38) Pharmacological basis for the treatment of GI disorders Flashcards
1
Q
What area of the GI tract are of pharmological importance?
A
- Gastric secretions
- Vomiting
- Gut motility
- Bile formation and excretion
2
Q
What are the anti-secretory agents?
A
- Chemicals that reduce the secretion of gastric acid
3
Q
What are H2 receptors antagonists used to treat?
A
- They are used to treat peptic ulcers and reflux oesophagitis
- They promote the healing of duodenal ulcers but if treatment stops relapse may occur
4
Q
How do H2 receptor antagonists work?
A
- The act on H2 receptors (the receptors histamine bind to) to prevent the secretion of gastric acid
- They inhibit histamine, ACh and gastrin stimulated acid secretions of the parietal cells
- This reduces gastric acid secretion and as a result reduces pepsin secretion
- This is because acid secretion is crucial for the conversion of pepsinogen (inactive) to pepsin (active)
- This results in a huge decrease in basal and food stimulated acid secretions
- Two examples are ranitidine and cimetidine
5
Q
What are some unwanted effects of H2 receptor antagonists?
A
- They may cause diarrhoea, muscle cramps, transient rashes and hypergastrinaemia (too much gastrin secretion)
- Cimetidine may cause gynaecomastia in men which can decrease sexual function
- Cimetidine may also inhibit P450 enzymes which decreases metabolism of many drugs metabolised by P450 (e.g. anticoagulants and antidepressants)
6
Q
Which H2 receptor antagonist is more active?
A
- Ranitidine is more potent than cimetidine as on a dose response curve ranitidine had a lower IC50 (less drug was needed to illicit half the response of the drug)
7
Q
What are proton pump inhibitors used for?
A
- To treat peptic ulcers
- To treat reflux oesophagitis
- As a component of therapy for H.pylori
- Can be used in the treatment for Zollinger-Ellison Syndrome
8
Q
How do proton pump inhibitors work?
A
- They are weak bases and so has the potential to accumulate in acidic components (e.g. stomach)
- It will concentrate in these areas and so will inhibit the H+/K+ ATPase pump
- Therefore there is decreased basal and food-stimulated gastric acid secretion
9
Q
What are some unwanted effects of proton pump inhibitors?
A
- Headache
- Diarrhoea
- Mental confusion
- Rashes
- Somnolence
- Impotence
- Gynaecomastia
- Dizziness
10
Q
What protects the gastric mucosa?
A
- Prostaglandins protect the gastric mucosa and are said to be gastroprotective
11
Q
How does prostaglandin protect the mucosa?
A
- If there is too much acid secretion prostaglandin will inhibit basal and food stimulated gastric acid secretion
- It will also inhibit histamine and caffeine induced gastric acid secretion
- As a result it inhibits the activity of parietal cells
- It also promotes the secretion of mucus and HCO3- as well as increases blood flow to the mucosa
12
Q
What gastroprotective agent (drug) is given to patients?
A
- Misoprostol (a stable analogue of prostaglandin)
13
Q
What gastroprotective agent (drug) is given to patients?
A
- Misoprostol (a stable analogue of prostaglandin)
14
Q
What is an unwanted effect of prostaglandin?
A
- Induces labour/ labour
15
Q
What gastroprotective agent (drug) is given to patients?
A
- Misoprostol (a stable analogue of prostaglandin)
16
Q
What is the effect of metoclopramide on gastric emptying and motility?
A
- It inhibits pre sympathetic dopamine receptors and post sympathetic dopamine receptors.
- It also inhibits 5-HT3 receptors in the CNS to inhibit vomiting
- They stimulate 5-HT4 receptors in the ENS and so promotes gut motility
17
Q
What are the effects of dopamine on the body?
A
- Dopamine acts on dopamine receptors
- It has relaxant effects n the gut by activating D2 receptors in the lower oesophageal sphincter and stomach
- Overall dopamine can induce contractions in proximal regions but can induce relaxations in the distal areas of the small intestines
- Dopamine can also inhibit the release of ACh which inhibits peristalsis (and decreases gut motility) and also inhibits some secretions
18
Q
How does metoclopramide promote gastric motility and emptying?
A
- Metoclopramide inhibit dopamine at D2 receptors
- This causes an increase in the release of ACh
- An increase in ACh increases the peristalsis which takes place (and thus increasing gastric motility)
- Increased ACh also increases intragastric pressure as the tone of the lower oesophageal sphincter increases and so the tone of gastric contractions also increases
- This improves the antroduodenal coordination which accelerates gastric emptying and relaxes the pyloric sphincter
- It also stimulates 5-HT receptors and inhibitory nitregeric neurones which causes coordinated gut motility
19
Q
What is another effect of metoclopramide?
A
- It is able to inhibit nausea and so has antiemetic properties via central effects
- It also relieves headaches via central effects
20
Q
What are the conditions in which metoclopramide is used?
A
- Antiemetic effects via central pathways
- Gastro-oesophageal reflux disease (GORD)
- Relief symptoms of gastroparesis as it promotes gastric emptying to stimulate gastric motility and accelerate gastric emptying
21
Q
What are antispasmodic agents?
A
- Drugs that decrease spasms in the bowel whilst also having a relaxant action on the smooth muscles of the GI tract
- They are useful in irritable bowel syndrome and diverticular disease (a congenital lesion which can be a source of bacterial overgrowth)
- Muscarinic receptor antagonists inhibit parasympathetic activity which reduces spasms of the bowel by inhibiting peristalsis
- Examples include propantheline (antimuscarinic), dicloxerine and mebverine
22
Q
What are the main goals in pharmacological intervention in gastric ulcers?
A
- Reduce acid secretion with H2 receptor agonist
- Neutralise secreted acids with antacids
- Attempt to eradicate H. pylori
- Inhibition of acid secretion removes the constant irritation and allows the ulcer to heal
23
Q
When can drugs be used to combat excess gastric acid secretion?
A
- In peptic ulcers
- Reflux oesophagitis (as gastric acid can damage the oesophagus)
- Zollinger- Ellison syndrome (gastrin producing tumour)
24
Q
Why do ulcers develop?
A
- It is unclear as to why they develop although H. pylori is a risk factor
- H. pylori is a gram negative bacteria which causes chronic gastritis which can lead to a duodenal ulcer
25
Q
How do antacids work?
A
- They neutralise gastric acid by increasing the pH of the gastric acid which inhibits the activity of peptic acid (as peptic activity stops at pH 5)
- Prolonged dosage can lead to healing of duodenal ulcers however it is less effective against gastric ulcers
26
Q
How does Bismuth chelate help with heartburn?
A
- It protects the gastric mucosa by forming a base over the crater of the ulcer
- It also absorbs pepsin while increasing HCO3- and prostaglandin
- It is also toxic against H. pylori and can be used as part of triple therapy to eradicate it
27
Q
What are some side effects of Bismuth chelate?
A
- It blackens tongue and stool
- It can cause Reye’s syndrome in children with chicken pox or flu-like symptoms
- Nausea
- Vomiting
- Can cause encephalopathy if renal impairment is present
28
Q
How does prostaglandin protect the stomach from damage?
A
- They stimulate the secretion of HCO3- which neutralises gastric acid
- They reduce H+ secretions
- They stimulate mucus production
- They promote vasodilation
29
Q
Why do NSAIDS cause gastric bleeding?
A
- They inhibit COX which inhibits synthesis of prostaglandin and as a result we loose the gastroprotective effects of prostaglandin resulting in gastric bleeding
30
Q
How is H. pylori treated?
A
- Antibiotics are required as it is a bacteria
- Protein pump inhibitors are also used to deal with the increased gastric secretion
31
Q
What advice is given to patients that are treating a H. pylori infection?
A
- Adhere to treatment
- Watch for resistance to metronidazole
- Alcohol must not be taken when under metronidazole as a disulfiram reaction can occur where patients may feel severely ill and stop taking the drug. Disulfiram inhibits acetaldehyde dehydrogenase causing a build up of acetaldehyde leading to unpleasant flushing and nausea.
- Do not give to pregnant women in the first trimester
32
Q
What is constipation?
A
- A subjective complaint where there is an obstruction causing bowel movement to be less frequent than normal
- Prolonged constipation does not cause harmful material to build up but rather causes hardening of the stool which is painful
33
Q
What are the consequences of constipation as a result of rectal distension?
A
- Headache
- Loss of appetite
- Nausea
- Abdominal distension and stomach pain
- Holding faecal matter leads to increased water loss and dryer faeces making it harder to defecate
34
Q
What are the causes of constipation?
A
- Decreased motility of the large intestine due to old age
- Damage to enteric nervous system of the colon as this may affect the vago-vagal reflex
- Poor diet
- Drugs
35
Q
What are factors that can increase colonic motility and prevent constipation?
A
- Increased fibre, cellulose and complex polysaccharides in diets
- Bran and some fruits and vegetables with high fibre
- Laxative however excessive use can decrease responsiveness
- Mineral oil which lubricates faeces
- Castor oil which stimulates motility of the colon
- Increase water intake
- Lifestyle changes
36
Q
What are the alarm signs and symptoms of chronic constipation?
A
- Acute onset of constipation in older individuals
- Weight loss
- Blood in stool
- Anaemia
- Family history of colon cancer or inflammatory bowl disease
37
Q
How can we treat constipation using purgatives?
A
- We use purgatives which modulate/hasten food transit through the intestines
- These include laxative, faecal softeners and stimulants
- Plant gums are polysaccharide polymers that retain water in the gut lumen (causing distension and promoting peristalsis) and they also increase the stool’s solid content
38
Q
How can we treat constipation using osmotic laxatives?
A
- They increase and maintain volume of fluid in the lumen of the bowel through osmosis
- They increase transfer of gut content into the intestine
- They increase the volume of gut content entering the colon leading to distention and purgation
- High doses can lead to flatulence, cramps, diarrhoea, vomiting and tolerance
39
Q
How do osmotic laxatives work?
A
- Lactulose reaches the colon unchanged where the colonic bacteria break it down into fatty acids
- These fatty acids cause osmotic pressure and biomass to increase
- These factors soften the faeces and increase the volume of the stool causing peristalsis to be stimulated
- As a result colonic transit time is shortened
40
Q
What is diarrhoea?
A
- The frequent passage of liquid faeces
41
Q
How do we deal with diarrhoea?
A
- Maintain body fluid and electrolytes
- Identify cause and treat with antibiotics if possible
- Modify secretions/absorbance balance
- Use anti-motility drugs
- Use anti-diarrhoeal agents
42
Q
What are the causes of diarrhoea?
A
- Infectious agents (e.g. cholera toxins)
- Toxins
- Anxiety
- Drugs
43
Q
How does acute diarrhoeal disease lead to electrolyte imbalance?
A
- Diarrhoea causes increased motility of the GI tract with increased secretions and decreased absorption of fluids
- This causes a decrease in electrolytes leading to electrolyte imbalance
44
Q
How do anti-diarrhoeal agents work?
A
- Loperamide is selective to the GI tract and decreases passage of faeces. This decreases the duration of the illness
- Loperamide also has anti-secretory actions as it decreases intestinal motility
- Bismuth subsalicylate decreases fluid secretions in the bowel
45
Q
What is the mechanism of action of loperamide?
A
- It is an opioid receptor agonist which binds to the (mu)-opioid receptor of the myenteric plexus of the large intestines
- This causes inhibition of the bowel function as it inhibits gastric emptying, increases sphincter tone, induces stationary motor patterns and blocks peristalsis
- It contains spasmolytic agents which reduce smooth muscle activity n the GI tract and hence reduces passage of the faeces
- It reduces the force and speed of colonic movement by increasing haustral mixing of the proximal colon while also inhibiting propulsive mass movement in the distal colon
- There is no CNS effect as they do not cross the blood-brain barrier
