Pharmacological Basis for Treatment of GI Disorders

Question 1

List some areas of GIT importance.

Answer 1

• gastric acid secretion
• vomiting
• gut motility
• bile formation and excretion

Question 2

What are two types of anti-secretory agents?

Answer 2

H2 receptor antagonists and proton pump inhibitors.

Question 3

What are the clinical uses of H2 receptor antagonists?

Answer 3

They inhibit histamine-, ACh- and gastrin-stimulated acid secretion on parietal cells.
They reduce gastric acid secretion and, as a consequence, reduce pepsin secretion.

They promote the healing of duodenal ulcers.

Question 4

List some examples of H2 receptor antagonists.

Answer 4

• Ranitidine
• Cimetidine
• Famotidine
• Nizartidine

Question 5

What are some side effects of H2 receptor antagonists?

Answer 5

They’re generally rare, but there may be:

• diarrhoea
• muscle cramps
• transient rashes
• hypergastrinaemia

Cimetidine, in particular, can cause gynaecomastia (man-boobs) in men (also decreased sexual function, but this is rare).
Cimetidine also inhibits P450 enzymes, meaning it decreases the metabolism of a number of drugs broken down by P450 enzymes (eg. anticoagulants, tricyclic antidepressants)

Question 6

How do proton pump inhibitors work?

Answer 6

They are weak bases; they’re inactive at a neutral pH.
They irreversibly inhibit the H+/K+-ATPase pump. This means that there is less H+ in the cell to combine to make HCl.
Thus, it decreases basal and food-stimulated gastric acid secretion.

Question 7

List examples of proton pump inhibitors.

Answer 7

• Omeprazole
• Lanzoprazole
• Pantoprazole
• Rabeprazole

Question 8

What are the clinical uses of proton pump inhibitors?

Answer 8

They are used against:

• peptic ulcers
• reflux oesophagitis
• as a component of therapy against H. Pylori
• can also be used in the treatment of Zollinger-Ellison syndrome (overproduction of gastric acid)

Question 9

What are some side effects of proton pump inhibitors?

Answer 9

• headaches
• diarrhoea
• mental confusion
• rashes
• somnolence (strong desire to sleep)
• impotence
• gynaecomastia
• dizziness

Question 10

Prostaglandins are gastroprotective.

How do they work?

Answer 10

• increase mucous secretion
• stimulate bicarbonate secretion
• promotes vasodilation
• negatively regulates parietal cells, so reduces H+ secretion

Question 11

Why do NSAIDs (eg. aspirin) cause gastric bleeding?

Answer 11

They cause gastric bleeding because they inhibit prostaglandin synthesis (meaning there is less gastric protection) and Thromboxane A2 synthesis (which is involved in healing).

It would be better to use selective COX-2 inhibitors (such as celecoxib, rofecoxib) as they cause less bleeding.

Question 12

What effect does dopamine have on the gut?

Answer 12

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.

Thus, if you want to increase motility, you want to stop dopamine’s effects.

Question 13

By which three mechanisms does metoclopramide promote gut motility?

Answer 13

• inhibition of pre- and post-synaptic D2 receptors
• stimulation of presynaptic, excitatory 5-HT4 receptors
• antagonism of presynaptic inhibition of muscarinic receptors

Question 14

What does metoclopramide promote the release of?

Answer 14

It promotes the release of ACh, which results in the following:

• increases LOS tone and gastric tone
• increases intragastric pressure
• improved antroduodenal coordination and accelerated gastric emptying

Question 15

Describe antispandmodic agents (what they work, examples, clinical uses).

Answer 15

They decrease spasms in the bowel. They have relaxant actions on the GIT (relax the smooth muscle in the GIT).

Examples include:

• propantheline (antimuscarinic agent)
• dicloxerine (dicyclomine)
• mebeverine

They may be useful in irritable bowel syndrome and diverticular disease.

Question 16

What are the goals of pharmacological intervention in gastric ulcers?

Answer 16

• reduce acid secretion with H2 receptor antagonists
• neutralise secreted acid with antacids
• attempt to eradicate H.pylori (if applicable)

Inhibition of acid secretion removes the constant irritation and allows the ulcer to heal.

Question 17

What is the general mechanism of antacids?

Answer 17

• neutralise gastric acid
• increase the pH of gastric acid (peptic activity stops at pH 5)
• prolonges dosing can lead to healing of duodenal ulcers (less effective for gastric ulcers)

Question 18

What are some examples of antacids?

Answer 18

• sodium alginate (eg. Galviscon)
• sodium bicarbonate
• calcium carbonate

Question 19

How does bismuth chelate work (and what is its prominent side effect)?

Answer 19

It protects the gastric mucosa:

• forms a base over the crater of the ulcer
• adsorbs pepsin
• increased HCO3- and PG secretion
• it’s toxic against H.pylori, and used as part of a triple therapy to eradicate it

The side effect is that it blackens the stool and tongue.

Question 20

How would you treat an H.pylori infection?

Answer 20

To treat it, we would use a combination therapy of at least three drugs (PPI and antibiotics):

• omeprazole, amoxicillin, and metronidazole
• [omeprazole, clarythromycin, and amoxicillin] or [tetracycline, metronidazole, and bismuth chelates]
• lansoprazole, clarythromycin, tinidazole, and bismuth chelates

To the patient, we would advise them to:

• adhere to the treatment
• watch out for resistance to metronidazole (you can’t take it with alcohol)

Question 21

What are some consequences of constipation as a result of rectal distention?

Answer 21

• headache
• loss of appetite
• nausea
• abdominal distention and stomach pain

Question 22

What are some causes of constipation?

Answer 22

• decreased motility of the large intestine
• old age
• damage to the enteric system of the colon

Question 23

List some factors that can improve colonic motility.

Answer 23

• increased fibre, cellulose and complex polysaccharides
• bran, some fruits and vegetables with high fibre
• laxatives (beware that excessive use can lead to decreased responsiveness)
• mineral oil, as it lubricates the faeces
• castor oil, as it stimulates the motility of the colon

Question 24

What are some alarm signs and symptoms of someone with chronic constipation?

Answer 24

• acute onset of constipation in older individuals
• weight loss (10 lbs)
• blood in the stool
• anaemia
• family history of colon cancer or IBD

Question 25

How would you manage constipation?

Answer 25

• change the diet, fluid intake and exercise
• increased fibre intake
• increased water intake (?)

Question 26

Describe bulk-forming/osmotic laxatives.

Answer 26

They work by retaining water in the gut lumen, thus promoting peristalsis, but they take a few days to work.

Examples would be plants gums (eg. sterculia, agar, linseed) and methylcellulose.

Bloating and flatulence are associated with their use.

Question 27

How do antidiarrhoeal agents work?

Answer 27

They maintain body fluids and electrolytes by modifying the secretion and absorption balance when treating diarrhoea.

Question 28

What is loperamide and how does it work?

Answer 28

It is a synthetic opioid receptor agonist. It’s a spasmolytic agent which reduces smooth muscle activity in the GIT, and thus, reduces the passage of faeces.

It:

• reduces the force and speed and colonic movement
• increases haustral mixing of the proximal colon
• inhibits propulsive mass movement of the distal colon