Flashcards in Lecture 14 Deck (35):
using our knowledge of ionisation and lipophilicity, what can we predict?
drug distribution around the body, and all the ADME processes (apart from metabolism) as they are all based on diffusion
What is the biological membrane made up of?
a bilayer of phospholipids where some proteins and transporters are embedded
membrane is semipermeable which only allows specific molecules to diffuse through
why can lipid molecules penetrate easily
the bilayer is lipid in nature so lipid molecules can penetrate easily
What is the major mechanism of drug transport?
what are the other mechanisms of drug transport?
is passive diffusion just through the bilayer?
no, it also goes through some channels
How is the mechanism of resistance to cancer drug based on transport systems?
The anti-cancer Drug bring administered can reach tumour cells,
ButThe transporter pumps the drug out of the cells via active transport.
Therefore the drug cannot come to the DNA site, so patient is resistant
We can Try to block the transporter on the membrane so the anticancer drug can remain in the cell to bind to DNA
What is the mechanism of passive diffusion?
Drug needs to be lipophilic, and has an affinity for the lipid bilayer.
Diffusion is about single molecules that means the drug needs to be dissolved, if not dissolved, it cannot diffuse well.
Need relatively high solubility, but how is this done when they are lipophilic? It is a balance.
If the solubility is too low it can be a rate limiting step
Passive diffusion is Concentration gradient driven
How does the ionisation of the drug affect its transport into the cell?
if the drug is ionised, its lipophilicity is poor so cant diffuse via passive transport
What is the pH partition theory?
PH changes the ionisation state, that means it changes the drug lipophilicity.
If pH changes the ionisation. The ionised drug cannot diffuse easily through the biological membrane.
Only the smaller molecules (less than 500MW)
But depends on administration route, for the skin the size can be bigger but need to be smaller than 1000
Small unionised molecules have no difficulty diffusing through
What is lipophilicity good for?
penetration and diffusion of drug through the membrane
What does it mean if the LogP is too high?
the drug is too lipophilic, thus water solubility will be too low, thus the concentration gradient it creates will be too low.
what does it mean when the log p is too high?
drugs with high log p tend to have a protein bound to it, making it very hard to get through the membrane
What is the rule of 5 we should consider when designing a new drug?
Log P should not be greater than 5 (otherwise water solubility will be too low)
Molecular weights should have no more than 5 hydrogen bond donors and no more than 10Hydrogen bond acceptors
Why is pH important?
determines the ionisation state of the drug
Is the equation positive for acids?
yes and it is negative for bases
do drugs only have one ionisation state?
no some drugs can have 2 or more
what is pka with respect to ionisation?
it is the pH where 50% of the drug is ionised and 50% is unionised
For a base, if the pH is one unit higher than the pKa, will there be more or less ionisation?
there will be less ionisation,
What can fick's law be used to predict?
the absorption rate
dM = amount of drug that goes across the membrane
M/t = absorption rate
What is the concentration gradient? / how is it calculated
it is the difference in the concentration / thickness
What do we generally talk about when referring to absorption?
we talk about absorption through a hollow gut.
if the surface area is large, there will be a faster absorption rate
Why can we simplify the equation so that it is only determined by the concentration of the drug in the gut?
because the concentration of tablet in the gut is much higher than that in the blood
what does it mean when most drugs are class II?
they are permeable but less soluble (i.e. more lipophilic)
why is drug permeability from the blood to the other tissue different?
we have a different parition barrier
Why can ionised drugs be absorbed sometimes?
when unionised, the balance will be broken so the ionised drugs have to maintain the supply as the ratio is determined by the pH
What can we use the euqation to predict?
how quickly the drug is absorbed.
What factors of drug absorption are changing?
pH, membrane thickness, convection of the flow and the unstirred layers
what happens if pH is different from the blood?
it may cause the blood to redistribute e.g. in the injection of a basic drug, you will find it accumulates in the GI tract.
Why does a basic drug accumulate in the GI tract?
for a basic drug in an environment of pH 7.4, has a higher concentration of the unionised form.
As there is a high concentration of the drug after injection, it can diffuse through the GI tract where the pH is low
But the basic drug in the GI tract which is ionsed will not be able to penetrate through the membrane, so it accumulates over time
How can we advise which drugs can be given to breast feeding women?
we know that the pH of milk is lower than in the blood, so basic drugs can easily accumulate in he milk
A basic drug in the plasma has a higher proportion which is unionsed so it can penetrate into the milk plasma membrane, however once in the milk environment, pH is lower so more of the drug becomes ionised
Can an acidic drug with a pka of 4 penetrate into the milk?
an acidic drug at pH 7 will be ionised, so will not penetrate into the milk easily.
This is why if a mother has mastitis, its better to use a basic drug which will become ionised in the milk, so can be trapped in the milk
What is the % of ionisation of a basic drug of pKa 7.24 in the plasma?
there will be 50% unionised in the plasma
this unionised form can penetrate anywhere including the milk
What is ion trapping?
when there is a higher ionised ratio, so prevents the drug from penetrating elsewhere