ANALGESICS 30 B$yr world

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ANALGESICS gt30 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...
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Prostaglandins synthesized from ARACHIDONIC acid
via the COX (cyclooxygenase) enzymes
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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
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ASPIRIN ACETYLSALICYLIC ACID (ASA) Leaves of
willow tree used to ease pain (of childbirth)
gt2400 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
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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 30M kg, about
50 in N America! (55B tabs) gt1012 tabs sold
since 1899
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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 E1 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
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ANTI-COAGULANT Thromboxanes and prostacyclins
promote and inhibit blood platelet aggregation,
and both are derived from arachidonic acid. ASA
inhibits thromboxane A2 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)
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HOWEVER TOO MUCH ASA (ARTHRITIC USE) THEN
CAUSES STOMACH TO BLEED 0.5-2 mL for each 500mg
of ASA HERE ASA IS AFFECTING THE COX-1 enzyme
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
!!!
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PAIN RELIEF optimum dose 600mg 2-3 regular or
1-2 extra strength tabs ARTHRITIS needs heavier
dose 1 - 1.5 g at time, BUT MAXIMUM dose
4g/24h 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.
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rat LD50 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)
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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.
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IBUPROFEN para-isobutylphenyl propionic acid
ADVIL, MOTRIN,....
200mg IBUPROFEN 650 mg ASA
so if you need 2x 650mg of ASA ( 1.3 g) only
need 400mg of 'ibu' properties of 'ibu' otherwise
similar to ASA so less mass of pill, less stomach
risk, less bleeding also toxicity of ASAIBU so
need a lot more 200mg pills to kill yourself
(gt100)
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effective dose for headache one 200mg pill (650
mg ASA) for arthritis 2-3
200mg pills (1.3-2 g ASA) But much easier on
stomach, like one 650mg ASA NOTE the 200mg
dose is OTC larger dose pills need prescription,
e.g. Motrin, Advil, Nuprin (cheaper to buy
generic and take several 200mg pills)
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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
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OTHER RELATED ANALGESICS
Indomethicin is an example of the many acetic
acid derivs, INDOCID (Can, Merck),
RHEUMACIN,....... also inhibit prostaglandin
synthesis Diflunisal is 5x more potent than
ASA, less bleeding DOLOBID (Merck, 250/500mg)
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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
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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
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19 weeks after launch 4.5M 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 200mg 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.
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This is current FDA website about these
drugs http//www.fda.gov/cder/drug/infopage/COX2/d
efault.htm Controversy Merck should have
warned customers earlier A 1999 study called
VIGOR showed that Vioxx caused 5x 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
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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 2.5B in
2003.
Aug 2004, FDA study of 1.4 million Kaiser
Permanente patients confirmed an increased
risk Sep 29th 2004 Merck withdrew Vioxx, lost
gt1/4 value of shares.Jul 2004 50, Oct 15th 26,
April 05 35, Dec 06 44
27,000 lawsuits settled at cost of 4.85B (2007)
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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 16th 2005
Canada permanently removes Bextra from market
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2007 Celebrex and Mobicox (meloxicam) available
in Canada Meloxicam (2000) is also generic, 7.5
or 15mg pills. Sold as Mobic in USA though they
dont 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
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May 2007 FDA does not approve Mercks 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 (CINODs) in trials does not
increase blood pressure Less heart
problems?? waiting for Big Pharma NicOx small
French biotech
http//www.nicox.com/update/HCT_3012.html
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ACETAMINOPHEN (TYLENOL in N. America) (DATRIL,
ANACIN, paracetamol in Europe)
LETHAL DOSE 15-25g Liver damage severe with gt10g
doses LD50 340mg/kg rats Appears to affect CNS
COX-enzymes more than peripheries, thus ANALGESIC
AND ANTI-PYRETIC ONLY, not an anti-inflammatory
or anti-coagulant
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DOSE 600 mg sold in 325/500 mg 8 x 500mg
4g/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
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Metabolism
damage to liver
glutathione removes this, reduces damage BUT
alcohol depletes glutathione, so bad news!!
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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.
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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
(30mins) 8-20 per pill lasts 4h Side
effects warm, tingly feeling, flushing,
dizziness, 4 pills not toxic.
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Some of the other 5HT1D receptor agonists (5HT
5-hydroxytryptophan serotonin)
RELPAX eletriptan
ZOMIG (AstraZeneca) 2.5 and 5 mg MAXALT (Merck)
5mg 10mg, is 10x as potent as sumatriptan
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Caffeine also contracts the head blood vessels,
so sometimes helps CAFERGOT (12 x 100mg 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
/caf1060.htm http//www.headaches.org/consumer/top
icsheets/cafergot.html http//www.pharma.us.novart
is.com/products/name/cafergot.jsp