Lecture 1 - Gastric acid secretion and its regulation. Drugs inhibiting gastric acid secretion Flashcards
2 GI tract hormonal innervation
- Endocrine secretions (bloodstream)
- Paracrine secretions (local)
- Endocrine secretions (bloodstream)
– Gastrin
– Cholecystokinin
* Synthesis in endocrine cells of mucosa
- Paracrine secretions (local)
– Histamine
– Acetylcholine
* Specialised cells
Give 5 elements of parietal cell
-Canalicular membrane
- canaliculus
- tubulovesicles
- basolateral membrane
- mitochondria
Describe Proton Pump action in the Canalicular
Membrane
H+/K+ ATPase
Cl- co-transporter
Release isotonic HCL
(pH <1)
Requires extrinsic
stimulation (hormones)
3 things that control acid secretion
- Gastrin
- Acetylcholine
- Histamine
what is the neurotransmitter released from vagal neurons which increases cytosolic Ca2+?
Acetylcholine
what is the peptide hormone which stimulates acid secretion, pepsinogen secretion, blood flow and ^ gastric motility and cytosolic Ca2+?
Gastrin
what is the hormone which increases cAMP and is a Sub-type specific action (H2 receptors) ?
Histamine
Diseases associated with acid
dysregulation?
- Dyspepsia (indigestion, upperabdom pain, bloat, sick)
- Peptic ulceration (prolonges excess acid sec. gastric and duodenal ulceration)
- Reflux oesophagitis (Damage to oesophagus by excess acid secretion)
- Zollinger-Ellison syndrome (Gastrin producing tumour)
How do we decrease secretions of gastric acid?
- Reducing proton pump function (pp inhib.)
- blocking histamine receptor function (H2 receptor antagonism)
- neutralising acid secretion w antacids
examples of PPI
Omeprazole
Lansoprazole
Irreversibly inhibit H+/K+ ATPase
describe the pharmacokinetics of PPI
- inactive at neutral pH
- weak bases- allows accumulation in acidic environment
- degrades rapidly at low pH (enteric coating)
- Single dosing 2-3 day acid secretion inhibition
where is PPI binding site ?
5, 6
What is the half life of Rabeprazole, omeprazole, lansoprazole and pantoprazole at pH=1.2
Rabeprazole 1.3
Omeprazole 2.8
Lansoprazole 2
Pantoprazole 4.6
What is the half life of Rabeprazole, omeprazole, lansoprazole and pantoprazole at pH=5.1
Rabeprazole 7.2
Omeprazole 84
Lansoprazole 90
Pantoprazole 282
What are the adverse effects PPIs (uncommon)
- headache
- diarrhoea
- rash
-Can mask the symptoms of gastric cancer!
– Care must be taken in high risk groups i.e.
Liver failure and pregnancy.
When are PPIs used?
- peptic ulcer
- reflux oesophagitis
- zollinger- Ellison
Exampls of Histamine H2 receptor antagonists
- cimetidine
- ranitidine
Where are Histamine H2 receptor antagonists used?
- peptic ulcer
- reflux oesophagitis
describe the pharmacokinetics of H2 receptor antagonists
- rapidly absorbes orally
- dosage varies with condition
- potent inhibitor of cytochrome P450’S
H2 receptor antagonists adverse effects (rare)
- diarrhoea
- dizzynes
- muscle pain
- Potent inhibitor of cytochrome P450’s –
reduces metabolism of anticoagulants and
tricyclic antidepressants.
what are antacids
Bases that raise gastric luminal pH by neutralising gastric acid
example of antacids
- sodium bicarbonate ,
- Mg2+/ Al 3+ hydroxide
when are antacids used
dyspepsia, oesophageal reflux
phacokinetics of antacids
- slow action
- effects often short lived
- acid rebound
adverse effects of Antacids
- diarroea, constipation , belching
- acid rebound
- alkalosis
-care with sodium content
Describe helicobacter pylori infections
- gram -ve bacillus
- peptide ulcur formation
- gastric cancer risk
- urea breath test - routine testing
peptic ulcer
formation
95% duodenal, 70% gastric
ulcers
how do you treat HPI
- treatment with comination triple therapy
- PPI , antibacterials and cytoprotective agent
what do cytoprotective agents do?
Enhance mucosal protection mechanisms or form
barriers over ulcer formations.
examples of cytoproective agents
- bismuth chelate
- sucralfate
- misopostol
what is bismuth chelate
- toxic to bacillus
- coats ulcer base , ^ prostaglandin and bicarbonate synthesis
what is sulcralfate
- stimulates mucus production and prevents degration
- ^ prostaglandin and biacarbonate synthesis
what is misoprostol
- prostaglandin analogue
- direct action on parietal cells (acid secretion)
what do NSAIDs do
- inhibit prostaglandin formation
- cause gastric bleeds , errosion > ulcer formation
- specific COX 2 inhibitiors cause less GI damage
what are prostaglandins
- synthesised by gastric mucosa
- increased mucus and bicarb secretion
- decreased acid sec
what acts upon arachidonic acid to produce leukotriens
lipoxygenase (LOX)
what acts upon arachidonic acid to produce postacyclin and thromboxanes
COX (cyclo-oxygenase)
what releases arachidonic acid from pospholipids in cell membrane?
phospholipase A2
what acts upon phospholipase A2 to incue lipocortin (protein inhibitor of Phopholipase A2)
Glucocorticosteroids
