Gastrointestinal
Pharmacology
PEACE MAWUNYO DOE
P. M. Doe 2022
[email protected] 1
Objectives
• By the end of this topic, students should be able to:
• Demonstrate knowledge of the GI system.
• Explain the pathophysiology and therapeutic
strategies of disorders of the GIT.
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Introduction
• GI pharmacology deals with the properties and
actions of drugs that affect the function of the GIT.
• These drugs normalize impaired function in the GIT.
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The Gastrointestinal Tract
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• The blood vessels and the glands (exocrine,
endocrine and paracrine) that comprise the GIT are
under both neuronal and hormonal control.
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Neuronal control
• There are two principal intramural plexuses in the
tract: the myenteric plexus (Auerbach’s plexus) submucous
plexus (Meissner’s plexus).
• These plexuses are interconnected, and their ganglion
cells receive preganglionic parasympathetic fibres
from the vagus, which are mostly cholinergic and
excitatory, although a few are inhibitory.
• The neurons within the plexuses constitute the enteric
nervous system and secrete Ach, NA, 5- HT e.t.c.
• The enteric plexus also contains sensory neurons,
which respond to mechanical and chemical stimuli
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Hormonal control
• The hormones of the GIT include both endocrine and
paracrine secretions.
• Endocrine secretions (i.e. substances released into the
bloodstream) are mainly peptides synthesised by endocrine cells
in the mucosa. E.g. gastrin and cholecystokinin.
• Paracrine secretions- regulatory peptides released from special
cells found throughout the wall of the tract. Act on nearby cells,
and in the stomach the most important of these is histamine. Can
function as neurotransmitters.
• Orally administered drugs are absorbed in the GIT.
• Functions of the GIT that are important from the viewpoint of
pharmacological intervention are: gastric secretion, vomiting
(emesis) and nausea, gut motility and defecation, the formation
M. Doeexcretion
P.and 2022 of bile. 7
Peptic Ulcer Disease (PUD)
• An ulcer is any type of sore that occurs from the loss of skin
and tissue on the surface of the skin or an internal membrane.
Ulcers of the digestive tract are called PUD.
• Pathogenesis is not fully understood; there are several major
causative factors and they are:
• Non-steroidal anti-inflammatory drug use
• Infection with gram negative Helicobacter pylori
• Increased HCL acid secretion
• Inadequate mucosal defense against gastric acid
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• PUD is the most common ulcer of an area of the GIT
that is usually acidic and thus extremely painful.
• Defined as mucosal erosions ≥ 0.5 cm. As many as
70–90% of such ulcers are associated with Helicobacter
pylori, a spiral-shaped bacterium that lives in the acidic
environment of the stomach;
• Contrary to general belief, 4X as many peptic ulcers arise
in the duodenum rather than in the stomach itself.
• About 4% of stomach ulcers are caused by a malignant
tumor, so multiple biopsies are needed to exclude cancer.
Duodenal ulcers are generally benign
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• In most patients with uncomplicated PUD, routine
laboratory tests usually are not helpful; instead,
documentation of PUD depends on radiographic and
endoscopic confirmation.
• Testing for H pylori infection is essential in all patients
with peptic ulcers.
• Upper GI endoscopy is the preferred diagnostic test
in the evaluation of patients with suspected PUD.
Provides an opportunity to visualize the ulcer, to
determine the presence and degree of active bleeding.
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• Most patients with PUD are treated successfully with cure
of H pylori infection and/or avoidance of NSAIDs, along
with the appropriate use of anti-secretory therapy.
• In the United States, the recommended primary therapy
for H pylori infection is PPI–based triple therapy.
• These regimens result in a cure of infection and ulcer
healing in approximately 85-90% of cases.
• Ulcers can recur in the absence of successful H pylori
eradication
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• In patients with NSAID-associated peptic ulcers, discontinuation
of NSAIDs is paramount, if it is clinically feasible.
• For patients who must continue with their NSAIDs, PPI
maintenance is recommended to prevent recurrences even after
eradication of H pylori.
• Prophylactic regimens that have been shown to dramatically
reduce the risk of NSAID-induced gastric and duodenal ulcers
include the use of a prostaglandin analog or a PPI.
• Maintenance therapy with anti-secretory medications (e.g., H2
blockers, PPIs) for 1 year is indicated in high-risk patients .
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• Although the idea was initially controversial, most
evidence now supports the assertion that H. pylori
and NSAIDs are synergistic with respect to the
development of PUD.
• A meta-analysis found that H. pylori eradication in
NSAID-naive users before the initiation of NSAIDs
was associated with a decrease in peptic ulcers.
• Corticosteroids alone do not increase the risk for
PUD; however, they can potentiate ulcer risk in
patients who use NSAIDs concurrently.
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Gastric acid
• Is a digestive fluid,
• pH of 1-3 and is composed of HCl (around 0.5%), and
large quantities of KCl and NaCl.
• The stomach secretes about 2.5 litres of gastric juice daily.
• The principal exocrine components are proenzymes such
as prorennin and pepsinogen secreted by
the chief or peptic cells, and HCl and intrinsic factor secreted
by the parietal or oxyntic cells.
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• Important for promoting proteolytic digestion of foodstuffs,
iron absorption and killing pathogens.
• Mucus-secreting cells also abound among the surface cells of
the gastric mucosa. Bicarbonate ions are secreted and trapped
in the mucus, creating a gel-like protective barrier that
maintains the mucosal surface at a pH of 6–7 in the face of a
much more acidic environment in the lumen.
• Alcohol and bile can disrupt this layer. Locally produced
‘cytoprotective’ prostaglandins stimulate the secretion of both
mucus and bicarbonate.
• Disturbances in these secretory and protective mechanisms are
thought to be involved in the pathogenesis of peptic ulcer, and
indeed in other types of gastric damage: GERD and injury
caused by NSAIDs.
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• The chief cells of the stomach secrete enzymes for
protein breakdown (inactive pepsinogen).
• HCl activates pepsinogen into the enzyme pepsin,
which then helps digestion by breaking the bonds
linking amino acids, a process known as proteolysis.
• In addition, many microorganisms have their growth
inhibited by such an acidic environment, which is
helpful to prevent infection.
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• Gastric acid secretion happens in several steps. Cl- and H+ ions are
secreted separately from the cytoplasm of parietal cells and mixed in the
canaliculi. Gastric acid is then secreted into the lumen of the oxyntic
gland and gradually reaches the main stomach lumen.
• Cl- and Na+ are secreted actively from the cytoplasm of the parietal cell
into the lumen of the canaliculus. This creates a –ve potential across the
parietal cell membrane that causes K+ ions and a small number of Na+
ions to diffuse from the cytoplasm into the parietal cell canaliculi.
• The enzyme carbonic anhydrase catalyses the reaction between CO2 and
H2O to form carbonic acid. This acid immediately dissociates into
hydrogen and bicarbonate ions. The hydrogen ions leave the cell through
H+/K+ ATPase antiporter pumps.
• At the same time sodium ions are actively reabsorbed. This means that
the majority of secreted K+ and Na+ ions return to the cytoplasm. In the
canaliculus, secreted hydrogen and chloride ions mix and are secreted
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into the lumen of the oxyntic gland.
A schematic illustration of the secretion of hydrochloric acid
by the gastric parietal cell.
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• The principal mediators that directly—or
indirectly—control parietal cell acid output are:
• histamine (a stimulatory local hormone)
• gastrin secreted by G cells (a stimulatory peptide
hormone)
• acetylcholine (a stimulatory neurotransmitter)
• prostaglandins E2 and I2 (local hormones that inhibit
acid secretion)
• somatostatin secreted by D cells (an inhibitory
peptide hormone).
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• There are three phases in the secretion of gastric acid:
• The cephalic phase: 30% of the total gastric acid to
be produced is stimulated by anticipation of eating
and the smell or taste of food.
• The gastric phase: 60% of the acid secreted is
stimulated by the distention of the stomach with
food. Plus, digestion produces proteins, which causes
even more gastrin production.
• The intestinal phase: The remaining 10% of acid is
secreted when chyme enters the small intestine, and is
stimulated by small intestine distention.
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• Nerve endings in the stomach secrete two stimulatory
neurotransmitters: acetylcholine and gastrin-releasing peptide.
• Their action is both direct on parietal cells and mediated through the
secretion of gastrin from G cells and histamine from
enterochromaffine-like cells.
• Gastrin acts on parietal cells directly and indirectly too, by
stimulating the release of histamine.
• The release of histamine is the most important positive regulation
mechanism of the secretion of gastric acid in the stomach.
• Its release is stimulated by gastrin and acetylcholine and inhibited by
somatostatin.
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Regulation of the acid-secreting gastric parietal cell, illustrating the site of
action of drugs influencing acid secretion.
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Neutralization of gastric acid
• In the duodenum, gastric acid is neutralized by sodium bicarbonate. This
also blocks gastric enzymes that have their optima in the acid range of ph.
The secretion of sodium bicarbonate from the pancreas is stimulated by
secretin. This polypeptide hormone gets activated and secreted from
so-called S cells in the mucosa of the duodenum and jejunum when the pH
in duodenum falls below 4.5 to 5.0.
• The neutralization is described by the equation:
• HCl + NaHCO3 → NaCl + H2CO3
• The carbonic acid instantly decomposes into carbon dioxide and water.
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Symptoms of PUD
• Abdominal pain, classically • Hematemesis (vomiting of blood);
epigastric with severity relating to this can occur due to bleeding
mealtimes, after around 3 hours of directly from a gastric ulcer, or
taking a meal (duodenal ulcers are from damage to the esophagus
classically relieved by food, while from severe/continuing vomiting.
gastric ulcers are exacerbated by it);
• Melena (tarry, foul-smelling feces
• Bloating and abdominal fullness; due to oxidized iron from
hemoglobin);
• Waterbrash
• Rarely, an ulcer can lead to a gastric
• Nausea, and copious vomiting; or duodenal perforation, which
• Loss of appetite and weight loss; leads to acute peritonitis. This is
extremely painful and requires
immediate surgery.
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• Epigastric pain is the most common symptom of
both gastric and duodenal ulcers. It is characterized
by a gnawing or burning sensation and occurs after
meals—classically, shortly after meals with gastric
ulcer and 2-3 hours afterward with duodenal ulcer.
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Treatment approaches of PUD
• Eradicating the H. pylori infection
• Reducing the secretion of gastric acid with the use of
H2 receptor antagonists/ PPI
• Provide agents that protect the gastric mucosa from
damage such as misoprostol and sucralfate.
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NOTE!!!!
• If patients are unable to tolerate the above therapies,
neutralizing the gastric acid with nonabsorbable
antacids is an option of treatment.
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Gastroesophageal Reflux Disease (GERD)
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• A condition which develops when the reflux of stomach
contents causes troublesome symptoms (i.e., at least two
heartburn episodes per week) and/or complications.
• Some gastroesophageal reflux is normal.
• Several factors may predispose patients to pathologic
reflux, including hiatus hernia, lower esophageal sphincter
hypotension, loss of esophageal peristaltic function,
abdominal obesity, increased compliance of the hiatal
canal, gastric hypersecretory states, delayed gastric
emptying, and overeating
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• Although gastroesophageal reflux is the most common
cause of heartburn, other disorders (e.g., achalasia and
eosinophilic esophagitis) may also cause or contribute to
heartburn.
• Lifestyle Modifications
• Dietary changes may be beneficial if there are obvious
dietary precipitants (coffee, chocolate, or fatty foods) &
lifestyle changes are warranted to reduce obesity,
smoking, or excessive alcohol use if present. However,
lifestyle modification alone is unlikely to eliminate
symptoms
• Medication- inhibiting gastric acid secretion, Reducing
the acidity of gastric juice ameliorates reflux symptoms
and
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• Approaches for the treatment • 2. Neutralization of gastric
of peptic ulcer are: acid (antacids)
• 1. Reduction of gastric acid • a. Systemic: sodium bicarbonate,
secretion sodium citrate
• a. H2 antihistamines: Cimetidine, • b. Nonsystemic: magnesium
ranitidine, famotidine and hydroxide, magnesium trisilicate,
roxatidine aluminium hydroxide
• b. Proton pump inhibitors: • gel, magaldrate, calcium
omeprazole, lansoprazole, carbonate
pantoprazole, rabeprazole,
esomeprazole • 3. Ulcer protective: sulcarlfate,
colloidal bismuth subcitrate
• c. Antichlolinergics: pirenzipine, (CBS)
propantheline, oxyphenonium
• 4. Anti-H pylori drugs:
• d. Prostaglandin analogue: amoxicillin, clarithromycin,
misoprostol metronidazole, tinidazole and
tetracycline
•
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• ANTIMICROBIAL • PROSTAGLANDINS
AGENTS
• Misoprostol
• Amoxicillin
• ANTACIDS
• Tetracycline
• Aluminium hydroxide
• Metronidazole
• Calcium carbonate
• H2 RECEPTOR BLOCKERS
• Sodium bicarbonate
• Cimetidine
• Magnesium hydroxide
• Ranitidine
• ANTIMUSCARINIC AGENTS
• Famotidine
• Dicyclomine
• nizatidine
• MUCOSAL PROTECTIVE
• PROTON PUMP AGENTS
INHIBITORS
• Bismuth subsalicylate
• Omeprazole
• sucralfate
• Esomeprazole
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• Lansoprazole
H2-receptor antagonists
• These are the first class of highly effective drugs for acid-peptic
disease. Block actions of histamine at all H2 receptors; no effect on
H1 receptors.
• Cimetidine was the first H2 blocker to be introduced clinically and is
described as the prototype though other H2 blockers are more
commonly used now.
• Chief clinical use is to inhibit gastric acid secretion (dose
dependently) particularly nocturnal acid secretion.
• No direct effect on gastric or esophageal motility & LES
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• Reduce intracellular concentrations of cyclic ADMP
thereby secretion of gastric acid.
• Are reversible competitive antagonist of Histamine
• Completely inhibit GAS by gastrin & histamine Partially
inhibit GAS by Ach & bethanechol
• The volume, pepsin content & intrinsic factor secretion
• Gastric ulceration due to stress & drugs (NSAIDs,
cholinergic, histaminergic) is prevented.
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Therapeutic uses
• PUD- duodenal & gastric ; recurrence is common after
treatment cessation.
• Acute stress disorders- administered IVly for stress ulcers
associated with major physical trauma
• GERD (Heartburn)- low doses appear to be effective for
prevention and treatment. 50%- no benefit now PPIs. H2
antagonists are effective for stopping acid secretion they cause
no immediate relief
• Stress ulcers and gastritis
• Zollinger-Ellison syndrome: It is a gastric hypersecretory state.
PPIs are the drug of choice
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Pharmacokinetics
• Administration- p.o; wide dist.- across placenta &
breast milk.
• Cimetidine- short serum half-life which is increased
in renal failure; inhibits CYP450 & can potentiate the
action of drugs like warfarin, diazepam, quinidine
• Ranitidine- longer acting; 5, 10X more potent;
minimal side effects; does not inhibit the mixed
function oxygenase system & does not affect other
drugs
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• Famotidine- has the same pharmacologic action as
ranitidine; 20- 50X more potent than cimetidine
• Nizatidine – also similar to ranitidine in action and
potency; eliminated principally by the kidney;
bioavailability is 100%; has no IV preparation.
• Cimetidine- Antacids reduce absorption
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Adverse effects
• Cimetidine- usually minor related to its action;
• Side effects are few and do not require discontinuation
• Headache, dizziness, diarrhea, muscle pain
• Cimetidine can have endocrine effects because of its
nonsteriodal androgenic action- galactorrhea, reduced
sperm count
• Except for famotidine, they all inhibit gastric first pass
metabolism of ethanol
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Proton pump inhibitors (PPIs)
• Omeprazole is the first class drug
• Are prodrugs with an acid-resistant enteric coating to protect from
GA degradation.
• Inhibit the final step in gastric acid secretion and have overtaken H2
blocker for acid-peptic disorders.
• They bind to the H+/K+ ATPase enzyme system (proton pump) of
the parietal cell thereby suppressing the secretion of H+ into the
gastric lumen.
• It is a powerful inhibitor of gastric acid : can totally abolish HCl
secretion , both resting as well as that stimulated by food or any
other secretagogues, without much effect on pepsin, intrinsic factor,
juice volume and gastric motility.
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Pharmacokinetics
• Omeprazole- oral absorption is approx. 50%; highly
plasma bound; rapidly metabolized by CYP3A4 &
CYP2C19; metabolites excreted in the urine.
• No dose modification required for the elderly.
• Bioavailability of all PPIs by ↓ food, should be taken
on an empty stomach followed 1hr after by a meal.
• All PPIs produce 80-98% suppression of 24hr acid
output; (secretion resumes 3-5days).
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Therapeutic uses
• Erosive esophagitis
• Active duodenal ulcers
• PUD
• Bleeding peptic ulcer: acid enhances clot dissolution promoting ulcer bleed.
Suppression of gastric acid has been found to facilitate clot formation reducing
blood loss and rebleed. PPI therapy profoundly inhibits gastric acid
• Zollinger- Ellison syndrome-PPI is more effective than H2 blockers in
controlling hyperacidity in Z-E syndrome.
• GERD- produces more round the clock inhibition of gastric acid resulting in
rapid symptom relief and is more effective than H2 blockers in promoting
healing of esophageal lesions.
• H.Pylori eradication
• Clinical studies have proven that PPIs reduce the risk of bleeding from an ulcer
caused by aspirin & other NSAIDS
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Pharmacokinetics
• All delayed-release formulations
• Effective orally
• Few are Also available for IV injection
• Metabolites are eliminated in the urine & feces
• H2 antagonists reduce the activity of the proton
pump & PPIs require active pumps to be effective
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Adverse effects
• Are generally well tolerated- long term safety concerns.
• Headache, diarrhoea (both sometimes severe) and rashes.
• PPIs should be used with caution in patients with liver
disease, or in women who are pregnant or breastfeeding.
The use of these drugs may ‘mask’ the symptoms of
gastric cancer.
• Omeprazole inhibits the metabolism of warfarin,
phenytoin, diazepam, cyclosporine; no drug interaction
with others
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H. pylori
• H. pylori is a gram negative bacillus uniquely adapted to survival in the
hostile environment of stomach.
• It attaches to the surface of epithelium beneath the mucus, has high urease
activity – produces ammonia which maintains a neutral microenvironment
around the bacteria.
• Eradication of H. pylori concurrently with H2 blocker/ PPI therapy of peptic
ulcer has been associated with faster ulcer healing and markedly lower
relapse rates.
• Anti- H. pylori therapy is now recommended in all ulcer patients who test
positive for H. pylori.
• Antimicrobials that have been found useful are amoxicillin, clarithromycin,
tetracycline and metronidazole/tinidazole. However any single drug is
relatively ineffective as resistance develops rapidly.
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Antimicrobial agents
• Optimal therapy for patients with PUD (D&G) infected with
H. pylori.
• Infection is documented with endoscopy biopsy of the gastric
mucosa, serologic tests & urea breath tests.
• Successful eradication of H. pylori is possible with various
combination of antimicrobial drugs
• Currently either triple therapy consisting of a PPI with either
metronidazole or amoxicillin + clarithromycin OR quadruple
therapy of bismuth salicylate and metronidazole + tetracycline
+ PPI administered over a 2 week course = 90% eradication
rate
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Antimuscarinic agents
• Muscarinic receptor stimulation increases GI motility and
secretory activity.
• Atropinic drugs reduce the volume of gastric juice without
raising its pH unless there is food in stomach to dilute the
secreted acid.
• Dicyclomine used as an adjunct in PUD, Zollinger-Ellison
syndrome
• Side effects- cardiac arrhythmias, dry mouth, constipation,
urinary retention.
• Introduction of H2 blockers and PPIs has sent them into
oblivion.
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Antacids
• Are weak bases which neutralize gastric acid and raise
pH of gastric contents.
• Antacids do not decrease acid production;
• React with gastric acid to form water & salt thereby
diminishing gastric acidity
• Reduce pepsin activity- pepsin is inactive at pH ˃ 4
• Depends on the content of the stomach
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Therapeutic uses
• PUD, GERD, duodenal ulcers - Antacids containing Al & Mg
• Little evidence for gastric ulcers
• ADVERSE EFFECTS- Al(OH)3- constipation, Mg(OH)2-
diarrhea
• symptomatic relief in peptic ulcer , dyspepsia, oesophageal reflux.
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Mucosal protective agents
• Also known as cytoprotective compounds.
• Prevent mucosal injury, reduce inflammation, heal
existing ulcers.
• SUCRALFATE- the complex of aluminium hydroxide
and sulfated sucrose binds to +ly charged proteins
• By forming complex gels with epithelial cells, it creates a
physical barrier that impairs the diffusion of HCl and
prevents degradation of mucus by pepsin and acid
• Also stimulates prostaglandin release, mucus &
bicarbonate output; inhibits peptic digestion
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• Sulcrafate heals duodenal ulcers & is used in long term
maintenance therapy to prevent their recurrence.
• Should not be adm with H2 antagonists or antacids; does
not heal gastric ulcers & does not prevent NSAID
induced ulcers
• BISMUTH SUBSALICYLATE: preparations of this
compound effectively heals PU; has antimicrobial actions,
inhibits pepsin, ↑ mucus secretion & interacts with
glycoproteins in neurotic mucosal tissue to coat and
protect the ulcer crater.
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Prostaglandins
• Prostaglandin E2 produced by the gastric mucosa inhibits HCL secretion,
stimulates mucus and bicarbonate secretion.
• Pathogenesis of PUD- prostaglandin deficiency
• Misoprostol, an analog of Prostaglandin E1
• Prevent gastric ulcers induced by NSAIDS
• Less effective than H2 antagonists and PPIs for PUD
• Has cytoprotective actions
• Clinically effective only at higher doses that diminish GAS
• Produces uterine contractions; contraindicated in pregnancy
ADVERSE EFFECTS- nausea and diarrhea which are dose related
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Prostaglandin analogue
• PGE2 and PGI2 are produced in the gastric mucosa and
appear to serve a protective role by inhibiting acid
secretion and promoting mucus +HCO3- secretion. In
addition PGs inhibit gastrin production, increase mucosal
blood flow and probably have an ill-defined
cytoprotective action.
• However, the most important appears to be their ability
to reinforce the mucus layer covering gastric and
duodenal mucosa which is buffered by HCO3- secreted
into this layer by the underlying epithelial cells.
• Misoprostol, Irsogladine, and Rebamipide
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Complications of PUD
• Gastrointestinal bleeding is the most common complication.
• Perforation (a hole in the wall) often leads to catastrophic consequences.
Erosion of the gastro-intestinal wall by the ulcer leads to spillage of stomach
or intestinal content into the abdominal cavity.
• Penetration is when the ulcer continues into adjacent organs such as the
liver and pancreas.
• Scarring and swelling due to ulcers causes narrowing in the duodenum
• Gastric outlet obstruction. Patient often presents with severe vomiting.
• Cancer is included in the differential diagnosis (elucidated by biopsy),
Helicobacter pylori as the etiological factor making it 3 to 6 times more
likely to develop stomach cancer from the ulcer.
•
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Stomach (architecture) Duodenum (erosion)
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INFLAMMATORY
BOWEL DISEASE (IBD)
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IBD
• Idiopathic chronic inflammation of GIT.
• The diagnosis of inflammatory bowel disease (IBD) with
its 2 main subforms,
• Crohn’s disease- full thickness inflammation involving any
part of the GIT (mouth to anus)
• Ulcerative colitis- limited to mucosal layer of colon
• UC- male ˃ female
• CD- female ˃ male
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Presentation
• Presentation of UC • Presentation of CD
• Depends on extent & • Diarrhea
severity of inflammation
• Chronic abdominal pain
• Bloody diarrhea
• Weight loss
• Abdominal cramping
• Fever
• Tenesmus-fecal urgency
• Perianal disease
• Systemic symptoms,
fever, decreased stamina, • Symptoms vary with type
weight loss & location of disease
(fistulizing)
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Goals of therapy in IBD
• Induce Remission of active disease
• Maintenance of remission
• Maintain/restore nutrition
• Avoid surgery
• Avoid complications (therapy or disease related)
• Quality of life
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TRADITIONAL THERAPIES
CLASS SIDE EFFECTS
5-ASA (Mesalamine)- Asacol, Pentasa Nausea, diarrhea, nephritis
Antibiotics- Flagyl, Ciprofloxacin Neuropathy, nausea
Corticosteroids- Budesonide, Diabetes, weight gain, moody, cataracts,
Prednisolone osteoporosis/necrosis
Immunomodulators- Methotrexate, Leukopenia, hepatitis, pancreatitis,
6-MP, Azathioprine lymphoma, infection
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Biologic Therapies: New Era
• Advent of biologic agents dramatically changed IBD
treatment
• Specifically target mediators of inflammation
• Anti-Tumor Necrosis Factor Alpha Antibodies
(Anti-TNF Ab)- intolerance, loss of efficacy-sec.
failure
• Infliximab therapy for UC
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EMESIS
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• Nausea and vomiting occur in a variety of conditions-
pregnancy, motion sickness, hepatitis
• Chemotherapeutic agents (cisplatin) induced nausea and
vomiting demand effective management
• Emesis affects the quality of life, leads to curative
neoplastic treatment rejection.
• Uncontrolled vomiting can produce dehydration,
profound metabolic imbalance & nutrient depletion
• Promethazine-severe morning sickness; scopolamine,
cyclizine- motion sickness
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Mechanisms that trigger emesis
• Two brain sites play key roles in the vomiting reflex
pathway.
- The Chemoreceptor trigger zone (CTZ): located in
the postrema outside the BBB. Responds to chemical
stimuli in the blood or CBF
- The vomiting center: located in the lateral reticular
formation of the medulla; coordinates the motor
mechanisms of vomiting
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Emetic actions of chemotherapeutic
agents
• Directly activate the medullary CTZ or vomiting center;
• Neuroreceptors like DA receptor Type 2, 5HT Type 3,
Ach, play critical roles.
• Color and smell of chemotherapeutic agents
• Act peripherally causing cell damage in the GIT and
releasing 5HT from the enterochromaffin cells of the
small intestinal mucosa.
• Released 5HT activates 5-HT3 receptor on vagal and
splanchnic afferent fibers, which carry sensory signals to
the medulla, leading to the emetic response
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Schematic diagram of the factors involved in the control of vomiting, with the probable
sites of action of antiemetic drugs.
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Antiemetic
drugs
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• Phenothiazine • Benzodiazepines
- Prochlorperazine -Alprazolam
• 5-HT3 blockers -Lorazepam
-Dolasetron • Corticosteroids
-Ondansetron -Dexamethasone
-Granisetron -Methylprednisolone
• Substituted benzamides • Cannabinoids
-Metoclopramide -Dronabinol
• Butyrophenones -Nabilone
-Droperidol • Substance P/ Neurokinin -
-Haloperidol 1 Receptor Blocker
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Phenothiazines
• Ist group of drugs shown to be effective antiemetics for
treating the more severe nausea and vomiting associated
with cancer, radiation therapy, cytotoxic drugs and other
drugs.
• Prochlorperazine acts by blocking DA receptors, effective
against low or moderate emetogenic chemotherapeutic
agents like fluorouracil, doxorubicin
• ↑ dose ↑antiemetic activity
• Side effects- hypotension, restlessness
• Adv Rxn – extrapyramidal symptoms, sedation
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5-HT3 receptor blockers
• Important in treating emesis-linked chemotherapy with Long
duration of action
• Selectively block 5-HT3 receptors in the periphery & the brain
• Administered as single dose prior to chemotherapy & effective
against all grades of emetogenic therapy
• Extensively metabolized by the liver adjusted for hepatic
insufficiency, eliminated through the urine.
• Ondansetron ˃ metoclopramide
• SE- Headache, ondansetron- no extrapyramidal S.E
• Dolasetron causes ECG changes- patients at risk receive with
caution.
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Substituted Benzamides
• Metoclopramide – D2 receptor antagonist closely related
to the phenothiazine group,
• Acts centrally on the CTZ and also has a peripheral
action on the GIT
• Highly effective at high doses against cisplatin in 30-40%
of patients ↓ emesis in the majority.
• Indicated in pregnancy; post-operative nausea; omitting
prophylaxis
• Antidopaminergic side effects- sedation, diarrhea,
extrapyramidal symptoms limits its high-dose
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Butyrophenones
• Act by blocking D2 receptors
• Are moderately effective antiemetics
• High dose haloperidol found to be nearly as effective
as high dose metoclopramide in preventing
cisplatin-induced emesis
• Droperidol (IV only) and haloperidol (Haldol)- used
in palliative medicine quite frequently for treatment
of nausea and vomiting.
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Benzodiazepines
• Low antiemetic potency
• Unknown mechanism of action
• Beneficial effects may be due to their sedative,
anxiolytic & amnesic properties.
• These same properties make them useful in treating
anticipatory vomiting
• Lorazepam (Ativan)
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Corticosteroids
• Methylprednisolone; dexamethasone
• MP may decrease 5-HT release
• When used alone, are effective against mild to
moderate emetogenic chemotherapy; but are recently
used in combination with other agents.
• Antiemetic mechanism- not known; may involve
blockade of prostaglandins
• Cause insomnia, hyperglycemia in patients with DM
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Cannabinoids
• Are marijuana derivatives effective against moderate
emetogenic chemotherapy.
• Sometimes effective where other drugs have failed.
• Not first-line antiemetics because of their serious SE-
dysphoria, hallucinations, sedation, vertigo &
disorientation.
• Dronabinol; nabilone
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Substance P/neurokinin-1 receptor
blocker
• Aprepitant
• New family of antiemetic agents
• Target the neurokinin receptor in the brain & blocks
the actions of the natural substance
• Adm p.o.
• Extensively metabolized by CYP3A4- affects the
metabolism of other drugs
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Combined Regimens
• Antiemetic drugs are often combined to increase
antiemetic activity or decrease toxicity
• Dexamethasone + metoclopramide/phenothiazine/
butyrophenone = ↑ antiemetic activity
• Diphenhydramine + metoclopramide =
↓extrapyramidal reactions or with corticosteroids to
counter metoclopramide- induced diarrhea
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ANTIDIARRHEALS
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Diarrhea
• There are numerous causes of diarrhoea, including
underlying disease, infection, toxins and even anxiety.
It may also arise as a side effect of drug or radiation
therapy.
• Globally, acute diarrheal disease is one of the
principal causes of death in malnourished infants,
especially in developing countries where medical care
is less accessible and 1–2 million children die each
year for want of simple counter-measures.
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• During an episode of diarrhoea there is :
*an increase in the motility of the GIT
*increased secretion
*decreased absorption of fluid, which leads to a loss of
electrolytes (particularly Na+) and water.
• Cholera toxins and some other bacterial toxins produce a
profound increase in electrolyte and fluid secretion by
irreversibly activating the G-proteins that couple the
surface receptors of the mucosal cells to adenylyl cyclase
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• There are three approaches to the treatment of severe
acute diarrhoea:
• Maintenance of fluid and electrolyte balance.
• Use of anti-infective agents- Many GI infections are
viral in origin, and because those that are bacterial
generally resolve fairly rapidly, the use of
anti-infective agents is usually neither necessary nor
useful.
• Use of spasmolytic or other anti-diarrhoeal agents.
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Antimotility Agents
• Diphenoxylate & Loperamide widely used to control
diarrhea.
• Have opioid-like actions on the gut, activating
presynaptic opioid receptors in the ENS to inhibit
Ach release and ↓ peristalsis.
• Lack analgesic effects at usual doses
• SE- drowsiness, abdominal cramps & dizziness.
• Not used in young children
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Adsorbents
• Bismuth Subsalicylate, Methylcellulose are used to
control diarrhea.
• Are presumed to act by adsorbing intestinal toxins or
microorganisms and/or by coating or protecting the
intestinal mucosa
• Less effective than antimotility agents
• Can interfere with the absorption of other drugs
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Agents that modify fluid and
electrolyte transport
• Bismuth subsalicylate used for traveler’s diarrhea, ↓
fluid secretion in the bowel.
• Action may be due to its salicylate component as well
as its coating action.
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LAXATIVES
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Constipation
• Constipation is a common clinical problem. Initial
management of chronic constipation should include
lifestyle maneuvers, and increased fiber and fluids.
• Polyethylene glycol, sodium picosulfate, bisacodyl,
prucalopride, lubiprostone, and linaclotide were all
more effective than placebo for treating chronic
idiopathic constipation.
• Many commonly used agents lack quality evidence
supporting their use.
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BULK AND OSMOTIC LAXATIVES
• Bulk laxatives include methylcellulose and certain plant extracts such
as sterculia, agar, bran and ispaghula husk. These agents are
polysaccharide polymers that are not digested in the upper part of the
gastrointestinal tract.
• They form a bulky hydrated mass in the gut lumen promoting peristalsis and
improving faecal consistency. They may take several days to work but have
no serious unwanted effects.
• Osmotic laxatives consist of poorly absorbed solutes—the saline
purgatives—and lactulose. The main salts in use are Mg sulfate and Mg
hydroxide.
• By producing an osmotic load, these agents trap increased volumes of fluid
in the lumen of the bowel, accelerating the transfer of the gut contents
through the small intestine.
• This results in an abnormally large volume entering the colon, causing
distension and purgation within an hour. Abdominal cramps can occur.
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• The amount of Mg absorbed after an oral dose is usually too small to
have adverse systemic effects, but these salts should be avoided in
small children and in patients with poor renal function, in whom they
can cause heart & neuromuscular block or CNS depression.
• While isotonic or hypotonic solutions of saline purgatives cause
purgation, hypertonic solutions can cause vomiting. Sometimes,
other sodium salts of phosphate and citrate are given rectally, by
suppository, to relieve constipation.
• Lactulose is a semisynthetic disaccharide of fructose and galactose. It
is poorly absorbed and produces an effect similar to that of the other
osmotic laxatives.
• Takes 2–3 days to act. Unwanted effects with high doses, include
flatulence, cramps, diarrhoea and electrolyte disturbance. Tolerance
can develop.
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• FAECAL SOFTENERS
• Docusate sodium is a surface-active compound that acts in the gastrointestinal tract
in a manner similar to a detergent and produces softer faeces.
• A weak stimulant laxative.
• Other agents that achieve the same effect include arachis oil, which is given as an
enema, and liquid paraffin, although this is now seldom used.
• STIMULANT LAXATIVES
• The stimulant laxative drugs act mainly by ↑ electrolyte and hence water secretion by
the mucosa, and also by ↑peristalsis—possibly by stimulating enteric nerves.
Abdominal cramping may be experienced as a side effect with almost any of these
drugs.
• Bisacodyl may be given by mouth but is often given by suppository. In the latter
case, it stimulates the rectal mucosa, inducing defaecation in 15–30 min.
• Glycerol suppositories act in the same manner. Sodium picosulfate and docusate
sodium have similar actions. The former is given orally and is often used in
preparation for intestinal surgery or colonoscopy.
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• Senna and dantron are anthroquinone laxatives. The active principle (after
hydrolysis of glycosidic linkages in the case of the plant extract, senna)
directly stimulates the myenteric plexus, resulting in increased peristalsis and
thus defaecation.
• Dantron is similar. As this drug is a skin irritant and may be carcinogenic, it
is generally used only in the terminally ill.
• Laxatives of any type should not be used when there is obstruction of the
bowel.
• Overuse can lead to an atonic colon where the natural propulsive activity is
diminished.
• In these circumstances, the only way to achieve defaecation is to take further
amounts of laxatives, so a sort of dependency arises.
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DRUGS THAT INCREASE GI MOTILITY
• Domperidone primarily used as an antiemetic, but it also increases GI
motility (although the mechanism is unknown). Clinically, it increases LES
pressure (thus inhibiting gastro-oesophageal reflux), increases gastric
emptying and enhances duodenal peristalsis. It is useful in disorders of
gastric emptying and in chronic gastric reflux.
• Metoclopramide (antiemetic) stimulates gastric motility, causing a marked
acceleration of gastric emptying. It is useful in gastro-oesophageal reflux and
in disorders of gastric emptying, but is ineffective in paralytic ileus.
• Now withdrawn (because it precipitated fatal cardiac
arrhythmias), cisapride stimulates Ach release in the myenteric plexus in the
upper GIT through a 5-HT4 receptor-mediated effect.
• Tegaserod (also recently withdrawn on account of suspected increase in
heart attacks and strokes) acts similarly. These drugs raise oesophageal
sphincter pressure and increase gut motility. They were used for treating
reflux oesophagitis and in disorders of gastric emptying.
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References
• John B. Furness (2007), Scholarpedia, 2(10):4064.
• MLA style: "Sir James W. Black - Facts". Nobelprize.org. Nobel Media AB
2014. Web. 12 Sep 2016.
http://www.nobelprize.org/nobel_prizes/medicine/laureates/1988/black-f
acts.html
• Medical Management of Constipation
• Meredith Portalatin, M.D.1 and Nathaniel Winstead, M.D.1 Clin Colon Rectal
Surg. 2012 Mar; 25(1): 12–19. doi: 10.1055/s-0032-1301754
PMCID: PMC3348737
• Saline purgatives act by releasing cholecystokinin.Harvey RF, Read AE
• Lancet. 1973 Jul; 2(7822):185-7.
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