Pharmacological Basis for Treatment of GI Disorders

Question 1

What are H2 receptor antagonists?

Answer 1

Anti-secretory agents: H2 receptor antagonists
H2 receptor antagonists (ranitidine, cimetidine, famotidine, nizatidine)
Clinical uses H2 receptor antagonists:
Peptic ulcer or reflex oesophagitis
Mechanism of action of H2 receptor antagonists
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? (hyperacidity converts pepsinogen to pepsin)
Inhibit histamine, Ach and gastrin stimulated acid secretion
Can decrease basal and food-stimulated acid secretion by 90%
Promote the healing of duodenal ulcers
But if treatment stops relapse occurs

Question 2

What did H2 receptor antagonists clinical trials show?

Answer 2

Clinical trials on H2 receptor antagonists:
Promote the healing of duodenal ulcers
But if you stop treatment, you get relapse
Unwanted effects of H2 receptor antagonists:
Generally rare but there may be diarrhoea, muscle cramps, transient rashes, hypergastrinemia
Cimetidine -> gynaecomastia 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 and amitriptyline)

Question 3

What are the effects of ranitidine and cimetidine on inhibition of acid secretion?

Answer 3

Which of the 2 drugs is more active?
Ranitidine is more potent than cimetidine:
IC50 for ranitidine= 0.07mcg/ml
IC50 for cimetidine= 0.44mcg/ml
The lower the IC50, the more active the drug

Question 4

How do proton pump inhibitors help in the treatment of gastric ulcers?

Answer 4

Examples: omeprazole, lansoprazole, pantoprazole, rabeprazole
Clinical uses of proton pump inhibitor:
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 hypersecretion of acid occurs e.g. Zollinger-Ellison syndrome
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
Unwanted effects:
Headache, diarrhoea, mental confusion, rashes, somnolence, impotence, gynecomastia; dizziness

Question 5

Which drugs protect the gastric mucosa?

Answer 5

Prostaglandins (PGE2 and PGI2) are gastroprotective
How are they gastroprotective?
They promote mucus secretion
They secrete bicarbonate
Promote blood flow
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
Caution:
Induces labour/abortion

Question 6

What are the effects of metoclopramide on gastric motility and emptying?

Answer 6

Metoclopramide has mixed effects; inhibits pre-and post-synaptic dopamine (D2) receptors as well as 5-HT3 receptors (CNS)- inhibits vomiting
Stimulates 5_HT4 (ENS)- prokinetic
Dopamine inhibits the release of Ach- dopamine inhibits the release of Ach from intrinsic myenteric cholinergic neurons by activating pre-synaptic 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

Question 7

How does metoclopramide promote gastric motility and emptying?

Answer 7

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 nitrergic neurons → coordinated gastric motility

Question 8

What is metoclopramide useful for?

Answer 8

Gastrointestinal reflux 
Simulates gastric motility
Accelerates gastric emptying
Clinical utility of metoclopramide 
Clinical utility of metoclopramide:
Symptoms of gastroparesis
Promotes gastric emptying 
Ani-emetic effects via central pathways

GORD; nausea due to surgery or cancer

Question 9

What are antispasmodic agents?

Answer 9

Examples: propantheline, dicloxerine (dicyclomine), mebeverine
↓ spasm in bowel. They have relaxant action on GIT (relax smooth muscle in GIT)
Propantheline = antimuscarinic agent
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 the spasm in the bowel

Question 10

How are ulcers pharmacologically managed?

Answer 10

Goal of pharmacological intervention in gastric ulcer are:
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 and allows the ulcer to heal
Drugs can be used to inhibit or neutralise gastric acid secretion for the following conditions:
Peptic ulcer
Reflux oesophagitis; gastric acid secretion can damage oesophagus
Zollinger-Ellison syndrome; gastrin-producing tumour
It is unclear why gastric ulcers develop
But H. pylori infection is a risk factor
H.pylori; a gram negative bacillus-> chronic gastritis-> duodenal ulcer

Question 11

How is heartburn pharmacologically managed?

Answer 11

General mechanism of action of antacids
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
Antacids with cytoprotective effects:
Bismuth chelate (Pepto-Bismol):
Protects gastric mucosa:
Forms a base over crater of the ulcer
Absorbs pepsin
↑ HCO3- and PG secretion
Toxic against H. pylori used as part of triple therapy to eradicate it
Blackens stool and tongue
Suspected heart burn or GORD must be investigated

Question 12

How are gastric ulcers pharmacologically managed?

Answer 12

Prostaglandins (PGs) protects the epithelial cells of the stomach against damage by:
Stimulating the secretion of HCO3- which neutralise gastric acid
Reducing H+ secretion
Stimulating mucus production
Promoting vasodilation
PGs protect the stomach against damage
Q- Why do NSAIDs (e.g. aspirin) cause gastric bleeding?
A- Aspirin inhibits COX which inhibits the synthesis of PGs
Celecoxib, rofecoxib (selective COX-2 inhibitors) → less bleeding
AMI = Acute mesenteric ischemia (AMI); inadequate blood flow through the mesenteric vessels →gangrene of the bowel wall

Question 13

How is an H.pylori infection treated?

Answer 13

H. Pylori is implicated in gastric acid production; it is a risk factor for gastric cancer
Combination therapy:
Omeprazole, amoxicillin and metronidazole
Omeprazole, clarithromycin and amoxicillin or tetracycline, metronidazole and bismuth chelates
Lansoprazole, clarithromycin, tinidazole and bismuth chelates
Some drugs protect the gastric mucosa e.g. bismuth chelate (colloidal bismuth subcitrate, tripotassium dicitratobismuthate). These have cytoprotective effects
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
Unwanted effects of bismuth chelate: nausea, vomiting, blackening of tongue and faeces
Warning: If the patient has renal impairment, [bismuth chelate]plasma may rise causing encephalopathy
Do not exceed the recommended dose

Question 14

What is the patients advice that comes with the treatment of H. Pylori infection?

Answer 14

Adhere to treatment
Resistance to metronidazole
Disulfiram-like reaction results if metronidazole is taken with alcohol:
The patient will feel severely ill and may stop taking the drug
Disulfiram inhibits acetaldehyde dehydrogenase, build-up of acetaldehyde -> unpleasant flushing and nausea
Do not give metronidazole in the first trimester

Question 15

How do proton pump inhibitors in the treatment of gastric ulcers?

Answer 15

Mechanism of action
Weak bases; inactive at neutral pH and irreversibly inhibit the H+/K+-ATPase pump
Decreases basal and food-stimulated gastric acid secretion

Question 16

How does one investigate constipation?

Answer 16

Subjective complaint
Obstruction -> constipation; investigate
Is your frequency of bowel movement normal?
Normal bowel opening= 1-3x per day, but hugely varies between people
One does not have to be regular to be physiologically adequate/normal
No toxic substances accumulate upon prolonged constipation
Consequences of constipation as a result of rectal distension:
Headache
Loss of appetite
Nausea
Abdominal distension and stomach
Holding of faecal matter → ↑ water loss and dryer faeces are painful and harder to defecate

Question 17

What are the causes of constipation?

Answer 17

↓ motility of large intestine
Old age
Damage to enteric nervous system of colon (-may affect the initiation of vago-vagal reflex)
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

Question 18

What are the causes, alarm signs and management of constipation?

Answer 18

Causes of constipation (elderly):
Diet
Inactivity
Drugs (polypharmacy)
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
Management of constipation:
Lifestyle changes
Diet, fluid intake and exercise and their effects on constipation (appealing?)
↑ fibre intake → bloating and flatulence (not appealing)
↑ water intake??

Question 19

How do you treat constipation through purgatives?

Answer 19

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
Other effects: bloating and flatulence

Question 20

how do osmotic laxatives treat constipation?

Answer 20

Osmotic laxatives: lactulose
↑ and maintains volume of fluid in the lumen of bowel by osmosis
↑ 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

Question 21

What are the therapeutic strategies for diarrhoea treatment?

Answer 21

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
Traveller’s diarrhoea:
Gorbach, 1987: Travelling broadens the mind and loosens the bowel
About 3 million people travel abroad/year & most will develop diarrhoea during their travel
But some infections may be self-limiting
Loperamide: Selective on GIT, decreases the passage of faeces;
Decreases duration of illness
Codeine & loperamide: Anti-secretory action;
↓ intestinal motility
Bismuth subsalicylate: Decreases fluid secretion in bowel;
Safe for young children;
May cause tinnitus and blackening of stool

Question 22

What is the mechanism of action of loperamide?

Answer 22

An opioid receptor agonist
Binds to the μ-opioid receptor of the myenteric plexus* of the large intestine – inhibition of bowel function
*Controls motility and secretion of GIT
Stimulation of the μ-opioid receptor by loperamide inhibits gastric emptying, increases sphincter tone, induces stationary motor patterns and blocks peristalsis
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 by:
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