DRUGS AFFECTING THE

GASTROINTESTINAL SYSTEM

Pharmacist: Hafsa Nawaz

The gastrointestinal tract serves many important
functions:
digestive, excretory, endocrine, exocrine, and so on.

These functions are the targets of several important

classes of drugs.
 TERMS RELATED TO
GIT
Acid-peptic disease

A group of disorders involving erosion or ulceration of the mucosal lining of the

gastrointestinal tract; includes GERD, gastric and duodenal ulcers, nonulcer dyspepsia, and
stress-related gastritis
Antiemetic

A drug that reduces nausea and vomiting

Gastroesophageal reflux disease (GERD)

Esophageal irritation or inflammation due to reflux of stomach acid; also known as heartburn

Gastroparesis

Paralysis of the muscles of the stomach and possibly other parts of the gastrointestinal tract
due to damage to gastrointestinal nerves or muscle; common in advanced diabetes and
advanced Parkinson’s disease
Inflammatory bowel disease (IBD)

Inflammatory disorder involving irritation and ulceration of the colon

and rectum (ulcerative colitis) or the colon plus more proximal parts
of the gastrointestinal tract (Crohn’s disease)
Irritable bowel syndrome (IBS)

Disease of unknown origin characterized by episodes of abdominal

discomfort and abnormal bowel function (diarrhea, constipation, or
both)
Prokinetic

A drug that promotes gastrointestinal motility

Proton pump

The parietal cell H+ /K+ ATPase that uses the energy of ATP to
secrete protons into the stomach final common target of drugs that
suppress acid secretion
 DRUGS USED IN ACID-PEPTIC
DISEASES

Ulceration and erosion of the lining of the upper portion of the gastrointestinal tract are

common problems that manifest as gastroesophageal reflux, peptic ulcer (gastric and
duodenal), and stress-related mucosal injury.
mucosal erosions or ulceration arise when the caustic effects of aggressive factors (acid,

pepsin, bile) overwhelm the defensive factors of the gastrointestinal mucosa (mucus and
bicarbonate secretion, prostaglandins, blood flow, and the processes of restitution and
regeneration after cellular injury).
Over 90% of peptic ulcers are caused by infection with the bacterium Helicobacter

pylori or by use of nonsteroidal anti inflammatory drugs (NSAIDs).

Drugs used in the treatment of acid-peptic disorders may be divided into two classes:

agents that reduce intragastric acidity

agents that promote mucosal defense.

 A G E N T S T H AT R E D U C E
INTRAGASTRIC ACIDITY

PHYSIOLOGY OF ACID SECRETION

The parietal cell contains receptors for gastrin (CCK-B),

histamine (H 2 ), and acetylcholine (muscarinic, M 3 )
When acetylcholine (from vagal postganglionic nerves) or
gastrin (released from antral G cells into the blood) bind to the
parietal cell receptors, they cause an increase in cytosolic
calcium, which in turn stimulates protein kinases that stimulate
acid secretion from a H + / K + -ATPase (the proton pump) on the
canalicular surface.
In close proximity to the parietal cells are gut endocrine cells
called enterochromaffin-like (ECL) cells.
ECL cells also have receptors for gastrin and acetylcholine,
which stimulate histamine release.
Histamine binds to the H 2 receptor on the parietal cell, resulting
in activation of adenylyl cyclase, which increases intracellular
cyclic adenosine monophosphate (cAMP) and activates protein
kinases that stimulate acid secretion by the H + /K + - ATPase.
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.
In contrast, acetylcholine provides potent direct parietal cell
stimulation.
 AGENTS

1. Antacids

2. H2-receptor antagonists

3. Proton pump inhibitors

4. Sucralfate

5. Misoprostol

6. Colloidal bismuth

7. Antibiotics
 1. ANTACIDS
Antacids are weak bases that neutralize stomach acid by reacting with protons in the lumen

of the gut and may also stimulate the protective functions of the gastric mucosa. When used
regularly in the large doses needed to significantly raise the stomach pH, antacids reduce
the recurrence rate of peptic ulcers.
The antacids differ mainly in their absorption and effects on stool consistency. Popular

antacids include magnesium hydroxide (Mg[OH]2) and aluminum hydroxide (Al[OH]3).

Neither of these weak bases is significantly absorbed from the bowel. Magnesium hydroxide
has a strong laxative effect, whereas aluminum hydroxide has a constipating action. These
drugs are available as single-ingredient products and as combined preparations.
Calcium carbonate and sodium bicarbonate are also weak bases, but they differ from

aluminum and magnesium hydroxides in being absorbed from the gut. Because of their
systemic effects, calcium and bicarbonate salts are less popular as antacids.
2 . H 2 - R E C E P T O R A N TA G O N I S T S

Cimetidine and other H2 antagonists (ranitidine,

famotidine, and nizatidine) inhibit stomach acid
production, especially at night. They are effective in the
treatment of GERD, peptic ulcer disease, and nonulcer
dyspepsia and in the prevention of stress-related gastritis
in seriously ill patients. Although they are still used widely,
their clinical use is being supplanted by the more effective
and equally safe proton pump inhibitors.
 3. PROTON PUMP INHIBITORS—


Omeprazole and other proton pump inhibitors (esomeprazole, (dex)lansoprazole, pantoprazole, and rabeprazole) are
lipophilic weak bases that diffuse into the parietal cell canaliculi, where they become protonated and concentrated more than
1000-fold.

There they undergo conversion to compounds that irreversibly inactivate the parietal cell H+ /K+ ATPase, the transporter that is
primarily responsible for producing stomach acid.

Oral formulations of these drugs are enteric coated to prevent acid inactivation in the stomach.

After absorption in the intestine, they are rapidly metabolized in the liver, with half-lives of 1–2 h. However, their durations of
action are approximately 24 h, and they may require 3–4 d of treatment to achieve their full effectiveness.
Proton pump inhibitors are more effective than H2 antagonists for GERD and peptic ulcer and equally effective in the treatment
of nonulcer dyspepsia and the prevention of stress-related mucosal bleeding. They are also useful in the treatment of Zollinger-
Ellison syndrome.
Adverse effects:


diarrhea, abdominal pain, and headache.

Chronic treatment with proton pump inhibitors may result in hypergastrinemia.

Proton pump inhibitors may decrease the oral bioavailability of vitamin B12 and certain drugs that require acidity for their
gastrointestinal absorption (eg, digoxin, ketoconazole).

small increase in the risk of respiratory and enteric infections.
 4. SUCRALFATE—

An aluminum sucrose sulfate, sucralfate is a small, poorly

soluble molecule that polymerizes in the acidenvironment of
the stomach. The polymer binds to injured tissue and forms
a protective coating over ulcer beds. Sucralfate accelerates
the healing of peptic ulcers and reduces the recurrence rate.
Unfortunately, sucralfate must be taken 4 times daily.
Sucralfate is too insoluble to have significant systemic
effects when taken by the oral route; toxicity is very low.
 5. MISOPROSTOL—

An analog of PGE1, misoprostol increases mucosal

protection and inhibits acid secretion.
 It is effective in reducing the risk of ulcers in
users of nonsteroidal anti-inflammatory drugs
(NSAIDs) but is not widely used because of the need
for multiple daily dosing and poorly tolerated
adverse effects (gastrointestinal upset and diarrhea)
6. COLLOIDAL BISMUTH—

Bismuthhas multiple actions, including formation of a

protective coating on ulcerated tissue, stimulation of
mucosal protective mechanisms, direct antimicrobial
effects, and sequestration of enterotoxins. Bismuth
subsalicylate, a nonprescription formulation of bismuth
and salicylate, reduces stool frequency and liquidity in
infectious diarrhea. Bismuth causes black stools.
 7.ANTIBIOTICS—

Chronic infection with H pylori is present in most

patients with recurrent non-NSAID-induced peptic ulcers.
Eradication of this organism greatly reduces the rate of
recurrence of ulcer in these patients. One regimen of
choice consists of a proton pump inhibitor plus a course
of clarithromycin and amoxicillin (or metronidazole in
patients with penicillin allergy).
 B . D R U G S T H AT P R O M O T E U P P E R
GASTROINTESTINAL MOTILITY

Prokinetic drugs that stimulate upper gastrointestinal motility are helpful for gastroparesis and for
postsurgical gastric emptying delay.
Their ability to increase lower esophageal sphincter pressures also makes them useful for some patients
with GERD.
In the past, cholinomimetic agonists such as bethanechol were used for GERD and gastroparesis, but the
availability of less toxic agents has supplanted their use. The acetylcholinesterase inhibitor neostigmine is
still used for the treatment of hospitalized patients with acute large bowel distention.
In the enteric nervous system, dopamine inhibits cholinergic stimulation of smooth muscle contraction.

Metoclopramide and domperidone are D2 dopamine receptor antagonists that promote gastrointestinal
motility. The D2 receptor-blocking action of these drugs in the area postrema is also of value in preventing
emesis after surgical anesthesia and emesis induced by cancer chemotherapeutic drugs. When used
chronically, metoclopramide can cause symptoms of parkinsonism, other extrapyramidal effects, and
hyperprolactinemia. Because it does not cross the blood-brain barrier, domperidone is less likely to cause
CNS toxicity. The macrolide antibiotic erythromycin promotes motility by stimulating motilin receptors. It
may have benefit in some patients with gastroparesis.
 C. LAXATIVES

Laxatives increase the probability of a bowel

movement by several mechanisms: an irritant or
stimulant action on the bowel wall; a bulk-forming
action on the stool that evokes reflex contraction of
the bowel; a softening action on hard or impacted
stool; and a lubricating action that eases passage of
stool through the rectum
T H E M A J O R L A X AT I V E M E C H A N I S M S A N D

S O M E R E P R E S E N TAT I V E L A X AT I V E D R U G S
 D. A N T I D I A R R H E A L A G E N T S

The most effective antidiarrheal drugs are the opioids and derivatives of opioids that have
been selected for maximal antidiarrheal and minimal CNS effect.
Of the latter group, the most important are diphenoxylate and loperamide, meperidine
analogs with very weak analgesic effects. Diphenoxylate is formulated with antimuscarinic
alkaloids (eg, atropine) to reduce the likelihood of abuse; loperamide is formulated alone.
Kaolin, a naturally occurring hydrated magnesium aluminum silicate, is combined with
pectin, an indigestible carbohydrate derived from apples in a popular nonprescription
preparation that absorbs bacterial toxins and fluid, resulting in decreased stool liquidity.
They can cause constipation and interfere with absorption of other drugs. Antidiarrheal
agents may be used safely in patients with mild to moderate acute diarrhea. However,
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.
 E . D R U G S U S E D F O R I R R I TA B L E
BOWEL SYNDROME

Irritable bowel syndrome (IBS) is associated with recurrent episodes of abdominal discomfort (pain,

bloating, distention, or cramps) plus diarrhea or constipation (or both).

The pharmacologic strategy is tailored to patients’ symptoms and includes antidiarrheal agents and

laxatives, and for the treatment of abdominal pain, low doses of tricyclic antidepressants .
The anticholinergic drugs dicyclomine and hyoscyamine are used as antispasmodics to relieve

abdominal pain; however, their efficacy has not been convincingly demonstrated. Alosetron, a potent 5-
HT3 antagonist, is approved for treatment of women with severe IBS with diarrhea.
Alosetron can cause constipation, including rare complications of severe constipation that have required

hospitalization or surgery, and rare cases of ischemic colitis. For this reason, its use is restricted.
Lubiprostone, a laxative that activates the type 2 chloride channels in the small intestine, is approved

for treatment of women with IBS with predominant constipation. Linaclotide has a similar therapeutic
effect but acts more indirectly: It binds to and activates guanylyl cyclase-C on the luminal intestinal
epithelial surface, resulting in increased intracellular and extracellular cGMP, which in turn leads to
activation of the type 2 chloride channels.
 F. D R U G S W I T H A N T I E M E T I C
ACTIONS

A variety of drugs are valuable in the prevention and treatment of vomiting, especially cancer
chemotherapy-induced vomiting. In addition to metoclopramide and other D2 dopamine receptor
antagonists, useful antiemetics are drugs with H1 histamine blocking activity including
diphenhydramine and several phenothiazines,antimuscarinic drugs such as scopolamine ,the
corticosteroid dexamethasone ,and the cannabinoid receptor agonists dronabinol and nabilone.
The 5-HT3 antagonists ondansetron, granisetron, dolasetron, and palonosetron are
particularly useful in preventing nausea and vomiting after general anesthesia and in patients
receiving cancer chemotherapy. Aprepitant, a newer antiemetic, is an antagonist of the neurokinin
1 (NK1) receptor, a receptor in the area postrema of the CNS that is activated by substance P and
other tachykinins. Aprepitant is approved for use in combination with other antiemetics for
prevention of the nausea and vomiting associated withhighly emetogenic chemotherapeutic
regimens. Aprepitant can cause fatigue, dizziness, and diarrhea. As a substrate and an inhibitor of
CYP3A4, aprepitant participates in many drug interactions.
G. D R U G S U S E D I N I N F L A M M AT O RY
BOWEL DISEASE (IBD)

1. Aminosalicylates

2. Other agents

 1 . A M I N O S A L I C Y L AT E S — D R U G S

containing 5-aminosalicylic acid (5-ASA) are used as topical therapy for IBD. The precise
mechanism of 5-ASA action is uncertain but may involve inhibiting the synthesis of prostaglandins
and inflammatory leukotrienes, and interfering with the production of inflammatory cytokines. 5-
ASA, known generically as mesalamine, is readily absorbed from the small intestine whereas
absorption from the colon is extremely low. Proprietary coated formulations of 5-ASA (Pentasa,
Asacol, Lialda) deliver 5-ASA to different segments of the small and large intestine (Figure 59–2).
Balsalazide, olsalazine, and sulfasalazine contain 5-ASA bound by an azo (N=N) bond to an inert
compound, another 5-ASA molecule, or sulfapyridine. The azo structure is poorly absorbed in the
small intestine. Sulfasalazine
(a combination of 5-ASA and sulfapyridine) has a higher incidence of adverse effects than the other
5-ASA drugs, due to the systemic absorption of the sulfapyridine moiety. These effects are dose
related and include nausea, gastrointestinal upset, headaches, arthralgias, myalgias, bone marrow
suppression, malaise, and severe hypersensitivity reactions. Other aminosalicylates, which do not
contain sulfapyridine, are well tolerated.
 2. OTHER AGENTS
Other drugs used in the treatment of ulcerative colitis and Crohn’s
disease include antibiotics, glucocorticoids (eg, budesonide;
immunosuppressive antimetabolites (eg, azathioprine, 6-
mercaptopurine, methotrexate; Chapters 54 and 55), antitumor
necrosis factor [TNF] drugs (eg, infliximab, adalimumab,
golimumab.Natalizumab is a humanized monoclonal antibody that
blocks integrins on circulating leukocytes. Because of a possible
association of natalizumab with multifocal leukoencephalopathy, it is
carefully restricted to patients with severe refractory Crohn’s disease.
Therapeutic pyramid approach to
inflammatory bowel disease
 H . PA N C R E AT I C E N Z Y M E
REPLACEMENTS

Steatorrhea, a condition of decreased fat absorption together

with an increase in stool fat excretion, results from inadequate
pancreatic secretion of lipase. The abnormality of fat
absorption can be significantly relieved by oral administration
of pancreatic lipase (pancrelipase or pancreatin) obtained
from pigs. Pancreatic lipase is inactivated at a pH lower than
4.0; the enzyme should be taken as enteric-coated capsules
unless the pH is raised with antacids or drugs that reduce acid
secretion.
Ursodiol

The formation of cholesterol gallstones can be

inhibited by the bile acid derivative ursodiol, which
decreases the cholesterol content of bile by
I . D R U G S T H AT
decreasing hepatic cholesterol secretion and has
INHIBIT THE
other effects on hepatocyte canalicular membranes.
F O R M AT I O N O F
Toxicity: uncommon.GALLSTONES