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
complications of GORD?
Barret’s oesophagus, oesophageal adenocarcinoma
scarring, causing a stricture- would cause dysphagia
how are peptic ulcers treated?
STOP NSAIDs
H2RA/PPI for 6 wks
H pylori eradication therapy= 1 wk of clarithromycin, + metronidazole or amoxicillin, and PPI- this is continued following wk of antibiotics.
what 3 aspects are there to gut motility control?
myogenic
neural
hormonal
which cells act as pacemakers to mediate movement throughout the gut tube?
interstitial cells of Cajal
where are interstitial cells of Cajal found?
stomach= cardia
duodenum
ileum
colon
what is myogenic control of gut motility?
Rhythmic contraction – slow waves of depolarisation throughout the smooth muscle, so passive current spread through gap junctions.
Pacemaker cells generate APs= interstitial cells of Cajal, drive electrical activity.
what name is given to the movement digested material enabled by interstitial cells of Cajal in the small intestine?
segmentation
intestinal gradient produced as APs produced more frequently at stomach end than at distal end.
what does contraction of circular smooth muscle in large intestine allow?
haustral shuttling= contents propelled slowly to sigmoid colon
via neural control, how is the force of contraction of gut increased?
stimulation of post-ganglionic cholinergic enteric nerves
what reflexes occur in the gut in terms of gut motility?
Intestino-intestinal inhibitory reflex= distension of one intestinal segment causes complete intestinal inhibition
Anointestinal inhibitory reflex= distension of the anus causes intestinal inhibition
Gastrocolic & Duodenocolic reflexes= stimulates motility after material has entered the stomach or duodenum, producing urge to defecate after eating.
NTs involved in gut motility?
Gastrin promotes acid secretion, G cells Secretin - duodenum, S cells Cholecyskinin - small intestine, I cells Motilin - small intestine Paracrine tranmitters – histamine, somatostatin and prostaglandins
describe the physiological process of emesis
The pyloric sphincter closes while the cardia and oesophagus relax.
Gastric contents propelled by contraction of abdominal wall and diaphragm.
Glottis closes with elevation of the soft palate preventing entry of vomitus into the trachea and nasopharynx
causes of vomiting?
drugs pregnancy- prevent toxins harming baby raised IC pressure pain rotational movement inflammation
preliminary signs to vomiting?
nausea sweating retching dilated pupils paleness increased salivation
NTs in vestibular apparatus involved in vomiting?
ACh
histamine (H1)
NT in 4th ventricle involved in vomiting?
dopamine
NTs in medullary centre in volved in vomiting?
centre acted upon by vestibular apparatus and 4th ventricle
ACh
histamine (H1)
5-HT
examples of D2 antagonsits used in anti-emesis?
domperidone
metoclopramide
where does domperidone act?
Postrema on the floor of the 4th ventricle
Stomach: increase rate of gastric emptying
why can domperidone be given to Parkinson’s disease ptnts to control ADR of vomiting of L-DOPA?
it doesn’t cross BB barrier, so doesn’t have EP effects which would cause worsening of parkinson’s symptoms.
why should metoclopramide NOT be given to Parkinson’s ptnts as an anti-emetic?
crosses BB barrier so can cause dystonia.
indication for domperidone?
acute nausea/ vomiting (esp. induced by Ldopa e.g. co-careldopa, or dopamine agonists e.g. ropinerole)
Route – Oral or PR (extensive 1st pass metabolism)
ADR of domperidone?
galactorrhoea as increases prolactin release (loss of inhibition by dopamine on anterior pituitary)
dystonia rare
dry mouth
how does 5-HT mediate vomiting?
vagal stimulation
*vagus nerve produces gag reflex
where is ondansetron, a 5-HT antagonist, effective?
Postrema on the floor of the 4th ventricle
Against vagal afferent nerves in GI
indication for ondansetron?
in high doses in radiation sickness and chemoRx / post-operative
route for ondansetron?
IV, IM or orally (dose dependent on indication)
how can the anti-emetic effect of ondansteron, a 5-HT antagonist, be enhanced?
single dose of a corticosteroid
ADRs of ondansetron?
headache
flushing (IV)
constipation
MOA of metoclopramide?
D2 antagonism (4th ventricle and gastric emptying), and Anti-cholinergic effects (GI), and blocks vagal afferent 5-HT3 R (GI)
indication for metoclopramide?
GI cause for N&V; Migraine; Post-op
given oral, or IM or IV acutely
t1/2 of metoclopramide?
4hrs
ADRs of metoclorpamide?
Extra-pyramidal reactions (dystonia) occur in
1% - therefore avoid in Parkinson’s disease, as can cross BB barrier
galactorrhoea
what is hyoscine?
ACh antagonist= direct antagonist of muscarinic cholinergic receptors
Used to treat motion sickness – oral- 30 minutes before and then 6hourly or patch
Effects usually short-lived (2 hours)
ADRs – systemic anti-cholingeric effects e.g. dry mouth, urinary retention, constipation;
bradycardia (low dose / transient)
Reports of tolerance to transdermal hyoscine
what is cyclizine?
H1 antagonist Has additional anti-muscarinic effects Used in acute nausea and vomiting Can be given oral, IV or IM Crosses the blood-brain barrier – sedative effect
non-pharm management of constipation?
Increase fluid intake
High fibre diet
Exercise
examples of drugs that can cause constipation?
opioids anti-cholinergics e.g. atropine, hyoscine verapamil SSRIs carbamazepine
MOA of bulk laxatives used in constipation?
distend the gut, which causes contraction and then perstalsis
describe bulk laxatives?
Vegetable fibre – resistant to digestive enzymes.
Take a few days to work
Attempt to re-establish normal bowel habit (chronic or
simple constipation related to IBS, pregnancy etc)
Normal fluid intake essential
ADR: flatulence
CI: adhesions / ulceration – may cause intestinal
obstruction
Ideally patients should increase fibre in their diet!
when might faecal softeners be used for constipation?
in IBS or preganancy as with bulk laxatives, but also in adhesions e.g. as occurs with Crohn’s disease, as no risk of obstruction, and in anal fissures / haemorrhoids
e.g. Arachis oil (enema) and glycerol (supp.) act by lubricating and softening stool
But not always effective
describe use of Mg and Na salts in constipation
= osmotically active laxatives
cause water retention in small / large bowel to
increase peristalsis
Act quickly and are severe
Usually PR
Would reserve for ‘resistant’ constipation and
if urgent relief required
describe the use of lactulose in constipation
osmotically active laxative
Lactulose –disaccharide (galactose / fructose)
Cannot be hydrolyzed by digestive enzymes
Fermentation of lactulose by colon bacteria
leads to acetic and lactic acid (osmotic
effect)
Oral
Takes 48 hours to work
Thus used in liver failure – reduced production of ammonia.
why can lactulose be used in tment of hyperammoniaemia in decompensated liver failure, that can produce encephalopathy?
fermenting by colon bacteria to acetic and lactic acid, which then converts NH3 to NH4+ which is unable to diffuse back into blood
why can movicol, an osmotically active laxative, prevent dehydration?
given as a powder, hence orally with fluid
Initial effects within hours
Takes 2-4 days to get full relief
Like all osmotic laxatives – caution required to
prevent intestinal obstruction
MOA of irritant/stimulant laxatives?
Excitation of sensory nerve endings leads to
water and electrolyte retention and thus
peristalsis
Used for rapid treatment – e.g. faecal impaction or surgical prep. Can act 6-8 hours (orally) so bedtime Rx Repeated use: • Colonic atony (and thus constipation) • Hypokalaemia
senna is an anthraquinone= type of irritant/stimulant laxative used in constipation. what might happen if overused?
melanosis coli= black spots in colon
describe the constipation-hypokalaemia feeback
constipation treated with laxatives, which increase Na+ and H20 loss from gut, stimulating RAAS- aldosterone release- promotes K+ loss, so enteral and renal loss of K+, causing hypokalaemia, which reduces movements in colon so moves more slowly, producing constipation.
3 key types of drugs for diarrhoea?
anti-motility
bulk forming- fluid absorbents
fluid adsorbents
examples of anti-motility drugs for dirrhoea?
loperamide=opiate analogue= more potent than morphine, and penetrates CNS more slowly
opioids e.g. codeine
good for chronic diarrhoea
what effects do loperamide and codeine have in bowel?
Bind to opioid receptors= GPCRs
Reduce bowel motility – increase time for fluid to
reabsorb
Increase anal tone and reduce sensory defecation
reflex
type of anti-diarrhoeal part useful in ptnts with IBS?
bulk forming
=a relatively small amount of faecal fluid
(10-20 ml) influences composition
Drugs such as ispaghula act via water
absorption
Particularly useful for patients with IBS
(constipation and diarrhoea) and those with an ileostomy
when might cholestyramine be used as an anti-diarrhoeal?
bile salt induced diarrhoea (Crohn’s / post-vagotomy)
other than bulk forming agents, what drugs can be given in IBS?
anti-spasmodics e.g. mebeverine
It relieves spasm of intestinal muscle.
It does not have troublesome systemic antimuscarinic
side effects.
Useful when combined with bulk forming agent
