Gastrointestinal Physiology 2

Question 1

Which route of delivery is generally favoured and why?

Answer 1

Oral

Very easy for patient to take medications orally therefore high patient compliance

Question 2

What are some of the issues encountered with delivering drugs orally?

Answer 2

The stomach and GIT are a harsh environment for drugs
Secretions such as pepsin (protease) make delivering drugs which are proteins (e.g. insulin) orally very difficult
HCl is also released, making the pH in the stomach as low as 1-2 leading to inactivation of certain drugs (e.g. penicillin G, erythromycin)

Question 3

How can we combat the low pH in the stomach through oral dosage forms?

Answer 3

Enteric coatings, protects the drug inside from exposure to acid
As the drug leaves the stomach and enters the small intestine, can then be released

Question 4

Where in the GIT tract are drugs absorbed?

Answer 4

Small intestine (majority) 
Stomach

Question 5

Which drugs can be absorbed in the stomach?

Answer 5

Lipid soluble drugs - can integrate into the lipid membrane and diffuse into the cell
Weakly acidic drugs - unionised in the pH of the stomach (pH 1-2)

Question 6

Give 3 examples of drugs which may be absorbed in the stomach.

Answer 6

Aspirin
Paracetamol
Warfarin

Question 7

Which equation demonstrates the relationship between pH and ionised form?

Answer 7

pH = pKa + log[A-]/[AH]

Question 8

Proteases digest proteins, our entire body, including the stomach, is made up of proteins, so why don’t we get self-digestion?

Answer 8

The reason we do not get ‘self-digestion’ is because the enzyme, pepsin, is secreted as the inactive form, pepsinogen (zymogen), into the stomach lumen and only becomes activated by acid into pepsin
This means that the cells lining the stomach are not usually exposed to pepsin, the active form

Question 9

The stomach contains concentrated hydrochloric acid, so why don’t we suffer 1st or 2nd degree burns in our stomach?

Answer 9

Foveolar cells in the stomach produce mucus
The mucus is alkaline in nature, it sits atop cells and protects them, when acid interacts it is neutralised
This layer of mucus also forms a physical protective barrier against pepsin

Question 10

Cells in the stomach are joined by what? And what is the function of these structures?

Answer 10

Tight junctions
These are protein complexes that lock epithelial cells together (type of ‘protein cement’ that sticks adjacent cells together)
This prevents the movement of acid and pepsin between cells to pass into underlying tissue

Question 11

The cells in the stomach have a high what? And what are the consequences of this?

Answer 11

High cell turnover
The cells lining the GIT are usually no older than 2-3 days
The GIT is constantly producing new cells, these are then shed on a daily basis
This means that if cells are damaged, they will only be that way for 2-3 days as new cells would migrate up and take their place

Question 12

Where are new cells (to line the GIT) produced?

Answer 12

Gastric pit

Question 13

What would happen if there was a breakdown in mucus barrier function?

Answer 13

Underlying epithelial cells would be exposed to HCl and pepsin
The outcome of this exposure is a gastric (stomach) or duodenal ulcer
Initially, the damage will be superficial but if not treated, it may extend deep into the wall of the GIT
This results in damage to the underlying blood vessels and haemorrhage (bleeding into the GIT)
In severe cases, can be complete erosion through the tract wall

Question 14

What term is used to describe complete erosion of the tract wall?

Answer 14

Perforated ulcer

Question 15

What is the major problem associated with a perforated ulcer?

Answer 15

Food, secretions and bacteria we take in can move out of the GIT and into the peritoneal cavity
This results in peritonitis (inflammation of the peritoneum) which requires hospitalisation
In a small number of cases, this can result in sepsis and multiple organ failure

Question 16

What is Helicobacter pylori and what does it cause?

Answer 16

A bacteria that infects the gastric mucosa
It grows on the surface of stomach tissue and as a result reduces barrier efficacy
Disruption to the barrier, and subsequent exposure to HCl and pepsin results in an ulcer

Question 17

How is H. pylori treated?

Answer 17

Usually treated with a combination of 2 antibiotics and a PPI
Commonly used combinations include,
Clarithromycin, Amoxicillin and Omeprazole
Clarithromycin, Metronidazole and Omeprazole

Question 18

Once food bolus, now as chyme, or medicines leave the stomach, where do they go next?

Answer 18

Enter the duodenum (a major site of both nutrient and drug absorption with a large surface area to absorb)

Question 19

How are contents moved out of the stomach, into the duodenum and along the small intestine?

Answer 19

By ‘peristalsis’ = a wave of muscular contraction

Question 20

Explain the process of peristalsis.

Answer 20

Circular muscles contract behind the food bolus or drug to prevent movement back up the GIT in the wrong direction
The longitudinal muscles contract and squeeze the GIT (like squeezing toothpaste out of a tube)
This process is then repeated, the circular muscles in the next area contract, followed by contraction of the longitudinal muscles, pushing the food bolus or drug along

Question 21

What is diarrhoea?

Answer 21

Watery content of the GIT

Question 22

How can we treat diarrhoea?

Answer 22

One way to treat diarrhoea is to target the activity of the longitudinal smooth muscles
If you reduce their activity, you can reduce peristalsis
Movement of the watery contents is slowed down, retained in the GIT for longer therefore can reabsorb more water reducing the water content of the faeces and making it more solid

Question 23

In terms of diarrhoea treatment, what is the main target?

Answer 23

The myenteric plexus (MP), a network of nerves that interact with and innervate the longitudinal small muscle

Question 24

What is the relationship between the different types of muscles involved?

Answer 24

In order from outside to inside, serosa, longitudinal muscle, MP, circular muscle, epithelium, lumen

Question 25

Name one common drug used to treat diarrhoea and explain how it works.

Answer 25

Loperamide (Imodium)
Works by targeting the μ opioid receptors in the myenteric plexus
Binds to the target, reduces contraction of the muscles allowing more time for water absorption

Question 26

What is a common side effect of opioids?

Answer 26

Constipation, particularly with opioid pain relief

Question 27

Where are bile acids synthesised?

Answer 27

Liver

Question 28

What is one of the main bile acids synthesised in the liver?

Answer 28

Taurocholic acid

Question 29

Where do bile acids go after leaving the liver?

Answer 29

Secreted into the small intestine

Question 30

What is the action of bile acids?

Answer 30

Act like ‘detergents’

Their release results in lipid emulsification (breakdown into smaller particles) and absorption

Question 31

Why is the action of bile acids important?

Answer 31

Some of the vitamins in our diets are dissolved in lipids e.g. A, D, E and K

Question 32

Where are bile acids stored?

Answer 32

Gall bladder

Question 33

What happens to bile acids when we take in food?

Answer 33

Released via bile duct into duodenum
They emulsify lipids so we can absorbed them
They then pass along the GIT and to the end of the small intestine where they are reabsorbed into the liver

Question 34

Which organic molecule is an intermediate in the production of bile acids?

Answer 34

Cholesterol

Question 35

In patients with high cholesterol, what is one of the target processes for drug therapy?

Answer 35

HMG-CoA reductase

Blocked by statins