Med Chem lecture on anti ulcer drugs

1. • Give the structure and uses of
ranitidine.(2013,2.5)
• How omeprazole inhibit acid secretion?
(2010,2.5)
• Write in short about the chemistry of
prostaglandin. (2010,2.5)
• How proton pump inhibitors heal ulcers?
(2009,2.5)
• Classify Anti-ulcer drugs (2008,5)

2. Anti-ulcer drugs
Ulcer is a very much a treatable
disease

3. Ulcer
• An ulcer is a kind of open wound accompanied by
inflammation. It can occur both on outer skin and
internal epithelium such as surface of the
stomach or inside the mouth.
• Ulcers start when the top layer (surface) of skin
or mucous membrane is hurt. This top layer dies.
When it dies, the skin or mucous membrane and
opens. This leaves an open sore called an ulcer.
• Ulcers can be from
– infection with H.pylori (responsible 90% 0f petide
ulcers)
– substances that will burn skin or mucous membranes,
such as stomach acid
– from pressure on a part of the skin.
– from cancer to diseases of blood vessels.

4. Foot Ulcer
Mouth ulcer
Tongue Ulcer
Foot Ulcer
Duodenal Ulcer Gastric Ulcer
Peptide ulcer

5. Acid secretion in stomach
• Within the gastric mucosa lies the oxystic glands those
parietal cells secrete about 2-3 litre of HCl of pH 1 into
the stomach
• The cells don’t store a reservoir of HCl acid. H+ and Cl-
are secreted separately into the stomach;H+ by
proton pumps and Cl- by chlorine ion channels
• The working of proton pump is controlled by various
regulators and drugs for ulcers have effect on them
– Histamine at H2 receptors
– Gastrin at G receptors
– Acetylcholine at M2 receptors
– Prostaglandin (PgE2)
– Somatostatin (SST)
Promote acid secretion
Inhibit acid secretion

6. Gastric Glands and their cell types,
secretion and functions

7. Proton pump stimulated by His, Ach
and Gastrin and inhibited by PgE2

8. Anti-ulcer Drugs classes
1) Reduction of gastric acid secretion
• H2 antihistamine: Cimetidine, ranitidine,
famotidine,roxantidine
• Proton Pump Inhibitors (PPTs): Omeprazole, Pantoprazole,
rabeprazole, esmoprazole
• Anticholinergics: Pirenzepine,Propantheline,Oxyphenonium
• Prostaglandin analogues: Misoprostol, enprostil, rioprostil
2) Neutralization of gastric acid (Antacids)
• Systemic: Sodium bicarbonate, Sodium citrate
• Non-systemic (Local): MgOH, Al(OH)3, CaCO3
3) Ulcer protectives: Sucralfate, CBS (Colloidal Bismuth
Subcitrate)
4) Ulcer healing Drugs: Carbenoxolone sodium
5) Anti-H. pyloric drugs: Amoxicillin, clarithromycin,
metronidazole, tinidazole, tetracycline

9. How H. Pylori causes ulcer?
• This bacteria burrows through the protective 1mm
thick mucus layer and attaches itself to the epithelial of
stomach walls to avoid acidic conditions. Furthermore
it also produces large amounts of urease, which breaks
down the urea present in the stomach to carbon
dioxide and ammonia. The ammonia protects it from
stomach acidity and is toxic to epithelial cells which
secrete mucus. It also produces cell damaging
chemicals such as proteases and vacuolating cytotoxin
A (VacA). All together the mucus barrier is damaged
and made thinner than 0.5 mm and in this state the
stomach becomes more susceptible to attack by acid
and pepsin

11. H2 Histamine antagonists
• Histamine is released from mast cell in gastric
mucosa by gastrin and acetylcholine
• MOA- Histamine acts on H2 receptor and
stimulates proton pump through the cAMP
pathway which leads to acid secretion. These
drug antagonize H2 receptor and block
Histamine mediated acid secretion
• They are associated with libido loss or erectile
dysfunction

12. SAR of H2 Histamine antagonists
• 1) Need an aromatic/hetero-aromatic ring. The imidazole ring is
not required but if it is present there must be electron donors at
position 5 to promote t tautomer .
• 2) The terminal nitrogen group should be polar but not basic for
maximal potency
• 3) Separation of the ring from the nitrogen group by 4 atoms
gives maximal potency

13. Normally both tautomers are equally favored
If at position 5 R’ = electron donating group
eg CH3, OH,NH3, then τ tautomer is favored
Imidazole

14. H2 anti-
histamine
drugs

15. Note
• All these contain the NHCH3 or NH2 group at
right terminal which are very basic. But the SAR
demands that this Nitrogen not be basic. So how
is it achieved?
• Same way the N in amide is not basic. The
presence of electron withdrawing group next to
the terminal nitrogen, in form of C=O as in amide
or CN, SO2NH2 and NO2 as in this case, attracts
N’s lone pair electron and can no longer share it
to act like a base. The C=N and C=C along with
the withdrawing groups that is attached to
terminal N account for polarity.

16. Cimetidine
• It is a imidazole derivative H2-antagonist
• It inhibits CYP, which leads to many drug–drug
interactions.
• It exhibits antiandrogenic action and can cause
gynecomastia if used for more than 1 month.
• It has 63-78% bioavailability
• Uses
– Peptide Ulcer, heartburn, Zollinger–Ellison syndrome,GERD
• MOA -Histamine acts on H2 receptor and stimulates
proton pump through the cAMP pathway which leads
to acid secretion. These drug antagonize H2 receptor
and block Histamine mediated acid secretion

17. •It is a furan derivative H2-antagonist, which is an
isostere of the imidazole ring.
•It is a weaker CYP inhibitor than cimetidine and has no
antiadrogenic effect
•It is about 6 times more potent than Cimetidine with a
longer Duration of action.
•It’s bioavailability is 52%.
•Uses
Peptide Ulcer, heartburn
•MOA -Histamine acts on H2 receptor and stimulates
proton pump through the cAMP pathway which leads to
acid secretion. These drug antagonize H2 receptor and
block Histamine mediated acid secretion
Ranitidine

18. Famotidine
• It is a thiazole derivative H2-anatgonist.
• It does not cause gynecomastia and is a weak
inhibitor of CYP.
• It is 40 times more potent than Cimetidine but it has
only 37 to 45% bioavailability.
• Uses
– Peptide Ulcer, heartburn,GERD
• MOA -Histamine acts on H2 receptor and stimulates
proton pump through the cAMP pathway which
leads to acid secretion. These drug antagonize H2
receptor and block Histamine mediated acid
secretion

19. Nizatidine
• It is a thiazole derivative similar to Ranitidine.
• It does not inhibit CYP and has no
antiandrogenic effect.
• It is 10 times more potent than Cimetidine. and it
has more than 98% bioavailability
• Uses
– Peptide Ulcer, heartburn,GERD
• MOA -Histamine acts on H2 receptor and stimulates
proton pump through the cAMP pathway which leads to
acid secretion. These drug antagonize H2 receptor and
block Histamine mediated acid secretion

20. Ranitidine ‘s Furan ring vs Nizatidine’s Thiazole ring
Note how only the rings are different in these 2 drugs
Ranitidine Nizatidine
6 X potent than
cimetidine
10 X potent than cimetidine
52% bioavailability > 98% bioavailability
Bioisoterism has powerful effect on drug efficacy and
biocompatibility!

21. Proton Pump Inhibitors (PPI)
Omeprazole Lansoprazole
Pantoprazole Rabeprazole

22. Proton Pump Inhibitors (PPI)
• Inhibition of Histamine receptor does not fully prevent acid
secretion because Ach and gastrin also separately promote
acid secretion.
• But all these 3 regulators ultimately act on proton pump. The
pump can also be independently inhibited which fully inhibits
acid secretion.
• Hence, PPI have stronger acid suppression and are thus
favored over H2-antagonists.
• PPI are irreversible antagonists too, which means once they
bind to a pump it cannot regain it’s function anymore and is
thus destroyed and replaced by a new one which takes time.
This makes their effect stronger and longer (drug action
persists even after it disappears from blood!)
• Also they have demonstrated antibacterial activity which is
an advantage against H.pylori infection.
• Because they prevent acid secretion very strongly than H2
anatgonists, they interfere absroption of drugs needing acidic
condition like antifungals, Iron salts, Digoxin, Ampicillin.

23. How PPI’s work?
1) Benzimidazole PPI’s are prodrug that are converted into
sulphenamide within the acidic environment of parietal cells
in stomach.
2) The sulfonamide then covalently and irreversibly interacts
with sulphahydryl groups in cysteine amino acid of the
binding site of the proton pump to create a disulphide bond.
• The disulphide bond between drug and pump is not
completely irreversible. There are enzymes capable of
reactivating the pump by breaking this disulphide bond. But
if this bond is made with a particular cysteine in the binding
sire, cysteine 822, then is ensures maximum resistance to
such reduction thus incurring longer duration of action.
• They are made into delayed release or enteric coated
formulation which prevents their release in the stomach.
This is done because if they are activated in the stomach
then the charged sulphonamide form won’t be easily
absorbded.

24. Acidic stomach
protonates
prodrug
Prodrug
converts into
active form
Benzimidazole Sulfenamide
Sulfenamide
bound to
Sulfhydryl of
proton pump
HS-Proton pump

25. Omeprazole
• It is an benzimidazole prodrug proton pump inhibitor
• It’s acid inhibition activity is far stronger than H2 antagonists
such that it is incompatible with drugs needing acidic
condition for absorption
• It duration of action is 24-72 hrs, even after it has cleared
from plasma due to its irreversible
• It’s S enantiomer is called esomeprazole and has more
potency and 3 times lower clearance than the R isomer.
Esomeprazole can be used against NSAIDS induced ulcer.
• Uses
– Peptide ulcer, GERD, heart burn, Zollinger-Ellision syndrome
MOA- It activates into sulphamide form in the acid
environment and bonds to sulphahydryl groups of cysteine
amino acids in the binding site of the proton pump

26. Lansoprazole
• It is an benzimidazole prodrug proton pump inhibitor
• It’s acid inhibition activity is far stronger than H2
antagonists such that it is incompatible with drugs
needing acidic condition for absorption
• It is highly plasma bound but bioavailability is double
than omeprazole
• Uses
– Peptide ulcer, GERD, heart burn, Zollinger-Ellision
syndrome, NSAIDS induced ulcers
MOA- It activates into sulphamide form in the acid
environment and bonds to sulphahydryl groups of
cysteine amino acids in the binding site of the proton
pump

27. Prantoprazole
• It is an benzimidazole prodrug proton pump inhibitor
• It’s acid inhibition activity is far stronger than H2
antagonists such that it is incompatible with drugs
needing acidic condition for absorption
• It is highly plasma bound and has better bioavailability
than omeprazole and is also extensively liver
metabolized
• Uses
– Peptide ulcer, GERD, heart burn, Zollinger-Ellision
syndrome
MOA- It activates into sulphamide form in the acid
environment and bonds to sulphahydryl groups of
cysteine amino acids in the binding site of the proton
pump

28. Rabeprazole
• It is an benzimidazole prodrug proton pump inhibitor
• It’s acid inhibition activity is far stronger than H2
antagonists such that it is incompatible with drugs
needing acidic condition for absorption
• It is highly plasma bound and has better bioavailability
than omeprazole and is also extensively liver
metabolized
• Uses
– Peptide ulcer, GERD, heart burn, Zollinger-Ellision syndrome
MOA- It activates into sulphamide form in the acid
environment and bonds to sulphahydryl groups of
cysteine amino acids in the binding site of the proton
pump

29. Try associating PK differences as a result of structural
variability (just note that any pattern u may find is
only valid in PPI, not other drug category)

30. Prostaglandins
• The prostaglandins are group of hormone like lipid
compounds containing 20-carbon unsaturated fatty acids
which is biosynthetically derived from metabolism of
arachidonic acid.
• They have a wide pharmacological actions on the
cardiovascular system, GI smooth muscle, the reproductive
system, the nervous system, platelets, kidney, the eye, etc.
• They are of interest as anti ulcer drugs because they can
not only inhibit acid secretion completely like PPI’s but also
suppress pepsin which prevents autodigestion of exposed
epithelial cells. On top of that, it also has maintains the
integrity of mucus layer, termed cytoprotection.

31. Misoprostal
• It is a prostaglandin based antiulcer drug
• It is semi-synthetic derivative of PgE1
• It has both anti-secretory and cytoprotective effect
• It is also a prodrug that after being quickly absorbed gets
deesterified rapidly into it’s active acid form
• It has 90% chance of inducing abortion
• Uses
– NSAIDS causes gastric ulcer
– Doudenal ulcer unresponsive to H2-antagonists
– In Arthritis in combination with diclofenac
– Off- label use to end pregnancy (before 12 weeks) with or
without mifepristone (anti-progesterone)
• MOA: It agonizes PgE receptors and mediates inhibition of
proton pump and also cytpprotective action is based on
increases in GI mucus an bicarbonate secretion

32. Future- Target H.Pylori
• Prevent Adhesion into stomach cells
• Inhibit urease breakdown

33. Thank You