Drugs used in Gastrointestinal

Disorders
 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 (GERD),
(gastric and duodenal) peptic ulcers, and stress-related mucosal
injury.
• Drugs used in the treatment of acid-peptic disorders may be divided
into two classes: agents that reduce intragastric acidity by
manipulating‫ التحكم‬systems controlling acid secretion, agents that
promote mucosal defense.
• In case of peptic ulcers, eradicate the bacterium Helicobacter pylori,
which is detectable in over 80% of patients with duodenal ulcers.
 Agents that Reduce Intragastric Acidity
• The parietal cell contains receptors for gastrin, histamine & Ach (M3

• When acetylcholine or gastrin 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.
• ECL (Enterochromaffin) cells also have receptors for gastrin and
acetylcholine, which stimulate histamine release.
• Histamine binds to the H2 receptor on the parietal cell, resulting in
activation of adenylyl cyclase, which increases cAMP and activates
protein kinases that stimulate acid secretion by the H+ /K+ ATPase.
• Gastrin indirectly stimulate acid secretion through the release of
histamine from ECL
• Acetylcholine provides potent direct parietal cell stimulation.
FIGURE 1: Schematic model for physiologic control of hydrogen ion (acid) secretion
by the parietal cells of the gastric fundic glands.
1. ANTACIDS
• are weak bases that react with gastric HCL to form a salt and water.
• Their mechanism of action is reduction of intragastric acidity. used for
the treatment of dyspepsia ‫عسر الهضم‬and acid-peptic disorders until the
advent of H2− receptor antagonists and proton pump inhibitors.
• A single dose of antacid given 1hr after a meal effectively neutralizes
gastric acid for up to 2 hours. The acid-neutralization capacity among
different antacids is highly variable, depending on their rate of
dissolution, water solubility, rate of reaction with acid, and rate of
gastric emptying.
• Sodium bicarbonate, Calcium carbonate reacts with HCL to produce
carbon dioxide, results in gastric distention and belching‫التجشؤ‬
• Excessive doses of either sodium bicarbonate or calcium carbonate
with calcium-containing dairy products can lead to hypercalcemia,
renal insufficiency, and metabolic alkalosis (milk-alkali syndrome).
• 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.
• Formulations containing magnesium hydroxide or aluminum
hydroxide react slowly with HCl to form magnesium chloride or
aluminum chloride and water.
• Belching does not occur, metabolic alkalosis is also uncommon because
of the efficiency of the neutralization reaction.
• Magnesium salts cause diarrhea and aluminum salts cause
constipation, these agents are commonly administered together in
formulations ( Gelusil, Maalox).
• Both magnesium and aluminum are absorbed and excreted by the
kidneys, Patients with renal insufficiency should not take these agents
long-term.
• Antacids should not be given within 2 hours of doses of tetracyclines,
fluoroquinolones, itraconazole(antifungals), and iron.
• They are often combined with alginates and anti-foaming agents.
• Alginates float on the stomach contents to form a neutralizing layer
preventing reflux of stomach acids up into the esophagus. Hence they
help to prevent acid reflux or heart burn, Anti-foaming agents such as
simethicone (dimethicone) prevent the formation of gases and reduce
flatulence
 H 2 -RECEPTOR ANTAGONISTS
• Famotidine (Pepcid ), Cimetidine (Tagamet)
• Ranitidine (Zantac), Nizatidine (Axid).

• They exhibit competitive inhibition at the parietal cell H2 receptor and

suppress basal and meal-stimulated acid secretion, The volume of
gastric secretion and the concentration of pepsin are also reduced.
• Rapidly absorbed from the intestine, undergo first-pass metabolism
resulting in a bioavailability of 50%, cleared by a combination of
hepatic metabolism, glomerular filtration, and renal tubular secretion.
• Cannot cure ulcers, but in certain cases they are useful in reducing
inflammation allowing the stomach to heal,.
• They are effective in the treatment of GERD(gastroesophageal reflux
disease), duodenal ulcers and have little effect on stomach ulcers, and
non ulcer dyspepsia and in the prevention of stress-related gastritis in
seriously ill patients.
 Adverse Effects
• Diarrhea, headache, fatigue, myalgias and constipation occur in less
than 3% of patients .
• IV H2 antagonists in elderly or who have renal or hepatic dysfunction
increase the risk of nosocomial pneumonia in critically ill patients,
confusion, hallucinations, agitation
• Rapid IV infusion may cause bradycardia and hypotension

• Cimetidine cause gynecomastia, galactorrhea by inhibit binding of

dihydrotestosterone to androgen receptors, inhibits metabolism of
estradiol, and increases serum prolactin levels.
• Cimetidine interferes with hepatic cytoP450 drug metabolism(inhibit
cy 450), the half-lives of drugs metabolized by these pathways may be
prolonged
• H2 antagonists compete with procainamide) antiarrhythmic class( for
renal tubular secretion.
 Proton Pump Inhibitors
• Omeprazole, Esomeprazole, Lansoprazole, Dexlansoprazole,
Rabeprazole, Pantoprazole.

• They are weak lipophilic bases undergo conversion to compounds that

irreversibly inactivate the 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
metabolized in the liver, with half-lives of 1–2 h, their durations of
action are approximately 24 h, and they may require 3–4 d of treatment
to achieve their full effectiveness.
• They 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, also useful in the
treatment of gastrinoma and other hypersecretory conditions.
 Adverse effects of proton pump inhibitors
• Occur infrequently and include diarrhea, abdominal pain, headache.
• Chronic treatment may result in hypergastrinemia)Too much gastrin
can causes severe peptic ulcer disease.(
• Prolonged enterochromaffin cell exposure to gastrin can start of
hyperplasia to neoplasia
• PPI Decrease the oral bioavailability of vitamin B12 and drugs that
require acidity for their gastrointestinal absorption (digoxin,
ketoconazole).
• Patients taking proton pump inhibitors may have a small increase in
the risk of respiratory and enteric infections.
4. Sucralfate
• An aluminum sucrose sulfate, is a small, poorly soluble molecule that
polymerizes in the acid environment 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, 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.
• Stimulate mucus and bicarbonate secretion and enhance mucosal blood
flow, it binds to a prostaglandin receptor on parietal cells, reducing
histamine-stimulated cAMP production and causing acid inhibition.
• It is effective in reducing the risk of ulcers in users of (NSAIDs) but is
not widely used because of the need for multiple daily dosing and
poorly tolerated adverse effects (gastrointestinal upset and diarrhea).
BISMUTH COMPOUNDS
• Bismuth subsalicylate, a nonprescription formulation ‫بدون وصفة طبية‬of
bismuth and salicylate.
• It undergoes rapid dissociation within the stomach, allowing absorption
of salicylate.
• Bismuth coats ulcers and erosions, creating a protective layer against
acid and pepsin also stimulate prostaglandin, mucus, and bicarbonate
secretion.
• Bismuth subsalicylate reduces stool frequency and liquidity in acute
infectious diarrhea, due to salicylate inhibition of intestinal
prostaglandin and chloride secretion.
• Has direct antimicrobial effects and binds enterotoxins, Accounting for
its benefit in preventing and treating traveler’s Diarrhea.
• Bismuth compounds have direct antimicrobial activity Against H
pylori.
• Bismuth causes harmless blackening of the stool, which may be
confused with gastrointestinal bleeding.
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 like
Omeprazole plus a course of clarithromycin and amoxicillin (or
metronidazole in patients with penicillin allergy).
 Drugs That Promote Upper 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.
 Neostigmine is used for the treatment of hospitalized patients with
acute large bowel distention.
 Metoclopramide and domperidone are D2-receptor antagonists.

 The primary prokinetic mechanism of action of these agents is

inhibition of dopamine receptors which inhibits cholinergic smooth
muscle stimulation.
 Metoclopramide and domperidone increase esophageal peristaltic
amplitude, increase lower esophageal sphincter pressure, and enhance
gastric emptying.
 Metoclopramide and domperidone also block D2 receptors in the
chemoreceptor trigger zone of the medulla, resulting in potent anti-
nausea and antiemetic action, when used chronically, metoclopramide
cause symptoms of parkinsonism, extrapyramidal effects &
hyperprolactinemia. This drug acts on the specific dopamine D-2
receptor antagonist in the pituitary. It binds to the receptors, and
through apoptosis inhibition in lactotrophs, it increases PRL
production)
 The macrolide antibiotic erythromycin promotes motility by
stimulating motilin receptors(located on smooth muscle).
 It may have benefit in some patients with gastroparesis(delayed
gastric emptying, is a disorder that slows or stops the movement of
food from stomach to small intestine)
Laxatives
• Laxatives increase the probability of a bowel movement by several
mechanisms:
1. An irritant or stimulant action on the bowel wall
2. A bulk-forming action on the stool that evokes reflex contraction of
the bowel
3. A softening action on hard or impacted stool
4. A lubricating action that eases passage of stool through the rectum.
1. Bulk-forming laxatives
• Indigestible, hydrophilic colloids that absorb water, forming a bulky,
emollient gel that distends the colon and promotes peristalsis.
• Psyllium, methylcellulose and synthetic fibers (polycarbophil).
2. Stool Surfactant Agents (Softeners)
• These agents soften stool material, permitting water and lipids to
penetrate.
• They may be administered orally or rectally.
• Common agents include docusate (oral or enema) and glycerin
suppository.
• In hospitalized patients, docusate is commonly
prescribed to prevent constipation and minimize
straining.
3. Osmotic Laxatives
 Are soluble but non-absorbable compounds that result in increased
stool liquidity due to an obligate increase in fecal fluid, used for the
treatment of acute constipation or the prevention of chronic
constipation.
 Magnesium hydroxide, Sodium phosphate preparations should not
be used in elderly patients have renal insufficiency, have significant
cardiac disease, or are unable to maintain adequate hydration during
bowel preparation.(If you are having a colonoscopy, you will need to
take a solution called Moviprep )‫(بشكل محلول‬to completely clear your
bowel before the procedure
 Sorbitol, lactulose are non absorbable sugars that are metabolized by
colonic bacteria, producing severe flatus and cramps.
4. Stimulant Laxatives (Cathartics):
• Induce bowel movements through a direct stimulation of the enteric
nervous system and colonic electrolyte and fluid secretion.
• Anthraquinone Derivatives (Aloe, senna, and cascara) occur
naturally in plants.
• Diphenylmethane Derivatives Bisacodyl used for the treatment of
acute and chronic constipation.
• It also is used in conjunction with PEG solutions (Polyethylene
glycol-electrolyte solution) for colonic cleansing prior to colonoscopy.
• It has minimal systemic absorption and appears to be safe for acute
and long-term use.
ANTIDIARRHEAL AGENTS
• May be used safely in patients with mild to moderate acute diarrhea,
also used to control chronic diarrhea caused by s irritable bowel
syndrome (IBS) or inflammatory bowel disease (IBD).
• Should not be used in patients with bloody diarrhea, high fever, or
systemic toxicity because of the risk of worsening the underlying
condition.
• They should be discontinued in patients whose diarrhea is worsening
despite therapy.
• The most effective antidiarrheal drugs are the opioids and derivatives
of opioids that have been selected for maximal antidiarrheal and
minimal CNS effect.
• Diphenoxylate and loperamide, meperidine analogs with very weak
analgesic effects (minimal CNS effect).
• It is a prescription opioid agonist that has no analgesic properties in
standard doses, higher doses have central nervous system effects, and
prolonged use can lead to opioid dependence.
• Is formulated with antimuscarinic alkaloids (atropine) to reduce the
likelihood (probability) of abuse (2.5 mg diphenoxylate with 0.025 mg
atropine).

• loperamide is formulated alone, a non prescription opioid agonist that

does not cross the blood-brain barrier and has no analgesic properties or
potential for addiction.

• Kaolin, a naturally occurring hydrated magnesium aluminum silicate,

is combined with pectin, an indigestible carbohydrate derived from
apples in a popular non-prescription preparation that absorbs bacterial
toxins and fluid resulting in decreased stool liquidity.
• They can cause constipation and interfere with absorption of other
drugs.
 Drugs Used for 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.
• For chronic abdominal pain, low doses of tricyclic antidepressants
(amitriptyline or desipramine), these agents have no effect on mood but
may alter central processing of visceral afferent information.
• The anticholinergic properties of these agents also may have effects on
gastrointestinal motility and secretion, reducing stool frequency and
liquidity, may alter receptors for enteric neurotransmitters such as
serotonin, affecting visceral afferent sensation.
• The anticholinergic drugs dicyclomine and hyoscyamine are used as
antispasmodics to relieve abdominal pain, their efficacy has not been
convincingly demonstrated.‫لم يتم اثبات فعاليتها بشكل مقنع‬
Alosetron
• a potent 5-HT3 antagonist, is approved for treatment of women with
severe IBS with diarrhea, 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
• It binds to and activates guanylyl cyclase-C on the luminal intestinal
epithelial surface, resulting in increased intracellular and extracellular
cGMP, which leads to activation of type 2 chloride channels.
Drugs with Antiemetic Actions
• Antiemetics include: metoclopramide D2 receptor antagonists, H1 antagonist
diphenhydramine and phenothiazines; antimuscarinic drugs such as scopolamine;
the corticosteroid dexamethasone; and the cannabinoid receptor agonists dronabinol
and nabilone.
• The 5-HT3 antagonist, Ondansetron is particularly useful in preventing nausea and
vomiting after general anesthesia and in patients receiving cancer chemotherapy.
• Aprepitant, and rolapitant, new anti emetics, are antagonists of the neurokinin 1
receptor, a receptor in the area postrema of the CNS that is activated by substance P.
Rolapitant is a selective and competitive antagonist of human substance P/NK1
receptors with antiemetic activity. Rolapitant crosses the blood–brain barrier and
occupies NK1 receptors in the brain.
• Aprepitant is It works by blocking the action of neurokinin, a natural substance in the
brain that causes nausea and vomiting.
• Aprepitant is approved for use in combination with other antiemetics for prevention
of the nausea and vomiting associated with highly emetogenic Chemotherapeutic
regimens. can cause fatigue, dizziness, and diarrhea
• As a substrate and an inhibitor of CYP3A4, it participates in many drug interactions.
 Drugs Used in Inflammatory Bowel Disease (IBD)
1. Aminosalicylates
• Drugs 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.
• 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,‫ التعب‬and severe hypersensitivity reactions.
• Other aminosalicylates, which do not contain sulfapyridine, are better
tolerated.
2. Other drugs used in the treatment of ulcerative colitis and Crohn’s
disease include antibiotics, glucocorticoids (budesonide);
immunosuppressive antimetabolites ( azathioprine, 6mercaptopurine,
methotrexate), and anti-tumor necrosis factor [TNF] drugs
(infliximab, adalimumab, golimumab).
3. Natalizumab is a humanized monoclonal antibody that blocks
integrins on circulating leukocytes. Because of a possible association
of natalizumab with progressive multifocal leukoencephalopathy
(PML), it is carefully restricted to patients with severe refractory
Crohn’s disease.(2004)
4. Vedolizumab is similar but directed against a different integrin and
the risk of inducing PML(Progressive multifocal
leukoencephalopathy) is extremely low. It has replaced natalizumab
as second-line treatment for patients with IBD who cannot take anti-
TNF agents(Tumor necrosis factor) or did not respond.