DDM023 GENERAL PHARMACOLOGY o NaCl → may exacerbate fluid retention in heart failure, hypertension

& renal insufficiency

MODULE 7: GASTROINTESTINAL DRUGS 2. Calcium Carbonate

(Chapter 62) • Example: Tums, Os-Cal
• Less soluble & reacts more slowly w/ HCl to form CO2 and CaCl2
Formula: CaCO3 + HCl → CO2 + CaCl2
PHYSIOLOGY OF ACID SECRETION • Effects:
▪ CO2 → gastric distention & belching
ACETYLCHOLINE Acetylcholine ▪ Excess CaCO3 → metabolic alkalosis
Vagal postganglionic Parietal (muscarinic, M3) • Excessive doses of NaHCO3 or CaCO3 + Calcium-containing dairy
nerves cell products can lead to:
Gastrin (CCK-B) o Hypercalcemia
GASTRIN o Renal insufficiency
antral G cells
ECL cell Histamine (H2) o Metabolic Alkalosis (Milk-Alkali Syndrome)

→activation of adenylyl cyclase ↑ cytosolic Ca2+ 3. Magnesium Hydroxide & Aluminum Hydroxide
→↑ intracellular cAMP • Example: Gelusil, Maalox, Mylanta
→activates protein kinases • Slowly react with HCl to form MgCl2 or AlCl3 and H2O
Formula: Mg(OH)2 + HCl → MgCl2 + H2O
*ECL: Enterochromaffin-like cells Stimulate acid secretion Al(OH)3 + HCl → AlCl3 + H2O
H+/K+ -ATPase (the proton pump)
• Because no gas is generated → belching DOES NOT occur
on the canalicular surface
• Metabolic alkalosis → uncommon because of efficiency of
3 Major Pathways Regulating Parietal Acid Secretion: neutralization reaction
1. Neural stimulation via acetylcholine (vagus nerve) • Effects:
2. Endocrine stimulation via gastrin (antral G cells) o MgCl2 → may cause osmotic diarrhea
o AlCl3 → may cause constipation
3. Paracrine stimulation by local release of histamine (ECL cells)
• Because of these side effects, they are commonly administered
together to minimize impact on bowel function
• Diseases:
• Pharmacokinetics:
➢ Gastroesophageal reflux disease (GERD)
o Both are absorbed & excreted by the kidneys
➢ Peptic Ulcer Disease:
-If with renal insufficiency → do not take for long-term
o Gastric
o Duodenal
B. H2-RECEPTOR ANTAGONISTS
➢ Stress-related Mucosal Injury
• “-tidines”; commonly referred to as H2 blockers
• Marked decrease in use due to:
o Recognition of the role of H pylori in ulcer disease (can be
treated with antibacterials)
o Advent of proton pump inhibitors

Mechanism of Action:
• Competitive inhibition of histamine (released from ECL cells by gastrin
or vagal stimulation) at the parietal cell H2 receptors
• Suppress basal and meal-stimulated acid secretion
➢ Effective in inhibiting nocturnal acid secretion (depends largely on
• Over 90% of peptic ulcers are caused by: histamine)
o Helicobacter pylori ➢ Raises nocturnal and fasting intragastric pH to 4-5
o NSAIDs ➢ Modest impact on meal-stimulated acid secretion stimulated by
• Drugs used in the treatment of acid-peptic disorders may be divided into 2 gastrin, acetylcholine, & histamine
classes: • Highly selective for H2 (no effect on H1 or H3 receptors)
1) Agents that reduce intragastric acidity
2) Agents that promote mucosal defense Pharmacokinetics:
• Absorption
Agents that REDUCE Intragastric Acidity o Dose: twice daily
A. ANTACIDS o Rapidly absorbed in the intestines
• Used for centuries in the treatment of: o Cimetidine, Ranitidine, Famotidine
o Dyspepsia These undergo first-pass metabolism
o Acid-peptic disorders Bioavailability of approximately 50%
• Mainstay of treatment for acid-peptic disorders until the advent of H2- o Nizatidine- little first-pass metabolism
receptor antagonists & proton pump inhibitors (PPIs) • Metabolism and Clearance
• Continued to be used a nonprescription remedies for: o T ½: 1.1 – 4 hours
o Heartburn o Duration of action is dose-dependent
o Dyspepsia o Cleared by a combination of:
➢ Hepatic metabolism
MOA: reduction of intragastric acidity ➢ Glomerular filtration
Pharmacokinetics: ➢ Renal tubular secretion
• Dosing: 1 hr after a meal o Decrease dose in patients with renal or hepatic insufficiency
-to effectively neutralize gastric acid for up to 2 hrs o Elderly
There is decline of up to 50% in drug clearance
• All antacids may affect the absorption of other medications by binding
Significant reduction in volume of distribution
the drug (↓ its absorption) or by ↑ intragastric pH (altered dissolution
Clinical Uses:
or solubility)
-GERD
• Antacids are weak bases
➢ Infrequent heartburn or dyspepsia (<3x/week)
o Reaction with gastric HCl → NaCl + H20
-For long-acting effect (6-10 hours)
• Have acid-neutralizing capacity:
-Taken prophylactically before a meal → to ↓ likelihood of
➢ But is variable among different proprietary formulations
heartburn
➢ Dependent on:
➢ Frequent heartburn- Take 2x daily
✓ Rate of dissolution (tablet vs. liquid)
➢ Promote healing in erosive esophagitis
✓ Water solubility
-Afford healing in <50% of patients, which is why PPI is preferred
✓ Rate of reaction with acid
✓ Rate of gastric emptying
-Peptic Ulcer Disease
• Should not be given within 2 hrs of doses of:
➢ Used for nocturnal acid suppression
➢ Tetracyclines
➢ Promotes effective ulcer healing in most patients with uncomplicated
➢ Fluoroquinolones
gastric and duodenal ulcers
➢ Itraconazole
-Administered once daily at bedtime
➢ Iron
➢ Not used for peptic ulcers caused by aspirin or NSAIDs
➢ Not effective against peptic ulcers caused by H. pylori
1. Sodium Bicarbonate
-For both cases used PPI instead
• Example: Baking soda, Alka Seltzer -For H. pylori → 2-3 antibiotics
• It reacts with hydrochloric acid producing CO2 and NaCl
Formula: NaHCO3 + HCl → CO2 + NaCl
• Effects: -Intermittent Nonulcer Dyspepsia
o CO2 → gastric distention & belching
o Excess NaHCO3 → metabolic alkalosis
-Prevention of Bleeding from Stress-Related Gastritis Pharmacokinetics:
➢ This occurs in 1-5% of critically-ill patients ➢ Route: Oral, IV
➢ ↓ bleeding from stress-related gastritis in critically-ill patients ➢ Inactive prodrug
➢ Given through IV or Continuous infusion o Acid-labile
-This is preferred over bolus infusion because it maintains consistent o Formulated for delay-release as acid-resistant, enteric-coated capsules
and sustained elevation of gastric pH or tablets
-After passing through the stomach into the alkaline intestinal lumen,
Adverse Effects: the enteric coatings dissolve and the prodrug is absorbed
➢ Generally considered extremely safe ➢ For children or patients with dysphagia or enteral feeding tubes:
➢ Adverse effects manifested in <3% of patients: Capsule formulations (not tablets) may be opened and the
o Diarrhea microgranules mixed with apple or orange juice or mixed with soft
o Headache foods (eg, applesauce)
o Fatigue
o Myalgias
o Constipation
➢ ↑ risk of nosocomial pneumonia in critically-ill patient if given IV
➢ Cimetidine → Mental status changes if given IV
o Confusion
o Hallucination
o Agitation
Commonly occurs in ICU patients, elderly or those with renal or
hepatic dysfunctions
➢ Cimetidine → Endocrine changes if used in long-term ➢ PPIs are lipophilic weak bases (pKa 4–5) and, after intestinal absorption,
o Gynecomastia & Impotence in males diffuse readily across lipid membranes into acidified compartments (eg,
o Galactorrhea in females parietal cell canaliculus)
Cimetidine inhibits binding of DHT to androgen receptors, inhibits ➢ Concentrated more than 1000-fold within parietal cell canaliculus by
metabolism of estradiol, and ↑ serum prolactin levels Henderson-Hasselbalch trapping
➢ Pregnancy: ➢ Converted to active, reactive thiophilic sulfonamide cation→ forms
o H2-antagonists cross the placenta covalent disulfide linkage with H+/K+ ATPase→ irreversible enzyme
Should not be administered to pregnant women unless inactivation
absolutely necessary ➢ 50% decrease in bioavailability with food
o Secreted into breast milk → may affect infants -Give PPI on empty stomach (1 hour before meal)
➢ Bloody dyscrasias (rare) ➢ Short T ½ of 1.5 hours
➢ Bradycardia & hypotension → Blockade of cardiac H2 receptors ➢ Concentrated and activated near site of action
➢ Reversible abnormalities in liver chemistries ➢ Long duration of action (inhibition lasts 24 hours)
➢ PPIs undergo rapid first-pass and systemic hepatic metabolism
Drug Interactions:
Cimetidine
-Interferes with important hepatic cytochrome P450 pathways:
o CYP1A2; CYP2C9; CYP2D6; CYP3A4
Ranitidine
-Binds 4–10 times less avidly than cimetidine to cytochrome P450
Nizatidine & Famotidine
-Negligible CYP interaction

-H2 antagonists compete with creatinine and certain drugs (eg, procainamide)
Clinical Uses:
for renal tubular secretion
-GERD
-All H2 antagonists (except Famotidine) inhibit gastric first-pass metabolism of
➢ 1st line treatment in symptomatic GERD
ethanol, especially in women → ↑ ethanol in blood
➢ Non-erosive and erosive reflux disease
➢ Peptic strictures
C. PROTON PUMP INHIBITORS (PPIs) ➢ Barrett’s esophagus
• Proton pump – final common pathway of acid secretion ➢ Extraesophageal complications (Use 2x daily for 3 mos.)
o Irreversibly inactive the parietal cell H+/K+ ATPase, the transporter that ▪ Asthma
is primarily responsible for producing stomach acid ▪ Chronic cough
o Proton pump inhibitors→blockade of proton pump→ inhibits fasting and ▪ Laryngitis
meal-stimulated acid secretion ▪ Noncardiac chest pain
• Replaced H2-receptor antagonists as major drugs for treatment of acid-
peptic disorders -Peptic Ulcer Disease
• Combination formulations: ➢ H. pylori-associated ulcers
o With sodium bicarbonate to compensate for long latency of PPIs in • Therapeutic goals:
general o Ulcer healing
o Added in NSAIDs to prevent gastric upset o Eradication of organism (H. pylori)
• Triple therapy (most recommended treatment) – 10-14 day regimen
• Chemistry of:
o Substituted benzimidazoles (hence, -azole) resembling H2-receptor o Clarithromycin – 500 mg BID
antagonists in structure o Amoxicillin – 1 g BID (Metronidazole 500 mg BID if allergic to
penicillin)
o PPI – BID, continued OD for 4-6 weeks
• Quadruple therapy (for clarithromycin resistance)

➢ NSAID-associated ulcer
• Proton pump inhibitors:
✓ Promote rapid ulcer healing
✓ Prevent ulcer complications
✓ ↓ ulcer incidence if ulcer NSAID therapy

➢ Prevention of Rebleeding from Peptic Ulcers

-Nonulcer Dyspepsia
-Stress-related Mucosal Bleeding Clinical Uses:
✓ Omeprazole – ↑ intragastric pH→ ↓ bleeding ➢ Given 1 g 4x daily on an empty stomach (1 hour before meals)
✓ For patients with nasoenteric tubes ➢ ↓ incidence of upper GIT bleeding in ICU patients
-PPI suspensions is used -Slightly less effective than IV H2-receptor antagonists
✓ For patients without a nasoenteric tube or with significant ileus ➢ Stress-related bleeding Alternative to acid-inhibitory therapies
-IV H2 Antagonists is used (antacids, H2 antagonists, & PPIs) which may ↑ risk of nosocomial
pneumonia
-Gastrinoma and other Hypersecretory Conditions
o Best treated with surgical resection Adverse Effects:
o But if it unresectable→ preventive therapy ✓ Virtually devoid of systemic adverse effects
PPI (Omeprazole) 60-120 mg/day ✓ Constipation (<2% of patients) because of aluminum salts
✓ Not for prolonged use if with renal insufficiency
Adverse Effects: Drug Interactions:
➢ Generally considered extremely safe ✓ Sucralfate may bind to other medications, impairing their absorption
➢ 1-5% of patients develop:
o Diarrhea Prostaglandin Analogs
o Headache • The human GI mucosa synthesizes a number of prostaglandins, major ones
o Abdominal pain are:
➢ ↑ risk of acute interstitial nephritis and chronic kidney disease o Prostaglandin E
➢ Nutrition o Prostaglandin F
o Minor ↓ in oral cyanocobalamin (B12) absorption • Misoprostol- a methyl analog of PGE1, has been approved for GI
-Acid is important in releasing vitamin B12 from food conditions
o ↓ absorption of Fe, Ca2+, Mg2+ Possible ↑ risk of hip, spine, & wrist
fractures, osteoporosis, hypomagnesemia, hypocalcemia Pharmacokinetics:
➢ Respiratory & Enteric Infections ➢ Rapidly absorbed and metabolized to a metabolically active free acid
o ↑ risk of community-acquired respiratory infections and ➢ T ½: <30 mins.
nosocomial pneumonia ➢ Administered 3-4x daily
o ↑ risk for C. difficile, Salmonella, Shigella, E. coli, and ➢ Excretion: Urine
Campylobacter infections ➢ Dose reduction not needed in case of renal insufficiency

➢ Potential problems due to ↑ serum gastrin (Hypergastrinemia)

o ECL and parietal cell hyperplasia leading to:
✓ Transient rebound acid hypersecretion
✓ ↑ dyspepsia or heartburn
o Abates within 2-4 weeks
o ↑ proliferative rate of colonic mucosa
➢ Potential problems due to ↓ gastric acidity
o Long-term acid suppression:
-May accelerate gastric gland atrophy (atrophic gastritis) and
intestinal metaplasia
This conditions may later lead to gastric adenocarcinoma
-Development of small benign gastric fundic-gland polyps
Mechanism of Action:
o It has both acid inhibitory and mucosal protective properties
➢ ↑ mucus and bicarbonate secretion
➢ ↑ mucosal blood flow
Clinical Uses:
➢ ↓ incidence of NSAID-induced ulcers to <3%
➢ ↓ incidence of ulcer complications by 50%
• Misoprostol has never achieved widespread use owing to its high adverse-
effect profile and need for multiple daily dosing
o Contraindicated in pregnancy→ abortifacient effect due to
induction of abnormally strong uterine contraction

Drug Interactions: Bismuth Compounds

➢ General • Nonprescription colloidal bismuth compounds
o PPIs → ↓ acidity→ altered absorption of drugs • Two bismuth compounds are available:
o PPIs are metabolized by CYP2C19 and CYP3A4 1. Bismuth subsalicylate
✓ ↓ activation of anticoagulant clopidogrel (prodrug requiring 2. Bismuth subcitrate potassium
CYP2C19)
✓ Co-administration of Omperazole or Esomeprazole with Pharmacokinetics:
clopidogrel is NOT recommended by FDA ➢ Bismuth subsalicylate undergoes rapid dissociation within the
✓ Inactivation of effects of clopidogrel may ↑ risk for cardiac events stomach, allowing absorption of salicylate
✓ Alternatives: weak inhibitors of CYP2C19 ➢ Bismuth
Rabeprazole and Pantoprazole - Have no significant interactions o Over 99% appears in stool
o <1% is absorbed
MUCOSAL PROTECTIVE AGENTS o Stored in many tissues
Mucosal defense mechanisms→ protect gastroduodenal mucosa against o Slow renal excretion
noxious effects of acid and pepsin ➢ Salicylate
➢ Mucus and Epithelial Tight Junctions o Readily absorbed and excreted in the urine
-Restrict back diffusion of acid and pepsin
➢ Epithelial Bicarbonate Secretions MOA: Precise mechanism of action of bismuth is unknown
-Establishes a pH gradient within the mucous layer in which the pH ➢ Bismuth coats ulcers and erosions → creating a protective layer against
ranges from 7 at the mucosal surface to 1–2 in the gastric lumen acid and pepsin
➢ Restitution ➢ It may also stimulate prostaglandin, mucus, and bicarbonate secretion
-A process in which migration of cells from gland neck cells seals ➢ Bismuth subsalicylate:
small erosions to reestablish intact epithelium ❖ ↓ stool frequency and liquidity in acute infectious diarrhea, due
➢ Mucosal Prostaglandins to salicylate inhibition of intestinal prostaglandin and chloride
-Important in stimulating mucus and bicarbonate secretion and secretion
mucosal blood flow ➢ Bismuth binds enterotoxins→beneficial in preventing and treating
traveler’s diarrhea
Sucralfate ➢ Bismuth has direct antimicrobial effects against H. pylori
Chemistry:
-Salt of sucrose complexed to sulfated aluminum hydroxide Clinical Uses:
➢ Nonprescription bismuth compounds (eg, Pepto-Bismol, Kaopectate)
Pharmacokinetics: are widely used by patients for nonspecific treatment of:
➢ In water or acidic solutions it forms a viscous, tenacious paste that binds o Dyspepsia
selectively to ulcers or erosions for up to 6 hours o Acute Diarrhea
➢ Has limited solubility ➢ Bismuth subsalicylate also is used for the prevention of traveler’s
➢ Breaks down into: diarrhea
o Sucrose sulfate (strongly negatively charged) ➢ Eradication of H. pylori infection
o Aluminum salt
➢ <3% of intact drug and aluminum is absorbed from the GIT Adverse Effects:
➢ Remainder is secreted in feces ➢ Excellent safety profile
➢ Causes harmless blackening of the stool (may be confused with GI
Pharmacodynamics: bleeding) and tongue
➢ Precise mechanism of action is unclear ➢ Used for short periods only and should be avoided in patients with renal
➢ MOA: Believed that the negatively charged sucrose sulfate binds to insufficiency
positively charged proteins in the base of ulcers or erosion→ forming a ➢ Prolonged use → bismuth toxicity (rare) → encephalopathy
physical barrier o Ataxia
*Effect of formed physical barrier: o Headaches
o Restricts further caustic damage o Confusions
o Stimulates mucosal prostaglandin and bicarbonate secretion o Seizures
➢ ↑ dose of bismuth subsalicylate → salicylate toxicity (nausea, vomiting,
fever, tinnitus)
DRUGS STIMULATING GASTROINTESTINAL MOTILITY ➢ Promote gastric emptying of blood before endoscopy in patients with
Prokinetic Drugs: acute upper GI hemorrhage
• Drugs that can selectively stimulate gut motor function
➢ ↑ lower esophageal sphincter pressure – useful in GERD LAXATIVES
➢ ↑ motility and gastric emptying – useful in: • Promotes colon evacuation in constipated patients
✓ Gastroparesis • Classified by their major mechanism of action, but several work via
✓ Postsurgical gastric emptying delay multiple mechanisms
➢ Stimulate the small intestine may be beneficial for:
✓ Postoperative ileus
✓ Chronic intestinal pseudo-obstruction
➢ Enhancement of colonic transit may be useful in the treatment of
constipation

Cholinomimetic Agents
Bethanechol
➢ Stimulate muscarinic M3 receptors on muscle cells and at myenteric
plexus synapses
➢ Used in the past for the treatment of:
o GERD
o Gastroparesis

Neostigmine
➢ Acetylcholinesterase inhibitor
➢ Enhances gastric, small intestine, and colonic emptying
➢ Treatment of Ogilvie’s syndrome: Bulk-Forming Laxative
o Acute large bowel distention • Indigestible, hydrophilic colloids that absorb water
o Acute colonic pseudo-obstruction • Forms a bulky, emollient gel that:
➢ 2 mg neostigmine→ prompt colonic evacuation of flatus and feces o Distends the colon
o Promotes peristalsis
Cholinergic Effects: Adverse Effects:
✓ Excessive salivation ➢ ↑ bloating and flatus due to bacterial digestion of plant fiber in colon
✓ Nausea
✓ Vomiting Preparations Available:
✓ Diarrhea ➢ Natural Plant Products
✓ Bradycardia o Psyllium
o Methylcellulose
Dopamine (D2) Receptor Antagonists ➢ Synthetic Fiber
Metoclopramide & Doperidone o Polycarbophil
MOA: Activation of dopamine receptors inhibits cholinergic smooth muscle
stimulation Stool Surfactant Agents (Softeners)
-Blockade of this effect is believed to be the primary prokinetic • They soften stool material, permitting water and lipids to penetrate
mechanism of action of these agents • Route: Oral or Rectal
➢ They also block dopamine D2 receptors in the chemoreceptor trigger zone
of the medulla→ antinausea and antiemetic action Common Agents:
➢ Docusate
Effects: o Oral or Enema
✓ ↑ esophageal peristaltic amplitude o Commonly prescribed in hospitalized patients to prevent constipation
✓ ↑ lower esophageal sphincter pressure and minimize straining
✓ Enhance gastric emptying ➢ Glycerin Suppository
✓ No effect on small intestine or colonic motility ➢ Mineral Oil
o Clear, viscous oil
Clinical Use: o It is not palatable but may be mixed with juices
-GERD o Lubricates fecal material → retarding water absorption from the stool
o Used mainly in combination with antisecretory agents in patients with
regurgitation or refractory heartburn Clinical Use:
-It is used to prevent and treat fecal impaction in young children and
-Impaired Gastric Emptying debilitated adults
o Used in the treatment of patients with delayed gastric emptying due
to postsurgical disorders (vagotomy, antrectomy) and diabetic Adverse Effect:
gastroparesis -Aspiration can result in a severe lipid pneumonitis
-Nonulcer Dyspepsia -Long-term use can impair absorption of fat-soluble vitamins (A, D, E, K)
-Preventing vomiting
-Postpartum lactation stimulation Osmotic Laxatives
o Domperidone is sometimes recommended to promote postpartum ➢ ↑ fecal water content by “absorption” due to ↑ osmolarity
lactation ➢ Treatment for acute constipation
➢ Prevention of chronic constipation
Adverse Effects: ➢ Can either be:
➢ Metoclopramide → affects CNS • Salt-containing
o Restlessness ✓ Magnesium hydroxide
o Drowsiness ✓ Magnesium citrate
o Insomnia ✓ Sodium phosphates
o Anxiety • Salt-free
o Agitation ✓ Polyethylene glycol (PEG)
➢ Extrapyramidal symptoms (EPS) due to central dopamine receptor ✓ Lactulose
blockade ✓ Sorbitol
• Metoclopramide (rare with domperidone)
o Dystonias Magnesium Hydroxide
o Akathisia • Milk of Magnesia
o Parkinsonian features • Most commonly used osmotic laxative
o Tardive dyskinesia – prolonged use
➢ Hyperprolactinemia (caused by both drugs) leading to: Adverse Effect:
o Galactorrhea -↑ risk of hypermagnesemia in prolonged treatment in patients with renal
o Gynecomastia insufficiency
o Impotence
o Menstrual disorders Magnesium Citrate, Sodium Phosphate
Domperidone is extremely well tolerated because it does not cross the ➢ Cause prompt bowel evacuation in 1-3 hours
BBB→ therefore neuropsychiatric & EPS effects are rare • Rapid movement of water into distal small bowel and colon ↑
volume of liquid stool → rapid relief of constipation
Macrolide (Antibiotics) ➢ Can be administered as enema
Erythromycin, Clarithromycin, Azithromycin
• Directly stimulate motilin receptors on GI smooth muscle and promote the Adverse Effects:
onset of a migrating motor complex ➢ Intravascular volume depletion
➢ Electrolyte fluctuations
Clinical Uses: o Hyperphosphatemia
➢ Gastroparesis (Tolerance rapidly develops) o Hypocalcemia
 o Hypernatremia
o Hypokalemia Clinical Uses:
Contraindications: ➢ Chronic constipation (Linaclotide 145 mcg OD; Plecanatide 3 mg OD)
• Frail and elderly ➢ Irritable bowel syndrome with constipation (Linaclotide ONLY)
• Renal insufficiency
• Significant cardiac disease (arrhythmia) Adverse Effects:
• Unable to maintain adequate hydration during bowel preparation ➢ Diarrhea – occurs up to 20% of patients
➢ Severe diarrhea – in 2% of patients
Sorbitol, Lactulose Contraindications:
➢ Nonabsorbable sugars that can be used to prevent or treat chronic Pediatric patients Reports of ↑ mortality in juvenile mice from dehydration
constipation
➢ Metabolized by colonic bacteria Crofelemer
➢ A small molecule with the opposite effect of Linaclotide & Plecanatide
Adverse Effect: MOA: It is an inhibitor of the CFTR channel
-Produces severe flatus and cramps ➢ Approved for the treatment of HIV-drug-induced diarrhea

Balanced Polyethylene Glycol (PEG) Opioid Receptor Antagonists

➢ Lavage solutions ➢ Effects mediated through intestinal mu(μ)-opioid receptors
➢ Components: • Inhibits peripheral μ-opioid receptors
• PEG – inert, nonabsorbable, osmotically active sugar ➢ Do not readily cross the BBB → no CNS effects
• With Na sulfate, Na chloride, Na bicarbonate, & KCl Designed this
way so that no significant intravascular fluid or electrolyte shifts Adverse Effect:
occur ➢ Acute and chronic therapy with opioids→ constipation Due to ↓ intestinal
motility → prolonging transit time & ↑ absorption of fecal water
Clinical Uses: ➢ If used for postsurgical treatment of pain → ↑ duration of postoperative
-Commonly used for complete colonic cleansing before GI endoscopic ileus
procedures
Methylnaltroxene Bromide
Adverse Effects: ➢ For the treatment of opioid-induced constipation in patients receiving
-Does NOT produce significant cramps or flatus palliative care for advanced illness who have had inadequate response to
-Generally safe for all patients other agents
➢ Route: Subcutaneous injection
Stimulant Laxatives (Cathartics)
➢ Induce bowel movements by: Alvimopan
• Direct stimulation of the enteric nervous system ➢ For short-term use in postoperative ileus in hospitalized patients who have
• Stimulation of colonic electrolyte and fluid secretion undergone small or large bowel resection
➢ May be required on long-term basis in: ➢ Route: Oral (within 5 hours before surgery & 2x daily after surgery)
• Neurologically impaired patients Adverse Effects: Cardiovascular toxicity
• Bed-bound patients in long-term care facilities
Serotonin 5-HT4-Receptor Agonists
Anthraquinone Derivatives ➢ Stimulation of 5-HT4 receptors on the presynaptic terminal of submucosal
➢ Aloe, Senna (Biguerlai), Cascara → occur naturally in plants intrinsic primary afferent nerves → enhanced release of CGRP
➢ Poorly absorbed o Calcitonin gene-related peptide (CGRP)
➢ Hydrolyzed in the colon ▪ Stimulate second-order enteric neurons → promote
➢ Route: Oral or Rectal peristaltic reflex by stimulating:
• Bowel movement within 6-12 hours if orally given • Proximal bowel contraction: via ACh & substance P
• Bowel movement within 2 hours if given rectally • Distal bowel relaxation: via nitric oxide & vasoactive
intestinal peptide
Adverse Effects: Tegaserod
-Melanosis coli ➢ Partial 5-HT4 agonist
Characteristic brown pigmentation of the colon in prolonged use • High-affinity for 5-HT4 receptors
• No appreciable binding to 5-HT3 or dopamine receptors
Diphenylmethane Derivatives ➢ Can inhibit 5-HT1B receptor → lead to ↑ cardiovascular events
➢ Bisacodyl (Dulcolax) ➢ Has been withdrawn from the market
• Tablet and suppository formulations
• Treatment of acute and chronic constipation Clinical Uses:
• Used in conjunction with PEG solution for colonic cleansing prior • Chronic constipation
to colonoscopy • IBS with predominant constipation
• Induces bowel movement within:
✓ 6-10 hours (Oral) Cisapride
✓ 30-60 minutes (Rectal) ➢ Partial 5-HT4 agonist
• Minimal systemic absorption
Adverse Effect: Associated with ↑ incidence of cardiovascular events
• Safe for acute and long-term use
-QT prolongation attributed to inhibition of cardiac hERG K+ channels
Chloride Secretion Activators
Prucalopride
Lubiprostone
• High-affinity 5-HT4 agonist
➢ Prostanoic acid derivative
➢ Minimal systemic absorption • No significant affinities for either hERG K+ channels or 5-HT1B receptors
(unlike Tegaserod & Cisapride)
Mechanism of Action: Acts by stimulating the type 2 chloride channel (ClC-2)
in the small intestine Clinical Use: Treatment of chronic constipation in women
-This ↑ chloride-rich fluid secretion into the intestine, which:
• ↑ intestinal motility
ANTIDIARRHEAL AGENTS
• ↓ intestinal transit time
➢ Used safely in patients with mild to moderate acute diarrhea
➢ Not for patients with:
Clinical Uses:
o Bloody diarrhea
➢ Chronic constipation
o High fever
➢ Irritable bowel syndrome (IBS) with predominant constipation
o Systemic toxicity
➢ Can also be used to control chronic diarrhea such as:
Adverse Effects:
o Irritable bowel syndrome (IBS)
➢ Abrupt discontinuation → return to constipation
o Inflammatory bowel disease (IBD)
➢ Delayed gastric emptying time → nausea in 30% of patients
➢ Pregnancy Category C (evidence of fetal damage in animal studies;
Opioid Agonists
administer only if benefits outweigh risks)
• Have significant constipating effect
Linaclotide, Plecanatide • ↑ colonic phasic segmenting activity due to inhibition of presynaptic
➢ Minimally absorbed cholinergic nerves Lead to ↑ colonic transit time and fecal water
➢ Short amino acid peptides absorption
• ↓ mass colonic movements & gastrocolic reflux
Mechanism of Action: It stimulate intestinal chloride secretion through a • Its CNS effects and potential for addiction limit the usefulness of most
different mechanism by binding to and activating guanylate cyclase-C on the
luminal surface Loperamide
-This leads to ↑ intracellular and extracellular cGMP with activation of the • Nonprescription opioid agonist
CFTR, followed by chloride-rich secretion and acceleration of intestinal transit • Does not cross the BBB
• No analgesic properties
 • No potential for addiction -MOA: Inhibition of hormonal secretion and may slow tumor
• Tolerance to long-term use has not been reported progression
• Typically administered in doses of 2 mg taken 1-4x daily • Other uses:
✓ Can be used for patients with pancreatic fistula
Diphenoxylate ✓ Can be used for treatment of pituitary tumors
• Prescription opioid agonist ✓ Sometimes used for GI bleeding
• No analgesic properties in standard doses
-However, higher doses have CNS effects Adverse Effects:
• Prolonged use can lead to opioid dependence • Steatorrhea due to impaired pancreatic secretion
• Preparation commonly contains small amounts of atropine • GI motility alteration
-This discourages overuse and it may also contribute to antidiarrheal o Nausea, abdominal pain, flatulence, and diarrhea
action • Formation of sludge or gallstones → acute cholecystitis (rare)
• Alter endocrine balance
Eluxodoline o Hyperglycemia (or Hypoglycemia)
• Prescription opioid agonist o Hypothyroidism
• High-affinity for the mu receptor • Bradycardia
• Low affinity for the delta receptor

MOA: When it binds to gut opioid receptors→ ↓ colonic transit and ↑ fecal DRUGS USED FOR IRRITABLE BOWEL SYNDROME (IBS)
fluid absorption Irritable Bowel Syndrome (IBS):
• An idiopathic chronic, relapsing disorder
Clinical Uses: • Characterized by abdominal discomfort (pain, bloating, distention, or
• Treatment of patients with diarrhea-predominant IBS cramps)
• Recommended for patients with prior cholecystectomy, mild to • Associated with alterations in bowel habits (diarrhea, constipation, or
moderate liver disease both)
❖ If with Predominant Diarrhea
Adverse Effects: o Tx: Antidiarrheal agents (especially Loperamide)
• Constipation ❖ If with Predominant Constipation
• Sphincter of Oddi spasms (<1%) resulting to: o Tx: Fiber supplementation, osmotic laxatives
o Abdominal pain ❖ For Chronic Abdominal Pain
o Pancreatitis o Tx: Low doses of tricyclic antidepressants
o Elevated pancreatic or liver enzymes ✓ Eg, amitryptiline, desipramine
Contraindications: ✓ No effect on mood but may alter central processing of
• History of pancreatitis visceral afferent information
• History of alcoholism ✓ With anticholinergic properties
• Sphincter of Oddi disease ▪ Have effects on GI motility & secretion
▪ ↓ stool frequency & liquidity
Colloidal Bismuth Compounds (Information is found at page 3) ✓ Alter receptors for enteric neurotransmitters (eg, serotonin)
→ affects visceral sensation
Bile Salt-Binding Resins
• Normally absorbed in the terminal ileum Antispasmodics (Anticholinergics)
-Disease of the terminal ileum (eg, Crohn’s disease) or surgical • Commonly used medications:
resection→ malabsorption of bile salts, which may cause colonic o Dicyclomine
secretory diarrhea o Hyoscyamine
• Decreases diarrhea caused by excess fecal bile acids MOA: inhibit muscarinic cholinergic receptors in the enteric plexus and on
smooth muscle
• Come in a variety of powder and pill formulations
• Taken 1-3x daily before meals
Clinical Use:
o For relief of abdominal symptoms
Adverse Effects:
✓ Work primarily through anticholinergic activities
• Bloating, flatulence, constipation, and fecal impaction
✓ Low doses: minimal autonomic effects
✓ High doses:
• Dry mouth
• Visual disturbances
• Urinary retention
• Constipation

Somatostatin Analog Serotonin 5-HT3-Receptor Antagonist

Somatostatin • 5-HT3 receptors in the GIT activate visceral afferent pain sensation via
• a 14-amino-acid peptide that is released in GIT and pancreas from: extrinsic sensory neurons from the gut to the spinal cord and CNS
✓ Paracrine cells • Inhibition of 5-HT3 receptors → reduce unpleasant visceral afferent
✓ D cells sensation
✓ Enteric nerves o Nausea
✓ Hypothalamus o Bloating
• It is a key regulatory peptide that has many physiologic effects: o Pain
1. It inhibits the secretion of numerous hormones and transmitters, Alosetron
including gastrin, cholecystokinin, glucagon, growth hormone, insulin, • 5-HT3 antagonist
secretin, pancreatic polypeptide, vasoactive intestinal peptide, and 5-HT • For treatment of patients with severe IBS with diarrhea
2. It reduces intestinal fluid secretion and pancreatic secretion • Other 5-HT3 antagonists:
3. It slows GI motility and inhibits gallbladder contraction ✓ Ondansetron
4. It reduces portal and splanchnic blood flow ✓ Granisetron
5. It inhibits secretion of some anterior pituitary hormones ✓ Dolasetron
• Clinical usefulness of somatostatin is limited by its short half-life in the ✓ Palonosetron
circulation (3 minutes) when it is administered by IV injection -These other 5-HT3 antagonists are used for the treatment of
nausea and vomiting (Antiemetics)
Octreotide
• A synthetic octapeptide with actions similar to somatostatin Pharmacokinetics & Pharmacodynamics:
• Highly potent
Pharmacokinetics: • Highly selective antagonist of the 5-HT3 receptor
• IV administration → serum T ½: 1.5 hours • Rapidly absorbed from the GIT
• SQ administration → 6-12 hour duration of action • Bioavailability of 50-60%
• Available also in IM injection → given once-monthly • T ½: 1.5 hrs.
• Undergoes hepatic CYP450 metabolism
Clinical Uses: • Renal excretion
• Other causes of diarrhea: • Dissociates slowly from 5-HT3 receptor
✓ Diarrhea due to vagotomy or dumping syndrome -This may account for its long duration of action compared with other 5-
✓ Diarrhea caused by short bowel syndrome or AIDS HT3 receptor antagonists
✓ Small bowel bacterial overgrowth or intestinal pseudo-obstruction
secondary to scleroderma Clinical Uses:
• Inhibition of endocrine tumor effects Treatment of WOMEN with severe IBS in whom diarrhea is the predominant
✓ Carcinoid tumor & VIPoma symptom
-These cause secretory diarrhea and systemic symptoms such as
flushing and wheezing
Adverse Effects:
• Serious gastrointestinal toxicity (rare) Clinical Uses:
• Constipation (30% of patients) -Chemotherapy-Induced Nausea & Vomiting
• Ischemic colitis (fatal) o 5-HT3-receptor antagonists are the primary agents for the prevention of
-Given the seriousness of these adverse events, alosetron is acute chemotherapy-induced nausea and emesis
restricted to WOMEN with severe diarrhea-predominant IBS o Little or no efficacy for the prevention of delayed nausea and vomiting
(occurring >24 hours after chemotherapy)
Chloride Channel Activators o IV injection 30 minutes prior to chemotherapy
Lubiprostone
• Prostanoic acid derivative -Postoperative and Postradiation Nausea & Vomiting
MOA: Stimulates the type 2 chloride channel (ClC-2) in the small intestine
Clinical Use: Adverse Effects:
• Approved for the treatment of WOMEN with IBS with predominant ➢ QT interval prolongation (most pronounce in Dolasetron)
constipation ➢ Serotonin syndrome (if combined with SSRIs or SNRIs)
➢ Headache
Linaclotide ➢ Dizziness
• Guanylyl cyclase-C agonist that leads to activation of the CFTR in the ➢ Constipation
small intestine with stimulation of chloride-rich intestinal secretion
Clinical Use: Corticosteroid
• Approved for treatment of ADULTS with IBS with constipation ➢ Dexamethasone & Methylprednisolone
➢ Enhance the efficacy of 5-HT3-receptor antagonists for prevention of acute
and delayed nausea and vomiting in patients receiving moderately to
ANTIEMETIC AGENTS highly emetogenic chemotherapy regimens
• Nausea and vomiting may be manifestations of a wide variety of
conditions, such as: Neurokinin 1 (NK1) Receptor Antagonists
o Adverse effects from medications ➢ MOA: Central blockade in the area postrema
o Systemic disorders or infections ➢ “-pitant” drugs:
o Pregnancy o Aprepitant
o Vestibular dysfunction o Netupitant- Oral formulation
o CNS infection or increased pressure o Rolapitant
o Peritonitis o Fosprepitant – IV formulation
o Hepatobiliary disorders ➢ Highly selective NK1-receptor antagonists
o Radiation or chemotherapy ➢ Cross the BBB
o GI obstruction ➢ Have no affinity for serotonin, dopamine, or corticosteroid receptors
o GI dysmotility
o GI infections Pharmacokinetics:
• Brainstem→ “vomiting center” Aprepitant
o Oral bioavilability – 65%
• 4 important sources of afferent input of vomiting center:
o T ½: 12 hrs.
1. The “chemoreceptor trigger zone” or area postrema
Netupitant – T ½: 90 hrs.
➢ Located at the caudal end of the 4th ventricle
Rolapitant – T ½: 180 hrs.
➢ Outside the BBB
-Since netupitant & rolapitant have longer half-lives→ allowed for single-
➢ Accessible to emetogenic stimuli in the blood or cerebrospinal fluid
administration
➢ Rich in:
✓ Dopamine D2 receptors
➢ All are metabolized by the liver (CYP3A4 pathway)
✓ Opioid receptors
✓ Serotonin 5-HT3 receptors
Clinical Uses:
✓ NK1 receptors
➢ Used in combination with 5-HT3- receptor antagonists and corticosteroids
for the prevention of acute and delayed nausea and vomiting from highly
2. The vestibular system
emetogenic chemotherapeutic regimens
➢ Important in motion sickness via cranial nerve VIII
➢ It is rich in:
Adverse Effects: Low incidence of fatigue & dizziness
✓ Muscarinic M1 receptors
Drug Interactions:
✓ Histamine H1 receptors
➢ May inhibit metabolism of chemotherapeutic drugs
➢ Drugs that inhibit CYP3A4 may ↑ levels of aprepitant
3. Vagal and spinal afferent nerves from the GIT
Examples: ketoconazole, ciprofloxacin, clarithromycin,
➢ Irritation of the GI mucosa by chemotherapy, radiation therapy,
nefazodone, ritonavir, nelfinavir, verapamil, quinidine
distention, or acute infectious gastroenteritis
➢ Aprepitant decreases the INR in patients taking warfarin
↓
Release of mucosal serotonin
↓
Antipsychotic Agents
Activation of receptors
Phenothiazines
↓
MOA: inhibition of dopamine and muscarinic receptors
Stimulate vagal afferent input to the vomiting
Drugs:
center and chemoreceptor trigger zone
o Prochlorperazine
➢ Rich in: 5-HT3 receptors
o Promethazine
o Thiethylperazine
4. The central nervous system
➢ Plays a role in vomiting due to psychiatric disorders, stress, and
Thienobenzodiazepines
anticipatory vomiting prior to cancer chemotherapy
MOA: inhibition of dopamine D2 and serotonin 5-HT1c and 5-HT3 receptors
Drug: Olanzapine
Serotonin 5-HT3 Antagonists
Mechanism of Action:
Butyrophenones
➢ Antiemetic effect is due to:
MOA: central dopaminergic blockade
o Mainly through blockade of peripheral 5-HT3 receptors on extrinsic
Drug: Droperidol
intestinal vagal and spinal afferent nerves
o Given IM or IV
o Partially through central 5-HT3 receptor blockade in the vomiting
o Extremely sedating
center and chemoreceptor trigger zone
o Uses:
➢ “-setron” drugs:
✓ Postoperative nausea & vomiting
o Ondansetron
✓ Sedation for surgical procedures along with opiates and
o Granisetron
benzodiazepines
o Dolasetron
✓ Neuroleptanalgesia
o Palonosetron
✓ Induction and maintenance of general anesthesia
o Tropisteron
Pharmacokinetics:
Adverse Effects:
➢ Ondansetron, Granisetron, Dolasetron
➢ Extrapyramidal effect
o T ½: 4-9 hrs.
➢ Hypotension
o Route: Oral or IV
➢ Not used in patients with QT prolongation
➢ Palonosetron
o Newer IV agent → greater affinity for 5-HT3 receptor
Substituted Benzamides
o T ½: 40 hrs.
MOA: Dopamine receptor blockade
➢ All undergo hepatic metabolism
Drugs:
➢ Elimination by renal and hepatic excretion
o Metoclopramide (discussed in page 4)
➢ Dose reduction is not required in geriatric & renal insufficiency
o Trimethobenzamide- it also has weak antihistamine activity
➢ Dose reduction may be required if with hepatic insufficiency
(Ondansetron)
Adverse Effects:
o Mainly extrapyramidal:
• Restlessness
• Dystonias
• Parkinsonian symptoms

H1 Antihistamine & Anticholinergic Drugs

➢ Have weak antiemetic activity when taken together
➢ They are particularly useful for the prevention or treatment of motion
sickness
Adverse Effects:
• Dizziness
• Sedation
• Confusion
• Dry mouth
• Cycloplegia
• Urinary retention

Aminosalicylates
• Contains 5-aminosalicylic acid (5-ASA) aka Mesalamine
• Works topically (not systemically) in areas of diseased GI mucosa
• 1st line of treatment for mild-moderate active ulcerative colitis
Benzodiazepines • 80% is absorbed from the small intestine and does not reach the distal
Drugs: small bowel or colon
o Lorazepam -To overcome the rapid absorption of 5-ASA from the proximal small
o Diazepam intestine, a number of formulations have been designed to deliver 5-ASA
to various distal segments of the small bowel or the colon→ Sulfasalazine,
Clinical Use: Olsalazine, Balsalazide, other forms of Mesalamine
Used before initiation of chemotherapy to reduce anticipatory vomiting or
vomiting caused by anxiety Pharmacokinetics:
• Unformulated 5-ASA → readily absorbed from the small intestines –
Cannabinoids -Absorption of 5-ASA from the colon is extremely low
Dronabinol • Undergoes N-acetylation in the gut epithelium and liver to a metabolite
➢ Δ9-tetrahydrocannabinol (THC) that does not possess significant anti-inflammatory activity
➢ Major psychoactive chemical in marijuana • Excreted in the kidneys

Pharmacokinetics: Pharmacodynamics:
➢ Almost completely absorbed after oral ingestion • MOA of 5-ASA is not certain
➢ Undergoes first-pass hepatic metabolism • It is thought that 5-ASA modulates inflammatory mediators derived from
➢ Metabolites excreted slowly in feces and urine both the cyclooxygenase and lipoxygenase pathways
• They also interfere with the production of inflammatory cytokines
Clinical Use: • They also inhibit the activity of nuclear factor-κB (NF-κB)
➢ Used medically as an appetite stimulant and as an antiemetic -NF-κβ → an important transcription factor for proinflammatory cytokines
➢ Uncommonly used for the prevention of chemotherapy-induced nausea • They may also inhibit cellular functions of natural killer cells, mucosal
and vomiting lymphocytes, and macrophages, and it may scavenge reactive oxygen
-Combination therapy with phenothiazines provides synergistic antiemetic metabolites
action and appears to attenuate the adverse effects of both agents
Clinical Uses:
Adverse Effects: • Induce and maintain remission in ulcerative colitis
• Euphoria • Proctitis (suppositories)
• Dysphoria • Proctosigmoiditis (enema)
• Sedation
• Hallucinations Azo Compounds
• Dry mouth • Sulfasalazine, Balsalazide, Olsalazine
• Increased appetite • They contain 5-ASA bound by an azo (N=N) bond to an inert compound or
• Tachycardia to another 5-ASA molecule
Autonomic
• Conjunctival injection ➢ The azo structure markedly reduces absorption of the parent drug
Effects
• Orthostatic hypotension from the small intestine
➢ In the terminal ileum and colon→ resident bacteria cleave the azo
Nabilone bond by means of an azoreductase enzyme, releasing the active 5-
• Closely related THC analog ASA
-Hence, high concentration of active drug are made available in these
segments

DRUGS USED TO TREAT INFLAMMATORY BOWEL DISEASE (IBD)

➢ Severe, prolonged, and inappropriate inflammatory response in the GIT
upon exposure to triggering factors
➢ Leads to changes in the normal architecture of the GIT
➢ Comprises 2 distinct disorders:
1. Ulcerative Colitis
2. Crohn’s disease
➢ Pharmacologic treatment of IBD:
o Involves drugs that belong to different therapeutic classes
o Drugs that have different but nonspecific mechanisms of anti-
inflammatory action
o Drugs are chosen on the basis of disease severity, responsiveness, and
drug toxicity
 Drug Interactions:
• Severe leukopenia when co-administered with allopurinol due to
Modified Mesalamine Compounds ↑ metabolism of 6-thioguanine nucleotides
• Formulation were done to deliver the drug to different segments of GIT
Methotrexate
Methotrexate
• Antimetabolite that has beneficial effects in a number of chronic
inflammatory diseases, including Crohn’s disease and rheumatoid arthritis,
and in cancer
Mechanism of Action:
• Inhibition of dihydrofolate reductase, an enzyme important in the
production of thymidine and purines
• Interfere with the inflammatory actions of IL-1
• Stimulate increased release of adenosine
• Stimulate apoptosis and death of activated T lymphocytes
Clinical Use:
• Induce and maintain remission in patients with Crohn’s disease
Adverse Effects:
• Bone marrow depression
• Megaloblastic anemia
• Alopecia
• Mucositis
Adverse Effects:
Anti-Tumor Necrosis Factor Therapy
• Hypersensitivity (rare)
• TNF is one of the key inflammatory cytokines in IBD
• Interstitial nephritis (rare)
• Binds to TNFR to initially activate components such as NF-κβ
• Drugs used are monoclonal antibodies
Glucocorticoids
Clinical Uses:
• ↓ inflammatory cytokines (TNF-α, IL-1) and chemokines (IL-8)
• Infliximab, Adalimumab, Certolizumab → for moderate to severe Crohn’s
• ↓ expression of inflammatory cell adhesion molecules
disease who have had inadequate response to conventional therapies
• ↓ gene transcription of nitric oxide synthase, phospholipase A2, COX-2, (hence, it is not a 1st line therapy)
and NF-κB
• Infliximab, Adalimumab, Golimumab → for the acute and chronic
treatment of moderate to severe ulcerative colitis
Clinical Use:
-Infliximab is more effective than adalimumab & golimumab in treating
• Treatment of moderate-severe IBD this disease
o Have intermediate duration of biologic activity, OD dosing possible Adverse Effects:
o Not useful for maintaining disease remission (aminosalicylates &
• Suppression of the TH1 inflammatory response
immunosuppresants preferred)
• Antibodies to the antibody may develop
• May attenuate serum sickness-like reaction
• Lymphoma

Adverse Effects:
• Cushing’s syndrome in prolonged use
• Hyperglycemia, hypertension, adrenal suppression, etc.
• When there is failure to maintain remission, consider gradual
withdrawal and replacement with immunosuppressive therapy

Purine Analogs
Azithioprine & 6-Mercaptopurine (6-MP)
Clinical Use: Agents in the induction and maintenance of remission of
ulcerative colitis and Crohn’s disease
• Purine antimetabolites that have immunosuppressive properties Anti-Integrin Therapy
Natalizumab
Pharmacokinetics:
• Humanized IgG4 monoclonal antibody targeted only against the α4 subunit
Azathioprine
• Blocks several integrins on circulating inflammatory cells
o 80% bioavailability
• Prevents binding to the vascular adhesion molecules and subsequent
o Rapidly converted to 6-MP
migration into surrounding tissues
o T ½: <2 hrs.
6-MP
Adverse Effects:
o 50% bioavailability
• Acute infusion reactions and small risk for opportunistic infection
o Metabolized to 6-thioguanine nucleotide
o T ½: <2 hrs. • Progressive Multifocal Leukoencephalopathy due to reactivation
-Active 6-thioguanine nucleotides are concentrated in cells resulting in a of a human polyomavirus (JC virus)
prolonged half-life of days
Vedolizumab
• The prolonged kinetics of 6-thioguanine nucleotide results in a median • Monoclonal antibody with activity directed specifically against the α4/β7
delay of 17 weeks before onset of therapeutic benefit from oral integrin
azathioprine or 6-MP is observed in patients with IBD • Blocks interaction of leukocytes with gut vascular endothelial cell adhesion
molecules
Adverse Effects: • Risk of reactivation of JC virus and PML is low
• Nausea, vomiting • Increasingly used as a second-line treatment for patients with moderate to
• Bone marrow depression severe ulcerative colitis or Crohn’s disease who cannot take anti-TNF
-Leads to leukopenia, macrocytosis, anemia, or thrombocytopenia agents
• Hepatic toxicity • Low incidence of serious adverse effects
• Lymphoma • Neutralizing antibodies may develop (2-10% of patients)
- ↑ risk for transplant recipients receiving long-term 6-MP or
Azithioprine therapy among patients with IBD
PANCREATIC ENZYME SUPPLEMENTS Adverse Effects:
Introduction: • Severe pruritus (25% of patients)
• Exocrine pancreatic insufficiency is most commonly caused by:
o Cystic fibrosis
o Chronic pancreatitis DRUGS USED TO TREAT VARICEAL HEMORRHAGE
o Pancreatic resection Introduction:
• Fat and protein digestion is impaired and can lead to: • Portal hypertension – consequence of chronic liver disease
steatorrhea, azotorrhea, vitamin malabsorption, and weight loss • Caused by increase blood flow & resistance to portal flow
• Varices can rupture, leading to massive upper GI bleeding
Pancreatic Enzyme Supplements: • Signs & Symptoms:
• Contain a mixture of amylase, lipase, and proteases o Hematemesis
• Mainstay of treatment for pancreatic enzyme insufficiency o Melena
• Administered with meal: improves digestion of fat, protein and • Several drugs are available that reduce portal pressures
carbohydrates -These may be used in the short term for the treatment of active variceal
hemorrhage or long term to reduce the risk of hemorrhage

GLUCAGON-LIKE PEPTIDE 2 ANALOG FOR SHORT-BOWEL SYNDROME

• Extensive surgical resection or disease of the small intestine may result
in short-bowel syndrome with malabsorption of nutrients and fluids

-Patients with <200 cm of small intestine (with or without colon

resection) usually are dependent on partial or complete parenteral
nutritional support to maintain hydration and nutrition

Teduglutide
• Glucagon-like peptide 2 analog
• MOA: Binds to enteric neurons and endocrine cells → stimulating
release of a number of trophic hormones (including insulin-like
growth factor) → stimulate mucosal epithelial growth and
enhance fluid absorption
• Given SQ
• A/E:
o ↑ risk of neoplasia
o Colorectal polyps

BILE ACID AGENTS

Ursodiol
• Ursodeoxycholic acid
• Naturally occurring bile acid Conjugated in the liver with glycine or taurine,
excreted in the bile
Pharmacokinetics:
• Conjugated ursodiol undergoes extensive enterohepatic recirculation
• T ½: 100 hours

Pharmacodynamics:
• Decreases the cholesterol content of bile by reducing hepatic
cholesterol secretion
• Stabilize hepatocyte canalicular membranes
-Possibly through a ↓ in the concentration of other endogenous bile
acids or through inhibition of immune-mediated hepatocyte destruction

Clinical Use:
• For dissolution of small cholesterol gallstones in patients with symptomatic
gallbladder disease who refuse cholecystectomy or who are poor surgical
candidates
• For the prevention of gallstones in obese patients undergoing rapid weight
loss therapy
• First-line agent used for the treatment of early primary biliary cirrhosis
(PBC)

Adverse Effects:
• Practically free of serious adverse effects
• Bile salt induced diarrhea

Obeticholic Acid
• Synthetic derivative of chenodeoxycholate (a naturally occurring bile acid)
• It is a nontoxic bile acid and is believed to reduce liver injury by decreasing
hepatic concentrations of more toxic endogenous bile acids
• It also is a ligand for the nuclear farnesoid X receptor
-Receptor that modulates hepatic inflammation, fibrosis, gluconeogenesis,
lipid synthesis, & insulin sensitivity
• Approved for treatment of PBC (combined with Ursodiol if inadequate
response to Ursodiol monotherapy)