharmacokinetics 7:373-400, 1982.
47. Garattini S: Toxic effects of chemicals: Difficulties in
extrapolating data from animals to man. CRC Critical Rev
Toxicol 16:1-29, 1985.
48. Williams RL, Mamelok RD: Hepatic disease and drug
pharmacokinetics. Clin Pharmacokinetics 5:528-547, 1980.
Anesth Prog 35:87-101 1988
49. Vesell ES: The influence of host factors on drug re-
sponse. VI. Hepatocellular disease. Rational Drug Therapy 15
(8), 1981.
50. Williams RL: Drug administration in hepatic disease.
New Engl J Med 309:1616-1622, 1983.
51. Piafsky KM: Disease-induced changes in the plasma
binding of basic drugs. Clin Pharmacokinetics 5:246-262,
1980.
52. Reidenberg MM: Kidney function and drug action. New
Engl J Med 313:816-818, 1985.
53. Verbeeck RK, Branch RA, Wilkinson GR: Drug metabo-
lites in renal failure: Pharmacokinetic and clinical implications.
Clin Pharmacokinetics 6:329-345, 1981.
54. Rikans LE: Drugs and nutrition in old age. Life Sci
39:1027-1036, 1986.
Pallasch 101
55. Vesell ES: Complex effects of diet on drug disposition.
Clin Pharmacol Therap 36:285-296, 1984.
56. Wolf S: The pharmacology of placebos. Pharmacol Rev
11:689-704, 1959.
57. Goodwin JS, Goodwin JM, Vogel AV: Knowledge and
use of placebos by house officers and nurses. Ann Int Med 91:
106-110, 1979.
58. Lasagna L: The placebo effect. J Allergy Clin Immunol
78:161-165, 1986.
59. Bush PJ: The placebo effect. J Am Pharmaceut Assoc
14:671-674, 1974.
60. Beecher HK: The powerful placebo. JAMA 159:1602-
1606, 1955.
61. Boume HR: Rational use of placebo. In: Clinical Phar-
macology (Melmon KL, Morelli HF, eds), 2nd ed, New York,
Macmillan, p. 1055, 1977.