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).
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.
Ach and gastrin exert their action directly as well as through release of histamine.
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).
The main strategies employed for the treatment of peptic ulcer disease and gastritis are to:
click to edit
Neutralize gastric acid by antacids.
Decrease secretion of acid in stomach.
Increase protective factors like mucus and bicarbonate.
Protect the ulcer by forming a layer over it.
Stimulate the healing of ulcer.
Kill H.pylori associated with peptic ulcer disease.
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.
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.
Simethicone
Simethicone is a water repellent, pharmacologically inert anti-foaming agent.
It reduces flatulence
and can also be used to prevent bed sores.
Drug interactions with antacids
Antacids decrease the absorption of acidic drugs
(acidic drugs are ionized in alkaline medium)
and tetracyclines by forming complexes.
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.
Drugs decreasing acid secretion:
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).
other important points of PPI
PPIs are given orally in early morning empty stomach(just before breakfast),
pantoprazole, esomeprazole and lansoprazole can be given IV.
These drugs have short t1/2 but can inhibit acid secretion for more than 24 hours
(hit and run drugs inhibit proton pump irreversibly).
In patients with nasoenteric tube, immediate release omeprazole by nasogastric tube is currently preferred.
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.
Lansoprazole is the most potent PPI.
Lansoprazole is the safest PPI in pregnancy.
Esomeprazole, lansoprazole and pantoprazole can be given by IV route.
Omeprazole and esomeprazole are microsomal enzyme inhibitors.
These may decrease the metabolism of diazepam.
Lansoprazole enhances the metabolism of theophylline.
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.
Why Cimetidine is not routinely used?
because:
it can cross blood brain barrier and result in mental state changes.
It inhibits binding of dihydrotestosterone to androgen receptors that can manifest as impotence in males.
It inhibits metabolism of estradiol and increases serum prolactin levels on long term use,
thus can cause gynaecomastia in males and galactorrhea in females.
It is a potent inhibitor of CYP enzymes and can increase plasma concentration of warfarin, theophylline and many other drugs.
It is the least potent H2 blocker.
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.
Nizatidine is having negligible first pass metabolism(100% bioavailability).
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.
Rebound hyperacidity
Acid suppressing agents like PPIs, H2 blockers can result in tolerance
and rebound hyperacidity due to secondary hypergastrinemia.
Drugs increasing protective factors:
PGE1, PGE2 and PGI2 acts as anti-ulcer drugs by increasing the release of mucus and bicarbonate
and by increasing the mucosal blood flow.
PGs also inhibit H+K+ATPase and decrease the acid production.
Misoprostol(PGE1 analogue) is the most specific drug
for treatment and prevention of NSAID induced peptic ulcer(DOC is PPI).
Enprostil and rioprostil(PGE1 analogue) are other drugs in this group.
Commonest side effect of PG analogues is diarrhoea and colicky abdominal pain.
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.
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.
Colloiadal bismuth subcitrate:
it also forms an acid resistant coating over the ulcer.
It also dislodges H.pylori from the surface of gastric mucosa and kills it.
Adverse effects: blackening of tongue and bismuth toxicity(osteodystrophy and encephalopathy).
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.
Anti-helicobacter pylori drugs:
H.pylori infection can be detected by urea breath test.
It is responsible for relapse of PUD.
Drugs used in the treatment of H.pylori include:
metronidazole/tinidazole, amoxicillin, clarithromycin, tetracycline, colloidal bismuth subcitrate and omeprazole/lansoprazole.
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.
Treatment of choice for H.pylori eradication therapy:
click to edit
Areas with low clarithromycin resistance:
Standard triple drug therapy: CAP
Clarithromycin 500mg + amoxycillin 1g(metronidazole 500mg) if penicillin allergy + lansoprazole 30mg twice daily for 14 days
Areas with high clarithromycin resistance:
standard quadruple drug therapy:
Lanoprazole 30mg BD + bismuth subcitrate 120mg QID + tetracycline 500mg QID + metronidazole 500 mg TDS for 14 days.
Potassium-Competitive Acid Blockers
click to edit
Revaprazan
Tegoprazan
Vonoprazan
Therapeutic uses
• Gastric ulcer
• Duodenal ulcer
• Gastroesophageal reflux disease
• Helicobacter pylori eradication
(vonoprazan)
• Generally well tolerated
• Only available in Asia