A brief history of pharmacology

Originating in the 19th century, the discipline makes drug development

possible.

Pharmacology is one of the cornerstones of the drug discovery process. The medicinal
chemist may create the candidate compound, but the pharmacologist is the one who
tests it for physiologic activity. A promising compound is investigated by many other
scientists—toxicologists, microbiologists, clinicians—but only after the
pharmacologist has documented a potential therapeutic effect. This article briefly
presents the historical development of pharmacology and some of the basic methods
used.

Etymologically, pharmacology is the science of drugs (Greek pharmakos, medicine or

drug; and logos, study). In actual use, however, its meaning is limited to the study of
the actions of drugs. Pharmacology has been defined as “an experimental science
which has for its purpose the study of changes brought about in living organisms by
chemically acting substances (with the exception of foods), whether used for
therapeutic purposes or not.”

Pharmacology studies the effects of drugs and how they exert their effects. There is a
distinction between what a drug does and how it acts. Thus, amoxicillin cures a strep
throat, and cimetidine promotes the healing of duodenal ulcers. Pharmacology asks
“How”? Amoxicillin inhibits the synthesis of cell wall mucopeptide by the bacteria
that cause the infection, and cimetidine inhibits gastric acid secretion by its antagonist
action on histamine H2 receptors.

The main tasks of pharmacologists in the search for and development of new
medicines are

• screening for desired activity,

• determining mode of action, and
• quantifying drug activity when chemical methods are not available.

Historical development
Synthetic organic chemistry was born in 1828, when Friedrich Wohler synthesized
urea from inorganic substances and thus demolished the vital force theory. The birth
date of pharmacology is not as clear-cut. In the early 19th century, physiologists
performed many pharmacologic studies. Thus, François Magendie studied the action
of nux vomica (a strychnine-containing plant drug) on dogs, and showed that the
spinal cord was the site of its convulsant action. His work was presented to the Paris
Academy in 1809. In 1842, Claude Bernard discovered that the arrow poison curare
acts at the neuromuscular junction to interrupt the stimulation of muscle by nerve
impulses.

Nevertheless, pharmacology is held to have emerged as a separate science only when

the first university chair was established. According to Walter Sneader, this occurred
in 1847, when Rudolf Buchheim was appointed professor of pharmacology at the
University of Dorpat in Estonia (then a part of Russia). Lacking outside funding,
Buchheim built a laboratory at his own expense in the basement of his home.
Although Buchheim is credited with turning the purely descriptive and empirical
study of medicines into an experimental science, his reputation is overshadowed by
that of his student, Oswald Schmiedeberg.

Oswald Schmiedeberg (1838–1921) is generally recognized as the founder of modern

pharmacology. The son of a Latvian forester, Schmiedeberg obtained his medical
doctorate in 1866 with a thesis on the measurement of chloroform in blood. He
worked at Dorpat under Buchheim, succeeding him in 1869. In 1872, he became
professor of pharmacology at the University of Strassburg, receiving generous
government support in the form of a magnificent institute of pharmacology. He
studied the pharmacology of chloroform and chloral hydrate. In 1869, Schmiedeberg
showed that muscarine evoked the same effect on the heart as electrical stimulation of
the vagus nerve. In 1878, he published a classic text, Outline of Pharmacology, and in
1885, he introduced urethane as a hypnotic.

In his 46 years at Strassburg, Schmiedeberg trained most of the men who became
professors at other German universities and in several foreign countries. He was
largely responsible for the preeminence of the German pharmaceutical industry up to
World War II.

In the United States, the first chair in pharmacology was established at the University
of Michigan in 1890 under John Jacob Abel, an American who had trained under
Schmiedeberg. In 1893, Abel went to Johns Hopkins University in Baltimore, where
he had a long and brilliant career. His major accomplishments include the isolation of
epinephrine from adrenal gland extracts (1897–1898), isolation of histamine from
pituitary extract (1919), and preparation of pure crystalline insulin (1926). His student
Reid Hunt discovered acetylcholine in adrenal extracts in 1906.

Today, there is a pharmacology department in every college of medicine or pharmacy.

Animal studies
Pharmacology depends largely on experiments conducted in laboratory animals, but
even the human animal may be used as a test subject. Friedrich Serturner, the German
pharmacist who isolated the first alkaloid from opium in 1805, administered a
whopping dose (100 mg) to himself and three friends. All experienced the symptoms
of severe opium poisoning for several days. The alkaloid was named morphine, for
Morpheus, the Greek god of sleep.

An interesting example of the use of humans for testing occurred in the 1940s.
Although digitalis had been a standard medication for heart disease for more than a
century, there were still no reliable methods for evaluating its potency. Biological
assays (bioassays) were performed on frogs, pigeons, and cats, but none were totally
satisfactory.

In 1942, a group of cardiologists published “a method for bioassay of digitalis in

humans”. The assay was based on quantitative changes in the electrocardiogram
(ECG) of patients in the cardiac clinics of two New York City hospitals. It was hard
to find patients whose ECGs could be standardized. Of 97 patients in whom
calibration of the ECG was tried, only 18 proved to be satisfactory assay subjects.
Fortunately, chemical research on the active glycosides of digitalis, and development
of analytical methods, soon rendered all digitalis bioassays obsolete.

Although humans are no longer used as ad hoc laboratory animals, they are essential
in clinical pharmacology. When a new drug compound has gone through sufficient
preclinical testing to show potential therapeutic action and reasonable safety on short-
term administration, and the data have been reviewed by the FDA, the compound is
administered to a small number of human volunteers under closely controlled and
monitored conditions. These Phase I clinical trials provide information about dosage
and the most common side effects to be expected.

The animals most frequently used in pharmacologic studies are mammals. Mice are
preferred because of their small size, ease of breeding, and short generation time.
Rats, guinea pigs, rabbits, and dogs are also used; each has special characteristics that
make it optimal for certain types of tests.

Basic techniques
Experimental pharmacology uses animals in various ways. Intact animals are essential
for the acute, subacute, and chronic toxicity tests that a new drug substance must
undergo, and for important special tests such as teratology and carcinogenicity.
Pharmacology per se tends to use excised (isolated) organs or tissues and animals that
are surgically prepared in various ways to aid in the detection and study of target
activities.

Early in the development of pharmacologic techniques, it was found that an isolated

organ or tissue remained functional for several hours in a bath containing a
physiologic solution of salts through which oxygen was bubbled. Henrick Magnus
(1802–1870) first applied this method to a strip of small intestine, Jean-François
Heymans (1904) worked with the mammalian heart, and Claude Bernard
experimented with isolated nerve–muscle preparations.

The organ or tissue is so suspended that the contraction or relaxation of the muscle is
mechanically transmitted to a stylet. The stylet writes on a drum covered with smoked
paper rotated by clockwork at a constant speed. This device, called a kymograph,
graphically records motion or pressure. The effects of drug substances added to the
bath can thus be visualized. The kymograph is a relatively crude device. In modern
laboratories, organ and tissue movements are transmitted by force transducers to
polygraph machines, which produce similar tracings. Or the polygraph is replaced by
computerized equipment that issues a digital record.

The surgical preparation of animals is illustrated by the following examples. As early

as 1849, the German anatomist Arnold Berthold transplanted testicular tissue into a
capon (a castrated rooster) and showed that this induced growth of the comb. This
basic method was used in the 20th century to isolate and study the male sex
hormones.

Similarly, in 1924, Americans Edgar Allen and Edward Doisy used ovariectomized
rats to test the action of estrogenic hormones. To study anti-inflammatory agents, rats
can be made arthritic by injection of an oily suspension of killed bacteria (Freund’s
adjuvant).
Drugs affecting gastric secretion may be studied in animals by forming a Heidenhain
pouch—a small sac of the stomach, vagally denervated and closed off from the main
cavity, but with an opening through the abdominal wall.

Rational design
Screening of candidate compounds and mode-of-action studies may focus on specific
tissues, organs, or systems or on actions, such as antihistaminic or anticonvulsant. As
knowledge of human biochemistry and molecular biology advances, pharmacology
zeroes in more often on enzymatic action and receptors.

Captopril (Capoten), developed by M. Ondetti and co-workers at Squibb in the 1970s,

exemplifies a molecule that was rationally designed to fit the active site of an enzyme
—angiotensin converting enzyme (ACE). This drug, and subsequent ACE inhibitors,
reduces blood pressure.

Knowledge of cell receptors is now on the cutting edge of pharmacology and drug
discovery. The concept was first proposed about a hundred years ago by Paul Ehrlich,
the great bacteriologist and chemist who synthesized salvarsan (also known as “606”)
for the treatment of syphilis. On the basis of his research on bacterial toxins, Ehrlich
postulated that the body’s cells possess a great many “receptors” by which they
combine with the food substances in the body fluids. He theorized that the metabolic
products of certain bacteria combine with the receptors of some cells, thus injuring the
cells. Ehrlich visualized receptors as unsatisfied chemical side chains. This is not far
from the modern idea of receptors as domains in enzymes or other proteins, with
which drugs of appropriate structure can combine.

Illustrating the importance of receptor research are drugs that act on the adrenergic
(sympathetic) nervous system. This system has both - and -receptors. Propranolol
(Inderal) was the first specific -adrenergic receptor blocking agent. Marketed in
1964, it ended a long drought in new heart medicines and soon became a major
therapy for angina pectoris, cardiac arrhythmias, hypertension, and essential tremor.
However, all -adrenergic receptors are not identical, and propranolol is nonselective.
Second-generation drugs such as atenolol (Tenormin) and metoprolol (Lopressor),
developed in the late 1970s, have a preferential effect on l receptors, which are
chiefly located in heart muscle. At higher doses, they also inhibit 2 receptors, which
are found mainly in the bronchial and vascular musculature. We also have blockers of
the -adrenoreceptors, such as prazosin (Minipress; early 1980s), and 1-blockers,
such as terazosin (Hytrin; 1987). And there are / -blockers: Labetolol (Normodyne)
and carvedilol (Coreg), developed in the mid-1990s, exhibit selective 1 and non
selective -blocking action.

The methods and approaches touched on in this article are merely a sampling.
Pharmacology is similar to medicinal chemistry in that it has developed a vast array of
techniques, both general and specialized. Building on its past, the ongoing progress of
pharmacology supports its critical role in modern drug discovery and augurs well for
the future.
The History of Pharmacology
The History of Pharmacology

Since the dawn of humankind, mixtures of animal parts, plants and minerals to treat
wounds, sores and ailments evolved from rudimentary pharmacological compounds
into more sophisticated experiments to create medical treatments. Egypt first
documented herbal amalgams for healing. Archives of ancient Greek texts reveal the
extent of their medicinal knowledge of herbal mixtures. Chinese and Arab peoples
advanced pharmacology research of herbal and mineral benefits for medical
treatments as well. Early in the 20th century, modern pharmacology emerged with the
first synthetic compound created in Europe.

Prehistoric
1. Knowledge of pharmacology practiced by humans before the Egyptian and
Greek writings comes from archaeological findings. Because prehistoric
humans had no understanding of the inner workings of the human body,
pharmacology was a rational application of what they could see. These early
people treated wounds, burns and broken bones with plants and locally
gathered materials to assist in the healing.

The Medical Book of Thoth

2. Ancient Egyptian life evolved around their many gods. Thoth, the Egyptian
Goddess of knowledge, left 42 books directing how Egyptians should live.
Among these records, one specifically provides cures from plant and animal
mixtures for human ailments. Court records from Egypt's 18th Dynasty (1550
to 1292 B.C.E.) are the first known reference to this tome.

Ebers Papyrus
3. The Ebers papyrus, the world's oldest preserved medical and pharmacological
record, is believed to be a copy of the book of Thoth. It measures nearly 20.23
m in length and 30 cm in height. The 110-page scroll from 1552 B.C.E.
contains 700 medical and pharmacological recipes for treatments from
crocodile bites to intestinal afflictions as well as diabetes and arthritis.

China
4.

Shen Nong recorded hundreds of Chinese medicinal herbs over 4,000 years
ago.

Included in China's Shen Nong's "The Divine Farmer's Herb-Root Classic" are
365 medicine compounds made from minerals, plants and animals. Shen Nong
 personally tested the properties of hundreds of medical herbs he identified
around 2000 B.C.E. His experiments and documentation are the forerunner to
the development of traditional Chinese (herbal) medicine still used today.

Arabic Pharmacolgy
5.

Page from a medical book from Baghdad around 1224 C.E.

The first pharmacological medicine written in Arabic provided formulas

organized by preparation--powders, tablets, ointments and syrups. This work,
written by al-Agrabadhin tly Sabur bin Sahl in 869 C.E. provides recipes with
methods and techniques to create pharmacological preparations along with the
dosages.

Modern Pharmacology
6.

Friedrich Wohler made the first modern pharmacological compound.

Synthetic organic chemistry (modern pharmacology) took hold in Europe with

Germany's Friedrich Wohler. By synthesizing urine from organic substances,
Wohler debunked the vital force theory (the old assumption that organic
compounds only form in living cells and that it is impossible to prepare them
in laboratories). Wohler's protégé--Rudolph Buchheim--turned historical
descriptive and empirical medical studies into an experimental science, giving
birth to modern pharmacology in 1847. The first published classic
text--"Outline of Pharmacology"--written by Oswald Schmiedeberg in 1878,
set the momentum for today's pharmacology advancement throughout the
world.