Introduction
All body functions, disease processes, and most drug actions occur
at the cellular level. Drugs are chemicals that alter basic processes
in body cells. They can stimulate or inhibit normal cellular func-
tions; however, they cannot change the type of function that
occurs normally. To act on body cells, drugs given for systemic
effects must reach adequate concentrations in the blood and
other tissue uids surrounding the cells. Thus, they must enter
the body and be circulated to their sites of action (target cells).
After they act on cells, they must be eliminated from the body.
How do systemic drugs reach, interact with, and leave body
cells? How do people respond to drugs? The answers to these ques-
tions are derived from cellular physiology, pathways and mecha-
nisms of drug transport, pharmacokinetics, pharmacodynamics,
and other basic concepts and processes that form the foundation
of rational drug therapy and the content of this chapter.
 Cellular Physiology
Cells are dynamic, busy “factories” (Box 2.1, Fig. 2.1) that take
in raw materials, manufacture products required to maintain
bodily functions, and deliver those products to their appropri-
ate destinations in the body. Although cells differ from one
tissue to another, their common characteristics include the
ability to
• Exchange materials with their immediate environment
• Obtain energy from nutrients
• Synthesize hormones, neurotransmitters, enzymes, struc-
tural proteins, and other complex molecules
• Reproduce
• Communicate with one another via various biologic
chemicals, such as neurotransmitters and hormone
 Drug Transport Through
Cell Membranes
Drugs must reach and interact with or cross the cell mem-
brane to stimulate or inhibit cellular function. Most drugs
are given to affect body cells that are distant from the sites
of administration (i.e., systemic effects). To move through
the body and reach their sites of action, metabolism, and
excretion (Fig. 2.2), drug molecules must cross numerous
cell membranes. For example, molecules of most oral drugs
must cross the membranes of cells in the gastrointestinal
(GI) tract, liver, and capillaries to reach the bloodstream,
circulate to their target cells, leave the bloodstream and
attach to receptors on cells, perform their action, return to
the bloodstream, circulate to the liver, reach drug-metabolizing
enzymes in liver cells, reenter the bloodstream (usually as
metabolites), circulate to the kidneys, and be excreted in
urine. Box 2.2 and Figure 2.3 describe the transport path-
ways and mechanisms used to move drug molecules through
the body.
 Pharmacokinetics
Pharmacokinetics involves drug movement through the body
(i.e., “what the body does to the drug”) to reach sites of action,
metabolism, and excretion. Specic processes are absorp-
tion, distribution, metabolism, and excretion. Metabolism
and excretion are often grouped together as drug elimination
or clearance mechanisms. Overall, these processes largely
 determine serum drug levels; onset, peak, and duration of drug
actions; therapeutic and adverse effects; and other important
aspects of drug therapy.
Drug Transport Pathways and Mechanism
Pathways
There are three main pathways of drug movement across
cell membranes. The most common pathway is direct pen-
etration of the membrane by lipid-soluble drugs, which
are able to dissolve in the lipid layer of the cell membrane.
Most systemic drugs are formulated to be lipid soluble so
they can move through cell membranes, even oral tablets
and capsules that must be su ciently water soluble to
dissolve in the aqueous uids of the stomach and small
intestine.
A second pathway involves passage through protein
channels that go all the way through the cell membrane.
Only a few drugs are able to use this pathway because
most drug molecules are too large to pass through the
small channels. Small ions (e.g., sodium and potassium)
use this pathway, but their movement is regulated by spe-
cic channels with a gating mechanism (a ap of protein
that opens briey to allow ion movement and then closes).
The third pathway involves carrier proteins that
transport molecules from one side of the cell membrane
to the other. All of the carrier proteins are selective in the
substances they transport; a drug’s chemical structure
determines which carrier will transport it.Mechanisms
Once absorbed into the body, drugs are transported to and
from target cells by passive diusion, facilitated diusion,
and active transport.
Passive diusion, the most common mechanism,
involves movement of a drug from an area of higher
concentration to one of lower concentration. For example,
after oral administration, the initial concentration of a drug
is higher in the gastrointestinal tract than in the blood.
This promotes movement of the drug into the bloodstream.
When the drug is circulated, the concentration is higher in
the blood than in body cells, so that the drug moves (from
capillaries) into the uids surrounding the cells or into the
cells themselves. Passive diusion continues until a state of
equilibrium is reached between the amount of drug in the
tissues and the amount in the blood.
Facilitated diusion is a similar process, except that
drug molecules combine with a carrier substance, such as
an enzyme or other protein.
In active transport, drug molecules are moved from an
area of lower concentration to one of higher concentration.
This process requires a carrier substance and the release of
cellular energy
Absorption
Absorption is the process that occurs from the time a drug
enters the body to the time it enters the bloodstream to be cir-
culated. Onset of drug action is largely determined by the rate of
absorption; intensity is determined by the extent of absorption. Numerous factors affect the rate and extent of drug absorption,
including dosage form, route of administration, blood ow to
the site of administration, GI function, the presence of food or
other drugs, and other variables. Dosage form is a major deter-
minant of a drug’s bioavailability (the portion of a dose that
eaches the systemic circulation and is available to act on body
cells). An intravenous (IV) drug is virtually 100% bioavailable.
In contrast, an oral drug is virtually always less than 100% bio-
available because some of it is not absorbed from the GI tract
and some goes to the liver and is partially metabolized before
reaching the systemic circulation.
Most oral drugs must be swallowed, dissolved in gastric uid,
and delivered to the small intestine (which has a large sur-
face area for absorption of nutrients and drugs) before they are
absorbed. Liquid medications are absorbed faster than tablets or
capsules because they need not be dissolved. Rapid movement
through the stomach and small intestine may increase drug
absorption by promoting contact with absorptive mucous mem-
brane; it also may decrease absorption because some drugs may
move through the small intestine too rapidly to be absorbed. For
many drugs, the presence of food in the stomach slows the rate
of absorption and may decrease the amount of drug absorbed.
Drugs injected into subcutaneous (subcut) or intramuscular
(IM) tissues are usually absorbed more rapidly than oral drugs
because they move directly from the injection site to the blood-
stream. Absorption is rapid from IM sites because muscle tissue
has an abundant blood supply. Drugs injected intravenously do
not need to be absorbed because they are placed directly into
the bloodstream.
Other absorptive sites include the skin, mucous membranes,
and lungs. Most drugs applied to the skin are given for local
effects (e.g., sunscreens). Systemic absorption is minimal from
intact skin but may be considerable when the skin is inamed
or damaged. Also, some drugs are formulated in adhesive skin
patches for absorption through the skin (e.g., clonidine, fenta-
nyl, nitroglycerin). Some drugs applied to mucous membranes
also are given for local effects. However, systemic absorption
occurs from the mucosa of the oral cavity, nose, eye, vagina,
and rectum. Drugs absorbed through mucous membranes p
irectly into the bloodstream. The lungs have a large surface
area for absorption of anesthetic gases and a few other drugs.
Distribution
Distribution involves the transport of drug molecules within
the body. After a drug is injected or absorbed into the blood-
stream, it is carried by the blood and tissue uids to its sites
of action, metabolism, and excretion. Most drug molecules
enter and leave the bloodstream at the capillary level, through
gaps between the cells that form capillary walls. Distribution
depends largely on the adequacy of blood circulation. Drugs
are distributed rapidly to organs receiving a large blood sup-
ply, such as the heart, liver, and kidneys. Distribution to other
internal organs, muscle, fat, and skin is usually slower.
Protein binding is an important factor in drug distribution
(Fig. 2.4). Most drugs form a compound with plasma proteins,
mainly albumin, which act as carriers. Drug molecules bound
to plasma proteins are pharmacologically inactive because the
large size of the complex prevents their leaving the blood-
stream through the small openings in capillary walls and reach-
ing their sites of action, metabolism, and excretion. Only the
free or unbound portion of a drug acts on body cells. As the
free drug acts on cells, the decrease in plasma drug levels causes
some of the bound drug to be released.
Protein binding allows part of a drug dose to be stored and
released as needed. Some drugs also are stored in muscle, fat,
or other body tissues and released gradually when plasma drug
levels fall. These storage mechanisms maintain lower, more
consistent blood levels and reduce the risk of toxicity. Drugs
that are highly bound to plasma proteins or stored extensively
in other tissues have a long duration of action.
Drug distribution into the central nervous system (CNS) is
limited because the blood–brain barrier, which is composed of
capillaries with tight walls, limits movement of drug molecules
into brain tissue. This barrier usually acts as a selectively per-
meable membrane to protect the CNS. However, it also can
make drug therapy for CNS disorders more difcult because
drugs must pass through cells of the capillary wall rather than
between cells. As a result, only drugs that are lipid soluble or
have a transport system can cross the blood–brain barrier and
reach therapeutic concentrations in brain tissue.
Drug distribution during pregnancy and lactation is also an
important consideration (see Chap. 6). During pregnancy, most
drugs cross the placenta and may affect the fetus. During lactation,
many drugs enter breast milk and may affect the nursing infant.
Metabolism
Metabolism, or biotransformation, is the method by which
drugs are inactivated or biotransformed by the body. Most often,
an active drug is changed into inactive metabolites, which are
then excreted. Some active drugs yield metabolites that are also
active and that continue to exert their effects on body cells until
they are metabolized further or excreted. Other drugs (called
prodrugs) are initially inactive and exert no pharmacologic
effects until they are metabolized. Most drugs are lipid soluble,
a characteristic that aids their movement across cell membranes.
However, the kidneys can excrete only water-soluble substances.
Therefore, one function of metabolism is to convert fat-soluble
drugs into water-soluble metabolites. Hepatic drug metabolism
or clearance is a major mechanism for terminating drug action
and eliminating drug molecules from the body.
Most drugs are metabolized by cytochrome P450 (CYP)
enzymes in the liver. Red blood cells, plasma, kidneys, lungs,
and GI mucosa also contain drug-metabolizing enzymes. The
CYP system consists of several groups of enzymes, some of
which metabolize endogenous substances and some of which
metabolize drugs. The drug-metabolizing groups are labeled
CYP1, CYP2, and CYP3. Individual members of the groups
usually metabolize specic drugs; more than one enzyme par-
ticipates in the metabolism of some drugs. In terms of impor-
tance in drug metabolism, the CYP3A4 enzymes are thought to
metabolize about 50% of drugs; CYP2D6 enzymes about 25%;
CYP2C8/9 about 15%; and CYP1A2, 2C19, 2A6, and 2E1 in
decreasing order for the remaining 10%.
CYP enzymes are complex proteins with binding sites for
drug molecules (and endogenous substances). They catalyze
the chemical reactions of oxidation, reduction, hydrolysis, and
conjugation with endogenous substances, such as glucuronic
acid or sulfate. With chronic administration, some drugs stimu-
late liver cells to produce larger amounts of drug-metabolizing
enzymes. This enzyme induction accelerates drug metabolism
because larger amounts of the enzymes (and more binding sites)
allow larger amounts of a drug to be metabolized during a given
period. As a result, larger doses of the rapidly metabolized drug
may be required to produce or maintain therapeutic effects.
Rapid metabolism may also increase the production of toxic
metabolites with some drugs (e.g., acetaminophen). Drugs
that induce enzyme production also may increase the rate of
metabolism for endogenous steroidal hormones (e.g., cortisol,
estrogens, testosterone, vitamin D). However, enzyme induc-
tion does not occur for 1 to 3 weeks after an inducing agent is
started, because new enzyme proteins must be synthesized.
Metabolism also can be decreased or delayed in a process
called enzyme inhibition, which most often occurs with concur-
rent administration of two or more drugs that compete for the
same metabolizing enzymes. In this case, smaller doses of the
lowly metabolized drug may be needed to avoid adverse effects
and toxicity from drug accumulation. Enzyme inhibition occurs
within hours or days of starting an inhibiting agent. Cimetidine,
a gastric acid suppressor, inhibits several CYP enzymes (e.g., 1A,
2C, 2D, 3A) and can greatly decrease drug metabolism. The
rate of drug metabolism also is reduced in infants (their hepatic
enzyme system is immature), in people with impaired blood ow
to the liver or severe hepatic or cardiovascular disease, and in
people who are malnourished or on low-protein diets.
When drugs are given orally, they are absorbed from the GI
tract and carried to the liver through the portal circulation.
Some drugs are extensively metabolized in the liver, with only
part of a drug dose reaching the systemic circulation for distri-
bution to sites of action. This is called the rst-pass effect or
presystemic metabolism.
Excretion
Excretion refers to elimination of a drug from the body.
Effective excretion requires adequate functioning of the circu-
latory system and of the organs of excretion (kidneys, bowel,
lungs, and skin). Most drugs are excreted by the kidneys and
eliminated (unchanged or as metabolites) in the urine. Some
drugs or metabolites are excreted in bile and then eliminated
in feces; others are excreted in bile, reabsorbed from the small
intestine, returned to the liver (called enterohepatic recircula-
tion), metabolized, and eventually excreted in urine. Some oral
drugs are not absorbed and are excreted in the feces. The lungs
mainly remove volatile substances, such as anesthetic gases.
The skin has minimal excretory function. Factors impairing
excretion, especially severe renal disease, lead to accumulation
of numerous drugs and may cause severe adverse effects if dos-
age is not reduced.
erum Drug Levels
A serum drug level is a laboratory measurement of the amount
of a drug in the blood at a particular time (Fig. 2.5). It reects
dosage, absorption, bioavailability, half-life, and the rates of
metabolism and excretion. A minimum effective concentration
(MEC) must be present before a drug exerts its pharmacologic
action on body cells; this is largely determined by the drug dose
and how well it is absorbed into the bloodstream. A toxic con-
centration is a level at which toxicity occurs; what is toxic for
some patients is not toxic for others (see subsequent discussion).
Toxic concentrations may stem from a single large dose, repeated
small doses, or slow metabolism that allows the drug to accumu-
late in the body. Between these low and high concentrations is
the therapeutic range, which is the goal of drug therapy—that is,
enough drug to be benecial but not enough to be toxic
For most drugs, serum levels indicate the onset, peak, and
duration of drug action. When a single dose of a drug is given,
onset of action occurs when the drug level reaches the MEC. The
drug level continues to climb as more of the drug is absorbed,
until it reaches its highest concentration and peak drug action
occurs. Then, drug levels decline as the drug is eliminated (i.e.,
metabolized and excreted) from the body. Although there may
still be numerous drug molecules in the body, drug action stops
when drug levels fall below the MEC. The duration of action is
the time during which serum drug levels are at or above the MEC.
When multiple doses of a drug are given (e.g., for chronic condi-
tions), the goal is usually to give sufcient doses often enough to
maintain serum drug levels in the therapeutic range and avoid the
toxic range.
In clinical practice, measuring serum drug levels is useful in
several circumstances:
• When drugs with a narrow margin of safety are given,
because their therapeutic doses are close to their toxic
doses (e.g., digoxin, aminoglycoside antibiotics, lithium)
• To document the serum drug levels associated with
particular drug dosages, therapeutic effects, or possible
adverse effects
• To monitor unexpected responses to a drug dose such as
decreased therapeutic effects or increased adverse effects
• When a drug overdose is suspected
Serum Half-Life
Serum half-life, also called elimination half-life, is the time
required for the serum concentration of a drug to decrease by
50%. It is determined primarily by the drug’s rates of metabo-
lism and excretion. A drug with a short half-life requires more
frequent administration than one with a long half-life.
When a drug is given at a stable dose, four or ve half-lives
are required to achieve steady-state concentrations and to
develop equilibrium between tissue and serum concentrations.
Because maximal therapeutic effects do not occur until equilib-
rium is established, some drugs are not fully effective for days or
weeks. To maintain steady-state conditions, the amount of drug
given must equal the amount eliminated from the body. When
a drug dose is changed, an additional four to ve half-lives are
required to reestablish equilibrium; when a drug is discontin-
ued, it is eliminated gradually over several half-lives.
 Pharmacodynamics
Pharmacodynamics involves drug actions on target cells and
the resulting alterations in cellular biochemical reactions and
functions (i.e., “what the drug does to the body”).
Receptor Theory of Drug Action
Like the physiologic substances (e.g., hormones, neurotrans-
mitters) that normally regulate cell functions, most drugs exert
their effects by chemically binding with receptors at the cel-
lular level (Fig. 2.6). Most receptors are proteins located on the
surfaces of cell membranes or within cells. Specic receptors
include enzymes involved in essential metabolic or regulatory
processes (e.g., dihydrofolate reductase, acetylcholinesterase);
proteins involved in transport (e.g., sodium–potassium adeno-
sine triphosphatase) or structural processes (e.g., tubulin); and
nucleic acids (e.g., DNA) involved in cellular protein  synthesis,
reproduction, and other metabolic activities.
When drug molecules bind with receptor molecules, the
resulting drug–receptor complex initiates physiochemical reac-
tions that stimulate or inhibit normal cellular functions. One
type of reaction involves activation, inactivation, or other
alterations of intracellular enzymes. Because enzymes catalyze
almost all cellular functions, drug-induced changes can mark-
edly increase or decrease the rate of cellular metabolism. For
example, an epinephrine–receptor complex increases the activ-
ity of the intracellular enzyme adenyl cyclase, which then causes
the formation of cyclic adenosine monophosphate (cAMP). In
turn, cAMP can initiate any one of many different intracellular
actions, the exact effect depending on the type of cell.
A second type of reaction involves changes in the perme-
ability of cell membranes to one or more ions. The receptor
protein is a structural component of the cell membrane, and
its binding to a drug molecule may open or close ion chan-
nels. In nerve cells, for example, sodium or calcium ion chan-
nels may open and allow movement of ions into the cell. This
movement usually causes the cell membrane to depolarize and
excite the cell. At other times, potassium channels may open
and allow movement of potassium ions out of the cell. This
action inhibits neuronal excitability and function. In muscle
cells, movement of the ions into the cells may alter intracellu-
lar functions, such as the direct effect of calcium ions in stimu-
lating muscle contraction.
A third reaction may modify the synthesis, release, or inac-
tivation of the neurohormones (e.g., acetylcholine, norepi-
nephrine, serotonin) that regulate many physiologic processes.
Box 2.3 describes additional elements and characteristics of the
receptor theory.
Nonreceptor Drug Actions
Relatively few drugs act by mechanisms other than combina-
tion with receptor sites on cells. Drugs that do not act on recep-
tor sites include the following:
• Antacids, which act chemically to neutralize the hydro-
chloric acid produced by gastric parietal cells and thereby
raise the pH of gastric uid
• Osmotic diuretics (e.g., mannitol), which increase the
osmolarity of plasma and pull water out of tissues into
the bloodstream
• Drugs that are structurally similar to nutrients required
by body cells (e.g., purines, pyrimidines) and that can be
incorporated into cellular constituents, such as nucleic
acids, which interfere with normal cell functioning.
Several anticancer drugs act by this mechanism.
• Metal chelating agents, which combine with toxic met-
als to form a complex that can be more readily excreted
 Variables that Aect Drug Actions
Historically, expected responses to drugs were based on those
occurring when a particular drug was given to healthy adult
men (18–65 years of age) of average weight (150 lb [70 kg]).
However, other groups (e.g., women, children, older adults,
ifferent ethnic or racial groups, patients with diseases or
 symptoms that the drugs are designed to treat) receive drugs
and respond differently from healthy adult men. As a result,
newer clinical trials include more representatives of these
groups. In any patient, however, responses may be altered by
both drug-related and patient-related variables.
Drug-Related Variables
Dosage
Dosage refers to the frequency, size, and number of doses;
it is a major determinant of drug actions and responses,
both therapeutic and adverse. If the amount is too small or
administered infrequently, no pharmacologic action occurs
because the drug does not reach an adequate concentration
at target cells. If the amount is too large or administered
too often, toxicity (poisoning) may occur. Overdosage may
occur with a single large dose or with chronic ingestion of
smaller doses.Dosages recommended in drug literature are usually those
that produce particular responses in 50% of the people tested.
These dosages usually produce a mixture of therapeutic and
adverse effects. The dosage of a particular drug depends on
many characteristics of the drug (reason for use, potency, phar-
macokinetics, route of administration, dosage form, and so on)
and of the recipient (age; weight; state of health; and function
of cardiovascular, renal, and hepatic systems). Thus, recom-
mended dosages are intended only as guidelines for individual-
izing dosages.
Even if the recommended dose controls a patient’s symp-
toms, he or she may need a special loading dose at the begin-
ning of drug therapy. This dose, which is larger than the regular
prescribed daily dosage of a medication, is used to attain a more
rapid therapeutic blood level of the drug. After the patient
has been taking the drug for a few days, a maintenance dose,
or quantity of drug that is needed to keep blood levels and/
or tissue levels at a steady state, or constant level, is usually
sufcient.
Additional Elements of the Receptor Theory of Drug ActionThe site and extent of drug action on body cells are
determined primarily by specic characteristics of
receptors and drugs. Receptors vary in type, location,
number, and functional capacity. For example, many
dierent types of receptors have been identied. Most
types occur in most body tissues, such as receptors
for epinephrine (whether received from stimulation
of the sympathetic nervous system or administra-
tion of drug formulations) and receptors for growth
hormone, thyroid hormone, and insulin. Some occur
in fewer body tissues, such as receptors for opioids
in the brain and subgroups of receptors for epineph-
rine in the heart (beta
1
-adrenergic receptors) and
lungs (beta
2
-adrenergic receptors). Receptor type and
location inuence drug action. The receptor is often
described as a lock into which the drug molecule ts
as a key, and only those drugs able to bond chemi-
cally to the receptors in a particular body tissue can
exert pharmacologic eects on that tissue. Thus, all
body cells do not respond to all drugs, even though
virtually all cell receptors are exposed to any drug
molecules circulating in the bloodstream.
The number of receptor sites available to interact
with drug molecules also aects the extent of drug
action. Drug molecules must occupy a minimal number
of receptors to produce pharmacologic eects. Thus, if
many receptors are available but only a few are occu-
pied by drug molecules, few drug eects occur. In this
instance, increasing the drug dosage increases the
pharmacologic eects. Conversely, if only a few recep-
tors are available for many drug molecules, receptors
may be saturated. In this instance, if most receptor sites
are occupied, increasing the drug dosage produces no
additional pharmacologic eect.
Drugs vary even more widely than receptors. Because
all drugs are chemical substances, chemical characteris-
tics determine drug actions and pharmacologic eects.
For example, a drug’s chemical structure aects its abil-
ity to reach tissue uids around a cell and bind with its
cell receptors. Minor changes in drug structure may pro-duce major changes in pharmacologic eects. Another
major factor is the concentration of drug molecules that
reach  receptor sites in body tissues. Drug-related and
patient-related variables that aect drug actions are
further described later in this chapter.
 •
When drug molecules chemically bind with cell recep-
tors, pharmacologic eects result from agonism or
antagonism. Agonists are drugs that produce eects
similar to those produced by naturally occurring
hormones, neurotransmitters, and other substances.
Agonists may accelerate or slow normal cellular pro-
cesses, depending on the type of receptor activated.
For example, epinephrine-like drugs act on the heart
to increase the heart rate, and acetylcholine-like
drugs act on the heart to slow the heart rate; both
are agonists. Antagonists are drugs that inhibit cell
function by occupying receptor sites. This strategy
prevents natural body substances or other drugs from
occupying the receptor sites and activating cell func-
tions. After drug action occurs, drug molecules may
detach from receptor molecules (i.e., the chemical
binding is reversible), return to the bloodstream, and
circulate to the liver for metabolism and the kidneys
for excretion.
 •
Receptors are dynamic cellular components that can
be synthesized by body cells and altered by endog-
enous substances and exogenous drugs. For example,
prolonged stimulation of body cells with an excitatory
agonist usually reduces the number or sensitivity of
receptors. As a result, the cell becomes less respon-
sive to the agonist (a process called receptor desen-
sitization or down-regulation). Prolonged inhibition
of normal cellular functions with an antagonist may
increase receptor number or sensitivity. If the antago-
nist is suddenly reduced or stopped, the cell becomes
excessively responsive to an agonist (a process called
receptor up-regulation). These changes in receptors
may explain why some drugs must be tapered in dos-
age and discontinued gradually if withdrawal symp-
toms are to be avoided
oute of Administration
Routes of administration affect drug actions and patient
responses largely by inuencing absorption and distribution.
For rapid drug action and response, the IV route is most effec-
tive because the drug is injected directly into the bloodstream.
For some drugs, the IM route also produces drug action within
a few minutes because muscles have a large blood supply. The
oral route usually produces slower drug action than parenteral
routes. Absorption and action of topical drugs vary according
to the drug formulation, whether the drug is applied to skin or
mucous membranes, and other factors.
Drug–Diet Interactions
A few drugs are used therapeutically to decrease food absorption
in the intestinal tract. For example, orlistat (Xenical) decreases
absorption of fats from food and is given to promote weight loss,
and ezetimibe (Zetia) decreases absorption of cholesterol from
food and is given to lower serum cholesterol levels. However,
most drug–diet interactions are undesirable because food often
slows absorption of oral drugs by slowing gastric emptying time
and altering GI secretions and motility.
QSEN Safety Alert
Giving medications 1 hour before or 2 hours after
a meal can minimize interactions that decrease
drug absorption.
In addition, some foods contain certain substances that
react with certain drugs. One such interaction occurs between
tyramine-containing foods and monoamine oxidase (MAO)
inhibitor drugs. Tyramine causes the release of norepineph-
rine, a strong vasoconstrictive agent, from the adrenal medulla
and sympathetic neurons. Normally, norepinephrine is quickly
inactivated by MAO. However, because MAO inhibitor drugs
prevent inactivation of norepinephrine, ingesting tyramine-
containing foods with an MAO inhibitor may produce severe
hypertension or intracranial hemorrhage. MAO inhibitors
include the antidepressants isocarboxazid and phenelzine and
the antiparkinson drugs rasagiline and selegiline.
QSEN Safety Alert
Tyramine-rich foods to be avoided by patients
 taking MAO inhibitors include aged cheeses,
 sauerkraut, soy sauce, tap or draft beers, and
red wines.
Another interaction may occur between warfarin
(Coumadin), an oral anticoagulant, and foods containing vita-
min K. Because vitamin K antagonizes the action of warfarin,
large amounts of spinach and other green leafy vegetables may
offset the anticoagulant effects and predispose the person to
thromboembolic disorders.
A third interaction occurs between tetracycline, an antibi-
otic, and dairy products, such as milk and cheese. The drug
combines with the calcium in milk products to form a nonab-
sorbable compound that is excreted in the feces.
Still another interaction involves grapefruit. Grapefruit
contains a substance that strongly inhibits the metabolism
of drugs normally metabolized by the CYP3A4 enzyme. This
effect greatly increases the blood levels of some drugs (e.g., the
widely used “statin” group of cholesterol-lowering drugs) and
the effect lasts for several days. Patients who take medications
metabolized by the 3A4 enzyme should be advised against eat-
ing grapefruit or drinking grapefruit juice.
Drug–Drug Interactions
The action of a drug may be increased or decreased by its
interaction with another drug in the body. Most interactions
occur whenever the interacting drugs are present in the body;
some, especially those affecting the absorption of oral drugs,
occur when the interacting drugs are taken at or near the same
time. The basic cause of many drug–drug interactions is altered
drug metabolism. For example, drugs metabolized by the same
enzymes compete for enzyme binding sites, and there may not
be enough binding sites for two or more drugs. Also, some drugs
induce or inhibit the metabolism of other drugs. Protein bind-
ing is also the basis for some important drug–drug interactions.
Interactions that can increase the therapeutic or adverse
effects of drugs include the following:
• Additive effects, which occur when two drugs with simi-
lar pharmacologic actions are taken (e.g., ethanol + sed-
ative drug increases sedative effects)
• Synergism, which occurs when two drugs with different
sites or mechanisms of action produce greater effects when
taken together (e.g., acetaminophen [nonopioid analgesic]
+ codeine [opioid analgesic] increases analgesic effects)
• Interference by one drug with the metabolism of a sec-
ond drug, which may result in intensied effects of the
second drug. For example, cimetidine inhibits CYP1A,
2C, and 3A drug-metabolizing enzymes in the liver
and therefore interferes with the metabolism of many
drugs (e.g., benzodiazepine antianxiety and hypnotic
drugs, several cardiovascular drugs). When these drugs
are given concurrently with cimetidine, they are likely
to cause adverse and toxic effects because blood levels
of the drugs are higher. The overall effect is the same
as taking a larger dose of the drug whose metabolism is
inhibited or slowed.
• Displacement (i.e., a drug with a strong attraction to
protein-binding sites may displace a less tightly bound
drug) of one drug from plasma protein-binding sites by
a second drug, which increases the effects of the displaced
drug. This increase occurs because the displaced drug,
freed from its bound form, becomes pharmacologically
active. The overall effect is the same as taking a larger
dose of the displaced drug. For example, aspirin displaces
warfarin and increases the drug’s anticoagulant effects.
Interactions in which drug effects are decreased include the
following:
• An antidote drug, which can be given to antagonize the
toxic effects of another drug. For example, naloxone is
commonly used to relieve respiratory depression caused
by morphine and related drugs. Naloxone molecules dis-
place morphine molecules from their receptor sites on
nerve cells in the brain so that the morphine molecules
cannot continue to exert their depressant effects
Decreased intestinal absorption of oral drugs, which
occurs when drugs combine to produce nonabsorbable
compounds. For example, drugs containing aluminum,
calcium, or magnesium bind with oral tetracycline (if
taken at the same time) to decrease its absorption and
therefore its antibiotic effect.
• Activation of drug-metabolizing enzymes in the liver, which
increases the metabolism rate of any drug metabolized
mainly by that group of enzymes and therefore decreases
the drug’s effects. Several drugs (e.g., phenytoin, rifampin)
and cigarette smoking are known enzyme inducers.
Patient-Related Variables
Age
The effects of age on drug action are especially important in
neonates, infants, and older adults. In children, drug action
depends largely on age and developmental stage.
During pregnancy, drugs cross the placenta and may harm the
fetus. Fetuses have no effective mechanisms for eliminating drugs
because their liver and kidney functions are immature. Newborn
infants (birth to 1 month) also handle drugs inefciently. Drug
distribution, metabolism, and excretion differ markedly in neo-
nates, especially premature infants, because their organ systems
are not fully developed. Older infants (1 month to 1 year) reach
approximately adult levels of protein binding and kidney function,
but liver function and the blood–brain barrier are still immature.
Children (1–12 years) have a period of increased activity
of drug-metabolizing enzymes so that some drugs are rapidly
metabolized and eliminated. Although the onset and dura-
tion of this period are unclear, a few studies have been done
with particular drugs. Theophylline, for example, is eliminated
much faster in a 7-year-old child than in a neonate or adult
(18–65 years). After about 12 years of age, healthy children
handle drugs similarly to healthy adults.
In older adults (65 years and older), physiologic changes
may alter all pharmacokinetic processes. Changes in the GI
tract include decreased gastric acidity, decreased blood ow, and
decreased motility. Despite these changes, however, there is lit-
tle difference in drug absorption. Changes in the cardiovascular
system include decreased cardiac output and therefore slower dis-
tribution of drug molecules to their sites of action, metabolism,
and excretion. In the liver, blood ow and metabolizing enzymes
are decreased. Thus, many drugs are metabolized more slowly,
have a longer action, and are more likely to accumulate with
chronic administration. In the kidneys, there is decreased blood
ow, decreased glomerular ltration rate, and decreased tubular
secretion of drugs. All these changes tend to slow excretion and
promote accumulation of drugs in the body. Impaired kidney and
liver function greatly increase the risks of adverse drug effects. In
addition, older adults are more likely to have acute and chronic
illnesses that require the use of multiple drugs or long-term drug
therapy. Thus, possibilities for interactions among drugs and
between drugs and diseased organs are greatly multiplied.
Body Weight
Body weight affects drug action mainly in relation to dose. The
ratio between the amount of drug given and body weight inu-
ences drug distribution and concentration at sites of action. In general, people who are heavier than average may need
larger doses, provided that their renal, hepatic, and cardiovascular
functions are adequate. Recommended doses for many drugs are
listed in terms of grams or milligrams per kilogram of body weight.
Genetic and Ethnic Characteristics
Drugs are given to cause particular effects in recipients.
However, when given the same drug in the same dose, by the
same route, and in the same time interval, some people expe-
rience inadequate therapeutic effects and others experience
 unusual or exaggerated effects, including increased  toxicity.
These variations in drug response are often attributed to
genetic or ethnic differences in drug metabolism.
Genetics
Genes determine the types and amounts of proteins produced
in body cells and thereby control both the physical and chemi-
cal functions of the cells. When most drugs enter the body, they
interact with proteins (e.g., in plasma, tissues, cell membranes,
drug receptor sites) to reach their sites of action, and they inter-
act with other proteins (e.g., drug-metabolizing enzymes in the
liver and other organs) to be biotransformed and eliminated
from the body. Genetic characteristics that alter any of these
proteins can alter drug responses. For example, metabolism of
isoniazid, an antitubercular drug, requires the enzyme acetyl-
transferase. People may metabolize isoniazid rapidly or slowly,
depending largely on genetic differences in acetyltransferase
activity. Clinically, rapid metabolizers may need larger-than-
usual doses to achieve therapeutic effects, and slow metaboliz-
ers may need smaller-than-usual doses to avoid toxic effects.
In addition, several genetic variations (called polymorphisms)
of the CYP450 drug-metabolizing enzymes have been identied.
Specic variations may inuence any of the chemical processes by
which drugs are metabolized. For example, CYP2D6 metabolizes
several antidepressant, antipsychotic, and beta-blocker drugs.
Some Caucasians (about 7%) metabolize these drugs poorly and
are at increased risk for drug accumulation and adverse effects.
CYP2C19 metabolizes diazepam, omeprazole, and some antide-
pressants. As many as 15% to 30% of Asians may metabolize these
drugs poorly and develop adverse effects if dosage is not reduced.
Still another example of genetic variation in drug metabo-
lism is that some people are decient in glucose-6-phosphate
dehydrogenase, an enzyme normally found in red blood cells
and other body tissues. These people may have hemolytic ane-
mia when given antimalarial drugs, sulfonamides, analgesics,
antipyretics, and other drugs.
The study of genetic variations (e.g., gene mutations that
produce changes in structure and function of drug-metabolizing
enzymes) that result in interindividual differences in drug
response is called pharmacogenetics. Research has increased
with awareness that genetic and ethnic characteristics are
important factors and that diverse groups must be included in
clinical trials. There is also increased awareness that each per-
son is genetically unique and must be treated as an individual
rather than as a member of a particular ethnic group. Research
is ongoing toward improving drug safety and “personalized
medicine,” in which prescribers can use a patient’s genetic
characteristics to design a drug therapy regimen to maximize
the therapeutic effects and minimize the adverse effects.
Genetic testing to determine a person’s reaction to drug
therapy is increasing, but clinical use is limited. Much research
is being done in this area, especially related to cardiovascular
and anticancer drugs (see the discussion of pharmacogenetics).
Ethnicity
Most drug information has been derived from clinical drug tri-
als using white men. Interethnic variations became evident
when drugs and dosages developed for Caucasians produced
unexpected responses, including toxicity, when given to peo-
ple from other ethnic groups. One common variation is that
African Americans respond differently to some cardiovascular
drugs. For example, for African Americans with hypertension,
angiotensin-converting enzyme (ACE) inhibitors and beta-
adrenergic blocking drugs are less effective and diuretics and
calcium channel blockers are more effective. Also, African
Americans with heart failure seem to respond better to a com-
bination of hydralazine and isosorbide than do Caucasian
patients with heart failure.
Another variation is that Asians usually require much smaller
doses of some commonly used drugs, including beta-blockers
and several psychotropic drugs (e.g., alprazolam, an antianxiety
agent, and haloperidol, an antipsychotic). Some documented
interethnic variations are included in later chapters.
Gender
Most drug-related research has involved men, and the results
have been extrapolated to women, sometimes with adjust-
ment of dosage based on the usually smaller size and weight
of women. Historically, gender was considered a minor inu-
ence on drug action except during pregnancy and lactation.
Now, differences between men and women in responses to drug
therapy are being increasingly identied, and since 1993, regu-
lations require that major clinical drug trials include women.
However, data on drug therapy in women are still limited.
Some identied differences include the following:
• Women who are depressed are more likely to respond to
the selective serotonin reuptake inhibitors (SSRIs), such
as uoxetine (Prozac), than to the tricyclic antidepres-
sants (TCAs), such as amitriptyline (Elavil).
• Women with anxiety disorders may respond less well
than men to some antianxiety medications.
• Women with schizophrenia seem to need smaller doses
of antipsychotic medications than men. If given the
higher doses required by men, women are likely to have
adverse drug reactions.
• Women may obtain more pain relief from opioid anal-
gesics (e.g., morphine) and less relief from nonopioid
analgesics (e.g., acetaminophen, ibuprofen), compared
with men.
Different responses in women are usually attributed
to anatomic and physiologic differences. In addition to
smaller size and weight, for example, women usually have
a higher percentage of body fat, less muscle tissue, smaller
blood volume, and other characteristics that may inuence
responses to drugs. In addition, women have hormonal uc-
tuations during the menstrual cycle. Altered responses have been demonstrated in some women taking clonidine, an
 antihypertensive;  lithium, a mood-stabilizing agent; phe-
nytoin, an anticonvulsant; propranolol, a beta- adrenergic
blocking drug used in the management of hypertension,
angina pectoris, and migraine; and antidepressants. In
addition, a signicant percentage of women with arthri-
tis, asthma, depression, diabetes mellitus, epilepsy, and
migraine experience increased symptoms premenstrually.
The increased symptoms may indicate a need for adjustments
in their drug therapy regimens. Women with clinical depres-
sion, for example, may need higher doses of antidepressant
medications premenstrually, if symptoms exacerbate, and
lower doses during the rest of the menstrual cycle.
There may also be differences in pharmacokinetic processes,
although few studies have been done. With absorption, it has
been noted that women absorb a larger percentage of an oral
dose of two cardiovascular medications than men (25% more
verapamil and 40% more aspirin). With distribution, women
may have higher blood levels of medications that distribute
into body uids (because of the smaller amount of water in
which the medication can disperse) and lower blood levels of
medications that are deposited in fatty tissues (because of the
generally higher percentage of body fat), compared with men.
With metabolism, the CYP3A4 enzyme metabolizes more
medications than other enzymes, and women are thought to
metabolize the drugs processed by this enzyme 20% to 40%
faster than men (and therefore may have lower blood lev-
els than men of similar weight given the same doses). The
CYP1A2 enzyme is less active in women so that women who
take the cardiovascular drugs clopidogrel or propranolol may
have higher blood levels than men (and possibly greater risks
of adverse effects if given the same doses as men). With excre-
tion, renally excreted medications may reach higher blood
levels because a major mechanism of drug elimination, glo-
merular ltration, is approximately 20% lower in women.
In general, women given equal dosages or equal weight-
based dosages are thought to be exposed to higher concentra-
tions of medications compared to men. Although available
data are limited, the main reasons postulated for the gender dif-
ferences are that women have a lower volume of distribution,
lower glomerular ltration, and lower hepatic enzyme activ-
ity (except for the medications metabolized by the CYP3A4
enzyme system, which is more active in women). As a result,
all women should be monitored closely during drug therapy
because they are more likely to experience adverse drug effects
than are men.
Other Considerations
Preexisting Conditions
Various pathologic conditions may alter some or all pharma-
cokinetic processes and lead to decreased therapeutic effects
or increased risks of adverse effects. Examples include the
following:
• Cardiovascular disorders (e.g., myocardial infarction,
heart failure, hypotension), which may interfere with all
pharmacokinetic processes, mainly by decreasing blood
ow to sites of drug administration, action, metabolism
(liver), and excretion (kidneys
 GI disorders (e.g., vomiting, diarrhea, inammatory
bowel disease, trauma or surgery of the GI tract), which
may interfere with absorption of oral drugs
• Hepatic disorders (e.g., hepatitis, cirrhosis, decreased
liver function), which mainly interfere with metabolism.
Severe liver disease or cirrhosis may interfere with all
pharmacokinetic processes.
• Renal disorders (e.g., acute or chronic renal failure),
which mainly interfere with excretion. Severe kidney
disease may interfere with all pharmacokinetic processes.
• Thyroid disorders, which mainly affect metabolism.
Hypothyroidism slows metabolism, prolonging drug
action and slowing elimination. Hyperthyroidism accel-
erates metabolism, shortening drug action and hastening
elimination.
Psychological Factors
Psychological considerations inuence individual responses
to drug administration, although specic mechanisms are
unknown. An example is the placebo response. A placebo is
a pharmacologically inactive substance. Placebos are used in
clinical drug trials to compare the medication being tested with
a “dummy” medication. Recipients often report both therapeu-
tic and adverse effects from placebos.
Attitudes and expectations related to drugs in general,
a particular drug, or a placebo inuence patient response.
They also inuence compliance or the willingness to carry out
the prescribed drug regimen, especially with long-term drug
therapy.
Tolerance and Cross-Tolerance
Drug tolerance occurs when the body becomes accustomed to
a particular drug over time so that larger doses must be given
to produce the same effects. Tolerance may be acquired to the
pharmacologic action of many drugs, especially opioid analge-
sics, alcohol, and other CNS depressants. Tolerance to phar-
macologically related drugs is cross-tolerance. For example,
a person who regularly drinks large amounts of alcohol becomes
able to ingest even larger amounts before becoming intoxi-
cated—this is tolerance to alcohol. If the person is then given
sedative-type drugs or a general anesthetic, larger-than-usual
doses are required to produce a pharmacologic effect—this is
cross-tolerance.
Tolerance and cross-tolerance are usually attributed to
activation of drug-metabolizing enzymes in the liver, which
accelerates drug metabolism and excretion. They also are
attributed to decreased sensitivity or numbers of receptor
sites.
 Adverse Eects of Drugs
As used in this book, the term “adverse effects” refers to
any undesired responses to drug administration, as opposed
to therapeutic effects, which are desired responses. Most
drugs produce a mixture of therapeutic and adverse effects;
all drugs can produce adverse effects. Adverse effects may
produce essentially any symptom or disease process and may involve any body system or tissue. They may be common or
rare, mild or severe, localized or widespread—depending on
the drug and the recipient. Some adverse effects occur with
usual therapeutic doses of drugs (often called side effects);
most are more likely to occur and to be more severe with high
doses. Box 2.4 describes common or serious adverse effects.
Although adverse effects may occur in anyone who takes
medications, they are especially likely to occur with some
drugs (e.g., insulin, warfarin) and in older adults, who often
take multiple drugs.
Black Box Warnings
For some drug groups and individual drugs that may cause
serious or life-threatening adverse effects, the Food and Drug
Administration (FDA) requires drug manufacturers to place
a BLACK BOX WARNING (BBW)
 on the label of a
prescription drug or in the literature describing it. A BBW
is usually added after a signicant number of serious adverse
effects have occurred, often several years after a drug is rst
marketed and after it has been used in large numbers of peo-
ple. The BBW is the strongest warning that the FDA can give
consumers and often includes prescribing or monitoring infor-
mation intended to improve the safety of using the particular
drug or drug group. In recent years, BBWs have been added to antidepressant drugs, nonopioid analgesics, and the antiu
drug oseltamivir (Tamiu).
Common or Serious Adverse Drug Eects
Central Nervous System Eects
Central nervous system (CNS) eects may result from CNS
stimulation (e.g., agitation, confusion, disorientation, hal-
lucinations, psychosis, seizures) or CNS depression (e.g.,
impaired level of consciousness, sedation, coma, impaired
respiration and circulation). CNS eects may occur with
many drugs, including most therapeutic groups, sub-
stances of abuse, and over-the-counter preparations.
Gastrointestinal Eects
Gastrointestinal (GI) eects (e.g., nausea, vomiting, con-
stipation, diarrhea) commonly occur. Nausea and vomiting
occur with many drugs as a result of local irritation of the
GI tract or stimulation of the vomiting center in the brain.
Diarrhea occurs with drugs that cause local irritation or
increase peristalsis. More serious eects include bleeding
or ulceration (most often with nonsteroidal anti-inamma-
tory agents such as ibuprofen) and severe diarrhea/colitis
(most often with antibiotics).
Hematologic Eects
Hematologic eects (excessive bleeding, clot formation
[thrombosis], bone marrow depression, anemias, leukopenia,
agranulocytosis, thrombocytopenia) are relatively common
and potentially life threatening. Excessive bleeding is often
associated with anticoagulants and thrombolytics; bone mar-
row depression is associated with anticancer drugs.
Hepatic Eects
Hepatic eects (hepatitis, liver dysfunction or failure, biliary
tract disorders) are potentially life threatening. The liver is
especially susceptible to drug-induced injury because most
drugs are circulated to the liver for metabolism and some
drugs are toxic to liver cells. Hepatotoxic drugs include acet-
aminophen (Tylenol), isoniazid (INH), methotrexate (Trexall),
phenytoin (Dilantin), and aspirin and other salicylates. In
the presence of drug- or disease-induced liver damage, the
metabolism of many drugs is impaired. Besides hepatotoxic-
ity, many drugs produce abnormal values in liver function
tests without producing clinical signs of liver dysfunction.
Nephrotoxicity
Nephrotoxicity (nephritis, renal insu ciency or failure)
occurs with several antimicrobial agents (e.g., gentamicin
and other aminoglycosides), nonsteroidal anti-inamma-
tory agents (e.g., ibuprofen and related drugs), and others.
It is potentially serious because it may interfere with
drug excretion, thereby causing drug accumulation and
increased adverse eects.
Hypersensitivity
Hypersensitivity or allergy may occur with almost any
drug in susceptible patients. It is largely unpredictable and
unrelated to dose. It occurs in those who have previously been exposed to the drug or a similar substance (antigen)
and who have developed antibodies. When readministered,
the drug reacts with the antibodies to cause cell damage and
the release of histamine and other substances. These sub-
stances produce reactions ranging from mild skin rashes
to anaphylactic shock. Anaphylactic shock is a life-threat-
ening hypersensitivity reaction characterized by respiratory
distress and cardiovascular collapse. It occurs within a few
minutes after drug administration and requires emergency
treatment with epinephrine. Some allergic reactions (e.g.,
serum sickness) occur 1 to 2 weeks after the drug is given.
Drug Fever
Drugs can cause fever by several mechanisms, including
allergic reactions, damaging body tissues, interfering with
dissipation of body heat, or acting on the temperature-
regulating center in the brain. The most common mechanism
is an allergic reaction. Fever may occur alone or with other
allergic manifestations (e.g., skin rash, hives, joint and mus-
cle pain, enlarged lymph glands, eosinophilia). It may begin
within hours after the rst dose if the patient has taken the
drug before or within about 10 days of continued adminis-
tration if the drug is new to the patient. If the causative drug
is discontinued, fever usually subsides within 48 to 72 hours
unless drug excretion is delayed or signicant tissue damage
has occurred (e.g., hepatitis). Many drugs have been impli-
cated as causes of drug fever, including most antimicrobials.
Idiosyncrasy
Idiosyncrasy refers to an unexpected reaction to a drug
that occurs the rst time it is given. These reactions are
usually attributed to genetic characteristics that alter the
person’s drug-metabolizing enzymes.
Drug Dependence
Drug dependence may occur with mind-altering drugs, such
as opioid analgesics, sedative-hypnotic agents, antianxiety
agents, and CNS stimulants. Dependence may be physiologic
or psychological. Physiologic dependence produces unpleas-
ant physical symptoms when the dose is reduced or the drug
is withdrawn. Psychological dependence leads to excessive
preoccupation with drugs and drug-seeking behavior.
Carcinogenicity
Carcinogenicity is the ability of a substance to cause
cancer. Several drugs are carcinogens, including some hor-
mones and anticancer drugs. Carcinogenicity apparently
results from drug-induced alterations in cellular DNA.
Teratogenicity
Teratogenicity is the ability of a substance to cause abnor-
mal fetal development when taken by pregnant women.
Drug groups considered teratogenic include antiepileptic
drugs and “statin” cholesterol-lowering drugs.
Pregnancy Categories
In 1979, the FDA assigned pregnancy categories to identify risk
of fetal injury from drugs used as directed by the mother during
pregnancy. The categories range from A (safest) to X (known
danger). The categories do not account for potential harm from
drugs or their metabolites found in breast milk.Five categories are identied:
• Category A. Risk to the fetus in the rst trimester (and
in later trimesters) has not been demonstrated in well-
controlled studies in pregnant women.
• Category B. Animal reproduction studies have not
demonstrated risk to the fetus, and there are no well-
controlled studies in pregnant women.
• Category C. Animal reproduction studies have not dem-
onstrated risk to the fetus, and there are no well-contro
studies in pregnant women; however, potential benets
may outweigh potential risk in use of drug in pregnant
women.
• Category D. Evidence of risk to the fetus has been demon-
strated. However, the benets may outweigh risk in pregnant
women if the drug is needed in a life-threatening situation
and other safer drugs cannot be used or are ineffective.
• Category X. Studies in humans or animals have demon-
strated fetal abnormalities or evidence of fetal risk, and
the risk clearly outweighs the benet. The drug is con-
traindicated in women who are pregnant or in those who
may become pregnant.
The Drugs at a Glance tables in this book give the pregnancy
category for each listed drug.
Toxicology: Drug Overdose
Drug toxicity (also called poisoning or overdose) results from
excessive amounts of a drug and may damage body tissues. It
is a common problem in both adult and pediatric populations.
It may result from a single large dose or prolonged ingestion
of smaller doses. Toxicity may involve alcohol or prescription,
over-the-counter, or illicit drugs. Clinical manifestations are
often nonspecic and may indicate other disease processes.
Because of the variable presentation of drug intoxication,
health care providers must have a high index of suspicion so
that toxicity can be rapidly recognized and treated.
When toxicity occurs in a home or outpatient setting and
the victim is collapsed or not breathing, call 911 for emergency
aid. If the victim is responsive, someone needs to contact the
National Poison Control Center by phone at 1-800-222-1222.
The caller is connected to a local Poison Control Center and,
if possible, needs to tell the responding pharmacist or physician
the name of the drug or substance that was taken as well as the
amount and time of ingestion. The poison control consultant
may recommend treatment measures over the phone or taking
the victim to a hospital emergency department.
It is possible that the patient or someone else may know the
toxic agent (e.g., accidental overdose of a therapeutic drug, use
of an illicit drug, a suicide attempt). Often, however, multiple
drugs have been ingested, the causative drugs are unknown, and
the circumstances may involve traumatic injury or impaired
mental status that make the patient unable to provide use-
ful information. The main goals of treatment are starting
treatment as soon as possible after drug ingestion, supporting
and  stabilizing vital functions, preventing further damage from
the toxic agent by reducing absorption or increasing elimina-
tion, and administering antidotes when available and indicated.
Box 2.5 describes general aspects of care, Table 2.1 lists selected
antidotes, and relevant chapters discuss specic aspects of care.
Most overdosed patients are treated in emergency departments
and discharged to their homes. A few are admitted to intensive
care units (ICUs), often because of unconsciousness and the
need for endotracheal intubation and mechanical ventilation.
Unconsciousness is a major toxic effect of several commonly
ingested substances such as benzodiazepine antianxiety and seda-
tive agents, TCAs, ethanol, and opioid analgesics. Serious car-
diovascular effects (e.g., cardiac arrest, dysrhythmias, circulatory
impairment) are also common and warrant admission to an ICU.
General Management of Toxicity
he rst priority is support of vital functions, as
indicated by rapid assessment of vital signs and level
of consciousness. In serious poisonings, an electrocar-
diogram is indicated, and ndings of severe toxicity
(e.g., dysrhythmias, ischemia) justify aggressive treat-
ment. Standard cardiopulmonary resuscitation (CPR)
measures may be needed to maintain breathing and
circulation. An intravenous (IV) line is usually needed
to administer uids and drugs, and invasive treatment
or monitoring devices may be inserted.
Endotracheal intubation and mechanical ventilation
are often required to maintain breathing (in unconscious
patients), correct hypoxemia, and protect the airway.
Hypoxemia must be corrected quickly to avoid brain
injury, myocardial ischemia, and cardiac dysrhythmias.
Serious cardiovascular manifestations often require
drug therapy. Hypotension and hypoperfusion may be
treated with inotropic and vasopressor drugs to increase
cardiac output and raise blood pressure. Dysrhythmias
are treated according to Advanced Cardiac Life Support
(ACLS) protocols.
Recurring seizures or status epilepticus requires treat-
ment with anticonvulsant drugs.
 •
For unconscious patients, as soon as an IV line is
established, some authorities recommend a dose of
naloxone (2 mg IV) for possible narcotic overdose and
thiamine (100 mg IV) for possible brain dysfunction
due to thiamine deciency. In addition,
a ngerstick blood glucose test should be done, and
if hypoglycemia is indicated, a 50% dextrose solution
(50 mL IV) should be given.
 •
After the patient is out of immediate danger, a thor-
ough physical examination and eorts to determine
the drug(s), the amounts, and the time lapse since
exposure are needed. If the patient is unable to supply
needed information, anyone else who may be able to
do so should be interviewed. It is necessary to ask
about the use of prescription and over-the-counter
drugs, alcohol, and illicit substances.
 •
There are no standard laboratory tests for poisoned
patients, but baseline tests of liver and kidney
function are usually indicated. Screening tests for
toxic substances are not very helpful because test
results may be delayed, many substances are not
detected, and the results rarely aect initial treatment.
Specimens of blood, urine, or gastric uids may be
obtained for laboratory analysis. Serum drug levels
are needed when acetaminophen, alcohol, aspirin,
digoxin, lithium, or theophylline is known to be an
ingested drug, to assist with treatment.
 •
For most orally ingested drugs, the initial and major
treatment is a single dose of activated charcoal.
Sometimes called the “universal antidote,” it is useful
in many poisonings because it adsorbs many toxins and
rarely causes complications. When given within
30 minutes of drug ingestion, it decreases absorption of
the toxic drug by about 90%; when given an hour
after ingestion, it decreases absorption by about 37%.
Activated charcoal (1 g/kg of body weight or 50–100 g)
is usually mixed with 240 mL of water (25–50 g in
120 mL of water for children) to make a slurry, which
is gritty and unpleasant to swallow. It is often given by
nasogastric tube. The charcoal blackens subsequent
bowel movements. If used with whole bowel irrigation
(WBI; see below), activated charcoal should be given
before the WBI solution is started. If given during WBI,
the binding capacity of the charcoal is decreased. Acti-
vated charcoal does not signicantly decrease absorp-
tion of some drugs (e.g., ethanol, iron, lithium, metals).
Multiple doses of activated charcoal may be given
in some instances (e.g., ingestion of sustained-release
drugs). One regimen is an initial dose of 50 to 100 g,
then 12.5 g every 1, 2, or 4 to 6 hours for a few doses.
Adverse eects of activated charcoal include pulmo-
nary aspiration and bowel obstruction from impaction of
the charcoal–drug complex.
QSEN Safety Alert
To prevent these eects, unconscious patients
should not receive activated charcoal until the
airway is secure against aspiration, and many
patients are given a laxative (e.g., sorbitol) to aid
removal of the charcoal–drug complex.
Ipecac-induced vomiting and gastric lavage are no
longer routinely used because of minimal eectiveness
and potential complications. Ipecac is no longer recom-
mended to treat poisonings in children in home settings;
parents should call a poison control center or a health
care provider. Gastric lavage may be benecial in serious
overdoses if performed within an hour of drug ingestion.
If the ingested agent delays gastric emptying (e.g., drugs
with anticholinergic eects), the 1-hour time limit for
gastric lavage may be extended. When used after inges-
tion of pills or capsules, the tube lumen should be large
enough to allow removal of pill fragments.
 •
WBI with a polyethylene glycol solution (e.g., Colyte)
may be used to remove toxic ingestions of long-act-
ing, sustained-release drugs (e.g., many beta-blockers,
calcium channel blockers, and theophylline prepara-
tions); enteric-coated drugs; and toxins that do not
bind well with activated charcoal (e.g., iron, lithium).
It may also be helpful in removing packets of illicit
drugs, such as cocaine or heroin. When used, 500 to
2000 mL/h are given orally or by nasogastric tube
until bowel contents are clear. Vomiting is the most
common adverse eect. WBI is contraindicated in
patients with serious bowel disorders (e.g., obstruc-
tion, perforation, ileus), hemodynamic instability, or
respiratory impairment (unless intubated).
 •
Urinary elimination of some drugs and toxic metabo-
lites can be accelerated by changing the pH of urine
(e.g., alkalinizing with IV sodium bicarbonate for
salicylate overdose), diuresis, or hemodialysis. Hemo-
dialysis is the treatment of choice in severe lithium
and aspirin (salicylate) poisoning.
 •
Specic antidotes can be administered when available
and as indicated by the patient’s clinical condition.
Available antidotes vary widely in eectiveness. Some
are very eective and rapidly reverse toxic manifesta-
tions (e.g., naloxone for opioids, specic Fab frag-
ments for digoxin).
When an antidote is used, its half-life relative to the
toxin’s half-life must be considered. For example, the
half-life of naloxone, a narcotic antagonist, is relatively
short compared with the half-life of the longer-acting
opioids such as methadone, and repeated doses may
be needed to prevent recurrence of the toxic st