ANALGESICS 30 B yr world Mild aspirin ASA acetaminophen Tylenol ibuprofen Advil

ANALGESICS [>30 B$/yr world] Mild: aspirin(ASA), acetaminophen(Tylenol), ibuprofen(Advil, Motrin), . . Narcotic: morphine, codeine, . . . In tissues, pain is sensitized by release of small amounts of hormones - prostaglandins cause pain signal, swelling, inflammation, redness. . .

Prostaglandins synthesized from ARACHIDONIC acid via the COX (cyclooxygenase) enzymes

Thromboxanes Prostacyclins Prostaglandins BLOCKING the COX enzyme stops the synthesis of these stops pain, reduces swelling, inflammation, and changes blood clotting The minor analgesic-antiarthritics are thus COX inhibitors

ASPIRIN ACETYLSALICYLIC ACID (ASA) Leaves of willow tree used to ease pain (of childbirth) >2400 yrs ago (Hippocrates) Willow bark used in London, UK ~1650 to reduce fever and malaria 1835 salicylic acid isolated from the bark -then synthesized from phenol in 1874 It reduces fever, but is sour and irritates Sodium salicylate better, but still irritates Bayer labs finally made acetylsalicylic acid -‘better’ tasting, less irritating -first SOLD in 1899

aspirin (ASA) salicylic acid phenol regular tablets = 324 mg (old English 5 grains) extra strength = 500 mg arthritic strength = 650 mg ( = 2 regulars) childrens/stroke. . = 81 mg (1/4 regular) World = 30 M kg, about 50% in N America! (55 B tabs); >1012 tabs sold since 1899

ASA acetylates both the COX-1 and COX-2 enzymes, inhibiting them and so has several effects: ANALGESIC - reduces pain - inhibits prostaglandin synthesis (mainly in peripheries) which sensitize pain ANTI-PYRETIC - reduces fever - resets hypothalamus (thermostat) - causes dilation of blood vessels to surface and hence loss of heat [inhibits prostaglandin E 1 in brain] ANTI-INFLAMMATORY - reduces swelling and inflammation - main use for ARTHRITIS [note: Tylenol (acetaminophen) does NOT do this] Prostaglandins increase the permeability of the capillaries leakage - swelling - redness

ANTI-COAGULANT Thromboxanes and prostacyclins promote and inhibit blood platelet aggregation, and both are derived from arachidonic acid. ASA inhibits thromboxane A 2 synthesis, and thus prevents the aggregation effect of these and so 'thins the blood' and so is ok for daily 'stroke prevention' typically 81 mg [note: Tylenol (acetaminophen) does NOT do this] So Tylenol lacks the anti-inflammatory and anti-coagulent properties of aspirin (ASA)

HOWEVER: TOO MUCH ASA (ARTHRITIC USE) THEN CAUSES STOMACH TO BLEED 0. 5 -2 m. L for each 500 mg of ASA HERE ASA IS AFFECTING THE COX-1 enzyme protects the stomach COX-2 enzyme involved in pain, inflammation so would like to only affect COX-2, but ASA COX-1/COX-2 ~ 10 -100 !!!

PAIN RELIEF optimum dose ~600 mg tabs 2 -3 regular or 1 -2 extra strength ARTHRITIS needs heavier dose 1 - 1. 5 g at time, BUT MAXIMUM dose 4 g/24 h otherwise severe stomach ulceration, loss of blood, liver problems (excess dose gives ringing in ears ) so ENTERIC COATED ASPIRIN also available - the coating stable in stomach.

rat LD 50 = 1. 5 to 2 g/kg, i. e. 5 tabs/kg but people more sensitive (~ 1 tab/kg) LETHAL DOSE TO HUMANS 20 -25 g = 40 -50 extra strength = 60 -75 regular tabs suicides by ASA second to barbiturates UK limiting sizes of packs (2004)

Other effects ALLERGIC - few % of population - causes asthma attack and sometimes death use Tylenol if this is the case Aspirin + alcohol gives increased bleeding NOT for children with flu symptoms or chickenpox can lead to swelling in brain (Reyes syndrome) fatal in 25% cases.

IBUPROFEN para-isobutylphenyl propionic acid ADVIL, MOTRIN, . . 200 mg IBUPROFEN ≡ 650 mg ASA so if you need 2 x 650 mg of ASA (= 1. 3 g) only need 400 mg of 'ibu' properties of 'ibu' otherwise similar to ASA so less mass of pill, less stomach risk, less bleeding also toxicity of ASA~IBU so need a lot more 200 mg pills to kill yourself (>100)

effective dose for headache: one 200 mg pill (~650 mg ASA) for arthritis: 2 -3 200 mg pills (1. 3 -2 g ASA) But much easier on stomach, like one 650 mg ASA NOTE: the 200 mg dose is OTC larger dose pills need prescription, e. g. Motrin, Advil, Nuprin (cheaper to buy generic and take several 200 mg pills)

‘ibu’ is racemic but only the (S)-enantiomer is active. OTHER SAME TYPE ANALGESICS (S)-Naproxen is an example of the many arylpropionic acids - NOTE sold CHIRAL ; ALEVE is Na salt Similar ones: Fenoprofen, Flurbiprofen, Ketoprofen

OTHER RELATED ANALGESICS Indomethicin is an example of the many acetic acid derivs, INDOCID (Can, Merck), RHEUMACIN, . . . . [also inhibit prostaglandin synthesis] Diflunisal is 5 x more potent than ASA, less bleeding DOLOBID (Merck, 250/500 mg)

Diclofenac Used as Na or K salt; use increased since removal of VIOXX Sold in Canada under a variety of names Apo-Diclo, Novo-Difenac, Nu-Diclo, Pennsaid, Voltaren, Arthrotec Similar ones are Etodolac, Sulindac, Ketorolac

MORE SELECTIVE (and controversial) COX-2 INHIBITORS: CELEBREX, VIOXX, BEXTRA Searle(Pfizer) (Jan 1999) Merck (May 1999 ) Pfizer (2001 ) 200 mg 12. 5/25 mg 10/20 mg Selectivity ratio COX-2/COX-1: = 6. 3 = 38

19 weeks after launch 4. 5 M prescriptions for Celebrex! (only exceeded by Viagra) The whole idea of these was that more selective for COX-2, so better for pain and inflammation, less stomach effects, bleeding etc BUT MUCH MORE EXPENSIVE ~$1 for 200 mg capsule In fact most people find they are about the same as far as pain, but are much better for stomach (000's die from stomach bleeding each year on older drugs) Despite the expense, they became very successful, even with some early government warnings to consumers.

This is current FDA website about these drugs http: //www. fda. gov/cder/drug/infopage/COX 2/default. htm Controversy: Merck should have warned customers earlier A 1999 study called VIGOR showed that Vioxx caused 5 x as many heart attacks as naproxen (or maybe naproxen reduced risk - aspirin) but less risk of stomach bleeding. Merck chose to interpret the data that Vioxx did not show the protective nature of naproxen! But it did not show that naproxen had a protective action

In 2000, Merck started a trial of use of Vioxx in a cancer study (against polyps in bowels); after about 3 years, this revealed a doubling of heart attack and stroke risk after 18 months treatment [15 cases per 1000 compared to 7. 5 cases per thousand for placebo]. In April 02, FDA ordered Vioxx labels to reflect increased risk of heart attack and stroke, still sales reached 2. 5 B$ in 2003. Aug 2004, FDA study of 1. 4 million Kaiser Permanente patients confirmed an increased risk Sep 29 th 2004 Merck withdrew Vioxx, lost >1/4 value of shares. Jul 2004 $50, Oct 15 th $26, April 05 $35, Dec 06 $44 27, 000 lawsuits settled at cost of 4. 85 B$ (2007)

2005 Pfizer plans trials of Celebrex and Bextra (which already has warnings) Feb 2005: FDA panel recommends that all three drugs to remain on market, but with strongest possible warnings because all three drugs increase risk; (Votes: 31 -1(Celebrex), 17 -13 (Bextra), 17 -15 (Vioxx)], Also recommended no direct advertising! April 2005 Health Canada removes Bextra from the Canadian market and new restrictions on celebrex; FDA asks for vol. removal Bextra Dec 16 th 2005: Canada permanently removes Bextra from market

2007: Celebrex and Mobicox (meloxicam) available in Canada Meloxicam (2000) is also generic, 7. 5 or 15 mg pills. Sold as Mobic in USA though they don’t list under COX-2 On-line you can easily buy VIOXX $130 for 100 tabs Made in India, …… Nov 2006: H-C approves Lumiracoxib “Prexige” from Novartis; acts as COX-2 inhib, but more like diclofenac in structure Oct 4, 2007 – H-C withdraws it from sale because of risk of serious liver hepatitis

May 2007 – FDA does not approve Merck’s Arcoxia (Etoricoxib) approved in 60 countries (not in Canada as far as I can tell) BUT: available on-line in Canada!!! Oct 2007: Naproxcinod is a cox inhibiting Nitric Oxide donator (CINOD’s) in trials does not increase blood pressure Less heart problems? ? waiting for Big Pharma [Nic. Ox small French biotech] http: //www. nicox. com/update/HCT_3012. html

ACETAMINOPHEN (TYLENOL in N. America) (DATRIL, ANACIN, paracetamol in Europe) LETHAL DOSE 15 -25 g Liver damage severe with >10 g doses LD 50 340 mg/kg rats Appears to affect CNS COX-enzymes more than peripheries, thus ANALGESIC AND ANTI-PYRETIC ONLY, not an anti-inflammatory or anti-coagulant

DOSE: 600 mg sold in 325/500 mg 8 x 500 mg = 4 g/day normal max dose probably best for simple headaches, relief of pain, even arthritis pain (not the inflammation though) Tylenol + alcohol = increased liver damage; Tylenol + garlic (sulfides) = reduced damage

Metabolism: damage to liver glutathione removes this, reduces damage BUT alcohol depletes glutathione, so bad news!!

MIGRAINES Migraines are caused by low SEROTONIN levels in the head, which causes the head blood vessels to be DILATED, applies pressure, causes pain - NOT usually relieved by the analgesics above (some do get relief, eg. from naproxen) Once this cause was identified, then an AGONIST for serotonin was searched for that would CONSTRICT head blood vessels, but not those elsewhere.

850 compounds tested before GLAXO found IMITREX = sumatriptan Available as 6 mg injections (as succinate): fastest (~10 mins) 5 mg and 20 mg nasal spray (as hemisulfate) OR 25, 50 and 100 mg oral tablets (~30 mins) $8 -20 per pill; lasts ~ 4 h Side effects: warm, tingly feeling, flushing, dizziness, 4 pills not toxic.

Some of the other 5 HT 1 D receptor agonists (5 HT = 5 -hydroxytryptophan = serotonin) RELPAX eletriptan ZOMIG (Astra. Zeneca) 2. 5 and 5 mg MAXALT (Merck) 5 mg 10 mg, is ~ 10 x as potent as sumatriptan

Caffeine also contracts the head blood vessels, so sometimes helps CAFERGOT (12 x 100 mg ~$40 on web) contains caffeine and an alkaloid ergotamine (comes from the ergot fungus found on rye, lysergic acid comes from same fungus!) These are vasoconstrictors http: //www. healthsquare. com/newrx/caf 1060. htm http: //www. headaches. org/consumer/topicsheets/cafergo t. html http: //www. pharma. us. novartis. com/products/name/cafer got. jsp