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Gastric mucosal barrier|Peptic ulcer pathophysiology,causes & treatment |Physiology|Pharmacology

We have seen this diagram of mechanism
of HCL secretion and another one on regulation of secretion of acid in
another video but it Hcll is an acid and gastric mucosa are needs to be
protective of its harmful effect. So what are these mechanism? So here this diagram
is showing these glands which are dipping into the mu cosa and then beneath the
mucosa there is submucosa- at top it is showing the lumen. We know that there
are various cells which line the gastric mucosa. There are surface
epithelial cells Mucous neck cells, then there are HCL
secreting cells at the base and the chief cells which secrete pepsinogen.
surface epithelial cells and mucus neck cells secrete mucus which forms a
viscous layer in the lumen of the stomach. This viscous layer is approximately one
millimeter thick. Also we have seen that with HCl secretion, bicarbonate goes
into the blood that is known as alkaline tide. The bicarbonate as it passes
through the blood, it is captured by these surface epithelial cells which
secrete this bicarbonate into the gastric lumen. So this forms a mucous
bicarbonate layer in the gastric lumen. Because of this layer there is a
gradient of pH at the surface that means that as HCl is being secreted, it comes
to the top. At the top of this layer the pH is around 1 to 2 but because of the
mucus and bicarbonate, slowly the pH increases along this layer and at the
surface, pH is approximately 7. Now that means the secreted HCl will not be able
to harm the mucosa but in case it manages to corrode epithelial layer,
nearby epithelial cells rapidly migrate to the site of the injury and cover i.t
This process is known as restitution. Thus there are layers of protection: Pre
epithelial- formed by the mucus bicarbonate layer, Epithelial layer where
epithelial cells are secreting the mucus- bicarbonate and
they can perform restitution plus there is Sub-epithelial layer protection due
to the blood flow. Now all these layers of protection are enhanced by
prostaglandins I2 and E2, the types of prostaglandins which are released by
the surface epithelial cells themselves. So these prostaglandins stimulate the
secretion of mucus, stimulate the secretion of bicarbonate, they increase
the ability of the cells for restitution, they also increase the submucosal blood
flow. So the secretion of these prostaglandins is very important for
maintaining gastric mucosal defence. Even then, in spite of all these preventive
mechanisms, ulceration does occur in gastric mucosa as well as in duodenal
mucosa. These ulcers caused due to imbalance in HCl secretion and
protective mechanisms is known as peptic ulcer.
So this peptic ulcer can be due to excess secretion of acid or due to
diminished defense mechanisms or maybe both. Both the factors that is excess
HCl secretion and diminished mucosal defense occur in H. pylori infection.
Now this bacteria has the ability to dig deep into the mucus layer and survive
there because of this there is continuous inflammation in the gastric
mucosa and also the defense mechanisms are decreased as it is invading the
mucus bicarbonate layer. Now diminished mucosal defenses occur by a group of
drugs known as NSAIDs that is non-steroidal anti-inflammatory drugs.
These are some anti-inflammatory drugs very commonly used. These drugs inhibit
COX enzyme- cyclooxygenase enzyme. Now this enzyme is responsible for formation
of prostaglandin I2 and E 2 and as we have seen how
these prostaglandins are essential for maintenance of mucosal defense mechanism.
In peptic ulcer the gastric mucosa gets corroded and there is ulcer formation.
This leads to severe pain in epigastric region. This pain has the tendency to be
relieved by food because food buffers some acid in the stomachs. So, the peptic
ulcer pain is relieved by food but if this ulceration keeps on progressing
it can even lead to perforation because the ulcer will extend into the
various layers of the stomach lining. So how to treat this peptic ulcer? Since
these two are the mechanisms of development of peptic ulcer, our drugs
should also act to correct these two processes. So there are drugs which
decrease acid secretion and there are drugs which improve mucosal defence. Now
the drugs which decrease acid secretion, they can act on various levels. They can
block the action of vagus on these cells or they can block the action of
gastrin on enterochromaffin like cells, on parietal cells but you see the drugs
which will be most effective will be those that act on lower levels of
secretion so the drugs which decrease the effect of histamine secreted from
ECL cells will be very effective. So histamine is secreted due to the effect
of vagus and gastrin also. So these drugs that block the action of histamine on
parietal cells are H2 receptor antagonists. We have seen in our
discussion of parietal cells that parietal cells have these H2 receptors
where histamine can stimulate the secretion of HCL. So H2 receptor
antagonists will block the effect of histamine on stimulation of the HCL
secretion. If you block at upper levels, alternate pathways of activation of
parietal cells are still intact. So suppose the release of gastrin is
inhibited even then vagus can stimulate ECL cells which are acting
on parietal cells. Now you may ask that even after inhibition of effect of histamine
gastrin and vagus are still able to stimulat eparietal cells. True! That is why
histamine receptor antagonists are not the most potent drugs to reduce HCl
secretion. The most potent drug for inhibiting HCl secretion are hydrogen
potassium ATPase inhibitors. So we have seen that hydrogen potassium ATPase pump
is the one which is secreting H+ ions, so there are drugs which block the
action of these pumps these are known as PPIs:
proton pump inhibitors. So drugs which decrease HCl secretion are
H2 receptor antagonists and proton pump inhibitors. Now there are drugs which
increase mucosal defence. One of the drug is sucralfate. This drug binds
with acid and forms a viscous paste that adheres selectively to ulcer base and
prevents further damage of the injured area. Then there are other drugs: bismuth
compounds- the mechanism of action of these drugs is not much known but they
increase mucosal defense. Then they are prostaglandin analogues we have seen
that how prostaglandin is so efficient in maintaining the gastric mucosal
barriers. Now these prostaglandin analogues are especially successful if
NSAIDs are given chronically since NSAIDs are blocking the production of
prostaglandins so along with NSAIDs if we give prostaglandin analogues
then it maintains the mucosal defence.

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