DRUGS ACTING ON THE GIT

FOR MEDICAL STUDENTS

1
PEPTIC ULCER DISEASE

Acid is secreted from gastric parietal cells by a

proton pump (K+/H+-ATPase).
The three endogenous secretagogues for acid
histamine, acetylcholine and gastrin.
Prostaglandins E2 and I2
inhibit acid, stimulate mucus and bicarbonate
secretion and dilate mucosal blood vessels.

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PEPTIC ULCER DISEASE
An imbalance between the mucosal-
damaging mechanisms and the
mucosal-protecting mechanisms
Peptic ulcer is a break in the gastric or
duodenal mucosa that arises

3
PEPTIC ULCER DISEASE
Three major causes of peptic ulcer disease are
recognized
1) Chronic H.pylori infection
2) Use of NSAIDS
3) Acid hypersecretory states eg Zollinger
Ellison syndrome (a rare condition which is
caused by a gastrin-producing tumour).

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5
PEPTIC ULCER DISEASE

The parietal cell contains receptors for gastrin,

histamine (H2), and acetylcholine (M3)
In humans, it is believed that the major effect of
gastrin upon acid secretion is mediated
indirectly through the release of histamine
from ECL cells
rather than through direct parietal cell stimulation.
Gastrin, which is produced by antral G cells, is
the most potent inducer of acid secretion.
Somatostatin (SST), which is produced by antral
D cells, inhibits gastric acid secretion.
6
Drugs used to treat peptic ulcer
Decreasing the secretion of acid
with H2-receptor antagonists or
proton-pump inhibitors
Neutralizing secreted acid with
antacids

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 ANTACIDS
Antacids have been used for centuries in the
treatment of patients with dyspepsia and acid-
peptic disorders.
They were the mainstay of treatment for acid-peptic
disorders until the advent of H2- receptor
antagonists and proton pump inhibitors.
They continue to be used commonly by patients as
nonprescription remedies for the intermittent
treatment of heartburn and dyspepsia.

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ANTACIDS

If diarrhea occurs or if there is renal failure,

a magnesium based preparation should
be discontinued.
The agents are generally safe, but some
patients resist because some of the
formulations are unpalatable and
expensive.

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 ANTACIDS

The rationale for the use of antacids in peptic ulcer

disease lies in the assumption that buffering of H
in the stomach permits healing.
Antacids are weak bases that react with gastric hydrochloric
acid to form a salt and water.
Their principle mechanism of action is reduction of
intra-gastric acidity
they may also promote mucosal defense mechanisms through
stimulation of mucosal prostaglandin production.
The antacids in common use are salts of Mg and Al

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 ANTACIDS

Magnesium hydroxide
Magnesium trisilicate
Aluminium hydroxide gel
Sodium bicarbonate
raise the pH of gastric juice to about 7.4.
Carbon dioxide is liberated.
The carbon dioxide stimulates gastrin secretion
can cause alkalosis
Should not it be given to patients who are on a sodium-restricted diet

Calcium carbonate: Like NaHCO2, calcium

carbonate may cause belching or metabolic
alkalosis
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ADR OF ANTACIDS
If sodium bicarbonate is absorbed, it can cause systemic
alkalization and sodium overload.
Calcium carbonate may induce hypercalcemia and a
rebound increase in gastric secretion
Magnesium hydroxide may produce osmotic diarrhea,
and the excessive absorption of Mg in patients with
renal failure may result in CNS toxicity.
Aluminum hydroxide is associated with constipation;
serum phosphate levels also may become depressed
The use of antacids in general may interfere with the
absorption of a number of antibiotics and other
medications.
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 H2-RECEPTOR ANTAGONISTS

H2-receptor antagonists (H2-blockers) were the most

commonly prescribed drugs in the world.
The use of prescription H2-blockers has declined
markedly.
With the recognition of the role of H pylori in ulcer disease
the advent of proton pump inhibitors,
They inhibit acid production by reversibly
competing with H for binding to H2 receptors on
parietal cells.
They reduce acid secretion stimulated by H as
well as by G and cholinomimetic agents
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 H2-BLOCKERS

Cimetidine, ranitidine, nizatidine and famotidine

Cimetidine, ranitidine, and famotidine undergo first-
pass hepatic metabolism resulting in a
bioavailability of approximately 50%.
Nizatidine has little first-pass metabolism and a bioavailability
of almost 100%.
Cimetidine is a potent CYP 450 enzyme inhibitor
and potentiates the effect of other drugs.
Dose reduction is required in patients with moderate
to severe renal (and possibly severe hepatic
insufficiency.
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15
H2-BLOCKERS
They are especially effective at inhibiting nocturnal acid secretion
(which depends largely
on histamine)
have a modest impact on meal-stimulated acid
secretion (which is stimulated by G, Ach and
H).
They block more than 90% of nocturnal acid
but only 6080% of daytime acid secretion.
Recommended prescription doses maintain
greater than 50% acid inhibition for 10 hours
Hence, these drugs are commonly given twice
daily.
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 CLINICAL USES

They continue to be prescribed commonly.

Due to their superior acid inhibition and safety profile,
they are steadily being replaced by PPI for most
clinical indications.
1. GERD
Patients with infrequent heartburn or
dyspepsia (fewer than 3 times per week)
may take either antacids or intermittent H2
antagonists.
The antacids afford faster symptom relief 17
 CLINICAL USES

But the effect of antacids is short-lived (12 hours)

compared with H2 antagonists (610 hours).
They may be taken prophylactically
before meals in an effort to reduce
the likelihood of heartburn.
Frequent heartburn is better treated with
twice daily H2 antagonists
Although higher doses of H2
antagonists increase healing rates,
PPI are preferred.
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CLINICAL USES

2. Peptic Ulcer Disease

PPI have largely replaced H2 antagonists in the
treatment of peptic ulcer disease.
Nocturnal acid suppression affords effective
ulcer healing in the majority of patients with
uncomplicated gastric and duodenal ulcers.
All the agents may be administered once daily
at bedtime for acute, uncomplicated ulcers
Use also for Prophylaxis of recurrent ulcer
(400mg at bed time)
High doses are used in the treatment of ZE syndrome
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CLINICAL USES

For patients with acute peptic ulcers caused by

H pylori, H2 antagonists no longer play a
significant therapeutic role.
For patients with ulcers caused by aspirin or
other NSAIDs, H2 antagonists provide rapid
ulcer healing so long as the NSAID is
discontinued.
If the NSAID must be continued for clinical
reasons despite active ulceration, a PPI
should be given to promote ulcer healing

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CLINICAL USES

3. Prevention of Bleeding from Stress-

Related Gastritis
They significantly reduce the incidence of
bleeding from stress-related gastritis in
seriously ill patients in the intensive
care unit.
They are given intravenously, either as
intermittent injections or continuous
infusions.

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CLINICAL USES

SE include diarrhea, headache,

drowsiness, fatigue, muscular
pain, and constipation.
Cimetidine sometimes causes
gynaecomastia in men and, rarely,
decrease in sexual function

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 PROTON-PUMP INHIBITORS (PPIS)

The most potent suppressors of gastric acid secretion

are inhibitors of the gastric H+,K+-ATPase
Five PPIs for clinical use: omeprazole, lansoprazole,
rabeprazole, pantoprazole, and esomeprazole.
PPIs are pro-drugs that require activation in an acid
environment
The activated form then binds covalently with
sulfhydryl groups of cysteines in the H+/K+-
ATPase, irreversibly inactivating the pump
molecule

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PPIS

gastritis, gastroesophageal reflux disease

PO 20mg/day for 4-8 weeks;
zollinger-Ellison syndrome
PO 60mg once daily initially -120mg/day.
Peptic ulcer disease: PO 10-60mg/day..
SE include headache, diarrhea and
rashes. Dizziness, somnolence, mental
confusion, impotence, gynaecomastia,
and pain in muscles and joints
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 MUSCARINIC ANTAGONISTS

The M1 muscarinic receptor antagonists

pirenzepine and telenzepine can reduce
basal acid production

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DRUGS THAT PROTECT THE MUCOSA

'cytoprotectives are said to enhance the

mucosal protection mechanisms and/or
provide a physical barrier
Sucralfate
Sucralfate is a complex of aluminium
hydroxide and sulfated sucrose..bind to
glycoproteins, etc.
It can form complex gels with mucus
It also stimulates the mucosal-protecting
mechanisms
The SE : constipation, dry mouth, nausea,
vomiting, headache and rashes. 26
 DRUGS THAT PROTECT THE MUCOSA

Bismuth chelate
is used in combination regimens to treat H. pylori
involvement in peptic ulcer.
Like sucralfate, bismuth probably coats ulcers and
erosions, creating a protective layer against acid
and pepsin.
It may also stimulate prostaglandin, mucus, and
bicarbonate secretion.
Bismuth causes blackening of the stool, nausea and
vomiting
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DRUGS THAT PROTECT THE MUCOSA

Misoprostol
is an analogue of prostaglandin E1, has been approved for use
in the prevention of NSAID drug induced ulceration.
It also is approved in some countries for the treatment of
peptic ulcer disease.
Misoprostol is absorbed rapidly after oral administration and
is hydrolyzed to the active compound.
It is metabolized by the liver and excreted mainly in the
urine.
Adverse effects include crampy abdominal pain, dose-related
diarrhea, and uterine contractions.
The last-named effect has led to its use in the control of
postpartum bleeding
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TREATMENT OF H. PYLORI INFECTION
Due to its critical role in the pathogenesis of peptic ulcers , to
eradicate this infection is standard care in patients with
gastric or duodenal ulcers.
Provided that patients are not taking NSAIDs
Five important considerations influence the
selection of an eradication regimen
1. single-antibiotic regimens are ineffective in eradicating
H. pylori infection and lead to microbial resistance.
2. a PPI inhibitor or H2-receptor antagonist significantly
enhances the effectiveness of H. pylori antibiotic
regimens containing amoxicillin or clarithromycin.

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TREATMENT OF H. PYLORI INFECTION

3. Third, a regimen of 10 to 14 days of treatment

appears to be better than shorter treatment
regimens
4. Fourth, poor patient compliance is linked to the
medication-related side effects
5. Finally, the emergence of resistance to
clarithromycin and metronidazole increasingly is
recognized as an important factor in the failure
to eradicate H. pylori.
In the presence of in vitro evidence of resistance to
metronidazole, amoxicillin should be used instead.
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TREATMENT OF H. PYLORI INFECTION
In areas with a high frequency of resistance to
clarithromycin and metronidazole, a 14-day,
quadruple-drug regimen (three antibiotics
combined with a PPI) generally is effective
therapy

Omeprazole + Amoxacillin + Metronidazole.

Omeprazole + Clarythromycin + Amoxacillin or
tetracycline or Metronidazole and bismuth
chelates.

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DRUGS USEFUL FOR TREATING
CONSTIPATION

Constipation is defined as two or less

bowel movements per week or excessive
difficulty and straining on defecation.
Constipation has many reversible or
secondary causes
lack of dietary fiber, drugs, hormonal
disturbances, neurogenic disorders, and
systemic illnesses.
In most cases of chronic constipation, no
specific cause is found.
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DRUGS USEFUL FOR TREATING
CONSTIPATION

The terms laxatives, cathartics, purgatives,

aperients, and evacuants often are used
interchangeably.
laxation (the evacuation of formed fecal
material from the rectum)
catharsis (the evacuation of unformed, usually
watery fecal material from the entire colon).
Laxatives promote and facilitate bowel
evacuation by acting locally to stimulate
intestinal peristalsis, to soften bowel contents,
or both.
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DRUGS USEFUL FOR TREATING
CONSTIPATION

They are classified as:

Bulk forming laxatives
Osmotic laxatives
Stimulant laxatives
Stool softners

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 BULK FORMING LAXATIVES
Indigestible, hydrophilic colloids that absorb
water, forming a bulky, emollient gel that
distends the colon and promotes peristalsis.
stimulates propulsive movements of the gut
musculature peristalsis
natural plant products (psyllium,
methylcellulose) and synthetic fibers
(polycarbophil).
Bacterial digestion of plant fibers within the
colon may lead to increased bloating and flatus.
A high-fiber diet is effective in the prevention of
constipation
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 OSMOTIC LAXATIVES

They are nonabsorbable particles that retain water

in the bowel by virtue of their osmotic action
Saline Laxatives
The intestinal mucosa is unable to maintain a higher
or lower osmotic pressure of the luminal contents.
Therefore, absorption of molecules (e.g., glucose,
NaCl) occurs isoosmotically, i.e., solute molecules
are followed by a corresponding amount of water.
Conversely, water remains in the bowel when
molecules cannot be absorbed.

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 OSMOTIC LAXATIVES

Laxatives containing magnesium cations or

phosphate anions commonly are called saline
laxatives: magnesium sulfate, magnesium
hydroxide, magnesium citrate, sodium phosphate.
Magnesium-containing laxatives may stimulate the
release of cholecystokinin, which leads to
intraluminal fluid and electrolyte accumulation
and to increased intestinal motility (Mg2+ ions are
believed to promote the release).

37
 OSMOTIC LAXATIVES

These so-called saline cathartics elicit a watery bowel

discharge 13 h after administration (preferably
in isotonic solution).
They are used to purge the bowel (e.g., before bowel
surgery) or to hasten the elimination of ingested
poisons.
Glaubers salt (high Na+ content, NaSO4) is
contraindicated in hypertension, congestive heart
failure, and edema.
Epsom salt (MgSO4) is contraindicated in renal
failure (risk of Mg2+ intoxication). 38
 STIMULANT (IRRITANT) LAXATIVES
The stimulant cathartics contain a variety of
drugs whose exact mode of action is not
known
it is thought that they act on the mucosa of the
intestine to stimulate peristalsis either by irritation
or by exciting reflexes in the myenteric plexuses.
Diphenylmethane Derivatives.
Phenolphthalein, once among the most popular
components of laxatives, has been withdrawn from
the market because of potential carcinogenicity.
Oxyphenisatin, another older drug, was 39
withdrawn due to hepatotoxicity.
 STIMULANT (IRRITANT) LAXATIVES

Bisacodyl and sodium picosulfate are converted by

gut bacteria into the active colon irritant principle.
The drug requires hydrolysis by endogenous
esterases in the bowel for activation
so the laxative effects after an oral dose usually are not
produced in less than 6 hours;
taken at bedtime, it will produce its effect the next morning.
Suppositories work much more rapidly, within 30 to
60 minutes.

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STIMULANT (IRRITANT) LAXATIVES

Castor Oil
This oil is a potent stimulant laxative.
It is hydrolyzed in the upper small
intestine to ricinoleic acid, a local
irritant that stimulates intestinal
motility.
Formerly used as a purgative to
clean the colon before procedures,
it is now seldom used.
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PROKINETIC AND OTHER AGENTS
FOR CONSTIPATION
the term prokinetic generally is reserved
for agents that enhance GI transit via
interaction with specific receptors
involved in the regulation of motility.
Currently available prokinetic agents are
not very useful in the treatment of
constipation.
However, newer agents, particularly the
more potent 5-HT4-receptor agonists such
as tegaserod, may be useful for the
treatment of chronic constipation. 42
PROKINETIC
Another useful agent is misoprostol
a synthetic prostaglandin analog primarily
used for protection against gastric ulcers
resulting from the use of nonsteroidal
antiinflammatory agents.
Prostaglandins can stimulate colonic
contractions, and this may account for
the diarrhea that limits the usefulness of
misoprostol as a gastroprotectant.
Colchicine has been shown to be effective
in constipation (mechanism unknown),
but its toxicity has limited widespread
use. 43
 VOMITING (EMESIS)

It is a physiologic response controlled by a

Medullary center which coordinates respiratory
and vasomotor centers with the GIT.
Can be stimulated by 4 different sources of afferent
input
1) Afferent vagal and splanchnic fibers from the
GIT.
They are rich in serotonin receptors.
2) Vestibular system which can be stimulated by
motion.
These fibers are rich in histamine & muscarinic receptors.
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VOMITING (EMESIS)

3) Higher CNS centers

From here certain sights, smells or emotions can
induce vomiting
4) Chemoreceptor trigger zone (CTZ) in
medulla which can be stimulated by
drugs (eg chemotherapeutic agents),
hypoxia, acidosis,
- This region is rich in serotonin-
5HT3 & dopaminergic receptors.
5) Irritation of the pharynx
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 ANTIEMETIC DRUGS

Classified according to the type of receptor

Dopamine receptor antagonists
Metoclopramide, Domperidone, and Phenothiazines: inhibit
dopamine receptor located in CTZ and gut.
Haloperidol: inhibit dopamine receptor CTZ
Serotonin receptor antagonists
Ondansetron and Granisetron: inhibit serotonin receptors
located in CTZ and gut.
Anti Muscarinics

Hyoscine: act at Vomiting center & Gut

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ANTIEMETIC DRUGS

Histamine Receptor antagonists

Cyclizine, Dimenhydrinate and Promethazine:
act at Vomiting center & gut
Other agents
Cisapride: act at CTZ & Gut
Dexamethasone: Used in vomiting
of chemotherapy
Lorazepam: Used in vomiting of
47
chemotherapy
Clinical condition Preferred drugs Comment

Motion sickness Hyoscine, cyclizine, They have a prophylactic action & are best
dimenhydrinate & taken 1 hr before exposure. Once motion
promethazine sickness has started oral administration fails
& I/M or I/V administration is warranted

Opioid induced Cyclizine Usually morphine is given in combination with

vomiting cyclizine. This combination is called
Cyclimorph

Vomiting due to Dexamethasone, Usually a combination of first three drugs is

chemotherapeutic lorazepam, most beneficial. Ondansetron is also useful in
agents metoclopramide & protracted cases.
ondansetron

Vomiting in Promethazine Drugs are usually not required. Assurance &

Pregnancy
diet control may suffice
48
 DIARRHEA

It is a defined as increased liquidity and/or

frequency (more than three bowel movements
per day).
it is important to first correct fluid and
electrolyte balance
oral rehydration therapy with glucose-electrolyte
solution (ORS) which is usually sufficient in most
cases.
Drugs form the second line of therapy
Antibiotics for infectious diarrhea, corticosteroids
& sulfasalzine for patients with inflammatory
bowel disease (Ulcerative colitis) and
antidiarrheal agents to increase viscosity of
stools.
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 ANTIDIARRHEALS
1) Drugs directly increasing viscosity of stool
kaolin, pectin & chalk which presumably act by coating the
bowel and adsorbing toxic substances.
2) Drugs that delay passage of gut contents
(antimotility drugs): these drugs serve to allow
time for more water to be absorbed by decreasing
motility of the gut.
OpioidDerivatives: These include codeine,
diphenoxylate & loperamide
Smooth muscle relaxants: Theses include
mebeverine & alverine
Anticholinergics: These include atropine, 50
mepenzolate & propentheline