Lecture 13 - Pharmacology of the Gastrointestinal Tract Flashcards
What triggers the cephalic phase?
Sight, smell, taste, or thought of food stimulates the vagus nerve which in turn stimulates gastric secretion (hydrochloric acid, pepsin)
What happens during the gastric phase?
Partially digested food stretches the stomach and activates myenteric and vagovagal nerve reflexes –> stimulate gastric secretions
What stimulatory molecules are present in the stomach during the gastric phase?
Histamine and gastirin
What happens during the intestinal phase?
Sypmpathetic nerve fibers suppress gastric activity while parasympathetic (vagal) stimulation of the stomach is inhibited.
What inhibits gastric secretion during the intestinal phase?
Secretin, cholecystokinin (CCK), and the enterogastric reflex
Describe the gastric cycle
1) ingested food buffers, stomach acid, elevating pH
2) elevated pH stimulates G cells that make up the pyloric gland
3) G cells secrete gastrin
4) Gastrin stimulates the chief cells and parietal cells on the gastric gland
5a) ACH, H2, and gastrin receptors on enterochromafflin-like cells secrete histamine
5b) Chief cells secrete pepsinogen
5c) Parietal cells secrete HCl
6) HCl converts pepsinogen to pepsin
7) Pepsin digests dietary protein
8a) Partially digected protein oligopeptides and amino acids buffer the stomach acid –> elevates pH
8b) Partially digested protein oligopeptides directly stimulate G cells
What molecules stimulate HCl secretion and where are they formed?
- Acetylcholine- parasympathetic postganglionic neurons
- gastrin- G cells
- histamine- neuroendocrine cells
What molecules inhibit HCl release?
CCK, somatostatin, and secretin
Where is pepsinogen (precursor to pepsin) secreted?
Chief (peptic) cells
What cells secrete somatostatin?
D cells
What do surface mucus cell secrete when stimulated?
Bicarbonate and mucus
- stimulated by prostagladins
What is secretin?
A digestive hormone
How are gastrin and cholecystokinin (CCK) related?
They are structurally and functionally related peptide hormones
What is somatostatin?
A cyclic peptide present in the GI tract, pancreas, and CNS
What type of receptors are somatostatin receptors?
Inhibitory GPCRs
What are Octreotide and Lanreotide and their uses?
- Mimic the action of somatostatin (act on somatostatin receptors located on gastric parietal cells)
- Clinical use for gastrinomas, gastric ulcers, and other disorders associated with excessive gastric acid secretion
What is a peptic ulcer?
An open sore that develop on the mucosal lining of the stomach and duodenum, where acid and pepsin activity are greatest
What are the symptoms of peptic ulcers?
- Periodic pain, nausea, vand vomitting
- loss of appetite
- heartburn
- perforation in the GI wall
Possible causes of peptic ulcers
- Helicobacter pylori
- Long-term use of NSAIDs
- Hyperacidity (genetic, environmental, inflammation)
How does H. pylori cause peptic ulcer?
- inflammatory mediators elicited by H. pylori inhibit somatostatin secretion by D cells –> disinhibition of gastrin release
- H. pylori produces ammonium hydroxide which increases gastric pH –> stimulates gastrin secretion
How do NSAIDs cause peptic ulcer disease?
- NSAIDs inhibit COX –> reduce production of prostaglandins –> increased gastric acid secretion, decreased bicarbonate/mucus production and blood flow
- Increased expression of intercellular adhesion molecules –> increeased neutrophil adherence to vascular endothelial cells –> mucosal damage due to neutrophil-derived free radicals and proteases
How does Bismuth and Antibiotics treat peptic ulcer?
Inhibit the H. pylori bacteria
What drugs are used to treat peptic ulcers?
- H2 blockers
- Muscarinic antagonists
- Proton pump inhibitors
- Antacids
- Coating agents
What do antihistamine receptor antagonists (H2 blockers) do?
Reduce interactions between histamine and H2 receptors –> pepsin and acid secretion decreases
Where do H2 antagonists act in the GI tract?
They are competitive antagonists of histamine at the parietal cell’s H2 receptor
Describe irreversible vs reversible proton pump inhibitors
Irreversible - inhibit the pump enzyme by covalently binding to the alpha-subunit of the pump
Reversible - mostly K+ competitive inhibitors
Clinical indications for antacids
- Hyperactivity associated with peptic ulcers, heartburn, etc
- Upset stomach
Antacid mechanism of action
- Reacts with HCl forming water and salts
- Administered orally and act locally
Examples of antacids
- Aluminum hydroxide\
- magnesium hydroxide
- sodium bicarbonate
- calcium carbonate
What could chronic use of antacids cause?
Acid rebound
Sucralfate (barrier enhancer) - Mechanism of action
- Forms a protective barrier over damaged mucosa by binding proteins exuded from damaged cells
- Does not affect pH
- locally effective, non-systemic
- affects absorption of some drugs
Metoclopramide (prokinetic drug)
- promotes the emptiness of stomach, stimulates the opening of the lower esophageal sphincter by enhancing the action of endogenous acetylcholine, enhancing tissue sensitivity to ACH
- Treats GERD and chemotherapy induced vomiting, antiemetic, antagonizes dopamine receptor
What is peristalsis?
A wavelike movement characteristic of the intestines, in which circular contraction and relaxation of the muscles propel the contents toward the rectum
What type of drugs are used to treat nonspecific diarrhea?
Adsorbents, anticholinergics, mu receptor agonist, 5-HT3 antagonist, and somatostatin mimics
How do adsorbents treat diarrhea?
- Symptomatic rather than curative
- Act within the intestines
- forms a complex with irritating substances and carries them into the feces
- bind with toxins of bacteria reducing hypermotility of the GI tract
- reduces inflammation
- acts as an antacid
Side effects of adsorbents
impairs systemic absorption of vitamins, minerals, and drugs
Example of an adsorbent
Bismuth subsalicylate
Diarrhea treaments
Atropine
- Anticholinergic
- decreases peristalsis, constricts sphincter
Diarrhea treaments
Difenoxen
- mu receptor agonist
- decrease peristalsis, constrict sphincter
- used in combo with atropine
Diarrhea treaments
Loperamide
- opiod-derivative, OTC, does not cross BBB
- used for nonspecific, acute, chronic, or travel diarrhea and IBS
Diarrhea treaments
Alosetron
- 5-HT3 antagonist
- seretonin released by enterochromaffin cells is inhibited to decrease gut motility
- used in women with IBS
Diarrhea treaments
Octreotide
- somatostatin receptor agonist
- half-life of 90-120 min
- treats severe diarrhea associated with carcinoid tumors
Constipation treatment
Stimulants
- Ex. caster oil
- irritates mucosal lining of intestine –> histamine released –> increased motility
Constipation treatment
Swelling agents
- Ex. natural fibers
- soak up water and swell
Constipation treatment
Osmotic laxatives
- Ex. lactulose –> non-absorbable synthetic disaccharide
- broken down in the large intestine into fryctose and galactose which draw water into the colon
Constipation treatment
Emollients
- Ex. mineral oil
- ease the passage of stool through the rectum, lubrication and softening
Constipation treatment
Mu-opiod receptor antagonists
Methylnaltrexone
Constipation treatment
Chloride channel activators
Lubiprostone
Lubiprostone - Mechanism of action
Chloride channels-2, present in the apical membrane of the intestine, are activated –> increased secretion of chloride-rich intestinal fluid
Antiemetic Medications
Antihistamines
- Ex. diphenhydramine, meclizine
- used for motion sickness
- centrally acting and anti-H1 receptor antagonists
Antiemetic Medications
5-HT3 antagonists
- Ex. Odansetron
- Used to treat nausea and vomiting from chemotherapy, surgeru or infections
- peripheral and centrally acting
Antiemetic Medications
Dopamine antagonists
- Ex. Metoclopramide, prochlorperazine
- Used for nausea realted to gastroenteritis or post-operative conditions
- centrally acting
Antiemetic Medications
Anticholinergics
- Ex. scopolamine
- used for motion sickness and nausea
