Pharmacology
Lecture 15 Gastrointestinal Drugs
1) Explain the mechanism of acid production by the parietal cells.
a) Neural stimulation - the dorsal motor nucleus of the vagal nerve (DMNV) sends
fibers to the stomach via the vagus nerve to synapse with ganglion cells of the
enteric nervous system (ENS). Acetylcholine release from postganglionic vagal
fibers can directly stimulate gastric acid secretion via muscarinic receptors on
parietal cells.
b) Endocrine stimulation - gastrin released from antral G cells.
c) Paracrine stimulation - local release of histamine from enterochromaffin-like
(ECL) cells or mast cells. The histamine in turn activates parietal cell H2
receptors that are linked to stimulation of adenylyl cyclase, causing activation of
the cAMP pathway. Gastrin and muscarinic stimuli may also act directly on the
parietal cell to activate calcium sensitive pathways either method stimulates
activation of H+, K+-ATPase on parietal cells with the consequent secretion of H+
at rates between 20 and 40 mEq per hour.
2) Identify the role of H. pylori in peptic ulcer disease. H. pylori is a spiral shaped,
flagellated, gram-negative bacteria which is a member of a new genus, Helicobacter.
They usually live in the stomach where the flagella allow motility in the gastric juice
and gastric mucus. They require urease enzyme to colonize the mucus layer because
it breaks down the urea in the gastric juice and generates enough bicarbonate and
ammonium ion to allow H. pylori safe passage through the gastric acid to the mucus
layer where it attaches to phospholipids and Louis B. antigens and delivers soluble
protease is in phospholipase which is harmful to the integrity of the mucus layer and
the underlying cells. The host reaction exacerbates disease but is ineffective in
eradicating the H. pylori.
3) List the approaches used to diagnose H. pylori infection. Approaches include
histology and culture at endoscopy (the most sensitive method), a rapid urease (CLO
test), serology tests (simplest and most widely available), and breath tests for
detection of the urease enzyme of H. pylori.
4) List the approaches used to eradicate H. pylori.
a) Omeprazole (Prilosec®, proton pump inhibitor) 20 mg, b.i.d. and amoxicillin 1 g,
b.i.d. for 7 to 14 days with a cost of about $130 and a cure rate of about 80% with
little side effects.
b) "Triple therapy" consists of administration of bismuth subsalicylate tablets
(PeptoBismol®) four times daily, tetracycline (500 mg, q.i.d.) and metronidazole
(250 mg, q.i.d.) With the cost of about $42 for a course of therapy and a cure rate
of about 85 to 90%.
c) "MOC therapy" b.i.d. administration of: metronidazole 500 mg, omeprazole 20
mg and clarithromycin 250 mg each for one week with 90% effectiveness.
5) Explain the role of the proton pump in secretion of acid. Secretion of H+ into the
lumen results from activity of parietal cell H+, K+-ATPase. The proton pump, H+, K+ATPase, can be activated by acetylcholine at muscarinic receptors, histamine at H2
receptors, and gastrin at gastrin receptors.
6) Define the mechanism of action of the proton-pump inhibitors. Inhibition of the
H+, K+-ATPase, proton pump, produces the most effective mechanism known to
inhibit gastric acid secretion. Omeprazole (Prilosec®) and esomeprazole (Nexium®)
are both H+, K+-ATPase inhibitors.
7) Localize the distribution of histamine receptor types. The H2 histamine receptor
occurs on the parietal cell in mediates the stimulatory effect of histamine on acid
secretion by parietal cells. H1 histamine receptors mediate a variety of histamine
actions on blood vessels, sensory nerves, bronchial smooth muscle and other cells.
8) Compare and contrast H2 receptor antagonists to other peptic ulcer medications.
Medication
Proton pump inhibitors
Omeprazole and esomeprazole
H2 receptor antagonists
cimetidine, famotidine, nizatidine,
and ranitidine
Anti-cholinergics
Atropine or scopolamine
Prostaglandins
Misoprostol
Action
Inhibits H+, K+-ATPase Reduces
gastric acid
Blocks parietal cell H2 histamine
receptors
Decreases acid-pepsin secretion
Blocks muscarinic cholinergic
receptors
Decreases acid secretion
Inhibit adenylate cyclase
stimulation by histamine
Cytoprotective effects
Side Effects
Omeprazole - gastric hyperplasia
in animals
Cimetidine - interferes with
cytochrome P450, binds
testosterone, causes confusion
Dry mouth, urinary retention,
constipation
Diarrhea, uterine stimulation
(especially during pregnancy)
Histamine is thought to stimulate adenylate cyclase in parietal cells, forming cAMP,
which acts through a protein kinase to activate the proton pump that secretes H+ into
the lumen. H2 receptor antagonists, cimetidine, famotidine, nizatidine, and ranitidine,
decrease acid and pepsin secretion by blocking parietal cell H2 histamine receptors to
allow the healing of ulcers in the mucosa.
9) Classify antacids as far as the side effects are concerned. (See question 10)
Systemic antacids - are absorbed into the bloodstream, can increase blood pH, and
alkalinize the urine.
Nonsystemic antacids - do not alter blood pH and do not alkalinize the urine.
10) Compare relative onset of action and effect on stool of different antacids.
Antacids
Sodium and
potassium salts
Onset of action
Almost immediate (pH
of 5-7) short duration
Calcium salts
Very rapid (pH of 4-5)
remains high until
stomach is emptied
Slow onset, maintains
desirable levels until
stomach is emptied
Magnesium and
aluminum salts
Magnesium
hydroxide
(milk of Magnesia)
Rapid onset (pH of 8-9)
Side effects (stool)
React with bicarbonate and carbonate secreted in the
pancreatic juice to form salts (excreted in the feces)
React with fatty acids to form soaps (also excreted)
Promotes gastrin and acid secretion "acid rebound" can
produce systemic hypercalcemia with formation of caluli
"milk alkali syndrome"
Magnesium is (laxative), can induce muscle weakness and
fatigue
Aluminum is (constipating), can bind phosphate leading to
phosphate deficiency, muscle weakness, and bone resorption
Magnesium is (laxative)
11) What are the two types of GI contractions & identify the mechanism of
prokinetic agents. The two types of GI contractions are: peristalsis (propulsion) and
segmentation contractions (mixing).
Metoclopramide and related prokinetic drugs are known to possess antagonist activity
at 5-hydroxytryptamine 5-HT3 receptors and agonist activity at 5-HT4 receptors.
Metoclopramide also possesses dopamine receptor antagonist properties, which
account for its antiemetic activity. The precise mechanism for increase of GI
contractions is not known, but may be related to increased release of acetylcholine at
the terminals of cholinergic neurons animating the GI smooth muscle, release of
acetylcholine at interneurons in the myenteric plexus, or even by blockade or
stimulation of certain types of 5-HT receptors.
Cisapride (Propulsid®) was withdrawn from the market as a prokinetic agent due to
cardiac arrhythmias. Tegaerod maleate (Zelnorm®) is a new 5-HT receptor agonists
approved for short-term treatment of women with irritable bowel syndrome.
12) Identify the mechanism of action of laxative substances.
Category
Secretary
Sailing
Emollient
Bulk
forming
Example
Castor oil, Ex-Lax (Senna),
bisacodyl
Magnesium hydroxide,
sodium phosphate or sulfate
Dioctyl sodium
sulfocuccinate, mineral oil
Bran, methylcellulose,
psyllium
Action
Stimulate secretion by activating adenylate cyclase in crypt
cells which increases cAMP to activate chloride channels
Decreases viscosity by retaining fluid in the lumen and
promoting flow through the bowel (often explosive)
Decreases viscosity by acting as an autumn Zorba lubricant
Increases bulk by hydrating non-digestible cellulose fibers
13) Describe the mechanism of antidiarrheal effect of opioids. In humans, opioids
increase segmenting contractions of the small and large intestines, thereby increasing
resistance to flow through the lumen, and promote mucosal absorption of fluid and
electrolytes. This allows for slowed transit through the gut and more complete fluid
absorption resulting in increased viscosity of luminal content and formed stools.
14) Identify conditions where use of opioids for antidiarrheal actions is
inappropriate. Morphine, codeine, and related agents can be used orally or by
injection as antidiarrheal drugs. However, the natural opioids possess abuse potential
and in overdose can have dangerous side effects. Opioid antidiarrheals should not be
employed in the systematic treatment of diarrhea induced by enteric infections with
invasive organisms, especially species out of Shigella and Salmonella. Diarrhea in
these infections may be protective and help to flush organisms from the gut; the delay
in transit of gut contents induced by opioids can exacerbate the infection.
Drugs
Opioids
α2 agonists
Anticholinergics
Somatostatin
(octreotide)
Bismuth
subsalicylate
Cholestyramine
Inhibit
propulsive
contractions
+++
Stimulate
nonpropulsive
contractions
+++
Enhance fluid
absorption
Decrease fluid
secretion
++
+
+++
+++
+++
++
+
+++
Bind luminal
secretagogues
+++
+++