University of Juba

College of Medicine
PHARMACOLOGY LECTURES
Gastrointestinal and Antiemetic Drugs

By
Dr. Rita Gabriel Tulba
Pharmacy Specialist
 Drugs Used to Treat Peptic Ulcer Disease

There are several major causative factors for peptic ulcer :

• Nonsteroidal anti-inflammatory drug (NSAID) use.
• Infection with gram-negative Helicobacter pylori.
• Increased hydrochloric acid secretion.
• Inadequate mucosal defense against gastric acid.
General management of peptic ulceration
• Stop smoking.
• Avoid ulcerogenic drugs (e.g. NSAIDs, alcohol, glucocorticosteroids).
• Reduce caffeine intake.
• Diet should be healthy (avoid obesity, and foods that give rise to symptoms).
• Test for the presence of H. pylori.
Treatment include:
1) Eradicating the H. pylori infection
2) Reducing secretion of gastric acid with the use of H2-receptor antagonists or PPIs,
and/or
3) Providing agents that protect the gastric mucosa from damage, such as misoprostol
and sucralfate.
4) If patients are unable to tolerate the above therapies, neutralizing gastric acid with
nonabsorbable antacids is an option)
Summary of drugs used to treat peptic
ulcer disease
 Antimicrobial agents
• Antimicrobial agents therapy needed for patients with peptic ulcer disease (both
duodenal and gastric ulcers) who are infected with H. pylori requires antimicrobial
treatment.
• The infection with H. pylori need to be documented with endoscopic biopsy of the
gastric mucosa or various noninvasive methods are , including serologic tests and urea
breath tests.
• Eradication of H. pylori results in rapid healing of active peptic ulcers and low
recurrence rates.
• Successful eradication of H. pylori (80 to 90 percent) is possible with various
combinations of antimicrobial drugs.
• Currently antimicrobial combinations, either triple therapy consisting of a PPI with
either metronidazole or amoxicillin plus clarithromycin.
• Or quadruple therapy of bismuth subsalicylate and metronidazole plus tetracycline
plus a PPI, are administered for a 2-week course.
• Bismuth salts do not neutralize stomach acid, but they inhibit pepsin and increase the
secretion of mucus, thus helping to form a barrier against the diffusion of acid in the
ulcer.
• Treatment with a single antimicrobial drug is less effective results in antimicrobial
resistance and is absolutely not recommended.
Regulation of gastric acid secretion
• Gastric acid secretion by parietal cells of the gastric mucosa is stimulated by
acetylcholine, histamine, and gastrin.
• The receptor-mediated binding of acetylcholine, histamine, or gastrin results in the
activation of protein kinases, which in turn stimulates the H+/K+ adenosine
triphosphatase (ATPase) proton pump to secrete hydrogen ions in exchange for K+ into
the lumen of the stomach.
• A Cl- channel couples chloride efflux to the release of H+.
• The result is formation of HCL acid.
 H2-receptor antagonists
• Antagonists of the histamine H2 receptor block the actions of histamine at all H2 receptors,
• Their chief clinical use is to inhibit gastric acid secretion, being particularly effective
against nocturnal acid secretion. By
• They competitively block the binding of histamine to H2 receptors, reduce the intracellular
concentrations of cyclic adenosine monophosphate and, thereby, secretion of gastric acid.
• The four drugs used in
• Ranitidine , Famotidine , and Nizatidine potently inhibit (greater than 90 percent) basal,
food-stimulated, and nocturnal secretion of gastric acid after a single dose.
• Cimetidine is the prototype histamine H2-receptor antagonist;
• Its utility is limited by its adverse effect profile and drug interactions.
Actions:
• The histamine H2-receptor antagonists.
• Selectively on H2 receptors in the stomach, blood vessels, and other sites, but they
have no effect on H1 receptors.
• They are competitive antagonists of histamine and are fully reversible.
• They only partially inhibit gastric acid secretion induced by acetylcholine or
bethanechol.
Therapeutic uses:
1.Peptic ulcers: All four agents are equally effective in promoting healing of duodenal and
gastric ulcers.
2.Acute stress ulcers: These drugs are useful in managing acute stress ulcers associated
with major physical trauma in high-risk patients in intensive care units.
They are usually injected intravenously.
3.Gastroesophageal reflux disease:
• Low doses of H2 antagonists, recently released for over-the-counter
sale, appear to be effective for prevention and treatment of heartburn
(gastroesophageal reflux).
• PPIs are now used preferentially in the treatment of this disorder.
Because H2-receptor antagonists act by stopping acid secretion, they
may not relieve symptoms for at least 45 minutes..
• Tolerance to the effects of H2 antagonists can be seen within 2 weeks of
therapy.
Pharmacokinetics
Cimetidine: Cimetidine and the other H2 antagonists are given orally, distribute into
breast milk and placenta and are excreted mainly in the urine.
• Cimetidine normally has a short serum half-life, can interfere in the metabolism of
many other drugs;
• The dosage of all these drugs must be decreased in patients with hepatic or renal
failure.
• Cimetidine inhibits cytochrome P450 and can slow metabolism (and, thus, potentiate
the action) of several drugs (for example, warfarin, diazepam, phenytoin, quinidine,
carbamazepine, theophylline, and imipramine
2.Ranitidine: ranitidine is longer acting and more potent. has minimal side effects and
does not inhibit the mixed-function oxygenase system in the liver ,thus does not affect the
concentrations of other drugs.
3.Famotidine: Famotidine is similar to ranitidine in its pharmacologic action. but more
potent than ranitidine.
4.Nizatidine: Nizatidine is similar to ranitidine in its pharmacologic action and potency.
Because little first-pass metabolism occurs with nizatidine, its bioavailability is nearly 100
percent. No intravenous preparation is available
Adverse effects: The adverse effects of cimetidine are usually minor and are associated
mainly with the major pharmacologic activity of the drug namely, reduced gastric acid
production.
 Inhibitors of the H+/K+-ATPase proton pump
(PPI)
• Omeprazole is the first of a class of drugs that bind to the H+/K+-ATPase enzyme
system (proton pump) of the parietal cell, thereby suppressing secretion of hydrogen
ions into the gastric lumen.
• The membrane-bound proton pump is the final step in the secretion of gastric acid.
Four additional
• PPIs are now available: Lansoprazole , Rabeprazole , Pantoprazole and Esomeprazole.
Therapeutic uses:
• Suppressing acid production and healing peptic ulcers, erosive esophagitis and active
duodenal ulcer
• PPIs reduce the risk of bleeding from an ulcer caused by Aspirin and other NSAIDs.
• They are also successfully used with antimicrobial regimens to eradicate H. pylori.
• For maximum effect, PPIs should be taken 30 minutes before breakfast or the largest
meal of the day.
Pharmacokinetics:
• All these agents are delayed-release formulations and are effective orally.
• Some are also available for intravenous injection.
• Metabolites of these agents are excreted in urine and feces.
Adverse effects:
• Omeprazole inhibits the metabolism of warfarin, phenytoin, diazepam, and cyclosporine.
• Prolonged therapy with PPI suppress gastric acid, may result in low vitamin B12, because
acid is required for its absorption.
• Increasing gastric pH increases the potential for incomplete absorption of calcium carbonate
products. An effective option would be to use calcium citrate as a source of calcium by
patients taking prolonged acid-suppressing medications. The absorption of the citrate salt is
not affected by gastric pH.
• There are increased reports of diarrhea and Clostridium difficile colitis in community
patients receiving PPIs; therefore, patients must be counseled to discontinue PPI therapy if
they have diarrhea for several days and to contact their physicians for further follow-up.
 Prostaglandins
• Prostaglandin E2, produced by the gastric mucosa, inhibits secretion of HCl and
stimulates secretion of mucus and bicarbonate (cytoprotective effect).
• A deficiency of prostaglandins is thought to be involved in the pathogenesis of peptic
ulcers.
• Misoprostol a stable analog of prostaglandin E1,
• Misoprostol has cytoprotective actions, it is clinically effective only at higher doses that
diminish gastric acid secretion.
• prostaglandins, misoprostol produces uterine contractions and is contraindicated during
pregnancy
 Antimuscarinic agents (anticholinergic agents)

• Muscarinic receptor stimulation increases gastrointestinal motility and secretory

activity.
• Dicyclomine is a cholinergic antagonist, , can be used as an adjunct in the management
of peptic ulcer diseases
• side effects (for example, cardiac arrhythmias, dry mouth, constipation, and urinary
retention) limit its use.
 Antacids
• Antacids are weak bases that react with gastric acid to form water and a salt, thereby
diminishing gastric acidity.
• Because pepsin is inactive at a pH greater than 4, antacids also reduce pepsin activity.
• The acid-neutralizing ability of an antacid depends on its capacity to neutralize gastric
HCl and on whether the stomach is full or empty.
• Food delays stomach emptying, allowing more time for the antacid to react.
Commonly used antacids are salts of aluminum and magnesium, such
as:
• Aluminum hydroxide (usually a mixture of Al(OH)3 and aluminum oxide
hydrates).
• Magnesium hydroxide [Mg(OH)2], either alone or in combination.
• Calcium carbonate [CaCO3] reacts with HCl to form CO2 and CaCl2 and is a
commonly used preparation.
• Systemic absorption of sodium bicarbonate [NaHCO3] can produce transient
metabolic alkalosis; therefore, this antacid is not recommended for long-term
use.
Therapeutic uses:
• Aluminum- and magnesium-containing antacids are used for symptomatic relief of
peptic ulcer disease.
• Treatment of acute gastric ulcers is less compelling; therefore, these agents are used as
last-line therapy.
• Note: Calcium carbonate preparations are also used as calcium supplements for the
treatment of osteoporosis.
Adverse effects:
• Aluminum hydroxide tends to be constipating, and magnesium hydroxide tends to produce
diarrhea.
• Preparations that combine these agents aid in normalizing bowel function.
• Systemic alkalosis, sodium bicarbonate liberates CO2, causing belching and flatulence.
• sodium content of antacids can be an important consideration in patients with hypertension
or congestive heart failure.
• patients with renal impairment, caused by accumulation of magnesium, calcium, sodium, and
other electrolytes.
• Excessive intake of calcium carbonate along with calcium foods can result in hypercalcemia.
 Mucosal protective agents
• These compounds, known as cytoprotective compounds, have several actions that
enhance mucosal protection mechanisms.
• Preventing mucosal injury, reducing inflammation, and healing existing ulcers
Sucralfate:
• A complex of aluminum hydroxide and sulfated sucrose.
• Binds to positively charged groups in proteins of mucosa.
• Forming a complex gels with epithelial cells, sucralfate creates a physical barrier that impairs diffusion of
HCl and prevents degradation of mucus by pepsin and acid.
• It also stimulates prostaglandin release as well as mucus and bicarbonate output, and it inhibits peptic
digestion.
• sucralfate effectively heals duodenal ulcers .
• Because it requires an acidic pH for activation sucralfate should not be administered with H2 antagonists
or antacids.
• This agent does not prevent NSAID-induced ulcers, nor does it heal gastric ulcers.
Bismuth subsalicylate:
• Effectively heal peptic ulcers.
• Have antimicrobial actions, they inhibit the activity of pepsin, increase secretion of
mucus.
• Interact with glycoproteins in mucosal tissue to coat and protect the ulcer crater.
 Antiemetic drugs
• Nausea and vomiting may occur in a variety of conditions (for example, motion sickness,
pregnancy, or hepatitis) and are always unpleasant for the patient.
• Emesis not only affects the quality of life but can lead to rejection of potentially
curative antineoplastic treatment.
• In addition, uncontrolled vomiting can produce dehydration, profound metabolic
imbalances, and nutrient depletion.
 Mechanisms that trigger vomiting
Two brainstem sites have key roles in the vomiting reflex pathway.
1.The chemoreceptor trigger zone:
• Which is located in the area postrema is outside the blood-brain barrier. Thus, it can
respond directly to chemical stimuli in the blood or cerebrospinal fluid.
2. The vomiting center :
• Which is located in the lateral reticular formation of the medulla, coordinates the motor
mechanisms of vomiting.
• The vomiting center also responds to afferent input from the vestibular system, the
periphery (pharynx and gastrointestinal tract), and higher brainstem and cortical
structures.
• The vestibular system functions mainly in motion sickness.
 Emetic actions of chemotherapeutic agents

• Chemotherapeutic agents (or their metabolites) can directly activate the medullary
chemoreceptor trigger zone or vomiting center.
• Neuroreceptors, including dopamine receptor Type 2 and serotonin Type 3 (5-HT3), play
critical roles.
• Also the color or smell of chemotherapeutic drugs (and even stimuli associated with
chemotherapy, such as cues in the treatment room or the physician or nurse who administers
the therapy) can activate higher brain centers and trigger emesis.
• Chemotherapeutic drugs can also act peripherally by causing cell damage in the
gastrointestinal tract and releasing serotonin from cells of the small intestinal mucosa.
• The released serotonin activates 5-HT3 receptors on vagal and splanchnic afferent fibers,
which then carry sensory signals to the medulla, leading to the emetic response
 Drugs Used to Control Nausea and Vomiting

• Considering the complexity of the mechanisms involved in emesis, antiemetics

represent a variety of classes and offer a range of efficacies.
• The major categories of drugs used to control nausea and vomiting including
chemotherapy-induced nausea and vomiting as the following:
1. Phenothiazines:
• The first group of drugs shown to be effective antiemetic.
• Prochlorperazine: acts by blocking dopamine receptors.
• It is effective against low or moderately emetogenic chemotherapeutic agents.
• side effects, including hypotension and restlessness, extrapyramidal symptoms and
sedation.
2. 5-HT3 receptor blockers:
• They have the advantage of a long duration of action.
• Ondansetron ,Granisetron, Palonosetron and Dolasetron selectively block 5-HT3 receptors in the
periphery (visceral vagal afferent fibers) and in the brain (chemoreceptor trigger zone).
• These drugs can be administered as a single dose prior to chemotherapy (intravenously or orally).
• Doses of these agents should be adjusted in patients with hepatic insufficiency.
• Headache is a common side effect.
• Electrocardiographic changes, such as prolongation of the QT interval, can occur with dolasetron;
• These drugs are costly.
3. Substituted benzamides:
• Metoclopramide :is highly effective at high doses against the highly emetogenic
• Antidopaminergic side effects including sedation, diarrhea, and extrapyramidal
symptoms.
4. Butyrophenones:
• Droperidol and haloperidol act by blocking dopamine receptors.
• The butyrophenones are moderately effective antiemetics.
• It may prolong the QT interval.
• Current practice reserves it for patients whose response to other agents is inadequate.
5. Benzodiazepines:
• The antiemetic potency of lorazepam and alprazolam is low. Their beneficial effects may be
due to their sedative, anxiolytic, and amnesic properties.
• Benzodiazepines useful in treating anticipatory vomiting.
6. Corticosteroids:
• Dexamethasone and methylprednisolone used alone, are effective against mildly to
moderately emetogenic chemotherapy.
• They are used in combination with other agents.
• Their antiemetic mechanism may involve blockade of prostaglandins.
• These drugs can cause insomnia as well as hyperglycemia in patients with diabetes mellitus.
7. Cannabinoids:
• Marijuana derivatives, Dronabinol and Nabilone.
• effective against moderately emetogenic chemotherapy. However, they are seldom first-line antiemetics
• because of their serious side effects .
8. Substance P/neurokinin-1 receptor blocker:
• Aprepitant.
• It targets the neurokinin receptor in the brain and blocks the actions of the natural substance.
• Aprepitant is usually administered orally with dexamethasone and palonosetron
• Aprepitant can also induce liver enzyme and, thus, affect responses to other agents; for example,
concomitant use with warfarin can shorten the half-life.
9. Combination regimens:
• Antiemetic drugs are often combined to increase antiemetic activity or decrease
toxicity.
• Corticosteroids, most commonly dexamethasone, increase antiemetic activity when
given with high-dose metoclopramide, a 5-HT3 antagonist, phenothiazine,
butyrophenone, a cannabinoid or benzodiazepine.
• Antihistamines, such as diphenhydramine, are often administered in combination with
• high-dose metoclopramide to reduce extrapyramidal reactions or with corticosteroids to
counter metoclopramide-induced diarrhea.
 Antidiarrheals
Increased motility of the gastrointestinal tract and decreased absorption of fluid are major
factors in diarrhea.
Antidiarrheal drugs include :
1.Antimotility agents,
2.Adsorbents, and
3.Drugs that modify fluid and electrolyte transport
• The most important aspect of the treatment of acute diarrhoea is the maintenance of fluid
and electrolyte balance, particularly in children and in the elderly.
• In non-pathogenic diarrhoea or viral gastroenteritis, antibiotics and antidiarrhoeal drugs
are best avoided.
• Initial therapy should be with oral rehydration preparations which contain electrolytes
and glucose.
• Antibiotic treatment is indicated for patients with systemic illness and evidence of
bacterial infection.
1.Antimotility agents
• Two drugs that are widely used to control diarrhea:
• Diphenoxylate and Loperamide
• Action: opioid-like actions on the gut, inhibit acetylcholine release and decrease
peristalsis.
• Side effects: include drowsiness, abdominal cramps, and dizziness.
• These drugs should not be used in young children or in patients with severe colitis.
2. Adsorbents
• Are used to control diarrhea.
• Bismuth subsalicylate, Methylcellulose and Aluminum hydroxide .
Action: These agents act by adsorbing intestinal toxins or microorganisms and/or by
coating or protecting the intestinal mucosa.
• They are much less effective than antimotility agents.
Side effects: They can interfere with the absorption of other drugs.
• Adsorbents, such as kaolin, are not recommended for diarrhoea.
• Bulk-forming drugs, such as Methylcellulose is useful in controlling faecal consistency in
ileostomy and colostomy.
3.Agents that modify fluid and electrolyte transport
• Bismuth subsalicylate, used for traveler's diarrhea, decreases fluid secretion in
the bowel.
• This is a syndrome of acute watery diarrhoea lasting for one to three days and
associated with vomiting, abdominal cramps.
• Resulting from infection by one of a number of enteropathogens, the most
common being enterotoxigenic Escherichia coli.
• Ciprofloxacin is occasionally used for prophylaxis against traveler's
diarrhea.
 Laxatives
• Laxatives are commonly used to accelerate the movement of food through the
gastrointestinal tract.
• These drugs can be classified on the basis of their mechanism of action:
• such as irritants or stimulants of the gut, bulking agents, stool softeners.
• They all have a risk of being habit-forming.
• Laxatives also increase the potential of loss of pharmacologic effect of poorly
absorbed, delayed-acting, and extended-release oral preparations by accelerating their
transit through the intestines. They may cause electrolyte imbalances when used
chronically.
As a general rule, laxatives should be avoided. They are employed:
• If straining at stool will cause damage (e.g. postoperatively, in patients with
haemorrhoids or after myocardial infarction); in hepatocellular failure to reduce formation
and/or
absorption of neurotoxins produced in the bowel.
• Occasionally in drug-induced constipation.
Drugs used to treat Constipation
1. Irritants and stimulants
• Senna is a widely used stimulant laxative. Its active ingredient is a group of sennosides
• Bisacodyl, available as suppositories and enteric-coated tablets.
• Taken orally, it causes evacuation of the bowels within 8 to 10 hours.
• Action: It causes water and electrolyte secretion into the bowel.
• Adverse effects include: abdominal cramps.
• Contraindication: Antacids should not be taken at the same time as the enteric-coated
tablets. The antacid would cause the enteric coating to dissolve prematurely in the stomach,
resulting in stomach irritation and pain. Milk, H2-receptor antagonists, and PPIs.
• It should be avoided by pregnant patients, because it may stimulate uterine contractions.
2. Bulk laxatives
• The bulk laxatives include hydrophilic colloids from indigestible parts of fruits and
vegetables also methylcellulose, psyllium seeds, and bran.
• Action: They form gels in the large intestine, causing water retention and intestinal
distension, thereby increasing peristaltic activity.
• Side effects: Bran usually causes some and bind calcium and zinc ions
• They should be used cautiously in patients who are bed-bound, due to the potential for
intestinal obstruction.
3.Saline and osmotic laxatives
• 1. Saline cathartics: such as magnesium citrate, magnesium sulfate (Epsom salt),
sodium phosphate, and magnesium hydroxide.
• Action: are nonabsorbable salts (anions and cations) that hold water in the intestine by
osmosis and distend the bowel,increasing intestinal activity and producing defecation in
a few hours.
• Electrolyte solutions containing polyethylene glycol (PEG) are used as colonic lavage
solutions to prepare the gut for radiologic or endoscopic procedures. PEG powder for
solution is available as a prescription and also an over-the-counter laxative (Saline
Enema).
• 2.Osmotic laxative: such as Lactulose is a semisynthetic
disaccharide sugar that also acts as
• Action: Oral doses are degraded in the colon by colonic bacteria
into lactic, formic, and acetic acids. This increases osmotic
pressure, thereby accumulating fluid, distending the colon,
creating a soft stool, and causing defecation.
4. Stool softeners (emollient or surfactants) laxatives
• Surface-active agents that become emulsified with the stool produce softer feces and
ease passage.
• These include:
Docusate sodium, Docusate calcium, and Docusate potassium.
5. Lubricant laxatives(Chemical stimulants)
Many of the agents in this class:
1.Mineral oil
2.Castor oil, phenolphthalein
3.Glycerin suppositories.
• They facilitate the passage of hard stools.
• Glycerol suppositories act as a rectal stimulant due to the local irritant action of glycerol
and are useful if a rapid effect is required.
• Mineral oil should be taken orally in an upright position to avoid its aspiration and potential
for lipid or lipoid pneumonia. (are now obsolete because of their toxicity)
 IRRITABLE BOWEL SYNDROME
• This motility disorder of the gut affects approximately 10% of the
population.
• The symptoms are mostly colonic, patients with the syndrome have
abnormal motility throughout the gut
• This may be precipitated by dietary items, such as alcohol or
wheat flour.
The important management principles are :
• First: to exclude a serious cause for the symptoms and then to determine
whether exclusion of certain foods or alcohol would be worthwhile.
• Second: An increase in dietary fibre over the course of several weeks may
also reduce the symptoms.
• Psychological factors may be important precipitants and counselling may
be helpful.
• Drug treatment is symptomatic and often disappointing.
Drug treatment
1.Anticholinergic drugs: such as Hyoscine, have been used for many years. The oral use of
better absorbed anticholinergics, such as Atropine, is limited by their side effects.
2. Mebeverine (135 mg before meals three times daily) directly relaxes intestinal smooth
muscle without anticholinergic effects.
3. Chlordiazepoxide HCL and Clidinium bromide :(benzodiazepine and
anticholinergic/antispasmodic)
4. Peppermint oil relaxes intestinal smooth muscle and is given in an enteric-coated capsule
which releases its contents in the distal small bowel. It is given before meals
three times daily.
5. Antidiarrhoeal drugs: such as loperamide, reduce associated
diarrhoea.
6.Psychotropic drugs: such as antipsychotics and antidepressants
with anticholinergic properties, have also been effective in some
patients.
In general, however, they should be avoided for such a chronic and
benign condition because of their serious adverse effects
THANK YOU
DR. RITA GABRIEL TULBA
Email: rita.tulba1969@gmail.com
Tel:+211912838737