DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

Pharmacodynamics: Molecular
Mechanisms of Drug Action
Donald K. Blumenthal and
James C. Garrison
Pharmacodynamics is the study of the biochemical and
physiological effects of drugs and their mechanisms of
action. Understanding pharmacodynamics can provide
the basis for the rational therapeutic use of a drug and
the design of new and superior therapeutic agents.
Simply stated, pharmacodynamics refers to the effects
of a drug on the body. In contrast, the effects of the
body on the actions of a drug are pharmacokinetic
processes (Chapter 2), and include absorption, distribution,
metabolism, and excretion of drugs (often
referred to collectively as ADME). Many adverse
effects of drugs and drug toxicities can be anticipated
by understanding a drug’s mechanism(s) of action, its
pharmacokinetics, and its interactions with other drugs.
Thus, both the pharmacodynamic properties of a drug
and its pharmacokinetics contribute to safe and successful
therapy. The effects of many drugs, both salutory
and deleterious, may differ widely from patient to
patient due to genetic differences that alter the pharmacokinetics
and the pharmacodynamics of a given drug.
This aspect of pharmacology is termed pharmacogenetics
and is covered in Chapter 7.
PHARMACODYNAMIC CONCEPTS
The effects of most drugs result from their interaction
with macromolecular components of the organism.
These interactions alter the function of the pertinent
component and initiate the biochemical and physiological
changes that are characteristic of the response to
the drug. The term drug receptor or drug target denotes
the cellular macromolecule or macromolecular complex
with which the drug interacts to elicit a cellular
response, i.e., a change in cell function. Drugs commonly
alter the rate or magnitude of an intrinsic cellular
response rather than create new responses. Drug receptors
are often located on the surface of cells, but may
also be located in specific intracellular compartments
such as the nucleus. Many drugs also interact with
acceptors (e.g., serum albumin) within the body.
Acceptors are entities that do not directly cause any
change in biochemical or physiological response.
However, interactions of drugs with acceptors such as
serum albumin can alter the pharmacokinetics of a
drug’s actions.
From a numerical standpoint, proteins form the
most important class of drug receptors. Examples
include the receptors for hormones, growth factors,
transcription factors, and neurotransmitters; the
enzymes of crucial metabolic or regulatory pathways
(e.g., dihydrofolate reductase, acetylcholinesterase, and
cyclic nucleotide phosphodiesterases); proteins
involved in transport processes (e.g., Na + ,K + -ATPase);
secreted glycoproteins (e.g., Wnts); and structural proteins
(e.g., tubulin). Specific binding of drugs to other
cellular constituents such as DNA is also exploited for
therapeutic purposes. For example, nucleic acids are
particularly important drug receptors for certain cancer
chemotherapeutic agents and antiviral drugs.
Physiological Receptors
A major group of drug receptors consists of proteins
that normally serve as receptors for endogenous regulatory
ligands. These drug targets are termed physiological
receptors. Many drugs act on physiological
receptors and are particularly selective because physiological
receptors have evolved to recognize and
respond to individual signaling molecules with great
selectivity. Drugs that bind to physiological receptors
and mimic the regulatory effects of the endogenous