The Pharmacological Basis of the Treatment of GI Disorders

Question 1

State the areas of the GI tract that are pharmacologically important

Answer 1

• Gastric acid secretion - 2.5L of gastric juice secreted a day
• Vomiting
• Gut motility
• Bile formation and excretion

Question 2

State some examples of H2 receptor antagonists and what they are used for

Answer 2

H2 receptor antagonists (ranitidine, cimetidine, famotidine, nizatidine)

Clinical uses of H2 receptor antagonists - peptic ulcers, reflux oesophagitis

Question 3

State the mechanism of action of H2 receptor antagonists

Answer 3

• They inhibit histamine, acetylcholine and gastrin stimulated acid secretion on parietal cells
• Reduce gastric acid secretion and as a consequence reduce pepsin secretion
• Can decrease basal and food stimulated acid secretion by 90%
• Promote the healing of duodenal ulcers but if treatment stops there is relapse

Question 4

What are some unwanted effects H2 receptor antagonists produce

Answer 4

• Generally rare but may be diarrhoea, muscle cramps, transient rashed and hypergastrinemia
• Cimetidine - gynaecomastia in men - decreased sexual function
• Cimetidine also inhibits P450 enzymes - decreased metabolism of a number of drugs metabolised by P450 enzymes e.g. anticoagulants, tricyclic antidepressants e.g. imipramine, dosulepin and amitriptyline

Question 5

Compare the effects of ranitidine and cimetidine on inhibition of acid secretion

Answer 5

• Graph shows that as serum concentration of ranitidine and cimetidine increases the % of acid inhibition also increases
• But ranitidine is more potent than cimetidine as it needs a lesser serum concentration to produce maximum % of acid inhibition
• IC50 for ranitidine is 0.07 mcg/ml while IC50 for cimetidine is 0.44 mcg/ml - the lower the IC50 the more active the drug

Question 6

Give examples of proton pump inhibitor drugs

Answer 6

Omeprazole, lansoprazole, pantoprazole, rabeprazole

Question 7

Describe what proton pump inhibitors are used for

Answer 7

• Peptic ulcers, 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 of acid occurs

Question 8

Describe the mechanism of action of proton pump inhibitors

Answer 8

• They are weak bases that are inactive at a neutral pH and irreversibly inhibit the H+/K+ ATPase pump
• Decreases the basal and food stimulated gastric acid secretion

Question 9

What are the unwanted effects of proton pump inhibitors

Answer 9

Headache, diarrhoea, mental confusion, rashes, somnolence, impotence, gynaecomastia, dizziness

Question 10

What type of drugs protect the gastric mucosa?

Answer 10

Prostaglandins are gastroprotective

Question 11

Describe what misoprostol does

Answer 11

• Inhibits basal and food stimulated gastric acid secretion
• Inhibits histamine and caffeine induced gastric acid secretion
• Inhibits the activity of parietal cells
• Increases the mucosal blood flow and can augment the secretion of HCO3- and mucus

Question 12

Describe the effects of metoclopramide on gastric motility/emptying

Answer 12

• Metoclopramide has mixed effects - inhibits pre and postsynaptic dopamine receptors as well as 5HT3 receptors - inhibits vomiting
• Also stimulates 5HT4 - prokinetic

Question 13

Describe the effects of dopamine

Answer 13

• Dopamine acts on different dopamine receptors
• Dopamine has relaxant effects on the gut by deactivating D2 receptors in the lower oesophageal sphincter and stomach (fundus and antrum)
• Overall dopamine has mixed effects on the gut - may induce contraction of the proximal small intestine but relaxation in the distal small intestine
• Dopamine inhibits the release of acetylcholine from intrinsic myenteric cholinergic neurons by activating presynaptic D2 receptors

Question 14

Explain what inhibition of dopamine by metoclopramide does in the GI tract

Answer 14

• Increases the release of acetylcholine which increases peristalsis of the duodenum, jejunum and ileum
• The increased acetylcholine leads to increased intragastric pressure due to increased lower oesophageal sphincter tone and increased tone of gastric contractions
• These improve antroduodenal coordination which accelerates gastric emptying and relaxes the pyloric sphincter
• Through additional prokinetic effects it stimulates the presynaptic excitatory 5HT receptors and inhibitory nitrergic neurons which leads to coordinated gastric motility

Question 15

What other areas does metoclopramide have use in?

Answer 15

• Metoclopramide has some antiemetic properties via central effects
• Metoclopramide relieves headaches via its central effects

Question 16

State some conditions in which metoclopramide may be used

Answer 16

• Antiemetic - nausea due to surgery or cancer
• Gastro-oesophageal reflux disease (GORD)
• Relieve symptoms of gastroparesis - promotes gastric emptying by stimulating gastric motility

Question 17

Summarise the effects of metoclopramide

Answer 17

1. Inhibits presynaptic and postsynaptic D2 receptors
2. Stimulates the release of acetylcholine/SP from enteric neurons
3. Elicits mixed 5HT agonist and antagonist effects e.g. stimulates excitatory 5HT4 receptors and inhibits 5HT3 receptors
4. Stimulates inhibitory nitrergic neurons - mediate NO release
5. Increases intragastric pressure - increased lower oesophageal sphincter and gastric tone
6. Motility stimulant - improves antroduodenal coordination and accelerated gastric emptying

Question 18

State some examples of antispasmodic drugs and what they do

Answer 18

• Examples - propantheline, dicloxerine, mebeverine
• Decrease the spasm of the bowel - they have a relaxant action of the GI tract (relax the smooth muscle of the GI tract)

Question 19

What type of drug is propantheline and what is it useful in as a treatment?

Answer 19

• Propantheline is an antimuscarinic agent (muscarinic receptor antagonists inhibit parasympathetic activity to reduce spasm of the bowel)
• May be useful in irritable bowel syndrome and diverticular disease - a congenital lesion may be a source of bacterial overgrowth

Question 20

State the goals of pharmacological treatment of gastric ulcers

Answer 20

• Reduce acid secretion with H2 receptor antagonists e.g. ranitidine
• Neutralise secreted acid with antacids e.g. gaviscon
• Attempt to eradicate H pylori

Question 21

Drugs that inhibit or neutralise acid secretion can be used to treat what?

Answer 21

• Peptic ulcers
• Reflux oesophagitis - gastric acid secretion can damage the oesophagus
• Zollinger ellison syndrome - gastrin producing tumour

Question 22

What is the general mechanism of antacids?

Answer 22

• Neutralise gastric acids
• Increase the pH of gastric acid
• Prolonged dosage can lead to healing of duodenal ulcers but is less effective for gastric ulcers

Question 23

Describe what bismuth chelate does

Answer 23

• Protects the gastric mucosa
• Forms a base over crater of the ulcer
• Absorbs pepsin
• Increases HCO3- and PG secretion
• Toxic against H pylori
• Blackens the stool and tongue

Question 24

How to prostaglandins protect epithelial cells of the stomach against damage?

Answer 24

• Stimulating the secretion of HCO3- which neutralises gastric acid
• Reducing H+ secretion
• Stimulating mucus production
• Promoting vasodilation

Question 25

How is H pylori treated?

Answer 25

- Omeprazole, amoxicillin and metronidazole - Omeprazole, clarithromycin and amoxicillin or tetracycline, metronidazole and bismuth chelates - Lansoprazole, clarithromycin, tinidazole and bismuth chelates

Question 26

Describe how bismuth chelate has cytoprotective effects

Answer 26

- Provides a physical barrier over the surface/base of the ulcer - Enhances local synthesis of prostaglandins - Promotes 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 - increases prostaglandin synthesis and absorbs pepsin

Question 27

State some unwanted effects of bismuth chelate

Answer 27

Nausea vomiting blackening of the tongue and faeces

Question 28

What is the patient advice when taking metronidazole?

Answer 28

- Adhere to the treatment - Disulfiram like reaction if metronidazole is taken with alcohol - patient will feel severely ill and may stop taking the drug

Question 29

What is normal bowel movement in a day?

Answer 29

Normal bowel opening is 1-3 x a day but hugely varies

Question 30

What symptoms can constipation produce?

Answer 30

Constipation causes rectal distension which can lead to - headache, loss of appetite, nausea and abdominal distension/stomach pain

Question 31

What are the causes of constipation?

Answer 31

Decreased motility of large intestine due to old age or damage to enteric nervous system of the colon

Question 32

What are some factors that increase colonic motility and increase constipation symptoms

Answer 32

- Increases fibre cellulose and complex polysaccharides - Bran some fruits and vegetables with high fibre - Laxatives - Mineral oil - it lubricates the faeces - Castor oil - stimulates motility of colon

Question 33

State the causes, alarm signs and management of constipation

Answer 33

Causes - - Diet - Inactivity - Drugs Alarm signs - - Acute onset constipation in older individuals - Weight loss - Blood in the stool - Anaemia - Family history of colon cancer or inflammatory bowel disease Management of constipation - - Diet, fluid intake and exercise - Increased fibre intake and increased water intake

Question 34

Describe the drug treatments available for constipation

Answer 34

Purgatives - - Can modulate/hasten food transit in the intestines - Laxatives, stool softeners and stimulants

Question 35

Describe what bulk and osmotic laxatives do

Answer 35

Bulk - - Bulk laxatives = methylcellulose - Plant gums e.g. agar, linseed, bran are polysaccharide polymers - They retain water in the gut lumen to promote peristalsis - Increase the stools solid content Osmotic laxatives - e.g. lactulose - Increases and maintains the volume of fluid in the lumen of bowel by osmosis - Increases transfer of gut contents into the intestine - Increases volume of gut content entering the colon - distension and purgation in 1hr - High doses cause flatulence, cramps, diarrhoea, vomiting and tolerance

Question 36

Describe the mode of action of lactulose in constipation

Answer 36

- The unchaged lactulose reaches the colon - The colonic bacteria breaks it down into short fatty acid chains - This increases osmotic pressure and increases biomass - There is then softening of the faeces/volume of the stool increases - Peristalsis is stimulated - Colonic transit time is shortened

Question 37

How is diarrhoea treated?

Answer 37

- Maintain body fluid and electrolytes - Identify causal organism and if possible treat with antibiotics - Modify secretion/absorption balance

Question 38

What are the causes of diarrhoea?

Answer 38

Infectious agents Toxins Anxiety Drugs

Question 39

What does diarrhoea do to fluid balance?

Answer 39

- Diarrhoea increases the motility of the GI tract - This increases secretion and decreases the absorption of fluid - This decreases electrolytes and water

Question 40

State 2 types of drugs used to treat diarrhoea

Answer 40

* Antidiarrhoeal drugs - decreases movement * Antispasmodic drugs - decrease movement - relax smooth muscle in GI tract

Question 41

State the main therapeutic strategies to diarrhoea treatment

Answer 41

- Maintain fluid and electrolyte balance through oral rehydration therapy - Use of anti-infectives as bacterial infections can resolve with time - if viral these may not be needed - Use of non microbial antidiarrheal agents - Use of anti motility drugs - absorbents an agents that modify fluid and electrolyte transport

Question 42

Describe what drugs are used to treat travellers diarrhoea

Answer 42

- Most develop diarrhoea while travelling - Loperamide- selective on GI tract - decreases passage of faeces and decreases duration of illness - Codeine and loperamide - antisecretory action - Decreases intestinal motility

Question 43

Describe the mechanism of action of loperamide

Answer 43

* Mechanism of action of loperamide - - An opioid receptor agonist - Binds to the u-opioid receptor of the myenteric plexus of the large intestine which inhibits bowel function - Controls motility and secretion of GI tract - Stimulation of the u-opioid receptor by loperamide inhibits gastric emptying, increases sphincter tone and induces stationary motor patterns and blocks peristalsis - Antispasmolytic agent which reduces smooth muscle activity in the GI tract and reduces passage of faeces * Reduce force and speed of colonic movement by: - Increasing haustral mixing in proximal colon - Inhibits propulsive mass movement in distal colon