Pharmacological basis for treatment of GI disorders

Question 1

What are areas of GIT of pharmacological importance

Answer 1

-gastric acid secretion
-vomiting
-gut motility
-bile formation

Question 2

What are clinical uses H2 receptor antagonists

Answer 2

peptic ulcer reflex oesophagitis

Question 3

What is the mechanism of action of H2 receptor antagonists

Answer 3

1) inhibit histamine, Ach and gastrin stimulated acid secretion on parietal cells

2) reduce gastric acid secretion and as a consequence reduce pepsin secretion

3) inhibit histamine, Ach and gastrin stimulated acid secretion

4) can decrease basal and food stimulated acid secretion by 90%

Question 4

What are clinical trials on H2 receptor antagonists

Answer 4

-promote the healing of duodenal ulcers
-but if you stop treatment, you get a relapse

Question 5

What are unwanted effects of H2 receptor antagonists

Answer 5

-generally rare but there may be diarrhoea, muscle cramps, transient rashes, hypergastrinaemia

-cimetidine—> gynaecomastia in men decreases sexual function although rare

Question 6

Explain the effect of cimetidine

Answer 6

-Cimetidine also inhibits P450 enzymes —> decreases metabolism of a number of drugs metabolised by P450 enzymes

Question 7

Describe what IC50 is

Answer 7

IC50- concentration that inhibits 50% of acid secretion

Question 8

Which drug would be more active

Answer 8

-the drug with lower IC50 is more active

Question 9

What are examples of proton pump inhibitors and clinical uses of them

Answer 9

Examples:
-omeprazole, lanzoprazole, pantoprazole, rabeprazole

Clinical uses of proton pump inhibitors:
-peptic ulcer, reflex oesophagitis; as a component of therapy for H.pylori
-can also be used in the treatment Zollinger-Ellison syndrome

Question 10

What is the mechanism of action of proton pump inhibitors

Answer 10

-weak bases: inactive at neutral pH and irreversibly inhibit the H+/K+- ATPase pump

-decreases basal and food stimulated gastric acid secretion

Question 11

What are unwanted effects of proton pump inhibitors

Answer 11

-headache
-diarrhoea
-mental confusion
-rashes
-somnolence
-impotence
-gynaecomastia
-dizziness

Question 12

What are drugs that protect the gastric mucosa

Answer 12

-prostaglandins (PGE2 AND PGI2) are gastroprotective

Question 13

How are they gastroprotective

Answer 13

-misoprostol is a stable analogue of PGE1

Question 14

What is the mode of action of misoprostol and what is a caution of this

Answer 14

1) inhibits basal and food stimulated gastric acid secretion

2) inhibits histamine, and caffeine induced gastric acid secretion

3) inhibits the activity of parietal cells

4) increases mucosal blood flow and can augment the secretion of HCO3- and mucus

Caution- induces labour/abortion

Question 15

What are the effects of metoclopromide on gastric motility and emptying

Answer 15

Metoclopromide has mixed effects:
-inhibits pre and post synaptic dopamine (D2) receptors as well as 5-HT3 receptors (inhibits vomiting)

-stimulates 5-HT4- pro kinetic

Question 16

What is an introduction of dopamine and the effects of dopamine on the gut

Answer 16

introduction:
-dopamine acts on different dopamine receptors
-dopamine has relaxant effects on the gut by activating D2 receptors in the lower oesophageal sphincter and stomach

Overall, dopamine has mixed effects on the gut:
May induce contraction in the proximal but relaxation in the distal small intestine

Question 17

how does dopamine inhibit the release of ACh

Answer 17

-dopamine inhibits the release of ACh from intrinsic myenteric cholinergic neurons by activating pre synaptic D2 receptors

Question 18

What are the effects of inhibition of dopamine at D2 receptors

Answer 18

1) increase the release of ACh (increase peristalsis of duodenum, jejunum and ileum)

2) increases ACh which leads to increase of intragastric pressure (due to increased LOS tone and increased tone of gastric contractions)

3) these improve antroduodenal coordination which accelerates gastric emptying —-> relaxes pyloric sphincter

Question 19

What happens through additional prokinetic effects

Answer 19

-it stimulates presynaptic excitatory 5-HT receptors and inhibitory nitrergic neurones—-> coordinated gastric motility

Question 20

Describe how metoclopromide has utility in other areas

Answer 20

-metoclopromide has some antiemetic properties via central effects

-relieves headache via central effects

Question 21

What is the clinical utility of metoclopromide

Answer 21

1) anti-emetic (nausea due to surgery or cancer) effects via central pathways

2) gastro oesophageal reflux disease (GORD)

3) relief symptoms of gastroparesis- promotes gastric emptying

4) stimulates gastric motility- it accelerates gastric emptying

5) pain killing effects

Question 22

Give a summary of the effects of metoclopromide

Answer 22

Metoclopromide promotes gut motility by the following mechanisms:

1. Inhibits presynaptic and postsynaptic D2 receptors,
2. Stimulates the release of ACh / SP from enteric neurons
3. Elicits mixed 5-HT agonist and antagonist effects, e.g., stimulates excitatory 5-HT4 receptors
   (ENS); but inhibits 5-HT3 receptors (CNS; see slide 10);
4. Stimulates inhibitory nitregic neurons – mediate NO release
5. Increases intragastric pressure -↑ LOS and gastric tones
6. Motility stimulant - improves antro-duodenal coordination and accelerated gastric emptying

Question 23

What are examples of antispasmodic agents and what do they do

Answer 23

examples:
-propantheline
-dicloxerine
-mebeverine

1) decreases spasm in bowel, they have relaxant action on the GIT (relax smooth muscle in GIT)

2) propantheline, dicyclomine, mebeverine= antimuscarinic agents

May be useful in irritable bowel syndrome and diverticicular disease

Question 24

What do muscarinic receptor antagonists do

Answer 24

-inhibit parasympathetic activity
-this reduces the spasm in the bowel

Question 25

What is the goal of pharmacological intervention in gastric ulcers

Answer 25

1) reduce acid secretion with H2 receptor antagonists 2) neutralise secreted acid with antacids 3) attempt to eradicate H.pylori Inhibition of acid secretion, removes the constant irritation and allows the ulcer to heal

Question 26

What are drugs that can be used to inhibit or neutralise gastric acid secretion

Answer 26

-peptic ulcer -reflux oesophagitis: gastric acid secretion can damage oesophagus -Zollinger-Ellison syndrome: gastrin producing tumour

Question 27

Explain the action of H.pylori

Answer 27

H.pylori- a gram negative bacillus, causes chronic gastritis which can lead to duodenal ulcer

Question 28

What is the general mechanism of action of antacids

Answer 28

1) neutralise gastric acid 2) increase the pH of gastric acid 3) prolonged dosing can lead to healing of duodenal ulcers; less effective for gastric ulcers

Question 29

Explain the mechanism of action for bismuth chelate (pepto bismol)

Answer 29

-decreases fluid secretion in bowel -protects gastric mucosa -forms a base over crater of the ulcer -absorbs pepsin -increases HCO3- and prostaglandin secretion Toxin against H.pylori

Question 30

How do prostaglandins protect the epithelial cells of the stomach

Answer 30

Prostaglandins (PGs) protect the epithelial cells of the stomach against damage by: -stimulating the secretion of HCO3- which neutralises gastric acid -reducing H+ secretion -stimulating mucus production -promoting vasodilation PGs protect the stomach against damage

Question 31

Explain combination therapy for treatment of H.pylori

Answer 31

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

Question 32

Which drugs protect the gastric mucosa

Answer 32

Some drugs protect the gastric mucosa e.g. bismuth chelate (colloidal bismuth subcitrate, tripotassium dicitratobismuthate). These have cytoprotective effects

Question 33

What does bismuth chelate do in the treatment of H.pylori

Answer 33

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

Question 34

What are unwanted effects and warnings of bismuth chelate

Answer 34

Unwanted effects of bismuth chelate: nausea, vomiting, blackening of tongue and faeces * Warning: If patient has renal impairment, [bismuth chelate]plasma may rise causing encephalopathy * Do not exceed the recommended dose

Question 35

What is patient advice for the treatment of H.pylori infection

Answer 35

*Adhere to treatment *Resistance to metronidazole *Disulfiram-like reaction results if metronidazole is taken with alcohol – 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 first trimester

Question 36

How to tell if your frequency of bowel movement normal

Answer 36

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*

Question 37

What are consequences of constipation as a result of rectal distension

Answer 37

Headache * Loss of appetite * Nausea * Abdominal distension and stomach pain

Question 38

What are causes of constipation

Answer 38

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

Question 39

What are factors that can increase colonic motility

Answer 39

↑ 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 40

What are causes of constipation in the elderly and alarm signs and symptoms of patients with chronic constipation

Answer 40

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

Question 41

What are lifestyle changes to help combat the lifestyle changes of constipation

Answer 41

Diet, fluid intake and exercise and their effects on constipation (appealing?) * ↑ fibre intake → bloating and flatulence (not appealing) * ↑ water intake??

Question 42

Explain characteristics of purgatives

Answer 42

Purgatives: Purgatives can modulate/hasten food transit in the intestine Laxatives, faecal softeners & stimulant. Bulk-forming and osmotic laxatives *Bulk laxatives: methylcellulose, *Plant gums (e.g. sterculia, agar agar, linseed, bran, ispaghula husk) are polysaccharide polymers They retain water in gut lumen → promotion of peristalsis, but take a few days to elicit their effects Increase the stool’s solid content

Question 43

What does osmotic laxatives: lactulose

Answer 43

↑ 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 44

What is the mode of action of lactulose in constipation

Answer 44

-Unchanged lactulose reaches the colon -Colonic bacteria breaks it down into short chain fatty acids * Lactulose is a carbohydrate source for lactobacilli and bifidobacteria * It ↑ growth of colonic bacteria -Osmotic pressure - Biomass increases increases -Softening of the faeces/volume of stool increases - Peristalsis is stimulated - Colonic transit time is shortened

Question 45

Explain characteristics of diarrhoea

Answer 45

-maintain body fluids and electrolytes -identify casual organism and if possible treat with antibiotics -modify secretion/absoprtion balance

Question 46

Explain the causes of diarrhoea and the acute diarrhoeal diseases

Answer 46

Causes of diarrhoea: Infectious agents - cholera toxins → profuse watery diarrhoea * Toxins * Anxiety * Drugs Acute diarrhoeal diseases: Diarrhoea → ↑ motility of GIT, with ↑ secretion and ↓ absorption of fluid → ↓ electrolyte (Na+) and H2O

Question 47

What are effects of diarrhoea

Answer 47

rough emergencies ——> discomfort —-> medical emergencies

Question 48

Describe the motility of the GI tract

Answer 48

The movement of substances in the gut can be modulated by: * Purgatives: ↑ passage of food through the intestine Agents that increase motility without → purgation: * Antidiarrhoeal drugs → ↓ movement * Antispasmodic drugs → ↓ movement; relax smooth muscles in GIT

Question 49

What are therapeutic strategies to diarrhoea treatment

Answer 49

-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

Question 50

Explain traveller’s diarrhoea

Answer 50

*About 3 million people travel abroad/year & most will develop diarrhoea during their travel *But some infections may be self-limiting (no need for treatment – exercise caution) Loperamide: Selective on GIT, decreases passage of faeces; *Decreases duration of illness Codeine & loperamide: Anti-secretory action *↓ intestinal motility

Question 51

What is a mechanism of action of loperamide

Answer 51

* An opioid receptor agonist * Binds to the B-opioid receptor of the myenteric plexus* of the large intestine – inhibition of bowel function * *Controls motility and to a very minor extent GI secretion * Stimulation of the -opioid receptor by loperamide inhibits gastric emptying, increases sphincter tone, induces stationary motor patterns (i.e., blocks peristalsis) * A spasmolytic agent which reduces smooth muscle activity in the GIT and thus reduces the passage of stool * Reduces force and speed of colonic movement by: * Increasing haustral mixing of the proximal colon * Inhibiting propulsive mass movement of the distal colon * No CNS effects, as does not cross the blood-brain barrier