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Therapeutic and toxic effects of the majority of drugs result
from their interactions with molecular targets, that is, receptors,
in the patient. The drug molecule (the ligand) interacts with the
receptor and initiates the chain of biochemical and physiologic
events leading to the drug’s observed effects. This ligand-receptor
interaction and its results are denoted as pharmacodynamics.
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The receptor concept has important practical consequences for
the development of drugs. It forms the basis for understanding the
actions and clinical uses of drugs described in almost every chapter
of this book. These consequences may be briefly summarized as follows:
First, receptors largely determine the quantitative relations between
dose or concentration of drug and pharmacologic effects. The receptor’s
affinity for binding a drug determines the concentration of drug required
to form a significant number of ligand-receptor complexes, and the
total number of receptors may limit the maximal effect a drug may
produce. Second, receptors are responsible for selectivity of drug
action. The molecular size, shape, and electrical charge of a drug
determine whether the drug will bind to a particular receptor among
the vast array of chemically different binding sites available in
the patient. Accordingly, changes in the chemical structure of a
drug can dramatically increase or decrease its affinities for different
classes of receptors, with resulting alterations in therapeutic
and toxic effects. Third, receptor activation and blockade play
a key role in the mechanisms of many clinical effects of drugs.
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As previously discussed (Chapter 1), receptors are specific molecules
with which drugs interact to produce changes in the function of
cells within the patient. Receptors must be selective in their binding
characteristics in order to respond to specific chemical stimuli.
The receptor site presents a unique three-dimensional configuration
for the drug to bind. The complementary configuration of the drug
is, in part, what creates the affinity of the drug for the receptor
site (Figure 2–1). Drugs that bind to a limited group of
receptor types may be classified as specific, whereas drugs binding to
a larger number of receptor types may be considered nonspecific.
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Drugs interact with receptors by means of chemical bonds. The
three major types of bonds are covalent, electrostatic, and hydrophobic.
Covalent bonds are strong and, in many cases, not reversible
under biologic conditions. Electrostatic bonds are weaker than
covalent bonds, more common, and often reversible. Hydrophobic bonds
are the weakest and are probably the most important in the interactions
of lipid-soluble drugs and in hydrophobic “pockets” of
receptors.