Download doc Notes on Lecture 2

World of chem drugs: lec 2 – Drug history (2) and Pain relievers (analgesics):
DRUG HISTORY 2:
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Anesthetics:
there used to be brain operations to release the demons
used to give alcohol, sort of like an anesthetic
other cutting operations were like amputations (for gangrene)
orthopedic surgeons (up until 30 yrs ago) almost exclusively male because they
were stronger and could cut through an arm faster
people used to die often after operations due to infection
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Sir Humphrey davy  nitrous oxide
He used it early in the 1800s (the course cares about the era eg. early 1800s not
1801)
It was used back then though for getting high
They called it FROLICS
Not used then for medical purposes
Nitrous oxide is the propellant gas in canned whipped cream
Note: operations were invasive and terrible for the patient
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Ether  William T.G. Morton (Dentist)
Used starting in 1850s
During these times, doctor was usually the dentist
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Jon Collins Warren
Doctors in that era liked to pose with a skull
Was a premiere surgeon at the boston general hospital in Massachusetts
Approached by a dentist that ether would work well, but he used to little and the
patient ran out screaming
Turned off to ether for a little while
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two main operations in the 1800s were amputations and surface tumors
Jon Collins was interested in using ether in tumor operations and was eventually
successful
Note that the doctors dressed formally, didn’t wash their hands, patients wore
socks etc.
1850s was when ether started to be used even more
Hopkins said  “ gentlemen this is no humbug” and then the use of ether caught
on because he was well known and respected
potassium bromide
it is a salt like sodium chloride
it was used very often in the 1800s
didn’t make anyone go under, but could relax them
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common term is to “take a bromide”  means take something that will make it go
away
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PATENT MEDICINES:
1850 – 1906  patent medicine period
period where people could take unpatented remedies and portray them in any way
that they wish
there were drug stores that had all manner of materials
people used to by bolsom for colds
people bought what was available
there used to be a bunch of over the top dramatic adds but that would sell product
eg. Wolcott’s instant pain annihilator
eg. Parker’s tonic  beet alcohol
eg. The best blood purifier  for epilepsy and dropsy (high blood pressure and
accumulation of water in the body)
eg. Riker’s expectorant  for curing coughs
eg. Dewitt’s little early risers and Most pleasant cathartic pill  make you go to
the bathroom more readily
eg. Hoffman’s Greatfind  contains boneset, alcohol, hazel, camphor 
basically things that taste like medicine so they assume it is good
eg. Dr Chase’s syrup of linseed and turpentine  also contains flax seed, and
spruce gum (gum from spruce trees), glycerine, sugar , magnesia, licorice
chloroform and codeine (a lot)
so it did have some action
too much would kill the patient  2 teaspoons might not be so bad
eg. Mrs Winslow’s soothing syrup  had codeine in it and some other kinds of
materials like cocaine  for children teething it would make them cry less
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With all of this bad stuff going on, magazines like Collier’s (important in US
until 60s and 70s), which tried to campaign for laws forbidding people from
selling these kinds of materials
Lydia E pinkham’s vegetable compound (still around today) used to claim that
they could cure all sorts of female troubles (ovarian trouble and bloating etc.) 
now were told that they couldn’t claim this anymore
Food and drug andministration act of 1906 helped clear this up
After Lydia pinkham said it was a healthy thing for the child (not for the mother
anymore)
Can still get it  contains Iron, Vit C, Vit E  they say it can help you feel better
on those “special days”
It is a variety of herbs including some iron, ascorbic acid (vit c), and ethyl alcohol
as a solvent and preservative (not meant to affect the individual)
The grandfather clauses  if it’s a natural material and it hasn’t shown any
difficulties for many years then it can stay in the medication without being tested
Be careful of herbs and spices since composed of many organic compounds that
have not had any testing done for toxicity
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In high []s they might cause problems though
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PROPER DRUGS:
Paul Ehrlich  nobel prize, 1908
Idea of a proper drug only evolved 100 yrs ago
Paul evolved a pretty effective cure for syphilis  won the prize for this
The cure was Salversan  aka 606 since he tried 605 other compounds before
this, had arsenic in this, but not necessarily toxic since it takes on multiple forms,
not all of which are toxic
Important in the world because it gave a cure for syphilis
Not used as a cure anymore
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Aspirin
Most widely used medication around the world
Can cause some bleeding in the stomach as a negative effect
For most people it is repaired rapidly
Discovered in a lab by the Bayer company in an effort to find some pain relieving
drug
Heroin was sold by bayer to treat persistent coughs
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1938 Federal Food, Drug, and Cosmetic act:
improvement on the 1906 food and drug act
required:
o Proof of safety
o Regulation of cosmetics
o Food standards
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Classic problems in drug testing:
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Thalidomide:
o Teratogen  causes birth defects
o Causes foreshortening of the arms and legs of individuals (effect is in the
first trimester)
o Only took place in the early 1960s and mostly in Europe
o Eg. Thomas Quasthoff  turned out to be a great singer, has extremely
short arms
o Person responsible for keeping this drug out of North America was Dr.
Frances Kelsey  Mcgill graduate working at the FDA
o She was honored by JFK for saying there wasn’t enough testing on this
drug
o Thalidomide has other uses: such as treating leprosy and certain cancers
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New Drugs:
to get a new drug on the market with all the testing it takes 10 – 15 years
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costs over 300 000 000 dollars
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can actually cost 800 million dollars overall (around half a billion dollars)
this is the timeline of the development of a drug
the money expenditures start getting crazy on the right side
many drug companies put all that money in and then get screwed when the drug
turns out to be a little toxic etc. and then they lose all that money
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NEW DRUG ORIGINS:
many places from which drugs can be obtained
eg. cantharidine  Spanish fly (more of an irritant)
you can have extractions from insects or small animals that have substances
within them that are neurotoxins, but can also have positive neurological effects
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eg. Periwinkle  contains vincristine
very powerful anticancer agent
what drug companies do is examine a preparation made by natives that has a
history of solving some kind of problem
Shaman = term for a matve that knows how to create these kinds of potions with
positive effects
Shaman knows what leaves ad how to boil them etc.
Shaman will dig up the rights, small the roots, grind the roots (like coffee)
Then a drug company will extract the natural material to see the compounds
present
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Molecular Modeling:
with computers it is possible to gain access to a particular molecule that has never
been made but has a particular shape such that it might fit into a certain receptor
site
if this were made it could be used as a drug
it is sort of an antiseptic way to look at new drugs that could be made in the lab
for molecular modeling it is important to represent the drug in such a way that the
spatial arrangement is clear
used by every drug company these days
World prescription drug sales = 600 billion dollars for the year 2006
Hard to get an exact number because not all countries report etc.
need to know that prescription drugs sales are much greater than over the counter
drug sales
which drugs are particularly lucrative for companies:
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cholesterol lowering drugs are the most lucrative
next are the drugs that reduce acid reflux problems
these are the top end of the sales in the US
don’t memorize the list but know the top 4 there
PFIZER is the big company  top maker in the world
Lipitor is their main one and it lowers LDL cholesterol (13 billion dollars
in sales)
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know some of the names of these top sellers
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in Canada prescription sales are pretty much the same:
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proton pump inhibitor is the thing for stomach acid
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only need the top ones
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this is another way of looking at this
this is the more accurate one
N.A. accounts for 50% of world sales
European union is 25%
And then the other part of the world is the rest of the %age
Japan is obviously relatively big because of huge population
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prescription sales go up 10% per year
this means that sales will double in about 7 yrs
note: 70 / % increase per year will the # of years it takes to double
o it just happens to be 70
o so if it is 10% it takes around 7 yrs
the reason for growth is more people, more prescriptions and also the notion that
you need to take something to get better
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rankings of prescriptions being given:
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used to be for pain
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now it is for cholesterol
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DRUG CATALOGING:
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cataloged in a host of ways
eg. Chemical type:
1) new molecular entity
2) new derivative
3) new formulation (old drug in a skin patch)
4) new combination (2 drugs not marketed together before)
5) already marketed drug product (patents expired)
6) New use for a drug product (minoxidil)
minoxidil was originally researched to treat high blood pressure but now it is used
to re-grow hair
a drug’s journey to failure
Torcetrapib:
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92  invention
phase II trial  8 yrs later
start a patient clinical trial to study it
set up a 90 million dollar plant in Ireland to make this
study 19 patients in detail
publish the info in the new England journal of medicine
it was shown to increase good cholesterol and lower bad cholesterol when mixed
with another drug
it was criticized as a combination pill
a year ago they reported an increase in blood pressure as a side-effect of the
mixed pill
then they decided to use it as a standalone pill
later they found higher BP problems
then the CEO of Pfizer said this is an important new drug but that they must halt it
because there was an increase in mortality in the clinical trial
82 died vs 52 not taking the pill
Pfizer lost a lot in the stock market
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SIDE-EFFECTS:
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most drugs have sideeffects
no matter what the drug, someone will have some kind of sideeffect to it
a cox – 2 inhibitor was invented to relieve pain with no stomach problems (vioxx)
vioxx was invented in order to compete with celebrex
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merck withdrew vioxx 3 years ago  caused big stock market problem
caused heart problems and strokes at a rate that was too troubling to keep it on the
market
it did a lot of good for many people though so the FDA allowed it back on the
market
very close vote in US
pretty unanimous in Canada to let it back on the market (12 to 1)
but now the regulatory agency is not allowing it to be sold but you can still buy it
on the internet from different countries
note: different countries can have different regulations on the same drug
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risk factors aren’t necessarily diseases:
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obesity and cigarette smoking are real problems
the real conclusion that most medical practitioners agree with is “comfort always,
cure rarely”
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PAIN RELIEVERS: (fenster)
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20 billion dollars in N.A. for OTC drugs (over the counter drugs)
OTC drugs are more widely used but are cheaper so generate less revenue overall
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cough cold is number 1
then pain relievers etc..
antacids are also popular by prescription
oral antiseptic = Listerine
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SAFETY:
problem with OTC drugs
for prescription drugs the doctor makes the decision for you as to what drug will
be appropriate
the problem with OTC products is that YOU make the decision on type and dose
but how much do you really know???!!!!
You choose prods over other ones based on advertising
People know very little in terms of indications  ie. What a drug is really for
They know very little about counter-indications  who should not take this
drug, or what not to mix it with etc.
People also know very little about side-effects and dosage
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eg. Bengay
 relieves sore muscles
 a few months ago Arielle Newman died from applying to much to her skin
 she was an athlete at notre dame university
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Pain relievers gross 3 billion dollars in N.A.
In Canada it is about 300 million dollars
This is 50 million tablets per year in N. America
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History:
in 16th century, if someone had a headache, they would treat it by warming up
their head in an oven
idea was that all the evil spirits would fly out and this would improve the painful
condition
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aspirin = most widely used pain relieving medication
most popular drug in the world (along with alcohol)
estimated that ~ 60 billion tablets a year worldwide are consumed
not so much in N.A. though, but around the world it is hugely popular
25000 scientific papers about ASA (discovering new uses for it and new
mechanisms of action etc.)
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History of ASA:
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starts out with the Willow tree
it belongs to the Salix family, which includes willow, poplar, beech, wintergreen,
meadowsweet etc.
there is a particular class of medications called SALICYLATES
the chemical name of bengay = methyl salicylate
bengay therefore belongs to the same family as aspirin (leads you to believe that
aspirin will have sideffects as well
the Sumerians at around 2,200 BC used Willow leaves to treat joint pain
the Sumerians also made 16 different types of beer  on midterm
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the Egyptians had different treatments for things:
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menoxidil isn’t that effective  works for very few people and only in the first
stages of male pattern baldness
ox liver makes sense because liver is a good source of vitamin A
they Egyptians also used Willow leaves to treat wound inflammation
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Hippocrates:
Said in 400 BC that women should chew on the bark of the willow tree during
childbirth
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Reverend Edward Stone: 1763 (18th century)
He was a Scottish clergy man
He rediscovered the use of this substance
He used a trial
Noticed that ague (fever) could be successfully treated with 20 grains of
powdered willow bark in a dram of water every 4 hours
Grain = ancient measurement of weight
Dram was also a measurement
So why did he pick the willow tree
He picked it based on the doctrine of signatures  states that if you can find an
association between a plant and a disease then the plant should be helpful in
treating that disease
Eg. the willow grows in marshy areas and these areas tend to be prone to fever
and aches
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Rev stone said that if the willow tree lives in this type of environment it must be
protected from these things
Using this theory, he chose the tree and then tested it
The first scientific medical report of the benefit of willow tree bark to relieve
fever:
this was how he explains it
apposite = opp of opposite
around this time it was noted that the bark of the Cinchona tree was good for
treating malaria (it is a Peruvian tree)  in 1829 the extract of the bark was
obtained and it was Quinine (used in treatment of malaria)
the British used to take tonic water to prevent malaria but it was bitter so they
improved the taste with gin
during the same year (1829)  the active ingredient in the willow bark was
extracted and it is was called SALICIN
Henri Leroux extracted it (he was a frenchman)
The early to mid 1800s was a time when multiple active ingredients were
extracted and also when opium was discovered
Salicin was a mixture
In 1838 Rafaelle Piria extracted the real active ingredient and called it
SALICYLIC ACID
It quickly became popular and was an effective:
o Analgesic
o Antipyretic
o Anti-inflammatory
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sideffects  very bitter and causes stomach irritation
there is something called COMPOUND W that eats away at warts  contains
salicylic acid, so we can imagine what this compound can do in the stomach
another use of salicylic acid is acne remedies  it exfoliates the skin and helps
remove the dead tissue that plugs up the pores thus causing acne
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around that time came FELIX HOFFMAN  he was working for the bayer
company
his father was taking salicylic acid for his arthritis but it caused problems
asked his son to fix this
the son was a doctor and went back to the lab and for the first time (1897)
synthesized a derivative of salicylic acid that was as effective and didn’t cause as
much gastric irritation
it was called ACETYL SALICYLIC ACID
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Felix hoffman wasn’t the first to synthesize this compound
The first preparation was carried out by Karl Friedrich Gerhardt in 1853
He synthesized acetyl salicylic acid in a very impure form
The synthesis wasn’t very good and he never published it
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95% of compounds on earth are organic
hoffman had the idea of treating this with acetic acid (active ingredient in vinegar)
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you end up getting:
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and you also form some water
it is called ASA because it is Acetyl Salycylic Acid
the group added on is an acetyl group
Aspirin is the brand name of this molecule
Aspirin = A for ASA, and Spirin if from SPIRIA (the general name for the willow
family)
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the genius of the marketing of aspirin for bayer was Carl Duisberg
o he was actually in the lab when it was synthesized
o people used to bring their dogs to the lab
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the patent for aspirin  what it says is that from now on, the structure will be
known as Aspirin
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can be used as a treatment of rheumatism (arthritis)
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the people who signed the patent were Bayer, Duisberg, Hoffman and Eichengrun
o the last guy is the person that first had the idea to synthesize aspirin but
was suppressed by the Nazis
o he was felix hoffman’s research director
o he gave hoffman the steps of how to do it basically
o the Nazis suppressed this though because he was jewish
o didn’t want a jewish scientist to get credit
o Eichengrun discovered something else called Cellulose Acetate which was
used for the making of film
o Until that time, film was made out of nitrocellulose which is extremely
flammable  as a result it was very common for cinemas to catch fire
o Eichengrun was sent to a concentration camp during the holocaust but
survived
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Carl Duisberg’s advertising genius:
o Promoted the use of aspirin
o Originally promoted in dutch  the phrase means aspirin overcomes all
pain
o The bayer cross was also well known
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originally aspirin was sold as a powder
in Australia it is still sold as a powder in glycine paper
o you say I want a powder of aspirin
o each “powder” contains 650 mg which is the same as a tablet
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Aspirin was introduced at the same time as heroin which was used as a treatment
for coughs
Stone street is the oldest street in new york (in wall street area)
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note: Heroin is made by almost the exact same process as ASA, except different
starting material:
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one way to check for a heroin lab is if someone ordered a lot of vinegar
Heroin labs use tons of vinegar so tend to stink like it
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when the germans lost WWI:
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bayer lost all patent rights to ASA
bayer lost patent right to the name aspirin
German Bayer lost the patent to the name BAYER
this means that in the US anyone can make ASA and call it ASPIRIN
the term aspirin has therefore become generic
Canada:
bayer lost patent right to ASA  anyone could make it
kept the right to the name aspirine
this means that in Canada, only the bayer company can call their product
aspirin
o any other company that makes ASA has to call it ASA
o there is no difference between bayer aspirin and ASA (besides the price)
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in the US, an American company bought the name BAYER (that the germans
lost)
and they started producing bayer aspirin and claimed it was better because it was
bayer aspirin (even though it wasn’t the original bayer)
Federal Trade commission put a stop to this and forbade them to claim that their
product was better
Note: in the US the german company bought the American company that had the
rights to the name so that they could recover the name BAYER in the US
In 1918 the American company bought the name bayer for 5 million dollars
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Then in 1994 the german bayer company bought that company for 1 billion
dollars
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Uses of aspirin:
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it is good for muscular pain but wont help visceral pain (deep rooted pain like
ulcers etc..)
in a particular study they looked to see if the feeling of pain was associated with
personality
ie. Do introverted people feel more pain than extroverted people?
The extroverted (really outgoing and happy people) that are more sensitive to pain
In this same study they tried to see if there was any association between the
feeling of pain and susceptibility to pain
Blondes feel more pain
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HOW ASA WORKS:
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determining the mechanism of action comes from the study of
PROSTAGLANDINS
Ulf Von Euler (1934)
Some of the prostaglandins are found in the prostate
Ulf got nobel prize in medicine in 1970
The have many functions in the body  tell us how ASA works and also explains
some of the side-effects
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John Vane  Mode of action of prostaglandins (1971)
Also showed how ASA works with prostaglandins to relieve pain
Got nobel prize in medicine for his discovery
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when cell is damaged it produces the above acid
that acid produces prostaglandins which act as messengers which trigger the
nerves that signal pain to the brain
the way ASA works is that it blocks the conversion of arachidonic acid into
prostaglandins
ASA works by blocking a specific enzyme called CYCLOOYGENASE
o It is required to do this conversion
o This enzyme is known as a COX enzyme (there are different types of
these)
o ASA is therefore a COX-Inhibitor
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Prostaglandins are involved in Fever  so if you block them it helps
Prostaglandins, bradykinin, and histamine are involved in Inflammation  so it
should help
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OTHER USES OF ASA:
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ASA also has positive applications with respect to heart disease
The most general use of ASA in N.A. today is to prevent heart attack among
people at risk
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a heart attack is a blockage of one of the main arteries that feeds oxygenated
oxygen to the heart
if there is a blockage the heart muscle dies = heart attack
ASA prevents the formation of blood clots
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Advertised to people who have had heart attacks and want to prevent a second one
In the past it was advertised as not affecting the heart! This was a good thing then
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“Physicians Health Study” :
o used around 20, 000 MALE ONLY physicians
o aged 40 to 84 years
o they were followed for 5 years
o males in general used to be more prone to heart attack
o but now women have caught up in this respect
o used to think women had hormones that prevented heart attacks, but now
due to level of smoking in women they have caught up
o LUNG CANCER is the largest cancer killer in women
o Today the proportion of young women who smoke is greater than that of
men
o ASA does not offer the same protection in women as it does in men in
terms of prevention of heart disease
o It isn’t clear why though
o Clear benefit is only in males  must have to do with hormonal balance
etc…
o Study:
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much lower incidence in people taking ASA than the placebo
ASA inhibits prostaglandins, one such is Thromboxane A2 which causes clotting
 it therefore thins the blood and reduces the risk of blood clots
Today we know that as little as 30 mg a day is enough  this is good since ASA
has sideeffects and we want to minimize these
Today you can buy lowstrength ASA for the prevention of heart disease
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the #1 use of ASA is for heart disease
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it seems that the acetyl group is what is important for protecting men from heart
disease
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ASA and cancer:
ASA may have some beneficial use against cancer
It was shown that chronic aspirin users have fewer colon cancer deaths
Colon cancer patients appear to have higher levels of COX enzymes (and ASA
blocks this enzyme remember)  note that it is death, not just cases of colon
cancer
We aren’t sure if it is a causative or associative relationship
Note: a side effect of aspirin is bleeding
Basically these people go to the doctor for this, the doctor catches the colon
cancer also at the same time he is running other tests...so you get less cases of
death because the cancer was caught earlier
Newest study shows that there IS a causative relationship between aspirin risk and
lower risk of colon cancer:
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had to use aspirin for at least 10 years to see these effects
problem is all the side-effects (bleeding)
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in 2004 the breast cancer thing made a big splash
a year later you saw a study contradicting it
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remember you have to look at all the studies and history before you make a
conclusion
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Dangers of ASA:
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Overdose of aspirin on the upswing
Anything can kill in a large enough dose
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SALICYLISM: (ASA poisoning)
Get this at 12 – 25 tablets
Major symptom is TINNITIS  ringing in the ears  can drive you crazy
Common side-effect of overdosing
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DEATH:
20 – 30 tablets (in one sitting)
note: whenever you take too much of a toxic substance it goes to the liver
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this is why children with lower body weights should take aspirin with lower
dosage
80 mg instead of 320 mg (it is ¼)
chewable orange flavor
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Gastric irritation:
This was a huge problem with salicylic acid
Still happens with aspirin though
You get bleeding and ulcers
Ulcers are a big problem and lead to 3000 deaths and 20000 hospital admissions
(in N.A.)
Rudolph valentino died of a bleeding ulcer in the early 1920s
Why does it cause these gastric problems?
o Because prostaglandins are involved in gastric function
o They regulate acid secretion
o They protect the stomach lining
o So when you inhibit this COX enzyme you also inhibit the production of
the beneficial prostaglandins
you get formulations that contain anti-acids
eg. Bufferin  reduces acidity of the stomach to reduce gastric irritation
eg. Aspirin plus by bayer  contains Stomach Guard (antacid)
another way to alleviate the gastric side effects = coating the aspirin
basically the coating is a polymer (like a plastic) that stops the ASA from being
released into the stomach (it gets released into the intestine where it is absorbed)
sometimes it dissolves in the stomach anyway and sometimes it just goes right
through
note: enteric means coated  ie meant to dissolve in the intestine
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ALLERGIC RXNS:
o Pretty rare
o Every year about 300 people die from a rxn to ASA
o Eg. man who was blinded by a mix of penicillin and ASA
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REYE SYNDROME:
o ASA is very strongly ASSOCIATED with this condition
o Named after doctor reye
o Mostly affects young children up to teenagers who have taken ASA after a
bout of fever (eg. associated with the flue or chicken pocks)
o Causes a swelling of the brain which can destroy brain cells
o The death rate was 50% for people who developed this
o It was a rare syndrome though
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so don’t give ASA products to young children, especially if they are fevered
also, prostaglandins are important in promoting uterine contraction, so you
shouldn’t take ASA in the last 3 months of pregnancy
if you take ASA right before delivery it makes it that much more difficult
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OTHER VARIATIONS:
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extra strength ASA tablets just contain more asa  about 1.5 tablets of reg.
strength aspirin
500 mg
the therapeutic dose is 2 tablets  650 mg
in some cases it is sold as caplets  coated and easier to swallow
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ANACIN:
o Contains what 2 of 3 doctors call the greatest pain reliever ever discovered
o This is just ASA
o Has 325 mg of ASA and 32 mg of caffeine (1/4 cup of coffee)
o There is some evidence that caffeine may make the medicine absorb faster
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MIDOL:
o Used for the treatment of menstrual cramps
o It contains 500 mg ASA and 32 mg caffeine
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CHASER (for hangover):
o Contains ASA and an antacid
o Very expensive
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Cost per 100 tablets of ASA variation:
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midol is very expensive
for children’s aspirin, you pay for the packaging
in any case it isn’t a good idea to give ASA to children
ACETAMINOPHEN:
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Structure:
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generic name for Tylenol
has become extremely popular
Works well for pain, fever, BUT NOT INFLAMMATION!!!!!
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Tylenol mentioned that:
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osteoarthritis is from wear and tear
the end is saying that Tylenol is effective
basically saying that you can use Tylenol for osteoarthritis but not rheumatoid
arthritis
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it is less effective than ASA at treating heart disease
this is because it doesn’t have the ACETYL GROUP
see:
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It is not associated with Reye syndrome though!!!
This is why acetaminophen is the active ingredient in Infant Tempra (for fever)
It is also much more soluble so you can put it in drops
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SIDE EFFECTS:
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Dosage:
o Should not exceed 12 tablets daily
o It is hazardous to do so
o Acetaminophen is especially damaging to the liver under very specific
conditions  ie over the maximum dosage or with alcohol
o There have been a number of deaths of people that drink too much alcohol
then get a headache and take Tylenol then take more and more until they
die
in Britain:
o built an antidote into the pill
o this antidote is methionine
o it converts to Glutathione which helps in the detoxification of
acetaminophen
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ASA free ANACIN:
o Contains acetaminophen
o One of the major benefits of this chemical is that it is far more gentle on
the stomach
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Excedrin:
o Acetaminophen
o Many of the pills that used to contain ASA now contain acetaminophen
o 325 mg in each (same relative relief factor as ASA), but also contains 65
mg of caffeine (1/2 a cup of coffee)
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1982: some Tylenol was found to be contaminated with cyanide
o some crazy person went to the pharmacy and replaced some caplets of
Tylenol with cyanide and put it back on the shelf
o this was possible because there were no safety seals at the time
o 7 people died as a result
o Johnson and Johnson did a really good job recalling this stuff from all
around N.S. though
o The guy was never caught
o Now there are safety seals on everything
o OTC are never in capsules anymore so it is way more difficult to tamper
with caplets or tablets
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Note: Tylenol is twice as expensive as the generic Acetaminophen
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IBUPROFEN:
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good for: Pain, fever, inflammation
doesn’t do anything for heart disease
doesn’t cause rye syndrome
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it actually relieves pain better
only need 200 mg for same effect (as 325 of ASA)
ibuprofen works well for menstrual pain
in contrast to Tylenol, it relieves inflammation
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causes Gastrointestinal problems
all NSAIDS (non steroidal anti-inflammatory drugs) have the side-effect in the GI
tract
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it seems that if you take ibuprofen at the same time as ASA (eg people that take it
for prevention of heart disease daily)
sept 12, 2006
ibuprofen seems to negate the effects of ASA
in Canada you can get it generically also
advil is more than 2x the price of the generic
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NAPROXEN SODIUM:
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it is what is found in ALEVE
“all day strong, all day long”
seems to be longer lasting than the other ones
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Other stuff:
acetaminophen is the most widely sold pain reliever in north America
mostly Tylenol instead of the generic type
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In Canada you need to have a prescription to get naproxen sodium
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all the NSAIDs have detrimental effects on the stomach
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Naproxen sodium is the pain reliever that seems to cause the least amount of
problems
o Available as an otc in the US but not in Canada
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ASPIRIN RESISTANCE:
people that use too much of ASA can become resistant to it
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COX-2 INHIBITORS:
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type of arthritis drug
prescription drug
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Problem with all the NSAIDs including ASA is that they inhibit both cox 1 and
cox 2
o cox 1  stomach protection
o cox 2  pain and inflammation
so blocking cox 1 leads to the gastro effects
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what you want to do is block COX 2 without blocking COX 1
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this new class of drugs is called COX-2 inhibitors
cause less gastro problems
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first one of these on market was CELEBREX (generic = CELECOXIB)
another one produced was VIOXX (generic = ROFECOXIB)  by merck
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kind of like molecular modeling:
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notice that it has a little tail with the sulfur group on it
this tail is the cox 1 site
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above you can see the cox 2 site
you can see in the above picture that a cox 1 site (in an NSAID) can fit into the
cox 1 site but also the cox 2 site
a conventional NSAID can fit into 2 receptor sites! This is bad news
celebrex has that little tail  so it fits into the cox 2 site, but there is no place for
the tail in the cox 1 site  therefore it acts only as a cox 2 inhibitor
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VIOXX linked to an increased risk of heart disease
Only in specific cases  eg. large amounts taken for large periods of time
Theory that merck was aware of these risks but didn’t report them
When the product was pulled, merck lost over 26 billion dollars in sales
In the US, everyone is suing merck about vioxx
There are 14000 cases
Some plaintiffs got huge amount of many  eg. 250 million
Reversed though
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in Canada, an advisory committee has suggested that it be put back on the market
there are benefits  less GI problems
FDA of Canada and US are also deciding to put it back on the market
But merck decided not too
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we constantly need to do risk-benefit analysis
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note: naproxen sodium seems to be associated with the least amount of risks for
heart disease (out of all the NSAIDs)
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