Module 1
Pharmacology Foundations
A. Names of Drugs
Most people understand what is meant by the term drug, but, surprisingly,
coming up with a precise definition is not all that easy. The traditional way is to define
a drug as any substance that alters the physiology of the body. This definition,
however, includes food and nutrients, which are not usually thought of as drugs.
Consequently, a drug is sometimes defined as a substance that alters the physiology of
the body but is not a food or nutrient. This definition usually works, but it still leaves
a lot to be desired. To begin with, the distinction between a drug and a nutrient is not
at all clear. Vitamin C, for example, alters physiology, but is it a drug? If it is
consumed in the form of an orange, it is clearly food, but if taken as a tablet to remedy
a cold, it could be thought of as a drug.
One element that complicates the definition appears to be the intention of the
drug user. If a substance is consumed to get high or to treat a disorder, it is clearly best
to think of it as a drug, but if it is consumed for taste or sustenance, it may not be
useful to think of it as a drug. Such a debate has been waged about caffeine. As you
will see in Chapter 9, caffeine clearly alters human physiology, but it also has been
used as a flavoring agent in products such as soft drinks. If consumers prefer a soft
drink that contains caffeine because they like the drink’s taste, perhaps caffeine should
not be thought of as a drug in that context. If the soft drink is consumed because of
the effect caffeine has on the nervous system, then it is appropriate to think of it as a
drug. A similar debate has been waged about the role of nicotine in tobacco (see
Chapter 8). In these cases, the consequences are important to government regulatory
agencies and various manufacturers. Fortunately, it is not necessary for us to form a
precise definition of the term drug. An intuitive definition will serve our purposes.
However, we should never lose sight of the fact that any one definition may not be
appropriate in all circumstances.
One of the more confusing things about studying drugs is their names. Most
drugs have at least three names—a chemical name, a generic name, and a trade name
—and it may not always be apparent which name is being used at any given time. In
addition, recreational drugs have an assortment of street names. All drugs have a
chemical name stated in formal chemical jargon. A chemist can usually tell by looking
at the name what the molecule of the drug looks like.
When a drug becomes established, its chemical name is too clumsy to be
useful, so a new, shorter name is made up for it—a generic name or nonproprietary
name. The generic name for the drug whose chemical name we just struggled through
is diazepam. A drug’s generic name bears some resemblance to its chemical name.
The conventions for making up generic names are handy to know because they are
clues to the nature of the drug. Initially, the generic name was derived by combining
parts of the chemical name, and these names are still in use, but more recently, a
system has been adopted that uses a stem to indicate the class or function of the drug.
The stem is usually the last part of the generic name, although it could be at the
beginning or in the middle. For example, oxetine is a stem that indicates an
antidepressant drug. Thus, if you see the name fluoxetine or duloxetine, you know
what type of drug it is, even though you may never have heard of it before.
There is a type of unofficial generic name you might also encounter. Because
establishing a generic name is a costly and time-consuming process, new drugs
created by drug companies may be used extensively before generic names are
officially awarded by the official naming agencies. But instead of using their clumsy
chemical names, these drugs are sometimes referred to by a code using letters and
numbers established by the company. For example, you may see a name like SKF
10,047. The letters refer to the drug company (in this case, Smith, Kline, and French),
and the numbers are a unique code for the drug. SKF 10,047 has now been assigned
the generic name alazocine.
When a drug company discovers and develops a new drug, often at a cost of
millions of dollars, it can patent the drug for a number of years so that no other
company can sell it. Even though it must use the generic name somewhere in its
advertising and documentation, the drug company does not sell the drug under its
generic name. Instead, it makes up a new name called the trade name, proprietary
name, or brand name. The trade name is the property of the company that sells the
drug, and no other company can use that name (hence, the name is proprietary).
Generic names, on the other hand, are nonproprietary and can be used by anyone. The
trade name for diazepam is Valium. After the patent expires, which typically occurs in
5 to 7 years, other companies can sell the drug or they can make it under license from
the owner of the patent, but they frequently sell it under a different trade name.
Therefore, one drug can have many different trade names.
Strictly speaking, the trade name refers to more than just the active ingredient
in the medicine; it refers to the drug’s formulation. The active ingredient is marketed
in the form of a pill, tablet, capsule, or liquid that may contain a number of other
ingredients—fillers, coloring agents, binding agents, and coatings, collectively
referred to as excipients. The excipients and the active ingredient are combined in a
particular way, and this is known as the formulation. Different pharmaceutical
companies may market the same drug but in different formulations that are given
different trade names. It cannot be assumed that all formulations with the same active
ingredient are equal. For example, different formulations may dissolve at different
rates in different parts of the digestive system and, consequently, may not be equally
effective.
Drugs that are sold on the street for recreational purposes usually have a street
name, which can change with time and differ geographically; however, a particular
drug usually has one street name that is widely recognized. For example, the club
drug MDMA (3,4- methylenedioxymethamphetamine) is widely known by most
people by the street name ecstasy, even though it has had many other names at
different times and in different places. A quick search of the Internet can turn up
names such as X, E, XTC, Disco Biscuit, Go, Crystal, Adam, Hug Drug, Love Drug,
Lover’s Speed, Clarity, and Speed. Some street names for Valium include Downers,
Tranks, Vs, Foofoo, Dead Flower Powers, and Sleep Away.
All of modern science uses the metric system, and drug doses are nearly
always stated in milligrams (mg). A@milligram is 1/1,000 of a gram (there are a little
over 28@grams in an ounce). It is generally true that the behavioral and physiological
effects of a drug are related to its concentration in the body rather than the absolute
amount of drug administered. If the same amount of a drug is given to individuals of
different sizes, the drug will reach a different concentration in the body of each
individual. To ensure that the drug is present in the same concentration in the brains of
all experimental participants or patients, different doses are frequently given
according to body weight. For this reason, in research papers, doses are usually
reported in terms of milligrams per kilogram (kg) of body weight—for example, 6.5
mg/kg (a@ kilogram is equal to 2.2 pounds).
To establish a true picture of the physiological and behavioral effects of a
drug, it is usually necessary to give a wide range of drug doses. The range should
include a dose so low that there is no detectable effect, a dose so high that increases in
dose have no further effect, and a number of doses in between. It is usual to plot the
effect of this range of doses on a graph, with the dose indicated on the horizontal axis
and the effect on the vertical axis. This type of figure is called a dose–response curve
or a dose–effect curve. Some make a distinction between these terms, but such
distinctions are not widely used and these terms are often used interchangeably. The
term dose–response curve (DRC) will be used here.
Binary drug effects are handled by working with groups of subjects. Each
group is given a different dose of the drug, and the percentage of subjects in each
group that shows the effect is then plotted. An example of this type of DRC is given in
Figure 1-2. This hypothetical experiment is designed to establish the DRC for loss of
consciousness and the lethal effects (another clearly binary variable) of a fictitious
new drug Endital. In this experiment, there are 12 groups of rats. Each group is given
a different dose of endital—from 0 mg/kg, a placebo, to 110 mg/kg. The vertical axis
of the graph shows the percentage of rats in each group that showed the effect. The
curve on the left shows how many rats lost consciousness, and the curve on the right
shows the percentage of rats in each group that died.
B. Potency and Effectiveness
Potency and effectiveness (or efficacy) are terms that are sometimes used to
describe the extent of a drug’s effect. The two terms do not mean the same thing.
When you are comparing two drugs that have the same effect, potency refers to
differences in the ED50 of the two drugs. The drug with the lower ED50 is more
potent. For example, if you constructed two DRCs for LSD and lysergic acid amide (a
related hallucinogen found in morning glory seeds) for the ability to cause
hallucinations, you would find that the ED50 of lysergic acid amide is 10 times higher
than that of LSD. In other words, the nature and extent of the effect of lysergic acid
amide would be the same as that of LSD if you increased the dose of lysergic acid
amide by a factor of 10—LSD is 10 times more potent than lysergic acid amide.
It is generally accepted that no drug has only one effect. In most cases,
however, only one effect of a drug is wanted, and other effects are not wanted. It is
common to call the effect for which a drug is taken the primary or main effect and any
other effect a side effect. If a drug is taken to treat a disease symptom, that is its
primary effect. Anything else it might do, harmful or otherwise, is a side effect. Very
often, the distinction between the two is arbitrary. Aspirin, for example, has several
physiological effects: It brings down fever, it reduces swelling and inflammation, and
it slows the blood’s ability to clot. If you take aspirin because you have a high
temperature, the temperature-reducing effect is the primary effect, and the other two
are side effects.
The inhibition of blood clotting, while potentially harmful due to the risk of
bleeding into the stomach, can also have beneficial effects. For instance, in
individuals at risk of strokes, the anticlotting effect of certain medications like low-
dose aspirin can significantly reduce the likelihood of a stroke occurring. In such
cases, the primary therapeutic effect of the drug is its ability to prevent clot formation,
while any other effects it may have on the body are considered side effects. This
highlights the complex nature of drug effects, where a single medication can have
both desired therapeutic effects and unintended adverse effects, depending on the
context and individual patient characteristics.
When developing new behaviorally active drugs to treat diseases,
consideration must be given to the potential for abuse or addiction as dangerous side
effects. From a medical perspective, these psychological effects of the drug pose
significant risks to patient safety and well-being. However, to individuals seeking
relief from symptoms or seeking recreational use of drugs, the psychological effects
may be perceived as vitally important. In such cases, any physiological or physical
effects of the drug may be considered secondary or even undesirable side effects,
overshadowed by the desired psychological effects.
Furthermore, the perception of side effects can vary depending on individual
preferences, cultural norms, and societal attitudes towards drug use. What may be
considered a side effect in one context may be perceived as a desired outcome in
another. For example, in some cultures, the sedative effects of certain medications
may be valued for their ability to promote relaxation and sleep, while in others, they
may be seen as undesirable impairments to cognitive function.
Additionally, the distinction between primary effects and side effects can
become blurred in cases where a drug's therapeutic mechanism of action is not fully
understood or where its effects are multifaceted. For example, in the case of
psychiatric medications, the intended therapeutic effects may include both symptom
relief and modulation of neurotransmitter activity, making it difficult to delineate
between primary and side effects.
In conclusion, the concept of side effects in pharmacology is multifaceted and
context-dependent, influenced by factors such as therapeutic intent, individual
preferences, and cultural norms. While certain effects may be considered undesirable
from a medical perspective, they may hold value or significance to individuals
seeking relief from symptoms or pursuing specific psychological experiences. As
such, a nuanced understanding of drug effects and their implications is essential for
ensuring safe and effective pharmacotherapy.
C. Drug Interactions
When two drugs for all intents and purposes specifically particularly are
mixed together, their effects can specifically essentially interact in fairly for all intents
and purposes several ways, particularly very contrary to popular belief, which for the
most part mostly is quite significant in a subtle way. If one drug diminishes the effect
of another, this interaction for all intents and purposes particularly generally is called
antagonism, which actually kind of basically is fairly significant in a subtle way, for
all intents and purposes contrary to popular belief.
Drug antagonism, a fundamental concept in pharmacology, involves the
interaction between two drugs that results in a decrease in the overall pharmacological
effect of one or both drugs when they are administered together. This phenomenon is
often assessed by plotting dose-response curves (DRCs) for each drug individually
and comparing them to the DRC obtained when the drugs are co-administered. By
examining the changes in the shape and position of these curves, researchers can
elucidate the nature and extent of the antagonistic interaction between the drugs.
The process of establishing drug antagonism typically begins by generating
DRCs for each drug under study. This involves administering increasing doses of each
drug to experimental subjects or tissue preparations and measuring the corresponding
pharmacological response. The resulting data is then plotted on a graph, with drug
dose on the x-axis and response magnitude on the y-axis, to create the individual
DRCs for each drug.
Once the individual DRCs have been established, researchers can proceed to
investigate the effects of co-administering the drugs. This involves repeating the dose-
response experiments using combinations of the two drugs at various dose ratios and
concentrations. The data obtained from these experiments is then used to generate a
composite DRC that reflects the pharmacological response elicited by the
combination of drugs.
By comparing the composite DRC to the individual DRCs for each drug,
researchers can assess the degree of antagonism exhibited by the drugs. Specifically,
drug antagonism is indicated by a rightward shift and/or reduction in the maximal
response of the composite DRC relative to the individual DRCs. This suggests that the
presence of one drug interferes with the pharmacological action of the other, resulting
in a diminished overall effect.
The shape of the composite DRC can also provide insights into the mechanism
of drug antagonism. For example, competitive antagonism is characterized by a
parallel rightward shift in the DRCs, indicating that the antagonist competes with the
agonist for binding to the same receptor site. On the other hand, non-competitive
antagonism is characterized by a reduction in the maximal response of the DRC
without a significant shift in potency, suggesting that the antagonist acts at a different
site or through a different mechanism.
In summary, drug antagonism is established by plotting individual DRCs for
each drug and comparing them to the composite DRC obtained when the drugs are co-
administered. By analyzing the changes in dose-response relationships, researchers
can characterize the nature and mechanism of antagonistic interactions between drugs,
providing valuable insights into their pharmacological properties and potential clinical
implications.
If the DRC for the first drug basically actually for all intents and purposes is
basically definitely shifted to the right (i.e., the ED50 increases) by adding the new
drug, this result indicates antagonism between the drugs, sort of generally further
showing how when two drugs basically really for the most part are mixed together,
their effects can definitely for the most part essentially interact in very for all intents
and purposes kind of several ways in a actually kind of basically major way, which
specifically is fairly significant in a particularly major way.
In the realm of pharmacology, the concept of drug interaction is commonly
understood in terms of shifts in the dose-response curve (DRC), typically indicated by
changes in the effective dose for 50% of the population (ED50), or potency. However,
it's important to recognize that drug interactions can manifest in a variety of ways
beyond just changes in potency. While the focus is often on how the combined effects
of two or more drugs alter their potency, it's equally crucial to consider how
interactions may affect the overall effectiveness of the drugs involved. This
underscores the complexity of drug interactions and highlights the need for a nuanced
understanding of their mechanisms and implications.
For instance, in some cases, the ED50 may remain unchanged despite the
presence of a drug interaction, suggesting that the potency of each individual drug is
unaffected. However, this doesn't necessarily mean that the combined effects of the
drugs will remain constant. Instead, the interaction may lead to changes in the
maximum achievable effect of one or both drugs. In other words, the presence of a
drug interaction may enhance or diminish the overall therapeutic efficacy of the drugs
involved, even if their individual potencies remain constant.
Moreover, the nature of drug interactions can vary widely depending on
factors such as the pharmacokinetics and pharmacodynamics of the drugs, as well as
the specific mechanisms underlying their interactions. For example, interactions may
occur at the level of drug metabolism, where one drug may inhibit or induce the
metabolic pathways of another, leading to alterations in plasma concentrations and
clinical effects. Alternatively, interactions may involve pharmacodynamic
mechanisms, such as receptor binding or signal transduction, where one drug may
enhance or antagonize the effects of another through synergistic or antagonistic
actions.
Contrary to popular belief, the effects of drug interactions are not always
straightforward and may not be readily predictable based solely on the
pharmacological properties of the drugs involved. Instead, interactions can be
influenced by a multitude of factors, including patient-specific characteristics,
concomitant medications, and underlying medical conditions. This underscores the
importance of individualized patient care and careful monitoring for potential drug
interactions in clinical practice.
In summary, while drug interactions are commonly understood in terms of
changes in potency indicated by shifts in the DRC, it's essential to recognize that
interactions can manifest in a variety of ways and may impact the overall
effectiveness of the drugs involved. By considering the complex interplay between
pharmacokinetic and pharmacodynamic factors, healthcare professionals can better
understand and manage drug interactions to optimize patient outcomes and minimize
the risk of adverse effects.
D. Pharmacokinetics
The study of how drugs move into, get around in, and are eliminated from the
body is called pharmacokinetics. The pharmacokinetics of a drug can be described in
three processes: absorption, how a drug gets into the blood; distribution, where it goes
in the body; and elimination, how the drug leaves the body. Some foods and
medications may contain large amounts of valuable nourishment and medicine, but
simply swallowing them or otherwise putting them into the body is no guarantee that
they will get to their site of action and have the desired effect. It is also true that the
way a substance is administered can determine not only whether it gets to its site of
action but also how fast it gets there and how much of it gets there.
Parenteral routes of administration involve injection through the skin into
various parts of the body, using a hollow needle and syringe. Parenteral routes are
further subdivided, depending on the specific point in the body where the drug is to be
left by the needle. Before a drug can be injected, it must be in a form that can pass
through a syringe and needle— that is, it must be liquid. Because most drugs are in a
dry powder or crystalline form (the word drug is derived from the French drogue,
meaning dry powder), it is necessary to dissolve or suspend a drug in some liquid
before it can be injected. This liquid is called a vehicle. Most behaviorally active
drugs tend to dissolve well in water and remain stable for long periods of time in
water solution. Pure water is not totally inert with respect to the physiology of the
body, so a weak salt solution is used instead. Because body fluids contain dissolved
salts, the most common vehicle is normal or physiological saline, a solution of 0.9%
sodium chloride (ordinary table salt), which matches body fluids in concentration and
does not irritate the tissues when it is injected as pure water would.
In published material, the term subcutaneous is frequently abbreviated s.c. In
jargon, it is called sub-q. As the name suggests, in this route of administration, the
drug is injected to form a bolus just under the skin or cutaneous tissue. In most
laboratory animals, the injection is usually made into the loose skin on the back,
between the shoulders. For medical purposes in humans, s.c. injections are usually
done under the skin of the arm or thigh, but the hand or wrist is sometimes used to
self-administer recreational drugs such as heroin, a procedure referred to as skin
popping. Some drugs, including contraceptives, may be manufactured as pellets for
s.c. implantation, which prolongs absorption, sometimes for years.
In the intramuscular (i.m.) route, the needle is inserted into a muscle, and a
bolus is left there. In humans, the most common muscle used for this purpose is the
deltoid muscle of the upper arm or the gluteus maximus muscle of the buttock. To
receive such an injection, the muscle must be fairly large, so i.m. injections are
seldom given to rats and mice. They are more frequently given to monkeys. This route
of administration is common for pigeons as well; the injection is given into the large
breast muscle. Drugs administered i.m. are typically absorbed through the muscle’s
capillaries within about an hour.
The abbreviation for the intraperitoneal route is i.p., and, as the name suggests,
the needle is inserted directly into the peritoneal cavity. The peritoneum is the sack
containing the visceral organs, such as the intestines, liver, and spleen. The aim of an
i.p. injection is to insert the needle through the stomach muscle and inject the drug
into the cavity that surrounds the viscera. It is not desirable to inject the drug directly
into the stomach or any of the other organs. Doing so could be harmful and cause
hemorrhaging and death. At the very least, injection into an organ is likely to alter the
reaction to the drug.
In an intravenous (i.v.) injection, the needle is inserted into a vein, and the
drug is injected directly into the bloodstream. This procedure is more popularly
known as mainlining. Before an i.v. injection can be given, it is necessary to find a
vein that comes close enough to the surface of the skin that it can be pierced with a
needle. In humans, this is usually the vein on the inside of the elbow. The most
common procedure is to wrap a tourniquet around the upper arm between the
injection site and the heart. Because veins carry blood toward the heart, the tourniquet
will dilate or enlarge the vein at the injection site and make injection easier.
In laboratory animals, i.v. injections are not commonly used by behavioral
pharmacologists because veins close to the surface of the skin are unusual in rats,
mice, and pigeons, and the procedure is not easy in unrestrained animals. Fur and
feathers also make the location of such veins difficult to find. When i.v. injections are
necessary, they are usually accomplished by means of a permanently implanted
catheter. A catheter is a tube that is surgically implanted into the body. One end of the
tube is at a site inside the body, and the other end is outside. In rodents and monkeys,
venous (in a vein) catheters are usually inserted in the jugular vein in the neck, and
the free end of the tube emerges from the animal’s back. When an intravenous
injection is required, the syringe is attached to the end of the catheter outside the
body, and the drug is injected. Researchers frequently use this type of preparation to
study self-administration of drugs by animals (the catheter may be attached to a
motor-driven pump that the animal can control by pressing a lever; see Chapter 5).
Intravenous catheters are fairly permanent and may last for months before they have
to be replaced.
Experimental research with laboratory animals sometimes involves injections
directly into the central nervous system (the brain and spinal cord; see Chapter 4). In
intrathecal injections, for example, the needle is inserted into the nervous system
between the base of the skull and the first vertebra. The drug is left in the
cerebrospinal fluid (CSF; the fluid that bathes the nervous system) and quickly
diffuses throughout the nervous system. A drug may also reach the CSF through an
intracerebroventricular injection directly into one of the brain’s ventricles, which are
chambers filled with CSF. To more precisely determine drug effects on specific areas
of the brain, intracerebral injections may be used in which a drug is administered
directly into brain tissue. These forms of drug administration are often done through a
cannula. A cannula is like a catheter, except it is a rigid tube resembling a hypodermic
needle. Cannulae are often attached to the animal’s skull using dental cement and can
remain permanently implanted.
With intravenous injections, the drug is put directly into the blood, but when
other sites are used, the drug must be absorbed into the circulatory system. The rate at
which a drug gets into the blood from an injection site is determined by a number of
factors associated with blood flow to the area. Generally, the volume of blood flow is
greater to the peritoneal cavity than to the muscles, and it is greater to the muscles
than under the skin. As a result, absorption is fastest from an i.p. injection and slowest
from an s.c. injection.
Heat and exercise can speed absorption from i.m. and s.c. sites because such
factors increase blood flow to muscles and skin. Thus, an i.m. injection will be
absorbed faster if the muscle is exercised after the injection, and the drug from a
subcutaneous site will get into the blood faster if heat is applied to the area and more
slowly if the area is chilled. To be absorbed into the bloodstream, a drug must pass
through the walls of the capillaries. A capillary is a tiny vessel through which blood
flows. Capillaries permeate most body tissues. They are so small in diameter that red
blood cells can barely pass through. It is through the walls of capillaries that nutrients
and oxygen pass out of the blood into body tissues, and it is also through these
capillary walls that waste products and carbon dioxide pass into the blood and are
removed. Blood leaves the heart and is distributed around the body in arteries. The
arteries divide into smaller and smaller branches until they become capillaries. The
blood in capillaries is eventually collected in veins, which carry the blood back to the
heart and the lungs.
Injected drugs pass into capillaries and the bloodstream through these pores by
simple diffusion. Diffusion is the process by which a substance tends to move from an
area of high concentration to an area of low concentration until the concentrations are
equal in both areas. If a drop of food coloring is placed in the corner of a tub of still
water, it will remain as a highly colored drop for only a short period of time. The
force of diffusion will soon distribute the coloring evenly throughout the tub of water.
Areas that are serviced by many capillaries will absorb drugs faster than areas
that have few capillaries. Because muscles use more oxygen, they have a richer
capillary supply than the skin; for this reason, absorption into the blood is faster from
i.m. injections than from s.c. injections. Drugs injected into the peritoneum have
access to an even greater number of capillaries; consequently, i.p. injections are
absorbed even more rapidly. Absorption through capillary walls is not a factor in
intravenous injections because the drug is placed directly into the blood. Blood in the
veins is transported to the heart and then redistributed around the body after a short
detour through the lungs (see Figure 1-5). The body has about 6 liters of blood, and
the heart pumps these 6 liters once a minute, so the drug in most i.v. injections is
distributed around the body about a minute after injection.
Some drugs need to be taken continuously or chronically to prevent the
symptoms of a disease or disorder from reappearing. The antipsychotic drugs (see
Chapter 12) are examples of drugs that sometimes need to be taken continuously for
many years. Often people do not like to take these drugs and do not continue to use
them after release from a hospital. As a result, they are readmitted regularly with
recurring psychotic symptoms. It is possible to give these people depot injections—
the drug is dissolved in a high concentration in a viscous oil (often sesame oil), which
is then injected into a muscle, usually in the buttock. The drug then slowly diffuses
from the oil into the body fluids over a long period of time. A single depot injection of
an antipsychotic drug can be effective as long as 4 weeks. This technique usually
works only with drugs that are highly lipid soluble (to be discussed shortly);
otherwise, they would be released too quickly. Fortunately, antipsychotic drugs have
this property (Lemberger, Schildcrout, & Cuff, 1987). Newer formulations use more
advanced techniques to generate synthetic polymer beads that have no physiological
effect, but degrade slowly in the body and release constant levels of a drug over an
extended period of time.
E. Inhalation
Every cell in the body requires oxygen and gives off carbon dioxide as a waste
product. The body has developed a very efficient system for absorbing gases from the
air (that is, the lungs) and distributing them quickly and completely throughout the
body (that is, the circulatory system). When drugs in the form of gases, vapors, or fine
mists are breathed into the lungs, this system gets them into the blood very rapidly.
The lungs are an extremely efficient gas exchange system. Their inside surface is
convoluted and contains many pockets of air so that the total surface area exposed to
the air is very large. This entire area is richly supplied with blood by capillaries,
which are close to the surface. When a gas or fumes of volatile substances (substances
that evaporate rapidly, such as solvents) are inhaled, they are very quickly absorbed
through the capillary walls and enter the circulating blood.
The principle that governs the movement of gases from inhaled air into the
blood and from the blood into the air within the lungs is diffusion. Gases move from
areas of high concentration to areas of low concentration. If the concentration of drug
in the inhaled air is higher than that in the blood, the drug will move from the air into
the blood, but the reverse is also true; the drug passes out of the blood into the air and
is exhaled so that the concentration of the gas in the blood reflects the concentration
in the gas that is breathed. Thus, the inhalation of gases provides a means of
controlling drug levels in the blood with considerable precision. This ability is one
reason gases are used widely as general anesthetics, and inhalation is the favored
route of administration for anesthesia. Volatile substances can also be exhaled from
the lungs, although the rate is determined by how rapidly the substance evaporates.
Gases and solvent vapors are not the only substances administered through the
lungs. Drugs that occur naturally in some plants may be administered by burning the
dried plant material and inhaling the smoke. Tobacco, opium, and marijuana are
traditionally ingested in this manner. When the dried plant material is burned, the
active ingredient remains either in the smoke as a vapor or in tiny particles of ash that
are inhaled into the lungs. When contact is made with the moist surface of the lungs,
the drug dissolves and diffuses into the blood. The major difference between smoke
and gases is that the drug in the smoke particles will not revaporize after it is
dissolved in the blood, and, consequently, it cannot be exhaled. These drugs must stay
in the body until they are eliminated by other means.
The problem with administration of solids and smoke by inhalation is the
susceptibility to damage of all the tissues in the respiratory system. Smoke from
burning marijuana and tobacco contains many substances in addition to the active
drug; there are tars, hydrocarbons, and other chemicals created by the burning
process. In time, these substances may cause respiratory diseases such as emphysema,
asthma, and lung cancer, and they may decrease the ability of the lungs to absorb
oxygen and eliminate carbon dioxide from the blood. Other forms of the drug with
unknown toxicity may also be created by the burning process. In addition, when most
substances burn in air, carbon monoxide gas is given off. Carbon monoxide is a very
toxic gas because it blocks the ability of the blood to carry oxygen.
Powdered drugs such as cocaine, heroin, and tobacco snuff are sometimes
sniffed into the nostrils. This practice is known as intranasal administration or
insufflation. On the street it is called snorting. What happens to the drug when given
in this manner is unclear. It appears that most of the drug sniffed in the nose is
dissolved in the moist mucous membranes of the nasal cavities and is absorbed into
the blood from there. Some drug enters the lungs, while more runs down the throat
into the stomach and digestive system and may be absorbed there. Although the nasal
cavity is not as richly supplied with blood as the lungs and although the area is not
designed to transport substances into the blood, it is a reasonably efficient system for
getting drugs into the blood.
F. Oral and Transdermal Administration
Drugs absorbed into the body through the digestive system are taken into the
mouth and swallowed—hence the term per oral or per os (p.o.). Sometimes
substances can get into the digestive system by other means. As just explained, snuff
from the nostrils can get down the throat and be swallowed. A drug may be taken into
the mouth and not swallowed, as with chewing tobacco. Although this is technically
an oral administration, the absorption into the body is through the buccal membranes,
or mucous membranes of the mouth, not the digestive system. The digestive system
may also be entered via its other end (intrarectal administration). Suppositories placed
in the rectum also cause the drug to be absorbed into the blood. Such absorption is not
as reliable as oral administration, but it can be a useful method of administering a
medication when it is impossible to give it orally (e.g., when a patient or animal is
unconscious or vomiting).
After a drug is swallowed, it goes directly to the stomach. The stomach churns
and secretes strong acids and digestive enzymes to break down food pieces and turn
them into a liquid that is then released slowly into the intestines, where nutrients are
absorbed. Drugs that are soluble in gastric fluids and resistant to destruction by
digestive enzymes may be absorbed from the stomach, but absorption is most efficient
in the intestines. The rate at which a swallowed drug will be absorbed may be
determined by the speed with which it gets through the stomach to the intestines.
Because solid food tends to be held in the stomach, taking a drug with a meal
generally slows its absorption. When a drug is taken on an empty stomach, it passes
quickly into the intestines and is absorbed rapidly.
Different drugs have different degrees of lipid solubility that are usually
expressed in terms of the olive oil partition coefficient. To test lipid solubility, equal
amounts of olive oil and water are placed in a beaker, and a fixed amount of drug is
mixed in. Later the oil and water are separated, and the amount of drug dissolved in
each one is measured. Drugs that are highly lipid soluble are more highly
concentrated in the oil. Poorly lipid-soluble drugs mostly end up in the water. This
test, although not perfectly accurate, predicts reasonably well the degree to which a
drug will dissolve in fat tissue in the body.
The easiest way to understand pKa is to imagine the following experiment
with a fictional drug called damital. A fixed amount of damital is dissolved in each of
15 bottles; each bottle contains a liquid with a different pH, ranging from 0 to 14. A
solution’s pH is a number that describes the degree to which it is either an acid or a
base. On this scale, 7 is completely neutral. Numbers less than 7 indicate increasing
acidity, and numbers greater than 7 indicate increasing alkalinity.
Most drugs are either weak acids or weak bases. Damital is a weak acid. If we
do this experiment again with a drug that is a weak base, we see something different.
One line in Figure 1-7 is a plot for an imaginary base, endital. The curve for the acid
damital starts with 0% ionization at the acid end of the scale, and ionization increases
as it moves toward the base end. Just the opposite is true for endital, the base. It starts
with 100% ionization in the acids, but its percentage of ionization decreases as the
solution gets more basic. The pKa for endital is calculated in the same way as that for
damital. In this case, the pKa for endital is 8. By knowing whether a drug is an acid or
a base and by knowing its pKa, it is possible to predict the degree to which it is likely
to be ionized in a solution of known pH. The pH at the lining of the intestine is about
3.5. In Figure 1-7, we can see that damital is about 5% ionized at this pH, and endital
is completely ionized. Because ionized molecules are not lipid soluble and do not pass
through membranes, we can conclude that endital will not be very effective when
taken orally, whereas damital will be readily absorbed.
It should be pointed out that significant absorption will take place even if only
a small percentage of molecules is not ionized. For example, if 97% of a drug is
ionized at digestive system pHs, only 3% will be lipid soluble, but as soon as that
percentage diffuses through the membrane and is removed by the blood, 3% of the
remaining drug loses its charge, so the 97% ionization figure will stay constant for the
drug remaining in the digestive system. The newly nonionized 3% now diffuses into
the blood, and 3% more can lose its ionization.
This process will continue until equilibrium is reached—that is, the
concentration of nonionized molecules is the same on either side of the membrane.
For this reason, it is not appropriate to think that the percentage of nonionized drug is
all that is absorbed. Rather, the percentage of nonionized molecules determines the
number of molecules available for absorption at any period of time and, therefore,
determines the rate of absorption. If 50% of the molecules are not ionized, absorption
will be rapid, but if 3% are not ionized, absorption will be much slower.
Some drugs can be absorbed through the skin. This is called transdermal
administration. The skin is composed of several layers, but the main barrier to
absorption is the epidermis, the outer layer of skin. It is made up of a continuous sheet
of flattened cells that are densely packed with keratin. This layer is virtually
impermeable to water and can be penetrated only by lipid-soluble substances. Even
then, absorption is very slow. The layer just under the epidermis, however, is made up
of connective tissue and serviced by capillaries; therefore, drugs applied to areas
where there is a break in the epidermis (as occurs when there is a cut or a wound) can
be absorbed.
The technology of transdermal administration has greatly improved with the
development of the patch technology where the drug is separated from the skin by a
special membrane that limits the rate of absorption. Using systems such as this, it is
possible to administer a drug at a constant rate and maintain a constant blood level for
an extended period of time. Nicotine patches were first developed in the 1980s for the
treatment of tobacco addiction (see Chapter 8), but now skin patches are used for the
controlled delivery of many drugs including opioid analgesics such as fentanyl (see
Chapter 11), methylphenidate for treating symptoms of Attention Deficit
Hyperactivity Disorder (ADHD; see Chapter 10), and hormones including the
contraceptive patch Ortho Evra.
G. Distribution of Drugs
Even though most drugs get transported widely around the body by the blood,
they tend to become concentrated in particular places and segregated from others.
This process is called the distribution of a drug. It has been stressed that lipid-soluble
substances can get through membranes easily, but as the olive oil partition coefficient
experiment shows, this capacity also means that highly lipid-soluble drugs tend to
stay in lipids wherever they encounter them. Consequently, highly lipid-soluble drugs
tend to concentrate in body fat outside the central nervous system. Because few drugs
have any effect in body fat, all of a drug dissolved in fat is, in effect, inactive. Very
often, the body fat acts like a sponge, absorbing a lipidsoluble drug, preventing it
from reaching its site of action, and diminishing its effect. Later, the drug is slowly
released back into the blood from the fat over a long period of time.
The pKa of a drug can also influence where a drug ends up in the body. As
pointed out earlier, drugs that are weak bases tend to ionize in acidic solutions, and
drugs that are weak acids tend to ionize in basic solutions. Since ionized molecules
are not lipid soluble, the pKa of a drug can hasten or retard its absorption and
excretion. This process was described earlier in the discussion of lipid solubility and
absorption of basic and acidic drugs from the digestive system. The same process
operates anywhere in the body where body fluids with different pHs are separated by
a membrane; drugs can get trapped on one side of the membrane. Drugs that are weak
bases will be concentrated in the fluid on the side of a membrane that is more basic,
and weak bases will be concentrated in the fluids on the more acidic side of a
membrane. The imbalance can be quite dramatic because a difference in pH of 1.0 on
either side of a membrane can cause a drug to be 10 times more concentrated on one
side than the other. The change in concentration is logarithmically related to the
concentration difference so that a difference in pH of 2.0 means that there will be a
100-fold difference in concentration, and a difference of 3.0 will create a 1,000-fold
difference in concentration.
Many years ago, it was discovered that when certain types of dyes were
injected into the blood, they would be distributed to all extracellular fluids except
those in the brain and the spinal cord. At that time, it was hypothesized that a special
barrier between the blood and the brain protected the central nervous system from free
diffusion of many materials out of the blood. This became known as the blood–brain
barrier. It has now been established that the blood–brain barrier is a result of special
cells in the central nervous system that wrap themselves around the capillaries and
block the pores through which substances normally diffuse. These cells provide a
solid lipid barrier so that non-lipid-soluble substances have great difficulty getting
into the brain. If not for the blood–brain barrier, the delicate balance of chemicals
inside and outside brain cells would be disrupted, even by the food we eat, altering the
ability of the cells to communicate one with another.
It is important for the body to get some non-lipid-soluble substances across
membranes, so special transport mechanisms exist. This process is carried out by
large protein molecules that span the cell membrane (visible in Figure@1-6) and may
involve either active or passive mechanisms. In the passive transport mechanism, the
large protein molecule may create a channel that allows the nonlipid-soluble molecule
to pass through in response to diffusion. In another variation it appears that the
nonlipid-soluble molecule attaches itself to a carrier protein or specialized molecule
that permits it to diffuse across the membrane and releases it on the other side. In this
way, a substance can move from areas of high to low concentration on either side of a
membrane as though it were lipid soluble without the expenditure of energy.
An active transport mechanism is similar to a passive mechanism except that it
can work against normal diffusion by concentrating a substance on one side of a
membrane. This is an active process that requires an expenditure of energy and takes
place only in living membranes. Mechanisms such as ion pumps, which maintain
electrical potentials of nerve cells, are examples of active transport systems. The
sodium–potassium transporter protein, illustrated in Figure 4-2 of Chapter 4, is one
example of an active transport system. The blood–brain barrier has a number of such
systems, many of which actively remove undesirable substances, like toxic waste
products, from the brain and some of which selectively concentrate substances, like
glucose (blood sugar) and some amino acids, in the brain.
The blood contains a number of large protein molecules that cannot diffuse out
of the pores in the capillaries because of their size. Some drugs attach, or bind,
themselves to these protein molecules so strongly that they remain attached until
metabolized. Consequently, they never get to their site of action. Other times,
proteinbound drug molecules may act like depot injections, becoming slowly released
as the blood concentration of the drug declines so that they reach their sites of action
and are eventually metabolized and excreted.
The blood of the fetus and the blood of the mother are not continuous.
Nutrients are transferred to (and waste products are transferred from) the blood of the
unborn child through a membrane similar to the blood–brain barrier. This transfer
takes place in the placenta, the intermediary organ between the fetus and the wall of
the uterus. Most behaviorally active drugs can be transferred from the mother’s blood
through the placenta to the fetus. Highly lipidsoluble substances cross more easily
than drugs with low lipid solubility. Drug concentration in the blood of the fetus
usually reaches 75% to 100% of that of the mother within 5@minutes of
administration. Thus, the fetus appears to have very little protection from any drug the
mother takes.
H. Elimination
There are some substances—for example, heavy metals such as lead and
mercury—that the body is not very good at getting rid of. Levels of these substances
can build up over time and accumulate to high and toxic concentrations. However, the
body has fairly efficient systems to rid itself of most unwanted substances, including
drugs, which would continue to exert their effects if not metabolized and excreted. It
has already been described how gases and volatile solvent vapors can be eliminated in
exhaled breath. Small amounts of many drugs are eliminated in sweat, saliva, and
feces, but the major job of elimination is done by the liver and the kidneys, the
dynamic duo of excretion.
The liver is a large organ located high in the abdomen, under the diaphragm.
Its function may best be compared to that of a chemical factory where molecules are
modified to form new substances useful to the body, and where toxic molecules are
changed into less harmful substances to be filtered out of the blood by the kidneys.
These molecular changes are achieved by molecules called enzymes. An enzyme is a
catalyst, a substance that controls a certain chemical reaction. The enzyme takes part
in the reaction, but when the reaction is finished, the enzyme is released unchanged
and is free to participate in another reaction in the same way. Without the presence of
the enzyme, the reaction would proceed very slowly or would not take place at all.
The body controls chemical reactions by controlling the amount of enzyme available
to act as a catalyst. Not all enzymes that metabolize drugs are located in the liver.
Some may be found in the blood and brain, or as we will see soon, in the digestive
system.
The process of restructuring molecules is referred to as metabolism, and the
products of metabolism are called metabolites. In general, metabolites are either more
useful to the body or less toxic than the original substance. Where drugs are
concerned, the metabolic process is sometimes called detoxification. Although this
term is appropriate some of the time, metabolites are not always less active or less
toxic than the original drug. Chloral hydrate, psilocybin, and THC, are good examples
of substances whose metabolites can be more active than the original drugs from
which they are formed. Drugs with active metabolites typically show a prolonged
action in the body, but these metabolites are eventually changed into inactive
watersoluble substances and excreted from the body by the kidneys.
Not all metabolism of drugs takes place after absorption and distribution have
occurred. Drugs that are absorbed from the digestive system are absorbed into blood
that goes to the liver before it returns to the heart. This means that any drug absorbed
from the digestive system will pass through the liver before going anywhere else in
the body and will be subjected to a certain amount of metabolism by liver enzymes.
This is known as first-pass metabolism, and it may be responsible for a significant
amount of the metabolism of some drugs. Drugs administered by other routes of
administration, including drugs absorbed from the nasal cavities and the membranes
of the mouth and rectum, are not subjected to first-pass metabolism by the liver and
may reach higher levels in the body. For a drug such as alcohol, some metabolism
takes place in the stomach and intestines even before it is absorbed. This is also
referred to as first-pass metabolism.
The kidneys are two organs, each about the size of a fist, located on either side
of the spine. Their primary function is to maintain the correct balance between water
and salt in body fluids. Along with the excretion of excess water in the form of urine,
the kidneys can also excrete molecules of unwanted substances, the by-products of
metabolism by liver enzymes. They function as a complex filtering system that
physically removes certain substances from the blood. The close-up portion of Figure
1-8 shows the nephron, the functional unit of the kidney. Each kidney has millions of
nephrons, all of which work in more or less the same way.
The kidney works not by filtering impurities out of the blood but by filtering
everything out of the blood and then selectively reabsorbing what is required.
Reabsorption in the nephron is accomplished by the mechanisms just described:
diffusion, lipid solubility, and active and passive transport. All lipid-soluble
substances diffuse through the nephron wall into the blood, unless a selective
transport mechanism is working against this diffusion. Desirable substances that are
not lipid soluble, such as glucose, have a transport mechanism that successfully
reclaims them into the blood. Unless they are reabsorbed by special transport systems,
ionized or non-lipid-soluble substances will be excreted. As with the digestive system,
pH influences the degree of ionization and, as a consequence, can influence
reabsorption. Urine tends to be acidic (pH = 6.0), and blood is basic (pH = 7.5), so,
much like in the digestive system, acids tend to pass through and to concentrate on the
blood side of the nephron wall, and bases tend to be retained in the urine and are
excreted more easily.
In most cases there are more than enough enzymes in the liver to handle a
drug so that when the drug arrives in the liver in high concentrations, a lot of the drug
will be metabolized at once. At low concentrations, the rate of metabolism will be
lower. Thus, as drug levels fall, the rate of metabolism slows. The curve that plots the
level of a drug in the blood over time is, therefore, not a straight line but tends to level
off to an asymptote. Because of this trailing off, the rate of excretion for most drugs
can be described in terms of a half-life. This is the time taken for the body to
eliminate half of a given blood level of a drug. In the example given in the top (A)
panel of Figure 1-9, half of the original blood level is eliminated in 30 minutes. Thirty
minutes later, the level has fallen to 25% of the original level, and 30 minutes after
that, it is down to 12.5%. Every 30 minutes, the body gets rid of half of the drug
circulating in the blood, so the half-life of the drug is 30 minutes. When the
elimination of a drug changes with concentration in this manner, it is said to have first
order kinetics.
I. Factors that Alter Drug Metabolism
A number of factors can influence the rate of metabolism of drugs in the liver
and, consequently, the intensity and duration of a drug’s effect. A great many
individual differences in response to drugs can be explained in terms of variations in
drug metabolism and enzyme systems that change according to such factors as age,
gender, species, past experience with drugs, and genetics. To illustrate how enzymes
work, we will use the metabolism of alcohol as an example. The steps in alcohol
metabolism are shown in Figure 1-10. In the first two steps, alcohol is converted to
acetaldehyde by the enzyme mentioned earlier: alcohol dehydrogenase. Then the
acetaldehyde is converted to acetyl coenzyme A by another enzyme called aldehyde
dehydrogenase.
When two drugs that use the same enzyme are introduced into the body at the
same time, the metabolism of each will be depressed because both will be competing
for the enzyme. In other cases, the activity of an enzyme can be blocked by another
drug. Again, we turn to the metabolism of alcohol as an example. Acetaldehyde is
converted into acetyl coenzyme A by aldehyde dehydrogenase. Disulfiram (Antabuse)
is a drug that blocks aldehyde dehydrogenase. Acetaldehyde levels then increase in
the body because the enzyme is not readily available to metabolize it (refer back to
Figure 1-10). Acetaldehyde is toxic and causes sickness and discomfort, so people
who take disulfiram and then drink alcohol will get sick because of the buildup of
high acetaldehyde levels. Disulfiram is sometimes used to discourage alcoholics from
drinking; alcoholics will feel well and stay that way if they refrain from ingesting
alcohol, but as soon as they take a drink, they will feel ill.
Even foods can alter drug metabolism. It was shown in the late 1990s that
there are substances in grapefruit juice that can block cytochrome P4503A4, an
enzyme located in the intestine. This important enzyme is responsible for the
significant first-pass metabolism of many drugs. It has been shown that drinking
grapefruit juice can significantly increase blood levels of many drugs. As a result,
people should avoid drinking grapefruit juice if they are taking any of a number of
drugs. These include the antianxiety drug buspirone (Buspar), the cholesterollowering
drugs lovastatin (Mevacor) and simvastatin (Zocor), and the erectile dysfunction drug
sildenafil (Viagra).
Enzyme systems are not fully functional at birth and may take time to develop
completely. For this reason, immature members of a species may metabolize drugs
differently from adults or may not metabolize them at all. For example, the liver of a
newborn human first converts theophylline to caffeine and then metabolizes caffeine
very slowly. In adults, theophylline is metabolized directly without this intermediate
stage. Theophylline is similar to caffeine and is found in tea but is sometimes given to
newborn babies to stimulate breathing. In infants, the effects of theophylline are
greatly enhanced because of the intermediate stage of metabolism involving caffeine.
For this reason, doses must be small and closely monitored to avoid overdose. A
similar problem is encountered when drugs are given to a woman immediately before
she gives birth. Drugs given at this time cross the placental barrier and circulate in the
blood of the fetus. As long as the child’s circulatory system is connected to the
mother, the mother’s liver can handle the drug, but if the baby is born and the
umbilical cord is cut before all the drug is metabolized, the drug remains in the
infant’s body and is dependent solely on the baby’s immature liver for metabolism, a
process that may take many days.
The vast majority of research in behavioral pharmacology uses species other
than human beings. Studies are usually done on rats, mice, pigeons, or primates. It is
important to understand how differences in drug metabolism can alter the intensity
and duration of a similar dose in different species. As an example, the levels of
alcohol dehydrogenase are quite different in different species. The liver of a rat or
mouse contains about 60% of the alcohol dehydrogenase per gram in a human liver,
but the liver of a guinea pig contains 160% of the level in a human liver. The liver of a
rhesus monkey has a concentration of alcohol dehydrogenase similar to that of a
human liver. As you can see, the same experiment, if performed on a guinea pig, a rat,
or a human, might reach quite different conclusions.
J. The Therapeutic Window
The effects of a drug change over time during a single administration. This
change reflects increasing and decreasing drug levels after administration. When these
varying effects are plotted on a graph, the result is usually called a time course (the
drug effect is usually represented on the vertical axis, and time is on the horizontal
axis). Figure 1-11 is a time course for the concentration of a drug in the blood after
administration. Note that there are three curves. One shows the time course of
absorption of a drug from the site of administration. This curve is hypothetical
because it assumes that while the drug is being absorbed, the liver and kidneys are not
working and no excretion is going on. The second curve is a hypothetical elimination
curve; it shows the rate of elimination of a drug, but assumes instantaneous
absorption. In reality, neither of these curves could exist. What is usually seen is a
combination of the first two curves, shown here as a third curve that has both an
ascending phase corresponding to the time when absorption is more rapid than
elimination and a descending phase when elimination is more rapid than absorption.
When drugs are given intravenously, the absorption phase is very steep; the
drug achieves high levels and is metabolized and excreted quickly. When drugs are
given orally, the absorption is slow, and blood levels do not reach the same high
concentrations seen after i.v. administration, but the drug lasts much longer in the
body. Intramuscular and subcutaneous routes are intermediate between i.v. and oral
routes. The route of administration can determine whether a drug reaches high levels
for a short period or lasts a long time at low levels. If the function of a drug depends
on maintaining constant blood levels, as with antibiotics, oral administration is
preferred. If it is necessary to achieve very high levels for brief periods, the drug is
best given intravenously.
When drugs are administered for therapeutic purposes, it is often important
that the right level of the drug be maintained in the blood for an extended period of
time. If the drug reaches too high a level, there will be an increase in unwanted side
effects and no increase in the therapeutic effect. If the drug falls below a certain level,
it will not have a therapeutic effect at all. To keep its concentration within this range, a
drug must be taken at the correct dose at regular intervals.
For drugs that are absorbed and excreted slowly, it is usually not difficult to
achieve a dosing regimen that keeps the blood level within this window, but the task is
more complicated for drugs that are absorbed and excreted rapidly. One such drug is
lithium carbonate, which is given to people with bipolar disorder. Lithium has a rather
narrow therapeutic window (the effective dose and a dose that causes side effects are
very close). Lithium is also absorbed and excreted rapidly, so it must be given in
small doses (as many as four times a day). To help solve this problem, pills have been
developed in which the lithium is embedded in a material that dissolves slowly to
delay the drug’s absorption and, hence, its peak blood level. Using this type of
medication makes it easier to keep the blood level within the therapeutic window and
reduce the number of doses to two a day.
With repeated use, individuals may build tolerance to some drugs (this will be
discussed further in Chapter 3). Tolerance for some drug effects may build more
quickly than tolerance for others. For example, tolerance to the analgesic effects of
opioids like morphine builds rapidly, requiring a larger dose of the drug in order for it
to be effective in relieving pain. Tolerance to the toxic effects of morphine builds
more slowly, moving the curve for the effective dose closer to the curve for the toxic
dose, increasing the risk of overdose and narrowing the therapeutic window.
