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7—DRUGS USED IN THE TREATMENT OF GASTROINTESTINAL DISEASES 277

naloxegol (oral) are peripherally acting µ-opioid receptor antagonists. They are devoid
of central effects; used to treat opioid-induced constipation in cancer patients. Adverse
effects are nausea, vomiting and diarrhoea.

Pharmacotherapy of Peptic Ulcer and Gastroesophageal

Reflux Disease PH1.34

Physiology of gastric secretion

The stomach secretes roughly about 2–3 litres of gastric juice per day. The chief
or peptic cells secrete pepsinogen, which is converted to pepsin by gastric acid. Parietal
or oxyntic cells secrete acid and intrinsic factor (IF). Superficial epithelial cells secrete
alkaline mucus and bicarbonate ions.
Regulation of gastric acid secretion
The secretion of gastric acid by parietal cells is regulated by ACh, histamine, gastrin and
prostaglandin E2 (PGE2). Binding of histamine, ACh and gastrin to their specific recep-
tors on the parietal cell results in increased secretion of gastric acid. In contrast, the
binding of PGE2 to its receptor decreases gastric acid secretion. There are various phases
of gastric acid secretion – basal, cephalic and hormonal. A membrane-bound proton
pump H!, K!-ATPase plays an important role in the final step of gastric acid secretion.
Damage to the mucosa and deeper tissue exposed to acid and pepsin is known as
peptic ulcer. The exact cause of peptic ulcer is not clear. In most of the cases, peptic
ulcers are caused by Helicobacter pylori infection or the use of nonsteroidal anti-inflam-
matory drugs (NSAIDs).

CLASSIFICATION OF DRUGS USED IN PEPTIC ULCER

Drugs used in peptic ulcer are classified as follows (Fig. 7.5):
1. Drugs that inhibit gastric acid secretion
(a) PPIs: Omeprazole, esomeprazole, lansoprazole, pantoprazole, rabeprazole.
(b) H2-receptor antagonists (H2-blockers): Cimetidine, ranitidine, famotidine, rox-
atidine, nizatidine.

Antacids Neutralize • PPIs

ACID Decrease • H2-blockers
secretion of • Prostaglandins
r
ce
Ul Protect • Sucralfate
• CBS

Fig. 7.5 Drugs used in peptic ulcer. PPIs, proton-pump inhibitors; CBS, colloidal bismuth
subcitrate.
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278 PHARMACOLOGY FOR MEDICAL GRADUATES

(c) Antimuscarinic agents (anticholinergic agents): Pirenzepine, telenzepine.

(d) Prostaglandin analogues: Misoprostol.
2. Ulcer protectives
Sucralfate, colloidal bismuth subcitrate (CBS).
3. Drugs that neutralize gastric acid (antacids)
(a) Nonsystemic antacids: Magnesium hydroxide, magnesium trisilicate, alumin-
ium hydroxide, calcium carbonate.
(b) Systemic antacids: Sodium bicarbonate, sodium citrate.
4. Anti-H. pylori agents
Amoxicillin, tetracycline, clarithromycin, metronidazole, tinidazole, bismuth
subsalicylate, H2-antagonists, PPIs.
Drugs That Inhibit Gastric Acid Secretion
Proton-Pump Inhibitors (PPIs). Proton pump (H!, K!-ATPase) is a membrane-bound
enzyme that plays an important role in the final step of gastric acid secretion (basal and
stimulated; Fig. 7.6). Omeprazole is the prototype drug. The other PPIs are lansoprazole,
pantoprazole and rabeprazole. PPIs (prodrugs) nabsorbed in small intestine n blood
n diffuse into parietal cells n canaliculi of the cell (acidic pH) n converted to sul-
phenamide (active, charged form). The activated form (sulphenamide) binds covalently
with SH group of the proton pump and irreversibly inactivates it. PPIs are the most
powerful inhibitors of gastric acid secretion. They inhibit both fasting and stimulated
acid secretion. As PPIs act in the final step of acid secretion, they are effective in inhibit-
ing acid production following any stimulation. PPIs are administered orally about
30 minutes before food because food stimulates secretion of acid (in the canaliculi
of parietal cell), which is necessary for activation of PPIs. Food decreases absorption of
PPIs. Though the half-life of PPIs is short (!1.5 hours), acid secretion is suppressed for
up to 24 hours as they cause irreversible inhibition of proton pumps. In the commonly
used doses, PPIs suppress acid production by about 80%–98%. PPIs are available as
enteric coated form or as powder containing sodium bicarbonate to prevent their acti-
vation by acid in the stomach. Esomeprazole, pantoprazole and lansoprazole have
higher oral bioavailability than omeprazole. Ilaprazole is more potent than omeprazole.
Parenteral (i.v.) formulations are available for esomeprazole, lansoprazole, pantoprazole

Canaliculi
Blood Parietal cell (acidic pH)

PPIs PPIs PPIs

Sulfenamide
Proton !
pump

Fig. 7.6 Mechanism of action of proton-pump inhibitors.

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7—DRUGS USED IN THE TREATMENT OF GASTROINTESTINAL DISEASES 279

and rabeprazole. They are highly bound to plasma proteins; extensively metabolized in
liver and metabolites are excreted in urine.

Therapeutic Uses
1. Peptic ulcer: PPIs are the most powerful acid suppressive agents. They inhibit all
phases of gastric acid secretion. PPIs are superior to H2-blockers as their onset of
action is rapid and cause faster ulcer healing. The standard dose of omeprazole is
20 mg, lansoprazole 30 mg and pantoprazole 40 mg once daily. Duodenal ulcers
require 4 weeks’ therapy and gastric ulcers require 6–8 weeks’ therapy for healing.
In acute bleeding ulcers, intravenous PPIs are preferred. By suppressing acid
secretion, they promote healing of ulcer.
H. pylori–associated ulcers: Combination therapy of two or three antimicrobials
and a PPI is the most effective regimen for these ulcers.
Stress ulcers (Curling ulcer): Prophylactic use of intravenous PPIs reduce the
incidence of stress ulcers in critically ill patients.
NSAID-induced ulcers: PPIs are more effective than H2-blockers for prevention
and treatment of NSAID-induced ulcers.
2. PPIs can be used preoperatively to reduce the risk of aspiration pneumonia.
3. Zollinger–Ellison (Z–E) syndrome: Z–E syndrome is characterized by hypergas-
trinaemia with multiple peptic ulcers. PPIs are the preferred agents for Z–E
syndrome. Higher doses of PPIs are needed for healing of ulcers. Surgery is the
definitive treatment. In inoperable cases, prolonged therapy with PPIs has been
recommended.
4. Gastroesophageal reflux disease: In GERD, the goal of therapy is to produce
symptom relief, heal erosive oesophagitis and prevent complications. PPIs are the
preferred agents for the treatment of GERD and are usually given once daily. They
are more effective than H2-blockers. Patients with erosive oesophagitis or peptic
ulcer with stricture need prolonged maintenance therapy with PPIs.
Adverse Effects. PPIs are generally well tolerated. The side effects are headache, nausea,
diarrhoea and abdominal pain. Skin rashes and arthralgia can rarely occur. Long-term
use of PPIs can decrease vitamin B12 absorption, increase the risk of infections (e.g.
hospital-acquired pneumonia) and osteoporosis. Chronic use also results in hypergastri-
naemia which may predispose to gastric tumours. Gynaecomastia and erectile dysfunc-
tion with omeprazole therapy have been reported.
Drug interactions. Omeprazole can inhibit the metabolism of drugs like phenytoin,
warfarin and diazepam. PPIs decrease the bioavailability of itraconazole, iron salts, etc.
Drug interactions are minimal with pantoprazole.
H2-Receptor Antagonists (H2-Blockers)
• Ranitidine
Parietal cell • Famotidine
Histamine
H2-receptors • Nizatidine
(Agonist)
• Cimetidine
(Antagonists)

Mechanism of Action. H2-receptor antagonists competitively block H2-receptors on

parietal cell and inhibit gastric acid production. They suppress all phases (basal, cephalic
and gastric) of acid secretion. They are mainly effective in suppressing nocturnal acid
secretion. H2-blockers also reduce acid secretion stimulated by ACh, gastrin, food, etc.
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280 PHARMACOLOGY FOR MEDICAL GRADUATES

They are less potent than PPIs – 24-hour acid secretion is suppressed by 60%–70%.
Cimetidine is the prototype drug and was the first H2-blocker developed. It is seldom
used now because of its adverse effects (Table 7.3).
H2-blockers are usually administered orally and are well absorbed; metabolized in
liver and the metabolites are excreted in urine. Cimetidine, ranitidine and famotidine
are also available for intravenous administration.
■ Nizatidine: All the features are similar to ranitidine but it has higher bioavailability

(almost 100%).
■ Famotidine: Most of the features are similar to ranitidine. It is more potent and

longer acting than ranitidine. It has no antiandrogenic effect. Drug interactions

are negligible.
■ Lafutidine: It is an H2-receptor blocker and decreases acid secretion. It increases

mucosal blood flow and mucin synthesis. Nitric oxide production is increased.

Therapeutic Uses
1. Peptic ulcer: H2-blockers are one of the commonly used drugs in peptic ulcer.
H2-blockers produce symptomatic relief within days and ulcer healing within
weeks. The duration of treatment for duodenal ulcer is 4–6 weeks. Gastric ulcer
requires prolonged therapy for 6–8 weeks. But, PPIs are more frequently used
because they have higher efficacy and are well tolerated.
■ H. pylori–associated ulcers: H2-blockers can be used along with antimicrobial

agents to treat H. pylori infection.

■ Stress ulcers are commonly seen in critically ill patients with severe medical or

surgical illness. They may be associated with upper gastrointestinal bleeding.

Intravenous H2-blockers are used to prevent and treat stress-related ulcer and
bleeding.
■ NSAID-induced ulcers: H2-blockers can be used for healing of NSAID-induced

ulcers but they are less effective than PPIs.

Table 7.3 Comparison of cimetidine and ranitidine

Cimetidine Ranitidine
1. H2-blocker (competitive blocker) H2-blocker (competitive blocker)
2. Less potent More potent
3. Has shorter duration of action (6–8 hours) Has longer duration of action (24 hours)
4. Cimetidine is an enzyme inhibitor, hence Has less affinity for hepatic cytochrome
increases the plasma concentration of P450 enzymes, hence drug interac-
many co-administered drugs, such as tions are rare
phenytoin, digoxin, theophylline, warfarin
and propranolol
5. Increases plasma prolactin level; can cause Has no antiandrogenic effect; does not
menstrual irregularities and galactorrhoea in increase prolactin secretion
women; gynaecomastia, oligospermia and
impotence in men
6. Crosses BBB and produces CNS side Poorly crosses BBB, CNS side effects
effects like confusion, headache and are rare
hallucinations
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7—DRUGS USED IN THE TREATMENT OF GASTROINTESTINAL DISEASES 281

2. Gastroesophageal reflux disease: In GERD, H2-blockers are effective and produce

symptomatic relief. PPIs are more effective than H2-blockers.
3. Zollinger–Ellison syndrome: In Z–E syndrome, surgery is the definitive therapy.
PPIs or H2-blockers are used to control the hypersecretion of acid. PPIs are the
preferred agents in Z–E syndrome.
4. H2-blockers are used preoperatively to reduce the risk of aspiration pneumonia.

Anticholinergic Agents. Pirenzepine and telenzepine, selective M1-receptor blockers, in-

hibit acid secretion. They are not commonly used because of their low efficacy and an-
ticholinergic side effects.

Prostaglandin Analogues. Misoprostol, a synthetic PG analogue (PGE1), is effective orally

for prevention and treatment of NSAID-induced gastric and duodenal ulcers.
PGs inhibit gastric acid secretion, increase mucus and bicarbonate secretion; they
also increase mucosal blood flow (cytoprotective effect). The common side effects are
diarrhoea and abdominal cramps. Misoprostol is contraindicated in pregnancy, as
it may cause uterine contractions. Because of its adverse effects and need for frequent
dosing, it is rarely used.
Ulcer Protectives
Sucralfate. It is a complex of aluminium hydroxide and sulphated sucrose. In the acidic
environment of stomach (pH & 4), sucralfate undergoes polymerization to form a
sticky polymer that adheres to the ulcer base and protects it. It also precipitates proteins
at the ulcer base – forms a barrier against acid–pepsin. It stimulates the release of PGs
and epidermal growth factor locally, thus produces cytoprotective effect. It also increases
mucus and bicarbonate secretion – enhances mucosal defence and repair.
Sucralfate is given orally on an empty stomach at least 1 hour before meals. It reduces
the absorption of drugs, such as digoxin, tetracyclines, ketoconazole and fluoroquino-
lones. Since it requires pH & 4 for activation, concurrent administration of antacids,
H2-blockers or PPIs should be avoided. Constipation is a common side effect. Nausea
may occur. Aluminium toxicity can occur in patients with renal failure.
After the introduction of PPIs, sucralfate is seldom used in peptic ulcer. Sucralfate
is effective for prevention of bleeding from stress ulcers and to reduce the risk of
aspiration pneumonia. It is also useful in GERD with oesophagitis, as it is a mucosal
protector. Other uses are oral mucositis, radiation proctitis, rectal ulcer, burns, bed
sores, etc.

Bismuth-Containing Preparations. Bismuth subsalicylate and CBS are the most commonly
used oral bismuth preparations. Their mode of action is not clear. They probably:
1. Precipitate proteins and protect ulcer base.
2. Stimulate the secretion of PGE2, mucus and bicarbonate.
3. Have antimicrobial effect against H. pylori.
They are one of the components in certain anti-H. pylori regimens. The side effects
are blackening of the tongue and stools.
Drugs that Neutralize Gastric Acid (Antacids)
Antacids are weak bases that neutralize gastric acid and raise the gastric pH. They do not
affect acid production. Acid neutralizing capacity reflects the potency of an antacid.
An Ideal Antacid
1. should be insoluble and capable of neutralizing acid.
2. should not liberate CO2.
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282 PHARMACOLOGY FOR MEDICAL GRADUATES

3. should be nonabsorbable.
4. should not disturb the acid–base balance of the body.

Types of Antacids
1. Nonsystemic: Magnesium hydroxide, magnesium trisilicate, aluminium hydrox-
ide gel and calcium carbonate.
2. Systemic: Sodium bicarbonate and sodium citrate.
Nonsystemic Antacids. Magnesium hydroxide, magnesium trisilicate, aluminium
hydroxide, calcium carbonate, etc. form respective chloride salts in stomach. When this
reaches the intestine, the chloride salt reacts with bicarbonate, so HCO3– is not available
for absorption; hence, there is no systemic alkalosis.
Combination of antacids produces various beneficial effects. They are as follows:
1. Aluminium salts cause constipation and magnesium salts cause diarrhoea,
so combination of these two can counteract the adverse effects of each other.
2. Magnesium hydroxide has a rapid onset of action, but aluminium hydroxide
acts slowly – the combined product produces rapid and sustained effect.
3. Dose of individual antacid is reduced; hence, systemic toxicity is minimized.
Calcium may be absorbed from its salts resulting in hypercalcaemia and hypercalciuria.
Systemic Antacids
Sodium bicarbonate (NaHCO3). It rapidly neutralizes gastric acid, but the duration
of action is short. The disadvantages of NaHCO3 are that (i) it is highly water soluble
and rapidly absorbed from the gut; (ii) it releases CO2 that can cause abdominal
distension and belching; (iii) it may cause metabolic alkalosis; and (iv) it produces
rebound acidity.
Sodium bicarbonate is also used to alkalinize urine and to treat acidosis. It should be
avoided in patients with hypertension and congestive cardiac failure (CCF), as it causes
sodium retention.
Formulations. Antacids are available as suspension, tablet and powder. Tablet should
be chewed and swallowed for better effect. Suspensions have better neutralizing capacity
than other formulations.
Drug Interactions. All antacids increase the pH of stomach and form insoluble and
nonabsorbable complexes with many drugs – iron, tetracyclines, fluoroquinolones, keto-
conazole, etc.; thus, antacids reduce the absorption of these drugs. There should be a gap
of 2 hours between administration of these drugs and antacids.

Antifoaming Agents
Methylpolysiloxane (simethicone and dimethicone): They are antifoaming agents, usu-
ally present in some antacid preparations. They decrease foaming and relieve flatulence.
Oxethazaine: It is a topical anaesthetic and is used to anaesthetize gastric mucosa.
It produces symptomatic relief in gastritis and GERD. It is available in combination
with antacids.
Sodium alginate: It forms froth on the contents in the stomach – prevents effects
of gastroesophageal reflux.

Anti-H. pylori Agents

H. pylori, Gram-negative, rod-shaped bacterium, is associated with gastritis, duodenal
ulcer, gastric ulcer and gastric carcinoma (Fig. 7.7).
The mechanism by which H. pylori causes mucosal inflammation and damage is not
clear. The ammonia produced by urease activity may directly damage the cells.
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7—DRUGS USED IN THE TREATMENT OF GASTROINTESTINAL DISEASES 283

Urease

Urea NH3

Fig. 7.7 Helicobacter pylori (H. pylori).

Many regimens are available for the eradication of H. pylori. Combination therapy
(triple/quadruple) is always recommended. The objectives of combination therapy are
as follows:
1. To prevent or delay the development of resistant organism.
2. To prevent relapse.
3. To promote rapid ulcer healing.
4. To eradicate H. pylori infection.
The duration of treatment could be 1 week or 2 weeks, of which 14-day therapy is
more effective.
The antimicrobials used in H. pylori infection are amoxicillin, tetracycline, clarithro-
mycin, metronidazole and tinidazole. Resistance develops rapidly to metronidazole and
clarithromycin but not to amoxicillin. Amoxicillin should be avoided in patients with
history of penicillin allergy. Other anti-H. pylori drugs are PPIs, H2-blockers and CBS.
Some of the recommended regimens are listed below:

Triple Therapy ! 14 Days (2 Weeks)

■ Lansoprazole 30 mg b.d !
■ Clarithromycin 500 mg b.d. !
■ Amoxicillin 1 g b.d.

Quadruple Therapy ! 14 Days (2 Weeks)

■ Omeprazole 20 mg b.d. !
■ CBS 120 mg q.i.d. !
■ Tetracycline 500 mg q.i.d.!

■ Metronidazole 400 mg t.i.d.

After completion of the above-recommended regimen, PPI should be continued for

6 more weeks to enhance ulcer healing.

DRUGS USEFUL IN GASTROESOPHAGEAL REFLUX DISEASE PH1.34

1. PPIs and H2-receptor blockers: They decrease acid secretion n pH of gastric
contents rise n relief of symptoms and healing of esophageal lesions. PPIs are
more effective than H2-blockers. They do not affect LES tone.