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- Dr. Chandini
Moderator: Dr. Chandralekha
1
Part I
2
3
Part 2
• History of
 Anaesthesia
 Alkaloids
 Antimicrobials/Antibiotics
 Drugs used in Endocrinology
 Cardiovascular drugs
 Prostaglandins
 OCPs
• Few scientists & their contributions
• History of Human experiments
HistoryofAnaesthesia
• 2 kinds of pain relief sought: Anaesthesia (General & local)
Analgesia
• Opium. Henbane & mandrake root
4
Humphrey Davy
• 1799 – Nitrous oxide
‘Laughing gas’ –
relieved toothache
• To relieve pain of surgery.
• Euphoria
Analgesia
Loss of consciousness
• Henry Hickman –
mixture of CO2 & NO in surgery.
5
Laughing gas party
6
Ether
• 1815: Michael Faraday – similar effect to nitrous oxide.
• Crawford Long
- ‘Ether frolics’
- studied the anaesthetic properties
of ether.
- 1842 – Was given before cyst excision.
- published his discovery in 1849.
7
8
Horace Wells
• Pioneered the use of anaesthesia in dentistry
• Nitrous oxide – painless tooth extraction
• Experimented on himself
(“A new era of tooth-pulling!”)
9
William Thomas Morton
• American dentist
• 1846 – 1st publicly demonstrated
the use of inhaled ether as a
surgical anaesthetic .
10
James Young Simpson
• Chloroform
• Used it to relieve pain of childbirth.
• 1853 – Queen Victoria permitted
it’s use by John Snow.
• NO & air machines, pethidine &
‘natural’ childbirth.
11
Local anaesthesia
(Cocaine)
• Coca leaves – South America
• Friedrich Gaedcke (1859 ) –
Cocaine alkaloid
‘Erythroxyline’
• For morphine addiction & in soft drinks
(Coca cola – coca leaves & kola nuts)
• Sigmund Freud (1883) –
medical use of cocaine
‘tongue-numbing’ capacity.
12
• Carl Koller (‘Coca Koller’)
– ophthalmic use
• William Halstead
– Father of American Surgery
- Nerve block anaesthesia
13
14
Spinal anaesthesia
• 1883 – August Bier & August Hildebrandt
• Injected cocaine into spinal canal
15
Historyofsomeimportant
Alkaloids
16
Quinine
• Crystalline alkaloid
• antipyretic, antimalarial,
analgesic, anti-
inflammatory
properties
• bark of the Cinchona tree
• Quechua Indians
of Peru and Bolivia
17
18
Discovery of Artemisinin (Qinghaosu)
• Malaria – global burden
• Countless treatments tested –
most of them failed
• Ancient China – leaves of sweet worm wood
• Han dynasty (earliest record)
– treatment for haemorrhoids
Ming dynasty – remedy for fever
• For 1500 yrs; not scientifically tested
Artemisia annua
19
China: 1960-1970
• Soldiers died from malaria
• 23 May 1967: ‘Project 523’ – massive,
multi-institute search
for a novel antimalarial drug
• Screening of traditional Chinese pharmacopoeias
 Yingzhao (Artabotrys hexapetalus) &
Qinghao (Artemisia annua)
• Early 1970s:
Active ingredient of qinghao – Artemisinin (Qinghaosu)
Artemether & Artesunate 20
Atropine Opium
21
Pilocarpine
• Chewing of leaves  salivation
• 1874 – 1st experiments by Coutinhou T.
• 1875 – alkaloid was isolated
• Weber – action on pupils &
sweat & salivary glands
South American shrub:
Pilocarpus
22
Physostigmine
• Calabar or ordeal bean; dried ripe
seed of Physostigma venenosum
• Native tribes of West Africa –
“ordeal poison” (trials of witchcraft)
• 1864 – pure alkaloid isolated by Jobst & Hesse
• 1877 – 1st therapeutic use by Lagueur for glaucoma
23
Curare
• South American arrow poisons
• Paralysis of skeletal muscles
• Strychnos species (Eastern Amazonia)
• Griffith & Johnson –
1st trial of curare for
promoting muscle relaxation
in GA (1942)
• King – structure of tubocurarine (1935)
24
Ergot alkaloids
• Claviceps purpurea – rye & other grains
• Rhine valley (857AD) – 1st outbreak of
gangrenous ergotism-
feet, legs, hands, and arms
• Extremities - dry, black
and mummified
25
• Limbs – ‘Holy Fire’ (burning sensation)
• Early 20th century – active principle isolated
26
Vinca Alkaloids
• Madagascar periwinkle plant,
Catharanthus roseus (Vinca rosea)
• Periwinkle extracts – hypoglycemic effects in diabetics
• Vincristine & Vinblastine –
regression of ALL in mice
- leukemias, lymphomas
& testicular cancer.
27
EvolutionofAnti-microbials
The three eras of Chemotherapy –
1. Alkaloids(natural plant products)
2. Synthetic Compounds
3. Antibiotics
28
Synthetic Compounds
Salvarsan
• Paul Ehrlich (1907)
• Magic bullet
• Treatment of syphilis
(until penicillin)
• Drawback:
required many painful injections
until cure
29
Discovery of Prontosil
• Gerhard Domagk (1895– 1964)
• 1st clinically useful sulfonamide
• Streptococcal infections.
• Prontosil  ‘Sulphanilamide’  bacteriostatic.
30
Evolution of the Sulpha drugs
• 1938: May & Baker firm – ‘M&B 693’
Sulphapyridine – pneumo- & streptococci
- nausea, kidney & bladder stones
• 1940: Sulphadiazine – kidney stones
Sulphasoxazole
• 1941: 1700 tonnes – 10 million Americans
puerperal fever, pneumonia, meningitis,
rheumatic fever etc..& Gonorrhoea.
• Resistance developed, replaced by Penicillin
31
Elixir Sulfanilamide disaster
(A tragic lesson)
• September 1937, US
• Massengill drug company – “Elixir Sulfanilamide”
(Sulfanilamide + Diethylene glycol)
• 100 deaths - DEG
• FDA - Food, Drug & Cosmetic Act, 1938
32
Antibiotics
33
Discovery of Penicillin
• Alexander Fleming (1881-1955) –
Penicillium notatum
• 1928 – culture dish contaminated
by mould spores
• ‘Penicillin’ –seeped out from
the mould  killed bacteria
near the mould
34
• 1935: Howard Florey & Ernst Chain –
investigated the anti-bacterial properties of Penicillin.
• Norman Heatley – isolated penicillin from the mould.
• Experimented with mice inoculated with streptococci
• Used it successfully to treat war wounds
• 1945: Fleming, Florey & Chain received Nobel prize
35
Discovery of Streptomycin
• 1946:
Waksman – Streptomyces griseus
(chicken’s throat)
Streptomycin
(cocci, spirochaetes, tb bacilli)
• 1st recorded cure of tb meningitis
• 1952 – Nobel prize
36
• Side effects – Ototoxicity & Nephrotoxicity
• 1953: Swedish researchers –
Vitamin A + Streptomycin
• German researchers –
Pantothenic acid + Streptomycin
• side effects (without diminishing antibiotic properties)
37
Discovery of Anti-TB drugs
• Streptomycin – promising cure
 prolonged treatment with high doses
Severe side effects & Resistance
• 1949 – Combination therapy:
Streptomycin + PAS
• 1951 – Isoniazid (INH) – hydrazide salt of isonicotinic acid
combined with streptomycin  dramatic results
• Early 1970s – 5 more antibiotics & 3 synthesized chemicals.
38
DrugsusedinEndocrinology
39
Discovery of Insulin
• 1st description of diabetes –
mid 17th century.
• Richard Bright –
Involvement of pancreas
• Early 19th century:
Paul Langerhans –
‘Islets of Langerhans’
• Hormone deficiency
disease – ‘Insulin’
(insula = island)
40
Banting & Best
• 1921: Frederick Banting – effective &
safe extract of insulin helped by
Charles Herbert Best
• Extracted insulin from a dog’s
degenerated pancreas.
• Saved the lives of diabetic dogs
• Published their findings in American Journal of
Physiology.
41
• 11th Jan 1922 – successfully injected
insulin to their 1st human patient
(14 yrs old Leonard Thompson)
• Toxic reactions minimised by
James B. Collip – Purified insulin
• 1923 – Only Banting received Nobel prize.
• 1926: John Jacob Abel –
prepared pure crystalline
Insulin
42
Discovery of Corticosteroids
• Began with Anti-TB campaign (1940s)
• Reichstein and Kendall
- 1st isolated & identified adrenal steroids
- effects on carbohydrate metabolism (glucocorticoids)
• World war II: Lewis Sarrett – Cortisone (from bile of cattle)
• Hench & Kendall – treatment of rheumatoid arthritis
• 1950s – skin grafts & kidney transplants
43
44
The Thyroid
• Thyroid gland deficiency (myxoedema) -
sheep thyroid extracts (1890s)
• 1914: Edward Kendall – purer, powerful
extract
‘Thyroxine’ (3 tons of pig thyroids!)
• 1927 – Synthetic thyroxine
45
History of some Cardiovascular drugs
46
Heparin
• Canine liver tissue (hepar = liver)
• 1916: Jay McLean & William Henry Howell
- fat soluble phosphatide anticoagulant
• 1918 – Howel coined the term ‘heparin’
47
Warfarin
• Spoiled sweet clover silage  Haemorrhagic disease in
cattle
• 1939: Campbell & Link – bishydroxycoumarin (dicoumarol)
• 1948: Warfarin
(WARF – Wisconsin Alumni
Research Foundation)
- synthetic congener
- rodenticide
• 1951: Coumarin anticoagulants –
prevention of thromboembolic diseases.
48
Aspirin
49
Nitrates
• 1846: 1st synthesized by Sobrero
• Alfred Nobel – stabilised nitroglycerine
- patented a detonator
• 1857: Lauder Brunton – found that
amyl nitrite relieved angina pain
in 30-60 sec
• William Murrell – established the use of
sublingual NTG in acute angina & for
prophylaxis of exertional angina
50
Alfred Nobel
Statins
• 1976: Endo & colleagues –
Penicillium citrinum (mould)
- inhibitors of cholesterol biosynthesis.
• Brown & Goldstein – act by inhibiting
HMG-CoA reductase.
• Compactin (Mevastatin) – 1st statin studied in humans
• Lovastatin - 1st statin approved for use in humans
- Aspergillus terreus
51
Discovery of Prostaglandins
• 1935 : Von Euler
– protein in human semen
 uterine smooth contraction
Prostaglandin (‘prostate’)
• 1965: synthetic form – used to induce
labour for the 1st time
• Inserted into vagina or cervix as
pessaries or creams –
preferred method of induction.
52
History of OCPs
• Early 20th century: Ludwig Haberlandt – 1st experiments.
• Early 1940s: Russel Marker –
extracted ‘diosgenin’ from yam
 Progesterone
Norethisterone/Norethindrone (1951)
• Norethynodrel – menstrual regulator & OCP
• Purified progesterone  Failure
53
• Original compound – traces of Estrogen
 Estrogen-Progesterone combined contraceptive pill
• Initial concern of unwanted pregnancies
Over-dosing women with estrogen
thrombo-embolism
fatal heart attacks & strokes
• Dec’1969: UK Committee on the Safety of Medicines
- Estrogen content not > 50 micrograms
54
• John Rock – Roman Catholic
Supported research on ‘the pill’
• Faced outrage from the Catholic Church
- natural means (‘safe method’ or ‘rhythm method’)
- forbade the use of unnatural contraception
• 1973 – 50 million women were using OCPs (12 drug
companies) – Era of Birth Control
55
Thalidomide Scandal
• 1950: Wilhelm Kunz – invented Thalidomide
• Sedative; but with no obvious toxic effects
• Approved as 1st safe sleeping pill
• Reports of side effects
56
• 1961: Dr. William McBride – Teratogenic effect
(babies with deformed limbs)
• 1962 – 7400 ‘thalidomide children’ worldwide
 withdrawal of drug
• 1968 – Committee on Safety of Medicines
57
Few Scientists & their contributions..
58
William Withering (1741-1799)
• Dropsy – edema that often
accompanies heart & kidney failure
• Fox glove tea
• Active ingredient – Digitalis
(fox glove leaves)
• 1785: An account of the fox glove
– Study of Digitalis
59
Otto Loewi
• 1921 – proved the chemical transmission
of nerve impulses
• Prototype experiment - existence of
chemical transmission in a synapse
• 1st chemical neurotransmitter
identified – Ach
• 1936 – Nobel prize, along
with Henry Dale
60
Sir Henry Hallet Dale
• 1914 - distinguished muscarinic & nicotininc receptors
- 1st identified Ach as a possible neurotransmitter
(shared the nobel prize with Loewi in 1936)
• Dale’s principle (Dale’s Law) –
Each neuron releases only 1 type of neurotransmitter
• Dale’s Vasomotor Reversal Phenomenon
61
James Black
• Developed propranolol –
best-selling drug
• 1975: 2nd major drug –
Cimetidine (Tagamet)
world’s 1st billion dollar drug
62
Daniel Bovet
• 1937: synthesized the 1st antihistaminic
Thymoxidiethylamine
• Discovered Pyrilamine (Mepyramine)
• 1947: Discovered Gallamine
• Isolated Succinylcholine
• 1957: Nobel prize in
Physiology/Medicine
63
Rudolf Buchheim
• World’s 1st pharmacology lab –
basement of his house
• Remembered for his pioneer work in
Experimental Pharmacology.
• He introduced the bio assay to pharmacology,
• Taken over by his student,
Oswald Schmiedeberg
64
Alfred Goodman Gilman
• American pharmacologist and
biochemist
• 1994 – Nobel prize in Physiology or
Medicine along with
Martin Rodbell for their discovery
of G proteins & their role in signal
transduction.
65
Historyofhumanexperiments
• During WWII (1940) : Nazis (Germany)
– series of medical experiments on
prisoners, including children. (Jews)
• No consent taken
• Death, trauma & permanent
disability, even execution
• Malaria, immunization,
mustard gas
& Sulphonamide experiments
66
• 1946: Doctors’ trial –
Nuremberg (Germany) led by US
Nuremberg Code of medical ethics
• Declaration of Helsinki (DoH)
 Human experimentation
 World Medical Association (WMA)
 1st significant effort to regulate research itself
 Basis of most subsequent documents
67
68
References :
1) A History of Medicine - Nancy Duin & Dr Jenny Sutcliffe
2) The Pharmacological Basis of Therepeutics -Goodman & Gilman, 12th
edition
3) Basic and clinical pharmacology : Katzung, Masters and Trevor, 11th
edition
4) Medical Pharmacology – Dr Padmaja Udaykumar, revised 4th edition
5) Rang & Dayle’s pharmacology, 7th edition
6) Pharmacognosy – Dr C.K Kokate, A.P Purohit, S. B Gokhale
7) Pictures & video from the internet
“History, if it has taught us anything at all, has taught us that the strange ideas
we derive today will one day be our celebrated truths.”
― Dan Brown, The Lost Symbol
69

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History of pharmacology ii

  • 1. - Dr. Chandini Moderator: Dr. Chandralekha 1
  • 3. 3 Part 2 • History of  Anaesthesia  Alkaloids  Antimicrobials/Antibiotics  Drugs used in Endocrinology  Cardiovascular drugs  Prostaglandins  OCPs • Few scientists & their contributions • History of Human experiments
  • 4. HistoryofAnaesthesia • 2 kinds of pain relief sought: Anaesthesia (General & local) Analgesia • Opium. Henbane & mandrake root 4
  • 5. Humphrey Davy • 1799 – Nitrous oxide ‘Laughing gas’ – relieved toothache • To relieve pain of surgery. • Euphoria Analgesia Loss of consciousness • Henry Hickman – mixture of CO2 & NO in surgery. 5
  • 7. Ether • 1815: Michael Faraday – similar effect to nitrous oxide. • Crawford Long - ‘Ether frolics’ - studied the anaesthetic properties of ether. - 1842 – Was given before cyst excision. - published his discovery in 1849. 7
  • 8. 8
  • 9. Horace Wells • Pioneered the use of anaesthesia in dentistry • Nitrous oxide – painless tooth extraction • Experimented on himself (“A new era of tooth-pulling!”) 9
  • 10. William Thomas Morton • American dentist • 1846 – 1st publicly demonstrated the use of inhaled ether as a surgical anaesthetic . 10
  • 11. James Young Simpson • Chloroform • Used it to relieve pain of childbirth. • 1853 – Queen Victoria permitted it’s use by John Snow. • NO & air machines, pethidine & ‘natural’ childbirth. 11
  • 12. Local anaesthesia (Cocaine) • Coca leaves – South America • Friedrich Gaedcke (1859 ) – Cocaine alkaloid ‘Erythroxyline’ • For morphine addiction & in soft drinks (Coca cola – coca leaves & kola nuts) • Sigmund Freud (1883) – medical use of cocaine ‘tongue-numbing’ capacity. 12
  • 13. • Carl Koller (‘Coca Koller’) – ophthalmic use • William Halstead – Father of American Surgery - Nerve block anaesthesia 13
  • 14. 14
  • 15. Spinal anaesthesia • 1883 – August Bier & August Hildebrandt • Injected cocaine into spinal canal 15
  • 17. Quinine • Crystalline alkaloid • antipyretic, antimalarial, analgesic, anti- inflammatory properties • bark of the Cinchona tree • Quechua Indians of Peru and Bolivia 17
  • 18. 18
  • 19. Discovery of Artemisinin (Qinghaosu) • Malaria – global burden • Countless treatments tested – most of them failed • Ancient China – leaves of sweet worm wood • Han dynasty (earliest record) – treatment for haemorrhoids Ming dynasty – remedy for fever • For 1500 yrs; not scientifically tested Artemisia annua 19
  • 20. China: 1960-1970 • Soldiers died from malaria • 23 May 1967: ‘Project 523’ – massive, multi-institute search for a novel antimalarial drug • Screening of traditional Chinese pharmacopoeias  Yingzhao (Artabotrys hexapetalus) & Qinghao (Artemisia annua) • Early 1970s: Active ingredient of qinghao – Artemisinin (Qinghaosu) Artemether & Artesunate 20
  • 22. Pilocarpine • Chewing of leaves  salivation • 1874 – 1st experiments by Coutinhou T. • 1875 – alkaloid was isolated • Weber – action on pupils & sweat & salivary glands South American shrub: Pilocarpus 22
  • 23. Physostigmine • Calabar or ordeal bean; dried ripe seed of Physostigma venenosum • Native tribes of West Africa – “ordeal poison” (trials of witchcraft) • 1864 – pure alkaloid isolated by Jobst & Hesse • 1877 – 1st therapeutic use by Lagueur for glaucoma 23
  • 24. Curare • South American arrow poisons • Paralysis of skeletal muscles • Strychnos species (Eastern Amazonia) • Griffith & Johnson – 1st trial of curare for promoting muscle relaxation in GA (1942) • King – structure of tubocurarine (1935) 24
  • 25. Ergot alkaloids • Claviceps purpurea – rye & other grains • Rhine valley (857AD) – 1st outbreak of gangrenous ergotism- feet, legs, hands, and arms • Extremities - dry, black and mummified 25
  • 26. • Limbs – ‘Holy Fire’ (burning sensation) • Early 20th century – active principle isolated 26
  • 27. Vinca Alkaloids • Madagascar periwinkle plant, Catharanthus roseus (Vinca rosea) • Periwinkle extracts – hypoglycemic effects in diabetics • Vincristine & Vinblastine – regression of ALL in mice - leukemias, lymphomas & testicular cancer. 27
  • 28. EvolutionofAnti-microbials The three eras of Chemotherapy – 1. Alkaloids(natural plant products) 2. Synthetic Compounds 3. Antibiotics 28
  • 29. Synthetic Compounds Salvarsan • Paul Ehrlich (1907) • Magic bullet • Treatment of syphilis (until penicillin) • Drawback: required many painful injections until cure 29
  • 30. Discovery of Prontosil • Gerhard Domagk (1895– 1964) • 1st clinically useful sulfonamide • Streptococcal infections. • Prontosil  ‘Sulphanilamide’  bacteriostatic. 30
  • 31. Evolution of the Sulpha drugs • 1938: May & Baker firm – ‘M&B 693’ Sulphapyridine – pneumo- & streptococci - nausea, kidney & bladder stones • 1940: Sulphadiazine – kidney stones Sulphasoxazole • 1941: 1700 tonnes – 10 million Americans puerperal fever, pneumonia, meningitis, rheumatic fever etc..& Gonorrhoea. • Resistance developed, replaced by Penicillin 31
  • 32. Elixir Sulfanilamide disaster (A tragic lesson) • September 1937, US • Massengill drug company – “Elixir Sulfanilamide” (Sulfanilamide + Diethylene glycol) • 100 deaths - DEG • FDA - Food, Drug & Cosmetic Act, 1938 32
  • 34. Discovery of Penicillin • Alexander Fleming (1881-1955) – Penicillium notatum • 1928 – culture dish contaminated by mould spores • ‘Penicillin’ –seeped out from the mould  killed bacteria near the mould 34
  • 35. • 1935: Howard Florey & Ernst Chain – investigated the anti-bacterial properties of Penicillin. • Norman Heatley – isolated penicillin from the mould. • Experimented with mice inoculated with streptococci • Used it successfully to treat war wounds • 1945: Fleming, Florey & Chain received Nobel prize 35
  • 36. Discovery of Streptomycin • 1946: Waksman – Streptomyces griseus (chicken’s throat) Streptomycin (cocci, spirochaetes, tb bacilli) • 1st recorded cure of tb meningitis • 1952 – Nobel prize 36
  • 37. • Side effects – Ototoxicity & Nephrotoxicity • 1953: Swedish researchers – Vitamin A + Streptomycin • German researchers – Pantothenic acid + Streptomycin • side effects (without diminishing antibiotic properties) 37
  • 38. Discovery of Anti-TB drugs • Streptomycin – promising cure  prolonged treatment with high doses Severe side effects & Resistance • 1949 – Combination therapy: Streptomycin + PAS • 1951 – Isoniazid (INH) – hydrazide salt of isonicotinic acid combined with streptomycin  dramatic results • Early 1970s – 5 more antibiotics & 3 synthesized chemicals. 38
  • 40. Discovery of Insulin • 1st description of diabetes – mid 17th century. • Richard Bright – Involvement of pancreas • Early 19th century: Paul Langerhans – ‘Islets of Langerhans’ • Hormone deficiency disease – ‘Insulin’ (insula = island) 40
  • 41. Banting & Best • 1921: Frederick Banting – effective & safe extract of insulin helped by Charles Herbert Best • Extracted insulin from a dog’s degenerated pancreas. • Saved the lives of diabetic dogs • Published their findings in American Journal of Physiology. 41
  • 42. • 11th Jan 1922 – successfully injected insulin to their 1st human patient (14 yrs old Leonard Thompson) • Toxic reactions minimised by James B. Collip – Purified insulin • 1923 – Only Banting received Nobel prize. • 1926: John Jacob Abel – prepared pure crystalline Insulin 42
  • 43. Discovery of Corticosteroids • Began with Anti-TB campaign (1940s) • Reichstein and Kendall - 1st isolated & identified adrenal steroids - effects on carbohydrate metabolism (glucocorticoids) • World war II: Lewis Sarrett – Cortisone (from bile of cattle) • Hench & Kendall – treatment of rheumatoid arthritis • 1950s – skin grafts & kidney transplants 43
  • 44. 44
  • 45. The Thyroid • Thyroid gland deficiency (myxoedema) - sheep thyroid extracts (1890s) • 1914: Edward Kendall – purer, powerful extract ‘Thyroxine’ (3 tons of pig thyroids!) • 1927 – Synthetic thyroxine 45
  • 46. History of some Cardiovascular drugs 46
  • 47. Heparin • Canine liver tissue (hepar = liver) • 1916: Jay McLean & William Henry Howell - fat soluble phosphatide anticoagulant • 1918 – Howel coined the term ‘heparin’ 47
  • 48. Warfarin • Spoiled sweet clover silage  Haemorrhagic disease in cattle • 1939: Campbell & Link – bishydroxycoumarin (dicoumarol) • 1948: Warfarin (WARF – Wisconsin Alumni Research Foundation) - synthetic congener - rodenticide • 1951: Coumarin anticoagulants – prevention of thromboembolic diseases. 48
  • 50. Nitrates • 1846: 1st synthesized by Sobrero • Alfred Nobel – stabilised nitroglycerine - patented a detonator • 1857: Lauder Brunton – found that amyl nitrite relieved angina pain in 30-60 sec • William Murrell – established the use of sublingual NTG in acute angina & for prophylaxis of exertional angina 50 Alfred Nobel
  • 51. Statins • 1976: Endo & colleagues – Penicillium citrinum (mould) - inhibitors of cholesterol biosynthesis. • Brown & Goldstein – act by inhibiting HMG-CoA reductase. • Compactin (Mevastatin) – 1st statin studied in humans • Lovastatin - 1st statin approved for use in humans - Aspergillus terreus 51
  • 52. Discovery of Prostaglandins • 1935 : Von Euler – protein in human semen  uterine smooth contraction Prostaglandin (‘prostate’) • 1965: synthetic form – used to induce labour for the 1st time • Inserted into vagina or cervix as pessaries or creams – preferred method of induction. 52
  • 53. History of OCPs • Early 20th century: Ludwig Haberlandt – 1st experiments. • Early 1940s: Russel Marker – extracted ‘diosgenin’ from yam  Progesterone Norethisterone/Norethindrone (1951) • Norethynodrel – menstrual regulator & OCP • Purified progesterone  Failure 53
  • 54. • Original compound – traces of Estrogen  Estrogen-Progesterone combined contraceptive pill • Initial concern of unwanted pregnancies Over-dosing women with estrogen thrombo-embolism fatal heart attacks & strokes • Dec’1969: UK Committee on the Safety of Medicines - Estrogen content not > 50 micrograms 54
  • 55. • John Rock – Roman Catholic Supported research on ‘the pill’ • Faced outrage from the Catholic Church - natural means (‘safe method’ or ‘rhythm method’) - forbade the use of unnatural contraception • 1973 – 50 million women were using OCPs (12 drug companies) – Era of Birth Control 55
  • 56. Thalidomide Scandal • 1950: Wilhelm Kunz – invented Thalidomide • Sedative; but with no obvious toxic effects • Approved as 1st safe sleeping pill • Reports of side effects 56
  • 57. • 1961: Dr. William McBride – Teratogenic effect (babies with deformed limbs) • 1962 – 7400 ‘thalidomide children’ worldwide  withdrawal of drug • 1968 – Committee on Safety of Medicines 57
  • 58. Few Scientists & their contributions.. 58
  • 59. William Withering (1741-1799) • Dropsy – edema that often accompanies heart & kidney failure • Fox glove tea • Active ingredient – Digitalis (fox glove leaves) • 1785: An account of the fox glove – Study of Digitalis 59
  • 60. Otto Loewi • 1921 – proved the chemical transmission of nerve impulses • Prototype experiment - existence of chemical transmission in a synapse • 1st chemical neurotransmitter identified – Ach • 1936 – Nobel prize, along with Henry Dale 60
  • 61. Sir Henry Hallet Dale • 1914 - distinguished muscarinic & nicotininc receptors - 1st identified Ach as a possible neurotransmitter (shared the nobel prize with Loewi in 1936) • Dale’s principle (Dale’s Law) – Each neuron releases only 1 type of neurotransmitter • Dale’s Vasomotor Reversal Phenomenon 61
  • 62. James Black • Developed propranolol – best-selling drug • 1975: 2nd major drug – Cimetidine (Tagamet) world’s 1st billion dollar drug 62
  • 63. Daniel Bovet • 1937: synthesized the 1st antihistaminic Thymoxidiethylamine • Discovered Pyrilamine (Mepyramine) • 1947: Discovered Gallamine • Isolated Succinylcholine • 1957: Nobel prize in Physiology/Medicine 63
  • 64. Rudolf Buchheim • World’s 1st pharmacology lab – basement of his house • Remembered for his pioneer work in Experimental Pharmacology. • He introduced the bio assay to pharmacology, • Taken over by his student, Oswald Schmiedeberg 64
  • 65. Alfred Goodman Gilman • American pharmacologist and biochemist • 1994 – Nobel prize in Physiology or Medicine along with Martin Rodbell for their discovery of G proteins & their role in signal transduction. 65
  • 66. Historyofhumanexperiments • During WWII (1940) : Nazis (Germany) – series of medical experiments on prisoners, including children. (Jews) • No consent taken • Death, trauma & permanent disability, even execution • Malaria, immunization, mustard gas & Sulphonamide experiments 66
  • 67. • 1946: Doctors’ trial – Nuremberg (Germany) led by US Nuremberg Code of medical ethics • Declaration of Helsinki (DoH)  Human experimentation  World Medical Association (WMA)  1st significant effort to regulate research itself  Basis of most subsequent documents 67
  • 68. 68
  • 69. References : 1) A History of Medicine - Nancy Duin & Dr Jenny Sutcliffe 2) The Pharmacological Basis of Therepeutics -Goodman & Gilman, 12th edition 3) Basic and clinical pharmacology : Katzung, Masters and Trevor, 11th edition 4) Medical Pharmacology – Dr Padmaja Udaykumar, revised 4th edition 5) Rang & Dayle’s pharmacology, 7th edition 6) Pharmacognosy – Dr C.K Kokate, A.P Purohit, S. B Gokhale 7) Pictures & video from the internet “History, if it has taught us anything at all, has taught us that the strange ideas we derive today will one day be our celebrated truths.” ― Dan Brown, The Lost Symbol 69

Editor's Notes

  1. From very early times, attempts were being made to find drugs to relieve pain – to relieve
  2. Suggested the use of NITROUS OXIDE to relieve the pain of surgery. Noted that it caused – euphoria - analgesia - loss of consciousness
  3. Pic - Humphry Davy testing the effects of laughing gas on the rich aristocrats of London at a laughing gas party
  4. Administration of ether (pic)
  5. Horace wells - was an American dentist who pioneered the use of anesthesia in dentistry, specifically nitrous oxide (or laughing gas). wanted to find out if nitrous oxide could be used for painless tooth extraction and decided to experiment on himself.one of his friends Dr . John Wells pulled out one of the molars of wells who after regaining consciousness exclaimed – “A new era of tooth-pulling !” However, the gas was improperly administered and the patient cried out in pain. The audience of students in the surgical theatre jeered "humbug“(fraud). Because of this embarrassment, Wells was discredited in the medical community
  6. American dentist First publicly demonstrated the use of inhaled ether as a surgical anaesthetic in 1846 – before removing a tumor from the neck of a young man (pic)
  7. Professor of midwifery @ Edinburgh, was dissatisfied with ether in obstetrics. He decided to try chloroform (which had been virtually discovered simultaneously in the US, france n Germany) …. However he faced an uproar as some physicians claimed that pain in labor was a biological necessity. Although he continued to use chloroform, the outcry did not die down until 1853 when Q. Victoria consented for the use of this volatile liquid for the birth of prince leopold, which was administered by john snow, britian’s 1st specialist anaesthetist who later went on to contribute majorly in the field of public health. After this chloroform’s position in obstetric anaesthesia was secure for more than a century until…
  8. The cocaine alkaloid was first isolated by the German chemist Friedrich Gaedcke in 1855. Gaedcke named the alkaloid "erythroxyline“ For the next 25 years it was used as a treatment for morphine addiction and as an ingredient in soft drinks. Coca-Cola was named back in 1885 for its two "medicinal" ingredients: extract of coca leaves and kola nuts
  9. Cocaine was also used as toothache drops", 1885 advertisement of cocaine for dental pain in children
  10. Crystalline alkaloid having antipyretic, antimalarial, analgesic, anti-inflammatory properties and a bitter taste. obtained from the bark of the Cinchona tree Long used by Quechua Indians of Peru and Bolivia , to halt shivering due to low temperatures
  11.  thus quinine became one of the most valuable commodities shipped from Peru to Europe.  When King Charles II was cured of malaria at the end of the 17th Century with quinine, it became popular in London.It remained the antimalarial drug of choice until the 1940s, when other drugs took over
  12. MALARIA HAS BEEN A DEVASTATING PARASITE DISEASE THAT HAS LIKELY KILLED ONE HALF OF ALL THE HUMAN BEINGS EVER LIVED ON THE EARTH Descriptions of such malaria-specific symptoms are found in ancient Chinese literatures compiled thousands of years ago. Although countless ways of treatments were tested over the thousands of years, success was occasional and failure was common. Historically, the epidemic of malaria has been considered as the likely cause for the fall of many major powers (including the Roman Empire) and defeat in wars. In the midst of time, the Quechuas “doctors” from Peru and Bolivia used the bark of the cinchona tree to produce a medicine to treat some fevers, whereas their counterparts on the other side of the world, in China, used the leaves of sweet wormwood (Artemisia annua) for the same effect. There are interesting stories on how qinghaosu (artemisinin) was extracted from Artemisia plants, used by Chinese herbalists for thousands of years as a remedy for many illnesses. The earliest record, written on a piece of silk unearthed from the Mawangdui Han Dynasty tombs (168 BC), described it as a treatment for hemorrhoids. during the Ming Dynasty, qinghao was specifically described as a remedy for fever. Although Qinghao has been recorded in Chinese medical books compiled about 1500 years ago for its effectiveness in treating malaria, those early practices were based on experiences instead of strict scientific tests
  13. Because soldiers were dying from malaria, effective antimalarial drugs were also needed in the battlefield immediately Since the late 1960s, The Chinese government started a massive effort to search for new drugs that are effective in treating the malaria resistant to such conventional drugs as chloroquine 23 May 1967 (thus named ‘Project 523’) a large-scale, multi-institute search for novel antimalarial drugs Screening of the traditional Chinese pharmacopoeia soon led to the identification of more than ten plants with good antimalarial activities, including yingzhao (Artabotrys hexapetalus) and qinghao (Artemisia annua). In the early 1970’s, the active ingredient of sweet wormwood was identified as artemisinin (qinghaosu) a powerful, though unstable in vitro antimalarial. Further studies lead to the development of more stable derivatives, a methyl-ether derivative, artemether and a water-soluble one, artesunate.
  14. Atropine - Belladonna’ (beautiful women) deadly nightshade, to dilate pupils by Italian women & also by Cleopatra Used by ancient Hindus to treat asthma. Bezold and Bloebaum (1867) showed that atropine blocked the cardiac effects of vagal stimulation, and Heidenhain (1872) found that it prevented salivary secretion produced by stimulation of the chorda tympani. Opium Purified opium – diarrhoea & dysentery in ayurveda Paracelsus – ‘stone of immortality’ - ‘Laudanum’ Cholera, dysentery, toothache, flatulence, insanity and menopause Opium wars Hypodermic syringe
  15. Pilocarpine is the chief alkaloid obtained from the leaflets of South American shrubs of the genus Pilocarpus. Although it was long known by the natives that the chewing of leaves of Pilocarpus plants caused salivation, the first experiments were apparently performed in 1874 by the Brazilian physician Coutinhou. T the alkaloid was isolated in 1875, and shortly thereafter the actions of pilocarpine on the pupil and on the sweat and salivary glands were described by Weber
  16. Physostigmine, also called eserine, is an alkaloid obtained from the Calabar or ordeal bean, the dried, ripe seed of Physostigma venenosum, a perennial plant found in tropical West Africa. The Calabar bean once was used by native tribes of West Africa as an "ordeal poison" in trials for witchcraft, in which guilt was judged by death from the poison, innocence by survival after ingestion of a bean. A pure alkaloid was isolated by Jobst and Hesse in 1864 and named physostigmine. The first therapeutic use of the drug was in 1877 by Laqueur, in the treatment of glaucoma, one of its clinical uses today.
  17. Curare is a generic term for various South American arrow poisons paralyzing wild animals used for food; death results from paralysis of skeletal muscles. Following the pioneering work of the scientist/explorer von Humboldt in 1805, the botanical sources of curare became the object of much field research. The curares from eastern Amazonia come from Strychnos species Griffith and Johnson reported the first trial of curare for promoting muscular relaxation in general anesthesia in 1942 King established the essential structure of tubocurarine in 1935
  18. Ergot is the product of a fungus (Claviceps purpurea) that grows on rye and other grains It was in the Rhine Valley, in 857 A.D., that the first major outbreak of gangrenous ergotism was documented Middle Ages, describing strange epidemics in which the characteristic symptom was l separated off without loss of blood. Limbs were said to be consumed by the holy fire, blackened like charcoal with agonizing burning sensations,  "Holy" because of the belief that this was a punishment from God. the disease was called holy fire or St. Anthony's fire in honor of the saint at whose shrine relief was said to be obtained . The relief that followed migration to the shrine of St. Anthony was probably real, for the sufferers received a diet free of contaminated grain during their sojourn at the shrine. dramatic abortive effect of ergot ingested during pregnancy. The active principles of ergot were isolated and chemically identified in the early 20th century
  19. Limbs were said to be consumed by the holy fire, blackened like charcoal with agonizing burning sensations,  "Holy" because of the belief that this was a punishment from God. the disease was called holy fire or St. Anthony's fire in honor of the saint at whose shrine relief was said to be obtained . The relief that followed migration to the shrine of St. Anthony was probably real, for the sufferers received a diet free of contaminated grain during their sojourn at the shrine. dramatic abortive effect of ergot ingested during pregnancy. The active principles of ergot were isolated and chemically identified in the early 20th century
  20. The beneficial properties of the Madagascar periwinkle plant, Catharanthus roseus (formerly called Vinca rosea), Periwinkle extracts attracted interest because of their hypoglycemic effects in diabetes. Purified alkaloids, including vinblastine and vincristine, caused regression of an acute lymphocytic leukemia in mice and were among the earliest clinical agents for treatment of leukemias, lymphomas, and testicular cancer. A closely related derivative, vinorelbine, has important activity against lung and breast cancer
  21. 3 distinct periods 1.Great antiquity;only substances capable of curing infection were natural plant products 2.Era of synthesis 3.Return to natural plant products,plants of lower order i.e bacteria nd moulds forming antibiotics
  22. drug invention became more allied with synthetic organic chemistry Study of dye interactions stimulated Paul Ehrlich to postulate the existence of chemical receptors in tissues that interacted with and "fixed" the dyes. Ehrlich thought that unique receptors on microorganisms or parasites might react specifically with certain dyes and that such selectivity could spare normal tissue. Ehrlich's work culminated in the invention of arsphenamine in 1907, which was patented as "salvarsan," suggestive of the hope that the chemical would be the salvation of humankind. This arsenic-containing compound and other organic arsenicals were invaluable for the chemotherapy of syphilis until the discovery of penicillin
  23. Following ehrlich’s spectacular success with salvarsan, researchers began to test virtually every substance that might be effective against infectious diseases Gerhard Johannes Paul Domagk (1895– 1964) During that period and thanks to the work of Gerhard Domagk, an azo dye, prontosil (the first clinically useful sulfonamide) was shown to be dramatically effective in treating streptococcal infections which fetched him a nobel prize. It was found that prontosil would only work when the compound split into 2 parts, & that 1 of the 2 parts – later called sulphanilamide – was largely responsible for pronotsil’s bacteriostatic action (did not kill the bacteria like an antibiotic, only prevented them from multiplying)
  24. However neither prontosil no sulphanilamide proved very effective against pneumococcal infections & scientists began to look for other drugs. In 1938 a british firm May & Baker developed ‘M&B 693’ later called sulphapyridine – not only worked well against pneumococcal infections but even better than sulphanilamide against strep. (Thus the family of sulphonamide drugs was born) however it was known to cause serious nausea & sometimes kidney & bladder stones. So the search began for a less toxic analogue – sulphadiazine in 1940, but this still produced kidney stones in a few patients taking large doses, so a much more soluble drug was developed – sulphasoxazole which was then almost exclusively used for treatment (while sulphadiazine continued to be used in small doses) By 1941, 1700 tonnes of these sulpha drugs were given to atleast 10 million americans, for conditions like – puerperal fever, pneumonia, meningitis, rheumatic fever etc..also proved to be the 1st successful treatment for gonorrhoea. Howvever eventually strains of sulpha-resistant streptococci appeared & spread widely. & soon they were overshadowed by the rising popularity of the 1st true antibiotic
  25. ELIXIR SULFONILAMIDE DISASTER Elixir sulfanilamide was an improperly prepared sulfanilamide medicine that caused mass poisoning in the United States in 1937. It caused the deaths of more than 100 people. In 1937, S. E. Massengill Company, a pharmaceutical manufacturer, created a preparation of sulfanilamide using diethylene glycol (DEG) as a solvent, and called the preparation "Elixir Sulfanilamide".[3] DEG is poisonous to humans and other mammals, but Harold Watkins, the company's chief pharmacist and chemist, was not aware of The company started selling and distributing the medication in September 1937.  Animal testing was not required by law, and Massengill performed none. By October 11, the American Medical Association received a report of several deaths caused by the medication. The Food and Drug Administration was notified, and an extensive search. verified that the excipient DEG was responsible for the fatal adverse effects. At least 100 deaths were blamed on the medication.  passing the 1938 Food, Drug, and Cosmetic Act, which required companies to perform animal safety tests on their proposed new drugs and submit the data to the FDA before being allowed to market their products.
  26. A 3-year-old boy before, and several weeks after receiving insulin in 1922. (pic)
  27. Shortly after synthetic cortisone became available, Hench and colleagues demonstrated its dramatic effect in the treatment of rheumatoid arthritis
  28. Hench, Kendall and Reichstein received Nobel Prize in 1950
  29. It was originally isolated from canine liver cells, hence its name (hepar or "ήπαρ" is Greek for "liver"). Heparin's discovery can be attributed to the research activities of Jay McLean and William Henry Howell. In 1916, McLean, a second-year medical student at Johns Hopkins University, was working under the guidance of Howell investigating procoagulant preparations, when he isolated a fat-soluble phosphatide anticoagulant in canine liver tissue. In 1918, Howell coined the term 'heparin' for this type of fat-soluble anticoagulant. . A posthumous attempt to nominate McLean for a Nobel Prize failed.[citation needed]
  30. hemorrhagic disorder in cattle ingestion of spoiled sweet clover silage, Campbell and Link, in 1939, identified the hemorrhagic agent as bishydroxycoumarin (dicoumarol). In 1948, a more potent synthetic congener was introduced as an extremely effective rodenticide; the compound was named warfarin as an acronym derived from the name of the patent holder, Wisconsin Alumni Research Foundation (WARF). Warfarin's potential as a therapeutic anticoagulant was recognized but not widely accepted, partly due to fear of unacceptable toxicity. 1951, an army inductee uneventfully survived an attempted suicide with massive doses of a preparation of warfarin intended for rodent control. Since then, these anticoagulants have become a mainstay for prevention of thromboembolic disease
  31. Story of aspirin
  32. Nitroglycerin was first synthesized in 1846 by Sobrero, who observed that a small quantity placed on the tongue elicited a severe headache until Alfred Nobel devised a process to stabilize the nitroglycerin and patented a specialized detonator in 1863 In 1857, T. Lauder Brunton of Edinburgh administered amyl nitrite, a known vasodepressor, by inhalation and noted that anginal pain was relieved within 30- 60 seconds , William Murrell surmised that the action of nitroglycerin mimicked that of amyl nitrite and established the use of sublingual nitroglycerin for relief of the acute anginal attack and as a prophylactic agent to be taken prior to exertion. Alfred Nobel himself was prescribed nitroglycerin by his physicians when he developed angina in 1890
  33. Statins were isolated from a mold, Penicillium citrinum, and identified as inhibitors of cholesterol biosynthesis in 1976 by Endo and colleagues Brown and Goldstein established that statins act by inhibiting HMG-CoA reductase . The first statin studied in humans was compactin, renamed mevastatin, which demonstrated the therapeutic potential of this class of drugs. Alberts and colleagues at Merck developed the first statin approved for use in humans, lovastatin (formerly known as mevinolin), which was isolated from Aspergillus terreus.
  34. History of pharmacology would be incomplete without mentioning this infamous event
  35. Recognized dropsy as the edema that often accompanies heart & kidney failure
  36. Otto loewi A German Pharmacologist 1921 He proved, the chemical transmission of the nerve impulses& in 1936 He received the Nobel price, with Henri Dale. He designed his most famous experiment, which provided the first evidence for the existence of chemical transmission in a synapse - became a prototype for all investigations of chemical factors in the nervous system The first chemical neurotransmitter that he identified - ACETYLCHOLINE
  37. SIR HENRY HALLET DALE 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 Dale's principle ( Dale's Law). This principle states that each neuron releases only one type of neurotransmitter. Dale’s Vasomotor Reversal Phenomenon
  38. Sir James Black A Scottish Pharmacologist He developed Propranolol while working for ICI , which later became the world's best-selling drug. 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. Sir James Black with a molecular model of propranolol (pic)
  39. Daniel bovet Italian pharmacologist In 1937 Bovet and his research student Anne Marie Staub succeeded in synthesizing the first antihistaminic was too toxic to be used so he continued with hundreds of experiments to find a more human body friendly antihistamine. After years of research he succeeded in discovering Pyrilamine (mepyramine) a very important antihistamine. In 1947 he discovered gallamine when he was looking for a synthetic substitute for curare Isolated succinylcholine, a muscle relaxant now used in conjunction with anesthesia during certain surgical procedures.  In 1957 he was awarded the Nobel Prize in Physiology or medicine for his discoveries.
  40. Rudolf Buchheim (a German pharmacologist) 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
  41. Alfred goodman gilman American pharmacologist and biochemist 1994 – Nobel prize in Physiology or Medicine along with Martin Rodbell for their discoveries regarding G-proteins.
  42. Nazi human experimentation was a series of medical experiments on large numbers of prisoners, including children, by Nazi Germany in its concentration camps in the early to mid 1940s, during World War II and the Holocaust. Chief target populations included Romani, Sinti, ethnic Poles, Soviet POWs, disabled Germans, and most prominently of all, Jews from across Europe. Nazi Physicians and their assistants forced prisoners into participating; they did not willingly volunteer and no consent was given for the procedures. Typically, the experiments resulted in death, trauma, disfigurement or permanent disability, while many others were executed after the tests were completed to study the effects post mortem.and as such are considered examples of medical torture. 1.5Malaria experiments 1.6Immunization experiments 1.7Mustard gas experiments 1.8Sulfonamide experiments
  43. On 19 August 1947, the doctors captured by Allied forces were put on trial in USA vs. Karl Brandt et al., commonly known as the Doctors' Trial. But this defense, which was in any case rejected by the Tribunal, The trials began on December 9, 1946 in Nuremberg, Germany and were led exclusively by the United States. led to the development of the Nuremberg Code of medical ethics.  The Declaration of Helsinki (DoH) is a set of ethical principles regarding human experimentation developed for the medical community by the World Medical Association (WMA). The Declaration is an important document in the history of research ethics as it is the first significant effort of the medical community to regulate research itself, and forms the basis of most subsequent documents.  "Even though the Declaration of Helsinki is the responsibility of the World Medical Association, the document should be considered the property of all humanity".  the Nuremberg Code and the related[4] Declaration of Helsinki are the basis for the Code of Federal Regulations ,governing federally funded human subjects research in the United States. * The Nuremberg code includes such principles as informed consent and absence of coercion; properly formulated scientific experimentation; and beneficence towards experiment participants.