GORD Flashcards
outline 6 mechanisms of gastric protection
- pH gradient
-mucus cells secrete bicarbonate + mucus in response to vagal stimulation + fundic distention - Surfactant like substances
-Prevents water soluble substances from reaching and damaging the gastric epithelium - Non-protein sulfhydryls
-Bind free radicals to prevent damage. - Rapid cell turnover
- Quick cell turn over (5-7 days) - Mucosal blood flow of sub-epithelium
- Supplies oxygen + nutrients to epithelium
-disposes of hydrogen ions + noxious agents - Prostaglandins
- maintain blood flow
-prevent vascular endothelial injury caused by ethanol
- has direct cytoprotective effects.
what is a normal stomach acid pH?
1.5 to 3.5
Outline how acid is produced ?
HCL is produced by parietal cells.
*Intracellular CO2 + H2O -> H2CO3 (by carbonic anhydrase)
*H2CO3 spontaneously dissociates -> H+ + HCO3-
* H+ is transported to gastric lumen via H+/K+ ATPase pump on apical end.
*HCO3- is pumped into blood on basolateral end by anion exchanger- exchanged for Cl-
*Cl- then transported out the apical end into lumen to combine with H+ to form HCL
Name 3 PPI’s, outline MOA and 2 ways that make them better than antacids/alginates
Omeprazole, Esomeprazole, Pantoprazole
MOA:
-> Absorbed from small intestine into general circulation
-> Concentrates in secretory canaliculi of gastric parietal cells where it is activated.
->IRREVERSIBLY binds to the H+/K+ ATPase pump on the luminal end of parietal cell, via covalent bond on cysteine residue of pump.
-> prevents the release of H+ into gastric lumen.
- This is the final common step in acid production so H+ stopped regardless of means by which it was stimulated to be released.
- Irreversible bond means that the parietal cell must make a new pump from scratch before it can counteract the PPI affect.
4 adverse affects of PPI use and 1 drug interaction
- Hypomagnesemia
- Reduced Vit B12 absorption (due to raised pH)
- Increased fracture risk in hip, wrist, spine
- C-diff
- Community acquired pneumonia.
Drug interaction:
*Clopidogrel -> clopidogrel is activated by CYP2C19
-> PPI’s can inhibit CYP2C19 thereby reducing metabolism of clopidogrel; reducing its systemic effects.
Outline 3 direct and 2 indirect routes of increasing acid production
Direct:
(1) Ach -> M3 receptors (mediated by vagus)
(2) G cells -> Gastrin -> CCK receptor
-> Both receptors are Gq PCR
-> results in activation of IP3
-> increases intracellular Calcium
-> H+/K+ ATPase pump out H+
(2) Histamine
->Enterochromaffin cells release histamine ->H2 receptors.
-> Gs PCR
-> activation of adenylyl cyclase
-> activation of cAMP
-> H+/K+ ATPase activation
Indirect:
(1) Gastrin -> ECL cells -> Histamine
(2) Gastrin releasing peptide -> G cells -> Gastrin
3 routes of gastric acid reduction
(1) Prostaglandins E2 + I2
-> inhibit cAMP
-> stimulates mucus production
-> dilates mucosal blood vessels.
(2) Somatostatin
-D cells -> somatostatin -> SST2 receptor
-> inhibits cAMP
-> inhibits G cells + ECL cells.
(3) Chyme in duodenum
-> Triggers enterogastric reflex
-> sends inhibitory signals to reduce vagal stimulation of acid production
list the 3 phases of gastric acid secretion and the mediators involved in each phase
(1) Cephalic
-> Ach from vagus
(2) Gastric
-> Ach (vagus)
-> Gastrin (G cells)
-> Histamine (ECL cells)
(3) Intestinal
-> Cholecystokinin (I cells)
-> Secretin (S cells)
-> Gastric inhibitory peptide (K cells)
-> Somatostatin (D cells)
How does cholecystokinin, Secretin, Gastric inhibitory pepitide and somatostatin function in intestinal phase of gastric acid secretion
These function during the intestinal phase of acid secretion
(1) Cholecystokinin (I cells)
-> Released from I cells
-> stimulates release of bile + digestive enzymes from pancreas + gall bladder
(2) Secretin (S cells)
-> Released from S cells of duodenum
-> stimulates water + bicarb release from pancreas to neutralise contents of duodenum
-> stimulates somatostatin release which in turn reduces H+ release by inhibiting cAMP, gastrin and histamine release
(3) GIP (K cells)
-> Inhibits gastrin release
(4) Somatostatin (D cells)
-> inhibits G + ECL cells
-> inhibits cAMP
How do NSAIDs contribute to ulcer formation
Outline 3 ways to reduce ulcer risk with NSAIDS
Inhibition of COX-1 mainly.
-> Inhibits PGE2 and PGI2 formation
-> PGE2 functions to inhibit gastric acid secretion + stimulates mucosal secretion.
-> PGI2 reduces acid secretion and contributes to mucosal blood flow.
-> reduction in these will result in reduced mucosal protection, increased acid production and vasoconstriction leading to mucosal injury and ulcer formation.
Reduce risk by:
(1) Use COX-2 selective NSAID - will better maintain PGE2
(2) Replace lost PGE with PGE analogue such as Misoprostol
(3) Co-prescribe a PPI
What type of bacteria is H-pylori.
List 3 regions in the GI tract where it is most commonly found.
What percentage of people with gastric/duodenal ulcers have H-pylori?
Gram negative, spiral shaped bacillus
Found in:
Antrum
Cardia
Gastric-type mucosa of barretts esophagus
Gastric 80%
Duodenal 95%
What are the factors that permit colonisation with H.pylori? (SUM-ACE)
What is the toxin produced by h.pylori? What does it do to stomach lining?
(1) Spiral shape and flagellated
-> motile
(2) Urease activity
-> Can generate ammonium to buffer acid
-> Hydrogenase allows for it to use H2 produced in stomach as an energy source
-> Oxidase for neutralising ROS produced against it
(3) Micro-aerophilic
-> can survive in low O2 environments in mucosa
(4) Adhesins
-> attachment to epithelial cells
(5) Evasion of immune response
-> LPS somewhat resembles glycans of normal cells
-> mucosal layer more immunologically priviledged.
Toxin produced is CAG-A
-> Triggers release of pro-inflammatory cytokines
-> Can precipitate ulceration/cancer development by dysregulating cell-signalling, proliferation, apoptosis, adhesions and polarity.
What is the triple therapy course for Hpylori eradication?
Clarithromycin 500mg every 12 hours
Amoxicillin 1g every 12 hours
PPI every 12 hours
for two weeks.
How does the breath test work for H.pylori?
List 3 other diagnostic tests
C-urea is given orally
Hydrolysed by urease
Labelled CO2 is expired and detected.
- Oesophago-gastro-duodenoscopy with biopsy (antral biopsy)
- Antibody serology tests
- Fecal antigen test
- Gram culture + Staining (warthin-silver)
List 5 factors for peptic ulcer
- NSAIDS
- H-pylori
- First degree relative with PUD
- Smoking
- Alcohol
- Zollinger-ellison disease (gastrinoma)
To what dermatomes will stomach pain be referred?
T5-T9 dermatomes
Visceral afferents travel back within sympathetic fibres and synapse on second-order neurons of T5-T9 dermatomes
What artery is most at risk by erosion of a duodenal ulcer? From what artery is it branching from?
Gastro-duodenal from the common hepatic artery
Define barrett’s oesophagus and outline what epithelial change is seen.
Barrett’s oesophagus is a metaplastic change in the distal oesophagus due to prolonged exposure to gastric acid. It is visible of endoscopy and confirmed as intestinal-type columnar epithelium on biopsy.
Non-keratinized stratified squamous -> non-cilliated columnar with goblet cells.
How is barrett’s oesophagus subclassified? What percentage of those with GORD will develop barrett’s?
Subclassified based on the distance the metaplasia extends beyond the squamo-columnar junction (Z line)
(1) Short segment
<3 cm beyond Z
0.07 % chance of malignant progression
(2) Long segment
>3cm beyond
0.25% chance of malignant progression
10% GORD -> Barretts
What does Atypia mean? List 3 things that can cause it
Atypia refers to cells that are abnormal in terms of colour, shape, size when compared to normal healthy cells in the same location.
Causes:
(1) Infection
(2) inflammation
(3) Radiation
(4) Pre-cancerous diseases.
What 2 types of cancers can arise in esophagus? Which one is most common overall and which one is assoc with barretts? What part of esophagus are they most commonly found?
Adenocarcinoma - barretts - distal third
Squamous cell carcinoma - most common - prox 2/3rd.
Define dysplasia
Dysplasia refers to the abnormal growth and proliferation of cells in response to a stimulus. It is considered non-neoplastic and can regress once stimulus is removed. However, it can progress to neoplasia.
Outcomes:
Regression
Persistance
Progression to neoplasia
Briefly describe the pattern of motility that moves food through the oesophagus.
- Primary peristalsis moves food through the esophagus. It involves co-ordinated contraction of circular and longitudinal layers of the muscularis region.
- Stretching of pharynx increases the afferent activity from the myenteric plexus. This results in contraction of the proximal esophagus through increased firing of efferent motor innervatiton -> Ach and substance P.
- Relaxation distal to the bolus is achieved through reduced motor activity, increased nitric oxide and increased VIP.
- Receptive relaxation of the lower esophageal sphincter and orad region of the somach is achieved through VIP from the vagus nerve.
