In the most general sense, a drug may be defined as any substance that brings about a change in
biologic function through its chemical actions. In the great majority of cases, the drug molecule
interacts with a specific molecule in the biologic system that plays a regulatory role. This molecule
is called a receptor. The nature of receptors is discussed more fully in Chapter 2: Drug Receptors &
Pharmacodynamics. In a very small number of cases, drugs known as chemical antagonists may
interact directly with other drugs, while a few other drugs (eg, osmotic agents) interact almost
exclusively with water molecules. Drugs may be synthesized within the body (eg, hormones) or
may be chemicals not synthesized in the body, ie, xenobiotics (from Gr xenos "stranger"). Poisons
are drugs. Toxins are usually defined as poisons of biologic origin, ie, synthesized by plants or
animals, in contrast to inorganic poisons such as lead and arsenic.
In order to interact chemically with its receptor, a drug molecule must have the appropriate size,
electrical charge, shape, and atomic composition. Furthermore, a drug is often administered at a
location distant from its intended site of action, eg, a pill given orally to relieve a headache.
Therefore, a useful drug must have the necessary properties to be transported from its site of
administration to its site of action. Finally, a practical drug should be inactivated or excreted from
the body at a reasonable rate so that its actions will be of appropriate duration.
The Physical Nature of Drugs
Drugs may be solid at room temperature (eg, aspirin, atropine), liquid (eg, nicotine, ethanol), or
gaseous (eg, nitrous oxide). These factors often determine the best route of administration. For
example, some liquid drugs are easily vaporized and can be inhaled in that form, eg, halothane,
amyl nitrite. The most common routes of administration are listed in Table 3–3. The various classes
of organic compounds—carbohydrates, proteins, lipids, and their constituents—are all represented
in pharmacology. Many drugs are weak acids or bases. This fact has important implications for the
way they are handled by the body, because pH differences in the various compartments of the body
may alter the degree of ionization of such drugs (see below).
Drug Size
The molecular size of drugs varies from very small (lithium ion, MW 7) to very large (eg, alteplase
[t-PA], a protein of MW 59,050). However, the vast majority of drugs have molecular weights
between 100 and 1000. The lower limit of this narrow range is probably set by the requirements for
specificity of action. In order to have a good "fit" to only one type of receptor, a drug molecule
must be sufficiently unique in shape, charge, etc, to prevent its binding to other receptors. To
achieve such selective binding, it appears that a molecule should in most cases be at least 100 MW
units in size. The upper limit in molecular weight is determined primarily by the requirement that
drugs be able to move within the body (eg, from site of administration to site of action). Drugs
much larger than MW 1000 will not diffuse readily between compartments of the body (see
Permeation, below). Therefore, very large drugs (usually proteins) must be administered directly
into the compartment where they have their effect. In the case of alteplase, a clot-dissolving
enzyme, the drug is administered directly into the vascular compartment by intravenous infusion.
Drug Reactivity and Drug-Receptor Bonds
Drugs interact with receptors by means of chemical forces or bonds. These are of three major types:
covalent, electrostatic, and hydrophobic. Covalent bonds are very strong and in many cases not
reversible under biologic conditions. Thus, the covalent bond formed between the activated form of
phenoxybenzamine and the receptor for norepinephrine (which results in blockade of the receptor)
is not readily broken. The blocking effect of phenoxybenzamine lasts long after the free drug has
disappeared from the bloodstream and is reversed only by the synthesis of new receptors, a
process that takes about 48 hours. Other examples of highly reactive, covalent bond-forming drugs
are the DNA-alkylating agents used in cancer chemotherapy to disrupt cell division in the neoplastic
tissue.
Electrostatic bonding is much more common than covalent bonding in drug-receptor interactions.
Electrostatic bonds vary from relatively strong linkages between permanently charged ionic
molecules to weaker hydrogen bonds and very weak induced dipole interactions such as van der
Waals forces and similar phenomena. Electrostatic bonds are weaker than covalent bonds.
Hydrophobic bonds are usually quite weak and are probably important in the interactions of highly
lipid-soluble drugs with the lipids of cell membranes and perhaps in the interaction of drugs with
the internal walls of receptor "pockets."
The specific nature of a particular drug-receptor bond is of less practical importance than the fact
that drugs which bind through weak bonds to their receptors are generally more selective than drugs
which bind through very strong bonds. This is because weak bonds require a very precise fit of the
drug to its receptor if an interaction is to occur. Only a few receptor types are likely to provide such
a precise fit for a particular drug structure. Thus, if we wished to design a highly selective shortacting
drug for a particular receptor, we would avoid highly reactive molecules that form covalent
bonds and instead choose molecules that form weaker bonds.
A few substances that are almost completely inert in the chemical sense nevertheless have
significant pharmacologic effects. For example, xenon, an "inert gas," has anesthetic effects at
elevated pressures.
Drug Shape
The shape of a drug molecule must be such as to permit binding to its receptor site. Optimally, the
drug's shape is complementary to that of the receptor site in the same way that a key is
complementary to a lock. Furthermore, the phenomenon of chirality (stereoisomerism) is so
common in biology that more than half of all useful drugs are chiral molecules, ie, they exist as
enantiomeric pairs. Drugs with two asymmetric centers have four diastereomers, eg, ephedrine, a
sympathomimetic drug. In the great majority of cases, one of these enantiomers will be much more
potent than its mirror image enantiomer, reflecting a better fit to the receptor molecule. For
example, the (S)(+) enantiomer of methacholine, a parasympathomimetic drug, is over 250 times
more potent than the (R)(–) enantiomer. If one imagines the receptor site to be like a glove into
which the drug molecule must fit to bring about its effect, it is clear why a "left-oriented" drug will
be more effective in binding to a left-hand receptor than will its "right-oriented" enantiomer.
The more active enantiomer at one type of receptor site may not be more active at another type, eg,
a receptor type that may be responsible for some unwanted effect. For example, carvedilol, a drug
that interacts with adrenoceptors, has a single chiral center and thus two enantiomers (Table 1–1).
One of these enantiomers, the (S)(–) isomer, is a potent -receptor blocker. The (R)(+) isomer is
100-fold weaker at the receptor. However, the isomers are approximately equipotent as -receptor
blockers. Ketamine is an intravenous anesthetic. The (+) enantiomer is a more potent anesthetic and
is less toxic than the (–) enantiomer. Unfortunately, the drug is still used as the racemic mixture.
Table 1–1. Dissociation Constants (Kd) of the Enantiomers and Racemate of Carvedilol.1
Form of
Carvedilol
Inverse of Affinity for Receptors
(Kd, nmol/L)
Inverse of Affinity for Receptors
(Kd, nmol/L)
R(+) enantiomer 14 45
S(–) enantiomer 16 0.4
R,S(+/–)
enantiomers
11 0.9
Note: The Kd is the concentration for 50% saturation of the receptors and is inversely proportionate
to the affinity of the drug for the receptors.
1Data from Ruffolo RR et al: The pharmacology of carvedilol. Eur J Pharmacol 1990;38:S82.
Finally, because enzymes are usually stereoselective, one drug enantiomer is often more susceptible
than the other to drug-metabolizing enzymes. As a result, the duration of action of one enantiomer
may be quite different from that of the other.
Unfortunately, most studies of clinical efficacy and drug elimination in humans have been carried
out with racemic mixtures of drugs rather than with the separate enantiomers. At present, only about
45% of the chiral drugs used clinically are marketed as the active isomer—the rest are available
only as racemic mixtures. As a result, many patients are receiving drug doses of which 50% or more
is either inactive or actively toxic. However, there is increasing interest—at both the scientific and
the regulatory levels—in making more chiral drugs available as their active enantiomers.
Rational Drug Design
Rational design of drugs implies the ability to predict the appropriate molecular structure of a drug
on the basis of information about its biologic receptor. Until recently, no receptor was known in
sufficient detail to permit such drug design. Instead, drugs were developed through random testing
of chemicals or modification of drugs already known to have some effect (see Chapter 5: Basic &
Clinical Evaluation of New Drugs). However, during the past 3 decades, many receptors have been
isolated and characterized. A few drugs now in use were developed through molecular design based
on a knowledge of the three-dimensional structure of the receptor site. Computer programs are now
available that can iteratively optimize drug structures to fit known receptors. As more becomes
known about receptor structure, rational drug design will become more feasible.
Receptor Nomenclature
The spectacular success of newer, more efficient ways to identify and characterize receptors (see
Chapter 2: Drug Receptors & Pharmacodynamics, How Are New Receptors Discovered?) has
resulted in a variety of differing systems for naming them. This in turn has led to a number of
suggestions regarding more rational methods of naming them. The interested reader is referred for
details to the efforts of the International Union of Pharmacology (IUPHAR) Committee on Receptor
Nomenclature and Drug Classification (reported in various issues of Pharmacological Reviews)
and to the annual Receptor and Ion Channel Nomenclature Supplements published as special issues
by the journal Trends in Pharmacological Sciences (TIPS). The chapters in this book mainly use
these sources for naming receptors.
Drug-Body Interactions
The interactions between a drug and the body are conveniently divided into two classes. The actions
of the drug on the body are termed pharmacodynamic processes; the principles of
pharmacodynamics are presented in greater detail in Chapter 2: Drug Receptors &
Pharmacodynamics. These properties determine the group in which the drug is classified and often
play the major role in deciding whether that group is appropriate therapy for a particular symptom
or disease. The actions of the body on the drug are called pharmacokinetic processes and are
described in Chapters 3 and 4. Pharmacokinetic processes govern the absorption, distribution, and
elimination of drugs and are of great practical importance in the choice and administration of a
particular drug for a particular patient, eg, one with impaired renal function. The following
paragraphs provide a brief introduction to pharmacodynamics and pharmacokinetics.
Pharmacodynamic Principles
As noted above, most drugs must bind to a receptor to bring about an effect. However, at the
molecular level, drug binding is only the first in what is often a complex sequence of steps.
Types of Drug-Receptor Interactions
Agonist drugs bind to and activate the receptor in some fashion, which directly or indirectly brings
about the effect. Some receptors incorporate effector machinery in the same molecule, so that drug
binding brings about the effect directly, eg, opening of an ion channel or activation of enzyme
activity. Other receptors are linked through one or more intervening coupling molecules to a
separate effector molecule. The several types of drug-receptor-effector coupling systems are
discussed in Chapter 2: Drug Receptors & Pharmacodynamics. Pharmacologic antagonist drugs, by
binding to a receptor, prevent binding by other molecules. For example, acetylcholine receptor
blockers such as atropine are antagonists because they prevent access of acetylcholine and similar
agonist drugs to the acetylcholine receptor and they stabilize the receptor in its inactive state. These
agents reduce the effects of acetylcholine and similar drugs in the body.
"Agonists" That Inhibit Their Binding Molecules and Partial Agonists
Some drugs mimic agonist drugs by inhibiting the molecules responsible for terminating the action
of an endogenous agonist. For example, acetylcholinesterase inhibitors, by slowing the destruction
of endogenous acetylcholine, cause cholinomimetic effects that closely resemble the actions of
cholinoceptor agonist molecules even though cholinesterase inhibitors do not—or only incidentally
do—bind to cholinoceptors (see Chapter 7: Cholinoceptor-Activating & Cholinesterase-Inhibiting
Drugs). Other drugs bind to receptors and activate them but do not evoke as great a response as socalled
full agonists. Thus, pindolol, a adrenoceptor "partial agonist," may act as either an agonist
(if no full agonist is present) or as an antagonist (if a full agonist such as isoproterenol is present).
(See Chapter 2: Drug Receptors & Pharmacodynamics.)
Duration of Drug Action
Termination of drug action at the receptor level results from one of several processes. In some
cases, the effect lasts only as long as the drug occupies the receptor, so that dissociation of drug
from the receptor automatically terminates the effect. In many cases, however, the action may
persist after the drug has dissociated, because, for example, some coupling molecule is still present
in activated form. In the case of drugs that bind covalently to the receptor, the effect may persist
until the drug-receptor complex is destroyed and new receptors are synthesized, as described
previously for phenoxybenzamine. Finally, many receptor-effector systems incorporate
desensitization mechanisms for preventing excessive activation when agonist molecules continue to
be present for long periods. See Chapter 2: Drug Receptors & Pharmacodynamics for additional
details.
Receptors and Inert Binding Sites
To function as a receptor, an endogenous molecule must first be selective in choosing ligands (drug
molecules) to bind; and second, it must change its function upon binding in such a way that the
function of the biologic system (cell, tissue, etc) is altered. The first characteristic is required to
avoid constant activation of the receptor by promiscuous binding of many different ligands. The
second characteristic is clearly necessary if the ligand is to cause a pharmacologic effect. The body
contains many molecules that are capable of binding drugs, however, and not all of these
endogenous molecules are regulatory molecules. Binding of a drug to a nonregulatory molecule
such as plasma albumin will result in no detectable change in the function of the biologic system, so
this endogenous molecule can be called an inert binding site. Such binding is not completely
without significance, however, since it affects the distribution of drug within the body and will
determine the amount of free drug in the circulation. Both of these factors are of pharmacokinetic
importance (see below and Chapter 3: Pharmacokinetics & Pharmacodynamics: Rational Dosing &
the Time Course of Drug Action).
Pharmacokinetic Principles
In practical therapeutics, a drug should be able to reach its intended site of action after
administration by some convenient route. In some cases, a chemical that is readily absorbed and
distributed is administered and then converted to the active drug by biologic processes—inside the
body. Such a chemical is called a prodrug. In only a few situations is it possible to directly apply a
drug to its target tissue, eg, by topical application of an anti-inflammatory agent to inflamed skin or
mucous membrane. Most often, a drug is administered into one body compartment, eg, the gut, and
must move to its site of action in another compartment, eg, the brain. This requires that the drug be
absorbed into the blood from its site of administration and distributed to its site of action,
permeating through the various barriers that separate these compartments. For a drug given orally
to produce an effect in the central nervous system, these barriers include the tissues that comprise
the wall of the intestine, the walls of the capillaries that perfuse the gut, and the "blood-brain
barrier," the walls of the capillaries that perfuse the brain. Finally, after bringing about its effect, a
drug should be eliminated at a reasonable rate by metabolic inactivation, by excretion from the
body, or by a combination of these processes.
Permeation
Drug permeation proceeds by four primary mechanisms. Passive diffusion in an aqueous or lipid
medium is common, but active processes play a role in the movement of many drugs, especially
those whose molecules are too large to diffuse readily.
Aqueous Diffusion
Aqueous diffusion occurs within the larger aqueous compartments of the body (interstitial space,
cytosol, etc) and across epithelial membrane tight junctions and the endothelial lining of blood
vessels through aqueous pores that—in some tissues—permit the passage of molecules as large as
MW 20,000–30,000.*
* The capillaries of the brain, the testes, and some other tissues are characterized by absence of the
pores that permit aqueous diffusion of many drug molecules into the tissue. They may also contain
high concentrations of drug export pumps (MDR pumps; see text). These tissues are therefore
"protected" or "sanctuary" sites from many circulating drugs.
Aqueous diffusion of drug molecules is usually driven by the concentration gradient of the
permeating drug, a downhill movement described by Fick's law (see below). Drug molecules that
are bound to large plasma proteins (eg, albumin) will not permeate these aqueous pores. If the drug
is charged, its flux is also influenced by electrical fields (eg, the membrane potential and—in parts
of the nephron—the transtubular potential).
Lipid Diffusion
Lipid diffusion is the most important limiting factor for drug permeation because of the large
number of lipid barriers that separate the compartments of the body. Because these lipid barriers
separate aqueous compartments, the lipid:aqueous partition coefficient of a drug determines how
readily the molecule moves between aqueous and lipid media. In the case of weak acids and weak
bases (which gain or lose electrical charge-bearing protons, depending on the pH), the ability to
move from aqueous to lipid or vice versa varies with the pH of the medium, because charged
molecules attract water molecules. The ratio of lipid-soluble form to water-soluble form for a weak
acid or weak base is expressed by the Henderson-Hasselbalch equation (see below).
Special Carriers
Special carrier molecules exist for certain substances that are important for cell function and too
large or too insoluble in lipid to diffuse passively through membranes, eg, peptides, amino acids,
glucose. These carriers bring about movement by active transport or facilitated diffusion and, unlike
passive diffusion, are saturable and inhibitable. Because many drugs are or resemble such naturally
occurring peptides, amino acids, or sugars, they can use these carriers to cross membranes.
Many cells also contain less selective membrane carriers that are specialized for expelling foreign
molecules, eg, the P-glycoprotein or multidrug-resistance type 1 (MDR1) transporter found in
the brain, testes, and other tissues, and in some drug-resistant neoplastic cells. A similar transport
molecule, the multidrug resistance-associated protein-type 2 (MRP2) transporter, plays an
important role in excretion of some drugs or their metabolites into urine and bile.
Endocytosis and Exocytosis
A few substances are so large or impermeant that they can enter cells only by endocytosis, the
process by which the substance is engulfed by the cell membrane and carried into the cell by
pinching off of the newly formed vesicle inside the membrane. The substance can then be released
inside the cytosol by breakdown of the vesicle membrane. This process is responsible for the
transport of vitamin B12, complexed with a binding protein (intrinsic factor), across the wall of the
gut into the blood. Similarly, iron is transported into hemoglobin-synthesizing red blood cell
precursors in association with the protein transferrin. Specific receptors for the transport proteins
must be present for this process to work. The reverse process (exocytosis) is responsible for the
secretion of many substances from cells. For example, many neurotransmitter substances are stored
in membrane-bound vesicles in nerve endings to protect them from metabolic destruction in the
cytoplasm. Appropriate activation of the nerve ending causes fusion of the storage vesicle with the
cell membrane and expulsion of its contents into the extracellular space
reference
Bertam G.Katzung
biologic function through its chemical actions. In the great majority of cases, the drug molecule
interacts with a specific molecule in the biologic system that plays a regulatory role. This molecule
is called a receptor. The nature of receptors is discussed more fully in Chapter 2: Drug Receptors &
Pharmacodynamics. In a very small number of cases, drugs known as chemical antagonists may
interact directly with other drugs, while a few other drugs (eg, osmotic agents) interact almost
exclusively with water molecules. Drugs may be synthesized within the body (eg, hormones) or
may be chemicals not synthesized in the body, ie, xenobiotics (from Gr xenos "stranger"). Poisons
are drugs. Toxins are usually defined as poisons of biologic origin, ie, synthesized by plants or
animals, in contrast to inorganic poisons such as lead and arsenic.
In order to interact chemically with its receptor, a drug molecule must have the appropriate size,
electrical charge, shape, and atomic composition. Furthermore, a drug is often administered at a
location distant from its intended site of action, eg, a pill given orally to relieve a headache.
Therefore, a useful drug must have the necessary properties to be transported from its site of
administration to its site of action. Finally, a practical drug should be inactivated or excreted from
the body at a reasonable rate so that its actions will be of appropriate duration.
The Physical Nature of Drugs
Drugs may be solid at room temperature (eg, aspirin, atropine), liquid (eg, nicotine, ethanol), or
gaseous (eg, nitrous oxide). These factors often determine the best route of administration. For
example, some liquid drugs are easily vaporized and can be inhaled in that form, eg, halothane,
amyl nitrite. The most common routes of administration are listed in Table 3–3. The various classes
of organic compounds—carbohydrates, proteins, lipids, and their constituents—are all represented
in pharmacology. Many drugs are weak acids or bases. This fact has important implications for the
way they are handled by the body, because pH differences in the various compartments of the body
may alter the degree of ionization of such drugs (see below).
Drug Size
The molecular size of drugs varies from very small (lithium ion, MW 7) to very large (eg, alteplase
[t-PA], a protein of MW 59,050). However, the vast majority of drugs have molecular weights
between 100 and 1000. The lower limit of this narrow range is probably set by the requirements for
specificity of action. In order to have a good "fit" to only one type of receptor, a drug molecule
must be sufficiently unique in shape, charge, etc, to prevent its binding to other receptors. To
achieve such selective binding, it appears that a molecule should in most cases be at least 100 MW
units in size. The upper limit in molecular weight is determined primarily by the requirement that
drugs be able to move within the body (eg, from site of administration to site of action). Drugs
much larger than MW 1000 will not diffuse readily between compartments of the body (see
Permeation, below). Therefore, very large drugs (usually proteins) must be administered directly
into the compartment where they have their effect. In the case of alteplase, a clot-dissolving
enzyme, the drug is administered directly into the vascular compartment by intravenous infusion.
Drug Reactivity and Drug-Receptor Bonds
Drugs interact with receptors by means of chemical forces or bonds. These are of three major types:
covalent, electrostatic, and hydrophobic. Covalent bonds are very strong and in many cases not
reversible under biologic conditions. Thus, the covalent bond formed between the activated form of
phenoxybenzamine and the receptor for norepinephrine (which results in blockade of the receptor)
is not readily broken. The blocking effect of phenoxybenzamine lasts long after the free drug has
disappeared from the bloodstream and is reversed only by the synthesis of new receptors, a
process that takes about 48 hours. Other examples of highly reactive, covalent bond-forming drugs
are the DNA-alkylating agents used in cancer chemotherapy to disrupt cell division in the neoplastic
tissue.
Electrostatic bonding is much more common than covalent bonding in drug-receptor interactions.
Electrostatic bonds vary from relatively strong linkages between permanently charged ionic
molecules to weaker hydrogen bonds and very weak induced dipole interactions such as van der
Waals forces and similar phenomena. Electrostatic bonds are weaker than covalent bonds.
Hydrophobic bonds are usually quite weak and are probably important in the interactions of highly
lipid-soluble drugs with the lipids of cell membranes and perhaps in the interaction of drugs with
the internal walls of receptor "pockets."
The specific nature of a particular drug-receptor bond is of less practical importance than the fact
that drugs which bind through weak bonds to their receptors are generally more selective than drugs
which bind through very strong bonds. This is because weak bonds require a very precise fit of the
drug to its receptor if an interaction is to occur. Only a few receptor types are likely to provide such
a precise fit for a particular drug structure. Thus, if we wished to design a highly selective shortacting
drug for a particular receptor, we would avoid highly reactive molecules that form covalent
bonds and instead choose molecules that form weaker bonds.
A few substances that are almost completely inert in the chemical sense nevertheless have
significant pharmacologic effects. For example, xenon, an "inert gas," has anesthetic effects at
elevated pressures.
Drug Shape
The shape of a drug molecule must be such as to permit binding to its receptor site. Optimally, the
drug's shape is complementary to that of the receptor site in the same way that a key is
complementary to a lock. Furthermore, the phenomenon of chirality (stereoisomerism) is so
common in biology that more than half of all useful drugs are chiral molecules, ie, they exist as
enantiomeric pairs. Drugs with two asymmetric centers have four diastereomers, eg, ephedrine, a
sympathomimetic drug. In the great majority of cases, one of these enantiomers will be much more
potent than its mirror image enantiomer, reflecting a better fit to the receptor molecule. For
example, the (S)(+) enantiomer of methacholine, a parasympathomimetic drug, is over 250 times
more potent than the (R)(–) enantiomer. If one imagines the receptor site to be like a glove into
which the drug molecule must fit to bring about its effect, it is clear why a "left-oriented" drug will
be more effective in binding to a left-hand receptor than will its "right-oriented" enantiomer.
The more active enantiomer at one type of receptor site may not be more active at another type, eg,
a receptor type that may be responsible for some unwanted effect. For example, carvedilol, a drug
that interacts with adrenoceptors, has a single chiral center and thus two enantiomers (Table 1–1).
One of these enantiomers, the (S)(–) isomer, is a potent -receptor blocker. The (R)(+) isomer is
100-fold weaker at the receptor. However, the isomers are approximately equipotent as -receptor
blockers. Ketamine is an intravenous anesthetic. The (+) enantiomer is a more potent anesthetic and
is less toxic than the (–) enantiomer. Unfortunately, the drug is still used as the racemic mixture.
Table 1–1. Dissociation Constants (Kd) of the Enantiomers and Racemate of Carvedilol.1
Form of
Carvedilol
Inverse of Affinity for Receptors
(Kd, nmol/L)
Inverse of Affinity for Receptors
(Kd, nmol/L)
R(+) enantiomer 14 45
S(–) enantiomer 16 0.4
R,S(+/–)
enantiomers
11 0.9
Note: The Kd is the concentration for 50% saturation of the receptors and is inversely proportionate
to the affinity of the drug for the receptors.
1Data from Ruffolo RR et al: The pharmacology of carvedilol. Eur J Pharmacol 1990;38:S82.
Finally, because enzymes are usually stereoselective, one drug enantiomer is often more susceptible
than the other to drug-metabolizing enzymes. As a result, the duration of action of one enantiomer
may be quite different from that of the other.
Unfortunately, most studies of clinical efficacy and drug elimination in humans have been carried
out with racemic mixtures of drugs rather than with the separate enantiomers. At present, only about
45% of the chiral drugs used clinically are marketed as the active isomer—the rest are available
only as racemic mixtures. As a result, many patients are receiving drug doses of which 50% or more
is either inactive or actively toxic. However, there is increasing interest—at both the scientific and
the regulatory levels—in making more chiral drugs available as their active enantiomers.
Rational Drug Design
Rational design of drugs implies the ability to predict the appropriate molecular structure of a drug
on the basis of information about its biologic receptor. Until recently, no receptor was known in
sufficient detail to permit such drug design. Instead, drugs were developed through random testing
of chemicals or modification of drugs already known to have some effect (see Chapter 5: Basic &
Clinical Evaluation of New Drugs). However, during the past 3 decades, many receptors have been
isolated and characterized. A few drugs now in use were developed through molecular design based
on a knowledge of the three-dimensional structure of the receptor site. Computer programs are now
available that can iteratively optimize drug structures to fit known receptors. As more becomes
known about receptor structure, rational drug design will become more feasible.
Receptor Nomenclature
The spectacular success of newer, more efficient ways to identify and characterize receptors (see
Chapter 2: Drug Receptors & Pharmacodynamics, How Are New Receptors Discovered?) has
resulted in a variety of differing systems for naming them. This in turn has led to a number of
suggestions regarding more rational methods of naming them. The interested reader is referred for
details to the efforts of the International Union of Pharmacology (IUPHAR) Committee on Receptor
Nomenclature and Drug Classification (reported in various issues of Pharmacological Reviews)
and to the annual Receptor and Ion Channel Nomenclature Supplements published as special issues
by the journal Trends in Pharmacological Sciences (TIPS). The chapters in this book mainly use
these sources for naming receptors.
Drug-Body Interactions
The interactions between a drug and the body are conveniently divided into two classes. The actions
of the drug on the body are termed pharmacodynamic processes; the principles of
pharmacodynamics are presented in greater detail in Chapter 2: Drug Receptors &
Pharmacodynamics. These properties determine the group in which the drug is classified and often
play the major role in deciding whether that group is appropriate therapy for a particular symptom
or disease. The actions of the body on the drug are called pharmacokinetic processes and are
described in Chapters 3 and 4. Pharmacokinetic processes govern the absorption, distribution, and
elimination of drugs and are of great practical importance in the choice and administration of a
particular drug for a particular patient, eg, one with impaired renal function. The following
paragraphs provide a brief introduction to pharmacodynamics and pharmacokinetics.
Pharmacodynamic Principles
As noted above, most drugs must bind to a receptor to bring about an effect. However, at the
molecular level, drug binding is only the first in what is often a complex sequence of steps.
Types of Drug-Receptor Interactions
Agonist drugs bind to and activate the receptor in some fashion, which directly or indirectly brings
about the effect. Some receptors incorporate effector machinery in the same molecule, so that drug
binding brings about the effect directly, eg, opening of an ion channel or activation of enzyme
activity. Other receptors are linked through one or more intervening coupling molecules to a
separate effector molecule. The several types of drug-receptor-effector coupling systems are
discussed in Chapter 2: Drug Receptors & Pharmacodynamics. Pharmacologic antagonist drugs, by
binding to a receptor, prevent binding by other molecules. For example, acetylcholine receptor
blockers such as atropine are antagonists because they prevent access of acetylcholine and similar
agonist drugs to the acetylcholine receptor and they stabilize the receptor in its inactive state. These
agents reduce the effects of acetylcholine and similar drugs in the body.
"Agonists" That Inhibit Their Binding Molecules and Partial Agonists
Some drugs mimic agonist drugs by inhibiting the molecules responsible for terminating the action
of an endogenous agonist. For example, acetylcholinesterase inhibitors, by slowing the destruction
of endogenous acetylcholine, cause cholinomimetic effects that closely resemble the actions of
cholinoceptor agonist molecules even though cholinesterase inhibitors do not—or only incidentally
do—bind to cholinoceptors (see Chapter 7: Cholinoceptor-Activating & Cholinesterase-Inhibiting
Drugs). Other drugs bind to receptors and activate them but do not evoke as great a response as socalled
full agonists. Thus, pindolol, a adrenoceptor "partial agonist," may act as either an agonist
(if no full agonist is present) or as an antagonist (if a full agonist such as isoproterenol is present).
(See Chapter 2: Drug Receptors & Pharmacodynamics.)
Duration of Drug Action
Termination of drug action at the receptor level results from one of several processes. In some
cases, the effect lasts only as long as the drug occupies the receptor, so that dissociation of drug
from the receptor automatically terminates the effect. In many cases, however, the action may
persist after the drug has dissociated, because, for example, some coupling molecule is still present
in activated form. In the case of drugs that bind covalently to the receptor, the effect may persist
until the drug-receptor complex is destroyed and new receptors are synthesized, as described
previously for phenoxybenzamine. Finally, many receptor-effector systems incorporate
desensitization mechanisms for preventing excessive activation when agonist molecules continue to
be present for long periods. See Chapter 2: Drug Receptors & Pharmacodynamics for additional
details.
Receptors and Inert Binding Sites
To function as a receptor, an endogenous molecule must first be selective in choosing ligands (drug
molecules) to bind; and second, it must change its function upon binding in such a way that the
function of the biologic system (cell, tissue, etc) is altered. The first characteristic is required to
avoid constant activation of the receptor by promiscuous binding of many different ligands. The
second characteristic is clearly necessary if the ligand is to cause a pharmacologic effect. The body
contains many molecules that are capable of binding drugs, however, and not all of these
endogenous molecules are regulatory molecules. Binding of a drug to a nonregulatory molecule
such as plasma albumin will result in no detectable change in the function of the biologic system, so
this endogenous molecule can be called an inert binding site. Such binding is not completely
without significance, however, since it affects the distribution of drug within the body and will
determine the amount of free drug in the circulation. Both of these factors are of pharmacokinetic
importance (see below and Chapter 3: Pharmacokinetics & Pharmacodynamics: Rational Dosing &
the Time Course of Drug Action).
Pharmacokinetic Principles
In practical therapeutics, a drug should be able to reach its intended site of action after
administration by some convenient route. In some cases, a chemical that is readily absorbed and
distributed is administered and then converted to the active drug by biologic processes—inside the
body. Such a chemical is called a prodrug. In only a few situations is it possible to directly apply a
drug to its target tissue, eg, by topical application of an anti-inflammatory agent to inflamed skin or
mucous membrane. Most often, a drug is administered into one body compartment, eg, the gut, and
must move to its site of action in another compartment, eg, the brain. This requires that the drug be
absorbed into the blood from its site of administration and distributed to its site of action,
permeating through the various barriers that separate these compartments. For a drug given orally
to produce an effect in the central nervous system, these barriers include the tissues that comprise
the wall of the intestine, the walls of the capillaries that perfuse the gut, and the "blood-brain
barrier," the walls of the capillaries that perfuse the brain. Finally, after bringing about its effect, a
drug should be eliminated at a reasonable rate by metabolic inactivation, by excretion from the
body, or by a combination of these processes.
Permeation
Drug permeation proceeds by four primary mechanisms. Passive diffusion in an aqueous or lipid
medium is common, but active processes play a role in the movement of many drugs, especially
those whose molecules are too large to diffuse readily.
Aqueous Diffusion
Aqueous diffusion occurs within the larger aqueous compartments of the body (interstitial space,
cytosol, etc) and across epithelial membrane tight junctions and the endothelial lining of blood
vessels through aqueous pores that—in some tissues—permit the passage of molecules as large as
MW 20,000–30,000.*
* The capillaries of the brain, the testes, and some other tissues are characterized by absence of the
pores that permit aqueous diffusion of many drug molecules into the tissue. They may also contain
high concentrations of drug export pumps (MDR pumps; see text). These tissues are therefore
"protected" or "sanctuary" sites from many circulating drugs.
Aqueous diffusion of drug molecules is usually driven by the concentration gradient of the
permeating drug, a downhill movement described by Fick's law (see below). Drug molecules that
are bound to large plasma proteins (eg, albumin) will not permeate these aqueous pores. If the drug
is charged, its flux is also influenced by electrical fields (eg, the membrane potential and—in parts
of the nephron—the transtubular potential).
Lipid Diffusion
Lipid diffusion is the most important limiting factor for drug permeation because of the large
number of lipid barriers that separate the compartments of the body. Because these lipid barriers
separate aqueous compartments, the lipid:aqueous partition coefficient of a drug determines how
readily the molecule moves between aqueous and lipid media. In the case of weak acids and weak
bases (which gain or lose electrical charge-bearing protons, depending on the pH), the ability to
move from aqueous to lipid or vice versa varies with the pH of the medium, because charged
molecules attract water molecules. The ratio of lipid-soluble form to water-soluble form for a weak
acid or weak base is expressed by the Henderson-Hasselbalch equation (see below).
Special Carriers
Special carrier molecules exist for certain substances that are important for cell function and too
large or too insoluble in lipid to diffuse passively through membranes, eg, peptides, amino acids,
glucose. These carriers bring about movement by active transport or facilitated diffusion and, unlike
passive diffusion, are saturable and inhibitable. Because many drugs are or resemble such naturally
occurring peptides, amino acids, or sugars, they can use these carriers to cross membranes.
Many cells also contain less selective membrane carriers that are specialized for expelling foreign
molecules, eg, the P-glycoprotein or multidrug-resistance type 1 (MDR1) transporter found in
the brain, testes, and other tissues, and in some drug-resistant neoplastic cells. A similar transport
molecule, the multidrug resistance-associated protein-type 2 (MRP2) transporter, plays an
important role in excretion of some drugs or their metabolites into urine and bile.
Endocytosis and Exocytosis
A few substances are so large or impermeant that they can enter cells only by endocytosis, the
process by which the substance is engulfed by the cell membrane and carried into the cell by
pinching off of the newly formed vesicle inside the membrane. The substance can then be released
inside the cytosol by breakdown of the vesicle membrane. This process is responsible for the
transport of vitamin B12, complexed with a binding protein (intrinsic factor), across the wall of the
gut into the blood. Similarly, iron is transported into hemoglobin-synthesizing red blood cell
precursors in association with the protein transferrin. Specific receptors for the transport proteins
must be present for this process to work. The reverse process (exocytosis) is responsible for the
secretion of many substances from cells. For example, many neurotransmitter substances are stored
in membrane-bound vesicles in nerve endings to protect them from metabolic destruction in the
cytoplasm. Appropriate activation of the nerve ending causes fusion of the storage vesicle with the
cell membrane and expulsion of its contents into the extracellular space
reference
Bertam G.Katzung
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