CONTRIBUTIONS OF
MANY CULTURES
The ancient Chinese wrote
extensively on medical subjects. The Pen
Tsao, for instance, was written about 2700 B.C. and contained classifications of individual
me-dicinal plants as well as compilations of plant mixtures to be used for
medical purposes. The Chinese doctrine
of signatures (like used to treat
like) enables us to un-derstand why medicines of animal origin were of such
great importance in the Chinese pharmacopoeia.
Ancient Egyptian medical
papyri contain numerous prescriptions. The largest and perhaps the most
impor-tant of these, the Ebers papyrus
(1550 B.C.), contains about 800
prescriptions quite similar to those written today in that they have one or
more active substances as well as vehicles (animal fat for ointments; and
water, milk, wine, beer, or honey for liquids) for suspending or dissolving the
active drug. These prescriptions also com-monly offer a brief statement of how
the preparation is to be prepared (mixed, pounded, boiled, strained, left
overnight in the dew) and how it is to be used (swal-lowed, inhaled, gargled,
applied externally, given as an enema). Cathartics and purgatives were particularly
in vogue, since both patient and physician could tell al-most immediately
whether a result had been achieved. It was reasoned that in causing the
contents of the gas-trointestinal tract to be forcibly ejected, one
simultane-ously drove out the disease-producing evil spirits that had taken
hold of the unfortunate patient.
The level of drug usage
achieved by the Egyptians undoubtedly had a great influence on Greek medicine
and literature. Observations on the medical effects of various natural
substances are found in both the Iliad
and the Odyssey. Battle wounds
frequently were cov-ered with powdered plant leaves or bark; their astrin-gent
and pain-reducing actions were derived from the tannins they contained. It may
have been mandrake root (containing atropinelike substances that induce a
twilight sleep) that protected Ulysses from Circe. The oriental hellebore,
which contains the cardiotoxic Veratrum alkaloids,
was smeared on arrow tips to in-crease their killing power. The fascination of
the Greeks with the toxic effects of various plant extracts led to an
increasing body of knowledge concerned primarily with the poisonous aspects of
drugs (the science of toxicol-ogy).
Plato’s description of the death of Socrates is an accurate description of the toxicological properties of the juice
of the hemlock fruit. His description of the paralysis of sensory and motor
nerves, followed eventu-ally by central nervous system depression and
respira-tory paralysis, precisely matches the known actions of the potent hemlock
alkaloid, coniine.
The Indian cultures of
Central and South America, although totally isolated from the Old World,
developed drug lore and usage in a fashion almost parallel with that of the
older civilization. The use of drugs played an inti-mate part in the rites,
religions, history, and knowledge of the South American Indians. New World
medicine also was closely tied to religious thought, and Indian cultures
treated their patients with a blend of religious rituals and herbal remedies.
Incantations, charms, and appeals to various deities were as important as the
appropriate ap-plication of poultices, decoctions, and infusions.
Early drug practitioners,
both in Europe and South America, gathered herbs, plants, animals, and minerals
and often blended them into a variety of foul-smelling and ill-flavored
concoctions. The fact that many of these preparations were so distasteful led
to an attempt to improve on the “cosmetic” properties of these mixtures to
ensure that patients would actually use them. Individuals who searched for
improved product formu-lations were largely responsible for the founding of the
disciplines of pharmacy (the science
of preparing, com-pounding, and dispensing medicines) and pharmacog-nosy (the identification and preparation of crude drugs from natural sources).
There has long been a
tendency of some physicians to prescribe large numbers of drugs where one or
two would be sufficient. We can trace the history of this polypharmaceutical
approach to Galen (A.D. 131–201), who was considered the greatest European physician
after Hippocrates. Galen believed that drugs had cer-tain essential properties,
such as warmth, coldness, dry-ness, or humidity, and that by using several
drugs he could combine these properties to adjust for deficien-cies in the
patient. Unfortunately, he often formulated general rules and laws before
sufficient factual informa-tion was available to justify their formulations.
By the first century A.D. it was clear to both
physi-cian and protopharmacologist alike that there was much variation to be
found from one biological extract to another, even when these were prepared by
the same individual. It was reasoned that to fashion a rational and
reproducible system of therapeutics and to study phar-macological activity one had
to obtain standardized and uniform medicinal agents.
At the turn of the nineteenth
century, methods be-came available for the isolation of active principles from
crude drugs. The development of chemistry made it pos-sible to isolate and
synthesize chemically pure com-pounds that would give reproducible biological
results. In 1806, Serturner (1783–1841) isolated the first pure ac-tive
principle when he purified morphine from the opium poppy. Many other chemically
pure active com-pounds were soon obtained from crude drug prepara-tions,
including emetine by Pelletier (1788–1844) from ipecacuanha root; quinine by
Carentou (1795–1877) from cinchona bark; strychnine by Magendie (1783– 1855)
from nux vomica; and, in 1856, cocaine by Wohler (1800–1882) from coca.
The isolation and use of pure
substances allowed for an analysis of what was to become one of the basic
con-cerns of pharmacology, that is, the quantitative study of drug action. It
was soon realized that drug action is pro-duced along a continuum of effects,
with low doses pro-ducing a less but essentially similar effect on organs and
tissues as high doses. It also was noted that the appear-ance of toxic effects
of drugs was frequently a function of the dose–response relationship.
Until the nineteenth century,
the rapid development of pharmacology as a distinct discipline was hindered by
the lack of sophisticated chemical methodology and by limited knowledge of
physiological mechanisms. The significant advances made through laboratory
studies of animal physiology accomplished by early investigators such as
Françoise Magendie and Claude Bernard pro-vided an environment conducive to the
creation of sim-ilar laboratories for the study of pharmacological phe-nomena.
One of the first laboratories
devoted almost exclu-sively to drug research was established in Dorpat,
Estonia, in the late 1840s by Rudolph Bucheim (1820– 1879) (Fig. 1.1). The
laboratory, built in Bucheim’s home, was devoted to studying the actions of
agents such as cathartics, alcohol, chloroform, anthelmintics, and heavy
metals. Bucheim believed that “the investi-gation of drugs . . . is a task for
a pharmacologist and not for a chemist or pharmacist, who until now have been
expected to do this.”
Although the availability of
a laboratory devoted to pharmacological investigations was important, much more
was required to raise this discipline to the same prominent position occupied
by other basic sciences; this included the creation of chairs in pharmacology
at other
academic institutions and the
training of a sufficient num-ber of talented investigators to occupy these
positions. The latter task was accomplished largely by Bucheim’s pupil and
successor at Dorpat, Oswald Schmiedeberg (1838–1921), undoubtedly the most
prominent pharma-cologist of the nineteenth century (Fig. 1.1). In addition to
conducting his own outstanding research on the pharma-cology of diuretics,
emetics, cardiac glycosides, and so forth, Schmiedeberg wrote an important
medical text-book and trained approximately 120 pupils from more than 20
countries. Many of these new investigators either started or developed
laboratories devoted to experimen-tal pharmacology in their own countries.
One of Schmiedeberg’s most
outstanding students was John Jacob Abel, who has been called the founder of
American pharmacology (Fig 1.1). Abel occupied the chair of pharmacology first
at the University of Michigan and then at Johns Hopkins University. Among his
most important research accomplishments is an examination of the chemistry and
isolation of the active principles from the adrenal medulla (a monobenzyl
derivative of epinephrine) and the pancreas (crystallization of in-sulin). He
also examined mushroom poisons, investigated the chemotherapeutic actions of
the arsenicals and anti-monials, conducted studies on tetanus toxin, and
de-signed a model for an artificial kidney. In addition, Abel founded the Journal of Experimental Medicine, the Journal of Biological Chemistry, and the Journal of Pharmacology and Experimental
Therapeutics. His devo-tion to pharmacological research, his enthusiasm for
the training of students in this new discipline, and his estab-lishment of
journals and scientific societies proved criti- cal to the rise of experimental
pharmacology in the United States.
Pharmacology, as a separate
and vital discipline, has interests that distinguish it from the other basic
sciences and pharmacy. Its primary concern is not the cataloguing of the
biological effects that result from the administra-tion of chemical substances
but rather the dual aims of providing an understanding of normal and abnormal
human physiology and biochemistry through the appli-cation of drugs as
experimental tools and (2) applying to clinical medicine the information gained
from funda-mental investigation and observation.
A report in the Status of Research in Pharmacology has
described some of the founding principles on which the discipline is based and
that distinguish pharmacol-ogy from other fields of study. These principles
include the study of the following:
·
The relationship between drug concentration and biological response Drug action over time
·
Factors affecting absorption, distribution, bind-ing, metabolism,
and elimination of chemicals Structure-activity
relationships
·
Biological changes that result from repeated drug use: tolerance,
addiction, adverse reactions, altered rates of drug metabolism, and so forth
·
Antagonism of the effects of one drug by an-other
·
The process of drug interaction with cellular macromolecules
(receptors) to alter physiolog-ical function (i.e., receptor theory)
In the past 100 years there
has been extraordinary growth in medical knowledge. This expansion of
infor-mation has come about largely through the contribu-tions of the
biological sciences to medicine by a system-atic approach to the understanding
and treatment of disease. The experimental method and technological advances
are the foundations upon which modern med-icine is built.
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