Gastrointestinal Pharmacology
Prof. Sri Agus Sudjarwo.,Ph.D
Learning Objectives
1. Know the major classes of acid-suppressive
drugs and their mechanisms of action
2. Know the common side effects of acid-
suppressive drugs
3. Know the specific treatment of acid-peptic
disorders
Peptic Ulcer Disease
Factors that
Factors that
Protect Against
Increase Acidity
Acidity
Peptic Ulcer Disease
Imbalance between defenses and aggressive factors
Defensive factors:
-Mucus: continually secreted, protective effect
-Bicarbonate: secreted from endothelial cells
-Blood flow: good blood flow maintains mucosal integrity
-Prostaglandins: stimulate secretion of bicarbonate and
mucus, promote blood flow, suppress secretion of gastric
acid
Aggressive factors:
-Helicobacter pylori: gram negative bacteria, can live in
stomach and duodenum, may breakdown mucus layer
=> inflammatory response to presence of the bacteria
also produces urease forms CO2 and ammonia which
are toxic to mucosa
-Gastric Acid: needs to be present for ulcer to form =>
activates pepsin and injures mucosa
-Decreased blood flow: causes decrease in mucus
production and bicarbonate synthesis, promote gastric
acid secretion
-NSAIDS: inhibit the production of prostaglandins
-Smoking: nicotine stimulates gastric acid production
Classes of Agents
1. Proton Pump Inhibitors
2. Histamine H2-Receptor Antagonists
3. Prostaglandin Analogs
4. Cytoprotectants
5. Antacids
1. Proton Pump Inhibitors
(PPIs)
PPIs
- Most potent suppressors of acid secretion
- 24-48 hr effects on acid suppression
- Irreversible inhibitor of proton pump; blocks 98% of
acid secretion in all forms of ulcer and hypersecretory
Zollinger-Ellison syndrome.
-The drug is given in gelatin coated capsule to resist
breakdown in stomach acid. It reaches the intestine,
well absorbed, enters blood stream,reaches the
parietal cell.
PPIs
Irreversibly inhibit H+/K+ATPase function to:
Block gastric acid secretion
Decrease pepsin concentration
Increase gastric pH
Secretion of acid only resumes when new
proton pumps are deployed
Steady-state inhibition (affecting 70% of
pumps) may take 2-5 days
PPI Pharmacology
Activated only when pH decreases below 4
Occurs only in parietal cell
Achieved only when parietal cell activation occurs
(after meals)
Most effective after a prolonged fast when large
amounts of active proton pumps are present (i.e.
breakfast)
Available PPIs
Esomeprazole (Nexium)
Lansoprazole (Prevacid) (iv)
Omeprazole (Prilosec, generic, OTC)
Pantoprazole (Protonix) (iv)
Rabeprazole (Aciphex)
PPI Metabolism
Rapidly absorbed
Highly protein bound
Extensively metabolized in the liver by the
P450 system (CYP2C19 and CYP3A4)
Sulfated metabolites are excreted in the
urine or feces
Hepatic disease reduces the clearance of
lansoprazole--reduce dose
Common PPI Side Effects
Headache (2.9-6.9%) vs. Placebo (2.5-6.3%)
Diarrhea (3%) vs. Placebo (3.1%)
Abdominal pain (2.4-5.2%) vs. Placebo (3.1-3.3%)
Constipation (1.1-1.5%) vs. Placebo (0-0.8%)
Drug-Drug Interactions
Ketoconazole and Digoxin absorption is
decreased due to reduced acidity.
Omeprazole may inhibit coumadin, diazepam
and phenytoin metabolism
2. Histamine H2-Receptor
Antagonists (H2RAs)
H2RAs
Reversibly compete with histamine for binding
to H2 receptors on the basolateral membrane
of parietal cells
Less potent than PPIs but still suppress acid
by 70% over 24 hrs
Available H2RAs
H2 receptor blockers:
Cimetidine (Tagamet)
First H2-blocker available
Inhibits P450 => Drug interaction
Ranitidine (Zantac)
Does not inhibit P450 => fewer side
effects
Nizatidine (Axid)
Famotidine (Pepcid)
Pharmacokinetics
Rapidly absorbed after oral administration
Serum concentrations peak in 1-3 hr
Therapeutic levels maintained up to 12 hrs
Small percentage is protein bound
10% to 35 % metabolized by the liver
Drugs and metabolites primarily excreted by
kidneys (**reduce doses in renal disease)
-inhibit 90% acid secretion in basal state as well as
food-induced and nocturnal acid production.
-they are helpful in healing gastric and duodenal
ulcers and prevent their recurrence. Have benefits in
preventing increased gastric acid secretion in
Zollinger-Ellison syndrome.
-Cimetidine Has several side effects, not a choice
now - Under Prescription.
Common H2RA Side Effects
All less than 3%
Diarrhea
Headache
Drowsiness
Fatigue
Muscular pain
Constipation
Much less common
Confusion, delirium in the elderly
Associated with thrombocytopenia
Cimetidine anti-androgen effects
Drug-Drug Interactions
-Inhibits CyP450: Inhibits the metabolism of
various drugs that are concomitantly taken:
phenytoin, warfarin, theophylinne, BZD.
-These adverse effects are relatively least with
ranitidine and famotidine
3. Prostaglandin Analogs:
Misoprostol
Protective Effects of Prostaglandins
PGE2 and PGI2 synthesized by gastric mucosa
Acid-reducing effects
Bind to EP3 receptors on parietal cells
Decrease acid production
Cytoprotective effects
Stimulation of mucin and bicarbonate
Increase mucosal blood flow
Contrast with NSAIDS which diminish prostaglandin
formation by inhibition of cycloxygenase and lead to
ulcer formation
Misoprostol: Cytotec
Synthetic analog of PGE1
Enhanced potency
Increased oral bioavailability
Inhibit basal acid secretion (85-95%)
Inhibit stimulated acid secretion (75-
85%)
Pharmacokinetics
Rapidly absorbed
Rapidly de-esterfied to misoprostol acid--
the active metabolite
Therapeutic effect peaks at 60-90 minutes
Lasts 3 hours (qid dose required)
Side Effects
Diarrhea abdominal cramps as high as 30%
Begins within 2 weeks and often resolves
spontaneously in 1 week
Can exacerbate inflammatory bowel disease
Contraindicated during pregnancy
4. Sucralfate: Carafate
Sucralfate
Sulfated polysaccharide
Acid activated
Administered on an empty stomach 1 hr before meals
Stimulates local prostaglandin synthesis, adsorbs
pepsin
Binds bile acids
Not absorbed => essentially free of side effects
Common Side Effects
Constipation (2%)
Avoid in renal failure
May impair absorption of other drugs
5. Antacids
Antacids
Sodium bicarbonate
CaCO3
Mg2+ hydroxides
Al3+ hydroxide
Antacids
Given orally 1-3 hrs after meals and bedtime
Mg+2 based preparations increase motility
Diarrhea
Al+3 based preparations relax smooth muscle
Constipation
Ca+2 based preparations release CO2
Belching, nausea, distension, and flatulence.
Common Side Effects
Aluminum toxicity with renal disease
Osteoporosis, enchephalopathy, myopathy
Hypercalcemia
Phosphate retention
Calcium precipitation in the kidney
Impair absorption of some drugs
Take 2 hrs before or after other drugs
Antibiotic ulcer therapy:
Combinations must be used:
-Bismuth (PeptoBismol) disrupts cell wall of H. pylori
-Clarithromycin inhibits protein synthesis
-Amoxicillin disrupts cell wall
-Tetracyclin inhibits protein synthesis
-Metronidazole used often due to bacterial resistance to
amoxicillin and tetracyclin, or due to intolerance by
the patient
Standard treatment regimen for peptic ulcer:
Omeprazole + amoxicillin + metronidazole
Laxatives
Constipation
Abnormally infrequent and difficult
passage of feces through the lower GI
tract
Symptom, not a disease
Disorder of movement through the
colon and/or rectum
Can be caused by a variety of diseases
or drugs
Laxatives :
Bulk forming
Emollient
Hyperosmotic
Saline
Stimulant
Laxatives:
Mechanism of Action
Bulk forming
High fiber
Absorbs water to increase bulk
Distends bowel to initiate reflex bowel
activity
Examples:
psyllium (Metamucil)
methylcellulose (Citrucel)
polycarbophil
Laxatives:
Mechanism of Action
Emollient
Stool softeners and lubricants
Promote more water and fat in the stools
Lubricate the fecal material and intestinal
walls
Examples:
Stool softeners: docusate salts (Colace,
Surfak)
Lubricants: mineral oil
Laxatives:
Mechanism of Action
Hyperosmotic
Increase fecal water content
Result: bowel distention, increased
peristalsis, and evacuation
Examples:
polyethylene glycol (GoLYTELY)
sorbitol
glycerin
lactulose (Chronulac)
Laxatives:
Mechanism of Action
Saline
Increase osmotic pressure within the
intestinal tract, causing more water to
enter the intestines
Result: bowel distention, increased
peristalsis, and evacuation
Saline laxative examples:
magnesium sulfate (Epsom salts)
magnesium hydroxide (MOM)
magnesium citrate
sodium phosphate (Fleet Phospho-
Soda, Fleet enema)
Laxatives:
Mechanism of Action
Stimulant
Increases peristalsis via intestinal nerve
stimulation
Examples:
castor oil
senna
cascara
bisacodyl
Laxatives: Side Effects
Bulk forming
Impaction
Fluid overload
Emollient
Skin rashes
Decreased absorption of vitamins
Hyperosmotic
Abdominal bloating
Rectal irritation
Laxatives: Side Effects
Saline
Magnesium toxicity (with renal insufficiency)
Cramping
Diarrhea
Increased thirst
Stimulant
Nutrient malabsorption
Skin rashes
Gastric irritation
Rectal irritation
Antidiarrheals
Causes of Diarrhea
Acute Diarrhea Chronic Diarrhea
Bacterial Tumors
Viral Diabetes
Drug induced Addisons disease
Nutritional Hyperthyroidism
Protozoal Irritable bowel syndrome
Antidiarrheals
Drugs that decrease peristalsis, thereby
allowing fluid absorption from the
intestinal contents
Examples:
Anticholinergics
Protectants/adsorbents
Opiate-related agents
Probiotics
Metronidazole
Antidiarrheals
Anticholinergics are used to treat tenemus and
vomiting
Examples:
Atropine
Aminopentamide
Isopropamide
Propantheline
Methscopolamine
Side effects include dry mucous membranes,
urine retention, tachycardia, and constipation
Antidiarrheals
Protectants/adsorbents coat inflamed
intestinal mucosa with a protective layer
(protectants) or bind bacteria and/or digestive
enzymes and/or toxins to protect intestinal
mucosa from damaging effects (adsorbents)
Examples:
Bismuth subsalicylate (bismuth + aspirin-like
product)
Kaolin/pectin
Activated charcoal
Side effects include constipation
Antidiarrheals
Opiate-related agents control diarrhea by
decreasing both intestinal secretions and the
flow of feces and increasing segmental
contractions
Examples:
Diphenoxylate
Loperamide
Paregoric
Side effects include CNS depression, ileus,
urine retention, bloat, and constipation
Antidiarrheals
Probiotics seed the GI tract with beneficial
bacteria; use is based on the theory that some
forms of diarrhea are caused by disruption of
the normal bacterial flora of the GI tract
Must be refrigerated to maintain the viability of
the bacteria
Examples:
Plain yogurt with active cultures
Variety of trade-name products
Antidiarrheals
A theory regarding the development of
diarrhea is that anaerobic bacteria may
increase due to disruption of normal GI
flora
One way to treat this is to use an
antibiotic effective against anaerobic
bacteria
Metronidazole is an example of an
antibiotic used to treat diarrhea
