Transcript No Slide Title

17. Medicines, Drugs
- part 2
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!
OTC - from A(antacids)
to Z(zits)
OTC = Over The Counter,
ie. non-prescription
North Americans selfmedicate ~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.
Over The Counter (OTC) Cold Medications
Type of Ingredient
Decongestant
Antitussive
(cough suppressant)
Name
Pseudoephedrine
Dextromethorphan
Expectorant
(loosen fluids in cough)
Guaifenesin
Analgesic/Antipyretic
(diminish pain/fever)
Acetaminophen
Antihistamine
Caffeine
Chlorpheniramine
Stimulant
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
Psychology and Drug Price
Expensive placebo’s 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
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 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
New Product Development*
12 -15 years(7 yrs. of ‘clinical trials’)
$300 - $400 million
3 of 10 'pay back'
'block-buster' = $1 billion(life-time sales)
Some Companies: AstraZeneca, Bayer, Bristol Myers/
Squibb, Glaxo-Smith-Kline, Warner Lambert
Hoffman LaRoche, Novartis, Merck(US),
Pharmacia, Pfizer, G D Searle, Eli Lilly
In Canada: Merck Frosst, BioChem Pharma,(Apotex#)
Ratiopharm#.
Proprietary/'Brand-name'* vs Generic#.
Brand/Trade - only by manufacturer (proprietary)
ie Tylenol , Motrin
Generic - generally accepted 'chemical name' (for
'easy' recognition by health professionals)
ie acetaminophen, ibuprophen
Patent protection
• Brand name is protected in perpetuity
• Active component has protection for 17 years in
Canada
• After that, Generic Co’s can make the drug and sell
it under another name
• Many legal disputes (IP law) Gowlings in Ottawa
• Polymorphs (different crystalline forms) can be
patented
• New applications of old drugs can be patented
Brand names!
• Who thinks them up?
• Big business!!
• But getting tougher to find simple ones :
beware of similarities
• Some are brilliant “Viagra” “Levitra”
Celebrex (anti-inflammatory)
World Top 10 prescription drugs in
2008
•
•
•
•
•
•
•
•
•
•
•
Lipitor Pfizer : lowers cholesterol
13.8B$
Plavix BMS: atherosclerotic events
8.3
Nexium AstraZeneca :Acid reflux symptoms
7.7
Serentide GlaxoSmith Kline :asthma
7.5
Enbrel Amgen: rheumatoid arthritis
5.6
Seroquel AstraZeneca: bipolar disorder,schizophrenia 5.1
Zyprexa Eli Lilly: schizophrenia
5.1
Risperdal J&J : schizophrenia
5.0
Remicade Centocor: Crohn’s Disease, Rheumatoid arth. 4.7
Singulair Merck: asthmas, Allergies
4.6
Overall sales increase vs. 2007: 8.3%
Steroids
Compounds
with a common tetracyclic
structure and a variety
of physiological functions
depending on functional
group arrangement.
Cholesterol(animal fat)
HO
Are all steroids anabolic?
• Consider cholesterol, cortisone etc.
Stanozolol
(Ben Johnson
’88 Olympics)
OH
HN
N
Anabolic Steroids Promote rapid muscle
growth & stamina (more workouts)
O
O
4-Androstene-3,17-dione
(Mark McGuire 90’s)
Detection: Mass Spectrometry of Drug
metabolites in urine
• Each compound has a unique “pattern”
Male Sex Hormones
(Androgens)
OH
O
Testosterone: also in females ,but only~2 % of level in
males; biosynthesized from cholesterol; affects libido in
both!
O
HO
Androsterone
The next generation of cheating
• Idea-just take more testosterone: undetectable
because the body makes it anyway!
Doping in Sports: Testosterone
• Floyd Landis tests positive for abnormal
amounts of testosterone: forfeits Tour de
France cycling championship in July 2006
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
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
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
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
Other bonds to be broken
•
•
13C-O
vs. 12C-O
13C-12C vs 12C-12C
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%!
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
Manny Ramirez : LA Dodgers
May 12, 2009 Manny gets caught!
• Urine showed elevated testosterone level
• Also high testosterone/epitestosterone ratio;
between 4:1 and 10:1
• Synthetic or “Manny made”?
• World anti-doping lab (Montreal) asked to do
carbon isotope test-find low 12C/13C ratio
• Result: Manny used synthetic testosterone
• 50 game suspension (without pay) by MLB
Female Sex Hormones
(Estrogens)
O
Estrone
HO
O
Estradiol
OH
HO
HO
Progesterone
(‘pregnancy hormone)
Steroids cont’d: Evolution of the BC pill
• 1st step (1960’s) 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
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
‘The Pill’ (Birth Control)
Ethynylestradiol
(synthetic estrogen)
HO
HO
+
Norethindrone
(synthetic progestin)
O
HO
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
The morning after pill RU-486
• Blocks the implantation
of a fertilized egg in the
uterine wall
• Developed in France
(CH3)2 N
O
HO
Antibacterials and Antibiotics
Many OTC and some prescription:
growing problem of resistance to
antibiotics!
Dr. Joseph Lister
• UK 1871
• found that mould inhibited growth of bacteria
• “discovered” antiseptic surgery by killing
bacteria
• “Listerine” named after him
Listerine and other mouthwashes
• Often contain up to 25% alcohol
• Long term use of high alcohol mouthwashes
increases risk of oral cancer
• Does Listerine kill germs? Yes, but many
more remain
• Salt water rinse an effective alternative
• Or use enzyme based ones
Serious infections: gingivitis,
trench mouth
• Require much stronger mouthwash than any
OTC available: See your Dentist or MD
• Careful tooth brushing and flossing and
thorough rinsing with water are best
preventative measures
Sulfa Drugs: the
st
1
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
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
Discovery of penicillin(20th
century’s 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
1928-1940
• Fleming grew a pure mould culture:
discovered it was Penicillium notatum
• Later isolated the pure chemical
“antibiotic”component, named it “penicillin”
• But needed a good large scale source of the
mould
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.
Penicillins('28-'44) - the -Lactams
Penicillin – the
general structure
OH
R
N
O
S
N
COOH
The first class of
'broad spectrum'
antibiotics; still the
most prescribed
worldwide.
Alexander Fleming 1881-1955
• Nobel Prize for Medicine/Physiology in 1945
• Knighted in 1944
Penicillin from fermentation
• Pharmaceutical grade obtained
The Process
• Start “cold stored” penicillium culture on agar plate
• Transfer to “shake flasks” ,with food (Sugars) and
nutrients (ammonium salts), aa’s 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.
Semi-synthetic derivatives
• Original penicillin was excreted too rapidlyurine recycling in early patients for recovery
of the drug
• Chemists modify original structure for
different properties and bio-availablity
the 'Evolution' of Penicillins - 1 step ahead!
OH
R
N
O
S
N
COOH
Cl
N
O
cloxacillin
N
O
oxacillin
penicillin G
CH2
penicillin V
CH2 O
ampicillin
CH
NH2
amoxicillin
CH
NH2
CH3O
methicillin
CH3O
OH
Incapacitating
those 'Nasty Bugs'
Varied structures indicate
varied 'mechanisms' to
kill bacteria.
eg.
• -lactams(penicillins) - breakdown cell walls
• tetracyclines/erythromycin/streptomycin inhibit various aspects of protein synthesis
• fluoroquinolones('cipro') - inhibit DNA replication
Some Antibiotics and Their Uses
Penicillins – ear/skin/respiratory/digestive/urinary
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
OTC Antibiotics
O
S
N
H
NH2
N
Cl
O
COOH
Cefaclor(cephalosporin)
CH3
L-Asn
D-Asp
L-His
CHCH2CH3
CH2NH2
O
D-Phe . . . . . . . . . . . . . H N CH
2
L-Lys
L-Ile
D-Orn
D-Glu
HO
HO
L-Ile
L-Leu
O
C
H2N O
O
HOH2C
CH2NH2
O
Bacitracin
Neomycin
HO
HO
O
NH2
O
OH
NH2
HO
NH2
Some Tetracyclines;prescription
needed
Cl HO CH
3
N(CH3)2
OH
OH
O
OH
O
HO
CONH2
Chlorotetracycline
(Aureomycin)
CH3 OH
N(CH3)2
OH
Doxycycline
OH
O
OH
O
HO
CONH2
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)
Anti-malarials
Malaria:infects 300-500 million /year
~2 million deaths (mostly Sub-Saharan
Africa)
Transmitted by female Anopheles
mosquito
Microscopic parasites in saliva-multiply
in human red blood cells
Why no antimalarial drug?
• Viewed as an African problem
• No money in it for the Pharmaceutical
industry
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 parasite’s 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
Quinine
• An alkaloid
• Also antipyretic, analgesic, antiinflammatory, anti-smallpox
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!
Tonic water
• ~80 cans per day to treat malaria!
Synthetic Antimalarial drugs
• Chloroquine
Chloroquine
• Used to prevent and treat malaria
• BUT…many 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
Perhaps some hope for Africa
• International Public-private partnership
funding research on antimalarial drugs
• Chinese antimalarial herbal medicine extract
“Artemisinin”
But too expensive to extract
• Synthetic analogues being made
• Hoffman La Roche (Basel)
• OZ277 looks promising
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
DDT; An effective
insecticide,but…….
• Some resistance to it now shown by
Anopheles mosquitos
• Use curtailed in 1970’s : environmental
pollution
• WHO currently advises use of 12 different
insecticides, including DDT
• Bednets also effective, since Anopheles feed
at night
World’s Top 10 Therapies 2008 (# of
prescriptions:in order)
•
•
•
•
•
•
•
•
•
•
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)
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
Drugs by
Physiological
Function….cont’d
• Uterine Action
• AntiParasitics
• Hormones
• Vitamins
• Antiviral Agents
• Blood Related Diseases
• for Neoplastic (eg. cancer) Diseases
• AntiMicrobials: synthetic & natural antibiotics
• Digestants, Antiseptics/Fungicides
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.)
Some Hormones
Name
Gland
Structure
Effect
HGH
Pituitary
protein
body growth
Oxytocin
Pituitary
peptide uterine contract’n.
Thyroxine
Thyroid a.a.deriv. cell metabolism
Insulin
Pancreas protein
glucose metab.
Cortisol
Adrenal
steroid
protein -> carbo
Aldosterone Adrenal
steroid
Na+ concn.
Adrenaline
Adrenal a.a.deriv. emergency stimulus
Estradiol
Ovary
steroid stimul. female char.
Progesterone Ovary
steroid reg. menst. cycle.
Testosterone Testis
steroid stimul. male char.
HGH
Another illegal “supplement”
Dangerous side effects
Lyle Alzado (NFL) Brian tumors
Legal supplements for atheletes
• Creatine, an amino acid (body makes~1-2
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)
Creatine
• Highest selling supplement ever! No known
hazards with long term use. Not a steroid/not
anabolic.
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)
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….?
Pregnant Mares Urine
• ~22,000 in Canada’s PMU farms
HOT hormones
• Estrone (a ketone in D ring) isolated from
PMU has similar have ~same activity as
estradiol, the principal human estrogen
Dangers of HRT (2002) Study
• Women’s 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.
Steroids from the Adrenal Cortex
Aldosterone (mineralocorticoid) regulates exchange of
Na+, K+, H+ in most cells;
promotes water retention
OH
CH 2OH
CO
O
CH 3
CH
H
H
H
O
(Hydro)cortisone - controls glucose prod'n in all cells;
(glucocorticoid) inhibits inflammatory response in cells
(dilate blood vessels-redness & swelling)
=>=>=>
Corticoids or corticosteroids
(anti-inflammatory)
HO
O
OH
HO
O
Cortisone(adrenal cortex)
HO
O
O
O
OH
Prednisone
(synthetic:
one C=C
extra)
Cortisone and Prednisone: Steroidal
Anti-inflammatory drugs (SAID’s)
• Both cortisone (natural: injected) ) and
Prednisone (synthetic: pills) act almost
instantaneously to reduce inflammation in
joints and other body tissue
• Wonder drugs???..............unfortunately not
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)
Cardiac Active
Steroids
O
O
Digitoxigenin
(aglycone) (isolated
from Digitalisfoxglove plant)
OH
OH
HO
Digoxin (the active form)
• Same structure as digitoxigenin except 3
glucose units bonded to C-3 of A ring
Why are many active steroids
glycosylated?
• Facilitates transport across cell membranes
and hence entry into the cell
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
Nurse Charles Cullen 2003
• Admitted to killing >40 hospital patients in
NJ and Penn with overdoses of Digoxin
• Not eligible for parole for 396 years!
Nurse Susan Nelles (Ontario)
• Charged in 1981 with murder of 4 babies at
Sick Children’s 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
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”
Diosgenin (YAM tuber extract)
Syntex Corporation
• Founded by Marker in 1944 in Mexico City
• Now based in Palo Alto CA.
• World’s largest commercial supplier of
Steroids, Hormones etc.
Antiviral agents
• In general, viruses are harder to handle than
bacteria!
Human Infectious Diseases
Bacterial Origin
Cholera
Diphtheria
Dysentery
Gonorrhea
Plaque
Syphilus
Tetanus
Tuberculosis
Typhoid fever
Whooping cough
Viral origin
AIDS
Chicken pox
Common cold
Encephalitis
Gastroenteritis
Genital Herpes
German measles
Hepatitis
Influenza
Measles
Meningitis
Mumps
Pneumonia
Polio
Rabies
Shingles
Smallpox
Warts
Yellow fever
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?
=>=>
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).
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
Typical ‘Nucleosidic’ Antivirals
O
Acyclovir(anti Herpes)
N
HN
Ribavirin/Virazole
(anti AIDS)
H2N
N
O
N
O
NH2
O
HO
N
N
O
N
OH OH
CH3
HN
OH
HO
N
O
O
AZT(azidothymidine)
(anti AIDS)
N3
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
Non Steroidal AntiInflammatory Drugs
COOH
COOH
O
ASA
CH3
O
Ibuprofen
COOH
H3CO
Naproxen
(Aleve)
Cl
COOH
H
N
Cl
Diclofenac
NSAIDS of Y2K: COX-2 inhibitors
analgesics,
anti-inflammatories
AND minimize
intestinal bleedingblock buster pain
SO3Me
killers!
SO3H
O
O
Vioxx
(Merck)
N
N
R
Celebrex
(Pfizer/Searle)
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 >47,000 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
Immune Response - Antibody vs Antigen
An antibody* is a specific protein(immunoglobulin, globulin) that is synthesized by white blood cells(Blymphocytes) 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).
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
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)
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'.
Antihistamines OTC Bestsellers
H
N
Histamine
N
H2N
H
N
NC
R
N
N
H
S
N
H
Cimetidine
(Tagamet)
N
N
Ph
HO
OH
Ph
Terfenadine(Seldane), R=CH3
Fexafenadine(Allegra),R=COOH
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
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).
HO
NHCH3
D = ephedrine(dilator)
L= pseudoephedrine
(decongestant)
Heart Disease : A major killer
Multifaceted: Heredity and lifestyle
both important
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.
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
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')
Keep the Blood
Flowing!
O
O
OH
O
Warfarin
(anti coagulant)
HO
O
O
O
O
a ‘…statin’
(anti-cholesterol)
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')
AntiHypertensive Heart Medications
H
N
Cl
O
H2 N S
O
S
O
CH3
CH2 ONO2
CH ONO2
CH2 ONO2
NH
O
HS
N
Captopril
H3C
OH
Propanolol
COOH
Nitroglycerine
Hydrochlorothiazide
O
O
N
H
H3CO2C
H
N
CH3
CO2CH3
NO2
Nifedipine
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
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,
30%diet/lack of exercise, 10%occupational
exposure, etc.)
10-20%genetics & 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.
Cancer Deaths in Canada (2002, est.)
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
How to Stop it(?)
Try to remove all 'outof-control' cells and
allow normal cells to
regain control 1) remove by surgery
2) kill with radiation
3) kill by using chemotherapy
Cancer Deaths – some good, some bad!
women
men
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
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)
Cancer Chemotherapies - General
O
OH
COCH2OH
OH
OCH3 O
OH
O
O
H
N
P
O
Cl
Cl
Pt
H3 N
NH2 Doxorubicin
O
Cyclophosphamide
CH3
HO
N(CH2CH2Cl)2
NH3
Cisplatin
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
Cancer Chemotherapies - General
O
SH 6-Mercaptopurine
F
N
N
N
H
N
N
H2 N
5-Fluorouracil
NH
N
H
COOH
N
O
N
N
NH2
N
CH3
N
H
Methotrexate
COOH
O
Cancer
Chemotherapy
- Specifics
vincristine(leukemia), taxol(ovary, cervix),
tamoxifen(breast), actinomycin(Hodgkin's),
estradiol(prostate), testosterone(breast)
Cancer
Chemotherapies
- Specific
O
O
CH3CO
OH
O
C6 H5C NH
O
C6 H5
O
OH
Taxol
HO
C6H5C
O
O
O
O
O
O
N(CH3)2
C6H5
C6H5
Tamoxifen
Taxol (semi synthetic)
• Isolate from bark of pacific Yew tree, then
modify it chemically
• Acts by cutting off blood supply to tumor
Chirality in Drugs
Thalidomide(early ’60’s)
H
N
O
H
N
O
N
D = antidepressant
(morning sickness)
O
O
O
H
N
O
H
O
H
N
N
H
O
L = teratogen
(birth defects)
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
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
The return of Thalidomide (1992)
• Now marketed in pure D form. Used to treat
complications arising from bone marrow
transplants
• Used in treating leprosy
Ibuprofen: prototypical NSAID
*
COOH
(+) = analgesic
(-) = no serious side effects
Albuterol (Ventolin, bronchial inhalers)
HO
OH
HO
D = bronchial dilator
L = serious side effects
*
NHC(CH3)3
Mixture removed in ’90 & chiral isomer introduced in ’96.
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)
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
(Parkinson’s) with no D isomer
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