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Transcript
World of chem drugs: lec 2 – Drug history (2) and Pain relievers (analgesics): DRUG HISTORY 2: 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 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 Ether William T.G. Morton (Dentist) Used starting in 1850s During these times, doctor was usually the dentist 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 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 1 common term is to “take a bromide” means take something that will make it go away 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 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 2 In high []s they might cause problems though 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 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 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 - Classic problems in drug testing: 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 New Drugs: to get a new drug on the market with all the testing it takes 10 – 15 years 3 costs over 300 000 000 dollars 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 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 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 4 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: 5 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) 6 know some of the names of these top sellers in Canada prescription sales are pretty much the same: proton pump inhibitor is the thing for stomach acid 7 only need the top ones 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 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 rankings of prescriptions being given: 8 used to be for pain now it is for cholesterol - DRUG CATALOGING: 9 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: 10 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 - SIDE-EFFECTS: 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 11 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 - risk factors aren’t necessarily diseases: obesity and cigarette smoking are real problems the real conclusion that most medical practitioners agree with is “comfort always, cure rarely” 12 PAIN RELIEVERS: (fenster) 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 cough cold is number 1 then pain relievers etc.. antacids are also popular by prescription oral antiseptic = Listerine 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 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 13 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 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 - 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.) - History of ASA: 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 the Egyptians had different treatments for things: 14 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 Hippocrates: Said in 400 BC that women should chew on the bark of the willow tree during childbirth 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 15 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 16 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 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 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 95% of compounds on earth are organic hoffman had the idea of treating this with acetic acid (active ingredient in vinegar) 17 you end up getting: 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) 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 the patent for aspirin what it says is that from now on, the structure will be known as Aspirin 18 can be used as a treatment of rheumatism (arthritis) 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 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 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 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) note: Heroin is made by almost the exact same process as ASA, except different starting material: 19 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 when the germans lost WWI: US: o o o o o o o o o 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) 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 20 Then in 1994 the german bayer company bought that company for 1 billion dollars - Uses of aspirin: 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 - HOW ASA WORKS: 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 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 21 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 Prostaglandins are involved in Fever so if you block them it helps Prostaglandins, bradykinin, and histamine are involved in Inflammation so it should help - OTHER USES OF ASA: 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 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 22 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 “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: 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 23 the #1 use of ASA is for heart disease it seems that the acetyl group is what is important for protecting men from heart disease 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: 24 had to use aspirin for at least 10 years to see these effects problem is all the side-effects (bleeding) in 2004 the breast cancer thing made a big splash a year later you saw a study contradicting it 25 remember you have to look at all the studies and history before you make a conclusion - Dangers of ASA: Overdose of aspirin on the upswing Anything can kill in a large enough dose 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 DEATH: 20 – 30 tablets (in one sitting) note: whenever you take too much of a toxic substance it goes to the liver 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 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 26 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 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 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 - OTHER VARIATIONS: 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 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 27 MIDOL: o Used for the treatment of menstrual cramps o It contains 500 mg ASA and 32 mg caffeine CHASER (for hangover): o Contains ASA and an antacid o Very expensive Cost per 100 tablets of ASA variation: 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: - Structure: 28 generic name for Tylenol has become extremely popular Works well for pain, fever, BUT NOT INFLAMMATION!!!!! Tylenol mentioned that: 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 it is less effective than ASA at treating heart disease this is because it doesn’t have the ACETYL GROUP see: 29 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 - SIDE EFFECTS: 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 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 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) 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 Note: Tylenol is twice as expensive as the generic Acetaminophen 30 IBUPROFEN: good for: Pain, fever, inflammation doesn’t do anything for heart disease doesn’t cause rye syndrome 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 causes Gastrointestinal problems all NSAIDS (non steroidal anti-inflammatory drugs) have the side-effect in the GI tract 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 NAPROXEN SODIUM: it is what is found in ALEVE “all day strong, all day long” seems to be longer lasting than the other ones Other stuff: acetaminophen is the most widely sold pain reliever in north America mostly Tylenol instead of the generic type 31 In Canada you need to have a prescription to get naproxen sodium all the NSAIDs have detrimental effects on the stomach 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 ASPIRIN RESISTANCE: people that use too much of ASA can become resistant to it 32 COX-2 INHIBITORS: - type of arthritis drug prescription drug - 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 what you want to do is block COX 2 without blocking COX 1 33 this new class of drugs is called COX-2 inhibitors cause less gastro problems first one of these on market was CELEBREX (generic = CELECOXIB) another one produced was VIOXX (generic = ROFECOXIB) by merck kind of like molecular modeling: notice that it has a little tail with the sulfur group on it this tail is the cox 1 site 34 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 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 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 we constantly need to do risk-benefit analysis note: naproxen sodium seems to be associated with the least amount of risks for heart disease (out of all the NSAIDs) 35