Gastrointestinal Physiology 2 Flashcards
Which route of delivery is generally favoured and why?
Oral
Very easy for patient to take medications orally therefore high patient compliance
What are some of the issues encountered with delivering drugs orally?
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)
How can we combat the low pH in the stomach through oral dosage forms?
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
Where in the GIT tract are drugs absorbed?
Small intestine (majority) Stomach
Which drugs can be absorbed in the stomach?
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)
Give 3 examples of drugs which may be absorbed in the stomach.
Aspirin
Paracetamol
Warfarin
Which equation demonstrates the relationship between pH and ionised form?
pH = pKa + log[A-]/[AH]
Proteases digest proteins, our entire body, including the stomach, is made up of proteins, so why don’t we get self-digestion?
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
The stomach contains concentrated hydrochloric acid, so why don’t we suffer 1st or 2nd degree burns in our stomach?
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
Cells in the stomach are joined by what? And what is the function of these structures?
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
The cells in the stomach have a high what? And what are the consequences of this?
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
Where are new cells (to line the GIT) produced?
Gastric pit
What would happen if there was a breakdown in mucus barrier function?
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
What term is used to describe complete erosion of the tract wall?
Perforated ulcer
What is the major problem associated with a perforated ulcer?
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
What is Helicobacter pylori and what does it cause?
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
How is H. pylori treated?
Usually treated with a combination of 2 antibiotics and a PPI
Commonly used combinations include,
Clarithromycin, Amoxicillin and Omeprazole
Clarithromycin, Metronidazole and Omeprazole
Once food bolus, now as chyme, or medicines leave the stomach, where do they go next?
Enter the duodenum (a major site of both nutrient and drug absorption with a large surface area to absorb)
How are contents moved out of the stomach, into the duodenum and along the small intestine?
By ‘peristalsis’ = a wave of muscular contraction
Explain the process of peristalsis.
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
What is diarrhoea?
Watery content of the GIT
How can we treat diarrhoea?
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
In terms of diarrhoea treatment, what is the main target?
The myenteric plexus (MP), a network of nerves that interact with and innervate the longitudinal small muscle
What is the relationship between the different types of muscles involved?
In order from outside to inside, serosa, longitudinal muscle, MP, circular muscle, epithelium, lumen
Name one common drug used to treat diarrhoea and explain how it works.
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
What is a common side effect of opioids?
Constipation, particularly with opioid pain relief
Where are bile acids synthesised?
Liver
What is one of the main bile acids synthesised in the liver?
Taurocholic acid
Where do bile acids go after leaving the liver?
Secreted into the small intestine
What is the action of bile acids?
Act like ‘detergents’
Their release results in lipid emulsification (breakdown into smaller particles) and absorption
Why is the action of bile acids important?
Some of the vitamins in our diets are dissolved in lipids e.g. A, D, E and K
Where are bile acids stored?
Gall bladder
What happens to bile acids when we take in food?
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
Which organic molecule is an intermediate in the production of bile acids?
Cholesterol
In patients with high cholesterol, what is one of the target processes for drug therapy?
HMG-CoA reductase
Blocked by statins
