Page 16 - Basic _ Clinical Pharmacology ( PDFDrive )

2 SECTION I Basic Principles

drug preparation and the medical uses of drugs—began to develop
Chemical
as the precursor to pharmacology. However, any real understand-
ing of the mechanisms of action of drugs was prevented by the
absence of methods for purifying active agents from the crude
Pharmacokinetics methods for testing hypotheses about the nature of drug actions.
materials that were available and—even more—by the lack of
Environment
Patient
In the late 18th and early 19th centuries, François Magendie
and his student Claude Bernard began to develop the methods
Other
Intended
targets
target
chemistry and the further development of physiology in the
tissues Unintended organisms of experimental physiology and pharmacology. Advances in
18th, 19th, and early 20th centuries laid the foundation needed
Pharmacodynamics Therapeutic Food Paradoxically, real advances in basic pharmacology during this
for understanding how drugs work at the organ and tissue levels.
chain
time were accompanied by an outburst of unscientific claims by
manufacturers and marketers of worthless “patent medicines.” Not
effects
until the concepts of rational therapeutics, especially that of the
controlled clinical trial, were reintroduced into medicine—only
about 60 years ago—did it become possible to adequately evaluate
Toxic More
effects organisms therapeutic claims.
Around the 1940s and 1950s, a major expansion of research
Medical pharmacology Environmental efforts in all areas of biology began. As new concepts and new
and toxicology toxicology
techniques were introduced, information accumulated about drug
action and the biologic substrate of that action, the drug receptor.
FIGURE 1–1 Major areas of study in pharmacology. The actions
of chemicals can be divided into two large domains. The first (left During the last 60 years, many fundamentally new drug groups
side) is that of medical pharmacology and toxicology, which is aimed and new members of old groups were introduced. The last four
at understanding the actions of drugs as chemicals on individual decades have seen an even more rapid growth of information
organisms, especially humans and domestic animals. Both beneficial and understanding of the molecular basis for drug action. The
and toxic effects are included. Pharmacokinetics deals with the molecular mechanisms of action of many drugs have now been
absorption, distribution, and elimination of drugs. Pharmacodynamics identified, and numerous receptors have been isolated, structurally
concerns the actions of the chemical on the organism. The second characterized, and cloned. In fact, the use of receptor identifica-
domain (right side) is that of environmental toxicology, which is tion methods (described in Chapter 2) has led to the discovery
concerned with the effects of chemicals on all organisms and their of many orphan receptors—receptors for which no ligand has
survival in groups and as species.
been discovered and whose function can only be guessed. Stud-
ies of the local molecular environment of receptors have shown
THE HISTORY OF PHARMACOLOGY that receptors and effectors do not function in isolation; they are
strongly influenced by other receptors and by companion regula-
Prehistoric people undoubtedly recognized the beneficial or toxic tory proteins.
effects of many plant and animal materials. Early written records Pharmacogenomics—the relation of the individual’s genetic
list remedies of many types, including a few that are still recog- makeup to his or her response to specific drugs—is becoming an
nized as useful drugs today. Most, however, were worthless or important part of therapeutics (see Chapter 5). Decoding of the
actually harmful. In the last 1500 years, sporadic attempts were genomes of many species—from bacteria to humans—has led
made to introduce rational methods into medicine, but none to the recognition of unsuspected relationships between recep-
was successful owing to the dominance of systems of thought tor families and the ways that receptor proteins have evolved.
(“schools”) that purported to explain all of biology and disease Discovery that small segments of RNA can interfere with protein
without the need for experimentation and observation. These synthesis with extreme selectivity has led to investigation of small
schools promulgated bizarre notions such as the idea that disease interfering RNAs (siRNAs) and micro-RNAs (miRNAs) as ther-
was caused by excesses of bile or blood in the body, that wounds apeutic agents. Similarly, short nucleotide chains called antisense
could be healed by applying a salve to the weapon that caused the oligonucleotides (ANOs), synthesized to be complementary to
wound, and so on. natural RNA or DNA, can interfere with the readout of genes and
Around the end of the 17th century, reliance on observation the transcription of RNA. These intracellular targets may provide
and experimentation began to replace theorizing in physiology the next major wave of advances in therapeutics.
and clinical medicine. As the value of these methods in the study Unfortunately, the medication-consuming public is still
of disease became clear, physicians in Great Britain and on the exposed to vast amounts of inaccurate or unscientific information
Continent began to apply them to the effects of traditional drugs regarding the pharmacologic effects of chemicals. This has resulted
used in their own practices. Thus, materia medica—the science of in the irrational use of innumerable expensive, ineffective, and