Gastrointestinal Pharmacology:- PDF / PPT

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                     PEACE MAWUNYO DOE

P. M. Doe 2022
                      [email protected] 1

• 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.

P. M. Doe 2022                                            2

• 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.

P. M. Doe 2022                                               3
                 The Gastrointestinal Tract

P. M. Doe 2022                                4
• The blood vessels and the glands (exocrine,
     endocrine and paracrine) that comprise the GIT are
     under both neuronal and hormonal control.

P. M. Doe 2022                                            5
                       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
P. M. Doe 2022                                                   6
                          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

P. M. Doe 2022                                                        8
P. M. Doe 2022   9
• 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
P. M. Doe 2022                                                    10
• 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.

P. M. Doe 2022                                              11
• 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
P. M. Doe 2022                                             12
• 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 .
    P. M. Doe 2022                                                  13
• 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.
P. M. Doe 2022                                            14
                       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.
P. M. Doe 2022                                                      15
• 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.
P. M. Doe 2022                                                         16
• 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.

P. M. Doe 2022                                           17
• 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
    P. M. Doe 2022                                                   18
  into   the lumen of the oxyntic gland.
      A schematic illustration of the secretion of hydrochloric acid
      by the gastric parietal cell.
P. M. Doe 2022                                                         19
• 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
• acetylcholine (a stimulatory neurotransmitter)
• prostaglandins E2 and I2 (local hormones that inhibit
     acid secretion)
• somatostatin secreted by D cells (an inhibitory
     peptide hormone).
P. M. Doe 2022                                           20
• 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.

P. M. Doe 2022                                             21
• 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

P. M. Doe 2022                                                              22
  Regulation of the acid-secreting gastric parietal cell, illustrating the site of
  action of drugs influencing acid secretion.
P. M. Doe 2022                                                                       23
        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.

P. M. Doe 2022                                                                     24
                      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
•   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.
     P. M. Doe 2022                                                            25
• 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.

P. M. Doe 2022                                               26
    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.

P. M. Doe 2022                                          27

• If patients are unable to tolerate the above therapies,
     neutralizing the gastric acid with nonabsorbable
     antacids is an option of treatment.

P. M. Doe 2022                                              28
                 Gastroesophageal Reflux Disease (GERD)

P. M. Doe 2022                                            29
• 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
P. M. Doe 2022                                                  30
• Although gastroesophageal reflux is the most common
  cause of heartburn, other disorders (e.g., achalasia and
  eosinophilic esophagitis) may also cause or contribute to

• 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

• Medication- inhibiting gastric acid secretion, Reducing
      the acidity of gastric juice ameliorates reflux symptoms
P. M. Doe 2022allows esophagitis to heal.                        31
• 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
    P. M. Doe 2022                                                    32
                           •   Misoprostol
•   Amoxicillin
                           •   ANTACIDS
•   Tetracycline
                           •   Aluminium hydroxide
•   Metronidazole
                           •   Calcium carbonate
                           •   Sodium bicarbonate
•   Cimetidine
                           •   Magnesium hydroxide
•   Ranitidine
                           •   ANTIMUSCARINIC AGENTS
•   Famotidine
                           •   Dicyclomine
•   nizatidine
                           •   MUCOSAL PROTECTIVE
•   PROTON PUMP                AGENTS
                           • Bismuth subsalicylate
• Omeprazole
                           • sucralfate
• Esomeprazole
   P. M. Doe 2022                                    33

• 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
     P. M. Doe 2022                                                34
• 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.
P. M. Doe 2022                                              35
                   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
P. M. Doe 2022                                                      36

• 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
P. M. Doe 2022                                            37
• 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

P. M. Doe 2022                                            38
                  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
P. M. Doe 2022                                                 39
     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.
P. M. Doe 2022                                                               40

• 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).
P. M. Doe 2022                                             41
                          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
      P. M. Doe 2022                                                          42

• 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

P. M. Doe 2022                                          43
                  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
P. M. Doe 2022                                                 44
                                   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.

  P. M. Doe 2022                                                              45
                  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
P. M. Doe 2022                                                      46
                 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
• Side effects- cardiac arrhythmias, dry mouth, constipation,
     urinary retention.
• Introduction of H2 blockers and PPIs has sent them into
P. M. Doe 2022                                                      47

• 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
P. M. Doe 2022                                           48
                     Therapeutic uses

• PUD, GERD, duodenal ulcers - Antacids containing Al & Mg
• Little evidence for gastric ulcers
• ADVERSE EFFECTS- Al(OH)3- constipation, Mg(OH)2-
• symptomatic relief in peptic ulcer , dyspepsia, oesophageal reflux.

    P. M. Doe 2022                                                 49
             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
P. M. Doe 2022                                                  50
• 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.
P. M. Doe 2022                                               51
• 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
P. M. Doe 2022                                                              52
                 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
P. M. Doe 2022                                               53
                 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.
P. M. Doe 2022                                                                    54
   Stomach (architecture)   Duodenum (erosion)

P. M. Doe 2022                                   55

P. M. Doe 2022    56

• 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
P. M. Doe 2022                                             57
P. M. Doe 2022   58

• 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
P. M. Doe 2022                                                59
                 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
P. M. Doe 2022                                       60
                    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

   P. M. Doe 2022                                                            61
        Biologic Therapies: New Era

• Advent of biologic agents dramatically changed IBD
• Specifically target mediators of inflammation
• Anti-Tumor Necrosis Factor Alpha Antibodies
     (Anti-TNF Ab)- intolerance, loss of efficacy-sec.
• Infliximab therapy for UC
P. M. Doe 2022                                           62
P. M. Doe 2022   63
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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
P. M. Doe 2022                                             65
    Mechanisms that trigger emesis

• Two brain sites play key roles in the vomiting reflex
 - 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
P. M. Doe 2022                                             66
 Emetic actions of chemotherapeutic
• 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
P. M. Doe 2022                                                    67
Schematic diagram of the factors involved in the control of vomiting, with the probable
sites of action of antiemetic drugs.
    P. M. Doe 2022                                                              68
P. M. Doe 2022            69
• 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
   P. M. Doe 2022
                               -Aprepitant        70

• 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
• 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
P. M. Doe 2022                                                   71
                 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
P. M. Doe 2022                                                     72
                 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
• Antidopaminergic side effects- sedation, diarrhea,
     extrapyramidal symptoms limits its high-dose
P. M. Doe 2022                                                 73

• 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.
P. M. Doe 2022                                               74

• 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)
P. M. Doe 2022                                         75

• 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
P. M. Doe 2022                                        76

• 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 &
• Dronabinol; nabilone
P. M. Doe 2022                                           77
   Substance P/neurokinin-1 receptor
• 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
P. M. Doe 2022                                           78
                 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

P. M. Doe 2022                                              79

P. M. Doe 2022   80

• 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
• 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.
P. M. Doe 2022                                             81
• 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
P. M. Doe 2022                                                    82
• 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
• Use of spasmolytic or other anti-diarrhoeal agents.

P. M. Doe 2022                                                83
                 Antimotility Agents

• Diphenoxylate & Loperamide widely used to control
• 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
P. M. Doe 2022                                            84

• 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
P. M. Doe 2022                                            85
             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.

P. M. Doe 2022                                            86

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• 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.
P. M. Doe 2022                                              88
                    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

• 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.
P. M. Doe 2022                                                                   89
• 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.
P. M. Doe 2022                                                              90
                               • 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

• 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.
P. M. Doe 2022                                                                            91
• 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

• Overuse can lead to an atonic colon where the natural propulsive activity is

• In these circumstances, the only way to achieve defaecation is to take further
     amounts of laxatives, so a sort of dependency arises.

P. M. Doe 2022                                                                      92
• 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.

P. M. Doe 2022                                                                    93
• John B. Furness (2007), Scholarpedia, 2(10):4064.
• MLA style: "Sir James W. Black - Facts". Nobel Media AB
     2014. Web. 12 Sep 2016.
• 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.

P. M. Doe 2022                                                              94