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Antiulcer drugs, Proton pump inhibitors:, H2 receptor antagonists:, Why…
Antiulcer drugs
Peptic ulcer disease arises from the imbalance between defensive factors(mucus, bicarbonate and mucosal blood flow)
and aggressive factors(acid, pepsin, NSAIDs and H.pylori).
Proton pump inhibitors:
these are prodrugs(active moiety is sulfenamide)
and act by irreversibly inhibiting H+K+ATPase in gastric parietal cells.
The drugs in this group include omeprazole, pantoprazole, esomeprazole, lansoprazole and rabeprazole.
These drugs are weak bases and can be destroyed by gastric acid.
To protect them from gastric acid, these are given as enteric coated tablets.
This coating dissolves in alkaline medium (intestinal juice)
and prodrugs are absorbed.
MOA: On reaching parietal cells, active moiety(sulfenamide) is formed and gets trapped.
These can inhibit both basal acid output(nocturnal acid secretion)
as well as meal stimulated acid output(maximal acid output).
H2 receptor antagonists:
these drugs competitively inhibit H2 receptors in parietal cells, thus inhibiting the acid secretion.
Ach and gastrin act partly by causing the release of histamine,
therefore acid secreting capacity of these agents is decreased by H2 blockers.
Drugs in this group are cimetidine, ranitidine, famotidine, roxatidine, nizatidine and loxatidine.
These drugs are more effective for reducing basal(nocturnal) acid secretion(histamine mediated)
than stimulated acid secretion(stimulated by gastrin, Ach as well as histamine).
These drugs can be used for GERD, PUD, ZES and prevention of stress induced ulcers.
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Sodium bicarbonate
Antacids may be systemic(absorbed from the GIT) or local(poorly absorbed).
Sodium bicarbonate is rapidly acting systemic antacid.
It is not indicated for long term use because
it releases CO2 that can cause belching and gastric distension(ulcer perforation can occur).
Sodium chloride formed in the neutralization reaction can be absorbed that can exacerbate fluid retention in patients of CHF and hypertension.
Systemic and urinary alkalosis may occur.
Rebound hyperacidity can occur.
Non-systemic antacids
Aluminium hydroxide, magnesium trisilicate, magaldrate and magnesium hydroxide
are non systemic antacids.
These are slower but longer acting drugs.
Rebound acidity doesn’t occur.
Aluminium hydroxide causes constipation whereas magnesium salts are responsible for diarrhea.
Most of the market preparations contain these agents in combination to minimize the impact on bowel movements.
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Side effects of PPI
PPIs are quite safe drugs and have diarrhea, headache and abdominal pain as adverse effects.
These have shown to be carcinogenic in rodents but no such case has been reported in humans.
Long term use of PPI is associated with subnormal vitamin B12 levels (reduced absorption),
increase in risk of hip fractures(reduced Ca2+ absorption),
increased risk of enteric bacterial infections like C.difficle infections, bacterial gastroenteritis and pneumonia.
other H2 blockers
Famotidine is the most potent H2 blocker.
All H2 blockers except famotidine inhibits the gastric first pass metabolism of ethanol.
Loxatidine is a non-competitive blocker of H2 receptors.
Nizatidine also possess anti-ACHE activity and can cause bradycardia and enhanced gastric emptying.
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Anticholinergics:
non selective antimuscarinic drugs like propantheline and oxyphenonium
can be used for decreasing gastric acid secretion.
However by increasing gastric emptying time,
these drugs prolong the exposure of ulcer bed to gastric acid.
Further anticholinergic adverse effects like dry mouth, blurred vision, constipation, and urinary retention
are commonly seen with these drugs.
Pirenzepine and telenzepine are selective M1 blockers
that are preferred antimuscarinic agents for peptic ulcer disease
as these are devoid of anticholinergic adverse effects.
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Sucralfate:
it is an aluminium salt of sulphated sucrose.
At pH below 4, its molecules polymerize to form a sticky layer that covers the ulcer base
and acts as a physical barrier to prevent acid exposure.
It can bind phosphates also and can result in hypophosphatemia.
It should not be given with antacids because it acts only in acidic medium(antacids raise the PH by neutralizing the gastric acid).
Most common side effect of sucralfate is constipation.
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Hydrochloric acid
Hydrochloric acid is secreted by gastric parietal cells
due to stimulation of H+K+ATPase(proton pump).
Histamine(through H2 receptors),
acetylcholine(through M1 and M3 receptors) and
gastrin through CCK receptors are important stimulators of proton pump.
Gastrin
Antral G cells produce gastrin on stimulation by dietary peptides.
Gastrin mainly stimulates release of histamine from enterochromaffin (ECL) cell
and weakly stimulates proton pump itself.
Vagus nerve
Parietal cells secrete H+ in the lumen through H+K+ATPase.
Vagus nerve(via Ach) help in increasing acid by three mechanism:
direct stimulation of proton pump,
stimulation of ECL cells to release histamine,
direct release of gastrin(by action of G-cells)
and inhibition of somatostatin by action on D-cells(latter inhibits the release of gastrin).
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Antacids:
these drugs are weak bases that neutralize gastric acid(donot increase the volume of acid secreted.)
Their major role in peptic ulcer is to provide prompt relief from ulcer pain.
Simethicone
Simethicone is a water repellent, pharmacologically inert anti-foaming agent.
It reduces flatulence
and can also be used to prevent bed sores.
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Milk alkali syndrome
Milk alkali syndrome(hypercalcemia, renal insufficiency and metabolic alkalosis)
may be caused by excessive doses of Na2CO3 or CaCO3 with calcium containing foods like milk.
Rebound hyperacidity
Acid suppressing agents like PPIs, H2 blockers can result in tolerance
and rebound hyperacidity due to secondary hypergastrinemia.
Ulcer protective agents:
these drugs form a protective covering over the ulcer bed that prevents its exposure to gastric acid.
Sucralfate and colloidal bismuth subcitrate are two important ulcer protective drugs.
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Rebamipide and ecabet
are cytoprotective drugs act by increase in PG generation
and by scavenging reactive oxygen species.
Ulcer healing drugs:
carbenoloxone is obtained from the roots of licorice.
It causes epithelialisation of ulcer without decreasing acid production.
It can displace aldosterone from plasma protein binding sites
and result in hypertension, sodium and water retention and hypokalemia.
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Bismuth
Bismuth subcitrate is used for peptic ulcer
whereas another salt, bismuth subsalicylate is used in travellers diarrhea.
It reduces stool frequency by inhibiting PG synthesis and chloride secretion
apart from having antimicrobial and gastroprotective effects.
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