Pharmacological Basis - Treatment of GI Disorders Flashcards
List some areas of GIT importance.
- gastric acid secretion
- gut motility
- bile formation and excretion
What are two types of anti-secretory agents?
H2 receptor antagonists and proton pump inhibitors.
What are the clinical uses of H2 receptor antagonists?
- Inhibit histamine-, ACh- and gastrin-stimulated acid secretion on parietal cells.
- Reduce gastric acid secretion ∴ reduce pepsin secretion.
- Promote the healing of duodenal ulcers
List some examples of H2 receptor antagonists.
- Ranitidine
- Cimetidine
- Famotidine
- Nizartidine
What are some side effects of H2 receptor antagonists?
- diarrhoea
- muscle cramps
- transient rashes
- hypergastrinaemia
What are some side effects specific to cimetidine?
- Gynaecomastia
- Inhibition of P450 enzyme ∴ reduced metabolism of drugs broken down by these enzymes
How do proton pump inhibitors work?
- Weak bases - inactive at a neutral pH.
- Irreversibly inhibit the H+/K+-ATPase pump ∴ less H+ in the cell to make HCl.
- Decreases basal and food-stimulated gastric acid secretion.
List examples of proton pump inhibitors.
- Omeprazole
- Lanzoprazole
- Pantoprazole
- Rabeprazole
What are the clinical uses of proton pump inhibitors?
- peptic ulcers
- reflux oesophagitis
- against H. Pylori
- against Zollinger-Ellison syndrome (overproduction of gastric acid)
What are some side effects of proton pump inhibitors?
- headaches
- diarrhoea
- mental confusion
- rashes
- somnolence (strong desire to sleep)
Prostaglandins are gastroprotective.
How do they work?
- Increase mucous secretion
- Stimulate bicarbonate secretion
- Promotes vasodilation
- Negatively regulates parietal cells, so reduces H+ secretion
Why do NSAIDs (eg. aspirin) cause gastric bleeding?
- Cause gastric bleeding
- Inhibit prostaglandin synthesis (meaning there is less gastric protection)
- Inhibit Thromboxane A2 synthesis (which is involved in healing).
What would be a good alternative for NSAIDS to reduce bleeding?
Selective COX-2 inhibitors (such as celecoxib, rofecoxib)
What effect does dopamine have on the gut?
- Relaxant effect on the gut by activating D2 receptors in the lower oesophageal sphincter and stomach (fundus and antrum).
- Inhibits ACh release.
What would you need to do with dopamine if you wanted to increase gut motility?
Reduce or stop its effects
By which three mechanisms does metoclopramide promote gut motility?
- Inhibition of pre- and post-synaptic D2 receptors
- Stimulation of presynaptic, excitatory 5-HT4 receptors
- Antagonism of presynaptic inhibition of muscarinic receptors
What does metoclopramide promote the release of?
It promotes the release of ACh
What are the effects of metoclopramide?
- increases LOS tone and gastric tone
- increases intragastric pressure
- improved antroduodenal coordination and accelerated gastric emptying
Describe how antispasmodic agents work
- Decrease spasms in the bowel.
- Relax the smooth muscle in the GIT
Give examples of antispasmodic agents.
- propantheline (antimuscarinic agent)
- dicloxerine (dicyclomine)
- mebeverine
When might an antispasmodic agent be useful clinically?
Irritable bowel syndrome and diverticular disease
What are the goals of pharmacological intervention in gastric ulcers?
- reduce acid secretion with H2 receptor antagonists
- neutralise secreted acid with antacids
- attempt to eradicate H.pylori
What is the general mechanism of antacids?
- Neutralise gastric acid
- Increase the pH of gastric acid
- Prolonged dosing can lead to healing of duodenal ulcers (less effective for gastric ulcers)
What are some examples of antacids?
- sodium bicarbonate
- calcium carbonate
How does bismuth chelate work?
It protects the gastric mucosa:
- forms a base over the crater of the ulcer
- adsorbs pepsin
- increased HCO3- and PG secretion
- toxic against H.pylori, and used as part of a triple therapy to eradicate it
What is the side effect of bismuth chelate?
Blackens the stool and tongue.
How would you treat an H.pylori infection?
- Use a combination therapy of at least three drugs (proton pump inhibitor and antibiotics):
- Advise patient to adhere to the treatment and watch out for resistance to metronidazole (you can’t take it with alcohol)
What are some possible drug combinations for H. pylori infections?
omeprazole, amoxicillin, and metronidazole
[omeprazole, clarythromycin, and amoxicillin] or [tetracycline, metronidazole, and bismuth chelates]
What are some consequences of constipation as a result of rectal distention?
- headache
- nausea
- abdominal distention and stomach pain
What are some causes of constipation?
- decreased motility of the large intestine
- old age
- damage to the enteric system of the colon
List some factors that can improve colonic motility.
- increased fibre, cellulose and complex polysaccharides
- laxatives
- mineral oil, as it lubricates the faeces
- castor oil, as it stimulates the motility of the colon
What are some alarm signs and symptoms of someone with chronic constipation?
- acute onset of constipation in older individuals
- weight loss (10 lbs)
- blood in the stool
- anaemia
- family history of colon cancer
How would you manage constipation?
- change the diet, fluid intake and exercise
- increased fibre intake
Describe bulk-forming/osmotic laxatives and how they work.
- Retain water in the gut lumen, thus promoting peristalsis
- Take a few days to work.
Give an example of a bulk-forming/osmotic laxative
Methylcellulose
What are the side effects of bulk-forming/osmotic laxatives?
Bloating
How do antidiarrhoeal agents work?
Maintain body fluids and electrolytes by modifying secretion and absorption balance
What is loperamide?
- Synthetic opioid receptor agonist.
- Spasmolytic agent which reduces smooth muscle activity in the GIT, and thus, reduces the passage of faeces.
What does loperamide do?
- Reduces the force and speed and colonic movement
- Increases haustral mixing of the proximal colon
- Inhibits propulsive mass movement of the distal colon
How is the H+/K+ pump activated by action of gastrin?
- Gastrin can activate cells to release histamine
- Binds to H2 receptors on parietal cells
- Activates the H+/K+ ATPase pump
What does IC50 mean?
What does it mean if a drug were to have a low IC50?
→ Inhibitory concentration
→ Drug is more powerful
What protects the gastric mucosa?
→ PGE1
→ PGE2
What drugs protect the gastric mucosa?
Misoprostol
What does misoprostol inhibit?
- Inhibits basal and food stimulates gastric acid secretion
- Inhibits histamine and caffeine-induced gastric secretion
- Inhibits the activity of parietal cells
What does misoprostol increase and induce?
- Increases mucosal blood flow and can augment the secretion of HCO3- and mucus
- Induces labour
What do 5HT3 receptors do?
Receptors which inhibits vomiting
What does dopamine do in the distal and proximal areas of the gut?
Induce contraction in the proximal and relaxation in the distal
What two properties does metoclopramide have?
Antiemetic properties and relieves headache via central effects
What is metoclopramide useful for?
→ GI reflux
What does metoclopramide stimulate and accelerate?
→ Stimulates: gastric motility
→ Accelerates: gastric emptying
What neurons does metoclopramide stimulate?
→inhibitory nitregic neurons
→mediate NO release
What are the effects of metoclopramide? PART 1
→Inhibits presynaptic and postsynaptic D2 receptors
→Stimulates the release of ACh 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);
What are the effects of metoclopramide? PART 2
→Stimulates inhibitory nitregic neurons – mediate NO release
→Increases intragastric pressure -↑ LOS and gastric tones
→Motility stimulant - improves antro-duodenal coordination and accelerated gastric emptying
What do muscarinic receptor antagonists do?
→inhibit parasympathetic activity which reduces spasm in the bowel
What type of bacteria is H.Pylori?
Gram negative bacillus
What can bismuth chelate cause?
Encephalopathy
What is H.Pylori a risk factor for?
Gastric cancer
What cytoprotective effects does bismuth chelate have?
→Provide a physical barrier over the surface of the ulcer
→Enhances local synthesis of prostaglandins
→Promote bicarbonate secretion
What reaction happens if metronidazole is taken with alcohol?
→Disulfiram like reaction
What does disulfiram do to alcohol?
→ Inhibits acetaldehyde dehydrogenase so acetaldehyde builds up
What can purgatives do?
Modulate food transit in the intestine
What do osmotic laxatives do?
→Increases and maintains the volume of fluid in the lumen of the bowel by osmosis
What do high doses of osmotic laxatives cause?
→ cramps
→diarrhoea
→ vomiting
What are 4 causes of diarrhoea?
→Infectious agents
→Toxins
→Anxiety
→Drugs
What does oral rehydration therapy do?
→maintain fluid and electrolyte balance
What does bismuth subsalicylate do?
→Decreases fluid secretion in bowel
→Safe for young children
→Tinnitus and blackening of stool
Where does loperamide exert its effects?
→Exerts effects on opioid receptor of the myenteric plexus of the large intestine
Why does loperamide not have CNS effects?
→ Does not cross the blood-brain barrier
