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17' Medicines, Drugs part 2

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Title: 17' Medicines, Drugs part 2


1
(No Transcript)
2
17. Medicines, Drugs -
part 2

3
The Pharmaceutical Industry
Worldwide, in 2007, 800 billion was spent
on legal/ ethical 'medications (doesn't include
vitamins/minerals/herbals).


By
'continent'
N.America 44, W.Europe 25,
Japan 16, Latin America 6, Asia
Pacific 4, other 6 NB. Where is Africa?? No
money not important!
4
OTC - from A(antacids) to Z(zits)
OTC Over The Counter, ie. non-prescription

North Americans self-medicate 10x/mo/person
Est. 75 of all 'illnesses' are treated from
the
drug-store shelves.
In USA ('97)
there were

144 categories
2000 compounds(some 'inactive')
300,000
formulations/products.
5
Over The Counter (OTC) Cold Medications
Type of Ingredient
Name Decongestant
Pseudoephedrine Antitussive
Dextromethorphan (cough
suppressant) Expectorant
Guaifenesin (loosen fluids in
cough) Analgesic/Antipyretic
Acetaminophen (diminish pain/fever)
Antihistamine
Chlorpheniramine Caffeine
Stimulant
6
OTC - Common Sense
Choose single-ingredient products, specific for
your condition
Save -
choose generics
Read labels follow instructions
Pay attention to
cautions and interactions with
alcohol or other medications
Always mention OTC
preparations to your MD Or. take chicken
soup, gargle with salt/water, use a water
vaporizer and get some sleep
7
Psychology and Drug Price
  • Expensive placebos work better than cheap ones!
  • Double blind study 2 placebos. Patients told
    cost of new pain reliever (10 cents vs 2.50
    per pill)
  • Pain relief much higher in group taking the
    expensive pill
  • Globe and Mail March 2008

8
The Business of Wellness
Research/Development-synthesis
20 - 25 ( 35 on
Human Clinical Evaluation
for DIN - Drug Identification Number)
Production/Scale-Up 20
Patents/Licensing 10

(17-20 yrs for a 'brand name' patent) delays

Marketing (Advertising) 10


For every
10,0000 - starting compounds
10 - to
preclinical trials

5 - to human trials

1 - to market
9
New Product Development
12 -15 years(7 yrs.
of clinical trials)
300 - 400
million
3 of 10 'pay back'

'block-buster' 1 billion(life-time
sales) Some Companies
AstraZeneca, Bayer, Bristol Myers/
Squibb, Glaxo-Smith-Kline, Warner Lambert
Hoffman LaRoche, Novartis, Merck(US),
Pharmacia, Pfizer, G D Searle,
Eli Lilly
In Canada Merck Frosst, BioChem
Pharma,(Apotex) Ratiopharm.

Proprietary/'Brand-name'
vs Generic.
10
Brand/Trade - only by manufacturer (proprietary)
ie Tylenol , Motrin
Generic - generally
accepted 'chemical name' (for
'easy' recognition by health professionals) ie
acetaminophen, ibuprophen
11
Patent protection
  • Brand name is protected in perpetuity
  • Active component has protection for 17 years in
    Canada
  • After that, Generic Cos can make the drug and
    sell it under another name
  • Many legal disputes (IP law) Gowlings in Ottawa
  • Polymorphs (different crystalline forms) can be
    patented
  • New applications of old drugs can be patented

12
Brand names!
  • Who thinks them up?
  • Big business!!
  • But getting tougher to find simple ones beware
    of similarities
  • Some are brilliant Viagra Levitra Celebrex
    (anti-inflammatory)

13
Top NA 10 prescription drugs in 2007
  • Lipitor Pfizer lowers cholesterol
    13.7B
  • Nexium AstraZeneca antiulcer
    6.9
  • Advair GaxoSmithKline asthma
    6.7
  • Plavix BMS atherosclerotic events
    5.8
  • Aranesp Amgen anemia
    5.1
  • Enbrel Amgen rheumatoid arthritis
    4.9
  • Zyprexa Eli Lilly schizophrenia
    4.9
  • Risperdal JJ schizophrenia
    4.8
  • Norvasc Pfizer hypertension
    4.5
  • Seroquel AstraZeneca Schiz. Bipolar disorder
    4.2

14
Steroids
Compounds with a
common tetracyclic structure and a variety
of physiological functions depending on
functional group arrangement.
Cholesterol(animal fat)
15
Are all steroids anabolic?
  • Consider cholesterol, cortisone etc.

16
Stanozolol (Ben Johnson 88 Olympics)
Anabolic Steroids Promote rapid muscle growth
stamina (more workouts)
4-Androstene-3,17-dione (Mark McGuire 90s)
17
Detection Mass Spectrometry of Drug metabolites
in urine
  • Each compound has a unique pattern

18
Male Sex Hormones (Androgens)
Testosterone
Androsterone
19
The next generation of cheating
  • Idea-just take more testosterone undetectable
    because the body makes it anyway!

20
Doping in Sports Testosterone
  • Floyd Landis tests positive for abnormal amounts
    of testosterone forfeits Tour de France cycling
    championship in July 2006

21
The tests and the Dope
  • Testosterone (T) is an anabolic (muscle enhancing
    steroid)
  • Epi-testosterone (E) is a stereoisomer, differing
    only in stereochemistry of the chiral centre in
    the D-ring, BUT it has no anabolic effects
  • If T is administered, the excretion rate of
    urinary T increases and that of E decreases

22
Measure the T/E ratio in urine!
  • The average for adult men is 1, and very rarely
    exceeds 4
  • Landis had a T/E ratio of 11.
  • Based on this test, he looks guilty
  • But he claimed someone tampered with his urine

23
Adding epitestosterone
  • Some have tried to beat the Urine T/E ratio test
    by taking in additional E
  • Thus another test needed to be developed

24
Kinetic Isotope Effect (KIE)
  • Biggest effect is in C-H vs C-D bond breakage
  • Rates of C-D bond breaking can be up to 7 times
    slower than C-H
  • Effects for 12C-H vs. 13C-H are obviously
    smaller, but bonds involving the heavier isotope
    are always harder to break

25
Other bonds to be broken
  • 13C-O vs. 12C-O
  • 13C-12C vs 12C-12C

26
Experimentally
  • Rates of 12C vs 13C have been measured to differ
    by up to 8 in one reaction 12C is always faster
  • So enrichment 12C/13C 1.08 for one reaction
  • If 5 reactions enrichment 1.08x1.08x1.08x1.08x1.
    08 ie. 1.46 or 46!

27
Isotope ratio test (new 2004)
  • Synthetically derived T has a slightly lower
    amount of the 13C isotope than does T produced in
    the body (Because more reactions needed to make
    it synthetically than in the body) 13C isotope
    reacts more slowly than 12C).
  • This is the well known Kinetic Isotope effect!
  • Mass spectrometry (detects isotopic abundances)
    used to measure the 13C to 12C ratio in
    testosterone Landis also failed this
    test..verdict GUILTY

28
Female Sex Hormones (Estrogens)
Estrone
Estradiol
Progesterone (pregnancy hormone)
29
Steroids contd Evolution of the BC pill
  • 1st step (1960s) progesterone (pregnancy
    hormone, prevents ovulation) was administered
  • Worked well if injected, but not effective if
    taken orally not acceptable for mass use
  • Synthesis of progesterone like compds
  • Similar structure except for D ring substituents

30
Progestins
  • Stopped ovulation
  • Could be taken orally
  • But small amount of breakthrough bleeding
  • Inclusion of a small amount of estrogen controls
    this
  • Combination Pill Progestin and estrogen
  • Dosage 1/day for 21 days, off for 7, can miss
    one

31
The Pill (Birth Control)
Ethynylestradiol (synthetic estrogen)

Norethindrone (synthetic progestin)
32
Side effects of the Pill
  • minor headaches, some dizziness
  • major combined with smoking, risk of blood
    clots
  • Risk increases with age and long term use

33
The morning after pill RU-486
  • Blocks the implantation of a fertilized egg in
    the uterine wall
  • Developed in France

34
Sulfa Drugs the 1st antibacterials
  • Benzene sulfonamides-not antibiotics, but did
    inhibit bacterial growth by disrupting folic acid
    synthesis
  • Developed in Germany 1932 (1st wonder drugs)
    could be applied as powders to wounds in the
    field WWII.
  • Superceded by less toxic antibiotics in 1944

35
Antibiotics - the Wonder Drugs
Antibiotic a compound that kills bacteria
(by destroying bacterial cell
walls.
isolated from moulds or bacteria, eg.
penicillins, cephalosporins,
erythromycin, streptomycin, but
sometimes 'synthetic', eg.
chloramphenicol, fluoroquinolones


Antibacterial agent antimetabolite (starves the
bacteria, often of folic acid), eg.
sulfa drugs
36
Discovery of penicillin(20th centurys most
important one?)
  • 1928 , Alexander Fleming grew Staphylococcus
    bacteria on an agar medium
  • Noticed inhibition of bacterial growth around a
    blue-green mould accidental contaminant

37
1928-1940
  • Fleming grew a pure mould culture discovered it
    was Penicillium notatum
  • Later isolated the pure chemical
    antibioticcomponent, named it penicillin
  • But needed a good large scale source of the mould

38
Antibiotics Mass production of
penicillin -following a world-wide search, a
mouldy canaloupe in Peoria Ill, in 1942 was found
to contain the highest quality penicillin! Led
to mass production(start of Pfizer) 2.3 million
tons available to Allied Soldiers for the
Normandy invasion in 1944.


39
Penicillins('28-'44) - the ?-Lactams
Penicillin the general structure
The first class of 'broad spectrum' antibiotics
still the most prescribed worldwide.
40
Alexander Fleming 1881-1955
  • Nobel Prize for Medicine/Physiology in 1945
  • Knighted in 1944

41
Penicillin from fermentation
  • Pharmaceutical grade obtained

42
The Process
  • Start cold stored penicillium culture on agar
    plate
  • Transfer to shake flasks ,with food (Sugars)
    and nutrients (ammonium salts), aas needed for
    growth
  • Resulting suspension can be transferred to seed
    tanks for further growth
  • Transfer to larger fermentation tank (30,000
    gallons)
  • After 3-5 days , isolation
  • Temp, pH, mixing essential, sterilized air pumped
    in.

43
Semi-synthetic derivatives
  • Original penicillin was excreted too
    rapidly-urine recycling in early patients for
    recovery of the drug
  • Chemists modify original structure for different
    properties and bio-availablity

44
the 'Evolution' of Penicillins - 1 step ahead!
penicillin G
penicillin V
ampicillin
amoxicillin
methicillin
cloxacillin
oxacillin
45
Incapacitating those 'Nasty Bugs'
Varied structures indicate varied
'mechanisms' to kill
bacteria.

eg.
?-lactams(penicillins) - breakdown cell
walls tetracyclines/erythromycin/streptomyci
n - inhibit various
aspects of protein synthesis
fluoroquinolones('cipro') - inhibit DNA
replication
46
Some Antibiotics and Their Uses
Penicillins ear/skin/respiratory/digestive/urina
ry infections, syphilis,
scarlet fever.
Tetracyclines respiratory/urinary infections,
acne, bronchitis, whooping
cough, typhus fever.
Cephalosporins ear/throat/skin/urinary
infections Chloramphenicol
typhoid fever, meningitis,
eye/ear infections
Erythromycins
skin/eye/respiratory/tissue
infections, diphtheria.

Spectinomycin gonorrhea
Gentamycin bone/skin/lungs/abdomen
infections
47
OTC Antibiotics
Cefaclor(cephalosporin)
Bacitracin
Neomycin
Neomycin
48
Some Tetracyclines
Chlorotetracycline (Aureomycin)
Doxycycline
49
Macrocylic Antibiotics
Erythromycin
Rifamycin
50
Antibiotic Resistance - can we win?
Partly due to overuse(abuse?), partly because
bacteria have short life-cycles there is a
serious and increasing problem of
emergence of antibiotic-resistant
bacteria. In
1999 EU used 4700 metric tons of antibiotics for
farmed animals(35 of total 50 in
NA!)).
There are antibiotic-resistant
strains of malaria, TB, typhoid, and
gonorrhea (1 in 7 new cases!). TB is increasing
in NA, especially among poor. More
reports of 'killer staph infections' in
hospitals. (C-Difficile)
51
Recall
  • Pseudoephedrine can be readily converted to
    crystal meth (Methamphetamine)

52
Why no antimalarial drug?
  • Viewed as an African problem
  • No money in it for the Pharmaceutical industry

53
Quinine and malaria treatment
  • Used since 1600, in bark of S.A.cinchona tree
  • Isolated and named in 1817 (Inca for bark quina
  • Inhibits the parasites heme polymerase
  • Not recommended for malaria prevention because of
    side effects and poor tolerability
  • High dosage required 8mg/kg every 8 hours or
    .56g x3 1.68g/day for 70kg person
  • If therapy is stopped, relapse occurs

54
Quinine
  • An alkaloid
  • Also antipyretic, analgesic, anti-inflammatory,
    anti-smallpox

55
Quinine in Tonic Water
  • British colonial days-quinine was added to
    water in an attempt to prevent malaria
  • Still present 20mg per can
  • Need 80 gin and tonics to get proper dose
  • Bitter taste-so add gin and lemon/lime!

56
Tonic water
  • 80 cans per day to treat malaria!

57
Synthetic Antimalarial drugs
  • Chloroquine

58
Chloroquine
  • Used to prevent and treat malaria
  • BUTmany adverse side effects itch, mood
    changes, blurred vision
  • Dangerous in overdose doubling the normal dosage
    can be fatal
  • Malaria parasites now have developed widespread
    resistance to it
  • New drugs needed

59
Perhaps some hope for Africa
  • International Public-private partnership funding
    research on antimalarial drugs
  • Chinese antimalarial herbal medicine extract
    Artemisinin

60
But too expensive to extract
  • Synthetic analogues being made
  • Hoffman La Roche (Basel)
  • OZ277 looks promising

61
Development of OZ277
  • Funded and coordinated by Malaria Venture (Swiss
    non-profit organization)
  • OZ277 being synthesized in India by Ranbaxy
    Laboratories on multi-kg scale
  • Kills the malaria parasite
  • Peroxide unit essential for activity

62
New Drugs for Canada (in 2001)
presc. Drug
(000s)
Meridia(anti-obesity) Remicade(anti-arthritic)
Nexium(anti-ulcer) Tequin(anti-infective)
Remeron(anti-depressant) Gleevac(immunomodulator)
Enbrel(anti-arthritic) Agenerase(anti-viral)
Zyvoxam(anti-infective) Rapamune(immunomodulator)

8796 7337 3977 2482 2331 1419 1130 829 678 601
63
Worlds Top 10 Therapies 2007
  • Anticancer
  • Lipid regulators
  • Respiratory agents
  • Anti ulcer
  • Antidiabetic
  • Antidepressant
  • Antipsychotic
  • Heart drugs
  • Anti-epileptics
  • Erythropoieten (EPO) Stimulates red blood cell
    formation in premature infants (also used
    illegally in blood doping)

64
Pfizer some Blockbusters(99)
Drug Use Global
sales( millions)
Lipitor Norvasc Zoloft Celebrex
Zithromax Viagra Zyrtec
cholesterol hypertension depression
arthritis infection ED
allergy
3670 3560 2630 1500 1340 1220 569
65
Drugs by Physiological Function
Central Nervous System (CNS) Active
a) anesthetics, b) hypnotics sedatives, c) for
psychiatric disorders, d) convulsive disorders,
e) muscle relaxants, f) analgesics
antipyretics, g) CNS stimulants
Local Anesthetics
Drugs Acting at
Nerve Junctions
Allergenics
Cardiovascular Drugs

a) digitalis, b) antiarrythmics, c)
vasodilators, d) antihypertensives, e)
anti atherosclerosis Renal (kidney)
Function
66
Drugs by Physiological Function.contd
Uterine Action
AntiParasitics

Hormones
Vitamins

Antiviral Agents
Blood Related Diseases
for Neoplastic (eg. cancer)
Diseases
AntiMicrobials synthetic natural antibiotics
Digestants,
Antiseptics/Fungicides
67
Intrabody Communication
Two major lines of chemical communication between
our external and internal
environments 1) CNS -
neurons/synapses/neurotransmitters 2)
Circulatory System - O2 transport, antibodies,

hormones, etc.

Hormones chemical messengers
Produced in special(endocrine) glands,
transported through circulatory system to other
parts of the body (heart, liver, kidneys, etc.)
to influence a variety of physiological
effects(metabolism, reproduction, growth, etc.)
68
Some Hormones
Name Gland Structure
Effect
HGH Oxytocin Thyroxine Insulin Cortisol
Aldosterone Adrenaline Estradiol Progesterone
Testosterone
Pituitary Pituitary Thyroid Pancreas
Adrenal Adrenal Adrenal Ovary Ovary
Testis
protein peptide a.a.deriv. protein steroid
steroid a.a.deriv. steroid steroid steroid
body growth uterine contractn. cell
metabolism glucose metab. protein -gt carbo Na
concn. emergency stimulus stimul. female
char. reg. menst. cycle. stimul. male char.
69
Legal supplements for atheletes
  • Creatine, an amino acid (body makes1-2 gr/day)
  • Seems to produce an increase in creatine
    phosphate, which is used to convert ADP to ATP,
    the main E source for muscle cells
  • Used medically to treat ALS (degenerative muscle
    disease)

70
Creatine
  • Highest selling supplement ever! No hazards with
    long term use. Not a steroid/not anabolic.

71
HRT (Hormone replacement therapy)
  • Menopausal women experience hot flashes
  • Body is reacting to a decreased supply of
    estrogen
  • confused hypothalamus part of the brain
    controlling appetite, sleep, temperature and sex
    hormones)

72
Solution HRT (or is it?)
  • Until 2002, estrogen was given to stop hot
    flashes and also to help with bone density issues
  • Drug used was Premarin, a mixture of estrogen
    like compounds (Wyeth Pharmaceuticals)
  • Origin pre..mar.in extracted from.?

73
Pregnant Mares Urine
  • 22,000 in Canadas PMU farms

74
HOT hormones
  • Estrone (a ketone in D ring) isolated from PMU
    has similar have same activity as estradiol, the
    principal human estrogen

75
Dangers of HRT (2002) Study
  • Womens Health Initiative (WHI) report sponsored
    by NIH in USA
  • Extended use of estrogens in HRT increases risk
    of heart attack, stroke, breast and uterine
    cancer
  • Decisions do benefits outweigh risks???
  • Many women still think so.

76
Steroids from the Adrenal Cortex
Aldosterone (mineralocorticoid) -
regulates exchange of Na, K, H in
most cells
promotes water retention
(Hydro)cortisone - controls glucose prod'n in all
cells (glucocorticoid) inhibits inflammatory
response in cells
(dilate blood vessels-redness swelling)

gtgtgt
77
Corticoids or corticosteroids
(anti-inflammatory)
Cortisone(adrenal cortex)
Prednisone (synthetic one CC extra)
78
Cortisone and Prednisone Steroidal
Anti-inflammatory drugs (SAIDs)
  • Both cortisone (natural injected) ) and
    Prednisone (synthetic pills) act almost
    instantaneously to reduce inflammation in joints
    and other body tissue
  • Wonder drugs???..............unfortunately not

79
Many side effects include
  • Sodium ( hence water) retention --?swelling
  • Increased appetite
  • Increased fat deposits
  • Sweating at night
  • Acne
  • Depletion of immune system
  • Increased sun sensitivity
  • Increased hair growth
  • Candida (yeast type infection) growth (oral)

80
Cardiac Active Steroids
Digitoxigenin (aglycone) (isolated from
Digitalis-foxglove plant)
81
Digoxin (the active form)
  • Same structure as digitoxigenin except 3 glucose
    units bonded to C-3 of A ring

82
Why are many active steroids glycosylated?
  • Facilitates transport across cell membranes and
    hence entry into the cell

83
Effects of Digoxin (Digitalis)
  • Treatment of irregular heart beat
  • But Digoxin has a narrow therapeutic index
    ie.only a small margin between effectiveness and
    toxicity
  • Also potentially dangerous interactions with some
    antibiotics and adrenaline

84
Nurse Charles Cullen 2003
  • Admitted to killing gt40 hospital patients in NJ
    and Penn with overdoses of Digoxin
  • Not eligible for parole for 396 years!

85
Nurse Susan Nelles (Ontario)
  • Charged in 1981 with murder of 4 babies at Sick
    Childrens hospital by overdoses of digoxin
  • Exonerated, no other charges laid
  • Given honorary degree from Queens U. in 1999 for
    work in promoting integrity in nursing

86
Commercial synthesis of hormones
  • Russell Marker (1903-1995)
  • 1934 (Penn State U)
  • Devised a 4 step synthesis of progesterone from
    tubers of a wild yam found in Mexico
  • No backers in US (too risky!)
  • Mexico City phonebook Laboratorios Hormona

87
Diosgenin (YAM tuber extract)
88
Syntex Corporation
  • Founded by Marker in 1944 in Mexico City
  • Now based in Palo Alto CA.
  • Worlds largest commercial supplier of Steroids,
    Hormones etc.

89
Human Infectious Diseases
Bacterial Origin Viral
origin
Cholera Diphtheria Dysentery Gonorrhea Plaque
Syphilis Tetanus Tuberculosis
Typhoid fever Whooping cough
AIDS Chicken pox Common cold
Encephalitis Gastroenteritis Genital Herpes
German measles Hepatitis Influenza
Measles Meningitis Mumps Pneumonia Polio
Rabies Shingles Smallpox
Warts Yellow fever
90
Antibiotics - some generalities
Antibiotics in NA 15 billion/yr(75
?-lactams) 5 of population is allergic to
penicillin many names end as '..in' or
'.mycin'
91
History of antibiotics contd
  • 1871England. Joseph Lister father of modern
    antisepsis (Listerine) found that urine samples
    contaminated with mould (fungi) did not allow
    growth of bacteria

92
Mould (fungi) vs. bacteria
  • Bacteria prokaryotic (no nucleus), rigid cell
    wallDNA in cells cytoplasm. Can be isolated in
    pure culture for identification
  • Mould (fungi) nonphotosynthetic microorganism,
    eukaryotic (has a nucleus and a cell wall).
  • Both bacteria and fungi are responsible for
    decomposition of dead organic material

93
More on mould bacteria
  • Fungi can be in yeast form or in filamentous form
    (mould)
  • Cell wall composition of bacteria responsible
    for Gram or Gram stain reaction.

94
Glycosidic Antibiotic
Puromycin
Streptomycin
Nucleosidic Antibiotic
95
Synthetic Antibiotics
Ciprofloxacin
Chloramphenicol
96
Specialized Antibiotics - Antiulcers
Omeprazole(Prilosec)
Ranitidine(Zantac)
97
Human Infectious Diseases
Bacterial Origin Viral
origin
Cholera Diphtheria Dysentery Gonorrhea Plaque
Syphilus Tetanus Tuberculosis
Typhoid fever Whooping cough
AIDS Chicken pox Common cold
Encephalitis Gastroenteritis Genital Herpes
German measles Hepatitis Influenza
Measles Meningitis Mumps Pneumonia Polio
Rabies Shingles Smallpox
Warts Yellow fever
98
Viruses - the other Infectious 'Enemy'
A virus contains a core of DNA or RNA(never both)
wrapped in a protective shell(usually protein,
maybe some carbos/lipids). Does not have any
'functional/ reactive' proteins , thus cannot
grow and reproduce by itself. Viruses
are parasites. They invade other organisms
(the host), take over their 'metabolic
machinery' to reproduce and eventually kill those
cells and move on.
Viruses do
not have alot of metabolic reactions to 'mess up'
chemically. What to do? gtgt
99
Fighting Viruses, 1 - Vaccines
Vaccination/Innoculation/Immunization A
weakened strain of the virus is injected into the
host so that antibodies can be produced against
that specific virus(an 'invading' compound).
These antibodies are then always ready to protect
against future exposure to that particular
virus(sometimes!).

Can occur 'naturally' if you survive an attack
of, eg. chicken pox/measles/polio(!). But doesn't
work for colds/'flu/HIV (many strains/always
mutating).
100
Fighting Viruses, 2 - Antiviral agents
General stop DNA synthesis with modified nucleic
acids
For HIV
inhibit production of the protein sheath
(proteases, reverse transcriptase inhibitors)
with non-nucleosidic compounds(since
'96) Worldwide 100 million people
infected(Africa!)
60 million already dead
101
Typical Nucleosidic Antivirals
Acyclovir(anti Herpes)
Ribavirin/Virazole (anti AIDS)
AZT(azidothymidine) (anti AIDS)
102
Non-Nucleosidic Antivirals
Nevirapine
Saquinavir
Ritonavir
103
Arthritis and NSAIDS
Rheumatoid diseases occur when the body mounts an
immunological attack against its own tissue,
usually connective tissue, eg. rheumatoid
arthritis. Controlled by cortisone-like
steroidscorticoids), but to avoid 'side effects'
from prolonged use many patients/physicians
prefer NSAIDS to alleviate pain, swelling and
tissue destruction. Also 'side effects',
ie. kidney problems, intestinal bleeding.


aspirin/ASA, (not
acetaminophen/Tylenol), ibuprofen/ Motrin,
naproxen, diclofenac
104
Non Steroidal AntiInflammatory Drugs
Ibuprofen
ASA
Naproxen
Diclofenac
105
The Ubiquitous Prostaglandins
The several dozen known prostaglandins have an
extraordinary range of biological effects, eg.
stimulate smooth muscle, affect platelet
formation, lower gastric secretions, and affect
inflammation/kidney function/reproductive
systems. Derivatives are used clinically to
induce labour, prevent clotting, relieve asthma,
for heart conditions (blood pressure, clotting)
106
NSAIDS - Prostaglandin Inhibitors
NSAIDS
O2
arachidonic acid
thromboxane-A2, contracts smooth muscle,
aggregates platelets
prostaglandin F2, induces labour, abortion,
menstruation
107
NSAIDS of Y2K
analgesics, anti-inflammatories
AND minimize intestinal bleeding
Celebrex (Pfizer/Searle)
Vioxx (Merck)
108
Deadly side effects of Vioxx!
  • Sept 30, 2004, Merck pulled Vioxx off the market
    after its own research showed that the
    blockbuster painkiller doubled the risk of
    heart attacks and strokes
  • Massive lawsuits filed by gt47,000 plaintiffs
  • Nov 9, 2007. Merck agrees to pay 4.85 Billion
    to settle these suits, but only binding if at
    least 85 of all plaintiffs agree

109
Immune Response - Antibody vs Antigen
An antibody is a specific protein(immunoglobulin,
?-globulin) that is synthesized by white blood
cells(B-lymphocytes) to eliminate/inactivate a
pathogen that enters our body. These 'invading'
compounds are usually disease-bearing bacteria or
viruses. The 'action' occurs in the extracellular
fluids, including the circulatory system.

The invading material that causes antibody
generation is termed an antigen. often lasts
indefinitely we can immunize with a vaccine
(weakened virus or bacteria).
110
If the 'invading material' gets by this first
line of defense and enters a cell, eg. a virus,
then another immune system springs into action,
the T-cells. If the T-cells get inactivated, eg.
by HIV, then the result is Acquired Immune
Deficiency Syndrome (AIDS). That person has no
immune protection and eventually succumbs to some
disease.
Antibody - Antigen complex
111
Immune Response - the Down Side
The immune system cannot distinguish 'good' from
'bad' antigens. Hence organ transplants can be
'rejected' so that immuno-suppressants must be
used with potentially dangerous consequences. An
overactive or misdirected immune system can
attack its own tissue, eg.
multiple
sclerosis(nerve sheaths)
rheumatoid
arthritis(connective tissue in joints)
type1 diabetes(cells for insulin in the
pancreas)
112
Allergies - Immune Response Reversal
The body generates an antibody to some antigen.
On subsequent exposure when the antibody/antigen
reaction occurs, certain cells(especially in nose
and bronchial system) are disrupted and release
some potent chemicals of which the best known is
histamine(from the amino acid, histidine).
These particular antigens are called
allergens.

Often the effects are minor, eg. runny
nose, itchy eyes, sneezing and can be suppressed
by taking an antihistamine. About 10 of NA
suffer from some allergy about 2 million
Canadians have 'hay fever'.
113
Antihistamines - OTC Bestsellers
Histamine
Cimetidine(Tagamet)
Terfenadine(Seldane), RCH3 Fexafenadine(Allegra)
,RCOOH
114
More Antihistamines!
Bromopheniramine (Dimetapp, Dimetame) cold
syrups-
Chlorpheniramine (Chlortrimeton)
-colds/coughs-
Diphenhydramine (Sleep-Eze) -sleep aids-
115
Anaphylaxis - Life-threatening Allergies
Allergic reactions can intensify to sore throat,
skin rashes and migraines. Food allergies are
particularly difficult to diagnose. Life
threatening effects include constricted breathing
and severe blood pressure drop(requiring
immediate injections of adrenaline and /or
prednisone) and are termed anaphylaxis. Often
these reactions are associated with penicillin,
insect venom, shellfish and nuts
116
Asthma a Bronchial Allergy
Asthma is an allergic reaction that causes
swelling of the bronchial passages and lungs. The
most effective treatments(still symptomatic) are
to reduce swellings with anti-inflammatory
steroids or enlarge restrictions by bronchial
dilators(ephedrine or albuterol).
albuterol(ventolin)
D ephedrine(dilator) L
pseudoephedrine (decongestant)
117
Prostaglandin 'Cousins
Trigger Asthma
Other compounds related to the prostaglandins and
causing a variety of physiological effects,
including inflammation, have been implicated in
the asthmatic response. These include the
prostacyclins, thromboxanes and especially the
leukotrienes.
118
Keeping your Heart Pumping
In 24hrs the human heart pumps 8000L of blood and
beats 100,000 times (70 beats/min)!
In NA 'heart disease'
causes 40 of all
deaths
accounts for 40 of all prescription
drug sales
(100 million)

Don't be a statistic

no smoking, not overweight, adequate 'cardio'
fitness keep sodium/alcohol low, lots of
'natural' antioxidants.
119
Heart Disease - multifaceted
Major categories(interrelated)
ischemic coronary artery
disease (inadequate O2 to
heart)
heart
arrhythmia(abnormal heart beat)
hypertension(high blood pressure)
congestive heart
failure 'Heart medications' try to
increase
blood(O2) supply
normalize rhythm
lower
blood pressure
prevent blockage of blood
vessels
120
Vascular Blockage
For blood clots or thickness Mild
platelet inhibitors(thinners), eg. aspirin
Medium anticoagulants/anticlotting, eg.
heparin, warfarin(rat poison)

Severe thrombolytics('clot busters' or 'clot
eating' enzymes), eg.
streptokinase, plasmin For blockage by fatty
plaque(artherosclerosis)
divert/slow cholesterol production in liver
with cholesterol-lowering drugs, eg.
Lipitor (a '...statin')
121
Keep the Blood Flowing!
Warfarin (anti coagulant)
a statin (anti-cholesterol)
122
Hypertension - many causes, many 'cures'
Eliminate water - decreases Na, decreases blood
volume use diuretics, eg. thiazides
Eliminate angina(chest
pain) - expand blood vessels use
vasodilators, eg. nitroglycerin
Slow down
stimulation(adrenaline) of heart muscle
by blocking ?-andrenergic receptors use '??-
blockers', eg. propanolol
Control
Ca involved in muscle contraction use Ca
channel blockers, eg. nifedipine
Control Angiotensin(pressure elevating
'factor') use ACE inhibitors, eg.
captopril(a '.pril')
123
AntiHypertensive Heart Medications
Nitroglycerine
Hydrochlorothiazide
Captopril
Nifedipine
Propanolol
124
Heart Attack! (Myocardial Infarction)
Relief of severe pain
use strong analgesics,

eg. morphine, demerol (narcotics!)

Control heart beat
Too slow use
stimulants, eg. adrenaline,
atropine,
digoxin
Too
fast use sedatives/tranquilizers
Irregular(arrythmia) use smooth muscle
relaxants, eg.
lidocaine
125
Cancer out-of-control cell growth
Can be benign or malignant. Can affect almost
every organ/tissue. Over 100 different
'types' WHO estimates causes as
80-90
'environmental' (30 cigarette smoking,
30diet/lack of exercise, 10occupational

exposure, etc.)

10-20genetics viruses
20 of
NAmericans will contract some form

of cancer.

Some success in establishing 'cures', eg. skin,
Hodgkin's, childhood leukemia, but some
'failures', eg. lung,
pancreas.
Early detection is
critical but difficult.
126
Cancer Deaths in Canada (2002, est.)
127
Cancer - starts with DNA
damage(?)
Fairly general agreement that DNA damage
(radiation, viruses, chemicals) is the cause. Two
'suspects' are mutations of
oncogenes, that promote cell
growth
tumor supressor gene, that inhibit cell growth
128
How to Stop it(?)
Try to remove all 'out-of-control' cells and
allow normal cells to regain control -

1) remove by surgery


2) kill with radiation
3) kill by
using chemotherapy
129
Cancer Deaths some good, some bad!
women
men
130
Cancer 5 year Survival Rates()
Oral Colon/rectum Pancreas
Lung Melanoma Breast
Cervix Uterine Ovarian
Prostate Testis
Bladder Leukemia
51 55 3 13 81 75 66 82 39 72 90 77
33
131
Cancer Chemotherapy - some Generalities
Interfere with an essential nutrient of
the cell, eg. methotrexate for
folic acid uptake
Inhibit blood supply
DNA 'modifiers'
cross-link, eg. cis-platin alkylating
agents, eg. cyclophosphamide(from 'mustard
gases) 'fake' nucleic acids, eg. 5-fluoro
uracil, 6-mercaptopurine change
shape(doxorubicin)
132
Cancer Chemotherapies - General
Cyclophosphamide
Cisplatin
Doxorubicin
133
Cis-platin mode of Action
  • Pt binds to N atom of guanine DNA base
  • Disrupts out of control (and normal) protein
    synthesis
  • Side effects hair loss

134
Cancer Chemotherapies - General
6-Mercaptopurine
5-Fluorouracil
Methotrexate
135
Cancer Chemotherapy - Specifics
vincristine(leukemia), taxol(ovary, cervix),

tamoxifen(breast),
actinomycin(Hodgkin's), estradiol(prostate),
testosterone(breast)
136
Cancer Chemotherapies - Specific
Taxol
Tamoxifen
137
Taxol (semi synthetic)
  • Isolate from bark of pacific Yew tree, then
    modify it chemically
  • Acts by cutting off blood supply to tumor

138
Chirality in Drugs
Thalidomide(early 60s)
L teratogen (birth defects)
D antidepressant (morning sickness)
139
Differing Opinions
  • US Pharmaceutical Co. Smith , Kline, French
    rejected thalidomide as a useless drug
  • German/Swiss firm of CIBA-Geigy deemed it useful
    and rat studies showed no adverse effects of
    either isomer. Not toxic LD50 value 600x higher
    than NaBr.
  • Market approval in 1959

140
Tragic results of selling the mixture
  • Suffer the Children (1979) Andre Deutch pub.
    Insight team of London (UK) Times
  • On Canadian Market April /61 until March/62
  • Taken off market 3 months after Europe banned it
    due to severe teratogenic effects if taken during
    the 1st trimester of pregnancy

141
The return of Thalidomide (1992)
  • Now marketed in pure D form. Used to treat
    complications arising from bone marrow
    transplants
  • Used in treating leprosy

142
Ibuprofen prototypical NSAID
() analgesic (-) no
serious side effects
Albuterol (Ventolin, bronchial inhalers)
D bronchial dilator L serious side
effects

Mixture removed in 90 chiral isomer introduced
in 96.
143
Chiral Synthesis
  • Biggest challenge in Organic chemistry
  • Devise ways to produce only one handed form of
    a molecule (saves , materials) and side effects
    of unwanted isomer
  • Use Chiral auxillaries (templates)

144
2001 Nobel Prize in Chemistry
  • Barry Sharpless (Scripps, MIT) Chiral epoxidation
  • William Knowles (Monsanto), Ryogi Noyori (Nagoya
    Univ.) chiral hydrogenation using a chiral
    rhodium catalyst
  • Led to 1st commercial Synthesis of L-DOPA
    (Parkinsons) with no D isomer

145
Global Sales of Chiral Drugs
  • Annual sales of single enantiomer (ie handed
    drugs) expected to be 15 Billion in 2008
  • Syngenta (Swiss) operates the largest scale
    chiral hydrogenation plant in the world

146
OTC
1999 figures for USA
7 billion-
contraception, dandruff, pregnancy
tests, vitamins, weight control
3
billion - analgesics
3 billion -
coughs, colds, allergies, sinus
1 billion - gastrointestinals

150 million - acne
30
million - sleep aids
?? -
antibiotic creams, mouthwash/gargles,
pH control, sunburn/sunscreen, etc.
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