Flashcards in Absorption Deck (53):
How does a drugs disposition characteristic change depending on the route of administration/absorption?
A drugs disposition characeteristic don’t change no matter which route of administartion is used/what the route of absorption is. What will change is the plasma conc/time profiles.
Name 4 common routes of administration
2.)Nasal and Pulmonary
When designing a drug, why would we prefer to make a drug that crosses the cell membrane transcellularly rather than paracellularly?
The surface area of the whole cell membrane is greater than that of the tight junctions and so the rate of absorption would be greater in transcellular transport.
What drug properties would limit a drugs ability to cross a cell membrane transcellularly?
The cell membrane is lipid, so only lipophilic drugs can pass this way
What drug properties would limit a drugs ability to cross a cell membrane paracellularly?
Molecular size, shape and charge.
What drug properties would limit a drugs ability to cross a cell membrane via a carrier? (active influx- need ATP)
The selectivity of the transporter for the chemical features of the drug
What drug properties would limit a drugs ability to cross a cell membrane via vesicles (ATP)?
This route is not important for small molecules but is for proteins/peptides e.g. endocytosis
What drug properties would limit a drugs ability to cross a cell membrane via active efflux carriers?
The selectivity of the transporter for the chemical features of the drug
Name 3 properties that would effect a drugs ability to permeate the membrane passively
1.) Steric = size, volume and shape of molecule
3.)Ionic properties = hydrogen bonding potential
Where would you find the 3 types of simple cells in the body?
simple squamous = lung alveoli
simple cuboidal = lung alveoli
simple columnar = proximal tubule of kidney
Where would you find the 3 types of stratified cells in the body?
stratified squamous = buccal and skin
stratified cuboidal = glands and ducts
stratified columnar = intestines
What is the name of the stratified columnar cells that line the vili of the small intestine?
What is the function of the microvilli that lie on the apical surface (surface facing the intestinal lumen) of the enterocytes?
They increase the surface area of the small intestine = more surface area available for absorption
List the complications that face a drug before if can become bioavailable
1.) In the stomach a drug can disintegrate in the acidic environment or form a complexation with food. It has to be in solution before it can cross the epithelial barrier of the intestines.
2.) crossing the epithelial barrier depends on the drugs phys/chem properties. The drug can also be metabolised here
3.) Once in the liver the drug undergoes 1st pass metabolism via liver enzymes and biliary excretions
4.) once in the circulation, a fraction of CO will return to the liver via the hepatic artery or drain from the intestines and so will be subject to metabolism again.
What is the role of the mucus secreted by goblet cells in the jejunum and ileum?
Protects the epithelium from viruses and bacteria ect
What happens in the duodenum?
This is the site where majority of food is degraded
What happens in the jejunum/ileum?
Absorption of nutrients
What happens in the large intestine?
Water absorbtion and storage and elimination of faecal waste
Name 4 things that will affect a drugs absorption ability / bioavailability
1.) solubility/lipophilicity balance
2.) Impact of pH on drug ionisation = solubility
3.) bacterial and intestinal enzymes effect on stability
4.)Enterocyte and hepatic 1st pass metabolism
5.) Are there drug transporters that are suitable in the enterocyte
6.) How long does the drug have in solution at the absorption surface (gut motility and gastric emptying)
What is a weak base?
A weak base will accept protons and be ionized in an acidic environment
How does a drugs ionized state affect absorption?
A non-ionized drug, depending on other phys-chem properties should be able to permeate cell membrane transcellularly
A drug in its ionized state will be more polar and so will be more water soluble. This is unfavourable in terms of partitioning into the membrane.
A weak acid will become ionised in a basic environment. If we increase the pH by one unit, how much of the drug will become ionized?
A weak acid will become ionised in a basic environment. If we increase the pH by two units, how much of the drug will become ionized?
Aspirin is a weak acid but is mostly absorbed in the intestine (alkaline environment. How is this possible?
1% of the drug will remain unionized and will be absorbed. In order to stay at equilibrium a further 1% will become unionized and so on until all drug has been absorbed.
Name 3 other ways highy ionised drugs are absorbed.
1.) Ion-pairing (+ and - charge come together)
2.) Microclimate pH = the microenvironment on the membrane could be completely different to the pH we measure, due to things like proton pumps.
4.) Effect of ''boundary'' layer
What is MMC- migrating myoelectric complex?
Burst of smooth muscle activity under the epithelial lining of the stomach which is repeated every 2 hours until a meal is ingested.
What happens in the 4 phases of gastric emtying in the fasting state?
1.) rare contractions
2.) increase in strength and frequency of contractions
3.)intense contractions = emtying of large solid particles e.g. e/c tablet
4.) transition phase
How will taking a drug with lots of food effect its onset of action?
Food slows down gastric emtying as it needs to be mixed and grinded via peristaltic contractions and broken down ready for the pancreatic enzymes in the intestine. So if a drug is taken with food, its onset will be delayed.
What happens in the fed state?
There are no phases in the fed state - moderate more consistent contractions
What will happen if you drink more than 150mL while in the fasting state?
The cycle will be moved into the fed state and it will lead to immediate and continuous emptying of liquid.
When is delayed gastric emptying undesirable?
1.) When fast onset of action is desired
2.) When drug absorption site is in the distal part of the intestine = delayed absorption
3.) When drug stability is compromised at low pH
4.) when drug dissolution is better at a higher pH = delayed dissolution
Except for a delay in gastric emptying, what other problem is associated with taking a drug with food?
Drugs can form complexes with food and this can affect absorption
When can taking a drug with food be beneficial?
When you want to avoid irritating the stomach lining e.g. NSAIDs
4 things that would effect the rate at which a drug crosses a membrane barrier
2.) Type of formultion e.g. slow release
3.) How it crosses e.g. para or trans cellularly
4.) The surface area of the membrane and how long the drug is exposed to it
In drug design, what are the implications of having a drug with poor solubility and poor permeability?
Costly, and take a longer time and more resources to develop
What are the names and mechanisms of the two superfamilies of transporters present in the cell membrane?
1.) ABC superfamily - ATP dependant efflux proteins
2.) SLC superfamily - carrier mechanism- work to bring drugs in and out of cells - not directly energy dependant
Where is the ABC transporter P-glycoprotein highly expressed?
In the enterocytes of the more distal parts of the small intestine and in the BBB
P-glycoproteins have broad specificity but what three properties do they prefer?
Hydrophobic, amphipathic (hydrophilic and lipophilic regions) or cationic molecules
In what 3 ways do P-gp and CYP3A work together?
1.) P-gp takes up drug that have entered the cell membrane of the enterocyte and send them back out via efflux in order to avoid bombarding CYP3A. This system ensures that the enzyme does not become saturated and that metabolism is effective.
2.)Levels of P-gp and CYP3A complement each other i.e. both are highly expressed in the distal part of the intestine
3.) P.gp transports the drug metabolites back out into the gut lumen.
How does grapefruit juice effect P-glycoprotein and CYP3A4?
Grapefruit juice inhibits the CYP enzyme, meaning that less drug is metabolized. P-gp has similar substrate so is also affected meaning less drug effluxes out of cell = faster rate of absorbtion
what 3 cell components contain SLC carriers as integral membrane proteins?
1.) Plasma membrane
SLC carriers are substrate selective in binding and translocation but how is membrane transport achieved?
The carriers alter their conformation in order to move substrates in and out of cell
What are the to types of SLC carriers?
1.) Facilitative transporters
2.) Secondary active transporters
How does a facilitative transporter work?
It allows a solute to flow down its electrochemical gradient = no energy needed
How does a secondary active transporter work?
Allows a solute to flow against its electrochemical gradient by coupling to another solute that is flowing downhill with its gradient. It uses the energy produced by the movement of the second solute to pump the first solid against its gradient.
What is a symporter?
A transporter that carries two solutes in the same direction
What is an antiporter?
A transporter that carries two solutes in the opposite direction
Name 3 SLC and SLCO transporters of significance in the intestine
1.) Organic anion transporting peptide
3.) Organic cation transporter
4.) Organic cation transporter (Na dependant)
5.) Monocarboxylate transporter
AZT is a drug with a LogP of -0.3 which suggests poor membrane permeability but it has a bioavailability of 64%. Suggest how this drug is able move from the gut lumen and across the enterocyte membrane.
AZT is a substrate for one of the SLC/SLCO transporters in the small intestine enterocytes. (In this case, the Organic cation transporter)
On which surface of the hepatocyte can ABC transporters be found and what is their role?
ABC transporters can be found on the apical membrane of the hepatocyte where a bile canaliculi can be found. The ABC transporters take up drug metabolites from the hepatocyte cytoplasm and into the canaliculi where they will be taken into the gall-bladder to be stored.
How do statins work?
Statins are competitive inhibitors of HMG-CoA reductase - an essential enzyme in the production of cholesterol. They work to decrease the synthesis of cholesterol in the liver . The body's reaction to this is to up-regulate the LDL receptors on the surface of the hepatocyte = more apolipoproteins (cholesterol carrying proteins) are taken up from the blood so there is a net effect of lowering plasma concentration of cholesterol carrying lipoproteins.
Statins are taken into hepatocytes via the SLC transporters - organic anion transporters. What is the beneficial pharmacokinetic and pharmacodynamic impact of this hepatocellular uptake?
Uptake of statins into the hepatocytes leads to a decreased plasma concentration which in turn reduces the risk of myotoxic (muscle) damage associated with increased statin plasma concs.
Uptake of statins into the hepatocyte is necessary for it to be able to inhibit HMG-CoA reductase and achieve the desired lipid lowering effect.