Drugs Used in the

Treatment of
Gastrointestinal
Diseases
Bezawit Alem (B.pharm, MSc pharmacology)
Email: Bezawita.alem@ju.edu.et
outlines
 drugs used for
o Peptic Ulcer Disease (PUD)
o Gastro esophageal Reflux Disease (GERD)
o Nausea and vomiting
o Constipation
Physiology of acid secretion
 The parietal cell contains receptors for
o gastrin (CCK-B),
o histamine (H2), and
o acetylcholine (muscarinic, M3)

acetylcholine (from vagal postganglionic nerves) and gastrin

(released from antral G cells into the blood) bind to the parietal
cell receptors

they cause acid secretion from

a H+/K+-ATPase (the proton pump) on the canalicular surface

Cont…
 Enterochromaffin-like (ECL) cells, witch are present
in close proximity to the parietal cells.

 also have receptors for gastrin and acetylcholine ,

• which stimulate histamine release.

 Histamine binds to the H2 receptor on the parietal

cell, resulting stimulate acid secretion by the H+ /K+ -
ATPase
 Peptic Ulcer Disease (PUD
• PUD- characterized by ulcer formation in the

esophagus, stomach, or duodenum areas of the

GI mucosa that are exposed to gastric acid and
pepsin
• Gastric ulcer

• Stress ulcer

• NSAIDs induced ulcer

 Aggressive Factors
o H. pylori
o Gastric Acid: needs to be present for ulcer to
form => activates pepsin and injures mucosa
o Decreased blood flow: causes decrease in mucus
production and bicarbonate synthesis, promote
gastric acid secretion
o NSAIDS: inhibit the production of prostaglandins
• ↓ Mucus, ↓ bicarbonate, ↓ blood flow, ↓ proliferation
of cells and ↑ gastric acid secretion
o Smoking: nicotine stimulates gastric acid
production
Gastro Esophageal Reflux Disease (GERD)
• Backflow of stomach acid into the esophagus
• Esophagus is not equipped to handle stomach acid => scaring
• Main symptoms are irritation and burning in chest or throat.
• Heartburn occurs after meals and worsens when lying down.
• Lifestyle changes can help with management of GERD.

• More severe symptoms: difficulty swallowing, chest pain

• In some patients (~10%), the normal esophageal lining or
epithelium may be replaced with abnormal (Barrett's)
epithelium.
• This condition (Barrett's esophagus) has been linked to cancer
of the esophagus
Factors that increases GERD
 Food (fatty food, alcohol, caffeine)
 Smoking

 Obesity

 Pregnancy

 Gastric distension

 Medications like B-adrnergics, CCBs and

nitrates
Treatment of GERD and PUD

 Anti-acids

 H2 Receptor Blockers

 Mucosal Protective Agents

 Proton Pump Inhibitors

 Anti-microbial Agents
 Antacids
•Anti acids are alkaline in nature
•React with HCl in the stomach
•Produce less acidic and poorly absorbed salts
•Raise the PH of gastric secretions
•neutralizes more than 90% of gastric acids and
•indirectly inhibiting activity of pepsin (pepsin is inactive above pH 4)
• Usually taken 1 hour after meal
Al compounds -Al(OH)3
•have low neutralizing capacity
•Slow onset of action
•Can cause constipation
•Rarely used alone
Antacids…..
Mg compounds (Mg(OH)2, Magnesium tri silicate
•High neutralizing capacity
•rapid onset of action
•Cause diarrhea and hypermagnesemia
•CI- renal failure
Ca compounds(Calcium Carbonate )
•Rapid onset of action
•May cause hypercalcemia
•Cause rebound acid secretion due to Gastrin release in large
doses
Rarely used in PUD
Commonly used antiacids are combinations of Al and Mg
compounds like mallox, mylanta.
H2 Receptor Blockers

• Inhibit secretion of gastric acid through competitive

inhibition of H2 receptors

• Prevention & treatment of PUD, Esophagitis, GI bleeding,

stress ulcers,
• With gastric and duodnal ulcer, healing occurs with in 4-8
weeks
• Suppresses 24 hour gastric secretion by 70%
Cimetidine
• Inhibit meal stimulated acid secretion

Use - 1. Prophylaxis of duodenal ulcer

2. Short term treatment of gastric ulcer

• Dose: - 400mg po bid, IV 200mg

Adverse Effect
• May alter the effects of other drugs through interactions with

CYP450(enzyme inhibitor)
• Sexual dysfunction, gynecomastia and menstrual abnormality by

inhibiting metabolism of estrogen

• Hepatotoxicity, Diarrhea, Dizziness and also Inhibit P 450 enzymes

 Ranitidine
• oral ranitidine reaches peak blood levels 1 to 3 hrs after

administration and is metabolized in the liver

• 5 times more potent than cimetidine

• Action is more selective and long duration of action

• Dose: - 150mg Bid or 300mg at bed time

Advantage
- Doesn't produce sexual dysfunction
- Doesn't interfere with hepatic Metabolism
Famotidine

• About 40 times more potent than cimetidine

• Well tolerated and posses fewer side effect

• Doesn't interfere with Hepatic drug metabolism

• Doses: - 20mg bid or 40mg once a day at bed time

 Proton-Pump inhibitor
• Parietal cells secrete H+ ions which are accomplished by an enzyme

H+/K+- ATPase (serve as a proton pump, exchanging K+ for H+ ions).

• Omeprazole, esomeprazole, lansoprazole, pantoprazole

MOA: irreversibly bind to H+/K+-ATPase enzyme and inactivate it

Effect
• Inhibit both daytime and nocturnal acid secretion

• More potent than H2–blocker

• Has longer duration of action

• Suppress gastric acid secretion more strongly

Omeprazole
• Dose: 20mg once a day

• Note: - combination with antibiotics can be used in treatment of H.

pylori infection.
• Acid inhibiting effects occur within 2 hrs and last 72 hrs and longer.

Adverse effect
• Nausea, diarrhea, headache

• Inhibit drug metabolizing enzyme, Hyper gastremia, Prolonged

complete suppression of the acid barrier to bacteria entry into the body
 Mucosal Protective Agents
• Sucralfate (carafate)
• A preparation of sulfated sucrose and Al(OH)3
• Can be used to prevent & treat PUD
• It requires an acid PH to activate
• Forms sticky polymer in acidic environment and adheres to the
ulcer site, forming a barrier
• May bind with other drugs and interfere with absorption
• Give approximately 2 hours before or after other drugs
• Take on an empty stomach before meals
• Chelated Bismuth
• Protects the ulcer crater and allows healing
• Some activity against H. pylori
• Should not be used repeatedly or for more than 2 months at a
time
Misoprostol

• Misoprostol has both acid inhibitory and mucosal protective

properties.
• A congener of prostaglandin E2

• Believed to stimulate mucus and bicarbonate secretion and

enhance mucosal blood flow.

• Approved for prevention of gastric ulcers induced by NSAIDs

especially at anti-inflammatory doses.

• It is less effective than H2 antagonists and the PPIs for acute

treatment of peptic ulcers.

Misoprostol cont….
• Cytoprotective actions are clinically observed only at higher

doses
• Routine prophylactic use of misoprostol may not be justified

except in patients who are taking NSAIDs and are at high risk of
NSAID-induced ulcers, such as the elderly or patients with ulcer
complications.
• Contraindication- pregnancy

• induce abortion, premature birth or birth defects.

• Dose-related diarrhea (10 to 40%) and nausea are the most

common adverse effects and limit the use of this agent.

 Helicobacter pylori
• patients with peptic ulcer disease (both duodenal and gastric

ulcers) who are infected with H. pylori requires antimicrobial

treatment.
• H. pylori are bacteria able to attach to the epithelial cells of the

stomach and duodenum which stops them from being washed out
of the stomach.
• Once attached, the bacteria start to cause damage to the cells by

secreting degradative enzymes, toxins and initiating a self-

destructive immune response.
Anti-H.pylori Therapy
• >85% PUD caused by H. pylori
• Antibiotic Ulcer Therapy - Used in Combinations
• Bismuth - Disrupts bacterial cell wall
• Clarithromycin - Inhibits protein synthesis
• Amoxicillin - Disrupts cell wall
• Tetracycline - Inhibits protein synthesis
• Metronidazole
Triple Therapy - 14 day treatment - Effective 80-85%
Proton pump inhibitor + amoxicillin/tetracycline +
metronidazone/clarithromycin
Quadruple Therapy - 7 day treatment, as efficacious as triple
therapy
- Add Bismuth to triple therapy
Nausea and Vomiting
Neurologic pathways involved in pathogenesis
of nausea and vomiting
Vomiting can be triggered by a variety of stimuli:
stimulation of the sensory nerve endings in the GI tract
and pharynx; drugs; endogenous emetic substances
produced as a result of radiation or disease; disturbance
of vestibular appratus; stimuli to the sensory nerves of the
heart and visera; endocrine factors; a rise in ICP;
nauseating smells; repulsive sights; disgusting experience
 Cont…
There are four important sources of afferent input to the
vomiting center:

1. The “chemoreceptor trigger zone” or area postrema

is located at the caudal end of the fourth ventricle.
• This is outside the blood-brain barrier and is accessible
to emetogenic stimuli in the blood or cerebrospinal
fluid.

• The chemoreceptor trigger zone is rich in dopamine

D2 receptors and opioid receptors, and possibly
serotonin 5-HT3 receptors and NK1 receptors.
 Cont…
2.The vestibular system is important in motion sickness
via cranial nerve VIII.
• It is rich in muscarinic M1 and histamine H1 receptors
3. Vagal and spinal afferent nerves from the
gastrointestinal tract
• are rich in 5-HT3 receptors.
• Irritation of the gastrointestinal mucosa by
chemotherapy, radiation therapy, distention, or
acute infectious gastroenteritis leads to release of
mucosal serotonin and activation of these receptors,
 which stimulate vagal afferent input to the vomiting
center and chemoreceptor trigger zone
 Cont…
4.The central nervous system
plays a role in vomiting due to psychiatric disorders,
stress, and anticipatory vomiting prior to cancer
chemotherapy
 Anti-emetic drugs
• Anti-cholinergic agents

• Dopamine antagonists

• H1 antihistamines

• 5HT3 blockers

• Corticosteroids

• Benzodiazepines

• Cannabinoids
Muscarinic receptor antagonists
Hyoscine (scopolamine),

o a prototypic muscarinic receptor antagonist,

o well absorbed from the gut and conjunctival membranes
o When applied in a suitable vehicle are even absorbed
across the skin (transdermal route).
o are widely distributed in in the CNS and

o Significant levels are achieved within 30 minutes to 1 hour

o and cause CNS effects (drowsiness, amnesia, fatigue)

Hyoscine (scopolamine) cont…..
o is one of the best agents for the prevention of motion
sickness.
o However, it has a very high incidence of
anticholinergic effects when given orally or
parenterally.

 It is better tolerated as a transdermal patch.

 Anti dopaminergic drugs
• The principal mechanism of action is antagonism of
dopamine receptor at the CTZ,
• They also have antimuscarnic action
• Clopromazine Prochlorperazine
• Metoclopromide
• Fluphenazine
• Haloperidol-
• effective against low or moderately emetogenic
chemotherapeutic agents
• Have Sedative properties
• Cause restlessness, dystonias, and parkinsonian like side
effects
 5-HT3 receptor antagonists (ondansetron, granisetron, dolasetron, and
palonosetron. )

• Selective 5-HT3-receptor antagonists

• have potent antiemetic properties

 mainly through blockade of peripheral 5-HT3 receptors on

extrinsic intestinal vagal and spinal afferent nerves and

 in part through central 5-HT3- receptor blockade in the vomiting

center and chemoreceptor trigger zone

 The antiemetic action of these agents is restricted to emesis

attributable to vagal stimulation (eg, postoperative) and
 H1 antihistamines
• Dimenhydrinate
• Diphenhydramine
• Promethazine
• Cyclizine
• Meclizine
• Most anti-histamines have additional anti-cholinergic
action
• are particularly useful for the prevention or treatment of
motion sickness.
• Their use may be limited by dizziness, sedation,
confusion, dry mouth, cycloplegia, and urinary retention
 Corticosteroids: Dexamethasone, prednisolone
• Mechanism of action not clear
• May be related to the inhibition of arachidonic acid
release
• Dexamethasone
• Prednisone
Benzodiazepines
• Good for anticipatory nausea and vomiting before
cancer therapy
• Diazepam
 Drugs used for constipation
 Constipation generally may be corrected by fiber-rich
(20–35 g daily) diet, adequate fluid intake,

 pharmacological approach to constipation remains

empirical and is usually based on nonspecific principle

 Laxatives: The terms laxatives, cathartics, purgatives,

aperients, and evacuants often are used interchangeably

 Laxatives relieve constipation and promote evacuation of

the bowel via the following:
Laxatives cont…

• enhancing retention of intraluminal fluid by hydrophilic

or osmotic mechanisms

• decreasing net absorption of fluid on small- and large-

bowel fluid and electrolyte transport

• altering motility by inhibiting segmenting contractions or

stimulating propulsive contractions

 These drugs can be classified on the basis of their

mechanism of action but many work through more than
one mechanism
 A. . Irritants and Stimulants Laxative
 induce bowel movements through direct stimulation of the
enteric nervous system and colonic electrolyte and fluid
secretion.

 Senna:
o These laxatives are poorly absorbed and
o after hydrolysis in the colon, produce a bowel movement
o It also causes water and electrolyte secretion into the bowel.
Irritants and Stimulants Laxative …..
 Bisacodyl:
o Available as suppositories and enteric-coated tablets,
o bisacodyl is a potent stimulant of the colon.
o It acts directly on nerve fibers in the mucosa of the
colon
o It induces a bowel movement within 6–10 hours
when given orally and 30–60 minutes when taken
rectally
o It has minimal systemic absorption and appears to be
safe for acute and long-term use
 Irritants and Stimulants Laxative…..
Castor oil:
o This agent is broken down in the small intestine to
ricinoleic acid,
o ricinoleic acid is very irritating to the stomach and
promptly increases peristalsis.
o Pregnant patients should avoid castor oil because it
may stimulate uterine contractions.
B. Bulk Forming laxatives
o Bulk-forming laxatives are indigestible, hydrophilic
colloids that absorb water, forming a bulky, emollient gel
that distends the colon and promotes peristalsis
o Common preparations include natural plant products
(psyllium, methylcellulose) and
o synthetic fibers (polycarbophil)
o They should be used cautiously in patients who are
immobile because of their potential for causing intestinal
obstruction.
C. Saline and osmotic laxatives
 such as magnesium citrate, magnesium hydroxide, and
sodium phosphate
o are nonabsorbable salts (anions and cations)
o that hold water in the intestine by osmosis.
o This distends the bowel, increasing intestinal activity and
o producing defecation in a few hours
D. Stool surfactant agents (softeners)
o Surface-active agents that become emulsified with the stool
produce softer feces and ease passage.
o Through permitting water and lipids to penetrate
o These include docusate sodium, docusate calcium, and
docusate potassium.
o They may take days to become effective and are often used
for prophylaxis rather than acute treatment.
o Stool softeners should not be taken concomitantly with
mineral oil because of the potential for absorption of the
mineral oil.
E. Lubricant laxatives
 Mineral oil and glycerin:

is a clear, viscous oil that lubricates fecal material,

retarding water absorption from the stool.

suppositories are considered to be lubricants and act by

facilitating the passage of hard stools.
THANK YOU !!

06/01/2024 46