All about gin drugs

1. 1
Drugs used to control peptic
ulcer disease

2. 2
HOW AND FROM WHERE IS AClD PRODUCED?
 Anatomical divisions: cardia,
fundus, body (corpus), antrum,
pylorus
 Gastric wall consists of mucosa,
submucosa, muscularis propria,
and serosa
 Mucosa has two compartments:
superficial foveolar (meaning
leaflike) compartment and
deeper glandular
compartment
 Glandular compartment exhibits
differences in thickness and
glandular composition in different
regions of the stomach
The Stomach
Fig. Anatomical regions of the stomach

3. 3
 Glandular compartment
 Cardia glands contain mucus secreting cells only
 Oxyntic (AKA gastric or fundic) glands contain parietal cells,
chief cells and endocrine cells
Parietal cells possess the H+-K+-ATPase that pumps out H+
in exchange for K+
Chief cells secrete pepsinogen I and II
 Anthral or pyloric glands contain mucus-secreting
cells and endocrine cells
Endocrine cells secrete, endocrinally or paracrinally, such
chemicals as
Gastrin (G-cells in antrum),
Histamine (in the body),
somatostatin (D-cells),
endothelin (x-cells)

4. 4
 Activators of proton pump
 Acetylcholine stimulates M3 Ach-Rs resulting in increase in
cytosolic Ca++ in parietal cells
 Gastrin activates gastrin Rs, resulting in increase in cytosolic
Ca++ in parietal cells
 Ach and Gastrin activate release of Histamine from
enterochromaffin-like cells (ECL) which stimulates H2 Rs on
parietal cells (the main pathway of proton pump activation)

5. 5
 Inhibitors of proton pump
 Somatostatin through somatostatin receptors
 Prostaglandins of the E series (Prostaglandins of the A, E, and
I type inhibit gastric acid secretion, stimulate increased mucus
and bicarbonate secretion by gastric mucosa)
 Epidermal growth factor

6. 6
Mucosal protection
 Mechanisms that protect the gastric mucosa from
autodigestion (damaging effects of gastric acidity and
peptic enzymes)
 Mucus secretion
 Bicarbonate secretion (surface epithelial cells)
 Epithelial barrier
 Mucosal blood flow
 Prostaglandin synthesis
Favour production of mucus and bicarbonate
Inhibit acid secretion by parietal cells
PGE and PGI improve mucosal blood flow

7. 7
Peptic ulcer disease (PUD)
 Peptic ulcers are chronic, most often solitary, lesions
that occur in any portion of the GIT exposed to the
aggressive action of acid-peptic juices.
 Causes: three major causes
H. pylori infection
NSAID use,
Pathologic gastric acid secretion
Rare causes include herpes simplex infection, major
physiologic stress (eg, critical illness, severe burns)

8. 8
Pathogenesis
 Imbalance between gastroduodenal mucosal defence
mechanisms and the damageing forces
 Many factors can disrupt the balance
Activation of aggressive factors
Suppression of protective factors
 H. pylori seen as an organism capable of disrupting
this balance

9. 9
Drug groups in PUD
 Proton pump inhibitors
 Histamine H2-receptor antagonists
 Antacids
 Gastric protectants

10. 10

11. 11
Cont…
• The inhibition of gastric acid secretion is a key
therapeutic target for ulcer disease,
gastroesophageal reflux disease (GERD), Zollinger-
Ellison syndrome (Z-E), and gastritis

12. 12
Ach-Muscarinic-Receptor Mediated
Acid Secretion
• Ach, released after vagal stimulation, binds to muscarinic
receptors present on both the acid secreting parietal cell and
the HA-secreting ECL-like cell
• Muscarinic receptors stimulate the secretion of acid,
pepsinogen, and mucus in the gastric mucosa.
• Autoradiographic techniques have shown that the M,
receptor is overexpressed in DU
– Therefore a selective M,-receptor antagonist may provide a useful
antisecretory therapy.
• Muscarinc receptors are currently subdivided into M1, M2,
M3, M4, and M5.
• However, the M3-receptor is also associated with smooth
muscle contraction and this may lead to unfavorable side
effects

13. 13
Structures and SAR of Anticholinergic Agents
• Muscarinic receptor heterogeneity and wide tissue
distribution, coupled with the low subtype specificity of the
early anticholinergics such as propantheline, dicyclomine, and
hyoscine bromide led to their being associated with
parasympathetic side effects such as dry mouth, dizziness,
constipation, and blurred vision.

14. 14
cont’
• Muscarinic antagonists, selective for receptors located
on the parietal cells, are considered more suitable
candidates for anticholinergic agents in the control of
acid secretion.
• Moreover, the overexpression of the M3 subtype in DU
patients has linked blockade of this receptor subtype to
decreased pain through reduced duodenal motility.
• Pirenzepine, which in addition to helping distinguish
muscarinic receptor subtypes, was developed as an
antisecretory agent mainly on the basis of its
preferential inhibition of receptors on the intramural
ganglia of the stomach wall.

15. 15
Cont’
• Compared to the H2 antagonist ranitidine,
pirenzepine alone was less effective in the inhibition
of acid secretion.
• The more potent derivative telenzepine improved
healing rates; however, the increased incidence of
side effects with the antimuscarinic agents, has
failed to dislodge the H2 antagonists as the
preferred antisecretory therapy.
• The effectiveness of antimuscarinic therapy may be
limited, given that pirenzepine, a muscarinic
antagonist, inhibited peptone meal-stimulated acid
secretion by 39%,
– whereas ranitidine, an H2-receptor antagonist,
produced 69% inhibition.
• In combination, however, the acid-secretory
response was almost completely inhibited (99%).
• Although this combination therapy is feasible, it is
unlikely to be used because of the side effects
associated with muscarinic antagonists.

16. 16
Structure of the Proton Pump
• The H+/K+-ATPase enzyme, present in tubulovesicular and
canalicular membranes of the gastric parietal cell, consists of
two subunits, a 114-kDa α-subunit and a 34-kDa β-subunit.
• The α -subunit has been shown to contain 10 transmembrane
helices, with the β -subunit possessing only a single
transmembrane helix
• The α -subunit carries out the catalytic and transport
functions of the enzyme because it contains both ATP and
cation binding sites
• When the parietal cell transforms from an active to resting
state, the heavily glycosylated β -subunit is required for
endocytic retrieval of the H+/K+-ATPase from the canalicular
membranes.
– This subunit may also contribute to proper folding and membrane
localization of the enzyme

17. 17
Acid Secretion and the Proton Pump
• When the resting parietal cell is stimulated by acid
secretagogues, the tubulovesicles are transformed into
the secretory canaliculus.
• The parietal cell has the largest mitochondrial content of
any mammalian cell (34% of cell volume) and the ATP
generated by this is mainly used for acid secretion.
• Hydrolysis of ATP results in a conformational change in
the protein that mediates the electroneutral exchange
of intracellular H+ and extracellular K+.
• The pump is activated only when it is associated with a
potassium chloride pathway in the canalicular
membrane

18. 18
Cont…
• This allows potassium chloride efflux into the
extracytoplasmic space and thus results in the secretion of
HCl at the expense of ATP hydrolysis.
• The stimulation of hydrogen ion secretion by the ATPase
leaves behind an equivalent number of hydroxide ions.
• These are converted to HCO, by the enzyme carbonic
anhydrase, which is closely associated with the secretory
membrane.
• The activity of the pump is determined by the access of K+ to
the extracytoplasmic surface of the pump.
• In the absence of K+ on this surface of the pump, the pump
cycle stops at the level of the phosphoenzyme.
• H+ /K+-ATPase therefore forms a critical component of the
ion-transport system mediating acid secretion in the stomach.

19. 19
Mechanism of Action of
Proton-Pump lnhibitors
• PPIs inhibit gastric acid secretion by inhibiting the enzyme H+/K+ -ATPase,
which is located on the luminal surface of gastric parietal cells.
• Currently prescribed PPIs are substituted benzimidazole based structures.
• When administered at neutral pH, these weak bases are chemically stable,
lipid-soluble, and have no effect on gastric acid secretion.
• The inactive PPI diffuses from the bloodstream into the parietal cells and
subsequently into the acid environment of the secretory canaliculi, where
it rearranges to form a sulfenic acid in equilibrium with a sulfenamide.
• Either chemical entity is then able to interact covalently with thiol groups
at cysteine residues located on the luminal surface of the α-subunit of the
H+/K+-ATPase.
• This covalent binding results in specific and essentially irreversible
inactivation of the enzyme, leading to long-lasting inhibition of gastric acid
secretion
• Such a profile is thus ideally suited to once-daily administration in the
management of acid-peptic disorders

20. 20
SAR of the Proton-Pump Inhibitors
• Timoprazole is one of the first well-defined inhibitors of
the newly discovered gastric proton pump
• 2-pyridylthioacteamide has acid-inhibitory properties
but toxic.
• This was find to be solved after removal of the
thioamide group like in case of timoprazole.
• Sulfur containing heterocycles, as benzimidazole-linked
sulfides (the corresponding S-oxide analogs proved to be
more potent
• The three main structural features of omeprazole:
– the substituted pyridine ring;
– the substituted benzimidazole; and
– the methylsulfinyl linking group,
• by which these two ring systems are attached to one
another are essential, either in generating the active
form from its inactive prodrug precursor or in binding
irreversibly with the H+/K+ -ATPase enzyme
Timoprazo
le
2-pyridylthioaceteamide
H2N
S
N
Omepra
zole

21. 21
Cont’
• for irreversible proton-pump inhibitors to achieve
selective biological activity, their mechanism of
action demands that they have relatively high
chemical stability around neutral pH, but be
readily activated at low pH
• The benzimidazole group of omeprazole has been
replaced by other heterocycles and its activity
retained, with the methoxyimidazopyridine
compound tenatoprazole being the most
advanced.
• Similarly, the fused benzene ring of the
benzimidazole group has been substituted by a
thiophene ring in the thieno[3,4-d]imidazole-
based compounds saviprazole and S-1924;
– however, examples of the corresponding
thieno[2,3-d]imidazole isomers (I), aIso described
by Hoechst, are much less effective, most likely
because of their greater chemical stability.
Tenatoprazole
Saviprazole
S-1924

22. 22
Cont’
• Although many of the compounds lack
substituents on the benzimidazole ring, the
presence of electron-donating groups at
the 5-position, such as methoxy
(omeprazole), S-337, and difluoromethoxy
(pantoprazole), also provided an optimum
balance of chemical stability and reactivity.
• In fact, the presence of electron
withdrawing substituents in this position,
such as nitro, methylsulfinyl, and
trifluormethyl, increases the basicity of the
benzimidazole ring to the point where the
behavior of these compounds is dominated
by activation at neutral pH, resulting in
compounds having poor chemical stability
and limited practical value
pantoprazole

23. 23
cont’
• increasing the nucleophilic character of the pyridine
ring, by the incorporation of electron-donating
substituents, enhances the rate of attack of the C-2
position of the benzimidazole group and thereby
promotes the acid-catalyzed rearrangement to the
active species

24. 24
ANTACIDS
• …….the antacids largely have been replaced by more effective
and convenient drugs.
• Although sodium bicarbonate effectively neutralizes acid, it is
very water-soluble and rapidly absorbed from the stomach,
and
– the alkali and sodium loads may pose a risk for patients with cardiac
or renal failure.
• Depending on particle size and crystal structure, CaCO3
rapidly and effectively neutralizes gastric H+,
– but the release of CO2 from bicarbonate- and carbonate-containing
antacids can cause belching, nausea, abdominal distention, and
flatulence.
• Calcium also may induce rebound acid secretion

25. 25
Cont’
• Combinations of Mg2+ (rapidly reacting) and Al3+ (slowly reacting)
hydroxides provide a relatively balanced and sustained neutralizing
capacity and are preferred by most experts.
• Magaldrate is a hydroxymagnesium aluminate complex that is converted
rapidly in gastric acid to Mg(OH)2 and Al(OH)3,
– which are absorbed poorly and thus provide a sustained antacid effect.
• Although fixed combinations of magnesium and aluminum theoretically
counteract the adverse effects of each other on the
bowel,…………………………. such balance is not always achieved in practice.
• Simethicone, a surfactant that may decrease foaming and hence
esophageal reflux, is included in many antacid preparations.
• However, other fixed combinations, particularly those with aspirin, that
are marketed for "acid indigestion" are irrational choices, are potentially
unsafe in patients predisposed to gastroduodenal ulcers, and should not
be used.

26. 26
Cont’
• For uncomplicated ulcers, antacids are given orally 1 and 3
hours after meals and at bedtime.
• This regimen, providing about 120 mEq of a Mg-Al
combination per dose, may be almost as effective as
conventional dosing with an H2-receptor antagonist.
• For severe symptoms or uncontrolled reflux, antacids can be
given as often as every 30 to 60 minutes.
• In general, antacids should be administered in suspension
form, as this probably has a greater neutralizing capacity than
do powder or tablet dosage forms.
• If tablets are used, they should be thoroughly chewed for
maximum effect.
• Antacids are cleared from the empty stomach in about 30
minutes.

27. 27
Cont’
• Antacids vary in the extent to which they are absorbed, and hence in their
systemic effects.
• In general, most antacids can elevate urinary pH by about one pH unit.
• Antacids that contain Al3+, Ca2+, or Mg2+ are absorbed less completely than
are those that contain NaHCO3.
• With normal renal function, the modest accumulations of Al3+ and Mg2+
do not pose a problem;
• with renal insufficiency, however, absorbed Al3+ can contribute to
osteoporosis, encephalopathy, and proximal myopathy.
• About 15% of orally administered Ca2+ is absorbed, causing a transient
hypercalcemia.
• Although this is not a problem in normal patients, the hypercalcemia from
as little as 3 to 4 g of CaCO3 per day can be problematic in patients with
uremia.
• In the past, when large doses of NaHCO3 and CaCO3 were administered
commonly with milk or cream for the management of peptic ulcer, the
milk-alkali syndrome (alkalosis, hypercalcemia, and renal insufficiency)
occurred frequently.

28. 28
Cont’
• By altering gastric and urinary pH, antacids may affect a number of drugs
(e.g., thyroid hormones, allopurinol, and imidazole antifungals, by altering
rates of dissolution and absorption, bioavailability, and renal elimination).
• Al3+ and Mg2+ antacids also are notable for their propensity to chelate
other drugs present in the GI tract, forming insoluble complexes that pass
through the GI tract without absorption.
• Thus, it generally is prudent to avoid concurrent administration of
antacids and drugs intended for systemic absorption.
• Most interactions can be avoided by taking antacids 2 hours before or
after ingestion of other drugs.

29. Any ???? Well come
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