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					A Brief History of Pharmacology
PROBLEM • "I have an earache" SOLUTION
• • • • • • 2000 BC1000 AD1850 AD1940 AD1985 AD2000 ADHere, eat this root That root is heathen, say this prayer That prayer is superstition, drink this potion That potion is snake oil, swallow this pill That pill is ineffective, take this antibiotic That antibiotic is artificial , here eat this root

Introduction
What is pharmacology?
Pharmacology is the study of how drugs exert their effects on living systems. Pharmacologists work to identify drug targets in order to learn how drugs work. Pharmacologists also study the ways in which drugs are modified within organisms.

What is a drug?
Drugs can be defined as chemical agents that uniquely interact with specific target molecules in the body, thereby producing a biological effect

Why do you need to know pharmacology?
• Percent of persons using at least one prescription drug in the past month: 45 (1999-2002) (National Center for Health Statistics) • At age 18-45: 251 drugs per 100 population • At age 45-65: 505 drugs per 100 population • At age 65+ : 1047 drugs per 100 population • The average patient seeking medical evaluation* was taking 3.5 prescription meds (this does not include OTC drugs) • The average number of prescription written during a medical evaluation* was 2.1 (2.2 for ER visit).
* Evaluation for a complaint, i.e. not a routine examination

History of Pharmacology
A history of pharmacology Ancient Times A series of scattered facts exists that speak of the early history of humankind's efforts to harness the healing properties of natural compounds. However, what we know for certain is that ancient peoples made extensive use of plant, animal and mineral sources for this purpose.

• “Medicinal Plants in a Middle Paleolithic Grave Shanidar IV” J. Ethanophramacology, 1992. • J. Leitava reports the discovery of pollen from plants lacking both “aromatic or decorative potential” in the burial sites of Homo neanderthalensis dated to ~60,000 years ago. These six plants are the source of demonstrably theraputic substances.

Assyria

Cuneiform tablets recovered from the library of Ashurbanipal (circa 2000 BCE) contain detailed descriptions of the preparation of numerous remedies

History of Pharmacology
The Ebers papyrus, written in Egypt in the 16th century B.C., lists the extensive pharmacopia of that civilization. Included in this are: beer, turpentine, myrrh, juniper berries, poppy, lead, salt and crushed precious stones. Also included were products derived from animals, including lizard's blood, swine teeth, goose grease, ass hooves and the excreta from various animals. The effects of many of these drugs on patients of antiquity can only be imagined. The Kahun papyrus (1825 BCE) describes a combination of crocodile dung, honey and sour milk as a highly effective contraceptive.

History of Pharmacology
From ancient China comes evidence of that culture's extensive efforts to heal through the use of natural products. The Pen Tsao Kang Mu, or Great Herbal, comprised forty volumes describing several thousands of prescriptions. It was complied during the Ming dynasty by Le Shih Chen (1518-1593AD) and widely translated both in the east & west.

History of Pharmacology
Interestingly, the eastern herb Artemisia annua L. (wormwood), used in China since antiquity to treat fevers, is the source of the modern drug qinghaosu (Artemisinin) which shows great promise as a modern anti-malarial compound. It is tolerated much better than “traditional” antimalarials and resistance to its effects have not been described.

History of Pharmacology
Antiquity to the modern era
The ancients considered disease a consequence of demonic possession, or the wrath of god. Thus, in ancient times, the treatment of illness with natural products was invariably accompanied by religious rituals deemed essential to the healing process. Some aspects of modern treatment continue to involve ritual.

History of Pharmacology
• A major impediment to the advancement of medicine & pharmacology was the humoral basis of medicine whose major proponent was Hippocrates: the four humor of the body were: black bile, yellow bile, phlegm and blood. Imbalance of these humors was responsible for disease and the temperament of the individual (melancholic, choleric, phlegmatic and sanguine). These correlated with Aristotle's four basic elements: earth (cold), fire (hot), water (wet) & air (dry).

History of Pharmacology
• Treatments to regain the humoral balance used combinations of “drugs” consisting of various amounts of characteristics of the elements (hot,cold,wet,dry). John Gerard (1545-1612) authored an herbal compendium which catalogued the characteristics of medicinal plants with respect to the four humors. Fever (too much heat) was treated with mendicants composed of cool and wet plants.

Paracelcus

Paracelsus
Paracelsus (11 November or 17 December 1493 in Einsiedeln, Switzerland - 24 September 1541) was an alchemist, physician, astrologer, and general occultist. Born Phillip von Hohenheim, he later took up the name Philippus Theophrastus Aureolus Bombastus von Hohenheim, and still later took the title Paracelsus, meaning "equal to or greater than Celsus", a Roman physician from the first century BC. “Bier is a really divine medicine”.
Paracelsus (1493 – 1541).

Paracelsus: Genius with bad press agent
• Attended Universities of Heidelberg, Freiburg, Ingolstadt, Cologne, Tübingen, Vienna, Erfurt and Ferrara, left without degree, drank to excess, and wandered over most of known world, took part in the Peasants War (1525) Practiced medicine in Spain, Portugal, England, Denmark, Poland, Prussia, Hungary, Arabia, Egypt, Turkey, probably other places as well, frequently aggravating established practitioners. Investigated the use of opium, coined the term laudanum for tincture of opium, an opium extract containing 40-80% ethanol. Pioneered use of chemicals, elements in medicine (Zn, Hg, Au) Introduced draining to replace amputation or cauterization Introduced dose-response concept Recognized the first industrial disease in miners

• • • • • •

Paracelsus
• Alle Ding' sind Gift und nichts ohn' Gift; allein die Dosis macht, dass ein Ding kein Gift ist. ("All things are poison and nothing is without poison, only the dose permits something not to be poisonous.”)

Paracelsus crater photographed by Apollo 15. An 83 km crater on the far side of the moon.

Paracelsus: a few weird facts
• • • • “Paracelsus” a 1943 film by Georg Wilhelm Pabst, essentially a Nazi propaganda film. Professor Bulwer in 1922 Murnau film 'Nosferatu' is a follower of Paracelsus “Paracelsus” (lengthy dramatic poem by Robert Browning) Paracelsus is mentioned as an inspiration to Victor Frankenstein, the main character in Mary Shelley's Frankenstein. Paracelsus is one of the people featured on a Chocolate Frog card in Harry Potter. A bust of Paracelsus is in the castle at Hogwarts, near Gryffindor, between the entrance to the Gryffindor common room and the Owlry, as mentioned in Order of the Phoenix

•

History of Pharmacology
With time, thoughts returned to the appreciation that the natural products themselves held the power to cure. Although, traditional remedies still generally consisted of complex mixtures of distinct herbs and minerals, perhaps only one of which possessed any activity. Many poisonous mixtures were made.

History of Pharmacology
For example, the purple foxglove, Digitalis purpurea, was one of twenty herbs used in a folk remedy to treat dropsy* in 17th century England. From the leaves of this plant was isolated the cardiac glycoside digitalis, a drug still used today to treat heart failure.
* An old term for the swelling of soft tissues due to the accumulation of excess water.

• The first major challenge to the Aristotelian approach grew out of the alchemy of the 16th century, a number of medical alchemist strayed from the search for transmutation to the extraction of more effective remedies for disease. Medical alchemists focused on extraction of agents from medicinal plants through the process of distillation. One of the most popular books “Kleines Destillierbuch” (Little Book on Distilling) by Hieronymus Brunschwig was published in 1500 and widely used throughout the 16th century for medicinal concoctions.

• Distillation was described as increasing the “viture” of the distillate. This was best described for the universal panacea; wine. The third distillate produced “aqua vitae” (brandy) the tenth distillate produce “aqua ardente” (also called “burning water”). Of course any complaint would be silenced by a few doses of aqua ardente. “Grandpas medicine”, many tonics and elixirs even into the 20th century contained large amounts of alcohol.

History of Pharmacology
Over time, as a more sophisticated view of illness evolved, an increasingly scientific approach to the isolation of drugs from natural products was taken. In the early 19th century,

morphine was isolated from the opium poppy (Papaver somniferum) and the anti-malarial compound quinine from the bark of the cinchona tree (Cinchona officinalis).

History of Pharmacology
Materia Medica
The ancient discipline of Materia Medica was devoted to understanding the origin, preparation and therapeutic applications of medicinal compounds. It postulated that: • Each disease has a unique cause for which there is a specific remedy. • Each remedy has an identifiable nature or essence that is extracted from the natural product by chemical extraction. • The administration of a remedy is based on testing the amount of drug needed to achieve an effect (dose-response).

History of Pharmacology
In 1897, Felix Hoffman, a research chemist employed by the "Farbenfabrikin vorm. Freidr. Bayer and Co." synthesized acetylsalicylic acid. On February 1, 1899, Aspirin® was registered as a trademark. On March 6th of the same year, this drug was registered with the Imperial Patent Office in Berlin. Aspirin quickly become popular worldwide, and remains an important drug today. (Interestingly, it was not until 1971 that Sir John Vane discovered the mechanism of action of aspirin, a feat that earned him the 1981 Nobel Prize for Medicine.)

History of Pharmacology
Paul Ehrlich described drug-receptor binding:

“Corpora non agunt nisi fixate”.
P. Ehrlich (1908)

(“Agents do not act unless they are bound”)
In the United States recognition of pharmacology as an independent science was marked by the creation of the American Society for Pharmacology and Experimental Therapeutics (ASPET) in 1908.

History of Pharmacology
The modern era These, and additional advances in the fields of chemistry and physiology, lead to the birth of modern pharmacology in the latter half of the 19th century. Thus, Materia Medica evolved into the experimental science of pharmacology, which is devoted to understanding the physiological action of these molecules.

History of Pharmacology
The 20th century has witnessed the discovery of a steady stream of important new drugs that have immeasurably improved the human condition. Not very long ago, vast numbers of humans perished prematurely or suffered an existence filled with pain due to the effects of infection or disorders that are now successfully treated.
chemotherapy of cancer microbial infections diabetes hypertension depression AIDS

Pharmacology
DEFINITIONS: Pharmacology is the study of how drugs exert their effects on living systems. Pharmacologists work to identify drug targets in order to learn how drugs work. Pharmacologists also study the ways in which drugs are modified within organisms. In most of the pharmacologic specialties, drugs are also used today as tools to gain insight into both normal and abnormal function.

Pharmacology
Divisions of Pharmacology • Pharmacokinetics • Pharmacodynamics • Pharmacogenomics

Pharmacokinetics
Is what the body does to the drug. The magnitude of the pharmacological effect of a drug depends on its concentration at the site of action. • Absorption • Distribution • Metabolism • Elimination

Pharmacodynamics
Is what the drug does to the body. Interaction of drugs with cellular proteins, such as receptors or enzymes, to control changes in physiological function of particular organs. • Drug-Receptor Interactions
– Binding

• Dose-Response
– Effect

• Signal Transduction
– Mechanism of action, Pathways

Pharmacogenetics
Area of pharmacology concerned with unusual responses to drugs caused by genetic differences between individuals. Responses that are not found in the general population, such as general toxic effects, allergies, or side effects, but due to an inherited trait that produces a diminished or enhanced response to a drug.
• Differences in Enzyme Activity – Acetylation polymorphism – Butylcholinesterase alterations – Cytochrome P450 aberration

Drugs
Drugs can be defined as chemical agents that uniquely interact with specific target molecules in the body, thereby producing a biological effect.

Drugs can be stimulatory or inhibitory

Drugs
• Drugs, as well as hormones, neurotransmitter, autocoids and toxins can make possible the transfer of information to cells by interaction with specific receptive molecules called “receptors”.

DRUG

Receptor

Drugs
• Drugs interact with biological systems in ways that mimic, resemble or otherwise affect the natural chemicals of the body. • Drugs can produce effects by virtue of their acidic or basic properties (e.g. antacids, protamine), surfactant properties (amphotericin), ability to denature proteins (astringents), osmotic properties (laxatives, diuretics), or physicochemical interactions with membrane lipids (general and local anesthetics).

Some Pharmacologists in History
• • • • • William Withering, 1741-1799 (digitalis) Claude Bernard 1813-1878 (d-tubo curare) Friedrich Sertürner 1783--1841 (morphine) Rudolf Buchheim 1820-1879 (1st Pharmacology Laboratory, University of Dorpat (now Tartu, Estonia) Oswald Schmiedeberg 1838-1921 (Strassburg, now Strasbourg, trained many pharmacologists) John Langley 1852--1926 (Receptor concept) Paul Ehrlich 1854-1915 (Receptor concept) Otto Loewi, Henry Dale (Neurotransmission)

• • •


				
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