Pharmacology 13: Drugs affecting acid secretion and gut motility Flashcards
what is raised intracellularly in parietal cells following gastrin and ACh binding in order for acid secretion?
Ca2+ concentration
how does histamine exert an effect on parietal cell acid secretion?
it activates adenylate cyclase, increasing cAMP.
physiologic substances capable of reducing acid secretion?
somatostatin gastric inhibitory peptide secretin glucagons PGE2
type of histamine receptor on parietal cells?
H2
4 primary H2 antagonist drugs?
cimetidine= CYP450 inhibitor
ranitidine
famotidine
nizatidine
examples of proton pump inhibitors which non-competitively bind and inactivate the ATPase?
omeprazole
lansoprazole
rabeprazole
esomeprazole
tests to confirm H pylori infection?
urease breath test
stool antigen test
blood test for H pylori antibodies
do proton pumps normally reside on the canalicular membrane in parietal cells?
NO
H+ pump as well as K+ and Cl- channels initially reside on intracellular membranes, and are transported and fused into canalicular membrane just prior to acid secretion.
where does H+ come from within parietal cells?
dissociation of H20- produces H+ and OH-, OH- combines with CO2 to form HCO3- which is moved out across BL membrane into the blood in exchange for Cl-= alkaline tide= slight elevation in blood pH, catalysed by carbonic anhydrase.
ion channels present on canalicular membrane of parietal cell just before acid secretion?
H+/K+ ATPase
Cl- channels
K+ channels
due to actions of gastrin and ACh through histamine, what is histamine known as?
the amplifier of action
defensive factors of gastric mucosa?
vascular supply- * affected by NSAIDs which cause vasoconstriction of submucosal arterioles.
mucous membrane barrier- constant HCO3- secretion
tight epithelium
deep crypts with stem cells for regeneration and restitution
aggressive factors of gastric mucosa?
acid
H pylori
drugs
receptors on the BL membrane of parietal cells (oxyntic cells) which mediate acid secretion?
H2-histamine
M3-ACh
CCK-B- gastrin
where specifically do PPIs bind to exert their action?
covalently to cysteines on the ATPase forming the H+/K+ ATPase transporter
why is the onset of action of PPIs delayed?
not all of the H+ pumps are active all of the time
why should loperamide NOT be given for diarrhoea occurring in ulcerative colitis?
can result in toxic megacolon (dilatation >6cm).
when is the efficacy of PPIs maximal?
after 2-3 days
why must H2 antagonsits be taken at least twice daily?
short t1/2
how often must alginates be taken?
4 or 5 times a day
ADRs of cimetidine?
gynaecomastia in males diarrhoea as altered pH in GI tract headache dizziness skin rashes myalgia
DDIs of cimetidine?
drugs metabolised by CYP450 system e.g. warfarin, as CYP450 inhibitor- so can reduce metabolism of warfarin, increasing INR and risk of bleeding.
when should PPIs be taken during the day?
around 30 mins before eating. Must eat food afterwards in order for PPI to be active as PPI= acid-activated pro-drug.
why is acid secretion not restored straight away on stopping PPIs?
must wait for de novo synthesis of H+/K+ ATPase pumps
what pathologies is H pylori implicated in?
gastric ulcers
dudoenal ulcers
gastric cancer- so eradication with triple therapy is VERY important.
gastritis
what is the pathogenesis of H pylori?
secretes lipopolysaccarides= can contribute to inflammation of the mucosa, and damage to protective mucosal barrier of mucus, so lining exposed to acid, which along with inflammation causes ulcers to form.
examples of antacids?
gaviscon
rennie
how do antacids work?
= buffer solutions, neutralise the acid, but pain returns when more acid produced
how do alginates work?
form a protective lining, forming a protective barrier over ulcers, and protects the gastric mucosa
example of alginate?
sodium alginate
ADRs of PPIs?
nausea diarrhoea constipation raised liver enzymes headache dizziness maybe C.difficile colitis as reducing gastric acidity
2 tment principles for GORD?
symptom control
healing of oesophagitis
aspects of symptom control tment in GORD?
step up= lifestyle e.g. stop smoking, drink less alcohol, weight loss- reduces pressure on gastric lumen, lift head of bed at night.
Antacids? Alginates
H2 RA
PPI
step down opp way, in hosp setting
5 physiological mechanisms which prevent reflux?
lower oesophageal sphincter
mucosal folds at OG junction which create a valve like effect
acute angle of entry of oesophagus into stomach which creates a valve like effect
R crus of diaphragm which acts as a pinch cock
+ve intra-abdom pressure which compresses walls of oesophagus together
what would be the next step if tried all tments for GORD, and PPI isn’t effective?
endoscope