A brief history of pharmacology

Originating in the 19th century, the discipIine makes drug

deveIopment possibIe.
Pharmacology is one oI the cornerstones oI the drug discovery process. The
medicinal chemist may create the candidate compound, but the pharmacologist is
the one who tests it Ior physiologic activity. A promising compound is investigated
by many other scientiststoxicologists, microbiologists, cliniciansbut only aIter
the pharmacologist has documented a potential therapeutic eIIect. This article
brieIly presents the historical development oI pharmacology and some oI the basic
methods used.
Etymologically, pharmacology is the science oI drugs (Greek pharmakos, medicine
or drug; and logos, study). In actual use, however, its meaning is limited to the
study oI the actions oI drugs. Pharmacology has been deIined as 'an experimental
science which has Ior its purpose the study oI changes brought about in living
organisms by chemically acting substances (with the exception oI Ioods), whether
used Ior therapeutic purposes or not.
Pharmacology studies the eIIects oI drugs and how they exert their eIIects. There is a distinction between what a
drug does and how it acts. Thus, amoxicillin cures a strep throat, and cimetidine promotes the healing oI duodenal
ulcers. Pharmacology asks 'How? Amoxicillin inhibits the synthesis oI cell wall mucopeptide by the bacteria that
cause the inIection, and cimetidine inhibits gastric acid secretion by its antagonist action on histamine H2 receptors.
The main tasks oI pharmacologists in the search Ior and development oI new medicines are
O screening Ior desired activity,
O determining mode oI action, and
O 6uantiIying drug activity when chemical methods are not available.
istoricaI deveIopment
Synthetic organic chemistry was born in 1828, when Friedrich Wohler synthesized urea Irom inorganic substances
and thus demolished the vital Iorce theory. The birth date oI pharmacology is not as clear-cut. In the early 19th
century, physiologists perIormed many pharmacologic studies. Thus, Franois Magendie studied the action oI nux
vomica (a strychnine-containing plant drug) on dogs, and showed that the spinal cord was the site oI 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 oI muscle by nerve impulses.
Nevertheless, pharmacology is held to have emerged as a separate science only when the Iirst university chair was
established. According to Walter Sneader,

this occurred in 1847, when RudolI Buchheim was appointed proIessor oI
pharmacology at the University oI Dorpat in Estonia (then a part oI Russia). Lacking outside Iunding, Buchheim
built a laboratory at his own expense in the basement oI his home. Although Buchheim is credited with turning the
purely descriptive and empirical study oI medicines into an experimental science, his reputation is overshadowed by
that oI his student, Oswald Schmiedeberg.
Oswald Schmiedeberg (18381921) is generally recognized as the Iounder oI modern pharmacology. The son oI a
Latvian Iorester, Schmiedeberg obtained his medical doctorate in 1866 with a thesis on the measurement oI
chloroIorm in blood. He worked at Dorpat under Buchheim, succeeding him in 1869. In 1872, he became proIessor
oI pharmacology at the University oI Strassburg, receiving generous government support in the Iorm oI a
magniIicent institute oI pharmacology. He studied the pharmacology oI chloroIorm and chloral hydrate. In 1869,
Schmiedeberg showed that muscarine evoked the same eIIect on the heart as electrical stimulation oI the vagus
nerve. In 1878, he published a classic text, :9line of Pharmacology, and in 1885, he introduced urethane as a
hypnotic.

OswaId Schmiedeberg, 1838-
1921. PHOTO: NATONAL LBRARY OF
MEDCNE
In his 46 years at Strassburg, Schmiedeberg trained most oI the men who became proIessors at other German
universities and in several Ioreign countries. He was largely responsible Ior the preeminence oI the German
pharmaceutical industry up to World War II.
In the United States, the Iirst chair in pharmacology was established at the University oI 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
oI epinephrine Irom adrenal gland extracts (18971898), isolation oI histamine Irom pituitary extract (1919), and
preparation oI pure crystalline insulin (1926). His student Reid Hunt discovered acetylcholine in adrenal extracts in
1906.
Today, there is a pharmacology department in every college oI medicine or pharmacy.
nimaI 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 Iirst alkaloid Irom opium in 1805,
administered a whopping dose (100 mg) to himselI and three Iriends. All experienced the symptoms oI severe opium
poisoning Ior several days. The alkaloid was named morphine, Ior Morpheus, the Greek god oI sleep.
An interesting example oI the use oI humans Ior testing occurred in the 1940s. Although digitalis had been a
standard medication Ior heart disease Ior more than a century, there were still no reliable methods Ior evaluating its
potency. Biological assays (bioassays) were perIormed on Irogs, pigeons, and cats, but none were totally satisIactory.
In 1942, a group oI cardiologists published 'a method Ior bioassay oI digitalis in humans. The assay was based on
6uantitative changes in the electrocardiogram (ECG) oI patients in the cardiac clinics oI two New York City
hospitals. It was hard to Iind patients whose ECGs could be standardized. OI 97 patients in whom calibration oI the
ECG was tried, only 18 proved to be satisIactory assay subjects. Fortunately, chemical research on the active
glycosides oI digitalis, and development oI 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 suIIicient preclinical testing to show potential therapeutic action and
reasonable saIety on short-term administration, and the data have been reviewed by the FDA, the compound is
administered to a small number oI human volunteers under closely controlled and monitored conditions. These
Phase I clinical trials provide inIormation about dosage and the most common side eIIects to be expected.
The animals most Ire6uently used in pharmacologic studies are mammals. Mice are preIerred because oI their small
size, ease oI breeding, and short generation time. Rats, guinea pigs, rabbits, and dogs are also used; each has special
characteristics that make it optimal Ior certain types oI tests.
asic techniques
Experimental pharmacology uses animals in various ways. Intact animals are essential Ior the acute, subacute, and
chronic toxicity tests that a new drug substance must undergo, and Ior 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 oI target activities.
Early in the development oI pharmacologic techni6ues, it was Iound that an isolated organ or tissue remained
Iunctional Ior several hours in a bath containing a physiologic solution oI salts through which oxygen was bubbled.
Henrick Magnus (18021870) Iirst applied this method to a strip oI small intestine, Jean-Franois Heymans (1904)
worked with the mammalian heart, and Claude Bernard experimented with isolated nervemuscle preparations.
The organ or tissue is so suspended that the contraction or relaxation oI 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 eIIects oI 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 Iorce transducers to polygraph machines, which produce similar tracings. Or the polygraph is
replaced by computerized e6uipment that issues a digital record.
The surgical preparation oI animals is illustrated by the Iollowing 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
oI 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 oI
estrogenic hormones. To study anti-inIlammatory agents, rats can be made arthritic by injection oI an oily
suspension oI killed bacteria (Freund`s adjuvant).
Drugs aIIecting gastric secretion may be studied in animals by Iorming a Heidenhain poucha small sac oI the
stomach, vagally denervated and closed oII Irom the main cavity, but with an opening through the abdominal wall.
#ationaI design
Screening oI candidate compounds and mode-oI-action studies may Iocus on speciIic tissues, organs, or systems or
on actions, such as antihistaminic or anticonvulsant. As knowledge oI human biochemistry and molecular biology
advances, pharmacology zeroes in more oIten on enzymatic action and receptors.
Captopril (Capoten), developed by M. Ondetti and co-workers at S6uibb in the 1970s, exempliIies a molecule that
was rationally designed to Iit the active site oI an enzymeangiotensin converting enzyme (ACE). This drug, and
subse6uent ACE inhibitors, reduces blood pressure.
Knowledge oI cell receptors is now on the cutting edge oI pharmacology and drug discovery. The concept was Iirst
proposed about a hundred years ago by Paul Ehrlich, the great bacteriologist and chemist who synthesized salvarsan
(also known as '606) Ior the treatment oI syphilis. On the basis oI his research on bacterial toxins, Ehrlich
postulated that the body`s cells possess a great many 'receptors by which they combine with the Iood substances in
the body Iluids. He theorized that the metabolic products oI certain bacteria combine with the receptors oI some cells,
thus injuring the cells. Ehrlich visualized receptors as unsatisIied chemical side chains. This is not Iar Irom the
modern idea oI receptors as domains in enzymes or other proteins, with which drugs oI appropriate structure can
combine.
Illustrating the importance oI receptor research are drugs that act on the adrenergic (sympathetic) nervous system.
This system has both - and -receptors. Propranolol (Inderal) was the Iirst speciIic -adrenergic receptor blocking
agent. Marketed in 1964, it ended a long drought in new heart medicines and soon became a major therapy Ior
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 preIerential eIIect on l receptors, which are chieIly located in heart
muscle. At higher doses, they also inhibit 2 receptors, which are Iound mainly in the bronchial and vascular
musculature. We also have blockers oI 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 oI techni6ues, both general and specialized. Building on its past, the
ongoing progress oI pharmacology supports its critical role in modern drug discovery and augurs well Ior the Iuture.