1. Contributions of various scientists in Pharmacology Dr. Harmanjit Singh Department of Pharmacology GMC, Patiala

2. INTRODUCTION & HISTORICAL DEVELOPMENT SOME HISTORICAL LANDMARKS GREAT SCIENTISTS & THEIR CONTRIBUTIONS PIONEERS OF PHARMACOLOGY NOBEL LAUREATES IN PHARMACOLOGY SERENDIPITY IN PHARMACOLOGY 2

3. A Brief History Of Pharmacology Pharmacologyis the science of drugs (Greek pharmakos, medicine or drug; and logos, study). It is the study of substances that interact with living systems through chemical processes, especially through binding to regulatory molecules and activating or inhibiting normal body processes. History of Pharmacology, Knowledge of drugs and their use in disease is as old as history of mankind But as a science Pharmacology is quite a young one The birth date of pharmacology is not as clear-cut 3

4. Primitive men gathered the knowledge of healing and medicine by observing the nature, noticing animals while ill and by personal experiences after consuming certain herbs and berries as remedies Hippocrates (460B.C.-377B.C. “The Father of Medicine” was the first to attempt to separate the practice of medicine from religion and superstition , developed his pledge of proper conduct for doctors “I will use treatment to help the sick according to my ability and judgment, but never with the view to injury and wrong doing…Into whatsoever houses I enter, I will enter to help the sick” 4

5. Ebers papyrus describes more than 700 drugs in extensive pharmacopeia of that civilization. Included in this are: beer, turpentine, berries, poppy, lead, salt and crushed precious stones etc.(Egyptian remedies) Dhanvantari : an early Indian medical practitioner and one of the world’s first surgeons., regarded as the source of Ayurveda. He perfected many herbal based cures and natural remedies and was credited with the discovery of the antiseptic properties of turmeric and the preservative properties of salt which he incorporated in his cures. Susruta Ancient Hindu Medical Text Describes 760 herbs CharkaSamhita describes more thnn 65O drugs of animal, plant and mineral origins are used. Chinese remedies 5

7. willow bark was used to treat fever and painsExtract of foxglove plant, used to treat dropsy (congestive heart failure) in 1785. Contains digitoxin and digoxin; today called digitalis William Withering( 1741-1799) discovered digitalis Synthetic organic chemistry was born in 1828, when Friedrich Wohler synthesized urea from inorganic substances and thus demolished the vital force theory. 6

8. Some Historical landmarks Morphine : Friedrich Serturner (1805) Atropine : Grieger & Hessie (1833) Histamine : Vogt (1907) Sulfanilamide : P. Gleno (1908) Oxytocin : Abel (1919) Insulin: Banting & Best (1922) Penicillins : A. Flemming (1928) Sulfonamides : Domagk (1932) Cortisone: Edward C.Kendall Streptomycin : Waksman (1944) Chloramphenicol : Bartz (1948) Tetracycline: Duggar (1948) Lithium : Cade (1950) 7

10. He personally researched each plant and its uses. About 65 AD, he wrote De MateriaMedica, "Regarding Medical Matters",on the "preparation, properties, and testing of drugs."

11. five volume book on the uses of over 1,000 plants and minerals.

12. For nearly 1500 years, De MateriaMedica was the supreme authority on medicine and pharmacology in western civilization.40 - 90-AD

13. FRANÇOIS MAGENDIE A French physiologist, considered a pioneer of experimental physiology. He is known for describing the foramen of Magendie. There is also a Magendie sign, a downward and inward rotation of the eye due to a lesion in the cerebellum Studied the action of nuxvomica (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. 9 (1783 – 1855)

14. François Magendie Established the idea of experimental physiology (an idea further popularized by Claude Bernard) He described in detail the effects of strychnine injections on animal subjects--and also proved that the poison reached the animal's spinal cord by the blood stream and not (as was then commonly believed) by the lymphatic system. Because of such experiments, Magendie was able to introduce into French medicine a variety of new drugs, including morphine, codeine, quinine and, strychnine. 10

15. Claude Bernard A French Physiologist Further expanded work of Francois Megendie In 1842, Claude Bernard discovered that the arrow poison curare acts at the neuromuscular junction to interrupt the stimulation of muscle by nerve impulses. Also k/a Father of Modern Experimental Medicine Bernard's experiments changed medicine (1813-1878) 11

16. Claude Bernard’s Contributions The discovery of the role of the pancreatic secretion in the digestion of fats (1848). The discovery of a new function of the liver--the "internal secretion" of glucose into the blood (1848). The production of sugar by washed excised liver (1855) and the isolation of glycogen (1857). The demonstration that curare specifically blocks motor nerve endings (1856). He also established the existence of Vasomotor system and observed Vasodilatation & Vasoconstriction 12

17. Pharmacology was held to have emerged as a separate science only when the first university chair was established. This occurred in 1847, when Rudolf Buchheim (a German pharmacologist) , was appointed professor of pharmacology at the University of Dorpat in Estonia . Today at the University of Giessen is the Rudolf Buchheim Institute for Pharmacology. Rudolf Buchheim (1820 – 1879) 13

18. R.Buchheim Lacking outside funding, Buchheim built the world’s 1st pharmacology laboratory at his own expense in the basement of his home Buchheim is remembered for his pioneer work in experimental pharmacology. He introduced the bioassay to pharmacology, His reputation is overshadowed by that of his student, Oswald Schmiedeberg 14

19. Oswald Schmiedeberg Generally recognized as the founder of modern pharmacology Schmiedeberg obtained his medical doctorate in 1866 with a thesis on the measurement of chloroform in blood In 1872, he became professor of pharmacology at the University of Strassburg In 1878, he published a classic text, Outline of Pharmacology In 1885, he introduced urethane as hypnotic 1838–1921) 15

20. Schmiedeberg In his 46 years at Strasburg, 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. 16

22. In the United States, the first chair in pharmacology was established at the University of Michigan in 1890 under John Jacob Abel.

23. In 1893, Abel went to Johns Hopkins University in Baltimore, where he had a long and brilliant career.

24. Also k/a FATHER OF AMERICAN PHARMACOLOGY 1857- 1938 17

26. He was second to isolate epinephrine (1897–1898) from adrenal gland extracts (first was Napoleon Cybulski in 1895)

27. Isolated amino acids from the blood (1914)

28. Isolation of histamine from pituitary extract (1919)

29. Preparation of pure crystalline insulin (1926).

30. His student Reid Hunt discovered acetylcholine in adrenal extracts in 1906.18

31. Friedrich Serturner,the German pharmacist who isolated the first alkaloid from opium in 1805, administered a very large dose (100 mg) to himself and three friends All experienced the symptoms of severe opium poisoning for several days. The alkaloid was namedmorphine, forMorpheus, the Greek god of sleep. Although humans are no longer used as laboratory animals, they are essential in clinical pharmacology 19

33. 1902 In London, in Starling’s laboratory, he met for the first time Henri Hallet Dale, who was to become a lifelong friend.

34. 1909 He was appointed to the Chair of Pharmaco logy in Graz.

35. 1921 He proved, the chemical transmission of the nerve impulses& in 1936 He received the Nobel price, with Henri Dale.1873 - 1961

36. OTTO LOEWI CONTRIBUTIONS He designed his most famous experiment, which provided the first evidence for the existence of chemical transmission in a synapse. The legend tells that he had the idea of the experiment in a dream and that he ran to the lab in the middle of the night. The experiment was very simple and became a prototype for all investigations of chemical factors in the nervous system. 21

37. OTTO LOEWI He cut out two hearts from frogs and perfused them with a warm physiological solution (Ringer). He then stimulated the vagus nerve to one of the hearts. As a consequence, there was a strong inhibition in this heart beats (R). The second heart was unaffected However, when he perfused the second heart with the outflow of the perfusion of the first one, he achieved exactly the same effect (D). It was therefore concluded that some substance produced at the parasympathetic synapse level in heart R, was able to induce a similar response in the muscles of heart D (acetylcholine) 22

39. Dale became the Director of the Deptt of Biochemistry and Pharmacology at the National Institute for Medical Research in London in 1914.

40. Also served asPresident of the Royal Society from 1940 to 19451875 - 1968 23

41. SIR HENRY HALLET DALE CONTRIBUTIONS IN PHARMACOLOGY Distinguished Muscarinic &Nicotinic receptors in 1914 First identified acetylcholine in 1914 as a possible neurotransmitter, Loewi showed its importance in the nervous system. (shared the 1936 Nobel Prize for Physiology or Medicine.) Dale's principle ( Dale's Law). This principle states that each neuron releases only one type of neurotransmitter. 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 24

43. Obtained MD degree from Cambridge University in 1908

44. In 1921 : Appointed as the first professor of pharmacology in newly established Calcutta School of Tropical Medicine and parallely headed the Department of pharmacology at he Calcutta medical college

45. From 1941 to 1957: he was Director of the Drug Research Lab at Srinagar 1882-1973

47. He pioneered research on herbal drugs in India

48. Indian Posts & Telegraph department has issued a commemorative stamp in his honor.26

49. Paul Ehrlich (1854-1915) German scientist in the fields of hematology, immunology, and chemotherapy He is noted for curing syphilis and for his research in autoimmunity He coined the term chemotherapy and popularized the concept of a magic bullet. Also coined the term Receptor(earlier called as receptive substance by Langley) Ehrlich skillfully transformed diphtheria antitoxin along with Emil Adolf von Behring, into an effective preparation, his first world renown achievement However, von Behring cheated Ehrlich out of both recognition and financial reward. Only von Behring received the first Nobel Prize in Medicine, in 1901, 27

50. Paul Ehrlich In 1906 he discovered the structural formula of atoxyl, a chemical compound which had been shown to be able to treat sleeping sickness In1908, Ehrlich was awarded the Nobel Prize in Medicine In 1909 he and his student SahachiroHata developed Salvarsan, a treatment effective against syphilis. Salvarsan became the most widely prescribed drug in the world, most effective drug for treating syphilis until penicillin became available in the 1940s Known as FATHER OF CHEMOTHERAPY 28

52. antibiotic penicillin from the mold Penicilliumnotatum in 1928 which was a discovery by chance. On 3 September 1928, Fleming returned to his lab. after vacation. Before leaving, he had stacked all his cultures of staphylococci on a bench in a corner of his laboratory.

53. On returning, Fleming noticed that one culture was contaminated with a fungus, and that the colonies of staphylococci that had immediately surrounded it had been destroyed, whereas other colonies farther away were normal

54. He shared the Nobel Prize in Physiology or Medicine in 1945 with Howard Florey and Ernst Chain who purified penicillin29

55. Sir Frederick Banting & Charles Best Sir Frederick Grant Banting, (1891 –1941) was a Canadian medical scientist & doctor Charles Best February (1899 – 1978)was his assistant Known for the discovery of the e insulin—one of the most significant advances in medicine, enabling an effective treatment for diabetes. In 1921, Banting traveled to Toronto to visit J.J.R. Macleod at University of Toronto, where he used his lab for this discovery. 30

56. Banting & Best He also supplied Banting with ten dogs to experiment on, and two medical students, Best and Clark Noble, to use as lab assistants. Since Bantingonly required one lab assistant, Best and Noble flipped a coin & Best won the coin toss, and took the first shift as Banting's assistant. Loss of the coin toss was very unfortunate for Noble as Best worked with Banting for the entire summer (and eventually shared half his Nobel Prize money and a large part of the credit for the discovery of insulin with the winner of the toss) In 1923, the Nobel Banting and J.J.R. Macleod won the Nobel Prize in Medicine for the discovery of insulin, & Nobel prize committee ignored Best. This incensed Banting, who voluntarily shared half of his award money with Best. 31

57. Gerhard Domagk (1895-1964) a German pathologist and bacteriologist Done extensive work on infections & antibiotics Credited with the discovery of Sulfonamidochrysoidine (KI-730) – the first commercially available antibiotic (marketed under the brand name Prontosil) He found the sulfonamide Prontosil to be effective against streptococcus, and treated his own daughter with it, saving her the amputation of an arm. In 1939, Domagk received the Nobel Prize in Physiology or Medicine for this discovery, the first drug effective against bacterial infections 32

59. Thymoxidiethylamine. was too toxic to be used so he continued with hundreds of experiments to find a more human body friendly antihistamine. 1907 - 1992

61. In 1947 he discovered gallamine when he was looking for a synthetic substitute for curare

62. Isolated succinylcholine, a muscle relaxant now used in conjunction with anesthesia during certain surgical procedures.

63. In 1957 he was awarded the Nobel Prize in Physiology or medicine for his discoveries.34

64. Louis Lasagna : Father of Clinical Pharmacology Famous American Clinical Pharmacologist Medical degree from Columbia University in 1947. Lasagna joined the faculty of Johns HopkinsUniversity in 1954, where he established the first ever clinical pharmacology department. In 1964, Lasagna revised the Hippocratic Oath Conceptualize controlled clinical trials and the placebo effect Lasagna's work led to the improvement of controlled clinical trials to test drug effectiveness, and improved the regulation of drugs for effectiveness and safety. Lasagna's Law : The incidence of patient availability sharply decreases when a clinical trial begins and returns to its original level as soon as the trial is completed. 35 1923-2003

65. Sir James Black A Scottish Pharmacologist Studied Medicine at Univ. of St. Andrew. in 1950, he joined the University of Glasgow He was interested in the effect of adrenaline on the human heart. Joined ICI Pharmaceuticals in 1958 1n 1964 he joined Smith, Kline and French for whom he worked for nine years until 1973 He was awarded the Nobel Prize for Medicine in 1988 for his work. 36 1924- 2010

66. Sir James Black : Major Contributions He established the Physiology Department at Univ of Glasgow He developed Propranololwhile working for ICI , which later became the world's best-selling drug. Black was developing a similar method of treatment for stomach ulcers, but ICI did not wish to pursue the idea so Black resigned in 1964 and joined Smith, Kline and French While there, Black developed his second major drug, cimetidine (brand name Tagamet ) in 1975 and soon outsold propranolol to become the world's 1st billion dollar drug. 37

67. Louis J. Ignarro, Robert Furchgott and FeridMurad Louis J. Ignarro (born May 31, 1941) is an Italian American pharmacologist Robert Francis Furchgott ( 1916 – 2009) was a n American biochemist. FeridMurad (born September 14, 1936) is an Albanian-American physician and pharmacologist Their main contribution is the Discoveries concerning nitric oxide as a signaling molecule in the cardiovascular system Co-winners of the 1998 Nobel Prize in Physiology or Medicine. 38 L.Ignaro R. Furchgott FeridMurad

68. Other Scientists & Their Contributions Thomas Renton Elliott: Elaboration of the Concept of Chemical Neurotransmission John Langley (1878) : Receptor concept (called it Receptive substance William Henry Howell & Jay McLean (1916) : Discovered Heparin from Canine Liver Raymond Ahlquist(1948) : Existence of two types of adrenergic receptors i.e. Alpha & Beta Receptors G.Brotzu (1948): discovered Cephalosporins Selman Waksman : discovered streptomycin: the first antibiotic effective against tuberculosis - Nobel Prize (1952) 39

69. Other Scientists & Their Contributions Ulf von Euler, Julius Axelrod, and Sir Bernard Katz: the processes involved with the biosynthesis, release, actions,and inactivation of neurotransmitters (Nobel Prize 1970) Earl Wilbur Sutherland Jr. : He discovered cAMP as 2nd messenger concerning the mechanisms of the action of hormones," especially epinephrine ( Nobel Prize in in 1971) Sir John Robert Vane: worked on aspirin & discovered that it inhibits prostaglandin biosynthesis ( Nobel Prize 1982) Martin Rodbell & Alfred G. Gilman: Known for their discovery of G-proteins and the role of these proteins in signal transduction in cells (Nobel Prize 1994) 40

70. Some Scientists in History of Anesthetics Nitrous oxide : Synthesized by Priestley in 1774, 1st clinically used by Humphery Davy who used it on himself for toothache and called it as Laughing gas Horace Wells : used N2O for tooth extraction & patient cried in pain. He became very frustrated and chloroform addict n committed suicide by cutting his femoral artery. Ether: prepared by ValeusCordusand was k/a ‘sweet oil of vitroil’.First public demonstration was given by W.T.G Morton on 16th October 1846 (World Anesthesia Day) Chloroform: first use was done by Simpson but John Snow popularized it by using it successfully in 4,000 patients (also used on Queen Victoria for birth of her 8th child) Cocainewas 1st used by Carl kollerfor anesthetizing cornea 41

71. Pioneers of Pharmacology Hippocrates: Father of Modern Medicine Claude Bernard: Father of Modern Experimental Pharmacology Oswald Schmiedberg: Father of Modern Pharmacology Paul Ehrlich: Father of Modern Chemotherapy John Jacob Abel: Father of American Pharmacology Ram Nath Chopra: Father of Indian Pharmacology Louis Lasagna: Father of Clinical Pharmacology 42

72. Nobel Laureates In Pharmacology 1908:Elie Metchnikoff, Paul Ehrlich: First antimicrobial drugs (“magic bullet”) 1923:Frederick Banting, John Macleod: Isolation and discovery of insulin and its application in the treatment of diabetes 1936: Sir Henry Dale, Otto Loewi: Chemical transmission of nerve impulses 1945:Ernst Chain, Sir Alexander Fleming, Sir Howard Florey : Discovery of penicillin and its curative effect in various infectious diseases 1950:Edward Kendall, Tadeus Reichstein, Philip S. Hench : Hormones of the adrenal cortex, their structure and biological effects 43

73. Nobel Laureates In Pharmacology 1957: Daniel Bovet: Antagonists that block biologically active amines, including the first antihistaminic 1970:Julius Axelrod, Sir Bernard Katz, Ulf von Euler: Transmitters in the nerve terminals and the mech. For storage, release, and inactivation 1971:Earl Sutherland Jr. : Mechanisms of the action of hormones with regard to inhibition and stimulation of cyclic AMP 1982:SuneBergström, Bengt Samuelsson, John R. Vane: Discovery of prostaglandins and the mechanism of action of aspirin which inhibits prostaglandin synthesis 44

74. Nobel Laureates In Pharmacology 1988:Sir James W. Black, Gertrude B. Elion, George H. Hitchings: Development of the first beta-blocker, propranolol, and anticancer agents that block nucleic acid synthesis 1994: Alfred Gilman, Martin Rodbell: Discovery of G proteins and the role of these proteins in signal transduction in cells 1998:Robert Furchgott, Louis Ignarro, FeridMurad: Role of NO as a signaling molecule in the cardiovascular system 2000: ArvidCarlsson, Paul Greengard, Eric Kandel: Role of dopamine in schizophrenia and signal transduction in the nervous system leading to long-term potentiation 45

75. Serendipity in Pharmacology Penicillin by Alexander Fleming. He failed to disinfect cultures of bacteria when leaving for his vacations, only to find them contaminated with Penicillium molds, which killed the bacteria. 5-fluorouracil's therapeutic action on actinic keratosis, was initially investigated for its anti-cancer actions Minoxidil's action on baldness; originally it was an oral agent for treating hypertension. It was observed that bald patients treated with it grew hair too. Viagra (sildenafil citrate), an anti-impotence drug. It was initially studied for use in hypertension and angina pectoris. Phase I clinical trials under the direction of Ian Osterlohsuggested that the drug had little effect on angina, but that it could induce marked penile erections. 46

76. SERENDIPITY The libido-enhancing effect of LEVODOPA The first anti-psychotic drug, chlorpromazine, was discovered by French pharmacologist Henri Laborit. He wanted to add an anti-histaminic to prevent surgical shock and noticed that patients treated with it were unusually calm before the operation. The first antidepressants, imipramine and iproniazid were 1st used in schizophrenics (imipramine) & in the t/t of TB (iproniazid). The psychedelic effects of LSD by Albert Hofmann, he unintentionally absorbed a small amount of it upon investigating its properties, and had the first acid trip in history, while cycling to his home in Switzerland; this is commemorated among LSD users annually as Bicycle Day. 47

77. Mustine – a derivative of mustard gas (a chemical weapon). In 1943, physicians noted that the white cell counts of US soldiers, accidentally exposed mustard gas shells were decreased, and mustard gas was investigated as a therapy for Hodgkin's lymphoma. The anesthetic nitrous oxide (laughing gas). its properties were discovered when British chemist Humphry Davy tested the gas on himself and some of his friends, and soon realised that nitrous oxide considerably dulled the sensation of pain, even if the inhaler was still semi-conscious 48 SERENDIPITY

79. Clinical Pharmacology : Bennett and Brown 10th edition

80. Basic and clinical pharmacology : Katzung,Masters and Trevor: 11th edition

81. A Brief History of Great Discoveries in Pharmacology.Rubin PR. Pharmacol Rev 2007; 59: 289–359.

82. "All Nobel Prizes in Physiology or Medicine". Nobelprize.org.49

83. "I have been trying to point out that in our lives chance may have an astonishing influence and, if I may offer advice to the young laboratory worker, it would be this - never to neglect an extraordinary appearance or happening.” Alexander Fleming Thank you 50

85. Claude Bernard 1813-1878 (d-tubo curare)

86. Friedrich Sertürner 1783--1841 (morphine)

87. Rudolf Buchheim 1820-1879 (1st Pharmacology Laboratory, University of Dorpat (now Tartu, Estonia)

88. Oswald Schmiedeberg 1838-1921 (Strassburg, now Strasbourg, trained many pharmacologists)

89. John Langley 1852--1926 (Receptor concept)

90. Paul Ehrlich 1854-1915 (Receptor concept)

91. Otto Loewi, Henry Dale (Neurotransmission)