Download Gastrointestinal Pharmacology

Gastrointestinal Pharmacology
Jan Kehr
Department of Physiology and Pharmacology
Gastrointestinal Pharmacology
v  Background
v  Peptic disorders
v  Constipation and Diarrhea
v  Chronic Bowel Disease
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The enteric nervous system (ENS) I
v  The autonomic nervous system has 3 divisions:
ü  sympathetic
ü  parasympathetic
ü  enteric
v  The enteric nervous system:
ü  located in the GI tissue, but can be modified by input from the brain
ü  a collection of nerve plexuses that surround the GI tract
ü  contain over 100 million neurons
ü  contain many different neurotransmitters (e.g. ACh, DA, NA, 5-HT)
and neuromodulators
v  The ENS regulates:
ü  rythmic contraction of intestinal smooth muscle
ü  secretory functions of intestinal epithelial cells
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The enteric nervous system (ENS) II
v  Neurons of the ENS clustered into:
ü  The submucosal plexus (Meisner’s plexus)
o  regulating GI blood flow and epithelial cell function
ü  The myenteric plexus (Auerbach’s plexus)
o  Control digestive tract motility
v  The nerve plexuses consist of:
ü  Sensory neurons –recieve information from sensory receptors (mechanical,
thermal, osmotic, chemical stimuli) in the mucosa and the muscles information on gut contents and the state of the GI wall.
ü 
Motor neurons – affect smooth muscle cells and gland in the GI tract and
control GI motility, secretion, and absorbtion
ü 
Interneurons largely responsible for integrating information from sensory
neurons and providing it to ("programming") enteric motor neurons
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Innervations of the of GI tract
The ENS can and does function autonomously - but normal digestive
function requires CNS communication.
v  Parasympathetic innervation of the GI tract
ü  vagus nerve stimulation (pharynx → distal colon)
ü  ACh
ü  stimulates: GI secretion, motor activity and contraction of GI
sphincters
v  Sympathetic innervation of the GI tract:
ü  postganglionic neurons
ü  NA
ü  inhibits: GI secretion, motor activity and contraction of GI
sphincters
v Bidirecttional communication: GI ↔ higher CNS centers
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GI hormones
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The Gastric pit
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Gastric acid I
v The best known component of gastric juice is HCl
v  Parietal cells
v  2 – 2.5 L gastric juice per day
v  Highly acidic environment
v  Activates pepsinogen to pepsin (degradation of proteins)
v  Inhibition of growth of microorganisms
v  Control of acid secretion:
ü  Acetylcholine
ü  Histamine (H2 receptors)
ü  Gastrin
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Gastric acid II
q  Gastrin – hormonal
regulation
q  ACh – nervous regulation
q  Histamine – released after
hormonal and nervous
regulation
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Mechanism of acid secretion
1
5
2
4
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1. H+ is generated from the
dissocation of water
2. The OH- from this reaction is
catalyzed to HCO33. HCO3- is transported out of the cell
in exchange of Cl4. Cl- and K+ → transported into the
lumen by conductance channels
5. H+ is pumped out of the cell in
exchange of K+ - K+ is effectively
recycled by the proton pump
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PEPTIC DISORDERS
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Peptic disorders
v  Gastroesophageal
reflux disease (GERD)
v  Gastritis
v  Ulcus
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Gastroesophageal reflux disease (GERD)
GERD occurs when the lower esophageal sphincter (LES) opens
spontaneously, for varying periods of time, or does not close
properly and stomach contents rise up into the esophagus.
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Gastroesophageal reflux disease (GERD)
GERD occurs when the lower esophageal sphincter (LES) opens
spontaneously, for varying periods of time, or does not close
properly and stomach contents rise up into the esophagus.
v  Persistent reflux that occurs more than twice a week is
considered GERD, and it can eventually lead to more serious
health problems.
v  Symptoms
ü  Heartburn (acid indigestion-burning pain)
ü  Regurgitation
ü  Dry cough
ü  Asthma symptoms
ü  Trouble swallowing
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Gastritis I
v  Inflammation of the stomach lining.
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Gastritis II
v  Inflammation of the stomach lining.
v Causes
ü  Infections – most common: Helicobacter pylori
ü  Injury
ü  Drugs - especially aspirin and other nonsteroidal anti-inflammatory
drugs
ü  Disorders of the immune system
v  Gastritis usually causes no symptoms.
v Gastritis can lead to ulcers, which may cause the symptoms to get worse
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Ulcus I
v  A peptic ulcer is a round or oval sore where the lining of the
stomach or duodenum has been eaten away by stomach acid and
digestive juices.
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Ulcus II
v  A peptic ulcer is a round or oval sore where the lining of the
stomach or duodenum has been eaten away by stomach acid and
digestive juices.
v Peptic ulcers can result from an infection with Helicobacter pylori
or from drugs that weaken the lining of the stomach or duodenum.
Symptoms
v  Gnawing, burning, aching, soreness, an empty feeling, and
hunger - The pain is steady and mild or moderately severe and
usually located just below the breastbone.
v  Bleeding - ↑ morbidity and mortality
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Helicobacter Pylori
The Nobel Prize in Physiology or Medicine 2005 was awarded
jointly to Barry J. Marshall and J. Robin Warren "for their
discovery of the bacterium Helicobacter pylori and its role in
gastritis and peptic ulcer disease"
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Helicobacter Pylori II
v  The most common infection in the world → 60-90% of the the
world’s population has been estimated to be infected
v Gastritis: 90-100%, ulcers: 70-80%
v  May cause of chronic gastritis and is associated with duodenal
ulcer disease, gastric ulcer disease, and gastric cancer
v  Gramnegative, gastric bacterium with a bundle of flagellas
v  Produces urease – enables the organism to survive in the acidic
stomach by creating an alkaline environment
v  Biopsy – positive culture, serologic tests or urea breath tests
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Helicobacter Pylori III
1. H. pylori penetrates the mucus layer
of the stomach and adheres to the
surface of gastric mucosal epithelial
cells.
2. Ammonia is produced which
neutralizes the gastric acid
3. The H. Pylori proliferates, and
migrates, and finally causes
inflammation.
4. Gastric ulcerization (or peptic
ulcers) is developed by the destruction
of the mucosa, inflammation and
mucosal cell death
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Treatment strategy
v  Lifestyle changes
ü  Diet
ü  Weight loss
ü  ↓Smoking and Alcohol habits
v  Pharmacological strategies:
1. Neutrilize secreted acid
2. Decrease the secretion of gastric acid
3. Protect the mucosa
4. ”Attack” the Helicobacter Pylori infection
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1. Antacids
Antacids (alkalines) perform a neutralization reaction:
-  increasing the pH to reduce acidity in the stomach
-  inhibiting the activity of peptic enzymes
Examples of antacids:
v  Magnesium Hydroxide
ü  forms MgCl2 in the stomach
v  Magnesium Trisilicate
ü  forms MgCl2 colloidal silica in the stomach
v  Aluminium Hydroxide gel
ü  forms AlCl in the stomach
v  Side effects (Novaluzid®):
ü  belching
ü  nausea
ü  flatulence
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2A. Histamine H2 receptor antagonists
v  Examples:
ü  Ranitidin (Stomacid®)
ü  Famotidin (Pepsin®)
v  Inhibits: Histamine-, gastrin- and ACh-stimulated secretion
v  Side effects:
ü  Diarrhoea
ü  Dizziness
ü  Muscle pain
ü  Alopecia
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2B. Protonpump inhibitors
v  Inhibits the H+/K+ ATPase pump irreversibly
v  Examples:
v  Omeprazole (Losec®) - prodrug
v  Esopremazole (Nexium®)
v  Side effects
ü  Diarrhea
ü  Dizziness
ü  Mental confusion
ü  Somnolence
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3A. Cytoprotective drugs I
v  Enhance the endodgenous mucosal protection mechanism and/or
provide a physical barrier over the surface of the ulcer
v  Sucralfate (Andapsin®)
ü  a complex of the disaccharide sugar, sucrose, combined with
sulfate and aluminum – releases aluminum in the presence of acid
ü  the complex carries a strong negative charge – binds to exposed
proteins to the surface of the ulcer
ü  coats the ulcer – complex gel with mucus
ü  inhibits pepsin
ü  may increase prostaglandin production
v Side effects:
ü  most common – constipation
ü  may reduce effectiveness of other drugs
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3B. Cytoprotective drugs II - Prostaglandine analogues
v  Examples: Misoprostol (Cytotec®)
v  Reduce gastric acid secretion
v  Cytoprotective by increasing:
ü  the mucosa layer
ü  the secretion of bicarbonate
ü  local blood flow
ü  the cell regeneration
v  Side effects
ü  Diarrhea
ü  Dysregulated menstruation
ü  Teratogenic
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4. Treatment of Helicopbacter pylori
v  Triple therapies: Proton pump inhibitor in combination antibiotics
v  Examples of antibiotics:
ü  Amoxelline (Amimox®)
ü  Clarithromycin (Klacid®)
ü  Metrondiazole (Flagyl®)
v Triple therapies:
ü  omeprazole 40 mg x 1, amoxicilline 500 mg x 3, metronidazol 400 mg x 3 for one week
ü  omeprazole 20 mg x 2, clarithromycin 250 mg x 2, metronidazole 400 mg x 2 for one week
ü  omeprazole 20 mg x 2, clarithromycin 500 mg x 2, amoxicilline 1 g x 2 for one week
Side effects:
ü  Metrondiazole – metallic taste
ü  Clarithromycin – nausea, diarrhoea, abdominal cramps
ü  Amoxelline - nausea, diarrhoea, abdominal cramps
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DRUGS USED IN CONSTIPATION
AND DIARRHEA
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Constipation
infrequent stools
v  hard stools
v  difficulty passing stools
v  a sense of incomplete emptying after a bowel movement
v 
Drugs that alter the motility of the GI tract may help:
v  Purgatives – accelerate the passage of food through the intestine
v  Agents that increase the motility of the GI smooth muscle without causing
purgation
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Purgatives/Laxatives I
1. 
2. 
3. 
Laxatives
Faecal softeners
Stimulant purgatives
1. Bulk laxatives
v  include methylcellulose and extracts (e.g. agar, bran)
v  non-absorbable, non-breakable polysaccharide polymers → forming a
hydrated mass in the gut lumen
v  promotes peristalsis and improving faecal consistency
v  They may take several days to work but have no serious side effects
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Purgatives/Laxatives II
2. Faecal softners
v  Mineral oil: non-absorbable - make the intestinal walls and stool moist and
slippery, thus facilitating defecation
v  “Detergents”: produces softer faeces
3. Stimulant laxatives
v  increases electrolyte and hence water secretion
v  stimulating the enteric nerves → increasing peristalsis
v  side effects: abdominal cramping
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Diarrhea
v  Numeral causes:
ü  underlying disease
ü  Infections
o  Bacterias: secret toxins → mucosal cells can not absorb H2O and
NaCl
o  Viruses: cause inflammation of the GI wall → increased fluid
secretion and increast peristalsis
ü  Toxins
ü  Anxiety
ü  Side effects of drug or radial therapy
In developing countries, acute diarrhea is one of the principal
causes of death of malnourished infants
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Treatment strategy - diarreha
v  Treatment of severe acute diarrhea
1.  Maintenance of fluid and electrolyte balance
ü  NaCl and glucose (Resorb®)
2.  Use of anti-infective agents
ü  Antibiotics
3.  Use of spasmolytic or other antidiarrheal agents
ü  Adsorbents (e.g. charcoal) – binds toxins → inactivation and
elimination
ü  Opioids – activates µ-receptors in the enteric nerve plexus
ü  Loperamide (Immodium®) – opioid do not pass the BBB
Side effects opioids:
ü  Constipation
ü  Abdominal cramps
ü  Drowsiness
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CHRONIC BOWEL DISEASES
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Chronic bowel diseases
1.  Irritable bowel disease
2.  Ulcerative colitis
3.  Crohn’s disease
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Crohn’s disease
Chronic inflammatory disease of the intestines. It primarily causes
ulcerations (breaks in the lining) of the small and large intestines, but
can affect the digestive system anywhere from the mouth to the anus
Symptoms
v  Chronic diarrhea (blood and mucous)
v  Weight loss
v  Rectal bleeding
v  Fever
v  Night sweats
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Crohn’s disease - treatment
There is no medication that can cure Crohn's disease – focus on
alleviating the symptoms of the patient.
v  Anti-inflammatory agents: 5- ASA compounds and glucocorticoids
v  Topical antibiotics
v  Immuno-modulators
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Anti-inflammatory agents
Sulfasalzaline (Salazopurin®) – is also used in RA
v  A chemical combination of sulfapyridin and 5-aminosalicylic acid (5-ASA)
ü  Prevents the absorption by the stomach
v  5-ASA (mesalazine) – bacterial activation in colon
v  5-ASA may reduce inflammation by:
ü  Scavenging free radicals
ü  Inhibiting :
o  prostaglandin production
o  leukotriene production
o  neutrophil chemotaxis
v Side effects: Diarrhea, salicylate sensitivity
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Immuno-modulators
Azathioprine (Azatriopin®)
v Metabolized to mercaptopurine
v  Both cell-mediated and antibody-mediated immune reactions are
depressed by Azathioprine
v Inhibits the clonal proliferation during the induction phase of the immune
response by a cytotoxic action on dividing cells
v  Side effects:
ü  Depression of the bone marrow
ü  Nausea
ü  Vomiting
ü  Skin eruptions
ü  Mild hepatotoxicity
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Summary I
Peptic Ulcers
Pharmacological strategies:
ü  Neutrilize secreted acid - Antacids
ü  Decrease the secretion of gastric acid – proton pump inhibitors, H2
receptor antagonists
ü  Protect the mucousa – Cytoprotective drugs
ü ”Attack” the Helicobacter Pylori infection – Antibiotics
Constipation
ü  Purgatives
ü  Laxatives
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Summary II
Diarrhea
Pharmacological strategies:
ü Maintenance of fluid and electrolyte balance – NaCl and glucose
ü  Use of anti-infective agents - Antibiotics
ü  Use of spasmolytic or other antidiarrheal agents- Adsorbents, Opioids
Chronic Bowel Diseases
ü  Surgery
Pharmacological strategies:
ü  Anti-inflammatory agents
ü  Immunomodulaters
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