Drugs Used in the Treatment of Gastrointestinal Diseases

1
Drugs Used in the Treatment of Gastrointestinal
Diseases

• Drugs used in Peptic Ulcer Diseases.
• Drugs Stimulating Gastrointestinal Motility.
• Laxatives.
• Antidiarrheal Agents.
• Drugs used in Irritable Bowel Syndrome.
• Antiemetic Agents.
• Drugs used in Inflammatory Bowel Disease.
• Pancreatic Enzyme Supplements.

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• Agents that Reduce Intragastric Acidity
• Physiology of Acid Secretion
• The parietal cell contains receptors for gastrin
  CCK-B (gastrin-cholecystokinin-B receptors),
  histamine (H2), and ACH (muscarinic, M3).
• When ACH or gastrin (released from antral G cells
  into the blood) bind to the parietal cell
  receptors, they cause an increase in cytosolic
  calcium, which in turn stimulates protein kinases
  that stimulate acid secretion from a H/K-ATPase
  (the proton pump) on the canalicular (A small
  canal or duct ) surface.

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• In close proximity to the parietal cells are gut
  endocrine cells called enterochromaffin -like
  (ECL) cells.
• ECL cells also have receptors for gastrin and
  acetylcholine, which stimulate histamine release.
  
• Histamine binds to the H2 receptor on the
  parietal cell, resulting in activation of
  adenylyl cyclase, which increases intra-cellular
  cAMP and activates protein kinases that stimulate
  acid secretion by the H/K-ATPase.
• In humans, the major effect of gastrin upon acid
  secretion is mediated indirectly through the
  release of histamine from ECL cells rather than
  through direct parietal cell stimulation.
• In contrast, acetylcholine provides potent direct
  parietal cell stimulation.

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(gastrin-cholecystokinin-B receptors)
5

• Antacids
• Nonprescription remedies for the treatment of
  heartburn and dyspepsia.
• Weak bases that react with gastric hydrochloric
  acid to form a salt and water.
• Given 1 hour after a meal effectively neutralizes
  gastric acid for up to 2 hours.
• Efficacy varies according to rate of dissolution,
  water solubility, rate of reaction with acid and
  the rate of gastric emptying.
• May affect the absorption of other medications by
  binding to drugs or by changing ph, therefore,
  dissolution.

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• Sodium bicarbonate
• Reacts rapidly with HCL to produce carbon dioxide
  and sodium chloride.
• CO2 results in gastric distention and belching.
• Unreacted alkali is readily absorbed, potentially
  causing metabolic alkalosis when given in high
  doses or to patients with renal insufficiency.
• may exacerbate fluid retention in patients with
  heart failure, hypertension, and renal
  insufficiency.

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• Calcium carbonate
• Less soluble.
• Reacts more slowly to form carbon dioxide and
  calcium chloride (CaCl2).
• May cause belching or metabolic alkalosis.
• Excessive doses of either sodium bicarbonate or
  calcium carbonate with calcium-containing dairy
  products can lead to hypercalcemia, renal
  insufficiency, and metabolic alkalosis
  (milk-alkali syndrome hypercalcemia caused by
  repeated ingestion of calcium and absorbable
  alkali (such as calcium carbonate, or milk and
  sodium bicarbonate).

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• Magnesium Hydroxide.
• Aluminum Hydroxide.
• React slowly and without gas formation.
• Metabolic alkalosis is also uncommon.
• Mg salts cause diarrhea.
• Aluminum salts cause constipation.
• Usually given in combination.
• Contraindicated in renal insufficiency.

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• H2-Receptor Antagonists
• Cimetidine, Ranitidine, Famotidine, and
  Nizatidine.
• Rapidly absorbed from the intestine.
• Cimetidine, ranitidine, and famotidine undergo
  first-pass hepatic metabolism, bioavailability
  50.
• Nizatidine has little first-pass metabolism.
• Duration of action610 hours, given twice daily.
  
• Inhibit 90 of nocturnal acid (which depends
  largely on histamine).
• Have a modest impact on meal-stimulated acid
  secretion (which is stimulated by gastrin,
  acetylcholine and histamine).
• Inhibit 60 of day-time, meal stimulated, acid.
• Inhibit 60-70 of total 24-h acid secretion.

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• Clinical Uses of H2-Receptor Antagonists
• Gastroesophageal Reflux Disease (GERD)
• Taken prophylactically before meals.
• In patients with erosive esophagitis H2
  antagonists afford healing in less than 50 of
  patients hence proton pump inhibitors are
  preferred.
• Non Ulcer Dyspepsia.
• Over-the-counter agents for treatment of
  intermittent dyspepsia not caused by peptic
  ulcer.
• Prevention of Bleeding from Stress-Related
  Gastritis
• IV H2 antagonists are preferable over intravenous
  proton pump inhibitors because of their proven
  efficacy and lower cost.
• Continuous infusions of H2 antagonists are
  preferred to bolus infusions because they achieve
  more consistent, sustained elevation of
  intragastric pH.

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• Peptic Ulcer Disease
• Replaced by PPI.
• Healing rate more than 80-90 after 6-8 weeks.
• Not effective in the presence of H. pylori
  infection
• H pylori should be treated with a 10- to 14-day
  course of a proton pump inhibitor and two
  antibiotics.
• If H pylori cannot be eradicated, H2 antagonists
  may be given daily at bedtime in half of the
  usual ulcer therapeutic dose to prevent ulcer
  recurrence.
• Not effective if NSAID is continued.

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• Adverse Effects
• 1-Extremely safe drugs. Diarrhea, headache,
  fatigue, myalgias, and constipation (3 of
  patients) .
• 2-Cimetidine inhibits binding of
  dihydrotestosterone to androgen receptors,
  inhibits metabolism of estradiol, and increases
  serum prolactin levels.
• 3- Long-term use may cause gynecomastia or
  impotence in men and galactorrhea in women
• 4- Crosses placental barrier and appear in breast
  milk

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• 5- Other Effects
• Rarely can cause blood dyscrasias, bradycardia
  and hypotension.
• Mental status changes (confusion, agitation
  hallucinations,) may occur with intravenous H2
  antagonists
• Drug Interactions
• Cimetidine can inhibit cytochrome P450 enzymes so
  can increase half life of many drugs.
• Ranitidine binds 4-10 times less.
• Nizatidine and famotidine binding is negligible.

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• Proton Pump Inhibitors (PPIs)
• Among the most widely prescribed drugs worldwide
  due to their outstanding efficacy and safety.
• Omeprazole (oral).
• Rabeprazole (oral).
• Lanzoprazole (oral and IV).
• Pantoprazole (oral and IV).
• Esmoprazole (oral and IV).
• Formulated as a prodrug which is released in the
  intestine.
• Immediate Release Suspension (contains sodium
  bicarbonate to protect the drug from acid
  degradation) results in rapid response.

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• Pharmacokinetics
• They are lipophilic weak bases (pKa 4-5).
• After absorption, they diffuse across lipid
  membranes into acidified compartments such as the
  parietal cell canaliculus.
• The prodrug becomes protonated and concentrated
  more than 1000-fold within the parietal cells.
• There, it undergoes a molecular conversion to the
  active form which covalently binds the H/K
  ATPase enzyme and inactivates it.
• Rabeprazole and immediate release omeprazole have
  faster onsets of action.
• Should be given one hour before meal, usually
  breakfast.

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• Have short half lives but effect lasts for 24
  hours due to irreversible inhibition.
• Inhibit both fasting and meal-stimulated
  secretion because they block the final common
  pathway of acid secretion (90-98 of 24-hour
  secretion).
• At least 18 hours are required for synthesis of
  new H/K-ATPase pump molecules.
• Up to 34 days of daily medication are required
  before the full acid-inhibiting potential is
  reached.

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• Clinical Uses of (PPIs)
• Gastroesophageal Reflux (GERD)
• They are the most effective agents in all forms
  of GERD and complications.
• Nonulcer Dyspepsia
• Modest activity.10-20 more beneficial than a
  placebo
• Stress- Related Gastritis
• Oral immediate- release omeprazole administered
  by nasogastric tube.
• For patients without a nasoenteric tube, IV
  H2-antagonists are preferred because of their
  proven efficacy.
• Gastrinoma and other Hypersecretory Conditions
• Usually high doses of omeprazole are used.

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• Peptic Ulcer Disease
• They heal more than 90 of cases within 4-6
  weeks.
• H.Pylori - associated ulcers
• PPI eradicate H.pylori by direct antimicrobial
  activity and by lowering MIC of the antibiotics.
• Triple Therapy
• PPI twice daily Clarithromycin 500mg twice
  daily Amoxicillin 1gm twice daily ,OR,
  Metronidazole 500mg twice daily.
• NSAID-associated ulcers
• PPIs promote ulcer healing despite continued
  NSAID use. Also used to prevent ulcer of NSAIDs
• Rebleeding peptic ulcer
• Oral or IV.
• High pH may enhance coagulation and platelet
  aggregation.

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• Adverse Effects of PPIs
• Diarrhea, headache, abdominal pain, not
  teratogenic in animals, but not used in
  pregnancy.
• Reduction of cyanocobalamine absorption.
• Increased risk of GI and pulmonary infection.
• Increased serum gastrin levels causes
• Hyperplasia of ECL cells and Carcinoid tumors in
  rats but not in humans.
• Increase proliferative rate of colonic mucosa,
  but no cancer developed.
• Chronic inflammation in gastric body.
• Atrophic gastritis and intestinal metaplasia (the
  transformation of epithelium, usually of the
  stomach or the esophagus , to a type that bears
  some resemblance to the intestine )

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• Drug Interactions
• May affect absorption of drugs due to decreased
  gastric acidity like digoxin and ketoconazole.
• Omeprazole can inhibit metabolism of coumadin
  (Warfarin ), diazepam and phenytoin.
• Rabeprazole and pantoprazole have no significant
  interaction.

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• Mucosal Protective Agents
• 1-Both mucus and epithelial cell-cell tight
  junctions restrict back diffusion of acid and
  pepsin.
• 2-Epithelial bicarbonate secretion establishes a
  pH gradient within the mucous layer in which the
  pH ranges from 7 at the mucosal surface to 12 in
  the gastric lumen.
• 3-Blood flow carries bicarbonate and vital
  nutrients to surface cells.
• 4-Areas of injured epithelium are quickly
  repaired by restitution, a process in which
  migration of cells from gland neck cells seals
  small erosions to reestablish intact epithelium.
• 5- Mucosal prostaglandins stimulates mucus and
  bicarbonate secretion and mucosal blood flow.

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• Sucralfate
• A salt of sucrose complexed to sulfated aluminum
  hydroxide.
• In the stomach, It breaks down into sucrose
  sulfate (strongly negatively charged) and an
  aluminum salt.
• The negatively charged sucrose sulfate binds to
• positively charged proteins in the base of ulcers
  or erosion, forming a physical barrier that
  restricts further caustic damage and stimulates
  mucosal prostaglandin and bicarbonate secretion.
• Acts for up to 6 hours. Less than 3 of intact
  drug and aluminum is absorbed from GIT.

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• Clinical Uses
• 1 g four times daily on an empty stomach
  (administered as a slurry through a nasogastric
  tube) reduces the incidence of upper
  gastrointestinal bleeding in critically ill
  patients hospitalized in the intensive care unit.
• Used for prevention of stress-related bleeding
  because of concerns that acid inhibitory
  therapies (antacids, H2 antagonists, and proton
  pump inhibitors) may increase the risk of
  nosocomial pneumonia (an infection of the lungs
  that occurs during a hospital stay ).

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• Adverse Effects
• Because it is not absorbed, sucralfate is
  virtually devoid of systemic adverse effects.
• Constipation occurs in 2 of patients due to the
  aluminum salt.
• Because a small amount of aluminum is absorbed,
  it should not be used for prolonged periods in
  patients with renal insufficiency.
• Drug Interactions
• Sucralfate may bind to other medications,
  impairing their absorption.

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• Prostaglandin Analogs
• Misoprostol,
• A methyl analog of PGE1.
• Half-life is less than 30 minutes administered
  3-4 times daily.
• It stimulates mucus and bicarbonate secretion and
  enhance mucosal blood flow.
• It binds to a prostaglandin receptor on parietal
  cells, reducing histamine-stimulated cAMP
  production and causing modest acid inhibition.
• Stimulates intestinal electrolyte fluid
  secretion, intestinal motility and uterine
  contractions.

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• Clinical Uses of Prostaglandin Analogs
• Prevention of NSAID-induced ulcers in high-risk
  patients.
• Not widely used for this purpose because of
• a- side effects.
• b. need for multiple daily dosing.
• c. PPI may be as effective and better tolerated.
• d. Cyclooxygenase2-selective NSAIDs are
  an option for such patients.
• Adverse Effects Drug Interactions
• Diarrhea and cramping abdominal pain occur in
  1020 of patients.
• it should not be used during pregnancy
• No significant drug interactions are reported.

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• Colloidal Bismuth Compounds
• Bismuth subsalicylate.
• Bismuth subcitrate.
• Bismuth is minimally absorbed from GIT (lt 1).
• Coats ulcers and erosions, creating a protective
  layer against acid and pepsin.
• It may stimulate prostaglandin, mucus, and
  bicarbonate secretion.
• Bismuth subsalicylate reduces stool frequency and
  liquidity in acute infectious diarrhea, due to
  salicylate inhibition of intestinal prostaglandin
  and chloride secretion.
• Bismuth has direct antimicrobial effects and
  binds enterotoxins, accounting for its benefit in
  preventing and treating traveler's diarrhea.
• Have direct antimicrobial activity against H
  pylori.

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• Widely used for the nonspecific treatment of
  dyspepsia and acute diarrhea.
• Bismuth subsalicylate also is used for the
  prevention of traveler's diarrhea.
• Used as second-line therapy for the eradication
  of H pylori infection (a PPI with bismuth
  subsalicylate , tetracycline and metronidazole
  for 1014 days).
• Adverse Effects
• Causes blackening of the stool and the tongue.
• Prolonged usage may rarely lead to bismuth
  toxicity, resulting in encephalopathy.

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• Drugs Stimulating Gastrointestinal Motility
• (prokinetic agents)
• Agents that increase lower esophageal sphincter
  pressures may be useful for GERD.
• Drugs that improve gastric emptying may be
  helpful for gastroparesis and postsurgical
  gastric emptying delay.
• Agents that stimulate the small intestine may be
  beneficial for postoperative ileus or chronic
  intestinal pseudo-obstruction.
• Agents that enhance colonic transit may be useful
  in the treatment of constipation.

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• Physiology of the Enteric Nervous System
• The ENT is composed of interconnected networks
  of ganglion cells and nerve fibers mainly located
  in the submucosa (submucosal plexus) and between
  the circular and longitudinal muscle layers
  (myenteric plexus).
• Extrinsic sympathetic and parasympathetic nerves
  project onto the submucosal and myenteric
  plexuses.
• The enteric nervous system can independently
  regulate gastrointestinal motility and secretion.
  
• Extrinsic primary afferent neurons project via
  the dorsal root ganglia or vagus nerve to the CNS.

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• Release of serotonin (5-HT) from intestinal
  mucosa enterochromaffin (EC) cells stimulates
  5-HT3 receptors on the extrinsic afferent nerves,
  stimulating nausea, vomiting,
• or abdominal pain.
• Serotonin also stimulates submucosal 5-HT1P
  receptors
• of the intrinsic primary afferentnerves (IPANs).

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• IPANs) contain calcitoningene-related peptide
  (CGRP) and acetylcholine and project to myenteric
  plexus interneurons.
• 5-HT4 receptors on the presynaptic terminals of
  the IPANs enhance release of CGRP or Ach.
• The myenteric interneurons control
• peristaltic reflex, promoting release of
  excitatory mediators proximally and inhibitory
  mediators distally.
• Motilin may stimulate excitatory neurons or
  muscle cells directly.
• Dopamine acts as an inhibitory neurotransmitter
  in the GIT, decreasing the intensity of
  esophageal and gastric contractions.

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Figure 624  Release of serotonin (5-HT) by
enterochromaffin (EC) cells from gut distention
stimulates submucosal intrinsic primary afferent
neurons (IPANs) via 5-HT1P receptors and
extrinsic primary afferent neurons via 5-HT3
receptors (5-HT1PR, 5-HT3R). Submucosal IPANs
activate the enteric neurons responsible for
peristaltic and secretory reflex activity.
Stimulation of 5-HT4 receptors (5-HT4R) on
presynaptic terminals of IPANs enhances release
of acetylcholine (ACh) and calcitoningene-related
peptide (CGRP), promoting reflex activity.
CNS, central nervous system ENS, enteric
nervous system.
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• Cholinomimetic Agents
• Bethanechol
• Stimulates muscarinic M3 receptors on muscle
  cells and at myenteric plexus synapses .
• Was used for the treatment of GERD and
  gastroparesis.
• Neostigmine
• AchE inhibitor can enhance gastric, small
  intestine, and colonic emptying.
• IV neostigmine used for the treatment of acute
  large bowel distention (acute colonic
  pseudo-obstruction).
• Administration of 2 mg results in prompt colonic
  evacuation of flatus and feces.
• Cholinergic effects include excessive salivation,
  nausea, vomiting, diarrhea, and bradycardia.

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• Dopamine D2-receptor antagonists.
• Metoclopramide Domperidone
• D2 Antagonists.
• DA inhibits cholinergic smooth muscle
  stimulation.
• These agents
• -increase esophageal peristaltic amplitude.
• -increase lower esophageal sphincter pressure.
• -enhance gastric emptying.
• -have no effect on small intestine or colonic
  motility.
• Also block dopamine D2 receptors in the
  chemoreceptor trigger zone of the medulla (area
  postrema), resulting in potent antinausea and
  antiemetic action.

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• Clinical Uses
• Gastroesophageal Reflux Disease
• Not effective with erosive esophagitis.
• Not superior to antisecretory agents.
• Used mainly in combination with antisecretory
  agents in patients with refractory heartburn.
• Impaired Gastric Emptying (Gastroparesis)
• widely used in the treatment of postsurgical and
  diabetic gastroparesis.
• Metoclopramide is used to promote advancement of
  nasoenteric feeding tubes from the stomach into
  the duodenum.
• Nonulcer Dyspepsia
• Prevention of Vomiting
• Postpartum Lactation Stimulation
• Domperidone is used to promote postpartum
  lactation

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• Adverse Effects
• Metclopromide crosses BBB so can cause
  Restlessness, drowsiness, insomnia, anxiety,
  agitation, extrapyramidal symptoms (dystonia,
  akathisia, parkinsonian features) and tardive
  dyskinesia.
• Domperidone does not cross the BBB, so does not
  cause CNS effects
• Both drugs can elevate serum prolactin levels
  causing galactorrhea, gynecomastia, impotence and
  menstrual disorders.

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• Laxatives
• Intermittent constipation is best prevented with
  a high-fiber diet, adequate fluid intake, regular
  exercise, and responding to nature's call.
• Bulk-Forming Laxatives
• Indigestible, hydrophilic colloids that absorb
  water, forming a bulky, emollient gel that
  distends the colon and promotes peristalsis.
• Common preparations include natural plant
  products (psyllium, methylcellulose) and
  synthetic fibers (polycarbophil).
• Bacterial digestion of plant fibers within the
  colon may lead to increased bloating and flatus.

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• Stool Surfactant Agents (Softeners)
• Soften stool material, permitting water and
  lipids to penetrate.
• Administered orally or rectally.
• Docusate (oral or enema) and glycerin
  suppository.
• Mineral oil
• Clear, viscous oil that lubricates fecal
  material, retarding water absorption from the
  stool.
• Used to prevent and treat fecal impaction.
• Aspiration can result in a severe lipid
  pneumonitis
• Long-term use can impair absorption of
  fat-soluble vitamins.

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• Osmotic Laxatives
• Soluble but nonabsorbable compounds that result
  in increased stool liquidity due to an increase
  in fecal fluid.
• Nonabsorbable Sugars or Salts
• Used for the treatment of acute constipation or
  the prevention of chronic constipation.
• Magnesium hydroxide (milk of magnesia)
• Not used for prolonged periods in patients with
  renal insufficiency due to the risk of
  hypermagnesemia.
• Large doses of magnesium citrate and sodium
  phosphate can cause Purgation
• rapid bowel evacuation within1-3 hours.
• This might cause volume depletion.

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• Sorbitol, Lactulose
• Sugars metabolized by bacteria producing severe
  flatus and cramps.
• Balanced Polyethylene Glycol
• PEG is an inert, nonabsorbable, osmotically
  active sugar with sodium sulfate, sodium
  chloride, sodium bicarbonate, and potassium
  chloride.
• Safe, no intrvascular fluid or electrolyte
  shifts.
• No cramps or flatus.
• Used for complete colonic cleansing before
  endoscopy
• For colonic cleansing, it should be ingested
  rapidly( 4 L over 2-4hs).
• For chronic constipation, PEG powder is mixed
  with water or juice.

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• Stimulant Laxatives
• Direct stimulation of the enteric nervous system
  and colonic electrolyte and fluid secretion.
• Anthraquinone Derivatives
• Aloe, senna, and cascara
• Occur naturally in plants. Poorly absorbed and
  after hydrolysis in the colon, produce a bowel
  movement in 612 hours when given orally and
  within 2 hours when given rectally.
• Chronic use leads to a brown pigmentation of the
  colon known as "melanosis coli.
• Not carcinogenic.

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• Bisacodyl
• Tablet and suppository for treatment of acute and
  chronic constipation.
• It also is used in conjunction with PEG solutions
  for colonic cleansing prior to colonoscopy.
• It induces a bowel movement within 610 hours
  when given orally and 3060 minutes when taken
  rectally.
• Safe for acute and long-term use.
• Phenolphthalein
• Removed from the market owing to concerns about
  possible cardiac toxicity

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• Opioid Receptor Antagonists
• Do not cross the blood-brain barrier.
• Block peripheral (µ) mu -opioid receptors without
  causing central analgesic effects.
• Methylnaltrexone
• Used for opioid- induced constipation in patients
  with advanced illness not responding to other
  agents.
• Given by S.C. injection every 2 days.
• Alvimopan
• Short-term use for postoperative ileus in
  hospitalized patients.
• Given orally within 5 hours before surgery and
  twice daily after surgery until bowel function
  has recovered, but for no more than 7 days,
  because of possible cardiovascular toxicity.

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• Antidiarrheal Agents
• Should not be used in patients with bloody
  diarrhea, high fever, or systemic toxicity
  because of the risk of worsening the underlying
  condition.
• Used to control chronic diarrhea caused by
  irritable bowel syndrome (IBS) or inflammatory
  bowel disease.

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• Opioid Agonists
• Inhibit presynaptic cholinergic nerves in the
  submucosal and myenteric plexuses and lead to
  increased colonic transit time and fecal water
  absorption.
• They also decrease mass colonic movements
• CNS effects and potential for addiction limit the
  usefulness of most.
• Loperamide
• Does not cross BBB. No analgesic or addiction
  potential.
• Diphenoxylate
• Not analgesic in standard doses.
• Higher doses have CNS effects.
• Can cause dependence.
• Commercial preparations contain small amounts of
  atropine which contribute to the antidiarrheal
  action.

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• Bile Salt-Binding Resins
• Cholestyramine
• Colestipol
• Colesevelam
• Malabsorption of bile salts (e. g . Crohn's
  disease or after surgical resection), can cause
  diarrhea.
• The drugs can bind bile salts and decrease
  diarrhea caused by excess fecal bile acids.
• Can cause bloating, flatulence, constipation and
  fecal impaction.
• Cholestyramine and colestipol reduce absorption
  of drugs and fat.
• Colesevelam have no effects on absorption of
  other drugs.

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• Octreotide
• Is a synthetic octapeptide with actions similar
  to somatostatin.
• Somatostatin
• A14 amino acid peptide released in the GIT and
  pancreas as well as from the hypothalamus
• 1. Inhibits release of many hormones.
• 2. Reduces intestinal fluid and pancreatic
  secretions.
• 3. Slows GIT motility and gallbladder
  contraction.
• 4. Contracts blood vessels.
• 5. Inhibits secretion of some anterior pituitary
  hormones.

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• Clinical Uses
• 1. Inhibition of endocrine tumor effects
• Carcinoid and VIPoma (neuroendocrine tumors
  that secrete vasoactive intestinal polypeptide
  (VIP) ) can cause secretory diarrhea, flushing
  and wheezing.
• 2. Diarrhea due to vagotomy or dumping syndrome
  (ingested foods bypass the stomach too rapidly)
  or short bowel syndrome and AIDS.
• 3. To stimulate motility in small bowel
  bacterial overgrowth or intestinal
  pseudo-obstruction secondary to scleroderma (a
  disease affecting the skin and other organs that
  is one of the autoimmune rheumatic diseases).

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• 4- Because it inhibits pancreatic secretion, it
  is used in patients with pancreatic fistula
  (leakage of pancreatic secretions from damaged
  pancreatic ducts ).
• 5- treatment of pituitary tumors (e.g.,
  acromegaly)
• 6- Sometimes used in gastrointestinal bleeding.
• Adverse Effects
• Impaired pancreatic secretion may cause
  steatorrhea (the presence of excess fat in feces
  ), which can lead to fat-soluble vitamin
  deficiency.
• Nausea, abdominal pain, flatulence, and diarrhea.
  
• Formation of sludge or gallstones, because of
  inhibition of gallbladder contractility and fat
  absorption.
• Hyper or hypoglycemia due to hormonal imbalance.
• Hypothyroidism.
• Bradycardia.

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• Drugs Used in the Treatment of Irritable Bowel
  Syndrome
• IBS is an idiopathic chronic, relapsing disorder
  characterized by
• Abdominal discomfort (pain, bloating, distention,
  or cramps) in association with alterations in
  bowel habits (diarrhea, constipation, or both).
• Pharmacologic therapies for IBS are directed at
  relieving abdominal pain and discomfort and
  improving bowel function.

52

• Antispasmodics (Anticholinergics)
• Dicyclomine and Hyoscyamine .
• Inhibit muscarinic cholinergic receptors in the
  enteric plexus and on smooth muscle.
• Their efficacy for relief of abdominal symptoms
  has never been convincingly demonstrated.
• Low doses cause minimal autonomic effects.
• Higher doses cause anticholinergic effects,
  including dry mouth, visual disturbances, urinary
  retention, and constipation.
• For these reasons, antispasmodics are
  infrequently used.

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• Serotonin 5-HT3-Receptor Antagonists
• Inhibition of afferent GIT
• 5-HT3 receptors reduce
• nausea, bloating, and pain.
• Blockade of central 5-HT3
• receptors also reduces the
• central response to visceral afferent
  stimulation.
• 5-HT3-receptor blockade on the terminals of
  enteric cholinergic neurons inhibits colonic
  motility, especially in the left colon,
  increasing total colonic transit time.

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• Alosetron
• Highly potent and selective antagonist of the
  5-HT3 receptor.
• Rapidly absorbed and has a plasma half-life of
  1.5 hours but a much longer duration of effect.
• Alosetron is restricted to women with severe
  diarrhea-predominant IBS not responding to
  conventional therapies.
• Can cause ischemic colitis, severe constipation
  requiring hospitalization and surgery.
• Its efficacy in men has not been established.

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• Serotonin 5-HT4-Receptor Agonists
• Stimulation of 5-HT4 receptors
• on the presynaptic terminal
• of submucosal intrinsic primary
• afferent nerves enhances the
• release of their neurotransmitters,
• which promote the peristaltic reflex.
• Tegaserod
• was approved for the short-term treatment of
  women with IBS who had predominant constipation.
• Removed from the market due to an increased
  number of cardiovascular deaths.
• Prucalopride
• High-affinity 5-HT4 agonist. No cardiovascular
  toxicity
• Used for the treatment of chronic constipation in
  women.

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• Chloride Channel Activator
• Lubiprostone
• PG analog
• Stimulates the type 2 chloride channel (ClC-2) in
  the small intestine and this increases liquid
  secretion in the intestine which stimulates
  intestinal motility and bowel movement within 24
  hours of taking one dose.
• Used in the treatment of chronic constipation.
• Approved for the treatment of women with IBS with
  predominant constipation.
• Its efficacy for men with IBS is unproven.
• Should be avoided in women of child-bearing age.
• May cause nausea in up to 30 of patients due to
  delayed gastric emptying.

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• Antiemetic Agents
• Nausea and vomiting may be manifestations of a
  wide variety of conditions, including
• Adverse effects from medications.
• systemic disorders or infections.
• Pregnancy.
• Vestibular dysfunction.
• CNS infection or increased pressure.
• Peritonitis.
• Hepatobiliary disorders.
• Radiation or chemotherapy.
• GIT obstruction, dysmotility, or infections.

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• Pathophysiology
• The brainstem "vomiting center" coordinates
  vomiting through interactions with cranial nerves
  VIII and X and neural networks in the nucleus
  tractus solitarius that control respiratory,
  salivatory, and vasomotor centers.
• Vomiting center contains high concentrations of
  Muscarinic M1 receptors.
• Histamine H1 receptors.
• Neurokinin 1 (NK1) receptors.
• Serotonin 5-HT3 receptors.

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• There are four important sources of afferent
  input to the vomiting center (VC)
• 1-The "chemoreceptor trigger zone (CTZ) or area
  postrema is outside the blood-brain barrier but
  is accessible to emetogenic stimuli in the blood
  or cerebrospinal fluid.
• It is rich in dopamine D2 receptors, opioid
  receptors, serotonin 5-HT3 receptors and
  neurokinin NK1 receptors.
• 2- The vestibular system is important in motion
  sickness via cranial nerve VIII.
• It is rich in muscarinic M1 and histamine H1
  receptors.

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• 3- Vagal and spinal afferent nerves from the GIT
  are rich in 5-HT3 receptors.
• Irritation of the GI mucosa by chemotherapy,
  radiation therapy, distention, or acute
  infectious gastroenteritis leads to release of
  mucosal 5-HT and activation of these receptors,
  which stimulate vagal afferent input to the VC
  and CTZ.
• 4- The CNS plays a role in vomiting due to
  psychiatric disorders, stress, and anticipatory
  vomiting prior to cancer chemotherapy.
• Combinations of antiemetic agents with different
  mechanisms of action are often used.

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• Serotonin 5-HT3 Antagonists
• Ondansetron oral 0r IV
• Granisetron half-life 49 h
• Dolasetron
• Palonosetron half-life 40 h
• Block central 5-HT3 and peripheral (main effect)
  5-HT3 receptors on extrinsic intestinal vagal and
  spinal afferent nerves.
• They prevent emesis due to vagal stimulation and
  chemotherapy.
• Other emetic stimuli such as motion sickness are
  poorly controlled.

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• Uses
• Prevention of acute chemotherapy-induced nausea
  and emesis and postoperative nausea and vomiting.
• Their efficacy is enhanced by combination therapy
  with dexamethasone and NK1-receptor antagonist.
• Prevention and treatment of nausea and vomiting
  in patients undergoing radiation therapy.
• Adverse effects
• Headache, dizziness, and constipation.
• Cause a small prolongation of the QT interval.

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• Neurokinin 1 Receptor (NK1) Antagonists
• Have antiemetic properties through central
  blockade in the area postrema.
• Aprepitant
• Used in combination with 5-HT3-receptor
  antagonists and corticosteroids for the
  prevention of acute and delayed nausea and
  vomiting from chemotherapy.
• Adverse effects
• May cause fatigue, dizziness, and diarrhea.

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• Antipsychotic drugs
• Prochlorperazine
• Promethazine
• Droperidol
• Antiemetics due to inhibition of dopamine and
  muscarinic receptors.
• Sedative effects due to antihistamine activity.
• Droperidol is extremely sedating.
• Extrapyramidal effects and hypotension may occur.
  
• Droperidol may prolong the QT interval, rarely.

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• Benzodiazepines
• Lorazepam
• Diazepam
• Reduce anticipatory vomiting caused by anxiety.

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• H1 Antihistamines Anticholinergic Drugs
• Particularly useful in motion sickness.
• May cause dizziness, sedation, confusion, dry
  mouth, cycloplegia, and urinary retention.
• Diphenhydramine, Dimenhydrinate
• Have significant anticholinergic properties.
• Meclizine
• Minimal anticholinergic properties and less
  sedating.
• Used for the prevention of motion sickness and
  the treatment of vertigo due to labyrinth
  dysfunction.
• Hyoscine (scopolamine)
• Very high incidence of anticholinergic effects.
• It is better tolerated as a transdermal patch.

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• Cannabinoids
• Dronabinol, Nabilone
• Delta-9- tetrahydrocannabinol from marijuana.
• Psychoactive agents.
• Used as appetite stimulants and for
  chemotherapy-induced vomiting.
• Mechanisms for these effects are not understood.
• Adverse effects
• Euphoria, dysphoria, sedation, hallucinations,
  dry mouth, and increased appetite.
• May result in tachycardia, conjunctival injection
  (redness of the white sclera of the eye) and
  orthostatic hypotension.

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• Drugs Used to Treat Inflammatory Bowel Disease
• Inflammatory bowel disease (IBD) comprises two
  distinct disorders
• Ulcerative colitis and Crohn's disease.
• Etiology and pathogenesis are unknown.
• For this reason, the drugs used belong to
  different classes and have nonspecific mechanisms
  of anti-inflammatory action.
• Drugs used are chosen on the basis of disease
  severity, responsiveness, and drug toxicity.

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• Aminosalicylates
• 5-aminosalicylic acid (5-ASA)
• Aminosalicylates work topically (not
  systemically) in areas of diseased
  gastrointestinal mucosa.
• Up to 80 of unformulated 5-ASA is absorbed from
  the small intestine and does not reach the distal
  small bowel or colon in appreciable quantities.
• A number of formulations deliver 5-ASA to various
  distal segments of the small bowel or the colon.

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• Azo Compounds
• Sulfasalazine, Balsalazide, Olsalazine
• 5-ASA bound by an azo (NN) bond to an inert
  compound or to another 5-ASA molecule
• The azo structure markedly reduces absorption of
  the parent drug from the small intestine.
• In the terminal ileum and colon, resident
  bacteria cleave the azo bond by means of an
  azoreductase enzyme, releasing 5-ASA.
• Consequently, high concentrations of active drug
  are made available in the terminal ileum or colon.

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• Mesalamine Compounds
• Pentasa
• Timed-release microgranules that release 5-ASA
  throughout the small intestine .
• Asacol
• 5-ASA coated in a pH-sensitive resin that
  dissolves at the pH of the distal ileum and
  proximal colon).
• 5-ASA also delivered as
• Enema (Rowasa)
• Suppositories (Canasa).

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• The mechanism of action of 5-ASA is not certain.
• 5-ASA modulates inflammatory mediators derived
  from both the cyclooxygenase and lipoxygenase
  pathways.
• Other potential mechanisms
• -Interferes with the production of inflammatory
  cytokines.
• -Inhibits the activity of nuclear factor- B (NF-
  B), an important transcription factor for
  proinflammatory cytokines.
• -May also inhibit cellular functions of natural
  killer cells, mucosal lymphocytes, and
  macrophages, and it may scavenge reactive oxygen
  metabolites.

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• Clinical Uses
• 5-ASA drugs are first-line agents for treatment
  of mild to moderate active ulcerative colitis.
• Their efficacy in Crohn's disease is unproven,
  although used as first-line therapy for mild to
  moderate disease involving the colon or distal
  ileum.
• Adverse Effects
• Due to systemic absorption especially in slow
  acetylators
• Nausea, headache, arthralgia, myalgia, bone
  marrow suppression, and malaise.
• Also allergic reactions, oligospermia, and folate
  deficiency.

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• Glucocorticoids
• Inhibit production of inflammatory cytokines and
  chemokines reduce expression of inflammatory
  cell adhesion molecules and inhibit gene
  transcription of nitric oxide synthase,
  phospholipase A2, cyclooxygenase-2, and NF- B.
• Clinical Uses
• Moderate to severe active IBD.
• Not useful for maintenance.
• Prednisolone Orally or IV.
• Hydrocortisone Rectally, preferred for rectal and
  sigmoid involvement.
• Budesonide
• A controlled-release oral formulation ,releases
  the drug in the distal ileum and colon.
• For ileal and proximal colon involvement.

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• Antimetabolites
• Azathioprim
• 6-Mercaotopurine.
• Are purine analogs which produce thioguanine
  nucleotides (Active form).
• Immunosuppressants.
• Inhibit purine nucleotide metabolism and DNA
  synthesis and repair, resulting in inhibition of
  cell division and proliferation and may promote
  T-lymphocyte apoptosis.

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• Clinical Use
• Onset delayed for 17 weeks.
• Used in induction and maintenance of remission.
• Allow dose reduction or elimination of steroids.
• Adverse Effects
• Nausea, vomiting, bone marrow suppression,
  hepatic toxicity and allergic reactions( fever,
  rash, pancreatitis, diarrhea and hepatitis).
• Allopurinol increases levels of the drugs.

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• Methotrexate
• Antimetabolite, Used in cancer chemotherapy,
  rheumatoid arthritis and psoriasis.
• Mechanism of action
• Inhibition of dihydrofolate reductase enzyme
  which is important in the synthesis of thymidine
  and purines.
• - At high doses it inhibits cellular
  proliferation.
• - At low doses used in IBD, it interferes with
  the inflammatory actions of interleukin-1,
  stimulates adenosine release, apoptosis and death
  of activated T lymphocytes.

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• Uses
• Induction and maintenance of remissions of
  Crohns Disease.
• Adverse effects
• At high doses, can cause bone marrow depression,
  megaloblastic anemia, alopecia and mucositis.
• Renal insufficiency may increase risk of hepatic
  accumulation and toxicity.
• Side effects counteracted by folate
  supplementation.

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• Anti-Tumor Necrosis Factor Therapy
• If the epithelial barrier is impaired, bacterial
  antigens can gain access to antigen-presenting
  cells (APC) such
• as dendritic cells in the lamina propria.
• These cells then present the antigen(s) to CD4
• lymphocytes and also secrete cytokines such
• interleukin (IL)-12 and IL-18, thereby inducing
  the differentiation of TH1 cells in Crohn's
  disease or IL-4, type 2 helper T cellTH2 in
  Ulcerative colitis.
• The TH1 cells produce cytokines, including
  interferon (IFN) and TNF , which in turn
  activate macrophages.
• Macrophages positively regulate TH1 cells by
  secreting additional cytokines, including IFN
  and TNF .

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• Recruitment of a variety of leukocytes is
  mediated by activation of resident immune cells
  including neutrophils.
• Cell adhesion molecules such as integrins are
  important in the infiltration of leukocytes.
• Anti- Integrin Therapy aimed at blocking
  leukocyte recruitment are effective at reducing
  inflammation.
• Site-specific intervention involve intestinal
  bacteria and therapy directed at TNF or IL-12.
• TNF-a is one of the principal cytokines mediating
  the TH1 (helper T cell type 1) immune response
  characteristic of Crohn's disease.

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CD4 lymphocytes
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• Infliximab
• is a chimeric immunoglobulin (25 mouse, 75
  human) that binds to and neutralizes TNF .
• Infliximab binds membrane-bound TNF and may
  cause lysis of these cells by antibody-dependent
  or cell-mediated cytotoxicity.
• Half life 8-10 days with persistence of
  antibodies in plasma for 8-12 weeks
• Used in acute and chronic treatment of patients
  with moderate to severe Crohn's disease.
• Given in repeated doses at 0, 2, and 6 weeks for
  induction by IV infusion.
• If response is adequate, infusions are repeated
  every 8 weeks.
• Response might be lost due to development of
  antibodies to infliximab.
• Infliximab is effective for refractory ulcerative
  colitis.

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• Side Effects
• Acute
• fever, chills, urticaria, or even anaphylaxis
• Subacute
• serum sicknesslike) reactions may develop after
  infliximab infusion, but lupus-like syndrome
  occurs only rarely.
• Antibodies to infliximab can decrease its
  clinical efficacy.
• Therapy is associated with increased incidence of
  respiratory infections reactivation of TB.
• Infliximab also is contraindicated in patients
  with severe congestive heart failure.
• there is concern about the possible increased
  incidence of non-Hodgkin's lymphoma.

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• Adalimumab
• is a humanized recombinant human IgG1 monoclonal
  antibody against TNF .
• It is effective in inducing remission in mild to
  moderate and severe Crohn's disease,given SC
• Certolizumab pegol
• is a pegylated (Polyethylene glycol ) humanized
  fragment antigen binding (Fab) that binds TNF .
• Also given SC.
• As effective as adalimumab and infliximab for the
  treatment of Crohn's disease.
• With both adalimumab and certolizumab pegol,
  immunogenicity appears to be less of a problem
  than that associated with infliximab.

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• Natalizumab
• Humanized IgG4 monoclonal antibody against the
  cell adhesion molecule a 4-integrin subunit.
• prevents binding of several integrins on
  circulating inflammatory cells to vascular
  adhesion molecules
• Used for patients with moderate to severe Crohn's
  disease who have failed other therapies
• Given by IV infusion every 4 weeks, and patients
  should not be on other immune suppressants to
  prevent the risk of progressive multifocal
  leukoencephalopathy (rare and usually fatal viral
  disease )
• Adverse effects include acute infusion reactions
  
• a small risk of opportunistic infections.

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• Pancreatic Enzyme Supplements
• Contain a mixture of amylase, lipase, and
  proteases.
• Used to treat pancreatic enzyme insufficiency.
• Pancrelipase.
• Available in both non-enteric-coated (given with
  acid suppression therapy ) and enteric-coated
  preparations.
• Administered with each meal and snack.
• Excessive doses may cause diarrhea and abdominal
  pain.
• The high purine content of pancreas extracts may
  lead to hyperuricosuria and renal stones.