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

OOH

O

O

ARACHIDONIC ACID (fish oils)

CYCLOXYGENASE ENZYMESCOX-1,COX-2

Thromboxanes(promote aggregation)

Prostacyclins(inhibit aggregation)

Prostaglandins(inflammation.....)

O

COOH

OH

HO

OH

O

COOH

HO

OH

OCOOH

OHHO

BLOCKING the COX enzyme stops the synthesis of thesestops pain, reduces swelling, inflammation, and changesblood clotting

Thromboxanes Prostacyclins Prostaglandins

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 = 30M kg, about 50% in N America! (55B tabs); >1012 tabs sold since 1899

O

OCH3

OH

O

OH

OH

O

OH

Ac2O i) KOH, CO2

ii) H+

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 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.

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

para-isobutylphenyl propionic acid

ADVIL, MOTRIN,....

COOH

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

MeO

COOH

H

S-Naproxen

N

COOH

ClO

MeO

indomethicinF F

COOH

OH

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

MeO

COOH

H

S-Naproxen

N

COOH

ClO

MeO

indomethicinF F

COOH

OH

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)

NH

Cl

Cl

COOH Diclofenac

Used as Na or K salt; use increased sinceremoval of VIOXX

Sold in Canada under a variety of namesApo-Diclo, Novo-Difenac, Nu-Diclo, Pennsaid, Voltaren, Arthrotec

Similar ones are Etodolac, Sulindac, Ketorolac

MORE SELECTIVE (and controversial) COX-2 INHIBITORS: CELEBREX, VIOXX, BEXTRA

NNCF3

SO2NH2

O

O

SO2Me

celecoxib rofecoxibCELEBREX VIOXX

NO

SO2NH2

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 etcBUT 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 withsome 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 inCanadaMeloxicam (2000) is also generic, 7.5 or 15mg pills. Sold as Mobic in USA though they don’t list underCOX-2

On-line you can easily buy VIOXX $130 for 100 tabsMade in India,……

Nov 2006: H-C approves Lumiracoxib “Prexige”from Novartis; acts as COX-2 inhib, butmore like diclofenac in structureOct 4, 2007 – H-C withdraws it from sale becauseof 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 trialsdoes 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:

HO NHCOCH3

acetaminophen

NAD

liver

NCOCH 3O

NHCOCH3

OH

S-glutathione

50-60% excreted as gluconeride

inhibits liver enzymes

Glutathione

excretes in urine

in urine

damage to liver

glutathione removes this, reduces damageBUT 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

NH

NH2

HO

NH

NMe2

SNH

O O

serotonin(5-hydroxytryptophan)

IMITREXsumatriptan

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.

NH

NMe2

NH

OH

O

ZOMIG

zolmatriptan

NH

NMe2

SN

O O

ALMOGRAN, AXERT

almotriptan

NH

NMe2

N

N

N

NH

CH3NHSO2

N

NARAMIG

naratriptan

MAXALT

rizatriptan

Some of the other 5HT1D receptor agonists(5HT = 5-hydroxytryptophan = serotonin)

ZOMIG (AstraZeneca) 2.5 and 5 mg

MAXALT (Merck) 5mg 10mg, is ~ 10x as potent as sumatriptan

S

NH

NO O

RELPAXeletriptan

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/cafergot.html

http://www.pharma.us.novartis.com/products/name/cafergot.jsp