Pharmacological basis of treatment of the GI disorders Flashcards
What are the areas of pharmacological importance in treating GI tract disorders?
Gastric acid secretion → 2.5L of gastric juice secreted/day
Vomiting
Gut motility
Bile formation & excretion
What is the main clinical use of H2 receptor agonists?
Give some examples of H2 receptor agonists
Peptic ulcer Reflex oesophagitis
ranitidine, cimetidine, famotidine, nizartidine
Describe the mechanism of action of H2 receptor agonists
What are the consequences?
Inhibit histamine-, ACh- and gastrin-stimulated acid secretion on parietal cells
Reduce gastric acid secretion and as a consequence reduce pepsin secretion – do you know how it does that?
Can decrease basal and food-stimulated acid secretion by 90%. Does food stimulate acid secretion – what is the mechanism?
Promote the healing of duodenal ulcers
But if you stop treatment, you get relapse
What are the unwanted effects of H2 receptor agonists?
Generally rare but there may be diarrhoea, muscle cramps, transient rashes, hypergastrinaemia
Cimetidine → gynecomastia in men (↓ sexual function, but this is rare)
Cimetidine also inhibits P450 enzymes → ↓ metabolism of a number of drugs metabolised by P450 enzymes, e.g. anticoagulants, tricyclic antidepressants (e.g. imipramine, dosulepin, amytriptyline, etc.)
Which is more effective: ranitidine and cimetidine on inhibition of acid secretion?
Ranitidine
Give some examples of anti-secretory agents: proton pump inhibitors in the treatment of gastric ulcers
Examples: omeprazole, lanzoprazole, pantoprazole, rabeprazole
What are the clinical uses of proton pump inhibitors?
Clinical uses of proton pump inhibitors
- Peptic ulcer, reflux oesophagitis; as a component of therapy for H. pylori
- Can also be used in the treatment of Zollinger-Ellison syndrome
- Drugs of choice, especially if hyper-secretion occurs, e.g. Zollinger-Ellison syndrome
Describe the mechanism of action of Proton pump inhibitors in the treatment of gastric ulcers
What are the adverse side effects (unwanted effects)?
Mechanism of action of proton pump inhibitors
- Weak bases; inactive at neutral pH and irreversibly inhibit the H+/K+-ATPase pump
- Decreases basal and food-stimulated gastric acid secretion
Headache, diarrhoea, mental confusion, rashes, somnolence, impotence, gynaecomastia; dizziness
What drugs protect the gastric mucosa?
Prostaglandins (PGE2 and PGI2) are gastroprotective
How are prostaglandins (PGE2 and PGI2) gastroprotective?
Using Misoprostol as an example
Misoprostol (a stable analogue of PGE1)
Mode of action of misoprostol
- Inhibits basal- and food-stimulated gastric acid secretion
- Inhibits histamine-, and caffeine-induced gastric acid secretion
- Inhibits the activity of parietal cells
- Increases mucosal blood flow and can augment the secretion of HCO3- and mucus
Describe the effects of metoclopramide on gastric motility and emptying
- Metoclopromide inhibits pre- and post-synaptic dopamine (D2) receptors as well as 5-HT3 receptors (CNS) – inhibits vomiting
- Stimulates 5-HT4 (ENS) - prokinetic
What effect does dopamine (metoclopramide) have on gastric motility and emptying?
- Dopamine inhibits the release of ACh
- Dopamine inhibits the release of ACh from intrinsic myenteric cholinergic neurons by activating prejunctional D2 receptors
- Dopamine has relaxant effects on the gut by activating D2 receptors in the lower oesophageal sphincter and stomach (fundus and antrum)
Dopamine acts on different dopamine receptors
- Overall, dopamine has mixed effects on the gut – may induce contraction in the proximal, but relaxation in the distal small intestine
Describe the effects of inhibition of dopamine at D2 receptors
- ↑ release of ACh (↑ peristalsis of duodenum, jejunum and ileum)
- ↑ ACh →↑intragastric pressure (due ↑ LOS tone and ↑ tone of gastric contractions)
- These improve antroduodenal coordination which accelerates gastric emptying; relaxes pyloric sphincter
Through additional prokinetic effects…
It stimulates presynaptic excitatory 5-HT receptors and inhibitory nitregeric neurons → coordinated gastric motility
What are the overall effects of Metoclopramide?
- Useful for gastrointestinal reflux [but useless in paralytic ileus (as it causes moderate to diffuse abdominal discomfort e.g. → abdominal distension, nausea/vomiting especially after meals, lack of bowel movement/flatulence]
- Stimulates gastric motility
- Accelerates gastric emptying
Describe the clinical utility of metoclopromide
Symptoms of gastroparesis
Promotes gastric emptying
Anti-emetic effects via central pathways
GORD; nausea due to surgery or cancer
Have a read of the summary of the effects of metoclopramide
Metoclopromide promotes gut motility by the following mechanisms:
- Inhibits presynaptic and postsynaptic D2 receptors,
- Stimulates the release of ACh / SP from enteric neurons
- Elicits mixed 5-HT agonist and antagonist effects, e.g., stimulates excitatory 5-HT4 receptors (ENS), but inhibits 5-HT3 receptors (CNS);
- Stimulates inhibitory nitregic neurons – mediate NO release
- Increases intragastric pressure -↑ LOS and gastric tones
- Motility stimulant - improves antro-duodenal coordination and accelerated gastric emptying
GORD; nausea due to surgery or cancer; symptoms of gastroparesis
- There is some evidence that metoclopramide leads to increased gastric emptying by enhancing antral contractions as well as decreasing postprandial fundus relaxation
- However, its prokinetic effects may be limited to the proximal gut
Give some examples of Antispasmodic agents
Examples: propantheline, dicloxerine (dicyclomine), mebeverine
What do Antispasmodic agents do?
What do they treat?
What type of agonists are they, what nervous system do they inhibit?
What does this cause?
- ↓ spasm in bowel. They have relaxant action on GIT (relax smooth muscle in GIT)
May be useful in irritable bowel syndrome and diverticular disease – a congenital lesion, may be a source of bacterial overgrowth.
Muscarinic receptor antagonists: inhibit parasympathetic activity. This reduces spasm in the bowel
What are the goals of pharmacological intervention in gastric ulcer?
Reduce acid secretion with H2 receptor antagonists
Neutralise secreted acid with antacids
Attempt to eradicate H. pylori
How is the removal of acid beneficial to ulcers?
Removes the constant irritation and allows the ulcer to heal
Drugs can be used to inhibit or neutralise gastric acid secretion for the following conditions:
What do these drugs treat?
Peptic ulcer
Reflux oesophagitis: gastric acid secretion can damage oesophagus
Zollinger-Ellison syndrome: gastrin-producing tumour
But H. pylori infection is a risk factor, to do with gastric ulcers
Why is this?
H. pylori: a Gram negative bacillus→ chronic gastritis → duodenal ulcer
Describe the general mechanism of action of antacids
What effect does this have on gastric ulcers?
- Neutralise gastric acid
- ↑ the pH of gastric acid (peptic activity stops at pH 5)
- Prolonged dosing can lead to healing of duodenal ulcers; less effective for gastric ulcers.
What does Bismuth chelate (an antacid) do?
What effect does it have on H. pylori?
What are the side effects?
- Protects gastric mucosa
- Forms a base over crater of the ulcer
- Adsorbs pepsin
- ↑ HCO3- and PG secretion
Toxic against H. pylori – used as part of triple therapy to eradicate it
Blackens stool and tongue
How do prostaglandins protect the stomach mucus from damage?
- Stimulating bicarbonate secretion
- Reducing H+ secretion
- Promoting vasodilation
PGs protect the stomach against damage
Why do NSAIDS (e.g. aspirin) cause gastric bleeding?
Q: Why do NSAIDS (e.g. aspirin) cause gastric bleeding?
A: Inhibit PG synthesis
What are the cytoprotective effects of drugs that protect the gastric mucosa? e.g bismuth chelate
Provide a physical barrier (coat) over the surface/base of the ulcer
Enhances local synthesis of PGs
Promote bicarbonate secretion
Bismuth chelate has toxic effects on the bacillus: it
prevents the adherence of H. pylori to the mucosa or inhibit its proteolytic activity; stimulates bicarbonate secretion; ↑ PG synthesis; adsorbs pepsin
What are the consequences of constipation as a result of rectal distension?
Why is holding faecal matter bad?
Headache
Loss of appetite
Nausea
Abdominal distension and stomach pain
Holding of faecal matter → ↑ water loss and dryer faeces (*painful and harder to defecate)
What are the causes of constipation?
↓ motility of the large intestine
Old age
Damage to the enteric nervous system of colon
What are the factors that can increase colonic motility (↑ distension of large intestine) and improve symptoms of constipation?
- ↑ fibre, cellulose and complex polysaccharides
- Bran, some fruits and vegetables with high fibre
- Laxatives, but excessive use → ↓ responsiveness
- Mineral oil – lubricates faeces
- Castor oil – stimulates motility of colon
What are the causes of constipation (elderly):
Diet
Inactivity
Drugs (polypharmacy)
What are the alarm signs and symptoms of patients with chronic constipation?
- Acute onset constipation in older individuals
- Weight loss (10lb)
- Blood in the stool
- Anaemia
- Family history of colon cancer or inflammatory bowel disease
How can we manage constipation?
Lifestyle changes
Diet, fluid intake and exercise and their effects on constipation (appealing?)
↑ fibre intake → bloating and flatulence (not appealing)
↑ water intake??
What are purgatives?
Purgatives: laxatives, faecal softeners & stimulant purgatives can modulate/hasten food transit in the intestine
Bulk-forming and osmotic laxatives
Bulk laxatives: methylcellulose,
Plant gums (e.g. sterculia, agar, linseed, bran, ispaghula husk- are polysaccharide polymers)
They retain water in gut lumen → promotion of peristalsis, but take a few days to work
Increase the stool’s solid content
Bloating and flatulence
What do Osmotic laxatives: lactulose do?
↑s and maintains volume of fluid in the lumen of bowel by osmosis
↑s transfer of gut contents into the intestine
Increases volume of gut content entering the colon → distension and purgation in 1hr
High doses → flatulence, cramps, diarrhoea, vomiting and tolerance
Describe the Mode of action of lactulose
On image
What do antidiarrhoeal agents do?
- Maintain body fluids and electrolytes
- Identify causal organism and if possible treat with antibiotics e.g. erythromycin for Campylobacter jejuni
- Modify secretion/ absorption balance
What are the effects of diarrhoea
Rough -> discomfort -> medical emergancy -> (liquid therapy)
Describe Acute diarrhoeal diseases
Diarrhoea → ↑ motility of GIT, with ↑ secretion and ↓ absorption of fluid → ↓ electrolyte (Na+) and H2O
Cholera toxins → loss of gut contents
Describe the therapeutic strategies for diarrhoea treatment
Maintain fluid and electrolyte balance: Oral rehydration therapy
•Use of anti-infectives: Bacterial infections may resolve with time
»Campylobacter sp: cause of gastroenteritis in the UK
»Use erythromycin or ciprofloxacin in severe infections
•If viral in nature, may not need to use anti-infectives
•Use of non-microbial anti-diarrhoeal agents
•Use of anti-motility drugs: adsorbents and agents that modify fluid and electrolyte transport
What can the movement of substances in the gut be modulated by?
• Purgatives: ↑ passage of food through the intestine
Describe agents that ↑ motility without → purgation:
Antidiarrhoeal drugs → ↓ movement
Antispasmodic drugs → ↓ movement; relax smooth muscles in GIT
Describe the treatments for Traveller’s diarrhoea
Loperamide:Selective on GIT, decreases passage of faeces;
•Decreases duration of illness
Codeine & loperamide: Anti-secretory action;
•↓ intestinal motility
Describe the mechanism of action of loperamide
An opioid receptor agonist
•Exerts effects on the -opioid receptor of the myenteric plexus* of the large intestine
- A spasmolytic agent which reduces smooth muscle activity in the GIT and thus reduces the passage of faeces
- Reduces force and speed of colonic movement
- Increases haustral mixing of the proximal colon
- Inhibits propulsive mass movement of the distal colon
- Does not cross the blood brain barrier, no CNS effects
- *Controls motility and secretion of GIT
- Stimulation of the -opioid receptor by loperamide inhibits gastric emptying, increases sphincter tone, induces stationary motor patterns and blocks peristalsis
