Pharmacological Basis for Treatment of GI Disorders I Flashcards
Gastrointestinal Tract
why is gastric acid secretion significant?
gut motility for gut? intestine?
what can dysfunction of bile formation and excretion lead to?
There is hormonal control of the gut, this includes endocrine secretions which release substances into the GIT (peptides e.g. gastrin).
Paracrine secretions which are regulatory peptides released by cells in the GIT wall (e.g. histamine).
- Some of the paracrine secretions function also as neurotransmitters e.g. CCK.
There are areas of the GIT which are of pharmacological importance as if there is dysregulation of the way the gut functions (more specifically secretions) then this can cause harm.
So, one is gastric acid secretion, as 2.5L of gastric juice is secreted/day.
If acid is fluxed out by vomiting this can cause damage (such as ulcers if not cleared).
Gut motility is also very important, because stasis of the gut increases the likelihood of reflux and also reduces ability of clearance of acid from oesophagus. In intestine could result in constipation.
Another important component is bile formation and excretion, as if it is not functioning properly can lead to things like gallstones // malnutrition.
Regulation of acid secretion in the GIT
Stimuli that act on parietal cells include:
name the 4
what is gastrin? what secretes it? what 3 things does it stimulate? what controls its release? why is ca2+ containing salts bad to control acid secretion?
What is Ach? what does it act on?
what is histamine? what does it act on and what increases its release?
what does PGE2 and PGI2 do and important for increasing what?
Gastrin
A peptide hormone that is secreted by the gastric mucosa and duodenum, it stimulates gastric secretion, blood flow and gastric motility. There is evidence that the parietal cells express gastric receptors.
The release of gastrin is controlled by neurotransmitters and other mediators e.g. Milk and Ca2+ containing solutions stimulate gastrin release in the stomach. So, do not use Ca2+-containing salts to control acid secretion.
Ach
A neurotransmitter that stimulates muscarinic Ach receptors on parietal cells and on histamine containing cells (and G-cells)
Histamine
A local hormone that acts on H2 receptors on parietal cells and mast cells. Its release can be increased by gastrin // Ach
PGE2 and PGI2
Inhibit acid secretion, important in increasing mucus secretion, bicarb secretion and blood flow.
Effects of Metoclopramide on Gastric Motility and the Emptying
what does stasis lead to?
effect on dopamine on gut and where does it act on?
what does dopamine inhibit the release of? effect of this?
what is metoclopramide useful for and useless for?
what does metoclopramide stimulate? what does it inhibit in order to do this? what else does it stimulate and effect to increase ach release?
what effect will the increase ach have?
when else can metoclopramide be used?
Too much stasis of gastric juice -> Damage.
Dopamine has a direct relaxant effect on the gut by activating D2 receptors in the lower oesophageal sphincter and stomach (fundus and antrum).
Dopamine also inhibits the release of Ach = prevent contraction of gut smooth muscle.
- If you want to increase motility = stop dopamine’s effects.
Metoclopramide is useful for gastrointestinal reflux but is useless in paralytic ileus (can cause symptoms such as moderate, diffuse abdominal discomfort e.g. abdominal distension, nausea/vomiting especially after meals)
- Metoclopramide stimulates gastric motility and accelerates gastric emptying.
o Promotes gut motility by inhibition of presynaptic and postsynaptic D2 receptors, so it inhibits dopamine effects.
o It also stimulates 5-HT4 receptors and there is also antagonism of presynaptic inhibitory muscarinic receptors for Ach (-ve feedback), thus it means there will be increased Ach release.
The increased Ach will increase LOS and gastric tone and increase intragastric pressure, as well as improving antroduodenal coordination which accelerates gastric emptying.
Metoclopramide can also be used in other areas, it appears to be quite useful in nausea. It has also been shown to help reduce pain.
We can see an overview of the effects summarised here. In terms of its antiemetic effects it has an effect on the vomiting centre of the brain and area postrema.
Metoclopramide summary:
- Is a motility stimulant
- One of its major actions is as a 5-hydroxytryptamine-4 (5-HT4) receptor agonist
- It also stimulates the release of Ach from enteric neurones
- Other pharmacological may contribute such as dopamine receptor antagonism
Uses of metoclopramide include GORD // nausea due to surgery or cancer.
Antispasmodic Agents
name an example
effect of this?
which drug has antimuscarinic effects?
what can these agents be used to treat?
Examples include mebeverine
These reduce spasm in the bowel and have a relaxant action on the GIT (relax smooth muscle in the GIT).
Propantheline has antimuscarinic effects -> help relaxation
• Antispasmodic agents may be useful in irritable bowel syndrome and diverticular disease
Muscarinic receptor antagonists inhibit parasympathetic activity which reduces spasm in the bowel.
Pharmacological Management of Heartburn or Gastric/Peptic Ulcers
3 goals of pharmacological intervention
what does inhibition of acid secretion allow to happen?
what 3 conditions can be treated via drugs?
what is a big risk factor for uclers?
The goals of pharmacological intervention in gastric ulcer are three
- Reduce acid secretion with H2 receptor antagonists
- Neutralise secreted acid with antacids
- Attempt to eradicate H. pylori
Inhibition of acid secretion removes the constant irritation of the epithelium and allows the ulcer to heal.
Drugs can be used to inhibit or neutralise gastric acid secretion for the following conditions
o Peptic ulcer
o Reflux oesophagitis (gastric acid secretion can damage the oesophagus)
o Zollinger-Ellison syndrome (gastrin-producing tumour)
But we know that H. pylori is a big risk factor, causes chronic gastritis = duodenal ulcer
Heartburn: Antacids
what do antiacids do?
what can prolonged dosing do?
what are these less effective against?
what do antiacids form? effect of this?
what does bismuth chelate do? the different effects?
other effects which allow it to be a triple threat?
what are side effects?
The general mechanism of antacids is that they neutralise gastric acid. They increase the pH of gastric acid (peptic activity stops at pH 5).
Prolonged dosing can lead to healing of duodenal ulcers; however, they seem to be less effective for gastric ulcers.
The antacids form a raft on top of the acidic chyme also which reduces the amount of acidic chyme that refluxes into and damages the oesophagus.
Bismuth chelate protects the gastric mucosa, it forms a base over the crater of ulcer and also sticks to pepsin (adsorbs it) and stops it from working.
It also increases HCO3- and PG secretion and on top of this is toxic against H. pylori, so is used as part of a triple therapy to eradicate it.
o However, it does blacken the stool and tongue.
Pharmacological Management of Gastric Ulcers
what can we use to treat gastric ulcers?
examples?
what do they inhibit? what does this decrease and consequence of this?
what are H2-receptor antagonists clinically used for?
what is more potent, ranitidine or cimetidine? which has a lower IC50 value?
4 ways prostaglandins protect the stomach mucosa against damage
Why do NSAIDs (e.g. Aspirin) cause gastric bleeding?
We can use H2 receptor antagonists such as ranitidine, cimetidine, famotidine, nizatidine.
These work by inhibiting histamine, Ach and gastrin mediated acid secretion.
Because they reduce gastric acid secretion as a consequence they reduce pepsin secretion. Note also that they decrease basal and food-stimulated ulcers by 90%.
They promote healing of duodenal ulcers.
H2-receptor antagonists are used clinically for peptic ulcers // reflux oesophagitis. In clinical trials we’ve seen that they promote healing of duodenal ulcers but if you stop treatment you get a relapse.
If we compare Ranitidine and Cimetidine we’ll see that Ranitidine has a lower IC50, this means at a lower concentration it is able to produce 50% response. Hence, Ranitidine is more potent than Cimetidine.
Prostaglandins protect the stomach mucosa against damage by
• Increasing mucus secretion
• Increasing bicarbonate secretion
• Increasing blood flow (by vasodilating)
• Reduce H+ secretion (by antagonising acid release)
Why do NSAIDs (e.g. Aspirin) cause gastric bleeding?
- Because they inhibit PG synthesis (less protection) and Thromboxane A2 (involved in healing)
If we use selective COX-2 inhibitors these are more stomach friendly causing less bleeding e.g. Celecoxib, rofecoxib
H. Pylori and Mucosal Damage
Causes crater, exposing epithelium to HCl, pepsin and cytotoxins
Mucosal damage By bacterial mucinase, etc
Inflammation by gastric acid, proteases and effector molecules
Mucosal cell death by cytotoxins
Treatment of H. Pylori Infection
what is H. pylori a risk factor of? what does it cause?
why do we need combination therapy for H. pylori? name a drug
what is the effect of bismuth chelate? 4 effects?
what happens with bismuth chelate if patient has renal impairment?
unwanted side effects of bismuth chelate?
what to do woth side effects and what substance not to take? why?
what is disulfiram? consequences of this?
examples of proton pump inhibitors? clinical uses of this?
key feature of proton pump inhibitors?
H. pylori is implicated in gastric acid production, it is also a risk factor for gastric cancer.
We need to use a combination therapy against H. pylori (drugs that will inhibit acid secretion and KILL the bacteria) e.g.
- Omeprazole, amoxicillin, metronidazole
Some drugs protect the gastric mucosa e.g. bismuth chelate, these have cytoprotective effects
- The provide a physical coat over the surface/base of the ulcer
- They enhance local synthesis of PGs
- They promote bicarbonate secretion
- Bismuth chelate also has toxic effects on bacillus, it prevents adherence of H. pylori to the mucosa or inhibits its proteolytic activity, and does the other things spoken of previously e.g. adsorbs pepsin
Warning however, if a patient has renal impairment [bismuth chelate]blood may rise causing encephalopathy.
Unwanted effects of bismuth chelate include nausea, vomiting, blackening of the tongue and faeces
- We must advise the patient to adhere to treatment and also be aware that sometimes there is resistance to metronidazole.
- They also cannot drink alcohol if they take metronidazole as it results in disulfiram like reaction, the patient will feel severely ill and may stop taking the drug.
Disulfiram inhibits aldehyde dehydrogenase causing a build-up of acetaldehyde, resulting in unpleasant flushing and nausea.
Also, do not give in the first trimester as it will affect the foetus and cause birth defects
Drug Acting on the ‘Proton Pump’ (H+/K+ ATPase): These proton pump inhibitors can be used in the treatment of gastric ulcers
Examples include: Omeprazole, lanzoprazole, rabeprazole
Clinical uses include
- For peptic ulcers, reflux oesophagitis and as a component of therapy for H. pylori
- Can also be used in treatment of Zollinger- Ellison Syndrome
They are the drugs of choice especially if hyper-secretion occurs such as Zollinger- Ellision syndrome
Proton pump inhibitors because they are weak bases, which are inactive when neutral but when pH drops they irreversibly bind to the H+/K+ ATPase. So, it doesn’t matter what stimulation is occurring (Ach/gastrin/Histamine) it cannot actually kick out the H+.
This decreases basal and food-stimulated gastric acid release.
We know that it doesn’t really seem to matter whether we give a high or low dosage.
