Gastrointestinal Physiology 3 Flashcards
What is the role of the small intestine?
Highly adapted for digestion and absorption
Has to be extremely efficient, if we don’t absorb enough nutrients then we cannot survive
How is the small intestine adapted to its function?
Large surface area
Minimal epithelial barrier
Enzymes
How does the small intestine achieve such a large surface area?
The surface of the small intestine possess fold like structures called plicae
These are also small finger like projections called villi (roughly 1mm in height)
Each villus is lined with a layer of epithelial cells
On the surface of these epithelial cells are many more tiny finger like projections called microvilli
This large surface area is in contact with the contents of the intestine
Calculations estimate the area of the small intestine to be equivalent to the size of a…
Tennis court
How does the small intestine achieve a minimal epithelial barrier?
The lining layer of the small intestine is only 1 cell thick
This means the barrier between the internal environment of the body and the contents of the small intestine is only 1 cell thick (can’t get much smaller)
What are the vast majority of the cells lining the small intestine?
Enterocytes
What is the role of enterocytes?
Absorb nutrients
The small intestine also contains a small number of which cell type?
Goblet cells
What is the role of goblet cells?
Mucus producing, aids the transit of material through the GIT
What can be found in the centre of each villus?
Lymph duct (lacteal) When lipids cross the epithelial barrier they drain down into the lymph duct Also arteries and arterioles, and veins and venules, the small intestine has a very good blood supply
The apical membrane faces…
The contents of the small intestine
Where can enzymes be found in the small intestine?
Expressed/located in the apical membrane of epithelial cells
What is the function of enzymes in the small intestine?
Convert non-absorbable macromolecules to absorbable small molecules
When we take in large proteins, complex carbohydrates etc., we are not able to absorb these, they have to be broken down into much smaller units in order to be absorbed
How does carbohydrate digestion occur in the small intestine?
Sucrose, lactose and maltose are all disaccharides and are too large to cross the apical membrane so are broken down by sucrase, lactase and maltase respectively
Give the equations for carbohydrate digestion in the small intestine.
Sucrose (sucrase) → Glucose + Fructose
Lactose (lactase) → Glucose + Galactose
Maltose (maltase) → Glucose + Glucose
What happens to the carbohydrates once they have been broken down into monosaccharides?
Once broken down, monosaccharides are transported into enterocytes
The transporters involved vary on which monosaccharide it is being absorbed
How are glucose and galactose absorbed?
Glucose and galactose enter enterocytes via the SGLT1 transporter
Requires a high concentration of Na+ cells in the lumen in order to work as Na+ binds along with glucose or galactose
How is fructose absorbed?
Fructose enters enterocytes via the GLUT5 transporter
Does not require Na+ ions for uptake
What happens to these monosaccharides once they have been transported?
Now inside the enterocyte, the monosaccharides diffuse across the basolateral membrane and into the bloodstream (more transporters are involved here to move the molecules out of the enterocyte)
How does protein digestion occur in the small intestine?
Need to break large protein molecules down into smaller units (small peptides and amino acids)
Proteases (also present in the stomach) are embedded in the apical membrane
When proteins come into contact with these they are chopped into smaller units
What happens to the proteins once they have been broken down into small peptides and amino acids?
Transported across the apical membrane into enterocytes by PEPT1 transporters
This transporter needs H+ in order to work
What is a problem associated with hydrophilic drugs?
They dissolve well in solution in the intestine, but are very difficult to get into the body as they don’t have the right chemical and physical characteristics to diffuse into the body and through lipid membranes
This has an impact on bioavailability
How can this problem (with hydrophilic drugs) be overcome?
Absorption via uptake transporters is extremely efficient (need to get nutrients, iron etc. into the body in order to stay alive)
This has been exploited by drug designers
They have studied the chemical structures of some natural products, and attempted to synthesise drugs to look like these natural products
These drugs can ‘fool’ the transporter into moving it across the membrane and into the enterocyte
Give some examples of drug PEPT1 substrates.
Cephalosporins Penicillins Enalapril α-Methyldopa-phenylalanine Val-acyclovir
Give some examples of drug organic cationic transporter (OCTN2) substrates.
Quinidine Verapamil Imatinib Valproic acid α-Methyldopa-phenylalanine Val-acyclovir
Give some examples of drug organic anion transporting polypeptide (OATP2B1) substrates.
Pravastatin
Rosuvastatin
Atorvastatin
Fexofenadine
Which type of transporter is beneficial to drug delivery?
Uptake transporters (things are taken up from the gut lumen into the body)
Which type of transporter can be detrimental to drug absorption?
Drug efflux transporters
Also found in the apical membrane
Where can drug efflux transporters be found?
Throughout the body in the intestine, liver and kidney
How are drug efflux transporters important in pharmacokinetics (PK)?
Affect absorption in the intestine
Also important once drugs are in circulation as they can pump drugs out in the liver and in the kidney into the urine
Where are drug efflux transporters highly expressed and what problem does this pose?
Capillaries in the brain
Major problem in delivery of drugs to the brain
How do drug efflux transporters work?
Drugs move into enterocytes Efflux pumps located in the membrane grab the drug and throw it back out into the lumen
This is an active process (uses ATP as energy to drive it)
What are 2 of the main efflux transporters in the intestine?
P-glycoprotein (P-gp)
Breast cancer resistance protein (BCRP) (named this way as expressed in some breast cancer cells and was found in research to reduce the amount of toxic chemotherapeutic drug entering the cancer cell)
Which drugs are substrates to the P-gp transporter?
HIV PI e.g. Indinavir
Immunosuppressants e.g. CsA, Tacrolimus
Antibiotics e.g. Erythromycin
Cardiotonics e.g. Digoxin, Quinidine (some of these drugs have a narrow therapeutic window)
Verapamil (pumped in by OCTN2, out by p-gp, competing transporters)
Quinidine (pumped in by OCTN2)
Imatinib (pumped in by OCTN2)
In which condition are drug efflux transporters particularly problematic?
Cancer
How can we bypass the problem of drug efflux transporters in cancer?
By using an infusion of chemotherapeutic drug
What problems does this solution to bypass the transporter cause in itself?
When the needle is removed from the patient, a little bit of the drug ‘leaks’ out, or if the drug leaks out of a blood vessel (extravasation), can cause necrosis (drug is very toxic, it is diluted once in the blood so isn’t as toxic)
How would anti-cancer drugs ideally be formulated?
As oral formulations
How could the problems associated with taking anti-cancer drugs orally, namely drug efflux transporters, be overcome?
By having the patient take a p-gp modulator (inhibitor) among with the anti-cancer agent
Leads to more of the anti-cancer agent being absorbed
This however does need to be balanced with toxicity, increased absorption = increased toxicity
Give some examples of oral anti-cancer agents.
Etoposide (anti-cancer drug) formulated with valspodar (p-gp modulator)
Doxorubicin formulated with valspodar
Paclitaxel formulated with VX-710
Drug efflux transporters are also relevant for…
Drug-drug interactions in patients
Runs the risk of toxicity
Name 3 clinical p-gp drug-drug interactions.
Digoxin and Ritonavir (blocks pump) - increase in digoxin AUC
Digoxin and Atorvastatin - increase in digoxin AUC
Digoxin and Talinolol - increase in digoxin AUC
