History of Pharmcology

This presentation is about birth of pharmacology, how Pharmacology evolved over the years and discovery important drugs

1. History of Pharmacology Dr. Manukumar Shetty Dept . Of Pharmacology Maulana Azad Medical College New Delhi Click to add text Click to add text 14th July 2018

2. Dr. Arvid Carlsson and his wife, Ulla-Lisa, after learning he would receive the  Nobel Prize (2000) in Physiology or Medicine.  June 29, 2018 Arvid Carlsson , Who Discovered a Treatment for Parkinson’s disease, Dies at 95 https://www.nytimes.com/2018/07/01/obituaries/arvid-carlsson-who-discovered-a-treatment-for-parkinsons-dies-at-95.html

3. Overview                                                                                                                                                                     TIME-45MIN

4. Why history of pharmacology? S cience is a permanent exchange between hypothesis  and experimental facts  Recollections of past events are key to understanding the discipline as it exists today and how it may evolve in the future. Building of knowledge onto knowledge (science) Review of previously missed opportunities to make fundamental advances (penicillin & sulphonamide ) Enables one to view his/her own research from a different perspective (herbal resaerch ) Rediscovery of the past (Thalidomide)

6. Some important definitions Pharmacology is the science of drugs (Greek  pharmakos , medicine or drug; and  logos , study) The study of the origin, chemistry, and uses of drugs and their effects on the body. “The subject of pharmacology is a broad one and embraces the knowledge of the source, physical and chemical properties, compounding, physiological actions, absorption, fate, and excretion, and therapeutic uses of drugs(GG) A drug is defined as (FDA) A substance recognized by an official pharmacopoeia or formulary. A substance intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease . A substance (other than food) intended to affect the structure or any function of the body. A substance intended for use as a component of a medicine but not a device or a component, part or accessory of a device.

7. Questions What is  Ethnopharmacology ? is the study of medicinal plant use in specific cultural groups or study of differences in response to drugs by different cultures What is Reverse-pharmacology? is the science of integrating documented clinical/experiential hits, into leads by transdisciplinary exploratory studies and further developing these into drug candidates by experimental and clinical research

8. Transition from traditional to modern medicine Traditional medicine discovery was through trial  and error method that related to cause-and-effect relationship to the use of plant or animal part First generation  drugs - They used whole or some part of the plant/animal for the therapeutical purpose(cinchona bark, digitalis leaf, poppy capsule) Using advanced technology , active component responsible for the therapeutic effect was identified, extracted, purified and used directly to treat various disease. Second generation drugs  –First in 1805, narcotic alkaloid morphine from opium then in 1820 quinine from cinchona bark,  later reserpine from R. serpentina , insulin from animals Third generation drugs - Isolated active component was modified chemically  (semi-synthetic) Fourth generation drugs -Started synthesizing the drugs chemically 

9. “medical pluralism” or more refined  research ?????????? The Indian health ministry proposes to promote the concept of “medical pluralism” and expose students of modern medicine to the  Ayurveda, Yoga and Naturopathy, Unani, Siddha and Homoeopathy. And  should be integrated into various national health-care programmes and delivery systems. Challeges - synergistic effects may exist among the compounds that occur in natural products, chemicals function alone or in conjunction with one another to produce the desired pharmacological effect. The modes and mechanisms of action are seldom very clear More research into how traditional medicine (complex mixture of naturally occurring compounds) is more effective and is better than modern medicine???????  can debatable 

10. Rudolf Buchheim (1820-1879 ) In 1847 - accepted the chair of Materia Medica, Dietetics and History and Encyclopaedia of Medicine at the University of Dorpat – soon transformed his post into a chair of pharmacology. He translated the popular book  "The Elements of Materia Medica and Therapeutics"  to German.  Ineffective drugs are omitted & replaced them by others Tried to give a rationale for therapy. Inserted the previously unknown heading- “Mode of Action” His pupil and successor Oswald Schmiedeberg said “ Rudolf   had no teacher other than himself”

11. Rudolf Buchheim (1820-1879) . Created first academic institute devoted to  study of  action of drug s

12. Oswald Schmiedeberg (1838- 1921) Father of modern pharmacology In 1866 Wrote his medical  thesis on "The determination and fate of chloroform in the blood" under Rudolf Buchheim . Advances into the study of drug action Hypnotic effects of urea derivatives and paraldehyde Action of digitalis on the heart muscle Nicotine blocking of cardiac vagal  ganglia Central and peripheral actions of caffeine Toxic actions of heavy metals and their organic complexes Advances into the study of drug action John Jacob Abel (1857-1938), a native of Ohio and pupil of Schmiedeberg - later called Abel as father of American pharmacology'..

13. Oswald Schmiedeberg He had about 150 students, from twenty different countries. he helped many of them to acquire good positions  around the world, spread the pharmacology to many countries Oswald schmiedeberg

14. Elaboration of the concept of chemical neurotransmission Thomas Renton Elliott

15. Further insights - chemical transmission Refined the understanding of acetylcholine's role in the nervous system Reported the  transient  nature of the actio n  of ACh, suggested that an esterase in tissue Dale’s Vasomotor Reversal Phenomenon : only fall in BP occurs when an alpha blocker is given before injecting adrenaline .He demonstrated this in cat & used Ergot alkaloids as alpha blocker In 1936-He shared the Nobel Prize with  Otto Loewi Sir Henry Dale  (1875–1968)

16. Evidence for chemical transmission at synapses when a scientist observes a fact, he has to accept the fact and abandon the theory  Otto Loewi  (1873–1961)

17. Synthetic compounds that inhibit or activate the action Advance the discipline of pharmaceutical chemistry Daniel Bovet  (1907–1992)

18. Neurotransmitters mechanism of storage, release, and inactivation Ulf Von Euler, Julius Axelrod, & Sir Bernard Katz- Birth of neuropharmacology Julius Axelrod (1912–2004)

19. Neuro /psychopharmacology.. Cont Seredipity played role In 1933, the French pharmaceutical company present Sanofi began to search for new anti-histamines. chlorpromazine  more effective than any of the old drugs, including morphine and scopolamine (hyoscine) combinations, for controlling excitement and agitation In 1940- Frank Milan Berger was looking for a preservative for penicillin, he noticed that  mephenesin calmed laboratory rodents.  Later because of short duration of action of mephenesin , chemically related  compound meprobamate came into market. 

20. Further progress of neuropsychopharmacology Further understanding of the complex functions of the brain- Arvid Carlsson (1923–2018) . Hypothesis - chemical transmission in the central nervous system, Dopamine is Neurotransmitter. Evidence - The administration of L-DOPA to animals not only repleted dopamine levels but also produced an abatement of the Parkinson-like symptoms. Conclusion -  The etiology of PD involves a selective depletion of dopamine levels in the substantia nigra of the brain Development -  L-dopa for PD Extended the Axelrod’s earlier work- -Developed an agent that block the neuronal uptake of serotonin without affecting norepinephrine uptake Reward - Awarded the Nobel Prize in 2000

21. Sir James Black(1924-2010) Revolutionalized cardiac diseases therapy  Black proposed that a better therapeutic strategy to treat coronary artery disease, his rationale was "heart rate was depressed by the blockade of sympathetic nerve activity" Discovery of propranolol - safer & more effective drug, Black, Stephenson, and their coworkers synthesized & screened for beta blocking action.  Black postulated that histamine binds to two different types of receptors Discovery of cimetidine - Black decided to build upon previous observations that patients with ulcers elicited an exaggerated response to histamine

22. Who is the editors of first edition Louis Sanford Goodman Alfred Zack Gilman Alfred Goodman Gilman

23. Alfred Goodman Gilman(1914-2015) Alfred Goodman Gilman as the son of Alfred Gilman, who with Louis Goodman first coauthored and then edited the classical textbook "The Pharmacological Basis of Therapeutics" 1969-  thesis work - The role of cAMP in the thyroid gland Contribution to basic understanding of signal transduction and how cells respond in an integrated manner to cellular messengers, Martin Rodbell and Alfred G. Gilman were jointly awarded the Nobel Prize in 1994.

24. Paul Ehrlich’s magic bullet-  salvarsan   F irst man-made chemotherapy agent:  elaborated the principles of drug discovery Hypothesis : Ehrlich predicated an infection caused by a microorganism could be cured if the drug of choice was selectively taken up by the invading microbes Evidence : His first success, ethylene blue to treat patients suffering from malaria (but not as effectively as quinine) Discovery : 1900s Ehrlich began to systematically investigate dyes as therapeutics, testing them for efficacy in infected animals-  Creation of a new medical subspecialty: venereology -  Salvarsans   Reward : In 1908, Ehrlich was awarded the Nobel Prize in Medicine for “outlining the principles of selective toxicity and for showing preferential eradication of cells by chemicals”

25. Gerhard Domagk:Sulfonamide   Without Domagk, there would be no sulfonamide! Without sulfonamide, there would be no penicillin! And without penicillin, there would be no antibiotics”  1909 Heinrich Hoerlein  found that adding the sulfonamide to azo dyes increased the ability of the dye to bind to wool.  he patented in 1909 1915- Jacob and Heidelberger -decided to synthesize and test a number of agents in the hope of finding one that was bacteriocidal , synthesized p- aminobenzene sulfonamide but ignored . 1935 Domagk proclaimed a 100% success rate, as assessed by the mouse protection assay, with  Prontosil (sulfanilamide was the sole active moiety)-“rediscovered” sulfanilamide Prontosil as the first effective chemotherapeutic agent administered sytemically   for treating systemic bacterial infections Nobel Prize had been awarded for the discovery of the clinical efficacy of Prontosil  and not for its synthesis,

26. Penicillin One sometimes finds what one is not looking for 1928, Mold called Penicillium notatum had contaminated his Petri dishes. Careful observation under microscope -  mold prevented the normal growth of the staphylococci. An article published by Fleming in the British Journal of Experimental Pathology in 1929 reads, “The staphylococcus colonies became transparent and were obviously undergoing lysis Fleming studied  basic properties of penicillin, including microbial specificity, its relative lack of toxicity,  and its ability to produce drug resistance. Abruptly terminated his work with penicillin The instability of the drug The lack of a purified solution of penicillin lack of cooperation from clinical colleagues to provide patients for a clinica l study

27.   Penicillin - Ability to follow up on potentially interesting biological findings and not because of aspirations to cure infectious diseases. Chain and Florey were unable to reproduce the bacteriolytic effect, then realized that penicillin would attack bacteria only when bacteria undergo at least one division. Fourteen years later!!!!  1942, Anne Miller became the first civilian patient to be successfully treated with penicillin. For the discovery of penicillin, Fleming, Florey, and Chain were awarded the Nobel Prize in 1945 Impact on world war II- The rate of Allied soldiers dying from infected war wounds inexorably declined, war ended little early because of penicillin

28. Selman Waksman- Streptomycin The student-teacher => drama of pathos, unresolved controversies Waksman convinced that microbes produce substances that prevents the growth of other microorganisms- microbial antagonism Waksman was awarded the Nobel Prize in 1952, the Nobel Committee acclaimed him as “one of the greatest benefactors to mankind”  1944- Albert Schatz( predoctoral student)-was assigned a basement laboratory several floors below Waksman’s office Schatz’s thesis work involved using the screening program developed by Waksman to isolate streptomycin producing strains of actinomycetes Waksman initiated and supervised a research program that directly led to the discovery of streptomycin, although Schatz actually made the discovery.

29. Gertrude Elion (1918–1999)  George Hitchings (1905–1998). Inhibition of bacterial growth by sulfonamides competitively antagonized by p-aminobenzoic acid (used by cells for folic acid synthesis) Hitchings and Elion postulated - deficiency in folic acid production would lead to aberrations in the synthesis of DNA. thus retard the growth of rapidly dividing cells, such as neoplastic cells and bacteria. 1951- discovered - 6-mercaptopurine, 6-thioguanine,first antiviral drug, acyclovir, allopurinol The discoveries of important principles relating to drug treatment made by Black, Elion, and Hitchings earned them the Nobel Prize in 1988.

30. Frederick Banting, Charles Best, John Macleod, James B. Collip Banting observed the rare case of a pancreatic stone that obstructed the main pancreatic duct. The occlusion had produced a degeneration of the acinar cells. Professor John Macleod provides Banting and Best(medical student to assist) with a laboratory to carry out the experiments Banting and Best published their first article “The Internal Secretion of the Pancreas” Macleod edited the first draft but declined to be listed as a coauthor Frederick Banting (1891–1941) and Charles Best (1899– 1978) pose with a dog that was rescued through administration of insulin. Banting wanted Collip to be a partner,   Collip  possessed significant knowledge of preparing tissue extracts. So he provided assistance with the purification process and achieved a less toxic and more effective product.

31. Eli Lilly- commercial success  Don’t be too generous, selling your invention  Banting did not claim a patent for insulin. He wanted to make it available to the world, so he magnanimously sold the patent to the University of Toronto for $1 In 1923 -  Banting and Macleod (not Best)  are awarded the Nobel Prize in Physiology or Medicine. Toronto group , collaborate with Eli Lilly to produce the extract commercially. First crystalline form of insulin by John Jacob Abel in 1926 and  amino acid sequence by Frederick Sanger- Nobel Prize in Chemistry for this work. Production of the first recombinant DNA insulin was announced in 1978 In 1950, this prestigious group acknowledged that an error had been made in 1923 and it “would have been right to include Best among the prize-winners

32. Evolution drug regulation in USA Ensuring the quality and safety of food and drugs

33. Evolution drug regulation in India India simply followed an international trend. British Rule -  Majority of the drugs were imported from abroad. “Quinine fraud,” government at both central and provincial level was slow to respond to the problem Drug inquiry committee under Sir Ram Nath Chopra also known as ‘Chopra Committee’  recommended ‘The Drug Bill’ later on amended to the Drugs and Cosmetic Act 1940 and Drugs and Cosmetic rules of 1945- into force from 1 April 1947 Justice Rajagopala Ayyanger Committee report (1958) came the era of Process Patent when India followed the socialist-inspired policies-  ‘process’ patents only India amended the Patent  Bill –2005, included the both product patent as well

34. Reference All pics and content taken from the follwing reference Rubin RP. A brief history of great discoveries in pharmacology: in celebration of the centennial anniversary of the founding of the American Society of Pharmacology and Experimental Therapeutics. Pharmacol Rev. 2007 Dec;59(4):289-359 . Willkommen H, Blümel J, Brorson K , et al. Meeting report-workshop on spike characterizations and virus removal by filtration: trends and new developments. PDA J Pharm Sci Technol. 2014 May-Jun;68(3): 215-20 E. Muscholl , The evolution of experimental pharmacology as a biological science : the pioneering work of Buchheim and Schmiedeberg . Bribsh Joumal of Phamacology (1995) 116, 2155 2159

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