Medicines acting on the

Gastro-Intestinal Tract
System

Dr TM Ndlovu
Department of Pharmacology and Therapeutics
Sefako Makgatho Health Sciences University
X4037, Room N517, BMS
e-mail: Thabisile.Ndlovu@smu.ac.za
Consultation hours: 13H00 – 15H00, Mon – Fri1
 Learning Goals
• Classes of drugs used to improve the function of the
gastrointestinal tract.
• Uses (indications) of different classes of GIT drugs.
• Mechanism of actions of different classes of GIT drugs.
• Absorption, distribution, metabolism and excretion of GIT
drugs.
• Adverse effects of GIT drugs.

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Gastrointestinal tract

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Peptic ulcers and gastro-oesophageal
reflux disease (GERD)
• Infection with gram-negative Helicobacter pylori.
• Use of non-steroidal anti-inflammatory drugs (NSAIDs).
• Increased hydrochloric acid secretion.
• Inadequate mucosal defence against gastric acid.

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 Treatment-Peptic ulcers and gastro-oesophageal reflux
disease (GERD)

• Classes of drugs:
• Proton pump inhibitors (PPIs)
• Esomeprazole, Lansoprazole, Omeprazole,
Pantoprazole, Rabeprazole sodium
• H2-receptor antagonists
• Cimetidine, Ranitidine
• Prostaglandins
• Misoprostol
• Other drugs:
• Alginic acid, Sucralfate and Bismuth subcitrate

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 Proton Pump Inhibitors
• Indicated for:
• Short-term management of peptic ulcer disease and GERD.
• Long-term prevention of relapse of GERD.
• H. pylori eradication in combination with appropriate
antibiotics.
• Treatment of Zollinger-Ellison syndrome.
• Treatment and prevention of NSAID-associated erosions
and ulcers.

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 Proton Pump Inhibitors: MoA
• They act by irreversibly binding to and inhibiting the H+/K+ ATPase enzyme
of the gastric parietal cell.

• https://www.youtube.com/watch?v=E8B97QS0aeA&list=PLKAP7UZR88_dltGZ
ujfFywfasDwHV_NS2&index=1&pp=gAQBiAQB
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 Proton Pump Inhibitors
• Pharmacokinetics:
• Effective orally.
• Should be taken 30 to 60 minutes before breakfast.
• Esomeprazole, lansoprazole and pantoprazole are available
in intravenous formulations.
• Plasma half-life is only a few hours.
• Have a long duration of action due to covalent bonding
with the H+/K+-ATPase enzyme.
• Metabolites excreted in urine and feces.

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 Proton Pump Inhibitors
• Adverse effects:
• Generally well tolerated (unless chronically used)
• May increase the risk of fractures (if used for 1 year or longer),
reduce the absorption of calcium.
• Prolonged use may result in low vitamin B12 because acid is
required for its absorption in a complex with intrinsic factor.
• Diarrhea and Clostridium difficile colitis may occur in patients
receiving PPIs.
• Hypomagnesemia and an increased incidence of pneumonia.
• Nausea and vomiting

• Drug interactions:
• Omeprazole and esomeprazole may decrease the effectiveness
of clopidogrel because they inhibit CYP2C19 and prevent the
conversion of clopidogrel to its active metabolite.

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 H2-receptor antagonists
• Indications:
• In the management of peptic ulcer disease.
• Acute stress ulcers
• Reflux oesophagitis.
• Hyper-secretory states such as Zollinger-Ellison syndrome.

• Drugs:
• Cimetidine
• Ranitidine

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 H2-receptor antagonists: MoA
• 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.
• By competitively blocking the binding of histamine to H2
receptors, H2 receptor antagonists reduce the secretion of
gastric acid.

See Image on slide 6

Note the difference between PPIs and H2-receptor antagonist MoA.

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 H2-receptor antagonists: Cimetidine
• Pharmacokinetics:
• Well absorbed orally, with 60-70% bioavailability.
• Widely distributed (including into breast milk and across
the placenta).
• Half-life of 2 hours.
• Partly metabolized in the liver, and mainly eliminated
renally.
• 48% of oral dose and 75% of parenteral dose is unchanged.

• Drug interactions:
• Cimetidine inhibits hepatic microsomal enzymes and has
the potential for multiple drug interactions.

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 H2-receptor antagonists: Cimetidine
• Adverse effects (Common):
• Diarrhoea, nausea, headache, myalgia, dizziness, skin
rashes (sometimes severe) and pruritus.
• CNS disturbances such as confusion, slurred speech,
hallucinations, seizures, delirium and coma, reversible
within a few days of withdrawing therapy, usually in
children, the elderly or very ill, such as those with renal
failure.

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 Treatment of peptic ulcer, GERD caused by
gram-negative Helicobacter pylori
• Antimicrobial agents
• Amoxicillin,
• Bismuth compounds,
• Clarithromycin,
• Metronidazole

• Triple therapy (PPI + metronidazole OR amoxicillin +

clarithromycin). A seven day regimen.
• Quadruple therapy (Bismuth subcitrate + metronidazole +
doxycycline + PPI)

• If a PPI is contraindicated an alternative is ranitidine + bismuth

subcitrate + two antibiotics 14
Nausea and Vomiting

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 Mechanisms that trigger vomiting
• Two brainstem sites have key roles in the vomiting reflex
pathway, the chemoreceptor trigger zone (CTZ) which is
located in the area postrema. It is outside the blood-brain
barrier.
• Thus it can respond directly to chemical stimuli in the blood or
cerebrospinal fluid.
• The second important site is the vomiting centre, which is
located in the lateral reticular formation of the medulla.
Coordinates the motor mechanisms of vomiting.
• The vomiting centre also respond to afferent input from the
vestibular system, the periphery (pharynx and GI tract), and
higher brainstem and cortical structures.
• The vestibular system functions mainly in motion sickness.
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Treatment: Antiemetics and Antinauseants
• Classes of drugs used to control CINV (chemotherapy-
induced nausea and vomiting):
• Phenothiazines: Prochlorperazine
• 5-HT3 receptor blockers: Granisetron, Ondansetron,
Palonosetron
• Substituted benzamides: Metoclopramide
• Butyrophenones: Droperidol, Haloperidol
• Benzodiazepines: Alprazolam, Lorazepam
• Corticosteroids: Dexamethasone, Methylprednisolone
• Substance P/neurokinin-1 receptor antagonists: Aprepitant
• Combination regimens:
• Most common is dexamethasone + metoclopramide
• Diphenhydramine + metoclopramide
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 Treatment: Nausea and vomiting of
pregnancy
• Management in the first place is by reassurance, attention to
emotional factors and general measures such as a cup of tea
with a biscuit before rising as well as light and frequent meals
with adequate fibre intake.
• If moderate nausea occurs, the patient should be investigated.
• In resistant cases, specific drug therapy may be necessary, for
an example: Doxylamine (antihistamine) is the best
documented antiemetic for use in pregnancy.
• Combination of dicyclomine, doxylamine and Vit B6.
• Combination of fructose or dextrose and orthophosphoric
acid.

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 Antiemetics and Antinauseants: MoA
• Act by blocking dopamine receptors in the CTZ (e.g.
Prochlorperazine, Droperidol).

• Selectively block 5-HT3 receptors in the periphery (visceral vagal

afferent fibers) and in the CTZ (e.g. Ondansetron).

• Target the neurokinin receptor in the vomiting center and block

the actions of substance P (e.g. Aprepitant).

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 Antiemetics and Antinauseants
Prochlorperazine
• Pharmacokinetics:
• Well absorbed orally and well distributed including the CNS.
• Extensively metabolized in the liver and excreted in the urine
and bile.
• Duration of antiemetic action is about 3-4 hours.
• Advese effects: Acute dystonic reactions, Constipation, Dry mouth,
Drowsiness, Blurred vision
Ondansetron
• Adverse effects (common):
• Headache, Flushing, Constipation, Pain, Redness and burning at
the injection site.

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 Diarrhoea
• Classification
• Diarrhea can be classified by the duration of symptoms:
• Acute diarrhea: ≤ 2 weeks
• Persistent diarrhea: > 2 weeks but < 4 weeks
• Chronic diarrhea: ≥ 4 weeks
• Additionally, diarrhea may be classified based on the underlying
etiology and pathophysiology:
• Infectious diarrhea:
– Inflammatory (invasion by an infectious organism)
– Non-inflammatory (no invasion of the mucosa by the
organism)
• Noninfectious diarrhea:
• Secretory (efflux of electrolytes and water)
• Osmotic (water is drawn into the intestinal lumen)
• Malabsorption (impaired nutrient absorption)
• Inflammatory (inflammatory process causing mucosal damage)
• Altered motility (rapid intestinal transit) 21
Treatment: Acute diarrhoea

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 Treatment: Diarrhoea
• Antidiarrhoeals: Rehydration formulations
• Solution of water, salt and sugar:
• Half level teaspoon of salt + 8 level teaspoon of sugar (e.g
anhydrous glucose) dissolved in 1 liter boiled water or safe
drinking water.
• Classification of rehydration formulations (electrolytes with
carbohydrates)
• IV rehydration fluids
• Ringer’s Lactate solution = 6g sodium chloride, 0.3g
potassium chloride, 0.2g calcium chloride, 3.1g sodium
lactate.
• Half-strength Darrow’s solution with 5% dextrose = 2g
sodium chloride, 1.3g potassium chloride, 2.9g sodium
lactate, 50g/L Dextrose
• Oral rehydration salt formulations
• 2g sodium chloride, 2.5g sodium bicarbonate, 1.5g
potassium chloride, 20g/L Glucose 23
 Treatment: Diarrhoea, Acute Non-
inflammatory
• Description:
• Diarrhoea without macroscopic blood or mucus, or
neutrophils on microscopy. Common causes include
viruses and enterotoxigenic strains of E. coli. Note:
Neutropenic patients may have inflammatory diarrhoea in
the absence of neutrophils.
• General measures:
• Rehydration is the cornerstone of management. This
should be done with oral rehydration solution (ORS) unless
the patient is vomiting or profoundly dehydrated.
• Medicine treatment:
• Loperamide, oral, 4 mg immediately, followed by 2 mg
after each loose stool. Maximum dose: 16 mg daily.
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 Antidiarrhoearal: MoA
• Loperamide
• Is a spasmolytic agent which reduces smooth muscle
activity in the GI tract to decrease the passage of faeces.
• It is an opioid receptor agonist and exerts it’s effects on the
µ-opioid receptors of the myenteric plexus of the large
intestine.

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 Antidiarrhoeals: Loperamide
• Pharmacokinetics:
• About 40% is absorbed orally
• Half life of 9-14 hours
• Protein binding is high
• Hepatic metabolism followed by faecal and renal excretion

• Adverse effects:
• Therapeutic doses are generally well tolerated.
• Uncommon: flatulence, constipation, dry mouth and
blurred vision.

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 Treatment: Acute Inflammatory Diarrhoea (Dysentry)
• Description:
• Diarrhoea with neutrophils, blood and/or mucus.
• General measures:
• Rehydration is the cornerstone of management. This should be done with oral
rehydration solution (ORS) unless the patient is vomiting or profoundly dehydrated. Stool
culture is advised.
• Medicine treatment: Loperamide is contraindicated as it may result in toxic megacolon.
• Antibiotic therapy
• Consider in patients with signs of sepsis and severe cases or significant underlying
disease:
• Ceftriaxone, IV 1g daily.
• Switch to oral therapy when clinically appropriate i.e. ciprofloxacin 500mg 12 hourly.
• For uncomplicated dysentry in patients with no co-morbidity:
• Ciprofloxacin, oral, 500 mg 12 hourly for 3 days.
• For uncomplicated dysentry in patients with significant co-morbidity e.g.
immunocompromised patients:
• Ciprofloxacin, oral, 500 mg 12 hourly for 7 days.
• REFERRAL
• Persistent diarrhoea with blood and mucus for longer than 2 weeks.
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 Intestinal anti-infectives

• Infection with organisms such as Salmonella typhi (S.typhi),

Vibrio cholerae (V. cholera) and amoebae, requires the early
institution of antibiotics.
• Ciprofloxacin and ofloxacin for 3 days will be appropriate for
Shigella.
• Infection with C. difficile (CDI) is recognized as a major cause
for diarrhea.
• Oral metronidazole is the drug of choice for mild to
moderate CDI or can be given IV if required.
• Oral vancomycin is the drug of choice for more severe CDI.
• Fidaxomicin is minimally absorbed and is bactericidal
against CDI.
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 Laxatives
• Laxatives are classified on the bases of their mechanism of action
• Bulk-forming laxatives
• Ispaghula (psyllium)
• Sterculia
• Contact / Irritant laxatives
• Bisacodyl
• Senna glycosides
• Sodium picosulphate with magnesium citrate
• Osmotically acting laxatives
• Lactulose
• Magnesium sulphate
• Magnesium hydroxide
• Polyethylene glycol combinations
• Sodium phosphate
• Wetting agents
• Docusate
• Mineral oil
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 Learning material
• Lippincott Illustrated Reviews: Pharmacology, 7th edition, by
Karen Whalen.
• Pharmacology Made Incredibly Easy, 4th edition, Wolters
Kluwer,
• Goodman and Gilman’s Manual of Pharmacology and
Therapeutics, 2nd edition, by Randa Hilal-Dandan and
Laurence Brunton.
• Basic and Clinical Pharmacology, 14th edition by Bertram
Katzung.
• Rang and Dale’s Pharmacology, 9th edition.

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 END!!!

Thank you for your attention.

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