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
COOH
ARACHIDONIC ACID
(fish oils)
CYCLOXYGENASE ENZYMES
COX-1,COX-2
O
O
OOH
Thromboxanes
(promote aggregation)
Prostaglandins
(inflammation.....)
Prostacyclins
(inhibit aggregation)
Thromboxanes
Prostacyclins
Prostaglandins
COOH
OH
O
HO
COOH
O
COOH
O
OH
HO
HO
OH
OH
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
O
O
OH
OH i) KOH, CO2
Ac2O
ii) H+
OCH3
OH
OH
O
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);
>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 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
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)
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 !!!
PAIN RELIEF
optimum dose ~600mg
tabs
2-3 regular or 1-2 extra strength
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.
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)
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
COOH
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 ASA~IBU
so need a lot more 200mg pills to kill yourself (>100)
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)
COOH
‘ibu’ is racemic
but only the (S)-enantiomer is active.
OTHER SAME TYPE ANALGESICS
COOH
OH
O
Cl
H
N
COOH
MeO
MeO
S-Naproxen
COOH
indomethicin
F
F
diflunisal
(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
COOH
OH
O
Cl
H
N
COOH
MeO
MeO
S-Naproxen
COOH
indomethicin
F
F
diflunisal
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)
Diclofenac
COOH
Cl
NH
Used as Na or K salt; use increased since
removal of VIOXX
Cl
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
SO2Me
SO2NH2
N
CF3
N
N
O
O
O
celecoxib
CELEBREX
SO2NH2
rofecoxib
VIOXX
valdicoxib
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 4.5M 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 ~$1 for 200mg capsule
In fact most people find they are about the same as far as pain,
but are much better for stomach
(000's die from stomach bleeding each year on older drugs)
Despite the expense, they became very successful, even with
some early government warnings to consumers.
This is current FDA website about these drugs
http://www.fda.gov/cder/drug/infopage/COX2/default.htm
Controversy: Merck should have warned customers earlier
A 1999 study called VIGOR showed that Vioxx caused 5x as
many heart attacks as naproxen (or maybe naproxen reduced
risk - aspirin) but less risk of stomach bleeding.
Merck chose to interpret the data that Vioxx did not show
the protective nature of naproxen!
But it did not show that naproxen had a protective action
In 2000, Merck started a trial of use of Vioxx in a cancer study
(against polyps in bowels); after about 3 years, this revealed a
doubling of heart attack and stroke risk after 18 months
treatment
[15 cases per 1000 compared to 7.5 cases per thousand for
placebo].
In April 02, FDA ordered Vioxx labels to reflect increased risk
of heart attack and stroke, still sales reached 2.5B$ in 2003.
Aug 2004, FDA study of 1.4 million Kaiser Permanente
patients confirmed an increased risk
Sep 29th 2004 Merck withdrew Vioxx, lost >1/4 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)
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
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 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 [NicOx small French biotech]
http://www.nicox.com/update/HCT_3012.html
ACETAMINOPHEN
(TYLENOL in N. America)
(DATRIL, ANACIN, paracetamol
in Europe)
HO
NHCOCH3
acetaminophen
LETHAL DOSE 15-25g
Liver damage severe with >10g 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
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
Metabolism:
Glutathione
NAD
HO
NHCOCH3
O
NHCOCH3
NCOCH3
liver
acetaminophen
inhibits liver enzymes
S-glutathione
OH
excretes in urine
50-60% excreted as gluconeride
in urine
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
NMe2
NH2
HO
NH
serotonin
(5-hydroxytryptophan)
NH
S
O O
NH
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.
Some of the other 5HT1D receptor agonists
(5HT = 5-hydroxytryptophan = serotonin)
NH
NMe2
S
N
S
O
NMe2
NH
O
O
H
NH
O
O
NH
O
N
RELPAX
eletriptan
ALMOGRAN, AXERT
almotriptan
N
ZOMIG
NMe2
N
zolmatriptan
CH3NHSO2
N
N
NH
NH
NARAMIG
naratriptan
MAXALT
riza triptan
ZOMIG (AstraZeneca) 2.5 and 5 mg
MAXALT (Merck) 5mg 10mg, is ~ 10x as potent as
sumatriptan
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/topicsheets/cafergo
t.html
http://www.pharma.us.novartis.com/products/name/cafer
got.jsp