HEALING ULCERS
Liquorice extract (licorice) for > 2000 years in China
.... helps ulcers heal
Prostaglandins are natural hormones that help heal holes
in the stomach wall, but an enzyme (15-hydroxyprostaglandin dehydrogenase) stops the prostaglandins from
working. Licorice blocks this enzyme, and so the
prostaglandins stick around longer, make ulcers heal.
HOWEVER chemistry always has a price,
licorice causes cortisol to bind to a protein
causing sodium to be retained, increases BP,
water retention, (*) head aches, lethargy,....
OH
O
OH
HO
H
H
H
O
(*) Addison’s disease is caused by a deficiency of cortisol, so liquorice helps that
The active ingredient was found in 1960
(a triterpenoid derived from glycyrrhizic acid)
COONa
O
H
RO = NaCOO(CH2)2COO-
RO
Carbenoxolone
and was sold as CARBENOXOLONE
the market leader for ulcer treatment for ~ 10 yrs,
but had the side effects above.
BISMUTH COMPOUNDS (1786 on)
PEPTOBISMOL today
1920's surge in use because also a syphilis treatment
Use rebounded in 1980's: Peptic ulcer patients have
larger than normal amounts of BACTERIUM
‘Helicobacter pylori’ (H. pylori), especially type O blood,
where bacterium links to stomach wall via a sugar.
Bismuth salts(*) inhibit this linking, and so with
Amoxicillin (a penicillin) which kills the bacteria,
have been used to treat ulcers since about 1990.
(*)Bismuth salicylate, carbonate or basic nitrate.
THE ANTI-HISTAMINES
In late 60's found that HISTAMINE is a signaling
compound, which causes release of stomach acid.
an AMINE
H2 N
N
NH
histamine
In 1972, the receptor (H-2), was recognized; different from
the H-1 receptor that causes allergies.
Eating, stress,.... causes histamine to be released, which
on triggering the H-2 receptor starts acid secretion.
RECEPTORs are like LOCKS, if an appropriate KEY
(CHEMICAL) is inserted, the LOCK will OPEN (the
RECEPTOR will TURN ON)
AGONIST: chemical that binds to a receptor and turns it
on (a key that goes in the lock and turns)
ANTAGONIST: chemical that binds the receptor but does
not turn it on (like a key that fits but jams the lock)
Thus an H-2 receptor ANTAGONIST was needed which
would bind to the receptor stronger than histamine itself,
but not promote the release, i.e. block the receptor
[an AGONIST binds and promotes the effect]
H-2 receptor ANTAGONIST
SMITH-KLINE-FRENCH launched TAGAMET
(chemical name cimetidine) in Nov 1976
NH
NH
S
N
CN
N
NH
cime tidine
fits lock and blocks it
By 1983 Tagamet world-wide sales were 1B$
(7000 ulcer related deaths in US in 1982)
Heals ca. 70-80% ulcers in 4 weeks; requires 3
doses per day of 150-300 mg
LD50 mice (rats) 2.6 (5) g/kg orally (lethal dose to kill
50% of population)
essentially non-toxic
cf. aspirin = ~0.4 g/kg in people
Generic cimetidine available in 90’s and now as an
OTC ‘over-the-counter’ drug, usually in lower doses,
eg. 100mg Tagamet-HB
An improvement was ZANTAC (ranitidine)
150mg twice per day
NO 2
Me2N
S
O
NH
NHMe
rani tidine
and then PEPCID-AC and MAALOX-H2 (famitidine)
NH 2
NH 2 N
H2N
N
S
N
SO2NH 2
S
fami tidine
OTC drugs now in 75mg or 100 mg doses
Few side effects: mild diarrhea, skin rash
~ 4 to 9x more effective than cimetidine
Also in Canada: Nizatidine (2006)
Need to find out more about a drug?
The CPS (Canadian Compendium of Pharmaceuticals
and Specialties) 2005 version in ELL 305 **
especially good on approved usages, doses, side effects
eg. Nizatidine is on page 162
The MERCK Index 13th Ed. in ELL 305
good for a quick overview of almost all chemicals
eg. Nizatidine is on page 1192
** updates thru http://www.pharmacists.ca/content/hcp/tools/drugnews/drugs.asp?Srch=ALL
Using the Merck Index
TURNING OFF THE ACID PUMP
Histamine is one of the signals that starts acid secretion,
however acid is not stored but generated by passage of
protons across a membrane (H+ one way, K+ the other).
This is caused by an ATP-ase enzyme: blocking this
enzyme, reduces the amount of acid pumped
ASTRA ZENECA were the first to patent Omeprazole for
this purpose, and in 1989 launched as:
PRILOSEC (USA), LOSEC (Canada)
PRILOSEC (USA), LOSEC (Canada)
OMe
NH
O
S
N
N
MeO
omeprazole
Advantage: One 20 mg pill per day;
self limiting - does not stop acid, reduces it
STOPS acid reflux into esophagus (Zollinger-Ellison
syndrome), very low (4g/kg) toxicity, few side effects.
Disadvantage: $2 per pill
By 2001, (PRI)LOSEC was THE #2 DRUG overall, with
sales of $6.1B but it has now dropped out of the top
10 due to competition from generics:
eg. apo-omeprazole in Canada (2003)(APO=Apotex)
And from NEXIUM (Mg salt of the S-enantiomer)
‘The Purple Pill’ has captured >40% of US market
thanks to heavy advertising (this does protect AZ’s
patents!).
2008: Nexium 7.7B$ (No. 3 prescribed drug in US)
Several new prazoles are now on the market:
PREVACID = lansoprazole
PEPTAZOL / PROTIUM = pantoprazole
PARIET / ACIPHEX = rabeprazole
NH
CF 2HO
O
CF 3
N
MeO
pantoprazole
N
S
N O
O
lansoprazole
NH
S
S
N
N
NH
N
O
MeO
O
(CH2)3OMe
rabeprazole
Starting June 2003: BC Pharmacare changed coverage of PPI
(proton pump inhibitors) for GERD (gastroesophageal reflux
disease)
LOSEC had to be approved by Pharmacare once per year;
forced to try PARIET = ACIPHEX(USA) = rabeprazole,
(Japan) is 40% cheaper than LOSEC but approval waived