Gastrointestinal tract PharmacologY

By: Monas K. (MSc/Pharmacology)

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 Contents

• Drugs used in acid-peptic

diseases
• Antiemetics

• Laxatives

• Antidiarrheal Agents

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 Common GI disorders
– Peptic ulcer disease/dyspepsia
– GERD
– Emesis
– Diarrhea
– Constipation
– Inflammatory bowel disease
– Irritable bowel syndrome

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1. Drugs used in acid-peptic diseases

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Drugs used in acid-peptic diseases

• Anti-secretary agents (Histamine receptor 2

antagonists, Proton pump inhibitors)
• Antacids (Neutralizing agents and chelaters)

• Cytoprotective Agent

• Antibiotics for Helicobacter Pylori Eradication

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Drugs used in acid-peptic diseases
• Acid-peptic diseases include gastroesophageal reflux,
peptic ulcer (gastric & duodenal), & stress-related
mucosal injury
• In all these conditions, mucosal erosions or ulceration
arise when the caustic effects of aggressive factors
(acid, pepsin, bile) overwhelm the defensive factors of
the GI mucosa (mucus & bicarbonate secretion,
prostaglandins, blood flow, & the processes of
restitution & regeneration after cellular injury)
• 90% of peptic ulcers are caused by infection with the
bacterium Helicobacter pylori or by use of
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nonsteroidal anti-inflammatory drugs (NSAIDs)
Fig. 1 Factors involved in maintaining acid balance
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Drugs used in acid-peptic diseases (cont…)

• Anti-ulcer drugs act in three basic ways to

promote ulcer healing.
– Reduce gastric acidity
• Ant-acids
• H2-receptor antagonists
• Proton pump inhibitors
– Enhance mucosal defenses
• Sucralfate and
• Misoprostol
– Eradicate H. Haramaya
PyloriUniversity
-antibiotics
1) Agents that reduce intra-gastric acidity:

A. Antacids
Antacids are weak bases that react with gastric
hydrochloric acid to form a salt and water
Their principal MOA is reduction of intra-gastric
acidity
Therapeutic uses: PUD; administered prior to
anesthesia to prevent aspiration pneumonitis; used
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prophylactically to prevent stress-ulcers
Antacids (Cont..)

 Formulations
Antacids are available in tablet and liquid formulations
• Antacid tablets should be chewed thoroughly &
followed with a glass of water or milk
• Liquid preparations should be shaken before
dispensing
• As a rule, liquids (suspensions) are more effective than
tablets
 Used alone or in combination
• Magnesium hydroxide, aluminum hydroxide,
Calcium carbonate
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Antacids (Cont..)

 Antacids & Antiflatulents

Antiflatulents: used to relieve the painful symptoms
associated with gas
Several agents are used to bind or alter intestinal gas
& are often added to antacid combination products
• E.g. Simethicone

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Antacids (Cont..)

 Antacids: Side Effects

Minimal, & depend on the compound used
• Aluminum & calcium: Constipation
• Magnesium: Diarrhea
• Calcium carbonate
• Produces gas & belching; often combined with
simethicone
 Antacids: Drug Interactions
should not be given within 2 hrs of doses of
• Tetracyclines, Fluoroquinolones,
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Agents that reduce intra-gastric acidity…

B. H2 Antagonists
– Includes: Ranitidine, cimetidine, famotidine, nizatidine
Fig. Showing how H2 receptor antagonists and proton-pump inhibitors
reduce the secretion of hydrochloric acid from the parietal cells of the
mucosa into the lumen of the stomach.

– Block histamine (H2) at the receptors of acid-producing

parietal cells
• Reduce acid secretion

– Indications: Gastroesophageal reflux disease (GERD),

PUD, Dyspepsia, Gastritis
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H2 Antagonists...

• Side effects
– Common:
• Diarrhea, headache, drowsiness, fatigue,
muscle pain, & constipation may occur
– Rare:
• CNS side effects: Confusion, delirium,
hallucinations, slurred speech, & headache can
occur
– These CNS effects are more likely to occur
with IV administration
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or in the elderly
H2 Antagonists ...

• Side effects (Cont..)

– Cimetidine only

• Gynecomastia (breast development in men) &

• Galactorrhea (lactation not associated with childbirth)

– Cimetidine inhibits binding of testosterone to the

androgen receptor, & as a CYP450 inhibitor, it
inhibits the hydroxylation of estradiol
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Agents that reduce intragastric acidity …

C. Proton Pump Inhibitors (PPIs)

– Includes: omeprazole, pantoprazole, lansoprazole,
esomeprazole, rabeprazole
– PPIs enter the parietal cell & bind to the proton
pump, resulting in an irreversible inactivation of the
pump
• This dramatically reduces the amount of H+ that is pumped
into the lumen of the stomach, & b/c the binding is
irreversible, the effects of PPIs persist until new pumps are
synthesized
– The reductionHaramaya
in gastric acid secretion can thus persist
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up to 48 hrs. after a single dose
Proton Pump Inhibitors (cont…)

 Indications
GERD maintenance therapy
Erosive esophagitis
Zollinger-Ellison syndrome
Tx of H. pylori–induced ulcers
 Adverse reactions
Most common: Headache, dizziness, D,
constipation, N

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2) Mucosal protective agents:

A. Sucralfate
– Cytoprotective agent
– Used for stress ulcers, erosions, PUD
– Attracted to & binds to the base of ulcers & erosions,
forming a protective barrier over these areas
– Protects these areas from pepsin, which normally
breaks down proteins (making ulcers worse)
– Little absorption from the gut
– May cause constipation, N, & dry mouth
– Do not administerHaramaya
with University
other medications
Mucosal protective agents …

B. Prostaglandin analogs: Misoprostol

Prostaglandins have Cytoprotective activity
• Protect gastric mucosa from injury by enhancing
local production of mucus or bicarbonate
• Promote local cell regeneration
• Help to maintain mucosal blood flow
Used for prevention of NSAID-induced gastric
ulcers
Doses that are therapeutic enough to treat duodenal
ulcers often produce abdominal
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Mucosal protective agents …

C. Bismuth compounds
Includes: bismuth subsalicylate, bismuth subcitrate
potassium
Bismuth coats ulcers & erosions, creating a
protective layer against acid & pepsin
It may also stimulate prostaglandin, mucus, and
bicarbonate secretion
Bismuth can impart a harmless black coloration to
the tongue and stool
• Pts should be forewarned
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Treatment of Helicobacter Pylori Infection

Recommended for HP-infected patients with GU,

DU, ulcer-related complications
First-line eradication therapy
a) PPI–based, three-drug regimen containing two antibiotics

 Usually clarithromycin and amoxicillin

 Reserving metronidazole for back-up therapy (e.g.,
clarithromycin–metronidazole in penicillin-allergic
patients)
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Treatment of Helicobacter Pylori Infection

PPI should be taken 30 to 60 minutes before a meal

along with the two antibiotics.
Although treatment is minimally effective if used for
7 days, 10–14 days of treatment is recommended
Antisecretory drug may be continued beyond
antimicrobial treatment in patients with a history of
complicated ulcer (e.g., bleeding or in heavy smokers)

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Treatment of Helicobacter Pylori Infection

b) Quadruple therapy using a PPI (with

bismuth, metronidazole, and tetracycline)
Achieves similar eradication rates as PPI based
triple therapy and permits a shorter treatment
duration (7 days)
However, this regimen is often recommended as
second-line treatment when a clarithromycin–
amoxicillin regimen is used initially.
All medications except the PPI should be taken with
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meals and at bedtime.
Treatment of Helicobacter Pylori Infection

 If the initial treatment fails to eradicate HP, second-

line empiric treatment should:
use antibiotics that were not included in the initial
regimen
include antibiotics that do not have resistance
problems
use a drug that has a topical effect (e.g., bismuth)
be extended to 14 days
 Thus, if a PPI–amoxicillin–clarithromycin regimen fails,
therapy should be instituted with a PPI, bismuth
subsalicylate, metronidazole, and TTC for 14 days
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Haramaya University
 2. Antiemetic Drugs

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Nausea and vomiting

• Nausea: inclination to vomit (feeling in the throat

or epigastric region alerting that vomiting is
imminent)
• Vomiting is the ejection/expulsion of gastric
content through the mouth.
• Are protective reflexes that prevent further
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absorption from the GIT
Causes of nausea and vomiting
• Pain
• Emotional disturbances
• Radiation therapy
• Motion sickness
• Pregnancy
• Drug therapy: especially w/alcohol, ASA,
digoxin, anticancer drugs, antimicrobials,
estrogen preparations and Opioids
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 Antiemetic Drugs
• The emetic response:
– Emesis is a complex reflex brought about by
activation of the Vomiting center, a nucleus of
neurons located in the medulla oblongata
– Some stimuli activate the Vomiting center directly;
others act indirectly
• Direct-acting stimuli include signals from the cerebral
cortex (anticipation or fear), signals from sensory organs
(upsetting sights, noxious odors, or pain), & signals from
the vestibular apparatus of the inner ear
• Indirect-acting stimuli first activate the chemoreceptor
trigger zone (CTZ), which in turn activates the V center
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Antiemetic Drugs…

• The emetic response…

– Activation of the CTZ occurs in 2 ways:
• By signals from the stomach & small intestine
(traveling along vagal afferents)
• By the direct action of emetogenic compounds
(eg, anticancer drugs, opioids, ipecac) that are
carried to the CTZ in the blood
– Once activated, the V center signals the stomach,
diaphragm, & abdominal muscles; the resulting
coordinated response expels gastric contents
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Antiemetic Drugs…
• The emetic response…
– Several types of receptors are involved in the emetic
response
– Important among these are receptors for serotonin,
dopamine, acetylcholine, histamine
• Several types of antiemetics are available
– Serotonin receptor antagonists
– Dopamine antagonists
– Anticholinergic agents
– Antihistamine agents
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 Pathophysiology of Emesis

Cancer chemotherapy
Cerebral cortex
Opioids Smell
Sight Anticipatory emesis
Thought
Chemoreceptor Vestibular
Vomiting Centre
Trigger Zone Motion nuclei
(medulla) sickness
(CTZ) Muscarinic, 5 HT3 & Muscarinic
(Outside BBB) Histaminic H1 Histaminic H1
Dopamine D2
5 HT3,,Opioid Chemo & radio therapy
Receptors Gastroenteritis

Pharynx & GIT

5 HT3 receptors
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Antiemetic & Antinausea agents (Cont…)

a) Anticholinergic agents (E.g. Hyoscine)

 Benefits derive from suppressing nerve traffic in the
neuronal pathway that connects the vestibular
apparatus of the inner ear to the vomiting center
 Most effective drug for prevention & treatment of
motion sickness
 The most common side effects are dry mouth,
blurred vision, & drowsiness
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Antiemetic & Antinausea agents (Cont…)

b) Antihistamine agents (H1 receptor blockers)

E.g. dimenhydrinate, diphenhydramine,

meclizine, promethazine
Inhibit ACh by binding to H1 receptors
• Prevent cholinergic stimulation in vestibular &
reticular areas, thus preventing N &V

They are also used for nonproductive cough,

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allergy symptoms, sedation
Antiemetic & Antinausea agents (Cont…)

c) Dopamine Antagonists
E.g. chlorpromazine, perphenazine,
triflupromazine
Block dopamine receptors on the CTZ

Are antipsychotics with potent antiemetic

property due to D2 antagonism
Also used forHaramaya
psychotic
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Antiemetic & Antinausea agents (Cont…)

d) Prokinetic agents

E.g. metoclopramide, cisapride

Block dopamine in the CTZ

• Cause CTZ to be desensitized to impulses it
receives from the GIT
Also stimulate peristalsis in GIT, enhancing
emptying of stomach contents
Also used for GERD,
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University gastric emptying
Antiemetic & Antinausea agents (Cont…)

e) Serotonin blockers

Block serotonin receptors in the GIT, CTZ, &

VC
E.g. dolasetron, granisetron, ondansetron

Used for N &V for patients receiving

chemotherapy & postoperative N & V

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Antiemetic & Antinausea agents (Cont…)

 Side Effects
Vary according to agent used
Stem from their nonselective blockade of various
receptors
 Implications
Assess complete N & V history, including
precipitating factors
Assess current medications
Assess for C/Is & potential drug interactions
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Constipation
 Fluid content is the principal determinant
of stool volume and consistency;
 Net stool fluid content reflects a balance
between luminal input (ingestion and
secretion of water and electrolytes) and output
(absorption) along the length of the GI tract.
 Neurohumoral mechanisms, pathogens, and
drugs can alter the balance  changes in
either secretion or absorption of fluid by the
intestinal epithelium.
 Decreased motility  excess fluid removal
 constipation.
 When the capacity of the colon to absorb
fluid is exceeded, diarrhea will occur
Constipation
 Normal stool frequency on a Western diet is at
least 3 times a week
 Decreased frequency, difficulty in initiation or
passage, passage of firm or small-volume feces, or a
feeling of incomplete evacuation.
 Causes
 Lack of dietary fiber, drugs, hormonal disturbances,
neurogenic disorders, and systemic illnesses.
 In most cases no specific cause is found.
 Laxatives cause the evacuation of
formed fecal material from the rectum

while
 Cathartics cause evacuation of
unformed, usually watery fecal
material from the entire colon.
Laxatives
1. Stool-surfactant agents (Stool
softeners)
– Docusate salts, glycerin suppository, Mineral oil

 Docusate salts
 Anionic surfactants that lower the surface tension
of the stool  mixing of aqueous and fatty
substances,  soft stool and easy defecation.
 Also stimulate intestinal fluid and electrolyte
secretion and alter intestinal mucosal permeability.
 Docusate sodium and docusate calcium
 2. Osmotic laxatives
 Saline Laxatives / Nonabsorbable Salts
 Laxatives containing magnesium cations or
phosphate anions:
Magnesium sulfate, magnesium hydroxide
(milk of magnesia), magnesium citrate, sodium
phosphate.
Osmotically mediated water retention 
stimulates peristalsis.
Magnesium- and phosphate-containing
preparations: generally well tolerated.
Use with caution or avoided in patients with
renal insufficiency, cardiac disease, or pre-
existing electrolyte abnormalities
When taking these agents, it is very important
that patients maintain adequate hydration
 3. Stimulant (Irritant) Laxatives
 Have direct effects on enterocytes, enteric
neurons, and GI smooth muscle.
 Diphenylmethane Derivatives
 Phenolphthalein, Sodium picosulfate, Bisacodyl

 The diphenylmethanes can damage the mucosa and

initiate an inflammatory response in the small bowel
and colon

 Bisacodyl (tablet and suppository)

 for acute and chronic constipation
 induces a bowel movement within 6–10 hours
when given orally and 30–60 minutes when
taken rectally.

 It has minimal systemic absorption and

appears to be safe for acute and long-term use.

 Phenolphthalein was removed from the

market owing to concerns about possible
cardiac toxicity.
Stimulant Laxatives (cont’d)
 Castor Oil
 Castor oil is derived from the bean of the castor
plant, Ricinus communis  contains ricin
(extremely toxic protein) and a triglyceride
ricinoleic acid.
 The triglyceride is hydrolyzed into glycerol and
ricinoleic acid  stimulates secretion of fluid
and electrolytes and speed intestinal transit.
ANTIDIARRHEAL AGENTS
 Diarrhea
 " too rapid evacuation of too much fluid
stools."
 Since stool weight is largely determined by
stool water, most cases of diarrhea result
from disorders of intestinal water and
electrolyte transport.
Excessive secretion of electrolytes and water
into the intestinal lumen
Exudation of protein and fluid from the mucosa
Altered intestinal motility resulting in rapid
transit
 Severe diarrhea  dehydration and
electrolyte imbalances
 Oral rehydration therapy therefore is a
cornerstone for patients with acute illnesses
resulting in significant diarrhea.
 Pharmacotherapy of diarrhea should be
reserved for patients with significant or
persistent symptoms.
 These agents should not be used in patients with
bloody diarrhea, high fever, or systemic toxicity
because of the risk of worsening the underlying
condition.
1. Bulk-Forming and Hydroscopic Agents
 Hydrophilic and poorly fermentable colloids
or polymers such as
carboxymethylcellulose and calcium
polycarbophil
Absorb water and increase stool bulk
The mechanism is not clear, but they may work
as gels to modify stool texture and viscosity
and to produce a perception of decreased
stool fluidity.
2. Bile Acid Sequestrants.
 Cholestyramine, colestipol, and colesevalam
bind bile acids and some bacterial toxins.
 In the treatment of bile salt-induced diarrhea
3. Bismuth.
 Bismuth subsalicylate + HCl  Bismuth
oxychloride (unabsorbable) + Salicylic acid
 Mechanism of action remains poorly
understood.
 Has antisecretory, antiinflammatory, and
antimicrobial effects. Nausea and abdominal
cramps also are relieved by bismuth.
 Use for the prevention and treatment of traveler's
diarrhea
Antimotility and Antisecretory Agents
 Opioids
Effects mediated through  - or -opioid
receptors on enteric nerves, epithelial cells, and
muscle
Effects on intestinal motility ( receptors),
intestinal secretion ( receptors), or absorption (
and  receptors).
Commonly used: diphenoxylate, difenoxin, and
loperamide act principally via peripheral -
opioid receptors and are preferred over opioids
that penetrate the CNS.
 Loperamide
 is an orally active antidiarrheal agent.
 40 to 50 times more potent than morphine as
an antidiarrheal agent and penetrates the
CNS poorly.
 It increases transit times, increases anal
sphincter tone, has antisecretory activity
(against cholera toxin)
 It lacks significant abuse potential
 Overdosage can result in CNS depression
(especially in children).
question?

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