Pharmacology of

Gastrointestinal Tract
By: - Belachew Boranto (B.Pharm, MSc)
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Gastrointestinal disorders

• Common disorders of the gastrointestinal tract

– Peptic ulcers and gastroesophageal reflux disease
(GERD)
– Chemotherapy-induced emesis
– Constipation
– Diarrhea

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Acid Related GIT Diseases
• They are induced or aggravated by gastric HCl.
–occur in 25% of adult people
• The most important of these diseases are:
–A. Gastroesophageal Reflux Disease (GERD)
Backflow of stomach acid into the esophagus
More common than peptic ulcer.
Reflux symptoms (e.g. heart burn) occur in 50% of
people.
–B. Acute gastritis and gastric erosions (in children).
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Gastroesophageal Reflux Disease (GERD)…

Endoscope of Barrett’s Esophagus

(can become malignant - needs
monitoring). 4
 Acid Related GIT Diseases …
• C. PUD- characterized by ulcer formation in the esophagus,
stomach, or duodenum areas of the GI mucosa that are exposed to
gastric acid & pepsin.

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Peptic Ulcer Disease (PUD)
• Duodenal ulcer (DU): the most common type; caused by ↑
HCl & chronic Helicobacter pylori (H. pylori) infection.
• Gastric ulcer (GU): usually caused by chronic NSAIDs
therapy.
• Stress ulcer: caused by severe medical or surgical stress.
• Zollinger-Ellison syndrome: ↑ HC1 secretion by a gastrin-
producing tumor → multiple ulcers.

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Regulation of HCl Secretion
• The parietal cells in gastric mucosa contain receptors for the
three main stimulants for HC1 secretion: gastrin (G), histamine
(H2) & ACh (M3)

• Activation of M3 & gastrin receptors on parietal cells →↑

Intracellular Ca2+ → stimulates proton pump (K +/ H+ ATPase)
→↑ HC1 secretion.

• Activation of M3 & gastrin receptors on gastric enterochromaffin

like (ECL ) cells → stimulate histamine release from ECL cells.
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 Regulation of HCl Secretion …

• Released histamine stimulates H2 receptors on parietal cells

→ activation of adenyl cyclase →↑cyclic AMP → stimulate
proton pump.

• PGE2 receptors activation in parietal cells →↓ histamine-

stimulated c-AMP production → Inhibit proton pump
→↓HCl secretion (PGE2 is protective)

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Regulation of HCl Secretion …

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Pathogenesis of peptic ulcer
• Most cases of peptic ulcer are caused by:
– H. pylori infection: a noninvasive, microaerophilic gram-negative
organism →↑ gastrin-induced HCI secretion, gastritis and its toxin
induces mucosal damage
– Chronic use of NSAIDs.

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 Pathogenesis of peptic ulcer …
• Peptic Ulcer results from an imbalance between aggressive &
defensive mechanisms in gastric or duodenal mucosa:

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Risk Factors for PU
• Stress.

• Smoking: ↑ HCl →↓ bicarbonate → induces VC

(leading to ischemia); antagonizes acid suppressive
drugs
• Alcohol, caffeine, theophylline (mucosal irritants →↑
HCl)
• Drugs decreasing PGs: NSAIDs & Corticosteroids

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HCl Secretion and Drug Targets

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Pathogenesis of Peptic Ulcer & Lines of
Treatment
• ↑ HCl secretion: treated by → antisecretory drugs (proton
pump inhibitors, H2 antagonists, anticholinergics &
misoprostol) and neutralization of secreted acid (antacids)

• Infection with H. pylori: treated by → anti H. pylori therapy

(antibiotics plus antisecretory drugs with or without bismuth).

• Inadequate mucosal defense against HCl: treated by →

mucosal or cytoprotective (sucralfate, misoprostol and
colloidal bismuth).
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Pathogenesis of Peptic Ulcer & Lines of
Treatment
• Treatment of gastric ulcer
–Treatment with anti-secretory drugs is the main line.
–Mucosal protective drugs & antacids are rarely needed.

• Treatment of duodenal ulcer

–Treatment with anti-secretory drugs.
–H. pylori eradication therapy.
–Mucosal protective drugs & antacids are rarely needed.

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Antacids
• Are weak bases that reduce gastric acidity by neutralizing HCl
(do not decrease the volume of acid secreted)
• Pharmacological Actions
– Neutralize gastric acid (duration 1-2 hrs).
– Decrease peptic activity (pepsin is inactive at pH > 4.5)
– Reduce H.pylori colonization.
– ↑ mucosal PG production (promote defense mechanism)
– Adsorbent (to pepsin, bile & toxins), astringent and
demulcent effects (with Al3+ & Mg2+ salts only)
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17
Choice of antacids

• Al3+ hydroxide & Mg2+ salts do not result in CO2 release or

systemic alkalosis
– thus they are the most commonly used antacids, alone or
combined (to neutralize the effects of each other on bowel habit)
• Antacids should be cautiously used in elderly & renal
impairment since:
– Al3+ antacids → Chelate phosphates thus may induce
osteomalacia, hypophosphatemia, encephalopathy & ↑ risk of
Alzheimer dementia.
– Mg2+ antacids → CNS depression 18
 Therapeutic uses

• Taken 1 and 3 hours after meals & at bedtime

– Rapidly relieve pain & help healing of peptic ulcer.

– Relieve dyspeptic symptoms.

– GERD (rapid pain relief).

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Drug Interactions

• Antacids can affect rates of dissolution, absorption,

bioavailability and renal elimination of many drugs through:

– Changing gastric or urinary pH.

– Delaying gastric emptying.

– Chelation: (Al3+salts with fluoroquinolones, tetracyclines,

digoxin and iron salts → ↓ absorption); (do not give

antacids within 2 hrs from administration of these drugs).

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 H2 Receptor Blockers
• Includes cimetidine, ranitidine, famotidine, nizatidine

• MOA: reversible competitive antagonists of H2 receptors on

parietal cells
• Complete inhibition of histamine mediated but partial
inhibition of ACh or gastrin mediated HCI secretion.
• Potent inhibition of nocturnal or fasting but less inhibition of
daytime (meal-stimulated) acid secretion
– Nocturnal HCl secretion depends on histamine, meal
stimulated secretion depends on gastrin, Ach & histamine 21
Clinical comparisons of H2-receptor blockers

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 Adverse Effects of H2 Blockers
• Headache, diarrhea or constipation.
• Tolerance, rebound hyperacidity & recurrence (upregulation of
H2 receptors).

• CNS: sedation, confusion, hallucination (mostly with

cimetidine)
• Antiandrogenic, ↑ prolactin, gynecomastia, galactorrhea,
impotence (mostly with cimetidine).
• Enzyme inhibition → drug interactions (mostly with cimetidine)
• Hypotension & bradycardia if given rapidly IV in intensive care
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Proton-Pump inhibitors
• Include omeprazole, lansoprazole, pantoprazole,
rabeprazole, esomeprazole
• Act on the final step of HCI secretion → Most effective acid
suppressants
• Are prodrugs; converted to active forms in the acidic medium
• MOA: act by irreversibly inhibiting H+ /K+ ATPase in gastric
parietal cells → inhibits H+ secretion into gastric lumen →↓
gastric acid production
• Inhibit basal & meal stimulated acid secretion (98% , 1-2 h
after 1st dose). 24
Proton-Pump inhibitors …

• Weak bases destroyed by gastric acidity & ionized in acid

stomach (not readily absorbed) →given in enteric-coated form,
readily absorbed in alkaline small intestine
• PPIs only inhibit active pumps; should be given about 30 – 60
minutes before meals → peak serum concentrations coincide
with maximal pump activity

• If H2 receptor antagonist is needed, it should be taken well after

the PPI for best effect.
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 Proton-Pump inhibitors …

• Food ↓ bioavailability by 50% (so taken on empty stomach).

– larger amplitude movements crush the protective coatings

• Repeated administration →↓ gastric acidity →↑ bioavailability

• Long duration (onset 1 hour & lasts for 24 hours)

− t1/2 = l h but PPIs bind covalently to PP and synthesis of new

pump requires 24 hours).

• Metabolized in the liver 26

Adverse effects
• GIT: abdominal pain, nausea, vomiting, diarrhea or constipation
• CNS: headache, dizziness, somnolence.
• Hypochlorhydria -
–↑ Risk of infection (e.g. hospital acquired pneumonia & H.
pylori).
–Gastric tumor (in animals): bacterial colonization →↑
carcinogenic nitroso compounds
• Vitamin B12 deficiency (long term use) →↓ absorption
• Enzyme inhibition (clinically insignificant)
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 Advantages of PPIs over H2 antagonists:

• Higher efficacy → better symptomatic relief & higher response

rates

• More prolonged effect (= 24hs → given in single daily dose;

versus twice daily dosing with H2 antagonists).

• More effective in anti H. pylori regimen.

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 Indications of Antisecretory Drugs
• Peptic ulcer
–PPIs are preferred especially in severe cases.

–H2 antagonists in mild or moderate cases (healing is delayed

for 8 weeks & recurrence is common).

• Anti- H. Pylori regimens
–PPIs are preferred.
–Ranitidine bismuth citrate may be used.
• GERD
–PPIs are preferred.
–H2 antagonists are used to cover the nocturnal HCI secretion
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 Indications of Antisecretory Drugs …
• Zollinger Ellison syndrome

– PPI are preferred.

– High dose of parenteral preparations are given early to cover

vomiting period.
• Stress ulcer: to ↓ risk of bleeding.

• Acute gastritis in children & gastric erosions.

• Bleeding oesophageal varices: to prevent recurrence.

• To avoid aspiration pneumonia during surgery

– e.g. obstetric anaesthesia before caesarian section. 30
Mucosal Protective Agents
• Sucralfate: Is an aluminum salt of sulfated sucrose.
• MOA:
– In acid medium, the negatively charged sulfate groups bind
to the positively charged proteins in the ulcer base, forming a
protective barrier against acid, bile and pepsin (also
inactivates the latter two).
– Increases PG synthesis and mucus and bicarbonate secretion.
• Uses
– Stress ulcer prophylaxis (mainly).
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Sucralfate …

• It should not be given with antacids (requires pH < 4)

• Should be taken 4 times a day on an empty stomach before
meals
• Adverse Effects
– Nausea, vomiting and dry mouth.
– Flatulence, constipation.
– Al3+ toxicity: chelates phosphates → osteomalacia &
encephalopathy in renal diseases

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Colloidal Bismuth
• Mechanism
– Anti-H. pylori activity (main effect).
– Mucosal protective:
 Chelates proteins in ulcer base → protective coat against
acid & pepsin (& inactivates pepsin) →↑ mucosal
bicarbonate, mucus & PG
• Use
– Anti- H. pylori therapy: as ranitidine bismuth citrate which
dissociates in stomach into bismuth (anti-H. pylori activity) &
ranitidine (antisecretory) 33
Colloidal Bismuth …

• Adverse Effects

–Teeth & tongue discoloration - black stools (confused with

bleeding).

–Encephalopathy and neurotoxicity especially in renal disease.

• N.B.: Do not give for more than 2 months & do not restart

within 1 year.

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 Misoprostol
• Synthetic PGE1 analog; cytoprotective
• MOA: ↓ HCI secretion (by acting on the PG receptors on
parietal cells →↓ histamine-stimulated c-AMP production).
• Increases mucosal blood flow → stimulates mucosal renewal.
• Stimulates secretion of mucus & bicarbonate
• Uses
–Selective for NSAID-induced gastric ulcer (healing effect) if
PPIs fail.
–It is also given prophylactically with NSAIDs /Corticosteroids
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Misoprostol …

• Adverse effects

– Diarrhea & colic (most common).

– Vaginal bleeding

– Uterine contractions

 Contraindicated in pregnancy → abortion

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Anti- H. pylori Drug Therapy
• Eradication of H. pylori infection results in rapid healing & ↓
recurrence.
• It is achieved by combination therapy with:
I. Antimicrobials:
–Clarithromycin:
Of choice due to better acid stability & efficacy (↓ recurrence)
In addition to its antimicrobial effect, it ↑ plasma level of
ranitidine bismuth citrate (enzyme inhibitor).
–Amoxicillin.
–Metronidazole (in patients allergic to amoxicillin), tinidazole. 37
Anti- H. pylori Drug Therapy …

• II. Acid suppressants (PPIs, or ranitidine bismuth citrate)

– Antibiotics alone are ineffective as organism hides inside
mucus, under epithelial folds to avoid HCl
– If HCl secretion is suppressed; organism comes out,
multiplies → ↑ susceptibility to antibiotics.
 Thus high dose acid suppressants are included in anti-H.
pylori regimens
• III. Colloidal bismuth: bismuth subcitrate or subsalicylate.

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High efficacy anti-H. pylori Triple therapy

• 14 days: Lansoprazole + Clarithromycin + Amoxicillin (or

metronidazole)

• Followed by 4-6 weeks: PPI therapy to allow ulcer heal.

• Quadruple therapy (with added bismuth) may also be used

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Anti H. pylori agents cont’d

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Anti-Muscarinic agent: Pirenzepine

• MOA: M1- receptor antagonist, blocks gastric acid

secretions mediated by Ach.

• About as effective as H2 blockers.

• Rarely used, primarily as adjunct therapy.

• Effect: beneficial in treatment of duodenal ulcer than

gastric ulcer
• S/E: Anticholinergic side effects such as anorexia, blurry
vision, constipation, dry mouth, sedation & headache 41
Nausea & Vomiting

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 Nausea & Vomiting
• Nausea and vomiting are not diseases, but are only
indications of altered physiological conditions.
• Some causes of vomiting

– Surgery – Pregnancy
– Alcohol – Motion sickness
– Drug side effect – Radiation
– Cerebral oedema – Chemotherapy
– Severe pain – General anesthesia
– Poisoning – Gastro enteritis 43
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Antiemetic Drugs
• Antiemetic drugs act by inhibiting inputs to vomiting center;
– D2 antagonists: - metoclopramide, domperidone, promethazine

– 5-HT3 receptor antagonists: e.g. ondansetron, granisetron

– Antihistamines: e.g. diphenhydramine, dimenhydrinate,
meclizine
– Anticholinergics: e.g. hyoscine (scopolamine)
– Sedatives: benzodiazepines e.g. lorazepam and diazepam.
• N.B.: - Corticosteroids such as prednisolone and dexamethasone
are potent antiemetics, with unknown mechanism
- Dronabinol is a cannabinoid acting on opioid receptors in CTZ45
Choices of Antiemetics
• Depends on the cause of vomiting
• Vomiting due to motion sickness (prophylactically better than
curatively).
– H1 antagonists: e.g. diphenhydramine, dimenhydrinate,
meclizine.
– Antimuscarinics: e.g. hyoscine (transdermal patch is better
tolerated).
• Vomiting due to drugs; toxins and uremia:
– D2 receptor antagonists e.g. metoclopramide & domperidone
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Choices of Antiemetics …
• Vomiting due to Chemotherapy (combinations of antiemetics
are used)
– 5-HT3 antagonists: ondansetron (1st choice, prophylaxis &
treatment).
– Corticosteroids potentiate ondansetron.
– Neurokinin-1 antagonists: aprepitant
– DA antagonists: domperidone & metoclopramide.
– Sedatives (prior to chemotherapy to avoid anticipatory
vomiting)
– Cannabinoids: Dronabinol
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Choices of Antiemetics …
• Postoperative & post radiation nausea & vomiting:
– Ondansetron, Metoclopramide.
• Anticipatory and psychogenic vomiting: sedatives.
• Nausea & vomiting of pregnancy: [if clearly indicated to
avoid teratogenicity]
– Meclizine + pyridoxine, doxylamine.
– Promethazine, metoclopramide, cortigen B6.
• N.B.: Cortigen B6 (a corticosteroid plus vit. B6) is used in
many types of vomiting
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 H1 antihistamines
• Are the most effective agents for prevention of the symptoms of

motion sickness.
• The antihistamines prevent or diminish vomiting and nausea

mediated by both the chemoreceptor and vestibular pathways

• The antiemetic action of these medications seems to be due to

their blockade of central H1 and muscarinic receptors

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Figure: Summary of
therapeutic advantages
and disadvantages of
some H1 histamine–
receptor blocking agents

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Ondansetron (5-HT3 Antagonist)
• Selective 5-HT3 receptor antagonist in CTZ & vomiting
center & in viscera.
• Usually given in combination with dexamethasone
• Uses
–Nausea and vomiting due to chemotherapy or
radiotherapy
–Postoperative nausea and vomiting.
• Adverse Effects
– Headache, constipation, warm or flushing sensation in
head or epigastrium 51
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Adverse effects
• Central D2 antagonist effects
– Drowsiness & nervousness (common).
– Extrapyramidal adverse reactions (dystonia, parkinsonism...).
– ↑ Prolactin, menstrual disturbances, galactorrhea,
gynecomastia, impotence.

• Peripheral prokinetic effect: diarrhea.

• Domperidone (antiemetic & prokinetic)

– Similar to metoclopramide; less extrapyramidal effects (does
not readily cross BBB) 53
Potency of anti-emetic drugs

• Active against highly emetogenic chemotherapy

– Ondansetron, Metoclopramide

• Active against mildly or moderately emetogenic chemotherapy

– Chlorpromazine, dexamethasone, haloperidol and dronabinol

• Minimally active

– Promethazine, benzodiazepines; lorazepam

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Emetics
• Emetics - for when an individual has consumed certain toxic
substances and must be expelled before absorption
─ Ammonia, chlorine bleach, toilet cleaners, or battery acid.
• Activated charcoal is given when emesis is CI [such as
kerosene and corrosive poisonings (acids and alkaline)]
• Ipecac Syrup - stimulates the CTZ in the medulla & acts
directly on the gastric mucosa
• S/E: diarrhea, sedation, lethargy (a lack of energy and
enthusiasm)
• Apomorphine is a morphine derive emetic 55
Thanks!!
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