GI Pharmacological Agents for medical students

Medical Pharmacology

Gi Agents

2. Gastrointestinal PharmacologyGastrointestinal Pharmacology
Lecture for MD StudentsLecture for MD Students
Fall - 2014Fall - 2014
Dr. Dr. Peyman MikailiPeyman Mikaili, Ph.D, Ph.D..

3. Acid-Peptic DiseasesAcid-Peptic Diseases
Acid-peptic diseases include:
•gastroesophageal reflux disease (GERD)
•peptic ulcer (gastric and duodenal)
•stress-related mucosal injury

4. Acid-Peptic DiseasesAcid-Peptic Diseases
In all these conditions:
•mucosal erosions or ulceration
arise
When:
the caustic
effects of
aggressive factors
(acid, pepsin, bile)
the defensive factors of
the gastrointestinal mucosa
(mucus and bicarbonate
secretion, prostaglandins,
blood flow, and the
processes of restitution
and regeneration
after cellular injury).
overwhelm

5. •Over 99% of peptic ulcers are caused by:
•infection with the bacterium Helicobacter pylori
•use of nonsteroidal anti-inflammatory drugs (NSAIDs).
•Drugs used in the treatment of acid-peptic disorders may
be divided into two classes:
•agents that reduce intragastric acidity and
•agents that promote mucosal defense.

6. Physiology of Physiology of
Acid Secretion Acid Secretion

7. Acid ProductionAcid Production

8. gastroesophageal
reflux disease
(GERD)

9. gastroesophageal
reflux disease (GERD)

10. Physiology of Acid SecretionPhysiology of Acid Secretion
ECL cell: enterochromaffin-like cell; G(CCK-B): gastrin-cholecystokini-nB
receptor; H: histamine; H2: histamine H2 receptor; M1, M3: muscarinic
receptors; ST2: somatostatin2 receptor; ATPase: K+/H+ ATPase proton pump.

11. Agents That Reduce Intragastric
Acidity: AntacidsAntacids
Antacids:
• have been used for centuries in the treatment of
patients with:
• They were the mainstay of treatment for acid-peptic
disorders until the advent of H2- receptor antagonists
and proton pump inhibitors.
•Commonly OTC (nonprescription remedies) for
heartburn and dyspepsia.
dyspepsia and acid-peptic disorders.

12. AntacidsAntacids
•Antacids: are weak bases that react with gastric
hydrochloric acid to form a salt and water.
•Although their principle mechanism of action is
neutralizing intragastric acidity, they may also
•promote mucosal defense mechanisms through
stimulation of mucosal prostaglandin production.
Antiacids + HCl a salt + water

13. AntacidsAntacids
•Sodium bicarbonate (eg, baking soda)
•Calcium carbonate
(Sodium bicarbonate)rapidly + HCl  CO2 + NaCl
(Calcium carbonate)slowly +HCl  CO2 + CaCl2
Gas gastric
distention and
belching
Unreacted alkali
absorption
metabolic alkalosis
high doses: patients
with renal
insufficiency
Exacerbate: fluid
retention in patients
with heart failure,
hypertension, and
renal insufficiency
Calcium carbonate:other indications Bone Mineral Homeostasis
CaCl2 hypercalcemia, renal insufficiency,
and metabolic alkalosis (milk-alkali syndrome).

14. AntacidsAntacids
•magnesium hydroxide
•aluminum hydroxide
slowly +HCl  magnesium chloride / aluminum chloride + water

no gas 
no
belching
Metabolic alkalosis:
uncommon because of
the efficiency of the
neutralization reaction
unabsorbed magnesium
salts  an osmotic
diarrhea
unabsorbed
aluminum salts 
constipation
Both magnesium and aluminum are absorbed and excreted by the kidneys .
Hence, patients with renal insufficiency should not take these agents long-term.

15. Antacids: Interactions
•All antacids may affect the absorption of other
medications by:
1) binding the drug  reducing its absorption
2) increasing intragastric pH  affects the drug's dissolution or
solubility (especially weakly basic or acidic drugs)
•Hence, antacids should not be given within 2 hours of
doses of tetracyclines, fluoroquinolones, itraconazole,
and iron.

16. H2-Receptor AntagonistsH2-Receptor Antagonists
•(commonly referred to as H2-blockers)
1) After recognition of H. pylori (which may be treated with appropriate
antibacterial therapy)
2) and the advent of proton pump inhibitors
1970s 1990s
the use of prescription H2-blockers has declined markedly.
but

18. Chemistry & PharmacokineticsChemistry & Pharmacokinetics
•Four H2 antagonists are in clinical use:
cimetidine, ranitidine, famotidine, and nizatidine
•All four agents are rapidly absorbed from the intestine.

19. Clinical Comparisons of Clinical Comparisons of
H2 Receptor BlockersH2 Receptor Blockers..

20. Pharmacodynamics
•H2 antagonists : competitive inhibition of parietal cell H2 receptor 
suppress acid secretion

•highly selectivity (no affect on H1 or H3 receptors)
•H2 antagonists reduce acid secretion through two mechanisms:
1) histamine released from ECL cells by gastrin or vagal stimulation is
blocked from binding to the parietal cell H2 receptor.
2)direct stimulation of the parietal cell by gastrin or acetylcholine
results in diminished acid secretion in the presence of H2 receptor
blockade.
•in parietal cell: reduced cAMP levels attenuate the intracellular
activation of protein kinases by gastrin or acetylcholine.

21. Clinical Uses
Adverse Effects
•Gastroesophageal Reflux Disease (GERD)
•Peptic Ulcer Disease
•Nonulcer Dyspepsia
•Prevention of Bleeding from Stress-Related Gastritis
•H2 antagonists are extremely safe drugs.
•Side effects occur in fewer than 3% of patients and include diarrhea,
headache, fatigue, myalgias, and constipation.
•Cimetidine interferes with several important hepatic cytochrome
P450 drug metabolism pathways, hence, the half-lives of drugs
metabolized by these pathways may be prolonged.
Drug Interactions

22. Proton Pump Inhibitors (PPI)
•Since their introduction in the late 1980s, these efficacious acid inhibitory
agents have rapidly assumed the major treatment of acid-peptic disorders.
They are now among the most widely selling drugs worldwide due to their
outstanding efficacy and safety.
•Their bioavailability is decreased approximately 50% by food; hence, the
drugs should be administered on an empty stomach.
•In a fasting state, only 10% of proton pumps are actively secreting acid and
susceptible to inhibition.
•Proton pump inhibitors should be administered approximately 1 hour before
a meal (usually breakfast or dinner), so that the peak serum concentration
coincides with the maximal activity of proton pump secretion.
•The drugs have a short serum half-life of about 1.5 hours; however, the
duration of acid inhibition lasts up to 24 hours due to the irreversible
inactivation of the proton pump.
•At least 18 hours are required for synthesis of new H+/K+ ATPase pump
molecules.
•Because not all proton pumps are inactivated with the first dose of
medication, up to 3–4 days of daily medication are required before the full
acid-inhibiting potential is reached. Similarly, after stopping the drug, it takes
3–4 days for full acid secretion to return.

24. Chemistry & Pharmacokinetics
•omeprazole, lansoprazole, rabeprazole,
pantoprazole, and esomeprazole.
•All resemble H2 antagonists structurally but completely different
functionally!
•All agents are available in oral formulations. Pantoprazole also IV.
•Proton pump inhibitors are administered as inactive prodrugs.
•To protect the acid-labile prodrug : acid-resistant enteric-coated
microgranules mixed with apple juice or applesauce.
•After passing through the stomach into the alkaline intestinal lumen,
the enteric coatings dissolve and the prodrug is absorbed. These
prodrugs are lipophilic weak bases (pKa 4–5) and therefore diffuse
readily across lipid membranes into acidified compartments (such
as the parietal cell canaliculus). Within the acidified compartment
the prodrug rapidly becomes protonated and is concentrated >
1000-fold within the parietal cell canaliculus.
•There, it rapidly is converted to the active, reactive sulfonamide
cation, which reacts with the H+/K+ ATPase, forms a covalent
disulfide linkage, and irreversibly inactivates the enzyme.

25. Omeprazole: Pharmacodynamics Pharmacodynamics
From a pharmacokinetic perspective, proton pump
inhibitors are ideal drugs:
•they have a short serum half-life, they are concentrated
and activated near their site of action, and they have a
long duration of action.
•In contrast to H2 antagonists, proton pump inhibitors
inhibit both fasting and meal-stimulated secretion
because they block the final common pathway of acid
secretion, the proton pump.

•In standard doses, proton pump inhibitors inhibit 90–98%
of 24-hour acid secretion.

26. Clinical UsesClinical Uses
•Gastroesophageal Reflux Disease (GERD)
•Peptic Ulcer Disease
•H. Pylori -Associated Ulcers
•NSAID -Associated Ulcers
•Prevention of Rebleeding from Peptic Ulcers
•Nonulcer Dyspepsia
•Prevention of Stress Gastritis
•Gastrinoma and Other Hypersecretory
Conditions

27. Adverse Effects
General
•Proton pump inhibitors are extremely safe. Diarrhea, headache, and
abdominal pain are reported in 1–5% of patients, however, safety
during pregnancy has not been established.

Nutrition
•Acid is important in releasing vitamin B12 from food. A minor
reduction in oral cyanocobalamin absorption occurs during proton
pump inhibition, potentially leading to subnormal B12 levels with
prolonged therapy. Acid also promotes absorption of food-bound
minerals (iron, calcium, zinc); however, no mineral deficiencies have
been reported with proton pump inhibitor therapy.
•Gastric acid is an important barrier to colonization and infection of
the stomach and intestine from ingested bacteria. Hypochlorhydria
from any cause increases the risk for enteric infections (eg,
salmonella, shigella). A small increased risk of enteric infections
may exist in patients taking proton pump inhibitors, especially when
traveling in underdeveloped countries.

28. Potential Problems Due to Increased Serum
Gastrin
•Gastrin levels are regulated by a feedback loop. During meals, intraluminal food
proteins stimulate gastrin release from antral G-cells. The rise in serum gastrin
stimulates parietal cell acid secretion.
•Increased intragastric acidity stimulates antral D-cells to release somatostatin, which
binds to receptors on adjacent antral G-cells, turning off further gastrin release. Acid
suppression alters this feedback inhibition so that gastrin levels rise two- to four-fold
in patients taking proton pump inhibitors. Upon stopping the drug, the levels
normalize.
•The rise in serum gastrin levels in patients receiving long-term therapy with proton
pump inhibitors has raised two theoretical concerns. First, gastrin is a trophic
hormone that stimulates hyperplasia of ECL cells. Hypergastrinemia due to
gastrinoma (Zollinger-Ellison syndrome) or atrophic gastritis is associated with the
development of gastric carcinoids in up to 3% of patients. In female rats given proton
pump inhibitors for prolonged periods, gastric carcinoid tumors developed in areas of
ECL hyperplasia. Although humans who take proton pump inhibitors for a long time
may exhibit ECL hyperplasia in response to hypergastrinemia, carcinoid tumor
formation has not been documented. Second, hypergastrinemia increases the
proliferative rate of colonic mucosa, potentially promoting carcinogenesis. In humans,
hypergastrinemia caused by vagotomy, atrophic gastritis, or Zollinger- Ellison
syndrome has not been associated with increased colon cancer risk. At present,
routine monitoring of serum gastrin levels is not recommended in patients receiving
prolonged proton pump inhibitor therapy.

29. Drug InteractionsDrug Interactions
•Decreased gastric acidity may alter absorption
of drugs for which intragastric acidity affects
drug bioavailability, eg, ketoconazole and
digoxin.
•All proton pump inhibitors are metabolized by
hepatic P450 cytochromes, including CYP2C19
and CYP3A4. Omeprazole may inhibit the
metabolism of coumadin, diazepam, and
phenytoin.

30. Defense mechanisms of gastroduodenal Defense mechanisms of gastroduodenal
mucosa against :acid and pepsinmucosa against :acid and pepsin
•Mucus
•epithelial cell-cell tight junctions
•Epithelial bicarbonate secretion
•Blood flow (carries bicarbonate and vital nutrients)
•Restitution: quickly repair of injured epithelium (in which
migration of cells from gland neck cells seals small erosions to reestablish
intact epithelium.)
•Mucosal prostaglandins : stimulating mucus and
bicarbonate secretion and mucosal blood flow.
•Sucralfate
•Prostaglandin Analogs
•Colloidal Bismuth Compounds
Mucosal Protective Agents

31. •Sucralfate is a salt of sucrose complexed to sulfated aluminum Sucralfate is a salt of sucrose complexed to sulfated aluminum
hydroxide. hydroxide.
•it forms (in water or acidic solutions) a viscous, tenacious paste that it forms (in water or acidic solutions) a viscous, tenacious paste that
binds selectively to ulcers or erosionsbinds selectively to ulcers or erosions for up to 6 hours. for up to 6 hours.
•Sucralfate has limited solubility, breaking down into sucrose sulfate Sucralfate has limited solubility, breaking down into sucrose sulfate
((strongly negativelystrongly negatively charged) and an aluminum salt. charged) and an aluminum salt.
•Less than 3% of intact drug and 0.01% of aluminum is absorbed from Less than 3% of intact drug and 0.01% of aluminum is absorbed from
the intestinal tract; the remainder is excreted in the feces.the intestinal tract; the remainder is excreted in the feces.
Sucralfate:Sucralfate: Chemistry & Chemistry &
PharmacokineticsPharmacokinetics

32. Pharmacodynamics
•Precise mechanism : unclear.
•It is believed that the: (1) 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 (2) stimulates mucosal
prostaglandin and bicarbonate secretion.
•(3) It may also bind epithelial growth factor and
fibroblast growth factor, enhancing mucosal
repair.

33. Clinical Uses
•Sucralfate is administered in a dosage of 1 g four times daily on an
empty stomach (at least 1 hour before meals).
•At present, its clinical uses are limited.
•It has been shown to be effective for the healing of duodenal ulcers,
but with the advent of more effective agents (proton pump
inhibitors), it is seldom used for this indication.
•In critically ill patients hospitalized in the intensive care unit,
sucralfate is effective for the prevention of bleeding from stress-
related gastritis. It is still unclear which is the preferred agent for this
indication: sucralfate (administered as a slurry through a nasogastric
tube), intravenous H2 antagonists, or intravenous proton pump
inhibitors.
•Some clinicians administer sucralfate to patients taking NSAIDs who
are experiencing dyspepsia. It is not an effective agent in preventing
or healing NSAID-induced ulcers.

34. Adverse EffectsAdverse Effects
•Is not absorbed  virtually no systemic side effects.
•Constipation occurs in 2% 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.
•Sucralfate may bind to other medications, impairing their
absorption.
Drug Interactions

35. Prostaglandin AnalogsProstaglandin Analogs: Chemistry
& Pharmacokinetics
•The human gastrointestinal mucosa synthesizes a
number of prostaglandins, however the primary ones are
prostaglandins E and F.
• Misoprostol, a methyl analog of PGE1, has been
approved for gastrointestinal conditions.
•Following oral administration, it is rapidly absorbed and
metabolized to a metabolically active free acid. The
serum half-life is less than 30 minutes; hence, it must be
administered 3–4 times daily. It is excreted in the urine,
however dose reduction is not needed in patients with
renal insufficiency.

36. Misoprostol: Pharmacodynamics Pharmacodynamics
•(1) acid inhibitory
- it binds to a prostaglandin receptor on parietal
cells, reducing histamine-stimulated cAMP
production and causing modest acid inhibition.
•(2) mucosal protective properties:
- stimulate mucus and bicarbonate secretion
- enhance mucosal blood flow.
•(3) Prostaglandins have a variety of other
actions, including stimulation of intestinal
electrolyte and fluid secretion, intestinal motility
and uterine contractions.

37. Clinical UsesClinical Uses
•Misoprostol reduces the incidence of NSAID-induced ulcers
• But:
•proton pump inhibitors may be as effective and better tolerated than
misoprostol for this indication.
•Cyclooxygenase-2-selective NSAIDs, which may have less
gastrointestinal toxicity
•Diarrhea and cramping abdominal pain occurs in 10–20% of
patients.
•Because misoprostol stimulates uterine contractions , it should not
be used during pregnancy or in women of childbearing potential
unless they have a negative serum pregnancy test and are
compliant with effective contraceptive measures.
•No significant drug interactions are reported.
Adverse Effects & Drug InteractionsAdverse Effects & Drug Interactions

38. Colloidal Bismuth CompoundsColloidal Bismuth Compounds
•Chemistry & Pharmacokinetics
•bismuth compound (e.g. in USA: bismuth subsalicylate): a
nonprescription formulation containing bismuth and salicylate.
•In other countries, bismuth subcitrate (in Iran) are also available.
•Bismuth subsalicylate undergoes rapid dissociation within the stomach,
allowing absorption of salicylate.
•Pharmacodynamics
•Like sucralfate, bismuth probably coats ulcers and erosions, creating a
protective layer against acid and pepsin. It may also stimulate
prostaglandin, mucus, and bicarbonate secretion.
•Bismuth has direct antimicrobial effects and binds enterotoxins, accounting
for its benefit in preventing and treating traveler's diarrhea.
•Bismuth compounds have direct antimicrobial activity against H pylori.
•Adverse Effects
•Bismuth causes blackening of the stool, which may be confused with
gastrointestinal bleeding.
•Liquid formulations may cause harmless darkening of the tongue.
•Bismuth agents should be used for only short periods and should be
avoided in patients with renal insufficiencyrenal insufficiency.

39. Drugs Stimulating Gastrointestinal Drugs Stimulating Gastrointestinal
Motility (prokinetic agents) 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.
•Finally, agents that enhance colonic transit may be
useful in the treatment of constipation.
•Unfortunately, only a limited number of agents are
available for clinical use at this time.

40. Physiology of the Enteric Nervous
System

41. Physiology of the Enteric Nervous
System
•The enteric nervous system 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).
•These networks give rise to nerve fibers that connect with the mucosa and deep
muscle. Although extrinsic sympathetic and parasympathetic nerves project onto the
submucosal and myenteric plexuses, the enteric nervous system can independently
regulate gastrointestinal motility and secretion.
•Afferent fibers present in the mucosa and muscularis connect to cell bodies in the
plexuses that mediate local reflexes. Myenteric plexus interneurons containing
calcitonin gene related peptide (CGRP) may be important in controlling the peristaltic
reflex, promoting release of excitatory mediators proximally and inhibitory mediators
distally. Excitatory muscle activity (contraction) is promoted by enteric interneurons
and motor neurons that release acetylcholine, serotonin, and substance P. Inhibition
of muscle activity and relaxation is promoted by enteric motor neurons that release
vasoactive intestinal peptide, nitric oxide, and ATP. Motilin may stimulate excitatory
neurons or muscle cells directly. Dopamine acts as an inhibitory neurotransmitter in
the gastrointestinal tract, decreasing the intensity of esophageal and gastric
contractions. Although there are at least 14 serotonin (5-HT) receptor subtypes, drug
development for gastrointestinal applications to date has focused on 5-HT3 receptor
antagonists and 5-HT4 receptor agonists. These agents—which have effects upon
gastrointestinal motility and visceral afferent sensation—are discussed under Drugs
Used for the Treatment of Irritable Bowel Syndrome and Antiemetics. Other drugs
acting on 5-HT receptors : Histamine, Serotonin, & the Ergot Alkaloids: Antipsychotic
Agents & Lithium, and Antidepressant Agents.

42. Cholinomimetic AgentsCholinomimetic Agents
•bethanechol stimulate muscarinic M3 receptors
on muscle cells and at myenteric plexus
synapses
•Bethanechol was used in the past for the
treatment of GERD and gastroparesis.
•The acetylcholinesterase inhibitor neostigmine
can enhance gastric, small intestine, and colonic
emptying.
•Cholinergic side effects include excessive
salivation, nausea, vomiting, diarrhea, and
bradycardia.

43. Metoclopramide, Domperidone, & Metoclopramide, Domperidone, &
CisaprideCisapride
The primary prokinetic mechanism :
•cholinergic stimulation.
•(Also) agonist activity at 5-HT4 receptors on enteric neurons, which
promotes release of acetylcholine,
•Cisapride: some antagonist activity at 5-HT3 receptors.
•Metoclopramide and domperidone (but not cisapride) are
dopamine D2 receptor antagonists. Within the gastrointestinal tract dopamine
receptor antagonism may potentiate cholinergic smooth muscle stimulation.
•Metoclopramide and domperidone also block dopamine D2
receptors in the chemoreceptor trigger zone of the medulla (area
postrema), resulting in potent antinausea and antiemetic action.
•These agents increase esophageal peristaltic amplitude, increase
lower esophageal sphincter (LES) pressure, and enhance gastric
emptying. Cisapride also enhances small bowel and colonic motility.

44. •Gastroesophageal Reflux Disease (GERD)
•Impaired Gastric Emptying
•Nonulcer Dyspepsia
•Prevention of Vomiting
•Metoclopramide: The most common in CNS: Restlessness, drowsiness, insomnia,
anxiety, and agitation occur in 10–20% of patients, especially the elderly.
Extrapyramidal effects (dystonias, akathisia, parkinsonian features) due to central
dopamine receptor blockade occur acutely in 25% of patients given high doses and in
5% of patients receiving long-term therapy. Tardive dyskinesia, sometime irreversible,
has developed in patients treated for a prolonged period with metoclopramide. For this
reason, long-term use should be avoided unless absolutely necessary, especially in the
elderly.
•Elevated prolactin levels (caused by both metoclopramide and domperidone) can
cause galactorrhea, gynecomastia, impotence, and menstrual disorders.
•Cisapride: Due to prokinetic effects in the colon, abdominal cramps and diarrhea occur
in up to 15% of patients taking; however significant problems are unusual.
•Cisapride is metabolized by the hepatic cytochrome P450 CYP3A4 enzyme. When
coadministered with drugs that inhibit this enzyme (such as ketoconazole, fluconazole,
macrolide antibiotics, and HIV protease inhibitors), significant increases in serum levels
of cisapride may occur that rarely lead to QT prolongation on the ECG and serious
cardiac arrhythmias. For this reason, cisapride was removed from the market by the
manufacturer.
Clinical UsesClinical Uses
AdverseAdverse EffectsEffects

45. MacrolidesMacrolides
•Macrolide antibiotics (such as erythromycin): directly
stimulate motilin receptors on gastrointestinal smooth
muscle and promote the onset of a migrating motor
complex.
•Intravenous erythromycin (3 mg/kg) is beneficial in some
patients with gastroparesis; however, tolerance rapidly
develops.
•Specific motilin agonists are under investigation.

46. Laxatives: IntroductionLaxatives: Introduction
•Self-prescription by a large portion of the population
although majority of people do not need laxatives.

•For most people, intermittent constipation is best
prevented with a high fiber diet, adequate fluid intake,
regular exercise.
•Patients not responding to dietary changes or fiber
supplements should undergo medical evaluation prior to
the initiation of long-term laxative treatment.
•Laxatives may be classified by their major mechanism
of action, but many work through more than one
mechanism.

47. Bulk-Forming LaxativesBulk-Forming Laxatives
•Are: indigestible, hydrophilic colloids that absorb
water, forming a bulky gel that distends the colon and
promotes peristalsis.
•)
مجح ی هدنهد شیازفا(
•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.

48. Stool Surfactant Agents (Softeners)Stool Surfactant Agents (Softeners)
•These agents soften stool material, permitting water and
lipids to penetrate.
•They may be administered orally or rectally.
•Common agents: docusate (oral or enema) or glycerin
suppository.
•In hospitalized patients, docusate is commonly
prescribed to prevent constipation and minimize
straining.
•Mineral oil is a clear, viscous oil that lubricates fecal
material, retarding water absorption from the stool. It is
used to prevent and treat fecal impaction in young
children and debilitated adults. It is not palatable but may
be mixed with juices. Aspiration can result in a severe
lipid pneumonitis. Long-term use can impair absorption
of fat-soluble vitamins (A, D, E, K).

49. Osmotic LaxativesOsmotic Laxatives
•The colon can neither concentrate nor
dilute fecal fluid: fecal water is isotonic
throughout the colon.
•Osmotic laxatives are soluble but
nonabsorbable compounds that result in
increased stool liquidity due to an obligate
increase in fecal fluid.

50. (1) Nonabsorbable Sugars or Salts(1) Nonabsorbable Sugars or Salts
•May be used for the treatment of acute constipation or the
prevention of chronic constipation.
•Magnesium oxide (milk of magnesia) is a commonly used
osmotic laxative. It should not be used for prolonged periods in
patients with renal insufficiency due to risk of hypermagnesemia.
•Sorbitol and lactulose are nonabsorbable sugars: prevent or treat
chronic constipation. These sugars are metabolized by colonic
bacteria, producing severe flatus and cramps.
•High doses  prompt bowel evacuation (purgation) within 1–3
hours.
•The most commonly used purgatives هدور ی هدننک هیلخت) ): magnesium
citrate and sodium phosphate.
•These hyperosmolar agents may lead to intravascular volume
depletion and electrolyte fluctuations; hence they should not be
used in patients who are frail, elderly, have renal insufficiency, or
have significant cardiac disease.

51. (2) Balanced Polyethylene Glycol (PEG)(2) Balanced Polyethylene Glycol (PEG)
•(1) Lavage solutions containing polyethylene glycol (PEG) are
used for complete colonic cleansing prior to gastrointestinal
endoscopic procedures.
•These balanced, isotonic solutions contain an inert, nonabsorbable,
osmotically active sugar (PEG) with sodium sulfate, sodium
chloride, sodium bicarbonate, and potassium chloride. The solution
is designed so that no significant intravascular fluid or electrolyte
shifts occur. Therefore, they are safe for all patients.
•The solution should be ingested rapidly (4 L over 2 hours) to
promote bowel cleansing.
•(2) For treatment or prevention of chronic constipation, smaller
doses of PEG powder may be mixed with water or juices (17 g/8 oz)
and ingested daily.
•In contrast to sorbitol or lactulose, PEG does not produce significant
cramps or flatus.

52. Stimulant LaxativesStimulant Laxatives
•Stimulant laxatives (cathartics) induce bowel movements through a number
of poorly understood mechanisms.
•These include: direct stimulation of the ENS and colonic electrolyte and fluid
secretion.
•There has been concern that long-term use of cathartics could lead to
dependency and destruction of the myenteric plexus, resulting in colonic
atony and dilation.
•More recent research suggests that long-term use of these agents probably
is safe in most patients. Useful in bed-bound patients in long-term care
facilities.
•Anthraquinone DerivativesAnthraquinone Derivatives
•Aloe, senna, and cascara (in plants): poorly absorbed -- hydrolysis in the
colon // Chronic use: brown pigmentation of the colon : "melanosis coli."
some concernof being carcinogenic, but no epidemiologic correlations.
•Diphenylmethane DerivativesDiphenylmethane Derivatives (eg, phenolphthalein) no use now due to
possible cardiac toxicity
•Castor Oil Castor Oil This oil is a potent stimulant laxative. It is hydrolyzed in the upper
small intestine to ricinoleic acid, a local irritant that stimulates intestinal
motility.

53. Antidiarrheal AgentsAntidiarrheal Agents
•Safely used in
(1) patients with mild to moderate acute diarrhea.
(2) to control chronic diarrhea caused by such conditions as irritable
bowel syndrome (IBS) or inflammatory bowel disease (IBD).
•However, they should not be used in patients with bloody diarrhea,
high fever, or systemic toxicity because of the risk of worsening the
underlying condition. They should be discontinued in patients whose
diarrhea is worsening despite therapy.
(1) Kaolin & Pectin(1) Kaolin & Pectin
•Kaolin is a naturally occurring hydrated magnesium aluminum
silicate (attapulgite), and pectin is an indigestible carbohydrate
derived from apples.
•Both absorbents of bacteria, toxins, and fluid, decreasing stool
liquidity and number.
•Use: acute diarrhea but are seldom used on a chronic basis.
•Kaolin-pectin formulations are not absorbed and have no significant
side effects except constipation. They should not be taken within 2
hours of other medications (to which they may bind).

54. (2) Opioid Agonists(2) Opioid Agonists
•Of significant constipating effects : They increase colonic phasic
segmenting activity through inhibition of presynaptic cholinergic
nerves in the submucosal and myenteric plexuses and lead to
increased colonic transit time and fecal water absorption.
•All opioids have antidiarrheal effects, but CNS effects and potential
for addiction limit the usefulness of most.
•Loperamide is a nonprescription opioid agonist that does not cross
the blood-brain barrier and has no analgesic properties or potential
for addiction.
•Diphenoxylate is another opioid agonist that has no analgesic
properties in standard doses; however, higher doses have CNS
effects and prolonged use can lead to opioid dependence.
Commercial preparations commonly contain small amounts of
atropine to discourage overdosage LomotilLomotil (2.5 mg diphenoxylate
with 0.025 mg atropine). The anticholinergic properties of atropine
may contribute to the antidiarrheal action.
•(3) Colloidal Bismuth Compounds(3) Colloidal Bismuth Compounds

55. AntiemeticsAntiemetics::
•A variety of drugs have been found to be of some value
in the prevention and treatment of vomiting, especially
cancer chemotherapy-induced vomiting.
•In addition to metoclopramide, useful antiemetic drugs
include dexamethasone; some H1 anti
­histamines;
several phenothiazines; the 5-HT3 inhibitors; and
dronabinol, the active ingre
­dient in marijuana. The 5-
HT3 inhibitors, ondansetron, granisetron, and
dolasetron, are extremely useful in preventing nausea
and vomiting after general anesthesia and in patients
receiving cancer chemotherapy.

56. Pancreatic Enzyme ReplacementsPancreatic Enzyme Replacements::
•Steatorrhea, a condition of :
decreased fat absorption coupled with an increase in stool
fat excretion, due to inadequate pancreatic secretion of
lipase.
Treatment by: pancreatic lipase (pancrelipase) obtained
from pigs.

Pancreatic lipase is inactivated at a pH be
­low 4.0, thus, up
to 90% of an administered dose will be destroyed in the
stomach, unless the pH is raised with antacids or drugs
that reduce acid secretion.

57. Drugs that Inhibit Drugs that Inhibit
the Formation of the Formation of GallstonesGallstones::
•The formation of cholesterol gallstones can
be inhibited by several drugs, though none
are dramatically effective.

•Such drugs include the bile acid derivatives
chenodiol and ursodiol.
•Chenodiol appears to reduce the secretion
of bile acids by the liver, while the
mechanism of action of ursodiol is unknown.

58. Drugs Used to Treat Inflammatory Bowel Drugs Used to Treat Inflammatory Bowel
Disease (IBD)Disease (IBD)
•Inflammatory bowel disease comprises two distinct disorders: ulcerative colitis and Crohn's
disease.
•The etiology and pathogenesis of these disorders remains unknown.  pharmacologic treatment:
of different therapeutic classes and have different but nonspecific mechanisms of anti-
inflammatory action.
Aminosalicylates
•Drugs that contain 5-aminosalicylic acid (5-ASA) have been used successfully
•Aminosalicylates are believed to work topically (not systemically) in areas of diseased
gastrointestinal mucosa.
•These include sulfasalazine, olsalazine, balsalazide, and various forms of mesalamine.
Azo Compounds
•Sulfasalazine, balsalazide, and olsalazine contain 5-ASA bound by an azo (N=N) bond to an inert
compound or to another 5-ASA molecule.
•In the terminal ileum and colon, resident bacteria cleave the azo bond by means of an
azoreductase enzyme, releasing the active 5-ASA.
Mesalamine Compounds
•A number of proprietary formulations have been designed that package 5-ASA in various ways in
order to deliver it to different segments of the small or large bowel. These 5-ASA formulations are
known generically as mesalamine.
•Pentasa is a mesalamine formulation that contains time-release microgranules that release 5-
ASA throughout the small intestine. Asacol has 5-ASA coated in a pH sensitive resin that
dissolves at pH 7 (the pH of the distal ileum and proximal colon). 5-ASA also may be delivered in
high concentrations to the rectum and sigmoid colon by means of enema formulations (Rowasa)
or suppositories (Canasa).

59. The EndThe End

60. Thank you for Thank you for

your Attentionyour Attention