2.

2
August 7, 2013
Rene Luis F. Filarca, M.D. Gastrointestinal
"Cultivation to the mind is as necessary as food to the body." ‒Marcus Tullius Cicero
Pharmacology

SECTION PAGE A. Ursodiol 14

I. Acid-Peptic Diseases X. Variceal Hemorrhage
A. Antacids A. Somatostatin and Octreotide 14
1. Sodium Bicarbonate 1 B. Vasopressin 14
2. Calcium Carbonate 2 C. Terlipressin 14
3. Magnesium Hydroxide and Aluminum D. Non-selective Beta Blockers 14
2
Hydroxide XI. Review Questions 15
4. Alginate 2
B. H2-Receptor Antagonists 2-3 TRANSMASTER'S NOTE
*Lecture-based content, side comments, or transmaster notes
C. Proton Pump Inhibitors 3-4
D. Mucosal Protectants TRANSMASTER'S NOTE
1. Sucralfate (Carafate) 4 *Markers for drugs
2. Prostaglandin Analogs 4  Drug name with asterisk (*) – not in lecture
3. Colloidal Bismuth 4-5
II. Prokinetic Agents ACID-PEPTIC DISEASES
A. Cholinomimetic Agents 5  Gastroesophageal reflux disease
B. Dopamine D2 Receptor Agonists 5-6  Peptic ulcer
o Gastric
C. Macrolide Antibiotics 6
o Duodenal
D. Chloride Channel Activators 6  Stress-related mucosal injury
III. Laxatives  90% caused by:
A. Bulk-Forming Laxatives 6 o Helicobacter pylori
B. Stool Surfactant Agents (Softeners) 6 o NSAIDs
C. Osmotic Laxatives 6
D. Stimulant Laxatives (Cathartics) 6-7 AGGRESSIVE FACTORS DEFENSIVE FACTORS
E. Chloride Channel Activators 7 Acid Mucus (HCO3)
F. Serotonin 5-HT4 Receptor Antagonists 7 Bile Blood flow
G. Guanylate Cyclase C Agonists 8 Pepsin Prostaglandin
IV. Antidiarrheals Restitution
Regeneration
A. Opioid Agonists 8
B. Colloidal Bismuth Compounds 8
C. Kaolin and Pectin 8 ANTACIDS
D. Bile Salt-Binding Resins 8  Used for centuries in the treatment of:
o Dyspepsia
E. Somatostatin and Octreotide 8-9
o Acid-peptic disorders
V. Irritable Bowel Syndrome
 Mainstay treatment for acid-peptic disorders until the
A. Treatment advent of:
1. Antispasmodics 9 o H2-receptor antagonists
2. 5-HT3 Receptor Antagonists 9 o Proton pump inhibitors
3. 5-HT4 Receptor Agonists 9  Continue to be used as nonprescription remedies for
4. Chloride Channel Activators 9 heartburn and dyspepsia
VI. Vomiting 9-10  Weak bases
A. Treatment o Reaction with gastric HCl  NaCl + H2O
1. 5-HT3 Receptor Antagonists 10  Mechanisms of action
o Reduction of intragastric acidity
2. Corticosteroids 10
o Promotion of mucosal defense mechanisms
3. Neurokinin Receptor Antagonists 10
 Given 1 hour after a meal to effectively neutralize gastric
4. Phenothiazines and acid for up to 2 hours
10-11
Butyrophenones  Acid neutralization capacity
5. Substituted Benzamides 11 o Variable among different proprietary formulations
6. Anticholinergic Antihistamines 11 o Dependent on:
7. Benzodiazepines 11  Rate of dissolution (tablet vs liquid)
8. Cannabinoids 11  Water solubility
VII. Inflammatory Bowel Disease  Rate of reaction with acid
A. Aminosalicylates 11-12  Rate of gastric emptying
B. Glucocorticoids 12
C. Purine Analogs 12-13 SODIUM BICARBONATE
(BAKING SODA, ALKA-SELTZER)
D. Methotrexate 13
E. Anti-TNF Therapy 13-14  Reacts rapidly with HCl  CO2 + NaCl
 NaHCO3 + HCl  NaCl + CO2 wherein absorption of:
F. Anti-Integrin Therapy 14
o NaHCO3
VIII. Exocrine Pancreatic Insufficiency 14  Renal insufficiency  metabolic alkalosis
IX. Bile Acid Therapy for Gallstones o CO2  gastric distention and belching

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 Gastrointestinal Pharmacology

o NaCl
 Heart failure, hypertension, renal insufficiency  PHARMACOKINETICS
exacerbation of fluid retention  Rapid enteric absorption
 Cimetidine, ranitidine, and famotidine
CALCIUM BICARBONATE o Undergo first-pass hepatic metabolism
(TUMS, OS-CAL) o Bioavailability of ~50%
 Less-soluble  Nizatidine
 Reacts more slowly than NaHCO3 with HCl to form CO2 and o Little first-pass metabolism*
CaCl2 o Bioavailability of almost 100%
 CaCO3 + HCl  CaCl2 + CO2  Serum t1/2 of these agents range from 1.1-4 hours
o CaCO3: belching and metabolic alkalosis  Duration of action – dose-dependent
 Excessive doses of NaHCO3 and CaCO3 with Ca-containing  Cleared by a combination of:
dairy products can lead to: o Hepatic metabolism
o Hypercalcemia o Glomerular filtration
o Renal insufficiency o Renal tubular secretion
o Metabolic alkalosis (milk-alkali syndrome)   dose in patients with insufficiencies

MAGNESIUM HYDROXIDE OR ALUMINUM HYDROXIDE PHARMACODYNAMICS

(GELUSIL, MAALOX, MYLANTA)
 Reacts slowly with HCl  Mg(OH)2 or Al(OH)3 + H2O
o Mg(OH)2 + HCl  MgCl2 +H2O wherein:
 MgCl2  osmotic diarrhea
o Al(OH)3 + HCl  AlCl3 + H2O wherein:
 AlCl3  constipation
 No gas generated  no belching
 Metabolic alkalosis – uncommon because of efficiency of
neutralization reaction
 Mg(OH)2 + Al(OH)2 commonly administered together to
minimize impact on bowel function (cancelling-out effect):
TRANSMASTER'S NOTE
Tips from one of my BSN professors. 
 Magnesium = magdudumi (diarrhea)
 Aluminum = alang dumi (constipation)
 Both absorbed and excreted by the kidneys
 Patients with renal insufficiency should not take them
long-term
 All antacids may affect absorption of other medications by:
o Binding to drug   absorption
o  intragastric pH  altered dissolution or solubilty
 Should not be given within 2 hours of doses of:
o Tetracycline
o Fluoroquinolones
o Itraconazole
o Iron
 Competitive inhibition at parietal cell H2 receptor
 Suppress basal and meal-stimulated acid secretion
o Effective in inhibiting nocturnal acid secretion
(depends largely on histamine)
o Modest impact on meal-stimulated acid secretion
stimulated by:
 Gastrin
 Acetylcholine
 Histamine
 Mechanisms of action in  acid secretion
o Blocking of histamine (released from ECL cells by
gastrin or vagal stimulation) binding to H2 receptors
o  effect of direct stimulation of parietal cell by gastrin
or acetylcholine in presence of H2 receptor blockade
 Highly selective (no effect on H1 or H3 receptors)
 Reduces the following:
o Volume of gastric secretions stimulated by:
 Histamine
 Gastrin
 Cholinomimetic agents
o Concentration of pepsin
 Raises nocturnal and fasting intragastric pH to 4-5
 Recommended prescription doses
o Maintain >50% acid inhibition for 10 hours
o BID (twice daily) administration
 Duration of inhibition in OTC formulations
o Less than that of prescription (<6 hours)

ALGINATE (GAVISCON) CLINICAL USES

 Active ingredients: 1. GASTROESOPHAGEAL REFLUX DISEASE
o Sodium alginate  Infrequent heartburn or dyspepsia (<3x/week)
o Bicarbonate o Antacids
o Calcium carbonate  Rapidly neutralize acid  faster relief
 Mechanism of action  Short-acting (1-2 hours)
o Reaction with HCl  protective viscous "foam"   o H2 receptor antagonists
contact of acid with gastric mucosa  Long-acting (6-10 hours)
 Treatment of heartburn and GERD  Taken prophylactically before a meal 
likelihood of heartburn
 Frequent heartburn
H2-RECEPTOR ANTAGONISTS
o H2 receptor antagonists
 Commonly referred to as H2 blockers  Taken BID
 Marked  in use due to:  Promote healing in erosive esophagitis
o Recognition of role of H. pylori in ulcer disease (can be
treated with antibacterials) 2. PEPTIC ULCER DISEASE
o Advent of proton pump inhibitors  H2 receptor antagonists
 Clinically significant H2-receptor antagonists: o Replaced by proton pump inhibitors
o Cimetidine (Tagamet) o Given OD HS (once daily before bedtime) in cases
o Ranitidine (Zantac) of persistent H. pylori
o Famotidine (Pepcid)
o Nizatidine (Axid) 3. INTERMITTENT NON-ULCER DYSPEPSIA

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 Gastrointestinal Pharmacology

o Lansoprazole (Prevacid)*
4. REBLEEDING FROM STRESS-RELATED GASTRITIS o Dexlansoprazole (Dexilant)
 H2 receptor antagonists o Rabeprazole (Aciphex)
o  bleeding from stress-related gastritis in critically- o Pantoprazole (Protonix)
ill patients
o Given TIV as intermittent or continuous infusions PHARMACOKINETICS
 Inactive prodrugs
ADVERSE EFFECTS o Acid-labile
 H2 receptor antagonists – extremely safe o Formulated for delayed-release as acid-resistant,
 Adverse effects manifested in <3% of patients: enteric-coated tablets or capsules
o Diarrhea  Can be mixed with juice
o Headache o Omeprazole – non-enteric-coated powder
o Fatigue  Concentrated more than 1000-fold within parietal cell
o Myalgias canaliculus by Henderson-Hasselbach trapping (refer to
o Constipation Chapter 1 in Katzung XD)
  risk of nosocomial pneumonia in critically ill patients  Converted to active, reactive thiophilic sulfonamide cation
 forms covalent disulfide linkage with H+/K+ ATPase 
1. CENTRAL NERVOUS SYSTEM irreversible enzyme inactivation
 Cimetidine  50% decrease in bioavailability with food
o Mental status changes in ICU patients: o Give PPI on empty stomach
 Confusion  Undergo rapid first-pass and systemic hepatic metabolism
 Hallucinations  Pharmacokinetically ideal drugs
 Agitation o Short t½ of 1.5 hours
o Concentrated and activated near site of action
2. ENDOCRINE o Long duration of action (inhibition lasts 24 hours)
 Cimetidine (if long-term)
o Inhibits the following: PHARMACODYNAMICS
 Dihydrotestosterone binding to androgen  Proton pump
receptors  gynecomastia and impotence o Final common pathway of acid secretion
 Estradiol metabolism  Proton pump inhibitors  blockade of proton pump 
o  serum prolactin  galactorrhea inhibits fasting and meal-stimulated acid secretion

3. PREGNANCY AND NURSING MOTHERS

CLINICAL USES
 H2 receptor antagonists
o Can cross placenta 1. GASTROESOPHAGEAL REFLUX DISEASE (GERD)
 Not administered unless absolutely necessary  First-line treatment in symptomatic GERD
o Secreted into breast milk  Non-erosive and erosive reflux disease
 Peptic strictures
4. OTHERS  Barrett's esophagus
 Blockade of cardiac H2 receptors  bradycardia and  Extraesophageal complications (PPI BID X12 weeks)
hypotension o Asthma
o Chronic cough
o Laryngitis
DRUG INTERACTIONS
o Noncardiac chest pain
 Cimetidine
o Interferes with important cytochrome P450 pathways: 2. PEPTIC ULCER DISEASE
 CYP1A2  H. pylori-associated ulcers
 CYP2C9 o Therapeutic goals:
 CYP2D6  Ulcer healing
 CYP3A4  Eradication of organism (H. pylori)
 Ranitidine o Triple therapy (best approach) – 10-14 day
o Binds 4-10 times less avidly than cimetidine to P450 regimen of:
 Famotidine and nizatidine  Clarithromycin 500 mg BID
o No interactions  Amoxicillin 1 g BID (metronidazole 500 mg
 Cimetidine, ranitidine, nizatidine BID if allergic to penicillin)
o Inhibit first-pass metabolism of ethanol   ethanol  PPI BID, continued OD X4-6 weeks
bioavailability   ethanol in blood  NSAID-associated ulcers
o Proton pump inhibitors
PROTON PUMP INHIBITORS  Promote rapid ulcer healing
 Replaced H2 receptor antagonists as major drugs for  Prevent ulcer complications
treatment of acid-peptic disorders   ulcer incidence if under NSAID therapy
 Significant decrease of rebleeding from peptic ulcers
CHEMISTRY
 Substituted benzimidazoles (hence, -azole) resembling 3. NON-ULCER DYSPEPSIA
H2 receptor antagonists in structure
 Clinically significant proton pump inhibitors: 4. STRESS-RELATED MUCOSAL BLEEDING
*racemic mixtures of R- and S-isomers  Omeprazole
o Omeprazole (Prilosec)* o  intragastric pH   bleeding
o Esomeprazole (Nexium)

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5. GASTRINOMA AND HYPERSECRETION PHARMACODYNAMICS

 Precise mechanism of action unclear
ADVERSE EFFECTS  Sucrose sulfate binds to positively charged proteins in
 Proton pump inhibitors – extremely safe base of ulcers or erosions  formation of physical barrier
o Restricts further caustic damage
1. NUTRITION o Stimulates mucosal prostaglandin and HCO3 secretion
 Minor  in oral cyanocobalamin (B12) absorption
  absorption of Fe, Ca2+, Mg2+, and Zn CLINICAL USES
 Given 1 g QID (four times daily) on empty stomach
2. RESPIRATORY AND ENTERIC INFECTIONS   incidence of upper GIT bleeding in ICU patients
  risk of community-acquired respiratory infections o Slightly less effective than IV H2 receptor antagonists
and nosocomial pneumonia  Stress-related bleeding
  risk for Clostridium difficile, Salmonella, Shigella, E. o Alternative to acid-inhibitory therapies (below) which
coli, and Campylobacter infections may  risk of nosocomial pneumonia:
 Antacids
3. EFFECTS OF HYPERGASTRINEMIA  H2 antagonists
 ECL and parietal cell hyperplasia leading to:  Proton pump inhibitors
o Transient rebound acid hypersecretion
o  dyspepsia or heartburn
ADVERSE EFFECTS
o Abates within 2-4 weeks
  proliferative rate of colonic mucosa  Virtually devoid of systemic adverse effects
 Aluminum salt
o Constipation (<2% of patients)
DRUG INTERACTIONS
 Not for prolonged use if with renal insufficiency
 General
o PPI   acidity  altered absorption of drugs
PROSTAGLANDIN ANALOGS
o CYP2C19 and CYP3A4 metabolism
  activation of anticoagulant clopidogrel (prodrug  GI mucosa – synthesizes prostaglandins
requiring CYP2C19) o Prostaglandins E and F
 Rabeprazole and pantoprazole
o No significant interactions MISOPROSTOL (CYTOTEC)

CHEMISTRY AND PHARMACOKINETICS

MUCOSAL PROTECTANTS
 Methyl analog of PGE1
 Mucosal defense mechanisms
 Rapid absorption
o Protect gastroduodenal mucosa against noxious
 Metabolized to metabolically active free acid
effects of acid and pepsin
 Serum half-life of <30 minutes
o TID or QID frequency
1. MUCUS AND EPITHELIAL TIGHT JUNCTIONS
 Excreted via urine
 Restrict back diffusion of acid and pepsin
PHARMACODYNAMICS
2. EPITHELIAL BICARBONATE SECRETIONS
 Establishes pH gradient within mucous layer in  Acid-inhibitory and mucosal protective properties
which pH ranges from: 7 (mucosal surface) to 1-2 o Stimulate mucus and bicarbonate secretion
(gastric lumen) o Enhance mucosal blood flow
o Stimulates intestinal electrolyte and fluid secretion
3. RESTITUTION o Stimulates intestinal motility and uterine contractions
 Migration of cells from gland neck cells  sealing of o Binds to prostaglandin receptor on parietal cells
small erosions  reestablish intact epithelium   histamine-stimulated cAMP production  modest
acid inhibition
4. MUCOSAL PROSTAGLANDINS
 Important in: CLINICAL USES
o Stimulating mucus and HCO3 secretion   incidence of:
o Mucosal blood flow o NSAID-induced ulcers
o Ulcer complications
SUCRALFATE (CARAFATE)  Prevention of NSAID-induced ulcers in high-risk patients

CHEMISTRY AND PHARMACOKINETICS ADVERSE EFFECTS

 Salt of sucrose complexed to sulfated Al(OH)3  Diarrhea and cramping abdominal pain
 Sucralfate + water or acidic solutions  formation of  Contraindicated during pregnancy or in women of
viscous tenacious paste (selectively binds to ulcers or childbearing potential
erosions for 6 hours)
 Limited solubility DRUG INTERACTIONS
o Breaks down into:
 No significant drug interactions are noted
 Sucrose sulfate (highly negatively charged)
 Aluminum salt
 <3% of intact drug and aluminum absorbed from GI
 Remainder excreted in feces

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 Gastrointestinal Pharmacology

TRANSMASTER'S NOTE
To review autacoids, misoprostol (Cytotec) is an CHOLINOMIMETIC DRUGS
analog of prostaglandin E. Prostaglandin and analogs can
induce abnormally strong uterine contractions, hence the BETHANECHOL (URECHOLINE)
abortifacient effect and its subsequent contraindication in  Stimulates muscarinic M3 receptors on muscle cells and
pregnancy. It is classified as a category X drug. at myenteric plexus synapses
 Treatment for GERD and gastroparesis
COLLOIDAL BISMUTH
NEOSTIGMINE (PROSTIGMIN)
CHEMISTRY AND PHARMACOKINETICS
 Acetylcholinesterase inhibitor
 Bismuth subsalicylate
 Enhances gastric, small intestine, and colonic emptying
o Nonprescription formulation containing bismuth and
 Treatment for:
salicylate
o Ogilvie’s syndrome
o Rapidly dissociates in the stomach allowing absorption
 Acute large bowel distension
of salicylate
 Acute colonic pseudo-obstruction
 Other compounds:
 2 mg neostigmine  prompt colonic evacuation
o Bismuth subcitrate potassium
of flatus and feces
o Bismuth dinitrate
 Cholinergic effects
 Bismuth
o Excessive salivation
o Over 99% of it appears in stool
o Nausea
o Minimal absorption (<1%)
o Vomiting
o Stored in many tissues
o Diarrhea
o Slow renal excretion
o Bradycardia
 Salicylate
o Readily absorbed and excreted in the urine
DOPAMINE D2 RECEPTOR ANTAGONISTS
PHARMACODYNAMICS METOCLOPRAMIDE AND DOMPERIDONE
 Precise mechanisms unknown  Domperidone
 Coats ulcers and erosions  protective layer against o Recommended to promote postpartum lactation
acid and pepsin  Mechanisms of action
 Stimulates prostaglandin, mucus, and bicarbonate secretion o Activation of GI dopamine receptors  inhibition
 Binds enterotoxins  beneficial in preventing and treating of cholinergic smooth muscle stimulation
traveler's diarrhea o Blockade of D2 receptors in chemoreceptor trigger
 Direct antimicrobial activity against H. pylori zone of medulla  antinausea and antiemetic action
o Second-line with tetracycline and metronidazole  Effects:
 Bismuth subsalicylate o  esophageal peristaltic amplitude
o Salicylate inhibition of intestinal prostaglandin and o  lower esophageal sphincter pressure
Cl- secretion   stool frequency and liquidity in o Enhance gastric emptying
acute infectious diarrhea o No effect on small intestine or colonic motility

CLINICAL USES CLINICAL USES

 Nonprescription bismuth compounds (Pepto-Bismol and 1. GASTROESOPHAGEAL REFLUX DISEASE (GERD)
Kaopectate)  with anti-secretory drugs in patients with regurgitation
o Non-specific treatment of: or refractory heartburn
 Dyspepsia
 Acute diarrhea 2. DELAYED GASTRIC EMPTYING due to:
 Bismuth subsalicylate  Postsurgical disorders (vagotomy, antrectomy)
o Prevention of traveler’s diarrhea  Diabetic gastroparesis
 Metoclopramide
ADVERSE EFFECTS o Promotes advancement of nasoenteric feeding
 Excellent safety profile tubes from stomach into duodenum
 Harmless blackening of stool (may be confused with
gastrointestinal bleeding) and of tongue 3. NON-ULCER DYSPEPSIA
 Used for short periods only and should be avoided in
patients with renal insufficiency 4. PREVENTION OF VOMITING
 Prolonged use  bismuth toxicity  encephalopathy
o Ataxia 5. POSTPARTUM LACTATION STIMULATION
o Headaches (domperidone)
o Confusion
o Seizures ADVERSE EFFECTS
  dose of bismuth subsalicylate  salicylate toxicity 1. CENTRAL NERVOUS SYSTEM
 Metoclopramide
PROKINETIC AGENTS o Restlessness
 Selectively stimulate gut motor function o Drowsiness
o  esophageal sphincter pressure – useful in GERD o Insomnia
o  motility and gastric emptying – useful in: o Anxiety
 Gastroparesis o Agitation
 Postsurgical gastric emptying delay

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2. EXTRAPYRAMIDAL EFFECTS (EPS) due to central  Aspiration  severe lipid pneumonitis

dopamine receptor blockade  Long-term  malabsorption of fat-soluble vitamins
 Metoclopramide
o Dystonias OSMOTIC LAXATIVES
o Akathisia  Soluble non-absorbable compounds
o Parkinsonian features  Obligate  in fecal fluid   stool liquidity
o Tardive dyskinesia – prolonged use
NONABSORBABLE SUGARS OR SALTS
3. HYPERPROLACTINEMIA leading to:
 Galactorrhea  Treatment for acute constipation
 Gynecomastia  Prevention of chronic constipation
 Impotence
 Menstrual disorders 1. MAGNESIUM HYDROXIDE (milk of magnesia)
 Most commonly used osmotic laxative
 Prolonged treatment in patients with renal
MACROLIDE ANTIBIOTICS
insufficiency   risk of hypermagnesemia
ERYTHROMYCIN
2. SORBITOL and LACTULOSE
 Directly stimulate motilin receptors
 Metabolized by colonic bacteria
 Promote onset of migrating motor complex (MMC)
 Induce severe flatus and cramps
 Treatment for gastroparesis
 Promotes gastric emptying of blood pre-endoscopy in
3. PURGATIVES
patients with upper GIT bleeding
 Magnesium citrate and sodium phosphate
 Osmotically active agents
CHLORIDE CHANNEL ACTIVATORS  Cause prompt bowel evacuation in 1-3 hours
o Rapid movement of water into distal small bowel
LUBIPROSTONE (AMITIZA)
and colon   volume of liquid stool  rapid
*Refer to Laxatives – Chloride Channel Activators (p. 7)
relief of constipation
 Adverse effects
LAXATIVES o Intravascular volume depletion
 Promote colon evacuation in constipated patients o Electrolyte fluctuations
 Classified by major mechanism of action but several work  Hyperphosphatemia
via multiple mechanisms (pleiotropic like antiepileptics XD)  Hypocalcemia
 Hypernatremia
BULK-FORMING LAXATIVES  Hypokalemia
 Indigestible, hydrophilic colloids that absorb water  Contraindications
 Forms a bulky, emollient gel that promotes: o Frail and elderly
o Colon distention o Renal insufficiency
o  peristalsis o Significant cardiac disease (arrhythmia)
 Bacterial digestion of plant fiber in colon   bloating o Unable to maintain adequate hydration during
and flatus bowel preparation

1. NATURAL PLANT PRODUCTS (oral or enema) BALANCED POLYETHYLENE GLYCOL (PEG)

 Psyllium fiber (iniinom ni Sir Chief para daw laging  Lavage solution
papa-ble –Henry Cavill) o Components:
 Methylcellulose  PEG – inert, nonabsorbable, osmotically active
 Sodium sulfate
2. SYNTHETIC FIBER  Sodium chloride
 Polycarbophil  Sodium bicarbonate
 Potassium chloride
STOOL SURFACTANT AGENTS (SOFTENERS) o Designed not to cause significant intravascular fluid or
 Soften stool material electrolyte shifts
 Permit water and lipids to penetrate  Complete colonic cleansing before GI endoscopy
 ROA – PO or rectal  Does not produce significant cramps or flatus
 Safe for all patients
1. DOCUSATE
 Oral or enema STIMULANT LAXATIVES (CATHARTICS)
 Commonly prescribed to prevent constipation and  Induce colonic movement by:
minimize straining o Direct stimulation of enteric nervous system
o Colonic electrolyte and fluid secretion
2. GLYCERIN SUPPOSITORY  May be required on a long-term basis in:
o Neurologically impaired patients
3. MINERAL OIL o Bedridden patients in long-term care facilities
 Clear viscous oil
 Not palatable but may be mixed with juices ANTHRAQUINONE DERIVATIVES
 Lubricates fecal material
 Aloe, senna, cascara
 Retards water absorption from stool
o Occur naturally in plants
 Prevent and treat fecal impaction in young children
o Poorly absorbed
and debilitated adults
o Hydrolyzed in colon  bowel movement in 6-12 hours

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o Chronic use  melanosis coli (characteristic brown ‒ Proximal bowel contraction (via acetylcholine
pigmentation of colon) and substance P)
‒ Distal bowel relaxation (via nitric oxide and
DIPHENYLMETHANE DERIVATIVES vasoactive intestinal peptide)
1. BISACODYL (Dulcolax)
 Tablet and suppository formulations TEGASEROD (ZELNORM)
 Treatment of acute and chronic constipation
 Used in conjunction with PEG solutions for colonic PHARMACODYNAMICS
cleansing prior to colonoscopy  Partial 5-HT4 agonist
 Induces bowel movement within:  High-affinity 5-HT4 agonist
o 6-10 hours (PO)  No appreciable binding to 5-HT3 or dopamine receptors
o 30-60 minutes (rectal)  Promotes gastric emptying
 Enhances bowel transit
2. PHENOLPHTHALEIN  No effect on esophageal motility
 No longer marketed due to possible cardiotoxicity  cAMP-dependent Cl- secretion   liquid stool
 Used as titration indicator in chemistry
PHARMACOKINETICS
CASTOR OIL*  Bioavailability of 10%
 Potent stimulant laxative o Further reduced by 50% with food
 Hydrolyzed to ricinoleic acid (local irritant) in upper  Metabolism
small intestine   intestinal motility o Gastric-acid hydrolysis
o Hepatic glucuronidation
CHLORIDE CHANNEL ACTIVATORS
CLINICAL USES
LUBIPROSTONE (AMITIZA)  Treatment for chronic constipation and irritable bowel
syndrome with predominant constipation
CHEMISTRY AND PHARMACOKINETICS
 Prostanoic acid derivative TOXICITY
 Minimal systemic absorption
 Voluntarily removed in 2007 due to  incidence of serious
cardiovascular events
MECHANISM OF ACTION o Attributed to inhibition of 5-HT1B receptor
 Stimulation of type 2 Cl- channels (ClC-2) in small
intestine   chloride-rich secretion into intestine   CISAPRIDE (PREPULSID)
intestinal motility and  intestinal transit time
 Partial 5-HT4 agonist
 Associated with  incidence of cardiovascular events
CLINICAL USES o Attributed to inhibition of cardiac hERG (human ether-
 Treatment for chronic constipation and irritable bowel a-go-go-related gene) K+ channels  QT prolongation
syndrome (IBS) with predominant constipation
PRUCALOPRIDE (RESOLOR)
ADVERSE EFFECTS  High-affinity 5-HT4 agonist
 Discontinuation  return of constipation  Treatment of chronic constipation in women
 Delayed gastric emptying  nausea in 30% of patients  No apparent significant affinities for hERG channels or
5-HT1B receptors
OPIOID RECEPTOR ANTAGONISTS
 Effects mediated through intestinal μ-opioid receptors PROKINETIC BENZAMIDES
o Inhibit peripheral μ-opioid receptors
 Do not readily cross blood-brain barrier  no CNS effects ITOPRIDE (GANATON)
 Inhibits D2 receptors and acetylcholinesterase
METHYLNALTREXONE BROMIDE (RELISTOR)   gastric emptying time*
 Treatment for opioid-induced constipation in palliative  Adverse effects
(end-of-life) care for advanced diseases o Dyspepsia
 ROA – subcutaneous injection o Anorexia
o Heartburn
o Regurgitation
ALVIMOPAN (ENTEREG)
o Bloating
 Short-term use in post-operative ileus in patients who o Nausea and vomiting
underwent bowel resection
 Possible cardiovascular toxicity
TRANSMASTER'S NOTE
Itopride is not in the book. According to the lecture,
SEROTONIN 5-HT4 RECEPTOR AGONISTS effect of itopride is increased gastric emptying time. However,
 Stimulation of 5-HT4 receptors on presynaptic terminal being a prokinetic (promotes motility), gastric emptying
of submucosal intrinsic primary afferent nerves  enhanced time should be decreased.
release of neurotransmitters
o Calcitonin gene-related peptide (CGRP)
 Stimulate second-order enteric neurons  promote
peristaltic reflex by stimulating:

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 Gastrointestinal Pharmacology

GUANYLATE CYCLASE C AGONISTS*

2. COLESEVELAM
LINACLOTIDE (LINZESS)*  No significant effects on absorption of other drugs
 Poorly absorbed 14-amino acid peptide
 Binds to guanylate cyclase C receptor on luminal ADVERSE EFFECTS OF BILE SALT-BINDING RESINS
surface of enterocytes  CFTR activation  stimulates  Bloating
fluid secretion  Flatulence
 Constipation
ANTIDIARRHEALS  Fecal impaction
 Treatment for mild to moderate acute diarrhea   bile acids  fat malabsorption
 Cautions:
o Bloody diarrhea SOMATOSTATIN
o High fever  14-amino acid peptide
o Systemic toxicity  Released in:
o GIT
OPIOID AGONISTS o Pancreas
 Significant constipating effects  Paracrine cells
 Inhibits presynaptic cholinergic nerves in submucosal  δ (delta) cells
and myenteric plexuses   colonic phasic segmenting   Enteric nerves
 colonic transit time and fecal water absorption o Hypothalamus
  mass colonic movement and gastrocolic reflex  Mechanisms of action
o Inhibits secretion of numerous hormones and
LOPERAMIDE (IMODIUM) neurotransmitters
 Gastrin
 Nonprescription opioid agonist
 Cholecystokinin
 Does not cross blood-brain barrier
 Glucagon
 No analgesic properties or potential for addiction
 GH
 Typically given 2 mg OD (once) to QID (four times daily)
 Insulin
 Secretin
DIPHENOXYLATE (LOMOTIL)  Pancreatic polypeptide
 Prescription opioid agonist  Vasoactive intestinal peptide
 No analgesic properties in standard doses  Serotonin
 Higher doses  CNS effects o  intestinal fluid secretion and pancreatic secretion
 Prolonged use  dependence o Slows GIT motility
o Combined with atropine to discourage overdosage o Inhibits gallbladder contraction
 Contributes to antidiarrheal action o Induces direct contraction of vascular smooth muscle 
 portal and splanchnic blood flow
COLLOIDAL BISMUTH COMPOUNDS o Inhibits secretion of anterior pituitary hormones
*Refer to Mucosal Protectants – Colloidal Bismuth (p. 5)  Half-life of 3 minutes in circulation
o Not clinically applicable
KAOLIN* AND PECTIN*
 Act as absorbents of bacteria, toxins, and fluid   stool OCTREOTIDE (SANDOSTATIN)
liquidity and number  Synthetic octapeptide with actions similar to somatostatin
 Useful in acute diarrhea  ROA
 Seldom used on a chronic basis o Subcutaneous – half-life of 1.5 hours
 Kaopectate – common commercial preparation o Intravenous – 6-12-hour duration of action
 No significant adverse effects except constipation o Intramuscular depot – longer-acting
 May bind to other drugs
o Not taken within 2 hours of other medications CLINICAL USES
1. INHIBITION OF ENDOCRINE TUMOR EFFECTS
KAOLIN*  Octreotide
 Naturally occurring hydrated magnesium aluminum silicate o  hormonal secretion   secretory diarrhea and
(attapulgite – component of Diatabs) systemic symptoms (flushing, wheezing) caused
by neuroendocrine tumors (carcinoid, VIPoma)
PECTIN* o May slow tumor progression
 Indigestible carbohydrate derived from apples
2. OTHER CAUSES OF DIARRHEA
 Octreotide
BILE SALT-BINDING RESINS
o Inhibits intestinal secretion
  diarrhea caused by excess fecal bile acids o Low doses  stimulates motility
ENTEROHEPATIC CIRCULATION  Treatment for:
 Terminal ileum – absorbs conjugated bile salts ‒ Small bowel bacterial overgrowth
 Crohn's disease or surgical resection  bile salt ‒ Intestinal pseudo-obstruction secondary
malabsorption  colonic secretory diarrhea to scleroderma
o High doses  inhibits motility
1. CHOLESTYRAMINE and COLESTIPOL  Given in treatment for diarrhea due to:
 Bind to a number of drugs ‒ Vagotomy
 Not given within 2 hours of other drugs ‒ Dumping syndrome

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 Gastrointestinal Pharmacology

‒ Short bowel syndrome  Inhibition of afferent GIT 5-HT3 receptors may reduce
‒ AIDS unpleasant visceral afferent sensations:
o Nausea
3. OTHER INDICATIONS o Bloating
 Pancreatic fistula o Pain
 Pituitary tumors  Central 5-HT3 receptor blockade   central response
 Gastrointestinal bleeding to visceral afferent stimulation
 5-HT3 receptor blockade in terminals of enteric
ADVERSE EFFECTS cholinergic neurons  inhibit colonic motility (especially
 Impaired pancreatic secretion  steatorrhea  fat- in left colon)   total colonic transit time
soluble vitamin deficiency
 Alterations in gastrointestinal motility: ALOSETRON (LOTRONEX)
o Nausea
o Abdominal pain PHARMACOKINETICS
o Flatulence  Rapid absorption from GIT
o Diarrhea  Bioavailability of 50-60%
 Inhibition of gallbladder contractility and alterations in fat  Plasma t1/2 of 1.5 hours but much longer duration of effect
absorption  sludge or gallstone formation  acute  Undergo extensive hepatic cytochrome P450 metabolism
cholecystitis (rarely occurs)
 Altered balance between insulin, glucagon, and GH  PHARMACODYNAMICS
hyperglycemia or mild hypoglycemia  Highly potent
 Prolonged treatment  hypothyroidism  Selective antagonist of 5-HT3 receptor
 Bradycardia  Binds with higher affinity and dissociates more slowly
from 5-HT3 receptors from other 5-HT3 antagonists 
IRRITABLE BOWEL SYNDROME (IBS) longer duration of action
 Idiopathic, chronic relapsing disorder
 Characterized by: CLINICAL USES
o Abdominal discomfort  Severe IBS with predominant diarrhea in women
 Chronic pain
‒ Low doses of tricyclic antidepressants ADVERSE EFFECTS
(amitriptyline or desipramide)
 Rare but serious gastrointestinal toxicity
 Bloating
 Constipation in patients with diarrhea-predominant IBS
 Distention
 Episodes of ischemic colitis
 Cramps
o Alterations in bowel habits
OTHER 5-HT3 ANTAGONISTS APPROVED FOR
 Predominant diarrhea
PREVENTION AND TREATMENT OF NAUSEA-VOMITING
‒ Antidiarrheals (loperamide)
 Predominant constipation  Ondansetron
‒ Fiber supplements  Granisetron
‒ Osmotic laxatives (milk of magnesia)  Dolasetron
 Episodes of pain or discomfort  change in bowel habits  Palonosetron

TREATMENT FOR IRRITABLE BOWEL SYNDROME SEROTONIN 5-HT4 RECEPTOR AGONISTS

ANTISPASMODICS TEGASEROD (ZELNORM)

 Provide relief of abdominal pain or discomfort *Refer to Laxatives – 5-HT4 Agonists (p. 7)
 Anticholinergic activities   spasms  Short-term treatment for irritable bowel syndrome with
predominant constipation in women
DICYCLOMINE AND HYOSCYAMINE
 Inhibit muscarininc cholinergic receptors in: CHLORIDE CHANNEL ACTIVATORS
o Enteric plexus LUBIPROSTONE (AMITIZA)
o Smooth muscles
*Refer to Laxatives – Chloride Channel Activators (p. 7)
 Low doses – minimal autonomic effects
 IBS with predominant constipation in women
 High doses – exhibit significant additional anticholinergic
effects such as:
o Dry mouth ANTIEMETIC AGENTS
o Visual disturbances
VOMITING OR EMESIS
o Urinary retention
o Constipation  Manifestations of a wide variety of conditions:
 Infrequently used because of these effects o Adverse effects from medications
o Systemic disorders or infections
o Pregnancy
SEROTONIN 5-HT3 RECEPTOR ANTAGONISTS
o Vestibular dysfunction
5-HT3 RECEPTOR PHYSIOLOGY o CNS infection or increased pressure
 GIT 5-HT3 receptors  activate visceral afferent pain o Peritonitis
sensation via extrinsic sensory neurons from gut to the o Hepatobiliary disorders
spinal cord and central nervous system o Radiation or chemotherapy
o Gastrointestinal obstruction

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 Gastrointestinal Pharmacology

o Dysmotility
o Infections APREPITANT (EMEND)
 Oral formulation
TREATMENT FOR NAUSEA AND VOMITING  Highly selective NK1 receptor antagonist
 Crosses blood-brain barrier
5-HT3 RECEPTOR ANTAGONISTS  Occupies brain NK1 receptors
 Potent antiemetic properties  No affinity for serotonin, dopamine, or corticosteroid
o Mediated through: receptors
 Peripheral 5-HT3 receptor blockade (main) on
extrinsic intestinal vagal and spinal afferent nerves PHARMACOKINETICS
 Central 5-HT3 receptor blockade in vomiting
 Bioavailability of 65%
center and chemoreceptor trigger zone
 Serum half-life of 12 hours
o Restricted in vomiting secondary to vagal stimulation
 Metabolized by CYP3A4
(post-operative) and chemotherapy
 Agents (* – t½ of 4-9 hours, administered IV):
o Ondansetron (Zofran)* CLINICAL USES
o Granisetron (Kytril)*  Combination therapy with 5-HT3 receptor antagonists
o Dolasetron (Anzemet)* and corticosteroids for the treatment of:
o Palonosetron (Aloxi) o Prevention of acute and delayed nausea and vomiting
 Newer intravenous agent from highly emetogenic chemotherapeutic regimens
 Greater affinity for 5-HT3 receptor o Prevents acute emesis
 Long half-life of 40 hours
 Undergo extensive hepatic metabolism ADVERSE EFFECTS
 Do not inhibit dopamine or muscarinic receptors  Fatigue
 No effects on esophageal or gastric motility  Dizziness
 May slow colonic transit  Diarrhea

CLINICAL USES DRUG INTERACTIONS

1. CHEMOTHERAPY-INDUCED NAUSEA AND VOMITING  May inhibit metabolism of other drugs metabolized by
 5-HT3 receptor antagonists the CYP3A4 pathway
o Primary agents for prevention of acute CINV  CYP3A4 inhibitors   plasma aprepitant
o Little to no efficacy for preventing of delayed   international normalized ratio (INR)
nausea and vomiting (>24 hours after
chemotherapy) FOSAPREPITANT
o IV injection 30 minutes pre-chemotherapy
 Intravenous formulation
o  efficacy by combination therapy with:
 Converted to aprepitant within 30 minutes after infusion
 Corticosteroid (dexamethasone)
 NK1 receptor antagonist (aprepitant)
PHENOTHIAZINES AND BUTYROPHENONES
2. POST-OPERATIVE AND POST-RADIATION NAUSEA PHENOTHIAZINES
AND VOMITING
 Antipsychotic agents
 Potent antiemetic and sedative properties
TOXICITY o Antiemetic properties
 Well-tolerated agents with excellent safety profiles  Mediated through inhibition of dopamine and
 Most common adverse effects: muscarinic receptors
o Headache o Sedative properties
o Dizziness  Antihistamine activity
o Constipation  Most commonly used:
 Dolasetron o Prochlorperazine
o Prolongation of QT interval o Promethazine
o Thiethylperazine
CORTICOSTEROIDS
 Corticosteroids with antiemetic properties: BUTYROPHENONES
o Dexamethasone  Central dopaminergic blockade  antiemetic properties
o Methylprednisolone
 Enhance efficacy of 5-HT3 receptor antagonists DROPERIDOL (INAPSINE)
 Prevention of acute and delayed nausea and vomiting
 Intramuscular or intravenous injection
in patients receiving moderately to highly emetogenic
 Extremely sedating in antiemetic doses
chemotherapy regimens

CLINICAL USES
DEXAMETHASONE (DECADRON)
 Postoperative nausea and vomiting
 8–20 mg intravenously before chemotherapy,
 Sedation for surgical and endoscopic procedures (in
 followed by 8 mg/d orally for 2–4 days.
conjunction with opiates and benzodiazepines)
 Neurolept analgesia
NEUROKININ RECEPTOR ANTAGONISTS  Induction and maintenance of general anesthesia
 Antiemetic properties
o Central blockade in area postrema

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ADVERSE EFFECTS o Major psychoactive chemical in marijuana

 Extrapyramidal symptoms
 Hypotension PHARMACOKINETICS
 QT prolongation rarely resulting in:  Significant first-pass hepatic metabolism
o Fatal episodes of ventricular tachycardia
o Torsades de pointes CLINICAL USES
 Appetite stimulant
CONTRAINDICATIONS  Antiemetic
 QT prolongation
DRUG INTERACTIONS
SUBSTITUTED BENZAMIDES  Dronabinol + phenothiazines
 Central blockade of dopamine receptors  antiemetic action o Synergistic antiemetic action
o Attenuation of adverse effects of both
TRIMETHOBENZAMIDE (TIGAN)
 Weak antihistaminic activity ADVERSE EFFECTS
 Intramuscular injection  Euphoria
 Dysphoria
METOCLOPRAMIDE (REGLAN)  Sedation
 Prevention and treatment of nausea and vomiting  Hallucination
 Dry mouth
  appetite
ADVERSE EFFECTS OF SUBSTITUTED BENZAMIDES
 Autonomic effects:
 Extrapyramidal symptoms o Tachycardia
o Restlessness o Conjunctival injection
o Dystonias o Orthostatic hypotension
o Parkinsonian symptoms
NABILONE (CESAMET)
ANTICHOLINERGIC-H1 ANTIHISTAMINES
 Closely-related THC analog
 Weak antiemetic activity
 Useful in prevention and treatment of motion sickness
INFLAMMATORY BOWEL DISEASE
 Use limited in:
o Dizziness  Comprises two distinct disorders:
o Sedation o Ulcerative colitis
o Confusion o Crohn's disease
o Dry mouth  Unknown pathogenesis
o Cycloplegia
o Urinary retention TREATMENT FOR INFLAMMATORY BOWEL DISEASE

DIPHENHYDRAMINE (BENADRYL)
 Dimenhydrinate
o Salt form of diphenhydramine
 Sedative properties
 Useful in treatment of emesis due to chemotherapy

MECLIZINE (BONAMINE)
 Minimal anticholinergic properties
 Less sedating

CLINICAL USES
 Prevention of motion sickness
 Treatment of vertigo due to labyrinth dysfunction

HYOSCINE OR SCOPOLAMINE (BUSCOPAN)

 Prototypic muscarinic receptor antagonist
 One of the best agents for prevention of motion sickness
 Transdermal patch > PO or parenteral administration

BENZODIAZEPINES
 Lorazepam or diazepam
 Given pre-chemotherapy to reduce anticipatory vomiting AMINOSALICYLATES (5-ASA)
or vomiting caused by anxiety
CHEMISTRY
CANNABINOIDS  5-aminosalicylic acid
o Differs from salicylic acid by addition of amino group
DRONABINOL (MARINOL) at 5-position
 Δ9-tetrahydrocannabinol (THC)

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 Gastrointestinal Pharmacology

PHARMACOKINETICS
 5-ASA 1. SULFASALAZINE (Azulfidine)
o Rapid absorption from proximal small intestine  5-ASA bound to sulfapyridine (compound responsible
o Does not reach distal small intestine or colon in for adverse effects of sulfasalazine)
appreciable quantities
o Extremely low absorption in colon 2. BALSALAZIDE (Colazal)
 N-acetylation in gut epithelium and liver  metabolite  5-ASA bound to 4-aminobenzoyl-β-alanine
with no anti-inflammatory activity  renal excretion
3. OLSALAZINE (Dipentum)
 2 molecules of 5-ASA bound together
MECHANISMS OF ACTION
 Inhibits COX  blocks prostaglandin synthesis
MESALAMINE COMPOUNDS
 Interfere with cytokine production
 Inhibits activity of nuclear factor-κB (NF-κB)  Proprietary formulations
o Transcription factor for proinflammatory cytokines
 Inhibit cellular functions of the following: 1. PENTASA
o Natural killer (NK) cells  Contains timed-release microgranules
o Mucosal lymphocytes  Release 5-ASA throughout small intestine
o Macrophages
 Scavenge reactive oxygen metabolites 2. ASACOL and APRISO
 5-ASA coated in pH-sensitive resin which dissolves at
pH 6-7 (pH of distal ileum and proximal colon)
CLINICAL USES
 Induce and maintain remission in ulcerative colitis 3. LIALDA
 Considered first-line agents for treatment of:  Uses pH-dependent resin encasing multimatrix core
o Mild to moderate active ulcerative colitis  Dissolves in colon  hydrophilic and lipophilic core
o Mild to moderate disease of distal ileum or colon penetrated by water
 Suppositories or enemas for:
o Rectum (proctitis) 4. ROWASA and CANASA
o Distal colon (proctosigmoiditis)  Delivers high 5-ASA concentrations to rectum and
 Azo compounds and mesalamine sigmoid colon
o Proximal colon  Formulations:
 Mesalamine o Rowasa – enema
o Crohn's disease involving small bowel o Canasa – suppository

ADVERSE EFFECTS GLUCOCORTICOIDS

 Sulfasalazine 1. PREDNISONE (Deltasone) and PREDNISOLONE
o High incidence of adverse effects:  Most commonly used
 Dose-related adverse effects:
‒ Nausea 2. HYDROCORTISONE (Solu-Cortef)
‒ Gastrointestinal upset  Topical treatment of active inflammatory bowel
‒ Headaches disease in rectum and sigmoid colon
‒ Arthralgias
‒ Myalgias 3. BUDESONIDE (Rhinocort)
‒ Bone marrow suppression  Potent synthetic analog of prednisolone
‒ Malaise  High affinity for glucocorticoid receptor
 Hypersensitivity to sulfapyridine:  Subject to rapid first-pass hepatic metabolism (partly
‒ Fever by CYP3A4)  low bioavailability
‒ Exfoliative dermatitis
‒ Pancreatitis
CLINICAL USES
‒ Pneumonitis
‒ Hemolytic anemia  Treatment for moderate to severe active inflammatory
‒ Pericarditis bowel disease
‒ Hepatitis  Tapered within 1-2 weeks to minimize adverse effects
 Oligospermia – reverses on discontinuation  Not useful to maintain disease remission
 Impaired folate absorption and processing
 Other aminosalicylates PURINE ANALOGS
o Well-tolerated
o Less common hypersensitivity reactions PHARMACOKINETICS
 Azathioprine
AZO COMPOUNDS o Bioavailability of 80%
o Rapid conversion by nonenzymatic process to 6-MP
 5-ASA bound by azo (N=N) bond to:
 6-mercaptopurine
o Inert compound
o Bioavailability of 50%
o Another 5-ASA molecule
o Complex biotransformation via competing catabolic
 Azo structure
enzymes (below)  inactive metabolites
o  absorption of parent drug from small intestine
 Xanthine oxidase
 Resident bacteria in terminal ileum and colon  cleave
 Thiopurine methyltransferase
azo bond by azoreductase enzyme  releases active
 Half-lives of <2 hours
5-ASA   concentration of active drug in terminal
 Active 6-thioguanine nucleotides
ileum or colon

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 Gastrointestinal Pharmacology

o Formed from inactive metabolites

o Concentrated in cells 2. ADALIMUMAB
o Prolonged half-lives in days  Fully humanized IgG1 subclass

MECHANISMS OF ACTION 3. CERTOLIZUMAB

 Intracellular 6-thioguanine  inhibition of purine  Polyethylene glycolated Fab fragment of humanized
nucleotide metabolism and DNA synthesis and repair anti-TNF
 inhibition of cell division and proliferation  Lacks an Fc portion
 May promote T-lymphocyte apoptosis

CLINICAL USES
 Induce and maintain remission in ulcerative colitis and
Crohn's disease

ADVERSE EFFECTS
 Nausea
 Vomiting
 Bone marrow depression leading to:
o Leukopenia
o Macrocytosis
o Anemia
o Thrombocytopenia
 Hepatic toxicity
  lymphoma in transplant recipients
o Measure thiopurine-S-methyltransferase (TPMT)
activity prior to therapy
PHARMACOKINETICS
DRUG INTERACTIONS
 Infliximab
 Allopurinol o Half-life of ~8-10 days
o  xanthine oxide catabolism of purine analogs  
active 6-thioguanine nucleotides  severe leukopenia
MECHANISMS OF ACTION
 High affinity binding to soluble TNF-α trimers  prevent
METHOTREXATE (TREXALL)
TNF-α from binding to TNF-α receptor
 Antimetabolite antineoplastic
 Beneficial in chronic inflammatory diseases including:
CLINICAL USES
o Crohn's disease
o Rheumatoid arthritis  Acute and chronic treatment of moderate to severe
Crohn's disease and ulcerative colitis
PHARMACOKINETICS
ADVERSE EFFECTS
 Oral bioavailability of 50-90%
 Suppression of TH1 inflammatory response  infection
 Reactivation of latent tuberculosis
MECHANISMS OF ACTION
o Done prior to anti-TNF therapy:
 Inhibition of dihydrofolate reductase (important in  Tuberculin skin test
production of thymidine and purines)  Interferon gamma release assay
 High doses  inhibition of cellular proliferation  Antibody formation against anti-TNF antibodies (ATA) 
 May interfere with inflammatory actions of IL-1 attenuation or elimination of clinical response
 May stimulate:  Infliximab IV  acute adverse infusion reactions
o  adenosine release o Mild reactions:
o Apoptosis of activated T-lymphocytes  Fever
 Headache
CLINICAL USES  Dizziness
 Induce and maintain remission in Crohn's disease  Urticaria
 Mild cardiopulmonary symptoms (chest pain,
TOXICITY dyspnea, hemodynamic instability)
 Adverse effects (reduced by folate supplementation): o Severe reactions:
o Bone marrow depression  Hypotension
o Megaloblastic anemia  Shortness of breath
o Alopecia  Muscle spasms
o Mucositis  Chet discomfort
 Lymphoma
ANTI-TUMOR NECROSIS FACTOR THERAPY
ANTI-INTEGRIN THERAPY
BIOCHEMISTRY
1. INFLIXIMAB NATALIZUMAB
 Chimeric mouse-human monoclonal antibody to  Humanized IgG4 monoclonal antibody
human TNF-α (IgG1 subclass)

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 Blocks several integrins on circulating inflammatory cells VARICEAL HEMORRHAGE

 prevents IgG binding to vascular adhesion molecules
and  migration to surrounding tissues PATHOPHYSIOLOGY
 Treatment for moderate to severe Crohn's disease if  Chronic liver disease  portal hypertension  portosystemic
other therapies have failed collaterals  gastric and esophageal varices  rupture 
massive upper GIT bleeding
EXOCRINE PANCREATIC INSUFFICIENCY
SOMATOSTATIN AND OCTREOTIDE
 Exocrine pancreatic insufficiency
o Enzyme secretion falls below 10% of normal *Refer to Antidiarrheals – Somatostatin and Octreotide (p. 8)
o Most commonly caused by:  Inhibition of release of glucagon and other gut peptides that
 Cystic fibrosis alter mesenteric blood flow   portal blood flow and
 Chronic pancreatitis variceal pressures
 Pancreatic resection  Effective in promoting initial hemostasis from bleeding
esophageal varices
 Generally administered for 3-5 days
PANCREATIC ENZYME SUPPLEMENTS
1. PANCREATIN
ARGININE VASOPRESSIN
 Alcohol-derived extract of hog pancreas with relatively
low concentrations of lipase and proteolytic enzymes  Used before advent of octreotide
 Use is declining  No longer used because of its high adverse-effect profile

2. PANCRELIPASE (CREON, PANCREAZE, ZENPEP) PHARMACODYNAMICS

 Available preparations:  Potent arteriolar vasoconstrictor
o Non-enteric-coated o Splanchic arterial vasoconstriction   splanchnic
o Enteric-coated perfusion   portal venous pressures
 Lipolytic activity – X12 more than that of pancreatin
 Proteolytic activity – X4 more than that of pancreatin ADVERSE EFFECTS
 Creon – most common  Effects of systemic and peripheral vasoconstriction:
 Administered with each meal and snack o Hypertension
o Myocardial ischemia or infarction
ADVERSE EFFECTS o Mesenteric infarction
 Oropharyngeal mucositis when chewed (remember,  Effects due to intestinal hyperactivity:
these are ENZYMES) o Nausea
 High purine content  hyperuricosuria and renal stones o Abdominal cramps
o Diarrhea
BILE ACID THERAPY FOR GALLSTONES  Effects due to retention of free water:
o Hyponatremia
URSODIOL (URSODEOXYCHOLIC ACID) o Fluid retention
 Naturally occurring bile acid o Pulmonary edema

PHARMACOKINETICS TERLIPRESSIN
 Conjugated in liver with glycine and taurine (remember  Vasopressin analog
bile physiology)  excreted in bile  Fewer adverse effects
 Conjugated ursodiol – undergoes excessive enterohepatic
recirculation NON-SELECTIVE BETA BLOCKERS
 Half-life of ~100 hours (PROPRANOLOL AND NADOLOL)
 Small amounts  pass into colon  either excreted or  Reduce portal venous pressures via  portal inflow
dehydroxylated by colonic bacteria to lithocholic acid  Mechanisms of action
(potentially hepatotoxic) o β1 blockade
  cardiac output
PHARMACODYNAMICS o β2 blockade
 Reduces hepatic cholesterol secretion   cholesterol  Splanchnic vasoconstriction due to unopposed
content of bile effect of systemic catecholamines on α receptors
 Expands bile acid pool  Significantly reduce rate of recurrent bleeding
 Stabilizes hepatocyte canalicular membranes presumably
by reduction in concentration of other endogenous bile "Bon apetit!"
acids or inhibition of immune-mediated hepatocyte
destruction

CLINICAL USES
 Dissolution of small cholesterol gallstones
 Patients with symptomatic gallbladder disease who
refuse cholecystectomy or are poor surgical candidates
 Prevention of gallstones in obese patients undergoing
rapid weight loss therapy
 Reduces liver function abnormalities and improves
liver histology in early-stage primary biliary cirrhosis

Martin, Nikka, Pesky, Ron, Barbs Page 14 of 15

 Gastrointestinal Pharmacology

REVIEW QUESTIONS
1. GI side effect of magnesium: 13. Antidiarrheal combined with atropine to discourage
a. Abdominal cramps overdose (together, known as Lomotil):
b. Burping a. Diphenoxylate
c. Constipation b. Imodium
d. Diarrhea c. Loperamide

2. Minimal first-pass metabolism among histamine H2 14. Bile salt-binding resin with no significant interactions:
receptor antagonists: a. Cholestyramine
a. Cimetidine b. Colesevelam
b. Famotidine c. Colestipol
c. Nizatidine
d. Ranitidine 15. Hormone analog used in inhibiting endocrine tumor
effects due to carcinoid tumors or VIPoma:
3. Class of drugs that block the final common pathway of a. Misoprostol
acid secretion by irreversibly inactivating H+/K+-ATPase: b. Nabilone
a. 5-HT4 receptor agonists c. Octreotide
b. H2 receptor antagonists
c. Proton pump inhibitors 16. Not a treatment for irritable bowel syndrome:
d. Substituted benzamides a. Alosetron
b. Tegaserod
4. Proton pump inhibitors cause the following effects except: c. None of the above
a. Enterochromaffin-like cell hyperplasia
b. Hypergastrinemia 17. Mechanism of action of antiemetic drug aprepitant:
c. Parietal cell hyperplasia a. Histamine receptor antagonist
d. None of the above b. Neurokinin receptor antagonist
c. Serotonin receptor antagonist
5. First-line treatment of GERD:
a. Alginate 18. All are used in inflammatory bowel disease except:
b. Antacids a. Aminosalicylates
c. H2 receptor antagonists b. Glucocorticoids
d. Proton pump inhibitors c. Methotrexate
d. Natalizumab
6. Ulcer coating is not a mechanism of action of this drug: e. None of the above
a. Colloidal bismuth
b. Misoprostol 19. Fully humanized IgG1 monoclonal antibody:
c. Sucralfate a. Adalimumab
b. Bevacizumab
7. Cytoprotective drug also used in traveler's diarrhea: c. Certolizumab
a. Colloidal bismuth d. Infliximab
b. Misoprostol e. Natalizumab
c. Sucralfate
20. Decreases portal blood flow by inhibiting release of
8. Prokinetic used in treating Ogilvie's syndrome: peptides which alter mesenteric blood flow:
a. Domperidone a. Nadolol
b. Erythromycin b. Octreotide
c. Neostigmine c. Propranolol
d. Terlipressin
9. Prokinetic that can cause hyperprolactinemia: e. Vasopressin
a. Bethanechol
b. Domperidone
c. Lubiprostone

10. Class of laxatives including psyllium and methylcellulose:

a. Bulk-forming
b. Cathartics
c. Softeners

11. Opioid receptor antagonist used for short-term treatment

of post-operative ileus:
a. Alvimopan
b. Methylnaltrexone
c. Naloxone

12. High affinity 5-HT4 agonist used in treatment of chronic

constipation in women:
a. Cisapride
b. Prucalopride
c. Tegaserod

Martin, Nikka, Pesky, Ron, Barbs Page 15 of 15