Antiulcer drugs

BY: Dr. Tanvi H.Desai

(M.Pharm, Ph.D)
 Antiulcer
• PEPTIC ULCER
Peptic ulcer occurs in the part of the gastrointestinal tract (g.i.t.) which is exposed
to gastric acid and pepsin, i.e. the stomach and duodenum.

Etiology - not clearly known.

It results probably due to an imbalance between the aggressive (acid, pepsin, bile
and H. pylori) and the defensive (gastric mucus and bicarbonate secretion,
prostaglandins, nitric oxide high mucosal blood flow, innate resistance of the
mucosal cells) factors.

A variety of psychosomatic, humoral and vascular derangements have been

concerned and the importance of Helicobacter pylori infection as a contributor to
ulcer formation and recurrence has been recognized.
• GASTRIC ACID SECRETION

• The stomach secretes about 2.5 litres of gastric juice daily.

• The principal exocrine components are proenzymes such a prorennin and

pepsinogen elaborated by the chief or peptic cells, and hydrochloric acid (HCl) and
intrinsic factor secreted by the parietal or oxyntic cells.

• The production of acid is important for promoting proteolytic digestion of

foodstuffs, iron absorption and killing pathogens.

• Mucus-secreting cells also proliferate in the gastric mucosa.

• Bicarbonate ions are secreted and trapped in the mucus, creating a gel-like
protective barrier that maintains the mucosal surface at a pH of 6–7 in the face of a
much more acidic environment (pH 1–2) in the lumen.
• Alcohol and bile can disrupt this protective layer.

• Locally produced ‘cytoprotective’ prostaglandins stimulate the secretion

of both mucus and bicarbonate.

• Disturbances in these secretory and protective mechanisms are thought

to be involved in the pathogenesis of peptic ulcer, and indeed in other
types of gastric damage such as gastrooesophageal reflux disease
(GORD)1 (a condition in which acidic gastric fluid flows backwards into
the oesophagus, resulting in heartburn.) and injury caused by
nonsteroidal anti-inflammatory drugs (NSAIDs).
• CLASSIFICATION
1. Reduction of gastric acid secretion
(a) H2 antihistamines: Cimetidine, Ranitidine, Famotidine, Roxatidine
(b) Proton pump inhibitors: Omeprazole, Esomeprazole, Lansoprazole,
Pantoprazole, Rabeprazole, Dexrabeprazole
(c) Anticholinergic drugs: Pirenzepine, Propantheline, Oxyphenonium
(d) Prostaglandin analogue: Misoprostol

2. Neutralization of gastric acid (Antacids)

(a) Systemic: Sodium bicarbonate, Sod. Citrate
(b) Nonsystemic: Magnesium hydroxide, Mag. trisilicate, Aluminium hydroxide gel, Magaldrate,
Calcium carbonate

3. Ulcer protectives (drugs that protect the mucosa): Sucralfate, Colloidal bismuth subcitrate (CBS)

4. Anti-H. pylori drugs: Amoxicillin, Clarithromycin, Metronidazole, Tinidazole, Tetracycline

• HISTAMINE H2 RECEPTOR ANTAGONISTS

• The discovery and development of histamine H2-blocking drugs by Blac and his
colleagues in 1972 was a major breakthrough in the treatment of gastric ulcers.

• H2 receptor antagonists competitively inhibit histamine actions at all H2 receptors, but

their main clinical use is as inhibitors of gastric acid secretion.

• They can inhibit histamine- and gastrin-stimulated acid secretion; pepsin secretion also
falls with the reduction in volume of gastric juice.

• These agents not only decrease both basal and food-stimulated acid secretion by 90% or
more, but numerous clinical trials indicate that they also promote healing of gastric and
duodenal ulcers.

• The main drugs used are cimetidine, ranitidine (sometimes in combination with
bismuth), nizatidine and famotidine.
• Pharmacokinetic aspects
• Cimetidine is adequately absorbed orally, though bioavailability is 60–80% due to first pass hepatic
metabolism.

• Absorption is not interfered by presence of food in stomach. It crosses placenta and reaches milk, but
penetration in brain is poor because of its hydrophilic nature.

• About 2/3 of a dose is excreted unchanged in urine and bile, the rest as oxidized metabolites.

• The elimination t½ is 2–3 hr. Dose reduction is needed in renal failure.

• Unwanted effects – very rare

• Diarrhoea, dizziness, muscle pains, alopecia, transient rashes, confusion in
the elderly and hypergastrinaemia

• Cimetidine sometimes causes gynaecomastia in men and, rarely, a decrease

in sexual function. This is probably caused by a modest affinity for androgen receptors.

• Cimetidine (but not other H2 receptor antagonists) also inhibits cytochrome

P450, and can retard the metabolism (and thus potentiate the action) of a range of drugs including oral
anticoagulants and tricyclic antidepressants.
• INTERACTIONS
• Cimetidine inhibits several cytochrome P-450 isoenzymes and reduces hepatic
blood flow, so it can inhibits the metabolism of many drugs like theophylline,
phenytoin, carbamazepine, phenobarbitone etc.

• Metabolism of propranolol and diazepam is also retarded, but this may not be
clinically significant.

• Antacids reduce absorption of all H2 blockers. When used concurrently a gap

of 2hr should be allowed. Ketoconazole absorption is decreased by cimetidine
(probably by other H2 blockers also).

• Cimetidine dose – 400mg BD or 800mg at BD. Orally for stress ulcer –

50mg/hr IV
• Ranitidine
• 5 times more potent than cimetidine with a lower incidence of side effects.
• Dose – 150 mg BD or 300mg HS or 50mg IM / slow IV in 6-8 hr.

• Roxatidine
• Pk, Pd & side effect profile is similar to Ranitidine bt its twice as potent &
longer acting.
• Dose – 75 mg BD or 150 mg HS

• Famotidine
• It is 5-8 times more potent than ranitidine
• Dose- 20 mg BD or 40 mg BD or 20mg I.V. / 12 hr.
• PROTON PUMP INHIBITORS

• The first proton pump inhibitor was omeprazole, which irreversibly inhibits the H+-K+-ATPase (the
proton pump), the terminal step in the acid secretory pathway.

• Hydrogen potassium ATPaseis the enzyme primarily responsible for the acidification of the stomach
contents and the activation of the digestive enzyme pepsin.

• Both basal and stimulated gastric acid secretion is reduced.

• The drug comprises a racemic mixture of two enantiomers.

• As a weak base, it accumulates in the acid environment of the canaliculi of the stimulated parietal cell
where it is converted into an achiral form and is then able to react with, and inactivate, the ATPase.

• This preferential accumulation means that it has a specific effect on these cells.

• Other proton pump inhibitors (all of which have a similar mode of activation and pharmacology) include
esomeprazole (the [S] isomer of omeprazole), lansoprazole, pantoprazole and rabeprazole.
• Pharmacokinetic aspects

• Orally administered but also injectable preparations are available.

• Omeprazole (orally), as it degrades rapidly at low pH, it is administere as capsules containing

enteric-coated granules.

• Following absorption in the small intestine, it passes from the blood into the parietal cells and then
into the canaliculi where it exerts its effects.

• Increased doses give excessively higher increases in plasma concentration (possibly because its
inhibitory effect on acid secretion improves its own bioavailability).

• half-life - 1 h, a single daily dose affects acid secretion for 2–3 days, partly because of the
accumulation in the canaliculi and partly because it inhibits the H+-K+-ATPase irreversibly.

• With daily dosage, there is an increasing antisecretory effect for up to 5 days, after which a
plateau is reached.
• Adverse Effects
• Nausea, loose stools, headache abdominal pain, constipation,
• Muscle & joint pain, dizziness, rashes
• Rare
• Gynaecomastia, erectile dysfunction
• Leucopenia and hepatic dysfunction
• Osteoporosis in elderly on prolonged use
• Hypergastrinemia (gastrin are higher than normal)

• Proton pump inhibitors should be used with caution in patients with liver disease, or in women
who are pregnant or breastfeeding.

• The use of these drugs may ‘mask’ the symptoms of gastric cancer.

• Interaction

• Omeprazole inhibits oxidation of certain drugs like Diazepam, Phenytoin and warfarin, so levels
may be increased.
• Clarithromycin inhibits omeprazole metabolism & increases its plasma concentration.
• Esomeprazole
• It is S-enantiomer of omeprazole, have higher bioavailability and to produce better
control of intragastric pH than omeprazole in GERD.
• Dose- 20-40 mg OD

• Lansoprazole
• More potent than omeprazole.
• Higher bioavailability. Dose should be reduced in liver diseases.
• Side effects are similar but drug interactions are less significant.
• Dose- 15-30 mg OD.

• Pantoprazole
• It is more acid stable and has higher bioavailability.
• It is also available for I.V. Administration.
• Dose- 20mg OD.
• ANTICHOLINERGICS

• Atropinic drugs reduce the volume of gastric juice without raising its pH
unless there is food in stomach to dilute the secreted acid.

• Stimulated gastric secretion is less completely inhibited.

• Effective doses (for ulcer healing) of nonselective antimuscarinic drugs

(atropine, propantheline, oxyphenonium) invariably produce intolerable
side effects.

• Introduction of H2 blockers and PPIs has sent them into oblivion (forgrtfullness).
Example: Pirenzepine
• PROSTAGLANDIN ANALOGUE

• PGE2 and PGI2 are produced in the gastric mucosa and appear to serve a protective role by
inhibiting acid secretion and promoting mucus as well as HCO3¯ secretion.

• PGs inhibit gastrin release, increase mucosal blood flow and probably have an ill-defined
“cytoprotective” action.

• However, the most important appears to be their ability to strengthen the

mucus layer covering gastric and duodenal mucosa which is buffered by HCO3 ¯ secreted
into this layer by the underlying epithelial cells.

• Example Misoprostol (methyl-PGE1 ester) - longer acting synthetic PGE1 derivative

• Misoprostol
• Inhibit gastric acid secretion
• Enhance local production of mucus or bicarbonate
• Help to maintain mucosal blood
• Therapeutic use:
• Prevention of NSAID-induced mucosal injury (rarely used because it needs frequent
administration – 4 times daily)

• Doses:
• 200 mcg 4 times a day

• ADRs:
• Diarrhoea and abdominal cramps
• Uterine bleeding
• Abortion
• Exacerbation of inflammatory bowel disease and should be avoided in patients with this disorder

• Contraindications:
• 1. Inflammatory bowel disease
• 2. Pregnancy (may cause abortion)
•2.ANTACIDS
• Antacids are the simplest way to treat the symptoms of excessive gastric acid
secretion.

• They directly neutralise acid and this also has the effect of inhibiting the activity of
peptic enzymes, which practically ceases at pH 5. Given in sufficient quantity for
long enough, they can produce healing of duodenal ulcers but are less effective for
gastric ulcers.

• Most antacids in common use are salts of magnesium and aluminums.

• Magnesium salts cause diarrhoea and aluminium salts, constipation – so mixtures of

these two can, happily, be used to preserve normal bowel function.

• Preparations of these substances (e.g. magnesium trisilicate mixtures and some

proprietary aluminium preparations) containing high concentrations of sodium
should not be given to patients on a sodium-restricted diet.
Magnesium hydroxide: is an insoluble powder that forms magnesium chloride in the
stomach.
It does not produce systemic alkalosis, because Mg2+ is poorly absorbed from the gut.
Magnesium trisilicate : is an insoluble powder that reacts slowly with the gastric juice,
forming magnesium chloride and colloidal silica.
This agent has a prolonged antacid effect, and it also adsorbs pepsin.
Magnesium carbonate: is also used.
Aluminium hydroxide gel: forms aluminium chloride in the stomach; when this
reaches the intestine, the chloride is released and is reabsorbed.
Aluminium hydroxide raises the pH of the gastric juice to about 4, and also adsorbs
pepsin.
Its action is gradual, and its effect continues for several hours.
Colloidal aluminium hydroxide: combines with phosphates in the gastrointestinal
tract and the increased excretion of phosphate in the faeces that occurs results in
decreased excretion of phosphate via the kidney.
• This effect has been used in treating patients with chronic renal failure. Other preparations
such as hydrotalcite contain mixtures of both aluminium and magnesium salts.

• Alginates or simeticone are sometimes combined with antacids.

• Alginates are believed to increase the viscosity and adherence of mucus to the oesophageal
mucosa, forming a protective barrier, where as simeticone is an anti-foaming agent,
intended to relieve bloating and flatulence.

• Drug interactions

• By raising gastric pH and by forming complexes, the non-absorbable antacids decrease the
absorption of many drugs, especially tetracyclines, iron salts, fluoroquinolones,
ketoconazole, H2 blockers, diazepam, phenothiazines, indomethacinetc.

• Stagger their administration by 2 hours. The efficacy of nitrofurantoin is also reduced by

alkalinization of urine.
4.DRUGS THAT PROTECT THE MUCOSA
Some agents, termed cytoprotective, are said to enhance endogenous mucosal protection
mechanisms and/or to provide a physical barrier over the surface of the ulcer.

Bismuth chelate: Bismuth chelate (tripotassium dicitratobismuthate) is sometimes used in

combination regimens to treat H. pylori.
It has toxic effects on the bacillus, and may also prevent its adherence to the mucosa or
inhibit its bacterial proteolytic enzymes.
It is also believed to have other mucosa-protecting actions, by mechanisms that are
unclear, and is widely used as an over-the-counter remedy for mild gastrointestinal
symptoms.
Very little is absorbed, but if renal excretion is impaired, the raised plasma concentrations
of bismuth can result in encephalopathy.
Unwanted effects :nausea and vomiting, and blackening of the tongue and faeces
Sucralfate: Sucralfate is a complex of aluminium hydroxide and sulfated sucrose, which
releases aluminium in the presence of acid.

The residual complex carries a strong negative charge and binds to cationic groups in
proteins, glycoproteins, etc.

It can form complex gels with mucus, an action that is thought to decrease the
degradation of mucus by pepsin and to limit the diffusion of H+ ions.

Sucralfate can also inhibit the action of pepsin and stimulate secretion of mucus,
bicarbonate and prostaglandins from the gastric mucosa. All these actions contribute to
its mucosa-protecting action.

Sucralfate is given orally and about 30% is still present in the stomach 3 h after
administration.

In the acid environment, the polymerised product forms a tenacious paste, which can
sometimes produce an obstructive lump (known as a bezoar6) that gets stuck in the
stomach.
It reduces the absorption of a number of other drugs, including
fluoroquinolone antibiotics, theophylline, tetracycline, digoxin and
amitriptyline. Because it requires an acid environment for activation,
antacids given concurrently or prior to its administration will reduce its
efficacy.

Unwanted effects are few,

the most common being constipation.

Less common effects apart from bezoar formation, include dry mouth,
nausea, vomiting, headache and rashes.
3.TREATMENT OF HELICOBACTER PYLORI INFECTION

H. pylori infection has been implicated as a causative factor in the production of gastric
and, more particularly, duodenal ulcers, as well as a risk factor for gastric cancer.

Eradication of H. pylori infection promotes rapid and long-term healing of ulcers, and it is
routine practice to test for the organism in patients presenting with suggestive symptoms.

If the test is positive, then the organism can generally be eradicated with a 1- or 2-week
regimen of ‘triple therapy’, comprising a proton pump inhibitor in combination with the
antibacterials amoxicillin and metronidazole or clarithromycin; other combinations are also
used.

Bismuth-containing preparations are sometimes added. While elimination of the bacillus

can produce long-term remission of ulcers, reinfection with the organism can occur.